The Health Consequences Of Smoking CHRONIC OBSTRUCTIVE LUNG DISEASE a report of the Surgeon General 1984 U.S. DEPARTMENT Of HEALTH AND HLMAN SERVICES P&tic Health Sewiie Offlce on Smckll end Heelth Rockvlile, Maryland 20857 For sale by the Supermtendent of Documents. U.S. Government Prmtmg Office Washmgtan, D.C 2040`2 It 15 a plP.sIIrP to tr2TSlnlt to the congress the surgeon General's Report on the Health Consequences Of Smoking, a5 mandated by Section R(a) of the Public Health Cigarette Smoking Act of 1969. This is the Public Health Services' 16th report on this topic ?nd, likp 211 of the earlier Reports, it identifies cigarette smoking as the chief preventable cause of death and dlsahllity in our SOClety. The enclosed report deals with the relationship between smok- ing and those disease cond~tlons described as chronic obstructive 1unp dlSCPSP, particularly chronic bronchitis and emphyseme. These diseases significantly increase patient loads in hospitals and other health care facl!lties and escalate this Nztion's health care costs. including expenditures under the Medicaid and MedIcare programs. This Department has a strong and ongoing comnitment to Its Pr `ogrnmmatlc and research effor*s I" the field Of disease prever.- ti on. In our view, it is essential to apprise ~ndlviduals of the consequences of smoking. A central part of our efforts is to identify ways to help smokers quit smoking, and to encourage indl"ld"alS, particularly the youth of this country, not to kgin smoking. 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 . . . Vlll 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 a,-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 indepth 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 . . . Xl,, 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 A. Sonia Buist, M.D., Professor of Medicine, department of Medicine, Oregon Health Sciences University, Portland, Oregon Louis Diamond, Ph.D., Professor and Dire&or- 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, Charming 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.0, Professor of Pathology, Department of Pathology, The University of British Columbia, Vancouver, British Columbia, Canada Martin J. Tobin, M.D., M.R.C.P.I., 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.0, 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 xvii 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 0. 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 Per-mutt, M.D., Professor of Medicine, Department of Medi- cine, Division of Pulmonary Medicine, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland Cheryl L. Perry, Ph.D., Assistant Professor, Division of Epidemiolo- gy, School of Public Health, University of Minnesota, Minneapolis, Minnesota Richard Peto, M.A., M.&Z., I.C.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 xv111 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- its General Corporation, Rockville, Maryland Clarice D. Brown, B&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 .............................................................. vii Preface ... ................................................................ x111 Acknowledgments ................................................... 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 . . . . , , . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 . . . . ..**.............................. 329 7. Passive Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 8. Deposition and Toxicity of Tobacco Smoke in the Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 9. Role of the Physician in Smoking Cessation ......... 451 10. Community Studies of Smoking Cessation and Preven- tion ............................................................... 499 Index .................................................................. 535 xx111 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 U.S. 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 1964 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: o Chapter 1. o Chapter 2. 0 Chapter 3. o Chapter 4. o Chapter 5. o Chapter 6. o Chapter 7. o Chapter 8. Introduction, Overview, and Conclusions Effect of Cigarette Smoke Exposure on Mea- sures of Chronic Obstructive Lung Disease Morbidity Mortality From Chronic Obstructive Lung Dis- ease Due to Cigarette Smoking Pathology of Lung Disease Related to Smoking Mechanisms by Which Cigarette Smoke Alters the Structure and Function of the Lung Low Yield Cigarettes and Their Role in Chronic Obstructive Lung Disease Passive Smoking Deposition and Toxicity of Tobacco Smoke in the Lung 5 o Chapter 9. Role of the Physician in Smoking Cessation o 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 F'EV, 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 F'EV, 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. 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- 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 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. 5. 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. 6. 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. 7. 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. 8. Differences between smokers and nonsmokers in measures of expiratory airflow are demonstrable by young adulthood and increase with number of cigarettes smoked per day. 9. 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 thRn 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 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. COLD Mortality 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 past decades, and their smoking fewer cigarettes, inhaling less deeply, and beginning to smoke later in life. 3. 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. 4. 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. 5. 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 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. 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 10 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 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 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. Low Tar and Nicotine Cigarettes 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 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. 2. 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. 3. 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. 4. Smokers who switih 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 12 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 pm, and particulate concentrations have been shown to range from 0.3 x lo9 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. 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). Role of the Physician in Smoking Cessation 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. 2. Current smoking prevalence among physicians in the United States is estimated at 10 percent. 3. 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. 4. 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. 5. 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. 6. Large controlled trials of cardiovascular risk reduction have demonstrated that counseling on individual specific risk fac- tors, including smoking cessation techniques, can be effective. 7. Studies of pulmonary and cardiac patients indicate that severity of illness is positively related to increased compliance 14 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 I__.--__-_.~- __-_ - Chronic Airflow Obstruction Introduction Prevalence of Airflow Obstruction Determinants of Airflow Obstruction Introduction Cigarette Smoking and Chronic Airflrlw Obstruction 19 Dose-Response Relationships Factors Other Than Cigarette Smoking ABH Secretor Status Air Pollution Airways Hyperreactivity Alcohol Consumption Atow 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 Alphal-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 phlegm), (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 19SOs, 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. (19681 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 Xenonl"3. 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 (19691, 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 NP 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 differentdensities, 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 (He&) mixture (AVrnax50% and AV&, and (b) a measurement of the lung volume at which the air and He02 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 (FEF75-85~); and (b) from the MEFV curve: maximal flow at 50 and 75 percent of the forced vital capacity, V,, 50% and V,, 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, Visof, and the slope of the alveolar plateau of the single breath N2 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 FEFZWSS. 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 FEVl 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 loo0 800 600 Smoktng Index ag/yr 10 0.7 L- 06 05 I II III IV FEV,WVC MMF RV percent predicted percent predcted 1 1 1 1 2 I II Ill IV 140 100 I II III IV I II Ill IV Pathology groups FIGURE l.--Comparison of increasing small airways disease (Groups I to Iv) to smoking index and various pulmonary diction tests, by mean +: S.E. `P f:`r:ed their limit of normality as the 95th percentile for each of the T~.~;tr~. CC/TI,C and the slope of the alveolar plateau had the highest ~,~~..~...:iPtl~r of abnormality among the smokers (47 and 44 percent, respectively), followed by CV/VC% (34 percent), V,,, 75% (33 percent), and V,,, 50% (30 percent). When the indices derived from the single breath Nz test were combined, 60 percent of their smokers had an abnormality in one or more of the measurements obtained from the test, whereas 52 percent had an abnormality in one or more measurements obtained from the forced expiratory maneuver. They pointed out that combining the measurements obtained from a test increases its sensitivity but decreases its specificity. In addition to the studies described above, which involved fairly large population groups, numerous studies have been carried out in smaller groups (McCarthy et al. 1972; Stanescu et al 1973; Gelb and Zamel 1973; Cochrane et al. 1974; Abboud and Morton 1975; Marcq and Minette 1976). These studies have also found the measurements obtained from the single breath NZ test and MEFV curve to be abnormal more often among smokers than among nonsmokers. There have been very few published studies using MEFV curves with air and He02 in reasonably large population groups. This is probably because the test is more difficult to perform than the single breath NB test or the forced expiration maneuver, and because of the wide range of within-individual and between-individual variability associated with these tests. Lam and coworkers (1981) obtained spirometry and MEFV curves with air and He02 in 423 subjects participating in epidemiologic health surveys in British Columbia. The subjects consisted of four groups: nonsmokers and smokers not exposed to air pollutants at work, and nonsmoking and smoking grain elevator workers. Reference values were established from the 78 healthy, asymptomatic nonsmokers who were not exposed to any air pollutant at work. They found that in the subjects not exposed to air pollutants at work, 0 max 50 was the best test for discriminating the effects of cigarette smoking, but &o,, 50 and VisoV were not significantly different between the smokers and the nonsmokers. Interestingly, the FEVl was the best discriminator of the effect of grain dust, and there was poor concordance among the FEV1, V,, 50 and AT,,, 50, and Visoo. They concluded that a comparison of MEFV curves breathing air and He02 is less helpful than the standard MEFV curves in distinguishing the effects of smoking and the effects of exposure to an air pollutant. A careful evaluation of moment analysis in a reasonably large population group of adults has not been published. The limited information in the literature comes from studies of small groups of children (Neuberger et al. 1976; Liang et al. 1979; MacFie et al. 1979) and adults (Permutt and Menkes 1979; MacFie et al. 1979). These preliminary studies look promising, but a more extensive evaluation of the technique in carefully chosen population groups must be carried out before conclusions are reached on the value of this approach. Moment analysis is particularly sensitive to changes in 31 the terminal part of the forced expiratory spirogram, which is particularly sensitive to an artifact in the MEFV curve when volume is measured by a spirometer at the mouth rather than by plethys- mography. This artifact relates to the fact that there are volume changes due to gas compression that are measured by plethysmogra- phy but not by a spirometer at the mouth. The appropriate method to measure volume in moment analysis is by plethysmography, but very few such measurements have been made, most measurements having been made by spirometry. The magnitude of the resulting error has not been assessed. In summary, the prevalence of abnormalities observed in any group of smokers depends on the age and characteristics of the group (how they were selected), on the reference values used (external reference values or reference values obtained from the population under study), and the cutoff used to define abnormality. However, this prevalence is uniformly higher in smoking than in nonsmoking populations. In a randomly selected sample of the general population below age 55, at least a third (and usually more) of the smokers can be classified as having small airways dysfunction. Dose-Response Relationship Between Amount Smoked and Small Airways Dysfunction In general, population-based studies involving adults of all ages with a reasonable range of cigarette consumption consistently show a fairly strong dose-response relationship between the number of cigarettes smoked and the degree of impairment. Burrows and coworkers (1977a1, studying a randomly stratified cluster sample of Tucson, Arizona, households comprised of 2,360 white, non-Mexican-American adults over age 14, found a highly significant quantitative relationship between pack-years of smoking and functional impairment, as measured by v-7546, FEVI percent predicted, and FEVl/FVC percent. The shift in the mean FEVl percent predicted and the distribution of the FEVl percent predicted with increasing cigarette consumption is illustrated in Figure 4. Buist and coworkers found a positive correlation between total cigarette consumption and the frequency of abnormalities in tests of small airways function in 524 smokers attending an emphysema screening center. However, tests of significance were not reported in the description of the relationship between pack-years and CV/VC and CC/TLC (Buist et al. 1973). Tests of significance were reported in the description of the relationship between the slope of the alveolar plateau and cigarette consumption (Buist and Ross 1973b); no clear relationship between daily cigarette consumption and an abnormal slope of the alveolar plateau was found. Among women who smoked more than 20 cigarettes a day, however, the prevalence of an abnormal slope of the alveolar plateau was significantly increased; 32 -1 SD Mean + 1 SD O-20 pack-years (578) 21-40 pack-years (2711 61 + pack-years (1001 40 60 60 100 120 140 160 Percent ore&ted FEV, FIGURE 4.-Percentage distribution of predicted forced expiratory volume in l-second (FEVI) values in subjects with varying pack-years of smoking * Subjects with "respiratory trouble" before age 16 are excluded. NOTE: Means, medians. and * 1 standard deviation of the data for each group are shown m the abscissae. SOURCE Bumws et al. (1977s). among men, a significant increase was found only for those who smoked more than 40 cigarettes a day. Somewhat similar conclusions were reached by Tockman and coworkers (1976) in their study of healthy Baltimore residents. These investigators found that the CC/TLC, the slope of the alveolar plateau, RV/TLC, the steady state diffusing capacity, and respira- tory symptoms were significantly different between smokers and nonsmokers, but there were no significant age-related differences for these variables. In contrast, tests of forced expiration (FEVI/FVC, 0 mm 50, and moment analysis) showed both differences between smokers and nonsmokers and increasing smoker versus nonsmoker differences with increasing age. These investigators interpreted their findings as suggesting that the tests of small airways function measure an all-or-none response that occurs at the onset of smoking but is not affected by duration of smoking. They proposed that the 33 measurements obtained from a forced expiration maneuver probably measure the effects of continued smoking and reflect increasing abnormality associated with longer duration of smoking. In their study of population samples in Manitoba, Manfreda and coworkers (1978) found a significant relationship between the current number of cigarettes smoked per day and the slope of the alveolar plateau and CC/TLC in both sexes and RV/TLC in women. These investigators found that an index of lifetime exposure to smoke had no effect after accounting for the effect of current smoking. Among all the lung function measurements, smoking status accounted for the largest proportion of variance due to the three smoking variables (smoker versus nonsmoker, number of cigarettes smoked per day, and lifetime amount smoked). They interpreted this finding as suggesting that responses on these lung function tests are related more to whether one does or does not smoke than to the amounts smoked. Buist and coworkers, in the three-city collaborative study de- scribed earlier (Buist et al. 1979a), considered the effect of smoking in two ways, first by means of multiple regression analysis using age and cigarette-years data from both smokers and nonsmokers. Using the pooled data from the three cities, they found that cigarette consumption had a significant effect on the CC/TLC, CV/VC, the slope of the alveolar plateau, and FEVI/FVC (only in women). In this analysis, the effect of aging was considerably greater than the effect of smoking. The second approach involved data only from smokers, and a linear regression of the percentage of the predicted value for each variable on cigarette-years was obtained. A significant regres- sion occurred in only one-third of the city/sex groups, and in each case the regression coefficients were very small. They concluded that a dose effect was not apparent when smokers only were considered, using both cigarettes per day and years smoked as indicators of cigarette consumption. They interpreted these findings similarly to Manfreda and coworkers (1978): it could be smoking itself and not the quantity of cigarettes smoked that is the crucial factor in the development of early functional impairment. The researchers sug- gest that absence of a clear-cut dose-response relationship in this study may also have resulted from the limited age range (25 to 54 years) and the relatively few heavy smokers in the study. They also speculate that the single breath NZ test variables, especially the slope of the alveolar plateau, may be so "sensitive" that they reflect an on- off effect of smoking rather than cumulative damage. Dosman and coworkers (1976) looked for a dose-response relation- ship in 49 smokers, aged 28 to 67, of whom 60 percent were attending a smoking cessation clinic. They found a significant relationship between a smoking index (cigarettes per day x years smoked) and VisoV and V,,,, SO. They did not find a significant relationship 34 between symptoms and frequency dependence of compliance, CC/TLC, the slope of the alveolar plateau, or V,,, 50 (Figure 5). Beck and coworkers (1981,1982), in a cross-sectional study of three communities (Lebanon and Ansonia, Connecticut, and Winnsboro, South Carolina) sought a dose-response relationship in 1,209 smok- ers. Dividing the sample into light smokers (1 to 20 cigarettes/day) and heavy smokers (> 20 cigarettes/day!, they found a trend of increasing dysfunction across smoking categories that was evident as early as age group 15 to 24 for both men and women. A difference between men and women occurred in terms of the relationship between residual lung function (observed-predicted FEV,) and pack- years of smoking. In male smokers, the combination of number of cigarettes smoked per day and duration of smoking was the best indicator of loss in lung function, as measured by residual lung function (FEVI, V,,,, XP+, and VX,). For women smokers, pack-years best explained lung function loss as measured by residual lung function. These investigators thus found a very definite dose-re- sponse relationship between the amount smoked and lung function loss. They do point out, however, that smoking variables and age accounted only for up to 15 percent of the variation in residual lung function. In summary, the data suggest a dose-response relationship between number of cigarettes smoked per day and the prevalence of abnormal results on tests of small airways function. That is, heavy smokers are more likely to have abnormal small airways function than light smokers. However, there is only a weak relationship between the degree of abnormality in small airways function and the number of cigarettes smoked per day or pack-years of smoking. In contrast, tests obtained from the forced expiration maneuver have a stronger dose-response relationship. This is consistent with the theory that cigarette smoking induces an inflammatory response in the small airways and that this response is more likely to happen in heavy smokers, as measured by sensitive measures of small airways function such as the single breath nitrogen test. The extent of chronic airway disease that reflects the dose and duration of the smoking habit is better measured by changes in the forced expirato- ry maneuver. How Soon Do Changes in Small Airway Function Occur! The first study to look at the prevalence of abnormalities on tests of small airways function by age in a large group of smokers was reported by Buist and coworkers (1973aJ These investigators found that abnormalities of small airways function could be detected before age 30 by means of the single breath N2 test, with CV/VC discriminating best between smokers and nonsmokers in the age decade of the twenties (Figure 6). 35 160 ' . A 120 Cdyn a 100 Cst (90 BPM) VlS.0~ Percent predacted Slope phase III Percent vreduted cc Percen1 predicted i Illax Percent predIcted symptoms score D . 100 50 0 0 1 2 3 4 Symptoms score FIGURE 5-A composite of six tests plotted against symptoms score SQURCl? Downan et al. (1976). 36 a0 f-J 264 lvonsmohers O 524 Smokers 3 266 Ex-smokers 60 2 E 40 a 20 0 .v= 7 3 4.7 20 30 26 32 51 63 80 66 64 32 21 11 3 7 a1 91 126 143 65 I1 < 20 x-29 30-39 40-49 50-59 6049 70-79 I a0 Age (years) FIGURE 6.-Prevalence of abnormal closing volume/vital capacity ratios in nonsmokers, smokers, and ex-smokers, by age decade SOURCE: Bubr et al. (1973). In their cross-sectional survey of residents in three separate communities in Connecticut and South Carolina, Beck and cowork- ers (1981, 1982) found that the age of onset of abnormalities in lung function may occur as early as age 15 to 24. Their approach used vesidual lung function (observed-predicted value) for FEV1, o,,,, 50%~ and o,, ~SB, with a negative residual indicating an observed value below prediction. Negative residuals for all three measurements began to occur in women in the age group 15 to 24 (Figure 7). Significant differences among smoking categories-nonsmokers, ex- smokers, light smokers (1 to 20 cigarettes/day), and heavy smokers ( > 20 cigarettes/day)-were seen for v,, 50% and o,, 75% in women aged 15 to 24 and for FEVl in age group 25 to 34 (Figure 8). In male smokers, negative residuals began to occur for all three measure- ments in the age 25 to 34 group. Significant differences among the smoking categories were seen for FEVl in the 35 to 44 age group and for e,, 5040 and v,, 76% in the 45 to 54 age group. Seely and coworkers (1971) found lower values for `?,, 50% and `?,, 7590 in a group of high school students with 1 to 5 years of smoking experience. These differences were significant in boys who smoked more than 15 cigarettes per day and in girls who smoked more than 10 cigarettes per day. Significant differences between the smokers and nonsmokers were not found for FEVl. Dosman and coworkers (1981) studied 1,202 adults, aged 25 to 59, living in Humboldt, Saskatchewan. Among smokers in the 25 to 29 37 01 0 5 -01 5 E - 2 42 u -03 1 Women (n -2.623) -0 4 0 Nonsmokers a Ex-smokers -05 - Light smokers (l-20 cigarettes/day) E3 Heavy smokers ( ,20 clgaretteslday) 06 o ?? ???????*?*? FIGURE 7.-Mean residual FEV, in women, by smoking status and age SOURCE Beck et al / 1981~ O2 rAge7-14 15-24 2534 35-44 45-54 55-64 65, -0.6 m LaghI smokers (l-20 cigarettes/day) m Heavy smokers ( > 20 agarettes/day) No observations FIGURE 8.-Mean residual FEVl in men, by smoking status and age SOURCE Beck et al. tl9Bli age group, 14.9 percent of the women and 18.5 percent of the men had an abnormal test value for the slope of the alveolar plateau, for CV/VC, or for both. Comparable rates of abnormality for FEVl/FVC 38 were 2.1 percent in women and 5.6 percent in men. For both the slope of the alveolar plateau and CV/VC, the prevalence of abnormal test value increased steadily with increasing age, so that 63.6 percent of the female smokers aged 55 to 59 and 46.2 percent of the male smokers aged 55 to 59 had abnormal values. Comparable rates for an abnormal FEVl/FVC were 4.5 and 19.2 percent in the women and men, respectively. Walter and coworkers (1979) studied 102 Indian male medical students in their late teens and early twenties. Of the 102 subjects, 60 were nonsmokers, 23 were light smokers (lifetime total of < 10,000 cigarettes), and 19 were heavy smokers (lifetime total of > 10,000 cigarettes). The researchers compared mean pulmonary function values obtained from the spirograms across the smoking categories. There was a consistent trend for all the lung function variables examined (FEFZSSOQ, FEFzx,s, FEFKHOS, FEF~~~~i, FEFsx~,, and FEVJFVCLwith the highest mean values being seen in the nonsmokers, intermediate values in the light smokers, and the lowest values in the heavy smokers. There were no significant differences among the three groups in height and weight. No information was given in this report about the type of cigarettes smoked. The consistency of results from the studies attempting to define the age of onset of measurable abnormalities in tests of small airways function is striking. Even though statistical significance was not always found, the trend is clear and provides strong evidence that measurable abnormalities of small airways function do occur in some smokers within a few years of smoking onset. Male-Female Differences in the Responses of the Small Airways to Cigarette Smoking When looking at variations between the sexes in response to cigarette smoking, one must take into account possible differences in the manner in which cigarettes are smoked, in the amount smoked, and in environmental exposures that may interact with smoking. Most investigators have found little or no difference based on sex for the relationship between the various tests of small airways function and age in nonsmokers. Thus, a difference between the sexes in response to smoking, if it exists, probably represents a true biological difference in the effect of smoking on lung function or variations in exposure dose resulting from method of smoking or amount smoked. Unfortunately, the information available in the literature about sex-related differences in small airways response to cigarette smok- ing is scanty and conflicting. Manfreda and coworkers (1978) found a higher prevalence of abnormality in tests of small airways function among male smokers than among female smokers in their study of two communities in Manitoba. The opposite finding has been 39 reported by Buist and coworkers (Buist and Ross 1973a, b; Buist et al. 1973, 1979a) in their studies of a screening center population and of population samples and groups in Montreal, Winnipeg, and Port- land. It is quite possible that selection bias in the screening center study limits the ability to extrapolate this study to the general population. The three-cities study, however, did not suffer from that flaw, and showed clear differences (women higher than men) in the prevalence of abnormalities of CV/VC and the slope of the alveolar plateau. The prevalence of abnormality of CC/TLC, on the other hand, was slightly higher in male smokers than in female smokers (32 and 29 percent, respectively). A surprising finding was that the prevalence of FEVJFVC abnormality was considerably higher among women who smoked than among men who smoked (25 and 7 percent, respectively). At this point, a generalization is not yet possible on sex-related differences in the response of the small airways to cigarette smoking. However, it seems likely that the contribution of sex difference is relatively small once age and dose are taken into account. JBfect of Smoking Cessation on Small Airway Function The correlation between abnormalities in tests of small airway function and the pathologic changes of inflammation of the small airways suggests that cessation of smoking may lead to a return toward normal in these tests. A number of authors have examined changes in tests of small airways function in cigarette smokers who have quit. Ingram and O'Cain (1971) examined six smokers with an abnormal frequency dependence of compliance who quit smoking. After 1 to 8 weeks of cessation, values in all six returned to the normal range. Bode et al. (1975) examined 10 subjects aged 29 to 61 with normal FEVl values while they were active smokers and again 6 to 14 months after they had stopped smoking. Static volume pressure curves, slope of phase III, and forced expiratory flow rates on air were unchanged by cessation. However, the maximum expiratory flow rates with helium at 50 and 25 percent of the vital capacity increased, and the volume of isoflow and closing volume decreased. McCarthy et al. (1976) followed 131 smokers aged 17 to 66 who volunteered to attend a smoking cessation clinic. Cessation resulted in a significant reduction in the closing capacity (CC/TLC%) and the slope of phase III within 25 to 48 weeks in the 15 persons who were able to abstain from cigarettes completely. Buist et al. (1976) followed a group of 25 cigarette smokers who attended a smoking cessation clinic and found that cessation resulted in significant improvements in the closing volume (CV,`VC%), closing capacity (CC/TLC%), and the slope of the alveolar plateau (phase III) at 6 and 12 months following cessation. 40 CC/TLC CVNC 140 r 4 \ \ & _____--- --* 120 100 0 20 . 10 . . 30 80 I:; 60 1 1 - O"m3S ---- Smolers FIGURE 9.-Mean values for the ratio of closing volume to vital capacity (W/W), of closing capacity to total lung capacity (CC/TLC), and slope of phase III of the single breath NZ test (ANp/L), expressed as a percentage of predicted value (12, 13) in 15 quitters and 42 smokers, during 30 months after two smoking cessation clinics * A significant difference from the initial value at p< 0.05. N0TF2 Data from amonth followup of the 1973 clinic and 4-month followup of the 1975 clinx have bean combmed. 88 have Gmonth and B-month data for the 1973 clinic. SOURCE: Buist et al. (197%). This study was expanded using a second group of subjects (Buist et al. 1979b) and a 30-month followup. Once again, the three parame- ters of the single breath Nz test showed improvement in smokers who quit; this improvement continued for 6 to 8 months, and then leveled off (Figure 91. In addition, the values for the single breath Nz test in those who quit returned to the levels predicted for nonsmokers, suggesting that the changes in the small airways can be substantial- ly reversed with cessation. Bake et al. (1977) also showed an improvement in the slope of phase III following cessation in a small group who were followed for 5 months. In summary, abnormalities in the small airways are substantially reversible in smokers who have not developed significant chronic airflow obstruction. This suggests that the inflammatory response in the small airways, which may be the earliest change induced by smoking, is also a change that reverses with the cessation of chronic exposure to the irritants in cigarette smoke. 41 480-144 0 - 85 - 3 Relationship Between Small Airways Disease and Chronic Airflow Obstruction There is no question that the information obtained over the past 15 years from studies of small airways function has helped to describe more accurately the natural history of chronic airflow obstruction. The practical question of the place of tests of small airways function in clinical practice has not yet been resolved, and will not be fully answered until longitudinal studies using the tests have been completed. The important issue to be addressed is whether the tests of small airways function can be be used to identify the smoker who will progress to develop irreversible airflow obstruction. This question can be answered satisfactorily only by following a fairly large group of smokers prospectively over a period of time long enough for some of the smokers to develop an abnormal FEVL If the tests of small airways function can be used alone, or in conjunction with other qualitative or quantitative data about risk factors, they will clearly be useful to the practicing physician. If they are too sensitive or have a poor predictive value, their use will be more limited. Buist and coworkers (1984) determined the positive and negative predictive value of tests of small airways function in their study of two cohorts followed prospectively over a `?- to ll-year period. They found that the positive and negative predictive values of the tests of small airways function varied greatly between the cohorts, largely because of the different ages and prevalences of an abnormal FEVl between the cohorts. They concluded that significant associations existed between the single breath Nz test variables and spirometric variables in smokers, but the weakness df these associations and the high misclassification rates suggest that small airways disease does not necessarily lead to clinical airflow obstruction. Over a period of 8 years, Marazzini and coworkers (Marazzini et al. 1977, 1981) followed a group of 69 asymptomatic workers in an iron foundry (49 smokers, 20 nonsmokers) living in the same area. They found that 39 percent of the smokers and 15 percent of the nonsmokers, initially diagnosed as having peripheral airways dis- ease, developed central airways obstruction (defined as 1 or more of the vital capacity WC), FEVl or FEVl/VC being more than 15 percent different from normal) within the ELyear followup. An indirect way to assess the predictive value of the tests of small airways function was proposed by Tattersall and coworkers (1978). These investigators proposed that any valid test of chronic airflow obstruction must yield results that are systematically worse in middle-aged smokers than in middle-aged nonsmokers, and that such a test should also correlate with the FEVl in middle-aged smokers. Using these criteria in a cross-sect.ional study of a sample of working 42 men in West London, they concluded that the most informative and repeatable tests were v max 75% and the slope of the alveolar plateau. Nemery and coworkers (1981) addressed the question of the significance of tests of small airways function in their study of 2,072 blue-collar workers, aged 45 to 55, from a steel plant near Brussels. They found that smokers with an abnormal CC/TLC or slope of the alveolar plateau and a normal FEVJFVC had a significantly lower FEVl/(heightP than subjects with normal CC/TLC and slope of the alveolar plateau. They interpret their data as suggesting that smokers with small airways dysfunction experience a more rapid decline in FEVl than smokers without small airways dysfunction, leading to a higher susceptibility to long-term smoking effects in the former group. The opposite conclusion was reached by Fletcher (1976), who examined the relationship between CV/VC, the slope of the alveolar plateau, and FEVl in 200 male smokers aged 40 to 55. In this group, he found a relatively poor correlation between FEVl and the single breath Nz variables. There is thus, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who is going to progress toward clinical airflow obstruction. The tests of small airways function are probably abnormal for many years before the FEVl becomes abnormal in those smokers who go on to develop airflow obstruction. However, many smokers with abnormal tests of small airways function may never develop clinically significant airflow obstruction. Therefore, functional changes in the small airways may not always be related to the widespread alveolar destruction seen in smokers or to the development of clinical airflow obstruction. It may be that varying degrees of inflammation and fibrosis occur in virtually all smokers, and that there is something very different about the smokers who develop extensive airway or emphysematous changes. Summary A number of tests have been developed that can identify small airways dysfunction in individuals with normal lung volumes and standard measures of forced expiratory airflow. These tests correlate well with the presence of pathologic changes in the airways 2 mm or less in diameter, particularly with peribronchiolar inflammation. Cigarette smokers have a significantly higher frequency of abnormal tests of small airways function. Heavy smokers have a greater prevalence of small airways dysfunction than light smokers, but there is only a weak dose-response relationship between numbers of cigarettes smoked per day or duration of smoking and the extent of small airways dysfunction. This suggests that the response of the 43 small airways may be an "all or nothing" inflammatory response to cigarette smoke irritants rather than a progressive response repre- senting a cumulative injury. Cessation of cigarette smoking results in significant improvement in small airways function, which in those smokers without evidence of chronic airflow obstruction, may return to normal. The relationship between changes in the small airways and the development of chronic airflow obstruction remains unclear. It seems likely that those smokers who will go on to develop ventilatory limitation will have abnormal small airways function before the FEVl becomes abnormal, but many smokers with small airways dysfunction may never progress to significant airflow obstruction. Therefore, the usefulness of tests of small airways function for identifying those who will develop ventilatory limitation remains to be established. 44 CHRONIC MUCUS HYPERSECRETION Introduction The association of cigarette smoking and chronic cough was recognized by the general public in the term "smokers cough" well before the demonstration of this association in epidemiologic studies. Cough is the symptom most frequently experienced by smokers, and it is often accompanied by excess mucus secretion resulting in phlegm production or a "productive" cough. Chronic bronchitis was defined by the Ciba Foundation Guest Symposium report (19591 as "the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree." The position was taken that any production of sputum was abnormal, and chronic was defined as "occurring on most days for at least 3 months of the year for at least 2 successive years." Also, the sputum production could not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. Measurement of Cough and Phlegm in Epidemiologic studies The increasing use of standardized questionnaires in interviews to ascertain the presence of cough, phlegm, or other symptoms of respiratory disease has improved the quality of measurements of prevalence and incidence of these symptoms and the validity of comparisons within and between studies. Similar attention has been given to developing questions about smoking habits, including questions about the type and number of cigarettes used at the time of interview and in the past. The first British Medical Research Council (BMRC) questionnaire published in 1960 (Medical Research Council 1960) had been tested, revised, modified, and extended, and many studies have resulted from its widespread use. However, difficulties in using this questionnaire in epidemiological studies of populations in the United States and the desire to collect additional information led to modification in individual studies and to a loss of comparabili- ty between studies. This motivated the American Thoracic Society and the Division of Lung Diseases of the National Heart, Lung, and Blood Institute to establish the Epidemiology Standardization Project. Extensive methodological studies were done, standardized questionnaires were developed, and techniques for measuring pulmo- nary function and evaluating chest radiographs were proposed (Ferris 1978). Samet (1978) has reviewed the history of the develop ment of respiratory symptom questionnaires. Although many inves- tigators now use the methods advocated by the BMRC or the Epidemiology Standardization Project, several of the studies re- viewed in this chapter of the Report are based on other, nonstandard questionnaires. A comparison between studies of different popula- 45 tions, or the same population studied at different times, must be made cautiously and only after careful consideration of technical and methodological issues. Low rates of participation and use of unrepresentative samples may cause biased estimates of the frequen- cy and distribution of symptoms. Attitudes toward smoking have changed, and comparisons of questionnaire responses and objective measurements of smoking habits indicate that at least in some situations, less reliance can now be placed on answers to questions about smoking habits (MRFIT Research Group 1982). Estimates of prevalence and incidence of respiratory symptoms are imprecise, and too much importance should not be attached to relatively small differences in rates of reporting cough and phlegm. Each author's criteria for detecting the presence of cough or phlegm should be considered, especially when combinations of symptoms or diagnostic labels such as chronic bronchitis or mucus hypersecretion are used. Notwithstanding methodological differences, however, consistent patterns or trends found in many studies indicate that the associa- tions between smoking and chronic mucus hypersecretion are real and that the findings are widely applicable. Prevalence of Cough and Phlegm Unpublished data from the National Center for Health Statistics estimate that there were almost 8 million persons with chronic bronchitis in the United States in 1981 (3.4 million men, 4.5 million women). This is probably an underestimate of the true frequency of cough and phlegm in the population, since people who had these symptoms were not counted as chronic bronchitics unless they responded affirmatively to the question about bronchitis. On the other hand, some cases of acute bronchitis may have been included incorrectly and inflated the estimate. The apparently higher preva- lence rates of chronic bronchitis in women than in men in the National Health Interview Surveys in 1970 and 1979 (3.4 and 3.7 percent for women in 1970 and 1979, respectively, and 3.1 and 3.2 percent for men in 1970 and 1979) are probably due to ascertainment being less complete for men (USDHEW 1980b). Prevalence rates of chronic bronchitis ranged from 4.2 percent at ages under 17 years to 2.7 percent at 17 to 44 years, 3.6 percent at 45 to 64, and 4.5 percent at ages over 65 years. The high rate in the youngest group is presumably because of the inclusion of cases of acute bronchitis. Standard questions about chronic cough were asked in the National Health and Nutrition Examination Surveys (NHANES) of representative samples -of the U.S. population. Some supplementary questions were asked about phlegm and other respiratory symptoms, and these data are presented in the appendix to this chapter. Prevalence rates of diagnosed chronic cough in 18- to 74-year-old participants in NHANES 1(1971-1975) were 3 percent for men and 2 46 0 4 I 31.1 r 16.7 ; 12.0 10.2 Il.6 7.1 r 1 1 1 FIGURE lO.-Percentage of recurring persistent cough attacks by sex and smoking status for adults 25-74, United States, 1971-1975 NOTE. Light smoker: 1-14 cigarettes per day Moderate smoker- l&24 c,garettea per day Heavy smoker 2 25 ngarettes per day SOURCE- Natmnal Canter for Health Statistics. Unpublished data from the first National Health Nutntion and Exammauon Survev lNHANl?S Ia percent for women; they increased with age from 1 percent at 18 to 24 years to 6 percent at 65 to 74 years for men, and from 1 percent at 18 to 24 years to 3 percent at 65 to 74 years for women (National Center for Health Statistics, unpublished data). The prevalence of self-reported recurring persistent cough by smoking status for men and women of different ages is presented in the appendix and in Figure 10 based on NHANES 1. For the entire NHANES population, the prevalence of the persistent cough in- creased threefold in male smokers and twofold in female smokers compared with nonsmokers (Figure lo), and the prevalence of cough increased with increasing cigarette consumption in both men and women. Relationship of Cough and Phlegm to Smoking Relationships between smoking and cough or phlegm are strong and consistent; they have been amply documented and are judged to be causal (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a, 1981). Associations between smoking and cough or sputum are apparent in the recent studies listed in Tables 2 and 3 and are illustrated in Figures 11 and 12. Although cough, phlegm, and 47 chronic bronchitis occur in nonsmokers, prevalence rates are consis- tently higher in cigarette smokers. The excess prevalence of cough and phlegm in cigarette smokers increases with the amount smoked (see below). The frequency of reporting cough and phlegm is at least twice as high for smokers as for nonsmokers except in some groups with minimal exposure. Differences in prevalence rates between smokers and nonsmokers tend to be greater at older ages among men, whereas differences in rates between smoking and nonsmoking women tend to be as great or greater at younger ages (Tables 2 and 3). Rates are not given for pipe or cigar smokers in most of these studies, presumably because the numbers of such smokers were too small for reliable rates; male pipe smokers and cigar smokers in Tecumseh reported cough and phlegm more frequently than nonsmokers or ex-smokers, but less frequently than cigarette smokers (Higgins et al. 1977). Individual studies have evaluated other factors as well as smoking, but smoking has been judged the most important determinant of symptom prevalence (Fletcher et al. 1976; Ferris et al. 1976; Kiernan et al. 1976; Bouhuys 1977; Higgins et al. 1977). Consideration of evidence from many different studies has led to the conclusion that cigarette smoking is the overwhelmingly most important cause of cough, sputum, chronic bronchitis, and mucus hypersecretion (Speiz- er and Tager 1979; USDHHS 198Ob). Effects of Smoking Cessation Cross-sectional information on ex-smokers suggests that stopping smoking is followed by a reduction in cough and phlegm because symptoms are less prevalent than in current smokers, but these symptoms are generally mere prevalent in ex-smokers than in lifelong nonsmokers (Huhti et al. 1978; Gulsvik 1979; Park 1981; Schenker et al. 1982). However, the differences between ex-smokers and nonsmokers were either very small or absent in the studies reported by Higgins et al. (1977) and Manfreda et al. (1978). The longitudinal studies cited in Table 3 strengthen the evidence from cross-sectional studies that cigarette smoking causes cough and phlegm. Prevalence rates were higher at followup examinations in persons who started to smoke after being nonsmokers at a previous examination (Kiernan et al. 1976; Leeder et al. 19771. Rates of reporting cough or phlegm decreased in smokers who stopped smoking in two British studies (Kiernan et al. 1976; Leeder et al. 1977) and in populations in the United States (Ferris et al. 1976; Friedman et al. 1980; Beck et al. 1982). Many people who stop smoking report a rapid reduction in cough and phlegm. Although remission of symptoms occurs in some persistent smokers, remission rates are generally higher and incidence rates lower in those who quit than in those who continue to smoke. 48 TABLE 2.-Prevalence (percent) of cough, phlegm, and other symptoms for nonsmokers (NS), smokers (SM), and es-smokers (EX), c rossactional studies Author, year, country Poplllation Other Comments Tager and 507 realidetlta, Speizer. esed 15-66+, 1976, U.S. EastBostoll Chronic bmnchitie Men NS 7.0 SM @chars) l-6 8.7 5-10 25.0 10-N 28.6 >20 47.5 Women NS 4.6 SM @uck-years) l-5 14.3 5-10 9.1 10-20 20.8 Chmnic bronchitie (cough and phlegm >3 no&r for 2 years); no sge trend for either eex after adjusting for smoline; prevalence greater for men than women at each a@; significant increase in chronic bronchitis with increased lifetime cigarette consumption for current smokers, but not ex+.mokem g TABLE Z-Continued Author, year, country Population Cwxh Phlegm Other Comments Dean et al.. 1978 United Kingdom 6,277 men and 6,459 women, aged S-67, England, Scotland. and W&S Morning cough NS 12.5 SM (filter) :-7 19.6 6-12 32.8 13-17 36.3 18-22 44.0 23-27 50.6 28-32 56.8 33+ 52.1 NS SM (filter) l-7 a12 l&17 18-22 23-h 9.8 16.9 25.8 29.6 45.1 56.6 NS SM (filter) Il.4 14.4 20.8 25.4 26.9 34.2 34.5 26.4 Women NS 7.5 SM (filter) 13.8 16.6 16.6 25.8 34.3 Bronchitis syndrome NS SM (filter) 3.5 5.1 8.6 9.4 8.5 1.0 8.7 13.8 NS SM (filter) 2.5 3.8 4.2 5.1 10.6 12.0 Bronchitis syndrome (cough and phlegm 3 moe/yr, shortness of breath); significant increase of all symptoms with age; prevalence of mugh, phlegm. and whesze increased with number of cigar&ten smoked; filter vs. nonftiter cigarette effecta small, nonsignificant for most eymPbme TABLE 2.-Continued Author, year, country Population cough Other Commenta Higeins 1977. U.S. et al., 4,699 men and women, aged B-74, Team& Chronic bmnchitii Men NS 5.1 Ex 2.6 SM