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 4,000; resulta probably not age adjusted Schenker et al., 1962, U.S. 5,686 women, aged 17-74 (mean 44.6), western Pennsylvania, telephone interviewn Chronic cough chronic phlegm Wheeze moat daye or nigh& Cough and phlegm meet strongly NS 5.6 NS 4.5 NS 7.2 related to current cigarettes/day; w 7.5 Ftx 6.7 Ex 8.3 tar content had independent SM SM SM effecte; age effect Been for l-14 9.1 1-14 7.2 1-14 14.4 nonsmokera, but not current 15-24 17.0 15-24 16.7 15-24 16.5 smokers; symptom 25t 31.8 25+ 24.8 St 28.0 prevalencee age adjusted TABLE a.-Prevalence (percent of cough, phlegm, and other symptoms for nonsmokers (NS), smokers (SM), and ex-smokers (MI, longitudinal studies Author, year, country Population Smoking habits SYmptoms Comments Ferris et al., 1,201 men and Cwrh Phlegm 72.3% of men, 78.4% of 1976, women, aged 25-74 1973 1967 1973 1967 1973 women followed up; 1973, U.S. in 1961, Berlin Men symptom prevalencea, ege New Hamphire NS 6.0 8.5 8.9 7.6 @usted to compare with 1967, Ex 20.5 9.7 23.3 15.9 showed little change SM l-14 22.2 25.5 17.9 27.5 15-24 35.4 26.5 31.6 30.0 25-34 26.1 26.7 33.8 32.4 St 50.6 56.4 37.1 51.9 Women NS 4.4 6.2 8.1 7.4 Ex 3.2 5.2 7.3 10.1 SM 1-14 10.7 10.0 11.6 9.8 15-24 19.5 16.3 21.8 9.8 2544 27.2 16.1 22.5 21.8 St 44.7 31.0 43.1 41.2 Kieman et al., 2,736 men and Cough day or night in winter Effecta of cheat illnem before age 1976. women, aged 26, born 1966 1971 1966 1971 2, father's vocation, and current Great Britain ill1946,eUIlllin NS NS 5.5 4.9 emokhg r$nikant; air pollution 1966 and 1971 NS SM 7.2 9.6 ' effect not aignif~cant; current SM SM 14.3 18.5 ' smoking had lanpst effects SM Ex 9.2 5.8 `Prevalence, 1966 vs. 1972 P <0.05 TABLE 3.-Continued Author, year, cmntly Population Smoking hahits Comments Leeder et al., 2,130 fathers, Cough/phlegm prevalence range In male ersmokers, prevalence 1977, mean age 31.0rt6.1, Men of cough/phlegm decreased Great Britain 2,146 mothers, let period 2nd period 1st syr period 2nd 3yr period over time; no signiicant mean age 27.9f5.3, NS NS 8.69.6 9.2-11.1 change in prevalence in female children horn NS SM 4.6-16.9 13.3-20.5 er+mokera. but numhera 19634965, SM SM 25.6-30.2 30.W4.0 were amall London, 6 year SM Ex 21.6-25.3 5.b20.7 r0110wup Women NS NS 4% 6.8 5% 7.3 NS SM 8.2-10.2 13.3-18.4 SM SM 16.3-22.4 23.0-28.4 SM Ex 4.1-22.5 12.2-14.3 Woolf and Zamel. 302 women, wed Cough and/or phlegm Breathleesneas 60% followcxl up; all subjects 1960. `E-54 at initial let exam Findexam let exam Finalexam maintained con&ent smoking Canada study. &year NS 10 14 10 5 habita for 5 years followup J%x 3 13 18 8 SM 56 54 25 21 --- ---_.-. -. ___.-__. .~_.. TABLE 3.-Continued Author, year, muntry Population Smoking habits Comments Beck et al.. 1982, U.S. 1,262 white residents, aged 7-55 t , Lebanon, Connect icut, exams in 1972 and 1978 1972 NS NS SM SM FX 1978 NS SM SM Ex Bx NS NS NS SM SM SM SM Ex Ex Ex Usual cowh 1972 1978 Men 5 2 0 0 23 21 25 2' 7 6 7 4 0 0 20 14 26 12 10 3 usual phlegm 1972 1978 7 3 0 4 22 26 18 8 12 15 5 6 0 9 15 11 8 16 4 1 65% followed up; health indiaza of respondents and non- respondents similar; symptom prevalence tended to decline, but few changes were. significant; `Prevalence, 1972 vs. 1978, p of the true popula- tion values. Nevertheless, the figures clearly portray the magnitude of the effect that smoking exerts on expiratorv flow rates in a national population sample. Airflow obstruction is also prevalent outside t.he United States (Table 5). The disease can be identified in both technologically advanced and less developed populations. As in the United States, in other countries the prevalence of airflow oba. 3667 . - Never smokers - - - Current agarette smokers ~_--- .~~~-~~.-~T--- - 25-34 35-44 45-54 Age group .---r..~---.-~--~ 5M4 65-74 3712 -===\y,-.L- 26*3 `. . `. ----._---. 2712 2533 o- i -_.. i.-~-.~ 25-34 3544 4554 Age group 55-64 65-74 FIGURE 23.-Mean forced vital capacity for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE Values udjusti by the direct method to reflect the age distribution of the US populatlan at the midpoint of the survey. SOURCE Kational Center for Health Sttltlstics Unpubhshed data from the first Natuxaal Health Nutrition and Fxamlnstion Surwy fNHANEX lr 91 `CAtiLK 6..--Pusbulat~:d risk factors for airflow obstruction during childhood _" _.~ -.... -.- . ..-_ -I-.-- Actwe clgaret& smokmg :&ir pollubiun. indoor and outdoor Airnajs hypeneartivity A~WY - . . .._- .-LX.. - . I_-.-- -----be-. -......- _ I-~II-. .-__ _.-. ..- .-_. _ .--.. , `3 .& .lSlED iit;+. F.~c'!I;~G FOR AIHF'LOW OFSTRLKTION DL'RIh'G ADULTHOOD _-I- -.---.---m-w-^--. __I_ Actlre cqawtte smoking Alpha,-antltrjpsin deficient) _~_ _._ _.. .----__----- _____- PI'TA iIVE ~1% P.1: IXXS FOR AIHFLGW OBSTRUC'I'ION DURING ADULTHOOD ABH secretor status Air pollution Airways hyperreactivity Alcohol consumption A~PY Childhood respiratory illnesses Familial factors Occupation Passive exposure to t&acco smoke Respiratory illnesses Scciwconomic status occupational groups (Table 10) with exposures that have little or no effect on lung function. The selected studies are all cross sectional in design and thus describe the relationship between cigarette smoking and lung function level at only a single point in time. Investigations in the United States, spanning the time period 1958 to 1977, convincingly demonstrate that cigarette smoking is a strong determinant of FEVl level and the prevalence of airflow obstruction (Table 8). In every population for which prevalence data are available, airflow obstruction is more common among smokers than among nonsmokers (Mueller et al. 1971; Knudson et al. 1976; Detels et al. 1979; Rokaw et al. 1980). In fact, in a multivariate analysis of determinants of airflow obstruction in East Boston, lifetime cigarette consumption was the only statistically significant predictor (Tager et al. 1978). Data from populations outside the United States (Table 9) and from a variety of occupational groups (Table 10) confirm the importance of cigarette smoking. Effects of cigarette smoking on FEVi level have been readily demonstrated in employed populations 92 TABLE &-Association between cigarette smoking and FEV, level in selected U.S. adult populations Author, year of study, Number and type location, reference of population Findings Ashley et al.. 1956. Framingham, Massachusetts, (1975) 1,236 men and women, 37 to 89 years of age By linear regression, significant decline of FEX,/FVC ratio with pack-years of cigarette consumption in men; similar decline demonstrated in women, but not significant for all ab!e mute Higgine and Kjelsberg 19% 1980, Tecumeeh, Mich!gan (1967) - Higgins et al., 1963, Marion County. West Virginia 1196all I_..------ Higgins et al., 1962-1965, l'rcumwh. lIichiian (1977) 5,140 men and women, 16 to 79 yeare of age 926 white men, 20 to 69 years of age 4,669 men and women, 20 to 14 years of age - Age-adjusted mean FEV, Oiters) Men Women Nonsmokers 3.32 2.34 Ex-smokera 3.31 2.34 Current smokers 3.12 2.26 Mean FEV, (liters) Nonsmokers 3.64 Ex+mokers 3.25 Current smokers 1-14/day 3.67 15-2.4lday 3.51 > mday 3.30 Mean normalized FEV, score Men Women Nonsmokers 10.2 10 1 Ex-emokers 9.9 10.0 Current smokers c2O/day 9.8 9.9 2 2oMay 9.5 9.6 -~.__l___-.__l~---- Prevalence of E'E:V : i FVC <: Go% Men Women Mlwl'r" ct n'. 1`W 1 . Glenwood, cid!LI f%)(l :xn and women. Nonsmokers 3 ; %;! to 69 JY'Ul-8 or age Current smokers 19 2 (2971) .- ~.-- Fen% et al., 1967, &rlin, 848 men and women, By multiple r-ion, in men and women, FEV, drops by New Iiampehire (197.3 3OtcW)yearsofage 0.01 liters for each cigarette smoked per day -.-._-- -. _-- _ _----- -~ ___--. .-.---__ Burrowe et al., 1972.-1!?7?. 2369 men and women, By multiple regression analysis, FEV, drops by 0.31 and Tucson, Arizona iI above 14 years of age 0.24 percent of predicted value per pack-year of smoking in men and women, respectively .____ --- ---..---- _- Knudson et al., 19X1973. 2,7.35 men and women, Pravalence (%) of abnormal FEV, and/or FIW,/FVC Tucson, Atiana (f97fJ all ages Asymptomatic nonsmokers 8.3 Asymptomatic smokers 13.3 __-- ---. --.~ Tsger and S+vr, 1973.397!. 633 men and women, By multiple regression, in men and women, significant FM Ftiton. Massachusett 15t years of age reduction of an FJXV, score with increasing lifetime /19707 consumption, and in smokers compared with nonsmokers Tagger et al., 197:%1974. East Boston, Msssarhwe!k !!9,3 1,251 men and woman, By multiple logistic analysis, lifetime cigarette consumption only significant pradictor of airflow obstruction, defmed as FEV, laea than 65% predicted 4.6W men and women, 7t yearsofage By multiple regression analysis, significant dose-response relationships of adjusted residual FJIV, with measurea of cigarette smoking: duration, pack-years. and cigarettes per day TABLE %-Continued Author, year of study, Number and type location, reference of population Findings Ferris et al., 1974-1977, U.S. communities (19791 Detele et al., Rokaw et al., 1973-1975, Burbank, Lan- mater, Long Beech, California (lhtels et al.. 1979, Rokaw et al., 1960) 8,480 men and women, 25to74yeareofage Approximately 8,000 men and women, 18 yeare or older Mean r&dual FEV, (liters) after correction for height and age Lifetime packs Men Women None 0.25 0.06 <3.ooo 0.21 0.04 3.~999 0.01 -0.05 9,ooo-17,999 -0.19 -0.20 2 l&o00 -0.45 -0.28 F'revalence (%Y of FEV, below 75% predicted, age and eex-adjusted Never smoked Current smoker 1859 years old Burbank 6.6 12.5 Lancaster 3.4 6.6 Long Bench 5.3 10.0 260 years old Burbank 15.9 23.5 Lancaster 13.4 21.7 TABLE 9.-Association between cigarette smoking and lung function in sele&ed non-U.S. populations Author, year of study, Number and type location, reference of population Findings Hi, 1956, VaIe of GlamorgaIl, wales mm 661 men and women, 25 to 74 yearn of age lr men, reduced peak tlow rates and indirect maximum v&ntary ventilation in smokers compared with nonsmokers; no effect of smoking in women Higgins et al., 1957 Stavely, England (1959l 776 men, aged 25 to 34and55to64 Mean indirect maximal breath capacity (liters) 25ta34yrE 55ta64yl-n Nonsmokers 145 101 Exsmokers 143 89 Current smokers Light 140 87 HWVY 133 80 H&inn et al., 1966, Rhondda 537 men, aged 36 to 64, Mean indimct maximal breathinx canacit~ titers). men Fa& -. - Walea (1961) and 173 women, aged55to64 Miners Nonminers Nonamokern 93.1 114.6 Ex+mokern 93.6 106.9 Current smokers Light 89.0 104.1 HeavY 88.3 99.4 No effect of smoking in women TABLE 9.-Continued Author, year of study, Number and type location, reference of population Findings College of General Practitioners, 787 men and 762 Age-adjusted mean PEFB' flitera/minute) 1966, Britain (1961) women, aged 40 to 64 Men Women Nonsmokers 448 316 Ex-nmokern 417 300 Current smokers 1-lllday 412 314 15-24/day 399 310 > 25lday 398 265 SluisCremer and Sichel, 533 men, 36 yearn Reduced FEV, and PEFR' with increased tobacco mnsumption 1962-1963, Carletonville, or older South Africa (1Si!7~ Huhti, 1961. Harjavalta, 420 men, 608 women, All women, nonsmokers; in men, reduced FEV, and PEFB ' in Finland (1967~ aged4ot.oe4 smokers mmpared with nonsmokers Wilhelmsen et al., 1963. 339 men. aged 50 Gi5teborg, Sweden (1969) Mean FEV, (liters) Nonsmokers 3.72 &-smokers 3.71 Current smokers 1-14 g/day 3.58 > 15 g/day 3.36 Huhti et al., 1968-1970, 1,162 men, aged 25 to Reduced FEV, in smokera compared with nonsmokers; increased Hankaaalmi. Finland (1978) 69 prevalence of FEV,/FVC ratio lese than 60% in smokers TABLE 9.-Continued Author, year of study. Iwatinn. reference Number and type of population Findings MimIca, 1969. Croatia, 4,214 men and women, Yugoslavia (1979 35 to 54 years of age Nonsmokers Ex+mokers Current smokers Light H-V Mean FEV, (liters) Men 3.56 3.57 3.42 3.42 Women 2.62 2.70 2.64 2.66 Neri et al, 19691973. Sudbury and Ottawa. Canada 11975 Manfreda et al, 1974, Portage la Prairie and Charleswoo& Canada (197x) --- -- Andemon. year not stated, Karkar Island. Papua New Gtinm 11976-I Anderson, year not stated, Lufa, Papua New Guinea (2979) 5,466 men and women, 14 years of age or older 502 men and women, 25toXiyearsofage 548 men and women, 25 years of age or older 733 men and women 25yearsofageor older Declining ratio of FEV!/FVC with number of cigarettes smoked MY Significant regression of FFV,/FVC ratio on number of cigarettes smoked daily Age and heightadjusted mean FEV, (liters) Men Women Nonsmokers 2.56 2.13 Smokers 2.40 2.01 Age and heighta&sted mean FEV, (liters) Men Women Nonsmoker 2.58 2.36 Exsmoker 2.62 2.27 Occasional 2.57 2.29 R@idw 2.63 243 TABLE IO.-Association between cigarette smoking and lung function level in selected occupational groups Author, year of study, Number and type location, reference of population Findings Sharp et al., 1960-1961, 1.667 men, aged 43 to Chicago, U.S. (1965) 56 years. employed at an electronics plant ..-_ --~___ Fletcher et al., 1961. 1,136 men aged 30 London, England (2976) to 59, employed at bank or in maintenance of transportation equipment f, --__ i- -- Goldsmith et al. 1961 San Francisco. U.S. ima' 3,311 longshoremen Mean FEV, (liters) Nonsmokers Smokers 40 cigarettes/day 3.15 3.02 2.90 3.28 3.16 2.81 3.05 2.99 2.94 100 97 93 93 94 E TABLE IO.-Continued Author. year of study, Number and type location, reference of population Rndinga Bidchum et al.. 1961, La 1,456 men employed in Prevalence (per 100) of FTV,/FVC ratio less than 70 percent Angeles, U.S. (I96ZI various induetrien Nonsmokers 1.6 Smokers 18.8 Coata et al.. 1962. Detroit, 1,584 male and female Reduced FFX, and FFX,/F'VC ratio in smokers of 25 or more U.S. (1965) pcwtal employees, cigarettes daily compared with nonsmokers aged 40 or older Deneen et al., 1961-1983, New York City, US. (2969) 12,500 males employed 88 postal or transit workers Age- end heightadjusted FJW, W..ere) Pcetal workers Transit workers Band6 et al., 1980-1975. Belgium (1980) 7.123 male military personnel, * few over age 45 white Nonwhite White Nonwhite Nonsmokers 3.29 3.05 3.39 3.08 Cigarette smokers <25gperday 3.14 2.95 3.15 3.00 2% B per &Y 3.06 2.93 3.02 2.95 By multiple regression, in crcesaxtional analyeie, signiiiwnt effect of smoking on FEV, level after age 35 Cornstock et al.. 1962-1963 and 1967. U.S. and Japan (19731 Three cme+eectional Mean FJW, level as percent predicted studies of men working U.S. Jaw for telephone company; Study 1 Study 2 U.S.-l,302 and Cigarettea per day 1,194 subjects, aged None 106 103 99 40 to 65. 6% in 1-14 104 101 100 study; Japan--592 15-24 98 92 98 subjecta, aged 40 to 60 2% 95 93 99 `I'ABLE l&--Continued Author, year of study, Number and type location, reference of p0pu1at10n Fmdings Khmla. 1964. Port Talbot, United Kingdom (1971) Schlesinger et al., 1966. 7,701 males employees Adjusted mean FEV, level (liters) in the ateel industry Never amokem /- Current smokers i 15 cigarettealday lb24 cigarett&day 25-34 cigar&tea/day 2 35 cigarettes/day 4.331 male civil servants, Mean value of the FEV,/FVC ratio Israel (1972) aged 45 or older Nonsmokera Jhmokem Current smokers 1-19 cigarettes/day - 3.70 3.57 3.48 3.41 3.37 - 76.0 74.3 73.9 2 20 cigarettes/day 72.7 Keateloot et al., 1968-1969, Belgium (2976) O'Donnell and de Hamel. 1969- 1970, New Zealand (1976) Linn et al., 1973, San Fran- cisco and Los Angeles, U.S. (1976) Rndelman et al.. year not stated. Baltimore. U.S. (1966) 4,961 males in the Belgian military, aged 15 to 59 1.079 male public sewante, up to age 65 644 male and female office workem aged 17 to 60 410 male volunteers, aged2otQ103 By multiple regression, FEW, reduced by 0.14 liters in smokers of 1-19 cigarettes daily and by 0.23 liters in smokere of 20 or more daily Beduoed mean FEV, in smokers of 10 or more cigarettes daily; increaeed prevalent of FEX, below 80 percent of predicted in smokers of more than two pa& daily By analysis of covariance, significant reduction of FJXV, in smokers compared with nonsmokers By partial regression analysis, significant reduction of FEW, in current and former cigarette smokem c 0 e TABLE 10.~-Continued Author. year of study, Number and type location, reference of population FlllilllgS Woolf and Suero, year not stated. Toronto (1971) Krumholz and Hedrick. year not steti, Dayton. U.S. (1973l 298 female volunteers employed at commercial film, aged 25-54 227 male executives. aged 3.544, selected to include nonsmokers (n = 136) and long- term smokers (n=91) Adjwted mean levels Nonsmokers Exsmokers Current smokers 70 cigarettes/week 71-140 cigarettes/week 2 140 cigarettes/week Mean values Nonsmokers Smokers EV, FEV,/FVC ratio 2.65 a.7 2.64 85.0 2.63 86.2 2.50 85.1 2.45 84.1 ___- EV, FEV,IFvC 3.80 71.3 3.42 73.6 Grimes and Hanes. year not stated, Los Angeles, U.S. (1973) Lefcoe and Wonnacott. year not stated. western Ontario, Canada ( 1974 1,059 male and female insurance company employees 1,072 males in four occupational groups By multiple regression, significant reduction of FEV, level in male smokers but not in female smokers By multiple regression. significant reduction of FEY, in current cigarette smoken Higgenbottam et al.. year not stated, London. England (1980) 18.403 male civil sewants. aged 4ota64 Reduced FEV, io cigarette smokers compared with nonsmokers, increased effect with increasing daily amount in current smokers (Table lo), even though people with symptomatic airflow obstruction may be likely to retire from their jobs. Recently, predictors of the incidence of airflow obstruction have been examined with multivariate techniques in data from popula- tion samples in Tecumseh, Michigan (Higgins et al. 19821, and in Tucson, Arizona (Lebowitz et al. 1984). In Tecumseh, the strongest predictors of airflow obstruction (defined as an FEVl less than 65 percent of predicted) were age, the number of cigarettes smoked daily, changing smoking habits, and the initial FEVl level (Higgins et al. 1982). The addition of other variables to the predictive model did not greatly improve its validity. In Tucson, these same variables, along with certain symptoms and illnesses, and skin test reactivity were significant predictors (Lebowitz et al. 1984). During the 10 years of followup of a population sample in Finland, incidence cases of chronic airflow obstruction (defined as FEV1/FVC ratio less than 60 percent) were observed only in those who continued to smoke (Huhti and Ikkala 1980). These studies of incidence highlight the importance of cigarette smoking in t.he etiology of airflow obstruc- tion; new cases are rare among nonsmokers. Dose-Response Relationships Dose-response relationships between FEVl level and the amount of cigarette smoking have been described with simple descriptive statistics and further characterized by multiple regression analysis. In cross-sectional data, the FEVl level varies inversely with the amount smoked. Although the variation in mean FEVl levels among strata of smoking appears clinically unimportant, the distributions of values in smokers and nonsmokers are quite different (Figure 4). Cigarette smokers more often have abnormal lung function, regard- less of the criteria applied to the population (Mueller et al. 1971; Knudson et al. 1976; Burrows et al. 1977a; Detels et al. 1979; Rokaw et al. 1980; Beck et al. 1981). This increased prevalence of abnormal function is a result of the skewed distribution of function in smokers, with a subgroup of the smokers showing a large decline rather than the entire group shifting by a small amount (Figure 4). As noted in this reference, however, there are decreasing numbers of smokers with FEVI above the mean for nonsmokers as pack-years increase, suggesting that all smokers are probably somewhat affected, even though only a minority eventually develop clinically significant airflow limitation. In several populations, the relationship between cigarette smoking and FEVl level has been examined in greater detail. Burrows et al. (1977a) used linear multiple regression analysis to examine the relationship between cigarette smoking and ventilatory function in a population sample in Tucson, Arizona. Pack-years, a cumulative- dose measure, was the strongest predictor of FEVi level among the 103 smoking variables considered. In currently smoking men and women, the FEVi declined by approximately 0.25 percent of the predict.ed value for each pack-year of cigarette smoking; the effect was of a similar magnitude in ex-smokers. Using data from three separate U.S. communities, Beck and colleagues (1981) assessed the importance of six separate smoking variables: amount smoked daily, use of filters, inhalation, age started, age stopped for ex-smokers, and cumulative pack-years. For the FEVi, the strongest predictors in male current smokers were the duration of smoking and the amount smoked; in female current smokers, only pack-year was statistically significant. The number of years of cessation was associated with FEVl in male but not in female ex-smokers. However, in both the multiple regression analysis reported by Beck et al. (1981) and that reported by Burrows et al. (1977a), the measured cigarette smoke variables accounted for only about 15 percent of the variation of age- and height-adjusted FEVi levels. Unmeasured aspects of cigarette smoking, other environmental exposures, and the characteristics of the smokers must contribute to the unexplained variation. A role for the type of cigarette smoked has not yet been established (USDHHS 19811, and the impact of differences in depth or pattern of inhalation and other aspects of the pattern of smoking remains to be investigated; they are discussed in more detail in the chapter on low tar and low nicotine cigarettes. Further studies of these aspects of cigarette smoking are needed to monitor the consequences of changing cigarettes. Factors Other Than Cigarette Smoking A number of risk factors other than cigarette smoking have been postulated as contributing to the development of airflow obstruction (Table 7). Of these, a definite role for a,-antitrypsin deficiency has been established, but only the small number of persons with homozygous deficiency incur markedly increased risk (Morse 1978). The current hypotheses on susceptibility to cigarette smoke postu- late roles for childhood respiratory illnesses (USDHEW 1979; Burrows and Taussig 1980; Samet et al. 19831, for endogenously determined hypersensitivity of the lung, and for other genetic and familial factors (Speizer and Tager 1979; USDHHS 1980aJ At present, these hypotheses remain largely untested. The data are similarly incomplete at present for the other factors listed as putative risk factors in Table 7. The status of each is briefly reviewed below. ABH Secretor Status Secretion of ABH antigens is a genetically determined trait that follows an autosomal dominant inheritance pattern; approximately 104 70 to 80 percent of the population excrete antigen into the body fluids (Cohen et al. 1980a). In a genetic-epidemiology study in Baltimore, Maryland (Cohen et al. 1980a), ABH nonsecretors had lower levels of FEVJFVC ratio and a higher proportion with FEVJFVC ratio below 69 percent. Studies in France (Kauffmann et al. 1982a, 1983) and in England (Haines et al. 1982) have confirmed reduced expiratory flow rates in ABH nonsecretors. In contrast, ABH secretor status did not predict the development of obstructive airways disease in the Tecumseh, Michigan, population (Higgins et al. 1982). Air Pollution Although exposure to air pollution at high levels may exacerbate the clinical condition of persons with chronic lung disease, a causal role for air pollution in the development of airflow obstruction has not been established (Tager and Speizer 1979; USDHHS 1980b). However, smoking is the major predictor for chronic airflow obstruction in areas of high as well as low atmospheric air pollution. Airways Hyperreactivity Orie and colleagues in the Netherlands (Orie et al. 1960) speculat- ed that bronchial hyperreactivity and allergy may predispose to asthma and chronic bronchitis. Findings from two small longitudinal studies have suggested that airways reactivity may influence indi- vidual susceptibility to cigarette smoke. Barter and colleagues followed 56 patients with mild chronic bronchitis during a 5-year period (Barter et al. 1974; Barter and Campbell 1976). The rate of decline of FEVl increased with the degree of airways reactivity, as measured by reversibility with isoproterenol or responsiveness to methacholine. Britt et al. (1980) measured change of FEVl in 20 young adult male relatives of patients with chronic obstructive pulmonary disease. The decline of FEVl was approximately five times larger in the nine subjects with a positive methacholine challenge test. In patients with clinically diagnosed airflow obstruc- tion, airways reactivity is also associated with more rapid decline of lung function (Kanner et al. 1979). Because airway reactivity would affect the FEV, directly as well as possibly influence the susceptibili- ty to smoke, it is difficult to ascertain from these data whether the relationship between airway reactivity and COLD is direct or spurious. Alcohol Consumption The epidemiological data on alcohol consumption are conflicting. A study of former alcoholics demonstrated an excess prevalence of lung function abnormalities, including airflow obstruction (Emergil 105 480-144 0 - 85 - 5 and Sobol 1977). In the Tucson population, alcohol consumption was a significant predictor of ventilatory function after the effect of smoking was controlled (Lebowitz 1981). The findings of an investiga- tion in Yugoslavia were similar (Saric et al. 1977). However, two large U.S. investigations did not demonstrate adverse effects of alcohol intake (Cohen et al. 1980b; Sparrow et al. 1983a). Cross-sectional data from the Tucson population suggest increased susceptibility to cigarette smoke in atopic people (Burrows et al. 1976). In subjects aged 15 to 54, the prevalence of an FEVAWC ratio below 90 percent of predicted value increased with skin test reactivity among both smokers and nonsmokers. Subsequent reports from this same study have not confirmed an overall relationship between FEVl level and atopy, but indicate that atopy may predis- pose to airfIow obstruction in a subset of the population (Burrows et al. 1977a, 1983). Burrows and coworkers (1981) also reported an increased level of IgE in smokers independent of their allergy skin test reactions, and the interrelationship of these factors is currently being examined. Childhood Respiratory Illness In a longitudinal investigation of 792 English working men, Fletcher and coworkers (Fletcher et al. 1976) found a cross-sectional association between childhood illness history and FEVl level. The decline of FEVl level during the study's longitudinal phase was not correlated with childhood illness variables. In contrast, a.nalyses of cross-sectional data from a population sample in Tucson suggested that childhood respiratory illnesses may increase susceptibility to cigarette smoke (Burrows et al. 1977b). In this population, people with a history of respiratory trouble before age 16 demonstrated excessive decline of ventilatory function with increasing age and with increasing cigarette consumption. Familial Factors Familial aggregation of lung function level, adjusted for age, height, and sex, has been demonstrated in populations in the United States and elsewhere (Higgins and Keller 1975; Tager et al. 1976; Schilling et al. 1977; Mueller et al. 1980). However, a recent report suggests that the familial aggregation of lung function may be a reflection of the familial aggregation of body habitus (Lebowitz et al. 1984). Relatively modest correlations of FEVI level have been demonstrated between siblings and between parent-child pairs. The role of familial factors is further supported by investigations demonstrating increased prevalence of airflow obstruction in rela- 106 tives of diseased subjects (Kueppers et al. 1977; Tager et al. 1978; Cohen 1980). This familial factor cannot be explained by familial resemblance of a,-antitrypsin phenotype or of ABH secretor status (Kueppers et al. 1977; Cohen 1980). In the Tecumseh population, however, family history of airflow obstruction did not predict the incidence of this disease. The results of twin studies are also consistent with genetic influences on FEVl level and suggest that genetic factors may influence susceptibility to cigarette smoke (Webster et al. 1979; Hankins et al. 1982; Hubert et al. 1982). Occupation Several population-based investigations suggest that occupational exposures other than those recognized as causing lung injury may have some effect on lung function level. In Tecumseh, mean age and height-adjusted FEVl scores in men were highest in farmers and lowest in laborers; the differences were not explained by smoking and were present in nonsmokers (Higgins et al. 1977). Similarly, in Tucson, men reporting employment in certain high risk industries or exposure to specific harmful agents had a higher prevalence of abnormal lung function (Lebowitz 1977a). In a Norwegian case- control study, men employed in workplaces characterized as polluted were at increased risk for clinically diagnosed emphysema (Kjuus et al. 1981). Longitudinal studies of industrial populations also show that occupational exposures may increase the rate of decline of FEVl (Jedrychowski 1979; Kauffmann et al. 1982b; Diem et al. 1982). For example, Kauffmann et al. (1982b) found that FEVl change during a 12-year period varied with job exposures in an employed industrial population. Effects of dust, gas, and heat were present, as was evidence for a dose-response relationship between increasing exposure and a greater rate of decline. In these studies, however, smoking effects were generally much greater than the occupational effects. Passive Exposure to Tobacco Smoke Passive exposure is discussed in detail elsewhere in this Report. Respiratory Illnesses In an 8-year followup study of London men, chest infections were not associated with a rate of FEVl decline (Fletcher et al. 1976). The findings of several smaller longitudinal studies were similarly negative with regard to respiratory infection (Howard 1970; John- ston et al. 1976). It is now apparent that mucus hypersecretion and airflow obstruction are separate pathophysiological entities that have a common cause-cigarette smoking (Fletcher et al. 1976; Peto et al. 1983). 107 Socioeconomic Status Weak effects of socioeconomic status on lung function level have been demonstrated in community samples in Tecumseh (Higgins et al. 1977) and in Tucson (Lebowitz 197713). In both populations, lung function appeared to be influenced independently by socioeconomic status indicators, even after controlling for cigarette smoking. In the Tecumseh study, FEVI increased slightly with increasing income and education level (Higgins et al. 1977); in the Tucson study, the proportion of people with an abnormal FEVl varied in a similar pattern with these indices (Lebowitz 1977al. Effects of socioeconomic status were present in nonsmokers in both investigations. Stebbings (19711, in a sample of nonsmokers in Hager&own, Maryland, also demonstrated an association between lung function level and socioeconomic status. In summary, there is evidence that a number of factors other than cigarette smoke may influence lung function, but the influence of these factors is small relative to the effect of smoking, and the major question is whether they can influence susceptibility to cigarette- induced lung injury rather than whether they, of themselves, result in lung disease in nonsmokers. Development of Airflow Obstruction At this time, the natural history of airflow obstruction has been only partially described; a population has not yet been followed from childhood to the development of airflow obstruction during adult- hood. However, the available data from separate investigations cover the entire course of the disease and support the conceptual model proposed in Figure 15. With aging, measures of function begin to deteriorate after age 25 to 30. In nonsmokers without respiratory disease, cross-sectional data generally show that the FEVl declines by 20 to 30 ml per year (Dickman et al. 1969; Morris et al. 1971; Cotes 1979; Crapo et al. 1981). Longitudinal data have been confirmatory (Tables 11 and 12). For example, Tockman (19791 measured the FEVi loss during an 8 year period in 399 male nonsmokers. In most, the FEVl declined at 25 ml annually; a few, with an initial FEVl lower than 2.5 1, lost 34 ml annually. Sufficient excessive loss leads to the development of airflow obstruction. However, many questions remain unanswered concern- ing this process of functional deterioriation. It is unclear whether the loss always occurs uniformly or if it develops in stages with intermittent and relatively steep declines (Bates 1979; Burrows 1981). The concept that the decline is nearly always gradual receives strong support from the findings of the &year longitudinal study conducted by Fletcher and coworkers (1976). In this investigation of 108 TABLE IL-Association between cigarette smoking and longitudinal change in lung function in selected population samples Author, years of study, Number and type location, reference of population Findings Higgins and Oldham, 1954-1959 Rhondda Fach. Wales (196.9~ 253 male miners, ex- miners, and nonmining controls Annual decline of indirect maximal breathing capacity (liters/min) Miners, ex-miners controls without pneumoconiosis Nonsmokers 1.6 0.8 Es-smokers 0.7 1.8 Current smokers 1-14 g/day 1.3 1.7 115g/day 1.6 2.2 Ashley et al.. 195S1968, Framingham. U.S. 11975) 399 men and 636 women. aged 37 to 69 in 1958 lo-year change in FEV,IFVC ratio (agestandardized to overall distribution for each sex) Men Nonsmokers 0.21 Gmtmued smokers -1.3 stopped. 1953-1963 0.51 Women -3.6 -4.1 -4.6 Higgins et al.. 1957-1966. 594 men, aged 25-34 Annual decline of FEVw, (ml/year) bv age and smoking in 1957 &ely. -- England (1968b) or 55-64 in 1957 2534 ;rs 5Gl yrs Nonsmokers 21 32 Exsmokem 29 44 Current smokers 1-14glday 37 54 2 15gida.v 38 37 E TABLE 1 l.-Continued Author, years of study. Number and type location, reference of population Huhtl and Ikkala. 196-1971. Harjavalta. Finland (1980) Wilhelmsen et al.. 1963-1967. Goteborg. Sweden (1969) 492 men and 671 women, aged 40 to 64 in 1961 313 men, aged 50 in 1963 Annual decline of FEV, (ml/year) Nonsmokers Ex-smokers Continued smokers Stopped. 196-1971 Annual decline of FEV, (ml/year) Nonsmokers Ex-smokers Current smokers I-llg/day 2 15glday StQDDd. 1963-1967 Men 33 45 44 51 43 33 70 70 40 Women 27 27 39 35 _ -- _ -. .,"II***.u~u Author. years of study. Number and type locatlon. reference of population Findings Oxho] et al.. 1963-1973, 269 men. aged 25 ctgslday 54 Annual decline of FEV, iml/year). adjusted for initial level Nonsmokers 40 Ex-smokers 44 Current smokers c 15 g/day 46 ? 15 g/day 51 5-year decline of FEV, as percent of mean, by 1973 smoking Nonsmokers 3 Ex-smokers 5 Current smokers 7 Annual decline of FEV, (ml/year) I.9821 - Nonsmokers Ex-smokers Continued smokers stopped, 1967-1977 37 39 49 48 E TABLE 12.-Continued Author. years of study, Number and type locatton. reference of population Findings Woolf and Zamel. years not gtven. Toronto. Canada r IY8O)xoI BOW et al, lYfxLlY68 to 1YtwlY74. Boston. II s ( I.WII 302 female volunteers, aged 25 to 54 at entry H50 male volunteers 5.year change m FEV, as percent of initial value Nonsmokers 15 Rx-smokers 0 8 Smokers <. 70 clgslweek 0.4 71-140 ctywveek `): 3.t,, 140 cigs! week 48 Annual declme of FEV, imllyearr. adjusted for age and mtttal level Nonsmokers 0.053 Ex-smokers 0.057 Current smokers 0085 Love and Mtllcr. 1957 to 1973 1.677 male coalmmers II-year declme tn FEV, Ilttersl Iaverage followup. 1 I years). UnIted Ktngdom ~l.Y&?b Nonsmokers 0.41 b-smokers 0.48 IntermIttent smokers 0.52 Current smokers 0.53 792 employed men, the individual patterns of temporal change of the FEVl were strongly variable, but the loss generally occurred gradually. Fletcher et al. further demonstrated that FEVl levei correlated with FEVl slope, a finding that they termed the "horse- racing effect." Correlation between slope and level would be antici- pated, if functional loss occurs gradually. This correlation has important implications for intervention; those losing FEVl more rapidly should become identifiable early as they develop a reduced FEVl level. Other studies, however, do not agree with either the pattern of FEVl decline or the "horse-racing" effect. Rapid declines to levels compatible with clinical disease or followed by a prolonged plateau have been described (Howard and Astin 1969; Howard 1970; Johnston et al. 1976). In a followup study of Canadian men with chronic bronchitis, steep declines of FEVl without subsequent improvement were frequently observed (Bates 1973). Additionally, correlation of FEVl level and slope has been. found in most other longitudinal investigations (Howard 1970; Petty et al. 1976; Huhti and Ikkala 1980; Bosse et al. 1981; Clement and van de Woestijne 1982; Kauffmann et al. 1982b), but not in all (Barter et al. 1974; Krzyzanowski 1980). Another unanswered question concerning functional deterioration is whether gradual decline occurs in a linear or a nonlinear fashion (Fletcher et al. 1976). Sufficient numbers of people have not yet been followed to distinguish alternative patterns, although the available data indicate acceleration of the decline with aging (Emergil et al. 1971; Fletcher et al. 1976). In spite of these uncertainties concerning the development of airflow obstruction, the available data indict cigarette smoking as the primary risk factor for excessive loss of FEVl (Tables 11 and 12). The findings in both general population samples (Table 11) and occupational and volunteer cohorts (Table 12) have been similar. Recent reports from Belgium (Bande et al. 1980; Clement and van de Woestijne 1982) and from Connecticut (Beck et al. 19821, not readily summarized in tabular form, also described a strong effect of smoking on FEVl decline. A few studies have not shown increased loss in cigarette smokers (Howard 1970; De Meyere and Vuylsteek 1971). Even in people with clinically diagnosed airflow obstruction, continued smoking maintains the excess decline of FEVl (Hughes et al. 19821, although not all findings are consistent (Ogilvie et al. 1973; Johnston et al. 1976). Dose-response relationships have been found in many investiga- tions between the amount smoked during followup and the FEVl decline (Tables 11 and 12). The reported increases from the lowest to the highest smoking categories range up to 10 to 15 ml annually. Although this additional loss in heavier smokers appears small, if sustained for long periods of time it would shorten the time interval 115 Never smoked or not suscepbbk? Its effects - Stopped at 45 Death 25 50 75 Age (years) FIGURE X-Risks for men with varying susceptibility to cigarette smoke and consequences of smoking cessation NOTE: + = death. SOURCE: Fletcher and Pet0 (1977). to the development of functional impairment. So far, favorable effects of filter tip smoking and declining tar content on the rate of decline have not been shown (Fletcher et al. 1976; Sparrow et al. 1983b). Generally, sustained smokers experience a greater loss than those who stop during followup. In the study by Fletcher et al. (1976) of London men, subjects who stopped smoking at the beginning of the followup period lost FEVI at the same rate as never smokers. The results of two U.S. studies of ex-smokers are similar (Bosse et al. 1981; Beck et al. 1982). This reduced loss in ex-smokers emphasizes the importance of active smoking and the immediate benefits of smoking cessation (Figure 24). Smokers with reduced FEVI may be protected from developing clinically significant loss by timely smoking cessation (Fletcher and Peto 1977). The distribution of FEVI decline has been characterized and described for some populations, including patient groups (Burrows and Earle 1969; Howard 1974; Barter et al. 19741, population samples (Milne 19781, and occupational cohorts (Howard 1970; Fletcher et al. 1976). Similar data are also available for the mid-maximum expira- tory flow, another measure of ventilatory function (Bates 1973; Woolf and Zamel 1980). In each of these investigations, the distribu- tion of FEVI decline is unimodal (Figure 25); that is, a distinct population with more rapid decline is not sharply separated from those with lesser rates. The modes and medians of the distributions 116 60 70 Mean 60 Nonsmokers and Q a-smokers ii 50 e 6 i 40 30 1 20 10 0 -160 -140 -120 -100 -60 -60 40 -20 0 +20 FIGURE 25.-Distribution of &year FEVl slope in 792 London men SOURCE: Fletcher et al. (1976). are generally negative, but some subjects have had positive slopes during the relatively brief followup period of investigations conduct- ed up to this time. The distributions tend to be skewed by subjects losing FEVl more rapidly. The proportion of cigarette smokers is increased among those in the tail of excess loss (Figure 25). For example, Clement and van de Woestijne (1982) examined subjects with excess FEVl decline in a prospective study of 2,406 members of the Belgian Air Force. Losses beyond those expected from nonsmokers affected 6 percent of nonsmokers, 7.5 percent of light smokers (< 20 cigarettes/day), and 12 percent of heavy smokers ( > 20 cigarettes/day). The shape of the distribution of FEVl decline has important implications for the development of airflow obstruction. Smokers are not sharply separated from nonsmokers (Figure 251, but more often lose FEVl at a rapid rate. Because of this spectrum of severity, not all smokers develop significant airflow obstruction. Although the fac- tors that lead to excessive loss in individual smokers remain uncertain, they may include differences in the pattern of smoking. It is apparent, however, that this susceptible minority can be protected by smoking cessation. 117 summary During the 20 years that have elapsed since the 1964 Surgeon General's Report, the relationship between cigarette smoking and airflow obstruction has been intensively investigated. Surveys of community samples and other groups have established that airflow obstruction is a common condition in the United States and elsewhere. In some populations, as high as 10 percent of adults are affected. Determinants of lung function level and of the prevalence of airflow obstruction have now been examined in many populations throughout the world. Cigarette smoking is the strongest predictor of abnormal measures of ventilatory function. A causal relationship between cigarette smoking and airflow obstruction is supported by the consistency of the many published reports, the strength of the association, and the evidence for dose-response. Many risk factors for airflow obstruction other than cigarette smoking have been postulated, including other harmful environmen- tal exposures and the inherent susceptibility of the smoker. Homozy- gous a,-antitrypsin deficiency can explain only a minute proportion of the disease burden. The development of airflo-w obstruction by only a minority of smokers indicates that the interaction of smoking with other factors may influence the risk for specific smokers. Current research emphasizes the potential roles of childhood respira- tory illness and airways hyperresponsiveness. Longitudinal studies have now partially described the prolonged natural history of airflow obstruction. Excessive loss of ventilatory function, beyond that expected from aging alone, results in the development of disease in cigarette smokers. Only a susceptible minority of cigarette smokers lose function at a rate that will eventually cause clinically significant impairment. For this group, timely smoking cessation can prevent the development of disease. 118 EMPHYSEMA JA-oduction Pulmonary emphysema is frequently present in the lungs of individuals with chronic obstructive lung disease. This section has three purposes: (1) to review the definition, types, and quantification of emphysema; (2) to summarize the physiological and radiographic feature of emphysema; and (3) to discuss critically the relationship of smoking to emphysema, based upon observations in people and in experimental animals. Current concepts of the pathogenesis of emphysema are reviewed elsewhere. Definition of Emphysema The generally accepted definition of emphysema is an anatomic condition of the lung characterized by abnormal dilation of air spaces distal to the terminal bronchioles accompanied by destruction of air space walls (American Thoracic Society 1962; Heard et al. 1979). Difficulties with this definition have been discussed by Thurlbeck (1983). Normal air space dimensions have not been determined, and criteria of destruction have not been defined. These limitations hamper attempts to investigate the earliest lesions of emphysema and the subtle effects of environmental agents on lung structure. Types of Emphysema British pathologists pointed out in the forties and fifties that emphysematous lesions in certain people involved the respiratory bronchioles, which appeared as grossly enlarged airspaces in the center of the primary lung lobules surrounded by normal lung. In other individuals, the alveolar ducts were involved early, and even mild involvement appeared grossly as a coarsening of the architec- ture of the entire lobule. They designated the two polar patterns of emphysema as centrilobular emphysema (CLE) and panlobular emphysema (PLE) (Heppleston and Leopold 1961). Many lungs either show both types of emphysema or are unclassifiable. Of 122 lungs with emphysema examined by one pulmonary pathologist, 73 were -considered mixed or unclassifiable and 49 were clearly CLE or PLE (Mitchell et al. 1970). When the agreement of three pathologists was required, only 27 of the original 122 lungs remained classifiable and 95 were mixed or could not be classified. There were no statistically significant differences between the groups classified as PLE or CLE in any clinical variables. The only nonsmokers in either group had CLE, and the proportion of light smokers (less than 25 pack-years) was very similar between groups. In this study and others (Anderson and Foraker 19731, CLE was most severe in the upper lobes and PLE was uniformly distributed. According to Thurlbeck (19761, a common 119 combination is CLE in the upper lobes and PLE in the lower lobes; where lobectomies are used for correlation, typing of emphysema is therefore a particularly empty exercise. When emphysema is far advanced, it is often impossible to recognize the site of the initial involvement. Thus, it is not clear whether the differences in prevalence of CLE and PLE are real or represent differences in interpretation by different observers. Several localized types of emphysema occur in areas around scar tissue (paracicatricial), along interlobar and interlobular septa (paraseptal), and as bullous lesions (which represent the most advanced and extreme distortion of normal lung structure). Bullous deformities occur with any type of emphysema, including CLE and PLE. Occasionally, bullous lesions occupy huge intrapulmonary volumes. Detection of Emphysema The detection of emphysema requires suitably prepared lung specimens. At a minimum, this means the lung must be fued in inflation (Thurlbeck 1964). Fume fixation or fixation by instillation of liquid fixative through the airways is satisfactory, but for optimal evaluation of the latter group, barium impregnation or paper- mounted whole-lung sections should be used. Because lungs with emphysema frequently also have some degree of intrinsic airways disease, the severity of emphysema and the clinical state of the patient may not correlate directly. Pathologists can easily recognize mild degrees of emphysema that are rarely associated with clinical disability. Quantification of Emphysema There are a number of techniques for quantifying the volume of lung involved with "obvious" emphysema that are adequately reproducible and correlate well with one another (Thurlbeck 1976; Bignon 1976). Semiquantitative or subjective scoring methods as well as point counting have been used. These approaches all require lungs inflated to a relevant volume, usually one approximating total lung capacity during life. This can be achieved by a distending pressure of 25 cm H& (Thurlbeck 1979; Berend et al. 1980). In the scoring method, the lung is divided into a number of units and the severity of emphysema in each unit is scored (mild, moderate, or severe receive 1,2, or 3 points, respectively). The scores for each unit are summed to give a total score for the lung (Ryder et al. 1969). Alternatively, lung slices may be matched by visual comparison to a set of graded standards to achieve an emphysema score (Thurlbeck et al. 1970). These methods include both severity and extent of emphysema, and although they involve subjective judgments, they have proved to be remarkably reproducible. 120 In the point counting approach, regularly spaced points are superimposed on a lung slice. Each point is recorded as falling on normal parenchyma, emphysematous parenchyma, or nonparenchy- ma (conducting airways or vessels). The volume proportion of emphysematous lung is recorded. This method can be objective (e.g., if an emphysematous space is taken to be one greater than 1 mm in diameter), but it includes only extent and not severity of emphyse- ma. Morphometric methods carried out on histologic sections, exempli- fied by the mean linear intercept (Lm) (Thurlbeck 1967a, b), are strictly objective, but they require careful attention to problems of sampling and are time consuming and insensitive to focal disease. For measurements of the Lm, histologic sections are made of blocks selected by stratified random sampling. The average distance between alveolar walls is determined from the number of intersec- tions of alveolar walls with a line of known length. The internal surface area of the lung can be calculated when the volume of the lung is known (Hasleton 1972). Pulmonary Function in Emphysema Because unequivocal proof of the presence of emphysema requires direct examination of lung tissue, the strategies used to characterize the pulmonary function abnormalities associated with emphysema have either involved comparison of functional data collected during life with autopsy or surgical material or have used measurements made exclusively on post-mortem specimens. Two important conclu- sions from these studies should be noted at the outset. First, impaired air flow during maximal expiratory maneuvers, as reflect- ed in reduced values for the FEV1, FEVIS, and FEF~~s, is neither sensitive nor specific for emphysema. It is possible to have severe emphysema without clinical obstructive lung disease (Thurlbeck 1977). It is also possible to have severe chronic obstructive lung disease without having emphysema, even though most patients with advanced chronic obstructive lung disease have some degree of emphysema (Mitchell et al. 1976). Second, none of the tests used to identify early obstructive lung disease, such as closing volume, the single breath NZ curve, or frequency dependence of compliance, distinguish diminished elastic recoil that may be related to emphyse- ma (see below) from increased resistance in small airways (Buist and Ducic 1979). Even the determination of density dependence of maximum expiratory airflow, once felt to be specific for detecting abnormalities in the caliber of small airways, is not immune to the effects of lung elastic recoil. A decreased effect on maximal expiratory air flow of using low density gas can be caused by decreased elastic recoil (Gelb and Zamel 1981). 121 Pulmonary function testing of individuals with proven emphyse- ma often shows increases of residual volume, functional residual capacity, and total lung capacity and decreases of maximal expirato- ry air flow (Boushy et al. 1971; Park et al. 1970; reviewed in Kidokoro et al. 1977). However, because individuals with emphysema commonly also have intrinsic airway disease (Casio et al. 1978) affecting the results of these pulmonary function tests in the same direction as emphysema, it is clear that these tests are not specific for emphysema. Accordingly, there has been interest in other, more distinctive tests. Among readily applicable tests, the diffusing capacity has proved to be directly related to the extent of emphyse- ma (Park et al. 1970; Boushy et al. 1971; Berend et al. 19791, presumably reflecting a diminution of internal surface area avail- able for gas exchange. The usefulness of the diffusing capacity to identify and estimate emphysema is limited, however, because the measurement is not sensitive to low grades of emphysema (Symonds et al. 1974) or specific for emphysema. Moreover, the results must be interpreted carefully in smokers because the values for diffusing capacity are lower than in nonsmokers, and the difference extends even to young smokers who are not likely to have emphysema (Enjeti et al. 1978; Miller et al. 1983). Mechanical Properties of the Lungs in Emphysema Measurements of the pressure-volume characteristics of the lung have generally been regarded as a reliable means of physiologically detecting and quantifying emphysema because (al patients with emphysema often have increased lung distensibility and correspond- ingly low transpulmonary pressures (loss of elastic recoil) and (b) the severity of emphysema has seemed to correlate with the change in elastic recoil. It has also been assumed that the regions of lung with emphysema are the cause of the decreased lung elastic recoil, an assumption that appears reasonable because elastic recoil results in part from surface forces at the air-liquid interface and there is less surface area in emphysema. Recent observations challenge these concepts. Berend and Thurl- beck (19821, using lungs obtained post mortem, could not demon- strate a relationship between indices of lung elasticity and the grade of emphysema in 48 lungs ranging in grade from 2 to 80 (on a scale of 100), and observed (Berend et al. 1981) in emphysematous lungs that the relative increase in compliance of the lower lobes was greater than the upper lobes, even though the emphysema was worse in the upper lobes. Others have also reported poor correlations between emphysema and elastic recoil. Silvers et al. (1980) found decreased elastic recoil and increased total lung capacity in excised human lungs with minimal emphysema, and Schuyler et al. (19781 noted in hamsters given small doses of elastase intravenously that there was 122 decreased lung elastic recoil at low lung volumes, although the lungs did not show morphometric changes. Guenter et al. (1981) noted that mild emphysema produced by pepsin caused greater changes in lung elasticity than similar degrees of lung destruction produced by endotoxin-induced repetitive leukocyte sequestration. They suggest- ed that these differences may be due to differences in the location of the connective tissue injury within the lung. Even among those who have reported an association between emphysema and elastic recoil, the correlations have been best when the emphysema was severe (Greaves and Colebatch 1980). Pare et al. (1982) found a correlation between emphysema grade and elastic properties of the lungs in 55 persons; however, in 5 whose surgically removed lung tissue received emphysema scores between 20 and 70 (out of a maximum of lOO), the elastic properties of the lungs tested preoperatively were indistinguishable from normal. While such discrepancies probably reflect the limitations of relating the overall elastic properties of both lungs to the morphology of a single lobe, it must also be recognized that the sensitivity of the pressure-volume diagram is limited, since a narrow range of pressure (to 20 cm HzO) depicts the average retractive force from millions of air spaces and the connective tissue network of the lung. From these recent findings it must be concluded that the relationship between elastic recoil and morphologic measures of emphysema is not highly predictable, and that the decrease of elastic recoil and increase of total lung capacity commonly seen in emphysematous lungs may not result entirely from abnormal mechanical properties in the areas showing emphysema. The mechanical abnormalities may also derive from areas that appear normal, although the possible reasons for this are obscure (reviewed by Thurlbeck 1983). An alternate explanation for this discordance between elastic recoil and morphologic emphysema may be the problems of sampling and grading intrinsic to these morphologic measures. The work of Michaels et al. (1979) introduces a further complexity to the use of pressur*volume curves as an indicator of emphysema. They found that inhalation of a bronchodilator shifted the curve of smokers in the direction of increased compliance, but had no effect in nonsmokers (Figure 26). Cessation of smoking had the same effect as a bronchodilator. These results were interpreted as indicating that smoking causes some peripheral airway units to constrict and become effectively closed. Thus, pressure-volume studies to detect early changes compatible with emphysema in smokers may give false negative results unless accompanied by studies with bronchodi- lators. 123 90 60 70 60 50 0 / I - .smoken p 6.0. [3--o Ncrwnckers M Nonsmokers p B.D I I I 1 4 6 12 16 P(stat)cmH& FIGURE 26.-The effect of nebulized bronchodilator on the pressure-volume characteristics of the lungs in 19 smokers (6 men and 13 women) and 16 nonsmokers (9 men and 7 women) NOTE: The mean age was approximately 40 years (range. 19 to 66) and smokers wed approximately 30 cigarettes per day. Male amoken, showed borderline significant differences in indicea of expiretory airflow and single breath Nz test data as mmpsred with the male nonsmokers. but there was no diRerace in these testa between female smokers and nonsmokers. As shown. smokers had significantly laes elastic recoil than nonsmokers. After the bronchcdiletor, the difference between smokers and nonsmokers increased further. particularly at high lung volume. B.D. = broncodilator; % pred. TLC = percent predicted total lung capacity: Rstat) = transpulmonary preeeure. *p SOURCE. Auerbach et al (1972) TABLE 16.-Means of the numerical values given lung sections at autopsy of female current smokers, standardized for age SubJects who never smoked regularly Current cigarette smoken Number of subjects Emphysema Fibrosis Thickening of arterioles Thickening of arteries 252 0.05 0.37 0.06 001 10 years stopped l Pack l Pack 66 51 131 0.70 1.08 1.69 1.74 2.44 3.30 0.93 1.25 1.59 0.16 0.36 0.61 NOTE: Numeneal values for each finding were determined by rating each lung section on scales of S4 for emphysema and thrckenmg of the arterioles, CL7 for librosis, and C-3 for thickenmg of the arteries. SOURCE Auerbach et al (1974) proteinase inhibitory activity and the demonstration of the frequent early development of emphysema in such subjects (Ore11 and Mazodier 1972) called attention to the critical step of fibrous tissue proteolysis in the remodeling of lung structure. It also pointed to at least one potential explanation for the variability in extent of emphysema among smokers. Together with data from animal experiments, the discovery of the PiZZ defect and its association with emphysema has led to general acceptance of a theory of imbalance between the extracellular levels of proteinase and proteinase inhibitor in the lung as the cause of panacinar emphysema in subjects with this deficiency. The patho- genetic lessons learned from a,-proteinase-inhibitor deficiency also afford plausible explanations for other forms of emphysema, espe- cially emphysema associated with cigarette smoking. Homozygous Deficien t-Pi22 In his classic description of the severe (PiZZ) deficiency of the aI- proteinase inhibitor, Eriksson (1965) did not indicate an effect of cigarette smoking on the development of emphysema. Later studies, however, did recognize smoking as a potential aggravating factor (Kueppers and Black 1974; Larsson 1978) and reported that PiZZ persons who smoked cigarettes were destined to experience shortness of breath 10 to 15 years earlier (Figure 27) and to die sooner than PiZZ persons who did not smoke (Figure 28). 130 I Men I Smokers Nonsmokers T women Smokers . 81. . . i 11. . . . . . . . . . T . . . . . Nonsmokers . . . . . . . i 0 o FIGURE 27.-Age at onset of dyspnea in 169 PiZZ individuals separated according to sex and smoking history NOTE The hormntal lines show the me&an values. The difference between nonsmokers and smokers was highly s~gnrficant for both sexes and was 13 and 15 years for men and women. respezt~vely SOURCE: Larsson /1978, More recent studies, however, have shown considerable variation in the rate of decline of lung function among middle-aged PiZZ adults (Buist et al. 19831. In a comparison of 22 persons with PiZZ phenotype who had never smoked with 36 PiZZ smokers, Black and Kueppers (1978) found variability in symptoms and lung function abnormalities in both groups. Smokers generally sought medical attention earlier, and those who reached the older age groups, such as 60 to 69, had smoked less and started to smoke later in life. There was overlap in these characteristics between the age groups, however, and some smokers did live into the 50 to 69 age range. In this analysis, the correlations between pulmonary function test abnormalities and pack-years of cigarette smoking were small. The British Thoracic Society, in a multicentered study of PiZZ individuals (Tobin et al. 19831, reported an association between 131 0 Nonsmokmg PiZ men and women A All Swedish women All Swedish men 20 30 40 60 60 70 60 90 100 Age (IIT yeam) FIGURE 28.-The cumulative probability of survival, given that 20 years of age is reached, in smoking and nonsmoking Swedish PiZZ individuals, compared with all Swedish men and women NUI'E Surv~al was tugher for PlZZ nonsmokers than for PiZZ smokers in both exe8 above age 35 SOURCE. Lamson (19781 cigarette smoking and the onset of pulmonary symptoms and deterioration of lung function, but demonstrated no significant correlation between the quantity of tobacco consumed and the extent of pulmonary dysfunction. A notable finding in this study, applicable to other studies of the natural history of disease related to a1- proteinase-inhibitor deficiency, was the impressive difference be- tween individuals found because of medical complaints (index cases) and those detected by surveys (nonindex cases). Nonindex cases had better pulmonary function and survived longer than index cases, irrespective of other variables such as age and smoking history. The distinction between these two categories of subjects suggests the importance of factors besides the PiZZ phenotype in the development of symptomatic lung disease in PiZZ persons. PiZZ individuals who smoke increase their risk for early onset of symptomatic chronic obstructive lung disease and for a shortened lifespan, compared with nonsmoking PiZZ individuals. However, pulmonary function data have shown only limited differences in diffusing capacity and elastic recoil between the smokers and the nonsmokers (Black and Kueppers 1978). 132 He terozygous De ficien t-Pi117 The PiMZ phenotype of a,-antiproteinase inhibitor occurs in approximately 3 percent of the population. Because of the high frequency of emphysema in PiZZ persons, it is important to establish whether PiMZ individuals also have an increased risk of emphysema and chronic obstructive lung disease. From the unpredictability of obstructive lung disease even among those with the PiZZ phenotype, however, one might expect difficulty in discerning the effect of the PiMZ phenotype. Among adults with symptomatic chronic obstructive lung disease, the PiMZ phenotype is more prevalent than expected (Mittman 1978). It is uncertain whether this means of subject identification is appropriate, as was noted concerning index and nonindex PiZZ individuals. Madison et al. (1981) emphasized the complexity of this issue by noting that the PiMZ phenotype was only one of several factors that appeared to be related to the risk of obstructive lung disease. Other factors identified as relevant included smoking, a family history of lung diseases, and being male. From studies of children and young adults it is evident that the PiMZ phenotype does not strongly predispose to chronic pulmonary disease. Thus, PiMZ children (Buist et al. 1980) failed to show any early changes of lung dysfunction analogous to what has been observed in some young PiZZ individuals; PiMZ adults below the age of 40 had the same results by spirometry and the single breath N2 test as PiMM individuals matched for smoking history (Buist et al. 1979b). Numerous studies involving older subjects indicate that PiMZ individuals preserve their lung function, as measured by spirometry, compared with controls matched for smoking (Tattersall et al. 1979, de Hamel and Carrel1 1981). The elastic properties of the lungs may be different in PiMZ persons, but if there are differences, they are small. Larsson et al. (1977) reported that 50-yearold PiMZ men who smoked had reduced elastic recoil at total lung capacity compared with PiMZ nonsmokers, even though they had no evidence of impaired air flow. The PiMZ nonsmokers were indistinguishable from PiMM nonsmokers. Tattersall et al. (1979) also found no effect upon airflow in PiMZ middle-aged men, and a statistically nonsignif- icant decrease in elastic recoil. Using an index of the slope of the pressur+volume curve, Knudson and Kaltenborn (1981) found no significant reduction in elastic recoil of PiMZ subjects compared with matched PiM controls. There is little direct information about the occurrence of emphyse- ma among PiMZ individuals. In an autopsy study, Eriksson et al. (1975) found emphysema among 13 of 26 subjects with diastase- resistant PASpositive inclusions in the liver, compared with an incidence of emphysema of only 18 percent in the controls. Although 133 these findings suggest an increased occurrence of emphysema with the PiMZ phenotype, this study should be interpreted cautiously because the smoking histories of the subjects and the quantification of the emphysema were not included. Moreover, the significance of the PAS-positive inclusions is not certain, because one recent study found that such inclusions represented immunoreactive al-protein- ase inhibitor in only half of the tissue studied (Qizilbash and Young- Pong 1983). It may be concluded from the studies involving a,-proteinase- inhibitor-deficient people that for those with the PiMZ phenotype, smoking has not been shown to promote a greater risk of emphysema than it does in PiMM persons. In the rare individual with PiZZ, the risk of emphysema is extremely high in both smokers and nonsmok- ers, but PiZZ smokers experience an earlier onset and more severe chronic obstructive lung disease than PiZZ nonsmokers. Observations in Experimental Animals Experimental animals have been subjected to cigarette smoke to examine whether changes typical of emphysema result. As noted below, it appears that cigarette smoke exposure can produce emphysematous-like changes in the lungs under experimental conditions, but the exposure must be quite prolonged and intense, or additional factors must be employed to "sensitize" the lungs to the effects of cigarette smoke. Pioneering studies in dogs exposed to cigarette smoke, by Hernan- dez et al. (1966) and by Auerbach et al. (19671, indicated effects consistent with emphysema, but these reports did not include quantitative morphology or data about the mechanical properties of the lungs. Moreoever, the exposures may have created problems of hypoxemia and infection that may have influenced the responses to cigarette smoke. Contrary to these findings, in later studies, beagles that inhaled cigarettes by face mask in four sessions per day for up to 1 year-an inhalation sufficient to raise the blood carboxyhemoglo- bin saturation to 5.4 + 0.9 percent-had no statistically significant changes in mean linear intercept or internal surface area, although their large airways showed epithelial cell hyperplasia, proliferation of goblet cells, and peribronchial inflammation (Park et al. 1977). Recently, Hoidal and Niewoehner (1983) presented data suggesting that cigarette smoke may be an important cofactor in the develop ment of elastase-induced emphysema. They found that inhalation of cigarette smoke led to severe emphysema in hamsters if used in conjunction with doses of elastase that did not produce emphysema when used alone. In this study, hamsters were exposed to cigarette smoke for 15 minute periods, six times per day, 6 days per week for 7 weeks in standardized chambers. The animals were challenged with small doses of elastase given intratracheally; controls consisted of 134 animals given either elastase or smoke exposure or neither. Animals receiving only smoke or only elastase showed no changes of mean linear intercept or volume-pressure relationship of the excised lungs, compared with animals given neither elastase nor smoke exposure. The combinations of smoking followed by elastase or smoking both before and after elastase produced statistically signifi- cant increases of mean linear intercept, displacement upward and to the left of the volume-pressure curves (Figure 29), and marked emphysema by light microscopy of inflation-fixed lungs. The mecha- nism of the synergism between elastase and smoking was not elucidated. One possibility considered was that cigarette smoke impaired the repair mechanism normally triggered by elastase exposure, a possibility supported by Osman et al. (19821, who found that hamsters exposed to cigarette smoke after intratracheal elas- tase did not show the heightened lung elastin synthesis typically seen after lung injury produced by elastase. summary Clinically significant degrees of emphysematous lung destruction are commonly present in individuals with COLD. Severe emphysema occurs almost exclusively in cigarette smokers and those with homozygous a,-antitrypsin deficiency. The extent of emphysematous change increases with increasing numbers of cigarettes smoked per day and with the duration of the smoking habit. While clinically significant emphysema is limited to a minority of those who smoke, most heavy smokers have some degree of emphysematous change by the sixth decade of life. Individuals with homozygous a,-antitrypsin deficiency have an exceptionally high risk of developing emphysema. This risk is present for both smokers and nonsmokers, but smokers with a,- antiprotease deficiency develop clinical symptoms earlier in life. It is unclear whether individuals with heterozygous antiprotease pheno- types are at increased risk of developing COLD. Summary and Conclusions 1. Cigarette smoking is the major cause of COLD morbidity in the United States; 80 to 90 percent of COLD in the United States is attributable to cigarette smoking. 2. In population-based studies in the United States, cigarette smoking behavior is often the only significant predictor for the development of COLD. Other factors improve the predictive equation only slightly, even in those populations where they have been found to exert a statistically significant effect. 3. In spite of over 30 years of intensive investigation, only cigarette smoking and a,-antiprotease deficiency (a rare genet- 135 o NO smoke, no elastase ? ~ontmuous smoke, no elastase * No smoke, elastase 0 Posf-elastase smoke A Pre-elastase smoke A ~ontmuous smoke. elastase p. ,05 compared wlh * No smoke. no elastase I I I I I I 5 10 15 20 25 30 Pressure (cmHtO) FIGURE 29.-The effects of combining cigarette smoking and elastase upon the pressure-volume characteristics of the lungs of experimental animals N(rTE. The m vttro measurements of lung volume are shown as percentage of predicted total lung capacity cTLCr relative to transpulmonary pressure of hamster lungs following m vwo exposure to venous combmatlons of agarette smoke and mtratracheally admlnlstered pancreatic elastase Values are the mean t SEM of messurement~ made dunng deflation Tbe animals that smoked and then recewed elastase tPre-Elastase Smoke) and those that smoked both kfore and after elastase lContmous Smoke. E1asta.wI had slgmficant changes m the elastx properties of the lungs There were no changes from control if elastase or smoking were used separately or when smoking occurred onI?. after elastase SOURCE Holdal and N,ewcehner / 19831 ic defect) are established causes of clinically significant COLD in the absence of other agents. 4. Within a few years after beginning to smoke, smokers experi- ence a higher prevalence of abnormal function in the small airways than nonsmokers. The prevalence of abnormal small airways function increases with age and the duration of the 136 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 than for light smokers. After the cessation of smoking, the rate of decline of lung function with increasing age appears to slow to approximately that seen in nonsmokers of the same age. Only a minority of smokers will develop clinically significant COLD, and this group will have demonstrated a more extensive decline in lung function than the average smoker. The data are not yet available to determine whether a rapid decline in lung function early in life defines the subgroup of smokers who are susceptible to developing COLD. 10. Clinically significant degrees of emphysema occur almost exclusively in cigarette smokers or individuals with genetic homozygous al-antiprotease deficiency. The severity of em- physema among smokers increases with the number of ciga- rettes smoked per day and the duration of the smoking habit. 137 Appendix Tables Ar.YYY a. --I'u v 1 IN wn~te adults, by smoking status, sex, and age, United States, 1971-1975 Both eexea Men Women Cigarette smoking etatua by age) N n Mean SD SE N " Mean SD SE N n Mean SD SE Never smokers L&74 3140' 21' 3669' 39' 2664' 191 25-34 6733 394 3607 791 51 2633 130 44.04 xi4 63 4099 264 3095 312 26 3.544 5278 291 3171 607 49 1669 61 3742 591 73 3609 210 2907 397 40 4.544 4642 353284a 594 35 1206 85 3487 626 72 3736 268 2631 401 29 55-64 3660 251 2511 589 31 &lo 59 3215 531 61 2781 192 2289 401 29 65-74 2875 235 2148 549 36 461 43 2856 627 96 2394 192 2oG6 402 36 Exsmokers 25-14 3112 24 3623 37 2651 28 25-34 2811 160 3677 810 60 1359 66 4303 627 92 1452 94 3091 441 55 35-44 3oF% 171 3566 767 69 1828 94 4013 643 70 1256 77 2916 361 44 45-54 3323 213 3155 742 65 2345 143 3414 663 69 978 70 2535 454 65 55-64 2669 181 2845 693 63 1826 130 3067 649 63 843 51 2319 456 90 6&7.! 1769 157 2366 6% 66 1270 121 2533 699 78 491) 36 2020 487 92 Smokers 25-74 2378 20 3281 32 2514 n ,I 2fAu 6665 487 3567 752 44 4792 239 4037 639 51 4093 248 3018 433 41 34-Mb 5849 320 3166 655 47 3027 156 3507 639 71 '2822 162 2800 439 43 4554 5606 374 2761 623 37 n43 182 3126 579 49 2863 192 2411 437 40 55-64 3251 192 2416 631 50 1700 106 2736 632 63 1551 84 2w4 m 50 65-74 933 84 2071 653 66 534 56 2222 556 79 400 28 1669 714 155 g TABLE A.--Continued Both eexea Men Women Qarette smoking ___ status (by age) N n Mean SD SE N n Mean SD SE N " Mean SD SE Light smokers 2s74 2534 3&44 454 55-64 65-74 Moderate smoker8 25-74 25-34 35-44 4.544 55-64 65-74 Heavy smokers 25-74 ?A-34 35-44 45-54 5544 &74 2951 38 3311 3425 650 97 879 43 3914 3106 618 93 308 17 37751 2683 490 73 383 24 3009 24@3 573 83 313 18 2919' 2150 737 165 131 11 222P 508 515 404 660 426 57 102 139 95 150 130 1283 70 a59 55 707 52 730 39 172 10 2626 52 3m WY 88 2891 479 83 2507 437 76 2190 350 62 2095' 901 3% 25 51 47 51 70 124 38 80 64 92 121 150 2162 113 1267 72 1090 76 1043 57 304 21 2678 23 3335 3671 810 60 2534 123 4136 3217 646 68 1214 66 3593 2679 634 53 1145 75 3106 2406 589 63 690 45 2776 2023 609 105 261 28 22.79 40 69 99 79 60 126 2466 2991 393 2836 395 2368 429 1977 408 1693' 4.84 684 624 622 455 572 1735 112 1199 64 1570 104 597 37 203 16 4269 235 2413 130 2715 179 1287 82 464 44 2785 32 3202 3514 699 70 1363 72 3927 3143 684 71 1505 75 3382 2930 649 70 1193 62 3164 2440 741 118 697 45 2619 2038' 606 151 130 16 2096' 52 82 89 75 133 172 2409 2979 393 2562 373 2411 440 lF&' 396 17&Y* 215 2417 136 2148 116 1779 118 922 53 154 18 597 646 579 737 638 1051 64 643 41 586 36 224 8 24 2 NOTE: N = weighted population estimate in thousands; n = number of people in sample; SD = standard deviatmn. SE = standard error. I Adjusted by the direct method to reflect the age distribution of the U.S. populatmn at the midpoint of the survey. ' Doe8 not meet ntanti of reliability. SOURtX National Center for Health Statiirca. Unpublished data fmm the first National Health Nutrition and Examination Survey (NHANFS 1). TABLE B.-Flow at 25 percent of FVC for white adults, by smoking status, sex, and age, United states, 1971-1975 Both sex.88 Men Women Cigarette smoking - statue by age) N n Mean SD SE N n Mean SD SE N " Mean SD SE Never smokers 25-74 2544 35-44 4554 5.544 65-74 Exsmokers w74 2534 3b4.4 4.544 5544 6s74 Smokers 25-74 2534 35-44 4554 55-64 65-74 6733 394 5278 291 4942 353 3660 251 2675 235 2811 160 3086 171 3323 213 2669 181 1769 157 487 320 374 192 84 6253' 6639 6377 5742 5368 46% 6093 6835 7020 6270 5763 4918 5647 6760 6157 5471 5123 3954 1591 1464 1566 1397 1576 1855 `2041 1896 1764 1946 1694 1740 1658 1815 1566 47' 7261' 98 2633 130 7871 114 1669 81 7715 90 1206 85 7262 101 880 59 6543 102 481 43 6097 62 7095 203 1359 66 6042 176 1828 94 7956 164 2345 143 6765 144 1826 130 6261 WI 1270 121 5194 47 6362 102 4792 239 7606 123 3027 158 6848 92 2743 182 6130 132 1700 108 5567 181 534 56 4199 1513 1545 1796 1593 1951 1715 !2059 1919 1820 2091 1663 1675 1763 2061 1745 91' 5343' 36' 157 4099 264 5847 1042 89 176 3609 210 5758 952 80 213 3736 268 5252 1141 70 265 2781 192 4996 1091 83 298 2394 192 4331 1303 108 107 5188 67 285 1452 94 5705 1126 165 232 1258 77 5659 965 116 185 978 70 5Q34 1176 151 160 I343 51 4749 1058 197 265 499 36 4213 1278 197 88 5002 52 126 4093 248 5769 1061 83 160 2822 162 5415 1200 102 137 2863 192 4840 1233 106 223 1551 84 4636 1372 169 238 400 28 3627 1274 255 c 4 TABLE B.--Continued L.. Both sexm Men Women Cigarette smokmg - data8 (by age) N n Mean SD SE N " Mean SD SE N n Mean SD SE Light smokers 2574 2.534 3544 45-54 !i5-64 65-74 Moderate smokers a-74 25-34 3.5-M 45-54 55-64 G-74 Heavy smokers 2.5-74 75-34 3!i44 4544 5.544 6574 2162 113 1267 72 1090 76 1043 57 304 21 4269 2413 2715 1287 464 2417 2146 1779 922 154 23.5 130 179 82 44 136 116 118 53 18 5834 6549 KM 5545 5222 3779 5661 6909 6384 5269 5065 3950 5485 6691 5964 5712 5090 415!'2 1652 1461 1476 1534 1272 1719 1786 1490 1787 1717 1659 1815 1940 2117 1653 91 6569 209 879 43 1688 211 308 17 7250' 217 383 24 6373 238 313 18 6096' 345 131 11 37421 66 6430 136 2534 123 7647 194 1214 66 7348 111 1145 75 5821 202 690 45 5576 304 261 28 4356 85 6219 l&i 1363 72 7468 198 1506 75 6363 207 1193 82 6326 321 697 45 5322 401 130 16 4180' 1690 1634 1572 1616 1279 1667 1736 1661 1897 1692 1640 1902 1920 2288 1758 142 5171 293 1283 70 5769 369 959 55 5653 311 707 52 5096 399 730 39 4849 462 172 10 3807' 118 164 1735 112 236 1199 64 183 1570 104 334 597 37 404 203 16 151 225 1054 64 261 643 41 251 586 36 434 224 8 463 24 2 4967 5831 5408 4867 4475 3427' 4822 5685 5031 4458 437P2 4023 2 1071 1193 1203 1333 1266 1120 1212 1202 1439 1285 1018 1084 1257 1202 904 112 140 188 193 249 489 76 132 170 137 265 319 111 176 18f 26f 3.x 62! NOTE: N = Weighted population estimate. in thousanda; n = number of people in sample; SD = standard deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ' Doea not meet Btandards of reliability ~UWE National Center for Health Statistics. Unpublished data from the first Natmnal Health Nutrition and Examination Survey (NHANES 1). TABLE C.-Flow at 50 percent of J?VC for white adults, by smoking status, sex, and age, United states, 1971-1975 Both eexee Men Women Cigarette smoking status (by age) N " Mean SD SE N " Mean SD SE N " Mean SD SE Never smokers 25-74 25-34 3544 4544 55-64 65-74 3743 ' 38' 40831 6733 394 4361 1194 69 2633 130 4998 5278 291 3904 1164 84 1669 81 4315 4942 353 3366 1212 84 1206 85 3972 3660 251 3090 1087 74 880 59 3736 2875 235 2535 1045 73 461 43 3157 86' 128 152 150 l&l 174 3342' 3964 3713 3170 2886 2410 34' 78 91 90 72 84 1255 1221 1287 1220 1060 4099 264 3609 210 3736 x33 2781 192 2.394 192 963 989 1119 955 996 Ex-smokers 25-74 25-34 35-44 45-54 s-64 65-74 Smokers 25-74 25-34 3!i-44 45-54 55-64 65-74 3579 59 4188 67 3123 81 2811 160 4329 1292 120 1359 66 5029 1243 3086 171 4249 1364 129 18'28 94 4702 1410 332.3 213 3474 1404 114 2345 143 3749 1426 2669 181 3110 1411 118 1826 130 3294 1362 1769 157 2524 1296 121 1270 121 2578 1364 195 1452 94 3674 949 114 180 1258 77 3590 1037 160 143 978 70 2816 1091 147 127 843 51 nil 1432 293 153 499 36 2384 1092 167 3475 4546 3764 3257 2193 1889 59 103 140 92 146 175 z 3325 2604 2361 1965 54 90 98 94 144 252 3169 39 4126 1268 74 3552 1296 87 2924 1208 76 2567 1248 107 1922 1220 159 s&35 487 5849 320 5606 374 3251 192 933 84 4792 239 3027 158 2743 182 1700 108 534 56 1296 1399 1278 1364 1174 4093 248 2822 162 2863 192 1551 84 400 28 1037 1137 1040 1062 1279 ;: TABLE C.-Continued Both eexen Men Women Cigarette smoking -___- status by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 2534 35-44 4544 5s64 t&74 Mcderate smokera &I4 25-34 35-44 45-a !s-& 65-74 Heavy smokers 25-74 25-34 3544 45-54 55-64 66-74 102 2162 113 1230 1248 994 162 1267 72 1076 943 1054 166 1090 76 864 969 771 103 1043 57 1375 1643 1080 200 304 21 1252 883 1415 425 3313 3964 3630 2911 2756 2056 74 169 879 43 151 308 17 107 383 24 205 313 18 292 131 11 3676 4617 4190' 3150 3542' 1706' 110 222 1263 70 226 959 55 197 707 52 395 730 39 366 172 10 2984 3516 3450 2781 2420 2321' 57 71 4269 235 1239 96 2534 123 1297 872 47 2413 130 1182 124 1214 66 1198 llcfl 142 2715 179 1205 111 1145 75 1243 1125 140 1287 82 1186 167 690 45 1191 1134 245 464 44 1239 218 261 28 1316 1047 266 3207 4246 3781 n75 2665 1881 3561 4640 4039 3079 2873 2131 79 126 1735 112 171 1199 64 124 1570 104 207 597 37 n9 203 16 2888 3671 3520 2553 2425 1558' 68 110 2417 136 1333 153 1363 72 1306 1295 247 2148 116 1469 166 1505 75 1103 185 1779 118 1355 147 1193 82 1377 1062 222 922 53 1123 173 697 45 1222 651 232 154 18 1113 285 130 16 1059 703 490 3043 4067 3239 3152 2284 1760' 3287 4326 3456 3458 2379 1559' 92 197 1054 64 m 64.3 41 168 5% 36 221 224 8 274 24 2 2828 3733 n3i 2526 1997' 28.34' NOTE N = weight& population eetunata. in thousanda; n = number of people io sample; SD = ntandard deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population st the midpoint of the .wrvey. * Doea not meet standards of reliiiity. SOURCF.. National Center for Health Statistics. Unpublished data from the funt National Health Nutrition and Examination Survey (NHANFS 1). TABLE D.-Flow at 75 percent of FVC for white adults, by smoking status, sex, and age, United states, 1971-197s Both eexe8 Men Women Cigarette smokii &ha (by age) N II Mean SD SE N n Mean SD SE N n MWII SD SE Never smokers 25-74 1230' 28' 1329' 42' 1073 ' 24' 25-34 6733 394 1776 714 52 Xi33 130 2065 649 72 4099 264 1690 691 62 36-44 5278 291 1277 621 49 1669 81 1478 8.43 129 3609 210 1184 456 32 `a-54 4942 353 1044 636 44 1206 85 1184 664 14 3736 268 999 620 53 55-64 3660 251 737 611 36 880 59 978 612 83 2781 192 661 449 34 65-74 2675 235 609 463 32 481 43 795 4x3 64 2394 192 572 465 38 Exsmokers 25-74 1152 29 1403 41 992 37 25-34 2811 160 1696 678 61 1359 66 1925 664 109 1452 94 1480 616 72 354 3086 171 1460 664 62 1828 94 1623 693 92 1258 77 1224 538 59 45-54 3323 213 10% 625 48 2346 143 1148 666 59 978 70 734 376 53 5544 2669 181 734 541 54 1826 130 178 446 41 843 51 638 694 156 65-74 1769 157 588 506 43 1270 121 592 516 47 499 36 578 481 87 Smokers 2574 967 22 1053 29 889 34 25-34 8885 487 1530 688 41 4792 239 1665 665 60 4093 248 1373 692 65 3M.4 5849 320 1062 552 34 3027 158 1134 599 57 2822 162 985 4% 35 45-54 5606 374 778 511 31 2743 182 866 530 41 2x63 192 693 478 43 c5.564 3251 192 631 536 42 1700 108 713 580 63 1551 84 541 468 56 6.5-14 933 84 452 689 loo 534 56 350 445 17 400 28 558 901 199 r ts TABLE D.-Continued Both @exe8 Men Women Cigarette smoking - statue (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 25-34 35-44 45-54 55-64 65-74 Moderate smokers 25-74 25-34 35-44 4x4 55-64 65-74 Heavy smokers 25-74 25-34 35-44 45-54 55-6-t 65-74 2162 113 1261 72 1090 76 1043 57 304 21 4269 235 2413 130 2715 179 1281 82 464 44 2417 136 2146 116 1719 118 922 53 154 18 1049 1460 1122 837 706 660 970 1603 1134 711 643 373 882 1447 940 836 529 297' 679 534 4.31 540 1040 685 499 480 598 366 689 595 589 410 453 44 94 879 43 63 309 17 57 383 24 85 313 18 264 131 11 28 57 2534 123 52 1214 66 49 1145 15 12 690 45 68 261 ?a 47 956 95 1363 72 1503 63 1505 15 995 57 1193 82 941 57 697 45 545 112 130 16 258' 1120 1641 1294' 840 931' 393' 1107 1755 1265 801 784 381 587 686 517 416 637 375 593 647 416 64 985 113 1283 IO 1366 101 959 55 1067 131 707 52 836 182 730 39 609 231 172 10 864' 41 846 82 1735 112 1362 78 1199 64 lOCKI 41 1570 104 656 119 597 37 481 85 203 16 363' 38 815 101 1054 64 1374 85 643 41 811 73 586 36 620 62 224 8 479' 98 24 2 505' 703 531 388 450 1244 620 443 514 503 353 790 422 438 388 603 67 127 73 42 88 414 32 76 58 67 69 103 82 172 69 79 160 420 NOTJC N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. `Does not meet standards of reliability. SoUfKT National Center for Health Statisticsa. Unpublished data from the first National Health Nutrition and Examination Survey (NHANFS 1). TABLE E.-FEVI/FVC ratio for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking etatua Car age) N " Mean SD SE N n Mean SD SE N n Mean SD SE Never smokers 25-74 25-34 3.544 45-54 55-64 65-74 Ersmokem 25-74 25-34 35-u 45-54 55-64 65-14 Smokers 25-74 25-34 35-M 45-54 55-64 674 79.1' 0.21' 82.5 6.06 0.34 60.3 5.67 0.37 78.7 5.84 0.38 11.6 5.03 0.35 76.5 6.41 0.52 11.9 ' 0.34 ' 80.1 5.91 0.69 18.8 5.25 0.64 71.5 5.95 0.17 15.8 5.13 0.81 13.5 7.59 1.14 80.2 ' 0.23 ' 83.6 5.93 0.44 80.9 5.73 0.45 79.0 5.75 0.41 78.2 4.85 0.39 71.0 5.97 0.55 18.1 0.41 82.4 5.81 0.18 80.4 5.26 0.69 77.0 5.04 0.69 76.0 6.60 1.36 15.3 6.58 1.05 17 5 0.39 81.1 6.85 0.61 78.2 6 16 0.41 15.4 6.32 0.52 16.0 6.61 0.15 73.6 8.67 2.09 6733 394 5278 291 4942 353 3660 251 2875 235 24233 130 1669 81 1206 85 880 59 481 43 4039 264 3609 210 3736 268 2781 192 2394 152 77.1 0.30 81.7 5.92 0.53 79.5 6.26 0.56 76.2 6.58 0.50 73.7 7.79 0.70 11.5 9.34 1.05 76.6 0.44 80.9 5.94 0.94 78.8 6.78 0.83 75.9 1.10 0.66 12.1 8.07 0.19 10.0 9.83 120 2811 160 3086 171 3323 213 2669 181 1169 157 1359 66 1828 94 2345 143 1826 130 1270 121 1452 94 1258 77 918 10 843 51 499 36 75.9 0.26 80.3 6.78 0.38 76.7 7.28 0.46 74.2 7.05 0.41 73.1 8.13 0.59 69.8 9.40 1.44 14.0 036 19.2 6.50 0.52 75.3 1.92 071 13.0 1.55 059 10.6 9.59 1.03 67.0 8.94 1.54 8885 5849 5606 3251 933 487 320 374 192 84 4792 3027 2743 1700 534 239 4093 248 2822 162 2863 192 1551 84 400 28 156 182 108 56 z TABLE E.-Continued al Both wxea Men Women Cigarette smoking statue (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 25-34 36-44 45-S 55-64 65-74 Moderate smoker8 25-74 25-34 3544 45.54 55-64 65-74 Heavy smokers 25-74 2x34 3544 45-54 5564 65-74 2162 1267 1090 1043 304 424% 2413 2715 1287 464 2417 2148 1779 922 154 77.3 0.47 113 80.9 7.43 0.84 72 78.4 6.18 0.79 76 76.5 4.94 0.66 57 76.9 7.06 0.97 21 71.4 10.59 2.65 75.8 0.36 235 80.4 6.36 0.53 130 77.9 6.18 0.65 179 73.6 7.48 0.69 82 73.2 7.46 0.81 44 69.3 8.30 1.46 75.1 0.58 136 79.1 6.65 0.73 116 14.2 8.24 0.92 118 73.7 7.21 0.74 53 68.9 10.08 1.42 18 68.0' 9.18 2.66 879 308 383 313 131 2534 1214 1145 690 %I 15.7 43 80.3 11 17.1' 24 75.1 18 74.8' 11 64.6' 74.6 123 19.3 66 77.3 75 71.3 45 72.1 28 68.4 72.8 72 78.0 75 73.3 82 74.0 45 67.1 16 66.9' 7.10 6.14 6.05 9.cQ IO.84 6.29 6.61 7.87 8.00 7.63 6.33 8.68 7.34 10.09 8.75 0.76 1.11 1.54 1.58 2.25 4.17 0.48 0.70 0.85 0.96 1.38 1.56 0.57 0.89 1.21 0.86 1.81 2.42 1283 959 107 730 172 1735 1199 1054 643 586 224 24 78.7 0.60 70 81.4 7.62 1.30 55 78.8 6.13 1.30 52 77.3 4.01 0.54 39 77.8 5.81 0.87 IO 76.5' 6.90 2.64 76.9 0.47 112 81.9 6.16 0.13 64 18.6 5.64 0.71 104 75.3 6.67 0.80 37 14.3 6.58 1.07 16 70.4' 893 2.42 77.2 1.06 64 81.9 6.90 1.16 41 76.2 6.64 1.15 36 73.2 6.91 1.30 8 74.6' 7.63 2.40 2 79.4' 6.66 4.63 NtX'Ez N = weighted population estimate. in thousands; n = number of people in sample; SD = standard deviation; SE = standard error. `Adjusted by the direa method to reflect the age distribution of the U.S. population at the midpoit of the survey. ' Lhm not meet .stan&rds of reli.tbility. SOURCE Natuxsd Center for Health St&tics. Unpublished data from the fii Natiaxal Health Nutrition and Examination Survey WGNES 1). TABLE F.-MMEF for white adults, by smoking status, sex, and age, United States, 1971-1975 Both wxw Men Women cigarette 8mokiLtg atah (by age) N " Mean SD SE N " Mean SD SE N n Mean SD SE Never emokera 2s74 25-34 35-44 4564 5M4 65-74 Exsmokers 25-74 2.5-34 35-44 4554 5544 65-14 Smokem 25-74 25-34 35-M 4.554 55-64 65-14 3020' 3748 3140 2724 2301 1891 29' 64 58 50 43 51 3392' 4357 3501 3198 2734 2314 52' 106 106 113 104 130 2664' 3357 2973 2512 2164 1806 26' 58 58 48 51 56 51 103 104 102 180 115 41 77 63 66 18 220 1023 821 837 6733 394 5278 291 4942 353 3660 251 2815 236 2633 130 1669 81 1206 85 880 59 481 43 lCJJ3 911 1021 163 827 4199 3609 3736 n81 234 264 210 268 192 192 820 in 703 663 611 730 619 2910 3753 3500 2800 2318 1826 41 102 106 91 75 82 3324 4321 3882 3021 2463 1865 66 162 157 114 81 99 2537 3222 2944 2270 2005 1128 1066 1165 1111 948 873 2811 160 3086 171 3323 213 2669 181 1769 157 1359 66 1828 94 2345 143 18% 130 u-70 121 1014 1237 1171 953 922 1452 54 1258 77 978 70 843 51 499 36 809 165 714 857 123 2553 3512 2850 2283 1955 1474 31 66 65 54 67 118 2786 3857 3033 2511 49 93 107 18 106 104 2343 3109 2654 2065 1813 l&i5 4792 3027 2743 4093 248 2822 162 2863 192 1551 84 403 28 872 8lm 109 654 995 8835 5849 5636 3251 933 437 320 374 192 84 1069 970 8-96 854 831 239 158 182 109 56 1101 1073 1007 1700 534 985 677 TABLE F.--Continued Both eerxa Men Women cigarette smoking 8tatf.M (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 25-34 35-44 45-54 55-64 65-74 Moderate smokers 2b-74 25-34 3544 45-64 5E-64 65-14 Heavy smokers 25-14 25-34 35-44 4544 55-64 65-74 2162 113 1267 72 1090 76 1043 57 304 21 424% 235 2413 130 2715 179 1287 82 464 44 2417 136 2146 116 1779 118 922 53 154 18 2736 3457 2936 2334 2252 1667 2542 3605 2993 2169 1894 1395 2404 3389 26243 2421 1706 1313' 1034 839 641 894 102-3 1106 907 82.3 811 738 1018 1663 1087 764 591 57 2985 144 819 43 3923 110 308 17 3`uma 84 383 24 2521 124 313 18 2694' 257 131 11 1339' 41 2848 93 2534 123 3S60 99 1214 66 3257 14 1145 75 2245 103 690 45 2144 12.6 261 28 1535 53 2620 120 1363 72 3614 119 1505 75 n77 125 1193 82 2663 166 697 45 1754 151 130 16 12471 1044 760 806 1239 563 1132 968 891 848 746 1045 1144 1145 828 601 93 2510 196 1283 70 3137 184 959 55 2787 173 707 52 2232 321 730 39 2063 238 172 10 1917' 64 2266 123 1735 112 3087 145 1199 64 2725 92 1570 104 2041 162 597 87 1604 159 203 16 1214* 72 2210 167 1054 64 3122 157 643 41 2280 150 536 36 1926 136 224 8 1557' 160 24 2 1665' 807 808 502 605 1206 828 752 744 655 687 911 135 766 439 369 17 153 124 68 87 404 40 98 92 95 106 157 87 187 123 185 169 NOTI? N = weighted population estimate. in thouann&; n = number of people in sample; SD = standard deviation: SE = standard ermr. ' Adjuted by the direct method to reflect theage distribution of the U.S. population at the midpoint of thesurvey. *Does not meet standa& of reliability. SOURCE: Natmnal Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANlB 1). TABLE G.-MEFR for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexen Men Women Cigarett.e smoking statue by age) N n Mean SD SE N " Mean SD SE N n Mean SD SE Never smokers 25-74 2544 36-44 45-54 lk5-64 65-74 Extlmokers s-14 2544 35-44 45-54 5!%4 65-74 Smokers %I4 25-34 35-44 45-54 66-64 65-74 6545' 7103 6144 5887 5260 4317 62' 123 144 110 98 112 7894' 8833 8519 7805 6722 6526 7809 9164 8789 7451 6532 5425 114' 167 223 268 226 269 5321' 5991 5923 5268 4824 3832 41' 94 103 86 98 118 83 167 131 191 245 220 55 101 94 113 171 263 5733 394 5278 291 4942 353 3660 251 2855 234 1895 1774 1625 1559 1776 2633 130 1669 81 1206 85 880 59 412 42 1551 1710 2106 1527 1863 4099 264 3609 210 3736 268 2781 192 2394 192 1081 1058 11% 1264 1394 5229 6453 7521 7664 6713 5644 4986 5914 7393 6712 5762 to30 3753 12 232 212 202 194 221 120 295 239 213 220 280 96 133 211 137 211 260 2311 160 171 213 181 157 2246 2241 2056 2002 2187 1359 66 1826 94 2345 143 1826 130 1270 121 1911 2006 1901 1997 2267 1452 94 5964 1153 1258 71 5759 1017 978 70 5146 1396 843 51 4671 1297 499 36 3867 1463 3086 3323 2669 1769 52 122 152 104 147 216 7041 8629 7780 5758 6834 4341 4691 5847 5566 4607 4149 2969 8885 5849 5606 3251 933 487 320 374 192 84 2019 1974 1864 1962 1662 4192 239 30!27 158 2743 182 1700 108 534 56 1728 1922 1819 2022 1961 4093 24.8 2.822 162 2863 192 1551 84 400 28 1216 1256 1332 1421 1373 z TABLE G.-Continued I- Both aexea MelI Women Cigarette smoking 8k3tu8 (by age) N " Mean SD SE N n Mm SD SE N n Mean SD SE Light smokers 25-74 2534 3544 45-54 5s64 65-74 Moderate smokers 25-74 25-34 35-44 4.5-54 55-64 65-74 Heavy smokers 25-14 2534 35-44 45.54 55-64 65-74 2162 113 1267 12 1090 76 1043 57 304 21 4269 235 2413 130 2715 179 1267 82 464 44 2417 136 2146 116 1119 118 922 53 154 18 6068 104 7085 7006 1792 233 879 43 8347 6450 1784 275 308 17 8275' %56 1632 232 383 24 6718 4979 1611 240 313 18 6142' 3535 1296 350 131 11 4054' 5921 76 7165 7616 2146 154 2534 123 8755 6819 1992 230 1214 66 8112 5513 1755 137 1145 75 6633 5100 1996 243 690 45 6122 3701 m4 373 261 28 4495 5755 98 6902 7356 1925 204 1363 12 8573 6751 x63 223 1505 75 7412 6167 2034 214 1193 82 6945 4989 2221 366 697 45 5410 41368 2060 496 130 16 4249' 1559 1918 1445 1903 1318 1864 1734 1799 1687 2122 1544 1996 1909 2187 177 5150 2.46 1283 70 6088 530 959 55 5864 269 767 52 xl80 478 730 39 4462 451 172 10 3228' 120 4798 176 1735 112 5952 264 1199 64 5511 181 1570 104 4769 261 591 37 3917 466 203 16 2681' 155 4120 192 1054 64 5781 289 643 41 5205 239 586 36 4561 433 224 8 3679 2 571 24 2 3535' 1294 1270 1425 1154 1157 1263 1241 1286 1640 1512 1010 1164 1280 1327 964 114 193 192 249 m8 388 376 671 N(JITI: N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviatmn; SE = @amlard ermr ' Adjusted by the direct method to reflect the age distribution of the U.S. population et the midpoint of the survey. ' Ihe not meet standard9 of reliability. SOURCE: Natmnal Center for Health Statistic-a Unpublished data from the first Natuxml Health Nutrition and Exammatlon Survey (NHANIB 1) TABLE H.-Forced vital capacity for white adults, by smoking status, sex, and age, United States, 1971-1975 Both aexea Men Women Cigarette smoking ~- Stahl8 (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Never smokers %I4 25-34 35-44 4544 55-54 65-74 Fzsmokere 25-14 25-34 3!%44 45-54 55-64 66-74 Smokers 2s74 25-34 35-44 45-54 55-64 65-74 3978' 4403 3972 3624 3252 2615 29' 67 65 45 47 46 52' 759 89 159 98 795 92 758 123 774 127 24' 32 54 39 38 43 32 68 49 79 79 99 35 50 55 4.5 59 185 130 5480 81 4761 85 4506 59 4265 43 3867 3712 3607 3340 6733 5278 4942 394 291 353 251 235 1052 814 182 820 719 4099 3609 3736 2780 2394 264 210 268 192 192 464 so 522 526 462 30 101 91 78 94 86 4703 5335 5096 4499 46 816 118 753 86 796 76 186 95 821 92 3357 3760 3633 3291 3044 2615 150 171 213 181 157 1043 972 915 898 864 1359 66 1826 94 2345 143 1826 130 1270 121 94 71 70 51 36 1256 978 843 499 1769 3793 4464 4146 3731 3316 2985 2% 55 59 49 66 118 4405 5111 4665 4264 38 784 59 750 81 678 65 730 71 141 117 461 320 374 192 84 248 3707 539 162 3588 546 1% 3202 532 84 2712 467 28 7533 815 977 851 814 84.5 870 4792 239 3027 158 2743 182 1700 108 534 56 5 TABLE H.-Continued Both aexea Men Women cigarette smoking statue by ege) N " Mean SD SE N n Mean SD SE N 0 Mean SD SE Light smokers 25-14 2x34 35-44 45-54 5564 65-74 Moderate smokers 25-74 25-34 35-44 4544 55-64 65-74 Heavy smoken, 25-14 25-34 35-44 4&54 554% 65-74 2162 1267 2417 136 2148 116 1779 118 922 53 154 18 113 72 76 57 21 235 130 179 82 44 3824 4260 3986 3521 3135 3042 3789 4584 4145 3658 3312 2928 3710 4244 3971 3524 3036' 857 875 680 704 917 1020 a46 852 854 820 988 a32 75-a 928 938 54 116 879 43 135 308 17 103 383 24 108 313 18 237 131 11 30 4454 14 2534 123 5217 90 1214 66 4671 73 1145 75 4351 99 690 45 3881 149 261 28 3327 43 91 a2 81 151 240 1363 12 1505 75 1193 82 697 45 130 16 3866' 3470 q 4364 5055 4609 4304 3851 3189' 641 768 555 636 555 793 812 131 696 734 ala 679 638 798 925 ai 118 235 155 141 159 1283 70 959 55 707 52 730 39 172 10 50 a0 1735 112 125 1199 64 111 1570 104 a9 591 31 172 203 16 61 102 1054 64 94 643 41 a4 586 36 142 22-i a 252 24 2 3342 3828 3686 3249 2822 2ll7 * 3190 3660 3612 3147 2651 2414' 3120 3644 3392 2%3' 2223' 64 705 118 671 119 580 107 451 87 1001 347 38 447 55 457 66 521 57 453 80 614 173 54 404 69 440 73 480 95 438 143 472 328 No'I'Ez N = weighted population estimate. in thousands; n = number of people in sample; SD = standani deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ' Doee not meet standa& of reliability. SOURCE: National Center for Health St&i&ice.. Unpublished data from the first National Health Nutrition and Examination Survey (NHANEZ 1). TABLE I.-Recurring persistent cough attacks for adults, by sex, age, and smoking status, United states, 1971-1975 Never Former Men Smoking statue Current Light Moderate Never Former Women Smoking status Current Light Moderate 2544 P SE ii 3.2 4.4 6.7 7.6 5.7 1.1 4.4 6.0 8.4 5.1 7.1 15.2 1.85 2.23 1.57 4.01 1.98 2.79 1.21 2.46 1.63 1.92 2.n 4.93 3319 168 1593 78 6608 321 1383 72 3335 160 1875 94 6416 399 1873 121 6304 367 2239 119 2642 164 1393 81 3.544 P 4.9 8.0 13.8 9.0 5.9 22.1 5.4 5.0 8.9 2.3 8.0 25.8 SE 2.59 3.47 3.17 6.39 2.69 6.40 1.60 2.46 1.89 1.21 2.85 7.37 ii 2114 101 2384 117 4412 226 614 33 1769 93 2029 100 5197 310 1771 107 4563 no 1776 103 1968 114 799 51 4554 P " 4.3 9.2 10.3 6.4 12.0 10.6 4.9 3.0 11.5 7.8 9.9 21.8 SE 1.61 2.28 2.07 2.13 3.65 3.53 1.55 1.97 2.16 2.61 2.99 4.04 i 1568 114 3290 204 4282 296 810 61 1705 122 1745 112 5989 435 1458 101 4&m 329 1497 18 2413 163 890 57 55-64 P 1.1 14.6 20.5 2.4 14.4 25.9 6.8 9.9 15.7 6.4 14.8 50.1 SE 1.06 3.21 3.27 8.88 4.33 5.87 1.65 3.35 3.46 3.17 3.93 15.8 F4 1320 94 2791 192 2990 205 708 50 1305 91 976 64 5599 394 1501 86 3014 178 1263 76 1369 a2 378 20 G cn ii TABLE I.-Continued Men Women Smoking status Smoking statue Never Former current Light Moderate Heavy Never Former Current Light Moderate H-W 65-74 P 7.5 17.5 23.7 3.6 34.4 25.4 8.1 5.4 `2.31 17.2 24.8 59.9' SE 3.16 3.44 4.55 2.31 6.96 10.1 1.52 2.85 4.93 6.06 8.02 22.31 E; 864 98 2232 232 1199 135 318 39 574 60 295 35 5467 461 958 61 952 a3 523 46 362 32 66 5 25-74 P' 3.9 9.6 13.4 10.2 12.0 16.7 5.7 5.8 12.4 7.1 11.6 31.1 SE' 0.92 1.51 1.30 2.22 1.66 2.31 0.66 1.25 1.19 1.32 1.84 5.63 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thousands. ' Adjwted by direct method to reflect the age dintribution of the U.S. population at the midpoint of the survey. * Dew not meet standards of reliability. SOURCE NatIonal Center for Health Statistics. Unpublished data from the fust National Health Nutrition and Examiition Survey (NHANFS 1). TABLE J.-Three-week periods of increased cough or phlegm for adults, by sex, age, and smoking status, united states, 1971-1975 Never Former Men Smoking et&u8 curre"t Light Moderate Never Former Women Smoking statue current Light Moderate 25-34 P 6.9 2.9 1.2 6.9 7.9 6.5 SE 2.39 1.67 1.83 4.04 2.63 2.33 ii 3319 168 1593 78 6608 321 1383 72 3335 160 1875 94 3.544 P 6.0 3.3 5.2 1.2 3.9 7.6 SE 2.43 1.98 1.68 1.20 2.06 2.86 ii 2114 101 2384 117 4412 226 614 33 1769 93 2229 100 4.544 P 1.7 3.9 6.3 0.3 5.5 9.8 SE 1.24 1.82 1.72 0.32 2.10 366 l 1568 114 3290 204 4282 298 810 61 1706 122 !745 112 5.5-64 P 1.2 2.9 11.4 6.8 10.2 16.2 SE 0.91 1.33 2.61 4.00 4.07 5.39 i 1320 94 2191 192 2990 205 708 50 1305 91 976 64 4.2 5.6 10.7 5.4 11.1 18.0 1.07 2.39 1.91 2.06 2.97 5.18 399 121 367 119 164 81 6416 1873 6304 2239 2642 1393 3.8 1.9 8.1 5.1 10.9 8.3 1.54 1.37 2.01 1.89 3.67 4.20 310 107 270 103 114 51 5197 1771 4563 1776 1968 799 3.5 6.1 10.8 8.4 a.4 21.6 1.00 2.39 2.14 2.93 2.12 6.49 435 101 329 109 163 57 5989 1458 4800 1497 2413 890 6.6 13.7 14.7 7.0 13.1 46.2 1.63 4.88 3.57 3.44 3.96 16.61 394 86 178 76 82 20 5599 1501 3014 1268 1369 378 TABLE J.--Continued Men Women Smoking statue Smoking status 65-14 P SE l Never Former Current Light Moderate Heavy Never Former Current Light Mcderab HMV 15 4.5 12.0 3.3 14.2 17 5 5.1 9.1 11.5 2.6 26.4 0.0 = 3.10 1.38 4.11 2.55 6.01 10.31 1.25 3.47 4.24 2.55 9.80 0.0 864 98 2232 232 1199 135 318 39 514 60 295 35 5487 461 958 81 952 a3 523 46 362 32 66 5 25-74 P' 4.6 3.4 79 3.8 7.6 10.5 4.5 6.9 11.0 SE' 1.04 0.93 102 1.43 1.31 2.04 0.63 1.34 1.26 NDl'E. P = proportion; SE _ standard rrror: n = number of people in sample. N = weighted population estimate. in thousands. I Adjusted by direct method LO reflect the age dkibutmn of the U S population at the midpoint of the 8urvey. * Ikea not meet standards of reliability SOURC'E Natr.mnl Center for Health Statistca. Unpublished data fmm the timt National Health Nutrition and Examination Survey (NHANE 1). 5.9 12.9 19.5 1.18 1.84 3.86 TABLE K.Qhortness of breath for adults, by sex, age, and smoking status, United States, 1971-1975 Never Former Men smoking atatua cumnt Light Women Smoking status Moderate H-V Never F0ITller Current Light Moderate H=V 25-34 P SE : 35-44 P SE i `S-54 P SE ii 554 P SE it 5.6 15.2 23.3 10.0 23.1 33.6 14.4 17.9 31.0 30.9 1.99 4.97 3.20 3.61 4.01 7.21 1.92 4.94 3.17 5.65 168 78 321 72 160 94 399 121 367 119 3319 1593 6eQ8 1383 3336 1875 6416 1873 6304 223s 20.1 3.56 164 2642 51.5 1.43 61 1393 17.1 19.9 22.9 15.6 15.9 31.2 22.5 26.5 39.0 36.4 45.3 30.3 4.62 4.89 3.26 7.08 4.71 5.46 2.42 5.32 4.62 5.48 7.07 7.08 101 117 226 33 93 100 310 107 no 103 114 51 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1966 799 19.3 21.2 35.5 25.4 34.9 41.3 28.1 32.5 42.5 30.3 46.1 47.9 4.07 3.56 2.99 6.35 4.64 5.40 2.85 6.05 3.93 5.01 4.95 7.57 114 204 296 61 122 112 4.35 101 329 109 163 57 1568 3290 4232 610 1706 1745 5989 1456 4m 1497 2413 690 25.6 31.3 42.2 37.7 42.4 45.2 38.0 56.8 39.0 29.8 43.1 54.6 5.79 3.94 4.37 9.57 6.14 6.39 2.94 6.24 4.60 6.65 6.06 16.51 94 192 205 50 91 64 394 86 178 76 82 20 1320 2791 2sso 708 1305 9761 5599 1501 3014 1266 1369 370 E TABLE K.-Continued Men Women Smoking at&us Smoking status Never Former Current Light Moderate H@W Never Former Current Light Moderate H@W 65-74 P 27.0 45.8 41.7 26.7 42.4 54.4 41.6 32.3 43.2 48.6 40.0 17.4' SE 5.46 4.06 4.59 7.87 6.86 9.12 2.92 5.63 6.70 9.64 10.66 16.12 i 664 98 2232 232 1199 136 318 39 574 60 296 35 5487 461 958 61 952 83 523 46 362 32 66 5 25-74 P' 17.1 25.2 31.4 21.5 29.9 39.2 27.0 31.8 38.2 34.1 38.2 42.4 SE' 1.69 2.38 1.75 2.64 2.31 2.74 1.27 2.82 2.03 2.59 2.88 5.07 NVl% P = prow'tion; SE = miandard error; n = number of people in sample: N = weighted population e&mate, in thouan&. ' Adjured by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey `Do% not meet standards of reliability. XXIRCE National Center for Health Statistics. Unpublished dats from the first National Health Nutrition and Examicmtioo Survey (NHANE3 1). TABLE L.-Wheezy chest sounds of adults, by sex, age, and smoking status, United States, 1971-1975 Men Women Smoking atatna Smoking status Never Former Current Light Moderate Hf=Y Never Former Current Light Mcderate HeaT 25.34 P 2.7 13.0 15.0 11.5 12.6 22.0 7.6 11.6 175 12.9 148 29.5 SE 1.17 4.67 2.42 4.43 2.72 6.14 1.46 3.54 2.33 3.13 2.94 6 13 : 3319 166 1593 70 6608 327 1363 72 3335 160 1876 94 6416 399 1873 121 6304 367 2239 119 2642 164 1393 RI 3iM-4 P 14.0 5.1 18.4 13.6 12.3 25.2 7.9 77 16.4 9.9 21.9 179 SE 4.72 2.12 3.28 6.14 4.03 5.61 1.83 2.98 2.56 3.77 4.53 4.89 it 2114 101 2384 117 4412 226 614 33 1769 93 2029 100 5197 310 1771 107 4563 no 1776 103 1968 114 799 51 45-54 P 4.3 12.3 18.8 10.2 23.2 18.7 8.5 5.3 22.7 12.9 24.1 35.7 SE 1.97 2.60 2.60 3.99 4.05 4.13 1.39 1 .a2 2.96 3.59 4.37 6.24 ii 1568 114 3290 204 4282 296 810 61 1706 122 1745 112 5969 435 1458 101 4800 329 1497 109 2413 163 890 57 6.544 P 12.0 13.6 26.9 29.9 26.6 22.1 12.7 22.0 27.3 19.5 31.0 40.0 SE 4.24 2.50 4.46 9.22 5.87 6.10 2.09 5.93 3.64 4.98 5.21 14.00 ii 1320 94 2791 192 2sso 205 708 50 1305 91 976 64 5599 394 1501 86 3014 178 1268 76 1369 A2 378 20 TABLE L..-Continued Men Women Smoking statue Smoking status Never Former Current Light Moderate Never Former current Light Moderate 65-74 P 5.0 20.7 33.1 34.7 31.6 35.6 15.1 21.5 28.6 34.6 18.1 39.02 SE 2.04 3.00 5.25 10.10 7.47 9.91 2.16 4.78 5.60 8.99 6.69 21.96 ii 864 98 2232 232 1199 135 316 39 574 60 295 35 461 81 03 46 32 5 5487 968 952 523 362 66 w74 P' 7.4 12.1 20.6 17.6 19.6 23.5 SE' 1.33 1.63 1.42 2.69 1.96 2.69 9.8 12.6 21.7 16.4 21.7 31.6 0.62 1.66 1.49 2.01 1.66 4.60 NOTE P : proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thousandn. ' Adjusted by direct method to reflect the age distribution of the U.S. `Doe not meet standards of reliability population at the midpoint of the survey. SOURCE National Gnter for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). TABLE M.-Diminis hed or absent breath sounds of adults, by sex, age, and smoking status, United stat43, 1971-1975 Never Former Men Smoking etatus Current Light Moderate Never Former Women Smoking status Current Light Moderate 25-34 P 1.8 0.0 0.3 0.4 0.0 0.7 0.1 0.0 0.6 0.3 0.0 2.2 SE 1.76 0.0 0.21 0.36 0.0 0.71 0.07 0.0 0.51 0.31 0.0 2.21 ii 3319 168 1593 78 6608 321 1383 72 3336 160 1875 94 6416 399 1873 121 6304 367 2239 119 2642 164 1393 61 3544 P 0.6 0.5 0.6 0.0 0.7 0.6 0.3 0.2 2.3 0.4 3.4 3.5 SE 0.61 0.47 0.55 0.0 0.73 0.57 0.26 0.22 1.56 0.44 3.33 3.39 Li 2114 101 2384 117 4412 2% 614 33 1769 93 2029 100 5197 310 1771 107 4563 270 1776 103 1968 114 799 51 45-54 P 0.7 1.0 5.9 0.4 9.8 4.7 0.8 2.4 14 1.0 1.6 1.5 SE 0.55 0.53 1.71 0.41 3.33 2.64 0.64 187 0.56 0.36 0.82 1.24 ; 1568 114 3290 xl4 42.82 2% 810 61 1706 122 1745 112 5989 435 1458 101 4t?.w 329 1497 109 2413 163 890 57 5.544 P 2.5 5.7 12.4 8.4 13.0 14.4 0.8 4.1 3.36 2.7 3.9 3.5 SE 2.12 1.66 3.15 4.75 4.57 4.99 0.53 2.51 1.44 1.82 2.40 3.55 ii 1320 94 n9i 192 2sw 205 708 50 1305 91 976 64 5.599 394 1501 86 3014 176 1268 76 1369 82 376 20 E w z TABLE M.-Continued Never Former Men Smoking status Current Light Moderate Never Former Women Smoking status Current Light Moderate 65-74 P 8.8 9.1 17.9 13.9 25.2 8.8 2.4 4.5 2.7 3.3 2.3 0.0' SE 3.53 2.57 3.76 8.10 5.86 4.5 0.81 2.63 1.58 2.34 2.27 0.0 i 664 98 2232 232 1199 135 318 39 574 60 295 35 5487 461 958 81 952 83 523 46 362 32 66 5 s-74 P' 2.2 2.44 5.8 3.3 7.5 5.0 0.7 1.9 1.9 1.32 2.1 2.3 SE' 0.72 0.46 0.96 1.33 1.47 1.08 0.20 0.71 0.46 0.49 0.88 1.16 NW: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate. in thouwand.% ' Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ' Doea not meet n&anti of reliabiiity. SOURCE Natronal Center for Health Sk&&a. Unpublished data from the fti National Health Nutrition and Examination Survey (NW 1). TABLE N.-Wheeze of adults, by sex, age, and smoking status, United States, 1971-1975 Never Former Men Smoking Btatua Current Light Moderate Never Former Women Smoking etatua Current Liiht Moderate 2L3.4 P SE i 35-44 P SE i 4544 P SE ii &64 P SE ii 0.0 1.2 1.7 1.1 1.6 2.2 0.4 0.0 0.7 0.0 13 0.0 0.0 1.24 0.77 1.06 1.25 1.28 0.29 00 0.37 0.0 0.79 0.0 166 78 327 72 160 94 399 121 367 119 164 81 3319 1593 8809 1363 3336 1875 6416 1873 6304 2239 2642 1393 0.0 1.0 1.3 0.0 0.9 2.1 0.3 0.0 3.2 0.0 3.6 9.6 0.0 0.75 0.67 0.0 0.89 1.22 0.26 0.0 126 0.0 1.50 4.97 101 117 226 33 93 100 310 107 no 103 114 51 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799 0.0 1.2 2.5 0.0 4.5 1.8 0.3 0.0 2.4 0.8 3.3 2.5 0.0 1.02 0.93 0.0 2.13 1.27 0.33 0.0 0.94 0.76 1.40 1.76 114 204 296 61 122 112 435 101 329 109 163 57 1568 3290 4262 810 1706 1745 5989 1456 48al 1497 2413 890 0.0 0.4 5.6 2.3 3.3 10.9 0.1 0.0 1.7 0.8 1.4 5.8 0.0 0.37 1.76 1.95 1.69 4.48 0.05 0.0 0.95 0.77 1.18 5.76 94 192 m5 50 91 64 394 86 178 76 82 `20 1320 nsi 2990 708 1305 976 5599 1501 3014 1266 1369 378 z TABLE N.-Continued Men Women Smoking status Smoking status Never Former Current Light Moderate H=V NWW Former CutTent Jight Moderate H=-Y 65-74 P 0.0 2.5 10.0 0.0 11.4 18.4 1.0 1.9 3.6 2.1 1.6 20.92 SE 0.0 1.11 3.75 0.0 5.27 10.98 0.56 1.85 2.14 2.66 1.64 18.53 i 864 96 2232 232 1199 135 318 39 574 60 295 35 5467 461 956 81 952 83 523 46 362 32 66 5 2%14 P' 0.0 1.2 3.4 0.7 3.5 5.5 0.4 0.2 2.1 0.7 2.3 6.3 SE' 0.0 0.46 0.71 0.46 0.92 1.65 0.14 0.25 0.45 0.41 0.46 2.79 NOTE P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, m thousands. 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MORTALITY FROM CHRONIC OBSTRUCTIVE LUNG DISEASE DUE TO CIGARETTE SMOKING 185 CONTENTS Introduction COLD Mortality Patterns in the United States Prospective Studies The British Doctors Study The American Cancer Society 25-&&e Study The U.S. Veterans Study The Canadian Veterans Study The American Cancer Society g-State Study California Men in Various Occupations The Swedish Study The Japanese Study of 29 Health Districts Cigarette Smoking and Overall COLD Mortality Retrospective Studies Male and Female Differences in COLD Mortality Amount Smoked and Mortality From COLD Inhalational Practice and Mortality From COLD Age of Initiation and COLD Mortality Smoking Cessation and COLD Mortality Pipe and Cigar Smoking Mortality From COLD International Comparison of COLD Death Rates a Smoking Habits: The Emigrant Studies COLD Mortality Among Populations With Low SI Rates Summary and Conclusions References Introduction The chronic obstructive lung diseases (COLD) that are causally related to cigarette smoking are chronic bronchitis, emphysema, and chronic obstructive pulmonary disease and allied conditions without mention of asthma, bronchitis, or emphysema. The last classification was introduced by the National Center for Health Statistics in response to the changes that occurred in the late 1960s in patterns of reporting causes of death on death certificates. During this period, physicians increasingly recorded deaths as due to "chronic obstruc- tive lung disease" rather than the more specific categories of "emphysema" or "chronic bronchitis" (NCHS 1982). Because of this shift in patterns of reporting, and in recognition of the difficulty of clinically separating these categories from one another as a cause of death, the discussion in this chapter combines all of these categories for analysis, where possible, which should result in a more complete description of death rates from COLD. COLD Mortality Patterns in the United States The three chronic obstructive lung diseases related to smoking may account for almost 62,000 deaths in 1983, compared with 56,920 deaths in 1982, according to provisional mortality data recently published by the National Center for Health Statistics. This data is based on a 10 percent sample of all deat.h certificates for the 12- month period ending in November (NCHS 1984). This is a dramatic increase from 1970, when slightly over 33,000 deaths were attributed to COLD. Complete mortality data are available through 1980, and Table 1 presents the numbers of male and female deaths from COLD for 1970,1975, and 1980. In addition to the relatively rapid rise in COLD deaths during these years, there was also a shift in the male to female ratio of these deaths. In 1970 male deaths outnumbered female deaths by a ratio of 4.3 to 1. By 1980 this ratio had declined to 2.36. The ageadjusted death rates for COLD during the years 1960 through 1980 are presented in Figure 1 for white men, white women, and men and women of other races. As described in the previous chapter, however, COLD is a slowly progressive disease, and death from COLD usually occurs only after extensive damage has devel- oped in the diseased lungs. Many individuals with COLD will die with their disease rather than because of it, and even those who do die of COLD are usually symptomatic for an extended period of time prior to death. Therefore, death rate data may not accurately reflect the true prevalence or incidence of COLD in the U.S. population. In addition, COLD is often not recorded as a cause of death in hospital records 189 TABLE l.-Number of and ratio of male to female chronic obstructive lung disease (COLD) deaths for three time periods, United States Cause of death 1970 1975 1980 Men Women Men Women Men Women Chronic bronchitis Emphysema COLD and allied conditions 4,262 1,564 3,260 1,452 2,380 1,348 18,901 3,820 14,649 3,946 10,133 3,744 3,601 848 13,411 4,182 24,820 10,734 Total COLD deaths 26,764 6,227 31,520 9,580 37,333 15,826 M:F ratio 4.30 3.29 2.36 SOURCE: National Center for Health Statistics (1982, and unpublished mortality data) OTHERd 15 10 WHITE? 5 OTHER? 1960 1965 1970 1975 1980 YEAR FIGURE l.-Age-adjusted COLD mortality rates for whites and nonwhites in the United States, 1960-1980 SOURCE National Center for Health Statistics (1962, and unpublisheddata). (Moriyama et al. 1966) or on death certificates (Mitchell et al. 1968), even though it may have played an important role in a person's death. In a recent prospective study, nearly half of the excess mortality associated with significantly lowered FEV, was attributed to other causes (Pete et al. 1983). Relatively advanced lung disease (as judged by pathologic examination) may also exist without clinical 190 recognition because of the lung's large ventilatory reserve (Mitchell et al. 1968; Hepper et al. 1969). A joint committee of the American College of Chest Physicians and the American Thoracic Society (ACCP-ATS 1975) has developed standardized definitions of these conditions that may improve the accuracy of mortality reporting in the future. As discussed in the chapter on morbidity in this Report, COLD in an individual is usually a combination of mucus hypersecretion, airway narrowing, and emphysema. The extent of damage represent- ed by each of these three processes can vary substantially from individual to individual, both in the absolute magnitude of the damage and in the proportional contribution of each of these three components. The majority of those with smoking-induced lung damage do not have enough damage to result in clinically significant disease, and only some of those with clinically significant disease have damage to the lung that results in death from COLD. The progressive loss of FEV, in smokers described in the preceding chapter is one measure of the extent and progression of lung damage, and individuals with a markedly reduced FEV, are far more likely to die of COLD (Peto et al. 1983). These deaths commonly occur secondary to the failure of these severely damaged lungs to carry out the gas exchange required for survival. Because death from COLD is the end result of lung damage accumulated over many years, these deaths would be expected to occur disproportionately in the older age groups; therefore, the presentation of a single age-adjusted death rate might not reflect a true picture of the changes in this disease with time. Figure 2 presents the age-specific death rates in 1977 for COLD in the different sexes and racial groups. Death rates increase rapidly over the age of 45, and this increase is particularly dramatic over the age of 65. In addition, the bulk of the difference between white men and men of other races, evident in Figure 2, occurs in those over age 65. Indeed, the COLD death rates for nonwhite men are actually higher than that for white men under age 55. The examination of age-specific death rates over time also presents a somewhat different picture from that presented by the age- adjusted numbers in Figure 1. The age-adjusted rates for white men in Figure 1 seem to have changed only slightly between 1968 and 1980. However, when the age-specific rates for the years 1968 and 1977 are examined (Figure 31, this apparent stability can be seen to be a product of counterbalancing trends in those under and over 65 years of age. The death rates from COLD declined in white men under age 65 between 1968 and 1977, but COLD death rates increased in white men over age 65 during the same years; this increase was particularly dramatic in those over age 75. 191 I 25-34 AGE FIGURE 2.-Age-specific COLD mortality rates for whites and nonwhites in the United States, 1977 SOURCE: National Center for Health Statida, (1982). Figure 4 presents the age-specific COLD mortality rates for white women in 1960, 1968, and 1977. As with the male rates, the female COLD death rates rise rapidly with age, but they are substantially lower than the male rates. In contrast with the male rates, however, the white female death rates increased steadily with time from 1960 through 1977 both above and below age 65. In each of the age groups over the age of 45, where significant numbers of COLD deaths would be expected, there was a steady increase in rates from 1960 to 1968 and from 1966 to 1977. As is discussed later in this chapter, these differences between men and women over time are consistent with their differences in smoking behavior. The effect of the normal aging process on the lung is small, rarely limits maximal exercise, and never results in ventilator-y failure. Therefore, death from chronic obstructive lung disease is never a natural part of the aging process; it is the result of an infectious or other disease process or of the cumulative damage of environmental respiratory toxins. The most important of these toxins in the United States is cigarette smoke. 192 25-34 35-44 45-54 55-64 65-74 75-84 85+ FIGURE 3.-Age-specific COLD mortality rates for white men in the United States, 1960, 1968, and 1977 SOURCE: National Center for Health Statistics (1982). In spite of the large ventilator-y reserve possessed by the lung, death from COLD is a major cause of U.S. mortality. This mortality is closely linked to cigarette smoking and has been examined extensively. Figure 5 shows the differences in COLD death rates for smokers and nonsmokers at different ages. From the rarity of COLD death in nonsmokers and the magnitude of the increased risk associated with smoking, it is clear that the overwhelming impor- tance of cigarette smoking as a determinant of abnormal lung function demonstrated in the previous chapter is matched by the importance of cigarette smoking as a determinant of death from COLD. Examination of the death rates from COLD in smokers and nonsmokers suggests that from 85 to 90 percent of the COLD deaths in the United States can be attributed to cigarette smoking. Prospective Studies The relationship between smoking and death from COLD has been evaluated in a large number of prospective mortality studies. There are eight major prospective studies of the disease consequences of smoking. They involve large numbers of smokers and nonsmokers 193 AGE FIGURE 4.-Age-specific COLD mortality rates for white women in the United States, 1960, 1968, and 1977 SOURCE Natmnal Center for Health Statmtics / 19H2 I and have examined the death rates from COLD in both groups. These studies cumulatively represent more than 17 million person- years of observation and over 330,000 deaths. The size of the populations studied allows a detailed examination of the relationship between smoking and death rates. The characteristics of the populations studied are summarized in Table 2 and are briefly reviewed here. The British Doctors Study The British doctors study (Doll and Hill 1954, 1956, 1964a, 1964b, 1966; Doll and Peto 1976, 1977; Doll and Pike 1972; Doll et al. 1980) of 40,000 male and female physicians in Britain was the first prospective study and is the longest running. Deaths from chronic bronchitis and emphysema were combined. Deaths from car pulmo- nale (i.e., heart failure secondary to lung disease) were separately analyzed by smoking category and probably include some deaths from chronic bronchitis and emphysema. 194 450 400 100 FIGURE - -1 ! I , ._ I ! I Z-Death rate for bronchitis, emphysema, or both, per 100,000 population, by age and smoking status I, U.S. veterans study, 16-year followup `Smoker LS defined as all people who smoke agarettes and those who have ever smoked other tohocco products SOURCE- Adapted fmm Fbgot and Murray / 19801 The American Cancer Society 25State Study The American Cancer Society 25-State study (Hammond 1965, 1966; Hammond and Garfinkel 1969; Hammond et al. 1976; Lee and Garfinkel 1981) represents the largest investigation. Deaths from emphysema were separately analyzed by smoking habit; deaths from car pulmonale were also separately recorded. The U.S. Veterans Study The mortality experience of approximately 294,000 U.S. veterans who held U.S. Government life insurance policies in December 1953 was examined in the U.S. veterans study (Darn 1959; Kahn 1966; Rogot 1974a, b; Rogot and Murray 1980). Deaths from COLD were recorded as "bronchitis and/or emphysema"; "bronchitis, underlying or contributory"; and "emphysema without bronchitis." The Canadian Veterans Study Initiated in 1955 by the Canadian Department of National Health and Welfare, the Canadian veterans study (Best 1966; Best et al. 1961) included 78,000 men and 14,000 women. Over the next 6 years of followup, there were 9,491 male and 1,794 female deaths. The cause of death in most of these cases was confirmed by autopsy. 195 z - TABLE 2 .-Outline of eight major prospective studies Doll Darn kat Weir GxiwkJf Aulhon Hill Hammond Krhn H~nyama JOUC ltammmd Dunn fibsy Pet0 Roaol Walker HW!l laden HNbc Rke BraloW Lonch Melee and Total population Ghfomu ProtaMity Bntinh femalea US of Gnadlan while m&a rmple of Sub@a I" 29hdth nuke I" do2lon I" votorura the 25 dmtncLs I" "UWU peMlolW" nme stata SW&h SlAkB JW mupllom pophtion Population aize wm l.~.~ mw 266.ooo ' 9zoal 187,oal wax) mm FellUka WQ 562.671 (1% lw?57 14,ma n.700 AIF nn% B435+ 3M.4 3544 40 3cao d up 504 D-64 18.4 Year of 1961 1960 1W 1966 1966 cnrdlment 1967 1962 1954 1969 Yeem of fdlowup 20-22 UY- 16 YAM 13 y- 6y- 4 Y- 54 Y- 10 yean Y- Number Of ll.166 150,ooO ICnJoo 39.100 11,oal I2m 4.700 4aO death Person y- of woo0 J%~.~ 35Qo.w 3.W~ WoaJ 670,ooO @A~ We cxpricmx The American Cancer Society S-State Study In the American Cancer Society g-State study (Hammond and Horn 1958a, b), 187,783 white men were followed for an average of 44 months by 22,000 American Cancer Society volunteers. All deaths from pulmonary disease (except pulmonary neoplasms) were consid- ered as one group and included deaths from pneumonia, asthma, tuberculosis, lung abscess, pneumoconiosis, bronchiectasis, and em- physema. California Men in Various Occupations The study of California men in various occupations (Dunn et al 1960; Weir and Dunn 1970) examined the mortality experience of 68,153 men, aged 35 to 64, drawn from labor union rolls in specified occupations. Deaths from emphysema were separately categorized. The Swedish Study The study of a probability sample of 55,000 Swedish men and women (Cederlof et al. 19751, aged 18 to 69, represents a detailed analysis of mortality by smoking status over a period of 10 years. The cause of death was ascertained by death certificates collected by the Central Bureau of Statistics for all of Sweden. The Japanese Study of 29 Health Districts In the fall of 1965, a total of 265,118 men and women in 29 health districts in Japan were enrolled in a prospective study (Hirayama 1967,1970,1972,1975a, 1975b, 1977, 1981). Mortality data regarding deaths from asthma and emphysema have recently been reported. Cigarette Smoking and Overall COLD Mortality The data from the major prospective studies relating smoking to mortality from COLD in men and women are presented in Table 3. These data demonstrate a uniform increase in death rates from COLD among male and female smokers when compared with nonsmokers of either sex. The mortality ratios for smokers compared with nonsmokers vary markedly, however, from 2.2 in the Japanese study to 24.7 in the study of British doctors. Some of this variability can be attributed to different patterns of certification of cause of death in different countries, but a number of other factors are also important. Perhaps the most important other factor is the age range of the population studied. As described earlier in this chapter, death rates from COLD rise steeply with age, particularly over the age of 65. Studies of populations under age 65 may significantly underesti- mate the impact of cigarette smoking on COLD because of the long duration of smoking required to damage enough lung to result in 197 death from COLD. The population under 65 contains large numbers of individuals who have significant airflow obstruction and who will die of COLD, but who have not done so prior to age 65. This effect is demonstrated in the American Cancer Society 25-State study, in which the COLD mortality ratio for male smokers aged 45 to 64 was 6.55, but increased to 11.41 in male smokers aged 65 to 79. A second reason for differences in mortality ratios is the selection of study populations who are currently employed, particularly if the duration of followup is relatively short. The incremental nature of the lung injury in COLD often results in a prolonged period of disability prior to resulting in death. This disability is usually incompatible with full-time work, particularly in those occupations requiring substantial exertion. Therefore, the study of a working population excludes those with significant existing disability from COLD and underestimates the COLD death rates in the general population. Unless the followup period is long enough to observe the progression of COLD from its asymptomatic stages through the development of disability and finally death, the impact of cigarette smoking on COLD death rates will be underestimated. This effect is particularly important because cigarette smoking is overwhelmingly the major determinant of COLD risk, and therefore an underestima- tion of the true COLD prevalence leads to an underestimation of the relative risk of smoking. As the followup period is extended for a duration sufficient to allow the full time course of COLD to be observed, the impact of cigarette smoking on COLD death rates also emerges from the small background rate of COLD death certification in nonsmokers (which includes those classified in error and those with disease induced by agents that results in a more rapid progression to death). This "healthy worker" effect is present to varying extents in all of the prospective studies and is one of the reasons the studies with the longest followup periods also tend to have the largest COLD mortality ratios. This is particularly evident in the study with the longest followup. The British doctors study, with a followup of 20 years, revealed a mortality ratio for male smokers of 24.7. A final reason for the differences in mortality ratios is the differences in the smoking habits of the various populations. As was discussed in the previous chapter, the extent of lung injury is influenced by both the number of cigarettes smoked per day and the duration of the smoking habit. As is shown in Table 4, some of the variability in mortality ratios among the studies disappears when the mortality ratios are reported by number of cigarettes smoked per day. However, there are also substantial differences in the pattern of cigarette use in different countries, particularly in the use of the milder types of tobacco cigarettes that are more likely to be inhaled and are smoked in the United States. For example, these cigarettes 198 TABLE 3.-COLD mortality ratios by disease category, eight prospective studies Study size of population Nonsmoker Emphysema Bronchitis Both Other Cfimments Brltlsh physicians Men Women 34.ooo 1.00 6.195 loo 24 7 Ratio for women by amount smoked only. see Table 4 Cahforma men m Yar\ous occupations Canadian veterans Men American Cancer Society 25-state Men Women US veterans Men Amcrlran Cancer Society 9.Stale Men 66.00(1 78.ooo 440.500 562.7llu 290K1.000 100 100 1.00 1.00 100 100 12 33 5 85 11.42 45-64' 6S79 ' 6 55 11.41 4 89 750 1482 5 II `Age range 1207 2.85 All pulmonary &eases uLher than cancer ipneumoma. mfluen~~. TB. asthma, bronchitis. lung abscess. etc.1 8 TABLE 3.-Continued SW.. of Study population Nonsmoker Emphysema Bronchltls Both Other Comments Swedish Men Women 27,0(x) 28.ooo 100 100 . 2.20 ' Number of deaths too small for statistical analysw Includes deaths due to asthma Japanese Men Women 12w.M 143,GGo loo 1.00 Data by amount smoked only; see Table 4 were not introduced into Japan in large numbers until after the Second World War. The chronicity of tobacco use, particularly of those forms of tobacco that are commonly inhaled, is probably more important than age per se in producing COLD death. The chronicity of tobacco use differs in different countries and between men and women in the same country; these differences would be expected to result in different COLD mortality ratios. In several of these prospective mortality studies, the mortality ratio for COLD deaths in smokers compared with nonsmokers was even larger than that found for lung cancer. This is consistent with the data in the previous chapter showing that cigarette smoking is the major predictor of decline in lung function and is also consistent with the clinical observation that clinically significant airflow obstruction is rare in the absence of a history of smoking. Retrospective Studies The relationship between smoking and mortality from COLD was also examined in several large retrospective studies. Wicken (1966) conducted a study of 1,189 men living in Ireland who died from chronic bronchitis. Smoking habits were determined through person- al interviews with relatives of the decedents. The relative risk for mortality from COLD was increased in smokers as compared with nonsmokers. Smokers of as few as 1 to 10 cigarettes per day had a 2.95fold higher risk for mortality from COLD as compared with nonsmokers. Dean and associates conducted two retrospective studies of the relationship between changes in smoking patterns and changes in mortality from bronchitis among a sample of the population in urban areas and in rural areas of northeast England. The periods of observation in the two studies were 1952 to 1962 (Wicken and Buck 1964; Wicken 1966) and 1963 to 1972 (Dean et al. 1977, 1978), respectively. Smoking status classifications in the two studies were similar, and were based upon questions relevant to the last 2 years before death or interview. In both studies, the relative risk for mortality from chronic bronchitis was substantially increased for smokers as compared with nonsmokers. In summary, data from both the prospective and the retrospective studies consistently demonstrate an increase in mortality from COLD for smokers as compared with nonsmokers. These studies include populations of widely different ages, social and ethnic groups, geographic locations, and occupations; nevertheless, they strongly support a causal relationship between smoking and COLD. 201 480-144 0 - 85 - 8 TABLE I.-COLD mortality rates for men and women, by number of cigarettes smoked per day, prospective studies Study MelI Women Cigarettes Mortality Cigarettes Mortality COLD disease per day ratios per day ratios classification British physicians Nonsmoker 1-14 1524 25+ U.S. veterans Nonsmoker 1-9 10-20 2139 40+ 1.03 17.00 26.00 36.00 1.00 3.63 4.51 4.57 8.31 Nonsmoker 1.00 1-14 10.50 l&224 28.50 25+ 32.00 Nonsmoker 1.M) l-9 5.33 l&19 14.04 2139 17.04 40+ 25.34 Emphysema Nonsmoker 1-9 l&19 2139 40+ 1.00 4.84 11.23 17.45 21.98 Chronic bronchitir and emphysema Canadian veterans Nonsmoker l.cMl l-9 7.02 10-20 13.65 2lf 14.63 Chronic bronchitis Nonsmoker Loo l-9 4.81 l&20 6.12 21-t 6.93 Emphysema Japanese Nonsmoker 1.00 Nonsmoker 1.00 < 100,m' 0.51 < 100,ooo 2.28 < 200,oGfl 2.57 <2CQOOO 3.14 > 3oo.ooo 1.93 > 300,oca 10.93 California men Nonsmoker2 1.00 in various About `12 pk 8.18 occupations About 1 pk 11.80 About 1'1, pk 20.66 Emphysema American Cancer Nonsmoker 1.00 Society l-9 1.67 sstate i&20 3.00 20- 3.64 All pulmonary diseases other than cancer3 Chronic bronchitb emphysema: or both Chronic bronchith Emphysema ' Data for the Japanese study are for lifetime exposure by > total number of crgarettea consumed `Nonsmoker m the Cabfornia occupations study aleo includes > smokers of pipes and cigars. a Pneumoma. mfluenza. TB. asthma, bronchitis, lung abscess. etc. 202 Male and Female Differences in COLD Mortality Mortality data presented by the National Center for Health Statistics indicate that in 1980 the number of deaths from COLD was 2.36 times higher among men than among women (9th ICDA nos. 490, 491, 492, and 494496). In the prospective studies reviewed above, it is also apparent that the relative risk for death from COLD was greater for male smokers than for female smokers, although both male and female smokers exhibited a greater risk than nonsmokers for death from COLD. These differences are most likely a consequence of differences in male and female smoking patterns. The women in these studies tended to smoke fewer cigarettes, inhale less deeply, and begin smoking later in life than the men. They more frequently smoked filtered and low tar and nicotine cigarettes and had less occupational exposure to pulmonary irritants than men. These differences in mortality from COLD are narrowing because of a more rapid rise in female mortality from COLD (see Table 1). Figures 6 and 7 help to explain the male-female differences in COLD mortality ratios in the prospective mortality studies and in U.S. COLD death rates. The figures are descriptions of the preva- lence of cigarette smoking in successive lO-year birth cohorts of men and women as those cohorts progressed through the years 1900-1980 (Harris 1983). Examination of these figures revealed several impor- tant findings. Relatively few women took up smoking prior to 1930. The heaviest smoking cohorts of men have a prevalence of over 70 percent compared with 45 percent of women, and the male cohorts with these peak prevalences are older than the female cohorts. However, as discussed earlier, the incremental and progressive nature of cigarette-induced lung injury results in both prevalence and duration of cigarette smoking having an impact on COLD death rates. Therefore, in examining Figures 6 and 7 it is important to consider the span of years of a given prevalence of smoking maintained by a given birth cohort as well as the peak prevalence achieved by that cohort. The COLD death rates should then be proportional to the area under the prevalence curve described by each cohort, rather than to the peak of that curve. A careful examination of Figure 6 reveals that the area under the prevalence curve for the cohort born between 1921 and 1930 is less than the area under the curve for the cohort born between 1911 and 1920, in spite of their similar peak prevalences. This difference is due to the more rapid decline in prevalence with age in the 1921 to 1930 cohort. Similarly, the cohort born between 1901 and 1910 partially compensates for a peak prevalence that is lower than the 1911 to 1920 cohort by having a somewhat a broader base. Each of the cohorts born prior to 1900 have substantially smaller areas under their curves than those born during the first three decades of this century. These differences in prevalence are reflected in the changes 203 1910 1920 1930 .R 1940 1950 1960 1970 I I 1 I Men i 1921-30 .7 .6 . .5 - .4 - 1891 1900 1910 -1920 1930 1940 1950 1960 1970 l! FIGURE &-Prevalence of cigarette smoking among successive birth cohorts of men, 1999-1999, derived from smoking histories in the National Health Interview Survey (HIS) SOURCE: Harris 1983. in age-specific death rates portrayed in Figure 8 and Table 5. The oldest age group (7584) continues to show a rapid rise in COLD death rates as those birth cohorts with increasing prevalence and duration of smoking move into this age range. In the age range 65-74 the rates rose rapidly from 1960 through the mid 19708, but seem to be leveling off, consistent with the fact that this age group is now made up entirely of men born after 1900. In the age range S5-64 the rates suggest a slight downturn beginning in the mid 197Os, coincident with the entry of the 1921 to 1930 birth cohort into this age group. The numbers for the age range 45-54 are too small to 204 2 2 1 1 0 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 FIGURE 7.-Prevalence of cigarette smoking among successive birth cohorts of women, 1900-1980, derived from smoking histories in the National Health Interview Survey (HIS) SOURCE: Hmie 1983 permit firm conclusions, but also suggest that a downturn in rates occurred in this group in the late 1960s. A close examination of Figures 6 and 7 also offers an explanation of the differences in mortality ratios for men and women observed in the prospective studies. COLD is a slow, progressive disease, and death from COLD usually results only after extensive lung damage has occurred. The fact that death from COLD is unusual prior to age 45 reflects, in part, the 30 or more years required for cigarette smoke to damage enough lung to result in death. The substantial ventilato- ry reserve of the lung allows a significant amount of damage to exist in a person without symptomatic limitation or risk of death from COLD. The prospective mortality studies were conducted in the 1950s and 1960s a point in time approximately 30 years after the beginning of the rise in smoking prevalence among women demon- strated in Figure 7. Even the older cohorts, where significant mortality might be expected, had begun smoking largely after 1930, and therefore had a shorter duration of smoke exposure than the men born in the same years. This shorter duration of the smoking habit, together with the previously described tendency of women to 1960 1965 1970 1975 YEAR FIGURE 8.-Age-specific COLD mortality rates for white men in the United States, 1960-1977 NOTE ICDA Nc.s 49@492 and 519.3 SOURCE Nat,onal Center for Health Statlstux 119821. smoke fewer cigarettes per day and to inhale less deeply, would be expected to result in less cumulative lung damage at any given age. This difference in extent of lung damage could explain the difference in COLD mortality ratios between men and women observed in the prospective mortality studies. The British doctors study examined the risk of COLD death for male and female physicians who smoked similar numbers of cigarettes per day (Table 41, and the mortality ratios were similar for similar numbers of cigarettes smoked per day. In summary, data from the prospective studies indicate that the: relative risk of death from COLD is greater for male smokers than for female smokers. These differences are most likely a consequence of differences in female smoking patterns. Women tend to smoke- fewer cigarettes, inhale less deeply, and begin to smoke later in life- than men. These differences in mortality from COLD are narrowing- because of a more rapid rise in female mortality from COLD than in male COLD mortality. This reflects the narrowing in differences between male and female smoking patterns and the rising preva- lence of female smokers in successive cohorts born between 1920 and 206 TABLE 5.-Age-specific COLD death rates per 100,000 population Year 45-54 55-65 65-74 75-a 1960 8.6 361 1961 7.6 38.7 1962 9.6 44.2 1963 11.7 52.3 1964 12.1 518 1965 12.4 57 8 1966 12.4 61.9 1967 12.4 61.2 1968 13.1 67.4 1969 13.9 67.5 1970 13.6 66.1 1971 13.5 67.4 1972 13.0 67.7 1973 12.7 69.9 1974 12.8 64.8 1975 11.9 64.7 1976 12.2 64.0 1977 11.4 60.1 SOURCE: Natmnal Center for Health Statimcs (1982) 82.9 101.8 87.9 111.8 107.2 136.7 131.2 169.6 131.6 181.9 153.6 216.6 161.9 244 8 164.8 248 6 1867 266.5 189.5 294.3 196.5 311.5 105 6 327 4 204.8 351.4 210.1 378.4 2048 3804 207.6 399.7 210.7 419 7 2061 4315 1950. These data are ominous for women, portending a rising mortality from COLD over the next decades. Amount Smoked and Mortality From COLD Six of the major prospective studies evaluated the influence of different smoking levels on mortality from COLD. These studies employed a variety of measures of tobacco exposure, including number of cigarettes smoked per day, grams of tobacco smoked, and total number of cigarettes smoked in a lifetime. The data, presented in Table 4, show a gradient in risk for mortality from COLD as the number of cigarettes smoked per day increases and as the cumula- tive number of lifetime cigarettes smoked increases. In the U.S. veterans study, smokers of two packs or more per day had 22 times the risk of COLD death of nonsmokers. Furthermore, mortality ratios between the two followup periods for bronchitis and emphyse- ma actually increased overall and by the amount smoked (Figure 9). The authors noted that this was the only major disease of those associated with cigarette smoking that showed such an increase, suggesting that mortality ratios have been increasing over time at all levels of smoking. In the British and Japanese studies, women smokers at the highest levels exhibited a 32- and an 11-fold higher risk for death from COLD (respectively) than their nonsmoking counterparts. The variability in COLD mortality ratios noted in 207 20 15 9 F f fi = 10 5 0 3 0112years m 16 years 17.45 12.07 .65 1 4.84 4.14 Ia 11.23 a.73 I Nmsmdtw All cigarette l-9 lo-20 2139 smokers Clgerenessmokedpwday 21.90 02 240 FIGURE O.-Bronchitis and emphysema for male smokers number of cigarettes smoked per day, U.S. veterans study, W/,-year and H-year followup Table 3 is much less evident when the mortality ratios are presented by amount smoked. In summary, the degree of tobacco exposure strongly affects the risk for death from COLD in men and in women. This clearcut dose- response relationship enhances the strength of the causal relation- ship between smoking and COLD. Inhalational Practice and Mortality From COLD The inhalation of tobacco smoke is the major mechanism whereby- bronchial and alveolar tissues are exposed to the potentially damaging effects of tobacco smoke. In the British doctors study, subjects who acknowledged inhaling exhibited a 1.53-fold higher risk- for COLD death as compared with those who stated they did not- inhale (see Table 6). However, all smokers, regardless of their inhalational practice, exhibited higher risk for COLD mortality than did nonsmokers. In the retrospective study from northeast England (Dean et al. 1977, 19781, the risk among men for mortality from chronic bronchitis steadily declined with a decrease in the depth of inhala- tion (Table 7). Among women, the risk for mortality from chronic bronchitis was lower for all other groups than for those who stated- they "inhaled a lot." TABLE 6.-COLD mortality by inhalation practice, British doctors study, men Cause of death Number of deaths Annualized death rate per Risk in Inhalers 100,ooO men responding compared wth unity to question: do you inhale? in noninhalers Chronic bronchitis and emphysema end pulmonary heart dieease Yes No 71 89 58 1.53 Table 7.-Relative risk for mortality by depth of inhalation, 1963-1972, second retrospective mortality study in northeast England Relative risk for chronic bronchitis Depth of inhalation Men Women A lot (baee~ 1.00 1.00 A fair emount 0.98 0.54 A little 062 0.41 None 0.58 0.58 SOURCE, Dean &al. 11977.19781 Results from prospective mortality studies comparing COLD death rates by inhalation are identical to those observed in the morbidity studies, which have consistently shown that COLD is more prevalent among inhalers than noninhalers (Ferris et al. 1972; Comstock et al. 1970; Rimington 1974). These data suggest that inhalational practice affects the risk of mortality from COLD. People who inhale deeply experience a higher risk for mortality from COLD than people who do not inhale. Regardless of their inhalational practice, however, smokers still experience higher rates of death from COLD than nonsmokers. Age of Initiation and COLD Mortality Another indicator of exposure to tobacco smoke that may influ- ence risk for mortality from COLD is the age of initiation of smoking. If their smoking habits are otherwise similar, people who take up smoking at a younger age have a greater total exposure to tobacco smoke than those who take up smoking later in life, and might be expected to experience greater adverse consequences from smoking. In the Japanese prospective study (Hirayama 19811, men who began to smoke before the age of 19 exhibited slightly higher mortality ratios for emphysema than did men who began to smoke after the TABLE S.-Number of deaths from chronic bronchitis, emphysema, and pulmonary heart disease in ex- cigarette smokers, by years of cessation, versus number of deaths in lifelong nonsmokers, British doctors study Number of deaths in ex-smokers, divided by Number of deaths number expected in lifelong smokers in nonsmokers Years of cessation 0' <5 69 lo-14 >14 35.6 34.2 47.7 7.3 8.1 2 age of 20. In the retrospective study from northeast England (Dean et al. 1977, 19781, the relative risk for death from chronic bronchitis among men who began to smoke after the age of 25 was 60 percent of that of men who began to smoke between the ages of 15 and 19. Among women in the same study who began to smoke between the ages of 15 and 19, the relative risk for death from chronic bronchitis was 1.28fold higher than for women who began to smoke after age 25; however, the number of deaths was small. Smoking Cessation and COLD Mortality The effects of smoking cessation on mortality from COLD were examined in the British doctors study and the U.S. veterans study. In the British doctors study, men who quit smoking experienced no change in mortality from COLD in the first 4 years and a rise in the next 5 years; presumably, this is related to the presence of many people in this group who quit smoking for health reasons (Table 8). Thereafter, ex-smokers experienced lower death rates from COLD, although their rates were still higher than those of the nonsmokers. Female ex-smokers also experienced lower mortality rates than current smokers, but the rates in ex-smokers were still higher than those in nonsmokers. In the U.S. veterans study, ex-smokers who had quit for reasons other than ill health experienced lower mortality rates for COLD than did current smokers. However, the benefit of cessation upon risk for mortality was heavily dependent upon the prior level of smoking and the length of time of cessation. These data are presented in Table 9. Ex-smokers who had smoked less than 10 cigarettes per day had a 1.64-fold higher risk for mortality from COLD than nonsmokers; in contrast, ex-smokers who smoked more than 39 cigarettes per day had a 9.91-fold higher rate of death from COLD than nonsmokers. For any given number of cigarettes smoked 210 TABLE O.-Mortality ratios for bronchitis and emphysema in nonsmokers and in ex-smokers and current smokers by number of cigarettes smoked daily and number of years of cessation, U.S. veterans study Cigarettes/day Smoking status 0 < 10 1620 21-39 >39 Nonsmoker 1.00 - Ex-smoker 1.64 5.35 7.68 9.91 Current smoker 4.84 11.23 17.45 21.98 Years of cessation CUTC3d Nonsmoker smoker <5 5-9 l&14 15-20 >20 1.00 12.07 11.66 14.35 10 19 5.66 2.64 per day, however, ex-smokers had a lower risk than current smokers. As in the British study, mortality ratios initially increased over the first 9 years of cessation. After the first 9 years, mortality ratios for ex-smokers fell, but never reached the level of the nonsmoker. Two studies have evaluated mortality rates from COLD among physicians, a group among whom many quit smoking to protect their health. Fletcher and Horn (1970) assessed the mortality rates from bronchitis among physicians in England and Wales. Among doctors aged 35 to 64, there was a 24 percent reduction in bronchitis mortality between 1953-1957 and 1961-1965, as compared with a reduction of only 4 percent in the national bronchitis mortality rates for men of the same age in England and Wales. Enstrom (1983) assessed mortality trends from COLD in a cohort of 10,130 physi- cians in California. The standardized mortality ratio for bronchitis, emphysema, and asthma among male California physicians relative to American white men declined from 62 during the period 1950 to 1959 to 35 during the period 1970 to 1979. In summary, cessation of smoking leads to a decreased risk for mortality from COLD as compared with that of current smokers. The residual risk of death for the ex-smoker is determined by the person's prior smoking status and the number of years of cessation. However, the residual risk remains larger than that of the nonsmok- er, presumably because of the presence of irreversible lung damage acquired during prior smoking. Pipe and Cigar Smoking Mortality From COLD Several of the prospective epidemiological studies examined the relationship between pipe and cigar smoking and mortality from COLD. The data from these studies indicate that pipe smokers and 211 TABLE lO.-COLD mortality ratios in male pipe and cigar smokers, prospective studies Type of smoking Study Catwry Total NOtI- Cigar pipe pipe and Cigarette smoker only only cigar tdy Mixed American Cancer Society 9-State COLD total Emphysema Bronchitis 1.00 1.29 1.77 2.85 British doctors Canadian veterans American Cancer Society 25-State COLD total Emphysema Bronchitis COLD total Emphysema Bronchitis COLD total Emphysema Bronchitis 1.00 9.33 24.67 11.33 1.00 4.00 7.oil 6.67 1.00 3.33 .75 5.65 1.00 3.57 2.11 11.42 1.00 1.37 6.55 ' U.S. veterans COLD total (E&year Emphysema followup~ Bronchitis U.S. veterans COLD total !&year Bmnchitis, followup) emphysema 1.00 .79 2.36 39 10.08 1.00 1.24 2.13 1.31 14.17 1.00 1.17 1.28 1.17 4.49 1.00 0.84 2 1.44' 4.75 ' 1.00 2.535 13.13' ' Mortality rake for agea 55 to 64 only BIT presented. ' Pure ctgar. ' Pure pipe cigar smokers also experience higher mortality from COLD as compared with nonsmokers. However, the risk of dying from COLD is less than that of current cigarette smokers (Table 10). International Comparison of COLD Death Rates and Smoking Habits: The Emigrant Studies Reid (1971) reported that age-adjusted mortality rates from chronic nonspecific lung disease among British citizens varied with migration patterns. British men living in the United Kingdom had a- chronic, nonspecific lung disease death rate of 125 per 100,000, whereas migrants to the United States experienced a mortality rate of only 24 per 100,000, which is similar to the rate found in the U.S. population. Differences in cigarette smoking and air pollution were identified as the major factors contributing to the real excess in bronchitis morbidity experienced by the British in the United Kingdom. Rogot (1978) conducted a study of British and Norwegian emigrants to the United States. The mortality rate from chronic nonspecific lung disease (CNSLD) in Great Britain is about fivefold 212 that in the United States, whereas the mortality rate from CNSLD in Norway is slightly lower than that in the United States. In contrast, the British migrant rates were about equal to those of native-born Americans and the Norwegian migrant rates were the lowest. Mortality rates for CNSLD were higher for smokers than for nonsmokers in all groups. These data suggest that ethnic origin plays a minor role, if any, in determining COLD risk. Regardless of country of origin, these studies indicate that tobacco smokers experience higher mortality rates for COLD than do nonsmokers. COLD Mortality Among Populations With Low Smoking Rates Numerous studies have reported that certain population groups who traditionally abstain from cigarette smoking for religious or other reasons have lower mortality rates from those diseases traditionally related to tobacco use. The 1982 and 1983 Reports of the Surgeon General, The Health Consequences of Smoking (USDHHS 1982, 19831, extensively reviewed this phenomenon as it relates to cancer and cardiovascular diseases among Mormons, Seventh Day Adventists, and others. Because Amish are seen as strict and fundamentalist in outlook, it is assumed that their use of tobacco is severely restricted. While cigarettes are largely considered taboo, pipe and cigar smoking and tobacco chewing are widespread (Hostetler 1968). Hamman et al. (1981) examined the major causes of death in Old Order Amish people in three settlements in Indiana, Ohio, and Pennsylvania to determine if their lifestyle altered their mortality risk compared with neighboring non-Amish. Mortality ratios from all respiratory diseases were significantly lower by over 80 percent in Amish men 40 to 69 years old, and by 50 percent in those 70 and older. In the chronic pulmonary disease categories including emphysema, bronchitis, and asthma, only one Amish male death occurred, whereas approximately 23 were expected. The pattern of mortality "om chronic respiratory diseases was similar for Amish women. Summary and Conclusions 1. Data from both prospective and retrospective studies consis- tently demonstrate a uniform increase in mortality from COLD for cigarette smokers compared with nonsmokers. Cigarette smoking is the major cause of COLD mortality for both men and women in the United States. 2. The death rate from COLD is greater for men than for women, most likely reflecting the differences in lifetime smoking patterns, such as a smaller percentage of women smoking in 213 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 eventually leads to a decreased risk of mortality from COLD compared with that of continuing smokers. The residual excess risk of death for the ex-smoker is directly proportional to the overall lifetime exposure to ciga- rette smoke and to the total number of years since one quit smoking. However, the risk of COLD mortality among former smokers does not decline to equal that of the never smoker even after 20 years of cessation. 6. Several prospective epidemiologic studies examined the rela- tionship between pipe and cigar smoking and mortality from COLD. 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PATHOLOGY OF LUNG DISEASE RELATED TO SMOKING 219 CONTENTS Introduction Lesions Associated With Chronic Airflow Obstruction Central Airways Mucus Other Abnormalities of Central Airways Peripheral (Small) Airways General Review Smoking and Lesions of Peripheral (Small) Airways Vascular Lesions Related to Smoking Emphysema Definition Classification Proximal Acinar Emphysema Panacinar (Panlobular) Emphysema Distal (Paraseptal) Acinar Emphysema Irregular Emphysema Tobacco Smoking and Emphysema Summary and Conclusions References 221 introduction It is usual to think of chronic airflow obstruction as being caused by airway narrowing or loss of airflow driving pressure-the elastic recoil of the lung (Macklem 1971J-or both. Lesions of the airways are often divided into those of the "large airways" and those of the "small airways." The reasons for this division are both historical and conceptual. Hogg et al. (1968) showed that in patients with chronic obstructive lung disease (COLD) the major site of airway obstruction lay in airways that were peripheral to the wedged catheter that the researchers used to partition airway resistance. The catheter was wedged in airways 2 or 3 mm in diameter, and thus the airways peripheral to the catheter included the smallest bronchi (airways with cartilage in their walls) and bronchioles (conducting airways without cartilage in their walls). Since both bronchi and bronchioles were involved, Hogg and associates used the term "small airways" to describe them, which has since become a popular term. Conceptual- ly, lesions of airways may consist of an intraluminal component (mucus) or a mural component. Most of the mucus in the airways is thought to be secreted by the tracheobronchial submucosal glands (Reid 1960); these are mainly confined to airways more than 2 or 3 mm in diameter, or large airways. Because of the documented association between chronic productive cough and airflow obstruc- tion (Fletcher et al. 1959), for a long time it was thought by many that intraluminal mucus was a major source of chronic airflow obstruction. Thus, the notion developed, without proper substantia- tion, that central airways obstruction was due to intraluminal mucus and peripheral airway obstruction was due to inflammation and narrowing. It is also true that many have equated emphysema with loss of elastic recoil, but when this has been examined in vivo (Park et al. 1970; Boushy et al. 1970; Gelb et al. 1973; Berend et al. 1979; Pare et al. 1982) or in excised lungs (Berend et al. 1980; Silvers et al. 1980), the association has not been close, with some notable exceptions (Niewoehner et al. 1975; Greaves and Colebatch 1980). Thurlbeck (1983) reviewed the evidence and argued that loss of recoil in emphysematous lungs may not be due to the lesions of emphyse- ma per se but to defects in apparently morphologically normal intervening lung tissue. The classical approach to considering the different sites of flow obstruction is used in this chapter to analyze the relationship between smoking and the morphologic lesions associated with chronic airflow obstruction in humans. Lesions of the large airways (bronchi) are discussed first, followed by small airways, and then by alveolated structures. It has very recently become apparent that it is important to include respiratory bronchiolitis as well as emphysema in the last category (Wright et al., in press); this issue is discussed in the paragraphs on peripheral (small) airways. Definitions and a brief 223 review of the diseases involved are provided. This chapter attempts to present the morphologic changes associated with chronic obstruc- tive lung disease. The detailed epidemiologic and experimental evidence relating cigarette smoking and COLD are presented elsewhere in this Report. Lesions Associated With Chronic Airflow Obstruction Central Airways MUCUS It is convenient to discuss intraluminal mucus and increased tracheobronchial mucus gland size together, because they are thought to be related (Reid 1960). Chronic bronchitis is defined as "the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree" (Ciba Foundation Guest Sympo- sium 1959). Because there is no way to accurately measure the amount of mucus secreted into the bronchi, the empirical approach was taken that production of any sputum was abnormal. Chronic was defined as "occurring on most days for at least 3 months of the year for at least 2 successive years" (Ciba Foundation Guest Symposium 1959). A further qualification was that such sputum production should not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. The initial step was to correlate chronic bronchitis, as defined above, with lesions in the central airways. This was first done by Reid (19601, who assessed gland size by comparing the thickness of the submucosal bronchial mucus glands in histologic sections to the thickness of the bronchial wall. The latter was defined as the distance from the basement membrane of the epithelium to the- inner periochondrium. This measurement is now known as the Reid Index. This increase has been confirmed by several observers (Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Mitchell et al. 1966; MacKenzie et al. 1969; Scott 1973), but not by all (Bath and Yates 1968; Karpick et al. 1970). An important observation was that there was a distinct overlap in the value of the Reid Index between bronchitics and nonbronchitics (Thurlbeck and Angus 1964) as opposed to Reid's 1960 finding that there were two completely separate groups. In practical terms, this meant that the Reid Index had limitations in predicting the presence or absence of chronic bronchitis. More important, it suggested a broad border between- health (nonbronchitis) and disease (bronchitis). For a variety of technical reasons (Jamal et al., in press), the Reid Index is a difficult measurement to use; thus, other measurements of mucus gland size- were developed. The most popular was the volume density of mucus glands, i.e., the ratio of area of mucus glands to area of the entire bronchial wall as seen on histologic slides (Hale et al. 1968; Dunnill 224 et al. 1969; Takizawa and Thurlbeck 1971; Oberholzer et al. 1978). Other methods included absolute gland size (Restrepo and Heard 1963; Bedrossian et al. 1971) and a radial intercept method (Alli 1975). The size of the acini (tubules) of mucus glands, the number per unit area, and the ratio of mucus to serous tubules have also been used (Reid 1960). The Reid Index, the volume density of mucus glands, and the ratio of mucus to serous acini have been examined in smokers and nonsmokers; the results are shown in Table 1. When one considers the overwhelming association between smoking and chronic bronchi- tis in living subjects, differences in mucus gland size are insignifi- cant. For example, three laboratories (Reid 1960; Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Scott 1973) have found a difference in Reid Index between smokers and nonsmokers; two have not (Bath and Yates 1968; Hayes 1969). The results from volume density of mucus glands are clearer-Ryder et al. (1971) found a higher volume density of mucus glands in both male and female subjects. In populations of mixed sex, Cosio et al. (1980) and Pratt et al. (1980) found a higher volume density of glands, but Sobonya and Kleiner- man (1972) and Scott (1973) did not. When observers have expressed their morphologic findings as either "normal" or "abnormal" (using different criteria), the smokers have been significantly abnormal in all the studies (Field et al. 1966; Megahed et al. 1967; Petty et al. 1967; Vargha 1969). The balance of the evidence is that there is an increase in mucus gland size in smokers. The discrepancy between the clinical and the morphologic findings may reflect several factors: the wide variation in mucus gland size in normal subjects, the difficulties in measuring the Reid Index and volume density of mucus glands, the different ways in which the cases have been collected, and the errors inherent in assessing smoking histories- from analysis of charts; also, the fact that mucus glands can enlarge terminally (Helgason et al. 1970) might obscure true differences between the two groups. In addition, submucosal gland enlargement is a nonspecific change that can also occur in pneumoconiosis and cystic fibrosis. Mucus is also secreted by goblet cells, most of which are in the major airways. Pratt et al. (1980) showed that goblet cells constituted 10.7 percent of the cells in the central airways of nonsmoking nontextile workers and 20.4 percent in smoking nontextile workers. Interestingly, they found an 18 percent frequency of goblet cells in nonsmoking textile workers; the frequency was about the same in smokers, whether or not they were textile workers. Other Abnormalities of Central Airways A variety of other changes have been described in the central airways in patients with chronic airflow obstruction, including 225 TABLE L-Comparison of mucus gland size in smokers and nonsmokers Findings in smoking category Assessment of mucus gland enlargement Author Light and NOW moderate Heavy smokers Smokers smokers smokers Reid index Reid (1960) 0.46 0.43 Thurlbeck et al. (19631 0.43 0.50 0.45 0.53 Thurlbeck and Angus 11964) 0.44 0.49 Bath and Yates 119681 0.45 0.49 Hayes (19691 0.32 0.33 Scott (1973) 0.41 0.46 Mucus gland proportion Ryder et al. (1971) (men) 14.5% 17.8% Ryder et al. (1971) women) 14.5% 17.1% Sobonya and Kleinerman (1972) 11.2% 10.7% Scott 119731 14.1% 14.4% C&o et al. (1980) Increased Pratt et al. 11980~ 9.3% 12.6% Frequency of cases Field et al. 119661 (men) with MGH ' expressedField et al. (1966) lwomenl as a percentage of Megahed et al. (1967) cases m the group Petty et al. (19671 Vargha 11969) 12% 37% 18% 26% 14% 61% 8.8% 37% 18% 44% 1 MGH = Mucus gland hypertrophy inflammation and edema of the wall (Reid 1954), increase in bronchial smooth muscle (Hossain and Heard 1970; Takizawa and Thurlbeck 19711, and diminished cartilage, which is related more to emphysema than to chronic bronchitis (Thurlbeck et al. 1974a). Peripheral (Small) Airways General Review As indicated, it was as recent as 1968 that the obstruction in patients with chronic airflow obstruction was conclusively shown to be due mainly to lesions in airways less than 2 or 3 mm in diameter. However, abnormalities in these airways had long been recognized. Indeed, Laennec (1962) pointed out in 1826 that air remained trapped in emphysematous lungs even when the major bronchi had been opened, and he reasoned that the source of the air-trapping was obstruction in the airways peripheral to the opened ones Since then, numerous descriptions have been made of the peripheral airways in severe chronic airflow obstruction (see Table 2). Smokers were not compared with nonsmokers in any of these series. The probable reason is that for a long time it was thought that bronchiolitis was an infective complication of chronic bronchitis. Only very recently, and from studies in patients with mild chronic airflow obstruction, 226 has the link between smoking and peripheral airway lesions become established. Hogg et al. (1968) not only found that the peripheral airways were the site of airflow obstruction in patients with severe disease, but also observed that peripheral airways contributed only about 15 percent of resistance to flow in normal lungs. It followed that considerable disease could be present in these peripheral airways without airway resistance being measurably increased. It was reasoned also that standard tests of expiratory function, such as the FEVl and the FEFww, might not be abnormal in the presence of significant disease. Thus a variety of "tests of small airway function" were devised; these evolved to the single breath nitrogen washout test and to flow volume studies, in some instances comparing the effect of breathing helium mixtures with the effect of breathing room air. It soon became apparent that these tests could be abnormal when the FEVl was greater than the 80 percent predicted and that tests of small airway function could return to normal after cessation of smoking (Buist et al. 1976, 1979; Beck et al. 1981; Bouse et al. 1981). The term "small airways disease" was and is often applied to these abnormalities. It then became of interest to determine what the lesions in the airways were. Long before this, Reid (1955) had studied nine lungs resected from patients with chronic bronchitis and two lungs from chronic bronchitics obtained at autopsy. She found excess intraluminal mucus and narrowing and obliteration of airways, as assessed subjectively. Because the surgical patients also had lung cancer, most likely they were chronic smokers. Matsuba and Thurlbeck (1973) compared the airways of chronic bronchitics to those of nonbronchitics in nonemphysematous lungs. All the bron- chitics were smokers and two nonbronchitics were smokers. Morpho- metrically, they found obvious narrowing of airways less than 2 mm in diameter, which also contained excess mucus. The important study by Cosio et al. (19781, using surgically resected lungs, showed for the first time that abnormal tests of small airway function were related to abnormal morphology. There were 34 smokers and 2 nonsmokers in their group. A variety of abnormali- ties were observed, including inflammation, squamous cell metapla- sia, ulceration, fibrosis, pigmentation, and increased muscle. They developed a score that summed the observed lesions (the total pathology score), and divided their patients into four groups on the basis of this score. They showed that as the total pathology score increased, tests of small airway function (single breath nitrogen test and flows on air and helium mixtures) deteriorated, as did standard tests of pulmonary function such as the FEVl and FEFzsx. The data concerning smoking are hard to interpret, but the smoking index (number of cigarettes smoked per day times number of years smoked) increased from groups I to III and was similar in groups III 227 TABLE 2.-Occurrence of lesions of peripheral airways in patients with severe chronic airflow obstruction Authors Disease invest:gated Abnormalities found Laennec (1962) Spain and Kaufman ( 1953) Reid (1954) Emphysema Chronic bronchitis Leopold and Gough (1957) Centrilobular emphysema McLean (1958) Emphysema Anderson and Foraker (1962) Pratt et al. (1965) Anderson and Foraker (1967) Hogg et al. (1968) Mitchell et al. (1968) Bqnon et al (1969. 1970) Karpick et al. 119701 Linhartova et al. (19711 Matauba and Thurlbeck (1972) Linhartova et al. 11973, 1974, 19771 Scott and Steiner (1975) Scott c 19761 Mitchell et al. (1976) Emphysema Emphysema Centrilobular emphysema Emphysema Emphysema with severe chronic airflow obstruction Chronic airflow obstruction and severe emphysema Cm pulmonale and centrilobular emphysema Respiratory failure Emphysema Severe emphysema and chronic airflow limitation Emphysema Car pulmonale Chronic airflow obstruction Chronic airflow obstruction obstruction Obstruction to flow in peripheral airways Mural inflammation and fibrosis of bronchioles Bronchiolitia, broncbiolar oblit- eration, and mxus plugging Inflammation, fibrosis with narrowing of 60% of bronchioles supplying centrilobular space Inflammation of proximal rea- piratory bronchioles, mucus plugging, and loss of bronchioles Collapse of bronchioles due to loss of alveolar attachments Loss or distortion of the radial support of bronchioles Loss of bronchioles in patients under age 70 Inflammation and fibrosis of bronchi and bronchioles and nNKus plugging Inflammation, atrophy, goblet cell metaplasia, squamous metaplasia, and mucus plugs in bronchioles Inflammatory narrowing and fibrosis, loss of bronchioles. and mucus plugging Goblet cell metaplasia Plugging of bronchioles with inflammatory cells and mucus Loss of lumen of airways less than 2 mm in diameter due primarily to narrowing and InUCus plugs Distortion, tortucsity, and irregular narrowing of bronchioles Lack of tilling bronchioles of less than 1 mm Loss of airway lumen Chronic inflammation (r=0.48), narrowing (OB), fibrosis (0.27). goblet cell metaplasia (0.241, and fewer small airways (-0.18) 228 and IV. The lesions that were different in group II from lesions in group I were squamous cell metaplasia, inflammation, and fibrosis. Fibrosis and squamous cell metaplasia increased steadily from groups I to III. Increased muscle and goblet cell metaplasia occurred only in group IV. One extrapolation of these data is that inflamma- tion in the peripheral airways is the initial event produced in response to cigarette smoke. This inflammation leads to, or is associated with, squamous metaplasia and mural fibrosis. Goblet cell metaplasia and increase in muscle subsequently occur and are associated with decrements of function. Berend et al. (1979) did a similar study on 21 smokers and 1 nonsmoker, and added the important information that airway narrowing occurred and was associated with abnormalities of the single breath nitrogen washout test and the FEFs75. The data were reanalyzed subsequently (E&end et al. 1981b) and showed that inflammation was the lesion associated with the most abnormalities in tests of expiratory function. Airway inflammation was significant- ly related to abnormalities of the FEV1, FEFzF~x, slope of phase III of the single breath nitrogen test, and closing volume expressed as a percentage of vital capacity. The authors also noted that as the total pathology score got worse, the airways diminished in caliber in surgically derived lungs, but not in autopsy lungs. They noted that airway caliber was larger in autopsy lungs than surgical lungs, and suggested that this represented functional narrowing due to in- creased muscle tone, which was caused by release of mediators affecting the muscle directly or reflexly. Studies of lungs at autopsy have shown correlations between airway lesions and abnormal tests of function. Petty et al. (1980, 1982) have shown that correlations exist between inflammation, and increased muscle and elevations in the closing capacity; that occlusion of airways by cells and mucus, inflammation, and in- creased airway muscle are related to abnormalities of the slope of phase III of the nitrogen washout; that airway narrowing is closely related to the FEVi, FEFs75, and slightly less well related to closing capacity. Similarly, Berend et al. (1981a) showed an association between post-mortem closing capacity and both peripheral airways inflammation and a total pathology score. Decrease in maximum flow at a transpulmonary pressure of 5 cm HzO was related to inflammation and the total pathology score, but not as well related to airway narrowing (Berend and Thurlbeck 1982). Morphologic abnormalities similar to those found in autopsy lungs have been found in surgically excised lungs derive* almost entirely from smokers, and these in turn have been related to abnormal tests of small airway function. Smoking and Lesions of Peripheral (Small) Airways An increase in goblet cells was the first abnormality of peripheral airways noted in smokers. The observation was made in bituminous coal workers. In nonsmokers, about 0.66 percent of peripheral airway cells were found to be goblet cells; in smokers, this rose to about 1.0 percent (Naeye et al 1971). The critical observation, both factually and conceptually, was that of Niewoehner et al. (1974). In an autopsy study of men under the age of 40 who died suddenly elsewhere than in the hospital, they compared lesions of bronchioles and respiratory bronchioles (airways with both nonrespiratory epithelium and alveoli in their walls) in smokers and nonsmokers. Emphysematous lungs were excluded, and the smoking history was obtained by personal interview with close relatives, using a standard questionnaire. The researchers found that intraluminal mucus, mural edema, peribronchiolar pigment, peribronchiolar fibrosis, denuded epithelium, mural inflammatory cells, and respiratory bronchiolitis were more severe in the smokers. The last three were significantly different statistically. They empha- sized the importance of respiratory bronchiolitis, which consisted of aggregates of brown macrophages in and around the first and second order respiratory bronchioles and was associated with edema, fibrosis, and epithelial hyperplasia in adjacent bronchioles and alveolar walls. Bronchiolitis was found in all of the smokers, but in only 5 of the 20 nonsmokers, and it was the lesion that showed the greatest difference between smokers and nonsmokers. Since respira- tory bronchiolitis was found in precisely the same regions where centrilobular emphysema is found in subjects 20 years older, the researchers suggested that this lesion might evolve into emphysema. This observation fits well the proteolytic-antiproteolytic hypothesis of the pathogenesis of emphysema. Ebert and Terracio (1975) compared the peripheral airways in resected lungs of 22 smokers and 3 nonsmokers and found that the number of Clara cells (the tall nonciliated airway cells thought to be secretory, although the nature of their secretion is not completely certain) was diminished, as assessed subjectively, and the number of goblet cells was increased, as assessed quantitatively. Two laboratories have concentrated on the association between smoking and lesions of vessels as well as of airways. One has used autopsy-derived lungs (Casio et al. 1980; Hale et al 1980); the other, surgically excised lungs (Wright et al. 1983a, b, in press). The first material has the advantage that the entire lung can be examined, but has the disadvantage that agonal changes may affect the airway; the second has the advantage that agonal changes are absent and structure-functional studies can be done, but has the serious disadvantage that usually only a part of the lung is examined. Because of the wide variation in severity of emphysema from lobe to 230 lobe, emphysema in the whole lung cannot be assessed from a single lobe. Also, airway inflammation may not be evenly distributed through the airways (Berend 1981; Hale et al. 1980). Cosio et al. (1980) studied 14 nonsmokers with an average age of 71.6 years and 25 long-term smokers with an average age of 58.4 years. The total pathology score was significantly higher in the smokers; in them, but not in the nonsmokers, the total pathology score was significantly related to age. Respiratory bronchiolitis was more common in the smokers, and of the components of the total pathology score, goblet cell metaplasia (p