The Health
Consequences
Of Smoking
CHRONIC OBSTRUCTIVE
LUNG DISEASE
a report of the
Surgeon General
1984
we SERVIC ge L
= ty,
© U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
z Public Health Service
Fr Office on Smoking and Health
, Rockville, Maryland 20857
For sale by the Superintendent of Documents, U.S. Government Printing Office
Washington, D.C. 20402
THE SECRETARY OF HEALTH AND HUMAN SERVICES
WASHINGTON. OC 20701
The Honorable Thomas P. C'Neill, Jr.
Speaker of the House of Representatives
Washington, D.C. 20515
Bear Mr. Speaker:
It is a pleasure to transmit to the Congress the Surgeon
General's Report on the Health Consequences of Smoking, as
mandated by Section 8(a) of the Public Health Cigarette Smoking
Act of 1969. This is the Public Health Services't 16th report on
this topic anc, like all of the earlier Reports, it identifies
cigarette smoking as the chief preventable cause of death and
disability in our society.
The enclosed report deals with the relationship between smok-
ing and those disease conditions described as chronic obstructive
lung disease, particularly chronic bronchitis and emphysema.
These diseases significantly increase patient loads in hospitals
and other health care facilities and escalate this Nation's
health care costs, including expenditures under the Medicaid and
Medicare programs.
This report indicates that chronic obstructive lung diseases
can be reduced and, in the case of emphysema, almost eradicated,
if individuals stop cigarette smoking. Moreover, stopping smok-
ing also would prevent the enormous suffering and human loss now
well-known to be associated with smoking.
This Department has a strong and ongoing commitment to its
programmatic and research efforts in the field of disease preven-
tion. In our view, it is essential to apprise individuals of the
consequences of smoking. A central part of our efforts is to
identify ways to help smokers quit smoking, and to encourage
individuals, particularly the youth of this country, not to begin
smoking.
Sincerely,
a ow,
Marggret M. Heckler
Seerftary
Enclosure
THE SECRETARY OF HEALTH AND HUMAN SERVICES
WASHENGTON OC 20201
The Honorable George Bush
President of the Senate
Washington, D.C. 20616
Dear Mr. President:
It is a pleasure to transmit to the Congress the Surprean
General's Report on the Health Consequences of Smoking, as
mandated by Section 8(a) of thea Publin Health Cirerette Smoking
Act of 1969. This is the Public Health Services’ 16th report or
this topic and, like ail of the ezrlier Peports, it identifies
cigarette smoking as the chief preventable cause of death enc
disability in our society.
The enclosed report deals with the relationship setweer sroy-
ing and those disease conditions described as chronic obstructive
lung disease, particularly chronic brorchitis and emphysema.
These diseases significantly increase patient loads in hospi
and other health care facilities and esealete this Naticn's
health care costs, including expenditures under the Medicaid and
Medicare programs.
This report indicates that chronic obstructive lung diseases
can be reduced and, in the case of emphysema, almost eradicated,
if individuals stop cigarette smoking. Moreover, stcpning srck-
ing also would prevent the enormous suffering and human toss now
well-known to be asscciated with smoking.
This Department has a strong and ongoing commitment to its
programmatic and research efforts in the field cf disease preven-
tion. In our view, it is essential to apprise individurls of the
consequences of smoking. A central part of our efforts is to
identify ways to help smokers quit smoking, and to encourage
individuals, particularly the youth of this country, not to beri:
smoking.
Sincerely,
Enclosure
FOREWORD
The 1984 Report on the Health Consequences of Smoking consti-
tutes a state-of-the-art review of the information currently available
regarding the occurrence and etiology of chronic obstructive lung
diseases.
Traditionally, chronic bronchitis and emphysema have been
subsumed under the term chronic obstructive lung diseases (COLD).
It is now recognized that COLD comprises three separate, but often
interconnected, disease processes: (1) chronic mucus hypersecretion,
resulting in chronic cough and phlegm production; (2) airway
thickening and narrowing with expiratory airflow obstruction; and
(3) emphysema, which is an abnormal dilation of the distal airspaces
along with destruction of alveolar walls. The last two conditions can
develop into symptomatic ventilatory limitation.
Although there were scientific reports of a link between cigarette
smoking and respiratory symptoms as early as 1870, it was not until
the comprehensive review in the first Report of the Advisory
Committee to the Surgeon General in 1964 that the nature of the
observed association was officially recognized by the Public Health
Service.
At that time the committee concluded that
Cigarette smoking is the most important of the causes of chronic
bronchitis in the United States and increases the risk of dying from
chronic bronchitis and emphysema. A relationship exists between
cigarette smoking and emphysema, but it has not been established that
the relationship is causal.
On the basis of the evidence reviewed in this volume, we are now
able to reach a much stronger conclusion:
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 morbidity and mortality far outweighs all other factors.
The Importance of Chronic Obstructive Lung Disease
Previous Reports on the health consequences of smoking empha-
Sized the impact of cigarette smoking on mortality from smoking-
related disease. It is estimated that more than 60,000 Americans
died last year owing to chronic obstructive respiratory conditions
vii
(chronic bronchitis, emphysema, and COLD and allied conditions).
From available epidemiologic and clinical evidence, it may be
reasonably estimated that approximately 80 to 90 percent of these
are attributable to smoking. Over 50,000 of the COLD deaths can
therefore be considered preventable and premature because these
individuals would not have died of COLD if they had not smoked.
While smoking-related COLD mortality is less than estimates for
smoking-related deaths due to coronary heart disease (170,000) and
those due to cancer (130,000), it nonetheless represents a significant
number of excess deaths.
COLD morbidity has a greater impact upon society than COLD
mortality. Death from COLD usually occurs only after an extended
period of disability, and many individuals with disability from COLD
will die from other causes before the disease progresses to a degree of
severity likely to cause death. The progressive loss of lung function
that characterizes COLD can lead to severe shortness of breath,
limiting the activity level. In recognizing the morbidity associated
with these diseases, it is important to realize that the frequency of
activity limitation with COLD exceeds that reported for any other
major disease category. In 1979, 52 percent of individuals with
emphysema reported that it limited their activity; 27 percent said it
resulted in one or more bed days that year; and 73 percent reported
at least one visit to a doctor during the preceding year due to
emphysema. Forty percent more people with emphysema than with
heart conditions reported limitation of activity. More recently, the
National Center for Health Statistics has estimated that over 10
million Americans suffer from either chronic bronchitis or emphyse-
ma.
The Changing Pattern of Mortality
The 1980 and 1982 Surgeon General’s Reports (The Health
Consequences of Smoking for Women and The Health Consequences of
Smoking: Cancer) reported a rapidly increasing rate of lung cancer
among women compared with the rate for men. As this Report
documents, the mortality ratio between men and women for COLD is
also narrowing. In just 10 years, while total deaths from COLD
increased from 33,000 in 1970 to 53,000 in 1980, the male-to-female
ratio narrowed from 4.3:1 in 1970 to 2.3:1 in 1980. This epidemic
increase in COLD among women reflects their later uptake of
smoking when compared with men.
Findings of the 1984 Report
The mortality ratios for COLD in cigarette smokers compared with
nonsmokers are as large as or larger than for lung cancer, the
viii
disease most people usually associate with smoking. In heavy
smokers, this risk can be as much as 30 times the risk in
nonsmokers. Perhaps even more important, in studies of cross-
sections of U.S. populations, cigarette smoking behavior is often the
only significant predictor for COLD. Even after 30 years of intensive
investigation, only cigarette smoking and o,-antiprotease deficiency
have been established as being able to cause COLD in the absence of
other agents.
The decline in lung function with age is steeper in smokers than in
nonsmokers, and the rate of decline increases with an increasing
number of cigarettes smoked per day. This excess decline in lung
function in smokers reflects the progressive lung damage that can
eventually lead to symptoms of COLD and ultimately death.
Therefore, it is not surprising that the risk of death from COLD
increases with an earlier age of smoking initiation, number of
cigarettes smoked per day, and deep inhalation of the smoke.
Abnormal lung function can be demonstrated in some cigarette
smokers within a few years of smoking initiation. These changes
initially reflect inflammation in the small airways of the lung and
may reverse with cessation. Beginning in their late twenties, some
smokers start to develop abnormal measures of expiratory airflow,
an excess decline in lung function that continues as long as they
continue to smoke. Some of these smokers will develop enough
functional loss to become symptomatic, and some of those who
become symptomatic will develop enough functional loss to die of
COLD. When the smoker quits, the rate of functional decline slows,
but there is little evidence to suggest that the smoker can regain the
function that has been lost.
We are also beginning to understand that the impact of cigarette
smoke on the lung is not limited to the active smoker. Children of
smoking parents have an increased risk of bronchitis and pneumonia
early in life, and seem to have a small, but measurable, difference in
the growth of lung function.
One of the major advances described in this volume is in the
understanding of the mechanisms by which cigarette smoking causes
COLD, particularly emphysema. There is now a clear, plausible
explanation of how emphysema might result from cigarette smoking.
The inflammatory response to cigarette smoke results in an in-
creased number of inflammatory cells being present in the lungs of
cigarette smokers. These cells can increase the amount of elastase in
the lung, and elastase is capable of degrading elastin, one of the
structural elements of the lung. In addition, cigarette smoke is
capable of oxidative inactivation of a,-antiprotease, a protein
capable of blocking the action of elastase. The net result is an excess
of elastase activity, degradation of elastin in the lung, destruction of
alveolar walls, and the development of emphysema.
ix
Research scientists continue to expand our understanding of the
process by which cigarettes damage the lung, but the important
public health focus must shift to how to prevent children from
becoming cigarette smokers and how to help those who now smoke to
quit.
Helping Smokers Quit
Smokers can realize a substantial health benefit from quitting
smoking, no matter how long they have smoked. As this Report
states, sufficient evidence now exists to document lung function
improvement in smokers who have quit. Ex-smokers can look
forward to improved future health, avoiding long-term and possibly
severe disability, or even death, from COLD.
Two chapters in this Report summarize research studies using two
vastly different cessation approaches. One focuses on the role of
physicians in assisting patient populations to quit smoking; the other
looks at communitywide intervention programs. Both can have a
significant impact on reducing the number of smokers in our
population.
In January of this year, the Food and Drug Administration
approved a nicotine chewing gum that physicians can prescribe for
their patients as an aid to cessation. Studies have shown encouraging
results when the gum is used as part of a complete behavior
modification program. It must be cautioned, however, that nicotine
chewing gum is not a magic cure. Smokers must be strongly
motivated to quit or they are unlikely to meet with long-term
success.
Public Attitudes and Knowledge
In 1981, a Federal Trade Commission staff report on cigarette
advertising revealed that a sizable portion of the population is not
aware of the link between cigarette smoking and chronic bronchitis
and emphysema. The report cited a 1980 Roper survey finding that
59 percent of the population, including 63 percent of smokers, did not
know that smoking causes most cases of emphysema. Over a third of
the general population and almost 40 percent of smokers do not
know that smoking causes many cases.
It is quite clear that physicians and other health professionals
must redouble their efforts to persuade more smokers to quit. As in
previous years, I call upon all segments of the health care communi-
ty to provide assistance and encouragement in whatever way
possible to reduce the health impact of cigarette smoking on our
society, by helping their patients to quit smoking and by encouraging
our young people not to take up the habit. It is only through efforts
x
such as these that we can reduce our country’s terrible burden of
disability and death due to cigarette smoking.
Edward N. Brandt, Jr., M.D.
Assistant Secretary for Health
xi
PREFACE
This Report The Health Consequences of Smoking: Chronic Ob-
structive Lung Disease completes an examination by the Public
Health Service of the three principal disease entities associated with
cigarette smoking. In 1982, the Service presented an in-depth review
of tobacco’s relationship to cancer, and in 1983, a review of its
relationship to cardiovascular disease. This 1984 Report evaluates
the contribution that tobacco makes to the suffering and premature
deaths due to the chronic obstructive lung diseases, including
emphysema and chronic bronchitis.
Cigarette smoking is causally related to chronic obstructive lung
disease, just as it is to cancer and coronary heart disease; severe
emphysema would be rare were it not for cigarette smoking. The
evidence presented in this Report supports my judgment and the
judgment of five preceding Surgeons General that cigarette smoking
is the chief, single, avoidable cause of death in our society and the
most important public health issue of our time.
This Report, as were all previous Surgeon General’s Reports
dealing with cigarette smoking, is the work of many experts both
within and outside the Federal establishment. To these authors,
editors, and reviewers I again express my great respect and sincere
thanks.
C. Everett Koop, M.D.
Surgeon General
xill
ACKNOWLEDGMENTS
This Report was prepared by the Department of Health and
Human Services under the general editorship of the Office on
Smoking and Health, Joanne Luoto, M.D., M.P.H., Director. Manag-
ing Editor was Donald R. Shopland, Technical Information Officer,
Office on Smoking and Health.
Senior scientific editor was David M. Burns, M.D., Assistant
Professor of Medicine, Division of Pulmonary and Critical Care
Medicine, University of California at San Diego, San Diego, Califor-
nia. Consulting scientific editors were John H. Holbrook, M.D.,
Associate Professor of Internal Medicine, University of Utah Medi-
cal Center, Salt Lake City, Utah; and Ellen R. Gritz, Ph.D., Director,
Macomber-Murphy Cancer Prevention Program, Division of Cancer
Control, Jonsson Comprehensive Cancer Center, University of
California at Los Angeles, Los Angeles, California.
The editors wish to acknowledge their grateful appreciation to the
National Heart, Lung, and Blood Institute, Claude Lenfant, M.D.,
Director, for the Institute’s invaluable assistance in the compilation
of this volume.
The following individuals prepared draft chapters or portions of
the Report:
Brenda E. Barry, Ph.D., Research Associate, Environmental Science
and Physiology, Harvard School of Public Health, Boston, Massa-
chusetts
Richard A. Bordow, M.D., Associate Director of Respiratory Medi-
cine, Brookside Hospital, San Pablo, California, and Assistant
Clinical Professor of Medicine, University of California at San
Francisco, San Francisco, California
Joseph D. Brain, Sc.D., Professor of Physiology and Director,
Respiratory Biology Program, Harvard School of Public Health,
Boston, Massachusetts o
A. Sonia Buist, M.D., Professor of Medicine, Department of Medicine,
Oregon Health Sciences University, Portland, Oregon
Louis Diamond, Ph.D., Professor and Dirextor-of the Pharmacody-
namics and Toxicology Division, University of Kentucky College of
Pharmacy, Lexington, Kentucky
XV
Terence A. Drizd, Statistician, Medical Statistics Branch, Division of
Health Examination Statistics, National Center for Health Statis-
tics, Public Health Service, Department of Health and Human
Services, Hyattsville, Maryland
Millicent W. Higgins, M.D., Professor of Epidemiology and Professor
of Internal Medicine, Department of Epidemiology, The University
of Michigan School of Public Health, Ann Arbor, Michigan
Gary W. Hunninghake, M.D., Director, Pulmonary Disease Division
and Professor, Department of Internal Medicine, The University of
Iowa Hospitals and Clinics, Iowa City, Iowa
Philip Kimbel, M.D., Chairman, Department of Medicine, The
Graduate Hospital, Philadelphia, Pennsylvania
Edgar C. Kimmel, Pharmacodynamics and Toxicology Division,
University of Kentucky College of Pharmacy, Lexington, Ken-
tucky
Charles Kuhn, M.D., Department of Pathology, Jewish Hospital at
Washington University Medical Center, St. Louis, Missouri
Alfred L. McAlister, Ph.D., The University of Texas Health Science
Center at Houston, Houston, Texas
John McCarren, M.D., Division of Pulmonary and Critical Care
Medicine, University of California at San Diego, San Diego,
California
Linda L. Pederson, Ph.D., Department of Epidemiology and Biosta-
tistics, University of Western Ontario, London, Ontario, Canada
John A. Pierce, M.D., Department of Medicine, Washington Univer-
sity Medical Center, St. Louis, Missouri
Jonathan M. Samet, M.D., Associate Professor of Medicine, The
University of New Mexico School of Medicine, Albuquerque, New
Mexico
Robert M. Senior, M.D., Professor of Medicine, Respiratory and
Critical Care Division, Jewish Hospital at Washington University
Medical Center, St. Louis, Missouri
Frank E. Speizer, M.D., Associate Professor of Medicine, Harvard
Medical School, and Associate Chief, Channing Laboratory, Brig-
ham and Women’s Hospital, Boston, Massachusetts
Ira B. Tager, M.D., M.P.H., Division of Infectious Disease, Beth Israel
Hospital and Channing Laboratory, Brigham and Women’s Hospi-
tal, and Assistant Professor of Medicine, Harvard Medical School,
Boston, Massachusetts
William M. Thurlbeck, M.D., F.R.C.P(C), Professor of Pathology,
Department of Pathology, The University of British Columbia,
Vancouver, British Columbia, Canada
Martin J. Tobin, M.D., M.R.C.P.L., Assistant Professor of Medicine,
Division of Pulmonary Medicine, Department of Internal Medi-
cine, The University of Texas Health Science Center at Houston,
Houston, Texas
Xvi
Adam Wanner, M.D., Professor of Medicine and Chief, Division of
Pulmonary Diseases, University of Miami School of Medicine,
Miami Beach, Florida
Scott T. Weiss, M.D., M.S., Associate Chief, Pulmonary Division,
Beth Israel Hospital, and Assistant Professor of Medicine, Har-
vard Medical School, Boston, Massachusetts
The editors acknowledge with gratitude the following distin-
guished scientists, physicians, and others who lent their support in
the development of this Report by coordinating manuscript prepara-
tion, contributing critical reviews of the manuscript, or assisting in
other ways.
Oscar Auerbach, M.D., Senior Medical Investigator, Veterans Ad-
ministration Medical Center, East Orange, New Jersey
John Bailar III, M.D., Ph.D., Office of the Assistant Secretary of
Health, Office of Disease Prevention and Health Promotion,
Washington, D.C.
David V. Bates, M.D., F.R.C.P.(C), Professor of Medicine, Department
of Health Care and Epidemiology, The University of British
Columbia, Vancouver, British Columbia, Canada
Benjamin Burrows, M.D., Division of Respiratory Science, University
of Arizona College of Medicine, Tucson, Arizona
Jacqueline Coalson, Professor of Pathology, School of Medicine,
University of Texas at San Antonio, San Antonio, Texas
Allen B. Cohen, M.D., Ph.D., Executive Associate Director and
Professor of Medicine, The University of Texas Health Center at
Tyler, Tyler, Texas
Manuel G. Cosio, M.D., Director, Pulmonary Laboratories, Royal
Victoria Hospital, Montreal, Quebec, Canada
Manning Feinleib, M.D., Dr.P.H., Director, National Center for
Health Statistics, Public Health Service, Department of Health
and Human Services, Hyattsville, Maryland
Benjamin G. Ferris, Jr., M.D., Professor of Environmental Health
and Safety, Department of Physiology, Harvard School of Public
Health, Boston, Massachusetts
Gareth M. Green, M.D., Professor and Chairman, Department of
Environmental Health Sciences, The Johns Hopkins University
School of Hygiene and Public Health, Baltimore, Maryland
Clarence A. Guenter, M.D., F.R.C.P.(C), Professor and Head, Depart-
ment of Medicine, The University of Calgary Foothills Hospital,
Calgary, Alberta, Canada
Ian T. T. Higgins, M.D., Professor of Epidemiology, Department of
Epidemiology, The University of Michigan School of Public
Health, Ann Arbor, Michigan
John R. Hughes, M.D., Assistant Professor, Department of Psychia-
try, University of Minnesota, Minneapolis, Minnesota
Xvli
Suzanne S. Hurd, Ph.D., Director, Division of Lung Diseases,
National Heart, Lung, and Blood Institute, National Institutes of
Health, Bethesda, Maryland
Roland H. Ingram, Jr., M.D., Director, Respiratory Division, Brig-
ham and Women’s Hospital, and Parker B. Francis Professor of
Medicine, Harvard Medical School, Boston, Massachusetts
Aaron Janoff, Ph.D., Professor and Experimental Pathologist, De-
partment of Pathology, School of Medicine and University Hospi-
tal, State University of New York at Stony Brook, Stony Brook,
New York
Lynn T. Kozlowski, Ph.D., Scientist, Clinical Institute of the Addic-
tion Research Foundation, Toronto, Ontario, Canada
Claude Lenfant, M.D., Director, National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, Maryland
Peter T. Macklem, M.D., F.R.S.C., Physician-in-Chief, Royal Victoria
Hospital, and Professor and Chairman, Department of Medicine,
McGill University, Montreal, Quebec, Canada
James O. Mason, M.D., Director, Centers for Disease Control,
Atlanta, Georgia
Kenneth M. Moser, M.D., Professor of Medicine and Director,
Division of Pulmonary and Critical Care Medicine, School of
Medicine, University of California at San Diego, San Diego,
California
C. Tracy Orleans, Ph.D., Division of Psychosomatic Medicine,
Department of Psychiatry, Duke University Medical Center,
Durham, North Carolina
Terry F. Pechacek, Ph.D., Assistant Professor, Division of Epidemiol-
ogy, School of Public Health, University of Minnesota, Minneapo-
lis, Minnesota
Solbert Permutt, M.D., Professor of Medicine, Department of Medi-
cine, Division of Pulmonary Medicine, The Johns Hopkins Univer-
sity School of Medicine, Baltimore, Maryland
Chery] L. Perry, Ph.D., Assistant Professor, Division of Epidemiolo-
gy, School of Public Health, University of Minnesota, Minneapolis,
Minnesota
Richard Peto, M.A., M.Sec., LC.R.S., Clinical Trial Service Unit,
Radcliffe Infirmary, University of Oxford, Oxford, England
Thomas L. Petty, M.D., Professor of Medicine, and Director, Webb
Waring Lung Institute, University of Colorado Health Sciences
Center, Denver, Colorado
James L. Repace, Office of Policy Analysis, U.S. Environmental
Protection Agency, Washington, D.C.
Attilio D. Renzetti, Jr.. M.D., University of Utah Medical Center,
Salt Lake City, Utah
John Repine, M.D., Webb Waring Lung Institute, Denver, Colorado
xviii
Eugene Rogot, Statistician, Division of Epidemiology and Clinical
Applications, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland
Marvin A. Sackner, M.D., Director, Medical Services, Mount Sinai
Medical Center, and Professor of Medicine, University of Miami
School of Medicine, Miami Beach, Florida
Roy J. Shephard, M.D., Ph.D., Director of School of Physical and
Health Education, University of Toronto, Toronto, Ontario, Cana-
da
Gordon L. Snider, M.D., Professor of Medicine and Director, Pulmo-
nary Center, Boston University School of Medicine, Boston,
Massachusetts
Donald F. Tierney, M.D., Department of Medicine, School of Medi-
cine, Center for the Health Sciences, University of California at
Los Angeles, Los Angeles, California
Nicholas J. Wald, M.R.C.P., F.F.C.M., Professor, Department of
Environmental and Preventive Medicine, The Medical College of
St. Bartholomew’s Hospital, University of London, London, Eng-
land
James B. Wyngaarden, M.D., Director, National Institutes of Health,
Bethesda, Maryland
The editors also acknowledge the contributions of the following
staff members and others who assisted in the preparation of this
Report.
Erica W. Adams, Copy Editor, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Richard H. Amacher, Director, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
John L. Bagrosky, Associate Director for Program Operations, Office
on Smoking and Health, Rockville, Maryland
Richard J. Bast, Medical Translation Consultant, Information Pro-
grams Division, Informatics General Corporation, Rockville, Mary-
land
Charles A. Brown, Programmer, Data Processing Services, Informat-
ics General Corporation, Rockville, Maryland
Clarice D. Brown, Bio-Statistician and Epidemiologist, Office on
Smoking and Health, Rockville, Maryland
Joanna B. Crichton, Copy Editor, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
Alicia Doherty, Information Specialist, Clearinghouse Projects De-
partment, Informatics General Corporation, Rockville, Maryland
Danny A. Goodman, Information Specialist, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land
XIX
Kit Hagner, Clerk-Typist, Office on Smoking and Health, Rockville,
Maryland
Rebecca C. Harmon, Publications Manager, Information Programs
Division, Informatics General Corporation, Rockville, Maryland
Karen Harris, Clerk-Typist, Office on Smoking and Health, Rock-
ville, Maryland
Douglas M. Hayes, Publications Systems Supervisor, Publishing
Services Division, Informatics General Corporation, Riverdale,
Maryland
Patricia E. Healy, Technical Information Clerk, Office on Smoking
and Health, Rockville, Maryland
Shirley K. Hickman, Data Entry Operator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land
Margaret H. Hindman, Publications Specialist, Information Pro-
grams Division, Informatics General Corporation, Rockville, Mary-
land
Robert S. Hutchings, Associate Director for Information and Pro-
gram Development, Office on Smoking and Health, Rockville,
Maryland
Leena Kang, Data Entry Operator, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
Margaret E. Ketterman, Public Information and Publications Spe-
cialist, Office on Smoking and Health, Rockville, Maryland
Julie Kurz, Graphic Artist, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Roberta L. Litvinsky, Secretary, Office on Smoking and Health,
Rockville, Maryland
William R. Lynn, Program Operations Technical Assistance Officer,
Office on Smoking and Health, Rockville, Maryland
Edward W. Maibach, Health Promotion Specialist, Informatics
General Corporation, Rockville, Maryland
Dixie P. McGough, Publications Specialist, Information Programs
Division, Informatics General Corporation, Rockville, Maryland
Patricia A. Mentzer, Data Entry Operator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land
Kurt D. Mulholland, Graphic Artist, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock-
ville, Maryland
Sally L. Nalley, Secretary, Office on Smoking and Health, Rockville,
Maryland
Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville,
Maryland
XX
Raymond K. Poole, Production Coordinator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land
Roberta A. Roeder, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Anne C. Ryon, Copy Editor, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Linda R. Sexton, Information Specialist, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land
Linda R. Spiegelman, Administrative Officer, Office on Smoking and
Health, Rockville, Maryland
Evelyn L. Swarr, Administrative Secretary, Data Processing Ser-
vices, Informatics General Corporation, Rockville, Maryland
Karen Weil Swetlow, Copy Editor, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
Debra C. Tate, Publications Systems Specialist, Publishing Services
Division, Informatics General Corporation, Riverdale, Maryland
Jerry W. Vaughn, Development Technician, University of California
at San Diego, San Diego, California
Jill Vejnoska, Writer-Editor, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Aileen L. Walsh, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Dee Whitley, Computer Operator, Data Processing Services, Infor-
matics General Corporation, Rockville, Maryland
Louise Wiseman, Technical Information Specialist, Office on Smok-
ing and Health, Rockville, Maryland
Pamela Zuniga, Secretary, University of California at San Diego,
San Diego, California
Xxi
TABLE OF CONTENTS
Foreword 2.0.00... cccccccce cece cence tenet ee ee enna eet eeeeeeet et nae sens vii
Preface .........c ccc ccce cece cece eee e eee ene e tds eee e nee een nee EE xili
Acknowledgments ..............ccceeeeeee eect cette eee eee eea sean ns XV
1. Introduction, Overview, and Conclusions ................. 1
2. Effect of Cigarette Smoke Exposure on Measures of
Chronic Obstructive Lung Disease Morbidity ......... 17
3. Mortality From Chronic Obstructive Lung Disease
Due to Cigarette Smoking ..................:cce pees ee ee es 185
4. Pathology of Lung Disease Related to Smoking..... 219
5. Mechanisms by Which Cigarette Smoke Alters the
Structure and Function of the Lung................... 251
6. Low Yield Cigarettes and Their Role in Chronic Ob-
structive Lung Disease.............. 20. .ccc sees eee e ee eee enes 329
7. Passive Smoking ..................ccccsccceeceeeeeeeee eee enees 361
8. Deposition and Toxicity of Tobacco Smoke in the
LUNG... cece cece cece eee ee eee e seen enced teat eae ee tes eneee ees 413
9. Role of the Physician in Smoking Cessation......... 451
10. Community Studies of Smoking Cessation and Preven-
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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
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 HeO2 mixture.
They found that an abnormal response to breathing HeQ: is not
necessarily indicative of either airway or parenchymal disease, and
concluded that the ability of the HeOs 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 HeQ:2 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 MEF'V 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. Sobol 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 (FEV)), the
forced expiratory flow over the middle half of the forced vital
capacity (FEF 25-75%), and the ratio of FEV: to the forced vital capacity
(FVC), FEVi/FVC. Neither study found a change in closing volume.
26
From this limited information, it can be reasonably concluded that
the large airways, rather than the small airways, respoud acutoly ta
the inhalation of cigarette smoke.
Chronic Response to Cigarette Smoke
In the late 1800s, Mendelssohn (1897) repurted that srnoking had:
deleterious effect on the respiratory system. The ea) Iv stud
hampered by the lack of sensitive physiologic tests of lung function
and relied heavily on differences between smokers and nonsmokers
in the prevalence of respiratory symptoms. Confirmation of the
structural basis of excessive respiratory symptoms seen in the
smokers came from the classic paper by Reid in 1954, in whicl, she
described the pathology of chronic bronchitis (Reid 1954). Ventilato-
ry limitation usually occurs late in the course of COLD. In centrost.
the inflammatory response of the small airways is demane:- i ts
relatively early in life in cigarette smokers.
es were
Smoking and Tests of Small Airways Function in Poprthation
Studies
A large number of studies using tests of small airways functicn
have been conducted over the past 15 years in groups and popula-
tions of various sizes, ages, and other characteristics. In some of
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 Ne
test, Buist and coworkers (Buist and Ross 1973b; Buist et al. 1973)
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 FEV and 21 percent had an
abnormal FEF2575%. 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, Oregon)(Buist
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 Ne variables (CV/VC, CC/TLC, and the slope of the alveolar
plateau) and for FEV:/FVC 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 FEV:/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 (1977) 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 max 75% and slope of phase III as well as for combined parameters of
the MEF'V curve and single breath Ne 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 Vmax 75%, and 33.9 percent had some abnormality on
either the single breath Netest 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 Ne test variables and
for FEVi/FVC 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
1 | Normal subjects
EZ} 1! Asymptomatic smokers
35 4 [24 1 Symptomatic subjects
3 30 4
Cc
8 26
&
&
& 204
a
§
€ 155
5
a
©
3 4
= 10
D
oO
5
a 54
V+Vmaxrs Slope FEV, CV/VO%
Phase fi! FEV,/FVG CC/TLO%
(Nz) V¥4+Vmaxso Phase lil
V4 V¥ max7s (Na)
Single sensitive test Combined parameters
FIGURE 2.—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 Ne concentration between 750
and 1,250 cm? of expired air (ANovs0-1250) rather than the more
traditional way of looking at the slope of the alveolar plateau. They
found that the mean values for ANo750-1250) 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
: EE] Portage ia Prairie
d © charleswood
Bercentad
PY%TLO CV % VCE CC%TLE Slope ltl FEV, %FVC
FiGURE 3.—Prevalence of lung function abnormalities
among smokers in an urban and a rural
community
SOUCRL EB: Monfreda et at L978
values, but no differences associated with age for CC/TLC, the slope
of the alveolar plateau, RV/TLC, the steady state diffusing capacity,
and the 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 FEV., FEF 25-75%, Vmax 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
theory should be tested as part of an evaluation of the predictive
vaiue of small airways function.
Nemery and coworkers (1981) used the single breath N> test and
MEF'V curves to study a group of 272 European blue-collar workers,
aged 45 to 55, from a steel plant near Brussels, Belgium. They first
abtained reference values from their asymptomatic nonsmokers and
iefined their limit of normality as the 95th percentile for each of the
tests. CC/TLC and the slope of the alveolar plateau had the highest
prevalence of abnormality among the smokers (47 and 44 percent,
Me
respectively), followed by CV/VC% (34 percent), Vinax 75% (33 percent),
and Vmax 50% (30 percent). When the indices derived from the single
breath Ne 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 N2 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 HeO: in reasonably large population groups. This is
probably because the test is more difficult to perform than the single
breath Nz 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 HeQ: 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, Vinexs0 was the best test for discriminating the
effects of cigarette smoking, but AWmax so and VisoV were not
significantly different between the smokers and the nonsmokers.
Interestingly, the FEV: was the best discriminator of the effect. of
grain dust, and there was poor concordance among the FEVi, Vmax 50
and AVmaxso, and VisoV, They concluded that a comparison of MEFV
curves breathing air and HeQ; is less helpful than the standard
MEF'V 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 (1977a), 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 Vmax 75%, FEV: percent
predicted, and FEV:/FVC percent. The shift in the mean FEV:
percent predicted and the distribution of the FEV: 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
-1S.D. Mean +18.D.
0 pack-years (945)
2
0-20 pack-years (578)
20
of
0
Cc
&
3 f
3 21-40 pack-years (277)
20 4
3 |
o 0-4 [|
g pT
< 0
8 41-60 pack-years (/59) 4
3
a 2-4 ma
0-4
61+ pack-years (700) 4
2044
“Lot
0
40 60 80 100 120 140 160
Percent predicted FEV,
FIGURE 4.—Percentage distribution of predicted forced
expiratory volume in 1-second (FEV;) 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 in the abscissae.
SOURCE: Burrows et al. (1977a).
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 (FEV:/FVC,
Vmax 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 FEV:/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 Nztest 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 Vinax 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 Vmax 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 (FEV:, Vinax sow, and Wiss). 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 (1973a). These investigators found
that abnormalities of small airways function could be detected before
age 30 by means of the single breath No test, with CV/VC
discriminating best between smokers and nonsmokers in the age
decade of the twenties (Figure 6).
35
160 7 . A
.
120 ; . :
Cdyn « 100 ; } , . ns
Cst 7 ' I t :
(908PM) 80 fF § . ° 1
40 +
i ah. 4. 4 L
. . .
300 » 8
PF a,
. . . 3 as
Visov 200 F ! 8 ft i
Percent predicted . Q i ° e
100 - 7 .
2 e
.
‘ .
0 4 1 4 4 2
120 r . c
AV maxso 80 t . : i j '
Percent preuicted : . ns
40 F ° . * j 3
: > . : :
0 4. in. in. a 4.
Q 1 2 3 4
Symptoms score
500 - o
Slope phase ill 400 F .
Percent predicted 300 . e
. ns
200 F t ’ i ‘ :
100 + 1 r } 3 ‘
0 i i i 4 de.
180 fF . E
160 F
CC 140 F : : . ns
Percent predicted 429 - : § 3 J ’
100 : ° ! : :
a0 i 4 iL ale, 4
F
150 [ . 7
‘ . 28
. . =
V maxso 100 F 1 ‘ -
2 : : p< .05
Percent predicted ‘ & 1 .
© FG he
50 J- .
§
.
0 1 1 i 1
0 1 2 3 4
Symptoms score
FIGURE 5.—A composite of six tests plotted against
symptoms score
SOURCE: Dosman et al. (1976).
36
[J 284 Nonsmokers
EE) 524 Smokers
80
TT 1
Py 268 Ex-smokers e
60 & 4
L 46
E 43 - 43 44
5 40- os fas 4
5 Th bd 36
° m Bo or
be o E ne “
20 + aps pope 18
L ae os 4
: ap ops
of 0°00 é Se is ne on 0
N= 7 3. 43° 20 30 26 3v §1 63 80 66 64 32 21.4113
7 81 94 126 143 65 14
<20 20-29 30-39 40-49 50-59 60-69 70-79 +80
Age (years)
FIGURE 6.—Prevalence of abnormal closing volume/ vital
capacity ratios in nonsmokers, smokers, and
ex-smokers, by age decade
SOURCE: Buist 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
residual lung function (observed-predicted value) for FEV, Vinax 50%,
and Vmax 75%, 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 Vmax sox and Vmax 735% in women
aged 15 to 24 and for FEV: 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 FEV: in the 35 to 44 age group and
for Vex sox and Vmax 75% in the 45 to 54 age group.
Seely and coworkers (1971) found lower values for Vmax sox and
Vinx 75% 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 FEV}.
Dosman and coworkers (1981) studied 1,202 adults, aged 25 to 59,
living in Humboldt, Saskatchewan. Among smokers in the 25 to 29
37
Oe
01
0
_~ ~O1
eg
s
= 02
lu
Le
“93
0.4
-0.5
06
Age 7-14
15-24
Women (n =2,623)
L. CI Nonsmokers
EE3 Ex-smokers
i. Light smokers (1-20 cigarettes/day)
ei Heavy smokers (.- 20 cigarettes/day)
_ ° No observations
25-34 35-44 45-54 55-64 654
DAAAAAAAAAAAN
BAA AAA AASAAAAAN
PLATS AAA
FIGURE 7.—Mean residual FEV: in women, by smoking
status and age
SOURCE: Beck et al, (1981)
0.2
0.1
QO
0.1
0.2
0.3
r FEV, (liters}
05
-0.6
0.7
O08
0.4
ba
be
ha
5 = 5 r
Le 3 3
a
A he A
4 2 7 g
A 4 1 8
s e KH A
kad a ’ 4
, 4 g
s A 3
g s oe
g g @
eH A He
Men (n = 2,067) 3 3
2
g s
CC) Nonsmokers Cs g
Ca) €x-smokers Z
GB Light smokers (1-20 cigarettes/day) Z
1M
ea
Age 7-14 15-24 25-34 35-44 45-54 55-64 65+
Heavy smokers ( > 20 cigarettes/day)
No observations
FIGURE 8.-—-Mean residual FEV: in men, by smoking status
and age
SOURCE: Beck et al. (2981).
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 FEVi/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 FEV:/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 (FEF 20-30%, FEF 35-65%, FEF 020%, FEF 80-90%,
FEF 25-75%, and FEV:/FVC),with 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 FEV:/FVC 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.
Effect 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
FEV: 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 IID at 6 and 12 months following cessation.
40
cvsvc CC/TLC AN,/L
Percent predicted
Quitters
—77* Smokers
Months after clinic
FIGURE 9.—Mean values for the ratio of closing volume to
vital capacity (CV/VO), of closing capacity to
total lung capacity (CC/TLC), and slope of
phase III of the single breath Nz test (ANe/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.
NOTE: Data from 3-month followup of the 1973 clinic and 4-month followup of the 1975 clinic have been
combined, as have 6-month and 8 month data for the 1973 clinic.
SOURCE: Buist et al. (1979a).
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 No test showed improvement in smokers who
quit; this improvement continued for 6 to 8 months, and then leveled
off (Figure 9). In addition, the values for the single breath Ne 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 - g5 - 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! FEV:. 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 7- to 11-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 FEV;
between the cohorts. They concluded that significant associations
existed between the single breath Nz test variables and spirometric
variables in smokers, but the weakness of 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 (VC), FEV: or FEV.i/VC being more than 15
percent different from normal) within the 8-year 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 FEV: in middle-aged smokers.
Using these criteria in a cross-sectional study of a sample of working
42
men in West London, they concluded that the most informative and
repeatable tests were Vmax 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 FEVi/FVC had a significantly lower
FEV:/(height)’ 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 FEV: 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), wh»
examined the relationship between CV/VC, the slope of the alveolar
plateau, and FEV in 200 male smokers aged 40 to 55. In this group,
he found a relatively poor correlation between FEV; and the single
breath Ne 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 FEV: 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
FEV: 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 (1959) 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
40
[ | Women 3h.t
30-4
Percent
Never Former Current Light Moderate Heavy
Smoked Smoker Smoker Smoker Smoker Smoker
FIGURE 10.—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: 15-24 Cigarettes per day
Heavy smoker: > 25 cigarettes per day
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey NHANES |)
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 10), 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 1980b).
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; Guisvik 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. 1977). 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
6h
TABLE 2.—Prevalence (percent) of cough, phlegm, and other symptoms for nonsmokers (NS), smokers
(SM), and ex-smokers (EX), cross-sectional studies
Author, year,
country Population Cough Phlegm Other Comments
Tager and 507 residents, Chronic bronchitis Chronic bronchitis (cough and
Speizer, aged 15-65+, Men Phlegm >3 mos/yr for 2 years);
1976, U.S. East Boston NS 7.0 no age trend for either sex after
SM (pack-years) adjusting for smoking; prevalence
1-5 8.7 greater for men than women at
5-10 25.0 each age; significant increase in
10-20 28.6 chronic bronchitis with increased
>20 47.5 lifetime cigarette consumption
for current smokers, but not
Women ex-smokers
NS 46
SM (pack-years)
1-5 143
5-10 91
10-20 20.8
>20 30.0
og
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Dean et al., 6,277 men and Morning cough Bronchitis syndrome Bronchitis syndrome (cough and
1978 6,459 women, Men phiegm 3 mos/yr, shortness of
United Kingdom aged 37-67, NS 12.5 NS 11.4 NS 3.5 breath); significant increase of all
England, SM (filter) SM (filter) SM (filter) symptoms with age; prevalence of
Scotland, and 1-7 19.6 144 5.1 cough, phlegm, and wheeze
Wales 8-12 32.8 20.8 86 increased with number of
13-17 36.3 25.4 9.4 cigarettes smoked; filter vs.
18-22 44.0 26.9 85 nonfilter cigarette effects
23-27 50.6 34.2 10 small, nonsignificant for most
28-32 56.8 34.5 8.7 symptoms
334 §2.1 28.4 13.8
Women
NS 98 NS 75 NS 25
SM (filter) SM (filter) SM (filter)
1-7 16.9 13.8 3.8
8-12 25.8 16.6 42
13-17 29.6 16.6 5.1
18-22 45.1 25.8 10.6
23+ 56.6 34.3 12.0
Tg
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Higgins et al., 4,699 men and Chronic bronchitis Chronic bronchitis (cough and
1977, women, aged Men phlegm >3 mo/yr); chronic
US. 20-74, Tecumseh NS 5.1 bronchitis increased with age
EX 26 for male smokers; no age trend
5M apparent for male or female
<20/day 13.4 nonsmokers; dose-response
> 20/day 29.9 relationship between chronic
Pipe/cigar 8.4 bronchitis and cigarette smoking
(age adjusted)
Women
NS 35
EX 47
SM
< 20/day 48
> 20/day 15.3
as
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Lebowitz and 2,857 men and Chronic cough and/or phlegm Male prevalence consistently
Burrows, women, aged 14-96, Men greater than female only in older
1977, US. Tucaon NS 10.3 age groups; frequency of
SM (pack years) symptoms increased with age;
<6 29.0 impossible to distinquish effects
6-20 35.8 of aging and increased duration
21-40 47.9 of smoking
41+ 61.1
Women
NS 12.1
SM (pack-years)
<6 21.0
6-20 33.1
21-40 40.5
41+ 60.4
&¢
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Bland et al., 6,320 first-year Morning cough Breathlessness No questions on phlegm; child’s
1978, secondary school Boys Boys smoking habits more important
Great Britain children, NS 3.1 NS 12 than parents’ smoking habits;
Derbyshire SM once 29 SM once 14 Parents’ smoking habits
Occas. 4.0 Occas. 22 independently related to most
1 per wk. 19.2 1 per wk 35 symptom frequencies for
boys and girls
Girls Girls
NS 18 NS 7
SM once 45 SM once 22
Occas. 6.0 Occas. 29
1 per wk. 13.5 lperwk. 40
Cough at other times
Boys
NS 20
SM once 27
Occas, 34
1 per wk. 47
Girls
NS 19
SM once 30
Occas. 35
1 per wk. 47
¥S
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Huhti et al., 1,162 men, All day in winter All day in winter Chronic bronchitis For total group, significant
1978, aged 25-65, Age NS NS Age NS increase with age of cough,
Finland Hankasalmi 25-39 2 5 25-39 9 phlegm, and severe breathlese-
40-49 2 2 40-49 2 ness; for nonsmokers, signficant
50-59 5 8 50-59 15 increase with age for phlegm
60-69 4 7 60-69 19 and breathlessness only
Age EX EX EX
25-39 = 11 25-39 11
40-49 - 10 40-49 14
50-59 4 8 50-59 ll
60-69 12 18 60-69 28
Age SM SM SM 1-14 g/day
26-39 9 14 25-39 29
40-49 19 29 40-49 39
50-59 19 24 50-59 31
60-69 30 7 60-69 39
SM 15-24 g/day
25-39 13
40-49 45
50-59 46
60-69 46
SM >25 g/day
25-39 50
40-49 63
50-59 57
60-69 53
g¢
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Manfreda et al., 273 men and 229 Most days >3 mo/yr Most days >3 mo/yr Wheeze apart from colds No consistent difference in
1978 women, aged Men symptom prevalence for two
Canada 24-55, two CH* PLP* CH PLP CH PLP communities; higher prevalence
communities NS 8.3 4.0 NS _ 4.0 NS 4.2 8.0 of cough, phlegm, and wheeze
in Manitoba EX 8.1 29 EX 108 5.7 EX 108 14.3 among smokers than
SM 25.4 31.5 SM 169 247 SM 268 31.5 nonsmokers or ex-smokers;
* CH=Charleswood
Women ** PLP=Portage la Prairie
NS — 40 NS — 4.0 NS 35 8.0
Ex — 10.0 EX — 5.0 EX 121 20.0
SM 203 31.7 SM 102 26.4 SM 254 302
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Rawbone et al., 10,498 secondary A little most days With colds Frequent colds * EXPER (ex-emokers and
1978, echool children, Age NS NS NS experimental smokers combined);
Great Britain aged 11-17, li 64 22.8 36.0 sex differences not significant;
Hounslow 13 16.7 25.3 32.3 nonstandard questions; higher
15 13.4 24.5 34.3 symptom prevalence in younger
EXPER * EXPER EXPER children not explained
11 20.5 32.3 42.2
13 173 31.2 36.1
15 11.3 29.6 36.3
SM SM SM
ll 24.3 56.1 51.1
13 25.9 49.6 50.4
15 27.4 53.6 39.8
A little every day
NS
11 13
13 42
15 47
EXPER
11 70
13 47
15 3.5
SM
11 29.2
13 17.8
15 13.4
Lg
TABLE 2.—Continued
Author, year,
country Population Cough Phiegm Other Comments
Bouhuys et al., 7,203 residents, Usual cough Smoking significantly associated
1979, aged 7-65+, LE* AN** WIt with cough, phlegm, wheeze, and
US. three communities Men dyspnea; prevalence increased
NS 8 100 15 significantly with age, slightly
SM 27 324 higher in urban community;
Women women had lower prevalence of
NS 7 12 9 phlegm and higher prevalence of
SM 13 17 uw dyspnea than men
* LE= Lebanon
** AN= Ansonia
t WI = Winnsboro
Burghard et. al., 29,138 students, Morning Breathlessness Prevalence of symptoms increased
1979, aged 14-18, NS 13.7 NS 14.1 with increasing cigarette
France Bas-Rhin Department SM 25.7 SM 22.2 consumption; girls had higher
Day or night prevalence of respiratory
NS 16.9 symptoms for each smoking
SM 29.1 category
Chronic
NS 2.7
SM 6.6
g¢
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Gulsvik, 19,988 people, Morning cough When coughing Cough and phlegm periods Cough and phlegm increased more
1979, aged 15-70, NS ll NS 10 NS 6 with age for smokers (10-19
Norway Oslo EX 15 EX 18 EX 8 cig/day) than nonsmokers; no
SM 36 SM 28 SM 16 significant relationship between
Daytime cough age and prevalence of periods of
NS 4 cough and/or phlegm;
EX 7 dose-response relationship
SM 16 between number of cigarettes and
ugh 3 mos/yr symptoms reported; data not
NS 3 given
EX 5
SM 14
Liard et al., 899 men and women, Men Respiratory symptoms (cough and/or
1980, aged 20-60+, NS 16.0 phlegm 3 mos/yr. for 2 years); not a
France (av. 39), Paris SM 25.4 random sample; male and female
Women smokers had similar symptom
NS 8.1 prevalence; female nonsmokers had
SM 26.5 lower prevalence
6¢
TABLE 2.—Continued
Author, year,
country Population Cough Phlegm Other Comments
Park, 856 university Morning Morning Breathlessness on exertion Symptom prevalences apparently
1981, men and women, NS 16.0 NS 20.1 NS 23.2 not age-adjusted; significance
Korea aged 18-29, EX 31.3 EX 22.9 EX 25.0 levels not reported; nonstand-
Seoul SM 34.0 SM 26.1 SM 29.7 ard questions; symptoms current
Daytime Daytime
NS 42 NS 2.1
EX 83 EX 146
SM 109 SM 12.0
Nightime Nightime
NS 13.5 NS 73
EX 18.8 EX 10.4
SM 19.9 SM 13.2
Neukirch et al., 2,266 secondary Usual cough and/or phlegm 21.8% of boys, 32.2% of girls
1982, school students, Boys were current smokers; girl
France aged < 11->18 NS 26.1 smbdkers had higher symptom
(mean 14.9), SM 34.9 prevalence than boys if total
Paris Girls lifetime cigarettes > 4,000; results
NS 26.9 probably not age adjusted
SM 44.7
Schenker et al., 5,686 women, Chronic cough Chronic phlegm Wheeze most days or nights Cough and phlegm most strongly
1982, aged 17-74 (mean NS 5.6 NS 45 NS 7.2 related to current cigarettes/day:
US. 44.6), western EX 75 EX 6.7 EX 8.3 tar content had independent
Pennsylvania, SM SM SM effects; age effect seen for
telephone interviews 1-14 91 1~14 72 1-14 14.4 nonsmokers, but not current
15-24 17.0 15-24 16.7 15-24 18.5 smokers; symptom
25+ 31.8 25+ 24.8 254 28.0 prevalences age adjusted
TABLE 3.—Prevalence (percent of cough, phlegm, and other symptoms for nonsmokers (NS), smokers
(SM), and ex-smokers (EX), longitudinal studies
Author, year,
country Population Smoking habits Symptoms Comments
Ferris et al., 1,201 men and Cough Phiegm 72.3% of men, 78.4% of
1976, women, aged 25-74 1973 1967 1973 1967 1973 women followed up; 1973,
US. in 1961, Berlin Men symptom prevalences, age
New Hampshire NS 6.0 85 89 76 adjusted to compare with 1967,
EX 20.5 9.7 23.3 159 showed little change
SM
1-14 22.2 25.5 17.9 275
15-24 35.4 26.5 31.8 30.0
25-34 26.1 25.7 33.8 32.4
35+ 50.6 56.4 37.1 519
Women .
NS 44 - 6.2 81 14
EX 3.2 5.2 73 10.1
SM
1-14 10.7 10.0 11.6 98
15-24 19.5 16.3 218 98
25-34 27.2 16.1 22.5 218
35+ 44.7 31.0 43.1 41.2
Kiernan et al., 2,738 men and Cough day or night in winter Effects of chest illness before age
1976, women, aged 25, born 1966 1971 1966 1971 2, father’s vocation, and current
Great Britain in 1946, exams in NS NS 55 49 smoking significant; air pollution
1966 and 1971 NS SM 72 9.6° effect not significant; current
SM SM 143 18.5* smoking had largest effects
SM EX 9.2 5.8 * Prevalence, 1966 vs. 1972,
p <0.05
TABLE 3.—Continued
Author, year,
country Population Smoking habits Symptoms Comments
Leeder et al., 2,130 fathers, Cough/phlegm prevalence range In male ex-smokers, prevalence
1977, mean age 31.0+6.1, Men of cough/phlegm decreased
Great Britain 2,148 mothers, 1st period 2nd _ period Ist 3-yr period 2nd 3-yr period over time; no significant
mean age 27.9+5.3, NS NS 8.6-9.6 9.2-11.1 change in prevalence in female
children born NS SM 48-16.9 13.3-20.5 ex-smokers, but numbers
1963-1965, SM SM 25.6-30.2 30.8-34.0 were small
London, 6 year SM EX 21.8-25.3 §.8-20.7
followup Women
NS NS 49- 68 5.8 7.3
NS SM 8.2-10.2 13.3-18.4
SM SM 16.3-22.4 23.0-28.4
SM EX 4.1-22.5 12.2-14.3
Woolf and Zamel, 302 women, aged Cough and/or phlegm Breathlessness 60% followed up; all subjects
1980, 25-54 at initial Ist exam Final exam lst exam Final exam maintained consistent smoking
Canada atudy, 5-year NS 10 14 10 5 habits for 5 years
followup EX 3 13 18 8
SM 56 54 25 21
69
TABLE 3.—Continued
Author, year,
country Population Smoking habits Symptoms Comments
Beck et al., 1,262 white Usual cough Usual phlegm 55% followed up; health indices
1982, residents, aged 7-55+, 1972 1978 1972 1978 1972 1978 of respondents and non-
US. Lebanon, Connect- Men respondents similar; symptom
icut, exams in NS NS 5 2 7 3 prevalence tended to decline, but
1972 and 1978 NS SM 0 0 0 4 few changes were significant,
SM SM 23 21 22 26 * Prevalence, 1972 vs. 1978,
SM EX 25 2° 18 8 p <05
EX EX 7 6 12 15
Women
NS NS 7 4 5 6
NS SM 0 0 0 9
SM SM 20 14 15 ll
SM EX 28 12 8
EX EX 10 4 1
Ex-smokers
urrently 1-20/day
60+
C] Never smoked
Pp
a
3 Currently > 20/day
45-59
Women
30-44
15-29
Age
85 +
BO 4
75
70 4
65 +
60
55
50 4
45 yp
40
35+
30 ah
25 >
20 +
1S
104
S+
QO
Men
3044
15-29
Age
[
85 5
80 4
75 4
70 +
60 +
rg o ° Lrg 2 e w 2 Lr >
we = y ¢ “= NN N = =
Percent prevalence
65 +
FIGURE 11.—Prevalence of chronic cough and/or chronic
sputum among samples of men and women in
Tucson, Arizona
SOURCE: Lebowitz and Burrows (1977).
Dose-Response Relationships
The most common measures of dose are the number of cigarettes
currently smoked per day and the pack-years of cigarette consump-
tion; the latter estimates lifetime exposure by integrating the
number of cigarettes smoked (by pack) and the duration of cigarette
use. Errors of memory compromise the accuracy of retrospective
information, which may also be biased by differential recall in those
63
50.0 =
>20
10-19
400 ~ Smokers
Cigarettes/day
o 1-9
Ss 300-4
5
5
€
2 200
=£
a
e Ex-smokers
10.0 —4 © Nonsmokers
0.0
T | t
18-23 24-27 28-32 233
Tar (mg/cigarette)
FIGURE 12.—Percentage of smokers with phlegm
production (adjusted for age), according to tar
yield of cigarettes
SOURCE: Higenbottam et al. (1980).
with and without smoking-related symptoms or diseases. Even
accurate reports of current smoking habits fail to take into account
all the sources of variation in exposure associated with the material
used in cigarette manufacture or generated in the burning of
cigarettes. The dose of noxious materials received is also influenced
by human behavior, including the number, volume, and timing of
puffs taken with each cigarette; retention of smoke in the mouth;
depth of inhalation; disposition of the cigarette between puffs; and
other aspects of smoking style that are not reproduced by the
smoking-machines used to measure tar and nicotine yield.
Prevalence rates of cough or phlegm, or both, generally increase as
the number of cigarettes smoked per day increases. The trends
illustrated in Figures 11 and 12 were present in both sexes and all
age groups (Lebowitz and Burrows 1977; Dean et al. 1978; Higgins et
al. 1977; Huhti et al. 1978; Higenbottam et al. 1980; Schenker et al.
1982), Bland et al. (1978) found a dose-response relationship in
secondary school children, among whom rates of reporting cough
were higher in those who smoked most, even though levels of
cigarette consumption were generally reported to be low. At the
other extreme of the age range the trend is also apparent, even
though symptomatic smokers are more likely than asymptomatic
smokers to stop smoking or to reduce their cigarette consumption
64
(Higgins 1974; Fletcher 1976). Symptoms were more prevalent
among heavier smokers of filter cigarettes as well as of nonfilter
cigarettes (Dean et al. 1971). Prevalence rates of cough, phlegm,
chronic bronchitis, and mucus hypersecretion show a similar pattern
of association with pack-years of exposure (Tager and Speizer 1976;
Lebowitz and Burrows 1977). Rates of incidence and remission
observed in longitudinal studies add further support to the strong
evidence that respiratory symptoms increase as exposure to cigarette
smoke increases (Table 3).
In their study of more than 18,000 male civil servants in London,
Higenbottam and colleagues (1980) found that the percentage of
smokers who produced phlegm increased with increased daily
cigarette consumption and also with increasing tar content of
cigarettes among those who smoked less than 20 cigarettes a day.
Symptoms were prevalent about equally among smokers of 20 or
more cigarettes per day, regardless of the tar yield of the brands they
used (Figure 12).
Schenker et al. (1982) reported the relationship of tar content of
cigarettes to respiratory symptoms in a cross-sectional telephone
survey of 5,686 adult women in rural Pennsylvania. The risk of
chronic cough and phlegm was more strongly affected by the number
of cigarettes smoked per day than by tar content. Cough and phlegm
were reported least often by never smokers and with increasing
frequency as the number of cigarettes smoked per day increased. Tar
content of cigarettes was significantly associated with symptoms of
chronic cough and phlegm—especially cough—and its effects were
independent of the number of cigarettes smoked per day in a
multiple logistic analysis. The risk (relative odds) of chronic cough
for smokers of high tar cigarettes (20 or more mg) was approximately
twice that for smokers of an equivalent number of low tar cigarettes
(10 or less mg). A limitation of this cross-sectional study was the
determination of tar content for current cigarettes only, rather than
for lifetime smoking habits. Although the apparent relationship
between tar content and symptoms could have been caused by
changes in smoking habits, this was considered unlikely because
symptomatic smokers tend to reduce their consumption of cigarettes
more than asymptomatic smokers (Fletcher et al. 1976) and may also
switch to low yield cigarettes. In this situation, any reported effect of
tar content on symptoms would be an underestimate.
In summary, the prevalence of symptoms increases with dose of
smoke exposure, when dose is measured by number of cigarettes
smoked per day or tar content of the cigarette smoked.
Relationship of Cough and Phlegm to Sex and Age
Prevalence rates of cough and phlegm ascertained in epidemiologi-
cal studies generally increase with age and are higher in men than
65
in women, as shown in Figure 11 and Tables 2 and 3. Rates also vary
with smoking habits. Rates in nonsmokers better clarify associations
of symptoms with age and sex than do rates in smokers, since they
are less confounded by variations in exposure to cigarette smoke.
However, recent evidence linking passive smoking with increased
prevalence of respiratory symptoms suggests that rates in nonsmok-
ers may be in excess of those that would be found in a population
compietely free of exposure to cigarette smoke (Lefcoe et al. 1983;
Weiss et al. 1983).
Rates of reporting cough or phlegm or both were roughly equal in
nonsmoking men and women in several cross-sectional studies
(Bland et al. 1978; Higgins et al. 1977; Lebowitz and Burrows 1977;
Manfreda et al. 1978; Neukirch et al. 1982; Rawbone et al. 1978).
Rates were higher in nonsmoking men in some populations (Dean et
al. 1977; Liard et al. 1980; Tager and Speizer 1976). Bouhuys et al.
(1979) found no sex difference in the prevalence of cough, but a
higher rate of reporting phlegm in male nonsmokers (Table 2). In
most of these studies, the rates were not corrected for exposures to
other respiratory irritants in the workplace or in the general
environment.
In general, symptoms are more prevalent in male smokers than in
female smokers (Table 3). However, differences in prevalence rates
between the sexes are generally smaller or absent when comparisons
are made between men and women who smoke similar numbers of
cigarettes. Lebowitz and Burrows (1977) found that the excess
prevalence of symptoms in male smokers compared with female
smokers tended to be greatest at older ages, where there are also the
greatest differences in smoking behavior. Men in these birth cohorts
tend to have begun smoking earlier in life, smoke more cigarettes
per day, inhale more deeply, and smoke higher tar and nicotine or
unfiltered cigarettes. Two studies from France, Burghard et al.
(1979) and Neukirch et al. (1982), concentrated on high school
students. In general, the prevalence of smoking was similar for both
boys and girls for the two studies, although the Neukirch group
found a somewhat higher rate among the girls (46 percent versus 39
percent). Slightly more boys than girls, however, smoked more than
10 cigarettes per day. In these two studies, the prevalence of
symptoms was higher among female smokers than among male
smokers. These data suggest that the past differences in prevalence
of symptoms between the sexes is largely attributable to differences
in cigarette consumption. These differences were substantial in the
past, and are still present among older adults, whereas current
smoking practices are about the same in male and female adoles-
cents and young adults.
Prevalence rates of cough, phlegm, and chronic bronchitis in-
creased with increasing age in the U.S. population samples studied
66
by the National Center for Health Statistics (1981) and in several of
the cross-sectional studies cited in Table 2. However, differences in
rates of reporting symptoms among people of different ages may
relate to effects of aging, differences in current exposures, or
differences in exposure to cigarette smoke or other noxious agents in
the past. It is therefore difficult or impossible to use cross-sectional
data to separate effects of aging from effects of duration, dose, and
nature of cigarette smoke exposure throughout life. Longitudinal
studies provide information on time trends, both in exposure and in
onset and course of disease. Nevertheless, conclusions may be
incorrect if people who drop out of longitudinal studies are different
from those who continue to participate.
Prevalence of symptoms increased with increasing age among men
in cross-sectional data from Tucson (Figure 11), but the trend was
more apparent among smokers and ex-smokers than among non-
smokers. However, Lebowitz and Burrows (1977) could not distin-
guish between an association caused by increasing age and an
association due to increasing duration of exposure to cigarette smoke
in smokers because the two were so highly correlated. Among
women, symptoms were reported more frequently at ages 30 to 44
than at ages 15 to 29 (except by ex-smokers), but prevalence rates
were essentially the same for the three groups over age 30. Higgins
et al. (1977) found that there was no increase in cough and phlegm
with increasing age in male or female nonsmokers in Tecumseh
(Michigan), whereas prevalence rates increased with increasing age
in male smokers. The pattern in female smokers was similar to that
in Tucson and showed an increase with age up to age 30 or 40, but
rates declined with increasing age after age 50. The extent to which
these patterns related to amount smoked or duration of smoking was
not reported, but these older birth cohorts of women probably began
to smoke later in life and smoked fewer cigarettes per day, according
to national smoking survey data.
In other cross-sectional studies cited in Table 2, symptom preva-
lence increased with age in the populations studied (Bouhuys et al.
1979; Dean et al. 1977; Gulsvik 1979; Huhti et al. 1978; Tager and
Speizer 1976), but the trend was noted by Gulsvik to be less in
nonsmokers. Huhti et al. found a significant increase with age
among nonsmokers for phlegm and dyspnea only. Schenker et al.
(1982) observed a trend for nonsmokers but not for smokers, and
Tager and Speizer found that adjusting for smoking eliminated the
trend with age.
Prevalence rates of cough and phlegm on two occasions 3 to 6 years
apart are shown in Table 3 for five recent longitudinal studies of
populations in the United States, Canada, and Great Britain.
Kiernan et al. (1976), Leeder et al. (1977), Woolf and Zamel (1980),
and Beck et al. (1982) found little change in the prevalence of
67
symptoms among continuing nonsmokers during the followup inter-
val of up to 6 years. The rates among nonsmokers reported by Ferris
et al. (1976) are similar on the two occasions, but symptoms were
presented by smoking habits at followup only, and any effect of age
was deliberately adjusted out because the authors’ purpose was to
evaluate effects of changes in smoking, changes in pollution, and
trends over time independent of changes in age. Cough and phlegm
appeared to be more frequent at followup in the persistent smokers
studied by Kiernan et al. (1976) and Leeder et al. (1977), and about
the same in women studied by Woolf and Zamel (1980) and in men
studied by Beck et al. (1982). However, rates were slightly lower at
followup in the female smokers followed by Beck. Even though
starting to smoke or quitting can be eliminated as the explanation
for increases or decreases in symptom prevalence over the course of
these studies, it is possible that changes in the number or type of
cigarettes smoked by persistent smokers influenced the prevalence
of symptoms. The duration of followup in all these studies was
relatively brief, and it is still difficult to distinguish between effects
of aging and effects of duration, amount, and nature of exposure to
cigarette smoke in smokers, even when major changes in smoking
behavior are controlled. However, available data suggest that age
itself is not the major factor responsible for differences in the
frequency or distribution of symptoms in populations of nonsmokers
and smokers.
Relationship of Cough and Phlegm to Airflow Obstruction
Many cross-sectional studies have found associations between
cough, phlegm, chronic bronchitis, or mucus hypersecretion and
reduced levels of pulmonary function. The forced expiratory volume
at 1 second (FEV) has been measured in most clinical studies and in
nearly all epidemiological studies, and mean levels of FEV: are
generally slightly lower in groups of people who report respiratory
symptoms (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a,
1981). Recent studies have compared other measures of pulmonary
function in people with and without symptoms and have provided
longitudinal data on pulmonary function for symptomatic and
asymptomatic smokers and nonsmokers. Attention has been given to
understanding the natural history of chronic airways obstruction
and the interrelationships of respiratory symptoms, levels and rates
of decline of pulmonary function, and their independent and
interrelated associations with cigarette smoking. Several investiga-
tors have emphasized the desirability of identifying in advance those
smokers who will develop severe COLD; symptoms and other
characteristics have been evaluated as potential predictors of
morbidity or mortality from COLD.
68
Fletcher and colleagues ( 1976) found that the age—height standard-
ized FEV at the initial survey of their population of working men in
London was inversely related to the volume of sputum produced in
the first hour after getting up. The regression of FEV; on age, given
height, was steeper for symptomatic cigarette smokers than for
asymptomatic smokers or nonsmokers. However, the authors cau-
tion that men may develop symptoms as they age and change from
one regression slope to the other.
Burrows et al. (1977a) found that an index of cough or sputum was
related to FEV: percent predicted when pack-years of smoking were
controlled in a multiple regression analysis. Regressions of FEV,
percent predicted on pack-years are shown for people with and
without chronic cough and sputum in Figure 13; the intercept at 0
pack-years was lower and the decline in FEV; with increasing pack-
years was significantly greater for those with chronic cough and
sputum than for those with no cough or sputum. The authors
calculated that values of FEV: were lower by about 10 percent in
people with cough and sputum, regardless of smoking habits, and
that values declined by about 4 percent of predicted for each 10 pack-
years of smoking in people with cough and sputum and by about 2
percent in subjects without productive cough. There was a signifi-
cant relationship between FEV; and pack-years of smoking in
asymptomatic smokers in this population. A weaker relationship
between cough and sputum and Vmax was also found to be
independent of pack-years of smoking; however, prediction equations
for flow rates have been revised substantially (Knudsen 1983), and
the extent to which relationships between the revised flow rates and
pack-years of smoking differ in symptomatic and asymptomatic
subjects has not been reported.
Dosman et al. (1976) found poor correlations between respiratory
symptoms and dynamic lung compliance, closing volume, closing
capacity, slope of phase III, and helium flow-volume curves in a
study of 49 smokers and 60 nonsmokers who were recruited from a
smoking cessation clinic, a personnel department, and the staff of a
laboratory.
In their community-based studies of children and adults, Bouhuys
and colleagues (1977) studied relationships between respiratory
symptoms and loss of lung function in smokers and nonsmokers.
They found that residual values (observed-predicted) of FVC, FEV),
PEF, MEF ‘sox, and MEF 2% were not significantly different in people
with no symptoms or only one symptom when analyses were done
separately for adult white male smokers and nonsmokers. When a
Symptom score was used to combine information on usual cough,
usual phlegm, wheeze, and dyspnea, decrements in lung function
were greatest among those with most symptoms.
69
No cough or
A sputum (n= 1,492)
Total population without
chronic cough and
chronic sputum (n = 1,803)
Percent FEV,
80 =4
70 4 Subjects with chronic
cough and chronic
5 sputum (n = 247)
0 v T T T
20 40 60 80
Pack-years
Figure 13.—Percentage distribution of predicted forced
expiratory volume in 1 second (FEV:) versus
pack-year of cigarettes smoked, by cough and
sputum history
SOURCE: Burrows et al. (1977a).
In a study (Detels et al. 1982) designed to assess the relative
sensitivity and specificity of symptoms, the flow-volume curve (FV),
the single breath nitrogen test (SBNT), and specific airway conduc-
tance (Scaw) for identifying COLD were compared with the
FEVi/FVC ratio and with one another in 1,201 residents of Los
Angeles 25 to 29 years old. The tests were done in 1978-1979 at a
followup examination of a previously defined cohort. Prevalence
rates of cough and sputum were 9 percent in never smokers, 26
70
percent in current smokers, and 33 percent in smokers of 20 or more
cigarettes a day. Prevalence rates of an abnormal FEV:/FVC ratio in
these groups were 8, 23, and 33 percent, respectively (the FEV:/FVC
ratio was considered abnormal if it was below the 95th percentile for
never smokers without a history of respiratory illness). The research-
ers found that there was very little overlap between the presence of
productive cough and abnormal tests, and that none of the tests of
function showed reasonable concordance with this symptom. Lack of
reasonable concordance meant that none of the other tests were
abnormal in 50 percent or more of the individuals with productive
cough. In this study, the FEV:/FVC ratio was used as the standard
against which the sensitivities of the other tests were judged; the
sensitivity of the FEV:/FVC itself was evaluated by its agreement
with those tests found to be sensitive in the study. The lack of an
independent method for identifying COLD, the cross-sectional na-
ture of these data, and the way in which analyses were done restrict
the ability to make biological inferences about the independence of
the effects of cigarette smoking that lead to cough and sputum or to
chronic airflow limitation. However, the authors note their findings
are consistent with the hypothesis that effects of smoking on cough
and sputum are independent of effects on airflow limitation.
Insights into the course and pathogenesis of COLD have been
developed by Fletcher and his colleagues from observations made
during their 8-year longitudinal studies of levels and rates of decline
in lung function in middle-aged working men in London (Fletcher
1976; Fletcher et al. 1976). These investigators found that various
measures of sputum production were correlated with FEV: standard-
ized for height and age, and that this correlation was weakened only
slightly by adjusting for smoking habits. The researchers maintained
that the association between sputum production and pulmonary
function could be due entirely to a common causation. Some men
with mucus hypersecretion had normal FEV;; conversely, some men
with airflow obstruction did not report phlegm. Nevertheless, the
relationship between phlegm and reduced FEV: was strong enough
to give rise to an estimated reduction in FEV) of about 0.1 liters for
every ml of sputum expectorated in the first hour after getting up.
However, because decline in FEV; (FEV: slope) was not related to
measures of sputum production when level of FEV; and smoking
habits were controlled, the researchers concluded that mucus
hypersecretion is not a cause of accelerated decline in FEV}.
Furthermore, there was no evidence that short-term changes in
sputum production were associated with short-term changes in
FEV:. The researchers concluded that the association between
expectoration and reduced FEV; is caused by the increased suscepti-
bility of some people to both expectoration and excessive loss of
FEV; when they are exposed to cigarette smoke or, presumably, to
71
other noxious materials. This study has made important contribu-
tions to understanding the natural history of chronic bronchitis and
emphysema, but the duration of followup was only 8 years, the men
were 30 to 59 years of age at the start of the study, and their mean
age was 51 years at the midpoint. Similar studies of younger men
and women and observations over longer periods of time are needed
to extend these findings.
Johnston et al. (1976) found that sputum volume was not related to
decline in FEV: in a 10-year followup study of chronic bronchitic
patients. There was no difference in sputum volume between
patients whose FEV: fell by more than 33 percent and controls
(matched on initial FEV: ) whose FEV: did not fall. Furthermore,
sputum volume was reduced in response to stopping smoking or to
antibiotic treatment, whereas rate of decline of FEV: was unaffected.
In this and other studies (Higgins et al. 1970; Fletcher et al. 1976;
Peto et al. 1983) FEV: was strongly predictive of morbidity and
mortality, whereas respiratory symptoms were not.
Woolf and Zamel (1980) studied “normal” employed women aged
25 to 54 in a longitudinal study designed to identify smokers at
increased risk of developing COLD. Ventilatory function was mea-
sured at the beginning and at the end of a 5-year period during
which smoking habits and symptoms were ascertained annually.
Differences between initial and followup values of pulmonary
function tests were expressed as a percentage of the initial value and
compared in persistent nonsmokers and persistent smokers who
either consistently reported or consistently denied cough or sputum.
The decline in FEV:, FEVi/FVC, and FEF275% was greater in
symptomatic smokers than in asymptomatic nonsmokers, but not
significantly different in asymptomatic smokers compared with
either nonsmokers or symptomatic smokers. The average number of
cigarettes smoked during the course of the study was greater for
smokers with cough and sputum. Change in FEF25-75% was evaluated
in individual smokers, and no association was detected between
cough and sputum and percentage change in this measure of lung
function. The investigators identified one group of smokers whose
decline in FEF2s-75%, was similar to that in nonsmoking women and
another group with a greater decline; cigarette consumption was
similar in the two groups. The investigators concluded that individu-
al susceptibility is an important determinant of the effect of
cigarette smoking, because some women develop symptoms and
others remain symptomless but experience rapid worsening of
ventilatory function. However, they noted a tendency for both cough
and sputum and rapid worsening of ventilatory function to coexist.
The number of women in some groups was very small, and the
measure of decline in lung function used by these researchers does
not take into account regression to the mean or assess absolute
72
reduction; those with smaller initial values will have greater
percentage reductions for a constant absolute reduction in function.
Followup studies at 10 and 15 years of the Tecumseh, Michigan,
population showed that incidence rates of obstructive airways
disease were higher in men and women who reported cough, phlegm,
or both symptoms (chronic bronchitis) at entry compared with those
who denied these symptoms (Figure 14) (Higgins et al. 1982). Both
cough and chronic bronchitis were significant predictors of obstruc-
tive airways disease in men even when smoking habits were
controlled in multiple logistic analyses. However, respiratory symp-
toms were poorer predictors of impaired pulmonary function at
followup than were smoking habits and baseline levels of lung
function. In a multiple logistic model with age, smoking habits, and
level of lung function as risk factors, over 60 percent of the 10-year
incidence cases developed among men and women in the top 10
percent of the risk distribution, whereas only 36 percent of incidence
cases were in the top decile of risk when cough, rather than FEV,
was used as a risk factor (Higgins 1984).
Summary
Cigarette smoking is associated with respiratory symptoms, in-
cluding mucus hypersecretion, and with prevalence and incidence of
COLD manifested by irreversibly impaired pulmonary function.
While some smokers develop both conditions, and those with cough
and phlegm are at increased risk of developing airways obstruction,
the conditions can occur separately by mechanisms that are imper-
fectly understood but appear to be different. The excess risk of
reduced FEV: or COLD in symptomatic smokers compared with
asymptomatic smokers may be a reflection of increased susceptibili-
ty in some individuals. However, it may also be a measure of
increased dose of cigarette smoke, in that smokers who report cough
and phlegm tend to smoke more heavily than smokers who deny
these symptoms, and measures such as numbers of cigarettes smoked
per day are not precise enough to control adequately for the amount
of smoke exposure. The rate, number, and volume of puffing as well
as the depth of inhalation can vary substantially between smokers
and are important additional measures of cigarette smoke exposure
dose.
73
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Men
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18
107
54
0
incidence of obstructive airways disease (percent)
FIGURE 14.—Age-adjusted 15-year incidence of obstructive
airways disease, by cough, phlegm, and
chronic bronchitis status at entry to the
study, Tecumseh, ages 16 to 64, 1962-1979
SOURCE: Higgins et al. (1982)
74
CHRONIC AIRFLOW OBSTRUCTION
Introduction
Airflow obstruction is the physiological consequence of disease
processes that narrow the airway. In asthma the obstruction is
reversible with pharmacologic bronchodilation, whereas the obstruc-
tion associated with airways damage and emphysema is often not
reversible. The terminology with regard to permanent airflow
obstruction has varied. The 1958 Ciba Foundation Guest Symposium
proposed “generalized obstructive Jung disease,” which was subdivid-
ed into “asthma” and “irreversible or persistent obstructive lung
disease” (1959); in the 1962 recommendations of the American
Thoracic Society, “chronic obstructive bronchitis” was the only
definition that mentioned abnormality of expiratory flow (American
Thoracic Society 1962). In 1975, a joint committee of the American
College of Chest Physicians and the American Thoracic Society
recommended the term “chronic obstructive pulmonary disease”
‘American College of Chest Physicians and American Thoracic
Society 1975). Thurlbeck (1976, 1977) has advocated the use of
“chronic airflow obstruction,” a functionally based definition that
does not specify the underlying disease processes. Previous Reports
of the Surgeon General have used varying terminology, including
“chronic bronchopulmonary disease” in 1964, “chronic obstructive
bronchopulmonary disease” in 1971, and “chronic obstructive lung
disease” in 1979 (USPHS 1964, 1971; USDHEW 1979).
These definitions, however, cannot be readily applied to identify
specific populations. Physiologists, epidemiologists, and clinicians
often use differing approaches in determining whether airflow
obstruction is present (Fletcher 1978). Physiologists, with the
capability for making sophisticated laboratory measurements of
airflow obstruction, may regard subtle early abnormalities of flow as
definitive. In the community, epidemiologists have generally used
spirometry as the primary method for assessing airflow obstruction.
For epidemiologic purposes, airflow obstruction is usually defined by
a forced expiratory volume in 1 second (FEV)) less than a particular
level after standardization for sex, age, and height, or by a ratio of
the FEV: to the forced vital capacity (FVC) below a specified value.
Tests of forced exhalation, such as the FEV 1, have the advantage of
sensitivity to abnormalities of both the lung parenchyma and the
airways (Mead 1979). Clinicians are more likely to detect and
diagnose airflow obstruction when it is advanced and symptomatic.
As would be anticipated, the differing approaches of physiologists,
epidemiologists, and clinicians may lead to differing estimates of the
frequency of airflow obstruction.
The natural history of chronic airflow obstruction in adults has
been partially described by several recent prospective investigations:
n
‘
or
Howard (1970), Bates (19733, Sharp et al. (1973), Fletcher et al. (1976),
Fletcher and Peto (1977), Bosse et al. (1981), Beck et al. (1982), and
Clement and van de Woestijne (1982). Although these investigations
did not characterize the course of airflow obstruction across the
entire human lifespan, the results provide a conceptual model for
considering its development (Figure 15). Ventilatory function, gener-
ally measured by the FEVi, increases during childhood and reaches a
maximum level during early adulthood (Cotes 1979; Knudson et al.
1983). From this peak; the FEV: gradually and progressively declines
with age. In people who develop airflow obstruction, a similar
gradual loss of function occurs, but at a more rapid rate (Fletcher et
al. 1976; Speizer and Tager 1979). Continued excessive loss of FEV:
eventually results in symptomatic airflow obstruction when ventila-
tory function reaches a level at which activities are limited and
dyspnea occurs. Evaluation by a physician for symptoms may lead to
a clinical diagnosis at this point in the natural history of the disease
process. This model may not satisfactorily describe the development
of airflow obstruction in all individuals (Burrows 1981), but the
accumulating evidence, reviewed below, indicates that a sustained
excessive loss of ventilatory function most often leads to the
development of clinically important chronic airflow obstruction.
In the conceptual model (Figure 15), there are three different
measures of the frequency of airflow obstruction in a particular
population: the prevalence of reduced ventilatory function as
measured by the FEV:, the FEV:/FVC ratio, or other physiological
parameters; the prevalence of physician-diagnosed airflow obstruc-
tion; and the frequency of excessive functional loss in a population
followed over time. The first two measures can be determined from a
single cross-sectional survey, whereas the third requires longitudinal
observation. At present, scant data are available for the third
category. The prevalence of physician-confirmed airflow obstruction
is determined not only by the proportion of affected people in the
population, but also by the patterns of medical care access and usage
and the diagnostic practices of individual physicians. Furthermore,
the clinical labels applied by physicians to people with airflow
obstruction are variable and may include “chronic bronchitis,”
“emphysema,” “COLD,” and other terms. Thus, estimates of disease
prevalence based on reported physician diagnoses may differ from
those derived from physiological assessment.
Prevalence of Airflow Obstruction
Numerous populations throughout the world have been surveyed
to assess the prevalence of airflow obstruction (Stuart-Harris 1968a,
1968b; Higgins 1974). Most often, the investigative techniques have
included a respiratory symptoms questionnaire and measurement of
pulmonary function, generally with a spirometer or peak flow meter.
76
34 N, A Normal
FEV, (ters)
SX.
\
Xu.
25 35 45 55 65 76
Years
FIGURE 15.—Decline of FEV; at normal rate (solid line)
and at an accelerated rate (dashed line)
NOTE: A: person who has attained a “normal” maximal FEV, during lung growth and development; B: person
whose maximal FEV; has been reduced by childhood respiratory infection.
SOURCE: Samet et al. (1983),
The latter technique has the disadvantage of effort dependence.
Early recognition of the potential problem of observer bias led to the
development of standardized methods (Cochrane et al. 1951; Higgins
1974; Ferris 1978). Thus, most investigators throughout the world
have used the British Medical Research Council questionnaire in the
original form or with some modifications (Samet 1978). Standardiza-
tion has been less uniform for lung function measurements, but
minor variations in procedures would not introduce important
differences in disease prevalence among the various populations
examined.
Although many different populations have been surveyed since
the 1950s, surprisingly few published reports provide data concern-
ing the prevalence of airflow obstruction in the general population
77
(Tables 4 and 5). Comparisons among the available studies are
limited by varying methodologies and inconsistent approaches in
calculating rates. For example, only crude rates are available in
some reports, and reference populations for age standardization also
vary. The investigations summarized in Tables 4 and 5 were selected
because they offer estimates of the prevalence of airflow obstruction
in defined community-based samples. Those reports that describe
mean levels of lung function parameters but not their distributions
were excluded. Investigations of specific occupational groups were
also excluded because prevalence estimates based on such popula-
tions may be biased by the overrepresentation of healthy persons
(Monson 1980) and workplace exposures may have affected the
frequency of disease.
For the United States, the available information spans the time
period 1961 to 1979 and covers most geographic regions (Table 4).
Regardless of the definition, it is apparent that airflow obstruction is
common among aduits in the United States. A higher proportion of
men than women is affected, and the prevalence increases with age
(Ferris and Anderson 1962; USPHS 1973; Lebowitz et al. 1975; Detels
et al. 1979; Samet et al. 1982). Few minority populations have been
studied. In New Mexico, Hispanic whites had a lower prevalence of
physician-diagnosed current chronic bronchitis or emphysema than
non-Hispanic whites (Samet et al. 1982). Although blacks have been
included in several surveys (Bouhuys et al. 1979), prevalence
estimates for this racial group have not been published. The
available data (Table 4) do not permit a satisfactory assessment of
changes in prevalence rates with time over the years 1961 to 1979.
The National Health and Nutrition Examination Surveys
(NHANES 1) included spirometry in their evaluation of a represen-
tative sample of the U.S. population. The numerical values for these
measures are reported by age, sex, and smoking status for the white
population in the tables in the appendix to this chapter. The changes
in mean values of these measures between age groups are also
presented for white male and female smokers and nonsmokers in
Figures 16 through 23. Differences between smokers and nonsmok-
ers are evident for each of these spirometric measures. These
differences are portrayed for successive age groups at one point in
time, and therefore cannot be used to describe the changes with age
or smoking status that one would expect in an individual or
copulation followed sequentially. These data represent only those
people in the study population who were willing and physically able
to maximally exert themselves on the various spirometry tests.
Others were disqualified by the examining physician because of
existing medical conditions. The sampling nonresponse was higher
among segments of tne population expected to perform less well on
the test. including necple with existing airflow limitation. Therefore,
TABLE 4.—Prevalence of indices of airflow obstruction in selected U.S. adult
populations
Author, year of study,
location, reference
Number and type
of population
Index
Prevalence (per 100)
Higgins and Kjelaberg,
1959-1960, Tecumseh,
Michigan (1967)
4,500 men and women,
20 years or older,
community sample
Emphysema based on physician
history and examination
Higgins, 1962-1979,
Tecumseh, Michigan
(1983)
4,916, 4,443, and 4,930
men and women, 16
to 74 years old, in
1962-65, 1967-69, 1978-79
Obstructive airways disease:
FEV, less than 65% predicted,
and FEV,/FVC ratio less
than 80%
Ferris and Anderson, 1961,
Berlin, New Hampehire
(1962)
1,167 men and women,
community sample
Irreversible obstructive
lung disease, including
wheezing, dyspnea, or
FEV,/FVC ratio less than
60%
Mueller et al., 1967, Glen-
wood Springs, Colorado
(1971)
US. Public Health Service,
1970, United States (1973)
609 men and women,
community sample
116,000 men and women,
nationwide sample
Chronic airway obstruction:
FEV,/FVC ratio less than
60%
Presence of the condition
during the previous year
Men 4.1!
Women Li!
Men Women
1962-65 48? 25?
1967-69 3.7? 14?
197& 79 3.7? 2.2?
Men 8.6!
Women Blt
Men 13.2!
Women 1.5)
Chronic bronchitis
Men 3.1!
Women 3.4!
Emphysema
Men 1.0!
Women 0.3
TABLE 4.—Continued
Author, year of study,
location, reference
Number and type
of population
Index
Prevalence (per 100)
Lebowitz et al., 1972-1973,
Tucson, Arizona (1975)
3,805 men and women,
adults and children,
community sample
Physician-confirmed illness,
current
Men over 44 years
Knudson et al., 1972-1973,
Tucson, Arizona (1976)
3,805 men and women,
adults and children,
community sample
FEV, and FEV,/FVC ratio
lower than 95th percentile
for “normal”
Detels et al., 1973-1974,
Burbank and Lancaster,
California (1979)
3,465 and 4,509 men
and women, in Burbank
and Lancaster, respectively,
community samples
FEV, less than 50% of
predicted value
Tager et al., 1973-1974,
East Boston, Massachusetts
(1978)
1,770 men and women,
community sample of
index subjects and
their relatives
FEV, less than 65% of
predicted
Ferris et al., 1974-1977,
six cities in the US.
(1979)
7,909 men and women,
community sampie
FEV,/FVC less than, equal
to 60%
Chronic bronchitis 10.2
Emphysema 13.3!
Women over 44 years
Chronic bronchitis 9.0!
Emphysema 4.3!
Asymptomatic cigarette smokers
FEV, 78°
FEV,/FVC 8.1!
Lancaster
18-59 yrs 0.8?
60 yrs 6.5°
Burbank
18-59 yrs 1.0?
60 yrs 6.2?
Men 56!
Women 3.47
Men 5.0'
Women 19°
T8
TABLE 4.—Continued
Author, year of study,
location, reference
Number and type
of population
Index
Prevalence (per 100)
Non-Hispanic whites
Samet et al., 1978-1979, 1,722 men and women, Physician-diagnosed current Men 3.6?
Albuquerque, New Mexico community sample chronic bronchitis or Women 3.4
(1982) emphysema
Hispanic whites
Men 0.8?
Women 1.8?
‘Crude rate.
” Age-adjusted rate.
* Age and sex-adjusted rate.
os
TABLE 5.—Prevalence of indices of airflow obstruction in selected adult non-U.S. populations
Author, year of study,
location, reference
Number and type
of population
Index
Prevalence (per 100)
Anderson et al., 1963,
Chilliwack, British
Columbia (1965)
558 men and women,
community sample
Obstructive lung disease,
including wheezing, dyspnea,
or FEV,/FVC ratio less than
60%
FEV,/FVC ratio less than
60%
Mimica, 1969, Croatia,
Yugoslavia (/975)
4,214 men and women,
samples of six
communities
FEV,/FVC ratio less than
60%
Sawicki, 1968, Krakow,
Poland (1977)
4,355 men and women,
community sample
FEV,/FVC ratio less than
60%
Huhti et al., 1968-1970,
Hankasalmi, Finland (1978)
1,162 men, community
sample
FEV,/FVC ratio less than
60%
Brown and Gajdusek, year
not stated, Western
Caroline Islands (1978)
240 men and women,
community sample
Chronic obstructive airway
disease: clinical and spiro-
metric criteria
Anderson, year not stated,
Lufa, Papua New Guinea
(1979)
770 men and women,
25 years or older,
community sample
FEV,/FVC ratio less than
60%
Men 12.6!
Women 87!
Men 7.3!
Women 3.5!
Men 8.3!
Women 1.9'
Men 7.0!
Women 5.0'
Men 76!
Men and
women 79!
Men 9.01
Women 3.6!
‘Crude rate.
the estimated means are probably overestimates of the true popula-
tion values. Nevertheless, the figures clearly portray the magnitude
of the effect that smoking exerts on expiratorv flow rates in a
national population sample.
Airflow obstruction is also prevalent outside the United States
(Table 5). The disease can be identified in both technologically
advanced and less developed populations. As in the United States, in
other countries the prevalence of airflow obstruction is higher
among men than among wamen.
Determinants of Airflow Obstructior
Introduction
Current understanding of the natural history of airflow obstruc-
tion suggests that risk factors operative during both childhood and
adulthood may influence the development of disease. In the concep-
tual model proposed in Figure 15, childhood factors might increase
the risk of airflow obstruction by lowering the maximum FEV;
attained during lung growth and development, by predisposing to
increased FEV: decline during adulthood, or by both mechanisms
(Speizer and Tager 1979). During adulthood, in the model of Figure
15, risk factors for airflow obstruction must increase the rate at
which lung function deteriorates.
Many endogenous and exogenous determinants of the develop-
ment of airflow obstruction have been postulated (Tables 6 and 7).
However, in spite of over 30 years of intensive investigation, the
available data are definitive only for cigarette smoking and for a,-
antitrypsin deficiency (Speizer and Tager 1979; USDHHS 1980).
Cigarette Smoking and Chronic Airflow Obstruction
In nearly every population studied worldwide, cigarette smoking is
the predominant determinant for the prevalence of airflow obstruc-
tion (Tables 8, 9, and 10). The uncommon exceptions primarily
involve populations in whom severe chest infections or wood smoke
exposure may have an etiological role (Wooicock et al. 1973:
Anderson 1979a). The relationship between cigarette smoking and
airflow obstruction has been variably described in the published
reports. In some, the prevalence of airflow obstruction has been
considered; in others, mean values of lung function parameters have
been compared across categories of smoking use. In several more
recent analyses, multiple regression or other multivariate tech-
niques have been used for more careful characterization of dose-
response relationships. Because the epidemiologic criteria for airflow
obstruction are gencrally based on the FEV), this section focuses on
studies that have included measurernents of this parameter. The
selected studies involve community samoles (Tubles & and 9) and
4500-4404
Men
4000 -4 ~~
! 4037 ~~
|
3500
E
ec 3000-4
a |
3 |
= i ~
' 2738 ~~~
2500 -~ ws
~~
i 2222
2000 "|
| — Never smokers
1500 ; --- Current cigarette smokers
0 —- ; ro
25-34 35-44 45-54 55-64 65-74
Age qroup
3500 - ; Women
E
c
a
o
=
ro “ T ~ T ~ T 7
25-34 35-44 45-54 55-64 65-74
Age group
FIGURE 16.—Mean FEV; for white persons by smoking
status, sex, and age, United States, 1971-1975
NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
midpoint of the survey.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey ‘NHANES 1).
84
8000-7874
ee 7715 Men
7500-+ seal
7606 a 7262
oN.
x NN
7000 ~ se —
— ne
‘ 6848 >. SA 6543
5500— N SN
A ae
é SN 8097
< 6000-< 6130 ~~
xs ~
> se
3 ~
5500— “N
5567*
N
‘\
5000 -- a
\,
\
4500 — \
—— Never smokers X
4000 4 ~—- Current cigarette smokers 4199
:
Op Ta pe Poe eee
25-34 35-44 45-54 55-64 65-74
Age group
6000—~ 5847 Women
5500 —
E 5000 |
c |
g .
= 4s00-| NL 4331
i
|
4000 \
i ~
NN
~
5
00 3627
.
2500 -- se
~N
~N
“N
' N
2000 -- “s
: ~-- Never smokers 1889
~—- Current cigarette smokers
1600 ~
Or i ae on
25-34 35-44 45-54 55-64 65-74
Age group
gas
4000-5 Se a Women
873
Oo
a
3500-- ae ~
3634 Te oN, att0
mS F170
33257 ~—
= 3000-- ~ 2886
= se ae
5 x me
a ae 2410
= 2500-- 2604 See ~
2361
2000-- me
1965
1500 --
(het - 7 . mo .
25-34 35-44 45-54 55-64 65-74
Age group
FIGURE 18.—Mean flow at 50 percent of FVC for white
persons by smoking status, sex, and age,
United States, 1971-1975
NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
midpoint of the survey
SOURCE: National Center for Health Statistics Unpublished data from the first National Health Nutrition and
Examination Survey (NHANES Li
86
| Men
| 2065
2000 +
= 1500 -
c
a
2 !
= 1000—
~ 795
—
500 —~— Never smokers ae
—-- Current cigarette smokers 350
0 T “4 ee ee oo
25-34 35-44 48-54 55-64 65-74
Age group
2000 Women
1500
E
§ 1000
vo
=
500
Q T T T T a 1
25-34 35-44 45-54 55-64 65-74
Age group
FIGURE 19.—Mean flow at 75 percent of FVC for white
persons by smoking status, sex, and age,
United States, 1971-1975
NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
midpoint of the survey.
SOURCE: Nationa] Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey (NHANES 1).
87
Men
85 +
80.7
BO 78.8
ae 77.5
= 9.2 OT ee 75.8
© 75 wee 73.
s 75.9 ~~ ~~~ 8s
ad 73.0 ~~~~~2 1
704 ~~
70.6 ~~~.
664 —— Never smokers 67.0
~~~ Current cigarette smokers
a
Qo T T T T TO
25-34 35-44 48-54 55-64 65-74
Age group
90 7 Women
85 +
804
z
§ 757
oo
=
705
65
LA
0 4 T T T T T
25-34 35-44 45-54 55-64 65-74
Age group
FIGURE 20.—Mean FEV1/FVC ratio for white persons by
smoking status, sex, and age, United States,
1971-1975
NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
midpoint of the survey.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey (NHANES 1).
85
4500-5
Men
4000 ->
3500 —
3188
= 3000 —
E ae 2734
Cc
3
= 2500-- ~~ ~ 2314
251s ad
2000 ~ os
2085 ~~~
SL .
1500 ~ oS
~+— Never smokers 1422
--~- Current cigarette smokers
1000 —
oi, } a wo ee
25-34 35-44 45-54 55-64 65-74
Age group
3500 7 3357 Women
E
c
©
o
2
Oo — Sanne ea
T T T q
25-34 35-44 45-54 55-64 65-74
Age group
FIGURE 21.—Mean MMEF for white persons by smoking
status, sex, and age, United States, 1971-1975
NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
midpoint of the survey.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey (NHANES 1).
89
9000 + Men
8500 ~
|
8000 4
|
|
7500 4
|
7000-|
= . ~—___8526
= 6500- 6758 ~.
o ~~
® ~~
= *A
6000 SS
| \,
5834°..
5500-4 ‘
! N
\
\
5000 4 \,
‘
4500 ~ —— Never smokers ‘\
' -—~ Current cigarette smokers 4341
4000 +
L
o-t T 7 7 T 7 7 a 7 >> rn — rn
25-34 35-44 45-54 55-64 65-74
Age group
5991 5
6000 > = 923 Women
5947 >
5500 ~
5000 --
= 4500 ~
c
a
»
2 4000 -
3500
3000 -
2500
0° : anne
25 34 35-44 45-54 55-64 65-74
Age group
FIGURE 22.—Mean MEFR for white persons by smoking
status, sex, and age, United States, 1971-1975
NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
midpoint of the survey
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey (NHANES 1).
90
5500 ]
Men
5000 -4
!
=> 4500-—
= 500 ;
<
oO
a
= 4000-—-
4500 +
| ~
| —-N ~
lever smokers 3925
‘ —-- Current cigarette smokers
3000 4
25-34 35-44 45-54 55-64 65-74
Age group
Women
E
Cc
°
2 LL 2603
2533
9 y 7 ee Ts ee rns ee ae
25-34 35-44 45-54 55-64 65-74
Age group
FIGURE 23.—Mean forced vital capacity for white persons
by smoking status, sex, and age, United
States, 1971-1975
NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the
midpoint of the survey.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and
Examination Survey (NHANES 1).
91
‘ABLE 6.~Postulaied risk factors for airflow obstruction
during childhood
Active cigarette smoking
Air pollution. indoor and outdoor
Airways hyperreactivity
Atopy
Familial factors
Passive expcsare to tobacco smoke
Respiratory illnesses
Socioeconomic .tatus
ABLE 7.—Moerindity
USTABLISHED Risk FACEORS FOR AIRFLOW OBSTRUCTION DURING ADULTHOOD
Active cigarette smoking
Alpha,-antitrypsin deficiency
PUTATIVE RISK } A: TORS FOR AIRFLOW OBSTRUCTION DURING ADULTHOOD
ABH secretor status
Air pollution
Airways hyperreactivity
Alcohol consumption
Atopy
Childhood respiratory illnesses
Familial factors
Occupation
Passive exposure to tobacco smoke
Respiratory illnesses
Socioeconomic status
occupational groups (Table 10) with exposures that have little or no
effect on lung function. The selected studies are all cross sectional in
design and thus describe the relationship between cigarette smoking
and lung function level at only a single point in time.
Investigations in the United States, spanning the time period 1958
to 1977, convincingly demonstrate that cigarette smoking is a strong
determinant of FEV: level and the prevalence of airflow obstruction
(Table 8). In every population for which prevalence data are
available, airflow obstruction is more common among smokers than
among nonsmokers (Mueller et al. 1971; Knudson et al. 1976; Detels
et al. 1979; Rokaw et al. 1980). In fact, in a multivariate analysis of
determinants of airflow obstruction in East Boston, lifetime cigarette
consumption was the only statistically significant predictor (Tager et
al. 1978). Data from populations outside the United States (Table 9)
and from a variety of occupational groups (Table 10) confirm the
importance of cigarette smoking. Effects of cigarette smoking on
FEV) level have been readily demonstrated in employed populations
92
£6
TABLE 8.—Association between cigarette smoking and FEV,
Author, year of study,
location, reference
Ashley et al., 1958,
Framingham, Massachusetts,
(1975)
Number and type
of population
1,238 men and women,
37 to 69 years of age
level in selected U.S. adult populations
Findings
By linear regression, significant decline of FEV 1/FVC ratio
with pack-years of cigarette consumption in men; similar
decline demonstrated in women, but not significant for all
age groupe
Age-adjusted mean FEV, (liters)
Higgins and Kjelsberg 1959. 5,140 men and women, Men Women
1960, Tecumseh, Michigan 16 to 79 years of age Nonsmokers 3.32 2.34
(1967) Ex-smokers 3.31 2.34
Current smokers 3.12 2.28
arena
Mean FEV, (liters)
Higgins et al., 1963, Marion 926 white men, 20 Nonsmokers 3.64
County, West Virginia to 69 years of age Ex-smokers 3.25
(1968a} Current smokers
1-14/day 3.67
15-24/day 3.51
2 25/day 3.30
Mean normalized FEV, score
Higgins et al, 1962-1965, 4,669 men and women, Men Women
Tecumseh, "fichigan (1977) 20 to 74 years of age Nonsmokers 10.2 10.1
Ex-smokers 9.9 10.0
Current smokers
< 20/day 98 99
2 20/day 95 96
eG
TABLE 8.—Continued
Author, year of study,
jocalion, reference
Number and type
of population
Findings
Mueller et al. 19€7,
Glenwood, Colorado
(1970
Ferrix et al., 1967, Berlin,
New Hampshire (1973)
Burrows et al., 1972-1972,
Tucson, Arizona (1977
Knudson et al., 1972-1973,
Tucson, Arizona (1976)
609 men and women,
20 to 69 years of age
848 men and women,
30 to 80 years of age
2,368 men and women,
above 14 years of age
2,735 men and women,
all ages
Prevalence of FEV, /FVC< 60%
Men Women
Nonsmokers 3 1
Current smokers 1g 2
By multiple regression, in men and women, FEV, drops by
0.01 liters for each cigarette smoked per day
By multiple regression analysis, FEV, drops by 0.31 and
0.24 percent of predicted value per pack-year of smoking
in men and women, respectively
Prevalence (%) of abnormal FEV, and/or FEV,/FVC .
Asymptomatic nonsmokers 83
Asymptomatic smokers 13.3
Tager and Speizer, 1973-1974,
East Boston, Massachusetts
(1978)
Tager et al., 1973-1974, East
Boston, Massachusetts (1979)
Beck et al, 1972-1974,
Lebanon and Ansonia, Con-
necticut, Winnsboro, South
Carolina (1987)
633 men and women,
15+ years of age
1,251 men and women,
4,690 men and women,
7+ years of age
By multiple regression, in men and women, significant
reduction of an FEV, score with increasing lifetime
consumption, and in smokers compared with nonsmokers
By multiple logistic analysis, lifetime cigarette consumption
only significant predictor of airflow obstruction, defined as
FEV, less than 65% predicted
By multiple regression analysis, significant dose-response
relationships of adjusted residual FEV, with measures of
cigarette smoking: duration, pack-years, and cigarettes per
day
S6
TABLE 8.—Continued
Author, year of study,
location, reference
Ferris et al., 1974-1977,
U.S. communities (1979)
Number and type
of population
8,480 men and women,
25 to 74 years of age
Findings
Mean residual FEV, (liters) after correction for height and age
Lifetime packs Men Women
None 0.25 0.06
< 3,000 0.21 0.04
3,000-8,999 0.01 0.05 |
9,000--17,999 0.19 0.20
> 18,000 0.45 ~0.28
Detels et al., Rokaw et al.,
1973-1975, Burbank, Lan-
caster, Long Beach,
California (Detels et al.,
1979, Rokaw et al., 1980)
Approximately 8,000
men and women, 18
years or older
Prevalence (%) of FEV, below 75% predicted, age and sex-adjusted
Never smoked Current smoker
18-59 years old
Burbank 6.6 12.5
Lancaster 3.4 6.6
Long Beach 5.3 10.0
>60 years old
Burbank 15.9 23.5
Lancaster 13.4 217
96
TABLE 9.—Association between cigarette smoking and lung function in selected non-U.S. populations
Author, year of study,
location, reference
Number and type
of population
Findings
Higgins, 1956, Vale of
Glamorgan, Wales (1957)
581 men and women,
25 to 74 years of age
Ir men, reduced peak flow rates and indirect maximum voluntary
ventilation in smokers compared with nonsmokers;
no effect of smoking in women
Higgins et al., 1957
Stavely, England
(1959)
776 men, aged 25 to
34 and 55 to 64
Mean indirect maximal breath capacity (liters)
25 to 34 yrs 55 to 64 yrs
Nonsmokers 145 101
Ex-smokers 143 89
Current smokers
Light 140 87
Heavy 133 80
Higgins et al., 1968, Rhondda
Fach, Wales (1961)
537 men, aged 35 to 64,
and 173 women,
aged 55 to 64
Mean indirect maximal breathing capacity (liters), men
Miners Nonminers
Nonsmokers 93.1 114.6
Ex-smokers 93.6 105.9
Current smokers
Light 89.0 104.1
Heavy 88.3 99.4
No effect of smoking in women
16
TABLE 9.—Continued
Author, year of study,
location, reference
Number and type
of population
Findings
College of General Practitioners,
1958, Britain (1962)
787 men and 782
women, aged 40 to 64
Age-adjusted mean PEFR! (liters/minute)
Men Women
Nonsmokers 448 318
Ex-smokers 4l7 300
Current smokers
1-14/day 412 314
15-24/day 399 310
> 25/day 398 265
Sluis-Cremer and Sichel,
1962-1963, Carletonville,
South Africa (1968)
Huhti, 1961, Harjavalta,
Finland (1967)
Wilhelmsen et al., 1963,
Goteborg, Sweden (7969)
533 men, 35 years
or older
420 men, 608 women,
aged 40 to 64
339 men, aged 50
Reduced FEV, and PEFR! with increased tobacco consumption
All women, nonsmokers; in men, reduced FEV, and PEFR' in
smokers compared with nonsmokers
Mean FEV, (liters)
Nonsmokers 3.72
Ex-smokers 371
Current smokers
1-14 g/day 3.58
> 15 g/day 3.36
Huhti et al., 1968-1970,
Hankasalmi, Finland (1978)
1,162 men, aged 25 to
69
Reduced FEV, in smokers compared with nonsmokers; increased
prevalence of FEV,/FVC ratio less than 60% in smokers
2
TABLE 9.—Continued
Author, year of study,
location, reference
Number and type
of population
Findings
Mimics, 1969, Croatia,
Yugoslavia (1975)
4,214 men and women,
35 to 54 years of age
Mean FEV, (liters)
Men Women
Nonsmokers 3.58 2.62
Ex-smokers 3.57 2.70
Current smokers
Light 3.42 2.64
Heavy 3.42 2.60
Neri et al, 1969-1973,
Sudbury and Ottawa, Canada
(1975)
5,488 men and women,
14 years of age
or older
Declining ratio of FEV,/FVC with number of cigarettes smoked
daily
Manfreda et al. 1974,
Portage la Prairie and
Charleswood, Canada
(1978)
502 men and women,
25 to 55 years of age
Significant regression of FEV,/FVC ratio on number of
cigarettes smoked daily
Anderson, year not stated,
Karkar Island, Papua New
Guinea (1976)
548 men and women, 25
years of age or older
Age and height-adjusted mean FEV, (liters)
Anderson, year not stated,
Lufa, Papua New Guinea
(1979)
733 men and women
25 years of age or
older
Men Women
Nonsmokers 2.56 2.13
Smokers 2.40 2.01
Age and height-adjusted mean FEV, (liters)
Men Women
Nonsmoker 2.58 2.36
Ex-smoker 2.62 2.27
Occasional 2.57 2.29
Regular 2.63 2.43
' Peak expiratory flow rate
66
TABLE 10.—Association between
groups
Author, year of study,
location, reference
Sharp et al., 1960-1961,
Chicago, U.S. (1965)
Fletcher et al., 1961,
London, England (1976)
tt
Goldsmith et al. 1961, San
‘Francisco, U.S. (1962)
cigarette smoking and lung function level in selected occupational
Number and type
of population
1,887 men, aged 43 to
58 years, employed at
an electronics plant
1,136 men aged 30
to 59, employed at bank
or in maintenance of
transporiation equipment
3,311 longshoremen
Findings
Mean FEV, (liters)
Nonsmokers
Smokers
one pack per day
Adjusted FEV, (iters)
Nonsmokers
Ex-amokers
Current smokers
1-4 cigarettes/day
5-14 cigarettes/day
15-24 cigarettes/day
225 cigarettes/day
Mean FEV, percent of predicted value
Never smokers
Ex-mokers
Current smokers
10 cigarettes/day
11-39 cigarettes/day
> 40 cigarettes/day
100
97
93
93
OOT
TABLE 10.—Continued
Author, year of study,
location, reference
Number and type
of population
Balchum et al., 1961, Loe
Angeles, U.S. (1962)
1,456 men employed in
various industries
Findings
Prevalence (per 100) of FEV,/FVC ratio less than 70 percent
Nonsmokers 76
Smokers 18.8
Coates et al., 1962, Detroit,
US. (1965)
1,584 male and female
postal employees,
Reduced FEV, and FEV,/FVC ratio in smokers of 25 or more
cigarettes daily compared with nonsmokers
aged 40 or older
Densen et al., 1961-1963, New 12,500 males employed Age- and height-adjusted FEV, (liters)
York City, U.S. (1969 as postal or transit
workers Postal workers Transit workers
White Nonwhite White Nonwhite
Nonsmokers 3.29 3.05 3.39 3.08
Cigarette smokers
<25 g per day 3.14 2.95 3.15 3.00
> 25 g per day 3.06 2.93 3.02 2.95
Bandé et al., 1960-1975,
Belgium (1980)
Comstock et al., 1962-1963
and 1967, U.S. and Japan
(1973)
7,123 male military
personnel, a few
over age 45
Three cross-sectional
studies of men working
for telephone company;
U.S.—1,302 and
1,194 subjects, aged
40 to 65, 6% in
study; Japan—592
subjects, aged 40 to 60
By multiple regression, in cross-sectional analysis,
significant effect of smoking on FEV, level after age 35
Mean FEV, level as percent predicted
US. Japan
Study 1 Study 2
Cigarettes per day
None 106 103 99
1-14 104 101 100
15-24 98 92 98
> 25 95 93 99
tor
TABLE 10.—Continued
Author, year of study,
location, reference
Khosla, 1964, Port Talbot,
Number and type
of population
7,701 males employees
Findings
Adjusted mean FEV, level (liters)
United Kingdom (1971) in the steel industry Never smokers 3.70
Current smokers
<15 cigarettes/day 3.57
15-24 cigarettes/day 3.48
25-34 cigarettes/day 3.41
> 35 cigarettes/day 3.37
Schlesinger et al., 1968, 4,331 male civil servants, Mean value of the FEV,/FVC ratio
Israel (1972) aged 45 or older Nonsmokers 76.0
Ex-smokers 74.3
Current smokers
1-19 cigarettes/day 73.9
2 20 cigarettes/day 72.7
Kesteloot et al., 1968-1969,
Belgium (1976)
O'Donnel] and de Hamel, 1969-
1970, New Zealand (1976)
Linn et al., 1973, San Fran-
cisco and Los Angeles,
US. (1976)
Endelman et al., year not
stated, Baltimore, U.S.
(1966)
4,961 males in the
Belgian military,
aged 15 to 59
1,079 male public
servants, up to age
65
644 male and female
office workers, aged
17 to 60
410 male volunteers,
aged 20 to 103
By multiple regression, FEV, reduced by 0.14 liters in
smokers of 1-19 cigarettes daily and by 0.23 liters in
smokers of 20 or more daily
Reduced mean FEV, in smokers of 10 or more cigarettes
daily; increased prevalence of FEV, below 80 percent of
predicted in smokers of more than two packs daily
By analysis of covariance, significant reduction of FEV,
smokers compared with nonsmokers
By partial regression analysis, significant reduction of
FEV, in current and former cigarette smokers
in
cOT
TABLE 10.-—-Continued
Author, year of study,
Number and type
location, reference of population Findings
Woolf and Suero, year not 298 female volunteers Adjusted mean levels
stated, Toronto (1971) employed at commercial FEV, FEV,/FVC ratio
firms, aged 25~54 Nonsmokers 2.65 86.7
Ex-smokers 2.64 85.0
Current smokers
70 cigarettes/week 2.63 85.2
71-140 cigarettes/week 2.50 85.1
> 140 cigarettes/week 2.45 84.1
Krumholz and Hedrick, year 227 male executives, Mean values
not stated, Dayton, US. aged 35-64, selected
(1973) to include nonsmokers FEV, FEV,/FVC
(n= 136) and long- Nonsmokers 3.80 77.3
term amokers (n=91) Smokers 3.42 73.6
Grimes and Hanes, year not 1,059 male and By multiple regression, significant reduction of FEV, level
stated, Los Angeles, US.
(1973)
Lefcoe and Wonnacott, year
not stated, western Ontario,
Canada (1974)
Higgenbottam et al, year not
stated, London, England (1980)
female insurance
company employees
1,072 males in four
occupational groups
18,403 male civil
servants, aged
40 to 64
in male smokers but not in female smokers
By multiple regression, significant reduction of FEV, in
current cigarette smokers
Reduced FEV, in cigarette smokers compared with nonsmokers,
increased effect with increasing daily amount in current
smokers
(Table 10), even though people with symptomatic airflow obstruction
may be likely to retire from their jobs.
Recently, predictors of the incidence of airflow obstruction have
been examined with multivariate techniques in data from popula-
tion samples in Tecumseh, Michigan (Higgins et al. 1982), and in
Tucson, Arizona (Lebowitz et al. 1984). In Tecumseh, the strongest
predictors of airflow obstruction (defined as an FEV; less than 65
percent of predicted) were age, the number of cigarettes smoked
daily, changing smoking habits, and the initial FEV; level (Higgins
et al. 1982). The addition of other variables to the predictive model
did not greatly improve its validity. In Tucson, these same variables,
along with certain symptoms and illnesses, and skin test reactivity
were significant predictors (Lebowitz et al. 1984). During the 10
years of followup of a population sample in Finland, incidence cases
of chronic airflow obstruction (defined as FEV:/FVC ratio less than
60 percent) were observed only in those who continued to smoke
(Huhti and Ikkala 1980). These studies of incidence highlight the
importance of cigarette smoking in the etiology of airflow obstruc-
tion; new cases are rare among nonsmokers.
Dose-Response Relationships
Dose-response relationships between FEV; level and the amount
of cigarette smoking have been described with simple descriptive
statistics and further characterized by multiple regression analysis.
In cross-sectional data, the FEV; level varies inversely with the
amount smoked. Although the variation in mean FEV; levels among
strata of smoking appears clinically unimportant, the distributions
of values in smokers and nonsmokers are quite different (Figure 4).
Cigarette smokers more often have abnormal lung function, regard-
less of the criteria applied to the population (Mueller et al. 1971:
Knudson et al. 1976; Burrows et al. 1977a; Detels et al. 1979; Rokaw
et al. 1980; Beck et al. 1981). This increased prevalence of abnormal
function is a result of the skewed distribution of function in smokers,
with a subgroup of the smokers showing a large decline rather than
the entire group shifting by a small amount (Figure 4). As noted in
this reference, however, there are decreasing numbers of smokers
with FEV, above the mean for nonsmokers as pack-years increase,
suggesting that all smokers are probably somewhat affected, even
though only a minority eventually develop clinically significant
airflow limitation.
In several populations, the relationship between cigarette smoking
and FEV; level has been examined in greater detail. Burrows et al.
(1977a) used linear multiple regression analysis to examine the
relationship between cigarette smoking and ventilatory function ina
population sample in Tucson, Arizona. Pack-years, a cumulative-
dose measure, was the strongest predictor of FEV; level among the
103
smoking variables considered. In currently smoking men and
women, the FEV; declined by approximately 0.25 percent of the
predicted value for each pack-year of cigarette smoking; the effect
was of a similar magnitude in ex-smokers. Using data from three
separate U.S. communities, Beck and colleagues (1981) assessed the
importance of six separate smoking variables: amount smoked daily,
use of filters, inhalation, age started, age stopped for ex-smokers, and
cumulative pack-years. For the FEV, the strongest predictors in
male current smokers were the duration of smoking and the amount
smoked; in female current smokers, only pack-year was statistically
significant. The number of years of cessation was associated with
FEV: in male but not in female ex-smokers.
However, in both the multiple regression analysis reported by
Beck et al. (1981) and that reported by Burrows et al. (1977a), the
measured cigarette smoke variables accounted for only about 15
percent of the variation of age- and height-adjusted FEV; levels.
Unmeasured aspects of cigarette smoking, other environmental
exposures, and the characteristics of the smokers must contribute to
the unexplained variation. A role for the type of cigarette smoked
has not yet been established (USDHHS 1981), and the impact of
differences in depth or pattern of inhalation and other aspects of the
pattern of smoking remains to be investigated; they are discussed in
more detail in the chapter on low tar and low nicotine cigarettes.
Further studies of these aspects of cigarette smoking are needed to
monitor the consequences of changing cigarettes.
Factors Other Than Cigarette Smoking
A number of risk factors other than cigarette smoking have been
postulated as contributing to the development of airflow obstruction
(Table 7). Of these, a definite role for a,-antitrypsin deficiency has
been established, but only the small number of persons with
homozygous deficiency incur markedly increased risk (Morse 1978).
The current hypotheses on susceptibility to cigarette smoke postu-
late roles for childhood respiratory illnesses (USDHEW 1979;
Burrows and Taussig 1980; Samet et al. 1983), for endogenously
determined hypersensitivity of the lung, and for other genetic and
familial factors (Speizer and Tager 1979; USDHHS 1980a). At
present, these hypotheses remain largely untested. The data are
similarly incomplete at present for the other factors listed as
putative risk factors in Table 7. The status of each is briefly reviewed
below.
ABH Secretor Status
Secretion of ABH antigens is a genetically determined trait that
follows an autosomal dominant inheritance pattern; approximately
104
70 to 80 percent of the population excrete antigen into the body
fluids (Cohen et al. 1980a). In a genetic-epidemiology study in
Baltimore, Maryland (Cohen et al. 1980a), ABH nonsecretors had
lower levels of FEVi/FVC ratio and a higher proportion with
FEV:/FVC ratio below 69 percent. Studies in France (Kauffmann et
al. 1982a, 1983) and in England (Haines et al. 1982) have confirmed
reduced expiratory flow rates in ABH nonsecretors. In contrast,
ABH secretor status did not predict the development of obstructive
airways disease in the Tecumseh, Michigan, population (Higgins et
al. 1982).
Air Pollution
Although exposure to air pollution at high levels may exacerbate
the clinical condition of persons with chronic lung disease, a causal
role for air pollution in the development of airflow obstruction has
not been established (Tager and Speizer 1979; USDHHS 1980b).
However, smoking is the major predictor for chronic airflow
obstruction in areas of high as well as low atmospheric air pollution.
Airways Hyperreactivity
Orie and colleagues in the Netherlands (Orie et al. 1960) speculat-
ed that bronchial hyperreactivity and allergy may predispose to
asthma and chronic bronchitis. Findings from two small longitudinal
studies have suggested that airways reactivity may influence indi-
vidual susceptibility to cigarette smoke. Barter and colleagues
followed 56 patients with mild chronic bronchitis during a 5-year
period (Barter et al. 1974; Barter and Campbell 1976). The rate of
decline of FEV: increased with the degree of airways reactivity, as
measured by reversibility with isoproterenol or responsiveness to
methacholine. Britt et al. (1980) measured change of FEV: in 20
young adult male relatives of patients with chronic obstructive
pulmonary disease. The decline of FEV: was approximately five
times larger in the nine subjects with a positive methacholine
challenge test. In patients with clinically diagnosed airflow obstruc-
tion, airways reactivity is also associated with more rapid decline of
lung function (Kanner et al. 1979). Because airway reactivity would
affect the FEV, directly as well as possibly influence the susceptibili-
ty to smoke, it is difficult to ascertain from these data whether the
relationship between airway reactivity and COLD is direct or
spurious.
Alcohol Consumption
The epidemiological data on alcohol consumption are conflicting.
A study of former alcoholics demonstrated an excess prevalence of
lung function abnormalities, including airflow obstruction (Emergil
105
480-144 0 - B85 -~ 5
and Sobol 1977). In the Tucson population, alcohol consumption was
a significant predictor of ventilatory function after the effect of
smoking was controlled (Lebowitz 1981). The findings of an investiga-
tion in Yugoslavia were similar (Saric et al. 1977). However, two
large U.S. investigations did not demonstrate adverse effects of
alcohol intake (Cohen et al. 1980b; Sparrow et al. 1983a).
Atopy
Cross-sectional data from the Tucson population suggest increased
susceptibility to cigarette smoke in atopic people (Burrows et al.
1976). In subjects aged 15 to 54, the prevalence of an FEV:/FVC ratio
below 90 percent of predicted value increased with skin test
reactivity among both smokers and nonsmokers. Subsequent reports
from this same study have not confirmed an overall relationship
between FEV: level and atopy, but indicate that atopy may predis-
pose to airflow obstruction in a subset of the population (Burrows et
al. 1977a, 1983). Burrows and coworkers (1981) also reported an
increased level of IgE in smokers independent of their allergy skin
test reactions, and the interrelationship of these factors is currently
being examined.
Childhood Respiratory Iliness
In a longitudinal investigation of 792 English working men,
Fletcher and coworkers (Fletcher et al. 1976) found a cross-sectional
association between childhood illness history and FEV: level. The
decline of FEV; level during the study’s longitudinal phase was not
correlated with childhood illness variables. In contrast, analyses of
cross-sectional data from a population sample in Tucson suggested
that childhood respiratory illnesses may increase susceptibility to
cigarette smoke (Burrows et al. 1977b). In this population, people
with a history of respiratory trouble before age 16 demonstrated
excessive decline of ventilatory function with increasing age and
with increasing cigarette consumption.
Familial Factors
Familial aggregation of lung function level, adjusted for age,
height, and sex, has been demonstrated in populations in the United
States and elsewhere (Higgins and Keller 1975; Tager et al. 1976;
Schilling et al. 1977; Mueller et al. 1980). However, a recent report
suggests that the familial aggregation of lung function may be a
reflection of the familial aggregation of body habitus (Lebowitz et al.
1984). Relatively modest correlations of FEV: level have been
demonstrated between siblings and between parent-child pairs. The
role of familial factors is further supported by investigations
demonstrating increased prevalence of airflow obstruction in rela-
106
tives of diseased subjects (Kueppers et al. 1977; Tager et al. 1978;
Cohen 1980). This familial factor cannot be explained by familial
resemblance of a.,-antitrypsin phenotype or of ABH secretor status
(Kueppers et al. 1977; Cohen 1980). In the Tecumseh population,
however, family history of airflow obstruction did not predict the
incidence of this disease. The results of twin studies are also
consistent with genetic influences on FEV; level and suggest that
genetic factors may influence susceptibility to cigarette smoke
(Webster et al. 1979; Hankins et al. 1982; Hubert et al. 1982).
Occupation
Several population-based investigations suggest that occupational
exposures other than those recognized as causing lung injury may
have some effect on lung function level. In Tecumseh, mean age and
height-adjusted FEV scores in men were highest in farmers and
lowest in laborers; the differences were not explained by smoking
and were present in nonsmokers (Higgins et al. 1977). Similarly, in
Tucson, men reporting employment in certain high risk industries or
exposure to specific harmful agents had a higher prevalence of
abnormal lung function (Lebowitz 1977a). In a Norwegian case—
control study, men employed in workplaces characterized as polluted
were at increased risk for clinically diagnosed emphysema (Kjuus et
al. 1981). Longitudinal studies of industrial populations also show
that occupational exposures may increase the rate of decline of
FEV: (Jedrychowski 1979; Kauffmann et al. 1982b; Diem et al. 1982).
For example, Kauffmann et al. (1982b) found that FEV, change
during a 12-year period varied with job exposures in an employed
industrial population. Effects of dust, gas, and heat were present, as
was evidence for a dose-response relationship between increasing
exposure and a greater rate of decline. In these studies, however,
smoking effects were generally much greater than the occupational
effects.
Passive Exposure to Tobacco Smoke
Passive exposure is discussed in detail elsewhere in this Report.
Respiratory Ilinesses
In an 8-year followup study of London men, chest infections were
not associated with a rate of FEV; decline (Fletcher et al. 1976). The
findings of several smaller longitudinal studies were similarly
negative with regard to respiratory infection (Howard 1970; John-
ston et al. 1976). It is now apparent that mucus hypersecretion and
airflow obstruction are separate pathophysiological entities that
have a common cause—cigarette smoking (Fletcher et al. 1976; Peto
et al. 1983).
107
Socioeconomic Status
Weak effects of socioeconomic status on lung function level have
been demonstrated in community samples in Tecumseh (Higgins et
al. 1977) and in Tucson (Lebowitz 1977b). In both populations, lung
function appeared to be influenced independently by socioeconomic
status indicators, even after controlling for cigarette smoking. In the
Tecumseh study, FEV1 increased slightly with increasing income and
education level (Higgins et al. 1977); in the Tucson study, the
proportion of people with an abnormal FEV: varied in a similar
pattern with these indices (Lebowitz 1977a). Effects of socioeconomic
status were present in nonsmokers in both investigations. Stebbings
(1971), in a sample of nonsmokers in Hagerstown, Maryland, also
demonstrated an association between lung function level and
socioeconomic status.
In summary, there is evidence that a number of factors other than
cigarette smoke may influence lung function, but the influence of
these factors is small relative to the effect of smoking, and the major
question is whether they can influence susceptibility to cigarette-
induced lung injury rather than whether they, of themselves, result
in lung disease in nonsmokers.
Development of Airflow Obstruction
At this time, the natural history of airflow obstruction has been
only partially described; a population has not yet been followed from
childhood to the development of airflow obstruction during adult-
hood. However, the available data from separate investigations cover
the entire course of the disease and support the conceptual model
proposed in Figure 15.
With aging, measures of function begin to deteriorate after age 25
to 30. In nonsmokers without respiratory disease, cross-sectional
data generally show that the FEV; declines by 20 to 30 ml per year
(Dickman et al. 1969; Morris et al. 1971; Cotes 1979; Crapo et al.
1981). Longitudinal data have been confirmatory (Tables 11 and 12).
For example, Tockman (1979) measured the FEV: loss during an 8-
year period in 399 male nonsmokers. In most, the FEV: declined at
25 ml annually; a few, with an initial FEV: lower than 2.5 1, lost 34
ml annually.
Sufficient excessive loss leads to the development of airflow
obstruction. However, many questions remain unanswered concern-
ing this process of functional deterioriation. It is unclear whether
the loss always occurs uniformly or if it develops in stages with
intermittent and relatively steep declines (Bates 1979; Burrows
1981). The concept that the decline is nearly always gradual receives
strong support from the findings of the 8-year longitudinal study
conducted by Fletcher and coworkers (1976). In this investigation of
108
60T
TABLE 11.—Association between cigarette smoking and longitudinal change in lung function in
selected population samples
Author, years of study,
location, reference
Number and type
of population
Findings
Higgins and Oldham, 1954-1959
Rhondda Fach, Wales (1962)
253 male miners, ex-
miners, and nonmining
controls
Annual decline of indirect maximal breathing capacity (liters/min)
Miners, ex-miners
Controls without pneumoconiosis
Nonsmokers 16 0.8
Ex-smokers 0.7 1.8
Current smokers
1-14 g/day 13 17
> 15g/day 1.6 2.2
Ashley et al., 1958-1968,
Framingham, U.S. (1975)
399 men and 636 women,
aged 37 to 69 in 1958
10-year change in FEV,/FVC ratio
(age-standardized to overall distribution for each sex)
Higgins et al., 1957-1966,
tavely, England (1968b)
594 men, aged 25-34
or 55-64 in 1957
Men Women
Nonsmokers 0.21 -3.6
Continued smokers -13 —41
Stopped, 1958-1968 0.51 —4.6
Annual decline of FEV75, (ml/year) by age and smoking in 1957
25-34 yrs 55-64 yrs
Nonsmokers 21 32
Ex-smokers 29 44
Current smokers
1-14g/day 37 54
> 15g/day 38 37
OTT
TABLE 11.—Continued
Author, years of study,
location, reference
Number and type
of population
Findings
Huhti and Ikkala, 1961-1971,
492 men and 671 women,
Annual decline of FEV, (ml/year)
Harjavalta, Finland (/980) aged 40 to 64 in 1961 Men Women
Nonsmokers 33 27
Ex-smokers 45 27
Continued smokers 44 39
Stopped, 1961-1971 51 35
Wilhelmsen et al., 1963-1967, 313 men, aged 50 Annual decline of FEV, (ml/year)
Goteborg, Sweden (1969) in 1963 Nonsmokers 43
Ex-smokers 33
Current smokers
1-14g/day 70
> l5g/day 70
Stopped, 1963-1967 40
TIT
ee WV eee eee
Author, years of study,
location, reference
Oxhoj et al. 1963-1973,
Goteborg, Sweden (same popu-
lation as Wilhelmsen et al.
1969) (1976)
Number and type
of population
269 men, aged 50
in 1963
Findi
Annual decline of FEV, (mi/year)
Nonsmokers
Ex-smokers
Current smokers
Stopped, 1963-1973
40
37
58
49
Van der Lende et al.,
894 men and women,
Mean annual decline of FEV,
Viaardingen, 1967-1978, and aged 25 and older Unadjusted Adjusted
Vlagtwedde, 1967-1976, Nonsmokers 13.3 16.6
Netherlands (/98/) Ex-smokers 15.8 13.4
Pipe/cigar 24.4 22.6
« 4 g/cig 3.6 8.7
5-14 gicig 22.2 20.9
15-24 g/cig 31.4 28.2
> 25 g/cig 35.8 34.0
Krzyzanowski, 1968-1973, 2,572 men and women, Annual decline of FEV, (ml/year)
Cracow, Poland (/980) aged 19 to 70 Men Women
Nonsmokers 56 44
Continued smokers 73 53
alt
TABLE 12.—Association between cigarette smoking and longitudinal change in lung function in
selected occupational or other groups
Author, years of study,
location, reference
Number and type
of population
Findings
Comstock et al., 1962-1963 to
1967 or 1969, various locations
670 male telephone
company employees,
Decline in FEV, (liters) between surveys
US. (1970) aged 40 to 65 Nonsmokers 0.28
Ex-smokers 0.17
All smokers 0.41
Howard, 1956 ta 1967, 159 male employees of Annual decline in FEV:s« (ml/year)
Sheffield, England |/970) an engineering works
Nonsmokers 0.036
Ex-smokers 0.025
Current smokers 0.031
DeMeyere and Vuyisteek, 1967
to 1970, Ghent, Belgium (/97/)
627 male railroad
workshop employees
Annual decline in FEV, (ml/year)
Nonsmokers
Ex-smokers
Current smokers
1-14 g/day
>15 g/day
Stopped, 1961-1971
SRR RS
€IT
TABLE 12.—Continued
Author, years of study,
location, reference
Number and type
of population
Findings
Fletcher et al., 1961 to
1969, London, England
(1976)
Kauffmann et al., 1960 to
1972, Paris, France (1979)
Jedrychowski, 1968 to 1973,
Cracow. Poland (1979)
Poukkula et al., 1967 to
1977, Oulu, Finland (7982)
792 male transport
maintenance or bank
workers, aged 30 to
59 at entry
575 male factory
workers, aged 30 to
54 in 1960
186 male employees of
a fertilizer factory
659 male pulp mill
employees, aged 18 to
64 in 1967
Annual decline of FEV, (ml/year)
Nonsmokers
Ex-smokers
Continued smokers
<5 cigs/day
5-15 cigs/day
15-25 cigs/day
>25 cigs/day
Annual decline of FEV, (ml/year), adjusted for initial level
Nonsmokers
Ex-smokers
Current smokers
«15 g/day
> 15 g/day
S-year decline of FEV, as percent of mean, by 1973 smoking
Nonsmokers
Ex-smokers
Current smokers
Annual decline of FEV, (ml/year)
Nonsmokers
Ex-smokers
Continued smokers
Stopped, 1967-1977
36
31
44
46
54
54
40
44
46
51
3
5
7
37
39
49
48
ry
¥
TABLE 12.—Continued
Author, years of study,
location, reference
Number and type
of population
Findings
Woolf and Zamel. vears not
given, Toronto, Canada (/980)
302 female volunteers,
aged 25 to 54 at entry
5-year change in FEV, as percent of initial value
Nonsmokers Lb
Ex-smokers 0.8
Smokers
< 70 cigs/week 0.4
71-140 cigs/week ‘, 3.65
140 cigs/week at
Bosse et al., 1963-1968 to
1969-1974. Boston, U.S.
(1981)
850 male volunteers
Annual decline of FEV, (ml/year),
adjusted for age and initial level
Nonsmokers 0.053
Ex-smokers 0.057
Current smokers 0.085
Love and Miller. 1957 to 1973
taverage followup, 11
years), United Kingdom (/982)
1,677 male coalminers
ll-year decline in FEV, (liters)
Nonsmokers 0.41
Ex-smokers 0.48
Intermittent smokers 0.52
Current smokers 0.53
792 employed men, the individual patterns of temporal change of the
FEV; were strongly variable, but the loss generally occurred
gradually. Fletcher et al. further demonstrated that FEV; level
correlated with FEV; slope, a finding that they termed the “horse-
racing effect.” Correlation between slope and level would be antici-
pated, if functional loss occurs gradually. This correlation has
important implications for intervention; those losing FEV: more
rapidly should become identifiable early as they develop a reduced
FEV; level. Other studies, however, do not agree with either the
pattern of FEV decline or the “horse-racing” effect. Rapid declines
to levels compatible with clinical disease or followed by a prolonged
plateau have been described (Howard and Astin 1969; Howard 1970;
Johnston et al. 1976). In a followup study of Canadian men with
chronic bronchitis, steep declines of FEV, without subsequent
improvement were frequently observed (Bates 1973). Additionally,
correlation of FEV, level and slope has been found in most other
longitudinal investigations (Howard 1970; Petty et al. 1976; Huhti
and Ikkala 1980; Bosse et al. 1981; Clement and van de Woestijne
1982; Kauffmann et al. 1982b), but not in all (Barter et al. 1974;
Krzyzanowski 1980).
Another unanswered question concerning functional deterioration
is whether gradual decline occurs in a linear or a nonlinear fashion
(Fletcher et al. 1976). Sufficient numbers of people have not yet been
followed to distinguish alternative patterns, although the available
data indicate acceleration of the decline with aging (Emergil et al.
1971; Fletcher et al. 1976).
In spite of these uncertainties concerning the development of
airflow obstruction, the available data indict cigarette smoking as
the primary risk factor for excessive loss of FEV: (Tables 11 and 12).
The findings in both general population samples (Table 11) and
occupational and volunteer cohorts (Table 12) have been similar.
Recent reports from Belgium (Bande et al. 1980; Clement and van de
Woestijne 1982) and from Connecticut (Beck et al. 1982), not readily
summarized in tabular form, also described a strong effect of
smoking on FEV; decline. A few studies have not shown increased
loss in cigarette smokers (Howard 1970; De Meyere and Vuylsteek
1971). Even in people with clinically diagnosed airflow obstruction,
continued smoking maintains the excess decline of FEV, (Hughes et
al. 1982), although not all findings are consistent (Ogilvie et al. 1973;
Johnston et al. 1976).
Dose-response relationships have been found in many investiga-
tions between the amount smoked during followup and the FEV,
decline (Tables 11 and 12). The reported increases from the lowest to
the highest smoking categories range up to 10 to 15 ml annually.
Although this additional loss in heavier smokers appears small, if
sustained for long periods of time it would shorten the time interval
115
Never smoked
or not susceptible
to smoke
~“
a
1
Smoked
FEV, (percent of value at age 25)
50 4 regularly an ~. ~— Stopped at 45
susceptible to ~
its effects swQ
Disability ~
mr rw ee Qe LLL UN
25 7
“SS Stopped at 65
Death
Sn ee. -M. LL
o T ¥ tT T T T T T ¥ T
25 50 75
Age (years)
FIGURE 24.—Risks for men with varying susceptibility to
cigarette smoke and consequences of smoking
cessation
NOTE: + = death.
SOURCE: Fletcher and Peto (1977).
to the development of functional impairment. So far, favorable
effects of filter tip smoking and declining tar content on the rate of
decline have not been shown (Fletcher et al. 1976; Sparrow et al.
1983b).
Generally, sustained smokers experience a greater loss than those
who stop during followup. In the study by Fletcher et al. (1976) of
London men, subjects who stopped smoking at the beginning of the
followup period lost FEV: at the same rate as never smokers. The
results of two U.S. studies of ex-smokers are similar (Bosse et al.
1981; Beck et al. 1982). This reduced loss in ex-smokers emphasizes
the importance of active smoking and the immediate benefits of
smoking cessation (Figure 24). Smokers with reduced FEV; may be
protected from developing clinically significant loss by timely
smoking cessation (Fletcher and Peto 1977).
The distribution of FEV; decline has been characterized and
described for some populations, including patient groups (Burrows
and Earle 1969; Howard 1974; Barter et al. 1974), population samples
(Milne 1978), and occupational cohorts (Howard 1970; Fletcher et al.
1976). Similar data are also available for the mid-maximum expira-
tory flow, another measure of ventilatory function (Bates 1973;
Woolf and Zamel 1980). In each of these investigations, the distribu-
tion of FEV: decline is unimodal (Figure 25); that is, a distinct
population with more rapid decline is not sharply separated from
those with lesser rates. The modes and medians of the distributions
116
80 4 Mean
ro F
© Smokers r:
60 J Nonsmokers and Ah
ex-smokers 7 eed
40 +
30 —
Number of men (total 792)
20 ~
T q v v F
-160 -140 -120 -100 -80 -60 40 -20 0 +20
FIGURE 25.—Distribution of 8-year FEV; slope in 792
London men
SOURCE: Fletcher et al. (1976).
are generally negative, but some subjects have had positive slopes
during the relatively brief followup period of investigations conduct-
ed up to this time.
The distributions tend to be skewed by subjects losing FEV: more
rapidly. The proportion of cigarette smokers is increased among
those in the tail of excess loss (Figure 25). For example, Clement and
van de Woestijne (1982) examined subjects with excess FEV, decline
in a prospective study of 2,406 members of the Belgian Air Force.
Losses beyond those expected from nonsmokers affected 6 percent of
nonsmokers, 7.5 percent of light smokers (< 20 cigarettes/day), and
12 percent of heavy smokers (> 20 cigarettes/day).
The shape of the distribution of FEV) decline has important
implications for the development of airflow obstruction. Smokers are
not sharply separated from nonsmokers (Figure 25), but more often
lose FEV) at a rapid rate. Because of this spectrum of severity, not al]
smokers develop significant airflow obstruction. Although the fac-
tors that lead to excessive loss in individual smokers remain
uncertain, they may include differences in the pattern of smoking. It
is apparent, however, that this susceptible minority can be protected
by smoking cessation.
117
summary
During the 20 years that have elapsed since the 1964 Surgeon
General’s Report, the relationship between cigarette smoking and
airflow obstruction has been intensively investigated. Surveys of
community samples and other groups have established that airflow
obstruction is a common condition in the United States and
elsewhere. In some populations, as high as 10 percent of adults are
affected.
Determinants of lung function level and of the prevalence of
airflow obstruction have now been examined in many populations
throughout the world. Cigarette smoking is the strongest predictor of
abnormal measures of ventilatory function. A causal relationship
between cigarette smoking and airflow obstruction is supported by
the consistency of the many published reports, the strength of the
association, and the evidence for dose-response.
Many risk factors for airflow obstruction other than cigarette
smoking have been postulated, including other harmful environmen-
tal exposures and the inherent susceptibility of the smoker. Homozy-
gous a,-antitrypsin deficiency can explain only a minute proportion
of the disease burden. The development of airflow obstruction by
only a minority of smokers indicates that the interaction of smoking
with other factors may influence the risk for specific smokers.
Current research emphasizes the potential roles of childhood respira-
tory illness and airways hyperresponsiveness.
Longitudinal studies have now partially described the prolonged
natural history of airflow obstruction. Excessive loss of ventilatory
function, beyond that expected from aging alone, results in the
development of disease in cigarette smokers. Only a susceptible
minority of cigarette smokers lose function at a rate that will
eventually cause clinically significant impairment. For this group,
timely smoking cessation can prevent the development of disease.
118
EMPHYSEMA
Introduction
Pulmonary emphysema is frequently present in the lungs of
individuals with chronic obstructive lung disease. This section has
three purposes: (1) to review the definition, types, and quantification
of emphysema; (2) to summarize the physiological and radiographic
feature of emphysema: and (3) to discuss critically the relationship of
smoking to emphysema, based upon observations in people and in
experimental animals. Current concepts of the pathogenesis of
emphysema are reviewed elsewhere.
Definition of Emphysema
The generally accepted definition of emphysema is an anatomic
condition of the lung characterized by abnormal dilation of air
spaces distal to the terminal bronchioles accompanied by destruction
of air space walls (American Thoracic Society 1962: Heard et al.
1979). Difficulties with this definition have been discussed by
Thurlbeck (1983). Normal air space dimensions have not been
determined, and criteria of destruction have not been defined. These
limitations hamper attempts to investigate the earliest lesions of
emphysema and the subtle effects of environmental agents on lung
structure.
Types of Emphysema
British pathologists pointed out in the forties and fifties that
emphysematous lesions in certain people involved the respiratory
bronchioles, which appeared as grossly enlarged airspaces in the
center of the primary lung lobules surrounded by normal lung. In
other individuals, the alveolar ducts were involved early, and even
mild involvement appeared grossly as a coarsening of the architec-
ture of the entire lobule. They designated the two polar patterns of
emphysema as centrilobular emphysema (CLE) and panlobular
emphysema (PLE) (Heppleston and Leopold 1961), Many lungs either
show both types of emphysema or are unclassifiable. Of 122 lungs
with emphysema examined by one pulmonary pathologist, 73 were
_considered mixed or unclassifiable and 49 were clearly CLE or PLE
(Mitchell et al. 1970). When the agreement of three pathologists was
required, only 27 of the original 122 lungs remained classifiable and
95 were mixed or could not be classified. There were no Statistically
significant differences between the groups classified as PLE or CLE
in any clinical variables. The only nonsmokers in either group had
CLE, and the proportion of light smokers (less than 25 pack-years)
was very similar between groups. In this study and others (Anderson
and Foraker 1973), CLE was most severe in the upper lobes and PLE
was uniformly distributed. According to Thurlbeck (1976), a common
119
combination is CLE in the upper lobes and PLE in the lower lobes;
where lobectomies are used for correlation, typing of emphysema is
therefore a particularly empty exercise. When emphysema is far
advanced, it is often impossible to recognize the site of the initial
involvement. Thus, it is not clear whether the differences in
prevalence of CLE and PLE are real or represent differences in
interpretation by different observers.
Several localized types of emphysema occur in areas around scar
tissue (paracicatricial), along interlobar and interlobular septa
(paraseptal), and as bullous lesions (which represent the most
advanced and extreme distortion of normal lung structure). Bullous
deformities occur with any type of emphysema, including CLE and
PLE. Occasionally, bullous lesions occupy huge intrapulmonary
volumes,
Detection of Emphysema
The detection of emphysema requires suitably prepared lung
specimens. At a minimum, this means the lung must be fixed in
inflation (Thurlbeck 1964). Fume fixation or fixation by instillation
of liquid fixative through the airways is satisfactory, but for optimal
evaluation of the latter group, barium impregnation or paper-
mounted whole-lung sections should be used. Because lungs with
emphysema frequently also have some degree of intrinsic airways
disease, the severity of emphysema and the clinical state of the
patient may not correlate directly. Pathologists can easily recognize
mild degrees of emphysema that are rarely associated with clinical
disability.
Quantification of Emphysema
There are a number of techniques for quantifying the volume of
lung involved with “obvious” emphysema that are adequately
reproducible and correlate well with one another (Thurlbeck 1976;
Bignon 1976). Semi-quantitative or subjective scoring methods as
well as point counting have been used. These approaches all require
lungs inflated to a relevant volume, usually one approximating total
lung capacity during life. This can be achieved by a distending
pressure of 25 cm H:20 (Thurlbeck 1979; Berend et al. 1980).
In the scoring method, the lung is divided into a number of units
and the severity of emphysema in each unit is scored (mild,
moderate, or severe receive 1, 2, or 3 points, respectively). The scores
for each unit are summed to give a total score for the lung (Ryder et
al. 1969). Alternatively, lung slices may be matched by visual
comparison to a set of graded standards to achieve an emphysema
score (Thurlbeck et al. 1970). These methods include both severity
and extent of emphysema, and although they involve subjective
judgments, they have proved to be remarkably reproducible.
120
In the point counting approach, regularly spaced points are
superimposed on a lung slice. Each point is recorded as falling on
normal parenchyma, emphysematous parenchyma, or nonparenchy-
ma (conducting airways or vessels). The volume proportion of
emphysematous lung is recorded. This method can be objective (e.g.,
if an emphysematous space is taken to be one greater than 1 mm in
diameter), but it includes only extent and not severity of emphyse-
ma.
Morphometric methods carried out on histologic sections, exempli-
fied by the mean linear intercept (Lm) (Thurlbeck 1967a, b), are
strictly objective, but they require careful attention to problems of
sampling and are time consuming and insensitive to focal disease.
For measurements of the Lm, histologic sections are made of blocks
selected by stratified random sampling. The average distance
between alveolar walls is determined from the number of intersec-
tions of alveolar walls with a line of known length. The internal
surface area of the lung can be calculated when the volume of the
lung is known (Hasleton 1972).
Pulmonary Function in Emphysema
Because unequivocal proof of the presence of emphysema requires
direct examination of lung tissue, the strategies used to characterize
the pulmonary function abnormalities associated with emphysema
have either involved comparison of functional data collected during
life with autopsy or surgical material or have used measurements
made exclusively on post-mortem specimens. Two important conclu-
sions from these studies should be noted at the outset. First,
impaired air flow during maximal expiratory maneuvers, as reflect-
ed in reduced values for the FEV, FEVi«, and FEFs75%, is neither
sensitive nor specific for emphysema. It is possible to have severe
emphysema without clinical obstructive lung disease (Thurlbeck
1977). It is also possible to have severe chronic obstructive lung
disease without having emphysema, even though most patients with
advanced chronic obstructive lung disease have some degree of
emphysema (Mitchell et al. 1976). Second, none of the tests used to
identify early obstructive lung disease, such as closing volume, the
single breath Ne curve, or frequency dependence of compliance,
distinguish diminished elastic recoil that may be related to emphyse-
ma (see below) from increased resistance in small airways (Buist and
Ducic 1979). Even the determination of density dependence of
maximum expiratory airflow, once felt to be specific for detecting
abnormalities in the caliber of small airways, is not immune to the
effects of lung elastic recoil. A decreased effect on maximal
expiratory air flow of using low density gas can be caused by
decreased elastic recoil (Gelb and Zamel 1981).
121
Pulmonary function testing of individuals with proven emphyse-
ma often shows increases of residual volume, functional residual
capacity, and total lung capacity and decreases of maximal expirato-
ry air flow (Boushy et al. 1971; Park et al. 1970; reviewed in
Kidokoro et al. 1977). However, because individuals with emphysema
commonly also have intrinsic airway disease (Cosio et al. 1978)
affecting the results of these pulmonary function tests in the same
direction as emphysema, it is clear that these tests are not specific
for emphysema. Accordingly, there has been interest in other, more
distinctive tests. Among readily applicable tests, the diffusing
capacity has proved to be directly related to the extent of emphyse-
ma (Park et al. 1970; Boushy et al. 1971; Berend et al. 1979),
presumably reflecting a diminution of internal surface area avail-
able for gas exchange. The usefulness of the diffusing capacity to
identify and estimate emphysema is limited, however, because the
measurement is not sensitive to low grades of emphysema (Symonds
et al. 1974) or specific for emphysema. Moreover, the results must be
interpreted carefully in smokers because the values for diffusing
capacity are lower than in nonsmokers, and the difference extends
even to young smokers who are not likely to have emphysema (Enjeti
et al. 1978; Miller et al. 1983).
Mechanical Properties of the Lungs in Emphysema
Measurements of the pressure-volume characteristics of the lung
have generally been regarded as a reliable means of physiologically
detecting and quantifying emphysema because (a) patients with
emphysema often have increased lung distensibility and correspond-
ingly low transpulmonary pressures (loss of elastic recoil) and (b) the
severity of emphysema has seemed to correlate with the change in
elastic recoil. It has also been assumed that the regions of lung with
emphysema are the cause of the decreased lung elastic recoil, an
assumption that appears reasonable because elastic recoil results in
part from surface forces at the air-liquid interface and there is less
surface area in emphysema.
Recent observations challenge these concepts. Berend and Thurl-
beck (1982), using lungs obtained post mortem, could not demon-
strate a relationship between indices of lung elasticity and the grade
of emphysema in 48 lungs ranging in grade from 2 to 80 (on a scale of
100), and observed (Berend et al. 1981) in emphysematous lungs that
the relative increase in compliance of the lower lobes was greater
than the upper lobes, even though the emphysema was worse in the
upper lobes. Others have also reported poor correlations between
emphysema and elastic recoil. Silvers et al. (1980) found decreased
elastic recoil and increased total lung capacity in excised human
lungs with minimal emphysema, and Schuyler et al. (1978) noted in
hamsters given small doses of elastase intravenously that there was
122
decreased lung elastic recoil at low lung volumes, although the lungs
did not show morphometric changes. Guenter et al. (1981) noted that
mild emphysema produced by pepsin caused greater changes in lung
elasticity than similar degrees of lung destruction produced by
endotoxin-induced repetitive leukocyte sequestration. They suggest-
ed that these differences may be due to differences in the location of
the connective tissue injury within the lung.
Even among those who have reported an association between
emphysema and elastic recoil, the correlations have been best when
the emphysema was severe (Greaves and Colebatch 1980). Pare et al.
(1982) found a correlation between emphysema grade and elastic
properties of the lungs in 55 persons; however, in 5 whose surgically
removed lung tissue received emphysema scores between 20 and 70
(out of a maximum of 100), the elastic properties of the lungs tested
preoperatively were indistinguishable from normal. While such
discrepancies probably reflect the limitations of relating the overall
elastic properties of both lungs to the morphology of a single lobe, it
must also be recognized that the sensitivity of the pressure-volume
diagram is limited, since a narrow range of pressure (to 20 cm H20)
depicts the average retractive force from millions of air spaces and
the connective tissue network of the lung.
From these recent findings it must be concluded that the
relationship between elastic recoil and morphologic measures of
emphysema is not highly predictable, and that the decrease of elastic
recoil and increase of total lung capacity commonly seen in
emphysematous lungs may not result entirely from abnormal
mechanical properties in the areas showing emphysema. The
mechanical abnormalities may also derive from areas that appear
normal, although the possible reasons for this are obscure (reviewed
by Thurlbeck 1983). An alternate explanation for this discordance
between elastic recoil and morphologic emphysema may be the
problems of sampling and grading intrinsic to these morphologic
measures.
The work of Michaels et al. (1979) introduces a further complexity
to the use of pressure-volume curves as an indicator of emphysema.
They found that inhalation of a bronchodilator shifted the curve of
smokers in the direction of increased compliance, but had no effect
in nonsmokers (Figure 26). Cessation of smoking had the same effect
as a bronchodilator. These results were interpreted as indicating
that smoking causes some peripheral airway units to constrict and
become effectively closed. Thus, pressure-volume studies to detect
early changes compatible with emphysema in smokers may give
false negative results unless accompanied by studies with bronchodi-
lators.
123
en
80 =
= 74
8
a
z
z
3 60 4 O--O Smokers
@——@ > Smokers B.D.
O--O Nonsmokers
. @——® Nonsmokers p B.D.
50 =—d
a
4
0 T T t v
4 8 12 16
P(stathomH,0
FIGURE 26.—The effect of nebulized bronchodilator on the
pressure-volume characteristics of the lungs
in 19 smokers (6 men and 13 women) and 16
nonsmokers (9 men and 7 women)
NOTE: The mean age was approximately 40 years (range, 19 to 56) and smokers used approximately 30
cigarettes per day. Male smokers showed borderline significant differences in indices of expiratory airflow and
single breath Nz test data as compared with the male nonsmokers, but there was no difference in these tests
between female smokers and nonsmokers. As shown, smokers had significantly less elastic recoil than nonsmokers.
After the bronchodilator, the difference between smokers and nonsmokers increased further, particularly at high
lung volume.
B.D. = broncodilator; % pred. TLC = percent predicted total lung capacity; P(stat) = transpulmonary pressure.
* p< 0.05; ** p< 0.01; *** p< 0.005.
SOURCE: Michaels et al. (1979).
Aging and Lung Structure
With advancing age, structural and functional changes occur in
the lungs of virtually all adults, even those who have no known
exposure to specific inhalants through occupation or personal habits
(Fishman 1982; Campbell and Lefrak 1983). The elastic recoil of the
lungs declines with aging, and the residual volume to total lung
capacity ratio increases. These changes are seen even in people who
have never smoked, do not have signs or symptoms of cardiorespira-
tory disease, and have the normal (MM) phenotype of a,-antiprotein-
124
ase (Knudson et al. 1977). Also with aging, the average distance
between alveolar walls increases (Thurlbeck 1967a; Hasleton 1972),
the proportion of lung volume that is composed of alveoli decreases,
and the proportion of alveolar ducts increases (Ryan et al. 1965).
Whether the differences in the lungs that occur with aging are a
consequence only of the passage of time or are the result of subtle
environmental insults summed over many years is unanswerable.
They are “normal” or “abnormal” depending on whether one
regards “normal” as a statistical concept or as the optimal state for
the tissue. In either case, the aging lung has some features similar to
emphysema. Age changes alone will not, however, contribute to or
obscure the diagnosis of centrilobular emphysema, which involves
mainly respiratory bronchioles, recognized macroscopically as focal
lesions against a background of normal lung. The age changes may
overlap with early panlobular emphysema (Anderson et al. 1970).
However, since smokers usually die at an earlier age than nonsmok-
ers, aging cannot account for the differences observed between the
lungs of smokers and nonsmokers at autopsy.
Emphysema and Cigarette Smoking
Studies of people and of experimental animals conclusively link
cigarette smoking to the development and extent of emphysema.
This information is summarized in the following discussion.
Observations in People
Post-mortem material, used to approach the problem in the 1960s
and 1970s, clearly established an association between smoking and
emphysema. Post-mortem lung tissue has continued to be used to
study emphysema, but the main goal of recent studies has been to
identify those physiologic features that correlate with emphysema
rather than to quantify the relationship between smoking and
emphysema. Studies of emphysema using surgically removed lung
tissue, a more recent approach to studying emphysema, have aimed
mainly at elucidating the physiology of the emphysematous lung.
The results of these studies have involved smokers almost exclusive-
ly because of the rarity of emphysema in nonsmokers.
Studies Using Post-Mortem Material
A number of studies have examined the relationship between
cigarette smoking and emphysema (Anderson et al. 1964, 1966;
Thurlbeck 1963; Thurlbeck et al. 1974; Ryder et al. 1971; Auerbach
et al. 1972, 1974; Spain et al. 1973). These data emphasize that not
only is cigarette smoking closely associated with the development
and extent of emphysema, but also it is extremely rare for the forms
125
of emphysema found in patients with COLD to be present to a
significant degree in nonsmokers.
Thurlbeck (1963) reported 19 patients who had severe emphysema
at autopsy. All 19 were cigarette smokers, in contrast to 18 smokers
out of 38 patients who did not have significant emphysema at
autopsy. Anderson et al. (1964) conducted a more systematic
evaluation of the relationship between cigarette smoking and the
degree of emphysema at autopsy. They found that 12 of 23 patients
without emphysema were cigarette smokers, whereas 55 of 84 with
mild emphysema, 30 of 33 with moderate emphysema, and 14 of 15
with severe emphysema were cigarette smokers. Petty et al. (1967)
reported similar findings, with 6 of 57 patients with moderate
emphysema at autopsy being nonsmokers and only 1 of 61 patients
with severe emphysema being a nonsmoker. Ryder et al. (1971) found
that of 21 patients whose lungs showed more than 25 percent
emphysema, only 1 was a nonsmoker.
Thurlbeck et al. (1974) examined the relationship of age to extent
of emphysema in smokers compared with nonsmokers in the
combined autopsy populations of the teaching hospitals in three
separate cities. The severity of emphysema was quantified using a
panel grading method, with a score under 25 representing mild
emphysema. They found that the degree of emphysema increased
slightly in nonsmokers beginning in the fifth decade and reached an
average score of 10 to 15 in men and 4 to 6 in women by the eighth
and ninth decades. In contrast, male smokers had an average score
of 25 to 30 by the seventh decade and maintained this level for the
next two decades.
Sutinen et al. (1978) (Table 13) examined the relationship between
prevalence and extent of emphysema and duration of the smoking
habit. As would be expected from previous studies, moderate or
severe emphysematous changes were limited to smokers. However,
these changes were also limited to those smokers who had smoked
for 20 or more years, and severe emphysema was reported only in
those who had smoked for 40 years or more. These data, coupled with
that of Thurlbeck et al. (1974) describing only mild emphysematous
changes in nonsmokers with advancing age, suggest that emphyse-
ma is a late pathologic change in cigarette-induced lung disease. This
correlates well with the clinical experience of severe emphysema
being rare prior to the fifth decade. It also suggests that cessation,
even among middle-aged smokers, may have substantial impact on
emphysema morbidity and mortality.
Dose-Response Relationships
Some studies have reported the extent of emphysematous change
in smokers of different numbers of cigarettes per day. Spain et al.
(1973) examined the lungs of 134 subjects who died suddenly and
126
TABLE 13.—Correlation between the severity of emphysema
at autopsy and total smoking duration
Prevalence of emphysema (percent) by total smoking years
Grade of emphysema 0 1-19 20-39 40 or more Total
No emphysema 61.6 81.6 21.2 8.8 43.1
Mild
(grades 5 to 20) 38.4 15.4 69.7 50.0 45.8
Moderate
(grades 30 to 50) - - 9.1 26.5 78
Severe
(grade 60 or more) - ~ - 14.7 3.3
All grades 38.4 15.4 78.8 918 56.9
Total number 73 13 33 34 153
NOTE: P < 0,005: X? test, with groups of moderate and severe emphysema and of smoking times 1-19 and 20—
39 years combined.
SOURCE: Sutinen et al. (1978)
who had no previous history of lung disease. They found emphysema-
tous changes greater than grade 20 (mild emphysema) in 10 percent
of nonsmokers, 36 percent of smokers of less than one pack per day,
and 39 percent of smokers of more than one pack.
A much larger study was conducted by Auerbach et al. (1972,
1974), who examined whole lung sections from 1,443 men and 388
women autopsied between 1963 and 1970. Table 14 describes the
relationship of age, smoking habits, and degree of emphysema
graded on a scale of 0 to 9, with 9 representing severe emphysema. It
is clear that severe emphysema is limited to smokers, and that the
severity of emphysematous change at autopsy increases with in-
creasing number of cigarettes smoked per day during life. This study
also found that almost all (94.5 percent) smokers of more than one
pack per day had some degree of emphysema (slight, moderate,
advanced, or far advanced) (Table 15). In contrast, 93.8 percent of
nonsmokers had either none or minimal emphysema. This evidence
would suggest that emphysematous change is a nearly universal
phenomenon in heavy smokers, but is rare in nonsmokers, and that
it is the large ventilatory reserve of the lungs that restricts clinically
manifest disease to those individuals with far advanced emphysema.
Similar results were reported in a more limited number of autopsies
done on female smokers (Auerbach et al. 1974) (Table 16).
A study of microscopic lung sections from the autopsies of 1,436
men and 388 women was also reported by Auerbach et al. (1974), and
closely paralleled the results of the whole lung study. However, they
also reported the results in smokers who had quit for more than or
less than 10 years prior to death (Table 17). The degree of
emphysematous change was still related to the amount smoked, but
127
TABLE 14.—Degree of emphysema in current smokers? and
in nonsmokers, according to age groups
Subjects Current
Age Degree of who never pipe or Current cigarette
group emphysema smoked cigar smokerst
regularly smokers
—_ hot ota lt 1 2t 2+ ¢
0-60.75 5a 1s 12 3 2 =
1 1.75 2 ll 4 9 24 4
2.2.75 1 2 Ww 130 56
< 60 33.95 1 5 12 50 3&
4475 4 8 7
5 6.75 4 5
7 9.00 3 1
Totals 55 31 23 45 221 112
Mean 0.10 0.83 1.29 2.37 2.56 2.86
SD 0.04 0.13 0.26 0.16 0.07 0.10
0.0.75 35 Wv 4 ~ -
1-1.75 1 x 1 - 4 1
2-2.75 2 3 4 5 37 23
60-69 343.75 2 2 2 9 42 24
44.75 1 3 1h 9
5-675 1 8 1
7-9.00 1 5 4
Totals 40 30 12 19 107 62
Mean 0.39 0.95 1.90 3.59 3.39 3.37
SD 0.13 0.16 0.34 0.35 0.15 0.20
0-0.75 68 2k 2 . .
1-1.75 4 28 10 8 2 2
2 2.74 i 2 13 23 40 9
70 or 3-38.75 4 8 5 10 38 8
older 44.75 2 i 7 ll 7
54.75 1 2 9 3
7- 9.00 1 12 5
Totals R] 82 3h 51 112 44
Mean 0.50 1.66 2.15 2.98 3.68 3.91
sD 0.39 OA] O17 0.20 0.17 0.27
* Subjects who smoked regularly up to time of terminal itlness
+Packages- day
SOURCE: Auerbach et al. (1972).
was less in those who had quit for more than 10 years prior to death,
suggesting that the cessation of smoking results in a slowing of the
128
TABLE 15.—Age-standardized percentage distribution of
male subjects in each of four smoking
categories, according to degree of emphysema
Subjects Current
Degree of who never pipe or Current
emphysema smoked cigar cigarette
regularly smokers smokers (%)
to) ry
" i+ *
0-0,.75 (none) ao.u 46.5 13.1 0.3
4-1.75 (minimal) 38 33.0 16.4 5.2
2-2.75 (slight) 3.38 13.0 33.7 12.6
3-3.75 {moderate} 29 63 25.1 32.7
4$-9.00 (advanced to far advanced} ( 12 Wt 19.2
Totals 1000 100.0 100.0 100.0
*Packages day.
SOURCE: Auerbach et al. (1972)
TABLE 16.—Means of the numerical values given lung
sections at autopsy of femaie current smokers,
standardized for age
Subjects who Current cigarette
never smoked smokers
regularly
<1 Pk. >1 Pk.
_
Number of subjects 252 33 64
Emphysema 0.05 1.37 1.70
Fibrosis 0.37 2.89 3.46
Thickening of arterioles 0.06 1.26 1.57
Thickening of arteries 0.01 0.40 0.64
NOTE: Numerical values were determined by rating each lung section on scales of 0-4 for emphysema and
thickening of the arterioles, 0-7 for fibrosis, and 0-3 for thickening of the arteries.
SOURCE: Auerbach et al. (1974).
rate of progression of emphysematous change in those who quit
compared with those who continue to smoke.
Studies of Alphas-Proteinase-Inhibitor-Deficient Individuals
The deficiency of a,-proteinase inhibitor is an experiment of
nature with broad implications for understanding the pathogenesis
of emphysema (Idell and Cohen 1983). Discovery of homozygous-
deficient subjects (type PiZZ) with only 10 percent of normal plasma
129
TABLE 17.—Means of the numerical values given lung
sections at autopsy of male former cigarette
smokers, standardized for age
Never smoked
regularly Stopped >10 years Stopped <10 years
Formerly smoked
<1 Pack >1 Pack <1 Pack >1 Pack
Number of 175 35 66 51 131
subjects
Emphysema 0.09 0.24 0.70 1.08 1.69
Fibrosis 0.40 114 1.74 2.44 3.30
Thickening of 0.10 0.57 0.93 1.25 1.59
arterioles
Thickening of 0.02 0.04 0.16 0.36 0.61
arteries
NOTE: Numerical values for each finding were determined by rating each lung section on scales of 0-4 for
emphysema and thickening of the arterioles, 0-7 for fibrosis, and 0-3 for thickening of the arteries.
SOURCE: Auerbach et al. (1974).
proteinase inhibitory activity and the demonstration of the frequent
early development of emphysema in such subjects (Orell and
Mazodier 1972) called attention to the critical step of fibrous tissue
proteolysis in the remodeling of lung structure. It also pointed to at
least one potential explanation for the variability in extent of
emphysema among smokers.
Together with data from animal experiments, the discovery of the
PiZZ defect and its association with emphysema has led to general
acceptance of a theory of imbalance between the extracellular levels
of proteinase and proteinase inhibitor in the lung as the cause of
panacinar emphysema in subjects with this deficiency. The patho-
genetic lessons learned from a,-proteinase-inhibitor deficiency also
afford plausible explanations for other forms of emphysema, espe-
cially emphysema associated with cigarette smoking.
Homozygous Deficient—PiZZ
In his classic description of the severe (PiZZ) deficiency of the a,-
proteinase inhibitor, Eriksson (1965) did not indicate an effect. of
cigarette smoking on the development of emphysema. Later studies,
however, did recognize smoking as a potential aggravating factor
(Kueppers and Black 1974, Larsson 1978) and reported that PiZZ
persons who smoked cigarettes were destined to experience
shortness of breath 10 to 15 years earlier (Figure 27) and to die
sooner than PiZZ persons who did not smoke (Figure 28).
130
Men Women
Smokers Nonsmokers Smokers Nonsmokers
704 e -
°
7 3 ° e r
e
60 4 e =
eae °
_ e
eo 7 { ° r
& oe
=~
ce egge —_eo——
o
D 8 } e e
g 4 =
bs tt
«4 t i fi |
83. °
4 ees —
30 4 a r—
4 ee =
e
e
20 + oe oe t
4 e —
FIGURE 27.—Age at onset of dyspnea in 169 PiZZ
individuals separated according to sex and
smoking history
NOTE: The horizontal lines show the median values. The difference between nonsmokers and smokers was
highly significant for both sexes and was 13 and 15 years for men and women, respectively.
SOURCE: Larsson ‘1978).
More recent studies, however, have shown considerable variation
in the rate of decline of lung function among middle-aged PiZZ
adults (Buist et al. 1983). In a comparison of 22 persons with PiZZ
phenotype who had never smoked with 36 PiZZ smokers, Black and
Kueppers (1978) found variability in symptoms and lung function
abnormalities in both groups. Smokers generally sought medical
attention earlier, and those who reached the older age groups, such
as 60 to 69, had smoked less and started to smoke later in life. There
was overlap in these characteristics between the age groups,
however, and some smokers did live into the 50 to 69 age range. In
this analysis, the correlations between pulmonary function test
abnormalities and pack-years of cigarette smoking were small.
The British Thoracic Society, in a multicentered study of PiZZ
individuals (Tobin et al. 1983), reported an association between
131
@ Smoking PiZ men and women
1.0
J O Nonsmoking PiZ men and women
S os A All Swedish women
2 & Ali Swedish men
a 4
6
z 06 +
a
g —_
a
&
© 04 44
>
3 =
J
§
g 02
TTT TTT rh lt
20 30 40 50 60 70 80 90 100
Age (in years)
FIGURE 28.—The cumulative probability of survival, given
that 20 years of age is reached, in smoking
and nonsmoking Swedish PiZZ individuals,
compared with all Swedish men and women
NOTE: Survival was higher for PiZZ nonsmokers than for PiZZ smokers in both sexes above age 35.
SOURCE: Larsson (1978).
cigarette smoking and the onset of pulmonary symptoms and
deterioration of lung function, but demonstrated no significant
correlation between the quantity of tobacco consumed and the extent
of pulmonary dysfunction. A notable finding in this study, applicable
to other studies of the natural history of disease related to ai-
proteinase-inhibitor deficiency, was the impressive difference be-
tween individuals found because of medical complaints (index cases)
and those detected by surveys (nonindex cases). Nonindex cases had
better pulmonary function and survived longer than index cases,
irrespective of other variables such as age and smoking history. The
distinction between these two categories of subjects suggests the
importance of factors besides the PiZZ phenotype in the development
of symptomatic lung disease in PiZZ persons.
PiZZ individuals who smoke increase their risk for early onset of
symptomatic chronic obstructive lung disease and for a shortened
lifespan, compared with nonsmoking PiZZ individuals. However,
pulmonary function data have shown only limited differences in
diffusing capacity and elastic recoil between the smokers and the
nonsmokers (Black and Kueppers 1978).
132
Heterozygous Deficient—PiMZ
The PiMZ phenotype of a,-antiproteinase inhibitor occurs in
approximately 3 percent of the population. Because of the high
frequency of emphysema in PiZZ persons, it is important to establish
whether PiMZ individuals also have an increased risk of emphysema
and chronic obstructive lung disease. From the unpredictability of
obstructive lung disease even among those with the PiZZ phenotype,
however, one might expect difficulty in discerning the effect of the
PiMZ phenotype.
Among adults with symptomatic chronic obstructive lung disease,
the PiMZ phenotype is more prevalent than expected (Mittman
1978). It is uncertain whether this means of subject identification is
appropriate, as was noted concerning index and nonindex PiZZ
individuals. Madison et al. (1981) emphasized the complexity of this
issue by noting that the PiMZ phenotype was only one of several
factors that appeared to be related to the risk of obstructive lung
disease. Other factors identified as relevant included smoking, a
family history of lung diseases, and being male.
From studies of children and young adults it is evident that the
PiMZ phenotype does not strongly predispose to chronic pulmonary
disease. Thus, PiMZ children (Buist et al. 1980) failed to show any
early changes of lung dysfunction analogous to what has been
observed in some young PiZZ individuals; PiMZ adults below the age
of 40 had the same results by spirometry and the single breath No
test as PiMM individuals matched for smoking history (Buist et al.
1979b).
Numerous studies involving older subjects indicate that PiMZ
individuals preserve their lung function, as measured by spirometry,
compared with controls matched for smoking (Tattersall et al. 1979,
de Hamel and Carrell 1981). The elastic properties of the lungs may
be different in PiMZ persons, but if there are differences, they are
small. Larsson et al. (1977) reported that 50-year-old PiMZ men who
smoked had reduced elastic recoil at total lung capacity compared
with PiMZ nonsmokers, even though they had no evidence of
impaired air flow. The PiMZ nonsmokers were indistinguishable
from PiMM nonsmokers. Tattersall et al. (1979) also found no effect
upon airflow in PiMZ middle-aged men, and a statistically nonsignif-
icant decrease in elastic recoil. Using an index of the slope of the
pressure-volume curve, Knudson and Kaltenborn (1981) found no
significant reduction in elastic recoil of PiMZ subjects compared
with matched PiM controls.
There is little direct information about the occurrence of emphyse-
ma among PiMZ individuals. In an autopsy study, Eriksson et al.
(1975) found emphysema among 13 of 26 subjects with diastase-
resistant PAS-positive inclusions in the liver, compared with an
incidence of emphysema of only 18 percent in the controls. Although
133
these findings suggest an increased occurrence of emphysema with
the PiMZ phenotype, this study should be interpreted cautiously
because the smoking histories of the subjects and the quantification
of the emphysema were not included. Moreover, the significance of
the PAS-positive inclusions is not certain, because one recent study
found that such inclusions represented immunoreactive a,-protein-
ase inhibitor in only half of the tissue studied (Qizilbash and Young-
Pong 1983).
It may be concluded from the studies involving a,-proteinase-
inhibitor-deficient people that for those with the PiMZ phenotype,
smoking has not been shown to promote a greater risk of emphysema
than it does in PiMM persons. In the rare individual with PiZZ, the
risk of emphysema is extremely high in both smokers and nonsmok-
ers, but PiZZ smokers experience an earlier onset and more severe
chronic obstructive lung disease than PiZZ nonsmokers.
Observations in Experimental Animals
Experimental animals have been subjected to cigarette smoke to
examine whether changes typical of emphysema result. As noted
below, it appears that cigarette smoke exposure can produce
emphysematous-like changes in the lungs under experimental
conditions, but the exposure must be quite prolonged and intense, or
additional factors must be employed to “sensitize” the lungs to the
effects of cigarette smoke.
Pioneering studies in dogs exposed to cigarette smoke, by Hernan-
dez et al. (1966) and by Auerbach et al. (1967), indicated effects
consistent with emphysema, but these reports did not include
quantitative morphology or data about the mechanical properties of
the lungs. Moreoever, the exposures may have created problems of
hypoxemia and infection that may have influenced the responses to
cigarette smoke. Contrary to these findings, in later studies, beagles
that inhaled cigarettes by face mask in four sessions per day for up to
1 year—an inhalation sufficient to raise the blood carboxyhemoglo-
bin saturation to 5.4 + 0.9 percent—had no statistically significant
changes in mean linear intercept or internal surface area, although
their large airways showed epithelial cell hyperplasia, proliferation
of goblet cells, and peribronchial inflammation (Park et al. 1977).
Recently, Hoidal and Niewoehner (1983) presented data suggesting
that cigarette smoke may be an important cofactor in the develop-
ment of elastase-induced emphysema. They found that inhalation of
cigarette smoke led to severe emphysema in hamsters if used in
conjunction with doses of elastase that did not produce emphysema
when used alone. In this study, hamsters were exposed to cigarette
smoke for 15 minute periods, six times per day, 6 days per week for 7
weeks in standardized chambers. The animals were challenged with
small doses of elastase given intratracheally; controls consisted of
134
animals given either elastase or smoke exposure or neither. Animals
receiving only smoke or only elastase showed no changes of mean
linear intercept or volume—pressure relationship of the excised
lungs, compared with animals given neither elastase nor smoke
exposure. The combinations of smoking followed by elastase or
smoking both before and after elastase produced statistically signifi-
cant increases of mean linear intercept, displacement upward and to
the left of the volume—pressure curves (Figure 29), and marked
emphysema by light microscopy of inflation-fixed lungs. The mecha-
nism of the synergism between elastase and smoking was not
elucidated. One possibility considered was that cigarette smoke
impaired the repair mechanism normally triggered by elastase
exposure, a possibility supported by Osman et al. (1982), who found
that hamsters exposed to cigarette smoke after intratracheal elas-
tase did not show the heightened lung elastin synthesis typically
seen after lung injury produced by elastase.
Summary
Clinically significant degrees of emphysematous lung destruction
are commonly present in individuals with COLD. Severe emphysema
occurs almost exclusively in cigarette smokers and those with
homozygous a,-antitrypsin deficiency. The extent of emphysematous
change increases with increasing numbers of cigarettes smoked per
day and with the duration of the smoking habit. While clinically
significant emphysema is limited to a minority of those who smoke,
most heavy smokers have some degree of emphysematous change by
the sixth decade of life.
Individuals with homozygous a,-antitrypsin deficiency have an
exceptionally high risk of developing emphysema. This risk is
present for both smokers and nonsmokers, but smokers with a.-
antiprotease deficiency develop clinical symptoms earlier in life. It is
unclear whether individuals with heterozygous antiprotease pheno-
types are at increased risk of developing COLD.
Summary and Conclusions
1. Cigarette 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.
2.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.
3.In spite of over 30 years of intensive investigation, only
cigarette smoking and a,-antiprotease deficiency (a rare genet-
135
120 F—- * i f
100 [-
S80 F
rz
oD
Ke
a —
&
2
2 60 -
oa
>
mn
Cc
3 |
@ Nosmoke, no elastase
O Continuous smoke, no elastase
40 Hl No smoke. elastase
C) Post-elastase smoke
s & Pre-elastase smoke
A Continuous smoke, elastase
20
p- ,05 compared with
* No smoke, no elastase
L r l i 1 |
5 10 15 20 25 30
Pressure (cmH,O)
FIGURE 29.—The effects of combining cigarette smoking
and elastase upon the pressure-volume
characteristics of the lungs of experimental
animals
NOTE: The in vitro measurements of lung volume are shown as percentage of predicted total lung capacity
(TLC) relative to transpulmonary pressure of hamster lungs following in vivo exposure to various combinations of
cigarette smoke and intratracheally administered pancreatic elastase. Values are the mean + SEM of
measurements made during deflation The animals that smoked and then received elastase (Pre-Elastase Smoke)
and those that smoked both before and after elastase (Continous Smoke, Elastase) had significant changes in the
elastic properties of the lungs. There were no changes from control if elastase or smoking were used separately or
when smoking occurred only after elastase.
SOURCE: Hoidal and Niewoehner (1983).
ic defect) are established causes of clinically significant COLD
in the absence of other agents.
4. 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
136
10.
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
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.
Clinically significant degrees of emphysema occur almost
exclusively in cigarette smokers or individuals with genetic
homozygous a,-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.
137
Appendix Tables
6ET
a+swrases ue—easv, lor white adults, by smoking status, sex, and age, United States, 1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE
Never smokers
25-74 3140! 21' 3669' 39! 2664! 19!
25-34 6733 394 3607 791 51 2633 130 4404 584 63 4099 264 3095 372 26
35-44 5278 291 3171 607 49 1669 81 3742 591 73 3609 210 2907 397 40
45-54 4942 353 2840 594 35 1206 85 3487 626 72 3736 268 2631 401 29
55-64 3660 251 2511 589 31 880 59 3215 531 81 2781 192 2289 401 29
65-74 2875 235 2148 549 36 481 43 2856 627 96 2394 192 2006 402 36
Ex-smokers
25-74 3112 24 3623 37 2651 28
25-34 2811 160 3677 810 80 1359 66 4303 627 92 1452 94 3091 441 55
35-44 3086 171 3566 767 69 1828 94 4013 643 70 1258 77 2916 361 44
45-54 3323 213 3155 742 65 2345 143 3414 683 69 978 70 2535 454 65
55-64 2669 181 2845 693 63 1826 130 3087 649 63 843 §1 2319 456 90
65-74 1769 157 2388 686 66 1270 121 2533 699 78 499 36 2020 487 92
Smokers
25-74 2878 20 3281 32 2514 27
, 2-34 8885 487 3567 752 44 4792 239 4037 639 51 4093 248 3018 435 41
3444“ 5849 320 3166 655 47 3027 158 3507 639 71 2822 162 2800 439 43
45-54 5606 374 2761 623 37 2743 182 3126 579 49 2863 192 2411 437 40
55-64 3251 192 2416 631 50 1700 108 2738 632 63 1551 84 2064 400 50
65-74 933 84 2071 653 86 534 56 2222 556 79 400 28 1869 714 155
OvT
TABLE A.—Continued
Both sexes Men Women
Cigarette smoking or
status (by age) N n Mean SD SE N hn Mean sD SE N Dn Mean SD SE
Light smokers
25-74 2951 38 3311 57 2626 52
25-34 2162 113 3425 650 97 879 43 3914 508 102 1283 70 3089 508 88
35-44 1267 72 3106 618 93 308 17 3775? 515 139 859 55 2891 479 83
45-54 1090 76 2683 490 73 383 24 3009 409 95 707 52 2507 437 76
55-64 1043 57 2408 573 83 313 18 2919? 660 150 730 39 2190 350 62
65-74 304 21 2150 137 185 131 Bl 2222? 426 130 172 10 2095? 901-305
Moderate smokers
25-74 2878 23 3335 40 2466 25
25-34 4269 235 3671 810 60 2534 123 4136 684 69 1735 112 2991 393 51
35-44 2413 130 3217 646 68 1214 66 3593 624 99 1199 64 2836 395 47
45-54 2715 179 2679 634 53 1145 15 3106 622 719 1570 104 2368 429 51
55-64 1287 82 2406 589 68 690 45 2776 455 60 597 37 1977 408 10
65-74 464 4 2023 609 105 261 28 2279 572 126 203 16 1693? 484 «124
Heavy smokers
25-74 2785 32 3202 52 2409 38
25-34 QAIT 136 3514 699 70 1363 72 3927 597 82 1054 64 2979 393 80
35-44 2148 116 3143 684 val 1505 75 3382 646 89 643 41 2582 373 64
45-54 1779 118 2930 649 70 1193 82 3184 579 15 586 36 24h 440 92
55-64 922 53 2440 741 118 697 45 2619 737 133 224 8 1883? 398 «121
65-74 154 18 20387 606 151 130 16 2096? 638 172 24 2 1733? 215 150
NOTE: N = weighted population estimate in thousands;
| Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
n = number of people in sample; SD = standard deviation; SE = standard error.
Trl
TABLE B.—Flow at 25 percent of FVC for white adults, by smoking status, sex, and age, United
States, 1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean SD SE N no Mean SD SE N n Mean SD SE
Never smokers
25-74 6253" 47' 7261' 91' 5343! 36!
25-34 6733 394 6639 1591 98 2633 130 7871 1513 157 4099 264 5847 1042 89
35-44 5278 291 6377 1484 114 1669 81 7715 1545 176 3609 210 §758 952 80
45-54 4942 353 5742 1586 90 1206 85 7262 1796 213 3736 268 5252 1141 70
55-64 3660 251 5368 1397 101 880 59 6543 1593 265 2781 192 4996 1091 83
65-74 2875 235 4626 1576 102 481 43 6097 1961 298 2394 192 4331 1303 108
Ex-smokers
25-74 6093 62 7095 107 5188 67
25-34 2811 160 6835 1855 203 1359 66 8042 1715 285 1452 94 5705 1126 165
35-44 3086 171 7020 2041 176 1828 94 7956 2059 232 1258 77 5659 965 116
45-54 3323 213 6270 1896 164 2345 143 6765 1919 185 978 70 5084 1176 151
55-64 2669 181 5783 1764 144 1826 130 6261 1820 160 843 51 4749 1058 197
65-74 1769 157 4918 1948 207 1270 121 5194 2091 265 499 36 4213 1278 197
Smokers
25-74 5647 47 6362 88 5002 52
25-34 8885 487 6760 1694 102 4792 239 7606 1663 126 4093 248 5769 1081 83
35-44 5849 320 6157 1740 123 3027 158 6848 1875 180 2822 162 5415 1200 102
45-54 5606 374 5471 1658 92 2743 182 6130 1783 137 2863 192 4840 1233 106
55-64 3251 192 §123 1815 132 1700 108 5567 2041 223 1551 84 4636 1372 169
65-74 933 84 3954 1586 181 534 56 4199 1745 238 400 28 3627 1274 255
ol
TABLE B.—Continued
Both sexes Men Women
Cigarette smoking ~
status (by age) N nh Mean SD SE N n Mean sD SE N n Mean sD SE
Light smokers
25-74 5834 91 6569 142 5171 112
25-34 2162 113 6549 1652 209 879 43 1688 1690 293 1283 70 5769 1071 140
35-44 1267 72 6045 1481 211 308 17 7250? 1634 369 959 55 5658 1193 188
45-54 1090 76 5545 1476 217 383 24 6373 1572 311 707 52 5096 1203-193
55-64 1043 57 5222 1534 238 313 18 6096? 1616 399 730 39 4849 1333 249
65-74 304 21 3779 1272 345 131 ll 3742? 1279 482 172 10 i? 1266 489
Moderate smokers
25-74 5661 66 6430 118 4967 76
25-34 4269 235 6909 1719 136 2534 123 7647 1667 164 1735 112 5831 1120-132
35-44 2413 130 6384 1786 194 1214 66 7348 1738 236 1199 64 5408 1212 =—-:170
45-54 2715 179 5269 1490 i 1145 75 5821 1661 183 1570 104 4867 1202137
55-64 1287 82 5065 1787 202 690 45 5576 1897 334 597 37 4475 1439-265
65-74 464 44 3950 1717 304 261 28 4356 1892 404 203 16 3427? 1285 = 319
Heavy smokers
25-74 5485 85 6219 151 4822 ll
25-34 QA1T 136 6691 1659 166 1363 12 7468 1640 225 1054 64 5685 1018 =: 17€
35-44 2148 116 5964 1815 198 1505 15 6363 1902 261 41 5031 1084 186€
45-54 1779 118 5712 1940 207 1193 82 6326 1920 251 586 36 4458 1257-266
55-64 922 53 5090 2117 321 697 45 §322 2288 434 224 8 4370? 1202-355
65-74 154 18 4155? 1653 401 130 16 4180? 1758 463 24 2 40237 904 = 626
NOTE: N = Weighted population estimate, in thousands; n = number of people in sample; SD = standard devia
' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and E:
tion; SE = standard error.
‘xamination Survey (NHANES 1).
ert
TABLE C.—Flow at 50 percent of FVC for white adults, by smoking status, sex, and age, United
States, 1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean SD SE N n Mean sD SE N n Mean SD SE
Never smokers
25-74 3743' 38! 4083' 86! 3342! 34!
25-34 6733 394 4381 1194 69 2633 130 4998 1255 128 4099 264 3984 963 78
35-44 5278 291 3904 1164 84 1669 81 4315 1221 152 3609 210 3713 989 91
45-54 4942 353 3366 1212 84 1206 85 3972 1287 150 3736 268 3170 1119 90
55-64 3660 251 3090 1087 74 880 59 3736 1220 180 2781 192 2886 955 72
65-74 2875 235 2535 1045 3 481 43 3157 1060 174 2394 192 2410 996 84
Ex-smokers
25-74 3579 59 4188 67 3123 81
25-34 2811 160 4329 1292 120 1359 66 5029 1243 195 1452 94 3674 949 114
35-44 3086 171 4249 1384 129 1828 94 4702 1410 180 1258 77 3590 1037 160
45-54 3323 213 3474 1404 114 2345 143 3749 1428 143 978 70 2816 1091 147
55-64 2669 181 3110 1411 118 1826 130 3294 1362 127 843 51 271 1432 293
65-74 1769 157 2524 1296 121 1270 121 2578 1364 153 499 36 2384 1092 167
Smokers
25-74 3169 39 3475 59 2892 54
25-34 8885 487 4126 1268 74 4792 239 4546 1296 103 4093 248 3634 1037 90
35-44 5849 320 3552 1298 87 3027 158 3764 1399 140 2822 162 3325 1137 98
45-54 5606 374 2924 1208 76 2743 182 3257 1278 92 2863 192 2604 1040 94
55-64 3251 192 2587 1248 107 1700 108 2793 1364 148 1561 84 2361 1062 144
65-74 933 84 1922 1220 159 534 56 1889 1174 175 400 2B 1965 1279 252
Per
TABLE C.—Continued
Both sexes Men Women
Cigarette smoking —
status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE
Light smokers
25-74 3313 14 3676 110 2984 102
25-34 2162 113 3964 1230 169 879 43 4617 1248 222 1283 70 3516 994 162
35-44 1267 72 3630 1076 151 308 \7 4190? 943 226 959 55 3450 1054 168
45-54 1090 76 2911 864 107 383 24 3150 969 197 707 52 2781 711 103
55-64 1043 57 2756 1375 205 313 18 3542? 1643 395 730 39 2420 1080 =. 200
65-74 304 21 2056 1252 292 131 11 1706" 883 366 172 10 23217 1415425
Moderate smokers
25-74 3207 57 3561 79 2888 71
25-34 4269 235 4246 1239 96 2534 123 4640 1297 126 1735 112 3671 872 47
35-44 2413 130 3781 1182 124 1214 66 4039 1198 171 1199 64 3520 1107 142
45-54 27115 179 2775 1205 111 1145 15 3079 1243 124 1570 104 2553 1125 140
55-64 1287 82 2665 1186 167 690 45 2873 1191 207 597 37 2425 11340245
65-74 464 44 1881 1239 218 261 28 2131 1316 279 203 16 1558? 1047-266
Heavy smokers
25-74 3043 68 3283 92 2828 110
25-34 2417 136 4067 1333 153 1363 72 4326 1305 197 1054 64 3733 1295247
35-44 2148 116 3239 1469 166 1505 15 3456 1550 227 643 41 2731 1103 185
45-54 1779 118 3152 1355 147 1193 82 3458 1377 168 586 36 2526 1062 9-222
55-64 922 53 2286 1123 173 697 45 2379 1222 221 224 8 1997? 651 232
66-74 154 18 1760? 1113 285 130 16 1559* 1059 274 2A 2 2834" 703 490
NOTE: N = weighted population estimate, in thousands; n = number of people in sample,
‘ Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
SD = standard deviation; SE = standard error.
SFI
TABLE D.—Flow at 75 percent of FVC for white adults, by smoking status, sex, and age, United
States, 1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N a Mean sD SE N Qo Mean SD SE N n Mean sD SE
Never smokers
25-74 1230! 28° 1329° 42! 1073" 24!
25-34 6733 394 1776 714 52 2633 130 2065 649 72 4099 264 1590 691 62
35-44 5278 291 1277 621 49 1669 81 1478 843 129 3609 210 1184 456 32
45-54 4942 353 1044 636 44 1206 85 1184 664 74 3736 268 999 620 53
55-64 3660 251 7137 611 36 880 59 978 612 83 2781 192 661 449 34
65-74 2875 235 609 463 32 481 43 795 408 64 2394 192 572 465 38
Ex-smokers
25-74 1152 29 1403 41 992 37
25-34 2811 160 1695 678 61 1359 66 1925 664 109 1452 94 1480 616 72
35-44 3086 171 1460 664 62 1828 94 1623 693 92 1258 71 1224 538 59
45-54 3323 213 1026 625 48 2345 143 1148 666 59 978 70 134 378 53
55-64 2669 181 134 541 54 1826 130 178 446 41 43 51 638 694 156
65-74 1769 157 588 506 43 1270 121 592 516 47 499 36 578 481 87
Smokers
25-74 967 22 1053 29 889 34
25-34 8885 487 1530 688 41 4792 239 1665 655 60 4093 248 1373 692 65
35-44 5849 320 1062 552 34 3027 158 1134 599 57 2822 162 985 486 35
45-54 5606 374 778 511 31 2743 182 866 530 41 2863 192 693 478 43
55-64 3251 192 631 536 42 1700 108 113 580 63 1551 84 541 468 56
65-74 933 84 452 689 100 534 56 350 445 77 400 2 588 901 199
OFT
TABLE D.—Continued
Both sexes Men Women
Cigarette smoking
status (by age) N D Mean sD SE N n Mean SD SE N n Mean SD SE
Light smokers
25-74 1049 44 1120 64 985 67
25-34 2162 113 1480 679 94 879 43 1647 606 113 1283 70 1366 703 127
35-44 1267 72 1122 534 63 308 17 1294? 484 101 959 55 1067 537 73
45-54 1090 76 837 431 57 383 24 840 500 137 707 52 836 388 42
55-64 1043 57 706 540 85 313 18 931? 652 182 730 39 609 450 88
65-74 304 21 660 1040 264 131 11 393? 587 231 172 10 864? 1244 414
Moderate smokers
25-74 970 28 1107 41 846 32
25-34 4269 235 1603 685 57 2534 123 1755 686 82 1735 112 1382 620 16
35-44 2413 130 1134 499 62 1214 66 1265 517 78 1199 64 1000 443 58
45-54 2715 179 TT 480 49 1145 15 801 416 47 1570 104 656 514 67
55-64 1287 82 643 598 72 690 45 184 637 119 597 37 481 503 69
65-74 464 44 373 366 68 261 28 381 375 85 203 16 363? 353-103
Heavy smokers
25-74 882 47 956 38 815 82
25-34 2417 136 1447 689 95 1363 12 1503 593 101 1054 64 1874 790 172
35-44 2148 6 940 595 63 1505 75 995 647 85 643 41 Bil 422 69
45-54 1779 118 836 589 57 1193 82 941 624 3 586 36 620 438 19
55-64 922 53 529 410 57 697 45 545 416 62 224 8 479? 388 160
65-74 154 18 2977 453 112 130 16 2587 408 98 24 2 505? 6038 420
NOTE: N = weighted population estimate, in thousands,
' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
n = number of people in sample; SD = standard deviation; SE = standard error.
SOURCE: National Center for Health Statistics. Unpublished data from the firat National Health Nutrition and Examination Survey (NHANES 1).
LPT
TABLE E.—FEV,/FVC ratio for white adults, by smoking status, sex, and age,
United States, 1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean sD SE N n Mean SD SE N n Mean sD SE
Never smokers
25-74 79.17 0.21' T79' 0.34! 80.2! 0.23!
25-34 6733 394 82.5 6.08 0.34 2633 130 80.7 5.91 0.69 4039 264 83.6 5.93 0.44
35-44 5278 291 80.3 §.67 0.37 1669 81 78.8 5.25 0.64 3609 210 80.9 5.73 0.45
45-54 4942 353 78.7 5.84 0.38 1206 85 775 5.95 0.77 3736 268 79.0 5.75 0.41
55-64 3660 251 77.6 §.03 0.35 880 59 75.8 5.13 0.81 2781 192 78.2 4.85 0.39
65-74 2875 235 76.5 6.41 0.52 481 43 73.5 7.59 1.14 2394 152 77.0 5.97 0.55
£x-smokers
25-74 117 0.30 76.6 0.44 78.7 0.41
25-34 2811 160 817 §.92 0.53 1359 66 80.9 5.94 0.94 1452 94 82.4 5.81 0.78
35-44 3086 171 79.5 6.26 0.56 1828 94 78.8 6.78 0.83 1258 7 80.4 5.26 0.69
45-64 3323 213 76.2 6.58 0.50 2345 143 159 7.10 0.66 978 70 77.0 5.04 0.69
55-64 2669 181 13.7 7.79 0.70 1826 130 72.7 8.07 0.79 843 51 76.0 6.60 1.36
65-74 1769 157 715 9.34 1.05 1270 121 70.0 9.83 1.20 499 36 75.3 6.58 1.05
Smokers
25-74 75.9 0.26 74.0 0.36 715 0.39
25-34 8885 487 80.3 6.78 0.38 4792 239 79.2 6.50 0.52 4093 248 817 6.85 0.61
35-44 5849 320 16.7 7.28 0.46 3027 158 75.3 7.92 0.71 2822 162 78.2 6.16 0.47
45-54 5606 374 74.2 7.05 0.41 2743 182 73.0 7.55 0.59 2863 192 75.4 6.32 0.52
55-64 3251 192 73.1 8.73 0.59 1700 108 70.6 9.59 1.03 1551 84 76.0 6.61 0.75
65-74 933 84 69.8 9.40 1.44 534 56 67.0 8.94 1.54 400 28 73.6 8.67 2.09
SPI
TABLE E.—Continued
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean sD SE N a Mean sD SE N n Mean SD SE
Light smokers
25-74 77.3 0.47 75.7 0.76 78.7 0.60
25-34 2162 113 80.9 7.43 0.84 879 43 80.3 7.10 1.11 1283 10 81.4 7.62 1.30
35-44 1267 72 78.4 6.18 0.79 308 17 771? 6.14 1.54 959 55 78.8 6.13 1.30
45-54 1090 16 76.5 4.94 0.66 383 24 751 6.06 1.58 107 52 W713 4.01 0.54
55-64 1043 57 76.9 7.06 0.97 313 18 74.8? 9.00 2.25 730 39 178 5.81 0.87
65-74 304 21 71.4 10.59 2.65 131 ll 64.67 10.84 47 172 10 765° 6.90 2.64
Moderate smokers
25-74 758 0.36 74.6 0.48 169 0.47
25-34 4269 235 80.4 6.36 0.53 2534 123 79.3 6.29 0.70 1735 112 81.9 6.16 0.73
35-44 2413 130 T19 6.18 0.65 1214 66 T1.3 6.61 0.85 1199 64 78.6 5.64 0.77
45-54 2715 179 13.6 7.48 0.69 1145 vii) 113 7.87 0.96 1570 104 75.3 6.67 0.80
55-64 1287 82 13.2 7.46 0.81 690 45 721 8.00 1.38 §97 37 743 658 1.07
65-74 464 44 69.3 8.30 1.48 261 28 68.4 7.63 1.58 203 16 70.4? 8.98 2.42
Heavy smokers
25-74 15.1 0.58 728 0.57 772 1.06
25-34 2417 136 79.1 6.85 0.73 1363 72 78.0 6.33 0.89 1054 64 819 6.90 1.16
35-44 2148 116 74.2 8.24 0.92 1505 15 13.3 8.68 1.21 643 41 16.2 6.64 1.15
45-54 1779 118 13.7 721 0.74 1193 82 74.0 1.34 0.86 586 36 73.2 6.91 1.30
55-64 922 53 68.9 10.08 1.42 697 45 67.1 10.09 1.81 22A 8 74.63 7.63 2.40
65-74 154 18 68.0? 9.78 2.65 130 16 65.9* 8.75 2.42 2A 2 79.4% 6.66 4.63
NOTE: N = weighted population estimate, in thousands; n =
* Adjusted by the direct method to reflect the age distribution o
1 Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
number of people in sample; SD =
standard deviation; SE = standard error.
f the U.S. population at the midpoint of the survey.
6FT
TABLE F.—MMEF for white adults, by smoking status, sex, and age, United States, 1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE
Never smokers
25-74 3020! 29" 3392' 52! 2684" 26
25-34 6733 394 3748 1023 64 2633 130 4357 1008 106 4199 264 3357 820 58
35-44 5278 291 3140 827 58 1669 81 3501 911 106 3609 210 2973 727 58
45-54 4942 353 2724 837 50 1206 85 3198 1021 119 3736 268 2572 703 48
55-64 3660 251 2301 730 43 880 59 2734 763 104 2781 192 2164 663 51
65-74 2875 235 1891 679 51 481 43 2314 827 130 2394 192 1806 611 56
Ex-mokers
25-74 2910 41 3324 66 2537 51
25-34 2811 160 3753 1066 102 1359 66 4321 1014 162 1452 54 3222 809 =: 108
35-44 3086 171 3500 1165 106 1828 94 3882 1237 157 1258 17 2944 765 104
45-54 3323 213 2800 1111 91 2345 143 3021 1171 114 978 70 2270 714 = 102
55-64 2669 181 2318 948 15 1826 130 2463 953 87 843 51 2005 857 ~—s-180
65-74 1769 157 1826 873 82 1270 121 1865 922 99 499 36 1728 7230115
Smokers
25-74 2553 31 2786 49 2343 41
25-34 8885 437 3512 1069 66 4792 239 3857 1101 93 4093 248 3109 872 17
35-44 5849 320 2850 970 65 3027 158 3033 1073 107 2822 162 2654 800 63
45-54 5606 374 2283 896 54 2743 182 2511 1007 78 2863 192 2065 709 66
55-64 3251 192 1955 854 67 1700 108 2065 985 106 1551 &4 1813 654 18
65-74 933 84 1474 831 118 534 56 1422 677 104 400 28 1545 995 220
OST
TABLE F.—Continued
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean sD SE N n Mean sD SE N n Mean SD SE
Light smokers
25-74 2736 57 2985 93 2510 71
25-34 2162 113 3457 1034 144 879 43 3923 1044 196 1283 10 3137 807 153
35-44 1267 72 2936 839 110 308 Vi 3400? 760 184 959 55 2787 808 124
45-54 1090 76 2334 641 84 383 24 2521 806 173 707 52 2232 502 68
55-64 1043 57 2252 894 124 313 18 2694* 1239 321 730 39 2063 605 87
65-74 304 21 1667 1023 257 131 li 13397 568 238 172 10 1917? 1206 404
Moderate smokers
25-74 2542 41 2848 64 2266 40
25-34 4269 235 3605 1106 93 2534 23 3960 1132 123 1735 112 3087 828 98
35-44 2413 130 2993 907 99 1214 66 3257 968 145 1199 64 2725 152 92
45-54 2715 179 2169 823 74 1145 15 2345 891 92 1570 104 2041 144 95
55-64 1287 82 1894 811 103 690 45 2144 848 162 597 87 1604 655 106
65-74 464 44 1395 738 126 261 28 1535 746 159 203 16 1214? 687 157
Heavy smokers
25-74 2404 53 2620 72 2210 87
25-34 2417 136 3389 1018 120 1363 72 3614 1045 167 1054 64 3122 911 187
35-44 2148 116 2628 1063 119 1505 15 2177 1144 157 643 41 2280 735 123
45-54 1779 118 2421 1087 125 1193 82 2663 1145 150 536 36 1926 786 = «185
55-64 922 53 1706 164 166 697 45 1754 828 136 224 8 1557? 439 s:169
65-74 154 18 1313* 591 151 130 16 1247? 601 160 24 2 1665? 369257
NOTE: N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviation; SE = standard error.
' Adjusted by the direct method to reflect the age distribution o!
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistica. Unpub!
{the U.S. population at the midpoint of the survey.
lished data from the first National Health Nutrition and Examination Survey (NHANES }).
TST
TABLE G.—MEFR for white adults, by smoking status, sex, and age, United States, 1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE
Never smokers
25-74 6545' 62! 7894! 114! 5327 ' 41!
25-34 5733 394 7103 1895 123 2633 130 8833 1551 167 4099 264 5991 1081 94
35-44 5278 291 6744 1774 144 1669 81 8519 1710 223 3609 210 5923 1058 103
45-54 4942 353 5887 1825 110 1206 85 7805 2106 268 3736 268 5268 1185 86
55-64 3660 251 §280 1559 98 880 59 6722 1527 228 2781 192 4824 1264 98
65-74 2855 234 4317 1776 112 472 42 6526 1863 289 2394 192 3882 1394 118
Ex-smokers
25-74 6453 72 7809 120 5229 83
25-34 2811 160 7521 2246 232 1359. 66 9184 1911 295 1452 94 5964 1153 167
35-44 3086 171 7554 2241 212 1828 94 8789 2006 239 1258 77 5759 1017 131
45-54 3323 213 6773 2056 202 2345 143 7451 1901 213 978 70 5146 1398 191
55-64 2669 181 5944 2002 194 1826 130 6532 1997 220 843 51 4671 1297 245
65-74 1769 157 4986 2187 221 1270 121 5425 2267 280 499 36 3867 1463 220
Smokers
25-74 5914 52 7041 96 4897 55
25-34 8885 487 7393 2019 122 4792 239 8629 1728 133 4093 248 5847 1216 101
35-44 5849 320 6712 1974 152 3027 158 7780 1922 211 2822 162 5566 1256 94
45-54 5606 374 5762 1864 104 2743 182 5758 1819 137 2863 192 4807 1332 3
55-64 3251 192 5030 1952 147 1700 108 5834 2022 211 1551 84 4149 1421 171
65-74 933 84 3753 1862 216 534 56 4341 1961 260 400 28 2969 1373 263
= TABLE G.—Continued
c
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean sD SE N n Mean SD SE N n Mean SD SE
Light smokers
25-74 6068 104 7085 177 5150 114
25-34 2162 113 7006 1792 233 879 43 8347 1559 246 1283 70 6088 1294 193
35-44 1267 72 6450 1784 275 308 17 8275? 1918 530 959 55 5864 1270 =—-:192
45-54 1090 76 5656 1632 232 383 24 6718 1445 269 707 52 5080 1425-249
55-64 1043 57 4979 1611 240 313 18 6142? 1903 478 730 39 4482 1154-208
65-74 304 21 3585 1295 350 131 ll 4054" 1318 457 172 10 3228? 1157-388
Moderate smokers
25-74 5921 76 7165 120 4798 89
25-34 4269 235 7616 2146 154 2534 123 8755 1864 176 1735 112 5952 1263-164
35-44 2413 130 6819 1992 230 1214 66 8112 1734 264 1199 64 5511 1241 150
45-54 2715 179 5513 1755 137 1145 75 6533 1799 181 1570 104 4769 1286 = «144
55-64 1287 82 5100 1996 243 690 45 6122 1687 261 597 37 3917 1640 =. 299
65-74 464 44 3701 2084 373 261 28 4495 2122 466 203 16 2681? 1512 376
Heavy smokers
25-74 5755 98 6902 155 4720 5
25-34 2417 136 7356 1925 204 1363 72 8573 1544 192 1054 64 5781 1010 + =170
35-44 2148 116 6751 2053 223 1505 75 7412 1995 289 643 41 5205 1164 196
45-54 1779 118 6167 2034 214 1193 82 6945 1909 239 586 36 4581 1280-254
55-64 922 53 4989 2221 366 697 45 5410 2285 433 224 8 3679* 1327-395
65-74 154 18 4136? 2060 496 130 16 42497 2187 571 24 2 3535? 964671
NOTE: N = weighted population estimate, in th ds; n = of people in ple; SD = standard deviation; SE = standard error.
* Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES }).
esl
TABLE H.—Forced vital capacity for white adults, by smoking status, sex, and age, United States,
1971-1975
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean SD SE N n Mean sD SE N n Mean SD SE
Never smokers
25-74 3978' 29! 4708! 52! 3320! 24!
25-34 6733 394 4403 1052 67 2633 130 5480 759 89 4099 264 3712 464 32
35-44 5278 291 3972 814 65 1669 81 4761 759 98 3609 210 3607 530 54
45-54 4942 353 3624 782 45 1206 85 4506 795 92 3736 268 3340 522 39
55-54 3660 251 3252 820 47 880 59 4265 758 123 2780 192 2932 526 38
65-74 2875 235 2815 719 48 481 43 3867 774 127 2394 192 2603 482 43
Ex-emokers
25-74 3996 30 4703 46 3357 32
25-34 2811 150 4522 1043 101 1359 66 5335 816 118 1452 94 3760 §33 68
35-44 3086 171 4500 972 91 1828 94 5096 153 86 1258 77 3633 450 49
45-54 3323 213 4143 915 78 2345 143 4499 796 76 978 70 3291 543 79
55-64 2669 181 3862 898 94 1826 130 4239 786 95 843 61 3044 489 79
65-74 1769 157 3335 864 86 1270 121 3594 821 92 499 36 2675 568 99
Smokers
25-74 3790 26 4405 38 3236 35
25-34 8885 487 4464 977 55 4792 239 5111 784 59 4093 248 3707 539 50
35-44 5849 320 4146 851 59 3027 158 4665 750 81 2822 162 3588 546 55
45-54 5606 374 3731 814 49 2743 182 4284 678 65 2863 192 3202 §32 45
55-64 3251 192 3315 845 66 1700 108 3866 730 71 1551 84 2712 467 59
65-74 933 84 2985 870 118 534 56 3325 747 117 400 2 2533 815 85
PST
TABLE H.—Continued
Both sexes Men Women
Cigarette smoking
status (by age) N n Mean SD SE N D Mean SD SE N n Mean SD SE
Light smokers
25-74 3824 54 4358 81 3342 64
25-34 2162 113 4260 857 116 879 43 4892 641 118 1283 70 3828 705 118
35-44 1267 72 3986 875 135 308 17 49227 768 235 959 55 3686 671 119
45-54 1090 76 3521 680 103 383 24 4022 555 155 707 52 3249 580 107
55-64 1043 57 3135 704 108 313 18 3866? 636 141 730 39 2822 457 87
65-74 304 21 3042 917 237 131 11 3470? 555 159 172 10 2717? 1001 347
Moderate smokers
25-74 3789 30 4454 50 3190 38
25-34 4269 235 4584 1020 74 2534 23 5217 793 80 1735 112 3660 447 55
35-44 2413 130 4145 846 90 1214 66 4671 812 125 1199 64 3612 457 66
45-54 2715 179 3658 852 73 1145 75 4357 737 111 1570 104 3147 521 57
55-64 1287 82 3312 854 99 690 45 3881 696 89 597 37 2654 453 80
65-74 464 44 2928 820 149 261 28 3327 734 172 203 16 2414? 614 173
Heavy smokers
25-74 3710 43 4364 61 3120 54
25-34 2417 136 4440 968 91 1363 72 5055 818 102 1054 64 3644 404 69
35-44 2148 116 4244 832 82 1505 75 4609 679 94 643 41 3392 440 3
45-54 1779 118 3971 758 81 1193 82 4304 638 84 586 36 3292 480 95
55-64 922 53 3524 928 151 697 45 3851 798 142 224 8 2508 ? 438 143
65-74 154 18 3036? 938 240 130 16 3189? 925 252 24 2 2223? 472 328
NOTE: N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviation; SE = standard error.
‘ Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistica. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
SCT
TABLE I.—Recurring persistent cough attacks for adults, by sex, age,
States, 1971-1975
and smoking status, United
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
25-34
P 3.2 44 6.7 76 5.7 V7 4.4 6.0 84 5.7 TA 15.2
SE 1.85 2.23 1.57 4.01 1.98 2.79 1.21 2.48 1.63 1.92 2.27 4.93
n 168 78 327 72 160 94 399 121 367 119 164 81
N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393
35-44
P 49 8.0 13.8 9.0 5.9 22.1 5.4 5.0 89 2.3 8.0 25.8
SE 2.59 3.47 3.17 6.39 2.69 6.40 1.60 2.46 1.89 1.21 2.85 7.37
n 101 117 226 33 93 100 310 107 270 103 114 51
N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799
45-54
Py 43 9.2 10.3 6.4 12.0 10.6 49 3.0 11.5 78 99 218
SE 1.61 2.28 2.07 2.73 3.65 3.53 1.55 1.97 2.16 2.61 2.99 4.04
n 114 204 296 61 122 112 435 101 329 109 163 57
N 1568 3290 4282 810 1705 1745 5989 1458 4800 1497 2413 890
55-64
P 11 146 20.5 2.4 14.4 25.9 6.8 9.9 15.7 6.4 14.8 50.1
SE 1.06 3.21 3.27 8.88 4.33 5.87 1.65 3.35 3.46 3.17 3.93 1568
a 94 192 205 50 91 64 394 86 178 76 82 20
N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378
TABLE I.—Continued
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
65-74
P 15 175 23.7 3.6 34.4 25.4 8.7 5.4 23.1 17.2 24.8 59.9?
SE 3.16 3.44 4.55 2.31 6.90 10.1 1.52 2.85 4.93 6.05 8.02 22.37
n 98 232 135 39 60 35 461 61 83 46 32 5
N 864 2232 1199 318 574 295 5487 958 952 523 362 66
25-74
P? 3.9 96 13.4 10.2 12.0 16.7 5.7 5.8 12.4 V1 11.6 31.1
SE! 0.92 151 1.30 2.22 1.66 2.31 0.66 1.25 1.19 1.32 1.84 5.63
NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands.
‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
TABLE J.—Three-week periods of increased cough or phlegm for adults, by sex, age, and smoking
status, United States, 1971-1975
Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
25-34
P 69 2.9 72 69 79 6.5 42 5.6 10.7 5.4 ill 18.0
SE 2.39 1.67 1.83 4.04 2.63 2.33 1.07 2.39 1.91 2.05 2.97 5.18
n 168 78 327 72 160 94 399 121 367 119 164 81
N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393
35-44
P 6.0 3.3 5.2 12 3.9 76 3.8 19 B.1 5.1 10.9 8.3
SE 2.43 1.98 1.68 1.20 2.08 2.86 1.54 1.37 2.01 1.89 3.67 4.20
n 101 117 226 33 93 100 310 107 270 103 114 51
N 2114 2384 4412 614 1769 2229 5197 1771 4563 1776 1968 799
45-54
P 17 3.9 6.3 0.3 5.5 98 3.5 6.1 10.8 84 8.4 216
SE 1.24 1.82 1.72 0.32 2.10 3.66 1.00 2.39 2.14 2.93 2.72 6.49
n 114 204 296 61 122 112 435 101 329 109 163 57
N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890
55-64
P 12 2.9 114 6.8 10.2 16.2 6.6 13.7 14.7 7.0 13.1 46.2
SE 0.91 1.33 2.61 4.00 4.07 5.39 1.63 4.88 3.57 3.44 3.96 16.61
n 94 192 205 50 91 64 394 86 178 16 82 20
N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378
TABLE J.—Continued
Men
Smoking status
Women
Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
65-74
P 75 45 12.0 3.3 14.2 175 5.1 9.1 115 2.6 26.4 0.07
SE 3.10 1.38 4.11 2.55 6.01 10.31 1.25 3.47 4.24 2.55 9.80 0.0
n 98 232 135 39 60 35 461 81 83 46 32 5
N 864 2232 1199 318 574 295 5487 958 952 523 362 66
25-74
P! 46 3.4 79 3.8 76 10.5 45 69 11.0 5.9 12.9 19.5
SE! 1.04 0.93 1.02 1.43 1.31 2.04 0.63 1.34 1.26 1.18 1.84 3.86
NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands.
1 Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
? Does not meet standards of reliability.
SOURCE: National! Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
6ST
TABLE K.—Shortness of breath for adults, by sex, age, and smoking status, United States, 1971-1975
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
25-34
P 5.6 15.2 23.3 10.0 23.1 33.6 14.4 17.9 31.0 30.9 20.1 515
SE 1.99 4.97 3.20 3.81 4.01 7.21 1.92 494 3.17 5.65 3.56 7.48
n 168 78 327 72 160 94 399 121 367 119 164 81
N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393
35-44
P 17.1 19.9 22.9 15.6 15.9 31.2 22.5 26.5 39.0 36.4 45.3 30.3
SE 4.62 4.89 3.26 7.08 4.71 5.46 2.42 5.32 4.62 5.48 7.07 7.08
n 101 117 226 33 93 100 310 107 270 103 114 51
N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799
45-54
P 19.3 27.2 35.5 25.4 34.9 413 28.1 32.5 42.5 30.3 48.1 47.9
SE 4.07 3.58 2.99 6.35 4.64 5.40 2.85 6.05 3.93 5.01 4.95 7.57
n 114 204 296 61 122 2 435 101 329 109 163 57
N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890
55-64
P 25.6 31.3 42.2 37.7 42.4 45.2 38.0 56.8 39.0 29.8 43.1 54.6
SE 5.79 3.94 4.37 9.57 6.14 6.39 2.94 6.24 4.60 6.85 6.06 16.51
n 94 192 205 50 91 64 394 86 178 76 82 20
N 1320 2791 2990 708 1305 9761 5599 1501 3014 1268 1369 378
i
>
Q
TABLE K.—Continued
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
65-74
P 27.0 45.8 41.7 26.7 42.4 54.4 416 32.3 43.2 48.6 40.0 17.4?
SE 5.46 4.05 4.59 787 6.86 9.12 2.92 5.63 6.70 9.64 10.85 16.12
n 98 232 135 39 60 35 461 81 83 46 32 5
N 864 2232 1199 318 574 295 5487 958 952 523 362 66
25-74
P! 17.1 25.2 31.4 21.5 29.9 39.2 270 31.8 38.2 34.1 38.2 42.4
SE! 1.89 2.38 1.75 2.84 2.31 2.74 1.27 2.82 2.08 2.59 2.88 5.07
NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands.
‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Doss not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
19T
TABLE L.—Wheezy chest sounds of adults, by sex, age, and smoking status,
United States, 1971-1975
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
25-34
P 2.7 13.0 15.0 11.5 12.6 22.0 7.6 11.6 17.5 12.9 14.8 29.5
SE 1.17 4,67 2.42 4.43 2.72 6.14 1.46 3.54 2.33 3.13 2.94 6.13
n 168 78 327 72 160 94 399 121 367 119 164 81
N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393
35-44
P 14.0 51 18.4 13.6 12.3 25.2 19 VT 16.4 99 219 179
SE 4.72 2.12 3.28 6.14 4.03 5.61 1.83 2.98 2.56 3.77 4.53 4.89
n 101 117 226 33 93 100 310 107 270 103 114 51
N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799
45-54
P 43 12.3 18.8 10.2 23.2 18.7 8.5 5.3 22.7 12.9 24.1 35.7
SE 1.97 2.60 2.60 3.99 4.05 4.13 1.39 1.82 2.98 3.59 4.37 6.24
n 114 204 296 61 122 112 435 101 329 109 163 57
N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890
55-64
P 12.0 13.6 25.9 29.9 26.6 22.1 12.7 22.0 27.3 19.5 31.0 40.0
SE 4.24 2.50 4.46 9.22 5.87 6.10 2.09 5.93 3.64 4.98 5.21 14.00
n 94 192 205 50 91 64 394 86 178 76 82 20
N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378
bt
TABLE L.—Continued
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
65-74
P 5.0 20.7 33.1 34.7 31.6 35.6 15.1 215 28.6 34.6 18.1 39.0?
SE 2.04 3.00 5.25 10.10 747 9.91 2.16 4.78 5.60 8.99 6.69 21.96
n 98 232 135 39 60 35 461 81 83 46 32 5
N 864 2232 1199 318 574 295 5487 958 952 523 362 66
25-74
P! 74 12.1 20.6 176 19.6 23.5 98 12.6 21.7 16.4 21.7 31.6
SE’ 1.33 1.83 1.42 2.68 1.98 2.69 0.82 1.68 1.49 2.01 1.88 4.80
NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands.
‘ Adjusted by direct method to reflect the age distribution of the U.S.
"Does not meet standards of reliability. population at the midpoint of the survey.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
egt
TABLE M.—Diminished or absent breath sounds of adults, by sex, age, and smoking status, United
States, 1971-1975
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
25-34
P 18 0.0 0.3 04 0.0 0.7 0.1 0.0 0.6 0.3 0.0 2.2
SE 1.76 0.0 0.21 0.36 0.0 0.71 0.07 0.0 0.51 0.31 0.0 2.21
n 168 78 327 72 160 94 399 121 367 119 164 81
N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393
35-44
P 0.6 0.5 0.6 0.0 0.7 0.6 0.3 0.2 2.3 0.4 3.4 3.5
SE 0.61 0.47 0.55 0.0 0.73 0.57 0.26 0.22 1.58 0.44 3.33 3.39
n 101 17 226 33 93 100 310 107 270 103 1l4 51
N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799
45-54
P 0.7 10 5.9 0.4 9.8 47 0.8 2.4 14 10 1.6 15
SE 0.55 0.53 al 0.41 3.33 2.64 0.64 1.87 0.56 0.36 0.82 1.24
n 114 204 296 61 122 112 435 101 329 109 163 57
N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890
55-64
P 25 5.7 12.4 8.4 13.0 14.4 0.8 41 3.36 2.7 3.9 35
SE 2.12 1.66 3.15 4.75 4.57 4.99 0.53 2.51 1.44 1.82 2.40 3.55
n 94 192 205 50 91 64 394 86 178 76 82 20
N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378
TABLE M.—Continued
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
65-74
P 88 97 179 13.9 25.2 88 24 45 2.7 3.3 2.3 0.0?
SE 3.53 2.57 3.76 8.10 5.86 45 0.81 2.63 1.58 2.34 2.27 0.0
n 98 232 135 39 60 35 461 81 83 46 32 5
N 864 2232 1199 318 574 295 5487 958 952 523 362 66
25-74
Pp! 2.2 2.44 58 3.3 15 5.0 0.7 19 19 1.32 21 23
SE' 0.72 0.46 0.95 1.33 1.47 1.06 0.20 0.71 0.46 0.49 0.88 1.16
NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands.
‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
* Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
got
TABLE N.—Wheeze of adults, by sex, age, and smoking status, United States, 1971-1975
Men Women
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
25-34
P 0.0 12 17 11 16 2.2 0.4 0.0 0.7 0.0 13 0.0
SE 0.0 124 0.77 1.06 1.25 1.28 0.29 0.0 0.37 0.0 0.79 0.0
n 168 78 327 72 160 94 399 121 367 119 164 81
N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393
35-44
P 0.0 1.0 13 0.0 0.9 2.1 0.3 0.0 3.2 0.0 3.6 96
SE 0.0 0.75 0.67 0.0 0.89 1.22 0.26 0.0 1.28 0.0 1.50 4.97
a 101 117 226 33 93 100 310 107 270 103 114 51
N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799
45-54
P 0.0 1.2 25 0.0 45 18 0.3 0.0 24 08 3.3 2.5
SE 0.0 1.02 0.93 0.0 2.13 1.27 0.33 0.0 0.94 0.78 1.40 1.76
n 114 204 296 61 122 112 435 101 329 109 163 57
N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890
55-64
P 0.0 0.4 5.6 23 3.3 10.9 0.1 0.0 1.7 08 14 58
SE 0.0 0.37 1.76 1.95 1.69 4.48 0.05 0.0 0.95 0.77 1.18 5.78
n 94 192 205 50 91 64 394 86 178 76 82 20
N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378
i
TABLE N.—Continued
Men
Smoking status Smoking status
Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy
65-74
P 2.6 10.0 0.0 114 18.4 1.0 19 3.6 2.7 16 20.9?
SE 0.0 lll 3.75 0.0 5.27 10.98 0.56 1.85 2.14 2.66 1.64 18.53
n 98 232 135 39 60 35 46] 81 83 46 32 5
N 864 2232 1199 318 574 295 5487 958 952 523 362 66
25-74
Pp! 0.0 1.2 3.4 0.7 3.5 55 0.4 0.2 2.1 0.7 2.3 6.3
SE 0.0 0.46 0.71 0.46 0.92 1.65 0.14 0.25 0.45 0.41 0.48 2.79
NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands.
‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey.
? Does not meet standards of reliability.
SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1).
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183
CHAPTER 3. MORTALITY FROM
CHRONIC
OBSTRUCTIVE LUNG
DISEASE DUE TO
CIGARETTE SMOKING
185
CONTENTS
Introduction
COLD Mortality Patterns in the United States
Prospective Studies
The British Doctors Study
The American Cancer Society 25-State Study
The U.S. Veterans Study
The Canadian Veterans Study
The American Cancer Society 9-State Study
California Men in Various Occupations
The Swedish Study
The Japanese Study of 29 Health Districts
Cigarette Smoking and Overall COLD Mortality
Retrospective Studies
Male and Female Differences in COLD Mortality
Amount Smoked and Mortality From COLD
Inhalational Practice and Mortality From COLD
Age of Initiation and COLD Mortality
Smoking Cessation and COLD Mortality
Pipe and Cigar Smoking Mortality From COLD
International Comparison of COLD Death Rates a
Smoking Habits: The Emigrant Studies
COLD Mortality Among Populations With Low S
Rates
Summary and Conclusions
References
Introduction
The chronic obstructive lung diseases (COLD) that are causally
related to cigarette smoking are chronic bronchitis, emphysema, and
chronic obstructive pulmonary disease and allied conditions without
mention of asthma, bronchitis, or emphysema. The last classification
was introduced by the National Center for Health Statistics in
response to the changes that occurred in the late 1960s in patterns of
reporting causes of death on death certificates. During this period,
physicians increasingly recorded deaths as due to “chronic obstruc-
tive lung disease” rather than the more specific categories of
“emphysema” or “chronic bronchitis” (NCHS 1982). Because of this
shift in patterns of reporting, and in recognition of the difficulty of
clinically separating these categories from one another as a cause of
death, the discussion in this chapter combines all of these categories
for analysis, where possible, which should result in a more complete
description of death rates from COLD.
COLD Mortality Patterns in the United States
The three chronic obstructive lung diseases related to smoking
may account for almost 62,000 deaths in 1983, compared with 56,920
deaths in 1982, according to provisional mortality data recently
published by the National Center for Health Statistics. This data is
based on a 10 percent sample of all death certificates for the 12-
month period ending in November (NCHS 1984). This is a dramatic
increase from 1970, when slightly over 33,000 deaths were attributed
to COLD.
Complete mortality data are available through 1980, and Table 1
presents the numbers of male and female deaths from COLD for
1970, 1975, and 1980. In addition to the relatively rapid rise in COLD
deaths during these years, there was also a shift in the male to
female ratio of these deaths. In 1970 male deaths outnumbered
female deaths by a ratio of 4.3 to 1. By 1980 this ratio had declined to
2.36.
The age-adjusted death rates for COLD during the years 1960
through 1980 are presented in Figure 1 for white men, white women,
and men and women of other races. As described in the previous
chapter, however, COLD is a slowly progressive disease, and death
from COLD usually occurs only after extensive damage has devel-
oped in the diseased lungs. Many individuals with COLD will die
with their disease rather than because of it, and even those who do
die of COLD are usually symptomatic for an extended period of time
prior to death.
Therefore, death rate data may not accurately reflect the true
prevalence or incidence of COLD in the U.S. population. In addition,
COLD is often not recorded as a cause of death in hospital records
189
TABLE 1.—Number of and ratio of male to female chronic
obstructive lung disease (COLD) deaths for
three time periods, United States
1970 1975 1980
Cause of death Men Women Men Women Men Women
Chronic bronchitis 4,282 1,564 3,260 1,452 2,380 1,348
Emphysema 18,901 3,820 14,849 3,946 10,133 3,744
COLD and
allied conditions 3,601 848 13,411 4,182 24,820 10,734
Total COLD deaths 26,784 6,227 31,520 9,580 37,333 15,826
M:F ratio 4.30 3.29 2.36
SOURCE: National Center for Health Statistics (1982, and unpublished mortality data).
30-
a5 wuire 3
S 20
o
oS
S OTHERS
a «1 5F
id
a.
ded
a
x 10
WHITE?
4
5b
OTHER
i i i J
1960 1965 1970 1975 1980
YEAR
FIGURE 1.—Age-adjusted COLD mortality rates for whites
and nonwhites in the United States, 1960-1980
SOURCE: National Center for Health Statistics (1982, and unpublished data).
(Moriyama et al. 1966) or on death certificates (Mitchell et al. 1968),
even though it may have played an important role in a person’s
death. In a recent prospective study, nearly half of the excess
mortality associated with significantly lowered FEV, was attributed
to other causes (Peto et al. 1983). Relatively advanced lung disease
(as judged by pathologic examination) may also exist without clinical
190
recognition because of the lung’s large ventilatory reserve (Mitchell
et al. 1968; Hepper et al. 1969). A joint committee of the American
College of Chest Physicians and the American Thoracic Society
(ACCP-ATS 1975) has developed standardized definitions of these
conditions that may improve the accuracy of mortality reporting in
the future.
As discussed in the chapter on morbidity in this Report, COLD in
an individual is usually a combination of mucus hypersecretion,
airway narrowing, and emphysema. The extent of damage represent-
ed by each of these three processes can vary substantially from
individual to individual, both in the absolute magnitude of the
damage and in the proportional contribution of each of these three
components. The majority of those with smoking-induced lung
damage do not have enough damage to result in clinically significant
disease, and only some of those with clinically significant disease
have damage to the lung that results in death from COLD. The
progressive loss of FEV, in smokers described in the preceding
chapter is one measure of the extent and progression of lung
damage, and individuals with a markedly reduced FEV, are far more
likely to die of COLD (Peto et al. 1983). These deaths commonly occur
secondary to the failure of these severely damaged lungs to carry out
the gas exchange required for survival.
Because death from COLD is the end result of lung damage
accumulated over many years, these deaths would be expected to
occur disproportionately in the older age groups; therefore, the
presentation of a single age-adjusted death rate might not reflect a
true picture of the changes in this disease with time. Figure 2
presents the age-specific death rates in 1977 for COLD in the
different sexes and racial groups. Death rates increase rapidly over
the age of 45, and this increase is particularly dramatic over the age
of 65. In addition, the bulk of the difference between white men and
men of other races, evident in Figure 2, occurs in those over age 65.
Indeed, the COLD death rates for nonwhite men are actually higher
than that for white men under age 55.
The examination of age-specific death rates over time also presents
a somewhat different picture from that presented by the age-
adjusted numbers in Figure 1. The age-adjusted rates for white men
in Figure 1 seem to have changed only slightly between 1968 and
1980. However, when the age-specific rates for the years 1968 and
1977 are examined (Figure 3), this apparent stability can be seen to
be a product of counterbalancing trends in those under and over 65
years of age. The death rates from COLD declined in white men
under age 65 between 1968 and 1977, but COLD death rates
increased in white men over age 65 during the same years; this
increase was particularly dramatic in those over age 75.
191
WHITES
400
oS
© 300
fom]
oS
a
a
ws 200+ OTHERS.
<<
Cc
roy WHITES
OTHER
25-34 35-44 46-54 55-64 65-74 75-84 85+
AGE
FIGURE 2.—Age-specific COLD mortality rates for whites
and nonwhites in the United States, 1977
SOURCE: National Center for Health Statistics (1982).
Figure 4 presents the age-specific COLD mortality rates for white
women in 1960, 1968, and 1977. As with the male rates, the female
COLD death rates rise rapidly with age, but they are substantially
lower than the male rates. In contrast with the male rates, however,
the white female death rates increased steadily with time from 1960
through 1977 both above and below age 65. In each of the age groups
over the age of 45, where significant numbers of COLD deaths would
be expected, there was a steady increase in rates from 1960 to 1968
and from 1968 to 1977. As is discussed later in this chapter, these
differences between men and women over time are consistent with
their differences in smoking behavior.
The effect of the normal aging process on the lung is small, rarely
limits maximal exercise, and never results in ventilatory failure.
Therefore, death from chronic obstructive lung disease is never a
natural part of the aging process; it is the result of an infectious or
other disease process or of the cumulative damage of environmental
respiratory toxins. The most important of these toxins in the United
States is cigarette smoke.
192
1977
400+
S
© 300+ 1968
So
So
oc
La
a
mw 200+
<
co
100} 1960
25-34 35-44 45-54 55-64 65-74 75-84 85+
AGE
FIGURE 3.—Age-specific COLD mortality rates for white
men in the United States, 1960, 1968, and 1977
SOURCE: National Center for Health Statistics (1982).
In spite of the large ventilatory reserve possessed by the lung,
death from COLD is a major cause of U.S. mortality. This mortality
is closely linked to cigarette smoking and has been examined
extensively. Figure 5 shows the differences in COLD death rates for
smokers and nonsmokers at different ages. From the rarity of COLD
death in nonsmokers and the magnitude of the increased risk
associated with smoking, it is clear that the overwhelming impor-
tance of cigarette smoking as a determinant of abnormal lung
function demonstrated in the previous chapter is matched by the
importance of cigarette smoking as a determinant of death from
COLD. Examination of the death rates from COLD in smokers and
nonsmokers suggests that from 85 to 90 percent of the COLD deaths
in the United States can be attributed to cigarette smoking.
Prospective Studies
The relationship between smoking and death from COLD has been
evaluated in a large number of prospective mortality studies. There
are eight major prospective studies of the disease consequences of
smoking. They involve large numbers of smokers and nonsmokers
193
1977
80+
7O-+ 1968
60}
50+
40+
1960
RATE PER 100,000
20+
10+
L L. 1. —4
25-34 35-44 45-54 55-64 65-74 75-84 86+
AGE
FIGURE 4.—Age-specific COLD mortality rates for white
women in the United States, 1960, 1968, and
1977
SOURCE: Nationa! Center for Health Statistics (1982)
and have examined the death rates from COLD in both groups.
These studies cumulatively represent more than 17 million person-
years of observation and over 330,000 deaths. The size of the
populations studied allows a detailed examination of the relationship
between smoking and death rates. The characteristics of the
populations studied are summarized in Table 2 and are briefly
reviewed here.
The British Doctors Study
The British doctors study (Doll and Hill 1954, 1956, 1964a, 1964b,
1966; Doll and Peto 1976, 1977; Doll and Pike 1972; Doll et al. 1980)
of 40,000 male and female physicians in Britain was the first
prospective study and is the longest running. Deaths from chronic
bronchitis and emphysema were combined. Deaths from cor pulmo-
nale (i.e., heart failure secondary to lung disease) were separately
analyzed by smoking category and probably include some deaths
from chronic bronchitis and emphysema.
194
450
Smoker
400
oo LY
S 300
so :
& |
~ |
o |
& |
2 200 1
=
i
100
Nonsmoker
o 4 + eS |
35-44 45-54 55-64 65-74 75-84
Age Group
FIGURE 5.—Death rate for bronchitis, emphysema, or both,
per 100,000 population, by age and smoking
status', U.S. veterans study, 16-year followup
‘Smoker is defined as al! people who smoke cigarettes and those who have ever smoked other tobacco products
SOURCE: Adapted from Rogot and Murray (1980)
The American Cancer Society 25-State Study
The American Cancer Society 25-State study (Hammond 1965,
1966; Hammond and Garfinkel 1969; Hammond et al. 1976; Lee and
Garfinkel 1981) represents the largest investigation. Deaths from
emphysema were separately analyzed by smoking habit; deaths from
cor pulmonale were also separately recorded.
The U.S. Veterans Study
The mortality experience of approximately 294,000 U.S. veterans
who held U.S. Government life insurance policies in December 1953
was examined in the U.S. veterans study (Dorn 1959; Kahn 1966;
Rogot 1974a, b; Rogot and Murray 1980). Deaths from COLD were
recorded as “bronchitis and/or emphysema”; “bronchitis, underlying
or contributory”; and “emphysema without bronchitis.”
The Canadian Veterans Study
Initiated in 1955 by the Canadian Department of National Health
and Welfare, the Canadian veterans study (Best 1966; Best et al.
1961) included 78,000 men and 14,000 women. Over the next 6 years
of followup, there were 9,491 male and 1,794 female deaths. The
cause of death in most of these cases was confirmed by autopsy.
195
96T
TABLE 2 .— Outline of eight major prospective
studies
Doll Weir Cedertof
: Dorn Best .
Authors mul Hammond Kahn Hirayama Jone Hammond Dunn Friberg
Peto t Walker Horn Linden Hrubec
Pike Breslow Lorich
Males and Total population . . Probability
California
British females US of Canadian White males in sample of
Subjects doctors n veterans = healt " various the
3 distnets in pensioners nine States occupations Swedish
States Japan Pe population
Population size 40,000 1,000,000 230,000 265,000 92,000 187,000 68,000 55,000
Females 6,000 562,671 300,000 1.93 > 300,000 10.93
California men Nonsmoker? 1.00 Emphysema
in various About '. pk 8.18
occupations About 1 pk 11.80
About 11, pk 20.86
American Cancer Nonsmoker 1.00 All pulmonary
Society 1-9 1.67 diseases other
9-State 10-20 3.00 than cancer?
20+ 3.64
‘Data for the Japanese study are for lifetime exposure by > total number of cigarettes consumed.
? Nonsmoker in the California occupations study also includes > smokers of pipes and cigars.
* Pneumonia, influenza, TB, asthma, bronchitis, lung abscess, etc.
202
Maile and Female Differences in COLD Mortality
Mortality data presented by the National Center for Health
Statistics indicate that in 1980 the number of deaths from COLD was
2.36 times higher among men than among women (9th ICDA nos.
490, 491, 492, and 494-496). In the prospective studies reviewed
above, it is also apparent that the relative risk for death from COLD
was greater for male smokers than for female smokers, although
both male and female smokers exhibited a greater risk than
nonsmokers for death from COLD. These differences are most likely
a consequence of differences in male and female smoking patterns.
The women in these studies tended to smoke fewer cigarettes, inhale
less deeply, and begin smoking later in life than the men. They more
frequently smoked filtered and low tar and nicotine cigarettes and
had less occupational exposure to pulmonary irritants than men.
These differences in mortality from COLD are narrowing because of
a more rapid rise in female mortality from COLD (see Table 1).
Figures 6 and 7 help to explain the male-female differences in
COLD mortality ratios in the prospective mortality studies and in
U.S. COLD death rates. The figures are descriptions of the preva-
lence of cigarette smoking in successive 10-year birth cohorts of men
and women as those cohorts progressed through the years 1900-1980
(Harris 1983). Examination of these figures revealed several impor-
tant findings. Relatively few women took up smoking prior to 1930.
The heaviest smoking cohorts of men have a prevalence of over 70
percent compared with 45 percent of women, and the male cohorts
with these peak prevalences are older than the female cohorts.
However, as discussed earlier, the incremental and progressive
nature of cigarette-induced lung injury results in both prevalence
and duration of cigarette smoking having an impact on COLD death
rates. Therefore, in examining Figures 6 and 7 it is important to
consider the span of years of a given prevalence of smoking
maintained by a given birth cohort as well as the peak prevalence
achieved by that cohort. The COLD death rates should then be
proportional to the area under the prevalence curve described by
each cohort, rather than to the peak of that curve.
A careful examination of Figure 6 reveals that the area under the
prevalence curve for the cohort born between 1921 and 1930 is less
than the area under the curve for the cohort born between 1911 and
1920, in spite of their similar peak prevalences. This difference is due
to the more rapid decline in prevalence with age in the 1921 to 1930
cohort. Similarly, the cohort born between 1901 and 1910 partially
compensates for a peak prevalence that is lower than the 1911 to
1920 cohort by having a somewhat a broader base. Each of the
cohorts born prior to 1900 have substantially smaller areas under
their curves than those born during the first three decades of this
century. These differences in prevalence are reflected in the changes
203
1910 1920 1930 1940 1950 1960 1970
T T T T T “tT T 8
Men
1921-30
1900 1910 1920 1930 1940 1950 1960 1970 1960
FIGURE 6.—Prevalence of cigarette smoking among
successive birth cohorts of men, 1900-1980,
derived from smoking histories in the National
Health Interview Survey (HIS)
SOURCE: Harris 1963.
in age-specific death rates portrayed in Figure 8 and Table 5. The
oldest age group (75-84) continues to show a rapid rise in COLD
death rates as those birth cohorts with increasing prevalence and
duration of smoking move into this age range. In the age range 65-74
the rates rose rapidly from 1960 through the mid 1970s, but seem to
be leveling off, consistent with the fact that this age group is now
made up entirely of men born after 1900. In the age range 55-64 the
rates suggest a slight downturn beginning in the mid 1970s,
coincident with the entry of the 1921 to 1930 birth cohort into this
age group. The numbers for the age range 45-54 are too small to
204
1910 1920 1930 1940 1950 1960 1970
T T T T T T T
1931-40
Women
1921-30
_ 44
o 1 1 0
1900 1910 1920 1930 1940 1950 1960 1970 1980
Year
FIGURE 7.—Prevalence of cigarette smoking among
successive birth cohorts of women, 1900-1980,
derived from smoking histories in the National
Health Interview Survey (HIS)
SOURCE: Harris 1983.
permit firm conclusions, but also suggest that a downturn in rates
occurred in this group in the late 1960s.
A close examination of Figures 6 and 7 also offers an explanation
of the differences in mortality ratios for men and women observed in
the prospective studies. COLD is a slow, progressive disease, and
death from COLD usually results only after extensive lung damage
has occurred. The fact that death from COLD is unusual prior to age
45 reflects, in part, the 30 or more years required for cigarette smoke
to damage enough lung to result in death. The substantial ventilato-
ry reserve of the lung allows a significant amount of damage to exist
in a person without symptomatic limitation or risk of death from
COLD. The prospective mortality studies were conducted in the
1950s and 1960s, a point in time approximately 30 years after the
beginning of the rise in smoking prevalence among women demon-
strated in Figure 7. Even the older cohorts, where significant
mortality might be expected, had begun smoking largely after 1930,
and therefore had a shorter duration of smoke exposure than the
men born in the same years. This shorter duration of the smoking
habit, together with the previously described tendency of women to
205
75-84
400+
Oo
S
2 300F
7
ao
a
E 200 b 65-74
Cc
100
ee 55-64
- = —— 45-54,
1960 1965 1970 1975
YEAR
FIGURE 8.—Age-specific COLD mortality rates for white
men in the United States, 1960-1977
NOTE: ICDA Nos. 490-492 and 519.3.
SOURCE: National Center for Health Statistics (1982).
smoke fewer cigarettes per day and to inhale less deeply, would be
expected to result in less cumulative lung damage at any given age.
This difference in extent of lung damage could explain the difference
in COLD mortality ratios between men and women observed in the
prospective mortality studies.
The British doctors study examined the risk of COLD death for
male and female physicians who smoked similar numbers of
cigarettes per day (Table 4), and the mortality ratios were similar for
similar numbers of cigarettes smoked per day.
In summary, data from the prospective studies indicate that the
relative risk of death from COLD is greater for male smokers than
for female smokers. These differences are most likely a consequence
of differences in female smoking patterns. Women tend to smoke
fewer cigarettes, inhale less deeply, and begin to smoke later in life
than men. These differences in mortality from COLD are narrowing
because of a more rapid rise in female mortality from COLD than in
male COLD mortality. This reflects the narrowing in differences
between male and female smoking patterns and the rising preva-
lence of female smokers in successive cohorts born between 1920 and
206
TABLE 5.—Age-specific COLD death rates per 100,000
population
Age
Year 45-54 55-65 65-74 75-84
1960 8.6 36.1 82.9 101.8
1961 7.6 38.7 87.9 1118
1962 9.6 44.2 107.2 136.7
1963 117 52.3 131.2 169.6
1964 12.1 51.8 131.6 181.9
1965 12.4 57.8 153.6 216.6
1966 12.4 61.9 161.9 244.8
1967 12.4 61.2 164.8 248.6
1968 13.1 7.4 186.7 286.5
1969 13.9 7.5 189.5 294.3
1970 13.6 68.1 196.5 311.5
1971 13.5 67.4 195.6 327.4
1972 13.0 67.7 204.8 351.4
1973 12.7 69.9 210.1 378.4
1974 12.8 64.8 204.8 380.4
1975 11.9 64.7 207.6 399.7
1976 12.2 64.0 210.7 419.7
1977 11.4 60.1 206.1 431.5
SOURCE: National Center for Health Statistics (1982).
1950. These data are ominous for women, portending a rising
mortality from COLD over the next decades.
Amount Smoked and Mortality From COLD
Six of the major prospective studies evaluated the influence of
different smoking levels on mortality from COLD. These studies
employed a variety of measures of tobacco exposure, including
number of cigarettes smoked per day, grams of tobacco smoked, and
total number of cigarettes smoked in a lifetime. The data, presented
in Table 4, show a gradient in risk for mortality from COLD as the
number of cigarettes smoked per day increases and as the cumula-
tive number of lifetime cigarettes smoked increases. In the U:S.
veterans study, smokers of two packs or more per day had 22 times
the risk of COLD death of nonsmokers. Furthermore, mortality
ratios between the two followup periods for bronchitis and emphyse-
ma actually increased overall and by the amount smoked (Figure 9).
The authors noted that this was the only major disease of those
associated with cigarette smoking that showed such an increase,
suggesting that mortality ratios have been increasing over time at
all levels of smoking. In the British and Japanese studies, women
smokers at the highest levels exhibited a 32- and an 11-fold higher
risk for death from COLD (respectively) than their nonsmoking
counterparts. The variability in COLD mortality ratios noted in
207
21.98
q
20 | 7 81/2 years
@ 16 years
17.45
Mortality ratio
Nonsmoker All cigarette 1-9 10-20 21-39 240
smokers
Cigarettes smoked per day
FIGURE 9.—Bronchitis and emphysema for male smokers
number of cigarettes smoked per day, US.
veterans study, 8’/,-year and 16-year followup
Table 3 is much less evident when the mortality ratios are presented.
by amount smoked.
In summary, the degree of tobacco exposure strongly affects the
risk for death from COLD in men and in women. This clearcut dose-—
response relationship enhances the strength of the causal relation-
ship between smoking and COLD.
Inhalational Practice and Mortality From COLD
The inhalation of tobacco smoke is the major mechanism whereby.
bronchial and alveolar tissues are exposed to the potentially
damaging effects of tobacco smoke. In the British doctors study,
subjects who acknowledged inhaling exhibited a 1.53-fold higher risk
for COLD death as compared with those who stated they did not.
inhale (see Table 6). However, all smokers, regardless of their.
inhalational practice, exhibited higher risk for COLD mortality than
did nonsmokers.
In the retrospective study from northeast England (Dean et al.
1977, 1978), the risk among men for mortality from chronic
bronchitis steadily declined with a decrease in the depth of inhala-
tion (Table 7). Among women, the risk for mortality from chronic
bronchitis was lower for all other groups than for those who stated
they “inhaled a lot.”
208
TABLE 6.—COLD mortality by inhalation practice, British
doctors study, men
Annualized death rate per Risk in inhalers
Number of 100,000 men responding compared with unity
Cause of death deaths to question: do you inhale? in noninhalers
Chronic bronchitis Yes No
and emphysema and 71 89 58 1.53
pulmonary heart disease
Table 7.—Relative risk for mortality by depth of
inhalation, 1963-1972, second retrospective
mortality study in northeast England
Relative risk for
chronic bronchitis
Depth of inhalation Men Women
A lot (base) 1.00 1.00
A fair amount 0.98 0.54
A little 0.62 0.41
None 0.58 0.58
SOURCE: Dean et al. (1977, 1978.
Results from prospective mortality studies comparing COLD death
rates by inhalation are identical to those observed in the morbidity
studies, which have consistently shown that COLD is more prevalent
among inhalers than noninhalers (Ferris et al. 1972; Comstock et al.
1970; Rimington 1974).
These data suggest that inhalational practice affects the risk of
mortality from COLD. People who inhale deeply experience a higher
risk for mortality from COLD than people who do not inhale.
Regardless of their inhalational practice, however, smokers still
experience higher rates of death from COLD than nonsmokers.
Age of Initiation and COLD Mortality
Another indicator of exposure to tobacco smoke that may influ-
ence risk for mortality from COLD is the age of initiation of smoking.
If their smoking habits are otherwise similar, people who take up
smoking at a younger age have a greater total exposure to tobacco
smoke than those who take up smoking later in life, and might be
expected to experience greater adverse consequences from smoking.
In the Japanese prospective study (Hirayama 1981), men who began
to smoke before the age of 19 exhibited slightly higher mortality
ratios for emphysema than did men who began to smoke after the
209
TABLE 8.—Number of deaths from chronic bronchitis,
emphysema, and pulmonary heart disease in ex-
cigarette smokers, by years of cessation, versus
number of deaths in lifelong nonsmokers,
British doctors study
Number of deaths in ex-smokers, divided by Number of deaths
number expected in lifelong smokers in nonsmokers
Years of
cessation 0* <6 5-9 10-14 >14
35.6 34.2 477 7.3 8.1 2
* Current smokers
age of 20. In the retrospective study from northeast England (Dean
et al. 1977, 1978), the relative risk for death from chronic bronchitis
among men who began to smoke after the age of 25 was 60 percent of
that of men who began to smoke between the ages of 15 and 19.
Among women in the same study who began to smoke between the
ages of 15 and 19, the relative risk for death from chronic bronchitis
was 1.28-fold higher than for women who began to smoke after age -
25; however, the number of deaths was small.
Smoking Cessation and COLD Mortality
The effects of smoking cessation on mortality from COLD were
examined in the British doctors study and the U.S. veterans study.
In the British doctors study, men who quit smoking experienced no
change in mortality from COLD in the first 4 years and a rise in the
next 5 years; presumably, this is related to the presence of many _
people in this group who quit smoking for health reasons (Table 8).
Thereafter, ex-smokers experienced lower death rates from COLD,
although their rates were still higher than those of the nonsmokers.
Female ex-smokers also experienced lower mortality rates than
current smokers, but the rates in ex-smokers were still higher than
those in nonsmokers.
In the U.S. veterans study, ex-smokers who had quit for reasons
other than ill health experienced lower mortality rates for COLD
than did current smokers. However, the benefit of cessation upon
risk for mortality was heavily dependent upon the prior level of
smoking and the length of time of cessation. These data are
presented in Table 9. Ex-smokers who had smoked less than 10
cigarettes per day had a 1.64-fold higher risk for mortality from
COLD than nonsmokers; in contrast, ex-smokers who smoked more
than 39 cigarettes per day had a 9.91-fold higher rate of death from
COLD than nonsmokers. For any given number of cigarettes smoked
210
TABLE 9.—Mortality ratios for bronchitis and emphysema
in nonsmokers and in ex-smokers and current
smokers by number of cigarettes smoked daily
and number of years of cessation, U.S. veterans
study
Cigarettes/day
Smoking status 0 <10 10-20 21-39 >39
Nonsmoker 1.00 — _ _ —
Ex-smoker _— 1.64 5.35 7.68 9.91
Current smoker _— 4.84 11.23 17.45 21.98
Years of cessation
Current
Nonsmoker smoker <5 5-9 10-14 15-20 >20
1.00 12.07 11.66 14.35 10.19 5.66 2.64
per day, however, ex-smokers had a lower risk than current smokers.
As in the British study, mortality ratios initially increased over the
first 9 years of cessation. After the first 9 years, mortality ratios for
ex-smokers fell, but never reached the level of the nonsmoker.
Two studies have evaluated mortality rates from COLD among
physicians, a group among whom many quit smoking to protect their
health. Fletcher and Horn (1970) assessed the mortality rates from
bronchitis among physicians in England and Wales. Among doctors
aged 35 to 64, there was a 24 percent reduction in bronchitis
mortality between 1953-1957 and 1961-1965, as compared with a
reduction of only 4 percent in the national bronchitis mortality rates
for men of the same age in England and Wales. Enstrom (1983)
assessed mortality trends from COLD in a cohort of 10,130 physi-
cians in California. The standardized mortality ratio for bronchitis,
emphysema, and asthma among male California physicians relative
to American white men declined from 62 during the period 1950 to
1959 to 35 during the period 1970 to 1979.
In summary, cessation of smoking leads to a decreased risk for
mortality from COLD as compared with that of current smokers. The
residual risk of death for the ex-smoker is determined by the
person’s prior smoking status and the number of years of cessation.
However, the residual risk remains larger than that of the nonsmok-
er, presumably because of the presence of irreversible lung damage
acquired during prior smoking.
Pipe and Cigar Smoking Mortality From COLD
Several of the prospective epidemiological studies examined the
relationship between pipe and cigar smoking and mortality from
COLD. The data from these studies indicate that pipe smokers and
211
TABLE 10.—COLD mortality ratios in male pipe and cigar
smokers, prospective studies
Type of smoking
Total
Non- Cigar Pipe pipe and Cigarette
Study Category smoker only only cigar only Mixed
American Cancer COLD total 1.00 1.29 177 2.85
Society 9-State Emphysema
Bronchitis
British doctors COLD total 1.00 9.33 24.67 11.33
Emphysema
Bronchitis 1.00 4.00 7.00 6.67
Canadian veterans COLD total
Emphysema 1.00 3.33 15 5.85
Bronchitis 1.00 3.57 2.11 11.42
American Cancer COLD total
Society 25-State Emphysema 1.00 1.37 6.55*
Bronchitis
US. veterans COLD total 1.00 .79 2.36 39 10.08
(8.5-year Emphysema 1.00 1.24 2.13 1.31 14.17
followup) Bronchitis 1.00 117 1.28 117 4.49
U.S. veterans COLD total 1.00 0.84? 1.443 4.75
(16-year Bronchitis,
followup) emphysema 1.00 2.53% 13.13*
' Mortality ratios for agea 55 to 64 only are presented.
* Pure cigar.
> Pure pipe.
* Pure cigarette.
cigar smokers also experience higher mortality from COLD as
compared with nonsmokers. However, the risk of dying from COLD
is less than that of current cigarette smokers (Table 10).
International Comparison of COLD Death Rates and Smoking
Habits: The Emigrant Studies
Reid (1971) reported that age-adjusted mortality rates from
chronic nonspecific lung disease among British citizens varied with
migration patterns. British men living in the United Kingdom had a
chronic, nonspecific lung disease death rate of 125 per 100,000,
whereas migrants to the United States experienced a mortality rate
of only 24 per 100,000, which is similar to the rate found in the US.
population. Differences in cigarette smoking and air pollution were
identified as the major factors contributing to the real excess in
bronchitis morbidity experienced by the British in the United:
Kingdom. Rogot (1978) conducted a study of British and Norwegian
emigrants to the United States. The mortality rate from chronic
nonspecific lung disease (CNSLD) in Great Britain is about fivefold
212
that in the United States, whereas the mortality rate from CNSLD
in Norway is slightly lower than that in the United States. In
contrast, the British migrant rates were about equal to those of
native-born Americans and the Norwegian migrant rates were the
lowest. Mortality rates for CNSLD were higher for smokers than for
nonsmokers in all groups. These data suggest that ethnic origin
plays a minor role, if any, in determining COLD risk. Regardless of
country of origin, these studies indicate that tobacco smokers
experience higher mortality rates for COLD than do nonsmokers.
COLD Mortality Among Populations With Low Smoking Rates
Numerous studies have reported that certain population groups
who traditionally abstain from cigarette smoking for religious or
other reasons have lower mortality rates from those diseases
traditionally related to tobacco use. The 1982 and 1983 Reports of
the Surgeon General, The Health Consequences of Smoking
(USDHHS 1982, 1983), extensively reviewed this phenomenon as it
relates to cancer and cardiovascular diseases among Mormons,
Seventh Day Adventists, and others. Because Amish are seen as
strict and fundamentalist in outlook, it is assumed that their use of
tobacco is severely restricted. While cigarettes are largely considered
taboo, pipe and cigar smoking and tobacco chewing are widespread
(Hostetler 1968). Hamman et al. (1981) examined the major causes of
death in Old Order Amish people in three settlements in Indiana,
Ohio, and Pennsylvania to determine if their lifestyle altered their
mortality risk compared with neighboring non-Amish. Mortality
ratios from all respiratory diseases were significantly lower by over
80 percent in Amish men 40 to 69 years old, and by 50 percent in
those 70 and older. In the chronic pulmonary disease categories
including emphysema, bronchitis, and asthma, only one Amish male
death occurred, whereas approximately 23 were expected. The
pattern of mortality *-om chronic respiratory diseases was similar
for Amish women.
Summary and Conclusions
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.
2. 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
213
214
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 eventually leads 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 overall 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.
. 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.
. 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.
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218
CHAPTER 4. PATHOLOGY OF LUNG
DISEASE RELATED TO
SMOKING
219
CONTENTS
Introduction
Lesions Associated With Chronic Airflow Obstruction
Central Airways
Mucus
Other Abnormalities of Central Airways
Peripheral (Small) Airways
General Review
Smoking and Lesions of Peripheral (Small)
Airways
Vascular Lesions Related to Smoking
Emphysema
Definition
Classification
Proxima] Acinar Emphysema
Panacinar (Panlobular) Emphysema
Distal (Paraseptal) Acinar Emphysema
Irregular Emphysema
Tobacco Smoking and Emphysema
Summary and Conclusions
References
221
Introduction
It is usual to think of chronic airflow obstruction as being caused
by airway narrowing or loss of airflow driving pressure—the elastic
recoil of the lung (Macklem 1971)—or both. Lesions of the airways
are often divided into those of the “large airways” and those of the
“small airways.” The reasons for this division are both historical and
conceptual. Hogg et al. (1968) showed that in patients with chronic
obstructive lung disease (COLD) the major site of airway obstruction
lay in airways that were peripheral to the wedged catheter that the
researchers used to partition airway resistance. The catheter was
wedged in airways 2 or 3 mm in diameter, and thus the airways
peripheral to the catheter included the smallest bronchi (airways
with cartilage in their walls) and bronchioles (conducting airways
without cartilage in their walls). Since both bronchi and bronchioles
were involved, Hogg and associates used the term “small airways” to
describe them, which has since become a popular term. Conceptual-
ly, lesions of airways may consist of an intraluminal component
(mucus) or a mural component. Most of the mucus in the airways is
thought to be secreted by the tracheobronchial submucosal glands
(Reid 1960); these are mainly confined to airways more than 2 or 3
mm in diameter, or large airways. Because of the documented
association between chronic productive cough and airflow obstruc-
tion (Fletcher et al. 1959), for a long time it was thought by many
that intraluminal mucus was a major source of chronic airflow
obstruction. Thus, the notion developed, without proper substantia-
tion, that central airways obstruction was due to intraluminal
mucus and peripheral airway obstruction was due to inflammation
and narrowing. It is also true that many have equated emphysema
with loss of elastic recoil, but when this has been examined in vivo
(Park et al. 1970; Boushy et al. 1970; Gelb et al. 1973; Berend et al.
1979; Pare et al. 1982) or in excised lungs (Berend et al. 1980; Silvers
et al. 1980), the association has not been close, with some notable
exceptions (Niewoehner et al. 1975; Greaves and Colebatch 1980).
Thurlbeck (1983) reviewed the evidence and argued that loss of recoil
in emphysematous lungs may not be due to the lesions of emphyse-
ma per se but to defects in apparently morphologically normal
intervening lung tissue.
The classical approach to considering the different sites of flow
obstruction is used in this chapter to analyze the relationship
between smoking and the morphologic lesions associated with
chronic airflow obstruction in humans. Lesions of the large airways
(bronchi) are discussed first, followed by small airways, and then by
alveolated structures. It has very recently become apparent that it is
important to include respiratory bronchiolitis as well as emphysema
in the last category (Wright et al., in press); this issue is discussed in
the paragraphs on peripheral (small) airways. Definitions and a brief
223
review of the diseases involved are provided. This chapter attempts
to present the morphologic changes associated with chronic obstruc-
tive lung disease. The detailed epidemiologic and experimental
evidence relating cigarette smoking and COLD are presented
elsewhere in this Report.
Lesions Associated With Chronic Airflow Obstruction
Central Airways
Mucus
It is convenient to discuss intraluminal mucus and increased
tracheobronchial mucus gland size together, because they are -
thought to be related (Reid 1960). Chronic bronchitis is defined as -
“the condition of subjects with chronic or recurrent excess mucus
secretion into the bronchial tree” (Ciba Foundation Guest Sympo- -
sium 1959). Because there is no way to accurately measure the
amount of mucus secreted into the bronchi, the empirical approach
was taken that production of any sputum was abnormal. Chronic
was defined as “occurring on most days for at least 3 months of the
year for at least 2 successive years” (Ciba Foundation Guest
Symposium 1959). A further qualification was that such sputum
production should not be on the basis of specific diseases such as
tuberculosis, bronchiectasis, or lung cancer.
The initial step was to correlate chronic bronchitis, as defined
above, with lesions in the central airways. This was first done by
Reid (1960), who assessed gland size by comparing the thickness of
the submucosal bronchial mucus glands in histologic sections to the”
thickness of the bronchial wall. The latter was defined as the-
distance from the basement membrane of the epithelium to the-
inner periochondrium. This measurement is now known as the Reid
Index. This increase has been confirmed by several observers
(Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Mitchell et al.
1966; MacKenzie et al. 1969; Scott 1973), but not by all (Bath and
Yates 1968; Karpick et al. 1970). An important observation was that
there was a distinct overlap in the value of the Reid Index between
bronchitics and nonbronchitics (Thurlbeck and Angus 1964) as
opposed to Reid’s 1960 finding that there were two completely
separate groups. In practical terms, this meant that the Reid Index
had limitations in predicting the presence or absence of chronic
bronchitis. More important, it suggested a broad border between’
health (nonbronchitis) and disease (bronchitis). For a variety of
technical reasons (Jamal et al., in press), the Reid Index is a difficult
measurement to use; thus, other measurements of mucus gland size"
were developed. The most popular was the volume density of mucus
glands, i.e., the ratio of area of mucus glands to area of the entire
bronchial wall as seen on histologic slides (Hale et al. 1968; Dunnill
224
et al. 1969; Takizawa and Thurlbeck 1971; Oberholzer et al. 1978).
Other methods included absolute gland size (Restrepo and Heard
1963; Bedrossian et al. 1971) and a radial intercept method (Alli
1975). The size of the acini (tubules) of mucus glands, the number per
unit area, and the ratio of mucus to serous tubules have also been
used (Reid 1960).
The Reid Index, the volume density of mucus glands, and the ratio
of mucus to serous acini have been examined in smokers and
nonsmokers; the results are shown in Table 1. When one considers
the overwhelming association between smoking and chronic bronchi-
tis in living subjects, differences in mucus gland size are insignifi-
cant. For example, three laboratories (Reid 1960; Thurlbeck et al.
1963; Thurlbeck and Angus 1964; Scott 1973) have found a difference
in Reid Index between smokers and nonsmokers; two have not (Bath
and Yates 1968; Hayes 1969). The results from volume density of
mucus glands are clearer—Ryder et al. (1971) found a higher volume
density of mucus glands in both male and female subjects. In
populations of mixed sex, Cosio et al. (1980) and Pratt et al. (1980)
found a higher volume density of glands, but Sobonya and Kleiner-
man (1972) and Scott (1973) did not. When observers have expressed
their morphologic findings as either “normal” or “abnormal” (using
different criteria), the smokers have been significantly abnormal in
all the studies (Field et al. 1966; Megahed et al. 1967; Petty et al.
1967; Vargha 1969). The balance of the evidence is that there is an
increase in mucus gland size in smokers. The discrepancy between
the clinical and the morphologic findings may reflect several factors:
the wide variation in mucus gland size in normal subjects, the
difficulties in measuring the Reid Index and volume density of
mucus glands, the different ways in which the cases have been
collected, and the errors inherent in assessing smoking histories-
from analysis of charts; also, the fact that mucus glands can enlarge
terminally (Helgason et al. 1970) might obscure true differences
between the two groups. In addition, submucosal gland enlargement
is a nonspecific change that can also occur in pneumoconiosis and
cystic fibrosis.
Mucus is also secreted by goblet cells, most of which are in the
major airways. Pratt et al. (1980) showed that goblet cells constituted
10.7 percent of the cells in the central airways of nonsmoking
nontextile workers and 20.4 percent in smoking nontextile workers.
Interestingly, they found an 18 percent frequency of goblet cells in
nonsmoking textile workers; the frequency was about the same in
smokers, whether or not they were textile workers.
Other Abnormalities of Central Airways
A variety of other changes have been described in the central
airways in patients with chronic airflow obstruction, including
225
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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250
CHAPTER 5. MECHANISMS BY
WHICH CIGARETTE
SMOKE ALTERS THE
STRUCTURE AND
FUNCTION OF THE
LUNG
251
CONTENTS
EFFECT OF CIGARETTE SMOKING ON
INFLAMMATORY AND IMMUNE
PROCESSES IN THE LUNG
Introduction
Effect of Smoking on Numbers and Types of
Inflammatory Cells
Effect of Smoking on the Morphology and Function of
Inflammatory Cells
Emphysema
Populations Deficient in Alpha,-antitrypsin
Alpha,-antitrypsin
Proteolytic Enzymes Inducing Emphysematous
Change
Papain
Pancreatic Elastase
Polymorphonuclear Leukocyte Elastase
Alveolar Macrophage Elastase
Protease-Antiprotease Hypothesis
Increased Elastase Owing io the Cellular
Response to Smoke
Number of Cells
Elastase Content
Release
Proximity
Milieu
Decreased Antiprotease Owing to Oxidation
Explanation for Upper Lobe Distribution
Animal Models of Emphysema
Spontaneous Emphysema
Experimentally Induced Emphysema
Oxides of Nitrogen
Cadmium Salts
Cigarette Smoke
253
The Effects of Smoking on Cellular and Immune Defense
Mechanisms
In Vitro Effects of Cigarette Smoke on Inflammatory
and Immune Effector Cells
The Effect of Cigarette Smoke on A
Production
ntibody
EFFECTS OF CIGARETTE SMOKE ON
AIRWAY MUCOCILIARY FUNCTION
Introduction
Normal Mucociliary Function
Cilia
Mucus
Mucociliary Interaction
Effects of Cigarette Smoke on Mucociliary Function
Short-Term Exposure
Cilia
Mucus
Mucociliary Interaction
Long-Term Exposure
Cilia
Mucus
Mucociliary Interaction
Fractionation and Filtering of
Effects of Filters
Cigarette Smoke
Mucociliary Function in Chronic Bronchitis
Cilia
Mucus
Mucociliary Interaction
Summary and Conclusions
References
254
EFFECT OF CIGARETTE SMOKING ON
INFLAMMATORY AND IMMUNE PROCESSES
IN THE LUNG
Cigarette smoke is a complex mixture of several thousand
different constituents that may produce physiologic and pathologic
changes. This discussion focuses on the cellular and immune
responses of the lung to cigarette smoke, the mechanism by which
smoking can cause emphysema, and the impact of smoking on
mucociliary clearance. The last 20 years have witnessed dramatical-
ly increased understanding of cigarette-induced lung injury, particu-
larly emphysema, thus enhancing our understanding of the process
by which cigarette smoking can lead to emphysema.
Introduction
Inhalation of cigarette smoke markedly alters the inflammatory
and immune processes in the lung, leading to increases in the total
number of inflammatory cells and to changes in cell type and
function. These effects of cigarette smoke on lung inflammatory cells
may play a role in decreased pulmonary host defenses against
various microorganisms and the development of lung cancer, chronic
bronchitis, and pulmonary emphysema (USPHS 1971, 1972, 1973,
1974, 1975; USDHHS 1981).
Effect of Smoking on Numbers and Types of Inflammatory
Cells
One of the most consistently observed effects of cigarette smoking
on the lung is a marked increase in the numbers of inflammatory
cells, especially at sites of disease. Increased numbers of inflammato-
ry cells have been seen in pathological studies of the lungs of
cigarette smokers, as well as in lungs of animals exposed to cigarette
smoke. In addition, increased numbers of inflammatory cells occur in
bronchoalveolar lavage fluid of cigarette smokers and in lavage fluid
of animals exposed to cigarette smoke.
Spain and Kaufman (1953) noted inflammatory changes in the
lung bronchi of cigarette smokers. Later, Anderson and Foraker
(1961) described the presence of an alveolitis, and McLean (1959)
described the presence of a bronchiolitis in these patients. In an
autopsy study of patients with early emphysema (McLaughlin and
Tueller 1971), numerous abnormal, brownish-pigmented alveolar
macrophages were found in adjacent, otherwise intact parenchyma,
but none were found in normal lungs. Identical pigmented macro-
phages were found in the sputum of patients obtained from
apparently healthy cigarette smokers. The frequency of occurrence
of these macrophages in the tissue appeared to be related to the
255
number of cigarettes consumed. Niewoehner et al. (1974) evaluated
the lungs of young smokers and controls of comparable age from a
population that had experienced sudden nonhospital deaths. In
smokers, a characteristic lesion occurred in the form of respiratory
bronchiolitis associated with clusters of pigmented alveolar macro-
phages. This lesion was present in the lungs of all smokers studied,
but was rarely seen in nonsmokers. Lungs of smokers also showed
small, but significant, increases in mural inflammatory cells and
denuded epithelium in the membranous bronchioles as compared
with controls. The researchers suggested that this respiratory
bronchiolitis may be a precursor of emphysema and may be
responsible for the subtle functional abnormalities that are observed
in young smokers. Mitchell et al. (1976) also noted the presence of
significant amounts of inflammation in the small airways of
cigarette smoker lungs, and Cosio et al. (1978) suggested that the
primary lesion in the small airways was a progressive inflammatory
reaction, leading to fibrosis with connective tissue deposition in the
airway walls. These lesions were closely correlated with abnormali-
ties in pulmonary function.
As noted above, most early investigators concentrated on the role
of the increased numbers of pigmented alveolar macrophages
present at disease sites in cigarette smokers. These pigmented
macrophages, because of their numbers and prominent coloration on
histologic sections, were initially the sole focus of research on the
inflammatory response in these patients. More recently, however,
Ludwig et al. (1983) evaluated the relationship between cigarette
smoking and the accumulation of neutrophils in the lungs of
smoking and nonsmoking humans. Human lungs were obtained from
autopsies of 10 cigarette smokers and 5 nonsmokers who experienced
nonhospital death. These studies indicated a marked increase in
neutrophil infiltration in the lungs of cigarette smokers compared
with nonsmokers, and identified the site of the accumulation as the
alveolar septa. Neutrophils were found in the alveolar walls of
smokers both with and without emphysema. The researchers con-
cluded that a marked neutrophil accumulation occurs in the lungs of
cigarette smokers, that it precedes the development of emphysema,
and that it continues once emphysema is established. They further
suggested that the neutrophils may play a role in the destruction of
the alveolar septa of the lungs in cigarette smokers. The presence of
increased numbers of neutrophils in cigarette smokers’ lungs has
also been documented by extracting inflammatory cells from open
lung biopsies of smokers and nonsmokers (Hunninghake and Crystal
1983). A higher percentage of these inflammatory cells were
neutrophils in smokers compared with nonsmokers. Finally, the
association between cigarette smoking and increased numbers of
inflammatory cells, including neutrophils, at disease sites has also
256
been confirmed in numerous animal studies (Frasca et al. 1971;
Dahlgren et al. 1972; Rylander 1974, Park et al. 1977).
Increased numbers of inflammatory cells in the lungs of smokers,
as compared with nonsmokers, have also been observed by all
investigators performing bronchoalveolar lavage studies (Davis et al.
1976; Demarest et al. 1979; Harris et al. 1970, 1975; Hunninghake et
al. 1979a, 1980a; Hunninghake and Crystal 1983; Hunninghake and
Gadek 1981-1982; Hunninghake and Moseley, in press; Reynolds et
al. 1977; Reynolds and Newball 1974, 1976; Rodriquez et al. 1977;
Warr et al. 1976, 1977; Warr and Martin 1974, 1978). Such increases
have been detected additionally in lavage fluid of animals chronical-
ly exposed to cigarette smoke (Davies et al. 1977; Flint et al. 1971;
Holt et al. 1973). The majority of these studies have demonstrated
increases in both the number of macrophages and the number of
neutrophils, although Hoidal and Niewoehner (1982) found increases
only in the former.
The presence of neutrophils in the lungs of cigarette smokers is of
interest because these cells contain elastase, an enzyme believed to
be important in the pathogenesis of emphysema (Lieberman 1976;
Karlinsky and Snider 1978; Kuhn and Senior 1978; Carp and Janoff
1978; Snider and Korthy 1978; Schuyler et al 1978; Janoff et al. 19717;
Hunninghake et al. 1979a; Hunninghake and Crystal 1983; Hun-
ninghake and Gadek 1981-1982, Hunninghake and Mosley 1984;
Laurell and Eriksson 1963). Alveolar macrophages have also been
implicated as a source of an elastase-like metalloprotease (Harris et
al. 1975; Rodriguez et al. 1977). This enzyme is not inhibited by
alpha,-antitrypsin (a, AT) (Banda and Werb 1981), the major anti-
elastase in the lower respiratory tract (Gadek et al. 1981). Although
macrophages are clearly present in large numbers in the alveolar
structures of smokers (Niewoehner et al. 1974; Harris et al. 1975),
several lines of evidence suggest that neutrophils may play a
significant and perhaps more important role in increasing the
elastase burden of the lungs.
First, neutrophils store and release significantly more elastase
than do alveolar macrophages (Barrett 1977; Rodriguez et al. 1977;
Levine et al. 1976). Comparative estimates of elastase production by
human neutrophils and alveolar macrophages suggest that neutro-
phils are at least 1,000 times more potent elastase producers (Janoff
et al. 1979).
Second, although alveolar macrophages of cigarette smokers have
been shown to release elastase in vitro (Rodriguez et al. 1977), it is
not clear whether the elastase was produced by these cells or was
secreted by other types of cells, such as neutrophils, and subsequent-
ly ingested by the macrophages (Janoff et al. 1977). In this regard,
recent studies by Campbell et al. (1979) and McGowan et al. (1983)
have shown that alveolar macrophages are capable of phagocytosing
257
neutrophil elastase via a receptor-mediated mechanism; some of the
elastase remains enzymatically active for up to 48 hours. These
findings suggest that alveolar macrophages may, in fact, be capable
of both decreasing and increasing the protease burden of the lung.
Third, once a neutrophil has left its vascular space, its lifespan is
only a few hours; when the neutrophil dies, it may release at least a
portion of its preformed enzymes, including elastase. Thus, when a
neutrophil is present within a tissue, it is possible that the tissue will
be exposed not only to the elastase secreted by the neutrophil while
it is functional, but also to the elastase stored by the neutrophil and
released when the neutrophil disintegrates. In this context, the
finding that neutrophils represent only a small percentage of all
inflammatory and immune effector cells in the smoker’s lungs would
not preclude the smoker’s exposure to a large chronic burden of
neutrophil elastase. In contrast, the alveolar macrophage has a half-
life of months to years (Thomas et al. 1976), and it stores little, if any,
elastase (Rodriguez et al. 1977; Levine et al. 1976).
Macrophages may also play an important role in this process by
secreting a potent chemotactic factor for neutrophils (Hunninghake
and Crystal 1983). This hypothesis is supported by the following
observation: alveolar macrophages of cigarette smokers spontaneous-
ly release a chemotactic factor for neutrophils, whereas alveolar
macrophages of nonsmokers do not. In addition, in vitro exposure to
cigarette smoke particulates results in the release of a chemotactic
factor from the alveolar macrophages of nonsmokers. The migration
of neutrophils to the lung in response to the chemotactic factor may
be augmented by factors in cigarette smoke. In this regard, McCusk-
er et al. (1983) have shown that nicotine is a potent chemokinetic
factor for neutrophils, enhancing the migration of these cells to
other chemotactic factors. Once neutrophils are present in the lung,
they may release elastase, because both cigarette smoke (Blue and
Janoff 1978) and the macrophage-derived chemotactic factor stimu-
late these cells to release the enzyme (Gadek et al. 1979a, b).
The postulated release of elastase by neutrophils could also partly
explain how the number of macrophages are increased in this
disorder. Fragments of elastin (which are probably generated by the
release of neutrophil elastase at sites of disease activity) are potent
chemoattractants for blood monocytes, the precursors of alveolar
macrophages (Senior et al. 1980; Hunninghake et al. 1981). These
fragments of elastin possess no chemotactic activity for neutrophils.
Effect of Smoking on the Morphology and Function of
Inflammatory Cells
No size differences have been observed between alveolar macro-
phages from smokers and those from nonsmokers when the cells are
258
fixed in suspension immediately after bronchoalveolar lavage (Table
1). Harris and coworkers (1970) observed a mean size of 23.3 ~m
(range, 10 to 47 pm) for nonsmokers and 26.4 pm (range, 12 to 53 pm)
for smokers. Reynolds and Newball (1974), using similar methods,
did not find any size differences between smoker and nonsmoker
alveolar macrophages.
The morphology of smoker macrophages clearly differs, however,
from that of nonsmokers (Table 1). Macrophages of smokers show
increased numbers of large lysosomes, phagolysosomes, endoplasmic
reticulum, ribosomes, and Golgi vesicles (Golde 1977; McLemore et
al. 1977; Martin 1973; Warr and Martin 1978; Rasp et al. 1978; Pratt
et al. 1971; Brody and Craighead 1975). These findings are generally
associated with activated mononuclear phagocytes, and these macro-
phages have probably become activated by the ingestion of the
particulates present in cigarette smoke. Smoker macrophages have
pigmented inclusions that appear to have platelike or needlelike
configurations when seen by electronmicroscopy (Golde 1977; Warr
and Martin 1978; Pratt et al. 1971; Brody and Craighead 1975).
Studies of the nature of these inclusions by X-ray analysis suggest
they may be, at least in part, particulates of aluminum silicate
(Brody and Craighead 1975). Together with in vitro studies showing
that alveolar macrophages are activated following phagocytosis of
particulates (Hunninghake et al. 1980a), these findings are compat-
ible with the notion that macrophages of smokers are activated in
vivo.
Alveolar macrophages from cigarette smokers have an increased
ability to generate superoxide anion (Hoidal et al. 1979a, 1980, 1981),
the functional effects of which include an increased capacity to kill
lung fibroblasts. These observations suggest that alveolar macro-
phages from cigarette smokers are increasingly able to injure lung
parenchymal cells, and that they may contribute to the observed loss
of lung cells in the alveoli of patients with pulmonary emphysema.
A variety of other effector functions of smokers’ alveolar macro-
phages have also been evaluated (Table 1). Alveolar macrophages
from cigarette smokers appear to have a normal or increased ability
to migrate in response to chemotactic factors (Demarest et al. 1979;
Warr and Martin 1974). They differ, however, from normal alveolar
macrophages in several other respects: for example, increased
glucose utilization has been reported in some studies (Harris et al.
1970), but was normal in others (Hoidal et al. 1979a). Oxygen
consumption has been reported to be normal (Hoidal et al. 1979a),
but the protein content of these cells has been increased (Harris et
al. 1975; Warr and Martin 1978). Alveolar macrophages from
smokers release less PGE, and thromboxane B, than normal
macrophages (Laviolette et al. 1981), suggesting that cigarette
smoking induces a lesion in phospholipid hydrolysis or the mecha-
259
TABLE 1.—Cigarette-smoking-
induced abnormalities in the
inflammatory and immune effector systems >
within human alveolar structures
Parameter
Findings in smokers
Cell types present
Total number of cells
Percent polymorphonuclear leukocytes
Percent T lymphocytes
Percent B lymphocytes
Lymphocyte function
Response to mitogens
Macrophage structure
Diameter
Ruffling of cell surface
Number and size of cytoplasmic structures
Abnormal cytoplasmic inclusions
Macrophage properties and function
Surface receptors
jgG-Fe
C3b
Phagocytosis and killing of microorganisms
Bacteria
Fungi
Effector and accessory cell function
responsiveness to chemotactic factors
Casein
Activated serum
Function as accessory cell to lymphocytes
Responsiveness to MIF
Production of neutrophil chemotactic factor
Secretion of superoxide anion
Secretion of elastase
Release of prostaglandin E, and
thromboxane B,
Miscellaneous properties and function
Glucose utilization
Oxygen consumption
Protein content
Content of various enzymes
Elastase
Acid protease
Neutral protease
Esterase
Acid phosphatase
B-glucuronidase
Lysozyme
Aryl hydrocarbon hydroxylase
Angiotensin-converting enzyme
Spreading and adherence properties
Pinocytosis
Content of a,-antiproteinase
Increased
Increased
Increased or normal
Normal
Decreased
Normal
Decreased
Increased
Pigmented inclusions,
particulates with plate or
needle-like configuration,
presence of aluminum silicate
Normal
Decreased
Normal or decreased
Normal
Increased
Normal
Decreased
Decreased
Increased
Increased
Increased
Decreased
Increased or normal
Normal
Increased
Increased
Increased
Normal
Increased
Increased
Increased
Normal or increased
Increased
Increased
Increased in presence of serum.
decreased nylon adherence
Decreased
Increased
SOURCE: Adapted from Hunninghake et al. ‘19791.
260
nism regulating hydrolysis. Smoker macrophages also appear to
have increased amounts of various enzymes, including acid protease
(Harris et al. 1975), neutral protease (Harris et al. 1975), esterase ~
(Harris et al. 1975), acid phosphatase (Martin 1973), angiotensin-
converting enzyme (Hinman et al. 1979), B-glucuronidase (Martin
1973), lysozyme (Martin 1973), and arylhydrocarbon hydrolase
(Cantrell et al. 1973; Harris et al. 1978; McLemore et al. 1977b, c,
1978; McLemore and Martin 1977). The functional significance of
increased amounts of these enzymes is not entirely clear.
In addition to its effects on the inflammatory and immune effector
cells in the lung, cigarette smoke may also affect the composition of
epithelial surface fluid. For example, some investigators have found
that the amount of immunoglobulin G (IgG) present in lavage fluid is
increased (Reynolds and Newball 1974); others have noted normal
levels (Warr et al. 1977). Interestingly, cigarette smoking appears to
cause a significant decrease in the secretory component of immuno-
globulin A (IgA) in the lavage fluid of some people who smoke
cigarettes (Merrill et al. 1980). This effect most likely indicates a
subtle injury to the epithelium of the lung that produces this factor.
The only additional factors that have been reported to be abnormal
in lavage fluid of cigarette smokers are an increase in the amounts of
fibronectin (Villiger et al. 1981) and a decrease in the function, but
not the amount, of a,AT (Gadek et al. 1979; Janoff et al. 1979). This
latter finding has been disputed by others (Stone et al. 1983).
Emphysema
A number of lines of evidence link the cellular changes described
above with the development of emphysema. They include observa-
tions in populations deficient in a, AT, in animal models of emphyse-
ma, and most important, in human cigarette smokers.
Populations Deficient in Alpha, -antitrypsin
Eriksson (1965) described the characteristic features of a,AT-
deficiency-associated lung disease. Approximately 60 percent of
affected individuals develop symptoms of airways obstruction by age
40, and 90 percent by age 50. Excluding the influence of cigarette
smoking, there is no sexual predominance of disease. Kueppers and
Black (1974) found that dyspnea occurred a decade earlier in
cigarette smokers (35 years in smokers versus 44 years in nonsmok-
ers), and estimated that 70 to 80 percent of all PiZZ persons (where
Pi= protease inhibitor) will develop lung disease. Larsson (1978) has
projected that nearly 60 percent of PiZZ people will ultimately die of
lung-related disease.
Orell and Mazodier (1972) reviewed the morphologic features of
a,AT-deficiency-associated emphysema and found primarily the
261
panacinar or panlobular form. Emphysematous lesions may be
distributed uniformly throughout the lungs (Orell and Mazodier
1972), but frequently show a predominant lower lobe distribution
(Greenberg et al 1973).
In people genetically deficient in a, AT, the increased numbers of
inflammatory cells found in the lungs of smokers probably present
an increased elastase burden to the lung and magnify the protease—
antiprotease imbalance. This may explain the deleterious effects of
cigarette smoke in this population. Kueppers and Black (1974)
reviewed data on the impact of cigarette smoking in people severely
deficient in a,AT and concluded that, in addition to experiencing
earlier onset of respiratory symptoms and pulmonary function
abnormalities, cigarette smokers die at an earlier age from respira-
tory failure than similiarly afflicted nonsmokers. The increased
prevalence of emphysema in populations deficient in a, AT, plus the
exacerbation of this lung disease by smoking, suggests that protease—
antiprotease imbalance may also play a role in the development of
emphysema by smokers who are not deficient in a,AT. This
suggestion has resulted in a substantial body of research that has
characterized a, AT, defined the nature of elastase-induced emphyse-
ma, and clarified and supported the protease-antiprotease hypothe-
sis of cigarette-induced emphysematous lung injury.
Alpha,-antitrypsin
The deficient constituent of o,-globulin was initially described by
Schultze et al. (1955) as a,-3,5-glycoprotein but later renamed o-
antitrypsin (a,AT) when it was found to inhibit trypsin activity
(Schultze et al. 1962). Subsequently, a, AT has been shown to inhibit
a variety of proteolytic enzymes including neutrophil elastase
(Ohlsson 1971), neutrophil collagenase (Tokoro et al. 1972; Ohlsson
1971), cathepsin-G (Travis et al. 1978), chymotrypsin (Travis et al.
1978; Rimon et al. 1966), plasmin (Rimon et al. 1966), thrombin
(Rimon et al. 1966), Hageman factor cofactor (Crawford and Ogston
1974), coagulation factor XI (Heck and Kaplan 1974), acrosin and
kallikrein (Fritz et al. 1972a, b), urokinase (Crawford and Ogston
1974; Clemmensen and Christensen 1976), and renin (Scharpe et al.
1976). Although the range of proteases inhibited by a,AT appears
broad, the association rate constants of these enzymes for a,AT
differ (leukocyte elastase > chymotrypsin > cathepsin-G > trypsin
> plasmin > thrombin) (Beatty et al. 1980), and the inhibitory role
of a, AT against enzymes with low association rate constants, such as
trypsin, may be negligible. The names a,-protease inhibitor or o1-
proteinase inhibitor better describe this broader range of inhibitory
functions and are preferred by some authors. In deference to
historical usage and in accord with the recommendations of the
262
Nomenclature Meeting for this substance (Cox et al. 1983), the name
a, AT has been retained in this discussion.
The inhibitor a, AT is a polymorphic plasma protein (Fagerhol and
Cox 1981; Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981;
Fagerhol and Braend 1965) encoded by two codominant autosomal
alleles and inherited as a single Mendelian trait. The basal serum
concentration is genetically determined (Eriksson 1964; Kueppers et
al. 1964; Fagerhol and Gedde-Dahl 1969; Talamo et al. 1966). More
than 31 allelic variants or Pi types (where Pi, or protease inhibitor, is
the symbol assigned the genetic locus of the a,AT allele) have been
identified (Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981). The
variants are designated by capital letters, B through Z, correspond-
ing to their approximate electrophoretic mobility, relative to the
anode, in acid starch gel electrophoresis or their relative positions on
polyacrylamide isoelectric focusing. New variants are named accord-
ing to the conventions established by the Fifth International
Workshop on Gene Mapping and the Nomenclature Meeting for
a,AT (Cox et al. 1980).
The M allele (PiM) has a gene frequency of about 0.9 and is the
most common Pi type in all populations tested (Kueppers 1978). The
a,AT serum concentration in PiMM homozygotes is between 1.3 and
2.2 g/liter (depending on the method of measurement and the purity
of standard) (Kueppers 1968; Jeppsson et al. 1978a) and, by conven-
tion, defines normal. Pi types with decreased circulating levels of
a,AT include (serum concentration expressed as percent normal)
null 0% (Feldman et al. 1975; Talamo et al. 1973), Mmalton and
Mduarte 12% (Cox 1976; Lieberman et al. 1976), Z 15% (Laurell and
Eriksson 1963; Fagerhol and Laurell 1970), P 30% (Fagerhol and
Hauge 1969), S 60% (Fagerhol 1969), and I 68% (Arnaud et al. 1978).
PiZ was the first variant recognized (Laurell and Eriksson 1963)
and is the Pi type most frequently associated with a serum deficiency
of a,AT (Kueppers 1978). Its allele frequency varies markedly
between different ethnic and racial groups. In the United States, the
allele frequency is greater than 0.010 in whites but nearly zero in
blacks (Kueppers 1978). Approximately 1 in 2,000 whites is homozy-
gous for the Z gene (Laurell and Sveger 1975).
Although a decrease in hepatic synthesis is probably the major
mechanism for quantitatively significant reductions in serum a, AT,
the factors that modulate such synthesis are only partially under-
stood (Morse 1978). Impaired hepatic secretion, as evidenced by the
presence of intrahepatic cytoplasmic inclusions containing accumu-
lations of o,AT polypeptides (Blenkensopp and Haffenden 1977),
occurs in persons with the PiZ genotype. It is uncertain if these
intrahepatic inclusions exert a negative feedback inhibition on the
hepatocyte and thereby retard biosynthesis of a,AT. Intrahepatic
inclusions are not found with the S and null Pi types (Carrell et al.
263
1982), suggesting that decreased synthesis, independent of impaired
secretion, iS primarily responsible for the reduced serum levels of
a, AT. Catabolic studies of the PiM and PiZ proteins have identified
similar half-lives in the circulation, 6 to 7 days and 5 days,
respectively (Laurell et al. 1977; Jeppsson et al. 1978b). It is therefore
unlikely that accelerated peripheral catabolism contributes signifi-
cantly to serum deficiencies in a, AT.
In addition to quantitative deficiencies in serum a, AT, a reduction
in serum inhibitory capacity could also result from a loss in the
functional activity of o,AT. Most genetic variants, however, are
functionally equivalent to normal a, AT (PiMM) in their capacities to
inhibit both trypsin and elastin (Billingsley and Cox 1982).
The inhibitor a,AT is a low molecular weight (51,000 daltons)
(Mega et al. 1980; Carrell et al. 1981; Chan et al. 1976; Pannell et al.
1974; Jeppsson et al. 1978) protein comprised of a single polypeptide
chain containing 394 amino acid residues. Three carbohydrate side
chains are attached, each containing terminal sialic acid residues
(Mega et al. 1980; Carrell et al. 1981). The a, AT reacts stoichiometri-
cally with free protease in a ratio of 1:1; one mole of a, AT inhibits
one mole of protease and yields a stable complex (Cohen 1979). An in
vitro study (James and Cohen 1978) found, however, that complete
inhibition of elastase requires molar ratios of a,AT to elastase
greater than 22:1. This phenomenon may be explained by elastase
having two major sites of attack on a,AT. Attack against one site
leads toa conformational change in a,AT and inhibition of elastase,
whereas attack against the other site results in cleavage and
inactivation of a,AT. The a,AT-protease complexes that form during
protease inhibition are not reutilized by the body (Balldin et al.
1978), and the body supplies of a,AT are replenished via de novo
synthesis by the liver.
In addition to hepatic biosynthesis, a,AT is synthesized by at least
two other endogenous sources. Both human peripheral lymphocytes -
and rat alveolar macrophages have been shown to synthesize a,AT. -
Ikuta et al. (1982) demonstrated that concanavalin A-stimulated
monocytes interact with human peripheral lymphocytes, causing a
threefold increase in a, AT synthesis. White et al. (1981) cultured rat
alveolar macrophages and recovered newly synthesized radio-labeled
(35S)a,AT from the cell culture medium. Macrophages and lympho-
cytes, by virtue of their close physical proximity to the sites of
connective tissue injury, may play a significant role in defense
against proteolytic destruction. The physiologic significance of
extrahepatic synthesis of a, AT remains speculative, however.
While certain chemical and physiological aspects of a,AT are
clear, the exact biochemical mechanism by which it causes protease
inhibition is uncertain. It is generally agreed that the reactive center -
of a,AT is located on a single serine-methionine segment peptide -
264
bond on the carboxyl-terminal end (Carrell et al. 1982; Kurachi et al.
1981).
Proteolytic Enzymes Inducing Emphysematous Change
Proteolytic enzymes have been a major focus of investigation
following the demonstration by Gross et al. (1965) of papain’s ability
to induce emphysematous changes in rats.
Papain
Papain, a proteolytic enzyme with a broad range of substrate
specificities (Bergmann and Fruton 1941; Kimmel and Smith 1953),
reproducibly causes emphysema-like lesions in a variety of experi-
mental animals following aerosolization or intracheal instillation
(Gross et al. 1965; Palecek et al. 1967; Goldring et al. 1968; Caldwell
1971; Pushpakom et al. 1970; Marco et al. 1969). A number of studies
have helped to clarify the critical importance of elastolysis in
papain-induced emphysema.
Snider et al. (1974) tested amorphous and crystalline forms of
papain and found that the emphysema-inducing properties of these
preparations were directly proportional to their abilities to degrade
and solubilize elastin. Heat inactivation of papain destroyed its
emphysema-inducing capabilities. Similarly, intratracheal pretreat-
ment of hamsters with human «,AT, an inhibitor of papain
elastolytic activity, ameliorates papain-induced emphysematous
changes (Martorana and Share 1976). Furthermore, Blackwood et al.
(1973) showed that the elastolytic activities of several microbial
enzymes, rather than their nonspecific protease activities, correlate
best with the enzyme’s ability to induce emphysematous changes
following intravenous administration to rats. Snider et al. (1977)
showed that enzymes lacking elastolytic activity, such as collagenase
or trypsin, do not produce emphysema in hamsters.
Whereas these studies support the notion that the early histologic
changes induced by papain are a direct consequence of its elastolytic
activity, they do not preclude the possibility that endogenous factors
‘may contribute to subsequent disease progression. Snider and
Sherter (1977) noted a gradual increase in static lung volumes in
hamsters following a single intratracheal injection of pancreatic
elastase. Stone et al. (1979) followed the fate of tritium-labeled
pancreatic elastase and found that enzymatically active prepara-
tions are retained longer within the lung than inactive preparations,
and that 4C-guanidated elastase remains bound to lung matrix for at
least 96 hours. This suggests that tissue-bound elastase may continue
to digest elastin for extended periods of time. Martorana et al. (1982)
found no progression in the mean linear intercept measurements or
internal surface areas in the lungs of papain-treated dogs between 3
265
480-144 0 - 85 - 10
and 6 months after treatment. However, the mean pulmonary
arterial pressure and pulmonary arteriolar resistance did increase
during this interval.
Papain-treated animals exhibit the expected physiologic changes
of emphysema: increased RV, FRC, and TLC, decreased elastic recoil,
increased static lung compliance at middle and low lung volumes,
and reduced diffusing capacity (DLcoVA and DLco) (Caldwell 1971;
Pushpakom et al. 1970; Marco et al. 1969; Giles et al. 1970; Johanson
and Pierce 1973). Studies by Kobrle et al. (1982) have shown that
following papain administration the elastic fibers are disrupted and
that the elastin content of the lung initially decreases, but later
returns to normal after a period of accelerated synthesis. The newly
synthesized fibers are disordered; however (Kuhn and Senior 1978;
Kuhn and Starcher 1980).
Pancreatic Elastase
The ability of porcine pancreatic elastase to rapidly hydrolyze
insoluble elastin (Partridge and Davis 1955) and its commercial
availability in a highly purified crystalline form have led to its
extensive use as an experimental agent for inducing emphysema in
animals (Karlinsky and Snider 1978). Lesions resembling human
panacinar emphysema can be induced in hamsters within 2 hours of
intratracheal instillation of pancreatic elastase (Kaplan et al. 1973).
The severity of the lesions, as assessed by histologic or physiologic
criteria, is dose related (Raub et al. 1982), with adult animals being
more susceptible to pancreatic elastase than young animals (Lucey
and Clark 1982). Within a few hours of intratracheal instillation in
hamsters, hemorrhagic lesions develop and an influx of polymorpho-
nuclear leukocytes is seen (Hayes et al. 1975; Kuhn and Tavassoli
1976). Digestion of elastin fibers is apparent in the pleura and in the
alveolar walls by 4 hours, but is more extensive at 24 and 48 hours -
(Kuhn et al. 1976). By day 4, there is a diminution in the number of
polymorphonuclear leukocytes (PMNs), but many macrophages
remain (Morris et al. 1981). The hemorrhage and cellular infiltration
resolves within 3 weeks, and the ensuing lesions resemble panacinar
emphysema (Kuhn et al. 1976). Over 95 percent of the detectable
urinary excretion of desmosine and isodesmosine, amino acid
markers of in vivo elastolysis, appears within 2 days of elastase
instillation; only small amounts can be detected by day 3 (Goldstein
and Starcher 1977). Kucich et al. (1980) developed a hemagglutina-
tion inhibition assay to measure elastin-derived peptides in serum,
and found that elastin-derived peptides could be detected in the
serum of dogs for a period of 12 days following administration of a 25
to 50 mg dose of porcine pancreatic elastase and for 40 days following
a 100 mg dose. Janoff et al. (1983b) found increases in urinary
desmosine excretion during the first 48 hours following endobronchi-
266
al instillation of pancreatic elastase to sheep; increases in mean
linear intercepts and decreases in lung ventilation and perfusion
were found after 4 weeks. All changes correlated positively with the
elastase dose. Studies have shown a decrease in the lung elastin
content within the first 24 hours of intratracheal injection of
elastase (Kuhn et al. 1976; Ip et al. 1980; Goldstein and Starcher
1977). Physiologic studies (Snider and Sherter 1977; Snider et al.
1977) of experimental animals after pancreatic elastase administra-
tion have shown increases in the lung compliances and in the volume
of air within the lungs at specified transpulmonary pressures (25 and
-~20 cm H?°). These physiologic alterations appear to progress in
severity for about 26 weeks following exposure to elastase (Snider
and Sherter 1977).
In spite of substantial experimental verification of ability of
pancreatic elastase to induce emphysematous changes in animals
following intratracheal instillation, there is little evidence implicat-
ing endogenous pancreatic elastase in the pathogenesis of pulmonary
emphysema in humans. A serine endopeptidase of pancreatic origin
(elastase 2) has been shown to circulate in human blood (Geokas et
al. 1977). However, the enzyme is rapidly bound to serum irhibitors
a,AT and a2-macroglobulin (a,M) and inactivated (Gustavsson et al.
1980). Although a,M-elastase complexes retain enzymatic activity
against low molecular weight synthetic elastin substrates (N-succi-
ny]-L-alanyl-L-alany]-L-alanine-4-nitroanilide) (Twumasi and Liener
1977; Barrett and Starkey 1973); high molecular weight proteins
such as elastin are prevented from reaching the enzyme and are not
hydrolyzed (Barrett and Starkey 1973).
Attempts to induce emphysematous changes via the intravenous
injection of elastase have met with limited success. Hamsters
injected intravenously with nonfatal doses of pancreatic elastase fail
to show histologic changes characteristic of emphysema (Schuyler et
al. 1978) and do not manifest detectable reductions in lung elastin (Ip
et al. 1980). However, elastic recoil is lost at low lung volumes
(Schuyler et al. 1978). Fierer et al. (1976) has noted enlargements in
the airspaces of rats treated intravenously with large doses (330 UV) of
pancreatic elastase. They also found increases in the mean linear
intercepts and rarefication of the amorphous components of elastin
within the lungs. It is doubtful, however, if proportionally similar
intravenous levels of pancreatic elastase occur in humans with
pulmonary emphysema.
Polymorphonuclear Leukocyte Elastase
Polymorphonuclear leukocytes (PMN) appear to be a more plausi-
ble source of endogenous elastase in the human lung than the
pancreas, and are more likely to be incriminated in the pathogenesis
of naturally occurring pulmonary emphysema. PMNs contain elasto-
267
lytic enzymes (Janoff 1973; Ohlsson and Ohlsson 1974; Rindler-
Ludwig et al. 1974) that can be released in active form within the
lung. Experimental studies have clearly demonstrated the ability of
PMN elastase to degrade lung elastin and to induce emphysematous
lesions in animals.
Marco et al. (1971) and Mass et al. (1972) induced experimental
emphysema in dogs by the administration of aerosolized crude
leukocyte homogenates. Using purified human leukocyte elastase,
Janoff et al. (1977) demonstrated the ability of the enzyme to digest
dog lung elastin in vitro and to cause significant dilation of terminal
respiratory structures when instilled into isolated perfused dog
lungs. The in vivo intratracheal instillation of human leukocyte
elastase in dogs produces foci of alveolar destruction within 90
minutes of administration (Janoff et al. 1977). Senior et al. (1977)
studied the effects of intratracheally injected human leukocyte
elastase on hamsters and found a reduction in lung elastin in treated
animals, as well as mild patchy airspace dilation. Sloan et al. (1981)
were able to show that purified dog leukocyte elastase could also
produce emphysematous lesions in dogs when instilled endobronchi-
ally.
Guenter et al. (1981) developed a dog model of experimentally
induced emphysema that avoided the necessity of intratracheal
instillation of enzymes. They repetitively injected E. coli endotoxin
intravenously, thereby inducing extensive leukocyte sequestration
within the lungs of the dogs. A previous study had shown that the
sequestered cells degranulate and disintegrate within the vascular
bed (Coalson et al. 1970). Histologic studies of these dogs revealed
mild airspace destruction and prominent intra-alveolar fenestra-
tions.
Alveolar Macrophage Elastase
In a widely cited article (Mass et a). 1972), dog alveolar macro-
phage homogenates (obtained by the method of Brain 1970), adminis-
tered to two mongrel dogs produced “some dilatation and nonuni-
formity in the size of the airspaces accompanied by some alveolar
wall destruction” in one of the dogs. The other dog showed no
evidence of emphysema.
In spite of the paucity of animal data, the pulmonary alveolar
macrophage (PAM) has been the focus of much investigation. Both
experimental and clinical evidence is available that implicates this
cell in the pathogenesis of pulmonary emphysema.
Two possible mechanisms by which macrophages may mediate
tissue injury are being actively studied. One mechanism involves the
release of elastolytic enzymes followed by unrestrained proteolysis.
The second mechanism involves either a direct or an indirect injury
268
following the release of toxic forms of partially reduced oxygen such
as superoxide anions, hydroxy] radicals, and hydrogen peroxide.
The ability of human alveolar macrophages to synthesize and
secrete an elastolytic enzyme distinct from PMN elastase is the
subject of controversy. Although human alveolar macrophages have
been shown to synthesize a metalloprotease distinct from the serine
protease (elastase) of the PMNs (DeCremoux et al. 1978), its
hydrolytic activity against insoluble elastin substrate has not been
conclusively demonstrated (Hinman et al. 1980; Levine et al. 1976).
Interpretation of the observation that human alveolar macrophages
raised in cell culture systems secrete an enzyme with true elastolytic
activity against insoluble elastin (Rodriguez et al. 1977; DeCremoux
et al. 1978) is complicated by the fact that alveolar macrophages bind
and internalize PMN elastase (Campbell and Greco 1982; White et
al. 1982; Campbell and Wald 1983). Hinman et al. (1980) detected a
calcium-dependent metalloprotease in the culture medium and in
the cell lysates of human alveolar macrophages and _ initially
demonstrated elastolytic activity against synthetic elastin substrate
and soluble elastin by both the culture medium fluid and the cell
lysates. However, after 3 and 5 days of culture, no detectable activity
against insoluble elastin was evident. The authors calculated that
the initial elastolytic activity observed could be quantitatively
explained by PMN contamination. The recognition that human
alveolar macrophages internalize human PMN elastase (Campbell
and Greco 1982; White et al. 1982: Campbell et al. 1979; Campbell
and Wald 1983) and that the internalized PMN elastase retains
enzymatic activity for at least 48 hours (McGowan et al. 1983)
suggests an alternative explanation.
Green et al. (1979) subcultured human alveolar macrophages for 3
months and found measurable elastase activity against solubilized
elastin during the entire period. They concluded that the elastase
activity appeared to be synthesized continuously rather than being
internalized from external sources.
In summary, human alveolar macrophages release elastolytic
enzymes capable of digesting connective tissue. Whether the elastase
released by these cells represents an enzyme synthesized de novo or
a previously internalized PMN elastase is uncertain and requires
further study.
Human alveolar macrophages, especially from cigarette smokers,
secrete highly reactive oxygen species (Hoidal et al. 1979a) that are
capable of directly injuring endothelial cells (Sacks et al. 1978) and
ibroblasts (Hoidal et al. 1981) and of inactivating a,AT (Carp and
fanoff 1979, Janoff 1979a).
Whole cigarette smoke inhibits PMN chemotaxis in vitro in a dose-
ependent manner (Bridges et al. 1977). However, when alveolar
1acrophages are exposed to cigarette smoke either in vitro or in
269
vivo, they release a PMN chemotaxic factor (Hunninghake et al.
1980c) (see above).
Protease-Antiprotease Hypothesis
The protease-antiprotease hypothesis proposes that enzymatic
digestion of lung parenchyma occurs as a direct consequence of a
genetic or acquired imbalance of the protease—antiprotease system
and that the subsequent repair of connective tissue is unable to
return the structures to normal. This hypothesis derives principally
from two observations: (1) people genetically deficient in a,AT
(Laurell and Eriksson 1963), the major antielastase of the lower
respiratory tract of humans (Gadek et al. 1981a), are at greatly
increased risk of developing pulmonary emphysema, and (2) proteo-
lytic enzymes produce physiologic and anatomic lesions resembling
emphysema when administered to experimental animals (Gross et
al. 1965). Attempts to integrate the clearly established relationship
of cigarette smoking and pulmonary emphysema with the protease—
antiprotease hypothesis have led investigators to search for ways in
which smoking perturbs this balance.
Increased Elastase Owing to the Cellular Response to Smoke
At least five variables, aside from the genetically determined level
of antiprotease activity, could influence the elastase burden of the
lungs. These variables include (1) an increase in the number of
elastase-containing cells within the lung, (2) an increase in the
quantity of prepackaged or newly synthesized elastase per cell, (3)
the quantity of elastase released from the cells, (4) the proximity of
the elastase to suitable substrate, and (5) the extracellular milieu
(i.e., pH, ionic strength, and factors such as platelet factor 4).
Number of Cells
As discussed earlier, the human cigarette smoker has increased
numbers of alveolar macrophages in the bronchoalveolar lavages
compared with nonsmokers (Rodriguez et al. 1977; Harris et al. 1975;
Reynolds and Newball 1974, Hoidal and Niewoehner 1982). Holt and
Keast (1973b) found sustained elevations of pulmonary macrophages
in mice exposed to cigarette smoke. Cigarette smoke has been shown
to recruit PMNs into the airways (Kilburn and McKenzie 1975;
Rylander 1974) and to induce alveolar macrophages to release a
chemotactic factor for PMNs (Hunninghake et al. 1980c). The
circulating PMNs are reported to be increased in cigarette smokers
(Corre et al. 1971; Galdston et al. 1977). Hunninghake et al. (1980c)
and Reynolds and Newball (1974) found increased numbers of PMNs
in the lavage fluid of smokers, but Hoidal and Niewoehner (1982)
reported similar numbers of PMNs in the lavages of cigarette
270
smokers and nonsmokers. Hunninghake and Crystal (1983) obtained
isolated cell suspensions from the bronchoalveolar lavage fluids and
from open lung biopsies of nonsmokers and cigarette smokers with
both normal lung parenchyma and sarcoidosis. They found a
significantly increased number of neutrophils and macrophages in
the lavage fluid and in the biopsy specimens from cigarette smokers
as compared with nonsmokers, both in patients with normal lung
parenchyma and in those with sarcoidosis.
Elastase Content
Harris et al. (1975) found an increase in the elastase-like esterase
and protease activity of macrophages obtained from smokers as
compared with nonsmokers. Galdston et al. (1977) found the PMN
elastase levels of circulating PMNs to be elevated in patients with
chronic obstructive lung disease and suggested that the intracellular
elastase levels may be genetically determined (Galdston et al. 1973).
Other investigators (Lam et al. 1979; Rodriquez et al. 1979) reported
similar findings, but Kramps et al. (1980) failed to find any
correlation between the PMN elastase levels and obstructive lung
disease in PiZZ patients, although they did note a difference in
PiMM patients. Lonky et al. (1980) demonstrated that dogs infected
with Type 3 pneumococcus had increased PMN elastase-like esterase
activity within their cells, suggesting an acute phase reaction.
Release
A variety of mechanisms may lead to the extracellular release of
lysosomal contents. These include cell lysis, regurgitation during
phagocytosis, reverse endocytosis, humoral mediation, and cytocha-
lasin B treatment of cells (Klebanoff and Clark 1978). Wright and
Gallin (1979) showed that migration of PMNs is associated with the
leakage of various enzymes. Sandhaus (1983) found that migrating
human neutrophils degrade elastin in vitro in the presence or
absence of human a,AT. A similar mechanism may occur during
neutrophil migration in vivo. Hutchison et al. (1980) found that the
soluble fraction of cigarette smoke suppressed the release of lysoso-
mal enzymes (acid phosphatase and acid ribonuclease) from PMNs
obtained from healthy persons, but not from the PMNs of emphy-
sematous patients. Blue and Janoff (1978) demonstrated that the
water-insoluble fraction of cigarette smoke has a cytotoxic effect on
PMNs in vitro and causes them to release their lysosomal contents,
including beta-glucuronidase, acid phosphatase, and elastase. Eliraz
et al. (1977) found that canine alveolar macrophages and PMNs,
when stimulated with the water-soluble fraction of cigarette smoke,
secrete elastase. Abboud et al. (1983), however, compared the release
of elastase and B-glucoaminodase from PMNs obtained from ciga-
271
rette smokers and with that from nonsmokers and found no
differences. In vitro stimulation of these cells by 2ither phagocytosis
or chemotactic polypeptides did not alter the results. These research-
ers concluded that chronic smoking does not affect neutrophil
elastase release in vitro and that among smokers there is no
significant relationship between in vitro neutrophil elastase release
and abnormalities in lung function. They speculated that some of the
differences between studies may be related to experimental condi-
tions, such as the concentrations of cigarette smoke.
Because the mechanisms involved in the release of intracellular
contents are complex and the representativeness of in vitro condi-
tions to in vivo events is uncertain, definite conclusions await
further studies.
Proximity
Elastolytic activity is conditioned by the absorption of elastase
onto elastin substrate (Robert and Robert 1970); the adsorption, in
turn, results from the electrostatic attraction between negatively
charged carboxylate groups of elastin and positively charged groups
of elastase (Hall and Czerkowski 1961; Gertler 1971). Campbell et al.
(1982) found that a,AT has less inhibitory activity against PMN
elastase derived from cells in contact with substrate than against ~
PMN elastase free in solution. They reasoned that the partial
exclusion of protease inhibitors from the PMN-connective tissue
interface may account for this phenomena and may be an important
factor in elastase-mediated injury. Focusing more on the macroenvi-
ronment within the lung, Janoff et al. (1983c) found that the
bronchoalveolar lavage fluids of young asymptomatic cigarette
smokers contain significantly more elastase activity than the lavage
fluids from nonsmokers. Kucich et al. (1983) found that the serum
lung elastin-derived peptides were elevated in some smokers and
most patients with COLD, suggesting that elastolysis may be taking
place in smokers and COLD patients.
Milieu
A number of in vitro experiments have examined the chemical and
physical conditions that modify neutrophil elastase kinetics. Lesti-
enne and Bieth (1980) demonstrated that human leukocyte elastase
activity is activated in the presence of substrate excess, hydrophobic
solvents, and increasing ionic strength. The adsorption of sodium
dodecyl sulfate (SDS), a hydrophobic, anionic ligand, onto the surface
of elastin enhances the elastolytic activity of pancreatic elastase
(Kagan et al. 1972). Lonky et al. (1978) showed that platelet factor 4
(PF,) in physiologic concentrations is capable of in vitro stimulation
of human neutrophil elastase (HLE) against lung elastin. Low doses -
272
of HLE instilled intratracheally in hamsters failed to induce
physiologic, morphologic, or biochemical changes, but following the
addition of PF,, a significant injury was evident, and the elastin
content of the lung was lowered by 20 percent (Lonky et al. 1978).
Boudier et al. (1981) demonstrated that human leukocyte cathepsin-
G, an enzyme in the azurophilic granules that possesses little
intrinsic elastolytic activity, stimulates the rate of solubilization of
human lung elastin by HLE. The elastolytic activity increased by
more than five times the HLE rate when the HLFE-cathepsin-G
mixture was present in equimolar concentrations. The relevance of
these findings to the physiologic conditions that prevail in vivo
requires further study.
Laurent et al. (1983) recently discovered that the water-soluble
components of filtered cigarette smoke suppress, in a dose-dependent
manner, the lysy] oxidase-catalyzed oxidation of the epsilon-amino
groups of lysine residues in tropoelastin. This step is essential for the
formation of covalent cross-links between neighboring elastin poly-
peptide chains that, in turn, are necessary for norma] elastic
strength within the lung.
Decreased Antiprotease Owing to Oxidation
A comprehensive review of the role of oxidative processes in
emphysema has recently been published by Janoff et al. (1983a). In
vitro studies have revealed that oxidants such as chloramine T
(Abrams et al. 1981) or ozone (Johnson 1980) cause a loss in the
inhibitory capacity of a, AT for neutrophil elastase. The mechanism
of inactivation has been identified as the oxidation of methionine
and tyrosine residues (Johnson and Travis 1979; Cohen 1979; Carp
and Janoff 1978) within the a,AT molecule. Chloramine T, when
administered differentially to dogs, reduces EIC > TIC of serum and
also results in emphysema (Abrams et al. 1981). Cigarette smoke is
also known to contain oxidants (Stedman 1968; Pryor et al. 1983).
Aqueous solutions of cigarette smoke reduce the elastase inhibitory
capacity of human serum (Carp and Janoff 1978) and result in less
binding of elastase to a,AT in vitro (Carp and Janoff 1978). Some
investigators have found that the a,AT activity is reduced in the
lavage fluids (BALF) obtained from human cigarette smokers and
from rats exposed to cigarette smoke (Gadek et al. 1979; Carp et al.
1982: Janoff et al. 1979a). Stone et al. (1983) reported similar levels of
functional a,-antitrypsin in the bronchoalveolar lavage fluids of
human smokers and nonsmokers. Janoff and Chan (1984) have
suggested that this difference in results may reflect the timing of the
lavage in these studies, as rats chronically exposed to cigarette
smoke had rapid inactivation of a,-antitrypsin following smoke
exposure, but also had a more rapid recovery of a,-antitrypsin
activity than did rats acutely exposed to smoke. Stone et al. also
273
recognized that their study may not have detected a reduction in
alpha,-antitrypsin activity if it was accompanied by a rapid recovery
to normal levels. Methionine sulfoxide peptide reductase, an enzyme
present in human PMNs, can reactivate a,AT oxidized by chlora-
mine T or by the myeloperoxidase system, but «,AT exposed to
cigarette smoke plus peroxide (Carp et al. 1983) has been shown to be
either resistant to reactivation by the myeloperoxidase system (Carp
et al. 1983) or incompletely reactivated (James et al. 1984).
Human ceruloplasmin has been shown to prevent myeloperoxi-
dase mediated oxidation of a,AT under specified conditions of pH
and solvency (Taylor and Oey 1982), although the role played by
ceruloplasmin in limiting oxidation by phagocytes in vivo is unclear.
Taylor et al. (1983) examined plasma and leukocyte lysosomal
samples from a group of COLD patients and measured the ability of
these samples to inhibit lipid peroxidation. While they reasoned that
inhibitors of peroxidation could protect a,AT from inactivation by
neutralizing lipid free radicals, they found that inhibition required
factors from both plasma and lysosomal extracts and that the factor
was not ceruloplasmin. Two of ten emphysematous patients had
reduced plasma factor activity, and one of these patients also had
reduced lysosomal factor. Controls had normal values for both of
these factors.
Galdston et al. (1984) examined serum ceruloplasmin concentra-
tions and antioxidant activity in male and female smokers. Smokers
of both sexes had higher serum ceruloplasmin concentrations than
did nonsmokers; women in both smoking categories had higher
concentrations than their male counterparts. Serum antioxidant
activity showed a significant positive correlation with serum cerulo-
plasmin levels; however, for comparable ceruloplasmin concentra-
tions, serum antioxidant activity was significantly lower in smokers
than in nonsmokers of both sexes. The researchers suggest that -
cigarette smoking may cause partial inactivation of serum antioxi-
dant activity that is accompanied by an insufficient increase in
ceruloplasmin concentration.
Endogenous phagocytes are also capable of generating oxidants
(Babior 1978; Klebanoff and Clark 1978). The phagocytic enzyme
myeloperoxidase, in the presence of hydrogen peroxide and halide
ions, oxidatively inactivates a,AT (Matheson et al. 1979, 1981).
Smoking, as described above, elevates the oxidative metabolism in
lung macrophages (Hoidal and Niewoehner 1982; Fox et al. 1979;
1980; 1981).
Thus, it is clear that the oxidants present in cigarette smoke and
the lung macrophages of smokers can inactivate a,AT. This inactiva-
tion, coupled with the increased elastase burden that may result
from the inflammatory cell response of the lung to smoke, could tip
274
the balance of the protease—antiprotease system in the direction of
elastin degradation.
Explanation for Upper Lobe Distribution
In accord with the protease—antiprotease hypothesis, emphysema-
tous lesions result from the unrestrained proteolytic digestion of
connective tissue elements. The regional distribution of lesions
within the lung is thought to be conditioned by both biochemical and
physiological variables.
The predilection of lower lobe involvement in persons with a,AT
deficiency is hypothesized to result from an increased number of
elastase-containing cells because of the higher vascular perfusion to
this area in erect man. This excess could occur because of the
deposition of senescent leukocytes in these areas of higher blood flow
(Guenter et al. 1981). In addition, inhaled particulates preferentially
deposit in the lower lobes (Milic-Emili et al. 1966; Dollfuss et al.
1967), and the leukocytes release their enzyme extracellularly
during the ingestion of these particulates. Because of the genetic
deficiency of a,AT, the proteolytic activity is unopposed and
destruction occurs.
The predominance of upper lobe lesions in cigarette smokers with
normal systemic levels of a,AT is again thought to result from
variations of ventilation and perfusion within the lung (Cockcroft
and Horne 1982). However, in normal individuals the proteolytic
activity due to the excess particulate deposition in the bases is
inhibited by a,AT that is replenished by the increased vascular
perfusion also occurring in the bases. The upper lobes, although less
well ventilated than the lower lobes, nevertheless have higher
ventilation:perfusion ratios because of the proportionately greater
fall in perfusion. The oxidative inactivation of a,AT by cigarette
smoke in the upper lobes therefore may not be compensated by
vascular repletion of the inactivated a,AT, and an imbalance of
protease-antiprotease may occur. The upper lobe injury may then be
magnified by mechanical stresses caused secondary to the negative
intrapleural pressures generated by gravitational forces in erect
man (West 1971).
Animal Models of Emphysema
Spontaneous Emphysema
Emphysema occurs spontaneously in animals in forms resembling
the types seen in human disease (Karlinsky and Snider 1978).
However, the low incidence and unpredictable occurrence of disease
in animals greatly limit their utility as experimental models.
tho
=]
or
Experimentaily Induced Emphysema
A number of insults, including oxides of nitrogen, cadmium salts,
whole cigarette smoke, ozone exposure, and proteolytic enzymes,
have been used to induce or augment emphysematous lesions in a
variety of experimental animals. The reader interested in a compre-
hensive review of this topic is referred to the well-documented article
by Karlinsky and Snider (1978). The evidence for each of these
insults, as they pertain to cigarette smoke, is reviewed below.
Oxides of Nitrogen
Oxides of nitrogen, present in the gas phase of smoke, appear to
induce or potentiate emphysema-like lesions in some animals
(Karlinsky and Snider 1978).
Nitrogen dioxide (NO,) exposure causes airway narrowing and an
increase in the proteolytic burden within the lungs of experimental
animals. Airway narrowing is postulated as a contributing factor in
the pathogenesis of pulmonary emphysema (Juhos et al. 1980):
Following exposure to NO., rats develop bronchiolar stenosis. The
nitrogen dioxide exposure also induces an influx of alveolar macro-
phages (AM) and polymorphonuclear leukocytes (PMNs) (cells
known to contain proteolytic enzymes) into the lungs (Juhos et al.
1980). Kleinerman et al. (1982) demonstrated an increased number of
alveolar macrophages and PMNs in lung lavages from hamsters
exposed to NO,. Although there is no detectable increase in the
elastolytic activity from lung lavages of NO.-exposed animals, the
cell-free culture medium from macrophage cultures of NO,-exposed
animals does show a twofold to fivefold increase in elastolytic
activity during the first 2 weeks of exposure (Kleinerman et al.
1982).
Nitrogen dioxide exposure has not been shown to cause alveolar
septal disruption, an essential feature of centrilobular emphysema,
but it does result in a significant reduction in the internal surface
area in the lungs of hamsters exposed for 12 to 14 months
(Kleinerman and Niewoehner 1973).
Cadmium Salts
Animals exposed to cadmium, a constituent found in the particu--
late phase of cigarette smoke, develop a number of histologic and-
biochemical changes that may lead to emphysematous lesions.
Exposed animals develop pulmonary edema, vascular congestion,
intraparenchymal hemorrhages, and a loss of Type I pneumocytes
(Palmer et al. 1975; Strauss et al. 1976), and PMNs and mononuclear
cells influx into the lungs (Snider et al. 1973). The animals develop
acute peribronchial damage followed by the accumulation of granu-
lation tissue near the respiratory bronchioles, thickened alveolar
276
septa, and distortion and distention of neighboring alveoli (Snider et
al. 1973). These histologic changes are more suggestive of the scar or
paracicatricial form of emphysema than the centrilobular form
reported in some industrial workers exposed to CdCl, (Princi 1947).
This disparity in response to CdCl, could be related to species
differences or the interaction of CdCl, with other factors.
When hamsters are exposed to CdCl, plus beta-amino proprioni-
trile (B-APN), an inhibitor of lysyl oxidase, they develop thin-walled
subpleural bullae and airspace enlargements resembling panlobular
emphysema (Niewoehner and Hoidal 1982). The mean linear dis-
tance between alveolar intercepts is significantly increased; pres-
sure—-volume studies show overinflation and increased compliance of
the lungs (Niewoehner and Hoidal 1982). This study suggests that
CdCl., perhaps in conjunction with some other as yet undetermined
agent, may be important in the pathogenesis of pulmonary emphyse-
ma. The fact that CdCl, is a constituent of cigarette smoke (Randi et
al. 1969) lends support to this hypothesis.
Cigarette Smoke
Cigarette smoking has been clearly identified as a major causal
factor in the development of pulmonary emphysema in humans
(Auerbach et al. 1972; 1974; Petty et al. 1967; Andersen et al. 1967;
Niewoehner et al. 1974; USDHEW 1979). However, an animal model
for the development of emphysema using the inhalation of cigarette
smoke alone has not been convincingly demonstrated. Parenchymal
disruption resembling human emphysema has been reported in some
dogs following prolonged cigarette exposure, but this histologic
pattern is not uniformly present (Hernandez et al. 1966; Auerbach et
al. 1967a; Zwicker et al. 1978).
This difficulty in developing an animal model for cigarette-induced
emphysema may relate to the reluctance of animals to inhale smoke
and the relatively long duration of exposure required to produce
emphysema in humans. However, it may also result from the need
for a combination or sequence of effects to induce emphysematous
change. That is, an increased elastase burden might be necessary
(secondary to the cellular response to smoke) before the oxidant
damage of smoke to a,AT, or to repair mechanisms, results in
emphysema. Hoidal and Niewoehner (1983) examined this question
in hamsters exposed to low doses of smoke and elastase. Neither
exposure alone resulted in significant emphysematous change, but
the combined exposure did cause change. This suggests that an
increased elastase burden may be a precondition for smoking-
induced emphysematous lung injury, and may also explain the long
exposure period required in humans prior to the demonstration of an
increased prevalence of emphysema in smokers.
277
Experimental studies have shown that cigarette smoke can induce
a number of cellular, biochemical, and metabolic changes within the
lungs that may be causally related to the development of emphyse-
ma. Macrophages and leukocytes, cells known to contain proteolytic
enzymes, are recruited to the lungs of hamsters (Kilburn and
McKenzie 1975) and guinea pigs (Flint et al. 1971) following exposure
to cigarette smoke, thereby increasing the proteolytic burden of the
lungs. Conversely, the a,AT activity decreases in rats after inhala-
tion of cigarette smoke (Janoff et al. 1979a). The increased proteolyt-
ic burden within the lungs coupled with the concomitant diminu-
tion in inhibitory capacity tends to create a protease—-antiprotease
imbalance and a situation whereby unrestrained connective tissue
destruction may occur.
The Effects of Smoking on Cellular and Immune Defense
Mechanisms
There are important functional differences between macrophages
from smokers and those from nonsmokers (Table 1). For example,
Warr and Martin (1977) demonstrated that receptors for the third
component of complement (C3b) are decreased in number or function
on the surface of smokers’ alveolar macrophages. The receptors for-
the Fe portion of IgG, however, are normal on these cells (Warr and
Martin 1977). An important function of the C3b receptor is to
augment the attachment and phagocytosis of microorganisms and
particulates by the macrophages. It is not clear whether this subtle
defect in cell function results in a significant alteration in phagocyto-
sis or clearance of particulates or microorganisms by these cells. In
this regard, the phagocytosis and killing of a variety of microorga-
nisms by smokers’ alveolar macrophages have been shown to be
normal by Harris et al. (1970) and Cohen and Cline (1977). One
report by Martin and Warr (1977), however, suggests that the
capacity of alveolar macrophages to kill bacteria is decreased in
smokers.
The observation that human alveolar macrophages from cigarette
smokers function normally to kill microorganisms appears to differ,
at first glance, from a number of animal studies demonstrating that
the capacity of alveolar macrophages to phagocytose and kill-
bacteria is impaired following exposure to cigarette smoke (Holt and
Keast 1973; Rylander 1971, 1973). In these animal studies, there was
an initial decrease in the numbers of alveolar macrophages and a
decrease in their bactericidal function following exposure to ciga-
rette smoke. With prolonged exposure, however, the number of -
macrophages increased and their ability to kill microorganisms
returned to normal (Rylander 1973, 1974). These observations
suggest that cigarette smoke, initially, is toxic to alveolar macro-
278
phages. However, it is likely that the macrophages, with time, adapt
to the presence of cigarette smoke. In addition, a subpopulation of
macrophages that are more resistant to cigarette smoke may
increase in number in the lung. The macrophages isolated from the
lungs of smokers resemble those isolated from animals following
prolonged exposure to cigarette smoke. The acute effects of cigarette
smoking on the number and functions of alveolar macrophages in
man has not been systematically evaluated.
Alveolar macrophages of cigarette smokers appear to interact in
an abnormal fashion with lymphocytes (Table 1). In this regard, the
alveolar macrophages from cigarette smokers function poorly as
accessory cells in presenting antigen to autologous lymphocytes
(Laughter et al. 1977). This latter defect may be further magnified by
the observation that lymphocytes from cigarette smokers also
respond poorly to mitogens (Neher 1974; Daniele et al. 1977).
Additional evidence for an abnormal interaction of macrophages and
lymphocytes in lungs of cigarette smokers is a decreased response of
alveolar macrophages to the lymphokine, macrophage migration
inhibitory factor (Warr 1979). These observations suggest that
cigarette smoking may have broad effects on the ability of the lung
to generate a cellular immune response.
In Vitro Effects of Cigarette Smoke on Inflammatory and
Immune Effector Cells
The most readily demonstrable effect of cigarette smoke, in vitro;
is a decrease in cell viability (Holt et al. 1974; Holt and Keast 1973;
Nulsen et al. 1974; Weissbecker et al. 1969). At relatively low
concentrations, cigarette smoke and its constituents rapidly kill
alveolar and peritoneal macrophages in vitro. Lymphocytes and
polymorphonuclear leukocytes are also very susceptible to these
agents (Holt et al. 1974; Blue and Janoff 1978).
When sublethal amounts of cigarette smoke are employed, a
number of metabolic and functional changes occur in macrophages.
Phagocytosis is depressed, as is the function of a number of
macrophage enzymes (Vassallo et al. 1973; Green 1968a, b, c, 1969,
1970; Green and Carolin 1966, 1967; Green et al. 1977; Powell and
Green 1971; Hurst and Coffin 1971). In addition; protein synthesis is
also depressed (Yeager 1969; Low 1974), and stimulatory effects have
been noted. While cigarette smoke depresses phagocytosis and
intracellular killing, nitrogen dioxide increases the metabolic activi-
ty of macrophages (Vassallo et al. 1973). Similar effects have been
observed under some conditions with cigarette smoke (Holt and
Keast 1973; Leuchtenberger and Leuchtenberger 1971). Results from
a number of investigators suggest that the balance between stimula-
tion and inhibition of macrophage activity is determined by dosage,
with stimulation occurring at low exposure levels and inhibition at
279
higher concentrations (Holt and Keast 1973; Lentz and DiLuzio 1974;
York et al. 1973). The most potent stimulation occurs after prolonged
exposure to low levels of the agent.
These in vitro effects of cigarette smoke are also seen acutely in
vivo following exposure to smoke. The immediate effect of exposure
to cigarette smoke, and to agents present in the smoke, is a decrease
in viability of the pulmonary alveolar macrophages (Holt and Keast
1973a, b; Rylander 1971, 1973; Coffin et al. 1968; Dowell et al. 1970;
Holt and Nulsen 1975; Gardner et al. 1969). Although not well
studied, it is also likely that cigarette smoke is toxic to polymorpho-
nuclear leukocytes (Blue and Janoff 1978). In support of these
observations are studies demonstrating that acute exposure of —
experimental animals to tobacco smoke, or to components of
cigarette smoke, also lowers their resistance to bacterial infection
(Rylander 1969, 1971; Acton and Myrick 1972; Gardner et al. 1969;
Goldstein et al. 1971; Huber and LaForce 1971; Huber et al. 1971). -
Short-term exposure to components of cigarette smoke, particularly
nitrogen oxide, has also reduced resistance to viral infection, -
probably by inhibiting interferon production by macrophages (Va-
land et al. 1970). As noted above, these in vitro and acute in vivo
effects of cigarette smoke are not seen following long-term in vivo
exposure in animals; very little work has been done on the effects of
cigarette smoke in vitro, using human cells. However, several studies
have shown that cigarette smoking and nicotine, at levels compara-
ble to those encountered in the circulation of smokers, produce a
slight but significant depression of PHA-stimulated DNA synthesis
in human peripheral blood lymphocytes (Neher 1974; Silverman et
al. 1975; Vos-Brat and Rumke 1969).
The Effect of Cigarette Smoke on Antibody Production
The available data on antibody production in human smokers
suggest that cigarette smoking may depress these responses. The
production of antibodies was investigated in a large study involving
influenza vaccination. Smokers in the population exhibited in-
creased susceptibility to infection during an influenza outbreak
(Finklea et al. 1969, 1971). Prior to immunization with influenza
vaccine, smokers exhibited significantly lower titers of specific
antibodies than did nonsmokers. Immediately following vaccination
of both groups, the smokers developed levels of antibodies compara-
ble to those of nonsmokers. However, the antibody titer in the
smokers fell below their nonsmoking counterparts within a few
weeks, and by a year after vaccination the smokers exhibited
markedly depressed levels of circulating antibodies.
The capacity of cigarette smoking to alter antibody production was
also studied by evaluating the capacity of a fetus to stimulate
lymphocytotoxic antibodies against HLA antigens in the mother
280
(Nyman 1974). Sera from a large number of pregnant women were
tested for the presence of lymphocytotoxic antibodies against a 48-
donor panel. The smokers exhibited a significantly lower incidence
of these antibodies than did nonsmokers, and the divergence
between groups increased with the number of deliveries. Infections
during pregnancy were observed significantly more often in the
smokers in this trial.
In several animal models, acute exposure to whole cigarette smoke
or components of cigarette smoke depressed the numbers of anti-
body-forming cells in the spleen and the serum levels of antibodies in
animals exposed to a variety of antigens (Miller and Zarkower 1974,
Zarkower and Marges 1972; Zarkower et al. 1970). The depression
was greatest when the antigen was administered by an aerosol
(rather than by systemic inoculation), indicating that smoke appears
to exert an effect close to the point of entry. Prolonged exposure
ultimately resulted in severe depression both in local and in systemic
antibody responses (Esber et al. 1973; Holt et al. 1976; Thomas et al.
1973, 1974a, 1974b, 1975).
Although it is tempting to relate these abnormalities in immune
response to the known association between cigarette smoking and
increased incidence of upper respiratory infection, it is not clear
whether the subtle defects in immune functions can entirely account
for the infections present in cigarette smokers. Clearance of bacteria
from the respiratory tract is a complex process that involves
interplay between a variety of different mechanisms, only some of
which include the function of alveolar macrophages and the capacity
of the lung to mount cellular and humoral immune responses. Other
abnormalities present in cigarette smokers that could account for
this increased incidence of infection include a markedly abnormal
tracheal bronchial clearance of particulates and an increased
adherence of bacteria to airway epithelium (reviewed in USPHS
1971, 1973, 1974).
281
EFFECTS OF CIGARETTE SMOKE ON AIRWAY
MUCOCILIARY FUNCTION
Introduction
There is extensive literature on the effects of cigarette smoke on
mucociliary clearance in the airways, with the majority of the
reports appearing between 1965 and 1975. Different experimental
approaches have been used, including in vivo measurement of
mucociliary function in animal models and in human subjects. The
results of some of these studies have been contradictory, presumably
because of differences in experimental technique or the influence on
mucociliary function of factors other than cigarette smoking. For
example, tracheal mucociliary transport appears to decline with age
in normal subjects (Goodman et al. 1978), an important phenomenon
to consider when assessing the effects of long-term cigarette smok-
ing. Another complicating factor is the clearly demonstrated impair-
ment of mucociliary function produced by chronic bronchitis even in
nonsmokers, such as in patients with cystic fibrosis (Wood et al.
1975) or immunoglobin deficiency (Mossberg et al. 1982). Therefore,
it is difficult to seperate the direct effects of cigarette smoke on
mucociliary function from those of smoking-associated chronic
bronchitis. Finally, in vitro bioassays for ciliotoxicity may not
reliably reflect the effects of cigarette smoke on the mucociliary
apparatus in the intact airways. Thus, Dalhamn et al. (1967) found
that smoke produced by cigarettes containing a high concentration
of hydrogen cyanide was more ciliotoxic in vitro than that produced
by cigarettes containing a low concentration of hydrogen cyanide,
and the two types of cigarettes caused a comparable reduction of
mucus transport in vivo.
This review is divided into three parts. The first part summarizes
the normal structure and function of the mucociliary system in the
airways. The second part deals with the direct effects of short-term
and long-term cigarette smoke exposure on mucociliary function,
and the third part discusses mucociliary function in chronic bronchi-
tis.
Normal Mucociliary Function
The principal function of the airway mucociliary system is its
contribution to host defenses. This is accomplished by physical
removal of inhaled foreign material from the ciliated airways by
mucous transport and by biochemical and immunological processes
that protect against invasion of the mucosa by infectious agents.
Normal mucociliary clearance depends upon an optimal interaction
between cilia and mucus.
283 -
Cilia
The respiratory mucosa from the proximal trachea to the terminal
bronchioles consists of a pseudostratified epithelium with cilia
protruding from the luminal surface of columnar cells (Figure 1).
The larynx contains a mucus-secreting squamous epithelium over
most of its surface, and cilia are present only in the posterior
commissure (Wanner 1977). The major cell types in the respiratory
mucosa are basal cells, intermediate cells, nonciliated columnar
cells, ciliated columnar cells, and goblet cells. In the larger airways,
the major part of the epithelial surface is ciliated. The ratio of
ciliated columnar cells to goblet cells is approximately 5:1 in the
trachea, with a relative decrease in the number of both cell types
toward the peripheral airways. The surface of each ciliated columnar
cell contains approximately 200 cilia with an average length of 6 4m
and diameter of 0.2 um. Both ciliated and nonciliated columnar cells
are characterized by microvilli on their luminal surface. These
measure 0.3 um in length and 0.1 pm in diameter. The ultrastruc-
ture of cilia in lower animals and mammals is remarkably similar.
Each cilium contains longitudinal microtubules that appear to
represent contractile elements. Two single microtubules form a
central core, and nine microtubules with a doublet structure are
erranged in a circular fashion in the periphery of the cilium. A basal
body in the apex of the cell corresponds to each cilium. Circular and
radial bridges have been demonstrated between the peripheral
microtubules and between the peripheral and central microtubules.
These bridges (dynein arms, nexin links, radial spokes) appear to be
crucial for ciliary bending.
Mucus
Respiratory secretions consist of mucus produced by submucosal
glands and goblet cells and tissue fluid. The total volume of all
mucus-producing structures has been estimated at approximately 4
ml in human lungs; submucosal glands make up most of this volume
(Wanner 1977). The submucosal glands are under parasympathetic
nervous control, with an estimated daily volume of respiratory
secretions between 10 and 100 ml. Human respiratory secretions -
contain approximately 95 percent water. The rest consists of
micromolecules (electrolytes and amino acids) and macromolecules
(lipids, carbohydrates, nucleic acid, mucins, immunoglobulins, en-
zymes, and albumin). In situ, the respiratory secretions take the
form of two layers, i.e., periciliary fluid (sol phase), and mucus (gel
phase), as shown in Figure 1. Mucus has been clearly identified as
the product of submucosal glands and goblet cells; the origin of the
periciliary fluid has not been definitely established, although
transepithelial water transport appears to be the most likely source.
In central airways, the mucus layer is 5 to 10 4m deep and may be
284
oS
|
FIGURE 1.—Schematic representation of normal mucosa
(central airway) with the components of the
mucociliary apparatus
NOTE: From top (airway lumen) to bottom, note mucus layer, periciliary fluid layer, epithelium with a
predominance of ciliated columnar cells and an interspersed goblet cell, basement membrane, and submucosal
gland.
SOURCE: Wanner (1979).
discontinuous. In peripheral airways where submucosal glands are
absent and goblet cells are rare, mucus is either absent or present
only in small quantities. Regeneration of injured ciliated respiratory
epithelium takes approximately 2 weeks in animals; the exact
regeneration time of damaged human tracheobronchial ciliated
epithelium is not known (Wanner 1977). It appears that regeneration
does not begin until 2 to 3 days following mechanical injury.
Mucociliary Interaction
Mucociliary interaction depends on ciliary activity, the rheologic
properties and depth of the mucus layer, and the depth of the
periciliary fluid layer. The viscoelastic properties of mucus are
determined by its biochemical characteristics (disulfide cross-linking
and hydrogen bonding between glycoprotein molecules and water)
(Wanner 1977). Cilia beat in one plane, with a fast effective stroke
(power stroke) in the cephalad direction and a recovery stroke that is
two to three times slower. Adenosine triphosphate has been identi-
fied as the energy source for ciliary bending. In mammals, the
average normal ciliary beat frequency is approximately 1,000 beats
per minute, with coordinated motion in adjacent cilia on an
individual cell and in cilia of adjacent cells. This interciliated
285
TABLE 2.—Measurement of airway mucociliary function in
humans
Method Reference
Clearance of inhaled radioactive Morrow et al. (1967)
aerosols from the lungs
Transport of discrete markers Friedman et al. (1977)
Sackner et al. (1973)
Central airway clearance of inhaled Yeates et al. (1975)
boli of radioactive microspheres
pattern of motion by which adjacent cilia beat one after another to
generate a wave of ciliary motion is called metachronism.
The “normal” thickness of the periciliary fluid layer is less than,
or at best equal to, the length of the ciliar shafts, which measure
approximately 6 pm in the central airways. The luminal surface of
the mucus layer appears smooth, whereas the surface in contact with
the cilia is irregular, and the mucus penetrates between the ciliary
shafts. This penetration and the claw-like projections at the cilia tips
may further facilitate the mechanical interaction between cilia and
mucus. In the trachea, the “normal” surface mucus transport
velocity is between 5 and 20 mm per minute depending upon the
method of measurement. Mucous transport velocity decreases
toward the peripheral airways.
The three principal methods for the measurement of tracheobron-
chial mucociliary function in humans are listed in Table 2. All of
these have been used in studies of the effects of cigarette smoke on
mucociliary function.
Theoretically, mucociliary dysfunction can result from alterations
in ciliary beat frequency and coordination, the quantity and visco-
elastic properties of mucus, and the thickness of the periciliary fluid
layer. In addition, focal destruction of the respiratory epithelium,
producing areas without cilia or mucus, is also associated with
impaired or absent mucociliary transport.
Effects of Cigarette Smoke on Mucociliary Function
The irritant effects of cigarette smoke on mucociliary clearance
were recognized by Mendenhall and Shreeve (1937). They observed a
decrease in the transport rate of carmine particles on the mucosa of
excised cat tracheas after bringing them in contact with cigarette
smoke, either directly or by dissolving it in the solution in which the
tracheas were immersed (Mendenhall and Shreeve 1937, 1940).
These early findings were confirmed by Hilding (1956) and Dalhamn
286
(1959) approximately 25 years ago. Since then, investigations to
assess the effects of cigarette smoke on ciliary activity and mucocili-
ary transport have proliferated. Because cigarette smoke can impair
mucociliary transport by interfering with ciliary activity or mucus
secretion, the studies relating to these two component functions are
discussed separately and are complemented by a review of experi-
ments involving mucociliary transport, the ultimate expression of
mucociliary function.
The effects of cigarette smoke on mucociliary function have been
extensively studied in vitro, in intact animal models, and in human
subjects. Comparison among the results of these experimental
approaches is difficult, as there are major differences in inhalation
patterns even between animal models and human subjects. Cigarette
smoke is modified during its passage through the upper airways, and
this may vary depending upon the mode of inhalation. By using
smoke produced by radio-tracer spiked cigarettes, it has been shown
that mice, who are obligatory nose breathers, retain 50 percent of
the inhaled radioactivity in the nasal passages, 20 percent in the
ijungs, and the rest in the esophagus, stomach, and other organs
(Page et al. 1973). Using artificial airways to bypass the nasopharynx
in experimental animals eliminates the problem of nasal cigarette
smoke absorption, but also prevents the oral modification of ciga-
rette smoke that is a typical feature of human smoking. In subjects
inhaling cigarette smoke from a smoke dosage apparatus that
delivers standard puffs, 86 to 99 percent of most components of gas
and particulate phases of cigarette smoke are retained, with the
exception of carbon monoxide (CO), of which only 54 percent is
retained (Dalhamn et al. 1968). Much of the smoke appears to be
retained in the mouth. In human subjects who hold cigarette smoke
in their mouth for 2 seconds, 60 percent of the water-soluble
components of the gas phase, 20 percent of the water-insoluble
components of the gas phase, and 16 percent of particulate matter
are absorbed or retained in the upper airways (Frances et al. 1970;
Stupfel et al. 1974). This marked modification of cigarette smoke
might decrease its ciliotoxic effect in the lower airways. Passing
unfiltered cigarette smoke through a chamber with wet surfaces
before bringing it in contact with ciliated epithelium decreased the
cilioinhibitory capacity of the cigarette smoke (Kaminski et al. 1968).
When filtered cigarette smoke was used, the wet surfaces had no
additional effect on ciliotoxicity, indicating that the mucosa of the
upper airway may serve as a filter (Kaminski et al. 1969). Similar
observations have been made when cigarette smoke was passed
through a water trap (Albert et al. 1969).
Because of the differences in inhalation pattern between humans
and animals, it might be argued that nasal mucociliary function
should be measured to assess the effects of inhaled cigarette smoke
287
TABLE 3.—Effects of cigarette smoke on airway
mucociliary system
Impaired mucociliary
Exposure Ciliary dysfunction Mucus hypersecretion clearance
Short term Yes ? ?
Long term Yes Yes Yes
in animal models. However, it has been clearly shown that nasal
mucociliary transport is not a good marker of tracheobronchial
mucociliary transport because of differential responses at the two
sites. For example, exposure to the whole cigarette smoke of up to 30
cigarettes does not impair nasal mucociliary transport in donkeys
(Frances et al. 1970), whereas the same number of cigarettes clearly
alters tracheobronchial deposition and clearance of radioactive
aerosols (Albert et al, 1969). Likewise, Hilding (1965) has concluded
from his studies that the nose is not an acceptable organ for the
study of the effects of cigarette smoke on mucociliary transport.
Realizing the problems with experimental models of ciliary
function in response to cigarette smoke inhalation, Dalhamn (1969)
postulated that a proper experimental design should fulfill the
following requirements: (1) the exposure pattern and level of
cigarette smoke inhalation should simulate that of natural smoking
in human subjects, (2) cigarette smoke should be delivered in air and
not as an aqueous solution, (3) the components of inhaled cigarette
smoke should be analyzed, and (4) exposure should be of long
duration. Although these criteria are obviously not met by many of
the studies quoted in this review, understanding these principles
allows a more critical assessment of the reported results as shown in
Table 3.
Short-Term Exposure
The effects of short-term cigarette smoke exposure on the mor-
phology of the respiratory mucosa have not been investigated in
man. Cigarette smoke residue has been shown to cause ciliary
damage in cultured rabbit tracheal epithelium with a contact-time-
dependent effect (Kennedy and Allen 1979). The most consistent
abnormalities were cellular desquamation and alterations in mito-
chrondria, cilia, and microvilli, some of which occurred as early as 1
hour after exposure commenced.
Cytotoxicity has also been observed after short-term exposure of _
ciliated epithelium to aqueous extracts of cigarette smoke conden-
sate in vitro (Donnelly 1969), but it is difficult to extrapolate data
from these in vitro studies to the in vivo conditions that occur during
cigarette smoking.
288
Cilta
With a few exceptions, e.g., Proetz (1939), most investigators have
demonstrated an irritant effect of smoke on ciliated epithelium,
usually characterized by ciliostasis. Residues of cigarette smoke
passed through an aqueous medium have been shown to produce
ciliostasis in protozoa (Weiss and Weiss 1964; Wang 1963) and in
fragments of human respiratory epithelium (Ballenger 1960). In
fragments of rat trachea, brief exposure to whole cigarette smoke
appears to elicit a biphasic response, with a short period of
stimulation during 1 to 2 minutes followed by a marked decrease in
ciliary beat frequency (Guillerm et al. 1961, 1972). In an excised
rabbit trachea model, 71 1-m) puffs or 35 10-m] puffs of whole
cigarette smoke were necessary to produce ciliostasis; similar
relationships were demonstrated in the tracheas of living cats
(Dalhamn 1970; Dalhamn et al. 1968). Several investigators have
established a stimulus—response relationship between dilutions of
aqueous cigarette smoke extract and the time of exposure required
for total stoppage of ciliary beat frequency in different experimental
models (Donnelly 1969, 1972; Das et al. 1970; Donnelly et al. 1981).
The mechanism by which cigarette smoke acutely depresses ciliary
function is not clearly known, but may involve enzyme inhibition of
adenylate kinase, thereby reducing adenosine triphosphate (ATP),
the energy source for ciliary bending (Mattenheimer and Mohr 1975;
Schabort 1967). Ciliary function in response to short-term cigarette
smoke inhalation has not been studied in man.
Mucus
Very little is known about the quantity and rheologic properties of
airway secretions after short-term cigarette smoke exposure. A brief
exposure of slugs to cigarette smoke has been reported to stimulate
the production of mucus containing an increased number of acid
glycoprotein fibers (Wilde 1981). The significance of this observation
with respect to the human respiratory tract is not clear, except that
an increased number of acid glycoprotein fibers has also been
demonstrated in sputum obtained from cigarette smokers.
Mucociliary Interaction
Using a variety of different techniques in animal experiments,
ciliary dysfunction and impairment of mucociliary transport by
short-term exposure to cigarette smoke have been demonstrated in
rats (Iravani 1972; Dalhamn 1964; Ferin et al. 1966), rabbits
(Dalhamn 1964; Holma 1969), cats (Carson et al. 1966; Dalhamn
1964, 1969: Kaminski et al. 1968), dogs (Guillerm et al. 1972;
Sakakura and Proctor 1972; Isawa et al. 1980), donkeys (Albert et al.
1974, 1969), chickens,-and sheep (Stupfel et al. 1974). A few reports
289
have not demonstrated that short-term exposure to smoke depresses
mucociliary function in animal models (La Belle et al. 1966; Bair and
Dilley 1967). The reasons for the discrepancy between these and the
previously listed studies are not clear, but may be related to
methodology and dose of exposure. Stimulus response curves be-
tween dose of cigarette smoke and the degree of mucociliary
inhibition have been shown in airways of chickens and dogs (Battista
and Kensler 1970b; Sakakura and Proctor 1972; Isawa et al. 1980). In
one study, for example, 9 puffs of nonfiltered cigarette smoke had
variable effects on tracheal mucociliary transport in intact dogs, but
tracheal mucociliary transport was consistently inhibited by 12 puffs
(Sakakura and Proctor 1972). Likewise, the number of 4-second
exposures to cigarette smoke (separated by 1 minute) required to
reduce mucus transport in intact chicken tracheas by more than 90
percent has been shown to increase with increasing dilutions (from
50 to 3 percent) of smoke in air (Battista and Kensler 1970b).
Measurements of mucociliary clearance in man immediately after
smoking one or more cigarettes have shown conflicting results, with
either increased (Albert et al. 1973; Camner et al. 1971; Albert et al. -
1975; Camner and Philipson 1971, 1974), inconsistent, or unchanged
rates (Yeates et al. 1975; Pavia et al. 1971; Goodman et al. 1978) or -
decreased (Nakhosteen et al. 1982) rates. Transient effects on
mucociliary clearance have been reported in both smokers and
nonsmokers (Hilding 1956; Pavia et al. 1971). Such differences
between human subjects may reflect a difference in the dose and
inhalation pattern of cigarette smoke.
Long-Term Exposure
In dogs inhaling cigarette smoke through a tracheostomy, histolog-
ic changes have been observed in the bronchi after 229 to 421 days of
exposure (Auerbach et al. 1967b). These changes consisted of
epithelial hyperplasia, decreased number of ciliated cells, and areas
of squamous metaplasia. This may be criticized as a poor model of
cigarette smoking in humans because the upper airway, which
absorbs part of the smoke and decreases its toxicity, is bypassed. The
irritant effect of cigarette smoke on the tracheobronchial mucosa
could be enhanced in this model. However, inflammatory changes in
the airways have also been observed in animals that inhaled
cigarette smoke via their upper airways (Leuchtenberger et al. 1958;
Rylander 1974; Mattenheimer and Mohr 1975; Park et al. 1977;
Basrur and Basrur 1976; Jones et al. 1973; Iravani 1973). Various
types of lesions have been observed, including tracheal and bronchial
epithelial hyperplasia (Park et al. 1977; Frasca et al. 1974), goblet
cell proliferation and submucosal gland hypertrophy (Jones et al.
1973; Park et al. 1977), bronchiolar metaplasia of mucus-secreting
cells (Basrur and Basrur 1976), increased quantities of airway mucus
290
that appear to be adherent to submucosal gland openings (Iravani
1973), and a decreased number of ciliated epithelial cells (Basrur and
Harada 1979). One study suggested a dose-dependence of the mucosal
lesions when comparing hamsters exposed to either four cigarettes
per day or eight cigarettes per day for 2 weeks (Basrur and Basrur
1976). The pathologic changes produced by long-term cigarette
smoke exposure appear to be reversible if the exposure time is not
excessive. Thus, inflammatory changes in the airways of hamsters
exposed to cigarette smoke for 4 weeks showed marked reversibility
with a recovery time of several weeks (Basrur and Harada 1979).
The histologic changes in the airways of cigarette smokers are
similar to those produced by cigarette smoke in animal models, and
consist of varying degrees of denudation of the ciliated epithelium,
an increase in the number of goblet cells, submucosal gland
hypertrophy, and squamous metaplasia (Regland et al. 1976; Jones
1981). Morphometric studies have demonstrated an increased quan-
tity of mucus in the airway lumen without histologic evidence of
coexistent emphysema or a history of obstructive lung disease,
whereas this is not observed in the lungs of healthy nonsmokers
(Niewoehner et al. 1974; Matsuba and Thurlbeck 1971). Electron
microscopic examination of ciliated epithelium in surgical lung
specimens obtained from cigarette smokers has revealed ciliary
abnormalities consisting of compound cilia, single axoneme, intra-
cyctoplasmic microtubular doublets, and cilia within periciliary
sheaths (McDowell et al. 1976). If bronchial biopsy material is used to
detect ciliary abnormality in cigarette smokers, the results must be
interpreted with caution, for a single biopsy may be misleading
owing to the focal nature of the lesions (Fox et al. 1981).
The morphologic changes of the respiratory mucosa in animals
exposed to cigarette smoke for prolonged periods and in human
cigarette smokers strongly suggests the presence of mucociliary
dysfunction. This has been clearly demonstrated, particularly with
respect to the production and clearance of mucus.
Cilia
Ciliary function after long-term cigarette smoke exposure has not
been extensively studied. Iravani and Melville (1974) demonstrated a
decrease in ciliary beat frequency in the airways of hamsters
exposed to cigarette smoke for 1 year; however, in rats also exposed
for 1 year under almost identical conditions, ciliary frequency was
generally increased, although there were zones of ciliary inactivity
or discoordination. A sustained inhibition of adenylate kinase
activity in ciliated tracheal cells of hamsters exposed to cigarette
smoke for up to 9 months has also been reported (Mattenheimer and
Mohr 1975). Because inhibition of this enzyme leads to a decreased
generation of adenosine triphosphate. the energy source of ciliary
291
bending, a decreased ciliary activity might be expected (Mattenheim-
er and Mohr 1975).
Mucus
Mucus hypersecretion has been clearly demonstrated in the
airways of several animal species exposed to cigarette smoke for
prolonged periods of time (Battista and Kensler 1970a; Iravani and
Melville 1974). Rheologic measurements of airway mucus have not
been reported in such animal experiments, but biochemical analysis
has revealed the presence of serum proteins that might have
cilioinhibitory effect (Dalhamn and Pira 1979; Battista 1980). Mucus
hypersecretion may occur as early as 1 month after beginning a
smoke inhalation equivalent to as little as one cigarette per day
(Battista and Kensler 1970a). Rheologic and biochemical examina-
tions of airway secretions in healthy smokers have not been carried
out, primarily because these subjects do not have a productive cough.
Once a smoker develops chronic productive cough, he or she is no
longer considered healthy, but by definition, has chronic bronchitis.
Mucociliary Interaction
Long-term effects of cigarette smoke on airway mucociliary
transport have been studied in different animal species. In purebred
beagle dogs exposed to cigarette smoke (100 cigarettes per week) for
13.5 months via a mask that administered cigarette smoke through
both the mouth and the nose for 1.5 hours twice daily, tracheal
mucus transport rate was decreased to approximately 30 percent of
that observed in control animals (Wanner et al. 1973). Pulmonary
function did not differ significantly between the two groups. It has
subsequently been shown that the abnormality in mucociliary
transport in beagles may already be present after 6 months of
cigarette smoke exposure (Park et al. 1977). An impairment of
mucociliary clearance with long-term cigarette smoke exposure has
also been demonstrated in rabbits, guinea pigs, rats, and chickens
(Okajima 1971; Rylander 1971b; Iravani and Melville 1974; Battista
and Kensler 1970a). In some of those experiments, impaired mucoci-
liary clearance was already observed 4 weeks after the beginning of
exposure.
The long-term effects of cigarette smoking on mucociliary function
in human subjects has been investigated by aerosol clearance
techniques and discrete marker transport techniques. Some of the
investigators using radioactive aerosols demonstrated no abnormali-
ty of overall clearance in habitual cigarette smokers, particularly in
those who already may have had symptoms of chronic bronchitis
(Sanchiz et al. 1972; Yeates et al. 1975; Pavia et al. 1970; Pavia and
Thomson 1970). However, the deposition of the inhaled radioactive
292
aerosol is more central in normal smokers and in patients with
chronic bronchitis than in nonsmokers (Lippman et al. 1970).
Because clearance is faster in central airways than in peripheral
airways, this centralization of aerosol deposition may compensate for
the overall decrease in mucociliary clearance. Investigations that
have related mucociliary clearance to deposition pattern have
generally found an impairment of mucociliary clearance in cigarette
smokers (Lourenco et al. 1971; Camner et al. 1973a; Camner and
Philipson 1972, 1974). Camner and Philipson (1972), in a study of 10
pairs of twins discordant for cigarette smoking, showed a significant-
ly lower average clearance rate in smokers compared with nonsmok-
ers; in 5 pairs clearance was slower in the smoker than in the
nonsmoker, whereas in the remaining 5 pairs there was no differ-
ence. Analysis of regional clearance has produced further evidence
that overall clearance of inhaled radioactive aerosols may fail to
detect an abnormality in mucociliary clearance. Thus, Bohning and
co-workers (1975) studied the deposition and clearance of 7 ym
diameter particles in the tracheobronchial tree of six pairs of
monozygotic twins, four of whom were discordant for cigarette
smoking. They found comparable overall mucociliary clearance in
the smoking and nonsmoking pairs, but more central deposition and
slower central clearance in the smokers. Others have reported an
impairment of peripheral mucociliary clearance and alveolar clear-
ance as well (Matthys et al. 1983; Cohn et al. 1979).
Discrete particle techniques involving either bronchoscopy or
radiography have been used to assess mucus transport in central
airways, notably the trachea. Most investigators have reported a
decrease of tracheal mucus velocity in healthy smokers, with values
ranging between 20 percent and 80 percent of those of nonsmoking
controls (Goodman et al. 1978; Toomes et al. 1981; Nakhosteen et al.
1982).
The bulk of the evidence indicates that long-term cigarette
smoking alters mucociliary transport mechanisms and that these
changes can occur as early as 1 year after smoking onset. Partial
recovery of mucociliary transport has been observed in cigarette
smokers after cessation for 3 months or more, but not after 1 week of
cessation (Camner et al. 1973). These observations have also been
supported by animal experiments (Albert et al. 1971).
Fractionation and Filtering of Cigarette Smoke
Whole cigarette smoke is composed of volatile elements and
particulate matter, and it has become customary to distinguish
between the gas phase and the particulate phase. The gas phase, by
definition, consists of the components that remain after cigarette
smoke has been “effectively” filtered by passing it through appropri-
ate filters (Dalhamn 1966; Kensler and Battista 1963; Falk et al.
293
1959). The major constituents of the particulate phase are nicotine,
phenols, hydrocarbons, aldehydes and ketones, organic acids, and
alcohols. Although 95 percent of the gas phase (approximately 300
ml per cigarette).congists of combustion precucts and admixed air
(nitrogen, oxygen, carbon dioxide, carbon monoxide) in concentra-
tions that do not affect mucociliary transport, some trace gases are
important (Battista et al. 1962). These include nitrogen dioxide,
ammonia, cyanides, aldehydes, ketones, acrolein, and acids. As is
shown below, some controversies still remain about whether the gas
phase or the particulate phase of cigarette smoke is primarily
responsible for its depressant effect on mucociliary activity. This
problem is relevant when comparing the effects on mucociliary
clearance of low tar versus high tar cigarettes, low nicotine versus
high nicotine cigarettes, and filtered versus nonfiltered cigarettes.
Dalhamn (1966) reviewed the controversy over the separate effects
of the gas and the particulate phases of cigarette smoke on
mucociliary function. In protozoa, both phases of cigarette smoke
have been shown to possess ciliotoxic properties (Kennedy and
Elliott 1970). Falk and associates (1959) reported that exposure to
whole cigarette smoke for 30 seconds resulted in a biphasic response,
with an initial stimulation, followed by depression with a minimum
value at about 15 minutes and a tendency toward recovery 45
minutes after exposure. Removal of the particulate matter in
cigarette smoke by passing it through filters decreased its depressant
effect on mucus transport, indicating that the major effect on
mucociliary clearance was related to the particulate phase. Similar
observations have been made by others (Rylander 1970; Falk et al.
1959). In contrast, Kensler and Battista (1963) incriminated the gas
phase of cigarette smoke; they exposed strips of rabbit trachea to
smoke from different cigarettes for 12 seconds and identified various
gas phase constituents as having a depressant effect on mucus
transport. These findings have also been confirmed by others in in
vitro and in in vivo animal experiments (Kensler and Battista 1963;
Hee and Guillerm 1973; Dalhamn 1956; Albert et al. 1974; Carson et
al. 1966).
The most comprehensive study of individual gas and semivolatile
constituents of cigarette smoke has been conducted by Petterson et
al. (1982). Using chicken tracheal organ cultures, they showed that
at a 5 mm concentration, 36 percent of 316 different compounds
caused ciliostasis after 15 seconds of exposure, but 50 percent were
without effect after an exposure time of 60 seconds. On the basis of
this criterion of separation, either alkylated phenylethers, benzoni-
triles, benzaldehydes, benzenes, napthalenes and indoles, or a-satu-
rated, B-unsaturated ketones and aldehydes, or aliphatic alcohols,
aldehydes, acids, and nitrates were found to be ciliotoxic. Inactive
compounds included benzoic acids, esters, polyaromatic hydrocar-
294
bons, amines, and N-heterocycles (except indoles). With respect to
aldehydes, the time to ciliostasis on tissues of rabbit trachea has
been reported shortest for formaldehyde, followed by acetaldehyde,
acrolein, crotonaldehyde, and methacrolein. The ciliotoxic effects of
aldehydes have been confirmed by others using different experimen-
tal approaches (Guillerm et al. 1968; Hee and Guillerm 1973;
Kensler and Battista 1963). It has also been shown that acute
acrolein inhalation causes denudation of ciliated cells, goblet cell
discharge, exfoliation of surface epithelial cells, and infiltration of
inflammatory cells in the lower airways of several different mam-
mals (Dahlgren et al. 1972). Another volatile constituent of cigarette
smoke with marked cilioinhibitory effects is hydrogen cyanide
(Wynder et al. 1965a).
Weissbecker et al. (1971) used a different approach to assess the
effects of several volatile cigarette smoke constituents on mucocili-
ary transport in the cat trachea. The addition of individual volatile
cigarette smoke components (isoprene, nitric oxide, and nitrogen
dioxide) to carbon-filtered cigarette smoke either aggravated the
impairment of tracheal mucus velocity produced by the filtered
smoke or abolished the protection afforded by the carbon filter.
When these constituents were added to whole cigarette smoke, no
further impairment of mucus transport velocity was observed,
indicating a saturation by whole cigarette smoke of receptors
responsible for mucociliary depression.
A direct relation has been reported between tar content and the
ciliotoxic effect of cigarette smoke (Dalhamn and Rylander 1967;
Falk et al. 1959). However, Falk and associates (1959) found no
difference between low tar and high tar cigarette residues with
regard to in vitro mucociliary transport. The effects of nicotine on
mucociliary transport are also controversial, although more investi-
gators have demonstrated a lack of effect (Falk et al. 1959; Guillerm
et al. 1972; Rakieten et al. 1952; Donnelly 1972) than a depression of
mucociliary transport (Carson et al. 1966). Indeed, a biphasic dose-
dependence has been suggested, with stimulation at lower concentra-
tions and depression at higher concentrations (Tsuchiya and Kensler
1959). The stimulation of mucociliary function may be related to
stimulation of nicotinic ganglionic receptors causing cholinergic
ciliostimulation. This is based on the observation that the stimulat-
ing effect of nicotine-containing cigarettes on the metachronal wave
frequency in the maxillary sinus of anesthetized rabbits is blocked by
atropine and hexamethonium (Hybbinette 1982).
Among the different cigarette tobacco additives, menthol does not
interfere with mucociliary transport (Rakieten et al. 1952). With
respect to phenols, one investigator has reported that the ciliotoxici-
ty of cigarette smoke produced by freeze-dried tobacco is the same as
that produced by conventionally cured tobacco although the former
295
contains less phenol (Enzell et al. 1971). On the other hand, phenols -
have been shown to impair mucociliary activity and mucus transport
both in vitro (Dalhamn and Lagerstedt 1966; Bernfeld et al. 1964;
Dalhamn 1968) and in vivo (Dalhamn 1968). Dalhamn and associates
(Dalhamn and Lagerstedt 1966; Dalhamn 1968) have even attempted
to relate the toxicity of various phenols to their boiling points.
Addition of the anti-inflammatory agents phenylvinyloxadiozole and
phenylmethyloxadiozole to tobacco has been shown to reduce the
ciliotoxicity of tobacco smoke (Dalhamn and Rylander 1971; Rylan-
der 1971b; Dalhamn 1969), and treatment of rats undergoing long-
term exposure to tobacco smoke with phenylmethyloxadiozole has
been shown to protect the animals against the cigarette-smoke-
induced increase in the number of goblet cells in the respiratory
mucosa (Jones et al. 1973). :
It can be concluded from these studies that both the particulate -
phase and the gaseous phase of cigarette smoke impair mucociliary
function, that a large number of volatile components are ciliotoxic,
that nicotine may or may not contribute to ciliotoxicity, and that the
additive phenol is ciliotoxic, but the anti-inflammatory agents
phenylmethyloxadiozole and phenylvinyloxadiozole afford partial
protection against the deleterious effects of cigarette smoke. The -
mechanisms by which the various constituents of cigarette smoke
interfere with mucociliary transport are unknown. On the basis of
experiments in the fresh water mussel, it has been suggested that -
ciliotoxicity depends on their pH in solution (Wynder et al. 1963). It -
should be noted, however, that such in vitro experiments requiring
an aqueous medium do not necessarily reflect the type of exposure
occurring in smokers in whom contact between cigarette smoke and —
the ciliated epithelium is made by impingement or bypass.
Effects of Filters
Because the toxic effect of cigarette smoke on mucociliary trans-
port mechanisms seems to reside both in the gas phase and in the
particulate phase, the filtering of cigarette smoke before inhalation
may be protective. It has been clearly shown that a longer exposure ~
time is needed for ciliostasis to occur with smoke from filtered
cigarettes than from unfiltered cigarettes, with respect to both
ciliary activity in vitro and mucociliary transport in vivo (Dalhamn -
and Rylander 1964; Dalhamn 1964).
Four major types of filters have been evaluated: cellulose acetate
(Cambridge filter), charcoal, glass fiber, and aqua. The histologic -
changes in the airways of guinea pigs exposed to unfiltered cigarette
smoke for 4 to 8 weeks were not seen when cigarette smoke was
passed through a Cambridge filter (Rylander 1974). Likewise, -
Kaminski and coworkers (1968) have shown that cellulose-acetate
filters provide protection for the mucociliary activity in the cat
296
trachea. Similar results have been obtained in other experiments
involving in vitro and in vivo systems (Dalhamn and Rylander 1968:
Donnelly 1972; Wynder et al. 1965b), and cellulose-acetate filters
have been found to reduce the inhibitory effect of cigarette smoke on
tracheal epithelial adenylate kinase activity in hamsters exposed for
1 to 5 days (Mattenheimer and Mohr 1975). Charcoal filters are also
capable of reducing the ciliotoxicity of cigarette smoke (Kaminski et
al. 1968; Kensler and Battista 1963; Battista and Kensler 1970a, b).
In one study involving cat tracheas, short-term exposure to a
standardized dose of cigarette smoke decreased particle transport
rates by 50 percent when unfiltered smoke was used, by 40 percent
when the cigarette smoke was passed through a cellulose-acetate
filter, and by 20 percent when a carbon-cellulose filter was used
(Carson et al. 1966). In another comparison of different studies, a
charcoal filter was more effective than a cellulose-acetate filter in
reducing the metachronal wave frequency and mucus transport of
the eulamellibranch gill in vitro (Wynder et al. 1965b). Glass-fiber
and aqua filters were generally less effective (Isawa et al. 1980;
Wynder et al. 1965b).
As expected, better protection might be provided by combined
filters because they remove components of the particulate and the
gaseous phase of cigarette smoke more effectively. Thus, a combina-
tion of cellulose-acetate and charcoal filter has been found to be
more effective than either filter alone (Dalhamn 1966; Wynder et al.
1965b).
Mucociliary Function in Chronic Bronchitis
Since chronic bronchitis is defined clinically as chronic productive
cough rather than by clearly defined morphologic or functional
abnormalities (American Thoracic Society 1962), some of the previ-
ously reviewed studies of mucociliary function in cigarette smokers
may have included patients with chronic bronchitis as well. Con-
versely, most patients with chronic bronchitis are cigarette smokers
or have been cigarette smokers in the past. Although it is very
difficult to separate the direct effects of cigarette smoke on mucocili-
ary transport from those related to the pathophysiologic changes of
chronic bronchitis, the discussion herein is limited to mucociliary
function in chronic bronchitis without considering the direct effects
of cigarette smoke on the mucosa.
The histologic changes of the mucociliary apparatus in chronic
bronchitis include hypertrophy and hyperplasia of the submucosal
glands, an increase in the number and distribution of goblet cells,
and goblet cell metaplasia in smaller airways (Reid 1967). In
addition, atrophy of the columnar epithelium (Wright and Stuart
1965) and spotty squamous metaplasia (Kleinerman and Boren 1974)
297
480-144 0 - 85 - 11
have been reported. A decrease in both the number of ciliated cells
and the mean ciliary length has been noted in the larger airways in
patients with chronic bronchitis (Wanner 1977), and electron micro-
scopic examinations of the airway epithelium show subtle abnormal-
ities in bronchial biopsy material (Miskovitz et al. 1974). Auerbach
and associates (1962), in a large post-mortem study of cigarette
smokers, reported epithelial lesions with loss of cilia in up to 30
percent of random sections, compared with approximately 15
percent of sections from nonsmokers. These ultrastructural changes
consisted of swelling and serration of the epithelium with transfor-
mation of the goblet cell granules. The capsule surrounding the cilia
was irregular, with areas of breakage and outward projections; some
cilia showed fibrillar degeneration or were fused to form compound
cilia.
The presence of visible respiratory secretions is a frequent
endoscopic finding in patients with chronic bronchitis, and increased
amount of bronchial secretions can be seen on pathologic sections of
the lung (Kleinerman and Boren 1974; Hogg et al. 1968). Thus, the
morphologic changes of chronic bronchitis involve both the ciliary
apparatus and the mucus-producing structures.
Cilia
In vitro examination of ciliated lower airway epithelial cells
obtained from chronic bronchitis patients by brushing has failed to
reveal an abnormality in beat frequency (Yager et al. 1980).
However, in vitro study of ciliary function is of limited informative
value since the ciliated cells are suspended in an artificial medium
and are not exposed to their natural milieu. This may explain the
discrepancy between this study and one reported by Iravani and Van
As (1972), in which ciliary motion was observed in vivo with an
incident light technique. In the carefully dissected tracheobronchial
tree of rats with experimental chronic bronchitis, the ciliary system
showed discoordination and zonal akinesia. In addition, reversals of
transport direction, whirlpool formations, and inactive zones without
ciliary motion as large as 2 mm by several hundred ym were seen.
Mucus
The distribution, amount, and rheologic properties of mucus
within the airways have not been studied in chronic bronchitis, but
extensive literature exists on the biochemistry (Boat and Mathews
1973) and rheology of expectorated sputum from patients with
chronic bronchitis. These results must be interpreted with caution,
partly because of contamination with saliva and the rapid physical
alteration of expectorated sputum, and partly because normal
respiratory secretions for comparison are virtually impossible to
obtain. Mucoid sputum of patients with chronic bronchitis is
298
biochemically similar to sputum of normal subjects induced by
hypertonic saline aerosol, with the exception of a slightly higher
fucose and neuraminic acid content in the former (Lopata et al.
1974). In purulent sputum from these patients, biochemical changes
typical of inflammatory conditions (increases in the dry weight and
deoxyribonucleic acid content and increased cross-linking by hydro-
gen bonding) were observed. Reid (1968) showed that the neuraminic
acid content of sputum is increased in chronic bronchitis, suggesting
augmented secretion by the mucus-producing structures. This find-
ing is supported by histochemical studies indicating distended acini
of the submucosal glands in patients with chronic bronchitis
compared with normal subjects, along with an increase in the
volume of both the acid and the neutral mucopolysaccharide-produc-
ing acini (Reid 1968).
Impaired mucus transport in chronic bronchitis may, in part, be
related to the rheologic abnormalities of respiratory secretions.
Deviation from the ideal ratio between viscosity and elasticity may
prevent an optimal interaction between cilia and mucus, thereby
decreasing mucus transport rates (Dulfano and Adler 1975; Adler
and Dulfano 1976). Higher values of sputum viscosity and lower
values of sputum elasticity have been observed during exacerbations
of chronic bronchitis than during clinical stability (Dulfano et al.
1971). In addition, purulent sputum has a higher viscosity than
mucoid sputum (Charman and Reid 1972; Mitchell-Heggs et al.
1974), suggesting a relationship between the concentration of certain
mucus constituents and mucus rheology. Indeed, examination of
sputum obtained from patients with chronic bronchitis has shown
positive correlations between protein content (particularly IgA) and
mucus glycoprotein content on the one hand and viscosity on the
other (Harbitz et al. 1980; Lopez-Vidriero and Reid 1978). That
altered rheologic properties of airway secretions play a role in
abnormal mucociliary clearance has been suggested by an observed
relationship between in vivo mucociliary clearance, in vitro trans-
portability of expectorated sputum (using the frog palate), and the
viscoelastic properties of sputum (Puchelle et al. 1980).
Mucociliary Interaction
Mucus transport has been studied either by directly or indirectly
observing the motion of discrete particles placed on the tracheal
mucosa (Santa Cruz et al. 1974; Goodman et al. 1978) or by the
deposition pattern and clearance rates of inpaled radioactive aero-
. sols (Lourenco 1970; Camner et al. 1973a, b; Luchsinger et al. 1968;
Patrick and Stirling 1977; Dulfano et al. 1971). In one study, a
marked slacking of tracheal mucus velocity sas found in 15 patients
with chronic bronchitis who were between 57 and 71 years of age
(Santa Cruz et al. 1974). Clinical examination and pulmonary
299
(mm . min)
TRACHEAL NUCOCILIARY TRANSPORT VELOCITY
FIGURE 2.—Comparison of mean (S.E. in bracket) tracheal
mucociliary transport velocity among young
nonsmokers (n=10), elderly nonsmokers (n=7),
healthy young ex-smokers (n=9), healthy
young smokers (n=15), and patients with
chronic bronchitis (n=14)
SOURCE: Goodman et al. (1978).
function tests diagnosed these patients as having both chronic
bronchitis and emphysema. Mucociliary clearance of inhaled aero-
sols is also altered in patients with chronic bronchitis. The clearance
of inhaled particles from the lung is influenced by the deposition
pattern, which in turn depends on particle size and flow regime in
the airways. Clearance rates, therefore, can be interpreted only if
particle deposition is carefully monitored (Pircher et al. 1965; Lopez-
Vidriero 1973). Coughing, which is difficult to control in such
patients, may also contribute to the clearance of particles (Toigo et
al. 1963). For these reasons, it is not surprising that mucociliary
clearance has been reported to be increased (Muller et al. 1975;
Luchsinger et al. 1968), normal (Thomson and Short 1969), or
decreased (Lourenco 1970; Camner et al. 1973a, b; Tiogo et al. 1963;
Mossberg and Camner 1980; Agnew et al. 1982) in patients with
chronic bronchitis.
Once a subject has developed chronic bronchitis, cessation of
smoking does not reverse the effect on mucociliary function, and a
similar impairment of mucociliary transport has been reported in
smokers and ex-smokers with this disorder (Agnew et al. 1982; Santa
Cruz et al. 1974; Goodman et al. 1978). Persistence of mucociliary
300
dysfunction in patients with chronic bronchitis after cessation of
smoking has also been reported in a small prospective study (Camner
et al. 1973b).
Thus, both patients with chronic bronchitis and healthy smokers
exhibit an impaired mucociliary function. However, the magnitude
of the impairment is not the same as suggested by Goodman et al.
(1978), who demonstrated a greater impairment of tracheal mucocili-
ary transport rates in smokers and nonsmokers with chronic
bronchitis than in healthy smokers (Figure 2).
The consequences of airway mucociliary dysfunction have not
been satisfactorily examined, but may include increased susceptibili-
ty to respiratory infections, airflow obstruction by excessive airway
secretions, and increased risk of carcinogenesis resulting from
prolonged contact between inhaled carcinogens and the respiratory
epithelium (Matthys et al. 1983; Hilding 1957; Moersch and McDon-
ald 1953).
Summary and Conclusions
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
and of decreased levels of a,-antiprotease secondary to oxida-
tion by cigarette smoke.
5. 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.
6. Cigarette smoke produces structural and functional abnormali-
ties in the airway mucociliary system.
7. 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
301
causes an impairment of mucociliary clearance. This impair-
ment is associated with epithelial lesions, mucus hypersecre-
tion, and ciliary dysfunction.
8. Chronic bronchitis in smokers and ex-smokers is characterized
by an impairment of mucociliary clearance.
9. Both the particulate phase and the gas phase of cigarette
smoke are ciliotoxic.
302
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328
CHAPTER 6. LOW YIELD
480-144 0 - 85 -
12
CIGARETTES AND
THEIR ROLE IN
CHRONIC
OBSTRUCTIVE LUNG
DISEASE
329
CONTENTS
Introduction
Problems of Measurement by Machine
Effect of Low Tar and Nicotine Cigarettes on Cough and
Phlegm Production and Development of Chronic
Obstructive Lung Disease
Epidemiologic Studies
Mechanisms of Lung Damage
Variation in Smoking Pattern With Switching to Low
Tar and Nicotine Cigarettes
Smoking Behavior
Carbon Monoxide Uptake
Nicotine Uptake
Role of Tar Content
Variations in Pattern of Cigarette Smoke Inhalation
Use of Additives in Low Tar and Nicotine Cigarettes
Research Recommendations
Summary and Conclusions
References
331
Introduction
Following the initial reports in the early 1950s linking cigarette
smoke with lung cancer, the pathogenic role of cigarette tar content
received considerable emphasis. Because the tar fraction of the
smoke contained the bulk of the carcinogenic effect of whole smoke,
and because lung cancer risk was closely related to other measures of
total smoke exposure (number of cigarettes smoked per day, depth of
inhalation, etc.), it was suggested that risk might be related to the
amount of tar generated by different cigarettes. This prompted
health authorities to advise smokers who were unable to quite
smoking to switch to low tar cigarettes (U.S. Senate 1967; Health
Department of the United Kingdom 1976). To facilitate this process,
the Federal Trade Commission published smoking-machine assays of
the tar and nicotine yield of different cigarette brands (Pillsbury et
al. 1969). This approach to low tar and nicotine cigarettes was based
on the assumption that smoking lower yielding brands, as deter-
mined by a smoking-machine, would result in a proportional
reduction in the lung’s exposure to these toxic substances. This
approach to “safer” cigarette smoking has been promoted by the
tobacco industry and apparently accepted by the smoking public, as
evidenced by the escalation in sales of low tar and nicotine
cigarettes. However, there is increasing evidence that this concept of
a “less hazardous” cigarette is misleading; although definitive
studies are still awaited, it appears that switching from regular to
low tar and nicotine cigarettes may not substantially reduce the risk
of chronic airflow obstruction.
Problems of Measurement by Machine
The first step in evaluating the relative health risks of different
cigarettes is to establish some standardized measure of the toxic
substances in different cigarettes in order to facilitate comparison.
Quantifying each of the several thousand constituents of cigarette
smoke for each brand of cigarette, and assessing the changes in these
constituents as the manufacturing and agricultural processes
change, would be a truly herculean task; therefore, a more modest
goal of quantifying tar and nicotine yields was accepted. To date, the
yields determined by the Federal Trade Commission have been the
most widely adopted. These measurements are obtained with a
laboratory smoking-machine, which consists of a syringe pump that
takes a 35 ml bell-shaped puff from a cigarette, over a 2-second
period, once per minute until a predetermined butt length is
reached, either 23 mm for nonfiltered cigarettes or 3 mm longer than
the filter overwrap for filter-tipped cigarettes (Pillsbury et al. 1969).
These parameters are based on observations of smoking patterns in
seven subjects in Europe in 1933 (Kozlowski 1983). Today’s cigarette
333
is markedly different from that smoked in 1967 when these
parameters were established, yet the same parameters are still
employed.
Measurements obtained using these parameters indicate a marked -
reduction in the tar and nicotine yield of cigarettes over the last
decade (Figure 1). In addition to the actual tar and nicotine yield of
the tobacco, the yield measured by a smoking-machine is influenced
by many factors, including cigarette length and diameter, porosity of
the cigarette paper, presence of a ventilated or an unventilated
filter, butt length, number of puffs, interpuff interval, puff volume,
puff duration, puff pressure profile, and frequency of puffing at
different stages of cigarette consumption. The number of puffs is
important in determining the tar yield of a cigarette, and the
number of puffs taken from some brands with the official smoking--
machine has significantly declined in recent years (Kozlowski 1981).
Since puffs are taken at 1-minute intervals, a more rapidly burning
cigarette will have a smaller number of puffs. The burning time of
the cigarette is determined by porosity of the cigarette paper, the.
amount of tobacco in the cigarette, and the diameter of the cigarette
column. In a survey of Canadian cigarettes between 1969 and 1974,
Kozlowski et al. (1980b) noted a significant reduction in the number-
of puffs taken in the official assays over this time period, which was
strongly correlated with a reduction in tar yield. Omission of the last.
few puffs can markedly affect tar yield, because tar delivery.
increases with each puff, and the last few puffs from a cigarette can
contain twice as much tar as the first few puffs (Wiley and Wickham
1974). Currently published yields do not indicate the number of puffs
taken, which may range from 7 to 12 and may result in a marked.
variation of the tar yield.
Ventilated cigarette filters, which cause inhaled smoke to be.
diluted with air, are one of the major methods of achieving low tar
yields (Gori and Lynch 1978). Cigarettes with ventilated filters
constituted about 25 percent of all cigarette sales in the United
States in 1979 (Hoffmann et al. 1980). During systematic interviews,
Kozlowski et al. (1980a) found that from 32 to 69 percent of low tar.
smokers block these filter perforations with their fingers or lips, a
feature unaccounted for by smoking-machines. This hole blocking
increased the yield of toxic products by 59 to 293 percent. :
If a person smokes a cigarette in a manner identical to the
smoking-machine, the delivery of tar and nicotine to the mouth will
be the same as that estimated by the machine. Human smoking
patterns are diverse, however, and show considerable variation from
the machine parameters; puff volumes range from less than 20 ml to
more than 90 ml (Tobin and Sackner 1982), compared with the fixed
35 ml volume employed by the machine. Differences in puff profile
from the bell-shaped puff used by the machine also alter cigarette
334
Tar mg Nicotine mg
40.0 40
T\
35.0 \ 35
300 20
wo
25.0 x 25
\
\ an
20.0 4 2.0
\ Nicotine PN
15.0 Ps 15
~ y ——
\Y ~ Ty~. NN
ad
~~
~
10.0 Sat 10
5.0 0.5
00 0.0
1950 1955 1960 1965 1970 1975 1980
FIGURE 1.—USS. sales-weighted average tar and nicotine
yields
SOURCE: American Cancer Society (1981).
yield. Numerous studies indicate that smokers compensate for lower
yielding cigarettes by altering their style of smoking. For each
different cigarette brand, smokers may have a different smoking
sattern. To provide more meaningful information, smoking-ma-
shines should be designed to reproduce variations in the manner of
smoking each cigarette brand, and their assays should provide both
in average and a range of tar and nicotine yields depending on the
ndividual pattern of smoking (USDHHS 1981).
Many investigators have examined the relationship between the
nachine-determined nicotine yield of a cigarette and the concentra-
ion of nicotine or its metabolites in blood or urine. A fair correlation
vas observed in some studies (Goldfarb et al. 1976; Herning et al.
983), but most studies have revealed a poor correlation (Russell et
1. 1975, 1980; Sutton 1982; Feyerabend 1982; Benowitz et al. 1983).
Aachine-determined nicotine yield accounts for only from 4 (Russell
t al. 1980) to 25 percent (Herning et al. 1983) of the variation in
leod nicotine concentration, whereas 50 to 60 percent of the
ifferences in blood nicotine levels are attributable to individual
335
smoking behavior. The overriding importance of the pattern of
smoking in determining nicotine delivery from a cigarette was
underlined in a recent study demonstrating that the nicotine content
of the unburned tobacco was similar for cigarettes with high and low
nicotine yields determined by smoking-machine assays (Benowitz et
al. 1983).
The concept of providing the smoker with information on cigarette
yield need not be abandoned. Smoking-machines can be designed tc
control the puff number, puff volume, puff pressure profile, puff
duration, puff interval, butt length, position of the cigarette during
and between puffs, and “restricted” or “free” smoking, i.e., whether
the butt end is closed or open (Creighton and Lewis (1978a, b). These
parameters should be determined and used to obtain an average and
a range of yields for each brand. Measurement of cigarette yield
should include assays not only of tar and nicotine but also of carbon
monoxide and other toxic substances, because compensatory smok-
ing behavior may alter the exposure to each substance beyond that
expected on the basis of tar and nicotine delivery.
Effect of Low Tar and Nicotine Cigarettes on Cough and
Phiegm Production and Development of Chronic Obstructive
Lung Disease
Cigarette smokers account for the vast majority of deaths from
chronic obstructive lung disease (COLD) (Peto et al. 1983), and the
relative risk for the effects of smoking on mortality from COLD is
even greater than that for lung cancer (see the chapter on Mortality
in this Report). Chronic obstructive lung disease in smokers may
take the following three forms: (1) cough and mucus hypersecretion,
(2) airway obstruction, and (3) emphysema. Frequently the three
components coexist, as all are related to cigarette smoking, but the
agents in cigarette smoke responsible for each type of lung injury
may be different. Over the past 25 years, considerable progress has
been made in our understanding of the role of cigarette smoking in
the pathogenesis and natural history of COLD, but most of the
available data have not related lung function to cigarette yield.
Epidemiologic Studies
The cardinal importance of cigarette smoking in the pathogenesis
of COLD has been repeatedly documented, and generally the
severity of disease increases with increasing cigarette consumption
(Ferris et al. 1976). Because of this dose-response relationship, it has
been hoped that a reduction in cigarette yield by filtration or other
means would reduce the risk of disease (Gori 1976). Available
epidemiologic studies of the effect of low yield cigarettes on the
development of COLD have shown variable results, which reflects
336
marked differences between the studies in terms of the population
studied, sample size, variation in cigarette brands, reference period
of the study, criteria of respiratory involvement, and type of
statistical analysis, and whether the study was of a cross-sectional or
a longitudinal design. Separating the studies by the three compo-
nents of smoking-induced COLD indicates that there is a growing
body of data on the effect of cigarette yield on the development of
mucus hypersecretion and airway obstruction, but currently no
information on the development of emphysema.
Several studies have examined the effect of cigarette yield on
respiratory symptoms and have observed a relationship between
reduction in cigarette yield and the prevalence of cough (Comstock et
al. 1970; Freedman and Fletcher 1976; Fletcher et al. 1976; Dean et
al. 1978; Schenker et al. 1982) and phlegm production (Comstock et
al. 1970; Rimington 1972; Hawthorne and Fry 1978; Higenbottam et
al. 1980b). Tar yield was not defined in some of these earlier studies
(Comstock et al. 1970; Rimington 1972; Dean et al. 1978; Hawthorne
and Fry 1978), but instead a comparison was made between smokers
of plain cigarettes and smokers of filter-tipped cigarettes. The tar
yield was specified in some studies: in the recent study by Schenker
et al. (1982) it ranged from 0.4 to 28 mg; in the studies by Freedman
and Fletcher (1976), from 17 to 20 mg; and in the studies by
Higenbottam et al. (1980b), from 18 to more than 33 ing, higher than
that observed in many of today’s cigarettes. In a cross-sectional
survey of over 18,000 men (Higenbottam et al. 1980b), the beneficial
effect of low tar cigarettes on phlegm production was lost when
subjects smoked 20 or more cigarettes per day, as their prevalence of
phlegm production increased to that observed in higher tar cigarette
smokers. In contrast, in another cross-sectional study of 5,686
women (Schenker et al. 1982), cigarette tar content was a significant
risk factor for chronic cough and of borderline significance for
phlegm production; this effect of cigarette tar content was indepen-
dent of the number of cigarettes smoked per day. Chronic cough or
phlegm production was approximately twice as common in smokers
of high tar (at least 20 mg) cigarettes as it was in low tar (less than 10
mg) smokers. In the latter study, however, multiple logistic regres-
sion analysis indicated that the risk of chronic cough and phlegm
production is more strongly affected by daily cigarette consumption
than by tar content: these symptoms were 4.5 times more common in
smokers of 25 or more cigarettes per day than in smokers of less than
15 cigarettes per day.
A small number of studies have examined the importance of
cigarette yield on change in pulmonary function. In a prospective
study of 680 men, Comstock et al. (1970) noted that smokers of plain
cigarettes, compared with smokers of filter-tipped cigarettes, had a
lower FEV, at entry into the study. Followup measurements showed
337
3.5
—___._™~_ tot 9 Cigarettes
30 —_— 30 smoked per day
FEV, (/1
25
2.0 T T T 1
18-23 24-27 28-32 +33
Tar per cigarette (mq)
FIGURE 2.—Relationship between mean FEV; of
asymptomatic smokers (adjusted for height and
weight) and tar yield of cigarettes, by number
of cigarettes smoked per day
SOURCE: Higenbottam et al. (1980b).
a greater mean reduction of FEV: in users of filter-tips, so that the
reduction was similar in the two groups after 5 to 6 years of followup.
Unfortunately, the variance of the data was not stated, and tests of
statistical significance were not performed. In another longitudinal
survey of 1,355 men, Sparrow et al. (1983) determined the effect of
cigarette tar content, which ranged from less than 16 mg to more
than 22 mg, on pulmonary function. Multiple regression analysis
indicated that tar content did not significantly influence baseline
spirometry or repeat measurements after 5 years of followup. Cross-
sectional epidemiologic surveys also indicate no relationship be-
tween abnormal pulmonary function and the use of filter-tipped
versus plain cigarettes (Beck et al. 1981) or cigarette tar content
(Higenbottam et al. 1980b) (Figure 2).
Interpretation of these studies as evidence that cigarette tar and
nicotine yield is not an important factor in the development of COLD
is premature. First, cross-sectional studies are limited in their
capability of defining the natural history of a disease. Second, COLD
has a very slow progress, and Fletcher et al. (1976) suggest that a
span of approximately 8 years is necessary to establish rates of
change of spirometric values with sufficient confidence even to
distinguish between smokers and nonsmokers. Third, we have no
information on the baseline pulmonary function of smokers at the
time they choose between high or low tar and nicotine cigarettes.
Significant differences in pulmonary function have been observed
between young adults who decide to smoke and those who avoid
cigarette smoking (Tashkin et al. 1983), and it is possible that similar
338
function differences may exist in subjects who choose between high
or low tar and nicotine cigarettes. Fourth, the yield of tar and
nicotine used in many of these studies does not lie in the same range
as that produced by many of today’s cigarettes.
However, the possibility that cigarette tar content is related to the
development of cough and phlegm, but not of dyspnea or airflow
obstruction, is consistent with current concepts of COLD. In a study
of 792 men followed over an 8-year period, Fletcher et al. (1976)
observed that cigarette smokers were susceptible to two distinct
chronic lung diseases—mucus hypersecretion and chronic airflow
obstruction. This has recently been confirmed in a large prospective
study (Peto et al. 1983) of 2,728 men, followed over 20 to 25 years,
which showed that the risk of death from COLD was strongly
correlated with initial degree of airflow obstruction, but bore no
relationship to initial mucus hypersecretion.
Given the evidence that mucus hypersecretion may depend on the
tar fraction of cigarette smoke, while development of airflow
obstruction is more closely linked to the tumber of cigarettes
smoked, Higenbottam et al. (1980b) reasoned that these differences
might be due to a reduction in the particulate phase products,
without a decrease in the gas phase products, in the low tar
cigarettes. They hypothesized that tar droplets and soluble gases,
such as sulfur dioxide and hydrogen cyanide, are more likely to be
deposited or absorbed in the large airways where mucus is produced.
The smaller airways, the earliest site of airflow obstruction, are
exposed to a lower concentration of tar, but to a full concentration of
insoluble gases such as nitrogen dioxide and ozone.
This line of reasoning is in agreement with several studies showing
a reduction in lung cancer with the use of low tar and nicotine
cigarettes (Wynder et al. 1970; Lee and Garfinkel 1981; Rimington
1981; Hammond et al. 1976). The tar fraction is the component of
cigarette smoke particularly linked with the development of both
lung cancer and mucus hypersecretion. Although clinicians have
long linked chronic bronchitis (mucus hypersecretion) with emphyse-
ma, recent evidence indicates that mucus hypersecretion is not
predictive of airflow obstruction, but is significantly greater in those
smokers who develop lung cancer (Peto et al. 1983).
Mechanisms of Lung Damage
Studies of the mechanism of cigarette-smoke-induced lung damage
have contributed significantly to the present understanding of
COLD. Cigarette smoke may initiate and aggravate lung injury by a
number of mechanisms and may also interfere with the lungs’
defense responses.
These mechanisms include the protease-insd'bitor imbalance theo-
ry for the pathogenesis of emphysema whereby alveolar wall
339
digestion results from an excess of proteases, a deficiency of their
inhibitors, or a combination of both factors (see the chapter on
Mechanisms in this Report). The sources of endogenous proteases
include polymorphonuclear neutrophils and alveolar macrophages,
both of which are found in increased number in the lungs of cigarette
smokers. Protease release from both macrophages and neutrophils is
increased in the presence of cigarette smoke (Rodriquez et al. 1977;
Blue and Janoff 1978). In health, proteases are continually inhibited
by au-antitrypsin, whereas proteases cause unimpeded digestion of
lung tissue in patients with aantitrypsin deficiency, with a
markedly increased risk of emphysema. In addition to increasing the
protease burden, cigarette smoke causes a functional inhibition of an- -
antitrypsin through the action of oxidants in cigarette smoke (Janoff ©
et al. 1979).
The relative potency of smoke from cigarettes of varying tar and
nicotine yields in stimulating protease production and release and in
inhibiting o1-antitrypsin has received scant scientific investigation. -
Travis et al. (1980) tested the effect of both filtered and unfiltered
cigarette smoke on the elastase inhibitory activity of oi-antitrypsin.
Filtered smoke reduced elastase inhibitory activity by 3 percent, and
a 19 percent reduction was observed with unfiltered smoke; the tar
content of the respective smokes was not stated. The researchers
reasoned that this small in vitro effect would be greatly magnified by
in vivo conditions in the lung, particularly through its huge surface
area. In addition to examining the effect of filters, Cohen and James
(1982) recently examined the effect of tar and nicotine content on the .
elastase inhibitory capacity of ai-antitrypsin. The oxidant capacity of ©
cigarette smoke was also examined using a chromogenic electron
donor. Aqueous condensates of cigarette smoke were obtained from a
variety of brands ranging in tar content from about 1 mg to more
than 20 mg. Reported tar and nicotine content correlated well with
the amount of measured oxidants and the ability of a brand to reduce .
the elastase inhibitory capacity of a:-antitrypsin. Filters were found
to remove 73 percent of the oxidants from the aqueous smoke
solutions. While these findings suggest that low tar and nicotine or
filter-tipped cigarettes could reduce a smoker’s predisposition to
enzymatic lung damage and consequent COLD, it should be noted
that neither study examined the effect of lower yield cigarettes on
protease production. Morosco and Gueringer (1979) demonstrated a
greater increase in elastase in dogs exposed to high nicotine cigarette
smoke compared with low nicotine cigarette smoke. More important,
these studies have not taken into account the compensatory changes
in smoking pattern likely to result with lower yield cigarettes.
The airway response to acute exposure to cigarette smoke has been
examined by several investigators employing spirometry (Da Silva
and Hamosh 1981), body plethysmograph (Nadel and Comroe 1961),_
340
and breathing pattern analysis (Tobin et al. 1982a). Airway narrow-
ing has been consistently observed by some investigators (Nadel and
Comroe 1961; Sterling 1967; Tobin et al. 1982a), but others report a
variable response (Higenbottam et al. 1980a; Rees et al. 1982). In
some studies, the acute airway response was unrelated to cigarette
yield (Higenbottam et al. 1980a), but in most investigations (Robert-
son et al. 1969; Tobin et al. 1982a: Rees et al. 1982), smoking a low tar
or filter-tipped cigarette induced less acute bronchoconstriction. The
acute airway response is probably localized to the larger alrways, as
acute cigarette exposure resulted in no change in the nitrogen
washout test of small airway function (Da Silva and Hamosh 1973;
Tobin et al. 1982a). These observations on the relative bronchocon-
strictor response of various types of cigarettes may be important in
our understanding of why some smoking novitiates persist with the
habit despite the initial unpleasant reactions (Tashkin et al. 1983),
but it is unlikely that repeated episodes of smoking-induced acute
airway narrowing finally result in COLD.
Future studies examining the mechanism of smoking-induced lung
injury must not only take into account the range of cigarette yields,
as determined by a smoking-machine, but also consider variations in
smoking behavior. Puff volumes may vary considerably with nomin-
al cigarette tar and nicotine content, thus altering the relative
amount of various toxic substances yielded by different cigarettes.
Similarly, inhalation profiles are of a diverse nature (Tobin et al.
1982b) and are likely to significantly alter the distribution, penetra-
tion, and retention of cigarette smoke constituents in the lungs.
Variation in Smoking Pattern With Switching to Low Tar and
Nicotine Cigarettes
Low tar and nicotine cigarettes have gained considerable populari-
ty among the smoking public, partly on the premise that a reduction
in the nominal tar and nicotine yield results in a proportional
reduction in the health hazards of cigarette smoking. The validity of
this approach to cigarette smoking is contingent on the accuracy of
smoking-machines in reflecting the actual manner of puffing and
also on the smoker not altering smoking behavior to compensate for
variations in nominal tar and nicotine content. Should smokers
develop compensatory alterations in their smoking behavior, this
would not only reduce the relevance of the smoking-machine assays
but might also alter the proportionate delivery of the different toxic
substances in cigarette smoke and expose the smoker to concentra-
tions beyond those predicted by the smoking-machine.
34]
Smoking Behavior
Nearly 40 years ago, Finnegan et al. (1945) studied the effect of
alterations in cigarette nicotine content on smoking behavior and
noted no change in cigarette consumption. It is only in the last
decade, with the increasing popularity of low tar and nicotine
cigarettes, however, that this question has attracted significant
interest. The results of 38 studies examining alterations in smoking
behavior with a reduction in cigarette yield are shown in Table 1.
Considerable differences can be observed between the studies, partly
reflecting variations in the level of cigarette yield reduction,
alterations in other cigarette constituents, type and duration of -
switching procedure, parameters evaluated, and techniques used in
their measurement.
Most studies agree that smokers rarely increase their daily
cigarette consumption upon switching from higher to lower yield
brands. Reports are almost equally divided as to whether a smoker
increases the number of puffs per cigarette or shows no change on
switching to a lower yielding brand. There is an almost unanimous
consensus that smokers take a larger puff volume from a lower
yielding brand. Studies of puff volume also indicate huge variation
between individual subjects (Guillerm and Radziszewski 1978; Hern- -
ing et al. 1981; Tobin and Sackner 1982; Herning et al. 1983) and
that considerable increases in puff volume may occur on switching
from a higher to a lower yielding brand, with certain subjects
increasing their puff volume by up to 75 percent (Tobin and Sackner
1982). This compensatory increase in puff volume may be observed
within a single experimental session (Tobin and Sackner 1982) and
maintained over several weeks (Rawbone et al. 1978; Stepney 1981).
Full compensation for a lower yielding cigarette is generally not
achieved by smokers taking a large puff volume (Rawbone et al.
1978; Herning et al. 1981; Tobin and Sackner 1982).
Instrumentation is required to quantitatively assess the pattern of
smoking, but it is important to realize that such instrumentation
may, in itself, alter usual smoking behavior. Puff volume has been
almost universally measured by using a specialized cigarette holder
incorporating different flowmeter designs (Frith 1971, Adams 1977;
Rawbone et al. 1978). These devices consist of two tubes connected to
a pressure transducer that measures the pressure drop across a
small resistance (a filter insert) in the holder; the flow measured is .
integrated to obtain volume. Use of a cigarette holder has been
shown to increase the rate of puffing and puff volume, compared
with measurements made with the cheek inductive plethysmogra-
phy coil (Tobin and Sackner 1982).
Unlike the compensatory increases in puff volume, measurements
of the subsequent inhalation volume—which includes the volume of
smoke mixed with air inhaled into the lung—have shown no change
342
PE
TABLE 1.—Effect of smoking low yield cigarettes on smoking pattern
CO parameters Nicotine parameters
Number Number Volume Duration Relationship Nicotine/cotinine | Mouth Relationship
Reference Experimental of cigs of Puff of of Expired to level exposure to
First author year design smoked puffs/cig volume inhalation inhalation COHb COQ nominal yield (blood/urine/saliva) index normal yield
Finnegan 1945 cs NC
Ashton 1970 VCF t t Poor
Frith 1971 cs f
Cohen 1971 cS NC Poor
Russell 1973 cS t | Good
Turner 1974 CS J /NC Poor
Russell 1975 CS t {¢NC Poor
Goldfarb 1976 cs t | Good
Forbes 1976 cs | Good
Adams 1977 cs NC NC NC
Wald 1977 SVS t
Sutton 1978 VCF NC | Poor \ Fair
Rawbone 1978 CS NC ; NC ‘ Poor
Schulz 1978 cs NC t
Creighton 1978a,b 8 ,
Adams 1978 CS j t
Guilerm 1978 CS t NC NC t Poor
Jarvik 1978 cs ' '
Ashton 1979 CS NC , Poor ‘ ‘ Poor
Garfinkel 1979 SVS NC
Hill 1980 cs NC Poor 7 Good
Robinson 1980 SVS i Good
Russell 1980 SVS NC Poor
Henningfield 1980 VCF NC t t NC
Wald 1980 SVS t
pre
TABLE 1.—Continued
CO parameters
Nicotine parameters
Number Number Volume Duration Relationship Nicotine/cotinine © Mouth Relationship
Reference Experimental of cigs of Puff of of Expired to level exposure to
First author year design smoked puffs/cig volume inhalation inhalation COHb CO nominal yield (blood/urine/saliva) index normal yield
Herning 1981 cs NC t t
Wald 1981 SVS NC ' Poor
Stepney 1981 cs NC t t t Fair | |
Jaffe 1981 SVS NC/{ NC Poor
Tobin 1982 CS NC t NC NC
Battig 1982 SVS NC ' NC
Sutton 1982 SVS ' Good Poor
Griffiths 1981 cs NC t
Jaffe 1982 cs NC/t NC Poor
Feyerabend 1982 SVS Poor
Herning 1983 cs Fur
Benowitz 1983 SVS
NOTE: CS - controlled switching; VCF = variable cigarette filters; SVS -
spontaneous voluntary switching, NC =
no change; f
— increase, |
= decrease; CO = carbon monoxide.
on switching to a low yield cigarette. Likewise, in one short-term
study (Tobin and Sackner 1982), duration of inhalation showed no
relationship to nominal cigarette yield. Perhaps compensatory
changes in inhalation parameters require a longer period of time
than puff volume does.
Measurement of carboxyhemoglobin (COHb) concentration has
been proposed as an index of the pattern of inhalation (Wald et al.
1975, 1978). While COHb provides valuable information on the
amount of carbon monoxide absorbed from the lung during compen-
satory alterations in smoking behavior, it is an indirect index and
provides complementary information on cigarette smoke inhalation
rather than replacing direct measurements of the volume of
inhalation.
Carbon Monoxide Uptake
Unlike tar and nicotine, which are present in the particulate
phase, carbon monoxide (CO) is a constituent of the vapor phase of
cigarette smoke. For this reason, cigarettes purported to produce a
low tar and nicotine yield may not necessarily provide a lower yield
of carbon monoxide. Compared with tar and nicotine yield, carbon
monoxide yield is more dependent on cigarette design, including
such features as paper porosity and perforations in the filter tips.
These factors regulate the dilution of smoke with air and the
burning profile of the cigarette, and thus can significantly reduce
carbon monoxide yield. Wald (1976) showed that the carbon monox-
ide yield of filter-tipped cigarettes was 28 percent higher than that of
plain cigarettes, although the average nicotine yield was lower in the
filter-tipped cigarettes. He reasoned that smoke passing through a
cigarette is diluted by air entering through the porous cigarette
paper. However, the filter of filter-tipped cigarettes is surrounded by
relatively nonporous paper, resulting in a higher content of carbon
monoxide exiting from the proximal cigarette end. Perforations in
the filter tip circumvent this problem and significantly reduce
carbon monoxide yield (Hoffmann et al. 1980; Wald and Smith 1973).
Many investigators have measured COHb or carbon monoxide
concentration in expired gas following cigarette smoking and
compared the levels achieved in smoking brands with different
nominal yields (see Table 1). An increase, decrease, or no change in
carbon monoxide intake has been observed, depending on relative
differences in cigarette design and experimental procedure. As
expected, unventilated filter-tipped cigarettes produced higher
COHb levels than those observed with unfiltered cigarettes (Wald et
al. 1977). This is in agreement with information provided by
smoking-machine assays (Wald et al. 1973), but the use of ventilated
filter-tipped cigarettes may produce COHb levels similar to those
observed with unfiltered cigarettes despite lower carbon monoxide
345
yields on smoking-machine assay (Wald et al. 1977). Comparison of
cigarettes with a marked difference in nominal carbon monoxide
yield usually results in a lower COHb level when the lower yielding
brand is being smoked (Russell et al. 1973; Turner et al. 1974; Sutton
et al. 1978; Ashton et al. 1979); but over the range of different carbon .
monoxide yields there is a poor correlation between levels of COHb
and measured carbon monoxide yield. Similar information has been
observed using expired carbon monoxide concentrations.
Nicotine Uptake
It has been long considered that nicotine might serve as a primary
reinforcer of cigarette smoking and that smokers might adjust their
smoking behavior to regulate their level of nicotine intake. Several
investigators have measured the blood, urinary, or salivary levels of
nicotine or its major metabolite cotinine during the smoking of
cigarettes of varying nominal nicotine yields (see Table 1). A
reduction in blood (Russell et al. 1975; Sutton et al. 1978; Ashton et
al. 1979; Hill and Marquardt 1980) and urinary (Goldfarb et al. 1976;
Ashton et al. 1979; Stepney 1981) nicotine levels or in plasma (Hill
and Marquardt 1980; Stepney et al. 1981) and urinary (Ashton et al.
1979; Hill and Marquardt 1980) cotinine levels has generally been
observed on switching to a cigarette with a lower nominal nicotine
yield. However, smokers show variable degrees of compensation for
the lower yield, as there is generally a poor relationship between
nominal nicotine yield and measured blood nicotine levels (Russell et
al. 1980; Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. -
1983).
Relating nominal nicotine yield and blood nicotine levels, Ashton
et al. (1979) estimated that smokers compensated for about two-
thirds of the difference in nominal yields when they switched from -
medium nicotine cigarettes to high or low nicotine brands. Using a
stepwise multiple regression analysis of nicotine yield and blood
nicotine concentration, Russell et al. (1980) observed a significant,
but very weak, correlation (r=0.21) between the two measurements,
but the nominal nicotine yield of the cigarettes accounted for only
4.4 percent of the variability in blood nicotine concentrations. The
use of absolute rather than logarithmic analysis in this study has
been criticized (Kozlowski et al. 1982; Herning et al. 1983), and the
criticism involved the problems of trying to predict doses to
individuals rather than the dose to groups. In another study using
log-linear regression analysis (Herning et al. 1983), a better correla- ~
tion was observed between nominal nicotine yield and the increasing
blood nicotine after smoking (r=0.5), but this study used Kentucky
reference cigarettes rather than commercial brands, and these low
yield cigarettes have less nicotine in the unburned tobacco than
commercial low yield brands. Such a relationship still accounted for
346
only 25 percent of the individual differences in blood nicotine levels,
whereas 50 to 60 percent was accounted for by individual differences
in smoking behavior (Herning et al. 1983).
Additional information on compensatory alterations in nicotine
intake has been provided by studying the mouth exposure index,
which is calculated from analysis of cigarette butts for nicotine
content and a knowledge of the retention efficiency of the filter tip
(Ashton and Watson 1970). Because the amount of nicotine retained
by a filter is proportional to the amount that passes through, it is
possible to estimate the amount of nicotine presented to the smoker
from the nicotine content of the filter. Results using this index have
revealed a greater variation between individual studies (see Table 1)
than observed with blood nicotine measurements. This may be
related to the fact that filter efficiency is usually determined by a
machine, but retention of nicotine is also dependent on the way the
cigarette is smoked; therefore, the retention efficiency of the filter
may vary between smokers.
Role of Tar Content
The observations that smokers adapt their smoking behavior
according to the nicotine delivery of a cigarette and that raany of the
toxic effects of smoking appear to be related to tar rather than
nicotine content has led to the suggestion that altering the tar to
nicotine ratio might produce a cigarette less hazardous to health
(Russell 1976; Stepney 1981). A cigarette with a medium nicotine,
low tar, and low carbon monoxide yield might be advantageous.
While nicotine has been the component most extensively studied, it
may not be the only substance responsible for the addictive power of
tobacco. It is not possible to separate the effects of tar and nicotine in
most studies, as their respective yields usually show a very close
correlation.
Using research cigarettes providing three different yields of
nicotine and two different yields of tar, Goldfarb et al. (1976) found
evidence of compensation for nicotine but not for tar content. The
authors urged cautious interpretation of the results because of the
limited range of tar yields examined. Examining a large number of
subjects smoking cigarettes of varying tar and nicotine yield, Wald et
al. (1981) found that both tar and nicotine were significantly related
to blood COHb, taken as an index of cigarette smoke inhalation. Two-
way analysis of variance of the data indicated that after allowing for
the effect of either tar or nicotine yield, the COHb index was no
longer significantly influenced by the other. A cross-over study of
medium tar smokers who were switched to low nicotine, low tar
cigarettes and medium nicotine, low tar cigarettes has been reported
by Stepney (1981). While the intake of carbon monoxide was least
with the medium nicotine, low tar cigarette, the mouth exposure
347
index to tar was similar among the brands. Indeed, the pattern of
smoking adopted by the subjects was more effective in reducing the
difference in tar delivery between the cigarettes than in compensat-
ing for nicotine delivery. Further evidence indicating the importance
of cigarette tar delivery in. determining smoking behavior was
reported by Sutton et al. (1982). Using multiple regression analysis,
they observed that when nicotine yield was controlled, smokers of
lower tar cigarettes had higher blood nicotine levels than smokers of
higher tar cigarettes, indicating that they inhaled a greater volume
of smoke. In contrast, when tar yield was controlled, smokers of
lower nicotine cigarettes had lower blood nicotine concentrations
than smokers of higher nicotine cigarettes, indicating that they
inhaled less smoke. These results suggest some compensation for tar
over and above any compensation for nicotine. It may be that
ncenpharmacologic, sensory stimulation by factors such as the flavor
of cigarette smoke may be more important than nicotine in
determining smoking behavior.
These new observations, especially on the role of tar delivery,
require further investigation. Most published research consists of
controlled switching experiments in which the subject smokes
cigarettes of varying yields (see Table 1). Further studies of smoking
behavior in sukjects who have voluntarily chosen cigarettes of
different yields are needed. The absence of an acceptable, palatable
“standard” research cigarette continues to be an impediment to -
research in this area.
Variations in Pattern of Cigarette Smoke Inhalation
While cigarette smoking is the single most important factor in the
development of COLD, the majority of smokers never develop
clinically significant airflow obstruction (Fletcher et al. 1976).
Despite the clear dose-response relationship between number of
cigarettes smoked and death from COLD, attempts at identifying the
individual susceptible smoker on the basis of number of cigarettes
smoked have had very limited success.
Another approach to identifying the susceptible smoker is to study
the manner of smoking, as this is probably a major determinant of
the lung’s exposure to cigarette smoke. Cigarette smoking consists of
two phases: initially, the smoker takes a puff into the mouth, and
after a variable 1 to 4 second pause, the smoke mixed with air is
inhaled into the lungs (Rawbone et al. 1978; Higenbottam et al.
1980a; Tobin and Sackner 1982). Individual differences in the
pattern of cigarette smoking such as the size of the puff volume, the
duration of holding the smoke in the oral cavity before inhalation,
and the depth and duration of inhalation are among the important
factors determining the relative concentration of smoke constituents
348
that reach the lung. Despite its significance in determining the
distribution and deposition of cigarette smoke, the mode of inhala-
tion following the puff has received scant scientific investigation.
A number of epidemiologic studies have examined the relationship
between cigarette smoke inhalation, based on the smoker’s subjec-
tive estimation, and the severity of pulmonary disease. Results of
these studies are conflicting; some investigators repcrted an associa-
tion between smoke inhalation and the presence of mucus hyperse-
cretion (Rimington 1974; Schenker et al. 1982; Dean et al. 1978) and
decline in pulmonary function (Ferris et al. 1976; Bosse et al. 1975),
and others observed no relationship between inhalation and pulmo-
nary dysfunction (Beck et al. 1981; Schenker et al. 1982). The
inconsistencies in these epidemiologic studies may be due to the
smokers’ inability to accurately describe their inhalation pattern.
There are three reports of the relationship between subjective
estimations of cigarette smoke inhalation and direct objective
measurement. Rawbone et al. (1978) found that the rating on a
visual analog scale was a good predictor of inhalation volume
(r=0.65). Conversely, Tobin et al. (1982a) noted no relationship
between inhalation volume and the smoker’s perception of depth of
inhalation, indicated on a visual analog scale (r—0.04); a similar
finding was reported by Adams et al. (1983) (r~0.04). Standardizing
the inhaled volume for vital capacity did not improve the relation-
ship. Other investigators using measurements of COHb observed a
weak relationship between self-estimated inhalation and COHb
concentration (Stepney 1982; Wald et al. 1978). Measurements of
COHb reflect the amount of cigarette smoke absorbed by the lung. In
addition to being affected by the depth of inhalation, COHb
concentration is influenced by the varying carbon monoxide yields of
different cigarettes, the number of puffs per cigarette, puff volume,
pulmonary function—particularly diffusing capacity and alveolar
ventilation—and hemoglobin concentration (Wald et al. 1978: Ric-
kert et al. 1980). Therefore, it yields valuable complementary
information, but it does not provide a direct measure of the pattern
of inhalation (Tobin et al. 1982a; Guyatt et al. 1983).
Direct measurements of the pattern of cigarette smoke inhalation
have been reported for a small number of smokers. Initially, the puff
from the cigarette is taken into the mouth, and after a variable
pause of 1 to 4 seconds, it is inhaled into the lungs (Rawbone et al.
1978; Higenbottaim et al. 1980a; Tobin and Sackner 1982; Tobin et al.
1982a; Adams et al. 1983). Higenbotiam et al.(1980a) reasoned that
this pause, while holding the smoke in the mouth, minimized the
irritant qualities cf cigarette smoke. In a group of five subjects who
were requested to inhale smoke directly into®keir lungs, without an
intervening pause in the mouth, consistent acute airway narrowing
was observed. In contrast, smokers adopting the usual two-phase
349
smoking pattern showed a variable airway response. The authors
suggested that buccal absorption of water-soluble compounds, such
as sulfur dioxide and acrolein, together with precipitation of tar,
minimized the irritating qualities of cigarette smoke. They observed
no relationship between the acute airway response and amount of
smoke inhaled in the regular two-phase smokers, although there
appeared to be a relationship in those directly inhaling smoke into
their lungs. However, there is a marked discrepancy in the inhala-
tion volumes reported in this study compared with the values
reported in other studies of cigarette smoke inhalation, probably due
to the inaccuracy of the magnetometers employed for the measure-
ments; therefore, a statement regarding the relationship between
depth of smoke inhalation and the acute airway response may be
misleading.
The report that acute airway narrowing is uncommon after
cigarette smoking is in disagreement with the findings of several
investigators who have observed bronchoconstriction to be a common
phenomenon after acute smoke exposure (Nadel and Comroe 1961;
Sterling 1967; Da Silva and Hamosh 1981; Tobin et al. 1982a);
however, it is certainly plausible that the response is greater in
smokers who inhale smoke directly into the lungs than in two-phase
smokers. The frequency of direct inhalation of cigarette smoke into
the lungs is unknown. In a small study of 10 smokers, Tobin and
Sackner (1982) observed 1 subject who showed an approximately 50
ml expansion of the abdominal compartment simultaneously with
taking the puff from the cigarette.
Adams et al. (1983) studied the relationship between puffing,
cigarette smoke inhalation, and partitioning of airflow between the
nose and mouth in 10 smokers. After taking the puff into the mouth,
two subjects actively exhaled 80 ml and 200 ml volumes, respective-
ly, before the subsequent inhalation. In this situation, the volumes of
smoke might be expelled from the mouth, and little, if any, would be
available for subsequent inhalation into the lungs. The frequency of
this smoking pattern was not given, but another report from the
same laboratory (Rawbone et al. 1978) indicated that it was
uncommon. There was marked intersubject variation in the parti-
tioning of airflow between the nose and mouth during smoking, with
four subjects inhaling almost exclusively through the mouth, four
inhaling predominantly through the nose, and the other two
demonstrating both patterns of inhalation. The importance of factors
in determining whether cigarette smoke is inhaled as a bolus
followed by a subsequent “chaser” of air or is evenly distributed
throughout the inhaled volume of air remains to be determined.
Considerable discrepancies exist between published reports of the
volume of air mixed with smoke that is inhaled into the lungs, with
reported mean inhalation volumes of 34 to 152 ml (Higenbottam et
350
30 Sum
20
Putt Putt
Volume (liters)
v
c
t
Puff Putt
1 id i Lt 1 jt i 1
10 20 30 40 50 60
Seconds
FIGURE 3.—Pattern of inhalation of cigarette smoke mixed
with air, in two smokers
SOURCE: Modified from Tobin et al. (1982b).
al. 1980a), 450 to 485 ml (Guillerm and Radziszewski 1978), 389 to
1,136 ml (Adams et al. 1983), 750 to 2,000 ml (Rawbone et al. 1978),
and 170 to 1,970 ml (Tobin et al. 1982b). A major factor in the
discrepancies between these studies is probably the inaccuracies
inherent in some of the methods employed in the measurements, as
discussed by Tobin and Sackner (1982). When inhalation volumes are
standardized for body size by relating them to vital capacity, marked
interindividual variation is still observed (Figure 3), with inhalation-
al volumes ranging from 9 to 47 percent of the vital capacity and a
group mean value of 20 percent (Tobin et al. 1982b). Smokers show
considerable variation in inhaled volumes while smoking a single
cigarette. The volume of inhalation bears no relationship to cigarette
consumption in terms of pack-years (Tobin et al. 1982b). Similarly,
duration of inhalation shows considerable variation between sub-
jects, with mean individual values ranging from 1.7 to 7.3 seconds
(Adams et al. 1983; Tobin et al. 1982b). Repeat measurements at
intervals of up to 10 months apart indicate that individual subjects
tend to maintain a fairly constant inhalation volume, duration of
inhalation, and associated breathhold time (Tobin et al. 1982b;
Adams et al. 1983).
351
The pattern of cigarette smoking shows a wide degree of intersub-
ject variability, including differences in the number of puffs, puff
volume, holding pause in the mouth, exhalation of smoke from the
mouth before inhalation, partitioning of airflow between the nose
and mouth, and volume and duration of inhalation. Given this
degree of variation, it is not surprising that smokers might show
wide differences in their individual susceptibilities to lung injury. In
a study relating inhalation volume—standardized for vital capaci-
ty—to the time-volume and flow-volume components of a forced vital
capacity maneuver, no significant correlation was observed (Tobin et
al. 1982b). Although this lack of a relationship might be interpreted
as indicating that the pattern of smoking is unimportant in the
development of lung disease, it may also reflect the fact that
pulmonary function was normal or near normal in the majority of
subjects and that the study was of a cross-sectional design.
Use of Additives in Low Tar and Nicotine Cigarettes
The nominal tar and nicotine yield of cigarettes has continually
decreased since the time of the initial reports linking smoking with
lung cancer (USDHHS 1981). In 1954, the average tar yield per
cigarette was 38 mg, and in 1980 it was less than 14 mg. Initially, tar
reduction was achieved by decreasing the cigarette tobacco content
or removing tar by smoke filtration, both of which probably resulted
in a lower smoke exposure. Since 1971, the reduction in tar yield has
exceeded the relative reduction in the weight of tobacco per
cigarette; this difference has increased since 1975 (USDHHS 1981).
Manufacturing technology has progressed beyond simple reduction
in tobacco content: the yield and composition of smoke can be
modified by genetic modification of the tobacco leaf (Tso 1972a),
changes in its cultivation and processing (Tso 1972b), changes in the
porosity of cigarette paper, and alterations in filter design (Kozlow-
ski et al. 1980b).
When initially introduced, lower yield cigarettes lacked palatabili-
ty and acceptability. Advertisements for the current low tar and
nicotine cigarettes emphasize their flavor, presumably achieved by
the use of additives in the processing of the tobacco. Additives
employed may include artificial tobacco substitutes (Freedman and
Fletcher 1976), flavor extracts of tobacco and other plants, exogenous
enzymes, powdered cocoa (Gori 1977), and other synthetic flavoring
substances. Perhaps more additives are being used in the new lower
tar and nicotine cigarettes than in the older brands, and new agents
may also be in use. Some of the substances, such as powdered cocoa,
have been shown to further increase the carcinogenicity of tar (Gori
1977), and others may result in increased or new and different
health risks. The pyrolytic products of these additive agents may
352
produce novel toxic constituents. A characterization of the chemical
composition and adverse biologic potential of these additives is
urgently required, but is currently impossible because cigarette
companies are not required to reveal what additives they employ in
the manufacture of tobacco (USDHHS 1981). No government agency
is empowered with supervisory authority in the manufacture of
tobacco products. With this lack of basic information and the usually
prolonged latent period before manifestation of the adverse effects of
smoking, it is likely that a long time period will elapse before we
know the hazards of the new cigarettes in current use.
Research Recommendations
1. Longitudinal epidemiologic studies are needed to determine
the risk for pulmonary symptoms and dysfunction in smokers
of cigarettes with the low tar and nicotine yields found in
currently popular brands.
2. Further research is needed to determine the relative potency of
high and low tar and nicotine cigarettes in inducing elastase
release and producing functional inhibition of ai-antitrypsin
activity.
3. Development of an animal model of cigarette-smoke-induced
emphysema would be advantageous in determining the relative
risk of lung injury of cigarettes of different composition.
4. More information is required on the smoking behavior of
smokers who have voluntarily switched from high to low tar
and nicotine cigarettes.
5. The role of cigarette tar, as opposed to nicotine content, in
determining smoking behavior needs to be defined.
6. Standard research cigarettes of varying tar and nicotine
contents that are palatable and acceptable to smokers need to
be developed.
7.The role of variation in smoking behavior in determining
susceptibility to lung injury needs to be defined. Studies are
required to determine the effect of smoking patterns on the
distribution and penetration of the smoke aerosol into the lung.
8. More information is needed on the composition and adverse
biologic effects of flavor additives in cigarettes and their
pyrolytic products.
Summary and Conclusions
1. 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
353
354
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.
Nicotine has long been regarded as the primary reinforcer of
cigarette smoking, but tar content may also be important in
determining smoking behavior.
. 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.
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.
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360
CHAPTER 7. PASSIVE SMOKING
361
480-144 0 - 85 - 13
CONTENTS
Introduction
Differences in Composition of Sidestream Smoke and
Mainstream Smoke
Measurement of Exposure
Acute Physiologic Response of the Airway to Smoke in
the Environment
Symptomatic Responses to Chronic Passive Cigarette
Smoke Exposure in Healthy Subjects
Respiratory Infections in Children of Smoking Parents
Pulmonary Function in Children of Smoking Parents
Pulmonary Function in Adults Exposed to Involuntary
Cigarette Smoke
The Effect of Passive Smoke Exposure on People With
Allergies, Asthma, and COLD
Summary and Conclusions
References
363
Introduction
This chapter explores recent data that relate involuntary cigarette
smoke exposure to the occurrence of physiologic changes, symptoms,
and diseases in nonsmoking adults and children. Health effects
related to fetal exposure in utero, a subject that has been extensively
studied, are not discussed, although instances where such exposure
may relate to potential development are pointed out. The interested
reader is referred to several excellent recent reviews for a more
complete treatment of this issue (USDHEW 1979; USDHHS 1980;
Abel 1980; Weinberger and Weiss 1981).
Differences in Composition of Sidestream Smoke and
Mainstream Smoke
Involuntary (passive) smoking is defined as the exposure of
nonsmokers to tobacco combustion products from the smoking of
others. Analysis of the health effects of passive smoking requires not
only some knowledge of the constituents of tobacco smoke, but also
some quantitation of tobacco smoke exposure. Tobacco smoke in the
environment is derived from two sources: mainstream smoke and
sidestream smoke. Mainstream smoke emerges into the environment
after having first been drawn through the cigarette, which filters
some of the active constituents. The smoke is then filtered by the
smoker’s own lungs, and exhaled. Sidestream smoke arises from the
burning end of the cigarette and enters directly into the environ-
ment. Differences in the temperature of combustion, the degree of
filtration, and the amount of tobacco consumed all lead to marked
differences in the concentration of the constituents of mainstream
smoke and sidestream smoke (USDHEW 1979; Sterling et al. 1982;
Brunneman et al. 1978; National Academy of Sciences 1981;
Rylander et al. 1984). Many potentially toxic gas phase constituents
are present in higher concentration in sidestream smoke than in
mainstream smoke (Brunneman et al. 1978) (Table 1), and nearly 85
percent of the smoke in a room results from sidestream smoke.
Smaller amounts of smoke are contributed to the environment from
the nonburning end of the cigarette by diffusion through the paper
wrapping and by the smoke exhaled by the smoker. Therefore, both
active and passive smokers may be similarly exposed to sidestream
smoke. Mainstream smoke is inhaled directly into the lungs and is
diluted only by the volume of air breathed in by the smoker when he
or she inhales. Sidestream smoke is generally diluted in a considera-
bly larger volume of air. Thus, passive smokers are subjected to a
quantitatively smaller and qualitatively different smoke exposure
than active smokers. The quantification of the exposure of a passive
smoker to these sidestream smoke constituents is often difficult.
Factors such as the type and number of cigarettes burned, the size of
365
the room, the ventilation rate, and the smoke residence time are all
important variables in determining levels of exposure. Thus, no
single variable accurately characterizes exposure to smoke constitu-
ents.
Repace and Lowrey (1980, 1982, 1983) have shown that, to a
reasonable approximation, exposure to the particulate phase is
predicted by the ratio of the smoker density to the effective
ventilation rate of the area in which the smokers are located.
Measurement of Exposure
Levels of indoor byproducts of tobacco smoke, with measurements
made under realistic exposure conditions, are presented in Table 2.
Among the constituents that have been measured, nitrogen oxide,
carbon monoxide, nicotine and respirable particulates, nitrosamines,
and aldehydes have been shown to be significantly elevated indoors
as a result of cigarette smoking. Nitrogen oxide is rapidly oxidized to
nitrogen dioxide (NOz) in air, and reaches equilibrium with outdoor
levels of NOz, provided there are suitable air exchange rates and no
other indoor sources, such as a gas stove. The particulate concentra-
tion indoors clearly increases with increasing numbers of smokers,
although the background level is determined by the outdoor level.
The conclusions from the few studies that actually measure ventila-
tion rates during exposure suggest that under “normal” air circula-
tion conditions, carbon monoxide (CO) levels will be relatively low,
but still may exceed the ambient air quality standard of 9 ppm
(NIOSH 1971). However, even modest reductions in ventilation rates
can lead to CO accumulation.
A variety of measures have been utilized to quantify the nonsmok-
er’s exposure to tobacco smoke. No single measure has been
uniformly accepted as characterizing the level of smoke. Nicotine is
the most tobacco-specific of these measures, but it is relatively
complicated and expensive to measure and settles out of the air with
the particulate phase, making it a poor measure of gas phase
constituents. In addition, nicotine may rapidly deposit on surfaces
and subsequently evaporate into the environment (Rylander et al.
1984), making it a poor measure of acute smoke exposure levels.
Measurements of total particulate matter are a broader measure of
smoke exposure, particularly if the measurements are limited to
particles in the respirable range and to environments without other
major sources of respirable particles. The smoke particles also settle
out of the air and therefore may not reflect the levels of gas phase
constituents, and a wide variety of other dusts may contribute
particulates to the air, particularly in the occupational setting. A
number of authors have measured levels of CO. This measurement is
relatively simple and a measure of absorption (carboxyhemoglobin)
366
L9E
TABLE 1.—Ratio of selected constituents in sidestream smoke (SS) to mainstream smoke (MS)
Gas phase constituents MS SS/MS ratio Particulate phase constituents MS SS/MS ratio
Carbon dioxide 20-60 mg 8.1 Tar 1-40 mg 1.3
Carbon monoxide 10-20 mg 25 Water 14 mg 24
Methane 1.3 mg 3.1 Toluene 108 pg 5.6
Acetylene 27 wg 08 Phenol 20-150 pg 2.6
Ammonia 80 pg 73.0 Methylnaphthalene 2.2 ug 28
Hydrogen cyanide 430 pg 0.25 Pyrene 50-200 pg 3.6
Methylfuran 20 pe 3.4 Benzofa}pyrene 20-40 pg 3.4
Acetonitrile 120 pg 39 Aniline 360 pg 30
Pyridine 32 ug 10.0 Nicotine 1.0-2.5 mg 2.7
Dimethylnitrosamine 10-65 yg 52.0 2-Naphthylamine 2 ng 39
Adapted from U.S. Department of Health, Education, and Welfare (1979).
898
TABLE 2a.—Acrolein measured under realistic conditions
Levels
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range
Badre et al. Cafes Varied Not given 100 mL samples 0.03-0.10 mg/m*
(1978) Room 18 smokers Not given 100 mL samples 0.185 mg/m*
Hospital lobby 12 to 30 smokers Not given 100 mL samples 0.02 mg/m*
2 train compartments 2 to 3 emokers Not given 100 mL samples 0.02-0.12 mg/m?
Car 3 smokers Natural, open 100 mL samples 0.03 mg/m*
2 smokers Natural, closed 100 mL samples 0.30 mg/m*
Fischer et al. Restaurant 50-80/470 m?® Mechanical 27 x 30 min samples 7 ppb
(1978) and Restaurant 60-100/440 m? Natural 29 x 30 min samples 8 ppb
Weber et al. Bar 30-40/50 m* Natural, open 28 x 30 min samples 10 ppb
(1979) Cafeteria 80-150/574 m? 11 changes/hr 24 x 30 min samples 6 ppb (5 ppb
nonsmoking section)
69€
TABLE 2b.—Aromatic hydrocarbons measured under realistic conditions
Levels Nonsmoking controls
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Benzene (mg/m*)
Badre et al. Cafes Varied Not given 100 mL samples 0.05-0.15
(1978) Room 18 smokers Not given 100 mL samples 0.109
Train compartments 2 to 3 smokers Not given 100 mL samples 0.02-0.10
Car 3 smokers Natural, open 100 mL samples 0.04
2 smokers Natural, closed 100 mL samples 0.15
Toulene (mg/m°) _
Cafes Varied Not given 100 mL samples 0.04~1.04
Room 18 smokers Not given 100 mL samples 0.215
Train compartments 2 to 3 smokers Not given 100 mL samples 1.87
Car 2 smokers Natural, closed 100 mL samples 0.50
Benzofa}pyrene (ng/m’)
Elliott and Rowe Arena 8,647-10,786 people Mechanical Not given TA
(1975) 12,000-12,844 people Mechanical Not given 99
13,000-14,277 people Mechanical Not given 21.7
Separate non- 0.69
activity days
Galuskinova Restaurant Not given Not given 20 days in summer 6.2
(1964)
18 days in the fall
28.2-144
OLE
TABLE 2b.—Continued
Levels Nonsmoking controls
Type of Monitoring
Study premises Occupancy Ventilation conditions Range Mean Range
Just et al. Coffee houses Not given Not given 6 hr continuous 0.25-10.1 4.0-9.3 (outdoors)
(1972)
Benzofelpyrene (ng/m*)
3.3-23.4 3.0-5.1 (outdoors)
Bei hi lene (ng/m*
5.9-10.5 6.9-13.8 (outdoors)
Perylene (ng/m?)
0.7-1.3 0.1-1.7 (outdoors)
Pyrene (ng/m’)
4.1-9.4 2.8-7.0 (outdoors)
Anthanthrene (ng/m‘)
05-19 0.5-1.8 (outdoors)
Coronene (ng/m’)
0.5-1.2 10-28
Phenols (1/m*)
TAALS
Benzofalpyrene (ng/m’)
Perry (1973) 14 public places Not given Not given Samples, 5 outdoor < 20-760 < 20-43
locations
TLE
TABLE 2c.—Carbon monoxide measured under realistic conditions
Levels (ppm) Nonsmoking controls (ppm)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Badre et al. 6 cafes Varied Not given 20 min samples 2-23 (outdoors) 0-15
(1978) Room 18 smokers Not given 20 min samples 50 0 (outdoors)
Hospital lobby 12 to 30 smokers Not given 20 min samples 5
2 train 2 to 3 smokers Not given 20 min samples 45
compartments
Car 3 smokers Natural, open 20 min samples 14 0 (outdoors)
2 smokers Natural, closed 20 min samples 20 0 (outdoors)
Cano et al. Submarines 157 cigarettes Yes <40 ppm
(1970) 66 m’ per day
94-103 cigarettes Yes <40 ppm
per day
Chappell and 10 offices Not given Values not 17 x 23 min 25 + 10 1.54.5 25 + 10 15-45
Parker given samples (outdoors)
(1977) 15 restaurants Not given Values not 17 x 23 min 40+ 25 1.0-9.5 25+ 15 1.0-5.0
given samples (outdoors)
14 nightclubs Not given Values not 19 x 23 min 13.0 + 7.0 3.0-29.0 3.0 + 2.0 1.0-5.0
and taverns given samples (outdoors)
Tavern Not given Artificial 16 x 23 min 85
samples
None 2x 23 min 35 (peak)
samples
Offices 1440 ft? Natural, open 2-3 min samples 10.0 (peak)
30 min after 1.0
smoking
oLe
TABLE 2c.—Continued
Levels (ppm) Nonsmoking controls (ppm)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Coburn et al. Rooms Not given Not given Not given 4.3-9.0
(1965) Nonsmokers’ rooms 2.2 + 0.98 0.44.5
Cuddeback Tavern 1 10-294 people 6 changes/hr 8 hr continuous 11.5 10-12 2 (outdoors)
et al. 2 hr after smoking ~l
(1976) Tavern 2 Not given 1-2 changes/hr 8 hr continuous 17 ~3-22 Values not given
2 hr after smoking ~12 Values not given
US. Dept. of 18 military 165-219 people Mechanical 6-7 hr continuous <25
Transportation planes
(1971 8 domestic 27-113 people Mechanical 1'/,-2", br <2
planes continuous
Elliott and Arena | 11,806 people Mechanical Not given 9.0 3.0 (nonactivity day)
Rowe Arena 2 2,000 people Natural Not given 25.0 3.0 (nonactivity day)
(1975¢ Nonsmoking 9.0
arena
Fischer et al. Restaurant 50-80/470 m? Mechanical 27 x 30 min 5.1 2.1-9.9 4.8 (outdoors)
(1978) and samples
Weber et al. Restaurant 60-100/440 m? Natural 29 x 30 min 2.6 1.4-3.4 1.5 (outdoors)
(1979) samples
Bar 30-40/50 m’ Natural, open 28 x 30 min 48 2.4-9.6 1.7 (outdoors)
samples
Cafeteria 80-150/574 m* 11 changes/hr 24 x 30 min 1.2 0.7-1.7 0.4 (outdoors)
Nonsmoking 0.5 0.3-0.8
room
Godin et al. Ferryboat Not given Not given 11 grab samples 18.4 + 87 3.0 + 2.4 (nonsmoking room)
(1972) Theater foyer Not given Not given Grab samples 34+ 08 1.4 + 0.8 (auditorium)
TABLE 2c.—Continued
Levels (ppm) Nonsmoking controls (ppm)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Harke Offices ~72 m? 236 m*/hr 30 min samples <25-46
(1974a) Offices ~78 m? Natural 30 min samples <25-9.0
Harke and Car 2 smokers Natural Samples 42 (peak) (Nonsmoking runs)
Peters (4 cigs) 13.5 (peak)
(19745 Mechanical Samples 32 (peak) (Nonsmoking runs)
15.0 (peak)
Harmeen and Train 1-18 smokers Natural Not given 0-40
Effenberger
(1957
Perry 14 public Not given Not given One grab sample <10
1973) places
Portheine Rooms Not given Not given Not given 5-25
t197)8
Sebben et al. 9 nightclubs Not given Varied 77 x 1 min 13.4 65-419
(1977 samples
Outdoors 9.2 3.0-35.0
14 restauranta Not given Not given Spot checks 99 + 55 Values not given
45 restaurants Not given Not given Spot checks 82 4 22 7.1 + 1.7 (outdoors)
33 stores Not given Not given Spot checks 10.0 + 4.2 115 + 69 (outdoors)
3 hospital Not given Not given Spot checks 438 Values not given
lobbies
ELE
PLE
TABLE 2c.—Continued
Levels (ppm) Nonsmoking controls (ppm)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Seiff Intercity bus Not given 15 changes/hr, 33 ppm
(1973) 23 cigarettes
burning
continuously
3 cigarettes 18 ppm
burning
continuously
Slavin and 2 conference Not given 8 changes/hr Continuous, 8 (peak) 1-2 (separate
Hertz rooms morning nonsmoking day)
(1975) 6 changes/hr Continuous, 10 (peak) 1-2 (separate
morning nonsmoking day)
Szadkowski 25 offices Not given Not given Continuous 2.78 + 1.42 259 + 2.23
et al. (separate nonsmoking
(1976) offices)
«Three cigarettes and one cigar smoked in 20 minutes.
>The Drager tube used is accurate only within + 25 percent.
©The MSA Monitaire Sampler used is accurate only within + 25 percent.
4 About 40 cigarettes/day were smoked.
* About 70 cigarettes/day were smoked.
Four filter cigarettes were smoked.
© No experimental deacription given.
wo
<1
on
TABLE 2d.—Nicotine measured under realistic conditions
Nonsmoking
Levels (ug/m?) controls
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Badre et al. 6 cafes Varied Not given 50 min sample 25-52
(1978) Room 18 smokers Not given 50 min sample 500
Hoapital lobby 12 to 30 smokers Not given 50 min sample 37
2 train compartments 2 to 3 smokers Not given 50 min sample 36-50
Car 3 smokers Natural, open 50 min sample
Natural, closed 50 min sample 1010
Cano et al. Submarines 157 cigarettes Yes 32 pg/m?
(1970) 66m‘ per day
94-103 cigarettes Yes 15-35 g/m?
per day
_Harmsen and Train Not given Natural, closed 30-45 min 07.-3.1
‘ Effenberger samples
(1967)
Hinds and First Train Not given Not given 2’, hr samples 49 Values not given
(1975) Bus Not given Not given 2 hr samples 6.3 Values not given
Bus waiting room Not given Not given 2, hr samples 1.0 Values not given
Airline waiting room Not given Not given 2%, hr samples 3.1 Values not given
Restaurant Not given Not given 2", hr samples 5.2 Values not given
Cocktail lounge Not given Not given 2, hr samples 10.3 Values not given
Student lounge Not given Not given 2‘, hr samples 28 Values not given
Weber and Fischer 44 offices Varied Varied 140 x 3 hr 0.9 + 19 13.8 (peak) Values not given
(1980 samples
* Background levels have been subtracted.
‘Control values (unoccupied rooms) have been subtracted.
OLE
TABLE 2e.—Nitrogen oxides measured under realistic conditions
Nonsmoking
Levels controls (ppb)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Fischer et al. Restaurant 50-80/470 m? Mechanical 27 x 30 min NO,: 76 59-105 63 (outdoors)
(1978) and samples NO: 120 36-218 115 (outdoors)
Weber et al. Restaurant 60-100/440 m? Natural 29 x 30 min NO,: 63 24-99 50 (outdoors)
(1979) samples NO: 80 14-21 11 (utdoors)
Bar 3040/50 m? Natural, 28 x 30 min NO, 21 1-61 48 (outdoors)
open samples
NO: 195 66-414 44 (outdoors)
Cafeteria 80-150/574 m? 11 changes/hr 24 x 30 min NO,: 58 35-103 34 (outdoors)
samples
NO: 9 2-38 4 (outdoors)
Other—non- NO,: 27 15-44
smokers room
NO: 5 2-9
Weber and 44 offices Varied Varied 348-354 NO,: 24 + 22 115 (peak) Values not given
Fischer samples
(1980) NO: 32 + 60 280 (peak) Values not given
"Control values (unoccupied rooms) have been subtracted.
LLE
TABLE 2f.—Nitrosamines measured under realistic conditions
Levels (ng/L)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range
N-Nitrosdimethylamine
Brunneman and Train bar car Not given Mechanical 90 min continuous 0.13
Hoffmann Train bar car Not given Natural 90 min continuous 0.11
(1978)
Brunneman et al.
(1977) Bar Not given Not given 3 hr continuous 0.24
Sports hall Not given Not given 3 hr continuous 0.09
Betting parlor Not given Not given 90 min continuous 0.05
Discotheque Not given Not given 2%, hr continuous 0.09
Bank Not given Not given 5 hr continuous 0.01
House Not given Not given 4 hr continuous < 0.005
House Not given Not given 4 hr continuous < 0.003
BLE
TABLE 2g.—Particulates measured under realistic conditions
Nonsmoking
Occupancy Monitoring Levels (ug/m*) controls (ug/m*)
Type of (active smokers conditions OTT ee
Study premises per 100 m*) Ventilation (min) Mean Std. dev. Mean Std. dev.
Repace and Cocktail party 0.75 Natural 15 351 + 38 24
Lowrey Lodge hall 1.26 Mechanical 50 697 + B 60'
(1980) Bar and grill 1.78 Mechanical 18 589 + 28 63'
Firehouse bingo 2.77 Mechanical 16 417 + 63 51'
Pizzeria 2.94 Mechanical 32 414 + 58 40!
Bar/cocktail lounge 3.24 Mechanical 26 334 + 120 50!
Church bingo game 0.47 Mechanical 42 279 + 18 30
Inn 0.74 Mechanical 12 239 + #9 22"
Bowling alley 1.53 Mechanical 20 202 + 19 491
Hoepital waiting room 2.15 Mechanical 12 187 + 52 58!
Shopping plaza restaurant
Sample 1 0.18 Mechanical 18 153 + 8 59!
Sample 2 0.18 Mechanical 18 163 + 4 36!
Barbeque restaurant 0.89 Mechanical 10 136 + 17 40'
Sandwich restaurant A
Smoking section 0.29 Mechanical 20 110 + % 40'
Nonsmoking section 0 Mechanical 20 55 + 5 30
Fast-food restaurant 0.42 Mechanical 40 109 + 38 24!
Sports arena 0.09? Mechanical 12 94 + 13 55!
Neighborhood restaurant/bar 0.40 Mechanical 12 93 + 55!
Hotel bar 0.59 Mechanical 12 93 + 2 30
Sandwich restaurant B
Smoking section 0.13 Mechanical 8 8 + 7 55
Nonsmoking section 0 Mechanical 21 51
Roadside restaurant 1.12 Mechanical (9.5 ach *) 18 107¢ 30
Conference room 3.54 Mechanical (4.3 ach *) 6 19474 55
6LE
TABLE 2g.—Continued
Nonsmoking
Occupancy Monitoring Levels (ug/m*) controls (ug/m *)
Type of (active smokers conditions
Study premises per 100 m*) Ventilation (min) Mean Std. dev. Mean Std. dev.
Repace and Dinner theater 0.14 Mechanical 44 145 + 43 47 +10
Lowrey Reception hall 1.19 Mechanical 20 31 + 30 33?
(1982) Bingo hall 0.93? Natural 2 1140 40!
0.93? Mechanical (1.39 ach?) 6 443° 40!
‘Sequential outdoor measurement (5 minute average).
* Estimated.
* Air changes per hour.
* Equilibrium level as determined from concentration va. time curve.
C3E
TABLE 2g.—Continued
Levels (yg/m*) Nonsmoking controls (yg/m°*)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Cuddleback et al. Tavern Not given 6 changes/hr 4x 8hr 310 233-346
(1976) continuous
Tavern Not given 1-2 changes/hr 8 hr continuous 986
U.S. Dept. of 18 military planes 165-219 people Mechanical 72 x 67 hr < 10-120
Transportation samples
(197) 8 domestic planes 27-113 people Mechanical 2 x 1%-2"%, hr Not given
samples
Dockery and Residences Not given Varied 24 hr samples 32
Spengler
(198D)
Elliott and Arena 1 11,806 people Mechanical During activities 323 42 (nonactivity day)
Rowe Arena 2 2,000 people Natural During activities 620 92 (nonactivity day)
(1975) Arena 3 (smoking 11,000 people Mechanical During activities 148 71 (nonactivity day)
prohibited)
Harmsen and Trains 15-120 people Natural Not given 46-440
Effenberger particles/em*
(1957) Nonsmokers’ cars 20-75
particles/cm*
Just et al. 4 coffee houses Not given Not given 6 hr averages 1150 500-1900 570 (outdoors) 100-1900
(1972)
Neal et al. Hospital unit Not given Mechanical 48 hr samples 21 + 14 3-58 73 + 25
(1978) Hospital unit Not given Mechanical 48 hr samples 40 + 21 13-79 72 + 25
T8€
TABLE 2g.—Continued
Levels (ug/m?) Nonsmoking controls (ug/m*)
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Spengler et al. Residences 2+ smokers Natural 24 hr samples 70 + 43 21 + 12 (outdoors)
(1981) 1 smoker Natural 24 hr samples 37 + 15 21 + 12 (outdoors)
Weber and 44 offices Varied Natural and 429 x 2 min 133 + 130! 962' (peak)
Fischer (1981) mechanical samples
Quant et al. Office No. 1 0.62? Mechanical Five 10 hr workday 45 39.54 5-15
(1982) Office No. 2 0.68? Mechanical averages; continuous 45 37-50 15-20
Office No. 3 1.46? Mechanical monitoring 68 42-89 15--20
Brunekreef and 26 houses 1-3 smokers Natural 2 mo averages 153* 60-340 55 20-90
Boleij (1982)
‘Values above background.
* Habitual smokers per 100 m *.
* Weighted mean
G8E
TABLE 2h.—Residuals measured under realistic conditions
Nonsmoking
Levels controls
Type of Monitoring
Study premises Occupancy Ventilation conditions Mean Range Mean Range
Acetone (mg/m'*)
Badre et al. 6 cafes Varied Not given 100 mL samples 0.91-5.88
(1978 Room 18 smokers Not given 100 mL samples 0.51
Hospital lobby 12 to 30 smokers Not given 100 mL samples 1.16
2 train 2 or 3 smokers Not given 100 mL samples 0.36-0.75
compartments
Car 3 smokers Natural, open 100 mL samples 0.32
Car 2 smokers Natural, closed 100 mL samples 1.20
Sulfates (ug/m*)
Dockery and Residences Not given Varied 24 hr samples 481
Spengler
(1981)
Sulfur dioxide (ppb)
Fischer et al. Restaurant 50-80/470 m* Mechanical 27 x 30 min samples 20 9-32 12 ppb
(1978) Restaurant 60-100/440 m’ Natural 29 x 30 min samples 13 5-18 6
Bar 30-40/50 m* Natural, open 28 x 30 min samples 30 13-75 8
Cafeteria 80-150/574 m* 11 ch/hr 24 xX 30 min samples 15 1-27 12
Other nonsmokers’ 7 3-13
room
Just et al. 4 coffee houses Not given Not given 6 hr continuous 12.0-15.3
(1972)
« See original paper for nine other residuals.
is also readily available. CO reflects the gas phase components of
smoke and thus may not reflect the levels of particulate phase
constituents. There are also a number of other CO sources in
addition to cigarettes, both in the external environment (e.g.,
automobiles) and in the indoor environment (e.g., gas stoves). As a
result, even the subtraction of external atmospheric levels may not
entirely eliminate the contribution of other sources of CO to the
indoor environment.
Given these problems, use of several of these measures, or the
tailoring of the measurement to the phenomenon being measured,
seems appropriate. The measurement of total particulate matter
may be a reasonable indicator of exposure to the particulate phase of
smoke, once the measurement is limited to respirable particulates
and once background levels with the same level of activity, but
without smoke, are subtracted. Relatively precise methods have been
developed to predict the levels of exposure to carbon monoxide
(Jones and Fagan 1975; Coburn et al. 1965) and total particulate
matter (Repace and Lowrey 1980) that would be expected in rooms of
different size and ventilation with different rates of smoking.
Stewart et al. (1974), using blood donors, found the median blood
carboxyhemoglobin level for smokers and nonsmokers in selected
populations to be 5.0 and 1.2 percent, respectively. This corresponds
to a steady state ambient CO level of 7 ppm, which represents a
combination of atmospheric pollution from cigarette smoke and the
background level of urban pollution and is consistent with the levels
described in Table 2. Exposure levels to carbon monoxide are highly
dependent on ventilation, occupancy, smoking rates, and background
levels in the ambient air. The half life of carboxyhemoglobin is
approximately 4 hours, making blood carboxyhemoglobin a useful
biologic monitor of acute exposure to passive smoking, but one that
does not provide useful data for chronic exposure.
Assessment of chronic exposure with a biologic marker requires
the ability to measure some accumulating product of smoke. To date,
substances such as cotinine (Matsukura et al. 1979; Langone et al.
1973; Williams et al. 1979; Feyerabend and Russell 1980; Russell et
al. 1982), thiocyanate (Bottoms et al. 1982; Cohen and Bartsch 1980),
and polonium-210 (Radford and Hunt 1964; Little and McGendy
1966) have been measured in active smokers. Plasma and urinary
nicotine, plasma and urinary cotinine, and salivary nicotine and
cotinine have been reported in nonsmokers exposed to tobacco smoke
(Jarvis and Russell 1984; Russell and Feyerabend 1975; Feyerbend et
al. 1982). Of these measures, it would appear that urinary cotinine
offers the most promise as an index of exposure. However, there are
no published data using these measures as biologic markers of
chronic involuntary smoke exposure.
383
In contrast to physiologic investigations, epidemiologic studies
have used the number of smokers in the home or in the working
environment as the principal exposure variable. These relatively
crude indices, in general, ignore time spent with the smoker and the
environmental factors known to influence ambient smoke concentra-
tion noted above.
In summary, involuntary smoking research deals with an expo-
sure that is qualitatively and quantitatively different from that of
active smoking. Adequate characterization of passive exposure in
both epidemiologic and physiologic studies is substantially more
difficult for involuntary exposure than for active smoking exposure.
While the active smoker’s total current cigarette consumption is
relatively easily quantitated, the lower dose and greater influence of -
ventilation and ambient environment for involuntary smoke expo-
sure makes assessment of exposure one of the most important
methodologic issues of this research. Clearly, a biologic marker of
chronic exposure that reflects the amount of tobacco smoke to which
nonsmoking persons are exposed would be a useful tool. In addition,
carefully formulated questionnaires quantifying passive smoking are
also necessary, and may prove equally valid for assessing exposure.
No single index has yet been accepted by all investigators, and
comparison between studies remains difficult. However, Repace and
Lowrey (1983) have estimated that the nonsmoking population may |
be exposed to from 0 to 14 mg of tar per day, with an average expo-
sure of 1.43 mg per day.
Acute Physiologic Response of the Airway to Smoke in the
Environment
Relatively little acute exposure data exist concerning the effects of
passive inhalation of cigarette smoke on pulmonary function (Table
3). The data that are available have been obtained in exposure -
chambers under carefully monitored and controlled circumstances -
(Pimm et al. 1978; Shephard et al. 1979; Dahms et al. 1981).
Pimm and colleagues (1978) exposed nonsmoking adults to smoke
in an exposure chamber. Relatively constant levels of carbon
monoxide (approximately 24 parts per million) were achieved in the
chamber during involuntary smoking. Peak blood carboxyhemoglo-
bin levels were always less than 1 percent in subjects before smoke
exposure, but were significantly greater during the study exposure.
Lung volumes, flow volume curves, and heart rate were measured
for all subjects. Measurements were made at rest and following
exercise under control conditions and smoke-exposure conditions.
Flow at 25 percent of the vital capacity decreased significantly with
smoke exposure at rest in men and with exercise in women. The
magnitude of the change was small: a 7 percent decrease in flow in
384
G8E
TABLE 3.
—Acute effects on pulmonary function of passive exposure to cigarette smoke
Study Type of exposure Magnitude of exposure Effects Comments
Pimm et al. Chamber 14.6 m? with Peak [CO] ~ 24 ppm; Men: 5% increase FRC, Nonsmokers, average age of
(1978) sparse furniture; smoking particulates >4 mg/m? 11% increase RV, 4% men = 22.7, women = 21.9;
machine in room decrease Vnax25 during sham exposure as control
exercise
Women: 7% decrease V maxzs
post exercise; no effects on
VC, TLC, FVC, FEV,,
maxi0)
Shepard et al. As above Low exposure: peak [CO] ~ Low exposure: 3% decrease Nonsmokers; average age of
(1979) 20 ppm, particulates ~ FEV,, 4% decrease Vioasso, men = 23, women = 25;
mg/m*; high exposure: (CO] 5% decrease Viexs with sham exposure as control;
~ 31 ppm exercise; no increased effect subjects estimated to have
with high exposure inhaled ~ 1/2 cigarette/2
hours
Dahms et al. Chamber 30 m'; climate Room levels not measured: 0.9% increase in FVC, 10 nonsmckers; age range
(1981) controlled estimated at peak (CO] ~ 5.2% increase in FEV,, 24-53 years; not blinded: no
20 ppm
2.2% increase in FEF 25-75 at
1 hour
sham exposure
men and 14 percent in women. No other consistent changes in lung
function were observed. Shepard and coworkers (1979) utilized a
similar crossover design in a chamber of exactly the same size as
Pimm’s. Their results were almost identical, with a small (3 to 4
percent) decrease in FVC, FEV, Vmaxso, and Vmax. They concluded
that these changes were of the magnitude anticipated from an
exposure of less than 1/2 cigarette in 2 hours (the exposure
anticipated for a passive smoker).
Dahms et al. (1981) used a slightly larger chamber with an
estimated peak CO level of approximately 20 parts per million. They
found no change in FVC, FEV, or FEF2s5-75 after 1 hour of exposure in
normal subjects. This experiment was not blinded and had no sham
exposure.
The data from these studies suggest that involuntary smoke
exposure can probably produce measurable, albeit small, changes in
the airways of normal individuals. This response is consistent with
the acute response to the inhalation of cigarette smoke by the active -
smoker, and it is not surprising that high dose involuntary exposure
to tobacco smoke might produce similar results. The magnitude of
these changes is small, even at moderate to high exposure levels, and -
it is unlikely that this change in airflow per se results in symptoms,
however, it may be only one manifestation of a broader irritant -
response to smoke in nonsmokers.
Symptomatic Responses to Chronic Passive Cigarette Smoke
Exposure in Healthy Subjects
Eye irritation is the most common complaint experienced by -
normal people acutely exposed to cigarette smoke. In one study, 69
percent of subjects reported ever experiencing this symptom (Speer
1968). Headache, nasal irritation, and cough were reported by
approximately one-third of the subjects in this and other investiga-
tions (Weber and Hertz 1976; Slavin and Hertz 1975). Several factors -
may alter the prevalence of irritant symptoms, including the amount
of smoking, the size of the area involved, the humidity and
temperature of ambient air, and the extent of ventilation (Johansson
1976). No longitudinal studies of these irritant effects (e.g., develop-
ment of increased sensitivity or tolerance) have been reported.
Weber (1984) has examined the effect of dose and duration of
exposure to environmental tobacco smoke on subjective reporting of
eye irritation and objective measurement of eye blink rate. Figure 1
reveals that both eye irritation and blink rate increase with
increasing dose of smoke exposure, and that substantial subjective
irritation and objective increase in blink rate occur at levels of
smoke exposure (CO levels of 20 to 24 ppm) equivalent to those used
to evaluate pulmonary function changes in response to environmen-
386
eye Irritation eye blink rate/min
very strong 5 7— eye irritation index r 80
leseseeee eye biink rate -
strong a> 60
medium 304 - 40
weak 27 - 20
none tT Ff T T T T , 0
QO 10 2c min
FOU q tT q q
co 1 11 22 32 42 43 ppm
ct q qt q T 4
NO 0.08 0.42 0.77 1.11 1.45 1.50 ppm
t q T } T q
HCHO 0.03 0.18 0.32 0.47 0.62 0.64 ppm
i q q i qT J
acrolein 0 0.05 0.11 0.16 0.20 0.20 ppm
rT
number of cig. 0 10 20
FIGURE 1.—-Mean subjective eye irritation, mean eye blink
rate, and concentrations of some pollutants
during continuous smoke production in an
unventilated climatic chamber
NOTE: Thirty-three subjects; ventilation rate 0.01 h'; eye irritation index calculated from the answers to four
questions concerning eye irritation; 0 min = measurement before smoke production.
SOURCE: Weber (1984).
tal tobacco smoke exposure. Both irritation and blink rate increase
with duration of exposure to environmental tobacco smoke (Figures
2 and 3). After 60 minutes of exposure, distinct changes are evident
in level of irritation with a smoke exposure of 1.3 ppm CO, and the
blink rate increased with smoke exposures as low as 2.5 ppm CO.
These levels of smoke exposure (1.3 to 2.5 ppm CO) are well within
those measured under realistic conditions (see Table 1). Therefore, it
is possible to demonstrate an objective irritant response in normal
subjects at levels of smoke exposure substantially lower than the
levels where an airway response (also presumably an irritant
response) has been demonstrated. Whether this difference represents
a difference in threshold for irritation in the eye and airway or a
limitation in the ability to measure subtle changes in the airway is
uncertain.
387
eye irritation index
35
fo 10 ppm
Lf ue 5 ppm
2- foe
¢ 2.5 ppm
{fv
/
7
/ _.--7 1.3 ppm
peneeriscnneamenecananents control
7 ES T T T T 1
0 20 40 60
exposure min
FIGURE 2.—Subjective eye irritation due to environmenta
tobacco smoke, related to smoke concentratio
and duration of exposure
NOTE: CO values are levels during smoke production minus background level before smoke production; 32 t
subjects; 0 min = measurements before smoke production.
SOURCE: Weber (1984).
Chronic respiratory symptoms have been reported most common
in children. Studies from several different countries (Table 4) ha
shown a positive relationship between parental cigarette smoki:;
and the reporting of the symptoms of chronic cough, chronic phlegi
and persistent wheeze (Colley et al. 1974; Bland et al. 1978; Lebow:
and Burrows 1976; Weiss et al. 1980; Ware et al. 1984; Schilling et :
1977; Kasuga et al. 1979; Schenker et al. 1983). Some of these studi
may be confounded by an increased reporting of symptoms in t
child by parents who smoke and have symptoms (Colley et al. 19”
Bland et al. 1978; Kasuga et al. 1979) or by the child’s own smoki
habits (Colley et al. 1974; Bland et al. 1978; Kasuga et al. 1979). N
all studies show statistical significance for all symptoms (Lebow
and Burrows 1976; Schilling et al. 1977; Schenker et al. 198
However, a consistent finding in all reported data is an increase
symptoms with an increased number of smoking parents in t
388
eye blink rate/min
40-
35-4
aT“ _7 10 ppm
/ \2
/
30-7 J
/ a wot 5 ppm
25 / Yo ~~
— le
v7
7 / 2.5 ppm
20- - 1.3 ppm
vat geceteteceveeeeneeeese control
way Oe
4
ot i T T T T tT
0 20 40 60
exposure min
FIGURE 3.—Effects of environmental tobacco smoke on eye
blink rate
NOTE: CO values are levels during smoke production minus background level before smoke production: 32 to 43
subjects; 0 min = measurements before smoke production.
SOURCE: Weber (1984).
home. This effect persists after controlling for parental cough and is
most marked in the first year of life.
British researchers, studying a birth cohort, demonstrated an
increased incidence of wheezing over a 5-year period among nonasth-
matic children who had two parents who smoked. However, when
examined by logistic regression, parental smoking was not a
significant predictor of occurrence of wheeze or the future occur-
rence of asthma (Bland et al. 1978). Ina subgroup of the cohort—861
children of asymptomatic parents, Leeder and colleagues (1976a)
found no significant trend in asthma—wheeze symptoms with in-
creasing levels of parental smoking over a 5-year period. In a study
of 650 children aged 5 to 10 years (Weiss et al. 1980), a significant
trend in the reported prevalence of chronic wheezing with current
parental smoking was found; the rates were 1.85 percent, 6.85
percent, and 11.8 percent for zero, one smoking parent, and two
smoking parents, respectively. Although the data given are for all
389
O6E
TABLE 4.
—Respiratory symptoms in children in relation to involuntary smoke exposure
Rates per 100 by
Respiratory number of smoking parents
Study Subjects symptoms or illness 0 1 2 Comment
Colley et al. 2,426 children, aged 6-14, Chronic cough assessed by 156 17.7 222 Trend significant; possible that
(1974) England questionnaire completed by symptoms in parents could result
parent in reporting bias; active smoking
in children could also bias results;
bias unlikely to explain full effect
of trend
Bland et al. 3,105 children, aged 12-13, who Cough during day or at night 164 190 235 Self-reported symptoms and
(1978) did not admit to ever smoking smoking history collected
cigarettes, England Morning cough 15 2.8 2.9 simultaneously from children;
difference between morning and
daytime cough suggested as
different diseases, but could be
difference in exposure, in that
exposure more likely in daytime
than when asleep
Weiss et al. 650 children, aged 5-9, United Chronic cough and phlegm 17 27 3.4 Trend not significant
(1980) States
Persistent wheeze 18 68 118 Trend significant
Ware et al. 8,528 children, aged 5-9, with Chronic cough 17 84 106 Adjusted for age, sex, and city
(1984) two parents of known smoking cohort effects; significant trends
status, six U.S. cities Persistent wheeze 99 110 131
166
TABLE 4.—Continued
Rates per 100 by
Respiratory number of smoking parents
Study Subjects symptoms or illness 0 1 2 Comment
Dodge 628 children, grades 3-4, in Wheeze 276 279 40.0 All trends significant; some of
(1982) two-parent households; effect might relate to parental
questionnaire response of Phlegm 64 109 120 symptoms, but not likely to
parents, United States influence trends
Cough 146 230 278
Schenker et al. 4,071 children, aged 5-14, in Chronic cough 6.3 70 8.3 None of these rates significant;
(1983) western Pennsylvania data not adjusted for parental
Chronic phlegm 4.1 48 4.0 symptoms
Persistent wheeze 7.2 V4 5.4
Never Parent
smoking smoking
Lebowitz and 1,252 children, <16 years Persistent cough 3.7 7.2 Higher rates in symptomatic
Burrows old, United States households with trends persisting,
(1976) Persistent phlegm 10 12.8 but not significant for
asymptomatic households
Wheeze 23.4 24.1
Schilling et al. 816 children, age 7+, United Cough, phlegm, wheeze No significant Specific data not provided
(1977) States effect
Kasuga et al. 1,937 children, aged 6-11, Wheeze, asthma Increased prevalence in families Data adjusted for distance of
(1979) Japan with a heavy smoker (>21 home from main traffic, highway
cig/day); leas clear effect in
family with a light smoker (< 21
cig/day)
households, when the analysis was restricted to those households
where neither parent reported symptoms, the results were identical,
suggesting that in this population, significant reporting bias was not
responsible for the observed results. Lebowitz and Burrows (1976), in
a group of 463 current-smoking and never-smoking households with
children below age 15, found trends—but no statistically significant
differences—for a variety of symptoms, including wheeze most days,
in households with smokers. In the same study, among 849 house- -
holds with older children and adults, there were no significant
differences for any symptom prevalence between current-smoking
and never-smoking household members. In a general population
study, Schilling et al. (1977) reported no association between wheeze
and involuntary smoking.
A preliminary report from one of the largest studies currently
under way (Speizer et al. 1980) indicated no association of persistent
wheeze with the presence of smoking in the household for approxi-
mately 8,000 children aged 6 to 11 in six communities. However,
subsequent analyses of these same cohorts with the addition of
approximately 2,000 more children and a more detailed assessment
of the smoking behavior of each parent revealed a positive relation-
ship that increased with the amount of maternal smoking and was
only modestly affected by taking into account the parents’ own -
symptoms (Ware et al. 1984). Dodge (1982), studying third and fourth
grade children, found that symptoms, including wheeze, were related
to both the presence of symptoms in the parents and the number of
smokers in the household. The gradient of the wheeze effect
persisted even after excluding the potential effect of reporting bias
by symptomatic parents. Few data are available on the level of
exposure necessary to produce symptoms or on the implication of
these symptoms for future lung growth and development. No data
are currently available on the relationship of passive smoking to
other putative risk factors for wheezing such as atopy, respiratory
infection, and increased levels of airways responsiveness, nor are
sufficient data available to estimate whether these early exposures
affect the occurrence of respiratory disease later in life. The
characteristics of the child who may be susceptible to this type of
exposure are unknown. However, the data are sufficiently consistent
to suggest that pediatricians should routinely inquire about smoking
habits of parents when caring for children with chronic or recurrent
respiratory symptoms and illnesses. It would also be prudent to
advise parents of children who are suffering from recurrent respira-
tory illnesses or persistent wheeze or asthma not to smoke.
392
Respiratory Infections in Children of Smoking Parents
Bronchitis and pneumonia and other lower respiratory illnesses
are significantly more common in the first year of life in children
who have one or two smoking parents (Table 5). Bonham and Wilson
(1981) showed that in 1970 the majority of homes with children
under 17 years of age had at least one smoker. Thus, passive smoking
by children, even in early childhood, is widespread. Harlap and
Davies (1974) studied 10,672 births in Israel between 1965 and 1968
and observed that infants whose mothers said they smoked (as
determined at a prenatal visit) experienced a 27.5 percent greater
hospital admission rate for pneumonia and bronchitis than children
of nonsmoking mothers. In addition, they demonstrated a dose—
response relationship between the amount of maternal smoking and
the number of hospital admissions for these conditions. It should be
noted that the mothers were reporting prenatal smoking and not
postnatal smoking for the first year of life.
British investigators studying live births between 1963 and 1965 in
London also observed an increased frequency of bronchitis and
pneumonia in the first year of life associated with involuntary
smoking that did not carry over to years 2 to 5 (Colley et al. 1974).
This effect was independent of parents’ own symptoms and increased
with the amount of smoking by parents. Bronchitis and pneumonia
also increased with an increased number of siblings, and this was not
controlled in the analysis.
Fergusson et al. (1981), studied 1,265 New Zealand children from
birth to age 3. They demonstrated an increase in both bronchitis and
pneumonia and lower respiratory illness during the first 2 years of
life in children whose mothers smoked. Corrections for maternal age,
family size, and socioeconomic status did not affect the linear
relationship between the degree of maternal smoking and the rate of
respiratory illness. This effect declined with the increasing age of the
child.
Leeder and colleagues (1976b) studied a British cohort of children
born between 1963 and 1965 and demonstrated that parental
cigarette smoking was associated significantly with bronchitis and
pneumonia during the first year of life. A dose-response association
persisted after correction for parental respiratory symptoms, sex of
the child, number of siblings, and a history of respiratory illness in
the siblings.
Pullan and Hey (1982) studied children who were hospitalized with
documented respiratory syncytial virus (RSV) infection in infancy.
They found a significant difference in the smoking habits of mothers
at the time of the infection, compared with children hospitalized for
other illnesses—including respiratory diseases for which RSV infec-
tion was not documented. These children reported an excess
occurrence of wheeze and asthma and had lower levels of pulmonary
393
“~AB8N-144 0 - R25 - 14
PEE
TABLE 5.—Early childhood respiratory illness and involuntary cigarette smoking
Study Subjects Findings Illness rates per 100 Comments
By cigarettes per day
0 1-10 11-20 -H+
Harlap and 10,672 births, 1965-1968, Hospitalized for 9.5 10.8 16.2 31.7 Smoking history obtained
Davies West Jerusalem, Israel bronchitis/pneumonia in first antenatally; maternal smoking
(1974) year of life only
RR'=1.38
Colley? 2,205 births, 1963-1965, Questionnaire on 76 4 itd 182 = Asymptomatic parents
(1974) London, England bronchitis/pneumonia in firet 10.3 15.1 14.5 23.2 = Symptomatic parents
year of life Neither controlied for number
RR=1.73 for one parent smoker of siblings or sex of smokers
RR=2.60 for two parent smokers
Fergusson et al. 1,265 births, 4 months, Questionnaires on doctor or 7.0 12.8 13.4 Maternal Combined effect significant for
(1981) 1977, Christchurch, New hospital visits for only maternal smoking in first year
Zealand bronchitis/pneumonia; check 70 46 88 Paternal of life only
by hogpital records only
Assessment at 4 months, 1, 2,
and 3 years
RR=2.04 if mother smoked
By number of smoking parents
0 1 2
Ware et al. 8,528 children, aged 5-9, Respiratory illness in last year 12.9 13.7 14.8 Adjusted for age, sex, and city
(1984) with two parents of known cohort effect; significant trends
smoking status, six U.S.
cities
S6E
TABLE 5.—Continued
Study Subjects Findings Illness rates per 100 Comments
Said et al. 3,920 children, aged 10-20, Tonsillectomy and/or 28.2 414 50.9 Self-reporting by children; not
(1978) France adenoidectomy, generally clear that smoking habits of
before age 5, as indicator of parents at time of reporting
frequent respiratory tract directly related to exposure
infection approximately 10+ years
earlier
Schenker et al. 4,071 children, aged 5-14, Chest illness before age 2 6.7 79 11.5 Trends for both significant
(1983) western Pennsylvania Chest illness >3 days in past 88 118 13.6
year
Cameron et al. 158 children, aged 6-9, Respiratory illness with 1.33 74 Illness reporting not verified;
(1969) parents completed telephone restricted activity and/or not clear how reporting adult
questionnaire, United States medical consultation in last was related to child
year
Leeder et al. 2,149 infants, born 1963- RR ~ 2.0 for infants with two Not provided Parents answered for children,
(1976a, b) 1965, Harrow, England smoking parents but response bias seems
unlikely because effects were
observed for infants of
asymptomatic parents; effects of
maternal vs. paternal smoking
not investigated
Sims et al. 35 children hospitalized Borderline significant increase Not provided No significant effect for
(1978) with RSV bronchiolitis, in maternal smoking during paternal smoking, average
35 controls, England
first year of life
RR=2.65
amount smoked greater for
parents of cases than for
controls
968
TABLE 5.—Continued
Study Subjects Findings Tliness rates per 100 Comments
Rantakallio 1,821 children of smoking Significant increase in Not provided Prospective followup of doctor
(1978) mothers, hospitalization for respiratory visits, hospitalizations, deaths
1,823 children of illness during first 5 years of up to age 5; only maternal
nonsmoking mothers life smoking evaluated
RR=1.74
Pullan and Hey 130 children admitted to Significant effect of maternal Not provided
(1982) hospital during first year of (RR=1.96) and paternal
life with RSV infection,
111 nonhospitalized controls
(RR=1.53) smoking at time of
study; significant maternal
effect of smoking during first
year of life (RR=1.55)
’ Relative risk for children of smoking mothers versus children of
king mothers
* These data are considered in a more expanded analysis provided by Leeder et al. (1976).
Jeulated from published data provided by J.M. Samet, M.D.
function that persisted to age 10. The authors could not distinguish
between the possibilities that infection caused damage that persisted
and affected the maturation of the lung or that these children were
already more susceptible to severe RSV infection. Greenberg et al.
(1984) examined the tobacco smoke exposure of infants in the first
year of life by measuring urinary cotinine-to-creatinine ratios. They
found that infants of mothers who smoked had a ratio of 351 ng per
mg, as contrasted with a ratio of 4 ng per mg in infants of mothers
who did not smoke. Breast-fed infants were excluded because of the
presence of nicotine in the breast milk of mothers who smoke. A
dose-response relationship was present between the cotinine-to-
creatinine ratio and the reported level of maternal smoking in the
previous 24 hours. This study suggests that infants of mothers who
smoke absorb measurable amounts of the smoke from this environ-
mental exposure.
Rantakallio (1978) studied over 3,600 children for 5 years, half of
whom had mothers who smoked and half of whom did not. Children
of mothers who smoked had a 70 percent greater chance of being
hospitalized for a respiratory illness than children of nonsmoking
mothers.
Some of these studies may be confounded by the increased
reporting of symptoms in the child by parents who smoke and have
symptoms (Cameron et al. 1969: Said et al. 1978; Leeder et al. 1976b),
but in those studies in which parental symptoms were controlled, the
effects persisted. Other studies may be influenced by the child’s own
smoking habits (Said et al. 1978), although the majority of research
examined children in an age range in which smoking would be
unlikely.
In summary, several studies Suggest important increases in severe
respiratory illnesses, particularly in the very young (less than 2
years old) children of smoking parents. Young children may repre-
sent a more susceptible population for adverse effects of involuntary
smoking than older children and adults. The amount of time spent
with active smokers, particularly by children under 2 years of age
with smoking mothers, may be an important factor. How in utero
exposure influences this risk is unknown.
Pulmonary Function in Children of Smoking Parents
In recent years, a number of studies have examined the relation-
ship of parental cigarette smoking to pulmonary function in children
(Table 6). The majority of these studies have been cross sectional
(Tager et al. 1979; Weiss et al. 1980; Vedal et al., in press; Burchfiel
et al., 1983; Tashkin et al. 1983; Hasselblad et al. 1981: Ware et al.
1984) and have demonstrated decreases in level of pulmonary
function (FEVo75, FEV), FEF»2.75, and flows at low lung volumes) in
397
children of smoking mothers compared with children of nonsmoking
mothers.
In some studies, there seems to be a dose-response relationship
(Tager et al. 1979; Weiss et al. 1980); i.e., the greater the number of
smokers in the home, the lower the level of function. When analyzed
by multiple regression techniques, maternal smoking has the
greatest impact (as would be expected from the greater contact time
with the child), and a dose-response relationship with the amount
smoked seems to exist (Weiss et al. 1980; Tager et al. 1979; Ware et
al. 1984; Vedal et al., in press). Younger children seem to be more
adversely affected than older children (Tager et al. 1979; Weiss et al.
1980), and clearly there is an added effect in older children if they
themselves smoke (Tager et al. 1979).
Tager and colleagues (1983) followed 1,156 children for 7 years to
determine the effect of maternal smoking on growth of pulmonary
function in children. After correcting for previous level of FEV:, age,
height, personal cigarette smoking, and correlation between moth-
er’s and child’s pulmonary function, maternal smoking was associ-
ated with a reduced rate of annual increase in FEV: and FEF 2-75. The
magnitude of the effect was consistent with a 3 to 5 percent decrease
in expected lung growth due to the maternal smoking effect,
constant over the time period of the study. Because so few mothers
changed their smoking habits, the study did not attempt to differen-
tiate between postnatal and in utero effects of involuntary smoke
exposure.
Ware et al. (1984) followed 10,106 white children for two successive
annual examinations. The FEV, was 0.6 percent lower in the
children of smoking mothers at the first examination and 0.9 percent
lower at the second examination. These differences were statistically
significant, but represent very small absolute differences. In this
study, and in the other studies that show smal] changes in
pulmonary function, it is not clear whether these changes represent
small changes occurring uniformly among the children of smoking
mothers or somewhat larger changes occurring in a small subpopula-
tion of susceptible children.
The available data demonstrate that maternal smoking affects
lung function in young children. However, the absolute magnitude of
the difference in lung function is small; it is unlikely that this small
difference, per se, is of functional significance. The concern generat-
ed by the demonstration of even small differences is directed at the
future lung function of those children, particularly if they become
active cigarette smokers as adults. The possibility that this differ-
ence in lung function may result from pathophysiologic mechanisms
similar to those present in active smokers raises the concern that
these children may be “sensitized” to smoke at an early age, and that
this “sensitization” may result in a more rapid decline in lung
398
66E
TABLE 6.—Pulmonary function in children exposed to involuntary smoking
Study
Subjects
Pulmonary function measure
Outcome
Comments
Schilling et al.
(1977)
Tager et al.
(1979)
Weise et al.
(1980)
Vedal et al.
(in press)
Lebowitz and
Burrows
(1976)
816 children, aged 7-17,
Connecticut and South
Carolina
444 children, aged 5-19,
East Boston, Massachusetts
650 children, aged 5-9, East
Boston, Massachusetts
4,000 children, aged 6-13
271 households with
complete histories of
parents’ smoking and of
pulmonary function of
children > age 6, Tucson,
Arizona
FEV, as percent predicted
MMEF in standard deviation
unite
MMEF in standard deviation
units
FEV25, FVC, Vinasso, Vmmax75,
Vrnaxo0
FEV,, FVC, Vinexs0, Vmax75
derived from MEF, V curves,
expressed as standard deviation
units
No effect of parental smoking
Significant effect of parental
smoking
Significant effect of parental
smoking
FVC positively associated, flows
negatively associated
No effect of parental smoking
No control for sibehip size or
correlation of siblings’
pulmonary function; when
analysis restricted to children
who never smoked, Vmexso
significantly less in children
with smoking mothers
Analysis controlled for sibehip
size and correlation of siblings’
pulmonary function
Analysis controlled for sibship
size and correlation of siblings’
pulmonary function
Flows dose-response with
amount smoked by mother
Suggestion that real differences
in indoor levels of exposure
compared with more northerly
climates may be occurring
OOF
TABLE 6.—Continued
Study
Subjects
Pulmonary function measure
Outcome
Comments
Dodge
(1982)
558 children, aged 8-10,
Arizona
FEV, by age change
FEV,/H* per year
No effect of parental smoking
Potential bias in participation
rates; cross-sectional data not
controlled for children’s height;
annual change in FEV,/H®* at
ages 8, 9, and 11 consistently
greater in nonsmoking
households than in two-parent
smoking households; statistical
test not significant, however
Tager et al.
(19839)
Burchfiel et al.
(1983)
Tashkin et al.
(1983)
Hasselblad et al.
(198)
1,156 children, aged 5-19 at
initial survey, East Boston,
Massachusetts
4,378 children, aged 0-19,
Tecumseh, Michigan
1,070 nonsmoking,
nonasthmatic children, Los
Angeles
16,689 children, aged 5-17,
seven geographic regions,
United States
FEV,, FEF 25-75
FVC, FEV,, Vmaxso
Vraax, Vmax75, Vmax2s, FEF 25-75
FEV7s as percent predicted
Significant decreased rate of
growth in FEV, and FEF2s5-75
for children of smoking
mothers
Decreased FEV, and FVC for
boys and Vwuazso for girls with
increased number of smoking
parents
Decreased Vinex, Vmax2s for boys
and FEF275, Vinas7s for girls
with at least a smoking mother
Significant effect of maternal
smoking, but not paternal
smoking
1-year followup; no effect of
paternal smoking; maximum
effect of maternal smoking on
fully developed lung not more
than 4 or 5 percent
Abetract; no distinction between
effects of maternal and
paternal smoking; effects most
prominent for boys and
youngest age groups
No effect of paternal smoking
Large number of children
excluded because of invalid
pulmonary function data or
missing parental smoking data
TOV
TABLE 6.—Continued
Study Subjects
Pulmonary function messure
Outcome
Comments
Speizer et al. 8,120 children, aged 6-10,
FVC and FEV, as percent
No effect for FEV, or FVC
Recent analysis of this cohort
(1980) in six US. cities predicted demonstrated an effect for FVC
and FEV,
Ware et al. 10,000 children, aged 6-11, FEV, and FVC FVC positively associated with FEV, dose-response with
(1984) in six US. cities
smoking, FEV, negatively
associated
amount smoked by mother
function as adults, particularly if they become smoking adults. NO
data are currently available to establish the role, if any, of the small
physiologic changes in children on the development of adult obstruc-
tive lung disease.
Pulmonary Function in Adults Exposed to involuntary
Cigarette Smoke
White and Froeb (1980) reported on 2,100 asymptomatic adults
drawn from a population about to enter a physical fitness program.
They demonstrated statistically significant decreases in FEV: and
MMEF as a percent of predicted in nonsmokers exposed to tobacco
smoke in the work environment compared with nonexposed workers.
The decrement was comparable to that seen in smokers inhaling 1 to
10 cigarettes per day. However, the absolute magnitude of the
difference in mean levels of function in the smoke-exposed and
unexposed groups was quite small: 160 ml (5.5 percent) for FEV: and
465 ml/sec (13.5 percent) for MMEF. Carbon monoxide levels were
measured in the workplace and ranged from 3.1 to 25.8 ppm. The
population was self-selected, response was related to current work-
place exposure and did not account for people who changed jobs, and
it is unclear how the ex-smokers in the population were handled in
the analysis.
Comstock et al. (1981) examined 1,724 subjects drawn from two
separate studies in Washington County, Maryland. They found no
statistically significant greater risk of having an FEV: less than 80
percent of predicted in male nonsmokers exposed to wives’ cigarette
smoke at home. Schilling et al, (1977) did not find an effect of passive
smoking exposure in adults. Both of these studies included adults in
their samples who were relatively young and generally would not
have had a long-term passive exposure in adult life. This point was
brought out by a recently reported large study from France.
Kauffmann et al. (1983) reported on a seven-city investigation in
which a total of 7,818 adults were studied. In a subsample of 1,985
nonsmoking women aged 25 to 29, in which 58 percent were exposed
to smoking husbands, there was a significant difference in level of
MMEF between truly nonsmoking women and women of comparable
ages exposed to passive smoking. This effect did not become apparent
until age 40. These changes were small, and although not adjusted
for differences in body size, may suggest a possible effect of long-term
exposure in adult life.
The physiologic and clinical significance of these small changes in
pulmonary function in adults remains to be determined. In addition,
variables such as ventilation, room size, number of rooms in the
home, duration of contact with the active smoker, and number of
cigarettes smoked could significantly influence total exposure and
402
need to be explored more fully. Differences in these exposure
variables and the characterization of exposure may explain some of
the differences in these study results (Table 7).
The Effect of Passive Smoke Exposure on People With
Allergies, Asthma, and COLD
There are very limited data on the effects of passive smoke
exposure in patients with preexisting pulmonary disease, and the
available data are conflicting. Clinical studies have suggested a
relationship between respiratory symptoms in asthmatics and expo-
sure to parental cigarette smoke, but methodologic problems compli-
cate the interpretation of the limited available data.
O’Connel! and Logan (1974) identified 37 asthmatic children who
were “bothered” by parental cigarette smoke. Parents of 20 of the
children stopped smoking and 18 (90 percent) of the 20 children had
an improvement in symptoms. The control group consisted of 15
children (2 were not followed up) whose parents did not stop
smoking. Only 4 (27 percent) of the children in the control group
improved. The self-selection of those parents who quit, subjective
criteria for improvement, and an unclear duration of followup limit
the interpretation of this data. Gortmaker and coworkers (1982)
studied two populations of children aged newborn to 17 years. They
found a significant association between parental reporting of chil-
dren’s asthma and maternal smoking. Maternal smoking alone was
associated with approximately 20 percent of all asthma. The effect
persisted when age and sex of the child, allergies, and family income
and education were controlled in the analysis. No control was
attempted for the children’s own smoking habits or for increased
reporting of symptoms in children of symptomatic parents. Other
population-based studies (Lebowitz and Burrows 1976; Speizer et al.
1980; Schilling et al. 1977) have not shown such results.
Dahms et al. (1981) studied 10 patients with bronchial asthma and
10 normal subjects passively exposed to smoke in an environmental
chamber. Pulmonary function was measured at 15-minute intervals
for 1 hour after smoke exposure. Blood carboxyhemoglobin levels
were measured before and after the 1-hour exposure. Carboxyhemo-
globin levels in subjects with asthma increased from 0.82 to 1.20
percent. In normal subjects the increase was from 0.62 to 1.05
percent. The increases in carboxyhemoglobin in the two study
groups were not significantly different. Asthmatic subjects had a
decrease in forced vital capacity (FVC), forced expiratory volume in 1
second (FEV:),and maximum mid expiratory flow rate (MMEF) to a
level significantly different from their preexposure values. The
decreases in asthmatic subjects were present at 15 minutes, but
worsened over the course of the hour to approximately 75 percent of
403
OP
TABLE 7.—Pulmonary function in adults exposed to involuntary smoking
Study Subjects Pulmonary function measure Outcome Comments
White and Froeb 2,100 adults, San Diego, FVC, FEV,, and MMF as Significant effect of office Potential bias in selection,
(1980) California percent predicted exposure to involuntary assessed only current
smoke cigarette smoke exposure
Comstock et al. 1,724 adulta, Washington FEV, as percent predicted No effect of wives’ smoking Includes adults aged 20+
(198D) County, Maryland on husbands’ pulmonary
function
Kauffmann et al. 7,818 adults, seven French FEV,, FVC, and MMEF Significant effect in wives Not adjusted for height,
(1983) cities, selected subgroups of smoking husbands in all dose-response to amount of
measures; significant only husbands’ smoking for
for MMEF in husbands of MMEF in wives, no effect
smoking wives below age 40
the preexposure values. Normal subjects had no change in pulmo-
nary function with this level of exposure. In this study, subjects were
not blinded as to the exposure and were selected because of
complaints about smoke sensitivity. Shephard et al. (1979), in a very
similar experiment, subjected 14 asthmatic subjects to a 2-hour
cigarette smoke exposure in a closed room (14.6 m‘). The carbon
monoxide levels (24 ppm) were similar to those predicted in the study
of Dahms and coworkers. No blood carboxyhemoglobin levels were
measured. Subjects were randomized and blinded to sham (no smoke)
and smoke exposure and tested on two separate occasions. Data were
expressed as a percentage change from the sham exposure. No
significant changes in FVC or FEV: were observed between sham
and smoke exposure periods, although 5 of 12 subjects did report
wheezing or tightness in the chest on the day of smoke exposure.
The limited existing data yield conflicting results concerning the
relationship between passive smoke exposure and symptoms in
patients with known pulmonary disease. Further study of this
important question is warranted.
Summary and Conclusions
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 norma! 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.
§. 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.
405
eld conflicting results concerning
7. The limited existing data yi
ke exposure and pulmo-
the relationship between passive smo
nary function changes in patients with asthma.
406
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412
CHAPTER 8. DEPOSITION AND
TOXICITY OF
TOBACCO SMOKE IN
THE LUNG
413
CONTENTS
CIGARETTE SMOKE DEPOSITION IN THE
LUNG
Introduction
Characterization of an Aerosol
Characterization of Cigarette Smoke Aerosols
Factors That Affect Particulate Deposition
Deposition of Cigarette Smoke Particulates
Particulate Retention in the Lung
Passive Smoking
Conclusions
CIGARETTE SMOKE TOXICOLOGY
Introduction
Preliminary Considerations
Effects on Airway Function and Ventilation
Human Studies
Animal Studies
Effects on Permeability of the Pulmonary Epithelium
Human Studies
Animal Studies
Effects on Mucociliary Structure and Function
Effects on Cells
Human Studies
Animal Studies
Effects on Protease Inhibitors
Human Studies
Animal Studies
Effects on Lung Tissue Repair Mechanisms
Human Studies
Animal Studies
ee
Summary and Conclusions
ee
References
415
CIGARETTE SMOKE DEPOSITION IN THE
LUNG
Introduction
Previous Reports of the Surgeon General on the health conse-
quences of smoking have focused on characterizing and quantifying
responses to the inhalation of cigarette smoke. Typically, dose is
given in terms of packs per day or cumulative pack years. However,
a more accurate description of dose would include how much smoke
is inspired into the respiratory tract, how much is deposited and fails
to exit with the expired air, and the fate of the deposited smoke.
A commonly held fallacy is that “living in New York is like
smoking two packs per day.” Is the amount of particles produced by
smoking comparable to that encountered in urban air pollution? A
person who smokes two packs of cigarettes per day with an average
tar rating of 20 mg per cigarette would breathe in 800 mg of material
per day, or 292 g of tar per year. A reasonable value for urban air
would be 100 wg, or 0.1 mg per cubic meter. The average person
breathes approximately 20,000 liters, or 20 cubic meters, of air per
day. Thus, 2 mg of material per day, or 0.73 g of particulate per year,
would be inspired. At the outset, it is evident that the amount of
smoke entering the lungs is considerably greater than the amount of
particulates from air pollution.
This chapter emphasizes the size and aerodynamic properties of
smoke and relates them to the fraction of the inspired smoke that
deposits in the lungs. Also considered is where the smoke deposits,
and its possible fate is described.
The particulate phase of cigarette smoke, commonly known as tar,
is inhaled as an aerosol into a smoker’s respiratory tract. An aerosol
is defined as a suspension of solid or liquid particles in a gas (Hinds
1982). In the case of cigarette smoke, the aerosol contains ambient
air as well as the gases, liquids, and solids produced during tobacco
combustion. The particulates include a wide variety of organic and
metallic compounds, many of which are toxic to lung tissues.
Hydrocarbons, aldehydes, ketones, organic acids, alcohols, nicotine,
and phenols are among them. Metallic compounds such as radioac-
ive lead and polonium are also present. The gas phase is also
‘complex; in addition to the nitrogen and oxygen in the air,
‘onsiderable amounts of carbon dioxide and carbon monoxide are
resent, and also significant amounts of cyanides, acrolein, nitrogen
xides, and ammonia. The precise quantitative composition of the
obacco smoke varies with many different factors, including the type
f tobacco plant grown, the soil used to grow the plant, the method of
uring the leaves, the temperature of combustion during smoking,
nd the composition and physical properties of the cigarette paper
417
and other additives. As the cigarette butt length decreases, many
substances that have previously condensed on the remaining tobacco
are revaporized. Generally, as butt length shortens, the smoke from
the cigarette contains an increasing concentration of these sub-
stances. Most of these constituents in smoke are toxic to lung tissues.
Their toxicity extends from impairment of mucociliary transport,
critical for clearing particles from the lungs, to carcinogenic and
cocarcinogenic activities (Wynder and Hoffmann 1979; Battista
1976). To understand where the numerous particulates in cigarette
smoke deposit in the lungs and how they are removed is important
for determining the pathologic effects of chronic cigarette smoking.
Characterization of an Aerosol
To predict the deposition patterns of any aerosol, such as cigarette
smoke, it is necessary to know the size, shape, and density of the
individual particles or droplets. Describing the distribution of
particle diameters is essential. It is convenient to describe particle
size aS an aerodynamic diameter rather than as an actual particle
size based on optical measurements, because the former is a better
predictor of aerodynamic behavior (Hinds 1982). Aerodynamic
diameter is defined as the diameter of a sphere of unit density that
has the same settling velocity as the particle being measured. This
may be expressed as a count median aerodynamic diameter (CMAD)
and a mass median aerodynamic diameter (MMAD). These are,
respectively, the diameters for which half of the number or mass of
the particles are less than that diameter and half are more.
Characterization of Cigarette Smoke Aerosols
The particulates in cigarette smoke ‘have been measured by
several investigators using a variety of analytical devices. Because of
different apparatus and different methods of smoke generation and
dilution, results vary but are reasonably consistent. McCusker et al.
(1983) used a device called the single particle aerodynamic relaxa-
tion time (SPART) analyzer to determine the size of particulates
from several brands of cigarettes, with and without filters. The mass -
median aerodynamic diameter (MMAD) for all brands averaged
approximately 0.46 pm; it was not markedly different when the -
filters were removed. These measurements showed that, even with a
filter, billions of particles are present in an average 35 ml puff of
cigarette smoke generated by an automatic smoking-machine. Par-
ticulate concentrations per ml ranged from 0.3 x 109 to 3.3 x 10°,
depending on whether the cigarettes were rated ultra-low, low, or
medium in tar content. The reduced particulate concentration
reported for low tar cigarettes results principally from filter ~
418
efficiency and air dilution of the smoke. When the specially designed
filters were removed or the vent holes were covered, as could be
accomplished by the smoker’s fingers, particulate concentrations per
milliliter increased to levels comparable to that for higher tar
content cigarettes.
Hinds (1978) compared the particulate size distribution in ciga-
rette smoke using an aerosol centrifuge and a cascade impactor.
Although these devices are based upon different physical principles,
Hinds found that the results were comparable. The MMAD values
ranged from 0.37 to 0.52 ym. Variations depended primarily upon
the dilution of the smoke. The MMAD and concentration values
reported by Hinds and coworkers (1983) were similar to those
reported by Keith and Derrick (1960), who used a specially modified
centrifuge, called a conifuge, to analyze cigarette smoke. Particulate
analysis by a light scattering photometer yielded an MMAD of 0.29
yum and particulate concentrations of 3 x 10!° per ml (Okada and
Matsunuma 1974). Carter and Hasegawa (1975) “fixed” cigarette
particulates with methyl cyanoacrylate, a method that may produce
artifacts, and measured a mean diameter of 0.48 ym from electron
micrographs of the particulates. Earlier methods of measurement
were based upon the collection of smoke particulates on various
surfaces. Harris (1960) reported a range of 0.16 to 0.54 ym from a
replica of cigarette smoke particulates that included a correction for
droplet-spreading during sample preparation. Langer and Fisher
(1956) found a median range of 0.6 um, but made no correction for
droplet-spreading during sample collection.
Time and concentration are important modifiers of tobacco smoke.
Cigarette smoke aerosols contain volatile components, and evapora-
tion gradually reduces particle diameters. It is also true that with
the extremely high particle concentrations encountered in main-
stream smoke, the aerosol can agglomerate rapidly because nearby
particles collide with each other and coalesce. If smoke is cooled
(reducing the vapor pressure of the volatile components) and diluted
(reducing the probability of particle collisions) the particle size will
be more stable. Thus, it is difficult to reliably measure the size and
concentration of particles in cigarette smoke produced under realis-
tic experimental conditions.
The size and concentration of the particulates are also affected by
the decreasing length of a cigarette as it is smoked. McCusker et al.
(1983) found the particulate concentration to be 67 percent greater in
the last three puffs of a filtered cigarette than in the first three.
Ishizu et al. (1978) also reported that particulate concentrations in
unfiltered cigarettes increased and that the mean geometric diame-
ter of the particles decreased with decreasing cigarette length. They
attributed the former effect to the decreased filtration by the tobacco
column and the latter effect to the shorter length traveled by the
419
particles to reach the butt end and, hence, the decreased time for
particulate coagulation. In addition, their results illustrate that
filters may trap the larger particles and generate more uniform
aerosols; McCusker et al. (1983) noted no change in MMAD between
the first and last three puffs of filtered cigarettes. Ishizu et al. (1978)
also reported that larger puff volumes decreased the average
particulate diameters. This can affect interpretation of experimental
data in that standard cigarette smoking-machines draw 35 ml puff
volumes, whereas Hinds et al. (1983) reported that 54 ml was the
average puff volume measured in smoking subjects.
Particle size is a critical factor in determining what fraction of the
particles that enter the respiratory tract will deposit there and fail
to exit with the expired air, as well as where they will deposit.
Submicrometric particles will deposit not only in small and large
airways, but also in alveoli. Breathing pattern is also important (see
review by Brain and Valberg 1979). Large tidal volumes will favor
alveolar deposition. Higher inspiratory flows will promote deposition
at bifurcations. Breath-holding is important, because the greater the
elapsed time before the next expiration, the higher the fraction
deposited (collection efficiency).
Individual anatomic differences may influence the amount and
distribution of deposited particles. The cross-section of airways will
influence the linear velocity of the inspired air. Increasing alveolar
size decreases alveolar deposition.
Factors That Affect Particulate Deposition
A typical puff volume is approximately 30 to 70 ml. It is usually
inspired with a volume of ambient air that is one to two times the
normal tidal volume. Particle size not only can change in experimen-
tal equipment as described above, but also may change within the
human respiratory tract.
After a volume of smoke is drawn into the mouth and upper
respiratory tract of a smoker, it may be retained in that humidified
air before deep inhalation. Here too, the particulates can change in
size through coagulation or evaporation. They can also grow because
of the particulates’ affinity for water, termed hygroscopicity (Davies
1974; Hiller 1982b). Other aspects of each smoker’s behavior may
also influence dose. Most manufacturers achieve low tar yields by
the use of ventilated cigarette holders; this causes the inhaled smoke
to be diluted with air. However, 32 to 69 percent of interviewed
smokers of “low” tar cigarettes reported that they blocked these
filter preparations with their fingers or lips. This causes dramatic
increases in the amount of tar and nicotine in a way not predicted by
studies using smoking-machines (Kozlowski et al. 1980).
420
Such individual differences in cigarette use as well as other
strategies designed to increase the inhalation of tar and nicotine
probably account for the poor correlation between the machine-
determined nicotine yield of a cigarette and the concentration of
nicotine or its metabolites in blood or urine (Russell et al. 1975, 1980,
Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. 1983). For
example, Herning and coworkers (1981) demonstrated that when low
nicotine cigarettes are used, most smokers compensate by increasing
the puff volume. In addition, Tobin and Sackner (1982) reported that
some subjects increase their puff volume by up to 70 percent after
switching to low tar cigarettes. In some instances, this compensatory
increase occurred during a single experimental session. In contrast,
a few smokers may reduce smoke deposition in their lungs by
retaining the smoke in their mouth for several seconds before
inhaling it. Stupfel and Mordelet-Dambrine (1974) showed that if a
smoker holds the smoke in his mouth for 2 seconds, 16 percent of the
particulate matter is removed. Also, 60 percent of the water-soluble
components of the gas phase are absorbed by the upper airways.
Chronic smoking also causes alterations in lung structure that
affect deposition patterns. Sanchis et al. (1971) studied the deposition
of an aerosol of radioactively labeled albumin inhaled by smokers
and nonsmokers. They found less aerosol deposition in the alveolar
region of smokers than of nonsmokers and suggested that the
difference may be the result of alterations in the small airways
produced by chronic smoking. Similar results were reported for
hamsters exposed to cigarette smoke for 3 weeks prior to a single
exposure of radioactively labeled cigarette smoke (Reznik and Samek
1980). More labeled smoke concentrate was found in the lungs of
hamsters not previously exposed to cigarette smoke.
The rate and pattern of breathing can also affect the total dose of
cigarette particulates deposited in the lungs. Dennis (1971) reported
that exercise increased the percent deposition of two experimentally
generated aerosols in human subjects. Increased deposition was also
measured in exercising hamsters that inhaled a radiolabeled aerosol
(Harbison and Brain 1983). These results are most relevant to those
who smoke when ventilation is increased while working or shortly
after a period of exercise.
Deposition of Cigarette Smoke Particulates
The factors discussed in the previous section illustrate that
experimental measurements of the size and concentration of ciga-
rette aerosols are insufficient for the prediction of deposition
patterns. Cigarette smoke is a mutable aerosol, which complicates
the collection of accurate and reproducible data regarding its
particulate composition. In addition, alterations in respiratory
421
structure and respiratory rate can affect the deposition of particu-
lates. These complexities stress the importance of actual measure-
ment of the regional deposition of cigarette smoke particulates in
human lungs. However, few data have been published on this
important area, despite the prevalence of smoking and its impact on
human health. Most of the available information on the deposition of
cigarette smoke particulates is based upon theoretical or physical
models of the lungs and measurements of differences in the
concentration of aerosol between inhaled air and exhaled air.
A model to predict the percent deposition of particles based upon
MMAD was presented by the Task Group on Lung Dynamics of the
International Commission on Radiological Protection (1966). The
respiratory tract was divided into three main regions: nasopharynx,
trachea and bronchi, and alveoli. In conjunction with estimates of
particulate clearance, deposition calculations were made for these
regions at three different inhalation volumes. This model suggests
that 30 to 40 percent of the particles within the size range present in
cigarette smoke will deposit in the alveolar region and 5 to 10
percent will deposit in the tracheobronchial region. This model also
emphasizes the impact of particle solubility on the total integrated
dose over time. Brain and Valberg (1974) developed convenient
nomograms and a computer program to demonstrate how particle
solubility and particle size significantly affect the net amount of
particulates retained in the lungs.
Aerosol deposition has also been studied in airway casts. Physical
models of the upper airways of human lungs have been made by a
double casting technique in order to study particulate deposition at
several airway generations (Schlesinger and Lippmann 1972). Lungs
obtained at autopsy were filled with wax or alloy. When these
materials became solid, the tissue was removed and the casts were
coated with silicon rubber or latex. The wax or alloy was then melted
and removed, leaving 4 cast of the original airways. Different flow
rates and particulate sizes were used to study deposition patterns.
Schlesinger and Lippman (1978) reported a correlation between the
deposition sites of test aerosols in the lung casts and the most
common sites of origin of bronchogenic carcinoma in humans. Both
occurred preferentially at bifurcations. Martonen and Lowe (1983)
added an oropharyngeal compartment and a replica cast of the
larynx to the tracheobronchial casts in order to better simulate air
flow patterns in the upper respiratory tract. They used these models
to evaluate the amount of cigarette smoke condensate deposited in
the airways at different flow rates. More condensate was present at
branching regions, especially at carinal ridges. Aerosol was also
deposited preferentially along posterior airway walls.
Most experiments designed to determine aerosol deposition in
human subjects measure differences in aerosol concentration before
422
and after inhalation. Hinds and associates (1983) measured the
percent mass of inhaled tobacco smoke particulates that deposited in
male and female smokers. A transducer placed in the filter of a
smoked cigarette relayed information to an automatic smoking-
machine to duplicate inhaled puff volume. This method was used to
produce a more natural smoking pattern. Comparisons were then
made between particulate mass concentrations in the machine-
generated smoke and the amount of smoke actually exhaled by the
smoker. With these measurements, a 57 percent deposition of
particulate mass was seen in men. This was greater than the
significant 40 percent collection efficiency measured in women
(p<0.01). No data regarding particulate size or deposition sites were
reported. Hiller and coworkers (1982b) also measured the deposition
fraction of an aerosol containing three different sizes of polystyrene
latex spheres in nonsmoking humans. They measured a 10 percent
deposition for 0.6 pm (MMAD) spheres, which is similar to the
results of Davies et al. (1972) and Muir and Davies (1967) using 0.5
um aerosols and of Heyder et al. (1973) using aerosols with a 0.2 to
1.0 pm range. The size ranges of these aerosols are comparable to
those experimentally measured in cigarette smoke, as previously
discussed. These percentages are lower than those observed by Hinds
et al. (1983), probably reflecting differences in breathing patterns.
The measurements of Hinds et al. (1983) were made with realistic
breathing patterns used during smoking; the other investigators had
used normal breathing patterns. Increased breath-holding following
inspiration probably accounts for the enhanced collection efficien-
cies.
Particulate Retention in the Lung
The amount of particulates retained in the lung at different times
following the inhalation of an aerosol such as cigarette smoke
depends upon the balance between the amount that deposits in the
respiratory tract and the efficiency of the lung clearance mecha-
nisms in the airways and alveoli. Particles depositing in the airways
are entrained in the mucus layer lining these passages. This layer is
swept toward the mouth by the action of ciliated cells and eventually
swallowed. Macrophages present in the airways may also phagocy-
tose deposited particulates and are also carried toward the mouth by
the mucociliary transport system. Particulates reaching the alveolar
region—those that are usually smaller than several micrometers in
size—are soon engulfed by alveolar macrophages. These cells gradu-
ally migrate toward the airways and exit the lung via the mucocili-
ary escalator. Dissolution is also an important clearance mechanism
for soluble particles. Clearance mechanisms are a dynamic compo-
nent of normal lung function and operate to keep the lung sterile.
423
Lung disease and cigarette smoking itself can affect particulate
clearance and retention in smokers’ lungs. Previous studies have
shown that smokers have different aerosol deposition patterns and
slower clearance rates than nonsmokers (Albert et al. 1969; Cohen et
al. 1979; Sanchis et al. 1971). These alterations in clearance are, in
part, caused by components in cigarette smoke that are ciliotoxic
(Battista 1976) and impair phagocytosis by alveolar macrophages
(Ferin et al. 1965). Clearance mechanisms in smokers may be further
compromised by lung diseases, such as emphysema and fibrosis, and
by exposure to air pollutants. Oxidants in photochemical smog, such
as ozone and nitrogen oxides, are toxic to ciliated cells and
macrophages (Bils and Christie 1980).
Measurements of retention of cigarette particulates in the lungs
over time are difficult to estimate from data obtained with airway
casts or from differences in the aerosol concentration of inhaled and
exhaled smoke because these methods do not take clearance
mechanisms into account. Unfortunately, few data are available
regarding the actual retention and sites of deposition of cigarette
smoke particulates in either humans or animals. The most accurate
method is quantification of particulate deposits in individual pieces
of tissue dissected from the lung. Impossible in living animals, this is
a tedious procedure with animal lungs or human material obtained
at surgery or autopsy and is especially difficult with large jungs.
Little et al. (1965) examined lungs from humans at autopsy and
suggested a correlation between the sites of bronchogenic carcinoma
in the lungs of smokers with the deposition of polonium?®, a
radioactive component of cigarette smoke. Resnik and Samek (1980)
used a radioactive marker to study the retention of smoke in
hamster lungs. They exposed hamsters to the smoke from cigarettes
containing a labeled component in the tobacco and then measured
the amount of radioactivity present in different lobes. They found
that more radioactivity was present in the lung tissue of hamsters
not previously exposed to unlabeled cigarette smoke. However, the
clearance of the labeled component from the lungs was slower in the
group previously exposed to smoke. There are problems with using -
animal models for smoke uptake. Most rodents are obligatory nose
breathers, and significant fractions of the smoke may be taken up as
it passes through the upper airways. Page et al. (1973) studied mice
using radiolabeled cigarettes. They found that 50 percent of the
deposited smoke was recovered from the nasal passages. About 30
percent was recovered from the esophagus, stomach, and other -
organs, and only 20 percent was present in the lungs. Exposing
animals via a tracheostomy avoids this excessive and unnatural
deposition in the nose, but it bypasses the mouth and larynx, which
may remove some particles during smoking in man.
424
Passive Smoking
Recently concern has increased regarding the health effects of
cigarette smoke inhaled by nonsmokers, a phenomenon called
passive smoking. The smoke is composed of that exhaled by the
smoker and the sidestream smoke produced by the burning cigarette
between inhalations. The concentration of respirable particulates in
areas where there are smokers can range from 100 to 700 pg/m?.
This is up to 25 times higher than that found in nonsmoking areas
(Repace and Lowrey 1980). Using mean deposition values of 11 and
70 percent for the passive smoker and the active smoker, respective-
ly, from the data presented by Hiller et al. (1982), the deposition
would be approximately 0.55 mg for a nonsmoker over an 8-hour day
in a room with 500 pg/m of smoke. In comparison, a smoker would
deposit approximately 400 mg of tar in his or her lungs if he or she
smoked two packs of cigarettes with an average tar rating of 20 mg
per cigarette during the same time period. As has been discussed
earlier, the rate and pattern of breathing can also affect the total
dose of cigarette particulates deposited in the lungs.
Although the amount of smoke depositing in the lungs of
nonsmokers during passive smoking is small compared to that
encountered by the active smoker, large numbers of people are
involved. In the United States in 1979, 36.9 percent of men and 28.2
percent of women were current smokers (USDHEW 1980).
Conclusions
Cigarette smoke is the most important cause of chronic obstructive
lung disease. This significant response is matched by the significant
dose of toxic particulates received by the respiratory tract of
smokers. The particle size of cigarette smoke is so small that little
protection is offered by the filtering capacity of the upper airways.
Cigarette smoke penetrates deep into the lungs and reaches the
small airways and alveoli. The fraction of the smoke deposited is
high because most smokers employ some breath-holding following
inhalation of a puff. Their attempt to enhance deposition of smoke is
successful, resulting in increased lung burdens of toxic smoke
products.
425
480-144 0 - 85 - 15
CIGARETTE SMOKE TOXICOLOGY
Introduction
The inhalation toxicity of tobacco smoke has become one of the
major public health problems of the 20th century. The chemical
complexity of tobacco smoke confounds the task of identifying its
toxic constituents. Tobacco smoke is comprised of thousands of
chemical components arising primarily from volatilization and
pyrolysis of the tobacco leaf (Stedman 1968; Green 1977). The
chemical gamut runs from traces of elemental metals, such as
cadmium, to nonvolatile whole tobacco leaf components that have
escaped degradation during the burning process (USDHHS 1981).
Approximately 90 percent of the individual constitutents are organic
compounds associated with both the particulate phase and the gas
phase (Guerin 1980). It is not surprising that chronic inhalational
exposure to this diverse mixture of potentially bioactive compounds
can evoke a wide variety of toxicologic responses. Over the years,
scientific and public concern has centered primarily on the carcino-
genic and atherogenic effects of tobacco smoke. In contrast, relative-
ly little is known about the involvement of tobacco smoke constitu-
ents in the pathogenesis of chronic obstructive lung disease (COLD)
(USDHHS 1981).
For the most part, smoke constituent toxicity studies, both
epidemiologic (Dean et al. 1977; Higenbottam et al. 1980) and
toxicologic (Walker et al. 1978; Lewis et al. 1979, Coggins et al. 1980),
have been confined to a comparison of the varying amounts of
particulate matter or tar delivered by smoke. In studies of this
nature, attempts have been made to distinguish between the relative
toxicities of the vapor phase and the particulate phase of tobacco
smoke. The general conclusion reached is that gas phase components
that penetrate to the small airways and alveoli may play a
significant role in the production of peripheral airway and parenchy-
mal diseases such as emphysema, whereas particulate phase compo-
nents that deposit in larger airways may play a role in the
development of disorders of the more proximal airways such as
chronic bronchitis (USDHHS 1981). This generalization may not
always hold, however. For example, in a review of the effects of
smoking on mucociliary clearance, Newhouse (1977) noted consider-
able disagreement among investigators with regard to whether the
vapor phase or the particulate phase was the major factor in smoke-
induced dysfunction of the mucociliary transport system. Also,
Coggins and associates (1980) observed an increase in both peripher-
al and central airway goblet cell number in rats after exposure to
tobacco smoke from which most of the vapor phase had been
removed. Cohen and James (1982) found that the level of oxidants in
tobacco smoke (oxidants have been implicated in the pathogenesis of
426
emphysema) correlated with the amount of particulate matter in
smoke from various brands of cigarettes. At present, therefore,
attempts to associate a specific toxicologic response solely with
either the vapor phase or the particulate phase of tobacco smoke are
not recommended.
Because so little is known regarding the role of specific constitu-
ents or phases of tobacco smoke in the pathogenesis of COLD, this
section of the Report is organized on the basis of specific insults to
the respiratory system that may be brought on by exposure to whole
tobacco smoke and that may lead to structural and functional
changes within the lung. Included, as available information permits,
are data on the known contribution of individual smoke constituents
or phases to a specific insult. Human and animal studies are
described separately to provide a perspective on the extent to which
animal research has verified or extended clinical research and vice
versa.
Preliminary Considerations
Tobacco smoking is generally accepted as the major cause of
COLD (USDHEW 1979; USDHHS 1981). COLD is often subdivided
into three categories: (1) uncomplicated bronchitis, characterized by
mucus hypersecretion and cough, (2) chronic bronchitis with bronchi-
olar inflammation and obstruction of distal airways, and (3) pulmo-
nary emphysema, characterized by distal air space enlargement with
loss of alveolar interstitium. These three pathologic conditions are
often considered collectively within the context of COLD because
they can coexist in the lungs of smokers and because signs and
symptoms associated with one condition may presage the develop-
ment of another.
Effects on Airway Function and Ventilation
Human Studies
Cigarette smoke appears to have both chronic and acute effects on
airway function. In adults, smoking over a period of years leads to
narrowing of and histopathologic abnormalities in small airways
(Ingram and O’Cain 1971; Cosio et al. 1980; Suzuki et al. 1983). Even
in teenagers, regular smoking for 1 to 5 years is sufficient to cause
demonstrable changes in tests of small airway function in some
smokers (Seely et al. 1971); the lungs of young cigarette smokers who
die suddenly show definite pathologic changes in the peripheral
airways (Niewoehner et al. 1974).
The acute response to cigarette smoke has been reported to involve
large airways, small airways, or both. Costello and associates (1975),
in a study of asymptomatic smokers and nonsmokers, found that
427
tests of small airway function (maximum expiratory flow volume
curves, closing volume, and frequency dependence of compliance)
were unaltered after smoking one cigarette, however, specific
airways conductance, 4 measure of large airway function, fell
significantly in both groups. Essentially the same results were
obtained by Gelb and associates (1979), who reported a decrease in
airways conductance but little or no change in volume of isoflow
(another test of small airway function) in healthy nonsmokers after
smoking one cigarette. Likewise, McCarthy and colleagues (1976),
using several different tests, found no evidence for an acute effect of
intensive cigarette smoking on small airways, but did demonstrate
increased large airways resistance. The decrease in conductance
caused by cigarette smoke has been shown to occur within 7 or 8
seconds of a single inhalation (Rees et al. 1982), and filtration seems
to reduce the degree of bronchoconstriction (Da Silva and Hamosh
1980). Irritant effects of tobacco smoke are not limited to the
particulate phase, because exposure to oxides of nitrogen at levels
present in cigarette smoke also can precipitate acute bronchospasm
(Tate 1977). Nicotine does not appear to be responsible for the acute
bronchoconstriction that accompanies cigarette smoking (Nadel and
Comroe 1961).
Zuskin and coworkers (1974) showed that in healthy human
subjects, smoking one or two cigarettes decreased flow rates on
maximum and partial flow-volume curves, and concluded that
smoking causes acute narrowing of small airways. Da Silva and
Hamosh (1973) and Sobol and colleagues (1977) measured airways
conductance, as well as maximum mid-expiratory flow rates, and
concluded that both large and small airways are probably affected by
the acute inhalation of cigarette smoke.
Though the bronchoconstrictive response to cigarette smoke has
most often been attributed to a cholinergic reflex originating with
stimulation of irritant receptors in the airways, there are data
suggesting that histamine may also be involved. Walter and Walter
(1982b) found a significant increase in the number of degranulated
basophils in the blood of smokers 10 minutes after smoking
compared with just before smoking. There is also some evidence to
indicate that smokers may differ from nonsmokers in their respon-
siveness to inhaled histamine (Brown et al. 1977; Gerrard et al. 1980)
as well as methacholine (Malo et al. 1982; Kabiraj et al. 1982; Buczko
et al. 1984), but smoking immediately prior to an inhalation test does
not appear to affect bronchial responsiveness to either histamine or
methacholine (McIntyre et al. 1982).
Asthmatic subjects have a greater than normal susceptibility to
the bronchoconstrictive effects of cigarette smoke when the smoke is -
actively inhaled. The question whether tobacco smoke plays a role in
428
allergic asthma has yet to be resolved completely (\USDHEW 1979;
Shephard 1982; Burrows et al. 1984).
Animal Studies
Binns and Wilton (1978) studied the acute ventilatory response to
cigarette smoke in rats. They found that within the first 3 minutes
after initiation of smoke exposure, tidal volume fell to 80 percent of
the preexposure level, then rose to 160 percent after 9 minutes of
exposure; respiratory rate dropped to 40 percent of the preexposure
level within 1 minute and remained there for the duration of the
exposure period. There was no adaptation of the acute ventilatory
response after 4 weeks of daily smoke exposures. In a similar study,
Coggins and associates (1982) found that rats exposed to a relatively
low dose of cigarette smoke demonstrated a persistent depression in
tidal volume and breathing frequency, whereas animals exposed to a
relatively high dose exhibited an increase in tidal volume with no
change in frequency.
Acute airway responses to cigarette smoke have not been studied
as extensively in animals as they have been in man. Experiments in
anesthetized dogs (Aviado and Palecek 1967), rabbits (Sellick and
Widdicombe 1971), and cats (Boushey et al. 1972) indicate that acute
smoke exposure elicits reflex bronchoconstriction. There also ‘s
evidence from experiments with isolated monkey lungs that smoke
exposures stimulate histamine release (Walter and Walter 1982a).
Histamine appears to be responsible, at least in part, for mediating
che increase in collateral resistance in dogs following administration
of cigarette smoke (Gertner et al. 1982).
The chronic effects of cigarette smoking on pulmonary function in
logs were studied by Park and coworkers (1977). Active inhalation of
100 and 200 puffs of diluted (1:4) smoke 5 days per week for periods
of 6 months and 1 year, respectively, did not produce any noteworthy
changes in pulmonary function. The effects of chronic cigarette
moke exposure on ventilation in rats were studied by Loscutoff and
‘oworkers (1982). Animals exposed for up to 24 months to cigarette
moke containing various amounts of tar and nicotine were found to
ave higher tidal volumes and lower respiratory rates than sham-
‘xposed animals. The most pronounced changes were seen in
nimals exposed to smoke from low tar, high nicotine cigarettes.
listopathologic examination of lungs taken from these animals
evealed primarily granulomatous lesions with no evidence of
mphysematous changes (Wehner et al. 1981). Roehrs and colleagues
1981) used operant conditioning techniques to get baboons to smoke
0 cigarettes per day for 3 years. Measurements of lung volumes,
ompliance, and expiratory flow showed no differences between
moking animals and sham animals, but airway reactivity to inhaled
iethacholine was decreased in animals that had smoked. Subse-
429
quently, Wallis and associates (1982) reported that both acute and
chronic imbalation of nicotine mimicked this effect of cigarette
smoke on bronchial reactivity in baboons.
Effects on Permeability of the Pulmonary Epithelium
The pulmonary epithelium functions to protect underlying struc-
tures from injuricus agents deposited in the airway lumen. Cigarette
smoke has been shown to diminish this protective function by
increasing epithelial permeability in all regions of the tracheobron-
chial tree (Simani et al. 1974). In the airways, irritant receptors
located just beneath epithelial tight junctions are more accessible
following exposure to tobacco smoke. Stimulation of these receptors
is thought to initiate rapid changes in ventilation and to induce
bronchoconstriction (Widdicombe 1977). Likewise, mast celis, a
source of potent bronchoconstrictive mediators, become more accessi-
ble to inhaled toxicants after smoke exposure (Guerzon et al. 1979).
In the alveolar region, an increase in epithelial permeability may
promote the transfer of noxious smoke constituents and endogenous
proteases to the interstitium, thereby facilitating disruption of
alveolar septa.
Human Studies
Subepithelial structures of the lung are important targets for
smoke-induced injury, and research has shown that tobacco smoke
alters epithelial permeability to allow offending agents to gain access
to these structures. Minty and colleagues (1981) showed that,
compared with nonsmokers, smokers had significantly shorter half-
time lung clearance as measured with inhaled radiolabeled aerosols.
After cessation of smoking, half-time clearance increased, but at 21 -
days it was still significantly less than that reported in nonsmokers.
Using similar techniques, Kennedy and colleagues (1984) compared
pulmonary epithelial permeability and bronchial reactivity to in- -
haled histamine in smokers and nonsmokers. These researchers
found increased permeability in smokers, but could find no evidence
of increased reactivity. Although the mechanism by which cigarette
smoke induces an increase in alveolar epithelial permeability is not
fully understood, it has been suggested that carbon monoxide may
play an important role, with possible additional contributions from
nicotine and oxides of nitrogen (Jones et al. 1980).
Animal Studies
In studies of rabbit tracheal rings exposed in vitro, just a few puffs
of diluted cigarette smoke have caused ultrastructural changes in
tracheal epithelial cells and an increase in the size of intracellular
spaces, but junctional complexes between cells remain intact (Davies
430
and Kistler 1975). Boucher and associates !1980) found that, com-
pared with controls, guinea pigs exposed to 100 or more puffs of
cigarette smoke exhibited a significantly faster transfer rate for
horseradish peroxidase across tracheal epithelium. These animals
also demonstrated a progressive disruption of epithelial tight
junctions as a function of the dose of tobacco smoke. Hulbert and
associates (1981) reported that smoke-induced increases in guinea
pig airway permeability were transient, reaching maximum levels at
30 minutes after acute exposure to 100 puffs and returning to control
levels 12 hours later. Gordon and associates (1983) reported that
acute exposure (48 hours) of hamsters to NO: caused a marked
increase in bronchiolar and alveolar epithelial permeability to
horseradish peroxidase. Restoration of the epithelial barrier was
noted 48 hours after exposure in these animals. Ranga and associates
(1980) demonstrated a similar increase in guinea pig tracheal
epithelial permeability upon exposure to NO» for 14 days.
Effects on Mucociliary Structure and Function
The mucociliary system provides the lung with one of its most
effective lines of defense against inhaled pollutants. Disruption of
this system enables pollutants to remain in contact with the
respiratory membranes for prolonged periods and increases the risk
of toxic damage. Tobacco smoke can adversely affect mucociliary
function by increasing the amount or viscosity of respiratory tract
secretions or by depressing ciliary activity directly (Newhouse 1977;
Wanner 1977).
Effects on Cells: Pulmonary Alveolar Macrophages and
Polymorphonuclear Leukocytes
Pulmonary emphysema is believed to result from the slow
degradation of the elastin framework of lung parenchyma! tissue.
Degradation of elastin is most likely initiated by elastolytic enzymes
released locally in the lung and not adequately inhibited by
endogenous antiproteases. Recent studies of the effects of cigarette
smoke on these cellular sources of elastolytic enzymes have provided
additional insights into the relationships between smoking and
pulmonary emphysema. (See chapter 5)
Human Studies
Normally, pulmonary alveolar macrophages (PAMs) function as 4
defense mechanism against particulate material deposited on the
respiratory surfaces of the lung. However, cigarette smoke can
induce a number of changes in PAMs that may promote excessive
degradation of native lung tissue. For example, PAMs from smokers
431
have elevated elastase levels, and these cells may secrete elastase in
vitro (Harris et al. 1975; Rodriguez et al. 1977; Hinman et al. 1980).
Further, PAMs from smokers have been shown in vitro and in vivo
to bind and internalize elastase released from polymorphonuclear
leukocytes (PMNs) (Campbell et al. 1979; White et al. 1982). It has
been suggested that during the phagocytosis of smoke particulates by
PAMs, elastolytic enzymes may be released into extracellular spaces
(Hocking and Golde 1979; Brain 1980; Kuhn and Senior 1978).
Numerous investigators have reported significantly greater yields of
PAMs from the lungs of smokers compared with nonsmokers (Green
et al. 1977; Roth et al. 1981, Hoidal and Niewoehner 1982). The
effects of smoking on PAM mobility are unclear. Some researchers
have reported a significant increase in chemotactic migration of
PAMs from smokers versus PAMs from nonsmokers (Warr and
Martin 1974), but others have been unable to observe such an effect
(Demarest et al. 1979).
Macrophages from smokers exhibit various morphologic, metabol-
ic, and functional abnormalities. Structural changes noted in the
PAMs of smokers include a slight increase in cellular diameter, the
presence of “smokers inclusions” consisting predominantly of kaolin-
ite particles (which have been shown to be cytotoxic to human PAMs
in vitro (Green et al. 1977)) and increased numbers of lysosomes and
phagolysosomes (Brody and Craighead 1975). Perturbations in sever-
al metabolic pathways have been observed in PAMs from smokers,
and acrolein in smoke has been implicated in this toxicity (Green et
al. 1977; Laviolette et al. 1981). The production of superoxide
radicals and hydrogen peroxide (H,0,), both of which inhibit lung
antiproteases, has been reported to be enhanced in the PAMs of
smokers (Hoidal et al. 1981). Smokers’ PAMs have also been shown
to release chemotactic substances for PMNs (Gadek et al. 1978;
Hunninghake et al. 1980). Additionally, there is evidence suggesting
that PAMs from smokers secrete factors that promote the release of
elastases from PMNs (Cohen et al. 1982).
As with PAMs, PMNs have been found in elevated numbers in the
lungs of smokers (Reynolds and Newball 1975; Hunninghake et al.
1980a; Hunninghake and Crystal 1983). Exposure of PMNs to
cigarette smoke condensate in vitro has been shown to promote the
release of elastolytic enzymes (Blue and Janoff 1978). Hutchison and
coworkers (1980) found that the particulate phase of cigarette smoke
stimulated the release of lysosomal enzymes from human PMNs, but
they did not quantitate this release specifically for elastases. A
recent study by Totti and colleagues (1984) showed that nicotine was
chemotactic for human PMNs and that it enhanced PMN responsive-
ness to other chemotactic factors. These results are in contrast with
a previous study by Bridges and coworkers (1977) showing that
nicotine, when used in higher concentrations than those employed
432
by Totti and colleagues, inhibited the chemotactic response of PMNs
to casein.
In a preliminary laboratory study, Janoff and colleagues (1983)
found that smokers have elevated levels of PMN elastase in their
lung fluids compared with nonsmokers. This finding is of particular
interest in that human PMN elastase has been shown to induce
emphysema in animals (Janoff et al. 1977; Senior et al. 1977; Snider
et al. 1984). There is also evidence that cigarette smoke alters PMN
metabolism in such a way as to favor the release of toxic oxygen
metabolites. PMNs from smokers with an elevated white blood cell
count show a marked increase in the release of superoxide anions
compared with PMNs from nonsmokers or with PMNs from smokers
with a normal white cell count (Ludwig and Hoidal 1982). These
unstable oxygen metabolites have harmful effects on various cells
and tissues in vivo and in vitro (Sachs et al. 1978; Fridovich 1978),
and are capable of injuring phagocytes and promoting the release of
proteolytic enzymes (Hoidal and Niewoehner 1982). Oxidants derived
from PMNs are also capable of inactivating lung antiproteases in
vitro; this may be yet another mechanism by which smoke-affected
PMNs contribute to the development of emphysema (Zaslow et al.
1983).
Animal Studies
Laboratory animal studies of the effects of cigarette smoke on lung
free-cell population and integrity have yielded results similar to
those obtained from human studies. Recruitment of PAMs to the
lungs following cigarette smoke exposure has been demonstrated in
a number of animal species, including mice (Matulionis and Traurig
1977; Guarneri 1977); hamsters (Hoidal and Niewoehner 1982), and
monkeys (DeLucia and Bryant 1980). In the rat, PAM recruitment in
response to smoke exposure appears variable. In two relatively
similar studies, one group of investigators (Drath et al. 1978) found a
depression in the number of PAMs in the lungs of rats exposed to
smoke for 30 days, whereas another group (Walker et al. 1978)
reported a significant increase in the number of PAMs after 6 weeks
of smoke exposure.
Several authors have described the effects of cigarette smoke
exposure on the morphology of rat PAMs. Observed changes include
increases in PAM size, lipid vacuoles, and lysosomes, as well as the
presence of “smokers inclusions” (Walker et al. 1978; Davies et al.
1978; Lewis et al. 1979). Cigarette smoke exposure of mice induces a
similar pattern of morphological changes in PAMs (Matulionis 1977).
Alterations of PAM phagocytic capacity have been demonstrated
in animals exposed to cigarette smoke. Fogelmark and colleagues
(1980) reported a dose-related increase in the rate of phagocytosis of
fungal spores in vitro by PAMs from hamsters and rats that had
433
been exposed to cigarette smoke. The ability of rats to mobilize
PAMs in response to a bacterial challenge does not appear to be
altered by cigarette smoke exposure (Guarneri 1977), nor is there a
significant effect upon PAM phagocytosis of Staphylococcus aureus
in rats after 30 days of smoke exposure (Drath et al. 1981).
Macrophages from mice exposed to cigarette smoke for 4 weeks
secrete significantly higher amounts of elastase than PAMs from
controls. However, it is not known whether this effect is due to the
stimulation of resident macrophages or to the recruitment of a
highly exudative population of macrophages to the lungs (White et
al. 1979).
A number of metabolic abnormalities have been noted in PAMs
from smoke-exposed animals (Low et al. 1977). Among these is an
increase in oxidative metabolism resulting in an increased produc-
tion of superoxide anions. Hoidal and Niewoehner (1982) showed
that enhanced oxidative metabolism in hamster PAMs was dimin-
ished if the particulates were filtered from the smoke. However,
other workers (Drath et al. 1981) studying smoke enhancement of rat
PAM oxidative metabolism have attributed this effect to the vapor
phase of smoke. In another study of PAM oxidative metabolism in
rats exposed to cigarette smoke for 180. days (Huber et al. 1980), it
was reported that metabolism was activated after 30 days, and at the
same time PAM superoxide dismutase (an enzyme that detoxifies
superoxide radical) activity was depressed by 30 percent.
Animal PAMs, like human PAMs, can secrete PMN-directed
chemotactic factor in response to various stimuli. For example,
Gadek and colleagues (1980) demonstrated that noninfectious partic-
ulate material stimulated the release of PMN-specific chemotactic
factor from guinea pig PAMs. Perhaps tobacco smoke particulates
might evoke a similar response.
Owing to the ease with which PMNs can be harvested from
peripheral blood, most research concerning the effects of tobacco
smoke on PMNs has been conducted using human cells. In one
laboratory study, hamsters exposed to cigarette smoke for 2, 8, and
20 hours showed a progressive recruitment of PMNs to the lungs.
Control saline aerosol and filtered smoke did not stimulate recruit-
ment of PMNs, suggesting that this effect of cigarette smoke resides
in the particulate phase (Kilburn and McKenzie 1975).
Effects on Protease Inhibitors
In addition to efforts to characterize the effects of tobacco smoke
on cellular sources of elastolytic enzymes, considerable research has
gone into delineating the effects of tobacco smoke on the protease ~
inhibitor defense mechanism in the lungs. While several protease
inhibitors have been identified, a,-protease inhibitor (a,Pi) is consid-
434
ered to be the most important in neutralizing the effects of elastase
(Gadek et al. 1981). Chemical oxidants are known to inactivate a,Pi
and diminish its capacity to inhibit elastase both in vitro and in vivo
(Abrams et al. 1980). Cigarette smcke is an abundant source of
chemical oxidants that can exert the same effect on a,Pi and therebv
reduce lung defenses against endogencus elastases.
Human Studies
The toxic effect of tobacco smoke on protease inhibitors has been
demonstrated in a variety of experimental situations. Janoff and
Carp (1977) reported that tobacco smoke condensate suppressed the
inhibitory action of human serum, purified «,Pi, and bronchopul:no-
nary lavage fluids on both porcine snd hu:nen elastase. The
suppression of human serum elastuse ‘ishibitory capacity by smoke
condensate solutions in vitro has also been demcastrated by others
‘Ohlsson et al. 1980).
Comparison of the protease inhibitory capacity of serum sarnples
from smokers and nonsmokers has revealed a significant depression
in smokers that is correlated with smoking history ‘Chowdhury
1981; Chowdhury et al. 1982). The latter studies also reported that
the depression of serum protease inhibitors was related to an effect
of smoke on the inhibitors per se. and not to a decrease in serum
antiprotease concentration. Still, the effect of tobacco smoke on
serum and lung lavage fluid antiprotease concentration and activity
remains controversial. Several investigators have reported that
smokers have elevated serum protease inhibitor levels (Rees et al.
1975; Ashley et al. 1980); others (Olsen et al. 1975: Warr et al. 1977).
like Chowdhury and colleagues, have shown no difference in serum
or lavage fluid protease inhibitor concentrations between smokers
and nonsmokers.
Gadek and associates (1979) compared «,Pi activity of lung lavage
fluids taken from smokers and nonsmokers and found that smokers
had a twofold depression of functional a,Pi activity. The activity of
a, Pi in this study was tested against porcine pancreatic elastase. Ina
similar study (Carp et al. 1982), in which human neutrophil elastase
was used, bronchoalveolar lavage fluids obtained from smokers had
40 percent less a,Pi activity than fluids from nonsmokers. However,
Stone and colleagues (1983) found that smokers’ bronchoalveolar
lavage fluids did not exhibit decreased functional «Pi activity when
tested against either porcine pancreatic elastase or human neutro-
phil elastase, and suggested that increased elastase derived from
neutrophils may be the main factor in the genesis of emphysema in
smokers.
Smokers may have a functional deficiency in bronchial mucus
protease inhibitor (BMPi) activity. A comparison of BMP: obtained
from tracheal aspirates of smokers with BMPi from nonsmokers
435
revealed that smokers’ BMPi was 20 percent less active against PMN
elastase than nonsmokers’ BMPi (Carp and Janoff 1980a).
Specific cigarette smoke constituents that may be responsible for
the inactivation of lung protease inhibitors have not been identified.
Nicotine and acrolein were studied for their ability to suppress a,Pi
activity and were found to be ineffective (Janoff and Carp 1977).
Several studies have shown that oxidizing compounds such as
chloramine-T and N-chlorosuccinimide can oxidize methionine
groups on 0,Pi and reduce its activity against porcine pancreatic and
human PMN elastases (Cohen 1979: Johnson and Travis 1979; Satoh
et al. 1979: Abrams et al. 1980; Beatty et al. 1980). This has led to the
current belief that oxidants in cigarette smoke may be involved in
the inactivation of protease inhibitors (Janoff et al. 1983). In addition
to free radicals (Pryor 1980), cigarette smoke contains oxides of
nitrogen possessing their own free radical properties and able to
react with olefins in the gas phase or with peroxides to generate
potent oxy-radicals (Dooley and Pryor 1982; Pryor et al. 1983).
As mentioned previously, smoke condensate solution suppresses
the elastase inhibitory capacity of serum a,Pi in vitro. This
suppression can be prevented by the incorporation of phenolic
antioxidants into the test media (Carp and Janoff 1978). Similarly,
BMPi suppression by smoke condensate can be prevented by
antioxidants (Carp and Janoff 1980a). Cohen and James (1982) used
o-dianisidine oxidation to quantify the levels of oxidants in tobacco
smoke condensates from various brands of cigarettes and found that
oxidant levels correlated with capacity to suppress a,Pi deactivation
of elastase. Further, this study provided evidence that peroxides and
superoxide anions were responsible for the loss of a,Pi activity,
because inclusion of catalase and superoxide dismutase in the test
system reduced smoke condensate effects on a,Pi activity. Bron-
choalveolar fluid from smokers contains some amount of oxidant-
inactivated a,Pi, as evidenced by the presence of methionine
sulfoxide residues (Carp et al. 1982).
in addition to the numerous oxidizing agents present in cigarette
smoke, byproducts of smoke-stimulated phagocyte metabolism repre-
sent another potential source of oxidants capable of inactivating
lung protease inhibitors. Carp and Janoff (1979) demonstrated that
phagocytosing human PMNs produce activated oxygen species that
diminish the elastase inhibitory capacity of human serum and pure
a,Pi in vitro. These workers presented evidence to show that
hydroxy! radicals resulting from the reaction between superoxide
anions and H,O,2 were responsible for this effect. The inactivation of
a,Pi by a myeloperoxidase-mediated reaction was also described in
the study, which concurs with other studies demonstrating that
purified myeloperoxidase, in conjunction with H.O, and a halide ion,
can inactivate a,Pi in vitro (Matheson et al. 1979, 1981). Further
436
work has shown that activation of human blood monocytes, PMNs,
and PAMs by use of a membrane-perturbing agent (as opposed to
phagocytosis) results in the release of superoxide anions and H,O,
and the suppression of serum elastase inhibitory capacity (Carp and
Janoff 1980b). Clark and colleagues (1981) have demonstrated that
the myeloperoxidase-H,O,-halide system from chemically stimulated
PMNs oxidizes a,Pi in vitro. Similar evidence ascribing inactivation
of BMPi to the myeloperoxidase-H,O,-halide system has been
reported (Carp and Janoff 1980a). In the studies noted above,
phagocyte-derived oxidants were shown to be capable of inactivating
a,Pi when porcine pancreatic elastase was used as the substrate.
These findings were recently extended to include the more pathophys-
iologically relevant protease, human neutrophil elastase (Zaslow et
al. 1983). Little is known about in vivo inactivation of protease
inhibitors by phagocyte-derived oxidants, other than that inactive
a,Pi (in the oxidized state) has been found in the synovial fluid of
patients with inflamed joints (Wong and Travis 1980). The extent to
which oxidants from stimulated phagocytes play a role in the
suppression of lung a,Pi activity in smokers is at present unknown.
Animal Studies
Although most of what is known about cigarette-smoke-induced
oxidant injury to lung protease inhibitors has been derived from
human studies, some work has gone into the effects of cigarette
smoke on lung protease inhibitors in laboratory animals. It has been
demonstrated that very brief exposure of rats to cigarette smoke can
cause a significant reduction in the elastase inhibitory capacity of
a,Pi obtained from lung lavage fluid (Janoff et al. 1979). Very likely
this toxic effect of cigarette smoke is caused by oxidant damage to
protease inhibitors, because treatment of the lavage fluid with a
reducing agent partially restored normal elastase inhibitory capaci-
ty and because animals rendered oxidant tolerant by preexposure to
ozone did not exhibit a significant reduction in a,Pi activity
following exposure to cigarette smoke.
Effects on Lung Tissue Repair Mechanisms
A preponderance of the research to elucidate mechanisms by
which cigarette smoking induces emphysema has focused on the
factors that initiate lung tissue degradation. Recent studies suggest,
however, that the increased risk of emphysema associated with
cigarette smoking may be due partially to the effects of smoke on
lung repair mechanisms.
437
Human Studies
For the most part, work concerning the effects of cigarette smoke
on jung repair mechanisms has been conducted in experimental
animals. It has been shown, however, that cigarette smoke contains
an inhibitor that can prevent the cross-linking of human fibrin
polymers and thereby impede normal tissue repair (Galanakis et al.
1982). Smoke and smoke constituents have also been shown to induce
membrane damage in human lung fibroblasts (Thelestam et al.
1980). Of 464 smoke constituents tested, approximately 25 percent
caused membrane damage. The most active constituents were
amines, strong acids, and alkylated phenols; nitriles and polycyclic
aromatic hydrocarbons were inactive.
Animal Studies
Cigarette smoke has been shown to affect elastin synthesis in vitro
and elastin repair in vivo. Laurent and coworkers (1983) determined
the effect of solutions of smoke condensate on elastogenesis in vitro
by measuring the formation of desmosine (one of the major cross-
linking amino acids of elastin) during conversion of tropoelastin to
elastin. Using a cell-free system of purified tropoelastin from chick
embryo aorta or porcine aorta and lysyl oxidase purified from chick
embryo or bovine lung, these investigators found that desmosine
synthesis was inhibited from 80 to 90 percent in the presence of an
aqueous solution of the gas phase of cigarette smoke. Elastin repair
in vivo has been reported to be retarded by tobacco smoke. Osman
and colleagues (1982) showed that hamsters with elastase-induced
lung injury resynthesized elastin at a reduced rate if they were
exposed to six or seven puffs of whole cigarette smoke hourly for 8
hours per day during the repair period.
Summary and Conclusions
1. The mass median aerodynamic diameter of the particles in
cigarette smoke has been measured to average approximately
0.46 pm, and particulate concentrations have been shown to
range from 0.3 x 10° to 3.3 x 10° per milliliter.
2. The particulate concentration of the smoke increases as the
cigarette is more completely smoked.
3 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.
4. Acute exposure to cigarette smoke results in an increase in
airway resistance in both animals and humans.
438
5. Exposure to cigarette smoke results in an increase in pulmo-
nary epithelial permeability in both humans and animals.
6. 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).
439
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