The Healthc a Consequences. : : ee | | | STON e OBSTRUCTIVE BOING DISEASE _ a report of the Surgeon General . \ % SA Public Health Service ‘%, ©) bilet-melale-jaale) diate M-lale Ma (-¥-11 60) ey. Rockville, Maryland 20857 d37q Pb i AN a Se & ) “ S . U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES OAK ST LIBRARY UNIVERSITY OF NOTICE: Return or renew all Library Materials! The Minimum Fee for each Lost Book is $50.00. The person charging this material is responsible for its return to the library from which it was withdrawn on or before the Latest Date stamped below. Theft, mutilation, and underlining of books are reasons for discipli- nary action and may result in dismissal from the University. To renew call Telephone Center, 333-8400 UNIVERSITY OF ILLINOIS LIBRARY AT URBANA-CHAMPAIGN AUG 25 | MAY 27 FEB L161—O-1096 The Health Consequences Of Smoking CHRONIC OBSTRUCTIVE LUNG DISEASE a report of the Surgeon General 1984 SERVIC gy > y Ny ~ U.S, DEPARTMENT OF HEALTH AND HUMAN SERVICES J Public Health Service % Office on Smoking and Health %, Rockville, Maryland 20857 he For sale by the Superintendent Documents, “4 S. Government Printing. Office i ea 0402 hington, D.C. : \ —e oe <= «a Kee co - ee Ob a, ' My x ; 7 * ‘ we 4 cheat) af! gee eS eee a ot ie - ™ f : oi oR ae + wri POT BONS keaphiteny Or ain ; oy THE SECRETARY OF HEALTH AND HUMAN SERVICES WASHINGTON, D.C. 20201 The Honorable Thomas P. O'Neill, Jr. Speaker of the House of Representatives Washington, D.C. 20515 Dear Mr. Speaker: It is a pleasure to transmit to the Congress the Surgeon General's Report on the Health Consequences of Smoking, as mandated by Section 8(a) of the Public Health Cigarette Smoking Act of 1969. This is the Public Health Services' 16th report on this topic end, like all of the earlier Reports, it identifies cigarette smoking as the chief preventable cause of death and disability in our society. The enclosed report deals with the relationship between smok- ing and those disease conditions described as chronic obstructive lung disease, particularly chronic bronchitis and emphysema. These diseases significantly increase patient loads in hospitals and other health care facilities and escalate this Nation's health care costs, including expenditures under the Medicaid and Medicare programs. This report indicates that chronic obstructive lung diseases can be reduced and, in the case of emphysema, almost eradicated, if individuals stop cigarette smoking. Moreover, stopping smok- ing also would prevent the enormous suffering and human loss now well-known to be associated with smoking. This Department has a strong and ongoing commitment to its programmatic and research efforts in the field of disease preven- tion. In our view, it is essential to apprise individuals of the consequences of smoking. A central part of our efforts is to identify ways to help smokers quit smoking, and to encourage individuals, particularly the youth of this country, not to begin smoking. Sincerely, A: ; et M. Heckler Secrétary Enclosure ~} f uw’ ie r 4? - hy @ , in 5 - 7 / a ’ ' - “4 ; a ’ 7 re 1 > sled « +? se } ree Bata i e Sie* tue Ce PAL Haue hoe ‘ a* it At)-g et i*eg4° 4% ts i re , aoe y) 7 $4 | oo ) ey ears rhe eng > 9eony Vr 4 <1 va, Vad eeaR oe 4 of a als)’ wee ' ifiw. tae eee Sf h a eee ipe® eo selon). oe am >aly ©& er ecrnee herbed eee pe Mt 7 , “3° DPved isons ‘\e irs Pitan 5 oO. vd i leet oe af Peet Sey tne i ¢hew lise, ide) pip Biveets mi wvi@ ae ot Wey aakeed: 7+ ine ete »S-97ea; AO ES ve ¥ wie eta ie ste S At l°. ® gee /leeedaet 74 Obed oF OF an ak al 2s «wey pre wai tL Ane { rae won “alas > cow ; it Coeuiteg «i Ane oS a tat > , Ps : eine? * aes eg eta y et . Fit) weal nd Wis ver ae THE SECRETARY OF HEALTH ANDO HUMAN SERVICES WASHINGTON, O.C. 20201 The Honorable George Bush President of the Senate Washington, D.C. 20519 Dear Mr. President: It is a pleasure to transmit to the Congress the Surgeon General's Report on the Health Consequences of Smoking, as mandated by Section 8(a) of tha Public Health Cigarette Smoking Act of 1969. This is the Public Health Services' 16th report on this topic and, like all of the earlier Reports, it identifies cigarette smoking as the chief preventable cause of death and disability in our society. The enclosed report deals with the relationship between smok- ing and those disease conditions described as chronic obstructive lung disease, particularly chronic bronchitis and emphysema. These diseases significantly increase patient loads in hospitals and other health care facilities and escalate this Nation's health care costs, including expenditures under the Medicaid and Medicare programs. This report indicates that chronic obstructive lung diseases can be reduced and, in the case of emphysema, almost eradicated, if individuals stop cigarette smoking. Moreover, stopping smok- ing also would prevent the enormous suffering and human Joss now well-known to be associated with smoking. This Department has a strong and ongoing commitment to its programmatic and research efforts in the field of disease preven- tion. In our view, it is essential to apprise individuals of the consequences of smoking. A central part of our efforts is to identify ways to help smokers quit smoking, and to encourage individuals, particularly the youth of this country, not to begin smoking. Sincerely, Enclosure - 9 ing, ’ * = ® | . a ‘ 2 4 - ~ é 2 a i , *. ~ . - mgs és V s oe 2ie dO Be OS ; ’ ‘ a7 a \, @eegyr ane iv ? re) : ’ plate ' «ashe G2 eee rR ;oe os sake ens tiene OTP | -e4 = vow “@q~ "6 i ’ i e - 1 Jagat terepart) Sei gue ; $ ~ onto << ag ' er ho Sy ole 29. een "'s eat Spey See eee a't9eeod @2 OS RR ) 7 f ~ shee ek) sien a) e a _ rer by ‘ yeas of Se ae i 4 vibe pots , a ef 8 6 . | at af i ¢eee* bal d i j 7 ”s fees cs a ‘3 “as a? é - — n . Pus 7 ot dip ee ; ‘ ‘< oe -' e- é a . ~ oder amt rm , me a er ee ee — i A 7 fr _ ‘, ty ; : & ie i ee i. ma » ' - 7 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 vill 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. 1x 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 Xx 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 xl ie tid aE eshte ba Cate t<, hf a “tA. w& ‘= a - ’ Lams oe: nate ik 4 pened wv Punks Rene EE eae oe et On ary. ‘al ges warding . ; (* Take Wy a : 7) raat a8 Sf é / “—n ee #\ ects i" erin ergy itil Ae de ‘ey . ; Web * ° ‘ ' i i + A 4 iY ca ee an ri : “il “4 ees ' ti + y" a > ai VO ae, a L, . 7 i i Rano y ee yun he rr Ss ie | - ee > a i ee Va i a A ce ra. a i a row ‘ ’ as 4 ‘ ave ral ide J : ‘at “i Cam : ; “S) PE fii ot, atvb nti ia thy a yieo® tga ; a *-% acguaia at Monk. Saag ‘omc ane a a mile wh, Md WA Tggignelieion vy rd an a i ae i ioendee goa Has ieee = yan ft ie ne: PREFACE This Report The Health Consequences of Smoking: Chronic Ob- structive Lung Disease completes an examination by the Public Health Service of the three principal disease entities associated with cigarette smoking. In 1982, the Service presented an in-depth review of tobacco’s relationship to cancer, and in 1983, a review of its relationship to cardiovascular disease. This 1984 Report evaluates the contribution that tobacco makes to the suffering and premature deaths due to the chronic obstructive lung diseases, including emphysema and chronic bronchitis. Cigarette smoking is causally related to chronic obstructive lung disease, just as it is to cancer and coronary heart disease; severe emphysema would be rare were it not for cigarette smoking. The evidence presented in this Report supports my judgment and the judgment of five preceding Surgeons General that cigarette smoking is the chief, single, avoidable cause of death in our society and the most important public health issue of our time. This Report, as were all previous Surgeon General’s Reports dealing with cigarette smoking, is the work of many experts both within and outside the Federal establishment. To these authors, editors, and reviewers I again express my great respect and sincere thanks. C. Everett Koop, M.D. Surgeon General Xili {AVIA i A: “_ S : —_.* ‘ - y = - , "i eg é ab ee ve : * 7 wes, - » - *? ee t 2 > = sh’ r ~s { HF " ; > ly ia! Sf * Sas Lee ee G i}, : ] 4 _ 1 s > Hii fee | , aw) F ¥ Aye ‘ tu ar 4 ar : t ay } gta) a Seas 2 a ous 9 iy % i +4 é 7 S 4 - \/ eq é ivi c < f “P 2 é revi Ds ) kl ] ‘i si 's. Peer ae — > Ae a ee r ~ - " " “ A ~ 5 . vier 2 Wer, «6 mie i gith< 1h fav 8 u “ A f gaat 9 ae 2 Yue Ges Os + A vis atraw sf ; arms bad, @ . oft | toxgnale t Sant Jerre iy eaowee preted ps riers ; Pees on +1 2 v7 A5.5 coo sg 4 é., lenattard smQepriae D i Ces coe 6s . ; 2+ re - ‘ iy : ’ yh : : ’ e > -_ re se 7 - ; + f = a: at “he, an iar © a i ; a — Ml EP ey Fan soy rit es 4 ™ b vey ola 4 Ra 49%) ")- aes a : wef * i os ee ee x in as ‘WO i - . aa 7 be 7 _ “4 acd howl ste “ong weno’ § ipa fy ome a oT pie bp em sprniny Sue 4 naied 1d 3K meg afb. Lite =. a da ~- 02 #170 ¢ me Sin) 2 st 4. “ih Ay AI EIS nrg oe *y : ‘tg oe Habape Ss wiysia 9 2 ae ieee. ER IES 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 Director 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 priteaee of Internal Medicine, eariga faa 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, lowa City, lowa Philip Kimbel, M.D., Chairman, Department of Medicine, The Graduate Hospital, Philadelphia, Pennsylvania Edgar C. Kimmel, Pharmacodynamics and Toxicology Division, University of Kentucky College of Pharmacy, Lexington, Ken- tucky Charles Kuhn, M.D., Department of Pathology, Jewish Hospital at Washington University Medical Center, St. Louis, Missouri Alfred L. McAlister, Ph.D., The University of Texas Health Science Center at Houston, Houston, Texas John McCarren, M.D., Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, California Linda L. Pederson, Ph.D., Department of Epidemiology and Biosta- tistics, University of Western Ontario, London, Ontario, Canada John A. Pierce, M.D., Department of Medicine, Washington Univer- sity Medical Center, St. Louis, Missouri Jonathan M. Samet, M.D., Associate Professor of Medicine, The University of New Mexico School of Medicine, Albuquerque, New Mexico Robert M. Senior, M.D., Professor of Medicine, Respiratory and Critical Care Division, Jewish Hospital at Washington University Medical Center, St. Louis, Missouri Frank E. Speizer, M.D., Associate Professor of Medicine, Harvard Medical School, and Associate Chief, Channing Laboratory, Brig- ham and Women’s Hospital, Boston, Massachusetts Ira B. Tager, M.D., M.P.H., Division of Infectious Disease, Beth Israel Hospital and Channing Laboratory, Brigham and Women’s Hospi- tal, and Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts William M. Thurlbeck, M.D., F.R.C.P.(C), Professor of Pathology, Department of Pathology, The University of British Columbia, Vancouver, British Columbia, Canada Martin J. Tobin, M.D., M.R.C.P.1., Assistant Professor of Medicine, Division of Pulmonary Medicine: Department of Internal Medi- cine, The University of Texas Health Science Center at Houston, Houston, Texas XVi Adam Wanner, M.D., Professor of Medicine and Chief, Division of Pulmonary Diseases, University of Miami School of Medicine, _ Miami Beach, Florida Scott T. Weiss, M.D., M.S., Associate Chief, Pulmonary Division, Beth Israel Hospital, and Assistant Professor of Medicine, Har- vard Medical School, Boston, Massachusetts The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Oscar Auerbach, M.D., Senior Medical Investigator, Veterans Ad- ministration Medical Center, East Orange, New Jersey John Bailar III, M.D., Ph.D., Office of the Assistant Secretary of Health, Office of Disease Prevention and Health Promotion, Washington, D.C. David V. Bates, M.D., F.R.C.P.(C), Professor of Medicine, Department of Health Care and Epidemiology, The University of British Columbia, Vancouver, British Columbia, Canada Benjamin Burrows, M.D., Division of Respiratory Science, University of Arizona College of Medicine, Tucson, Arizona Jacqueline Coalson, Professor of Pathology, School of Medicine, University of Texas at San Antonio, San Antonio, Texas Allen B. Cohen, M.D., Ph.D., Executive Associate Director and Professor of Medicine, The University of Texas Health Center at Tyler, Tyler, Texas Manuel G. Cosio, M.D., Director, Pulmonary Laboratories, Royal Victoria Hospital, Montreal, Quebec, Canada Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Public Health Service, Department of Health and Human Services, Hyattsville, Maryland Benjamin G. Ferris, Jr., M.D., Professor of Environmental Health and Safety, Department of Physiology, Harvard School of Public Health, Boston, Massachusetts Gareth M. Green, M.D., Professor and Chairman, Department of Environmental Health Sciences, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland Clarence A. Guenter, M.D., F.R.C.P.(C), Professor and Head, Depart- ment of Medicine, The University of Calgary Foothills Hospital, Calgary, Alberta, Canada Ian T. T. Higgins, M.D., Professor of Epidemiology, Department of Epidemiology, The University of Michigan School of Public Health, Ann Arbor, Michigan John R. Hughes, M.D., Assistant Professor, Department of Psychia- try, University of Minnesota, Minneapolis, Minnesota 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 O. Mason, M.D., Director, Centers for Disease Control, Atlanta, Georgia Kenneth M. Moser, M.D., Professor of Medicine and Director, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at San Diego, San Diego, California C. Tracy Orleans, Ph.D., Division of Psychosomatic Medicine, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Terry F. Pechacek, Ph.D., Assistant Professor, Division of Epidemiol- ogy, School of Public Health, University of Minnesota, Minneapo- lis, Minnesota Solbert Permutt, M.D., Professor of Medicine, Department of Medi- cine, Division of Pulmonary Medicine, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland 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.Sc., LC.R.S., Clinical Trial Service Unit, Radcliffe Infirmary, University of Oxford, Oxford, England Thomas L. Petty, M.D., Professor of Medicine, and Director, Webb Waring Lung Institute, University of Colorado Health Sciences Center, Denver, Colorado James L. Repace, Office of Policy Analysis, U.S. Environmental Protection Agency, Washington, D.C. Attilio D. Renzetti, Jr.. M.D., University of Utah Medical Center, Salt Lake City, Utah John Repine, M.D., Webb Waring Lung Institute, Denver, Colorado XVili Eugene Rogot, Statistician, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Marvin A. Sackner, M.D., Director, Medical Services, Mount Sinai Medical Center, and Professor of Medicine, University of Miami School of Medicine, Miami Beach, Florida Roy J. Shephard, M.D., Ph.D., Director of School of Physical and Health Education, University of Toronto, Toronto, Ontario, Cana- da Gordon L. Snider, M.D., Professor of Medicine and Director, Pulmo- nary Center, Boston University School of Medicine, Boston, Massachusetts Donald F. Tierney, M.D., Department of Medicine, School of Medi- cine, Center for the Health Sciences, University of California at Los Angeles, Los Angeles, California Nicholas J. Wald, M.R.C.P., F.F.C.M., Professor, Department of Environmental and Preventive Medicine, The Medical College of St. Bartholomew’s Hospital, University of London, London, Eng- land James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland : The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Erica W. Adams, Copy Editor, Information Programs Division, Informatics General Corporation, Rockville, Maryland Richard H. Amacher, Director, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Richard J. Bast, Medical Translation Consultant, Information Pro- grams Division, Informatics General Corporation, Rockville, Mary- land Charles A. Brown, Programmer, Data Processing Services, Informat- ics General Corporation, Rockville, Maryland Clarice D. Brown, Bio-Statistician and Epidemiologist, Office on Smoking and Health, Rockville, Maryland Joanna B. Crichton, Copy Editor, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Alicia Doherty, Information Specialist, Clearinghouse Projects De- partment, Informatics General Corporation, Rockville, Maryland Danny A. Goodman, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land xix Kit Hagner, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Rebecca C. Harmon, Publications Manager, Information Programs Division, Informatics General Corporation, Rockville, Maryland Karen Harris, Clerk-Typist, Office on Smoking and Health, Rock- ville, Maryland | Douglas M. Hayes, Publications Systems Supervisor, Publishing Services Division, Informatics General Corporation, Riverdale, Maryland Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Margaret H. Hindman, Publications Specialist, Information Pro- grams Division, Informatics General Corporation, Rockville, Mary- land Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Leena Kang, Data Entry Operator, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Spe- cialist, Office on Smoking and Health, Rockville, Maryland Julie Kurz, Graphic Artist, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Roberta L. Litvinsky, Secretary, Office on Smoking and Health, Rockville, Maryland William R. Lynn, Program Operations Technical Assistance Officer, Office on Smoking and Health, Rockville, Maryland Edward W. Maibach, Health Promotion Specialist, Informatics General Corporation, Rockville, Maryland Dixie P. McGough, Publications Specialist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Patricia A. Mentzer, Data Entry Operator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Kurt D. Mulholland, Graphic Artist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock- ville, Maryland | Sally L. Nalley, Secretary, Office on Smoking and Health, Rockville, Maryland Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland XX Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Roberta A. Roeder, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Anne C. Ryon, Copy Editor, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Linda R. Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Evelyn L. Swarr, Administrative Secretary, Data Processing Ser- vices, Informatics General Corporation, Rockville, Maryland Karen Weil Swetlow, Copy Editor, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Debra C. Tate, Publications Systems Specialist, Publishing Services Division, Informatics General Corporation, Riverdale, Maryland Jerry W. Vaughn, Development Technician, University of California at San Diego, San Diego, California Jill Vejnoska, Writer-Editor, Information Programs peor 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 “4 " ¢ a" ; As . + 6 Oth i tiny . o® - i? - + - *~ ' > £ ¢ wr es at > ‘ v. ad 4 A os ghana Mae nut ena rigor 6a" pear ne oro ¥, oli¥ine aca are + er Phi a me a aga sis ised rte Rit DES s geet agin utminl 198 5a cea, r ; ~~ te . "4 i Bee Tee ya = “el ear ian Nes si : a a cake wl ae parte " : $5 ite ee | g? aibaa ’ naa a j i’ q ¥ r. ‘ P cs ‘ am, v, lth A 8 a ‘ % £, t, Pry? * ¥ ' bes rg t ad Pe eS Paniarlere! abs VRQ 2 Pie } te ] ‘. 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A difference between men and women occurred in terms of the relationship between residual lung function (observed—predicted FEVi) 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, Vmax 50%, and V75~). For women smokers, pack-years best explained lung function loss as measured by residual lung function. These investigators thus found a very definite dose—re- sponse relationship between the amount smoked and lung function loss. They do point out, however, that smoking variables and age accounted only for up to 15 percent of the variation in residual lung function. | In summary, the data suggest a dose-response relationship between number of cigarettes smoked per day and the prevalence of abnormal results on tests of small airways function. That is, heavy smokers are more likely to have abnormal small airways function than light smokers. However, there is only a weak relationship between the degree of abnormality in small airways function and the number of cigarettes smoked per day or pack-years of smoking. In contrast, tests obtained from the forced expiration maneuver have a stronger dose-response relationship. This is consistent with the theory that cigarette smoking induces an inflammatory response in the small airways and that this response is more likely to happen in heavy smokers, as measured by sensitive measures of small airways function such as the single breath nitrogen test. The extent of chronic airway disease that reflects the dose and duration of the smoking habit is better measured by changes in the forced expirato- ry maneuver. How Soon Do Changes in Small Airway Function Occur? The first study to look at the prevalence of abnormalities on tests of small airways function by age in a large group of smokers was reported by Buist and coworkers (1973a). These investigators found that abnormalities of small airways function could be detected before age 30 by means of the single breath Ne test, with CV/VC discriminating best between smokers and nonsmokers in the age decade of the twenties (Figure 6). 35 Cdyn x 100 Cst (90 BPM) VisoV Percent predicted AV maxso Percent preuicted Symptoms score Slope phase III Percent predicted CC Percent predicted V maxso Percent predicted 0 1 2 3 4 Symptoms score FIGURE 5.—A composite of six tests plotted against symptoms score SOURCE: Dosman et al. (1976). 36 [4 284 Nonsmokers ["] 524 Smokers FA 268 Ex-smokers 80 60 p= ov) 5 a E 41 ° 40 : uf 5 36 a ats ae pt =r * . ay ae Oh oe oe “Ie fess} 24 21 = m oy ee Shag oo bp19 0 By i) 18 20 oe ee oe a CIR $3) = UN Ssh DS os 12 ui ' os = a) Bs ee oe See oe 1 Ce ee XA, ge on oe par te Th oo he okt cs oy oS Us Sd Se o{ 000 Z SSE Sle ot ee N=? 343 20 2 26 32 51 63 80 66 64 32 21 113 7 81 91 126 143 65 11 <20 20-29 30-39 40-49 50-59 60-69 70-79 >80 Age (years) FIGURE 6.—Prevalence of abnormal closing volume/Vvital capacity ratios in nonsmokers, smokers, and ex-smokers, by age decade SOURCE: Buist et al. (1973). In their cross-sectional survey of residents in three separate communities in Connecticut and South Carolina, Beck and cowork- ers (1981, 1982) found that the age of onset of abnormalities in lung function may occur as early as age 15 to 24. Their approach used residual lung function (observed—predicted value) for FEVi, Vmax 50%, and Vmax 75%, With a negative residual indicating an observed value below prediction. Negative residuals for all three measurements began to occur in women in the age group 15 to 24 (Figure 7). Significant differences among smoking categories—nonsmokers, ex- smokers, light smokers (1 to 20 cigarettes/day), and heavy smokers (>20 cigarettes/day)—were seen for Vmax 50% and Vmax 75% in women aged 15 to 24 and for FEV: in age group 25 to 34 (Figure 8). In male smokers, negative residuals began to occur for all three measure- ments in the age 25 to 34 group. Significant differences among the smoking categories were seen for FEV: in the 35 to 44 age group and for Vmax 50% and Vmax 75% in the 45 to 54 age group. Seely and coworkers (1971) found lower values for Vmax 50% and Vmex 75% in a group of high school students with 1 to 5 years of smoking experience. These differences were significant in boys who smoked more than 15 cigarettes per day and in girls who smoked more than 10 cigarettes per day. Significant differences between the smokers and nonsmokers were not found for FEV:. Dosman and coworkers (1981) studied 1,202 adults, aged 25 to 59, living in Humboldt, Saskatchewan. Among smokers in the 25 to 29 37 0.2 Age 7-14 15-24 25-34 35—44 45-54 55-64 65+ 0.1 = A es aT Te GE e Sg 2 ua a g S Z — 0.1 S o Ss s ” gs @ g @ 2 a = 7) & = @ ¢ o s - 0.2 A s g > AZ @ g tu eo Ss ue g g Z name 3 gs Women (n= 2,623) a g oH 0.4 [J Nonsmokers 2 EJ &x-smokers 0.5 te Light smokers (1-20 cigarettes/day) cc Heavy smokers (> 20 cigarettes/day) 0.6 ° No observations FIGURE 7.—Mean residual FEV: in women, by smoking status and age SOURCE: Beck et al. (1981). Age 7-14 15-24 25-34 3544 45-54 55-64 65+ 0 - S Se 2) ze A GE Hie Ue On s s s 4 4 3 e 2 Bahn 3 % > wo , § ci cae cies ¢ = 03 @ 4 3 : 4 4 IB HE i 0.4 g g s - Men (n=2,067) g S 2 -0.5 g 6 (_]} Nonsmokers - sg O06 (Cs) +Ex-smokers é GH Light smokers (1-20 cigarettes/day) b -0.7 g 4 Heavy smokers (> 20 cigarettes/day) -0.8 © No observations FIGURE 8.—Mean residual FEV: in men, by smoking status and age SOURCE: Beck et al. (1981). 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 FEV:i/FVC 38 were 2.1 percent in women and 5.6 percent in men. For both the slope of the alveolar plateau and CV/VC, the prevalence of abnormal test value increased steadily with increasing age, so that 63.6 percent of the female smokers aged 55 to 59 and 46.2 percent of the male smokers aged 55 to 59 had abnormal values. Comparable rates for an abnormal FEV:/FVC were 4.5 and 19.2 percent in the women and men, respectively. Walter and coworkers (1979) studied 102 Indian male medical students in their late teens and early twenties. Of the 102 subjects, 60 were nonsmokers, 23 were light smokers (lifetime total of <10,000 cigarettes), and 19 were heavy smokers (lifetime total of >10,000 cigarettes). The researchers compared mean pulmonary function values obtained from the. spirograms across the smoking categories. There was a consistent trend for all the lung function variables examined (FEF 20-30%, FEF%s555%, FEF 70-80%, FEF'so-90%, FEF 25-75%, and FEV:/FVC),with the highest mean values being seen in the nonsmokers, intermediate values in the light smokers, and the lowest values in the heavy smokers. There were no significant differences among the three groups in height and weight. No information was given in this report about the type of cigarettes smoked. | The consistency of results from the studies attempting to define the age of onset of measurable abnormalities in tests of small airways function is striking. Even though statistical significance was not always found, the trend is clear and provides strong evidence that measurable abnormalities of small airways function do occur in some smokers within a few years of smoking onset. Male-Female Differences in the Responses of the Small Airways to Cigarette Smoking When looking at variations between the sexes in response to cigarette smoking, one must take into account possible differences in the manner in which cigarettes are smoked, in the amount smoked, and in environmental exposures that may interact with smoking. Most investigators have found little or no difference based on sex for the relationship between the various tests of small airways function and age in nonsmokers. Thus, a difference between the sexes in response to smoking, if it exists, probably represents a true biological difference in the effect of smoking on lung function or variations in exposure dose resulting from method of smoking or amount smoked. Unfortunately, the information available in the literature about sex-related differences in small airways response to cigarette smok- ing is scanty and conflicting. Manfreda and coworkers (1978) found a higher prevalence of abnormality in tests of small airways function among male smokers than among female smokers in their study of two communities in Manitoba. The opposite finding has been 39 reported by Buist and coworkers (Buist and Ross 1973a, b; Buist et al. 1973, 1979a) in their studies of a screening center population and of population samples and groups in Montreal, Winnipeg, and Port- land. It is quite possible that selection bias in the screening center study limits the ability to extrapolate this study to the general population. The three-cities study, however, did not suffer from that flaw, and showed clear differences (women higher than men) in the prevalence of abnormalities of CV/VC and the slope of the alveolar plateau. The prevalence of abnormality of CC/TLC, on the other hand, was slightly higher in male smokers than in female smokers (32 and 29 percent, respectively). A surprising finding was that the prevalence of FEVi/FVC abnormality was considerably higher among women who smoked than among men who smoked (25 and 7 percent, respectively). At this point, a generalization is not yet possible on sex-related differences in the response of the small airways to cigarette smoking. However, it seems likely that the contribution of sex difference is relatively small once age and dose are taken into account. Effect of Smoking Cessation on Small Airway Function The correlation between abnormalities in tests of small airway function and the pathologic changes of inflammation of the small airways suggests that cessation of smoking may lead to a return toward normal in these tests. A number of authors have examined changes in tests of small airways function in cigarette smokers who have quit. Ingram and O’Cain (1971) examined six smokers with an abnormal frequency dependence of compliance who quit smoking. After 1 to 8 weeks of cessation, values in all six returned to the normal range. Bode et al. (1975) examined 10 subjects aged 29 to 61 with normal FEV: values while they were active smokers and again 6 to 14 months after they had stopped smoking. Static volume pressure curves, slope of phase III, and forced expiratory flow rates on air were unchanged by cessation. However, the maximum expiratory flow rates with helium at 50 and 25 percent of the vital capacity increased, and the volume of isoflow and closing volume decreased. McCarthy et al. (1976) followed 131 smokers aged 17 to 66 who volunteered to attend a smoking cessation clinic. Cessation resulted in a significant reduction in the closing capacity (CC/TLC%) and the slope of phase III within 25 to 48 weeks in the 15 persons who were able to abstain from cigarettes completely. Buist et al. (1976) followed a group of 25 cigarette is 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 CV/VC CC/TLC AN2/L Percent predicted Quitters = = SMOKETS Months after clinic FIGURE 9.—Mean values for the ratio of closing volume to vital capacity (CV/VOC), of closing capacity to total lung capacity (CC/TLC), and slope of phase III of the single breath Nz: test (AN2/L), expressed as a percentage of predicted value (12, 13) in 15 quitters and 42 smokers, during 30 months after two smoking cessation clinics * A significant difference from the initial value at p< 0.05. NOTE: Data from 3-month followup of the 1973 clinic and 4-month followup of the 1975 clinic have been combined, as have 6-month and 8-month data for the 1973 clinic. SOURCE: Buist et al. (1979a). This study was expanded using a second group of subjects (Buist et al. 1979b) and a 30-month followup. Once again, the three parame- ters of the single breath N2test showed improvement in smokers who quit; this improvement continued for 6 to 8 months, and then leveled off (Figure 9). In addition, the values for the single breath Ne test in those who quit returned to the levels predicted for nonsmokers, suggesting that the changes in the small airways can be substantial- ly reversed with cessation. Bake et al. (1977) also showed an improvement in the slope of phase III following cessation in a small group who were followed for 5 months. In summary, abnormalities in the small airways are substantially reversible in smokers who have not developed significant chronic airflow obstruction. This suggests that the inflammatory response in the small airways, which may be the earliest change induced by smoking, is also a change that reverses with the cessation of chronic exposure to the irritants in cigarette smoke. 41 480-144 0 - 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 FEV. If the tests of small airways function can be used alone, or in conjunction with other qualitative or quantitative data about risk factors, they will clearly be useful to the practicing physician. If they are too sensitive or have a poor predictive value, their use will be more limited. Buist and coworkers (1984) determined the positive and negative predictive value of tests of small airways function in their study of two cohorts followed prospectively over a 7- to 11-year period. They found that the positive and negative predictive values of the tests of small airways function varied greatly between the cohorts, largely because of the different ages and prevalences of an abnormal FEV: between the cohorts. They concluded that significant associations existed between the single breath N2 test variables and spirometric variables in smokers, but the weakness of these associations and the high misclassification rates suggest that small airways disease does not necessarily lead to clinical airflow obstruction. Over a period of 8 years, Marazzini and coworkers (Marazzini et al. 1977, 1981) followed a group of 69 asymptomatic workers in an iron foundry (49 smokers, 20 nonsmokers) living in the same area. They found that 39 percent of the smokers and 15 percent of the nonsmokers, initially diagnosed as having peripheral airways dis- ease, developed central airways obstruction (defined as 1 or more of the vital capacity (VC), FEV: or FEV:i/VC being more than 15 percent different from normal) within the 8-year followup. An indirect way to assess the predictive value of the tests of small airways function was proposed by Tattersall and coworkers (1978). These investigators proposed that any valid test of chronic airflow obstruction must yield results that are systematically worse in middle-aged smokers than in middle-aged nonsmokers, and that such a test should also correlate with the FEV: in middle-aged smokers. Using these criteria in a cross-sectional study of a sample of working 42 men in West London, they concluded that the most informative and repeatable tests were Vmax 75% and the slope of the alveolar plateau. Nemery and coworkers (1981) addressed the question of the significance of tests of small airways function in their study of 2,072 blue-collar workers, aged 45 to 55, from a steel plant near Brussels. They found that smokers with an abnormal CC/TLC or slope of the alveolar plateau and a normal FEV:/FVC had a significantly lower FEV:/(height)3 than subjects with normal CC/TLC and slope of the alveolar plateau. They interpret their data as suggesting that smokers with small airways dysfunction experience a more rapid decline in FEV; than smokers without small airways dysfunction, leading to a higher susceptibility to long-term smoking effects in the former group. The opposite conclusion was reached by Fletcher (1976), wh» examined the relationship between CV/VC, the slope of the alveolar plateau, and FEV: in 200 male smokers aged 40 to 55. In this group, he found a relatively poor correlation between FEV: and the single breath Ne variables. There is thus, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who is going to progress toward clinical airflow obstruction. The tests of small airways function are probably abnormal for many years before the FEV: becomes abnormal in those smokers who go on to develop airflow obstruction. However, many smokers with abnormal tests of small airways function may never develop clinically significant airflow obstruction. Therefore, functional changes in the small airways may not always be related to the widespread alveolar destruction seen in smokers or to the development of clinical airflow obstruction. It may be that varying degrees of inflammation and fibrosis occur in virtually all smokers, and that there is something very different about the smokers who develop extensive airway or emphysematous changes. Summary A number of tests have been developed that can identify small airways dysfunction in individuals with normal lung volumes and standard measures of forced expiratory airflow. These tests correlate well with the presence of pathologic changes in the airways 2 mm or less in diameter, particularly with peribronchiolar inflammation. Cigarette smokers have a significantly higher frequency of abnormal tests of small airways function. Heavy smokers have a greater prevalence of small airways dysfunction than light smokers, but there is only a weak dose-response relationship between numbers of cigarettes smoked per day or duration of smoking and the extent of small airways dysfunction. This suggests that the response of the 43 small airways may be an “all or nothing” inflammatory response to cigarette smoke irritants rather than a progressive response repre- senting a cumulative injury. Cessation of cigarette smoking results in significant improvement in small airways function, which in those smokers without evidence of chronic airflow obstruction, may return to normal. The relationship between changes in the small airways and the development of chronic airflow obstruction remains unclear. It seems likely that those smokers who will go on to develop ventilatory limitation will have abnormal small airways function before the FEV: becomes abnormal, but many smokers with small airways dysfunction may never progress to significant airflow obstruction. Therefore, the usefulness of tests of small airways function for identifying those who will develop ventilatory limitation remains to be established. 44 CHRONIC MUCUS HYPERSECRETION Introduction The association of cigarette smoking and chronic cough was recognized by the general public in the term “smokers cough” well before the demonstration of this association in epidemiologic studies. Cough is the symptom most frequently experienced by smokers, and it is often accompanied by excess mucus secretion resulting in phlegm production or a “productive” cough. Chronic bronchitis was defined by the Ciba Foundation Guest Symposium report (1959) as “the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree.” The position was taken that any production of sputum was abnormal, and chronic was defined as “occurring on most days for at least 3 months of the year for at least 2 successive years.” Also, the sputum production could not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. Measurement of Cough and Phlegm in Epidemiologic Studies The increasing use of standardized questionnaires in interviews to ascertain the presence of cough, phlegm, or other symptoms of respiratory disease has improved the quality of measurements of prevalence and incidence of these symptoms and the validity of comparisons within and between studies. Similar attention has been given to developing questions about smoking habits, including questions about the type and number of cigarettes used at the time of interview and in the past. The first British Medical Research Council (BMRC) questionnaire published in 1960 (Medical Research Council 1960) had been tested, revised, modified, and extended, and many studies have resulted from its widespread use. However, difficulties in using this questionnaire in epidemiological studies of populations in the United States and the desire to collect additional information led to modification in individual studies and to a loss of comparabili- ty between studies. This motivated the American Thoracic Society and the Division of Lung Diseases of the National Heart, Lung, and Blood Institute to establish the Epidemiology Standardization Project. Extensive methodological studies were done, standardized questionnaires were developed, and techniques for measuring pulmo- nary function and evaluating chest radiographs were proposed (Ferris 1978). Samet (1978) has reviewed the history of the develop- ment of respiratory symptom questionnaires. Although many inves- tigators now use the methods advocated by the BMRC or the Epidemiology Standardization Project, several of the studies re- viewed in this chapter of the Report are based on other, nonstandard questionnaires. A comparison between studies of different popula- 45 tions, or the same population studied at different times, must be made cautiously and only after careful consideration of technical and methodological issues. Low rates of participation and use of unrepresentative samples may cause biased estimates of the frequen- cy and distribution of symptoms. Attitudes toward smoking have changed, and comparisons of questionnaire responses and objective measurements of smoking habits indicate that at least in some situations, less reliance can now be placed on answers to questions about smoking habits (MRFIT Research Group 1982). Estimates of prevalence and incidence of respiratory symptoms are imprecise, and too much importance should not be attached to relatively small differences in rates of reporting cough and phlegm. Each author’s criteria for detecting the presence of cough or phlegm should be considered, especially when combinations of symptoms or diagnostic labels such as chronic bronchitis or mucus hypersecretion are used. Notwithstanding methodological differences, however, consistent patterns or trends found in many studies indicate that the associa- tions between smoking and chronic mucus hypersecretion are real and that the findings are widely applicable. Prevalence of Cough and Phlegm Unpublished data from the National Center for Health Statistics estimate that there were almost 8 million persons with chronic bronchitis in the United States in 1981 (3.4 million men, 4.5 million women). This is probably an underestimate of the true frequency of cough and phlegm in the population, since people who had these symptoms were not counted as chronic bronchitics unless they responded affirmatively to the question about bronchitis. On the other hand, some cases of acute bronchitis may have been included incorrectly and inflated the estimate. The apparently higher preva- lence rates of chronic bronchitis in women than in men in the National Health Interview Surveys in 1970 and 1979 (3.4 and 3.7 percent for women in 1970 and 1979, respectively, and 3.1 and 3.2 percent for men in 1970 and 1979) are probably due to ascertainment being less complete for men (USDHEW 1980b). Prevalence rates of chronic bronchitis ranged from 4.2 percent at ages under 17 years to 2.7 percent at 17 to 44 years, 3.6 percent at 45 to 64, and 4.5 percent at ages over 65 years. The high rate in the youngest group is presumably because of the inclusion of cases of acute bronchitis. Standard questions about chronic cough were asked in the National Health and Nutrition Examination Surveys (NHANES) of representative samples of the U.S. population. Some supplementary questions were asked about phlegm and other respiratory symptoms, and these data are presented in the appendix to this chapter. Prevalence rates of diagnosed chronic cough in 18- to 74-year-old participants in NHANES 1 (1971-1975) were 3 percent for men and 2 46 Percent Never Former Current Light Moderate Heavy Smoked Smoker Smoker Smo ker Smoker Smoker FIGURE 10.—Percentage of recurring persistent cough attacks by sex and smoking status for adults 25-74, United States, 1971-1975 NOTE: Light smoker: 1-14 cigarettes per day Moderate smoker: 15-24 cigarettes per day Heavy smoker: > 25 cigarettes per day SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). percent for women; they increased with age from 1 percent at 18 to 24 years to 6 percent at 65 to 74 years for men, and from 1 percent at 18 to 24 years to 3 percent at 65 to 74 years for women (National Center for Health Statistics, unpublished data). The prevalence of self-reported recurring persistent cough by smoking status for men and women of different ages is presented in the appendix and in Figure 10 based on NHANES 1. For the entire NHANES population, the prevalence of the persistent cough in- creased threefold in male smokers and twofold in female smokers compared with nonsmokers (Figure 10), and the prevalence of cough increased with increasing cigarette consumption in both men and women. Relationship of Cough and Phlegm to Smoking Relationships between smoking and cough or phlegm are strong and consistent; they have been amply documented and are judged to be causal (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a, 1981). Associations between smoking and cough or sputum are apparent in the recent studies listed in Tables 2 and 3 and are illustrated in Figures 11 and 12. Although cough, phlegm, and 47 chronic bronchitis occur in nonsmokers, prevalence rates are consis- tently higher in cigarette smokers. The excess prevalence of cough and phlegm in cigarette smokers increases with the amount smoked (see below). The frequency of reporting cough and phlegm is at least twice as high for smokers as for nonsmokers except in some groups with minimal exposure. Differences in prevalence rates between smokers and nonsmokers tend to be greater at older ages among men, whereas differences in rates between smoking and nonsmoking women tend to be as great or greater at younger ages (Tables 2 and 3). Rates are not given for pipe or cigar smokers in most of these studies, presumably because the numbers of such smokers were too small for reliable rates; male pipe smokers and cigar smokers in Tecumseh reported cough and phlegm more frequently than nonsmokers or ex-smokers, but less frequently than cigarette smokers (Higgins et al. 1977). Individual studies have evaluated other factors as well as smoking, but smoking has been judged the most important determinant of symptom prevalence (Fletcher et al. 1976; Ferris et al. 1976; Kiernan et al. 1976; Bouhuys 1977; Higgins et al. 1977). Consideration of evidence from many different studies has led to the conclusion that cigarette smoking is the overwhelmingly most important cause of cough, sputum, chronic bronchitis, and mucus hypersecretion (Speiz- er and Tager 1979; USDHHS 1980b). Effects of Smoking Cessation Cross-sectional information on ex-smokers suggests that stopping smoking is followed by a reduction in cough and phlegm because symptoms are less prevalent than in current smokers, but these symptoms are generally more 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. 1977). Rates of reporting cough or phlegm decreased in smokers who stopped smoking in two British studies (Kiernan et al. 1976; Leeder et al. 1977) and in populations in the United States (Ferris et al. 1976; Friedman et al. 1980; Beck et al. 1982). Many people who stop smoking report a rapid reduction in cough and phlegm. 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Dose-Response Relationships The most common measures of dose are the number of cigarettes currently smoked per day and the pack-years of cigarette consump- tion; the latter estimates lifetime exposure by integrating the number of cigarettes smoked (by pack) and the duration of cigarette use. Errors of memory compromise the accuracy of retrospective information, which may also be biased by differential recall in those 63 50.0 >20 10-19 40.0 Smokers Cigarettes/day 30.0 20.0 Phlegm percentage @ Ex-smokers 10.0 @ Nonsmokers 0.0 18-23 24-27 28-32 >33 Tar (mg/cigarette) FIGURE 12.—Percentage of smokers with phlegm production (adjusted for age), according to tar yield of cigarettes SOURCE: Higenbottam et al. (1980). with and without smoking-related symptoms or diseases. Even accurate reports of current smoking habits fail to take into account all the sources of variation in exposure associated with the material used in cigarette manufacture or generated in the burning of cigarettes. The dose of noxious materials received is also influenced by human behavior, including the number, volume, and timing of puffs taken with each cigarette; retention of smoke in the mouth; depth of inhalation; disposition of the cigarette between puffs; and other aspects of smoking style that are not reproduced by the smoking-machines used to measure tar and nicotine yield. Prevalence rates of cough or phlegm, or both, generally increase as the number of cigarettes smoked per day increases. The trends illustrated in Figures 11 and 12 were present in both sexes and all age groups (Lebowitz and Burrows 1977; Dean et al. 1978; Higgins et al. 1977; Huhti et al. 1978; Higenbottam et al. 1980; Schenker et al. 1982). Bland et al. (1978) found a dose-response relationship in secondary school children, among whom rates of reporting cough were higher in those who smoked most, even though levels of cigarette consumption were generally reported to be low. At the other extreme of the age range the trend is also apparent, even though symptomatic smokers are more likely than asymptomatic smokers to stop smoking or to reduce their cigarette consumption 64 (Higgins 1974; Fletcher 1976). Symptoms were more prevalent among heavier smokers of filter cigarettes as well as of nonfilter cigarettes (Dean et al. 1971). Prevalence rates of cough, phlegm, chronic bronchitis, and mucus hypersecretion show a similar pattern of association with pack-years of exposure (Tager and Speizer 1976; Lebowitz and Burrows 1977). Rates of incidence and remission observed in longitudinal studies add further support to the strong evidence that respiratory symptoms increase as exposure to cigarette smoke increases (Table 3). In their study of more than 18,000 male civil servants in London, Higenbottam and colleagues (1980) found that the percentage of smokers who produced phlegm increased with increased daily cigarette consumption and also with increasing tar content of cigarettes among those who smoked less than 20 cigarettes a day. Symptoms were prevalent about equally among smokers of 20 or more cigarettes per day, regardless of the tar yield of the brands they ~ used (Figure 12). Schenker et al. (1982) reported the relationship of tar content of cigarettes to respiratory symptoms in a cross-sectional telephone survey of 5,686 adult women in rural Pennsylvania. The risk of chronic cough and phlegm was more strongly affected by the number of cigarettes smoked per day than by tar content. Cough and phlegm were reported least often by never smokers and with increasing frequency as the number of cigarettes smoked per day increased. Tar content of cigarettes was significantly associated with symptoms of chronic cough and phlegm—especially cough—and its effects were independent of the number of cigarettes smoked per day in a multiple logistic analysis. The risk (relative odds) of chronic cough for smokers of high tar cigarettes (20 or more mg) was approximately twice that for smokers of an equivalent number of low tar cigarettes (10 or less mg). A limitation of this cross-sectional study was the determination of tar content for current cigarettes only, rather than for lifetime smoking habits. Although the apparent relationship between tar content and symptoms could have been caused by changes in smoking habits, this was considered unlikely because symptomatic smokers tend to reduce their consumption of cigarettes more than asymptomatic smokers (Fletcher et al. 1976) and may also switch to low yield cigarettes. In this situation, any reported effect of tar content on symptoms would be an underestimate. In summary, the prevalence of symptoms increases with dose of smoke exposure, when dose is measured by number of cigarettes smoked per day or tar content of the cigarette smoked. Relationship of Cough and Phlegm to Sex and Age Prevalence rates of cough and phlegm ascertained in epidemiologi- cal studies generally increase with age and are higher in men than 65 in women, as shown in Figure 11 and Tables 2 and 3. Rates also vary with smoking habits. Rates in nonsmokers better clarify associations of symptoms with age and sex than do rates in smokers, since they are less confounded by variations in exposure to cigarette smoke. However, recent evidence linking passive smoking with increased prevalence of respiratory symptoms suggests that rates in nonsmok- ers may be in excess of those that would be found in a population completely free of exposure to cigarette smoke (Lefcoe et al. 1983; Weiss et al. 1983). Rates of reporting cough or phlegm or both were roughly equal in nonsmoking men and women in several cross-sectional studies (Bland et al. 1978; Higgins et al. 1977; Lebowitz and Burrows 1977; Manfreda et al. 1978; Neukirch et al. 1982; Rawbone et al. 1978). Rates were higher in nonsmoking men in some populations (Dean et al. 1977; Liard et al. 1980; Tager and Speizer 1976). Bouhuys et al. (1979) found no sex difference in the prevalence of cough, but a higher rate of reporting phlegm in male nonsmokers (Table 2). In most of these studies, the rates were not corrected for exposures to other respiratory irritants in the workplace or in the general environment. In general, symptoms are more prevalent in male smokers than in female smokers (Table 3). However, differences in prevalence rates between the sexes are generally smaller or absent when comparisons are made between men and women who smoke similar numbers of cigarettes. Lebowitz and Burrows (1977) found that the excess prevalence of symptoms in male smokers compared with female smokers tended to be greatest at older ages, where there are also the greatest differences in smoking behavior. Men in these birth cohorts tend to have begun smoking earlier in life, smoke more cigarettes per day, inhale more deeply, and smoke higher tar and nicotine or unfiltered cigarettes. Two studies from France, Burghard et al. (1979) and Neukirch et al. (1982), concentrated on high school students. In general, the prevalence of smoking was similar for both boys and girls for the two studies, although the Neukirch group found a somewhat higher rate among the girls (46 percent versus 39 percent). Slightly more boys than girls, however, smoked more than 10 cigarettes per day. In these two studies, the prevalence of symptoms was higher among female smokers than among male smokers. These data suggest that the past differences in prevalence of symptoms between the sexes is largely attributable to differences in cigarette consumption. These differences were substantial in the past, and are still present among older adults, whereas current smoking practices are about the same in male and female anole cents and young adults. Prevalence rates of cough, phlegm, and chronic bronchitis in- creased with increasing age in the U.S. population samples studied 66 by the National Center for Health Statistics (1981) and in several of the cross-sectional studies cited in Table 2. However, differences in rates of reporting symptoms among people of different ages may relate to effects of aging, differences in current exposures, or differences in exposure to cigarette smoke or other noxious agents in the past. It is therefore difficult or impossible to use cross-sectional data to separate effects of aging from effects of duration, dose, and nature of cigarette smoke exposure throughout life. Longitudinal studies provide information on time trends, both in exposure and in onset and course of disease. Nevertheless, conclusions may be incorrect if people who drop out of longitudinal studies are different from those who continue to participate. Prevalence of symptoms increased with increasing age among men in cross-sectional data from Tucson (Figure 11), but the trend was more apparent among smokers and ex-smokers than among non- smokers. However, Lebowitz and Burrows (1977) could not distin- guish between an association caused by increasing age and an association due to increasing duration of exposure to cigarette smoke in smokers because the two were so highly correlated. Among women, symptoms were reported more frequently at ages 30 to 44 than at ages 15 to 29 (except by ex-smokers), but prevalence rates were essentially the same for the three groups over age 30. Higgins et al. (1977) found that there was no increase in cough and phlegm with increasing age in male or female nonsmokers in Tecumseh (Michigan), whereas prevalence rates increased with increasing age in male smokers. The pattern in female smokers was similar to that in Tucson and showed an increase with age up to age 30 or 40, but rates declined with increasing age after age 50. The extent to which these patterns related to amount smoked or duration of smoking was not reported, but these older birth cohorts of women probably began to smoke later in life and smoked fewer cigarettes per day, according to national smoking survey data. In other cross-sectional studies cited in Table 2, symptom preva- lence increased with age in the populations studied (Bouhuys et al. 1979; Dean et al. 1977; Gulsvik 1979; Huhti et al. 1978; Tager and Speizer 1976), but the trend was noted by Gulsvik to be less in nonsmokers. Huhti et al. found a significant increase with age among nonsmokers for phlegm and dyspnea only. Schenker et al. (1982) observed a trend for nonsmokers but not for smokers, and Tager and Speizer found that adjusting for smoking eliminated the trend with age. Prevalence rates of cough and phlegm on two occasions 3 to 6 years apart are shown in Table 3 for five recent longitudinal studies of populations in the United States, Canada, and Great Britain. Kiernan et al. (1976), Leeder et al. (1977), Woolf and Zamel (1980), and Beck et al. (1982) found little change in the prevalence of 67 symptoms among continuing nonsmokers during the followup inter- val of up to 6 years. The rates among nonsmokers reported by Ferris et al. (1976) are similar on the two occasions, but symptoms were presented by smoking habits at followup only, and any effect of age was deliberately adjusted out because the authors’ purpose was to evaluate effects of changes in smoking, changes in pollution, and trends over time independent of changes in age. Cough and phlegm appeared to be more frequent at followup in the persistent smokers studied by Kiernan et al. (1976) and Leeder et al. (1977), and about the same in women studied by Woolf and Zamel (1980) and in men studied by Beck et al. (1982). However, rates were slightly lower at followup in the female smokers followed by Beck. Even though starting to smoke or quitting can be eliminated as the explanation for increases or decreases in symptom prevalence over the course of these studies, it is possible that changes in the number or type of cigarettes smoked by persistent smokers influenced the prevalence of symptoms. The duration of followup in all these studies was relatively brief, and it is still difficult to distinguish between effects of aging and effects of duration, amount, and nature of exposure to cigarette smoke in smokers, even when major changes in smoking behavior are controlled. However, available data suggest that age itself is not the major factor responsible for differences in the frequency or distribution of symptoms in populations of nonsmokers and smokers. Relationship of Cough and Phlegm to Airflow Obstruction Many cross-sectional studies have found associations between cough, phlegm, chronic bronchitis, or mucus hypersecretion and reduced levels of pulmonary function. The forced expiratory volume at 1 second (FEV:) has been measured in most clinical studies and in nearly all epidemiological studies, and mean levels of FEV: are generally slightly lower in groups of people who report respiratory symptoms (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a, 1981). Recent studies have compared other measures of pulmonary function in people with and without symptoms and have provided longitudinal data on pulmonary function for symptomatic and asymptomatic smokers and nonsmokers. Attention has been given to understanding the natural history of chronic airways obstruction and the interrelationships of respiratory symptoms, levels and rates of decline of pulmonary function, and their independent and interrelated associations with cigarette smoking. Several investiga- tors have emphasized the desirability of identifying in advance those smokers who will develop severe COLD; symptoms and _ other characteristics have been evaluated as potential predictors of morbidity or mortality from COLD. 68 Fletcher and colleagues (1976) found that the age-height standard- ized FEV; at the initial survey of their population of working men in London was inversely related to the volume of sputum produced in the first hour after getting up. The regression of FEV: on age, given height, was steeper for symptomatic cigarette smokers than for asymptomatic smokers or nonsmokers. However, the authors cau- tion that men may develop symptoms as they age and change from one regression slope to the other. Burrows et al. (1977a) found that an index of cough or sputum was related to FEV: percent predicted when pack-years of smoking were controlled in a multiple regression analysis. Regressions of FEV: percent predicted on pack-years are shown for people with and without chronic cough and sputum in Figure 13; the intercept at 0 pack-years was lower and the decline in FEV: with increasing pack- years was significantly greater for those with chronic cough and sputum than for those with no cough or sputum. The authors calculated that values of FEV: were lower by about 10 percent in people with cough and sputum, regardless of smoking habits, and that values declined by about 4 percent of predicted for each 10 pack- years of smoking in people with cough and sputum and by about 2 percent in subjects without productive cough. There was a signifi- cant relationship between FEV: and pack-years of smoking in asymptomatic smokers in this population. A weaker relationship between cough and sputum and Vmax25% was also found to be independent of pack-years of smoking; however, prediction equations for flow rates have been revised substantially (Knudsen 1983), and the extent to which relationships between the revised flow rates and pack-years of smoking differ in symptomatic and asymptomatic subjects has not been reported. Dosman et al. (1976) found poor correlations between respiratory symptoms and dynamic lung compliance, closing volume, closing capacity, slope of phase III, and helium flow-volume curves in a study of 49 smokers and 60 nonsmokers who were recruited from a smoking cessation clinic, a personnel department, and the staff of a laboratory. In their community-based studies of children and adults, Bouhuys and colleagues (1977) studied relationships between respiratory symptoms and loss of lung function in smokers and nonsmokers. They found that residual values (observed—predicted) of FVC, FEV, PEF, MEF sox, and MEF»25~ were not significantly different in people with no symptoms or only one symptom when analyses were done separately for adult white male smokers and nonsmokers. When a symptom score was used to combine information on usual cough, usual phlegm, wheeze, and dyspnea, decrements in lung function were greatest among those with most symptoms. 69 No cough or sputum (n= 1,492) 90 A Total population without chronic cough and chronic sputum (n= 1,803) Percent FEV, 80 Ve 70 Subjects with chronic cough and chronic sputum (n= 247) 20 40 60 80 Pack-years Figure 13.—Percentage distribution of predicted forced expiratory volume in 1 second (FEV:) versus pack-year of cigarettes smoked, by cough and sputum history SOURCE: Burrows et al. (1977a). In a study (Detels et al. 1982) designed to assess the relative sensitivity and specificity of symptoms, the flow-volume curve (FV), the single breath nitrogen test (SBNT), and specific airway conduc- tance (Scaw) for identifying COLD were compared with the FEV:/FVC ratio and with one another in 1,201 residents of Los Angeles 25 to 29 years old. The tests were done in 1978-1979 at a followup examination of a previously defined cohort. Prevalence rates of cough and sputum were 9 percent in never smokers, 26 70 percent in current smokers, and 33 percent in smokers of 20 or more cigarettes a day. Prevalence rates of an abnormal FEV:i/FVC ratio in these groups were 8, 23, and 33 percent, respectively (the FEVi/FVC ratio was considered abnormal if it was below the 95th percentile for never smokers without a history of respiratory illness). The research- ers found that there was very little overlap between the presence of productive cough and abnormal tests, and that none of the tests of function showed reasonable concordance with this symptom. Lack of reasonable concordance meant that none of the other tests were abnormal in 50 percent or more of the individuals with productive cough. In this study, the FEV:i/FVC ratio was used as the standard against which the sensitivities of the other tests were judged; the sensitivity of the FEV:/FVC itself was evaluated by its agreement with those tests found to be sensitive in the study. The lack of an independent method for identifying COLD, the cross-sectional na- ture of these data, and the way in which analyses were done restrict the ability to make biological inferences about the independence of the effects of cigarette smoking that lead to cough and sputum or to chronic airflow limitation. However, the authors note their findings are consistent with the hypothesis that effects of smoking on cough and sputum are independent of effects on airflow limitation. Insights into the course and pathogenesis of COLD have been developed by Fletcher and his colleagues from observations made during their 8-year longitudinal studies of levels and rates of decline in lung function in middle-aged working men in London (Fletcher 1976; Fletcher et al. 1976). These investigators found that various measures of sputum production were correlated with FEV: standard- ized for height and age, and that this correlation was weakened only slightly by adjusting for smoking habits. The researchers maintained that the association between sputum production and pulmonary function could be due entirely to a common causation. Some men with mucus hypersecretion had normal FEV;; conversely, some men with airflow obstruction did not report phlegm. Nevertheless, the relationship between phlegm and reduced FEV: was strong enough to give rise to an estimated reduction in FEV; of about 0.1 liters for every ml of sputum expectorated in the first hour after getting up. However, because decline in FEV: (FEV: slope) was not related to measures of sputum production when level of FEV: and smoking habits were controlled, the researchers concluded that mucus hypersecretion is not a cause of accelerated decline in FEV13. Furthermore, there was no evidence that short-term changes in sputum production were associated with short-term changes in FEV:. The researchers concluded that the association between expectoration and reduced FEV; is caused by the increased suscepti- bility of some people to both expectoration and excessive loss of FEV: when they are exposed to cigarette smoke or, presumably, to 71 other noxious materials. This study has made important contribu- tions to understanding the natural history of chronic bronchitis and emphysema, but the duration of followup was only 8 years, the men were 30 to 59 years of age at the start of the study, and their mean age was 51 years at the midpoint. Similar studies of younger men and women and observations over longer periods of time are needed to extend these findings. Johnston et al. (1976) found that sputum volume was not related to decline in FEV: in a 10-year followup study of chronic bronchitic patients. There was no difference in sputum volume between patients whose FEV: fell by more than 33 percent and controls (matched on initial FEV: ) whose FEV; did not fall. Furthermore, sputum volume was reduced in response to stopping smoking or to antibiotic treatment, whereas rate of decline of FEV: was unaffected. In this and other studies (Higgins et al. 1970; Fletcher et al. 1976; Peto et al. 1983) FEV: was strongly predictive of morbidity and mortality, whereas respiratory symptoms were not. Woolf and Zamel (1980) studied “normal” employed women aged 25 to 54 in a longitudinal study designed to identify smokers at increased risk of developing COLD. Ventilatory function was mea- sured at the beginning and at the end of a 5-year period during which smoking habits and symptoms were ascertained annually. Differences between initial and followup values of pulmonary function tests were expressed as a percentage of the initial value and compared in persistent nonsmokers and persistent smokers who either consistently reported or consistently denied cough or sputum. The decline in FEV:, FEV:/FVC, and FEF25-75% was greater in symptomatic smokers than in asymptomatic nonsmokers, but not significantly different in asymptomatic smokers compared with either nonsmokers or symptomatic smokers. The average number of cigarettes smoked during the course of the study was greater for smokers with cough and sputum. Change in FEF 25-75% was evaluated in individual smokers, and no association was detected between cough and sputum and percentage change in this measure of lung function. The investigators identified one group of smokers whose decline in FEF 25-75% was similar to that in nonsmoking women and another group with a greater decline; cigarette consumption was similar in the two groups. The investigators concluded that individu- al susceptibility is an important determinant of the effect of cigarette smoking, because some women develop symptoms and others remain symptomless but experience rapid worsening of ventilatory function. However, they noted a tendency for both cough and sputum and rapid worsening of ventilatory function to coexist. The number of women in some groups was very small, and the measure of decline in lung function used by these researchers does not take into account regression to the mean or assess absolute 72 reduction; those with smaller initial values will have greater percentage reductions for a constant absolute reduction in function. Followup studies at 10 and 15 years of the Tecumseh, Michigan, population showed that incidence rates of obstructive airways disease were higher in men and women who reported cough, phlegm, or both symptoms (chronic bronchitis) at entry compared with those who denied these symptoms (Figure 14) (Higgins et al. 1982). Both cough and chronic bronchitis were significant predictors of obstruc- tive airways disease in men even when smoking habits were controlled in multiple logistic analyses. However, respiratory symp- toms were poorer predictors of impaired pulmonary function at followup than were smoking habits and baseline levels of lung function. In a multiple logistic model with age, smoking habits, and level of lung function as risk factors, over 60 percent of the 10-year incidence cases developed among men and women in the top 10 percent of the risk distribution, whereas only 36 percent of incidence cases were in the top decile of risk when cough, rather than FEV:, was used as a risk factor (Higgins 1984). Summary Cigarette smoking is associated with respiratory symptoms, in- cluding mucus hypersecretion, and with prevalence and incidence of COLD manifested by irreversibly impaired pulmonary function. While some smokers develop both conditions, and those with cough and phlegm are at increased risk of developing airways obstruction, the conditions can occur separately by mechanisms that are imper- fectly understood but appear to be different. The excess risk of reduced FEV: or COLD in symptomatic smokers compared with asymptomatic smokers may be a reflection of increased susceptibili- ty in some individuals. However, it may also be a measure of increased dose of cigarette smoke, in that smokers who report cough and phlegm tend to smoke more heavily than smokers who deny these symptoms, and measures such as numbers of cigarettes smoked per day are not precise enough to control adequately for the amount of smoke exposure. The rate, number, and volume of puffing as well as the depth of inhalation can vary substantially between smokers and are important additional measures of cigarette smoke exposure dose. 73 480-144 0 - 85 - 4 w (oe) w fo) = qn Incidence of obstructive airways disease (percent) FIGURE 14.—Age-adjusted 15-year incidence of obstructive airways disease, by cough, phlegm, and — chronic bronchitis status at entry to the poy Tecumseh, ages 16 to 64, 1962-1979 SOURCE: Higgins CHRONIC AIRFLOW OBSTRUCTION Introduction Airflow obstruction is the physiological consequence of disease processes that narrow the airway. In asthma the obstruction is reversible with pharmacologic bronchodilation, whereas the obstruc- tion associated with airways damage and emphysema is often not reversible. The terminology with regard to permanent airflow obstruction has varied. The 1958 Ciba Foundation Guest Symposium propose “generalized obstructive lung disease,” which was subdivid- ed into “asthma” and “irreversible or persistent obstructive lung disease” (1959); in the 1962 recommendations of the American Thoracic Society, “chronic obstructive bronchitis” was the only definition that mentioned abnormality of expiratory flow (American Thoracic Society 1962). In 1975, a joint committee of the American College of Chest Physicians and the American Thoracic Society recommended the term “chronic obstructive pulmonary disease” (American College of Chest Physicians and American Thoracic Society 1975). Thurlbeck (1976, 1977) has advocated the use of “chronic airflow obstruction,” a functionally based definition that does not specify the underlying disease processes. Previous Reports of the Surgeon General have used varying terminology, including “chronic bronchopulmonary disease” in 1964, ‘chronic obstructive bronchopulmonary disease” in 1971, and “chronic obstructive lung disease” in 1979 (USPHS 1964, 1971; USDHEW 1979). These definitions, however, cannot be readily applied to identify specific populations. Physiologists, epidemiologists, and clinicians often use differing approaches in determining whether airflow obstruction is present (Fletcher 1978). Physiologists, with the capability for making sophisticated laboratory measurements of airflow obstruction, may regard subtle early abnormalities of flow as definitive. In the community, epidemiologists have generally used spirometry as the primary method for assessing airflow obstruction. For epidemiologic purposes, airflow obstruction is usually defined by a forced expiratory volume in 1 second (FEV;) less than a particular level after standardization for sex, age, and height, or by a ratio of the FEV: to the forced vital capacity (FVC) below a specified value. Tests of forced exhalation, such as the FEVi, have the advantage of sensitivity to abnormalities of both the lung parenchyma and the airways (Mead 1979). Clinicians are more likely to detect and diagnose airflow obstruction when it is advanced and symptomatic. As would be anticipated, the differing approaches of physiologists, epidemiologists, and clinicians may lead to differing estimates of the frequency of airflow obstruction. The natural history of chronic airflow obstruction in adults has been partially described by several recent prospective investigations: 75 Howard (1970), Bates (1973), Sharp et al. (1973), Fletcher et al. (1976), Fletcher and Peto (1977), Bosse et al. (1981), Beck et al. (1982), and Clement and van de Woestijne (1982). Although these investigations did not characterize the course of airflow obstruction across the entire human lifespan, the results provide a conceptual model for considering its development (Figure 15). Ventilatory function, gener- ally measured by the FEV3, increases during childhood and reaches a maximum level during early adulthood (Cotes 1979; Knudson et al. 1983). From this peak; the FEV: gradually and progressively declines with age. In people who develop airflow obstruction, a similar gradual loss of function occurs, but at a more rapid rate (Fletcher et al. 1976; Speizer and Tager 1979). Continued excessive loss of FEV: eventually results in symptomatic airflow obstruction when ventila- tory function reaches a level at which activities are limited and dyspnea occurs. Evaluation by a physician for symptoms may lead to a clinical diagnosis at this point in the natural history of the disease process. This model may not satisfactorily describe the development of airflow obstruction in all individuals (Burrows 1981), but the accumulating evidence, reviewed below, indicates that a sustained excessive loss of ventilatory function most often leads to the development of clinically important chronic airflow obstruction. In the conceptual model (Figure 15), there are three different measures of the frequency of airflow obstruction in a particular population: the prevalence of reduced ventilatory function as measured by the FEVi, the FEV:i/FVC ratio, or other physiological parameters; the prevalence of physician-diagnosed airflow obstruc- tion; and the frequency of excessive functional loss in a population followed over time. The first two measures can be determined from a single cross-sectional survey, whereas the third requires longitudinal observation. At present, scant data are available for the third category. The prevalence of physician-confirmed airflow obstruction is determined not only by the proportion of affected people in the population, but also by the patterns of medical care access and usage and the diagnostic practices of individual physicians. Furthermore, the clinical labels applied by physicians to people with airflow obstruction are variable and may include “chronic bronchitis,” “emphysema,” “COLD,” and other terms. Thus, estimates of disease prevalence based on reported physician diagnoses may differ from those derived from physiological assessment. Prevalence of Airflow Obstruction Numerous populations throughout the world have been surveyed to assess the prevalence of airflow obstruction (Stuart-Harris 1968a, 1968b; Higgins 1974). Most often, the investigative techniques have included a respiratory symptoms questionnaire and measurement of pulmonary function, generally with a spirometer or peak flow meter. 76 3 PIN A Normal FEV, (liters) ax ae i. B Normal 25 35 45 55 65 75 Years FIGURE 15.—Decline of FEV: at normal rate (solid line) and at an accelerated rate (dashed line) NOTE: A: person who has attained a “normal” maximal FEV; during lung growth and development; B: person whose maximal FEV; has been reduced by childhood respiratory infection. SOURCE: Samet et al. (1983). The latter technique has the disadvantage of effort dependence. Early recognition of the potential problem of observer bias led to the development of standardized methods (Cochrane et al. 1951; Higgins 1974; Ferris 1978). Thus, most investigators throughout the world have used the British Medical Research Council questionnaire in the original form or with some modifications (Samet 1978). Standardiza- tion has. been less uniform for lung function measurements, but minor variations in procedures would not introduce important differences in disease prevalence among the various populations examined. Although many different populations have been surveyed since the 1950s, surprisingly few published reports provide data concern- ing the prevalence of airflow obstruction in the general population 77 (Tables 4 and 5). Comparisons among the available studies are limited by varying methodologies and inconsistent approaches in calculating rates. For example, only crude rates are available in some reports, and reference populations for age standardization also vary. The investigations summarized in Tables 4 and 5 were selected because they offer estimates of the prevalence of airflow obstruction in defined community-based samples. Those reports that describe mean levels of lung function parameters but not their distributions were excluded. Investigations of specific occupational groups were also excluded because prevalence estimates based on such popula- tions may be biased by the overrepresentation of healthy persons (Monson 1980) and workplace exposures may have affected the frequency of disease. For the United States, the available information spans the time period 1961 to 1979 and covers most geographic regions (Table 4). Regardless of the definition, it is apparent that airflow obstruction is common among adults in the United States. A higher proportion of men than women is affected, and the prevalence increases with age (Ferris and Anderson 1962; USPHS 1973; Lebowitz et al. 1975; Detels et al. 1979; Samet et al. 1982). Few minority populations have been studied. In New Mexico, Hispanic whites had a lower prevalence of physician-diagnosed current chronic bronchitis or emphysema than non-Hispanic whites (Samet et al. 1982). Although blacks have been included in several surveys (Bouhuys et al. 1979), prevalence estimates for this racial group have not been published. The available data (Table 4) do not permit a satisfactory assessment of changes in prevalence rates with time over the years 1961 to 1979. The National Health and Nutrition Examination Surveys (NHANES 1) included spirometry in their evaluation of a represen- tative sample of the U.S. population. The numerical values for these measures are reported by age, sex, and smoking status for the white population in the tables in the appendix to this chapter. The changes in mean values of these measures between age groups are also presented for white male and female smokers and nonsmokers in Figures 16 through 23. Differences between smokers and nonsmok- ers are evident for each of these spirometric measures. These differences are portrayed for successive age groups at one point in time, and therefore cannot be used to describe the changes with age or smoking status that one would expect in an individual or population followed sequentially. These data represent only those people in the study population who were willing and physically able to maximally exert themselves on the various spirometry tests. Others were disqualified by the examining physician because of existing medical conditions. The sampling nonresponse was higher among segments of the population expected to perform less well on the test, including people with existing airflow limitation. 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Nevertheless, the figures clearly portray the magnitude of the effect that smoking exerts on expiratory flow rates in a national population sample. Airflow obstruction is also prevalent outside the United States (Table 5). The disease can be identified in both technologically advanced and less developed populations. As in the United States, in other countries the prevalence of airflow obstruction is higher among men than among women. Determinants of Airflow Obstruction Introduction Current understanding of the natural history of airflow obstruc- tion suggests that risk factors operative during both childhood and adulthood may influence the development of disease. In the concep- tual model proposed in Figure 15, childhood factors might increase the risk of airflow obstruction by lowering the maximum FEV; attained during lung growth and development, by predisposing to increased FEV: decline during adulthood, or by both mechanisms (Speizer and Tager 1979). During adulthood, in the model of Figure 15, risk factors for airflow obstruction must increase the rate at which lung function deteriorates. Many endogenous and exogenous determinants of the develop- ment of airflow obstruction have been postulated (Tables 6 and 7). However, in spite of over 30 years of intensive investigation, the available data are definitive only for cigarette smoking and for a,- antitrypsin deficiency (Speizer and Tager 1979; USDHHS 1980). Cigarette Smoking and Chronic Airflow Obstruction In nearly every population studied worldwide, cigarette smoking is _the predominant determinant for the prevalence of airflow obstruc- tion (Tables 8, 9, and 10). The uncommon exceptions primarily involve populations in whom severe chest infections or wood smoke exposure may have an etiological role (Woolcock et al. 1973; Anderson 1979a). The relationship between cigarette smoking and airflow obstruction has been variably described in the published reports. In some, the prevalence of airflow obstruction has been considered; in others, mean values of lung function parameters have been compared across categories of smoking use. In several more recent analyses, multiple regression or other multivariate tech- niques have been used for more careful characterization of dose— response relationships. Because the epidemiologic criteria for airflow obstruction are generally based on the FEVi, this section focuses on studies that have included measurements of this parameter. The selected studies involve community samples (Tables 8 and 9) and 83 4500 4404 Men 4000 3500 3000 Mean (ml) 2500 —— Never smokers 1500 | —-- Current cigarette smokers 25-34 35-44 45-54 55-64 65-74 Age group 3500 Women 3000 2500 Mean (ml) 2000 25-34 35-44 45-54 55-64 65-74 Age group FIGURE 16.—Mean FEV; for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. SOURCE: National Center for Health Statistics. 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people with symptomatic airflow obstruction may be likely to retire from their jobs. Recently, predictors of the incidence of airflow obstruction have been examined with multivariate techniques in data from popula- tion samples in Tecumseh, Michigan (Higgins et al. 1982), and in Tucson, Arizona (Lebowitz et al. 1984). In Tecumseh, the strongest predictors of airflow obstruction (defined as an FEV; less than 65 percent of predicted) were age, the number of cigarettes smoked daily, changing smoking habits, and the initial FEV: level (Higgins et al. 1982). The addition of other variables to the predictive model did not greatly improve its validity. In Tucson, these same variables, along with certain symptoms and illnesses, and skin test reactivity were significant predictors (Lebowitz et al. 1984). During the 10 years of followup of a population sample in Finland, incidence cases of chronic airflow obstruction (defined as FEV:/FVC ratio less than 60 percent) were observed only in those who continued to smoke (Huhti and Ikkala 1980). These studies of incidence highlight the importance of cigarette smoking in the etiology of airflow obstruc- tion; new cases are rare among nonsmokers. Dose-Response Relationships Dose-response relationships between FEV: level and the amount of cigarette smoking have been described with simple descriptive statistics and further characterized by multiple regression analysis. In cross-sectional data, the FEV: level varies inversely with the amount smoked. Although the variation in mean FEV; levels among strata of smoking appears clinically unimportant, the distributions of values in smokers and nonsmokers are quite different (Figure 4). Cigarette smokers more often have abnormal lung function, regard- less of the criteria applied to the population (Mueller et al. 1971; Knudson et al. 1976; Burrows et al. 1977a; Detels et al. 1979; Rokaw et al. 1980; Beck et al. 1981). This increased prevalence of abnormal function is a result of the skewed distribution of function in smokers, with a subgroup of the smokers showing a large decline rather than the entire group shifting by a small amount (Figure 4). As noted in this reference, however, there are decreasing numbers of smokers with FEV: above the mean for nonsmokers as pack-years increase, suggesting that all smokers are probably somewhat affected, even though only a minority eventually develop clinically significant airflow limitation. In several populations, the relationship between cigarette smoking and FEV; level has been examined in greater detail. Burrows et al. (1977a) used linear multiple regression analysis to examine the relationship between cigarette smoking and ventilatory function in a population sample in Tucson, Arizona. Pack-years, a cumulative- dose measure, was the strongest predictor of FEV: level among the 103 smoking variables considered. In currently smoking men and women, the FEV: declined by approximately 0.25 percent of the predicted value for each pack-year of cigarette smoking; the effect was of a similar magnitude in ex-smokers. Using data from three separate U.S. communities, Beck and colleagues (1981) assessed the importance of six separate smoking variables: amount smoked daily, use of filters, inhalation, age started, age stopped for ex-smokers, and cumulative pack-years. For the 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 FEV1in male but not in female ex-smokers. However, in both the multiple regression analysis reported by Beck et al. (1981) and that reported by Burrows et al. (1977a), the measured cigarette smoke variables accounted for only about 15 percent of the variation of age- and height-adjusted FEV: levels. Unmeasured aspects of cigarette smoking, other environmental exposures, and the characteristics of the smokers must contribute to the unexplained variation. A role for the type of cigarette smoked has not yet been established (USDHHS 1981), and the impact of differences in depth or pattern of inhalation and other aspects of the pattern of smoking remains to be investigated; they are discussed in more detail in the chapter on low tar and low nicotine cigarettes. Further studies of these aspects of cigarette smoking are needed to monitor the consequences of changing cigarettes. Factors Other Than Cigarette Smoking A number of risk factors other than cigarette smoking have been postulated as contributing to the development of airflow obstruction (Table 7). Of these, a definite role for a,-antitrypsin deficiency has been established, but only the small number of persons with homozygous deficiency incur markedly increased risk (Morse 1978). The current hypotheses on susceptibility to cigarette smoke postu- late roles for childhood respiratory illnesses (USDHEW 1979; Burrows and Taussig 1980; Samet et al. 1983), for endogenously determined hypersensitivity of the lung, and for other genetic and familial factors (Speizer and Tager 1979; USDHHS 1980a). At present, these hypotheses remain largely untested. The data are similarly incomplete at present for the other factors listed as putative risk factors in Table 7. The status of each is briefly reviewed below. ABH Secretor Status Secretion of ABH antigens is a genetically determined trait that follows an autosomal dominant inheritance pattern; approximately 104 70 to 80 percent of the population excrete antigen into the body fluids (Cohen et al. 1980a). In a genetic-epidemiology study in Baltimore, Maryland (Cohen et al. 1980a), ABH nonsecretors had lower levels of FEVi/FVC ratio and a higher proportion with FEV:/FVC ratio below 69 percent. Studies in France (Kauffmann et al. 1982a, 1983) and in England (Haines et al. 1982) have confirmed reduced expiratory flow rates in ABH nonsecretors. In contrast, ABH secretor status did not predict the development of obstructive airways disease in the Tecumseh, Michigan, population (Higgins et al. 1982). Air Pollution Although exposure to air pollution at high levels may exacerbate the clinical condition of persons with chronic lung disease, a causal role for air pollution in the development of airflow obstruction has not been established (Tager and Speizer 1979; USDHHS 1980b). However, smoking is the major predictor for chronic airflow obstruction in areas of high as well as low atmospheric air pollution. Airways Hyperreactivity Orie and colleagues in the Netherlands (Orie et al. 1960) speculat- ed that bronchial hyperreactivity and allergy may predispose to asthma and chronic bronchitis. Findings from two small longitudinal studies have suggested that airways reactivity may influence indi- vidual susceptibility to cigarette smoke. Barter and colleagues followed 56 patients with mild chronic bronchitis during a 5-year period (Barter et al. 1974; Barter and Campbell 1976). The rate of decline of FEV: increased with the degree of airways reactivity, as measured by reversibility with isoproterenol or responsiveness to methacholine. Britt et al. (1980) measured change of FEV: in 20 young adult male relatives of patients with chronic obstructive pulmonary disease. The decline of FEV: was approximately five times larger in the nine subjects with a positive methacholine challenge test. In patients with clinically diagnosed airflow obstruc- tion, airways reactivity is also associated with more rapid decline of lung function (Kanner et al. 1979). Because airway reactivity would affect the FEV, directly as well as possibly influence the susceptibili- ty to smoke, it is difficult to ascertain from these data whether the relationship between airway reactivity and COLD is direct or spurious. | Alcohol Consumption The epidemiological data on alcohol consumption are conflicting. A study of former alcoholics demonstrated an excess prevalence of lung function abnormalities, including airflow obstruction (Emergil 105 480-144 0 - 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). Atopy Cross-sectional data from the Tucson population suggest increased susceptibility to cigarette smoke in atopic people (Burrows et al. 1976). In subjects aged 15 to 54, the prevalence of an FEV:/FVC ratio below 90 percent of predicted value increased with skin test reactivity among both smokers and nonsmokers. Subsequent reports from this same study have not confirmed an overall relationship between FEV; level and atopy, but indicate that atopy may predis- pose to airflow obstruction in a subset of the population (Burrows et al. 1977a, 1983). Burrows and coworkers (1981) also reported an increased level of IgE in smokers independent of their allergy skin test reactions, and the interrelationship of these factors is currently being examined. Childhood Respiratory Iliness In a longitudinal investigation of 792 English working men, Fletcher and coworkers (Fletcher et al. 1976) found a cross-sectional association between childhood illness history and FEV; level. The decline of FEV; level during the study’s longitudinal phase was not correlated with childhood illness variables. In contrast, analyses of cross-sectional data from a population sample in Tucson suggested that childhood respiratory illnesses may increase susceptibility to cigarette smoke (Burrows et al. 1977b). In this population, people with a history of respiratory trouble before age 16 demonstrated excessive decline of ventilatory function with increasing age and with increasing cigarette consumption. Familial Factors Familial aggregation of lung function level, adjusted for age, height, and sex, has been demonstrated in populations in the United States and elsewhere (Higgins and Keller 1975; Tager et al. 1976; Schilling et al. 1977; Mueller et al. 1980). However, a recent report suggests that the familial aggregation of lung function may be a reflection of the familial aggregation of body habitus (Lebowitz et al. 1984). Relatively modest correlations of FEV: level have been demonstrated between siblings and between parent-child pairs. The role of familial factors is further supported by investigations demonstrating increased prevalence of airflow obstruction in rela- 106 tives of diseased subjects (Kueppers et al. 1977; Tager et al. 1978; Cohen 1980). This familial factor cannot be explained by familial resemblance of a,-antitrypsin phenotype or of ABH secretor status (Kueppers et al. 1977; Cohen 1980). In the Tecumseh population, however, family history of airflow obstruction did not predict the incidence of this disease. The results of twin studies are also consistent with genetic influences on FEV: level and suggest that genetic factors may influence susceptibility to cigarette smoke (Webster et al. 1979; Hankins et al. 1982; Hubert et al. 1982). Occupation Several population-based investigations suggest that occupational exposures other than those recognized as causing lung injury may have some effect on lung function level. In Tecumseh, mean age and height-adjusted FEV: scores in men were highest in farmers and lowest in laborers; the differences were not explained by smoking and were present in nonsmokers (Higgins et al. 1977). Similarly, in Tucson, men reporting employment in certain high risk industries or exposure to specific harmful agents had a higher prevalence of abnormal lung function (Lebowitz 1977a). In a Norwegian case— control study, men employed in workplaces characterized as polluted were at increased risk for clinically diagnosed emphysema (Kjuus et al. 1981). Longitudinal studies of industrial populations also show that occupational exposures may increase the rate of decline of FEV: (Jedrychowski 1979; Kauffmann et al. 1982b; Diem et al. 1982). For example, Kauffmann et al. (1982b) found that FEV: change during a 12-year period varied with job exposures in an employed industrial population. Effects of dust, gas, and heat were present, as was evidence for a dose-response relationship between increasing exposure and a greater rate of decline. In these studies, however, smoking effects were generally much greater than the occupational effects. Passive Exposure to Tobacco Smoke Passive exposure is discussed in detail elsewhere in this Report. Respiratory Ilinesses In an 8-year followup study of London men, chest infections were not associated with a rate of FEV: decline (Fletcher et al. 1976). The findings of several smaller longitudinal studies were similarly negative with regard to respiratory infection (Howard 1970; John- ston et al. 1976). It is now apparent that mucus hypersecretion and airflow obstruction are separate pathophysiological entities that have a common cause—cigarette smoking (Fletcher et al. 1976; Peto et al. 1983). 107 Socioeconomic Status Weak effects of socioeconomic status on lung function level have been demonstrated in community samples in Tecumseh (Higgins et al. 1977) and in Tucson (Lebowitz 1977b). In both populations, lung function appeared to be influenced independently by socioeconomic status indicators, even after controlling for cigarette smoking. In the Tecumseh study, FEV: increased slightly with increasing income and education level (Higgins et al. 1977); in the Tucson study, the proportion of people with an abnormal FEV: varied in a similar pattern with these indices (Lebowitz 1977a). Effects of socioeconomic status were present in nonsmokers in both investigations. Stebbings (1971), in a sample of nonsmokers in Hagerstown, Maryland, also demonstrated an association between lung function level and socioeconomic status. In summary, there is evidence that a number of factors other than cigarette smoke may influence lung function, but the influence of these factors is small relative to the effect of smoking, and the major question is whether they can influence susceptibility to cigarette- induced lung injury rather than whether they, of themselves, result in lung disease in nonsmokers. Development of Airflow Obstruction At this time, the natural history of airflow obstruction has been only partially described; a population has not yet been followed from childhood to the development of airflow obstruction during adult- hood. However, the available data from separate investigations cover the entire course of the disease and support the conceptual model proposed in Figure 15. With aging, measures of function begin to deteriorate after age 25 to 30. In nonsmokers without respiratory disease, cross-sectional data generally show that the FEV: declines by 20 to 30 ml per year (Dickman et al. 1969; Morris et al. 1971; Cotes 1979; Crapo et al. 1981). Longitudinal data have been confirmatory (Tables 11 and 12). For example, Tockman (1979) measured the FEV: loss during an 8- year period in 399 male nonsmokers. In most, the FEV: declined at 25 ml annually; a few, with an initial FEV: lower than 2.5 1, lost 34 ml annually. Sufficient excessive loss leads to the development of airflow obstruction. However, many questions remain unanswered concern- ing this process of functional deterioriation. It is unclear whether the loss always occurs uniformly or if it develops in stages with intermittent and relatively steep declines (Bates 1979; Burrows 1981). The concept that the decline is nearly always gradual receives strong support from the findings of the 8-year longitudinal study conducted by Fletcher and coworkers (1976). 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WIAVL 114 792 employed men, the individual patterns of temporal change of the FEV: were strongly variable, but the loss generally occurred gradually. Fletcher et al. further demonstrated that FEV: level correlated with FEV: slope, a finding that they termed the “horse- racing effect.” Correlation between slope and level would be antici- pated, if functional loss occurs gradually. This correlation has important implications for intervention; those losing FEV: more rapidly should become identifiable early as they develop a reduced FEV; level. Other studies, however, do not agree with either the pattern of FEV: decline or the “horse-racing” effect. Rapid declines to levels compatible with clinical disease or followed by a prolonged plateau have been described (Howard and Astin 1969; Howard 1970; Johnston et al. 1976). In a followup study of Canadian men with chronic bronchitis, steep declines of FEV: without subsequent improvement were frequently observed (Bates 1973). Additionally, correlation of FEV: level and slope has been found in most other longitudinal investigations (Howard 1970; Petty et al. 1976; Huhti and Ikkala 1980; Bosse et al. 1981; Clement and van de Woestijne 1982; Kauffmann et al. 1982b), but not in all (Barter et al. 1974; Krzyzanowski 1980). Another unanswered question concerning functional deterioration is whether gradual decline occurs in a linear or a nonlinear fashion (Fletcher et al. 1976). Sufficient numbers of people have not yet been followed to distinguish alternative patterns, although the available data indicate acceleration of the decline with aging (Emergil et al. 1971; Fletcher et al. 1976). In spite of these uncertainties concerning the Hevelopment of airflow obstruction, the available data indict cigarette smoking as the primary risk factor for excessive loss of FEV: (Tables 11 and 12). The findings in both general population samples (Table 11) and occupational and volunteer cohorts (Table 12) have been similar. Recent reports from Belgium (Bande et al. 1980; Clement and van de Woestijne 1982) and from Connecticut (Beck et al. 1982), not readily summarized in tabular form, also described a strong effect of smoking on FEV: decline. A few studies have not shown increased loss in cigarette smokers (Howard 1970; De Meyere and Vuylsteek 1971). Even in people with clinically diagnosed airflow obstruction, continued smoking maintains the excess decline of FEV: (Hughes et al. 1982), although not all findings are consistent (Ogilvie et al. 1973; Johnston et al. 1976). Dose-response relationships have been found in many investiga- tions between the amount smoked during followup and the FEV: decline (Tables 11 and 12). The reported increases from the lowest to the highest smoking categories range up to 10 to 15 ml annually. Although this additional loss in heavier smokers appears small, if sustained for long periods of time it would shorten the time interval 115 Never smoked or not susceptible 100 Le to smoke f 75 Z © to) = pe art —_ w = s Smoked “ae S 50 cad “~ . — Stopped at 45 fo) tible t = suscep ible to et ® its effects ~ x. Ps Disability 8 atin aS oo oe eee ee ee ee ee io) Via Io eee S025 ~ tL aac Stopped at 65 Death eerie Da ae EO ea ep eS 0 25 50 75 Age (years) FIGURE 24.—Risks for men with varying susceptibility to cigarette smoke and consequences of smoking cessation NOTE: + = death. SOURCE: Fletcher and Peto (1977). to the development of functional impairment. So far, favorable effects of filter tip smoking and declining tar content on the rate of decline have not been shown (Fletcher et al. 1976; Sparrow et al. 1983b). Generally, sustained smokers experience a greater loss than those who stop during followup. In the study by Fletcher et al. (1976) of London men, subjects who stopped smoking at the beginning of the followup period lost FEV: at the same rate as never smokers. The results of two U.S. studies of ex-smokers are similar (Bosse et al. 1981; Beck et al. 1982). This reduced loss in ex-smokers emphasizes the importance of active smoking and the immediate benefits of smoking cessation (Figure 24). Smokers with reduced FEV: may be protected from developing clinically significant loss by timely smoking cessation (Fletcher and Peto 1977). The distribution of FEV: decline has been characterized and described for some populations, including patient groups (Burrows and Earle 1969; Howard 1974; Barter et al. 1974), population samples (Milne 1978), and occupational cohorts (Howard 1970; Fletcher et al. 1976). Similar data are also available for the mid-maximum expira- tory flow, another measure of ventilatory function (Bates 1973; Woolf and Zamel 1980). In each of these investigations, the distribu- tion of FEV: decline is unimodal (Figure 25); that is, a distinct population with more rapid decline is not sharply separated from those with lesser rates. The modes and medians of the distributions 116 EJ Smokers () Nonsmokers and ex-smokers Number of men (total 792) > oO Ce all , -0 +4 -160 -140 -120 -100 -80 0 ie rte. -20 0 +20 FIGURE 25.—Distribution of 8-year FEV: slope in 792 London men SOURCE: Fletcher et al. (1976). are generally negative, but some subjects have had positive slopes during the relatively brief followup period of investigations conduct- ed up to this time. The distributions tend to be skewed by subjects losing FEV: more rapidly. The proportion of cigarette smokers is increased among those in the tail of excess loss (Figure 25). For example, Clement and van de Woestijne (1982) examined subjects with excess FEV: decline in a prospective study of 2,406 members of the Belgian Air Force. Losses beyond those expected from nonsmokers affected 6 percent of nonsmokers, 7.5 percent of light smokers (< 20 cigarettes/day), and 12 percent of heavy smokers (> 20 cigarettes/day). The shape of the distribution of FEV: decline has important implications for the development of airflow obstruction. Smokers are not sharply separated from nonsmokers (Figure 25), but more often lose FEV1at 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 airflow obstruction by only a minority of smokers indicates that the interaction of smoking with other factors may influence the risk for specific smokers. Current research emphasizes the potential roles of childhood respira- tory illness and airways hyperresponsiveness. Longitudinal studies have now partially described the prolonged natural history of airflow obstruction. Excessive loss of ventilatory function, beyond that expected from aging alone, results in the development of disease in cigarette smokers. Only a susceptible minority of cigarette smokers lose function at a rate that will eventually cause clinically significant impairment. For this group, timely smoking cessation can prevent the development of disease. 118 EMPHYSEMA Introduction Pulmonary emphysema is frequently present in the lungs of individuals with chronic obstructive lung disease. This section has three purposes: (1) to review the definition, types, and quantification of emphysema; (2) to summarize the physiological and radiographic feature of emphysema; and (3) to discuss critically the relationship of smoking to emphysema, based upon observations in people and in experimental animals. Current concepts of the pathogenesis of emphysema are reviewed elsewhere. Definition of Emphysema The generally accepted definition of emphysema is an anatomic condition of the lung characterized by abnormal dilation of air spaces distal to the terminal bronchioles accompanied by destruction of air space walls (American Thoracic Society 1962; Heard et al. 1979). Difficulties with this definition have been discussed by Thurlbeck (1983). Normal air space dimensions have not been determined, and criteria of destruction have not been defined. These limitations hamper attempts to investigate the earliest lesions of emphysema and the subtle effects of environmental agents on lung structure. Types of Emphysema British pathologists pointed out in the forties and fifties that emphysematous lesions in certain people involved the respiratory bronchioles, which appeared as grossly enlarged airspaces in the center of the primary lung lobules surrounded by normal lung. In other individuals, the alveolar ducts were involved early, and even mild involvement appeared grossly as a coarsening of the architec- ture of the entire lobule. They designated the two polar patterns of emphysema as centrilobular emphysema (CLE) and panlobular emphysema (PLE) (Heppleston and Leopold 1961). Many lungs either show both types of emphysema or are unclassifiable. Of 122 lungs with emphysema examined by one pulmonary pathologist, 73 were considered mixed or unclassifiable and 49 were clearly CLE or PLE (Mitchell et al. 1970). When the agreement of three pathologists was required, only 27 of the original 122 lungs remained classifiable and 95 were mixed or could not be classified. There were no statistically significant differences between the groups classified as PLE or CLE in any clinical variables. The only nonsmokers in either group had CLE, and the proportion of light smokers (less than 25 pack-years) was very similar between groups. In this study and others (Anderson and Foraker 1973), CLE was most severe in the upper lobes and PLE was uniformly distributed. According to Thurlbeck (1976), a common 119 combination is CLE in the upper lobes and PLE in the lower lobes; where lobectomies are used for correlation, typing of emphysema is therefore a particularly empty exercise. When emphysema is far advanced, it is often impossible to recognize the site of the initial involvement. Thus, it is not clear whether the differences in prevalence of CLE and PLE are real or represent differences in interpretation by different observers. Several localized types of emphysema occur in areas around scar tissue (paracicatricial), along interlobar and interlobular septa (paraseptal), and as bullous lesions (which represent the most advanced and extreme distortion of normal lung structure). Bullous deformities occur with any type of emphysema, including CLE and PLE. Occasionally, bullous lesions occupy huge intrapulmonary volumes. Detection of Emphysema The detection of emphysema requires suitably prepared lung specimens. At a minimum, this means the lung must be fixed in inflation (Thurlbeck 1964). Fume fixation or fixation by instillation of liquid fixative through the airways is satisfactory, but for optimal evaluation of the latter group, barium impregnation or paper- mounted whole-lung sections should be used. Because lungs with emphysema frequently also have some degree of intrinsic airways disease, the severity of emphysema and the clinical state of the patient may not correlate directly. Pathologists can easily recognize mild degrees of emphysema that are rarely associated with clinical disability. Quantification of Emphysema There are a number of techniques for quantifying the volume of lung involved with “obvious” emphysema that are adequately reproducible and correlate well with one another (Thurlbeck 1976; Bignon 1976). Semi-quantitative or subjective scoring methods as well as point counting have been used. These approaches all require lungs inflated to a relevant volume, usually one approximating total lung capacity during life. This can be achieved by a distending pressure of 25 cm H:0 (Thurlbeck 1979; Berend et al. 1980). In the scoring method, the lung is divided into a number of units and the severity of emphysema in each unit is scored (mild, moderate, or severe receive 1, 2, or 3 points, respectively). The scores for each unit are summed to give a total score for the lung (Ryder et al. 1969). Alternatively, lung slices may be matched by visual comparison to a set of graded standards to achieve an emphysema score (Thurlbeck et al. 1970). These methods include both severity and extent of emphysema, and although they involve subjective judgments, they have proved to be remarkably reproducible. 120 In the point counting approach, regularly spaced points are superimposed on a lung slice. Each point is recorded as falling on normal parenchyma, emphysematous parenchyma, or nonparenchy- ma (conducting airways or vessels). The volume proportion of emphysematous lung is recorded. This method can be objective (e.g., if an emphysematous space is taken to be one greater than 1 mm in diameter), but it includes only extent and not severity of emphyse- ma. Morphometric methods carried out on histologic sections, exempli- fied by the mean linear intercept (Lm) (Thurlbeck 1967a, b), are strictly objective, but they require careful attention to problems of sampling and are time consuming and insensitive to focal disease. For measurements of the Lm, histologic sections are made of blocks selected by stratified random sampling. The average distance between alveolar walls is determined from the number of intersec- _ tions of alveolar walls with a line of known length. The internal surface area of the lung can be calculated when the volume of the lung is known (Hasleton 1972). Pulmonary Function in Emphysema Because unequivocal proof of the presence of emphysema requires direct examination of lung tissue, the strategies used to characterize the pulmonary function abnormalities associated with emphysema have either involved comparison of functional data collected during life with autopsy or surgical material or have used measurements made exclusively on post-mortem specimens. Two important conclu- sions from these studies should be noted at the outset. First, impaired air flow during maximal expiratory maneuvers, as reflect- ed in reduced values for the FEV:1, FEVix, and FEF 25-75~, is neither sensitive nor specific for emphysema. It is possible to have severe emphysema without clinical obstructive lung disease (Thurlbeck 1977). It is also possible to have severe chronic obstructive lung disease without having emphysema, even though most patients with advanced chronic obstructive lung disease have some degree of emphysema (Mitchell et al. 1976). Second, none of the tests used to identify early obstructive lung disease, such as closing volume, the single breath Ne curve, or frequency dependence of compliance, distinguish diminished elastic recoil that may be related to emphyse- ma (see below) from increased resistance in small airways (Buist and Ducic 1979). Even the determination of density dependence of maximum expiratory airflow, once felt to be specific for detecting abnormalities in the caliber of small airways, is not immune to the effects of lung elastic recoil. A decreased effect on maximal expiratory air flow of using low density gas can be caused by decreased elastic recoil (Gelb and Zamel 1981). 121 Pulmonary function testing of individuals with proven emphyse- ma often shows increases of residual volume, functional residual capacity, and total lung capacity and decreases of maximal expirato- ry air flow (Boushy et al. 1971; Park et al. 1970; reviewed in Kidokoro et al. 1977). However, because individuals with emphysema commonly also have intrinsic airway disease (Cosio et al. 1978) affecting the results of these pulmonary function tests in the same direction as emphysema, it is clear that these tests are not specific for emphysema. Accordingly, there has been interest in other, more distinctive tests. Among readily applicable tests, the diffusing capacity has proved to be directly related to the extent of emphyse- ma (Park et al. 1970; Boushy et al. 1971; Berend et al. 1979), presumably reflecting a diminution of internal surface area avail- able for gas exchange. The usefulness of the diffusing capacity to identify and estimate emphysema is limited, however, because the measurement is not sensitive to low grades of emphysema (Symonds et al. 1974) or specific for emphysema. Moreover, the results must be interpreted carefully in smokers because the values for diffusing capacity are lower than in nonsmokers, and the difference extends even to young smokers who are not likely to have emphysema (Enjeti et al. 1978; Miller et al. 1983). Mechanical Properties of the Lungs in Emphysema Measurements of the pressure-volume characteristics of the lung have generally been regarded as a reliable means of physiologically detecting and quantifying emphysema because (a) patients with emphysema often have increased lung distensibility and correspond- ingly low transpulmonary pressures (loss of elastic recoil) and (b) the severity of emphysema has seemed to correlate with the change in elastic recoil. It has also been assumed that the regions of lung with emphysema are the cause of the decreased lung elastic recoil, an assumption that appears reasonable because elastic recoil results in part from surface forces at the air-liquid interface and there is less surface area in emphysema. Recent observations challenge these concepts. Berend and Thurl- beck (1982), using lungs obtained post mortem, could not demon- strate a relationship between indices of lung elasticity and the grade of emphysema in 48 lungs ranging in grade from 2 to 80 (on a scale of 100), and observed (Berend et al. 1981) in emphysematous lungs that the relative increase in compliance of the lower lobes was greater than the upper lobes, even though the emphysema was worse in the upper lobes. Others have also reported poor correlations between emphysema and elastic recoil. Silvers et al. (1980) found decreased elastic recoil and increased total lung capacity in excised human lungs with minimal emphysema, and Schuyler et al. (1978) noted in hamsters given small doses of elastase intravenously that there was 122 decreased lung elastic recoil at low lung volumes, although the lungs did not show morphometric changes. Guenter et al. (1981) noted that mild emphysema produced by pepsin caused greater changes in lung elasticity than similar degrees of lung destruction produced by endotoxin-induced repetitive leukocyte sequestration. They suggest- ed that these differences may be due to differences in the location of the connective tissue injury within the lung. Even among those who have reported an association between emphysema and elastic recoil, the correlations have been best when the emphysema was severe (Greaves and Colebatch 1980). Pare et al. (1982) found a correlation between emphysema grade and elastic properties of the lungs in 55 persons; however, in 5 whose surgically removed lung tissue received emphysema scores between 20 and 70 (out of a maximum of 100), the elastic properties of the lungs tested preoperatively were indistinguishable from normal. While such discrepancies probably reflect the limitations of relating the overall elastic properties of both lungs to the morphology of a single lobe, it must also be recognized that the sensitivity of the pressure-volume diagram is limited, since a narrow range of pressure (to 20 cm H20) depicts the average retractive force from millions of air spaces and the connective tissue network of the lung. From these recent findings it must be concluded that the relationship between elastic recoil and morphologic measures of emphysema is not highly predictable, and that the decrease of elastic recoil and increase of total lung capacity commonly seen in emphysematous lungs may not result entirely from abnormal mechanical properties in the areas showing emphysema. The mechanical abnormalities may also derive from areas that appear normal, although the possible reasons for this are obscure (reviewed by Thurlbeck 1983). An alternate explanation for this discordance between elastic recoil and morphologic emphysema may be the problems of sampling and grading intrinsic to these morphologic measures. The work of Michaels et al. (1979) introduces a further complexity to the use of pressure-volume curves as an indicator of emphysema. They found that inhalation of a bronchodilator shifted the curve of smokers in the direction of increased compliance, but had no effect in nonsmokers (Figure 26). Cessation of smoking had the same effect as a bronchodilator. These results were interpreted as indicating that smoking causes some peripheral airway units to constrict and become effectively closed. Thus, pressure-volume studies to detect early changes compatible with emphysema in smokers may give false negative results unless accompanied by studies with bronchodi- lators. 123 90 80 2 70 3 a 32 ® 5 3 60 O-—-—-O Smokers @—®@ Smokers p B.D. O—-O Nonsmokers @—® Nonsmokers p B.D. 50 P(stat)cmH,O0 FIGURE 26.—The effect of nebulized bronchodilator on the pressure-volume characteristics of the lungs in 19 smokers (6 men and 13 women) and 16 nonsmokers (9 men and 7 women) NOTE: The mean age was approximately 40 years (range, 19 to 56) and smokers used approximately 30 cigarettes per day. Male smokers showed borderline significant differences in indices of expiratory airflow and single breath Ne test data as compared with the male nonsmokers, but there was no difference in these tests between female smokers and nonsmokers. As shown, smokers had significantly less elastic recoil than nonsmokers. After the bronchodilator, the difference between smokers and nonsmokers increased further, particularly at high lung volume. B.D. = broncodilator; % pred. TLC = percent predicted total lung capacity; P(stat) = transpulmonary pressure. *p<0.05; ** p<0.01; *** p< 0.005. SOURCE: Michaels et al. (1979). Aging and Lung Structure With advancing age, structural and functional changes occur in the lungs of virtually all adults, even those who have no known exposure to specific inhalants through occupation or personal habits (Fishman 1982; Campbell and Lefrak 1983). The elastic recoil of the lungs declines with aging, and the residual volume to total lung capacity ratio increases. These changes are seen even in people who have never smoked, do not have signs or symptoms of cardiorespira- tory disease, and have the normal (MM) phenotype of a,-antiprotein- 124 ase (Knudson et al. 1977). Also with aging, the average distance between alveolar walls increases (Thurlbeck 1967a; Hasleton 1972), the proportion of lung volume that is composed of alveoli decreases, and the proportion of alveolar ducts increases (Ryan et al. 1965). Whether the differences in the lungs that occur with aging are a consequence only of the passage of time or are the result of subtle environmental insults summed over many years is unanswerable. They are “normal” or “abnormal” depending on whether one regards “normal” as a statistical concept or as the optimal state for the tissue. In either case, the aging lung has some features similar to emphysema. Age changes alone will not, however, contribute to or obscure the diagnosis of centrilobular emphysema, which involves mainly respiratory bronchioles, recognized macroscopically as focal lesions against a background of normal lung. The age changes may overlap with early panlobular emphysema (Anderson et al. 1970). However, since smokers usually die at an earlier age than nonsmok- ers, aging cannot account for the differences observed between the lungs of smokers and nonsmokers at autopsy. Emphysema and Cigarette Smoking Studies of people and of experimental animals conclusively link cigarette smoking to the development and extent of emphysema. This information is summarized in the following discussion. Observations in People Post-mortem material, used to approach the problem in the 1960s and 1970s, clearly established an association between smoking and emphysema. Post-mortem lung tissue has continued to be used to study emphysema, but the main goal of recent studies has been to identify those physiologic features that correlate with emphysema rather than to quantify the relationship between smoking and emphysema. Studies of emphysema using surgically removed lung tissue, a more recent approach to studying emphysema, have aimed mainly at elucidating the physiology of the emphysematous lung. The results of these studies have involved smokers almost exclusive- ly because of the rarity of emphysema in nonsmokers. Studies Using Post-Mortem Material A number of studies have examined the relationship between cigarette smoking and emphysema (Anderson et al. 1964, 1966; Thurlbeck 1963; Thurlbeck et al. 1974; Ryder et al. 1971; Auerbach et al. 1972, 1974; Spain et al. 1973). These data emphasize that not only is cigarette smoking closely associated with the development and extent of emphysema, but also it is extremely rare for the forms 125 of emphysema found in patients with COLD to be present to a significant degree in nonsmokers. Thurlbeck (1963) reported 19 patients who had severe emphysema at autopsy. All 19 were cigarette smokers, in contrast to 18 smokers out of 38 patients who did not have significant emphysema at autopsy. Anderson et al. (1964) conducted a more systematic evaluation of the relationship between cigarette smoking and the degree of emphysema at autopsy. They found that 12 of 23 patients without emphysema were cigarette smokers, whereas 55 of 84 with mild emphysema, 30 of 33 with moderate emphysema, and 14 of 15 with severe emphysema were cigarette smokers. Petty et al. (1967) reported similar findings, with 6 of 57 patients with moderate emphysema at autopsy being nonsmokers and only 1 of 61 patients with severe emphysema being a nonsmoker. Ryder et al. (1971) found that of 21 patients whose lungs showed more than 25 percent emphysema, only 1 was a nonsmoker. Thurlbeck et al. (1974) examined the relationship of age to extent of emphysema in smokers compared with nonsmokers in the combined autopsy populations of the teaching hospitals in three separate cities. The severity of emphysema was quantified using a panel grading method, with a score under 25 representing mild emphysema. They found that the degree of emphysema increased slightly in nonsmokers beginning in the fifth decade and reached an average score of 10 to 15 in men and 4 to 6 in women by the eighth and ninth decades. In contrast, male smokers had an average score of 25 to 30 by the seventh decade and maintained this level for the next two decades. Sutinen et al. (1978) (Table 13) examined the relationship between prevalence and extent of emphysema and duration of the smoking habit. As would be expected from previous studies, moderate or severe emphysematous changes were limited to smokers. However, these changes were also limited to those smokers who had smoked for 20 or more years, and severe emphysema was reported only in those who had smoked for 40 years or more. These data, coupled with that of Thurlbeck et al. (1974) describing only mild emphysematous changes in nonsmokers with advancing age, suggest that emphyse- ma is a late pathologic change in cigarette-induced lung disease. This correlates well with the clinical experience of severe emphysema being rare prior to the fifth decade. It also suggests that cessation, even among middle-aged smokers, may have substantial impact on emphysema morbidity and mortality. Dose-Response Relationships Some studies have reported the extent of emphysematous change in smokers of different numbers of cigarettes per day. Spain et al. (1973) examined the lungs of 134 subjects who died suddenly and 126 TABLE 13.—Correlation between the severity of emphysema at autopsy and total smoking duration Prevalence of emphysema (percent) by total smoking years Grade of emphysema 0 1-19 20-39 40 or more Total No emphysema 61.6 81.6 oh 8.8 43.1 Mild (grades 5 to 20) 38.4 15.4 69.7 50.0 45.8 Moderate (grades 30 to 50) - - 91 26.5 7.8 Severe (grade 60 or more) - - - 14.7 3.3 All grades 38.4 15.4 78.8 91.8 56.9 Total number 73 13 33 34 153 NOTE: P <0.0005; X? test, with groups of moderate and severe emphysema and of smoking times 1-19 and 20— 39 years combined. SOURCE: Sutinen et al. (1978). who had no previous history of lung disease. They found emphysema- tous changes greater than grade 20 (mild emphysema) in 10 percent of nonsmokers, 36 percent of smokers of less than one pack per day, and 39 percent of smokers of more than one pack. A much larger study was conducted by Auerbach et al. (1972, 1974), who examined whole lung sections from 1,443 men and 388 women autopsied between 1963 and 1970. Table 14 describes the relationship of age, smoking habits, and degree of emphysema graded on a scale of 0 to 9, with 9 representing severe emphysema. It is clear that severe emphysema is limited to smokers, and that the severity of emphysematous change at autopsy increases with in- creasing number of cigarettes smoked per day during life. This study also found that almost all (94.5 percent) smokers of more than one pack per day had some degree of emphysema (slight, moderate, advanced, or far advanced) (Table 15). In contrast, 93.8 percent of nonsmokers had either none or minimal emphysema. This evidence would suggest that emphysematous change is a nearly universal phenomenon in heavy smokers, but is rare in nonsmokers, and that it is the large ventilatory reserve of the lungs that restricts clinically manifest disease to those individuals with far advanced emphysema. Similar results were reported in a more limited number of autopsies done on female smokers (Auerbach et al. 1974) (Table 16). A study of microscopic lung sections from the autopsies of 1,436 men and 388 women was also reported by Auerbach et al. (1974), and closely paralleled the results of the whole lung study. However, they also reported the results in smokers who had quit for more than or less than 10 years prior to death (Table 17). The degree of emphysematous change was still related to the amount smoked, but 127 TABLE 14.—Degree of emphysema in current smokers? and in nonsmokers, according to age groups Subjects Current Age Degree of who never pipe or Current cigarette group emphysema smoked cigar smokerst regularly smokers 1 Pk. Number of subjects 252 33 64 Emphysema 0.05 1.37 1.70 Fibrosis 0.37 2.89 3.46 Thickening of arterioles 0.06 1.26 1.57 Thickening of arteries 0.01 0.40 0.64 NOTE: Numerical values were determined by rating each lung section on scales of 04 for emphysema and thickening of the arterioles, 0—7 for fibrosis, and 0-3 for thickening of the arteries. SOURCE: Auerbach et al. (1974). rate of progression of emphysematous change in those who quit compared with those who continue to smoke. Studies of Alpha:-Proteinase-Inhibitor-Deficient Individuals The deficiency of a,-proteinase inhibitor is an experiment of nature with broad implications for understanding the pathogenesis of emphysema (Idell and Cohen 1983). Discovery of homozygous- deficient subjects (type PiZZ) with only 10 percent of normal plasma 129 TABLE 17.—Means of the numerical values given lung sections at autopsy of male former cigarette smokers, standardized for age Never smoked regularly Stopped >10 years Stopped <10 years Formerly smoked <1 Pack >1 Pack <1 Pack >1 Pack Number of 175 35 66 51 131 subjects Emphysema 0.09 0.24 0.70 1.08 1.69 Fibrosis 0.40 1.14 1.74 2.44 3.30 Thickening of 0.10 0.57 0.93 1.25 1.59 arterioles Thickening of 0.02 0.04 0.16 0.36 0.61 arteries NOTE: Numerical values for each finding were determined by rating each lung section on scales of 0 for emphysema and thickening of the arterioles, 0-7 for fibrosis, and 0-3 for thickening of the arteries. SOURCE: Auerbach et al. (1974). proteinase inhibitory activity and the demonstration of the frequent early development of emphysema in such subjects (Orell and Mazodier 1972) called attention to the critical step of fibrous tissue proteolysis in the remodeling of lung structure. It also pointed to at least one potential explanation for the variability in extent of emphysema among smokers. Together with data from animal experiments, the discovery of the PiZZ defect and its association with emphysema has led to general acceptance of a theory of imbalance between the extracellular levels of proteinase and proteinase inhibitor in the lung as the cause of panacinar emphysema in subjects with this deficiency. The patho- genetic lessons learned from a,-proteinase-inhibitor deficiency also afford plausible explanations for other forms of emphysema, espe- cially emphysema associated with cigarette smoking. Homozygous Deficient—PiZZ In his classic description of the severe (PiZZ) deficiency of the a,- proteinase inhibitor, Eriksson (1965) did not indicate an effect of cigarette smoking on the development of emphysema. Later studies, however, did recognize smoking as a potential aggravating factor (Kueppers and Black 1974; Larsson 1978) and reported that PiZZ persons who smoked cigarettes were destined to experience shortness of breath 10 to 15 years earlier (Figure 27) and to die sooner than PiZZ persons who did not smoke (Figure 28). 130 Smokers Nonsmokers Smokers Nonsmokers Age (in years) FIGURE 27.—Age at onset of dyspnea in 169 PiZZ individuals separated according to sex and smoking history NOTE: The horizontal lines show the median values. The difference between nonsmokers and smokers was highly significant for both sexes and was 13 and 15 years for men and women, respectively. SOURCE: Larsson (1978). More recent studies, however, have shown considerable variation in the rate of decline of lung function among middle-aged PiZZ adults (Buist et al. 1983). In a comparison of 22 persons with PiZZ phenotype who had never smoked with 36 PiZZ smokers, Black and Kueppers (1978) found variability in symptoms and lung function abnormalities in both groups. Smokers generally sought medical attention earlier, and those who reached the older age groups, such as 60 to 69, had smoked less and started to smoke later in life. There was overlap in these characteristics between the age groups, however, and some smokers did live into the 50 to 69 age range. In this analysis, the correlations between pulmonary function test abnormalities and pack-years of cigarette smoking were small. The British Thoracic Society, in a multicentered study of PiZZ individuals (Tobin et al. 1983), reported an association between 131 ® Smoking PiZ men and women O Nonsmoking PiZ men and women A All Swedish women 0.8 A All Swedish men 0.6 0.4 0.2 Cumulative probability of survival 20 30 40 50 60 70 80 90 100 Age (in years) FIGURE 28.—The cumulative probability of survival, given that 20 years of age is reached, in smoking and nonsmoking Swedish PiZZ individuals, compared with all Swedish men and women NOTE: Survival was higher for PiZZ nonsmokers than for PiZZ smokers in both sexes above age 35. SOURCE: Larsson (1978). cigarette smoking and the onset of pulmonary symptoms and deterioration of lung function, but demonstrated no significant correlation between the quantity of tobacco consumed and the extent of pulmonary dysfunction. A notable finding in this study, applicable to other studies of the natural history of disease related to a,- proteinase-inhibitor deficiency, was the impressive difference be- tween individuals found because of medical complaints (index cases) and those detected by surveys (nonindex cases). Nonindex cases had better pulmonary function and survived longer than index cases, irrespective of other variables such as age and smoking history. The distinction between these two categories of subjects suggests the importance of factors besides the PiZZ phenotype in the development of symptomatic lung disease in PiZZ persons. PiZZ individuals who smoke increase their risk for early onset of symptomatic chronic obstructive lung disease and for a shortened lifespan, compared with nonsmoking PiZZ individuals. However, pulmonary function data have shown only limited differences in diffusing capacity and elastic recoil between the smokers and the nonsmokers (Black and Kueppers 1978). 132 Heterozygous Deficient—PiMZ The PiMZ phenotype of a,-antiproteinase inhibitor occurs in approximately 3 percent of the population. Because of the high frequency of emphysema in PiZZ persons, it is important to establish whether PiMZ individuals also have an increased risk of emphysema and chronic obstructive lung disease. From the unpredictability of obstructive lung disease even among those with the PiZZ phenotype, however, one might expect difficulty in discerning the effect of the PiMZ phenotype. Among adults with symptomatic chronic obstructive lung disease, the PiMZ phenotype is more prevalent than expected (Mittman 1978). It is uncertain whether this means of subject identification is appropriate, as was noted concerning index and nonindex PiZZ individuals. Madison et al. (1981) emphasized the complexity of this issue by noting that the PiMZ phenotype was only one of several factors that appeared to be related to the risk of obstructive lung disease. Other factors identified as relevant included smoking, a family history of lung diseases, and being male. From studies of children and young adults it is evident that the PiMZ phenotype does not strongly predispose to chronic pulmonary disease. Thus, PiMZ children (Buist et al. 1980) failed to show any early changes of lung dysfunction analogous to what has been observed in some young PiZZ individuals; PiMZ adults below the age of 40 had the same results by spirometry and the single breath Ne test as PiMM individuals matched for smoking history (Buist et al. 1979b). Numerous studies involving older subjects indicate that PiMZ individuals preserve their lung function, as measured by spirometry, compared with controls matched for smoking (Tattersall et al. 1979, de Hamel and Carrell 1981). The elastic properties of the lungs may be different in PiMZ persons, but if there are differences, they are small. Larsson et al. (1977) reported that 50-year-old PiMZ men who smoked had reduced elastic recoil at total lung capacity compared with PiMZ nonsmokers, even though they had no evidence of impaired air flow. The PiMZ nonsmokers were indistinguishable from PiMM nonsmokers. Tattersall et al. (1979) also found no effect upon airflow in PiMZ middle-aged men, and a statistically nonsignif- icant decrease in elastic recoil. Using an index of the slope of the pressure-volume curve, Knudson and Kaltenborn (1981) found no significant reduction in elastic recoil of PiMZ subjects compared with matched PiM controls. There is little direct information about the occurrence of emphyse- ma among PiMZ individuals. In an autopsy study, Eriksson et al. (1975) found emphysema among 13 of 26 subjects with diastase- resistant PAS-positive inclusions in the liver, compared with an incidence of emphysema of only 18 percent in the controls. Although 133 these findings suggest an increased occurrence of emphysema with the PiMZ phenotype, this study should be interpreted cautiously because the smoking histories of the subjects and the quantification of the emphysema were not included. Moreover, the significance of the PAS-positive inclusions is not certain, because one recent study found that such inclusions represented immunoreactive a,-protein- ase inhibitor in only half of the tissue studied (Qizilbash and Young- Pong 1983). It may be concluded from the studies involving a,-proteinase- inhibitor-deficient people that for those with the PiMZ phenotype, smoking has not been shown to promote a greater risk of emphysema than it does in PiMM persons. In the rare individual with PiZZ, the risk of emphysema is extremely high in both smokers and nonsmok- ers, but PiZZ smokers experience an earlier onset and more severe chronic obstructive lung disease than PiZZ nonsmokers. Observations in Experimental Animals Experimental animals have been subjected to cigarette smoke to examine whether changes typical of emphysema result. As noted below, it appears that cigarette smoke exposure can produce emphysematous-like changes in the lungs under experimental conditions, but the exposure must be quite prolonged and intense, or additional factors must be employed to “sensitize” the lungs to the effects of cigarette smoke. Pioneering studies in dogs exposed to cigarette smoke, by Hernan- dez et al. (1966) and by Auerbach et al. (1967), indicated effects consistent with emphysema, but these reports did not include quantitative morphology or data about the mechanical properties of the lungs. Moreoever, the exposures may have created problems of hypoxemia and infection that may have influenced the responses to cigarette smoke. Contrary to these findings, in later studies, beagles that inhaled cigarettes by face mask in four sessions per day for up to 1 year—an inhalation sufficient to raise the blood carboxyhemoglo- bin saturation to 5.4 + 0.9 percent—had no statistically significant changes in mean linear intercept or internal surface area, although their large airways showed epithelial cell hyperplasia, proliferation of goblet cells, and peribronchial inflammation (Park et al. 1977). Recently, Hoidal and Niewoehner (1983) presented data suggesting that cigarette smoke may be an important cofactor in the develop- ment of elastase-induced emphysema. They found that inhalation of cigarette smoke led to severe emphysema in hamsters if used in conjunction with doses of elastase that did not produce emphysema when used alone. In this study, hamsters were exposed to cigarette smoke for 15 minute periods, six times per day, 6 days per week for 7 weeks in standardized chambers. The animals were challenged with small doses of elastase given intratracheally; controls consisted of 134 animals given either elastase or smoke exposure or neither. Animals receiving only smoke or only elastase showed no changes of mean linear intercept or volume—pressure relationship of the excised lungs, compared with animals given neither elastase nor smoke exposure. The combinations of smoking followed by elastase or smoking both before and after elastase produced statistically signifi- cant increases of mean linear intercept, displacement upward and to the left of the volume—pressure curves (Figure 29), and marked emphysema by light microscopy of inflation-fixed lungs. The mecha- nism of the synergism between elastase and smoking was not elucidated. One possibility considered was that cigarette smoke impaired the repair mechanism normally triggered by elastase exposure, a possibility supported by Osman et al. (1982), who found that hamsters exposed to cigarette smoke after intratracheal elas- tase did not show the heightened lung elastin synthesis typically seen after lung injury produced by elastase. Summary Clinically significant degrees of emphysematous lung destruction are commonly present in individuals with COLD. Severe emphysema occurs almost exclusively in cigarette smokers and those with homozygous a,-antitrypsin deficiency. The extent of emphysematous change increases with increasing numbers of cigarettes smoked per day and with the duration of the smoking habit. While clinically significant emphysema is limited to a minority of those who smoke, most heavy smokers have some degree of emphysematous change by the sixth decade of life. Individuals with homozygous a,-antitrypsin deficiency have an exceptionally high risk of developing emphysema. This risk is present for both smokers and nonsmokers, but smokers with a,- antiprotease deficiency develop clinical symptoms earlier in life. It is unclear whether individuals with heterozygous antiprotease pheno- types are at increased risk of developing COLD. Summary and Conclusions 1. Cigarette smoking is the major cause of COLD morbidity in the United States; 80 to 90 percent of COLD in the United States is attributable to cigarette smoking. 2.In population-based studies in the United States, cigarette smoking behavior is often the only significant predictor for the development of COLD. Other factors improve the predictive equation only slightly, even in those populations where they have been found to exert a statistically significant effect. 3.In spite of over 30 years of intensive investigation, only cigarette smoking and a,-antiprotease deficiency (a rare genet- 135 120 100 80 60 Lung volume (% pred TLC) @ Nosmoke, no elastase O Continuous smoke, no elastase 40 @ Nosmoke, elastase QO) Post-elastase smoke A Pre-elastase smoke A Continuous smoke, elastase 20 p<,05 compared with * No smoke, no elastase 5 10 15 20 25 30 Pressure (cmH,0) FIGURE 29.—The effects of combining cigarette smoking and elastase upon the pressure-volume characteristics of the lungs of experimental animals NOTE: The in vitro measurements of lung volume are shown as percentage of predicted total lung capacity (TLC) relative to transpulmonary pressure of hamster lungs following in vivo exposure to various combinations of cigarette smoke and intratracheally administered pancreatic elastase. Values are the mean + SEM of measurements made during deflation. The animals that smoked and then received elastase (Pre-Elastase Smoke) and those that smoked both before and after elastase (Continous Smoke, Elastase) had significant changes in the elastic properties of the lungs. There were no changes from control if elastase or smoking were used separately or when smoking occurred only after elastase. SOURCE: Hoidal and Niewoehner (1983). ic defect) are established causes of clinically significant COLD in the absence of other agents. 4. Within a few years after beginning to smoke, smokers experi- ence a higher prevalence of abnormal function in the small airways than nonsmokers. The prevalence of abnormal small airways function increases with age and the duration of the 136 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. 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(Saye yi +! IOs § ee ~ -2 om) st } TOE, * I “ ! Ab sti ee. a 2 ce “aS ohn = 2a ( KEN 4: TET USPS” tite tly Me : . ‘i , i ay A 7% Ww 7. fey Oe so ebaeR Mitag ert. “ ie in ae Ris P 7 Oe At! : aoa BLidnh “Peer eRI T wend Basi0e ‘ea ‘aves fs CHAPTER 3. MORTALITY FROM CHRONIC OBSTRUCTIVE LUNG DISEASE DUE TO CIGARETTE SMOKING 185 Ayo eri jAT ROW ol or sua Zi meet [OMZ TITARAOWD or a , a me) LG MHD . & SITTOu TT2aoO CONTENTS Introduction COLD Mortality Patterns in the United States Prospective Studies The British Doctors Study The American Cancer Society 25-State Study The U.S. Veterans Study The Canadian Veterans Study The American Cancer Society 9-State Study California Men in Various Occupations The Swedish Study The Japanese Study of 29 Health Districts Cigarette Smoking and Overall COLD Mortality Retrospective Studies Male and Female Differences in COLD Mortality Amount Smoked and Mortality From COLD Inhalational Practice and Mortality From COLD Age of Initiation and COLD Mortality Smoking Cessation and COLD Mortality Pipe and Cigar Smoking Mortality From COLD International Comparison of COLD Death Rates and Smoking Habits: The Emigrant Studies COLD Mortality Among Populations With Low Smoking Rates Summary and Conclusions References A EE me A A LLLP LL A ce A i i I LGA AEE LAA ee — “othe ome wok iW aricitaiaqot aromh NY HI mene Ae AAA oA —_———— at a ee 4 asiniS batinU ei? oF anraisat % —— AAR LLALA ALA ALAA, vboi2 erotpod £ yp 1S steJe-OS FO va 4 fod b wtisS if soit agri ght snared < vise anawete¥ shin “ybuse sie qemom tsons0 3 apotacimoD exotieY ik nal 8 Ail yh Be atsivteift dilesH 8S to yhise, ih viilenoM GO 1.100 fisavO bus an owe Ms | | “plbute tiie GIGO ab essmease sisms — ie me - 5} lt eee aeeemeemanmmmentiate: sill ¢} 10 ' (got viilatioM hae v2 iD mors wii ‘latol ben gol = oan saientthh inna naar tighti ae a ae | giilasroht (iGO bes vaile rol 300,000 1.93 > 300,000 10.93 California men Nonsmoker? 1.00 Emphysema in various About '/, pk 8.18 occupations About 1 pk 11.80 About 1'/, pk 20.86 American Cancer Nonsmoker 1.00 All pulmonary Society 1-9 1.67 diseases other 9-State 10-20 3.00 than cancer * 20+ 3.64 1 Data for the Japanese study are for lifetime exposure by > total number of cigarettes consumed. ? Nonsmoker in the California occupations study also includes > smokers of pipes and cigars. ’ Pneumonia, influenza, TB, asthma, bronchitis, lung abscess, etc. 202 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 10-year birth cohorts of men and women as those cohorts progressed through the years 1900-1980 (Harris 1983). Examination of these figures revealed several impor- tant findings. Relatively few women took up smoking prior to 1930. The heaviest smoking cohorts of men have a prevalence of over 70 percent compared with 45 percent of women, and the male cohorts with these peak prevalences are older than the female cohorts. However, as discussed earlier, the incremental and progressive nature of cigarette-induced lung injury results in both prevalence and duration of cigarette smoking having an impact on COLD death rates. Therefore, in examining Figures 6 and 7 it is important to consider the span of years of a given prevalence of smoking maintained by a given birth cohort as well as the peak prevalence achieved by that cohort. The COLD death rates should then be proportional to the area under the prevalence curve described by each cohort, rather than to the peak of that curve. A careful examination of Figure 6 reveals that the area under the prevalence curve for the cohort born between 1921 and 1930 is less than the area under the curve for the cohort born between 1911 and 1920, in spite of their similar peak prevalences. This difference is due to the more rapid decline in prevalence with age in the 1921 to 1930 cohort. Similarly, the cohort born between 1901 and 1910 partially compensates for a peak prevalence that is lower than the 1911 to 1920 cohort by having a somewhat a broader base. Each of the cohorts born prior to 1900 have substantially smaller areas under their curves than those born during the first three decades of this century. These differences in prevalence are reflected in the changes 203 1910 1920 1930 1940 1950 1960 1970 1921-30 1900 1910 1920 1930 1940 1950 1960 1970 1980 Year FIGURE 6.—Prevalence of cigarette smoking among successive birth cohorts of men, 1900-1980, derived from smoking histories in the National Health Interview Survey (HIS) | SOURCE: Harris 1983. in age-specific death rates portrayed in Figure 8 and Table 5. The oldest age group (75-84) continues to show a rapid rise in COLD death rates as those birth cohorts with increasing prevalence and duration of smoking move into this age range. In the age range 65-74 the rates rose rapidly from 1960 through the mid 1970s, but seem to be leveling off, consistent with the fact that this age group is now made up entirely of men born after 1900. In the age range 55-64 the rates suggest a slight downturn beginning in the mid 1970s, coincident with the entry of the 1921 to 1930 birth cohort into this age group. The numbers for the age range 45-54 are too small to 204 1910 1920 1930 1940 1950 1960 1970 1931-40 Women 1921-30 1911-20 > 4 1901-10 , 1891-1900 JF} reat ee 1900 1910 1920 1930 1940 1950 1960 1970 1980 Year FIGURE 7.—Prevalence of cigarette smoking among successive birth cohorts of women, 1900-1980, derived from smoking histories in the National Health Interview Survey (HIS) SOURCE: Harris 1983 permit firm conclusions, but also suggest that a downturn in rates occurred in this group in the late 1960s. A close examination of Figures 6 and 7 also offers an explanation of the differences in mortality ratios for men and women observed in the prospective studies. COLD is a slow, progressive disease, and death from COLD usually results only after extensive lung damage has occurred. The fact that death from COLD is unusual prior to age 45 reflects, in part, the 30 or more years required for cigarette smoke to damage enough lung to result in death. The substantial ventilato- ry reserve of the lung allows a significant amount of damage to exist in a person without symptomatic limitation or risk of death from COLD. The prospective mortality studies were conducted in the 1950s and 1960s, a point in time approximately 30 years after the beginning of the rise in smoking prevalence among women demon- strated in Figure 7. Even the older cohorts, where significant mortality might be expected, had begun smoking largely after 1930, and therefore had a shorter duration of smoke exposure than the men born in the same years. This shorter duration of the smoking habit, together with the previously described tendency of women to 205 75-84 400 © S ets it Cc cc oe Ee eno 65-74 Ce 100 55-64 45-54 1960 1965 1970 1975 YEAR FIGURE 8.—Age-specific COLD mortality rates for white men in the United States, 1960-1977 NOTE: ICDA Nos. 490-492 and 519.3. SOURCE: National Center for Health Statistics (1982). smoke fewer cigarettes per day and to inhale less deeply, would be expected to result in less cumulative lung damage at any given age. This difference in extent of lung damage could explain the difference in COLD mortality ratios between men and women observed in the prospective mortality studies. The British doctors study examined the risk of COLD death for male and female physicians who smoked similar numbers of cigarettes per day (Table 4), and the mortality ratios were similar for similar numbers of cigarettes smoked per day. In summary, data from the prospective studies indicate that the relative risk of death from COLD is greater for male smokers than for female smokers. These differences are most likely a consequence of differences in female smoking patterns. Women tend to smoke fewer cigarettes, inhale less deeply, and begin to smoke later in life than men. These differences in mortality from COLD are narrowing because of a more rapid rise in female mortality from COLD than in male COLD mortality. This reflects the narrowing in differences between male and female smoking patterns and the rising preva- lence of female smokers in successive cohorts born between 1920 and 206 TABLE 5.—Age-specific COLD death rates per 100,000 population Age Year 45-54 55-65 65-74 75-84 1960 8.6 36.1 82.9 101.8 1961 7.6 38.7 87.9 111.8 1962 9.6 44.2 107.2 136.7 1963 11.7 52.3 131.2 169.6 1964 12.1 51.8 131.6 181.9 1965 12.4 57.8 153.6 216.6 1966 12.4 61.9 161.9 244.8 1967 12.4 61.2 164.8 248.6 1968 13.1 67.4 186.7 286.5 1969 13.9 67.5 189.5 294.3 1970 13.6 68.1 196.5 311.5 1971 13.5 67.4 195.6 327.4 1972 13.0 67.7 204.8 351.4 1973 12.7 69.9 210.1 378.4 1974 12.8 64.8 204.8 380.4 1975 11.9 64.7 207.6 399.7 1976 12.2 64.0 210.7 419.7 1977 11.4 60.1 206.1 431.5 SOURCE: National Center for Health Statistics (1982). 1950. These data are ominous for women, portending a rising mortality from COLD over the next decades. Amount Smoked and Mortality From COLD Six of the major prospective studies evaluated the influence of different smoking levels on mortality from COLD. These studies employed a variety of measures of tobacco exposure, including number of cigarettes smoked per day, grams of tobacco smoked, and total number of cigarettes smoked in a lifetime. The data, presented in Table 4, show a gradient in risk for mortality from COLD as the number of cigarettes smoked per day increases and as the cumula- tive number of lifetime cigarettes smoked increases. In the U.S. veterans study, smokers of two packs or more per day had 22 times the risk of COLD death of nonsmokers. Furthermore, mortality ratios between the two followup periods for bronchitis and emphyse- ma actually increased overall and by the amount smoked (Figure 9). The authors noted that this was the only major disease of those associated with cigarette smoking that showed such an increase, suggesting that mortality ratios have been increasing over time at all levels of smoking. In the British and Japanese studies, women smokers at the highest levels exhibited a 32- and an 11-fold higher risk for death from COLD (respectively) than their nonsmoking counterparts. The variability in COLD mortality ratios noted in 207 21.98 81/2 20 O years @ 16 years : 17.45 1 45.02 15 2 Ee 12.07 4 11.23 é 11.13 oO = 10 | a (0) J Nonsmoker All cigarette 10-20 21-39 >40 smokers Cigarettes smoked per day FIGURE 9.—Bronchitis and emphysema for male smokers number of cigarettes smoked per day, U.S. veterans study, 8’/.-year and 16-year followup Table 3 is much less evident when the mortality ratios are presented by amount smoked. In summary, the degree of tobacco exposure strongly affects the risk for death from COLD in men and in women. This clearcut dose— response relationship enhances the strength of the causal relation- ship between smoking and COLD. inhalational Practice and Mortality From COLD The inhalation of tobacco smoke is the major mechanism whereby bronchial and alveolar tissues are exposed to the potentially damaging effects of tobacco smoke. In the British doctors study, subjects who acknowledged inhaling exhibited a 1.53-fold higher risk for COLD death as compared with those who stated they did not inhale (see Table 6). However, all smokers, regardless of their inhalational practice, exhibited higher risk for COLD mortality than did nonsmokers. In the retrospective study from northeast England (Dean et al. 1977, 1978), the risk among men for mortality from chronic bronchitis steadily declined with a decrease in the depth of inhala- tion (Table 7). Among women, the risk for mortality from chronic bronchitis was lower for all other groups than for those who stated they “inhaled a lot.” 208 TABLE 6.—COLD mortality by inhalation practice, British doctors study, men Annualized death rate per Risk in inhalers Number of 100,000 men responding compared with unity Cause of death deaths to question: do you inhale? in noninhalers Chronic bronchitis Yes No and emphysema and 71 89 58 1.53 pulmonary heart disease Table 7.—Relative risk for mortality by depth of inhalation, 1963-1972, second retrospective mortality study in northeast England Relative risk for chronic bronchitis Depth of inhalation Men Women A lot (base) 1.00 1.00 A fair amount 0.98 0.54 A little 0.62 0.41 None 0.58 0.58 SOURCE: Dean et al. (1977, 1978). Results from prospective mortality studies comparing COLD death rates by inhalation are identical to those observed in the morbidity studies, which have consistently shown that COLD is more prevalent among inhalers than noninhalers (Ferris et al. 1972; Comstock et al. 1970; Rimington 1974). These data suggest that inhalational practice affects the risk of mortality from COLD. People who inhale deeply experience a higher risk for mortality from COLD than people who do not inhale. Regardless of their inhalational practice, however, smokers still experience higher rates of death from COLD than nonsmokers. Age of Initiation and COLD Mortality Another indicator of exposure to tobacco smoke that may influ- ence risk for mortality from COLD is the age of initiation of smoking. If their smoking habits are otherwise similar, people who take up smoking at a younger age have a greater total exposure to tobacco smoke than those who take up smoking later in life, and might be expected to experience greater adverse consequences from smoking. In the Japanese prospective study (Hirayama 1981), men who began to smoke before the age of 19 exhibited slightly higher mortality ratios for emphysema than did men who began to smoke after the 209 TABLE 8.—Number of deaths from chronic bronchitis, emphysema, and pulmonary heart disease in ex- cigarette smokers, by years of cessation, versus number of deaths in lifelong nonsmokers, British doctors study Number of deaths in ex-smokers, divided by Number of deaths number expected in lifelong smokers in nonsmokers Years of cessation 0* <5 5-9 10-14 >14 35.6 34.2 47.7 Ta 8.1 2 * Current smokers. age of 20. In the retrospective study from northeast England (Dean et al. 1977, 1978), the relative risk for death from chronic bronchitis among men who began to smoke after the age of 25 was 60 percent of that of men who began to smoke between the ages of 15 and 19. Among women in the same study who began to smoke between the ages of 15 and 19, the relative risk for death from chronic bronchitis was 1.28-fold higher than for women who began to smoke after age 25; however, the number of deaths was small. Smoking Cessation and COLD Mortality The effects of smoking cessation on mortality from COLD were examined in the British doctors study and the U.S. veterans study. In the British doctors study, men who quit smoking experienced no change in mortality from COLD in the first 4 years and a rise in the next 5 years; presumably, this is related to the presence of many people in this group who quit smoking for health reasons (Table 8). Thereafter, ex-smokers experienced lower death rates from COLD, although their rates were still higher than those of the nonsmokers. Female ex-smokers also experienced lower mortality rates than current smokers, but the rates in ex-smokers were still higher than those in nonsmokers. In the U.S. veterans study, ex-smokers who had quit for reasons other than ill health experienced lower mortality rates for COLD than did current smokers. However, the benefit of cessation upon risk for mortality was heavily dependent upon the prior level of smoking and the length of time of cessation. These data are presented in Table 9. Ex-smokers who had smoked less than 10 cigarettes per day had a 1.64-fold higher risk for mortality from COLD than nonsmokers; in contrast, ex-smokers who smoked more than 39 cigarettes per day had a 9.91-fold higher rate of death from COLD than nonsmokers. For any given number of cigarettes smoked 210 TABLE 9.—Mortality ratios for bronchitis and emphysema in nonsmokers and in ex-smokers and current smokers by number of cigarettes smoked daily and number of years of cessation, U.S. veterans study Cigarettes/day Smoking status 0 <10 10-20 21-39 >39 Nonsmoker 1.00 —_— a —_ = Ex-smoker — 1.64 5.35 7.68 9.91 Current smoker — 4.84 11.23 17.45 21.98 Years of cessation Current Nonsmoker smoker <5 5-9 10-14 15-20 > 20 1.00 12.07 11.66 14.35 10.19 5.66 2.64 per day, however, ex-smokers had a lower risk than current smokers. As in the British study, mortality ratios initially increased over the first 9 years of cessation. After the first 9 years, mortality ratios for ex-smokers fell, but never reached the level of the nonsmoker. Two studies have evaluated mortality rates from COLD among physicians, a group among whom many quit smoking to protect their health. Fletcher and Horn (1970) assessed the mortality rates from bronchitis among physicians in England and Wales. Among doctors aged 35 to 64, there was a 24 percent reduction in bronchitis mortality between 1953-1957 and 1961-1965, as compared with a reduction of only 4 percent in the national bronchitis mortality rates for men of the same age in England and Wales. Enstrom (1983) assessed mortality trends from COLD in a cohort of 10,130 physi- cians in California. The standardized mortality ratio for bronchitis, emphysema, and asthma among male California physicians relative to American white men declined from 62 during the period 1950 to 1959 to 35 during the period 1970 to 1979. In summary, cessation of smoking leads to a decreased risk for mortality from COLD as compared with that of current smokers. The residual risk of death for the ex-smoker is determined by the person’s prior smoking status and the number of years of cessation. However, the residual risk remains larger than that of the nonsmok- er, presumably because of the presence of irreversible lung damage acquired during prior smoking. Pipe and Cigar Smoking Mortality From COLD Several of the prospective epidemiological studies examined the relationship between pipe and cigar smoking and mortality from COLD. The data from these studies indicate that pipe smokers and 211 TABLE 10.—COLD mortality ratios in male pipe and cigar smokers, prospective studies Type of smoking Total Non- Cigar Pipe pipe and Cigarette Study Category smoker only only cigar only Mixed American Cancer COLD total 1.00 1.29 1.77 2.85 Society 9-State Emphysema Bronchitis British doctors COLD total 1.00 9.33 24.67 11.33 Emphysema Bronchitis 1.00 4.00 7.00 6.67 Canadian veterans COLD total Emphysema 1.00 3.33 15 5.85 Bronchitis 1.00 3.57 2.11 11.42 American Cancer COLD total Society 25-State Emphysema 1.00 1.37 6.55! Bronchitis U.S. veterans COLD total 1.00 .79 2.36 99 10.08 (8.5-year Emphysema 1.00 1.24 2.13 1.31 14.17 followup) Bronchitis 1.00 ha 1.28 Cir 4.49 U.S. veterans COLD total 1.00 0.84? 1.443 4.754 (16-year Bronchitis, followup) emphysema 1.00 2.53° 13.134 1 Mortality ratios for ages 55 to 64 only are presented. ? Pure cigar. > Pure pipe. *Pure cigarette. cigar smokers also experience higher mortality from COLD as compared with nonsmokers. However, the risk of dying from COLD is less than that of current cigarette smokers (Table 10). International Comparison of COLD Death Rates and eg 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, 1983), extensively reviewed this phenomenon as it relates to cancer and cardiovascular diseases among Mormons, Seventh Day Adventists, and others. Because Amish are seen as strict and fundamentalist in outlook, it is assumed that their use of tobacco is severely restricted. While cigarettes are largely considered taboo, pipe and cigar smoking and tobacco chewing are widespread (Hostetler 1968). Hamman et al. (1981) examined the major causes of death in Old Order Amish people in three settlements in Indiana, Ohio, and Pennsylvania to determine if their lifestyle altered their mortality risk compared with neighboring non-Amish. Mortality ratios from all respiratory diseases were significantly lower by over 80 percent in Amish men 40 to 69 years old, and by 50 percent in those 70 and older. In the chronic pulmonary disease categories including emphysema, bronchitis, and asthma, only one Amish male death occurred, whereas approximately 23 were expected. The pattern of mortality *-om chronic respiratory diseases was similar for Amish women. Summary and Conclusions 1. Data from both prospective and retrospective studies consis- tently demonstrate a uniform increase in mortality from COLD for cigarette smokers compared with nonsmokers. Cigarette smoking is the major cause of COLD mortality for both men and women in the United States. 2. The death rate from COLD is greater for men than for women, most likely reflecting the differences in lifetime smoking patterns, such as a smaller percentage of women smoking in \ 213 214 past decades, and their smoking fewer cigarettes, inhaling less deeply, and beginning to smoke later in life. . Differences in lifetime smoking behavior are less marked for younger age cohorts of smokers. The ratio of male to female mortality from COLD is decreasing because of a more rapid rise in mortality from COLD among women. .The dose of tobacco exposure as measured by number of cigarettes or duration of habit strongly affects the risk for death from COLD in both men and women. Similarly, people who inhale deeply experience an even higher risk for mortality from COLD than those who do not inhale. . Cessation of smoking eventually leads to a decreased risk of mortality from COLD compared with that of continuing smokers. The residual excess risk of death for the ex-smoker is directly proportional to the overall lifetime exposure to ciga- rette smoke and to the total number of years since one quit smoking. However, the risk of COLD mortality among former smokers does not decline to equal that of the never smoker even after 20 years of cessation. . Several prospective epidemiologic studies examined the rela- tionship between pipe and cigar smoking and mortality from COLD. Pipe smokers and cigar smokers also experience higher mortality from COLD compared with nonsmokers; however, the risk is less than that for cigarette smokers. . There are substantial worldwide differences in mortality from COLD. Some of these differences are due to variations in terminology and in death certification in various countries. 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Environmental Personal Factors in Lung Cancer and Bronchitis Mortality in Northern Ireland, 1960-62. Research Paper No. 9. London, England, Tobacco Research Council, 1966, 84 pp. WICKEN, A.J., BUCK, S.F. Report on a Study of Environmental Factors Associated with Lung Cancer and Bronchitis Mortality in Areas of Northeast England. Research Paper No. 8. London, England, Tobacco Research Council, 1964. 218 CHAPTER 4. PATHOLOGY OF LUNG DISEASE RELATED TO SMOKING 219 HE yr inti he 7% ‘ — = p _ ~ 2 a .f a avon aii om wif sts ah ak ~ a mth eae ex. Wegertenctt ot oh in 8 4... ( foe’ ua, } iN cvs oe! peta aft "felith:, N = wi rm = abevogy Dewaall:, Te es ms ‘eel ne con @wetaléy dona + 3 5 Syren . taal ia ; se ve id at} oa. | ad é . é 55 : : ; arg. (Ce iy cate rer att yo reg ik Mn) , a sty {ww Plier 9 Sitel “sips oh a nighe o ir a ) n } mn gol! ORS nnd ti. ‘ mn Fus bows! ieccoty Wa Ay Wi by, ; ; i. -— 4 > a » - : d it wi: LIMA yi : ‘ t Aeorert a atpean (ae Ure * Dien lib ad mua ) _ eae rat ORE a it oaith N t yee j MASS all ES... , wes yee, 4 Pee me M % } oy " i 4 “i Tr J] Aes a oh as 4 s “1 vi eoutst | | is Se a ; ' r a 4 Porre re ‘i ‘ yy) - ~~) 7 ie “ip 7A F une 4 7 ' ¥ f co" me , wea Ravenel eee Na w i ¥ , a Toa rae Lid 7 pe! LW: 4 i” Sal td ‘i. i i’. - —— ’ °r 2 a " ‘ er i. ge so ake ie i. SP QS TAINA ACA if JMIMOMe “4 PAL aS, ot , 4 “in 7é tp q } ~ i T = » "y 4 } oe 1» . ' an ; ¥ - ad § ‘ > ¥ : ; a — te =. ade ae a a —,” See 406) ee 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 - ego ea a Ay ce hed Se ae a a ee ae ee ontunsedt). wore oo reewriwe, lantern to saiiilanrwadk & . ; 73, Se avawrtsA. (hee) ae a ts, amokae) mesrthroteats WA ereriben Te yh » Daal cas its arent i e) PL OPPs i". Sat . Drom Fyear iten pt artagees, I roid ae i j i} soggy’ “tericty Lente opel seoatom” (tehidolia ts te nies am dow? sect desqeantal) Fats 7 : amaayepatd. aduperel - eee ee — ~ » —— ne lt es a “he . tn Se iy . ALP aY OEE Melee» ae ro / 2 ad ” ~ te ——— ee — ; a k: sat ~ ¥ ot jeu isIG? | a] ’ “he, 5 * i ' é \ ' “ f A Introduction It is usual to think of chronic airflow obstruction as being caused by airway narrowing or loss of airflow driving pressure—the elastic recoil of the lung (Macklem 1971)—or both. Lesions of the airways are often divided into those of the “large airways” and those of the “small airways.” The reasons for this division are both historical and conceptual. Hogg et al. (1968) showed that in patients with chronic obstructive lung disease (COLD) the major site of airway obstruction lay in airways that were peripheral to the wedged catheter that the researchers used to partition airway resistance. The catheter was wedged in airways 2 or 3 mm in diameter, and thus the airways peripheral to the catheter included the smallest bronchi (airways with cartilage in their walls) and bronchioles (conducting airways without cartilage in their walls). Since both bronchi and bronchioles were involved, Hogg and associates used the term “small airways” to describe them, which has since become a popular term. Conceptual- ly, lesions of airways may consist of an intraluminal component (mucus) or a mural component. Most of the mucus in the airways is thought to be secreted by the tracheobronchial submucosal glands (Reid 1960); these are mainly confined to airways more than 2 or 3 mm in diameter, or large airways. Because of the documented association between chronic productive cough and airflow obstruc- tion (Fletcher et al. 1959), for a long time it was thought by many that intraluminal mucus was a major source of chronic airflow obstruction. Thus, the notion developed, without proper substantia- tion, that central airways obstruction was due to intraluminal mucus and peripheral airway obstruction was due to inflammation and narrowing. It is also true that many have equated emphysema with loss of elastic recoil, but when this has been examined in vivo (Park et al. 1970; Boushy et al. 1970; Gelb et al. 1973; Berend et al. 1979; Pare et al. 1982) or in excised lungs (Berend et al. 1980; Silvers et al. 1980), the association has not been close, with some notable exceptions (Niewoehner et al. 1975; Greaves and Colebatch 1980). Thurlbeck (1983) reviewed the evidence and argued that loss of recoil in emphysematous lungs may not be due to the lesions of emphyse- ma per se but to defects in apparently morphologically normal intervening lung tissue. The classical approach to considering the different sites of flow obstruction is used in this chapter to analyze the relationship between smoking and the morphologic lesions associated with chronic airflow obstruction in humans. Lesions of the large airways (bronchi) are discussed first, followed by small airways, and then by alveolated structures. It has very recently become apparent that it is important to include respiratory bronchiolitis as well as emphysema in the last category (Wright et al., in press); this issue is discussed in the paragraphs on peripheral (small) airways. Definitions and a brief 223 review of the diseases involved are provided. This chapter attempts to present the morphologic changes associated with chronic obstruc- tive lung disease. The detailed epidemiologic and experimental evidence relating cigarette smoking and COLD are presented elsewhere in this Report. Lesions Associated With Chronic Airflow Obstruction Central Airways Mucus It is convenient to discuss intraluminal mucus and increased tracheobronchial mucus gland size together, because they are thought to be related (Reid 1960). Chronic bronchitis is defined as “the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree” (Ciba Foundation Guest Sympo- sium 1959). Because there is no way to accurately measure the amount of mucus secreted into the bronchi, the empirical approach was taken that production of any sputum was abnormal. Chronic was defined as “‘occurring on most days for at least 3 months of the year for at least 2 successive years’ (Ciba Foundation Guest Symposium 1959). A further qualification was that such sputum production should not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. The initial step was to correlate chronic bronchitis, as defined above, with lesions in the central airways. This was first done by Reid (1960), who assessed gland size by comparing the thickness of the submucosal bronchial mucus glands in histologic sections to the thickness of the bronchial wall. The latter was defined as the distance from the basement membrane of the epithelium to the inner periochondrium. This measurement is now known as the Reid Index. This increase has been confirmed by several observers (Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Mitchell et al. 1966; MacKenzie et al. 1969; Scott 1973), but not by all (Bath and Yates 1968; Karpick et al. 1970). An important observation was that there was a distinct overlap in the value of the Reid Index between bronchitics and nonbronchitics (Thurlbeck and Angus 1964) as opposed to Reid’s 1960 finding that there were two completely separate groups. In practical terms, this meant that the Reid Index had limitations in predicting the presence or absence of chronic bronchitis. More important, it suggested a broad border between health (nonbronchitis) and disease (bronchitis). For a variety of technical reasons (Jamal et al., in press), the Reid Index is a difficult measurement to use; thus, other measurements of mucus gland size were developed. The most popular was the volume density of mucus glands, i.e., the ratio of area of mucus glands to area of the entire bronchial wall as seen on histologic slides (Hale et al. 1968; Dunnill 224 et al. 1969; Takizawa and Thurlbeck 1971; Oberholzer et al. 1978). Other methods included absolute gland size (Restrepo and Heard 1963; Bedrossian et al. 1971) and a radial intercept method (Alli 1975). The size of the acini (tubules) of mucus glands, the number per unit area, and the ratio of mucus to serous tubules have also been used (Reid 1960). The Reid Index, the volume density of mucus glands, and the ratio of mucus to serous acini have been examined in smokers and nonsmokers; the results are shown in Table 1. When one considers the overwhelming association between smoking and chronic bronchi- tis in living subjects, differences in mucus gland size are insignifi- cant. For example, three laboratories (Reid 1960; Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Scott 1973) have found a difference in Reid Index between smokers and nonsmokers; two have not (Bath and Yates 1968; Hayes 1969). The results from volume density of mucus glands are clearer—Ryder et al. (1971) found a higher volume density of mucus glands in both male and female subjects. In populations of mixed sex, Cosio et al. (1980) and Pratt et al. (1980) found a higher volume density of glands, but Sobonya and Kleiner- man (1972) and Scott (1973) did not. When observers have expressed their morphologic findings as either “normal” or “abnormal” (using different criteria), the smokers have been significantly abnormal in all the studies (Field et al. 1966; Megahed et al. 1967; Petty et al. 1967; Vargha 1969). The balance of the evidence is that there is an increase in mucus gland size in smokers. The discrepancy between the clinical and the morphologic findings may reflect several factors: the wide variation in mucus gland size in normal subjects, the difficulties in measuring the Reid Index and volume density of mucus glands, the different ways in which the cases have been collected, and the errors inherent in assessing smoking histories from analysis of charts; also, the fact that mucus glands can enlarge terminally (Helgason et al. 1970) might obscure true differences between the two groups. In addition, submucosal gland enlargement is a nonspecific change that can also occur in pneumoconiosis and cystic fibrosis. Mucus is also secreted by goblet cells, most of which are in the major airways. Pratt et al. (1980) showed that goblet cells constituted 10.7 percent of the cells in the central airways of nonsmoking nontextile workers and 20.4 percent in smoking nontextile workers. Interestingly, they found an 18 percent frequency of goblet cells in nonsmoking textile workers; the frequency was about the same in smokers, whether or not they were textile workers. Other Abnormalities of Central Airways A variety of other changes have been described in the central airways in patients with chronic airflow obstruction, including 225 TABLE 1.—Comparison of mucus gland size in smokers and nonsmokers Findings in smoking category Assessment of Light and mucus gland Non- moderate Heavy enlargement Author smokers Smokers smokers’ smokers Reid index Reid (1960) 0.46 0.43 Thurlbeck et al. (1963) 0.43 0.50 0.45 0.53 Thurlbeck and Angus (1964) 0.44 0.49 Bath and Yates (1968) 0.45 0.49 Hayes (1969) 0.32 0.33 Scott (1973) 0.41 0.46 Mucus gland Ryder et al. (1971) (men) 14.5% 17.8% proportion Ryder et al. (1971) (women) 14.5% 17.1% Sobonya and Kleinerman (1972) 11.2% 10.7% Scott (1973) 14.1% 14.4% Cosio et al. (1980) Increased Pratt et al. (1980) 9.3% 12.6% Frequency of cases Field et al. (1966) (men) 12% 37% with MGH* expressed Field et al. (1966) (women) 18% 26% as a percentage of |§ Megahed et al. (1967) 14% 61% cases in the group Petty et al. (1967) 8.8% 37% Vargha (1969) 18% 44% *MGH = Mucus gland hypertrophy. inflammation and edema of the wall (Reid 1954), increase in bronchial smooth muscle (Hossain and Heard 1970; Takizawa and Thurlbeck 1971), and diminished cartilage, which is related more to emphysema than to chronic bronchitis (Thurlbeck et al. 1974a). Peripheral (Small) Airways General Review As indicated, it was as recent as 1968 that the obstruction in patients with chronic airflow obstruction was conclusively shown to be due mainly to lesions in airways less than 2 or 3 mm in diameter. However, abnormalities in these airways had long been recognized. Indeed, Laennec (1962) pointed out in 1826 that air remained trapped in emphysematous lungs even when the major bronchi had been opened, and he reasoned that the source of the air-trapping was obstruction in the airways peripheral to the opened ones. Since then, numerous descriptions have been made of the peripheral airways in severe chronic airflow obstruction (see Table 2). Smokers were not compared with nonsmokers in any of these series. The probable reason is that for a long time it was thought that bronchiolitis was an infective complication of chronic bronchitis. Only very recently, and from studies in patients with mild chronic airflow obstruction, 226 has the link between smoking and peripheral airway lesions become established. Hogg et al. (1968) not only found that the peripheral airways were the site of airflow obstruction in patients with severe disease, but also observed that peripheral airways contributed only about 15 percent of resistance to flow in normal lungs. It followed that considerable disease could be present in these peripheral airways without airway resistance being measurably increased. It was reasoned also that standard tests of expiratory function, such as the FEV: and the FEF25-75, might not be abnormal in the presence of significant disease. Thus a variety of “tests of small airway function” were devised; these evolved to the single breath nitrogen washout test and to flow volume studies, in some instances comparing the effect of breathing helium mixtures with the effect of breathing room air. It soon became apparent that these tests could be abnormal when the FEV: was greater than the 80 percent predicted and that tests of small airway function could return to normal after cessation of smoking (Buist et al. 1976, 1979; Beck et al. 1981; Bouse et al. 1981). The term “small airways disease” was and is often applied to these abnormalities. It then became of interest to determine what the lesions in the airways were. Long before this, Reid (1955) had studied nine lungs resected from patients with chronic bronchitis and two lungs from chronic bronchitics obtained at autopsy. She found excess intraluminal mucus and narrowing and obliteration of airways, as assessed subjectively. Because the surgical patients also had lung cancer, most likely they were chronic smokers. Matsuba and Thurlbeck (1973) compared the airways of chronic bronchitics to those of nonbronchitics in nonemphysematous lungs. All the bron- chitics were smokers and two nonbronchitics were smokers. Morpho- metrically, they found obvious narrowing of airways less than 2 mm in diameter, which also contained excess mucus. The important study by Cosio et al. (1978), using surgically resected lungs, showed for the first time that abnormal tests of small airway function were related to abnormal morphology. There were 34 smokers and 2 nonsmokers in their group. A variety of abnormali- ties were observed, including inflammation, squamous cell metapla- sia, ulceration, fibrosis, pigmentation, and increased muscle. They developed a score that summed the observed lesions (the total pathology score), and divided their patients into four groups on the basis of this score. They showed that as the total pathology score increased, tests of small airway function (single breath nitrogen test and flows on air and helium mixtures) deteriorated, as did standard tests of pulmonary function such as the FEV: and FEF»25-75. The data concerning smoking are hard to interpret, but the smoking index (number of cigarettes smoked per day times number of years smoked) increased from groups I to III and was similar in groups III 227 TABLE 2.—Occurrence of lesions of peripheral airways in patients with severe chronic airflow obstruction Authors Disease investigated Abnormalities found Laennec (1962) Spain and Kaufman (1953) Reid (1954) Leopold and Gough (1957) McLean (1958) Anderson and Foraker (1962) Pratt et al. (1965) Anderson and Foraker (1967) Hogg et al. (1968) Mitchell et al. (1968) Bignon et al. (1969, 1970) Karpick et al. (1970) Linhartova et al. (1971) Matsuba and Thurlbeck (1972) Linhartova et al. (1973, 1974, 1977) Scott and Steiner (1975) Scott (1976) Mitchell et al. (1976) 228 Emphysema Emphysema Chronic bronchitis Centrilobular emphysema Emphysema Emphysema Centrilobular emphysema Emphysema Emphysema with severe chronic airflow obstruction Chronic airflow obstruction and severe emphysema Cor pulmonale and centrilobular emphysema Respiratory failure Emphysema Severe emphysema and chronic airflow limitation Emphysema Cor pulmonale Chronic airflow obstruction Chronic airflow obstruction obstruction Obstruction to flow in peripheral airways Mural inflammation and fibrosis of bronchioles Bronchiolitis, bronchiolar oblit- eration, and mucus plugging Inflammation, fibrosis with narrowing of 60% of bronchioles supplying centrilobular space Inflammation of proximal res- piratory bronchioles, mucus plugging, and loss of bronchioles Collapse of bronchioles due to loss of alveolar attachments Loss or distortion of the radial support of bronchioles Loss of bronchioles in patients under age 70 Inflammation and fibrosis of bronchi and bronchioles and mucus plugging Inflammation, atrophy, goblet cell metaplasia, squamous metaplasia, and mucus plugs in bronchioles Inflammatory narrowing and fibrosis, loss of bronchioles, and mucus plugging Goblet cell metaplasia Plugging of bronchioles with inflammatory cells and mucus Loss of lumen of airways less than 2 mm in diameter due primarily to narrowing and mucus plugs Distortion, tortuosity, and irregular narrowing of bronchioles Lack of filling bronchioles of less than 1 mm Loss of airway lumen Chronic inflammation (r=0.48), narrowing (0.29), fibrosis (0.27), goblet cell metaplasia (0.24), and fewer small airways (-0.18) 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 FEF 25-75. The data were reanalyzed subsequently (Berend et al. 1981b) and showed that inflammation was the lesion associated with the most abnormalities in tests of expiratory function. Airway inflammation was significant- ly related to abnormalities of the FEVi, FEF 25-75, 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, FEF 25-75, and slightly less well related to closing capacity. Similarly, Berend et al. (198la) showed an association between post-mortem closing capacity and both peripheral airways inflammation and a total pathology score. Decrease in maximum flow at a transpulmonary pressure of 5 cm H2O was related to inflammation and the total pathology score, but not as well related to airway narrowing (Berend and Thurlbeck 1982). Morphologic abnormalities similar to those found in autopsy lungs have been found in surgically excised lungs derived almost entirely from smokers, and these in turn have been related to abnormal tests of small airway function. 229 Smoking and Lesions of Peripheral (Small) Airways An increase in goblet cells was the first abnormality of peripheral airways noted in smokers. The observation was made in bituminous coal workers. In nonsmokers, about 0.66 percent of peripheral airway cells were found to be goblet cells; in smokers, this rose to about 1.0 percent (Naeye et al 1971). The critical observation, both factually and conceptually, was that of Niewoehner et al. (1974). In an autopsy study of men under the age of 40 who died suddenly elsewhere than in the hospital, they compared lesions of bronchioles and respiratory bronchioles (airways with both nonrespiratory epithelium and alveoli in their walls) in smokers and nonsmokers. Emphysematous lungs were excluded, and the smoking history was obtained by personal interview with close relatives, using a standard questionnaire. The researchers found that intraluminal mucus, mural edema, peribronchiolar pigment, peribronchiolar fibrosis, denuded epithelium, mural inflammatory cells, and respiratory bronchiolitis were more severe in the smokers. The last three were significantly different statistically. They empha- sized the importance of respiratory bronchiolitis, which consisted of aggregates of brown macrophages in and around the first and second order respiratory bronchioles and was associated with edema, fibrosis, and epithelial hyperplasia in adjacent bronchioles and alveolar walls. Bronchiolitis was found in all of the smokers, but in only 5 of the 20 nonsmokers, and it was the lesion that showed the greatest difference between smokers and nonsmokers. Since respira- tory bronchiolitis was found in precisely the same regions where centrilobular emphysema is found in subjects 20 years older, the researchers suggested that this lesion might evolve into emphysema. This observation fits well the proteolytic-antiproteolytic hypothesis of the pathogenesis of emphysema. Ebert and Terracio (1975) compared the peripheral airways in resected lungs of 22 smokers and 3 nonsmokers and found that the number of Clara cells (the tall nonciliated airway cells thought to be secretory, although the nature of their secretion is not completely certain) was diminished, as assessed subjectively, and the number of goblet cells was increased, as assessed quantitatively. Two laboratories have concentrated on the association between smoking and lesions of vessels as well as of airways. One has used autopsy-derived lungs (Cosio et al. 1980; Hale et al 1980); the other, surgically excised lungs (Wright et al. 1983a, b, in press). The first material has the advantage that the entire lung can be examined, but has the disadvantage that agonal changes may affect the airway; the second has the advantage that agonal changes are absent and structure-functional studies can be done, but has the serious disadvantage that usually only a part of the lung is examined. Because of the wide variation in severity of emphysema from lobe to 230 lobe, emphysema in the whole lung cannot be assessed from a single lobe. Also, airway inflammation may not be evenly distributed through the airways (Berend 1981; Hale et al. 1980). Cosio et al. (1980) studied 14 nonsmokers with an average age of 71.6 years and 25 long-term smokers with an average age of 58.4 years. The total pathology score was significantly higher in the smokers; in them, but not in the nonsmokers, the total pathology Score was significantly related to age. Respiratory bronchiolitis was more common in the smokers, and of the components of the total pathology score, goblet cell metaplasia (p <0.001), inflammation of the bronchiolar wall (p <0.01), and smooth muscle hypertrophy (p <0.05) were significantly more abnormal in the smokers. Smokers had an excess of airways less than 400 u in diameter, also related to the total pathology score. Because goblet cell metaplasia and increased smooth muscle were not significantly increased in the researchers’ previous study of young smokers (Niewoehner et al. 1974), they concluded that these lesions were a late complication of cigarette smoking. They noted that there was a considerable similarity of all lesions of both smokers and nonsmokers, and felt that this indicated the existence of other causes of small airway lesions. They also made the interesting suggestion that the relation- ship between the total pathology score and the proportion of airways less than 400 » in diameter might indicate a predisposition of subjects with small airways to develop peripheral airway lesions. Wright et al. (1983b) studied 9 nonsmokers, 51 current smokers, 18 ex-smokers who had quit less than 2 years, and 19 ex-smokers who had quit more than 2 years. The only lesion of the bronchioles that distinguished the nonsmokers from the smokers and the long-term ex-smokers was goblet cell metaplasia, although there were obvious differences in pulmonary function among these groups. The signifi- cance of goblet cell metaplasia may be related to mucus production in airways not usually lined by mucus. There is evidence that they are lined by surfactant. If this is displaced by mucus with a higher surface tension it will produce narrowing difficult to detect by standard morphological methods. Respiratory bronchiolitis was more severe in the smokers and ex-smokers than in the nonsmokers. No differences were noted between the ex-smokers and smokers. This study has recently been extended (Wright et al., in press), and correlations between both bronchiolar inflammation and respiratory bronchiolitis and the FEV: were evident. When the FEV: was greater than the 80 percent predicted, the most important determinant of abnormalities of tests of small airway function was respiratory bronchiolitis. Thus, respiratory bronchiolitis may not only represent a stage in the pathogenesis of centrilobular emphysema, but also result in abnormalities of the single breath nitrogen test and other tests of small airway function. 231 It is not certain why cessation of smoking results in improvement of lung function. The most likely reversible parameter is inflamma- tion; the lack of difference between nonsmokers and the other groups in the study by Wright et al. (1983b) is very surprising in view of the observations of Niewohner et al. (1974) and Cosio et al. (1980), but may be due to the very small number of nonsmokers studied and the fact that the nonsmokers had lung lesions for which resection was performed. An additional factor is the use of lobes in the study, which in the small group of normals may produce distortions in the data because of lobar variations in the total pathology score. Vascular Lesions Related to Smoking At first sight it may appear surprising that vascular lesions are detectable in asymptomatic smokers or those with only mild or moderate chronic airflow obstruction. On reflection, this could be anticipated. Severe chronic airflow obstruction, usually related to smoking, is often accompanied by pulmonary artery hypertension; mild chronic airflow obstruction might be associated with mild pulmonary artery hypertension and vascular lesions. The first study (Hale et al. 1980) involved the same cases reported by Cosio et al. (1980). They found that the smokers had an increased number of arteries less than 200 » in diameter and also an increased medial and intimal thickness of the pulmonary arteries. The intimal thickness was increased more in those vessels of less than 200 up in diameter. Both intimal and medial thickness were directly related to the total pathology score. Wright et al. (1983a) found an increase in the vessel area from an average of 0.12 mm? in nonsmokers to approximately 0.3 mm? in smokers. Intimal area expressed as a proportion of vessel area increased; there was an absolute increase of the medial area, but no proportional change. The adventitial area also increased in absolute terms, but the adventitial proportional area was decreased and was related to the pulmonary wedge pressure. Pulmonary artery pressures were normal at rest, but abnormal and reversible by oxygen on exercise in the smokers with the worst airway inflammation and emphysema. Emphysema Of the lesions associated with chronic airflow obstruction, em- physema has been the one most clearly associated with tobacco smoking. There are several different types of emphysema, however, and cigarette smoking has not been clearly linked to, or examined in, all forms of the disorder. Therefore, the definition and classification of emphysema are reviewed before discussing the association be- tween smoking and emphysema. 232 AS Alveolus AD RB, TB FIGURE 1.—Components of the acinus NOTE: TB: terminal bronchiole; RB:, RBz, RBs: the three orders of respiratory bronchioles; AD: alveolar duct; AS: alveolar sac. SOURCE: Thurlbeck (1976). Definition Emphysema is defined as an abnormal enlargement of the air spaces of the lung accompanied by destruction of alveolar walls (World Health Organization 1961; American Thoracic Society 1962). Thus, emphysema is a disorder of anatomy, and one must know the appropriate normal anatomy in order to understand the pathology of emphysema. The structure involved is the acinus, the unit gas- exchanging structure of that part of the lung containing alveoli. The last purely conducting airway is the terminal bronchiole; structures distal to it constitute the acinus. The acinus is a complex unit, but a simplified model will suffice (Figure 1). The structures immediately before the terminal bronchiole are the respiratory bronchioles, which, as indicated previously, have both alveoli and nonalveolated epithelium forming their walls; thus, respiratory bronchioles both conduct and exchange gas. Proceeding distally, progressively more alveoli appear in the walls of respiratory bronchioles, of which there are three orders in the usual model of the acinus. Alveolar ducts succeed respiratory bronchioles, and their walls are entirely alveo- lated. Alveolar ducts lead into alveolar sacs, the terminal respiratory structures, which are likewise completely alveolated. Classification Emphysema is classified by the way it involves the acinus, and four forms of emphysema are usually recognized (Thurlbeck 1976): (1) proximal acinar emphysema, (2) panacinar (panlobular) emphyse- 233 480-144 0 85:.- 9 ma, (3) distal (paraseptal) acinar emphysema, and (4) irregular emphysema. Proximal Acinar Emphysema In proximal acinar emphysema, the respiratory bronchioles are selectively or dominantly involved. Emphysema involving the proxi- mal part of the acinus is found in two different circumstances— centrilobular emphysema and focal emphysema. Proximal acinar emphysema is the common form of nonindustrial emphysema and is associated with inflammation of the distal airways (Leopold and Gough 1957) and of the walls of emphysema- tous spaces. This form of emphysema is usually referred to as centrilobular emphysema (Figure 2) because the lesions lie close to the center of the secondary lobules. The emphysematous spaces are found more frequently in the upper zones of the lungs, and centrilobular emphysema is usually more severe there (Thurlbeck 1963a). Involvement of the lung is characteristically quite uneven; some respiratory bronchioles are spared or slightly involved, whereas others close by may be severely affected, producing large emphysematous spaces. Centrilobular emphysema is frequently associated with chronic bronchitis, and is the form of emphysema most commonly encountered in patients with symptomatic chronic airflow obstruction. Focal emphysema, or simple pneumoconiosis of coalworkers, also involves the proximal part of the acinus. It can be distinguished from centrilobular emphysema in that there is always a heavy deposit of coal around the emphysematous spaces, the enlargement of respira- tory bronchioles is usually moderate, and the process is more uniform through the lung. Simple pneumoconiosis is usually associ- ated with only mild impairment of function, producing only minor abnormalities of gas exchange (Morgan and Seaton 1975). Panacinar (Panlobular) Emphysema In panacinar or panlobular emphysema, there is more or less uniform involvement of the acinus (Figure 3). Controversy exists concerning the distinction between centrilobular and panacinar emphysema; some believe them to be different conditions (Anderson and Foraker 1973), but others believe them to have the same clinical and functional associations (Mitchell et al. 1970). The reason for this disagreement is discussed below. Four different associations of panacinar emphysema are described (Thurlbeck 1976), each with its specific clinicopathologic associations. This view is not shared by all, however. The classical association of panacinar emphysema is with a,- antitrypsin deficiency (Eriksson 1965), most commonly with the PiZ 234 Inflamed FIGURE 2.—Centrilobular emphysema NOTE: See footnote to Figure 1 for definitions. SOURCE: Thurlbeck (1976). Septum FIGURE 3.—Panlobular emphysema NOTE: See footnote to Figure 1 for definitions. SOURCE: Thurlbeck (1976). 235 phenotype. It is probable that other forms of Pi-associated emphyse- ma, such as PiSZ, are also panacinar in type. Familial emphysema unassociated with a,-antiprotease deficiency has been shown to be panacinar (Martelli et al. 1974). Familial emphysema is characteris- tically worse in the lower zones of the lung. Severe, pure panacinar emphysema is uncommon. Localized panacinar emphysema is found fairly frequently at autopsy (Thurlbeck 1963a). It is found more commonly in older people and is usually not associated with clinical evidence of chronic airflow obstruction. Under these circumstances, it is more frequent in the lower and anterior parts of the lung. It may represent a focal exaggeration of the aging process in the lung, which includes a well documented set of changes (Thurlbeck 1976), including changes in the shape of the lung with an increase in anteroposterior diameter, loss of volume density of alveolar walls, increase in the distance between alveolar walls, decrease of alveolar surface area, increase in volume density of alveolar ducts, and decrease of volume density of alveoli. The reason for referring to these changes with age as the “aging lung” rather than “senile emphysema” is that it is a normal change, affecting virtually all people. The definiticn of emphysema requires that the enlargment and destruction of respiratory tissue be abnormal; therefore, it is probably inappropriate to categorize these changes as emphysema. Bronchial and bronchiolar obliteration may be associated with panacinar emphysema. Most commonly it is associated with Swyer- James (1953) or MacLeod’s (1954) syndrome of unilateral pulmonary hyperlucency, in which one lung or a major portion of the lung is unduly transradiant. The involved region or regions of the lung characteristically trap air on expiration so that the mediastinum then moves to the unaffected side. The syndrome is usually due to severe acute bronchitis and bronchiolitis in childhood, resulting in obliteration of airways. A detailed study of the lung parenchyma in cases of unilateral pulmonary transradiancy has never been reported, but it seems likely that emphysema may not be present in the affected lung tissue. However, when emphysema is present, it is panacinar in type. Panacinar emphysema may be found in the lower zones of the lung in patients with upper zonal centrilobular emphysema. The combi- nation of the two forms of emphysema is probably the classical finding in patients with severe chronic airflow obstruction, and it is also one reason for the controversy concerning similarities or differences between centrilobular and panacinar emphysema. Tran- sitions, real or imagined, may be apparent between the upper zonal centrilobular emphysematous spaces and lower zonal panacinar emphysema in this situation. Some believe the transitions are real, and maintain that centrilobular emphysema has progressed to 236 AS AD RB, RBs RB, FIGURE 4.—Distal or paraseptal acinar emphysema NOTE: See footnote to Figure 1 for definitions. SOURCE: Thurlbeck (1976). panacinar emphysema and that these lungs should be classified as examples of centrilobular emphysema. Others feel that it is panaci- nar emphysema, and thus the same lung may be classified different- ly. Distal (Paraseptal) Acinar Emphysema Distal (paraseptal) acinar emphysema is the third generally recognized form of emphysema. In this form, the alveolar ducts and sacs are predominantly involved, and there may be substantial associated fibrosis (Figure 4). Since the distal acinus abuts on pleura, vessels, airways, and lobular septa, the emphysema is worse in these regions. The occurrence of distal acinar emphysema along the lobular septa had led to the term “paraseptal emphysema.” A characteristic clinical association of distal acinar emphysema is spontaneous pneumothorax of young adults (Edge et al. 1966). Irregular Emphysema In irregular emphysema, the acinus is irregularly enlarged (Figure 5). It is nearly always associated with scarring. It may be the most common form of emphysema, because nearly all lungs on close examination will disclose a scar associated with emphysema. The majority of these examples of irregular emphysema are unassociated with symptoms. 237 FIGURE 5.—Irregular emphysema NOTE: See footnote to Figure 1 for definitions. SOURCE: Thurlbeck (1976). Tobacco Smoking and Emphysema The apparently neat and orderly classification described above and the classical examples of emphysema illustrated in original articles and monographs should not obscure the lack of agreement between expert observers in the classification of severely emphysematous lungs (Thurlbeck et al. 1968, Mitchell et al. 1970). Severe emphyse- ma is usually atypical in morphology, and often more than one type of emphysema is present. It might be more rational to speak of ‘‘end stage emphysema” when describing an extensively damaged lung, rather than attempting to fit all of the damage under one classifica- tion. These differences in classification may lead to differing assess- ments of degrees of association between smoking and individual forms of emphysema. For example, Anderson and Foraker (1973) found that all of their 21 patients with centrilobular emphysema were cigarette smokers, whereas 8 of the 17 patients with panacinar emphysema were cigarette smokers. Contrarily, Mitchell et al. (1970) found that 20 of their 21 patients with centrilobular emphysema were cigarette smokers and all 6 of their patients with panacinar emphysema were cigarette smokers. Including all of the different abnormalities described above under the single term “emphysema” may lead to confusion about the © relationship between smoking and emphysema. Each of the different forms of emphysema may have different etiologies; while cigarette smoking is clearly implicated in the etiology of centrilobular emphysema (Mitchell et al. 1970, Anderson and Foraker 1973), it may not play a role in irregular or distal acinar emphysema and is 238 clearly not implicated in the etiology of unilateral pulmonary transradiancy. Another problem is the sensitivity with which emphysema is recognized. Thurlbeck (1976) reviewed the incidence of emphysema found at autopsy in 28 series. An extremely wide variation has been recorded, including three series with an incidence of 100 percent. The variation in incidence probably represents the care with which the lung is examined and the threshold for defining emphysema being present as much as a true difference in incidence. It is not relevant to the present discussion whether rare or unusual disease processes can cause abnormal enlargement of the air spaces or whether, after careful and exhaustive search, all lungs demonstrate minute areas of focal enlargement. The lung has substantial ventilatory reserve; therefore, what is significant is not the presence or absence of any emphysema, but rather the extent or severity of the emphysematous change in the lung. What is both clear and relevant to the present discussion is that the relationship between smoking and emphysema represents an association between smoking and the severity of emphysema, and that the relationship is between smoking and those forms of emphysema commonly found in patients with COLD. In 1963, clinicopathologic findings (Thurlbeck 1963b) in a group of patients dying at the Massachusetts General Hospital showed that 18 of 38 patients without emphysema were cigarette smokers, whereas all of the 19 patients with severe emphysema were cigarette smokers. A formal study of the relationship between emphysema and smoking was first made by Anderson et al. (1964), who showed that one-third of patients without emphysema, 19 of 37 patients with mild emphysema, 19 of 23 patients with moderate emphysema, and all 6 patients with severe emphysema were smokers. In 1966, an extended study (Anderson et al. 1966) found in the four groups, respectively, that 12 of 33 patients, 58 of 84 patients, 30 of 33 patients, and 14 of 15 patients were smokers. Mitchell et al. (1964) found 62 smokers among 85 patients with no or mild emphysema and 39 smokers among 40 patients with moderate or severe emphysema. These researchers also extended their series (Petty et al. 1967) and found 6 nonsmokers among 57 patients with moderate emphysema and 1 nonsmoker among 61 patients with severe emphysema. A very dramatic difference was shown between smokers and nonsmokers by Ryder et al. (1971). Figures 6 and 7 indicate very graphically the rarity of emphysema of even moderate severity in nonsmokers and the high incidence of emphysema in smokers over 50 years of age. Of the 21 patients in their series whose lungs had a more than 25 percent involvement by emphysema, only 1 was a nonsmoker. 239 Nonsmokers 70 60 50 40 30 20 Percentage volume of emphysema Age (in years) FIGURE 6.—Percentage of lung occupied by emphysema in nonsmokers SOURCE: Ryder et al. (1971). Only a small effect of smoking was noted in coal miners by Naeye et al. (1971), an increase from 24.3 percent of the lung involved in nonsmokers to 30 percent in smokers. A much greater effect of smoking was noted by Auerbach et al. (1972), who studied lungs from 2,613 autopsies and were able to obtain smoking histories in 1,831 of the patients. They found that 10 percent of male patients who had not smoked had emphysema; this percentage rose to 53.5 percent for pipe smokers and cigar smokers, 86.9 percent for smokers of less than a pack per day, and 99.7 percent for smokers of more than a pack per day. Of the 130 patients with severe emphysema, 126 smoked more than a pack a day, 2 smoked less than a pack, 2 were pipe or cigar smokers, and none were nonsmokers. Their findings were subsequently extended and confirmed by histologic examina- tion of these lungs (Auerbach et al. 1974). Findings in women were similar. Spain et al. (1973) studied lungs from 134 persons who died suddenly and unexpectedly and who had no previous known pulmonary disease. In men, they found an incidence of emphysema of more than grade 20 (mild emphysema) of 10 percent in nonsmok- ers, 36 percent in smokers of less than a pack per day, and 39 percent 240 Smokers Percentage volume of emphysema yet e r oe ®e @ ee @ @ ee ce a ye at 3 a8 85°58 ares Age (in years) FIGURE 7.—Percentage of lung occupied by emphysema in smokers SOURCE: Ryder et al. (1971). in smokers of more than a pack. In women the incidences in the same categories were 0, 17, and 23 percent, respectively. Bonfiglio and Schenk (1974) found that the diagnosis of emphysema was made in 40 percent of autopsy protocols from smokers and in 12 percent from nonsmokers. Using the autopsy populations of teaching hospitals in three separate cities, Thurlbeck et al. (1974b) reported the average emphysema score per decade for male and female nonsmokers (Figure 8) and for male and female smokers combined with ex- smokers (Figure 9). The severity of emphysema is expressed using the panel grading method (Thurlbeck et al. 1970). With this method, a score of up to 25 is “mild emphysema.” As Figure 8 indicates, in nonsmokers there is an increasing average severity of emphysema with age, starting in the fifth decade, reaching an average score in the eighth and ninth decades of 10 to 15 in men and 4 to 6 in women. There is a dramatic difference in male heavy smokers and ex- smokers, for whom the average score of 25 to 30 in the seventh decade is maintained for the next two decades. The number of heavy smoking and ex-smoking women is very small, and the effects in 241 15 Montreal Cardiff 19 c 0) N81 © = fe) = ® © o = 2 Ue aes = ~ ao © N 3553 oli. 14 25 of rr Men 20 16 + N = Score FIGURE 8.—Average emphysema score in male and female nonsmokers in Montreal, Cardiff, and Malm6é, by decade NOTE: All: The average for the three cities. SOURCE: Thurlbeck et al. (1974b). 242 s 10 2 2 £ y A ie bie | 4g en Se . i Xs oa | om 2o2 << Va ee Tied Bue’ NG | mA i | \: So EST | A eae ; 14 3 1 1 Women Malmo All Decade Montreal 10 7 18 23 9 50 Men 56 48 40 N ~ 24 16 8 0 Score FIGURE 9.—Average emphysema score in male and female heavy cigarette smokers (>pack per day) and ex-smokers, by decade NOTE: All: The average for the three cities. SOURCE: Thurlbeck et al. (1974b). 243 women are more modest, with an average emphysema score of 8 to 12 from the sixth to the ninth decade. Pratt et al. (1980) studied the effect of smoking on cotton textile workers and on workers not exposed to cotton. They found that the incidence of centrilobular emphysema was 6.7 percent in non- smoking non-cotton-textile workers, 6.9 percent in nonsmoking cotton-textile workers, 26.5 percent in smoking non-cotton-textile workers, and 26.2 percent in smoking cotton-textile workers. The variation in the incidence of centrilobular emphysema involving more than 25 percent of the lung was even more dramatic—1.1, 0.4, 11.0, and 12.6 percent for the respective categories. } Thus, despite the limitations in interpretation of the types of emphysema and in recognition of the presence of emphysema, the association between smoking and emphysema—particularly severe emphysema—is overwhelming. In the various series referred to, of the 227 patients with severe emphysema, only 3 were nonsmokers. Summary and Conclusions 1. Smoking induces changes in multiple areas of the lung, and the effects in the different areas may be independent of each other. In the bronchi (the large airways), smoking results in a modest increase in size of the tracheobronchial glands, associated with an increase in secretion of mucus, and in an increased number of goblet cells. 2. In the small airways (conducting airways 2 or 3 mm or less in diameter consisting of the smallest bronchi and bronchioles) a number of lesions are apparent. The initial response to smoking is probably inflammation, with associated ulceration and squamous metaplasia. Fibrosis, increased muscle mass, narrowing of the airways, and an increase in the number of goblet cells follow. 3. Inflammation appears to be the major determinant of fil airways dysfunction and may be reversible after cessation of smoking. 4. The most obvious difference between smokers and nonsmokers is respiratory bronchiolitis. 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MECHANISMS BY WHICH CIGARETTE SMOKE ALTERS THE STRUCTURE AND FUNCTION OF THE LUNG 251 Wid, Lyon, & RG, SRR, eume . Age Z e \ Mey of «> physeet In feSegey Cpe! (oa i ote i , oa? > > mem: Boe of Raoep eneey Dinense WRT: Se, Ferra : Apa Qoary lot Clatiuchiny Anes ow “i ape os Beat teta Alice Ailing, 5 ls (if). fe om Ce Pudtosale ~ rie ‘hk j “ay ot any @utai *; epi s u a " A as * PARE PD. MOOPE RO, ? ee. .. ee its ied me aithon sav en 4 mir iti /4 Tene Peat » Keo sari a - ‘ ne ae 8 art ’ ¢ es =e it r = Re ce 4 a ‘* ot » at iT ne “jt hs ‘ af! a i Si Er, : spel YH 2v2ivV iM wo as Owe y (AH ee A « ATIVAAADW HNAW » , » é ¢ 7. © = if i... . AEITIA THOMe a 3 PMY LGA 2A To ; -: rgery Tia sd my sae it? s ew" kad hw Lis ¥ OF mod - MAG rs A - ag ; . alt yt : ape he i ‘ i = li ie i . i i ama tee ae r Pee 7 CONTENTS EFFECT OF CIGARETTE SMOKING ON INFLAMMATORY AND IMMUNE PROCESSES IN THE LUNG Introduction Effect of Smoking on Numbers and Types of Inflammatory Cells Effect of Smoking on the Morphology and Function of Inflammatory Cells Emphysema Populations Deficient in Alpha,-antitrypsin Alpha,-antitrypsin Proteolytic Enzymes Inducing Emphysematous Change Papain Pancreatic Elastase Polymorphonuclear Leukocyte Elastase Alveolar Macrophage Elastase Protease—Antiprotease Hypothesis Increased Elastase Owing to the Cellular Response to Smoke Number of Cells Elastase Content Release Proximity Milieu Decreased Antiprotease Owing to Oxidation Explanation for Upper Lobe Distribution Animal Models of Emphysema Spontaneous Emphysema Experimentally Induced Emphysema Oxides of Nitrogen Cadmium Salts Cigarette Smoke 253 The Effects of Smoking on Cellular and Immune Defense Mechanisms In Vitro Effects of Cigarette Smoke on Inflammatory and Immune Effector Cells The Effect of Cigarette Smoke on Antibody Production EFFECTS OF CIGARETTE SMOKE ON AIRWAY MUCOCILIARY FUNCTION Introduction Normal Mucociliary Function Cilia Mucus Mucociliary Interaction Effects of Cigarette Smoke on Mucociliary Function Short-Term Exposure Cilia Mucus Mucociliary Interaction Long-Term Exposure Cilia Mucus Mucociliary Interaction Fractionation and Filtering of Cigarette Smoke Effects of Filters Mucociliary Function in Chronic Bronchitis Cilia Mucus Mucociliary Interaction Summary and Conclusions References 254 EFFECT OF CIGARETTE SMOKING ON INFLAMMATORY AND IMMUNE PROCESSES IN THE LUNG Cigarette smoke is a complex mixture of several thousand different constituents that may produce physiologic and pathologic changes. This discussion focuses on the cellular and immune responses of the lung to cigarette smoke, the mechanism by which smoking can cause emphysema, and the impact of smoking on mucociliary clearance. The last 20 years have witnessed dramatical- ly increased understanding of cigarette-induced lung injury, particu- larly emphysema, thus enhancing our understanding of the process by which cigarette smoking can lead to emphysema. Introduction Inhalation of cigarette smoke markedly alters the inflammatory and immune processes in the lung, leading to increases in the total number of inflammatory cells and to changes in cell type and function. These effects of cigarette smoke on lung inflammatory cells may play a role in decreased pulmonary host defenses against various microorganisms and the development of lung cancer, chronic bronchitis, and pulmonary emphysema (USPHS 1971, 1972, 1973, 1974, 1975; USDHHS 1981). Effect of Smoking on Numbers and Types of Inflammatory Cells | One of the most consistently observed effects of cigarette smoking on the lung is a marked increase in the numbers of inflammatory cells, especially at sites of disease. Increased numbers of inflammato- ry cells have been seen in pathological studies of the lungs of cigarette smokers, as well as in lungs of animals exposed to cigarette smoke. In addition, increased numbers of inflammatory cells occur in bronchoalveolar lavage fluid of cigarette smokers and in lavage fluid of animals exposed to cigarette smoke. Spain and Kaufman (1953) noted inflammatory changes in the lung bronchi of cigarette smokers. Later, Anderson and Foraker (1961) described the presence of an alveolitis, and McLean (1959) described the presence of a bronchiolitis in these patients. In an autopsy study of patients with early emphysema (McLaughlin and Tueller 1971), numerous abnormal, brownish-pigmented alveolar macrophages were found in adjacent, otherwise intact parenchyma, but none were found in normal lungs. Identical pigmented macro- phages were found in the sputum of patients obtained from apparently healthy cigarette smokers. The frequency of occurrence of these macrophages in the tissue appeared to be related to the 255 number of cigarettes consumed. Niewoehner et al. (1974) evaluated the lungs of young smokers and controls of comparable age from a population that had experienced sudden nonhospital deaths. In smokers, a characteristic lesion occurred in the form of respiratory bronchiolitis associated with clusters of pigmented alveolar macro- phages. This lesion was present in the lungs of all smokers studied, but was rarely seen in nonsmokers. Lungs of smokers also showed small, but significant, increases in mural inflammatory cells and denuded epithelium in the membranous bronchioles as compared with controls. The researchers suggested that this respiratory bronchiolitis may be a precursor of emphysema and may be responsible for the subtle functional abnormalities that are observed in young smokers. Mitchell et al. (1976) also noted the presence of significant amounts of inflammation in the small airways of cigarette smoker lungs, and Cosio et al. (1978) suggested that the primary lesion in the small airways was a progressive inflammatory reaction, leading to fibrosis with connective tissue deposition in the airway walls. These lesions were closely correlated with abnormali- ties in pulmonary function. As noted above, most early investigators concentrated on the role of the increased numbers of pigmented alveolar macrophages present at disease sites in cigarette smokers. These pigmented macrophages, because of their numbers and prominent coloration on histologic sections, were initially the sole focus of research on the inflammatory response in these patients. More recently, however, Ludwig et al. (1983) evaluated the relationship between cigarette smoking and the accumulation of neutrophils in the lungs of smoking and nonsmoking humans. Human lungs were obtained from autopsies of 10 cigarette smokers and 5 nonsmokers who experienced nonhospital death. These studies indicated a marked increase in neutrophil infiltration in the lungs of cigarette smokers compared with nonsmokers, and identified the site of the accumulation as the alveolar septa. Neutrophils were found in the alveolar walls of smokers both with and without emphysema. The researchers con- cluded that a marked neutrophil accumulation occurs in the lungs of cigarette smokers, that it precedes the development of emphysema, and that it continues once emphysema is established. They further suggested that the neutrophils may play a role in the destruction of the alveolar septa of the lungs in cigarette smokers. The presence of increased numbers of neutrophils in cigarette smokers’ lungs has also been documented by extracting inflammatory cells from open lung biopsies of smokers and nonsmokers (Hunninghake and Crystal 1983). A higher percentage of these inflammatory cells were neutrophils in smokers compared with nonsmokers. Finally, the association between cigarette smoking and increased numbers of inflammatory cells, including neutrophils, at disease sites has also 256 been confirmed in numerous animal studies (Frasca et al. 1971; Dahlgren et al. 1972; Rylander 1974; Park et al. 1977). Increased numbers of inflammatory cells in the lungs of smokers, as compared with nonsmokers, have also been observed by all investigators performing bronchoalveolar lavage studies (Davis et al. 1976; Demarest et al. 1979; Harris et al. 1970, 1975; Hunninghake et al. 1979a, 1980a; Hunninghake and Crystal 1983; Hunninghake and Gadek 1981-1982; Hunninghake and Moseley, in press; Reynolds et al. 1977; Reynolds and Newball 1974, 1976; Rodriquez et al. 1977; Warr et al. 1976, 1977; Warr and Martin 1974, 1978). Such increases have been detected additionally in lavage fluid of animals chronical- ly exposed to cigarette smoke (Davies et al. 1977; Flint et al. 1971; Holt et al. 1973). The majority of these studies have demonstrated increases in both the number of macrophages and the number of neutrophils, although Hoidal and Niewoehner (1982) found increases only in the former. The presence of neutrophils in the lungs of cigarette smokers is of interest because these cells contain elastase, an enzyme believed to be important in the pathogenesis of emphysema (Lieberman 1976; Karlinsky and Snider 1978; Kuhn and Senior 1978; Carp and Janoff 1978; Snider and Korthy 1978; Schuyler et al 1978; Janoff et al. 1977; Hunninghake et al. 1979a; Hunninghake and Crystal 1983; Hun- ninghake and Gadek 1981-1982; Hunninghake and Mosley 1984; Laurell and Eriksson 1963). Alveolar macrophages have also been implicated as a source of an elastase-like metalloprotease (Harris et al. 1975; Rodriguez et al. 1977). This enzyme is not inhibited by alpha,-antitrypsin (a,AT) (Banda and Werb 1981), the major anti- elastase in the lower respiratory tract (Gadek et al. 1981). Although macrophages are clearly present in large numbers in the alveolar structures of smokers (Niewoehner et al. 1974; Harris et al. 1975), several lines of evidence suggest that neutrophils may play a significant and perhaps more important role in increasing the elastase burden of the lungs. First, neutrophils store and release significantly more elastase than do alveolar macrophages (Barrett 1977; Rodriguez et al. 1977; Levine et al. 1976). Comparative estimates of elastase production by human neutrophils and alveolar macrophages suggest that neutro- phils are at least 1,000 times more potent elastase producers (Janoff et al. 1979). Second, although alveolar macrophages of cigarette smokers have been shown to release elastase in vitro (Rodriguez et al. 1977), it is not clear whether the elastase was produced by these cells or was secreted by other types of cells, such as neutrophils, and subsequent- ly ingested by the macrophages (Janoff et al. 1977). In this regard, recent studies by Campbell et al. (1979) and McGowan et al. (1983) have shown that alveolar macrophages are capable of phagocytosing 257 neutrophil elastase via a receptor-mediated mechanism; some of the elastase remains enzymatically active for up to 48 hours. These findings suggest that alveolar macrophages may, in fact, be capable of both decreasing and increasing the protease burden of the lung. Third, once a neutrophil has left its vascular space, its lifespan is only a few hours; when the neutrophil dies, it may release at least a portion of its preformed enzymes, including elastase. Thus, when a neutrophil is present within a tissue, it is possible that the tissue will be exposed not only to the elastase secreted by the neutrophil while it is functional, but also to the elastase stored by the neutrophil and released when the neutrophil disintegrates. In this context, the finding that neutrophils represent only a small percentage of all inflammatory and immune effector cells in the smoker’s lungs would not preclude the smoker’s exposure to a large chronic burden of neutrophil elastase. In contrast, the alveolar macrophage has a half- life of months to years (Thomas et al. 1976), and it stores little, if any, elastase (Rodriguez et al. 1977; Levine et al. 1976). Macrophages may also play an important role in this process by secreting a potent chemotactic factor for neutrophils (Hunninghake and Crystal 1983). This hypothesis is supported by the following observation: alveolar macrophages of cigarette smokers spontaneous- ly release a chemotactic factor for neutrophils, whereas alveolar macrophages of nonsmokers do not. In addition, in vitro exposure to cigarette smoke particulates results in the release of a chemotactic factor from the alveolar macrophages of nonsmokers. The migration of neutrophils to the lung in response to the chemotactic factor may be augmented by factors in cigarette smoke. In this regard, McCusk- er et al. (1983) have shown that nicotine is a potent chemokinetic factor for neutrophils, enhancing the migration of these cells to other chemotactic factors. Once neutrophils are present in the lung, they may release elastase, because both cigarette smoke (Blue and Janoff 1978) and the macrophage-derived chemotactic factor stimu- late these cells to release the enzyme (Gadek et al. 1979a, b). The postulated release of elastase by neutrophils could also partly explain how the number of macrophages are increased in this disorder. Fragments of elastin (which are probably generated by the release of neutrophil elastase at sites of disease activity) are potent chemoattractants for blood monocytes, the precursors of alveolar macrophages (Senior et al. 1980; Hunninghake et al. 1981). These fragments of elastin possess no chemotactic activity for neutrophils. Effect of Smoking on the Morphology and Function of — inflammatory Cells No size differences have been observed between alveolar macro- phages from smokers and those from nonsmokers when the cells are 258 fixed in suspension immediately after bronchoalveolar lavage (Table 1). Harris and coworkers (1970) observed a mean size of 23.3 um (range, 10 to 47 um) for nonsmokers and 26.4 um (range, 12 to 53 um) for smokers. Reynolds and Newball (1974), using similar methods, did not find any size differences between smoker and nonsmoker alveolar macrophages. The morphology of smoker macrophages clearly differs, however, from that of nonsmokers (Table 1). Macrophages of smokers show increased numbers of large lysosomes, phagolysosomes, endoplasmic reticulum, ribosomes, and Golgi vesicles (Golde 1977; McLemore et al. 1977; Martin 1973; Warr and Martin 1978; Rasp et al. 1978; Pratt et al. 1971; Brody and Craighead 1975). These findings are generally associated with activated mononuclear phagocytes, and these macro- phages have probably become activated by the ingestion of the particulates present in cigarette smoke. Smoker macrophages have pigmented inclusions that appear to have platelike or needlelike _ configurations when seen by electronmicroscopy (Golde 1977; Warr and Martin 1978; Pratt et al. 1971; Brody and Craighead 1975). Studies of the nature of these inclusions by X-ray analysis suggest they may be, at least in part, particulates of aluminum silicate (Brody and Craighead 1975). Together with in vitro studies showing that alveolar macrophages are activated following phagocytosis of particulates (Hunninghake et al. 1980a), these findings are compat- ible with the notion that macrophages of smokers are activated in Vivo. Alveolar macrophages from cigarette smokers have an increased ability to generate superoxide anion (Hoidal et al. 1979a, 1980, 1981), the functional effects of which include an increased capacity to kill lung fibroblasts. These observations suggest that alveolar macro- phages from cigarette smokers are increasingly able to injure lung parenchymal cells, and that they may contribute to the observed loss of lung cells in the alveoli of patients with pulmonary emphysema. A variety of other effector functions of smokers’ alveolar macro- phages have also been evaluated (Table 1). Alveolar macrophages from cigarette smokers appear to have a normal or increased ability to migrate in response to chemotactic factors (Demarest et al. 1979; Warr and Martin 1974). They differ, however, from normal alveolar macrophages in several other respects: for example, increased glucose utilization has been reported in some studies (Harris et al. 1970), but was normal in others (Hoidal et al. 1979a). Oxygen consumption has been reported to be normal (Hoidal et al. 1979a), but the protein content of these cells has been increased (Harris et al. 1975; Warr and Martin 1978). Alveolar macrophages from smokers release less PGE, and thromboxane B, than normal macrophages (Laviolette et al. 1981), suggesting that cigarette smoking induces a lesion in phospholipid hydrolysis or the mecha- 259 TABLE 1.—Cigarette-smoking-induced abnormalities in the inflammatory and immune effector systems > within human alveolar structures Parameter Cell types present Findings in smokers Total number of cells Increased Percent polymorphonuclear leukocytes Increased Percent T lymphocytes Increased or normal Percent B lymphocytes Normal Lymphocyte function Response to mitogens Decreased Macrophage structure Diameter Normal Ruffling of cell surface Decreased Number and size of cytoplasmic structures Increased Abnormal cytoplasmic inclusions Macrophage properties and function Surface receptors Pigmented inclusions, particulates with plate or needle-like configuration, presence of aluminum silicate IgG-Fc Normal C3b Decreased Phagocytosis and killing of microorganisms Bacteria Normal or decreased Fungi Normal Effector and accessory cell function responsiveness to chemotactic factors Casein Increased Activated serum Normal Function as accessory cell to lymphocytes Decreased Responsiveness to MIF Decreased Production of neutrophil chemotactic factor Increased Secretion of superoxide anion Increased Secretion of elastase Increased Release of prostaglandin E, and thromboxane B, Decreased Miscellaneous properties and function Glucose utilization Increased or normal Oxygen consumption Normal Protein content Increased Content of various enzymes Elastase Increased Acid protease Increased Neutral protease Normal Esterase Increased Acid phosphatase Increased B-glucuronidase Increased Lysozyme Normal or increased Aryl hydrocarbon hydroxylase Increased Angiotensin-converting enzyme Increased Spreading and adherence properties Pinocytosis Content of a,-antiproteinase SOURCE: Adapted from Hunninghake et al. (1979). 260 Increased in presence of serum, decreased nylon adherence Decreased Increased nism regulating hydrolysis. Smoker macrophages also appear to have increased amounts of various enzymes, including acid protease (Harris et al. 1975), neutral protease (Harris et al. 1975), esterase (Harris et al. 1975), acid phosphatase (Martin 1973), angiotensin- converting enzyme (Hinman et al. 1979), B-glucuronidase (Martin 1973), lysozyme (Martin 1973), and arylhydrocarbon hydrolase (Cantrell et al. 1973; Harris et al. 1978; McLemore et al. 1977b, c, 1978; McLemore and Martin 1977). The functional significance of increased amounts of these enzymes is not entirely clear. In addition to its effects on the inflammatory and immune effector cells in the lung, cigarette smoke may also affect the composition of epithelial surface fluid. For example, some investigators have found that the amount of immunoglobulin G (IgG) present in lavage fluid is increased (Reynolds and Newball 1974); others have noted normal levels (Warr et al. 1977). Interestingly, cigarette smoking appears to cause a significant decrease in the secretory component of immuno- globulin A (IgA) in the lavage fluid of some people who smoke cigarettes (Merrill et al. 1980). This effect most likely indicates a subtle injury to the epithelium of the lung that produces this factor. The only additional factors that have been reported to be abnormal in lavage fluid of cigarette smokers are an increase in the amounts of fibronectin (Villiger et al. 1981) and a decrease in the function, but not the amount, of a, AT (Gadek et al. 1979; Janoff et al. 1979). This latter finding has been disputed by others (Stone et al. 1983). Emphysema A number of lines of evidence link the cellular changes described above with the development of emphysema. They include observa- tions in populations deficient in a,AT, in animal models of emphyse- ma, and most important, in human cigarette smokers. Populations Deficient in Alpha,-antitrypsin Eriksson (1965) described the characteristic features of a,AT- deficiency-associated lung disease. Approximately 60 percent of affected individuals develop symptoms of airways obstruction by age 40, and 90 percent by age 50. Excluding the influence of cigarette smoking, there is no sexual predominance of disease. Kueppers and Black (1974) found that dyspnea occurred a decade earlier in cigarette smokers (35 years in smokers versus 44 years in nonsmok- ers), and estimated that 70 to 80 percent of all PiZZ persons (where Pi= protease inhibitor) will develop lung disease. Larsson (1978) has projected that nearly 60 percent of PiZZ people will ultimately die of lung-related disease. Orell and Mazodier (1972) reviewed the morphologic features of a,AT-deficiency-associated emphysema and found primarily the 261 panacinar or panlobular form. Emphysematous lesions may be distributed uniformly throughout the lungs (Orell and Mazodier 1972), but frequently show a predominant lower lobe distribution (Greenberg et al 1973). , In people genetically deficient in a,AT, the increased numbers of inflammatory cells found in the lungs of smokers probably present an increased elastase burden to the lung and magnify the protease— antiprotease imbalance. This may explain the deleterious effects of cigarette smoke in this population. Kueppers and Black (1974) reviewed data on the impact of cigarette smoking in people severely deficient in a,AT and concluded that, in addition to experiencing earlier onset of respiratory symptoms and pulmonary function abnormalities, cigarette smokers die at an earlier age from respira- tory failure than similiarly afflicted nonsmokers. The increased prevalence of emphysema in populations deficient in a,AT, plus the exacerbation of this lung disease by smoking, suggests that protease— antiprotease imbalance may also play a role in the development of emphysema by smokers who are not deficient in a,AT. This suggestion has resulted in a substantial body of research that has characterized a,AT, defined the nature of elastase-induced emphyse- ma, and clarified and supported the protease—antiprotease hypothe- sis of cigarette-induced emphysematous lung injury. Alpha, -antitrypsin The deficient constituent of a,-globulin was initially described by Schultze et al. (1955) as a,-3,5-glycoprotein but later renamed a,- antitrypsin (a,AT) when it was found to inhibit trypsin activity (Schultze et al. 1962). Subsequently, a, AT has been shown to inhibit a variety of proteolytic enzymes including neutrophil elastase (Ohlsson 1971), neutrophil collagenase (Tokoro et al. 1972; Ohlsson 1971), cathepsin-G (Travis et al. 1978), chymotrypsin (Travis et al. 1978; Rimon et al. 1966), plasmin (Rimon et al. 1966), thrombin (Rimon et al. 1966), Hageman factor cofactor (Crawford and Ogston 1974), coagulation factor XI (Heck and Kaplan 1974), acrosin and kallikrein (Fritz et al. 1972a, b), urokinase (Crawford and Ogston 1974; Clemmensen and Christensen 1976), and renin (Scharpe et al. 1976). Although the range of proteases inhibited by a,AT appears broad, the association rate constants of these enzymes for a,AT differ (leukocyte elastase > chymotrypsin > cathepsin-G > trypsin > plasmin > thrombin) (Beatty et al. 1980), and the inhibitory role of a, AT against enzymes with low association rate constants, such as trypsin, may be negligible. The names a,-protease inhibitor or a,- proteinase inhibitor better describe this broader range of inhibitory functions and are preferred by some authors. In deference to historical usage and in accord with the recommendations of the 262 Nomenclature Meeting for this substance (Cox et al. 1983), the name a,AT has been retained in this discussion. The inhibitor a,AT is a polymorphic plasma protein (Fagerhol and Cox 1981; Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981; Fagerhol and Braend 1965) encoded by two codominant autosomal alleles and inherited as a single Mendelian trait. The basal serum concentration is genetically determined (Eriksson 1964; Kueppers et al. 1964; Fagerhol and Gedde-Dahl 1969; Talamo et al. 1966). More than 31 allelic variants or Pi types (where Pi, or protease inhibitor, is the symbol assigned the genetic locus of the a,AT allele) have been identified (Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981). The variants are designated by capital letters, B through Z, correspond- ing to their approximate electrophoretic mobility, relative to the anode, in acid starch gel electrophoresis or their relative positions on polyacrylamide isoelectric focusing. New variants are named accord- ing to the conventions established by the Fifth International Workshop on Gene Mapping and the Nomenclature Meeting for a,AT (Cox et al. 1980). The M allele (PiM) has a gene frequency of about 0.9 and is the most common Pi type in all populations tested (Kueppers 1978). The a,AT serum concentration in PiMM homozygotes is between 1.3 and 2.2 g/liter (depending on the method of measurement and the purity of standard) (Kueppers 1968; Jeppsson et al. 1978a) and, by conven- tion, defines normal. Pi types with decreased circulating levels of a,AT include (serum concentration expressed as percent normal) null 0% (Feldman et al. 1975; Talamo et al. 1973), Mmalton and Mduarte 12% (Cox 1976; Lieberman et al. 1976), Z 15% (Laurell and Eriksson 1963; Fagerhol and Laurell 1970), P 30% (Fagerhol and Hauge 1969), S 60% (Fagerhol 1969), and I 68% (Arnaud et al. 1978). PiZ was the first variant recognized (Laurell and Eriksson 1963) and is the Pi type most frequently associated with a serum deficiency of a,AT (Kueppers 1978). Its allele frequency varies markedly between different ethnic and racial groups. In the United States, the allele frequency is greater than 0.010 in whites but nearly zero in blacks (Kueppers 1978). Approximately 1 in 2,000 whites is homozy- gous for the Z gene (Laurell and Sveger 1975). Although a decrease in hepatic synthesis is probably the major mechanism for quantitatively significant reductions in serum a,AT, the factors that modulate such synthesis are only partially under- stood (Morse 1978). Impaired hepatic secretion, as evidenced by the presence of intrahepatic cytoplasmic inclusions containing accumu- lations of a,AT polypeptides (Blenkensopp and Haffenden 1977), occurs in persons with the PiZ genotype. It is uncertain if these intrahepatic inclusions exert a negative feedback inhibition on the hepatocyte and thereby retard biosynthesis of a,AT. Intrahepatic inclusions are not found with the S and null Pi types (Carrell et al. 263 1982), suggesting that decreased synthesis, independent of impaired secretion, is primarily responsible for the reduced serum levels of a,AT. Catabolic studies of the PiM and PiZ proteins have identified similar half-lives in the circulation, 6 to 7 days and 5 days, respectively (Laurell et al. 1977; Jeppsson et al. 1978b). It is therefore unlikely that accelerated peripheral catabolism contributes — cantly to serum deficiencies in a, AT. In addition to quantitative deficiencies in serum a, AT, a reduction in serum inhibitory capacity could also result from a loss in the functional activity of a,AT. Most genetic variants, however, are functionally equivalent to normal a,AT (PiMM) in their capacities to inhibit both trypsin and elastin (Billingsley and Cox 1982). The inhibitor a,AT is a low molecular weight (51,000 daltons) (Mega et al. 1980; Carrell et al. 1981; Chan et al. 1976; Pannell et al. 1974; Jeppsson et al. 1978) protein comprised of a single polypeptide chain containing 394 amino acid residues. Three carbohydrate side chains are attached, each containing terminal sialic acid residues (Mega et al. 1980; Carrell et al. 1981). The a,AT reacts stoichiometri- cally with free protease in a ratio of 1:1; one mole of a,AT inhibits one mole of protease and yields a stable complex (Cohen 1973). An in vitro study (James and Cohen 1978) found, however, that complete inhibition of elastase requires molar ratios of a,AT to elastase greater than 2.2:1. This phenomenon may be explained by elastase having two major sites of attack on a,AT. Attack against one site leads to a conformational change in a,AT and inhibition of elastase, whereas attack against the other site results in cleavage and inactivation of a, AT. The a,AT-protease complexes that form during protease inhibition are not reutilized by the body (Balldin et al. 1978), and the body supplies of a,AT are replenished via de novo synthesis by the liver. In addition to hepatic biosynthesis, a,AT is synthesized by at least two other endogenous sources. Both human peripheral lymphocytes and rat alveolar macrophages have been shown to synthesize a,AT. Ikuta et al. (1982) demonstrated that concanavalin A-stimulated monocytes interact with human peripheral lymphocytes, causing a threefold increase in a,AT synthesis. White et al. (1981) cultured rat alveolar macrophages and recovered newly synthesized radio-labeled (3S)a,AT from the cell culture medium. Macrophages and lympho- cytes, by virtue of their close physical proximity to the sites of connective tissue injury, may play a significant role in defense against proteolytic destruction. The physiologic significance of extrahepatic synthesis of a, AT remains speculative, however. While certain chemical and physiological aspects of a,AT are clear, the exact biochemical mechanism by which it causes protease inhibition is uncertain. It is generally agreed that the reactive center of a,AT is located on a single serine—methionine segment peptide 264 bond on the carboxyl-terminal end (Carrell et al. 1982; Kurachi et al. 1981). Proteolytic Enzymes Inducing Emphysematous Change Proteolytic enzymes have been a major focus of investigation following the demonstration by Gross et al. (1965) of papain’s ability to induce emphysematous changes in rats. Papain Papain, a proteolytic enzyme with a broad range of substrate specificities (Bergmann and Fruton 1941; Kimmel and Smith 1953), reproducibly causes emphysema-like lesions in a variety of experi- mental animals following aerosolization or intracheal instillation (Gross et al. 1965; Palecek et al. 1967; Goldring et al. 1968; Caldwell 1971; Pushpakom et al. 1970; Marco et al. 1969). A number of studies have helped to clarify the critical importance of elastolysis in papain-induced emphysema. Snider et al. (1974) tested amorphous and crystalline forms of papain and found that the emphysema-inducing properties of these preparations were directly proportional to their abilities to degrade and solubilize elastin. Heat inactivation of papain destroyed its emphysema-inducing capabilities. Similarly, intratracheal pretreat- ment of hamsters with human a,AT, an inhibitor of papain elastolytic activity, ameliorates papain-induced emphysematous changes (Martorana and Share 1976). Furthermore, Blackwood et al. (1973) showed that the elastolytic activities of several. microbial enzymes, rather than their nonspecific protease activities, correlate best with the enzyme’s ability to induce emphysematous changes following intravenous administration to rats. Snider et al. (1977) showed that enzymes lacking elastolytic activity, such as collagenase or trypsin, do not produce emphysema in hamsters. Whereas these studies support the notion that the early histologic changes induced by papain are a direct consequence of its elastolytic activity, they do not preclude the possibility that endogenous factors may contribute to subsequent disease progression. Snider and Sherter (1977) noted a gradual increase in static lung volumes in hamsters following a single intratracheal injection of pancreatic elastase. Stone et al. (1979) followed the fate of tritium-labeled pancreatic elastase and found that enzymatically active prepara- tions are retained longer within the lung than inactive preparations, and that 14C-guanidated elastase remains bound to lung matrix for at least 96 hours. This suggests that tissue-bound elastase may continue to digest elastin for extended periods of time. Martorana et al. (1982) found no progression in the mean linear intercept measurements or internal surface areas in the lungs of papain-treated dogs between 3 265 480-144 O - 85 - 10 and 6 months after treatment. However, the mean pulmonary arterial pressure and pulmonary arteriolar resistance did increase during this interval. Papain-treated animals exhibit the expected physiologic changes of emphysema: increased RV, FRC, and TLC, decreased elastic recoil, increased static lung compliance at middle and low lung volumes, and reduced diffusing capacity (DLcoVA and DLco) (Caldwell 1971; Pushpakom et al. 1970; Marco et al. 1969; Giles et al. 1970; Johanson and Pierce 1973). Studies by Kobrle et al. (1982) have shown that following papain administration the elastic fibers are disrupted and that the elastin content of the lung initially decreases, but later returns to normal after a period of accelerated synthesis. The newly synthesized fibers are disordered; however (Kuhn and Senior 1978; Kuhn and Starcher 1980). Pancreatic Elastase The ability of porcine pancreatic elastase to rapidly hydrolyze insoluble elastin (Partridge and Davis 1955) and its commercial availability in a highly purified crystalline form have led to its extensive use as an experimental agent for inducing emphysema in animals (Karlinsky and Snider 1978). Lesions resembling human panacinar emphysema can be induced in hamsters within 2 hours of intratracheal instillation of pancreatic elastase (Kaplan et al. 1973). The severity of the lesions, as assessed by histologic or physiologic criteria, is dose related (Raub et al. 1982), with adult animals being more susceptible to pancreatic elastase than young animals (Lucey and Clark 1982). Within a few hours of intratracheal instillation in hamsters, hemorrhagic lesions develop and an influx of polymorpho- nuclear leukocytes is seen (Hayes et al. 1975; Kuhn and Tavassoli 1976). Digestion of elastin fibers is apparent in the pleura and in the alveolar walls by 4 hours, but is more extensive at 24 and 48 hours (Kuhn et al. 1976). By day 4, there is a diminution in the number of polymorphonuclear leukocytes (PMNs), but many macrophages remain (Morris et al. 1981). The hemorrhage and cellular infiltration resolves within 3 weeks, and the ensuing lesions resemble panacinar emphysema (Kuhn et al. 1976). Over 95 percent of the detectable urinary excretion of desmosine and isodesmosine, amino acid markers of in vivo elastolysis, appears within 2 days of elastase instillation; only small amounts can be detected by day 3 (Goldstein and Starcher 1977). Kucich et al. (1980) developed a hemagglutina- tion inhibition assay to measure elastin-derived peptides in serum, and found that elastin-derived peptides could be detected in the serum of dogs for a period of 12 days following administration of a 25 to 50 mg dose of porcine pancreatic elastase and for 40 days following a 100 mg dose. Janoff et al. (1983b) found increases in urinary desmosine excretion during the first 48 hours following endobronchi- 266 al instillation of pancreatic elastase to sheep; increases in mean linear intercepts and decreases in lung ventilation and perfusion were found after 4 weeks. All changes correlated positively with the elastase dose. Studies have shown a decrease in the lung elastin content within the first 24 hours of intratracheal injection of elastase (Kuhn et al. 1976; Ip et al. 1980; Goldstein and Starcher 1977). Physiologic studies (Snider and Sherter 1977; Snider et al. 1977) of experimental animals after pancreatic elastase administra- tion have shown increases in the lung compliances and in the volume of air within the lungs at specified transpulmonary pressures (25 and -20 cm H?°). These physiologic alterations appear to progress in severity for about 26 weeks following exposure to elastase (Snider and Sherter 1977). In spite of substantial experimental verification of ability of pancreatic elastase to induce emphysematous changes in animals following intratracheal instillation, there is little evidence implicat- ing endogenous pancreatic elastase in the pathogenesis of pulmonary emphysema in humans. A serine endopeptidase of pancreatic origin (elastase 2) has been shown to circulate in human blood (Geokas et al. 1977). However, the enzyme is rapidly bound to serum inhibitors a,AT and a2-macroglobulin (a.M) and inactivated (Gustavsson et al. 1980). Although a,M-elastase complexes retain enzymatic activity against low molecular weight synthetic elastin substrates (N-succi- nyl-L-alanyl-L-alany]-L-alanine-4-nitroanilide) (Twumasi and Liener 1977; Barrett and Starkey 1973); high molecular weight proteins such as elastin are prevented from reaching the enzyme and are not hydrolyzed (Barrett and Starkey 1973). Attempts to induce emphysematous changes via the intravenous injection of elastase have met with limited success. Hamsters injected intravenously with nonfatal doses of pancreatic elastase fail to show histologic changes characteristic of emphysema (Schuyler et al. 1978) and do not manifest detectable reductions in lung elastin (Ip et al. 1980). However, elastic recoil is lost at low lung volumes (Schuyler et al. 1978). Fierer et al. (1976) has noted enlargements in the airspaces of rats treated intravenously with large doses (330 U) of pancreatic elastase. They also found increases in the mean linear intercepts and rarefication of the amorphous components of elastin within the lungs. It is doubtful, however, if proportionally similar intravenous levels of pancreatic elastase occur in humans with pulmonary emphysema. Polymorphonuclear Leukocyte Elastase Polymorphonuclear leukocytes (PMN) appear to be a more plausi- ble source of endogenous elastase in the human lung than the pancreas, and are more likely to be incriminated in the pathogenesis of naturally occurring pulmonary emphysema. PMNs contain elasto- 267 lytic enzymes (Janoff 1973; Ohlsson and Ohlsson 1974; Rindler- Ludwig et al. 1974) that can be released in active form within the lung. Experimental studies have clearly demonstrated the ability of PMN elastase to degrade lung elastin and to induce emphysematous lesions in animals. Marco et al. (1971) and Mass et al. (1972) induced experimental emphysema in dogs by the administration of aerosolized crude leukocyte homogenates. Using purified human leukocyte elastase, Janoff et al. (1977) demonstrated the ability of the enzyme to digest dog lung elastin in vitro and to cause significant dilation of terminal respiratory structures when instilled into isolated perfused dog lungs. The in vivo intratracheal instillation of human leukocyte elastase in dogs produces foci of alveolar destruction within 90 minutes of administration (Janoff et al. 1977). Senior et al. (1977) studied the effects of intratracheally injected human leukocyte elastase on hamsters and found a reduction in lung elastin in treated animals, as well as mild patchy airspace dilation. Sloan et al. (1981) were able to show that purified dog leukocyte elastase could also produce emphysematous lesions in dogs when instilled endobronchi- ally. Guenter et al. (1981) developed a dog model of experimentally induced emphysema that avoided the necessity of intratracheal instillation of enzymes. They repetitively injected E. coli endotoxin intravenously, thereby inducing extensive leukocyte sequestration within the lungs of the dogs. A previous study had shown that the sequestered cells degranulate and disintegrate within the vascular bed (Coalson et al. 1970). Histologic studies of these dogs revealed mild airspace destruction and prominent intra-alveolar fenestra- tions. Alveolar Macrophage Elastase In a widely cited article (Mass et al. 1972), dog alveolar macro- phage homogenates (obtained by the method of Brain 1970), adminis- tered to two mongrel dogs produced “some dilatation and nonuni- formity in the size of the airspaces accompanied by some alveolar wall destruction” in one of the dogs. The other dog showed no evidence of emphysema. In spite of the paucity of animal data, the pulmonary alveolar macrophage (PAM) has been the focus of much investigation. Both experimental and clinical evidence is available that inrplacates this cell in the pathogenesis of pulmonary emphysema. Two possible mechanisms by which macrophages may mediate tissue injury are being actively studied. One mechanism involves the release of elastolytic enzymes followed by unrestrained proteolysis. The second mechanism involves either a direct or an indirect injury 268 following the release of toxic forms of partially reduced oxygen such as superoxide anions, hydroxyl radicals, and hydrogen peroxide. The ability of human alveolar macrophages to synthesize and secrete an elastolytic enzyme distinct from PMN elastase is the subject of controversy. Although human alveolar macrophages have been shown to synthesize a metalloprotease distinct from the serine protease (elastase) of the PMNs (DeCremoux et al. 1978), its hydrolytic activity against insoluble elastin substrate has not been conclusively demonstrated (Hinman et al. 1980; Levine et al. 1976). Interpretation of the observation that human alveolar macrophages raised in cell culture systems secrete an enzyme with true elastolytic activity against insoluble elastin (Rodriguez et al. 1977; DeCremoux et al. 1978) is complicated by the fact that alveolar macrophages bind and internalize PMN elastase (Campbell and Greco 1982; White et al. 1982; Campbell and Wald 1983). Hinman et al. (1980) detected a calcium-dependent metalloprotease in the culture medium and in the cell lysates of human alveolar macrophages and _ initially demonstrated elastolytic activity against synthetic elastin substrate and soluble elastin by both the culture medium fluid and the cell lysates. However, after 3 and 5 days of culture, no detectable activity against insoluble elastin was evident. The authors calculated that the initial elastolytic activity observed could be quantitatively explained by PMN contamination. The recognition that human alveolar macrophages internalize human PMN elastase (Campbell and Greco 1982; White et al. 1982; Campbell et al. 1979; Campbell and Wald 1983) and that the internalized PMN elastase retains enzymatic activity for at least 48 hours (McGowan et al. 1983) suggests an alternative explanation. Green et al. (1979) subcultured human alveolar macrophages for 3 months and found measurable elastase activity against solubilized elastin during the entire period. They concluded that the elastase activity appeared to be synthesized continuously rather than being internalized from external sources. In summary, human alveolar macrophages release elastolytic enzymes capable of digesting connective tissue. Whether the elastase released by these cells represents an enzyme synthesized de novo or a previously internalized PMN elastase is uncertain and requires further study. Human alveolar macrophages, especially from cigarette smokers, secrete highly reactive oxygen species (Hoidal et al. 1979a) that are capable of directly injuring endothelial cells (Sacks et al. 1978) and fibroblasts (Hoidal et al. 1981) and of inactivating a,AT (Carp and Janoff 1979, Janoff 1979a). Whole cigarette smoke inhibits PMN chemotaxis in vitro in a dose- dependent manner (Bridges et al. 1977). However, when alveolar macrophages are exposed to cigarette smoke either in vitro or in 269 vivo, they release a PMN chemotaxic factor (Hunninghake et al. 1980c) (see above). Protease—Antiprotease Hypothesis The protease—antiprotease hypothesis proposes that enzymatic digestion of lung parenchyma occurs as a direct consequence of a genetic or acquired imbalance of the protease—antiprotease system and that the subsequent repair of connective tissue is unable to return the structures to normal. This hypothesis derives principally from two observations: (1) people genetically deficient in a,AT (Laurell and Eriksson 1963), the major antielastase of the lower respiratory tract of humans (Gadek et al. 1981la), are at greatly increased risk of developing pulmonary emphysema, and (2) proteo- lytic enzymes produce physiologic and anatomic lesions resembling emphysema when administered to experimental animals (Gross et al. 1965). Attempts to integrate the clearly established relationship of cigarette smoking and pulmonary emphysema with the protease— antiprotease hypothesis have led investigators to search for ways in which smoking perturbs this balance. Increased Elastase Owing to the Cellular Response to Smoke At least five variables, aside from the genetically determined level of antiprotease activity, could influence the elastase burden of the lungs. These variables include (1) an increase in the number of elastase-containing cells within the lung, (2) an increase in the quantity of prepackaged or newly synthesized elastase per cell, (3) the quantity of elastase released from the cells, (4) the proximity of the elastase to suitable substrate, and (5) the extracellular milieu (i.e., pH, ionic strength, and factors such as platelet factor 4). Number of Cells As discussed earlier, the human cigarette smoker has increased numbers of alveolar macrophages in the bronchoalveolar lavages compared with nonsmokers (Rodriguez et al. 1977; Harris et al. 1975; Reynolds and Newball 1974; Hoidal and Niewoehner 1982). Holt and Keast (1973b) found sustained elevations of pulmonary macrophages in mice exposed to cigarette smoke. Cigarette smoke has been shown to recruit PMNs into the airways (Kilburn and McKenzie 1975; Rylander 1974) and to induce alveolar macrophages to release a chemotactic factor for PMNs (Hunninghake et al. 1980c). The circulating PMNs are reported to be increased in cigarette smokers (Corre et al. 1971; Galdston et al. 1977). Hunninghake et al. (1980c) and Reynolds and Newball (1974) found increased numbers of PMNs in the lavage fluid of smokers, but Hoidal and Niewoehner (1982) reported similar numbers of PMNs in the lavages of cigarette 270 smokers and nonsmokers. Hunninghake and Crystal (1983) obtained isolated cell suspensions from the bronchoalveolar lavage fluids and from open lung biopsies of nonsmokers and cigarette smokers with both normal lung parenchyma and sarcoidosis. They found a significantly increased number of neutrophils and macrophages in the lavage fluid and in the biopsy specimens from cigarette smokers as compared with nonsmokers, both in patients with normal lung parenchyma and in those with sarcoidosis. Elastase Content Harris et al. (1975) found an increase in the elastase-like esterase and protease activity of macrophages obtained from smokers as compared with nonsmokers. Galdston et al. (1977) found the PMN elastase levels of circulating PMNs to be elevated in patients with chronic obstructive lung disease and suggested that the intracellular elastase levels may be genetically determined (Galdston et al. 1973). Other investigators (Lam et al. 1979; Rodriquez et al. 1979) reported similar findings, but Kramps et al. (1980) failed to find any correlation between the PMN elastase levels and obstructive lung disease in PiZZ patients, although they did note a difference in PiMM patients. Lonky et al. (1980) demonstrated that dogs infected with Type 3 pneumococcus had increased PMN elastase-like esterase activity within their cells, suggesting an acute phase reaction. Release A variety of mechanisms may lead to the extracellular release of lysosomal contents. These include cell lysis, regurgitation during phagocytosis, reverse endocytosis, humoral mediation, and cytocha- lasin B treatment of cells (Klebanoff and Clark 1978). Wright and Gallin (1979) showed that migration of PMNs is associated with the leakage of various enzymes. Sandhaus (1983) found that migrating human neutrophils degrade elastin in vitro in the presence or absence of human a,AT. A similar mechanism may occur during neutrophil migration in vivo. Hutchison et al. (1980) found that the soluble fraction of cigarette smoke suppressed the release of lysoso- mal enzymes (acid phosphatase and acid ribonuclease) from PMNs obtained from healthy persons, but not from the PMNs of emphy- sematous patients. Blue and Janoff (1978) demonstrated that the water-insoluble fraction of cigarette smoke has a cytotoxic effect on PMNs in vitro and causes them to release their lysosomal contents, including beta-glucuronidase, acid phosphatase, and elastase. Eliraz et al. (1977) found that canine alveolar macrophages and PMNs, when stimulated with the water-soluble fraction of cigarette smoke, secrete elastase. Abboud et al. (1983), however, compared the release of elastase and B-glucoaminodase from PMNs obtained from ciga- 271 rette smokers and with that from nonsmokers and found no differences. In vitro stimulation of these cells by 2ither phagocytosis or chemotactic polypeptides did not alter the results. These research- ers concluded that chronic smoking does not affect neutrophil elastase release in vitro and that among smokers there is no significant relationship between in vitro neutrophil elastase release and abnormalities in lung function. They speculated that some of the differences between studies may be related to experimental condi- - tions, such as the concentrations of cigarette smoke. Because the mechanisms involved in the release of intracellular contents are complex and the representativeness of in vitro condi- tions to in vivo events is uncertain, definite conclusions await further studies. Proximity Elastolytic activity is conditioned by the absorption of elastase onto elastin substrate (Robert and Robert 1970); the adsorption, in turn, results from the electrostatic attraction between negatively charged carboxylate groups of elastin and positively charged groups of elastase (Hall and Czerkowski 1961; Gertler 1971). Campbell et al. (1982) found that a,AT has less inhibitory activity against PMN elastase derived from cells in contact with substrate than against PMN elastase free in solution. They reasoned that the partial exclusion of protease inhibitors from the PMN-connective tissue interface may account for this phenomena and may be an important factor in elastase-mediated injury. Focusing more on the macroenvi- ronment within the lung, Janoff et al. (1983c) found that the bronchoalveolar lavage fluids of young asymptomatic cigarette smokers contain significantly more elastase activity than the lavage fluids from nonsmokers. Kucich et al. (1983) found that the serum lung elastin-derived peptides were elevated in some smokers and most patients with COLD, suggesting that elastolysis may be taking place in smokers and COLD patients. Milieu A number of in vitro experiments have examined the chemical and physical conditions that modify neutrophil elastase kinetics. Lesti- enne and Bieth (1980) demonstrated that human leukocyte elastase activity is activated in the presence of substrate excess, hydrophobic solvents, and increasing ionic strength. The adsorption of sodium dodecyl] sulfate (SDS), a hydrophobic, anionic ligand, onto the surface of elastin enhances the elastolytic activity of pancreatic elastase (Kagan et al. 1972). Lonky et al. (1978) showed that platelet factor 4 (PF,) in physiologic concentrations is capable of in vitro stimulation of human neutrophil elastase (HLE) against lung elastin. Low doses 272 of HLE instilled intratracheally in hamsters failed to induce physiologic, morphologic, or biochemical changes, but following the addition of PF,, a significant injury was evident, and the elastin content of the lung was lowered by 20 percent (Lonky et al. 1978). Boudier et al. (1981) demonstrated that human leukocyte cathepsin- G, an enzyme in the azurophilic granules that possesses little intrinsic elastolytic activity, stimulates the rate of solubilization of human lung elastin by HLE. The elastolytic activity increased by more than five times the HLE rate when the HLE-cathepsin-G mixture was present in equimolar concentrations. The relevance of these findings to the physiologic conditions that prevail in vivo requires further study. Laurent et al. (1983) recently discovered that the water-soluble components of filtered cigarette smoke suppress, in a dose-dependent manner, the lysyl oxidase-catalyzed oxidation of the epsilon-amino groups of lysine residues in tropoelastin. This step is essential for the formation of covalent cross-links between neighboring elastin poly- peptide chains that, in turn, are necessary for normal elastic strength within the lung. Decreased Antiprotease Owing to Oxidation A comprehensive review of the role of oxidative processes in emphysema has recently been published by Janoff et al. (1983a). In vitro studies have revealed that oxidants such as chloramine T (Abrams et al. 1981) or ozone (Johnson 1980) cause a loss in the inhibitory capacity of a, AT for neutrophil elastase. The mechanism of inactivation has been identified as the oxidation of methionine and tyrosine residues (Johnson and Travis 1979; Cohen 1979; Carp and Janoff 1978) within the a,AT molecule. Chloramine T, when administered differentially to dogs, reduces EIC > TIC of serum and also results in emphysema (Abrams et al. 1981). Cigarette smoke is also known to contain oxidants (Stedman 1968; Pryor et al. 1983). Aqueous solutions of cigarette smoke reduce the elastase inhibitory capacity of human serum (Carp and Janoff 1978) and result in less binding of elastase to a,AT in vitro (Carp and Janoff 1978). Some investigators have found that the a,AT activity is reduced in the lavage fluids (BALF) obtained from human cigarette smokers and from rats exposed to cigarette smoke (Gadek et al. 1979; Carp et al. 1982; Janoff et al. 1979a). Stone et al. (1983) reported similar levels of functional a,-antitrypsin in the bronchoalveolar lavage fluids of human smokers and nonsmokers. Janoff and Chan (1984) have suggested that this difference in results may reflect the timing of the lavage in these studies, as rats chronically exposed to cigarette smoke had rapid inactivation of a,-antitrypsin following smoke exposure, but also had a more rapid recovery of a,-antitrypsin activity than did rats acutely exposed to smoke. Stone et al. also 273 recognized that their study may not have detected a reduction in alpha,-antitrypsin activity if it was accompanied by a rapid recovery to normal levels. Methionine sulfoxide peptide reductase, an enzyme present in human PMNs, can reactivate a,AT oxidized by chlora- mine T or by the myeloperoxidase system, but a,AT exposed to cigarette smoke plus peroxide (Carp et al. 1983) has been shown to be either resistant to reactivation by the myeloperoxidase system (Carp et al. 1983) or incompletely reactivated (James et al. 1984). Human ceruloplasmin has been shown to prevent myeloperoxi- dase mediated oxidation of a,AT under specified conditions of pH and solvency (Taylor and Oey 1982), although the role played by ceruloplasmin in limiting oxidation by phagocytes in vivo is unclear. Taylor et al. (1983) examined plasma and leukocyte lysosomal samples from a group of COLD patients and measured the ability of these samples to inhibit lipid peroxidation. While they reasoned that inhibitors of peroxidation could protect a,AT from inactivation by neutralizing lipid free radicals, they found that inhibition required factors from both plasma and lysosomal extracts and that the factor was not ceruloplasmin. Two of ten emphysematous patients had reduced plasma factor activity, and one of these patients also had reduced lysosomal factor. Controls had normal values for both of these factors. Galdston et al. (1984) examined serum ceruloplasmin concentra- tions and antioxidant activity in male and female smokers. Smokers of both sexes had higher serum ceruloplasmin concentrations than did nonsmokers; women in both smoking categories had higher concentrations than their male counterparts. Serum antioxidant activity showed a significant positive correlation with serum cerulo- plasmin levels; however, for comparable ceruloplasmin concentra- tions, serum antioxidant activity was significantly lower in smokers than in nonsmokers of both sexes. The researchers suggest that cigarette smoking may cause partial inactivation of serum antioxi- dant activity that is accompanied by an insufficient increase in ceruloplasmin concentration. Endogenous phagocytes are also capable of generating oxidants (Babior 1978; Klebanoff and Clark 1978). The phagocytic enzyme myeloperoxidase, in the presence of hydrogen peroxide and halide ions, oxidatively inactivates a,AT (Matheson et al. 1979, 1981). Smoking, as described above, elevates the oxidative metabolism in lung macrophages (Hoidal and Niewoehner 1982; Fox et al. 1979; 1980; 1981). Thus, it is clear that the oxidants present in cigarette smoke and the lung macrophages of smokers can inactivate a,AT. This inactiva- tion, coupled with the increased elastase burden that may result from the inflammatory cell response of the lung to smoke, could tip 274 the balance of the protease—antiprotease system in the direction of elastin degradation. Explanation for Upper Lobe Distribution _ In accord with the protease—antiprotease hypothesis, emphysema- tous lesions result from the unrestrained proteolytic digestion of connective tissue elements. The regional distribution of lesions within the lung is thought to be conditioned by both biochemical and physiological variables. The predilection of lower lobe involvement in persons with a,AT deficiency is hypothesized to result from an increased number of elastase-containing cells because of the higher vascular perfusion to this area in erect man. This excess could occur because of the deposition of senescent leukocytes in these areas of higher blood flow (Guenter et al. 1981). In addition, inhaled particulates preferentially deposit in the lower lobes (Milic-Emili et al. 1966; Dollfuss et al. 1967), and the leukocytes release their enzyme extracellularly during the ingestion of these particulates. Because of the genetic deficiency of a,AT, the proteolytic activity is unopposed and destruction occurs. ; The predominance of upper lobe lesions in cigarette smokers with normal systemic levels of a,AT is again thought to result from variations of ventilation and perfusion within the lung (Cockcroft and Horne 1982). However, in normal individuals the proteolytic activity due to the excess particulate deposition in the bases is inhibited by a,AT that is replenished by the increased vascular perfusion also occurring in the bases. The upper lobes, although less well ventilated than the lower lobes, nevertheless have higher ventilation:perfusion ratios because of the proportionately greater fall in perfusion. The oxidative inactivation of a,AT by cigarette smoke in the upper lobes therefore may not be compensated by vascular repletion of the inactivated a,AT, and an imbalance of protease—antiprotease may occur. The upper lobe injury may then be magnified by mechanical stresses caused secondary to the negative intrapleural pressures generated by gravitational forces in erect man (West 1971). Animal Models of Emphysema Spontaneous Emphysema Emphysema occurs spontaneously in animals in forms resembling the types seen in human disease (Karlinsky and Snider 1978). However, the low incidence and unpredictable occurrence of disease in animals greatly limit their utility as experimental models. 275 Experimentally Induced Emphysema A number of insults, including oxides of nitrogen, cadmium salts, whole cigarette smoke, ozone exposure, and proteolytic enzymes, have been used to induce or augment emphysematous lesions in a variety of experimental animals. The reader interested in a compre- hensive review of this topic is referred to the well-documented article by Karlinsky and Snider (1978). The evidence for each of these insults, as they pertain to cigarette smoke, is reviewed below. Oxides of Nitrogen Oxides of nitrogen, present in the gas phase of smoke, appear to induce or potentiate emphysema-like lesions in some animals (Karlinsky and Snider 1978). Nitrogen dioxide (NO.) exposure causes airway narrowing and an increase in the proteolytic burden within the lungs of experimental animals. Airway narrowing is postulated as a contributing factor in the pathogenesis of pulmonary emphysema (Juhos et al. 1980). Following exposure to NO., rats develop bronchiolar stenosis. The nitrogen dioxide exposure also induces an influx of alveolar macro- phages (AM) and polymorphonuclear leukocytes (PMNs) (cells known to contain proteolytic enzymes) into the lungs (Juhos et al. 1980). Kleinerman et al. (1982) demonstrated an increased number of alveolar macrophages and PMNs in lung lavages from hamsters exposed to NO,. Although there is no detectable increase in the elastolytic activity from lung lavages of NO.-exposed animals, the cell-free culture medium from macrophage cultures of NO.-exposed animals does show a twofold to fivefold increase in elastolytic activity during the first 2 weeks of exposure (Kleinerman et al. 1982). Nitrogen dioxide exposure has not been shown to cause alveolar septal disruption, an essential feature of centrilobular emphysema, but it does result in a significant reduction in the internal surface area in the lungs of hamsters exposed for 12 to 14 months (Kleinerman and Niewoehner 1973). Cadmium Salts Animals exposed to cadmium, a constituent found in the particu- late phase of cigarette smoke, develop a number of histologic and biochemical changes that may lead to emphysematous lesions. Exposed animals develop pulmonary edema, vascular congestion, intraparenchymal hemorrhages, and a loss of Type I pneumocytes (Palmer et al. 1975; Strauss et al. 1976), and PMNs and mononuclear cells influx into the lungs (Snider et al. 1973). The animals develop acute peribronchial damage followed by the accumulation of granu- lation tissue near the respiratory bronchioles, thickened alveolar 276 septa, and distortion and distention of neighboring alveoli (Snider et al. 1973). These histologic changes are more suggestive of the scar or paracicatricial form of emphysema than the centrilobular form reported in some industrial workers exposed to CdCl, (Princi 1947). This disparity in response to CdCl, could be related to species differences or the interaction of CdCl, with other factors. When hamsters are exposed to CdCl, plus beta-amino proprioni- trile (B-APN), an inhibitor of lysyl oxidase, they develop thin-walled subpleural bullae and airspace enlargements resembling panlobular emphysema (Niewoehner and Hoidal 1982). The mean linear dis- tance between alveolar intercepts is significantly increased; pres- sure—volume studies show overinflation and increased compliance of the lungs (Niewoehner and Hoidal 1982). This study suggests that CdCl., perhaps in conjunction with some other as yet undetermined agent, may be important in the pathogenesis of pulmonary emphyse- ma. The fact that CdCl, is a constituent of cigarette smoke (Randi et al. 1969) lends support to this hypothesis. Cigarette Smoke Cigarette smoking has been clearly identified as a major causal factor in the development of pulmonary emphysema in humans (Auerbach et al. 1972; 1974; Petty et al. 1967; Andersen et al. 1967; Niewoehner et al. 1974; USDHEW 1979). However, an animal model for the development of emphysema using the inhalation of cigarette smoke alone has not been convincingly demonstrated. Parenchymal disruption resembling human emphysema has been reported in some dogs following prolonged cigarette exposure, but this histologic pattern is not uniformly present (Hernandez et al. 1966; Auerbach et al. 1967a; Zwicker et al. 1978). This difficulty in developing an animal model for cigarette-induced emphysema may relate to the reluctance of animals to inhale smoke and the relatively long duration of exposure required to produce emphysema in humans. However, it may also result from the need for a combination or sequence of effects to induce emphysematous change. That is, an increased elastase burden might be necessary (secondary to the cellular response to smoke) before the oxidant damage of smoke to a,AT, or to repair mechanisms, results in emphysema. Hoidal and Niewoehner (1983) examined this question in hamsters exposed to low doses of smoke and elastase. Neither exposure alone resulted in significant emphysematous change, but the combined exposure did cause change. This suggests that an increased elastase burden may be a precondition for smoking- induced emphysematous lung injury, and may also explain the long exposure period required in humans prior to the demonstration of an increased prevalence of emphysema in smokers. 277 Experimental studies have shown that cigarette smoke can induce a number of cellular, biochemical, and metabolic changes within the lungs that may be causally related to the development of emphyse- ma. Macrophages and leukocytes, cells known to contain proteolytic enzymes, are recruited to the lungs of hamsters (Kilburn and McKenzie 1975) and guinea pigs (Flint et al. 1971) following exposure to cigarette smoke, thereby increasing the proteolytic burden of the lungs. Conversely, the a,AT activity decreases in rats after inhala- tion of cigarette smoke (Janoff et al. 1979a). The increased proteolyt- ic burden within the lungs coupled with the concomitant diminu- tion in inhibitory capacity tends to create a protease—antiprotease imbalance and a situation whereby unrestrained connective tissue destruction may occur. The Effects of Smoking on Cellular and Immune Defense Mechanisms There are important functional differences between macrophages from smokers and those from nonsmokers (Table 1). For example, Warr and Martin (1977) demonstrated that receptors for the third component of complement (C3b) are decreased in number or function on the surface of smokers’ alveolar macrophages. The receptors for the Fc portion of IgG, however, are normal on these cells (Warr and Martin 1977). An important function of the C3b receptor is to augment the attachment and phagocytosis of microorganisms and particulates by the macrophages. It is not clear whether this subtle defect in cell function results in a significant alteration in phagocyto- sis or clearance of particulates or microorganisms by these cells. In this regard, the phagocytosis and killing of a variety of microorga- nisms by smokers’ alveolar macrophages have been shown to be normal by Harris et al. (1970) and Cohen and Cline (1977). One report by Martin and Warr (1977), however, suggests that the capacity of alveolar macrophages to kill bacteria is decreased i smokers. : The observation that human alveolar macrophages from cigarette smokers function normally to kill microorganisms appears to differ, at first glance, from a number of animal studies demonstrating that the capacity of alveolar macrophages to phagocytose and kill bacteria is impaired following exposure to cigarette smoke (Holt and Keast 1973; Rylander 1971, 1973). In these animal studies, there was an initial decrease in the numbers of alveolar macrophages and a decrease in their bactericidal function following exposure to ciga- rette smoke. With prolonged exposure, however, the number of macrophages increased and their ability to kill microorganisms returned to normal (Rylander 1973, 1974). These observations suggest that cigarette smoke, initially, is toxic to alveolar macro- 278 phages. However, it is likely that the macrophages, with time, adapt to the presence of cigarette smoke. In addition, a subpopulation of macrophages that are more resistant to cigarette smoke may increase in number in the lung. The macrophages isolated from the lungs of smokers resemble those isolated from animals following prolonged exposure to cigarette smoke. The acute effects of cigarette smoking on the number and functions of alveolar macrophages in man has not been systematically evaluated. Alveolar macrophages of cigarette smokers appear to interact in an abnormal fashion with lymphocytes (Table 1). In this regard, the alveolar macrophages from cigarette smokers function poorly as accessory cells in presenting antigen to autologous lymphocytes (Laughter et al. 1977). This latter defect may be further magnified by the observation that lymphocytes from cigarette smokers also respond poorly to mitogens (Neher 1974; Daniele et al. 1977). Additional evidence for an abnormal interaction of macrophages and _lymphocytes in lungs of cigarette smokers is a decreased response of alveolar macrophages to the lymphokine, macrophage migration inhibitory factor (Warr 1979). These observations suggest that cigarette smoking may have broad effects on the ability of the lung to generate a cellular immune response. In Vitro Effects of Cigarette Smoke on Inflammatory and Immune Effector Cells The most readily demonstrable effect of cigarette smoke, in vitro; is a decrease in cell viability (Holt et al. 1974; Holt and Keast 1973; Nulsen et al. 1974; Weissbecker et al. 1969). At relatively low concentrations, cigarette smoke and its constituents rapidly kill alveolar and peritoneal macrophages in vitro. Lymphocytes and polymorphonuclear leukocytes are also very susceptible to these agents (Holt et al. 1974; Blue and Janoff 1978). When sublethal amounts of cigarette smoke are employed, a number of metabolic and functional changes occur in macrophages. Phagocytosis is depressed, as is the function of a number of macrophage enzymes (Vassallo et al. 1973; Green 1968a, b, c, 1969, 1970; Green and Carolin 1966, 1967; Green et al. 1977; Powell and Green 1971; Hurst and Coffin 1971). In addition; protein synthesis is also depressed (Yeager 1969; Low 1974), and stimulatory effects have been noted. While cigarette smoke depresses phagocytosis and intracellular killing, nitrogen dioxide increases the metabolic activi- ty of macrophages (Vassallo et al. 1973). Similar effects have been observed under some conditions with cigarette smoke (Holt and Keast 1973; Leuchtenberger and Leuchtenberger 1971). Results from a number of investigators suggest that the balance between stimula- tion and inhibition of macrophage activity is determined by dosage, with stimulation occurring at low exposure levels and inhibition at 279 higher concentrations (Holt and Keast 1973; Lentz and DiLuzio 1974; York et al. 1973). The most potent stimulation occurs after prolonged exposure to low levels of the agent. These in vitro effects of cigarette smoke are also seen acutely in vivo following exposure to smoke. The immediate effect of exposure to cigarette smoke, and to agents present in the smoke, is a decrease in viability of the pulmonary alveolar macrophages (Holt and Keast 1973a, b; Rylander 1971, 1973; Coffin et al. 1968; Dowell et al. 1970; Holt and Nulsen 1975; Gardner et al. 1969). Although not well studied, it is also likely that cigarette smoke is toxic to polymorpho- nuclear leukocytes (Blue and Janoff 1978). In support of these observations are studies demonstrating that acute exposure of experimental animals to tobacco smoke, or to components of cigarette smoke, also lowers their resistance to bacterial infection (Rylander 1969, 1971; Acton and Myrick 1972; Gardner et al. 1969; Goldstein et al. 1971; Huber and LaForce 1971; Huber et al. 1971). Short-term exposure to components of cigarette smoke, particularly nitrogen oxide, has also reduced resistance to viral infection, probably by inhibiting interferon production by macrophages (Va- land et al. 1970). As noted above, these in vitro and acute in vivo effects of cigarette smoke are not seen following long-term in vivo exposure in animals; very little work has been done on the effects of cigarette smoke in vitro, using human cells. However, several studies have shown that cigarette smoking and nicotine, at levels compara- ble to those encountered in the circulation of smokers, produce a slight but significant depression of PHA-stimulated DNA synthesis in human peripheral blood lymphocytes (Neher 1974; Silverman et al. 1975; Vos-Brat and Rumke 1969). The Effect of Cigarette Smoke on Antibody Production The available data on antibody production in human smokers suggest that cigarette smoking may depress these responses. The production of antibodies was investigated in a large study involving influenza vaccination. Smokers in the population exhibited in- creased susceptibility to infection during an influenza outbreak (Finklea et al. 1969, 1971). Prior to immunization with influenza vaccine, smokers exhibited significantly lower titers of specific antibodies than did nonsmokers. Immediately following vaccination of both groups, the smokers developed levels of antibodies compara- ble to those of nonsmokers. However, the antibody titer in the smokers fell below their nonsmoking counterparts within a few — weeks, and by a year after vaccination the smokers exhibited markedly depressed levels of circulating antibodies. The capacity of cigarette smoking to alter antibody production was also studied by evaluating the capacity of a fetus to stimulate lymphocytotoxic antibodies against HLA antigens in the mother 280 (Nyman 1974). Sera from a large number of pregnant women were tested for the presence of lymphocytotoxic antibodies against a 48- donor panel. The smokers exhibited a significantly lower incidence of these antibodies than did nonsmokers, and the divergence between groups increased with the number of deliveries. Infections during pregnancy were observed significantly more often in the smokers in this trial. In several animal models, acute exposure to whole cigarette smoke or components of cigarette smoke depressed the numbers of anti- body-forming cells in the spleen and the serum levels of antibodies in animals exposed to a variety of antigens (Miller and Zarkower 1974; Zarkower and Marges 1972; Zarkower et al. 1970). The depression was greatest when the antigen was administered by an aerosol (rather than by systemic inoculation), indicating that smoke appears to exert an effect close to the point of entry. Prolonged exposure ultimately resulted in severe depression both in local and in systemic antibody responses (Esber et al. 1973; Holt et al. 1976; Thomas et al. 1973, 1974a, 1974b, 1975). Although it is tempting to relate these abnormalities in immune response to the known association between cigarette smoking and increased incidence of upper respiratory infection, it is not clear whether the subtle defects in immune functions can entirely account for the infections present in cigarette smokers. Clearance of bacteria from the respiratory tract is a complex process that involves interplay between a variety of different mechanisms, only some of which include the function of alveolar macrophages and the capacity of the lung to mount cellular and humoral immune responses. 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Ato Gea% Pena Lavoe aX '~ , ” ~* as Sm fof) eer\aerodlope) adpeneion Gee ie ~ ‘ val —— . e = ; ve ee Gdn hat Fee Me Oa <> f of : ‘ iat et ee 1 ‘of w rile indutty ? i _ “4 ayy + ‘ 3 ay be S i ua % hal Wine 4 at J A , ay CSS ‘ ha ° ay ay 7. | c. ‘ ‘ » j 4 , iF t* s t “ 4 * | as » 9 = vif \ aes ' ¢ > 072 * i os 4 . 4 5° , “a ane 079 blero é' . j sie ‘ JECOLS ALOE: at |S , pute vv ar get sh =\ + ae ' sem ’ i) Lhe ge Oo a pool PVG cian ee Ney. ee pee pnisne i seat PLA, ealtiges EFFECTS OF CIGARETTE SMOKE ON AIRWAY MUCOCILIARY FUNCTION Introduction There is extensive literature on the effects of cigarette smoke on mucociliary clearance in the airways, with the majority of the reports appearing between 1965 and 1975. Different experimental approaches have been used, including in vivo measurement of mucociliary function in animal models and in human subjects. The results of some of these studies have been contradictory, presumably because of differences in experimental technique or the influence on mucociliary function of factors other than cigarette smoking. For example, tracheal mucociliary transport appears to decline with age in normal subjects (Goodman et al. 1978), an important phenomenon to consider when assessing the effects of long-term cigarette smok- ing. Another complicating factor is the clearly demonstrated impair- ment of mucociliary function produced by chronic bronchitis even in nonsmokers, such as in patients with cystic fibrosis (Wood et al. 1975) or immunoglobin deficiency (Mossberg et al. 1982). Therefore, it is difficult to separate the direct effects of cigarette smoke on mucociliary function from those of smoking-associated chronic bronchitis. Finally, in vitro bioassays for ciliotoxicity may not reliably reflect the effects of cigarette smoke on the mucociliary apparatus in the intact airways. Thus, Dalhamn et al. (1967) found that smoke produced by cigarettes containing a high concentration of hydrogen cyanide was more ciliotoxic in vitro than that produced by cigarettes containing a low concentration of hydrogen cyanide, and the two types of cigarettes caused a comparable reduction of mucus transport in vivo. This review is divided into three parts. The first part summarizes the normal structure and function of the mucociliary system in the airways. The second part deals with the direct effects of short-term and long-term cigarette smoke exposure on mucociliary function, and the third part discusses mucociliary function in chronic bronchi- tis. Normal Mucociliary Function The principal function of the airway mucociliary system is its contribution to host defenses. This is accomplished by physical removal of inhaled foreign material from the ciliated airways by mucous transport and by biochemical and immunological processes that protect against invasion of the mucosa by infectious agents. Normal mucociliary clearance depends upon an optimal interaction between cilia and mucus. 283 Cilia The respiratory mucosa from the proximal trachea to the terminal bronchioles consists of a pseudostratified epithelium with cilia protruding from the luminal surface of columnar cells (Figure 1). The larynx contains a mucus-secreting squamous epithelium over most of its surface, and cilia are present only in the posterior commissure (Wanner 1977). The major cell types in the respiratory mucosa are basal cells, intermediate cells, nonciliated columnar cells, ciliated columnar cells, and goblet cells. In the larger airways, the major part of the epithelial surface is ciliated. The ratio of ciliated columnar cells to goblet cells is approximately 5:1 in the trachea, with a relative decrease in the number of both cell types toward the peripheral airways. The surface of each ciliated columnar cell contains approximately 200 cilia with an average length of 6 um and diameter of 0.2 um. Both ciliated and nonciiiated columnar cells are characterized by microvilli on their luminal surface. These measure 0.3 ym in length and 0.1 pm in diameter. The ultrastruc- ture of cilia in lower animals and mammals is remarkably similar. Each cilium contains longitudinal microtubules that appear to represent contractile elements. Two single microtubules form a central core, and nine microtubules with a doublet structure are arranged in a circular fashion in the periphery of the cilium. A basal body in the apex of the cell corresponds to each cilium. Circular and radial bridges have been demonstrated between the peripheral microtubules and between the peripheral and central microtubules. These bridges (dynein arms, nexin links, radial spokes) appear to be crucial for ciliary bending. Mucus Respiratory secretions consist of mucus produced by submucosal glands and goblet cells and tissue fluid. The total volume of all mucus-producing structures has been estimated at approximately 4 ml iin human lungs; submucosal glands make up most of this volume (Wanner 1977). The submucosal glands are under parasympathetic nervous control, with an estimated daily volume of respiratory secretions between 10 and 100 ml. Human respiratory secretions contain approximately 95 percent water. The rest consists of micromolecules (electrolytes and amino acids) and macromolecules (lipids, carbohydrates, nucleic acid, mucins, immunoglobulins, en- zymes, and albumin). In situ, the respiratory secretions take the form of two layers, i.e., periciliary fluid (sol phase), and mucus (gel phase), as shown in Figure 1. Mucus has been clearly identified as the product of submucosal glands and goblet cells; the origin of the periciliary fluid has not been definitely established, although transepithelial water transport appears to be the most likely source. In central airways, the mucus layer is 5 to 10 um deep and may be ¢ 284 ponte FY —=- A, SES Le => FIGURE 1.—Schematic representation of normal mucosa (central airway) with the components of the mucociliary apparatus NOTE: From top (airway lumen) to bottom, note mucus layer, periciliary fluid layer, epithelium with a predominance of ciliated columnar cells and an interspersed goblet cell, basement membrane, and submucosal gland. SOURCE: Wanner (1979). discontinuous. In peripheral airways where submucosal glands are absent and goblet cells are rare, mucus is either absent or present only in small quantities. Regeneration of injured ciliated respiratory epithelium takes approximately 2 weeks in animals; the exact regeneration time of damaged human tracheobronchial ciliated epithelium is not known (Wanner 1977). It appears that regeneration does not begin until 2 to 3 days following mechanical injury. Mucociliary Interaction Mucociliary interaction depends on ciliary activity, the rheologic properties and depth of the mucus layer, and the depth of the periciliary fluid layer. The viscoelastic properties of mucus are determined by its biochemical characteristics (disulfide cross-linking and hydrogen bonding between glycoprotein molecules and water) (Wanner 1977). Cilia beat in one plane, with a fast effective stroke (power stroke) in the cephalad direction and a recovery stroke that is two to three times slower. Adenosine triphosphate has been identi- fied as the energy source for ciliary bending. In mammals, the average normal ciliary beat frequency is approximately 1,000 beats per minute, with coordinated motion in adjacent cilia on an individual cell and in cilia of adjacent cells. This interciliated 285 TABLE 2.—Measurement of airway mucociliary function in humans Method Reference Clearance of inhaled radioactive Morrow et al. (1967) aerosols from the lungs Transport of discrete markers Friedman et al. (1977) Sackner et al. (1973) Central airway clearance of inhaled Yeates et al. (1975) boli of radioactive microspheres pattern of motion by which adjacent cilia beat one after another to generate a wave of ciliary motion is called metachronism. The “normal” thickness of the periciliary fluid layer is less than, or at best equal to, the length of the ciliar shafts, which measure approximately 6 um in the central airways. The luminal surface of the mucus layer appears smooth, whereas the surface in contact with the cilia is irregular, and the mucus penetrates between the ciliary shafts. This penetration and the claw-like projections at the cilia tips may further facilitate the mechanical interaction between cilia and mucus. In the trachea, the “normal” surface mucus transport velocity is between 5 and 20 mm per minute depending upon the method of measurement. Mucous transport velocity decreases toward the peripheral airways. The three principal methods for the measurement of tracheobron- chial mucociliary function in humans are listed in Table 2. All of these have been used in studies of the effects of cigarette smoke on mucociliary function. Theoretically, mucociliary dysfunction can result from alterations in ciliary beat frequency and coordination, the quantity and visco- elastic properties of mucus, and the thickness of the periciliary fluid layer. In addition, focal destruction of the respiratory epithelium, producing areas without cilia or mucus, is also associated with impaired or absent mucociliary transport. Effects of Cigarette Smoke on Mucociliary Function The irritant effects of cigarette smoke on mucociliary clearance were recognized by Mendenhall and Shreeve (1937). They observed a decrease in the transport rate of carmine particles on the mucosa of excised cat tracheas after bringing them in contact with cigarette smoke, either directly or by dissolving it in the solution in which the tracheas were immersed (Mendenhall and Shreeve 1937, 1940). These early findings were confirmed by Hilding (1956) and Dalhamn 286 (1959) approximately 25 years ago. Since then, investigations to assess the effects of cigarette smoke on ciliary activity and mucocili- ary transport have proliferated. Because cigarette smoke can impair mucociliary transport by interfering with ciliary activity or mucus secretion, the studies relating to these two component functions are discussed separately and are complemented by a review of experi- ments involving mucociliary transport, the ultimate expression of mucociliary function. The effects of cigarette smoke on mucociliary function have been extensively studied in vitro, in intact animal models, and in human subjects. Comparison among the results of these experimental approaches is difficult, as there are major differences in inhalation patterns even between animal models and human subjects. Cigarette smoke is modified during its passage through the upper airways, and this may vary depending upon the mode of inhalation. By using smoke produced by radio-tracer spiked cigarettes, it has been shown that mice, who are obligatory nose breathers, retain 50 percent of the inhaled radioactivity in the nasal passages, 20 percent in the lungs, and the rest in the esophagus, stomach, and other organs (Page et al. 1973). Using artificial airways to bypass the nasopharynx in experimental animals eliminates the problem of nasal cigarette smoke absorption, but also prevents the oral modification of ciga- rette smoke that is a typical feature of human smoking. In subjects inhaling cigarette smoke from a smoke dosage apparatus that delivers standard puffs, 86 to 99 percent of most components of gas and particulate phases of cigarette smoke are retained, with the exception of carbon monoxide (CO), of which only 54 percent is retained (Dalhamn et al. 1968). Much of the smoke appears to be retained in the mouth. In human subjects who hold cigarette smoke in their mouth for 2 seconds, 60 percent of the water-soluble components of the gas phase, 20 percent of the water-insoluble components of the gas phase, and 16 percent of particulate matter are absorbed or retained in the upper airways (Frances et al. 1970; Stupfel et al. 1974). This marked modification of cigarette smoke might decrease its ciliotoxic effect in the lower airways. Passing unfiltered cigarette smoke through a chamber with wet surfaces before bringing it in contact with ciliated epithelium decreased the cilioinhibitory capacity of the cigarette smoke (Kaminski et al. 1968). When filtered cigarette smoke was used, the wet surfaces had no additional effect on ciliotoxicity, indicating that the mucosa of the upper airway may serve as a filter (Kaminski et al. 1969). Similar observations have been made when cigarette smoke was passed through a water trap (Albert et al. 1969). Because of the differences in inhalation pattern between humans and animals, it might be argued that nasal mucociliary function should be measured to assess the effects of inhaled cigarette smoke 287 TABLE 3.—Effects of cigarette smoke on airway mucociliary system Impaired mucociliary Exposure Ciliary dysfunction Mucus hypersecretion clearance Short term Yes 7 Fg Long term Yes Yes Yes in animal models. However, it has been clearly shown that nasal mucociliary transport is not a good marker of tracheobronchial mucociliary transport because of differential responses at the two sites. For example, exposure to the whole cigarette smoke of up to 30 cigarettes does not impair nasal mucociliary transport in donkeys (Frances et al. 1970), whereas the same number of cigarettes clearly alters tracheobronchial deposition and clearance of radioactive aerosols (Albert et al, 1969). Likewise, Hilding (1965) has concluded from his studies that the nose is not an acceptable organ for the study of the effects of cigarette smoke on mucociliary transport. Realizing the problems with experimental models of ciliary function in response to cigarette smoke inhalation, Dalhamn (1969) postulated that a proper experimental design should fulfill the following requirements: (1) the exposure pattern and level of cigarette smoke inhalation should simulate that of natural smoking in human subjects, (2) cigarette smoke should be delivered in air and not as an aqueous solution, (3) the components of inhaled cigarette smoke should be analyzed, and (4) exposure should be of long duration. Although these criteria are obviously not met by many of the studies quoted in this review, understanding these principles allows a more critical assessment of the reported results as shown in Table 3. Short-Term Exposure The effects of short-term cigarette smoke exposure on the mor- phology of the respiratory mucosa have not been investigated in man. Cigarette smoke residue has been shown to cause ciliary damage in cultured rabbit tracheal epithelium with a contact-time- dependent effect (Kennedy and Allen 1979). The most consistent abnormalities were cellular desquamation and alterations in mito- chrondria, cilia, and microvilli, some of which occurred as cant asl hour after exposure commenced. Cytotoxicity has also been observed after short-term exposure of ciliated epithelium to aqueous extracts of cigarette smoke conden- sate in vitro (Donnelly 1969), but it is difficult to extrapolate data from these in vitro studies to the in vivo conditions that occur during cigarette smoking. 288 Cilia With a few-exceptions, e.g., Proetz (1939), most investigators have demonstrated an irritant effect of smoke on ciliated epithelium, usually characterized by ciliostasis. Residues of cigarette smoke passed through an aqueous medium have been shown to produce ciliostasis in protozoa (Weiss and Weiss 1964; Wang 1963) and in fragments of human respiratory epithelium (Ballenger 1960). In fragments of rat trachea, brief exposure to whole cigarette smoke appears to elicit a biphasic response, with a short period of stimulation during 1 to 2 minutes followed by a marked decrease in ciliary beat frequency (Guillerm et al. 1961, 1972). In an excised rabbit trachea model, 71 1-ml puffs or 35 10-ml puffs of whole cigarette smoke were necessary to produce ciliostasis; similar relationships were demonstrated in the tracheas of living cats (Dalhamn 1970; Dalhamn et al. 1968). Several investigators have established a stimulus—response relationship between dilutions of aqueous cigarette smoke extract and the time of exposure required for total stoppage of ciliary beat frequency in different experimental models (Donnelly 1969, 1972; Das et al. 1970; Donnelly et al. 1981). The mechanism by which cigarette smoke acutely depresses ciliary function is not clearly known, but may involve enzyme inhibition of adenylate kinase, thereby reducing adenosine triphosphate (ATP), the energy source for ciliary bending (Mattenheimer and Mohr 1975; Schabort 1967). Ciliary function in response to short-term cigarette smoke inhalation has not been studied in man. Mucus Very little is known about the quantity and rheologic properties of airway secretions after short-term cigarette smoke exposure. A brief exposure of slugs to cigarette smoke has been reported to stimulate the production of mucus containing an increased number of acid glycoprotein fibers (Wilde 1981). The significance of this observation with respect to the human respiratory tract is not clear, except that an increased number of acid glycoprotein fibers has also been demonstrated in sputum obtained from cigarette smokers. Mucociliary Interaction Using a variety of different techniques in animal experiments, ciliary dysfunction and impairment of mucociliary transport by short-term exposure to cigarette smoke have been demonstrated in rats (Iravani 1972; Dalhamn 1964; Ferin et al. 1966), rabbits (Dalhamn 1964; Holma 1969), cats (Carson et al. 1966; Dalhamn 1964, 1969; Kaminski et al. 1968), dogs (Guillerm et al. 1972; Sakakura and Proctor 1972; Isawa et al. 1980), donkeys (Albert et al. 1974, 1969), chickens,-and sheep (Stupfel et al. 1974). A few reports 289 have not demonstrated that short-term exposure to smoke depresses mucociliary function in animal models (La Belle et al. 1966; Bair and Dilley 1967). The reasons for the discrepancy between these and the previously listed studies are not clear, but may be related to methodology and dose of exposure. Stimulus response curves be- tween dose of cigarette smoke and the degree of mucociliary inhibition have been shown in airways of chickens and dogs (Battista and Kensler 1970b; Sakakura and Proctor 1972; Isawa et al. 1980). In one study, for example, 9 puffs of nonfiltered cigarette smoke had variable effects on tracheal mucociliary transport in intact dogs, but tracheal mucociliary transport was consistently inhibited by 12 puffs (Sakakura and Proctor 1972). Likewise, the number of 4-second exposures to cigarette smoke (separated by 1 minute) required to reduce mucus transport in intact chicken tracheas by more than 90 percent has been shown to increase with increasing dilutions (from 50 to 3 percent) of smoke in air (Battista and Kensler 1970b). Measurements of mucociliary clearance in man immediately after smoking one or more cigarettes have shown conflicting results, with either increased (Albert et al. 1973; Camner et al. 1971; Albert et al. 1975; Camner and Philipson 1971, 1974), inconsistent, or unchanged rates (Yeates et al. 1975; Pavia et al. 1971; Goodman et al. 1978) or decreased (Nakhosteen et al. 1982) rates. Transient effects on mucociliary clearance have been reported in both smokers and nonsmokers (Hilding 1956; Pavia et al. 1971). Such differences between human subjects may reflect a difference in the dose and inhalation pattern of cigarette smoke. Long-Term Exposure In dogs inhaling cigarette smoke through a tracheostomy, histolog- ic changes have been observed in the bronchi after 229 to 421 days of exposure (Auerbach et al. 1967b). These changes consisted of epithelial hyperplasia, decreased number of ciliated cells, and areas of squamous metaplasia. This may be criticized as a poor model of cigarette smoking in humans because the upper airway, which absorbs part of the smoke and decreases its toxicity, is bypassed. The irritant effect of cigarette smoke on the tracheobronchial mucosa could be enhanced in this model. However, inflammatory changes in the airways have also been observed in animals that inhaled cigarette smoke via their upper airways (Leuchtenberger et al. 1958; Rylander 1974; Mattenheimer and Mohr 1975; Park et al. 1977; Basrur and Basrur 1976; Jones et al. 1973; Iravani 1973). Various types of lesions have been observed, including tracheal and bronchial epithelial hyperplasia (Park et al. 1977; Frasca et al. 1974), goblet cell proliferation and submucosal gland hypertrophy (Jones et al. 1973; Park et al. 1977), bronchiolar metaplasia of mucus-secreting cells (Basrur and Basrur 1976), increased quantities of airway mucus 290 that appear to be adherent to submucosal gland openings (Iravani 1973), and a decreased number of ciliated epithelial cells (Basrur and Harada 1979). One study suggested a dose-dependence of the mucosal lesions when comparing hamsters exposed to either four cigarettes per day or eight cigarettes per day for 2 weeks (Basrur and Basrur 1976). The pathologic changes produced by long-term cigarette smoke exposure appear to be reversible if the exposure time is not excessive. Thus, inflammatory changes in the airways of hamsters exposed to cigarette smoke for 4 weeks showed marked reversibility with a recovery time of several weeks (Basrur and Harada 1979). The histologic changes in the airways of cigarette smokers are similar to those produced by cigarette smoke in animal models, and consist of varying degrees of denudation of the ciliated epithelium, an increase in the number of goblet cells, submucosal gland hypertrophy, and squamous metaplasia (Regland et al. 1976; Jones 1981). Morphometric studies have demonstrated an increased quan- tity of mucus in the airway lumen without histologic evidence of coexistent emphysema or a history of obstructive lung disease, whereas this is not observed in the lungs of healthy nonsmokers (Niewoehner et al. 1974; Matsuba and Thurlbeck 1971). Electron microscopic examination of ciliated epithelium in surgical iung specimens obtained from cigarette smokers has revealed ciliary abnormalities consisting of compound cilia, single axoneme, intra- cyctoplasmic microtubular doublets, and cilia within periciliary sheaths (McDowell et al. 1976). If bronchial biopsy material is used to detect ciliary abnormality in cigarette smokers, the results must be interpreted with caution, for a single biopsy may be misleading owing to the focal nature of the lesions (Fox et al. 1981). The morphologic changes of the respiratory mucosa in animals exposed to cigarette smoke for prolonged periods and in human cigarette smokers strongly suggests the presence of mucociliary dysfunction. This has been clearly demonstrated, particularly with respect to the production and clearance of mucus. Cilia Ciliary function after long-term cigarette smoke exposure has not been extensively studied. Iravani and Melville (1974) demonstrated a decrease in ciliary beat frequency in the airways of hamsters exposed to cigarette smoke for 1 year; however, in rats also exposed for 1 year under almost identical conditions, ciliary frequency was generally increased, although there were zones of ciliary inactivity or discoordination. A sustained inhibition of adenylate kinase activity in ciliated tracheal cells of hamsters exposed to cigarette smoke for up to 9 months has also been reported (Mattenheimer and Mohr 1975). Because inhibition of this enzyme leads to a decreased generation of adenosine triphosphate, the energy source of ciliary 291 bending, a decreased ciliary activity might be expected (Mattenheim- er and Mohr 1975). Mucus Mucus hypersecretion has been clearly demonstrated in the airways of several animal species exposed to cigarette smoke for prolonged periods of time (Battista and Kensler 1970a; Iravani and Melville 1974). Rheologic measurements of airway mucus have not been reported in such animal experiments, but biochemical analysis has revealed the presence of serum proteins that might have cilioinhibitory effect (Dalhamn and Pira 1979; Battista 1980). Mucus hypersecretion may occur as early as 1 month after beginning a smoke inhalation equivalent to as little as one cigarette per day (Battista and Kensler 1970a). Rheologic and biochemical examina- tions of airway secretions in healthy smokers have not been carried out, primarily because these subjects do not have a productive cough. Once a smoker develops chronic productive cough, he or she is no longer considered healthy, but by definition, has chronic bronchitis. Mucociliary Interaction Long-term effects of cigarette smoke on airway mucociliary transport have been studied in different animal species. In purebred beagle dogs exposed to cigarette smoke (100 cigarettes per week) for 13.5 months via a mask that administered cigarette smoke through both the mouth and the nose for 1.5 hours twice daily, tracheal mucus transport rate was decreased to approximately 30 percent of that observed in control animals (Wanner et al. 1973). Pulmonary function did not differ significantly between the two groups. It has subsequently been shown that the abnormality in mucociliary transport in beagles may already be present after 6 months of cigarette smoke exposure (Park et al. 1977). An impairment of mucociliary clearance with long-term cigarette smoke exposure has also been demonstrated in rabbits, guinea pigs, rats, and chickens (Okajima 1971; Rylander 1971b; Iravani and Melville 1974; Battista and Kensler 1970a). In some of those experiments, impaired mucoci- liary clearance was already observed 4 weeks after the beginning of exposure. The long-term effects of cigarette smoking on mucociliary function in human subjects has been investigated by aerosol clearance techniques and discrete marker transport techniques. Some of the investigators using radioactive aerosols demonstrated no abnormali- ty of overall clearance in habitual cigarette smokers, particularly in those who already may have had symptoms of chronic bronchitis (Sanchiz et al. 1972; Yeates et al. 1975; Pavia et al. 1970; Pavia and Thomson 1970). However, the deposition of the inhaled radioactive 292 aerosol is more central in normal smokers and in patients with chronic bronchitis than in nonsmokers (Lippman et al. 1970). Because clearance is faster in central airways than in peripheral airways, this centralization of aerosol deposition may compensate for the overall decrease in mucociliary clearance. Investigations that have related mucociliary clearance to deposition pattern have generally found an impairment of mucociliary clearance in cigarette smokers (Lourenco et al. 1971; Camner et al. 1973a; Camner and Philipson 1972, 1974). Camner and Philipson (1972), in a study of 10 pairs of twins discordant for cigarette smoking, showed a significant- ly lower average clearance rate in smokers compared with nonsmok- ers; in 5 pairs clearance was slower in the smoker than in the nonsmoker, whereas in the remaining 5 pairs there was no differ- ence. Analysis of regional clearance has produced further evidence that overall clearance of inhaled radioactive aerosols may fail to detect an abnormality in mucociliary clearance. Thus, Bohning and co-workers (1975) studied the deposition and clearance of 7 um diameter particles in the tracheobronchial tree of six pairs of monozygotic twins, four of whom were discordant for cigarette smoking. They found comparable overall mucociliary clearance in the smoking and nonsmoking pairs, but more central deposition and slower central clearance in the smokers. Others have reported an impairment of peripheral mucociliary clearance and alveolar clear- ance as well (Matthys et al. 1983; Cohn et al. 1979). Discrete particle techniques involving either bronchoscopy or radiography have been used to assess mucus transport in central airways, notably the trachea. Most investigators have reported a decrease of tracheal mucus velocity in healthy smokers, with values ranging between 20 percent and 80 percent of those of nonsmoking controls (Goodman et al. 1978; Toomes et al. 1981; Nakhosteen et al. 1982). The bulk of the evidence indicates that long-term cigarette smoking alters mucociliary transport mechanisms and that these changes can occur as early as 1 year after smoking onset. Partial recovery of mucociliary transport has been observed in cigarette smokers after cessation for 3 months or more, but not after 1 week of cessation (Camner et al. 1973). These observations have also been supported by animal experiments (Albert et al. 1971). Fractionation and Filtering of Cigarette Smoke Whole cigarette smoke is composed of volatile elements and particulate matter, and it has become customary to distinguish between the gas phase and the particulate phase. The gas phase, by definition, consists of the components that remain after cigarette smoke has been “effectively” filtered by passing it through appropri- ate filters (Dalhamn 1966; Kensler and Battista 1963; Falk et al. 293 1959). The major constituents of the particulate phase are nicotine, phenols, hydrocarbons, aldehydes and ketones, organic acids, and alcohols. Although 95 percent of the gas phase (approximately 300 ml per cigarette) consists of combustion products and admixed air (nitrogen, oxygen, carbon dioxide, carbon monoxide) in concentra- tions that do not affect mucociliary transport, some trace gases are important (Battista et al. 1962). These include nitrogen dioxide, ammonia, cyanides, aldehydes, ketones, acrolein, and acids. As is shown below, some controversies still remain about whether the gas phase or the particulate phase of cigarette smoke is primarily responsible for its depressant effect on mucociliary activity. This problem is relevant when comparing the effects on mucociliary clearance of low tar versus high tar cigarettes, low nicotine versus high nicotine cigarettes, and filtered versus nonfiltered cigarettes. Dalhamn (1966) reviewed the controversy over the separate effects of the gas and the particulate phases of cigarette smoke on mucociliary function. In protozoa, both phases of cigarette smoke have been shown to possess ciliotoxic properties (Kennedy and Elliott 1970). Falk and associates (1959) reported that exposure to whole cigarette smoke for 30 seconds resulted in a biphasic response, with an initial stimulation, followed by depression with a minimum value at about 15 minutes and a tendency toward recovery 45 minutes after exposure. Removal of the particulate matter in cigarette smoke by passing it through filters decreased its depressant effect on mucus transport, indicating that the major effect on mucociliary clearance was related to the particulate phase. Similar observations have been made by others (Rylander 1970; Falk et al. 1959). In contrast, Kensler and Battista (1963) incriminated the gas phase of cigarette smoke; they exposed strips of rabbit trachea to smoke from different cigarettes for 12 seconds and identified various gas phase constituents as having a depressant effect on mucus transport. These findings have also been confirmed by others in in vitro and in in vivo animal experiments (Kensler and Battista 1963; Hee and Guillerm 1973; Dalhamn 1956; Albert et al. 1974; Carson et al. 1966). The most comprehensive study of individual gas and semivolatile constituents of cigarette smoke has been conducted by Petterson et al. (1982). Using chicken tracheal organ cultures, they showed that at a 5 mm concentration, 36 percent of 316 different compounds caused ciliostasis after 15 seconds of exposure, but 50 percent were without effect after an exposure time of 60 seconds. On the basis of this criterion of separation, either alkylated phenylethers, benzoni- triles, benzaldehydes, benzenes, napthalenes and indoles, or a-satu- rated, B-unsaturated ketones and aldehydes, or aliphatic alcohols, aldehydes, acids, and nitrates were found to be ciliotoxic. Inactive compounds included benzoic acids, esters, polyaromatic hydrocar- 294 bons, amines, and N-heterocycles (except indoles). With respect to aldehydes, the time to ciliostasis on tissues of rabbit trachea has been reported shortest for formaldehyde, followed by acetaldehyde, acrolein, crotonaldehyde, and methacrolein. The ciliotoxic effects of aldehydes have been confirmed by others using different experimen- tal approaches (Guillerm et al. 1968; Hee and Guillerm 1973; Kensler and Battista 1963). It has also been shown that acute acrolein inhalation causes denudation of ciliated cells, goblet cell discharge, exfoliation of surface epithelial cells, and infiltration of inflammatory cells in the lower airways of several different mam- mals (Dahlgren et al. 1972). Another volatile constituent of cigarette smoke with marked cilioinhibitory effects is hydrogen cyanide (Wynder et al. 1965a). Weissbecker et al. (1971) used a different approach to assess the effects of several volatile cigarette smoke constituents on mucocili- ary transport in the cat trachea. The addition of individual volatile cigarette smoke components (isoprene, nitric oxide, and nitrogen dioxide) to carbon-filtered cigarette smoke either aggravated the impairment of tracheal mucus velocity produced by the filtered smoke or abolished the protection afforded by the carbon filter. When these constituents were added to whole cigarette smoke, no further impairment of mucus transport velocity was observed, indicating a saturation by whole cigarette smoke of receptors responsible for mucociliary depression. A direct relation has been reported between tar content and the ciliotoxic effect of cigarette smoke (Dalhamn and Rylander 1967; Falk et al. 1959). However, Falk and associates (1959) found no difference between low tar and high tar cigarette residues with regard to in vitro mucociliary transport. The effects of nicotine on mucociliary transport are also controversial, although more investi- gators have demonstrated a lack of effect (Falk et al. 1959; Guillerm et al. 1972; Rakieten et al. 1952; Donnelly 1972) than a depression of mucociliary transport (Carson et al. 1966). Indeed, a biphasic dose- dependence has been suggested, with stimulation at lower concentra- tions and depression at higher concentrations (Tsuchiya and Kensler 1959). The stimulation of mucociliary function may be related to stimulation of nicotinic ganglionic receptors causing cholinergic ciliostimulation. This is based on the observation that the stimulat- ing effect of nicotine-containing cigarettes on the metachronal wave frequency in the maxillary sinus of anesthetized rabbits is blocked by atropine and hexamethonium (Hybbinette 1982). Among the different cigarette tobacco additives, menthol does not interfere with mucociliary transport (Rakieten et al. 1952). With respect to phenols, one investigator has reported that the ciliotoxici- ty of cigarette smoke produced by freeze-dried tobacco is the same as that produced by conventionally cured tobacco although the former 295 contains less phenol (Enzell et al. 1971). On the other hand, phenols have been shown to impair mucociliary activity and mucus transport both in vitro (Dalhamn and Lagerstedt 1966; Bernfeld et al. 1964; Dalhamn 1968) and in vivo (Dalhamn 1968). Dalhamn and associates (Dalhamn and Lagerstedt 1966; Dalhamn 1968) have even attempted to relate the toxicity of various phenols to their boiling points. Addition of the anti-inflammatory agents phenylvinyloxadiozole and phenylmethyloxadiozole to tobacco has been shown to reduce the ciliotoxicity of tobacco smoke (Dalhamn and Rylander 1971; Rylan- der 1971b; Dalhamn 1969), and treatment of rats undergoing long- term exposure to tobacco smoke with phenylmethyloxadiozole has been shown to protect the animals against the cigarette-smoke- induced increase in the number of goblet cells in the respiratory mucosa (Jones et al. 1973). It can be concluded from these studies that both the particulate phase and the gaseous phase of cigarette smoke impair mucociliary function, that a large number of volatile components are ciliotoxic, that nicotine may or may not contribute to ciliotoxicity, and that the additive phenol is ciliotoxic, but the anti-inflammatory agents phenylmethyloxadiozole and phenylvinyloxadiozole afford partial protection against the deleterious effects of cigarette smoke. The mechanisms by which the various constituents of cigarette smoke interfere with mucociliary transport are unknown. On the basis of experiments in the fresh water mussel, it has been suggested that ciliotoxicity depends on their pH in solution (Wynder et al. 1963). It should be noted, however, that such in vitro experiments requiring an aqueous medium do not necessarily reflect the type of exposure occurring in smokers in whom contact between cigarette smoke and the ciliated epithelium is made by impingement or bypass. Effects of Filters Because the toxic effect of cigarette smoke on mucociliary trans- port mechanisms seems to reside both in the gas phase and in the particulate phase, the filtering of cigarette smoke before inhalation may be protective. It has been clearly shown that a longer exposure time is needed for ciliostasis to occur with smoke from filtered cigarettes than from unfiltered cigarettes, with respect to both ciliary activity in vitro and mucociliary transport in vivo (Dalhamn and Rylander 1964; Dalhamn 1964). Four major types of filters have been evaluated: cellulose acetate (Cambridge filter), charcoal, glass fiber, and aqua. The histologic changes in the airways of guinea pigs exposed to unfiltered cigarette smoke for 4 to 8 weeks were not seen when cigarette smoke was passed through a Cambridge filter (Rylander 1974). Likewise, Kaminski and coworkers (1968) have shown that cellulose-acetate filters provide protection for the mucociliary activity in the cat 296 trachea. Similar results have been obtained in other experiments involving in vitro and in vivo systems (Dalhamn and Rylander 1968; Donnelly 1972; Wynder et al. 1965b), and cellulose-acetate filters have been found to reduce the inhibitory effect of cigarette smoke on tracheal epithelial adenylate kinase activity in hamsters exposed for 1 to 5 days (Mattenheimer and Mohr 1975). Charcoal filters are also capable of reducing the ciliotoxicity of cigarette smoke (Kaminski et al. 1968; Kensler and Battista 1963; Battista and Kensler 1970a, b). In one study involving cat tracheas, short-term exposure to a standardized dose of cigarette smoke decreased particle transport rates by 50 percent when unfiltered smoke was used, by 40 percent when the cigarette smoke was passed through a cellulose-acetate filter, and by 20 percent when a carbon-cellulose filter was used (Carson et al. 1966). In another comparison of different studies, a charcoal filter was more effective than a cellulose-acetate filter in reducing the metachronal wave frequency and mucus transport of the eulamellibranch gill in vitro (Wynder et al. 1965b). Glass-fiber and aqua filters were generally less effective (Isawa et al. 1980; Wynder et al. 1965b). As expected, better protection might be provided by combined filters because they remove components of the particulate and the gaseous phase of cigarette smoke more effectively. Thus, a combina- tion of cellulose-acetate and charcoal filter has been found to be more effective than either filter alone (Dalhamn 1966; Wynder et al. 1965b). Mucociliary Function in Chronic Bronchitis Since chronic bronchitis is defined clinically as chronic productive cough rather than by clearly defined morphologic or functional abnormalities (American Thoracic Society 1962), some of the previ- ously reviewed studies of mucociliary function in cigarette smokers may have included patients with chronic bronchitis as well. Con- versely, most patients with chronic bronchitis are cigarette smokers or have been cigarette smokers in the past. Although it is very difficult to separate the direct effects of cigarette smoke on mucocili- ary transport from those related to the pathophysiologic changes of chronic bronchitis, the discussion herein is limited to mucociliary function in chronic bronchitis without considering the direct effects of cigarette smoke on the mucosa. The histologic changes of the mucociliary apparatus in chronic bronchitis include hypertrophy and hyperplasia of the submucosal glands, an increase in the number and distribution of goblet cells, and goblet cell metaplasia in smaller airways (Reid 1967). In addition, atrophy of the columnar epithelium (Wright and Stuart 1965) and spotty squamous metaplasia (Kleinerman and Boren 1974) 297 480-144 0 - 85 - 11 have been reported. A decrease in both the number of ciliated cells and the mean ciliary length has been noted in the larger airways in patients with chronic bronchitis (Wanner 1977), and electron micro- scopic examinations of the airway epithelium show subtle abnormal- ities in bronchial biopsy material (Miskovitz et al. 1974). Auerbach and associates (1962), in a large post-mortem study of cigarette smokers, reported epithelial lesions with loss of cilia in up to 30 percent of random sections, compared with approximately 15 percent of sections from nonsmokers. These ultrastructural changes consisted of swelling and serration of the epithelium with transfor- mation of the goblet cell granules. The capsule surrounding the cilia was irregular, with areas of breakage and outward projections; some cilia showed fibrillar degeneration or were fused to form compound cilia. The presence of visible respiratory secretions is a frequent endoscopic finding in patients with chronic bronchitis, and increased amount of bronchial secretions can be seen on pathologic sections of the lung (Kleinerman and Boren 1974; Hogg et al. 1968). Thus, the morphologic changes of chronic bronchitis involve both the ciliary apparatus and the mucus-producing structures. Cilia In vitro examination of ciliated lower airway epithelial cells obtained from chronic bronchitis patients by brushing has failed to reveal an abnormality in beat frequency (Yager et al. 1980). However, in vitro study of ciliary function is of limited informative value since the ciliated cells are suspended in an artificial medium and are not exposed to their natural milieu. This may explain the discrepancy between this study and one reported by Iravani and Van As (1972), in which ciliary motion was observed in vivo with an incident light technique. In the carefully dissected tracheobronchial tree of rats with experimental chronic bronchitis, the ciliary system showed discoordination and zonal akinesia. In addition, reversals of transport direction, whirlpool formations, and inactive zones without ciliary motion as large as 2 mm by several hundred ym were seen. Mucus The distribution, amount, and rheologic properties of mucus within the airways have not been studied in chronic bronchitis, but extensive literature exists on the biochemistry (Boat and Mathews 1973) and rheology of expectorated sputum from patients with chronic bronchitis. These results must be interpreted with caution, partly because of contamination with saliva and the rapid physical alteration of expectorated sputum, and partly because normal respiratory secretions for comparison are virtually impossible to obtain. Mucoid sputum of patients with chronic bronchitis is 298 biochemically similar to sputum of normal subjects induced by hypertonic saline aerosol, with the exception of a slightly higher fucose and neuraminic acid content in the former (Lopata et al. 1974). In purulent sputum from these patients, biochemical changes typical of inflammatory conditions (increases in the dry weight and deoxyribonucleic acid content and increased cross-linking by hydro- gen bonding) were observed. Reid (1968) showed that the neuraminic acid content of sputum is increased in chronic bronchitis, suggesting augmented secretion by the mucus-producing structures. This find- ing is supported by histochemical studies indicating distended acini of the submucosal glands in patients with chronic bronchitis compared with normal subjects, along with an increase in the volume of both the acid and the neutral mucopolysaccharide-produc- ing acini (Reid 1968). Impaired mucus transport in chronic bronchitis may, in part, be related to the rheologic abnormalities of respiratory secretions. - Deviation from the ideal ratio between viscosity and elasticity may prevent an optimal interaction between cilia and mucus, thereby decreasing mucus transport rates (Dulfano and Adler 1975; Adler and Dulfano 1976). Higher values of sputum viscosity and lower values of sputum elasticity have been observed during exacerbations of chronic bronchitis than during clinical stability (Dulfano et al. 1971). In addition, purulent sputum has a higher viscosity than mucoid sputum (Charman and Reid 1972; Mitchell-Heggs et al. 1974), suggesting a relationship between the concentration of certain mucus constituents and mucus rheology. Indeed, examination of sputum obtained from patients with chronic bronchitis has shown positive correlations between protein content (particularly IgA) and mucus glycoprotein content on the one hand and viscosity on the other (Harbitz et al. 1980; Lopez-Vidriero and Reid 1978). That altered rheologic properties of airway secretions play a role in abnormal mucociliary clearance has been suggested by an observed relationship between in vivo mucociliary clearance, in vitro trans- portability of expectorated sputum (using the frog palate), and the viscoelastic properties of sputum (Puchelle et al. 1980). Mucociliary Interaction Mucus transport has been studied either by directly or indirectly observing the motion of discrete particles placed on the tracheal mucosa (Santa Cruz et al. 1974; Goodman et al. 1978) or by the deposition pattern and clearance rates of inhaled radioactive aero- sols (Lourenco 1970; Camner et al. 1973a, b; Luchsinger et al. 1968; Patrick and Stirling 1977; Dulfano et al. 1971). In one study, a marked slacking of tracheal mucus velocity was found in 15 patients with chronic bronchitis who were between 57 and 71 years of age (Santa Cruz et al. 1974). Clinical examination and pulmonary 299 TRACHEAL NUCOCILIARY TRANSPORT VELOCITY (mm - min=1) @ © FIGURE 2.—Comparison of mean (S.E. in bracket) tracheal mucociliary transport velocity among young nonsmokers (n=10), elderly nonsmokers (n=7), healthy young ex-smokers (n=9), healthy young smokers (n=15), and patients with chronic bronchitis (n=14) SOURCE: Goodman et al. (1978). function tests diagnosed these patients as having both chronic bronchitis and emphysema. Mucociliary clearance of inhaled aero- sols is also altered in patients with chronic bronchitis. The clearance of inhaled particles from the lung is influenced by the deposition pattern, which in turn depends on particle size and flow regime in the airways. Clearance rates, therefore, can be interpreted only if particle deposition is carefully monitored (Pircher et al. 1965; Lopez- Vidriero 1973). Coughing, which is difficult to control in such patients, may also contribute to the clearance of particles (Toigo et al. 1963). For these reasons, it is not surprising that mucociliary clearance has been reported to be increased (Muller et al. 1975; Luchsinger et al. 1968), normal (Thomson and Short 1969), or decreased (Lourenco 1970; Camner et al. 1973a, b; Tiogo et al. 1963; Mossberg and Camner 1980; Agnew et al. 1982) in patients with chronic bronchitis. Once a subject has developed chronic bronchitis, cessation of smoking does not reverse the effect on mucociliary function, and a similar impairment of mucociliary transport has been reported in smokers and ex-smokers with this disorder (Agnew et al. 1982; Santa Cruz et al. 1974; Goodman et al. 1978). Persistence of mucociliary 300 dysfunction in patients with chronic bronchitis after cessation of smoking has also been reported in a small prospective study (Camner et al. 1973b). Thus, both patients with chronic bronchitis and healthy smokers exhibit an impaired mucociliary function. However, the magnitude of the impairment is not the same as suggested by Goodman et al. (1978), who demonstrated a greater impairment of tracheal mucocili- ary transport rates in smokers and nonsmokers with chronic bronchitis than in healthy smokers (Figure 2). The consequences of airway mucociliary dysfunction have not been satisfactorily examined, but may include increased susceptibili- ty to respiratory infections, airflow obstruction by excessive airway secretions, and increased risk of carcinogenesis resulting from prolonged contact between inhaled carcinogens and the respiratory epithelium (Matthys et al. 1983; Hilding 1957; Moersch and McDon- ald 1953). Summary and Conclusions 1. Increased numbers of inflammatory cells are found in the lungs of cigarette smokers. These cells include macrophages and, probably, neutrophils, both of which can release elastase in the lung. 2.Human neutrophil elastase produces emphysema when in- stilled into animal lungs. 3. Alpha,-antiprotease inhibits the action of elastase, and a very small number of people with a homozygous deficiency of a,- antiprotease are at increased risk of developing emphysema. The a,-antiprotease activity has been shown to be reduced in the bronchoalveolar fluids obtained from cigarette smokers and from rats exposed to cigarette smoke. 4. The protease—antiprotease hypothesis suggests that emphyse- ma results when there is excess elastase activity as the result of increased concentrations of inflammatory cells in the lung and of decreased levels of a,-antiprotease secondary to oxida- tion by cigarette smoke. 5. Cigarette smokers have been shown to have a more rapid fall in antibody levels following immunization for influenza than nonsmokers. Whole cigarette smoke has been shown to depress the number of antibody-forming cells in the spleens of experi- mental animals. 6. Cigarette smoke produces structural and functional abnormali- ties in the airway mucociliary system. 7. Short-term exposure to cigarette smoke causes ciliostasis in vitro, but has inconsistent effects on mucociliary function in man. 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ZARKOWER, A., RHOADES, R.A., ROTHENBACHER, H.J. Effect of inhaled carbon on immune response in mice and rats. Proceedings of the Canadian Saciety of Biological Sciences 13: 641, 1970. ZWICKER, G.M., FILIPY, R.E., PARK, J.F.. LOSCUTOFF, S.M., RAGAN, H.A., STEVENS, D.L. Clinical and pathological effects of cigarette smoke exposure in beagle dogs. Archives of Pathology and Laboratory Medicine 102(12): 623-628, December 1978. 328 CHAPTER 6. LOW YIELD CIGARETTES AND THEIR ROLE IN CHRONIC OBSTRUCTIVE LUNG DISEASE 329 480-144 0 - 85 - 12 > ae ~ : ie - A) ta ay GTR. ON ey On ‘sage Aokdbey, Sine of ghee 2tetloup of Declegg =a —= ws : Pus tae? ow = ; VAMER, OS (22 eTS AD ad is “ite Nabiew Of ayes me ees! gare in Che bore 2 | a1: Aree ES a ot >) ee : LMEDELE er c ‘ ae > Yet ae S aa my @og? tye) a rae . im a 2% 7 nore je 7. ; 4) > a) ’ ‘> ® () a4 ba 4 . e > «t ~<— “> ds A cncratio YOY she ny ' : ro ‘ re, ' ~~, : “0 ae i) at \ ae ' ets ! vag ' : i, ‘ j P a baw z ’ it te | he ul ‘ oe ie .? é SU “9 ‘ ° a > m Ui. % ot es 7 “ , .) fei PRS ¥ ’ Hs ie Rinse . ; ; tie € weet y i ‘ ~ é > 4 . . Z ‘ , ri 2 APL ) % ' - . i ¥. « 2 i ty ar F = oS "7 ? ute xa a) ; : .. y@ t ster P sy } ) i sS s ad - ia ss wrt z << Q ; r i | » [- (eee 2.) eg t 7 > t! } . ’ ya t i © E , cx = iy, SMS — 4 7 { ¥ an nm, of = er at) re 4 4% CONTENTS Introduction Problems of Measurement by Machine Effect of Low Tar and Nicotine Cigarettes on Cough and Phlegm Production and Development of Chronic Obstructive Lung Disease Epidemiologic Studies Mechanisms of Lung Damage Variation in Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Smoking Behavior Carbon Monoxide Uptake Nicotine Uptake Role of Tar Content Variations in Pattern of Cigarette Smoke Inhalation Use of Additives in Low Tar and Nicotine Cigarettes Research Recommendations Summary and Conclusions References 331 ee ee ee ee ‘i 4” —_— - -<—~ an - a ee - Se = ce ne tae “5 i ») widen bar “at Wok ah Gee ag : suitor) va faeotered — at sh) iO drier qoaev “ti Boe nor u sensei] gels saihuse) ory of onemnet gud Yo sae ‘ota wT @ oe oe eS ee i iy ay cours ST Pary: surf Fo rordisS . a - « ~ = es bs - — — eee = a - ~~ Asge' - . na — mes ee apt — re ye need . ~ 4 ee 1 CU Lovee oe : ins 7 ‘6 a ~ -1~<“_5~ es - enoiey toa) i Introduction Following the initial reports in the early 1950s linking cigarette smoke with lung cancer, the pathogenic role of cigarette tar content received considerable emphasis. Because the tar fraction of the smoke contained the bulk of the carcinogenic effect of whole smoke, and because lung cancer risk was closely related to other measures of total smoke exposure (number of cigarettes smoked per day, depth of inhalation, etc.), it was suggested that risk might be related to the amount of tar generated by different cigarettes. This prompted health authorities to advise smokers who were unable to quite smoking to switch to low tar cigarettes (U.S. Senate 1967; Health Department of the United Kingdom 1976). To facilitate this process, the Federal Trade Commission published smoking-machine assays of the tar and nicotine yield of different cigarette brands (Pillsbury et al. 1969). This approach to low tar and nicotine cigarettes was based on the assumption that smoking lower yielding brands, as deter- mined by a smoking-machine, would result in a proportional reduction in the lung’s exposure to these toxic substances. This approach to “safer” cigarette smoking has been promoted by the tobacco industry and apparently accepted by the smoking public, as evidenced by the escalation in sales of low tar and nicotine cigarettes. However, there is increasing evidence that this concept of a “less hazardous” cigarette is misleading; although definitive studies are still awaited, it appears that switching from regular to low tar and nicotine cigarettes may not substantially reduce the risk of chronic airflow obstruction. Problems of Measurement by Machine The first step in evaluating the relative health risks of different cigarettes is to establish some standardized measure of the toxic substances in different cigarettes in order to facilitate comparison. Quantifying each of the several thousand constituents of cigarette smoke for each brand of cigarette, and assessing the changes in these constituents as the manufacturing and agricultural processes change, would be a truly herculean task; therefore, a more modest goal of quantifying tar and nicotine yields was accepted. To date, the yields determined by the Federal Trade Commission have been the most widely adopted. These measurements are obtained with a laboratory smoking-machine, which consists of a syringe pump that takes a 35 ml bell-shaped puff from a cigarette, over a 2-second period, once per minute until a predetermined butt length is reached, either 23 mm for nonfiltered cigarettes or 3 mm longer than the filter overwrap for filter-tipped cigarettes (Pillsbury et al. 1969). These parameters are based on observations of smoking patterns in seven subjects in Europe in 1933 (Kozlowski 1983). Today’s cigarette 333 is markedly different from that smoked in 1967 when these parameters were established, yet the same parameters are still employed. Measurements obtained using these parameters indicate a marked reduction in the tar and nicotine yield of cigarettes over the last decade (Figure 1). In addition to the actual tar and nicotine yield of the tobacco, the yield measured by a smoking-machine is influenced by many factors, including cigarette length and diameter, porosity of the cigarette paper, presence of a ventilated or an unventilated filter, butt length, number of puffs, interpuff interval, puff volume, puff duration, puff pressure profile, and frequency of puffing at different stages of cigarette consumption. The number of puffs is important in determining the tar yield of a cigarette, and the number of puffs taken from some brands with the official smoking- machine has significantly declined in recent years (Kozlowski 1981). Since puffs are taken at 1-minute intervals, a more rapidly burning cigarette will have a smaller number of puffs. The burning time of the cigarette is determined by porosity of the cigarette paper, the amount of tobacco in the cigarette, and the diameter of the cigarette column. In a survey of Canadian cigarettes between 1969 and 1974, Kozlowski et al. (1980b) noted a significant reduction in the number of puffs taken in the official assays over this time period, which was strongly correlated with a reduction in tar yield. Omission of the last few puffs can markedly affect tar yield, because tar delivery increases with each puff, and the last few puffs from a cigarette can contain twice as much tar as the first few puffs (Wiley and Wickham 1974). Currently published yields do not indicate the number of puffs taken, which may range from 7 to 12 and may result in a marked variation of the tar yield. Ventilated cigarette filters, which cause inhaled smoke to be diluted with air, are one of the major methods of achieving low tar yields (Gori and Lynch 1978). Cigarettes with ventilated filters constituted about 25 percent of all cigarette sales in the United States in 1979 (Hoffmann et al. 1980). During systematic interviews, Kozlowski et al. (1980a) found that from 32 to 69 percent of low tar smokers block these filter perforations with their fingers or lips, a feature unaccounted for by smoking-machines. This hole blocking increased the yield of toxic products by 59 to 293 percent. If a person smokes a cigarette in a manner identical to the smoking-machine, the delivery of tar and nicotine to the mouth will be the same as that estimated by the machine. Human smoking patterns are diverse, however, and show considerable variation from the machine parameters; puff volumes range from less than 20 ml to more than 90 ml (Tobin and Sackner 1982), compared with the fixed 35 ml volume employed by the machine. Differences in puff profile from the bell-shaped puff used by the machine also alter cigarette 334 Tar mg Nicotine mg 4.0 35.0 3.5 30.0 3.0 25.0 2.5 20.0 2.0 1950 1955 1960 1965 1970 1975 1980 15.0 5.0 O'S ae nom | IN ats ma hme: eed eee 0.0 FIGURE 1.—U.S. sales-weighted average tar and nicotine yields SOURCE: American Cancer Society (1981). yield. Numerous studies indicate that smokers compensate for lower yielding cigarettes by altering their style of smoking. For each different cigarette brand, smokers may have a different smoking pattern. To provide more meaningful information, smoking-ma- chines should be designed to reproduce variations in the manner of smoking each cigarette brand, and their assays should provide both an average and a range of tar and nicotine yields depending on the individual pattern of smoking (USDHHS 1981). Many investigators have examined the relationship between the machine-determined nicotine yield of a cigarette and the concentra- tion of nicotine or its metabolites in blood or urine. A fair correlation was observed in some studies (Goldfarb et al. 1976; Herning et al. 1983), but most studies have revealed a poor correlation (Russell et al. 1975, 1980; Sutton 1982; Feyerabend 1982; Benowitz et al. 1983). Machine-determined nicotine yield accounts for only from 4 (Russell et al. 1980) to 25 percent (Herning et al. 1983) of the variation in blood nicotine concentration, whereas 50 to 60 percent of the differences in blood nicotine levels are attributable to individual 335 smoking behavior. The overriding importance of the pattern of smoking in determining nicotine delivery from a cigarette was underlined in a recent study demonstrating that the nicotine content of the unburned tobacco was similar for cigarettes with high and low nicotine yields determined by smoking-machine assays (Benowitz et al. 1983). The concept of providing the smoker with information on cigarette yield need not be abandoned. Smoking-machines can be designed to control the puff number, puff volume, puff pressure profile, puff duration, puff interval, butt length, position of the cigarette during and between puffs, and “restricted” or “free” smoking, i.e., whether the butt end is closed or open (Creighton and Lewis (1978a, b). These parameters should be determined and used to obtain an average and a range of yields for each brand. Measurement of cigarette yield should include assays not only of tar and nicotine but also of carbon monoxide and other toxic substances, because compensatory smok- ing behavior may alter the exposure to each substance beyond that expected on the basis of tar and nicotine delivery. Effect of Low Tar and Nicotine Cigarettes on Cough and Phiegm Production and Development of Chronic Obstructive Lung Disease Cigarette smokers account for the vast majority of deaths from chronic obstructive lung disease (COLD) (Peto et al. 1983), and the relative risk for the effects of smoking on mortality from COLD is even greater than that for lung cancer (see the chapter on Mortality in this Report). Chronic obstructive lung disease in smokers may take the following three forms: (1) cough and mucus hypersecretion, (2) airway obstruction, and (3) emphysema. Frequently the three components coexist, as all are related to cigarette smoking, but the agents in cigarette smoke responsible for each type of lung injury may be different. Over the past 25 years, considerable progress has been made in our understanding of the role of cigarette smoking in the pathogenesis and natural history of COLD, but most of the available data have not related lung function to cigarette yield. Epidemiologic Studies The cardinal importance of cigarette smoking in the pathogenesis of COLD has been repeatedly documented, and generally the severity of disease increases with increasing cigarette consumption (Ferris et al. 1976). Because of this dose-response relationship, it has been hoped that a reduction in cigarette yield by filtration or other means would reduce the risk of disease (Gori 1976). Available epidemiologic studies of the effect of low yield cigarettes on the development of COLD have shown variable results, which reflects 336 marked differences between the studies in terms of the population studied, sample size, variation in cigarette brands, reference period of the study, criteria of respiratory involvement, and type of statistical analysis, and whether the study was of a cross-sectional or a longitudinal design. Separating the studies by the three compo- nents of smoking-induced COLD indicates that there is a growing body of data on the effect of cigarette yield on the development of mucus hypersecretion and airway obstruction, but currently no information on the development of emphysema. Several studies have examined the effect of cigarette yield on respiratory symptoms and have observed a relationship between reduction in cigarette yield and the prevalence of cough (Comstock et al. 1970; Freedman and Fletcher 1976; Fletcher et al. 1976; Dean et al. 1978; Schenker et al. 1982) and phlegm production (Comstock et al. 1970; Rimington 1972; Hawthorne and Fry 1978; Higenbottam et al. 1980b). Tar yield was not defined in some of these earlier studies ‘(Comstock et al. 1970; Rimington 1972; Dean et al. 1978; Hawthorne and Fry 1978), but instead a comparison was made between smokers of plain cigarettes and smokers of filter-tipped cigarettes. The tar yield was specified in some studies: in the recent study by Schenker et al. (1982) it ranged from 0.4 to 28 mg; in the studies by Freedman and Fletcher (1976), from 17 to 20 mg; and in the studies by Higenbottam et al. (1980b), from 18 to more than 33 mg, higher than that observed in many of today’s cigarettes. In a cross-sectional survey of over 18,000 men (Higenbottam et al. 1980b), the beneficial effect of low tar cigarettes on phlegm production was lost when subjects smoked 20 or more cigarettes per day, as their prevalence of phlegm production increased to that observed in higher tar cigarette smokers. In contrast, in another cross-sectional study of 5,686 women (Schenker et al. 1982), cigarette tar content was a significant risk factor for chronic cough and of borderline significance for phlegm production; this effect of cigarette tar content was indepen- dent of the number of cigarettes smoked per day. Chronic cough or phlegm production was approximately twice as common in smokers of high tar (at least 20 mg) cigarettes as it was in low tar (less than 10 mg) smokers. In the latter study, however, multiple logistic regres- sion analysis indicated that the risk of chronic cough and phlegm production is more strongly affected by daily cigarette consumption than by tar content; these symptoms were 4.5 times more common in smokers of 25 or more cigarettes per day than in smokers of less than 15 cigarettes per day. A small number of studies have examined the importance of cigarette yield on change in pulmonary function. In a prospective study of 680 men, Comstock et al. (1970) noted that smokers of plain cigarettes, compared with smokers of filter-tipped cigarettes, had a lower FEV: at entry into the study. Followup measurements showed 337 3.5 Soanrs Sinn tions bea: Cigarettes 30 —__ > smoked per day ee FEV, (1) 74's 2.0 18-23 24-27 28-32 >33 Tar per cigarette (mg) FIGURE 2.—Relationship between mean FEV: of asymptomatic smokers (adjusted for height and weight) and tar yield of cigarettes, by number of cigarettes smoked per day SOURCE: Higenbottam et al. (1980b). a greater mean reduction of FEV: in users of filter-tips, so that the reduction was similar in the two groups after 5 to 6 years of followup. Unfortunately, the variance of the data was not stated, and tests of statistical significance were not performed. In another longitudinal survey of 1,355 men, Sparrow et al. (1983) determined the effect of cigarette tar content, which ranged from less than 16 mg to more than 22 mg, on pulmonary function. Multiple regression analysis indicated that tar content did not significantly influence baseline spirometry or repeat measurements after 5 years of followup. Cross- sectional epidemiologic surveys also indicate no relationship be- tween abnormal pulmonary function and the use of filter-tipped versus plain cigarettes (Beck et al. 1981) or cigarette tar content (Higenbottam et al. 1980b) (Figure 2). Interpretation of these studies as evidence that cigarette tar and nicotine yield is not an important factor in the development of COLD is premature. First, cross-sectional studies are limited in their capability of defining the natural history of a disease. Second, COLD has a very slow progress, and Fletcher et al. (1976) suggest that a span of approximately 8 years is necessary to establish rates of change of spirometric values with sufficient confidence even to distinguish between smokers and nonsmokers. Third, we have no information on the baseline pulmonary function of smokers at the time they choose between high or low tar and nicotine cigarettes. Significant differences in pulmonary function have been observed between young adults who decide to smoke and those who avoid cigarette smoking (Tashkin et al. 1983), and it is possible that similar 338 function differences may exist in subjects who choose between high or low tar and nicotine cigarettes. Fourth, the yield of tar and nicotine used in many of these studies does not lie in the same range as that produced by many of today’s cigarettes. However, the possibility that cigarette tar content is related to the development of cough and phlegm, but not of dyspnea or airflow obstruction, is consistent with current concepts of COLD. In a study of 792 men followed over an 8-year period, Fletcher et al. (1976) observed that cigarette smokers were susceptible to two distinct chronic lung diseases—mucus hypersecretion and chronic airflow obstruction. This has recently been confirmed in a large prospective study (Peto et al. 1983) of 2,728 men, followed over 20 to 25 years, which showed that the risk of death from COLD was strongly correlated with initial degree of airflow obstruction, but bore no relationship to initial mucus hypersecretion. Given the evidence that mucus hypersecretion may depend on the tar fraction of cigarette smoke, while development of airflow obstruction is more closely linked to the number of cigarettes smoked, Higenbottam et al. (1980b) reasoned that these differences might be due to a reduction in the particulate phase products, without a decrease in the gas phase products, in the low tar cigarettes. They hypothesized that tar droplets and soluble gases, such as sulfur dioxide and hydrogen cyanide, are more likely to be deposited or absorbed in the large airways where mucus is produced. The smaller airways, the earliest site of airflow obstruction, are exposed to a lower concentration of tar, but to a full concentration of insoluble gases such as nitrogen dioxide and ozone. This line of reasoning is in agreement with several studies showing a reduction in lung cancer with the use of low tar and nicotine cigarettes (Wynder et al. 1970; Lee and Garfinkel 1981; Rimington 1981; Hammond et al. 1976). The tar fraction is the component of cigarette smoke particularly linked with the development of both lung cancer and mucus hypersecretion. Although clinicians have long linked chronic bronchitis (mucus hypersecretion) with emphyse- ma, recent evidence indicates that mucus hypersecretion is not predictive of airflow obstruction, but is significantly greater in those smokers who develop lung cancer (Peto et al. 1983). Mechanisms of Lung Damage Studies of the mechanism of cigarette-smoke-induced lung damage have contributed significantly to the present understanding of COLD. Cigarette smoke may initiate and aggravate lung injury by a number of mechanisms and may also interfere with the lungs’ defense responses. These mechanisms include the protease-inhibitor imbalance theo- ry for the pathogenesis of emphysema whereby alveolar wall 339 digestion results from an excess of proteases, a deficiency of their inhibitors, or a combination of both factors (see the chapter on Mechanisms in this Report). The sources of endogenous proteases include polymorphonuclear neutrophils and alveolar macrophages, both of which are found in increased number in the lungs of cigarette smokers. Protease release from both macrophages and neutrophils is increased in the presence of cigarette smoke (Rodriquez et al. 1977; Blue and Janoff 1978). In health, proteases are continually inhibited by ai-antitrypsin, whereas proteases cause unimpeded digestion of lung tissue in patients with aui-antitrypsin deficiency, with a markedly increased risk of emphysema. In addition to increasing the protease burden, cigarette smoke causes a functional inhibition of a1- antitrypsin through the action of oxidants in cigarette smoke (Janoff et al. 1979). The relative potency of smoke from cigarettes of varying tar and nicotine yields in stimulating protease production and release and in inhibiting o1-antitrypsin has received scant scientific investigation. Travis et al. (1980) tested the effect of both filtered and unfiltered cigarette smoke on the elastase inhibitory activity of ai-antitrypsin. Filtered smoke reduced elastase inhibitory activity by 3 percent, and a 19 percent reduction was observed with unfiltered smoke; the tar content of the respective smokes was not stated. The researchers reasoned that this small in vitro effect would be greatly magnified by in vivo conditions in the lung, particularly through its huge surface area. In addition to examining the effect of filters, Cohen and James (1982) recently examined the effect of tar and nicotine content on the elastase inhibitory capacity of a1-antitrypsin. The oxidant capacity of cigarette smoke was also examined using a chromogenic electron donor. Aqueous condensates of cigarette smoke were obtained from a variety of brands ranging in tar content from about 1 mg to more than 20 mg. Reported tar and nicotine content correlated well with the amount of measured oxidants and the ability of a brand to reduce the elastase inhibitory capacity of ai-antitrypsin. Filters were found to remove 73 percent of the oxidants from the aqueous smoke solutions. While these findings suggest that low tar and nicotine or filter-tipped cigarettes could reduce a smoker’s predisposition to enzymatic lung damage and consequent COLD, it should be noted that neither study examined the effect of lower yield cigarettes on protease production. Morosco and Gueringer (1979) demonstrated a greater increase in elastase in dogs exposed to high nicotine cigarette smoke compared with low nicotine cigarette smoke. More important, these studies have not taken into account the compensatory changes in smoking pattern likely to result with lower yield cigarettes. The airway response to acute exposure to cigarette smoke has been examined by several investigators employing spirometry (Da Silva and Hamosh 1981), body plethysmograph (Nadel and Comroe 1961), 340 and breathing pattern analysis (Tobin et al. 1982a). Airway narrow- ing has been consistently observed by some investigators (Nadel and Comroe 1961; Sterling 1967; Tobin et al. 1982a), but others report a variable response (Higenbottam et al. 1980a; Rees et al. 1982). In some studies, the acute airway response was unrelated to cigarette yield (Higenbottam et al. 1980a), but in most investigations (Robert- son et al. 1969; Tobin et al. 1982a; Rees et al. 1982), smoking a low tar or filter-tipped cigarette induced less acute bronchoconstriction. The acute airway response is probably localized to the larger airways, as acute cigarette exposure resulted in no change in the nitrogen washout test of small airway function (Da Silva and Hamosh 1973; Tobin et al. 1982a). These observations on the relative bronchocon- strictor response of various types of cigarettes may be important in our understanding of why some smoking novitiates persist with the habit despite the initial unpleasant reactions (Tashkin et al. 1983), but it is unlikely that repeated episodes of smoking-induced acute airway narrowing finally result in COLD. Future studies examining the mechanism of smoking-induced lung injury must not only take into account the range of cigarette yields, as determined by a smoking-machine, but also consider variations in smoking behavior. Puff volumes may vary considerably with nomin- al cigarette tar and nicotine content, thus altering the relative amount of various toxic substances yielded by different cigarettes. Similarly, inhalation profiles are of a diverse nature (Tobin et al. 1982b) and are likely to significantly alter the distribution, penetra- tion, and retention of cigarette smoke constituents in the lungs. Variation in Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Low tar and nicotine cigarettes have gained considerable populari- ty among the smoking public, partly on the premise that a reduction in the nominal tar and nicotine yield results in a proportional reduction in the health hazards of cigarette smoking. The validity of this approach to cigarette smoking is contingent on the accuracy of smoking-machines in reflecting the actual manner of puffing and also on the smoker not altering smoking behavior to compensate for variations in nominal tar and nicotine content. Should smokers develop compensatory alterations in their smoking behavior, this would not only reduce the relevance of the smoking-machine assays but might also alter the proportionate delivery of the different toxic substances in cigarette smoke and expose the smoker to concentra- tions beyond those predicted by the smoking-machine. 341 Smoking Behavior Nearly 40 years ago, Finnegan et al. (1945) studied the effect of alterations in cigarette nicotine content on smoking behavior and noted no change in cigarette consumption. It is only in the last decade, with the increasing popularity of low tar and nicotine cigarettes, however, that this question has attracted significant interest. The results of 38 studies examining alterations in smoking behavior with a reduction in cigarette yield are shown in Table 1. Considerable differences can be observed between the studies, partly reflecting variations in the level of cigarette yield reduction, alterations in other cigarette constituents, type and duration of switching procedure, parameters evaluated, and techniques used in their measurement. Most studies agree that smokers rarely increase their daily cigarette consumption upon switching from higher to lower yield brands. Reports are almost equally divided as to whether a smoker increases the number of puffs per cigarette or shows no change on switching to a lower yielding brand. There is an almost unanimous consensus that smokers take a larger puff volume from a lower yielding brand. Studies of puff volume also indicate huge variation between individual subjects (Guillerm and Radziszewski 1978; Hern- ing et al. 1981; Tobin and Sackner 1982; Herning et al. 1983) and that considerable increases in puff volume may occur on switching from a higher to a lower yielding brand, with certain subjects increasing their puff volume by up to 75 percent (Tobin and Sackner 1982). This compensatory increase in puff volume may be observed within a single experimental session (Tobin and Sackner 1982) and maintained over several weeks (Rawbone et al. 1978; Stepney 1981). Full compensation for a lower yielding cigarette is generally not achieved by smokers taking a large puff volume (Rawbone et al. 1978; Herning et al. 1981; Tobin and Sackner 1982). Instrumentation is required to quantitatively assess the pattern of smoking, but it is important to realize that such instrumentation may, in itself, alter usual smoking behavior. Puff volume has been almost universally measured by using a specialized cigarette holder incorporating different flowmeter designs (Frith 1971; Adams 1977; Rawbone et al. 1978). These devices consist of two tubes connected to a pressure transducer that measures the pressure drop across a small resistance (a filter insert) in the holder; the flow measured is integrated to obtain volume. Use of a cigarette holder has been shown to increase the rate of puffing and puff volume, compared with measurements made with the cheek inductive plethysmogra- phy coil (Tobin and Sackner 1982). Unlike the compensatory increases in puff volume, measurements of the subsequent inhalation volume—which includes the volume of smoke mixed with air inhaled into the lung—have shown no change 342 SAS O86T PIEM ON | | ON AOA O86T pleysuruuey 100g ON SAS 0861 [lessny poor) t SAS 0861 uosuIqgoy poor t 100g ON so 0861 tH ON SAS 6L61 jayuyser 100g t t 100g t ON So 6L61 uojyysy | | So 8L6I ylaser 100g | ON ON | SO 8L6I wa]]Iny | | SO SL6I swepy | Ss q'eg 61 wozYysI91) { ON So 8L61 Z[NYIS 100g f ON | ON So 8L61 auoqmey eg t 100q t ON AOA 8L6I u033Ng | SAS LL6I PIEM ON ON ON So LL6I suepy poor) t so 9L6I S$aqloy poor) t | So 9L6I qiejpor) 00g ON/ Tt | so GL6I Tlessny 100g ON/ 1 SO PL6I JauIN], poor I | SO €L6I [lessny 100g ON SO IL61 uayo) | So IL6I yw 100g | | AOA OL6I uojysy ON So CPr6I uesouuly pletA [eulIouU xepul (BAI[eS/auLIN/poolq) pyatd [eulmou QO qHOO uorlyefeyUI uUoTyefeyUI suUIN[OA 310/sjjnd peyours usisep Ieak JoyyNe 4SIIy 0} einsodxe [ee] 0} peitdxq jo jo jyng jo S310 jo [eyueulliedxy aoudlajoy diysuonjejey YyNo-, esUIUT}OO/aUTIOOIN diysuoeley uorzeing ouIN[oOA JequinN Jequinny Sloyoureied BUTJOOIN sisjeweied OO ui9}jed SUTYOUIS UO $9}}01BSID P[eIA MOT SUTHOUIS JO 499jJq—1 AIAVL 343 ea atid OR a": > Aa as ‘eprxououl UOgIBs = QO ‘eseeldep = f ‘aseaiour = | ‘aZueyo ou = ON ‘8uTyozIms ArejunToA snosuejzuods = SAS ‘s19}[IJ a}3018B1I0 a[quLIBA = YODA ‘ZUTYo}LMS peT[o1jzuOD = GD “ALLON SAS €s6T Z}LMOUS qe] SO €86T Suruiey 100g SAS Z86T pueqeiekey 100g ON 4 /ON SO 2861 ayer | ON so TS61 SsuD 100g poor | SAS 2861 u043ng ON | ON SAS 2861 aye ON ON | ON SO 2861 UIgoL 100g ON 4 /ON SAS I86T ayer t t qe t | | ON SO T86T faudayg 100d | ON SAS T861 PIEM / | ON so 1861 sure] Plath [eulIou xXepul (BAI[BS/AULIN/poojq) pyatk jeulmou Oo qHOD uoljefeyuI uOTyeTeyUT eUNjOA 310/syjnd peyouls udIsep reef . JoyyNeE 4SILy 04 einsodxa [ee] 0} poidxq jo jo yng jo s310 Jo [eyueUllIedxq s0Uualejoyy diysuoneey YyyNoW eUTUTIOO/eUTIOOINY drysuorjeay u0ljze1ng ouINjoA JaqunyN Jequiny slsjoureied sUTIOOIN slojoureied OO 344 penurnuoj—T WIaViL on switching to a low yield cigarette. Likewise, in one short-term study (Tobin and Sackner 1982), duration of inhalation showed no relationship to nominal cigarette yield. Perhaps compensatory changes in inhalation parameters require a longer period of time than puff volume does. Measurement of carboxyhemoglobin (COHb) concentration has been proposed as an index of the pattern of inhalation (Wald et al. 1975, 1978). While COHb provides valuable information on the amount of carbon monoxide absorbed from the lung during compen- satory alterations in smoking behavior, it is an indirect index and provides complementary information on cigarette smoke inhalation rather than replacing direct measurements of the volume of inhalation. Carbon Monoxide Uptake Unlike tar and nicotine, which are present in the particulate phase, carbon monoxide (CO) is a constituent of the vapor phase of cigarette smoke. For this reason, cigarettes purported to produce a low tar and nicotine yield may not necessarily provide a lower yield of carbon monoxide. Compared with tar and nicotine yield, carbon monoxide yield is more dependent on cigarette design, including such features as paper porosity and perforations in the filter tips. These factors regulate the dilution of smoke with air and the burning profile of the cigarette, and thus can significantly reduce carbon monoxide yield. Wald (1976) showed that the carbon monox- ide yield of filter-tipped cigarettes was 28 percent higher than that of plain cigarettes, although the average nicotine yield was lower in the filter-tipped cigarettes. He reasoned that smoke passing through a cigarette is diluted by air entering through the porous cigarette paper. However, the filter of filter-tipped cigarettes is surrounded by relatively nonporous paper, resulting in a higher content of carbon monoxide exiting from the proximal cigarette end. Perforations in the filter tip circumvent this problem and significantly reduce carbon monoxide yield (Hoffmann et al. 1980; Wald and Smith 1973). Many investigators have measured COHb or carbon monoxide concentration in expired gas following cigarette smoking and compared the levels achieved in smoking brands with different nominal yields (see Table 1). An increase, decrease, or no change in carbon monoxide intake has been observed, depending on relative differences in cigarette design and experimental procedure. As expected, unventilated filter-tipped cigarettes produced higher COHb levels than those observed with unfiltered cigarettes (Wald et al. 1977). This is in agreement with information provided by smoking-machine assays (Wald et al. 1973), but the use of ventilated filter-tipped cigarettes may produce COHb levels similar to those observed with unfiltered cigarettes despite lower carbon monoxide 345 yields on smoking-machine assay (Wald et al. 1977). Comparison of cigarettes with a marked difference in nominal carbon monoxide yield usually results in a lower COHb level when the lower yielding brand is being smoked (Russell et al. 1973; Turner et al. 1974; Sutton et al. 1978; Ashton et al. 1979); but over the range of different carbon monoxide yields there is a poor correlation between levels of COHb and measured carbon monoxide yield. Similar information has been observed using expired carbon monoxide concentrations. Nicotine Uptake It has been long considered that nicotine might serve as a primary reinforcer of cigarette smoking and that smokers might adjust their smoking behavior to regulate their level of nicotine intake. Several investigators have measured the blood, urinary, or salivary levels of nicotine or its major metabolite cotinine during the smoking of cigarettes of varying nominal nicotine yields (see Table 1). A reduction in blood (Russell et al. 1975; Sutton et al. 1978; Ashton et al. 1979; Hill and Marquardt 1980) and urinary (Goldfarb et al. 1976; Ashton et al. 1979; Stepney 1981) nicotine levels or in plasma (Hill and Marquardt 1980; Stepney et al. 1981) and urinary (Ashton et al. 1979; Hill and Marquardt 1980) cotinine levels has generally been observed on switching to a cigarette with a lower nominal nicotine yield. However, smokers show variable degrees of compensation for the lower yield, as there is generally a poor relationship between nominal nicotine yield and measured blood nicotine levels (Russell et al. 1980; Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. 1983). Relating nominal nicotine yield and blood nicotine levels, Ashton et al. (1979) estimated that smokers compensated for about two- thirds of the difference in nominal yields when they switched from medium nicotine cigarettes to high or low nicotine brands. Using a stepwise multiple regression analysis of nicotine yield and blood nicotine concentration, Russell et al. (1980) observed a significant, but very weak, correlation (r=0.21) between the two measurements, but the nominal nicotine yield of the cigarettes accounted for only 4.4 percent of the variability in blood nicotine concentrations. The use of absolute rather than logarithmic analysis in this study has been criticized (Kozlowski et al. 1982; Herning et al. 1983), and the criticism involved the problems of trying to predict doses to individuals rather than the dose to groups. In another study using log-linear regression analysis (Herning et al. 1983), a better correla- tion was observed between nominal nicotine yield and the increasing blood nicotine after smoking (r=0.5), but this study used Kentucky reference cigarettes rather than commercial brands, and these low yield cigarettes have less nicotine in the unburned tobacco than commercial low yield brands. Such a relationship still accounted for 346 only 25 percent of the individual differences in blood nicotine levels, whereas 50 to 60 percent was accounted for by individual differences in smoking behavior (Herning et al. 1983). Additional information on compensatory alterations in nicotine intake has been provided by studying the mouth exposure index, which is calculated from analysis of cigarette butts for nicotine content and a knowledge of the retention efficiency of the filter tip (Ashton and Watson 1970). Because the amount of nicotine retained by a filter is proportional to the amount that passes through, it is possible to estimate the amount of nicotine presented to the smoker from the nicotine content of the filter. Results using this index have revealed a greater variation between individual studies (see Table 1) than observed with blood nicotine measurements. This may be related to the fact that filter efficiency is usually determined by a machine, but retention of nicotine is also dependent on the way the cigarette is smoked; therefore, the retention efficiency of the filter may vary between smokers. Role of Tar Content The observations that smokers adapt their smoking behavior according to the nicotine delivery of a cigarette and that many of the toxic effects of smoking appear to be related to tar rather than nicotine content has led to the suggestion that altering the tar to nicotine ratio might produce a cigarette less hazardous to health (Russell 1976; Stepney 1981). A cigarette with a medium nicotine, low tar, and low carbon monoxide yield might be advantageous. While nicotine has been the component most extensively studied, it may not be the only substance responsible for the addictive power of tobacco. It is not possible to separate the effects of tar and nicotine in most studies, as their respective yields usually show a very close correlation. Using research cigarettes providing three different yields of nicotine and two different yields of tar, Goldfarb et al. (1976) found evidence of compensation for nicotine but not for tar content. The authors urged cautious interpretation of the results because of the limited range of tar yields examined. Examining a large number of subjects smoking cigarettes of varying tar and nicotine yield, Wald et _al. (1981) found that both tar and nicotine were significantly related to blood COHb, taken as an index of cigarette smoke inhalation. Two- way analysis of variance of the data indicated that after allowing for the effect of either tar or nicotine yield, the COHb index was no longer significantly influenced by the other. A cross-over study of medium tar smokers who were switched to low nicotine, low tar cigarettes and medium nicotine, low tar cigarettes has been reported by Stepney (1981). While the intake of carbon monoxide was least with the medium nicotine, low tar cigarette, the mouth exposure 347 index to tar was similar among the brands. Indeed, the pattern of smoking adopted by the subjects was more effective in reducing the difference in tar delivery between the cigarettes than in compensat- ing for nicotine delivery. Further evidence indicating the importance of cigarette tar delivery in determining smoking behavior was reported by Sutton et al. (1982). Using multiple regression analysis, they observed that when nicotine yield was controlled, smokers of lower tar cigarettes had higher blood nicotine levels than smokers of higher tar cigarettes, indicating that they inhaied a greater volume of smoke. In contrast, when tar yield was controlled, smokers of lower nicotine cigarettes had lower blood nicotine concentrations than smokers of higher nicotine cigarettes, indicating that they inhaled less smoke. These results suggest some compensation for tar over and above any compensation for nicotine. It may be that nonpharmacologic, sensory stimulation by factors such as the flavor of cigarette smoke may be more important than nicotine in determining smoking behavior. These new observations, especially on the role of tar delivery, require further investigation. Most published research consists of controlled switching experiments in which the subject smokes cigarettes of varying yields (see Table 1). Further studies of smoking behavior in subjects who have voluntarily chosen cigarettes of different yields are needed. The absence of an acceptable, palatable “standard” research cigarette continues to be an impediment to research in this area. Variations in Pattern of Cigarette Smoke Inhalation While cigarette smoking is the single most important factor in the development of COLD, the majority of smokers never develop clinically significant airflow obstruction (Fletcher et al. 1976). Despite the clear dose-response relationship between number of cigarettes smoked and death from COLD, attempts at identifying the individual susceptible smoker on the basis of number of cigarettes smoked have had very limited success. Another approach to identifying the susceptible smoker is to study the manner of smoking, as this is probably a major determinant of the lung’s exposure to cigarette smoke. Cigarette smoking consists of two phases: initially, the smoker takes a puff into the mouth, and after a variable 1 to 4 second pause, the smoke mixed with air is inhaled into the lungs (Rawbone et al. 1978; Higenbottam et al. 1980a; Tobin and Sackner 1982). Individual differences in the pattern of cigarette smoking such as the size of the puff volume, the duration of holding the smoke in the oral cavity before inhalation, and the depth and duration of inhalation are among the important factors determining the relative concentration of smoke constituents 348 that reach the lung. Despite its significance in determining the distribution and deposition of cigarette smoke, the mode of inhala- tion following the puff has received scant scientific investigation. A number of epidemiologic studies have examined the relationship between cigarette smoke inhalation, based on the smoker’s subjec- tive estimation, and the severity of pulmonary disease. Results of these studies are conflicting; some investigators reported an associa- tion between smoke inhalation and the presence of mucus hyperse- cretion (Rimington 1974; Schenker et al. 1982; Dean et al. 1978) and decline in pulmonary function (Ferris et al. 1976; Bosse et al. 1975), and others observed no relationship between inhelation and pulmo- nary dysfunction (Beck et al. 1981; Schenker et al. 1982). The inconsistencies in these epidemiologic studies may be due to the smokers’ inability to accurately describe their inhalaticn pattern. There are three reports of the relationship between subjective estimations of cigarette smoke inhalation and direct objective measurement. Rawbone et al. (1978) found that the rating on a visual analog scale was a good predictor of inhalation volume (r=0.65). Conversely, Tobin et al. (1982a) noted no relationship between inhalation volume and the smoker’s perception of depth of ’ inhalation, indicated on a visual analog scale (r=0.04); a similar finding was reported by Adams et al. (1983) (r=0.04). Standardizing the inhaled volume for vital capacity did not improve the relation- ship. Other investigators using measurements of COEb observed a weak relationship between self-estimated inhalation and COHb concentration (Stepney 1982; Wald et al. 1978). Measurements of COHb reflect the amount of cigarette smoke absorbed by the lung. In addition to being affected by the depth of inhalation, COHb concentration is influenced by the varying carbon monoxide yields of different cigarettes, the number of puffs per cigarette, puff volume, pulmonary function—particularly diffusing capacity and alveolar ventilation—and hemoglobin concentration (Wald et ai. 1978; Ric- kert et al. 1980). Therefore, it yields valuable complementary information, but it does not provide a direct measure of the pattern of inhalation (Tobin et al. 1982a; Guyatt et al. 1983). Direct measurements of the pattern of cigarette smoke inhalation have been reported for a small number of smokers. Initially, the puff from the cigarette is taken into the mouth, and after a variable pause of 1 to 4 seconds, it is inhaled into the lungs (Rawbone et al. 1978; Higenbottam et al. 1980a; Tobin and Sackner 1982; Tobin et al. 1982a; Adams et al. 1983). Higenbottam et al. (1980a) reasoned that this pause, while holding the smoke in the mouth, minimized the irritant qualities of cigarette smoke. In a group of five subjects who were requested to inhale smoke directly into their lungs, without an intervening pause in the mouth, consistent acute airway narrowing was observed. In contrast, smokers adopting the usual two-phase 349 smoking pattern showed a variable airway response. The authors suggested that buccal absorption of water-soluble compounds, such as sulfur dioxide and acrolein, together with precipitation of tar, minimized the irritating qualities of cigarette smoke. They observed no relationship between the acute airway response and amount of smoke inhaled in the regular two-phase smokers, although there appeared to be a relationship in those directly inhaling smoke into their lungs. However, there is a marked discrepancy in the inhala- tion volumes reported in this study compared with the values reported in other studies of cigarette smoke inhalation, probably due to the inaccuracy of the magnetometers employed for the measure- ments; therefore, a statement regarding the relationship between depth of smoke inhalation and the acute airway response may be misleading. The report that acute airway narrowing is uncommon after cigarette smoking is in disagreement with the findings of several investigators who have observed bronchoconstriction to be a common phenomenon after acute smoke exposure (Nadel and Comroe 1961; Sterling 1967; Da Silva and Hamosh 1981; Tobin et al. 1982a); however, it is certainly plausible that the response is greater in smokers who inhale smoke directly into the lungs than in two-phase smokers. The frequency of direct inhalation of cigarette smoke into the lungs is unknown. In a small study of 10 smokers, Tobin and Sackner (1982) observed 1 subject who showed an approximately 50 ml expansion of the abdominal compartment simultaneously with taking the puff from the cigarette. Adams et al. (1983) studied the relationship between puffing, cigarette smoke inhalation, and partitioning of airflow between the nose and mouth in 10 smokers. After taking the puff into the mouth, two subjects actively exhaled 80 ml and 200 ml volumes, respective- ly, before the subsequent inhalation. In this situation, the volumes of smoke might be expelled from the mouth, and little, if any, would be available for subsequent inhalation into the lungs. The frequency of this smoking pattern was not given, but another report from the same laboratory (Rawbone et al. 1978) indicated that it was uncommon. There was marked intersubject variation in the parti- tioning of airflow between the nose and mouth during smoking, with four subjects inhaling almost exclusively through the mouth, four inhaling predominantly through the nose, and the other two demonstrating both patterns of inhalation. The importance of factors in determining whether cigarette smoke is inhaled as a bolus followed by a subsequent “chaser” of air or is evenly distributed throughout the inhaled volume of air remains to be determined. Considerable discrepancies exist between published reports of the volume of air mixed with smoke that is inhaled into the lungs, with reported mean inhalation volumes of 34 to 152 ml (Higenbottam et 350 3.0 Sum 2.0 1.0 o 0 : ; 2 Puff Puff Puff = iS) > nd Puff Puff Seconds FIGURE 3.—Pattern of inhalation of cigarette smoke mixed with air, in two smokers SOURCE: Modified from Tobin et al. (1982b). al. 1980a), 450 to 485 ml (Guillerm and Radziszewski 1978), 389 to 1,136 ml (Adams et al. 1983), 750 to 2,000 ml (Rawbone et al. 1978), and 170 to 1,970 ml (Tobin et al. 1982b). A major factor in the discrepancies between these studies is probably the inaccuracies inherent in some of the methods employed in the measurements, as discussed by Tobin and Sackner (1982). When inhalation volumes are standardized for body size by relating them to vital capacity, marked interindividual variation is still observed (Figure 3), with inhalation- al volumes ranging from 9 to 47 percent of the vital capacity and a group mean value of 20 percent (Tobin et al. 1982b). Smokers show considerable variation in inhaled volumes while smoking a single cigarette. The volume of inhalation bears no relationship to cigarette consumption in terms of pack-years (Tobin et al. 1982b). Similarly, duration of inhalation shows considerable variation between sub- jects, with mean individual values ranging from 1.7 to 7.3 seconds (Adams et al. 1983; Tobin et al. 1982b). Repeat measurements at intervals of up to 10 months apart indicate that individual subjects tend to maintain a fairly constant inhalation volume, duration of inhalation, and associated breathhold time (Tobin et al. 1982b; Adams et al. 1983). 351 The pattern of cigarette smoking shows a wide degree of intersub- ject variability, including differences in the number of puffs, puff volume, holding pause in the mouth, exhalation of smoke from the mouth before inhalation, partitioning of airflow between the nose and mouth, and volume and duration of inhalation. Given this degree of variation, it is not surprising that smokers might show wide differences in their individual susceptibilities to lung injury. In a study relating inhalation volume—standardized for vital capaci- ty—to the time-volume and flow-volume components of a forced vital capacity maneuver, no significant correlation was observed (Tobin et al. 1982b). Although this lack of a relationship might be interpreted as indicating that the pattern of smoking is unimportant in the development of lung disease, it may also reflect the fact that pulmonary function was normal or near normal in the majority of subjects and that the study was of a cross-sectional design. Use of Additives in Low Tar and Nicotine Cigarettes The nominal tar and nicotine yield of cigarettes has continually decreased since the time of the initial reports linking smoking with lung cancer (USDHHS 1981). In 1954, the average tar yield per cigarette was 38 mg, and in 1980 it was less than 14 mg. Initially, tar reduction was achieved by decreasing the cigarette tobacco content or removing tar by smoke filtration, both of which probably resulted in a lower smoke exposure. Since 1971, the reduction in tar yield has exceeded the relative reduction in the weight of tobacco per cigarette; this difference has increased since 1975 (USDHHS 1981). Manufacturing technology has progressed beyond simple reduction in tobacco content: the yield and composition of smoke can be modified by genetic modification of the tobacco leaf (Tso 1972a), changes in its cultivation and processing (Tso 1972b), changes in the porosity of cigarette paper, and alterations in filter design (Kozlow- ski et al. 1980b). When initially introduced, lower yield cigarettes lacked palatabili- ty and acceptability. Advertisements for the current low tar and nicotine cigarettes emphasize their flavor, presumably achieved by the use of additives in the processing of the tobacco. Additives employed may include artificial tobacco substitutes (Freedman and Fletcher 1976), flavor extracts of tobacco and other plants, exogenous enzymes, powdered cocoa (Gori 1977), and other synthetic flavoring substances. Perhaps more additives are being used in the new lower tar and nicotine cigarettes than in the older brands, and new agents may also be in use. Some of the substances, such as powdered cocoa, have been shown to further increase the carcinogenicity of tar (Gori 1977), and others may result in increased or new and different health risks. The pyrolytic products of these additive agents may 352 produce novel toxic constituents. A characterization of the chemical composition and adverse biologic potential of these additives is urgently required, but is currently impossible because cigarette companies are not required to reveal what additives they employ in the manufacture of tobacco (USDHHS 1981). No government agency is empowered with supervisory authority in the manufacture of tobacco products. With this lack of basic information and the usually prolonged latent period before manifestation of the adverse effects of smoking, it is likely that a long time period will elapse before we know the hazards of the new cigarettes in current use. Research Recommendations 1. Longitudinal epidemiologic studies are needed to determine the risk for pulmonary symptoms and dysfunction in smokers of cigarettes with the low tar and nicotine yields found in currently popular brands. 2. Further research is needed to determine the relative potency of high and low tar and nicotine cigarettes in inducing elastase release and producing functional inhibition of a:-antitrypsin activity. 3. Development of an animal model of cigarette-smoke-induced emphysema would be advantageous in determining the relative risk of lung injury of cigarettes of different composition. 4.More information is required on the smoking behavior of smokers who have voluntarily switched from high to low tar and nicotine cigarettes. 5. The role of cigarette tar, as opposed to nicotine content, in determining smoking behavior needs to be defined. 6.Standard research cigarettes of varying tar and nicotine contents that are palatable and acceptable to smokers need to be developed. 7.The role of variation in smoking behavior in determining susceptibility to lung injury needs to be defined. Studies are required to determine the effect of smoking patterns on the distribution and penetration of the smoke aerosol into the lung. 8. More information is needed on the composition and adverse biologic effects of flavor additives in cigarettes and their pyrolytic products. Summary and Conclusions 1. The recommendation for those who cannot quit to switch to smoking cigarette brands with low tar and nicotine yields, as determined by a smoking-machine, is based on the assumption that this switch will result in a reduction in the exposure of the 353 354 lung to these toxic substances. The design of the cigarette has markedly changed in recent years, and this may have resulted in machine-measured tar and nicotine yields that do eH reflect the real dose to the smoker. . Smoking-machines that take into account compensatory changes in smoking behavior are needed. The assays could provide both an average and a range of tar and nicotine yields produced by different individual patterns of smoking. . Although a reduction in cigarette tar content appears to reduce the risk of cough and mucus hypersecretion, the risk of shortness of breath and airflow obstruction may not be reduced. Evidence is unavailable on the relative risks of developing COLD consequent to smoking cigarettes with the very low tar and nicotine yields of current and recently marketed brands. . Smokers who switch from higher to lower yield cigarettes show compensatory changes in smoking behavior: the number of puffs per cigarette is variably increased and puff volume is almost universally increased, although the number of ciga- rettes smoked per day and inhalation volume are generally unchanged. Full compensation of dose for cigarettes with lower yields is generally not achieved. . Nicotine has long been regarded as the primary reinforcer of cigarette smoking, but tar content may also be important in determining smoking behavior. . Depth and duration of inhalation are among the most impor- tant factors in determining the relative concentration of smoke constituents that reach the lung. Considerable interindividual variation exists between smokers with respect to the volume and duration of inhalation. This variation is likely to be an important factor in determining the varying susceptibility of smokers to the development of lung disease. | . 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Journal of the American Medical Association 213(13): 2221-2228, September 28, 1970. 360 CHAPTER 7. PASSIVE SMOKING 480-144 0 - 85 -. 13 361 ros. 7] ine 2bS CONTENTS Introduction Differences in Composition of Sidestream Smoke and Mainstream Smoke Measurement of Exposure Acute Physiologic Response of the Airway to Smoke in the Environment Symptomatic Responses to Chronic Passive Cigarette Smoke Exposure in Healthy Subjects Respiratory Infections in Children of Smoking Parents Pulmonary Function in Children of Smoking Parents Pulmonary Function in Adults Exposed to Involuntary Cigarette Smoke The Effect of Passive Smoke Exposure on People With Allergies, Asthma, and COLD Summary and Conclusions References 363 j ha” Wr She « 7 re ~ i vA = ' - 9 e id ‘ ‘ . 7 : v cae 7 ° > 4 A ) - ® ber - — Fea ee ey tema —— Ee Sa : _ —_ »4 oie ow.) aviseas™s occoim'!) a seed aaa! GY Gee MOU a pon BOOTING grilstel aot of 7 : 7 —— Ce me gy F j itek’ ) ‘ t i ' 4 bi ' /- ; ae OS | a Ne UMS th Bee , -_ — Sone - ————= «rm —— ee il teen el 2S nriviom? lo desbiad ab pole bowogsd atiyhA af Aoi - ~ - a — —_ eS ee + j f ro? a ¥ sigce'l nc erpecer’ eine er wivysy bh Chita) : ug = ie = ~~ ere — cm ¥ 4 - v tay are? # f ' — cy ty es 7 | Pes: pray Introduction This chapter explores recent data that relate involuntary cigarette smoke exposure to the occurrence of physiologic changes, symptoms, and diseases in nonsmoking adults and children. Health effects related to fetal exposure in utero, a subject that has been extensively studied, are not discussed, although instances where such exposure may relate to potential development are pointed out. The interested reader is referred to several excellent recent reviews for a more complete treatment of this issue (USDHEW 1979; USDHHS 1980; Abel 1980; Weinberger and Weiss 1981). Differences in Composition of Sidestream Smoke and Mainstream Smoke Involuntary (passive) smoking is defined as the exposure of nonsmokers to tobacco combustion products from the smoking of others. Analysis of the health effects of passive smoking requires not only some knowledge of the constituents of tobacco smoke, but also some quantitation of tobacco smoke exposure. Tobacco smoke in the environment is derived from two sources: mainstream smoke and sidestream smoke. Mainstream smoke emerges into the environment after having first been drawn through the cigarette, which filters some of the active constituents. The smoke is then filtered by the. smoker’s own lungs, and exhaled. Sidestream smoke arises from the burning end of the cigarette and enters directly into the environ- ment. Differences in the temperature of combustion, the degree of filtration, and the amount of tobacco consumed all lead to marked differences in the concentration of the constituents of mainstream smoke and sidestream smoke (USDHEW 1979; Sterling et al. 1982; Brunneman et al. 1978; National Academy of Sciences 1981; Rylander et al. 1984). Many potentially toxic gas phase constituents are present in higher concentration in sidestream smoke than in mainstream smoke (Brunneman et al. 1978) (Table 1), and percent of the smoke in a room results from sidestream smoke. Smaller amounts of smoke are contributed to the environment from the nonburning end of the cigarette by diffusion through the paper ~ wrapping and by the smoke exhaled by the smoker. Therefore, both active and passive smokers may be similarly exposed to sidestream smoke. Mainstream smoke is inhaled directly into the lungs and is diluted only by the volume of air breathed in by the smoker when he or she inhales. Sidestream smoke is generally diluted in a considera- bly larger volume of air. Thus, passive smokers are subjected to a quantitatively smaller and qualitatively different smoke exposure than active smokers. The quantification of the exposure of a passive smoker to these sidestream smoke constituents is often difficult. Factors such as the type and number of cigarettes burned, the size of 365 the room, the ventilation rate, and the smoke residence time are all important variables in determining levels of exposure. Thus, no single variable accurately characterizes exposure to smoke constitu- ents. Repace and Lowrey (1980, 1982, 1983) have shown that, to a reasonable approximation, exposure to the particulate phase is predicted by the ratio of the smoker density to the effective ventilation rate of the area in which the smokers are located. Measurement of Exposure Levels of indoor byproducts of tobacco smoke, with measurements made under realistic exposure conditions, are presented in Table 2. Among the constituents that have been measured, nitrogen oxide, carbon monoxide, nicotine and respirable particulates, nitrosamines, and aldehydes have been shown to be significantly elevated indoors as a result of cigarette smoking. Nitrogen oxide is rapidly oxidized to nitrogen dioxide (NOz2) in air, and reaches equilibrium with outdoor levels of NOz, provided there are suitable air exchange rates and no other indoor sources, such as a gas stove. The particulate concentra- tion indoors clearly increases with increasing numbers of smokers, although the background level is determined by the outdoor level. The conclusions from the few studies that actually measure ventila- tion rates during exposure suggest that under “normal” air circula- tion conditions, carbon monoxide (CO) levels will be relatively low, but still may exceed the ambient air quality standard of 9 ppm (NIOSH 1971). However, even modest reductions in ventilation rates can lead to CO accumulation. A variety of measures have been utilized to quantify the nonsmok- er’s exposure to tobacco smoke. No single measure has been uniformly accepted as characterizing the level of smoke. Nicotine is the most tobacco-specific of these measures, but it is relatively complicated and expensive to measure and settles out of the air with the particulate phase, making it a poor measure of gas phase constituents. In addition, nicotine may rapidly deposit on surfaces and subsequently evaporate into the environment (Rylander et al. 1984), making it a poor measure of acute smoke exposure levels. Measurements of total particulate matter are a broader measure of smoke exposure, particularly if the measurements are limited to particles in the respirable range and to environments without other major sources of respirable particles. The smoke particles also settle out of the air and therefore may not reflect the levels of gas phase constituents, and a wide variety of other dusts may contribute particulates to the air, particularly in the occupational setting. A number of authors have measured levels of CO. 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WIAVL 391 households, when the analysis was restricted to those households where neither parent reported symptoms, the results were identical, suggesting that in this population, significant reporting bias was not responsible for the observed results. Lebowitz and Burrows (1976), in a group of 463 current-smoking and never-smoking households with children below age 15, found trends—but no statistically significant differences—for a variety of symptoms, including wheeze most days, in households with smokers. In the same study, among 849 house- holds with older children and adults, there were no significant differences for any symptom prevalence between current-smoking and never-smoking household members. In a general population study, Schilling et al. (1977) reported no association between wheeze and involuntary smoking. A preliminary report from one of the largest studies currently under way (Speizer et al. 1980) indicated no association of persistent wheeze with the presence of smoking in the household for approxi- mately 8,000 children aged 6 to 11 in six communities. However, subsequent analyses of these same cohorts with the addition of approximately 2,000 more children and a more detailed assessment of the smoking behavior of each parent revealed a positive relation- ship that increased with the amount of maternal smoking and was only modestly affected by taking into account the parents’ own symptoms (Ware et al. 1984). Dodge (1982), studying third and fourth grade children, found that symptoms, including wheeze, were related to both the presence of symptoms in the parents and the number of smokers in the household. The gradient of the wheeze effect persisted even after excluding the potential effect of reporting bias by symptomatic parents. Few data are available on the level of exposure necessary to produce symptoms or on the implication of these symptoms for future lung growth and development. No data are currently available on the relationship of passive smoking to other putative risk factors for wheezing such as atopy, respiratory infection, and increased levels of airways responsiveness, nor are sufficient data available to estimate whether these early exposures affect the occurrence of respiratory disease later in life. The characteristics of the child who may be susceptible to this type of exposure are unknown. However, the data are sufficiently consistent to suggest that pediatricians should routinely inquire about smoking habits of parents when caring for children with chronic or recurrent respiratory symptoms and illnesses. It would also be prudent to advise parents of children who are suffering from recurrent respira- tory illnesses or persistent wheeze or asthma not to smoke. 392 Respiratory Infections in Children of Smoking Parents Bronchitis and pneumonia and other lower respiratory illnesses are significantly more common in the first year of life in children who have one or two smoking parents (Table 5). Bonham and Wilson (1981) showed that in 1970 the majority of homes with children under 17 years of age had at least one smoker. Thus, passive smoking by children, even in early childhood, is widespread. Harlap and Davies (1974) studied 10,672 births in Israel between 1965 and 1968 and observed that infants whose mothers said they smoked (as determined at a prenatal visit) experienced a 27.5 percent greater hospital admission rate for pneumonia and bronchitis than children of nonsmoking mothers. In addition, they demonstrated a dose— response relationship between the amount of maternal smoking and the number of hospital admissions for these conditions. It should be noted that the mothers were reporting prenatal smoking and not postnatal smoking for the first year of life. British investigators studying live births between 1963 and 1965 in London also observed an increased frequency of bronchitis and pneumonia in the first year of life associated with involuntary smoking that did not carry over to years 2 to 5 (Colley et al. 1974). This effect was independent of parents’ own symptoms and increased with the amount of smoking by parents. Bronchitis and pneumonia also increased with an increased number of siblings, and this was not controlled in the analysis. Fergusson et al. (1981), studied 1,265 New Zealand children from birth to age 3. They demonstrated an increase in both bronchitis and pneumonia and lower respiratory illness during the first 2 years of life in children whose mothers smoked. Corrections for maternal age, family size, and socioeconomic status did not affect the linear relationship between the degree of maternal smoking and the rate of respiratory illness. This effect declined with the increasing age of the child. Leeder and colleagues (1976b) studied a British cohort of children born between 1963 and 1965 and demonstrated that parental cigarette smoking was associated significantly with bronchitis and pneumonia during the first year of life. A dose-response association persisted after correction for parental respiratory symptoms, sex of the child, number of siblings, and a history of respiratory illness in the siblings. Pullan and Hey (1982) studied children who were hospitalized with documented respiratory syncytial virus (RSV) infection in infancy. They found a significant difference in the smoking habits of mothers at the time of the infection, compared with children hospitalized for other illnesses—including respiratory diseases for which RSV infec- tion was not documented. These children reported an excess occurrence of wheeze and asthma and had lower levels of pulmonary 393 480-144 0 - 85 - 14 Cw 6 ot te ee ee Te Se 5 Be wee Oe SS eee serz10 ‘SN x18 ‘snyeys ZuTyoUIS spual} JUBOITUBIS ‘yajjo 7.10409 UMOUY JO sjuered OM} ZIM (7861) Ayia pue ‘xas ‘a8e 10j poysnfpy SFT Lgl 621 qeak 4se] Ul sseuT! 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A1oyeridsey ‘6-9 pede ‘uaIp[TYyo gcT ‘Te 30 WoIUTED) Ieak 9°¢T ST 8'8 ysed ul shup ¢< sseUT]! 7894) wruealAsuueg W1e}s9M (£861) yuBoyTUsIs Y}Oq 10} spur], GIT = 6L Lg Z a88 alojeq sseuT[! 3804) ‘pI-G pose ‘uaiptty TL0F ‘Te 38 JexUEYIS Jaq] 18e sivok +0] Aleyeurtxoidde UOT}esUI amsodxa 0} poze[al AT}eIIp youl, A10jeridsel yuenbely BZutplodal jo aut, ye s}Uered JO 1O}BOIpul SB ‘Gg a28 a10jaq jo syiqey Zuryouls yey} Iee[9 Ajje1eues ‘Aulopepiouepe eouBly (8261) you ‘uarpiryo Aq Zutj1odel-j[ag 60S VIP 086 Jo/pue AWoweT[Isuo], ‘OZ-O01 pose “uerpiryo 0Z6'e Te ¥ Pres 8] USUTUIO,) OOT Jed sey81 sseul[] ssurpuly syefqng Apnig penurnu0oj—s WIdVL 395 ‘OLET) Te 92 Jepee] Aq poptaoid stsXteus popuedxe asour v ul paiepisuco are ByEp aseu], , ‘CW “ures "Wf Aq peptaoad Byep peystiqnd wiosy poyetnopeo sreyjouI SuTYOUIsUOU Jo UaIpiTyD sneiaA 8194}0UI ZUTHOUIS JO UaIP|TYO 10j YSLI saryepoy , (GC T= yt] Jo reek {sul ZULINp ZuTyouIs jo peo [eulajem yuBoLTUsIS ‘Apnys g[o1ju0o peztTeyidsoyuou TTT JO aul} ye SuTyouls (g¢°[ = YY) “WOTeFUT ASY YIA ayty [euleyed pue (961 = YY) jo eek yar SuLnp [eyideoy (2861) peptaoid jon [euiayeU jo ~aye yUBOYTUSIC 0} poyTUpe UaIP[TYO OKT Aey pue using bLT=au peyenyeas Zuryous aT] siayj0ul ZuTyOUIsuOU [euiszeul Ajuo ‘¢ ae 04 dn jo sieeX g 4s11J ZULINp sseuT]I JO UaIP[TyD E7B‘T Syyeep ‘suorjeztTeyidsoy ‘syIsta Aroyendsel Joy uorjeziyeyidsoy ‘s19y}0U1 (8L61) oy0p Jo dnmorjoy aatyedsoig pepiaoid 40N Ul esBatoUT JUBOIFTUZIC ZuTyous Jo wsIp[iyo 17g ‘T orfeyey Tey —eeee—— eee OOT Jed seq81 ssoul[] agurpuly syefqng Apnyg s}uauTMOD : penuyu0)—'s AIdViL 396 function that persisted to age 10. The authors could not distinguish between the possibilities that infection caused damage that persisted and affected the maturation of the lung or that these children were already more susceptible to severe RSV infection. Greenberg et al. (1984) examined the tobacco smoke exposure of infants in the first year of life by measuring urinary cotinine-to-creatinine ratios. They found that infants of mothers who smoked had a ratio of 351 ng per mg, as contrasted with a ratio of 4 ng per mg in infants of mothers who did not smoke. Breast-fed infants were excluded because of the presence of nicotine in the breast milk of mothers who smoke. A dose-response relationship was present between the cotinine-to- creatinine ratio and the reported level of maternal smoking in the previous 24 hours. This study suggests that infants of mothers who smoke absorb measurable amounts of the smoke from this environ- mental exposure. Rantakallio (1978) studied over 3,600 children for 5 years, half of whom had mothers who smoked and half of whom did not. Children of mothers who smoked had a 70 percent greater chance of being hospitalized for a respiratory illness than children of nonsmoking mothers. Some of these studies may be confounded by the increased reporting of symptoms in the child by parents who smoke and have symptoms (Cameron et al. 1969; Said et al. 1978; Leeder et al. 1976b), but in those studies in which parental symptoms were controlled, the effects persisted. Other studies may be influenced by the child’s own smoking habits (Said et al. 1978), although the majority of research examined children in an age range in which smoking would be unlikely. In summary, several studies suggest important increases in severe respiratory illnesses, particularly in the very young (less than 2 years old) children of smoking parents. Young children may repre- sent a more susceptible population for adverse effects of involuntary smoking than older children and adults. The amount of time spent with active smokers, particularly by children under 2 years of age with smoking mothers, may be an important factor. How in utero exposure influences this risk is unknown. Pulmonary Function in Children of Smoking Parents In recent years, a number of studies have examined the relation- ship of parental cigarette smoking to pulmonary function in children (Table 6). The majority of these studies have been cross sectional (Tager et al. 1979; Weiss et al. 1980; Vedal et al., in press; Burchfiel et al., 1983; Tashkin et al. 1983; Hasselblad et al. 1981; Ware et al. 1984) and have demonstrated decreases in level of pulmonary function (FEVo75, FEVi, FEF 25-75, and flows at low lung volumes) in 397 children of smoking mothers compared with children of nonsmoking mothers. In some studies, there seems to be a dose-response relationship (Tager et al. 1979; Weiss et al. 1980); i.e., the greater the number of smokers in the home, the lower the level of function. When analyzed by multiple regression techniques, maternal smoking has the greatest impact (as would be expected from the greater contact time with the child), and a dose-response relationship with the amount smoked seems to exist (Weiss et al. 1980; Tager et al. 1979; Ware et al. 1984; Vedal et al., in press). Younger children seem to be more adversely affected than older children (Tager et al. 1979; Weiss et al. 1980), and clearly there is an added effect in older children if they themselves smoke (Tager et al. 1979). Tager and colleagues (1983) followed 1,156 children for 7 years to determine the effect of maternal smoking on growth of pulmonary function in children. After correcting for previous level of FEVi, age, height, personal cigarette smoking, and correlation between moth- er’s and child’s pulmonary function, maternal smoking was associ- ated with a reduced rate of annual increase in FEV: and FEF»25-75. The magnitude of the effect was consistent with a 3 to 5 percent decrease in expected lung growth due to the maternal smoking effect, constant over the time period of the study. Because so few mothers changed their smoking habits, the study did not attempt to differen- tiate between postnatal and in utero effects of involuntary smoke exposure. Ware et al. (1984) followed 10,106 white children for two successive annual examinations. The FEV, was 0.6 percent lower in the children of smoking mothers at the first examination and 0.9 percent lower at the second examination. These differences were statistically significant, but represent very small absolute differences. In this study, and in the other studies that show small changes in pulmonary function, it is not clear whether these changes represent small changes occurring uniformly among the children of smoking mothers or somewhat larger changes occurring in a small subpopula- tion of susceptible children. The available data demonstrate that maternal smoking affects lung function in young children. However, the absolute magnitude of the difference in lung function is small; it is unlikely that this small difference, per se, is of functional significance. The concern generat- ed by the demonstration of even small differences is directed at the future lung function of those children, particularly if they become active cigarette smokers as adults. The possibility that this differ- ence in lung function may result from pathophysiologic mechanisms similar to those present in active smokers raises the concern that these children may be “sensitized” to smoke at an early age, and that this “sensitization” may result in a more rapid decline in lung 398 wuozLiy ‘uosony, ‘9 ese < UeIpTTYy SZULLMI00 9q ABUI sezBUITTD syrun jo uorouny Areuownd Ajieyyiou axoul yy pareduico UoTyBLAep pepuEys se posseidxe jo puw Zuryouis sjuered (9261) amsodxa JO S[aA9] JOOPUT UI ‘saAIND A ‘YAW WoOl pealiep JO seLiojsty 34e[duI00 SMOLING seoualaysip [Bal 3ey} woNsedsng Zuryours Teyuared jo yeyjo ON sume A ‘orem A ‘OAT “ADA Guim sproyssnoy Tz puw zjLMoge] Jaqjour Aq peyouls yunoure peyersosse A]aAT}eZe0u ogrem A, (sseid ut) qj esuodsel-os0p SMOL,J SMoly ‘payetoosse ATaatzisod DAT ‘aixemA ‘orm A ‘OAT “ARI 1-9 pose ‘UeIP[TY 000'F Te 3 [EPPA uorouny Areuoultnd SsuTqis JO UOIyeTaLI0O puB azis Sutyouis s}run S}jJosNyoesseyy ‘U0jsOg (0861) drysqis 10j pe[jorjuco siskfeuy [eyuered jo yoyja yWBIITUSIC UOTyBIAep pepuEys Ul FAWN qseq ‘6-G pede ‘uerp[ryo Ogg [2 32 SSIOM uonouny Areuoultnd ABUT[GIS JO UOTETaLI0O puw szIs Sutyqouis syrun s}osnyoussey] “UOjsog 7sey 6267) drysqis Joy peljorjuoo sishjeuy [ejuered jo yoya JUBIITUZIC uONBIAep pepueys WU ATW ‘6I-G pase ‘uaIpiIy Fh ‘TB 32 1038], Si9yjOU SUTHOUIS YIM UaIpP[TYyD UT ssa] ApUBOYTUsIS orem “payouIs JaAdU OYA UaIPTTYS 0} payLyser sisXfeus wey ‘uoTuny ATeuound BUT[OIBD ABUTGIS JO UOTZB]aL100 qynog puw ynoreuuoy | (2261) Jo az1s drysqis 10J [01000 ON Zuryous [eyuered JO yee ON peyrpeid yusoied sB ‘AUT ‘LI-L pede ‘uarpiryo 91g ‘Te 32 BurTITYIS S}USUIUIOZ au109jNO aInseeul uoT~UN ATeUOUTTNg syefqng Apnyg Suryours AreyuN][OAUT 0} pasodxe usip[Iyo Ul uoOToUNJ AreuOm[Ng—9 WIEVL 399 Byep Zuryouls [eyuered Zursstur JO 8j8p uoTUTy Areuournd SuTyours 89}8}G poyluE PITBAUI JO asneoeq pepn[oxa [eurezed you ynq ‘Buryous ‘suotsel otydeis0e8 uasas (1861) UeIpTTYy jo Jequnu aZrey] [BusSzSU JO Poe JUBOIFTUSIC peyorpeid yuacsed se ATT ‘LI-G pose ‘uarprrys 689‘9T TS 99 pelqiessey Jayj,0UI ZuTyOUSs B 4SBa] 4B YI sejesuy SAIS Joy suxem A ‘i-WFAY pue 80] “UsIp|TYyS o1yeuTYyseu0T (6861) Suryouls [euleyed jo yaya on 8A0q Oj FMA “re pagEaIa”] Be aa A SE ALA ‘Suryousuou 0/0'T ‘ye je UTyYsB], sdnoig a%e ysesunok pus skoq 10} yuauTU01d s}uered qS0Ul syajjo ‘suTyOUIS [euE}ed SuTyouls jo Joqumu posvelour pus [eula}BUI jo saya YIM spIs I0j OFF) puw skoq uestyoTW ‘Yyesumoey, (6867) UseMjeq UOTPUTISIpP OU “pBIISqY 10} OAM Pue "AG posveiseq ommmA “ATT ‘OAT ‘61-0 pose ‘uarpiryo gz¢'p Te 98 Joyyong quedied ¢ JO 7 UBY} aioul you sun] pedojeasp Any 8194}0UI Uo ZUTYOUIS [eUJayBUI Jo yoyo SUTYOUS JO UaIPTTyD 103 S}jesnyoessey] UMNUTxeUl ‘Zuryous [euiezed “CITT Pus "AGT Ul yymois ‘Uoysog yseq ‘AeAINS [BIyTUT (£867) JO waye ou ‘dnmoljoy Ieak-y JO 981 posealdep JUBIIFIUSIC eed “ATA 98 61-G pede ‘uarpiryo gcT‘T ‘TS 32 sede], JaABMOY “JUBOYTUBIS JOU 489} [2013813898 -spjoyesnoy Suryours quered-0m} Ul UBYy} spfoyesnoy Suryoulsuou ul J3yee13 Ayyuaystsu0o [] pue ‘6 ‘g soze ¥ ¢H/‘AGA Wt e8ueyo [enuue “‘WYSIOY 8,Warp[TYyo 10y peyjorzu09 70U BBP [BUOT}Es-s80I9 ‘saqB1 wok Jed .H/'AdA BuozLIy (2861) uornsdiored ul seiq [eyUe}0g Suryous [eyuared jo yeya on esueyo ase Aq 'Aqg ‘OI-@ pese ‘uerpltyo gcc e3poq ee ee s}USUIWIO, eul09jng einseeul uoTyuNy Areuou[Ng spefqng Apnyg penunuoj—'s ATAVL S ~ ee ee peyBto0sse Jayjou Aq peyouls yunoure Ajeatyezou 'AQy ‘Buryous setjzld “S'f) xis UI (F861) yytm esuodsai-se0p "AW YUM peyeroosse Apaatyisod OAT OAM pus "Add ‘II-9 pede ‘uarpiry> 000'0T Te 30 SBM "Add pus OAM J0¥ Poe we peyesjsuowep peyrpeid SOT}D “S'f) xs Ul (086) Hoyoo sty} jo siskjeue yUS0eY OAd 10 'AGA 10} Yee ON queosed 8B "AMY Pue OAT ‘OI-9 pose ‘uerpiryo OZT'S ‘Te 32 Jezedg nn nnn EEE s}USUIWIOZ) Elis (eaa hig) einseeul uoT~uUNy Areuoul[Ng syefqng Apnig 8s > 2a 2s ss SSS oo penuryu0j— 9s WIV 401 function as adults, particularly if they become smoking adults. No data are currently available to establish the role, if any, of the small physiologic changes in children on the development of adult obstruc- tive lung disease. Pulmonary Function in Adults Exposed to Involuntary Cigarette Smoke White and Froeb (1980) reported on 2,100 asymptomatic adults drawn from a population about to enter a physical fitness program. They demonstrated statistically significant decreases in FEV: and MMEF as a percent of predicted in nonsmokers exposed to tobacco smoke in the work environment compared with nonexposed workers. The decrement was comparable to that seen in smokers inhaling 1 to 10 cigarettes per day. However, the absolute magnitude of the difference in mean levels of function in the smoke-exposed and unexposed groups was quite small: 160 ml (5.5 percent) for FEV: and 465 ml/sec (13.5 percent) for MMEF. Carbon monoxide levels were measured in the workplace and ranged from 3.1 to 25.8 ppm. The population was self-selected, response was related to current work- place exposure and did not account for people who changed jobs, and it is unclear how the ex-smokers in the population were handled in the analysis. Comstock et al. (1981) examined 1,724 subjects drawn from two separate studies in Washington County, Maryland. They found no statistically significant greater risk of having an FEV: less than 80 percent of predicted in male nonsmokers exposed to wives’ cigarette smoke at home. Schilling et al. (1977) did not find an effect of passive smoking exposure in adults. Both of these studies included adults in their samples who were relatively young and generally would not have had a long-term passive exposure in adult life. This point was brought out by a recently reported large study from France. Kauffmann et al. (1983) reported on a seven-city investigation in which a total of 7,818 adults were studied. In a subsample of 1,985 nonsmoking women aged 25 to 29, in which 58 percent were exposed to smoking husbands, there was a significant difference in level of MMEF between truly nonsmoking women and women of comparable ages exposed to passive smoking. This effect did not become apparent until age 40. These changes were small, and although not adjusted for differences in body size, may suggest a possible effect of long-term exposure in adult life. The physiologic and clinical significance of these small changes in pulmonary function in adults remains to be determined. In addition, variables such as ventilation, room size, number of rooms in the home, duration of contact with the active smoker, and number of cigarettes smoked could significantly influence total exposure and 402 need to be explored more fully. Differences in these exposure variables and the characterization of exposure may explain some of the differences in these study results (Table 7). The Effect of Passive Smoke Exposure on People With Allergies, Asthma, and COLD There are very limited data on the effects of passive smoke exposure in patients with preexisting pulmonary disease, and the available data are conflicting. Clinical studies have suggested a relationship between respiratory symptoms in asthmatics and expo- sure to parental cigarette smoke, but methodologic problems compli- cate the interpretation of the limited available data. O’Connel! and Logan (1974) identified 37 asthmatic children who were “bothered” by parental cigarette smoke. Parents of 20 of the children stopped smoking and 18 (90 percent) of the 20 children had an improvement in symptoms. The control group consisted of 15 children (2 were not followed up) whose parents did not stop smoking. Only 4 (27 percent) of the children in the control group improved. The self-selection of those parents who quit, subjective criteria for improvement, and an unclear duration of followup limit the interpretation of this data. Gortmaker and coworkers (1982) studied two populations of children aged newborn to 17 years. They found a significant association between parental reporting of chil- dren’s asthma and maternal smoking. Maternal smoking alone was associated with approximately 20 percent of all asthma. The effect persisted when age and sex of the child, allergies, and family income and education were controlled in the analysis. No control was attempted for the children’s own smoking habits or for increased reporting of symptoms in children of symptomatic parents. Other population-based studies (Lebowitz and Burrows 1976; Speizer et al. 1980; Schilling et al. 1977) have not shown such results. Dahms et al. (1981) studied 10 patients with bronchial asthma and 10 normal subjects passively exposed to smoke in an environmental chamber. Pulmonary function was measured at 15-minute intervals for 1 hour after smoke exposure. Blood carboxyhemoglobin levels were measured before and after the 1-hour exposure. Carboxyhemo- globin levels in subjects with asthma increased from 0.82 to 1.20 percent. In normal subjects the increase was from 0.62 to 1.05 percent. The increases in carboxyhemoglobin in the two study groups were not significantly different. Asthmatic subjects had a decrease in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV:),and maximum mid expiratory flow rate (MMEF) to a level significantly different from their preexposure values. The decreases in asthmatic subjects were present at 15 minutes, but worsened over the course of the hour to approximately 75 percent of 403 a OF a38 Moleq SOALM ZUTHOUIS qoeye OU -SeALM UT TWN jo spueqsny Ut FaWW 4° Jo} ZurTyouls spueqeny ATao yWeOTUsIS ‘seInsBoul jo yunoure 0} esuodsel—ss0p [je Ul spueqsny Zuryours jo sdnoi3qns peye[es ‘setz10 (£861) ‘jystey Joy paysn{pe jon SOALM UT Poa JUBIYTUSIC TAWW pue ‘OAd “AGA youaiy woaes ‘s}Npe gTg'L TS 72 TUvAyNey OS eS SO uorjuny Areuowynd spueqsny uo pueyArey ‘Ajun0D (I861) +0¢ pede s}[npe sepnpouy BuTYOUIS SOALM JO 102]j9 ON peyrpeid yusoied se "AWA uoysuTyse Mm ‘S}[NPS HZL‘T ‘TB 32 Yooysw0y oe ee ee SS SS SS SO eS ee amsodxe exHOUIs 944018319 eyouls yueLmo) ATUO pessesse Areyunjoaul 0} ainsodxe peptpeid yueosed BIUIOFITBD (0861) “UOTPe[Es Ul SBIq [BI}U9}0g BOIJO JO Payja JUBOYTUSIC se JAW Pus “AA ‘OAd ‘oBalq UBg “BIMpPe OOT'Z qeoly pues sz M a S}USUIUIOZ) aU0IjNO ainseeu uoTUNy ArTeuOUI[Ng spetqng Apnig a Suryours AreyuNpOAuT 0} pesodxa s}[Nps ul uoyouny ArsuOWNd—ZL WTAVL 404 the preexposure values. Normal subjects had no change in pulmo- nary function with this level of exposure. In this study, subjects were not blinded as to the exposure and were selected because of complaints about smoke sensitivity. Shephard et al. (1979), in a very similar experiment, subjected 14 asthmatic subjects to a 2-hour cigarette smoke exposure in a closed room (14.6 m3). The carbon monoxide levels (24 ppm) were similar to those predicted in the study of Dahms and coworkers. No blood carboxyhemoglobin levels were measured. Subjects were randomized and blinded to sham (no smoke) and smoke exposure and tested on two separate occasions. Data were expressed as a percentage change from the sham exposure. No significant changes in FVC or FEV: were observed between sham and smoke exposure periods, although 5 of 12 subjects did report wheezing or tightness in the chest on the day of smoke exposure. The limited existing data yield conflicting results concerning the relationship between passive smoke exposure and symptoms in patients with known pulmonary disease. Further study of this important question is warranted. 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. 405 406 7. The limited existing data yield conflicting results concerning the relationship between passive smoke exposure and pulmo- nary function changes in patients with asthma. References ABEL, E.L. Smoking during pregnancy: A review of effects on growth and develop- ment of offspring. 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New England Journal of Medicine 302(13): 720-723, March 27, 1980. WILLIAMS, C.L., ENG, A., BOTVIN, G.J., HILL, P.. WYNDER, E.L. Validation of students’ self-reported cigarette smoking status with plasma cotinine levels. American Journal of Public Health 69(12): 1272-1274, December 1979. 412 CHAPTER 8. DEPOSITION AND TOXICITY OF TOBACCO SMOKE IN THE LUNG 413 ah; = 5 te 4 + ' ear ALN 6. ve SATA. FR y how x ; “ij ~e,! a, awh rey bd iad thes in urt level or a a] ai wii peice 0 elite ” Anerinat Meee oF & 1 os . waiasy teeth : , , ' .@ ‘ 4 : Y MEPS Ger oetion iy Lm * ¢ oub . a> & : Ye - na ne ” = + = Te a areas! Nn a Meru ims 4] 2) yy wy NORE,* Le fe Sarit, epeking sate wit yee 7 ‘ Pas 5 con » he _ i. . A _ ; ¥" 7) > ¢ * -* s 4 bd i y tc? As _ Ae Bal? 2 ae ‘ »- {. ‘ ~- = » YTINIXOF - >» @ se] ' 4 ‘ ry nn < ‘f ° be g ? ; 9 ; ya 5s , : : < ~ , r , -' v4 ‘ \ 1 , aa) . 7 , + ; ‘ ‘ } ’ 4 » aa até , a j Tp a oh ad r i f fi Gey is +" ; oe Tad CONTENTS CIGARETTE SMOKE DEPOSITION IN THE LUNG Introduction Characterization of an Aerosol Characterization of Cigarette Smoke Aerosols Factors That Affect Particulate Deposition Deposition of Cigarette Smoke Particulates Particulate Retention in the Lung Passive Smoking Conclusions CIGARETTE SMOKE TOXICOLOGY Introduction Preliminary Considerations Effects on Airway Function and Ventilation Human Studies Animal Studies Effects on Permeability of the Pulmonary Epithelium Human Studies Animal Studies Effects on Mucociliary Structure and Function Effects on Cells Human Studies Animal Studies Effects on Protease Inhibitors Human Studies Animal Studies Effects on Lung Tissue Repair Mechanisms Human Studies Animal Studies Summary and Conclusions References 415 TO OR ee Oe oe Se ie EE ee RG ee ee ee eee - 8 6 | EY eOrrrrenari wiraro * atiT a MOT (40STHG CP ie | YO: ; 7 - loxoweA as tO neneSraae » ys . = és rT * 7 e 2 mat, glom= offeresi.) 16 Soma “iipoe i oa if wet toot A inaT ee i ¢ rr : 4 ra a ivonis4 slomd slezani tae Ss wl avid nl coltasteit s soiimobiang) Hea f ongrd yvewsiA no @ 3 eeibut® cteous/ ee 20ihies: Jeni J c ‘ ilies nw wo 2u% nothove tipo - 7; r 4? ae Fz; ' t¥ Mi - , a's ao Ae a1 Ee 7 : othiwit same r ¢ s 7 ; aerbowe soi 7 — ° - Lom 4 wHiduial easiord 66a ‘huss cue? i) - e - ¢ 7 | sinus lee setronioeM! tinassl euserl gant se asibot asa anibite incret - mee. o dnois ys ystH (QZ86T) ‘Te 38 euexoQ 9=N Sf ‘Zurjesunoo uwerisdyg v=N SZ ‘Zuljesunoo [ENpLarpuy sdno1g usemjeq eoualajjip G=N ($Z6[) Uoslepuepy queoyrusis ou ‘syuered ysu Yat syyuOW ¢ 02 ‘uoTBOyTpoU JOLABYoY pue 10hey] dnoid [o1jW09 ON qeak | cy OOT=N ‘IN-490d (SL6I) ‘Te 38 nokeyw ureidoid [etyuepise: ‘dnoid [o1j}U00 ON syzUOUT g €¢ Sh=N ‘ASU YSTY ([861) ‘Te 38 a0TeW aorape jo A1OUIOUI pues AjLIeAes peAleoied 10} s1eyouIs (ZZ6[) “oVlequieg -Xa9 UseMjoq seoUeJeyIp ‘dno1d [o1yW00 ON IBak [| Go IZE=N ‘TN-390d pues uByseley (S1ayOUIs $9) (0861) dno1Z [013009 ON syyuOU F OF GOI=N ‘TN490d AajMeg pue pAory (siayouls ¢¢) OOLT=N ‘Asedins ssedAq Areu0l00 dnoid jo1ju00 ON SYy}UOU ¢ L9 iaye syuayeg (2861) ‘Te 38 playuioy quaoied ¢'Q] ‘2381 woryda0ep Peles Hp 6€=N aqissed “(NOS WMNJes) UoIyEprTeA aAtyoelqg SY}UOU § peyiodel 6F ‘eseosip [BLIOLIY (0861) ‘Te 3 F4TY , SJUSUIMIOZ dnaoyjoy (queo1ed) sdnoi‘ Apnyg jo uoreing ayel Ng penuyu0)—s ATaV.L 472 dnoi# jo2ju00 ou ‘Apnys ureySururelg siBvek 9 03 Z siey_ouls 9y} Ul TW Zurdojaaep seyours jo dnmojjoy sqeueA 8% Z06=N ‘IW450d (SL6I) ‘Te 30 moLedg ty P8=N ‘Jo1}U0D re ‘O8=N ‘uTjesun0o | pues astolexy T€ 88=N ‘eslolexy (£867) ssouaeyIp JUBOIFTUBIS ON syyuoW g IW-490g ‘7S 32 welereals quacsed §Z ‘ay81 PeyLioaA [TG uondasep afqissod ‘uoryepitea aatyalqQ Teak | peyiodsi gg I6=N ‘TW-390d (SL6I) ‘Te 3° HeTTIS Te) OHM JO Hed seek F 63 9EL=N “YSU Yat (0861) ‘Te 38 e804 9S=N ‘Q8BaSIP 917019[980194}8 (IZ61) dnoig [013000 ON Waals 3ON vy yy pezipeyidsopy nyANYop/) Puw soy 9€ PIL=N ‘UonueAIezUy (8261) UoyTUre] puw esoy jo dnmojjoy seek § peyiodar 30N T€L=N ‘O189 [BULION (2861) ‘Te 3 eB0y 9€ PIL=N ‘UOT}WAAIG}0] (8261) eseasip Aloyeridse1orpreo JO} Ast Ystyy siBak § PI TEL=N ‘e1Bd [BULION MOTTE PUR quaosed g'g ‘ay81 worjde0ep PeyLisa LY (sieyouls [[T) ayqissed ‘(qHOO) YoIepITeA eatoelqQ sIBek BT 0} F peyodal [¢ LIT=N ‘IW480d (I861) ‘Te 38 Weuoy oP GO=N ‘[O1}UOD ef ZZ=N ‘Advisyy dno sousleyIp JUEOYTUSIS ON sieek p TW490d (6261) Te 99 eyY siayouls (2861) a109 prey (NOS) UoEprpea aaryoelqo eek | PeIOA 0G ZV=N ‘WSU 4atH ploury pue [jemog , S}UaUTTIOZ dnaoyjoj (yueo1ed) sdnoiy , Apnig jo uorjeing ayB1 7G penunu0)—s AITAVL 473 *pe}BOIpUl O8 seIpNys as0y} UI A[UO peuLlojied sem sOUsUTISqe ZUTHOUIS Jo 710de1-J[98 JO UOTJBPITBA aatqelGQ , aseastp JO AjLIaAes pus aZe ZUISseeINUI 10j aroqouls (GL61) puBe SI@HOUIS-xXe UseMjeq SeOUsle}jsIG syjuoul ¢ gS POS=N ‘IW-790g ‘Te 32 WOSssTUTOUTIM (6867) dnoig) aatyB10qeT]Op UOTTPUOD [O1}UOO ON greek fF 9 OLL'=N “YS 4stTH uvedoing OHM 61 ZEh=N ‘CHOON og 9FI=N ‘eusuy (1261) @sBasIP JO AjLIaAas 10} [01]U0D s1Bek ¢'p 0g €8Z=N ‘IW-390d TE 38 HBIQUIOM , S}USUIIOZ) dnmoyjoj (yue01ed) sdnosy Apnyg jo uorjyeing aye1 3nd penuyju0oj—s ATAVL 474 varied from routine to strong. Results have generally been better when stronger advice was delivered (Burling et al. 1982). For example, in an experimental test of the effect of intense advice on post-MI cessation, Burt et al. (1974) routinely assigned 210 male patients to intense or to routine advice conditions. Abstinence rates were higher in the intense advice condition, 62 versus 27.5 percent. The intense intervention consisted of telling the patient repeated- ly—in the critical care unit, during convalescence, and during followup—never to smoke again in his lifetime, plus giving him a pamphlet. However, other attempts to increase cessation rates by using group counseling (Rahe et al. 1979) or exercise with or without counseling (Sivarajan et al. 1983) showed no differences in absten- tion rates for treatment groups and control groups. Fourth, a variety of subject and environmental factors that may influence cessation have rarely been systematically examined or controlled. These include age, sex, race, severity of the MI, and personality and environmental factors. Age is not found to be related to cessation in most studies (e.g., Baile et al. 1982; Croog and Richards 1977; Salonen 1980; Sparrow et al. 1978; Weinblatt et al. 1971). Both of the studies presenting data on sex differences in post- MI cessation have noted somewhat higher cessation rates among males; however, sample sizes were small and the differences were not statistically significant (Baile et al. 1982, Sparrow et al. 1978). Racial data have not been available for nonwhite populations. Greater severity of an MI has been associated with higher smoking cessation rates (Baile et al. 1982, Wilhelmsson et al. 1975). Personali- ty and environmental factors are complex, and only a few relation- ships have been explored. For example, neither Baile et al. (1982) nor Croog and Richards (1977) found associations with any of the sociodemographic or Health Belief Model variables measured, but Baile et al. (1982) did identify an environmental factor—being offered cigarettes by visitors—that influenced resumption of smok- ing among hospitalized post-MI patients. The descriptive study by Baile et al. (1982) provided several suggestions for intervention with post-MI patients—introducing the intervention prior to hospital discharge and as early in the hospitali- zation as is feasible, even in the critical care unit, and involving family members and visitors in the effort to prevent resumption of smoking. This study was not designed to assess the mechanism by which relapse was negatively associated with severity of the MI, but the authors offered several possibilities: the presence of subjective factors such as specific illness symptoms, general malaise or level of fear, communications from the medical staff regarding severity of heart attack, intense and specific advice to quit smoking, or differential medical treatment that might have affected the patients’ smoking behavior. These factors should be considered in the design 475 of future experimental evaluation of post-MI smoking cessation interventions. Moving on from the patient with established cardiovascular disease to people classified as “at risk,” it is found that a number of large controlled trials of risk reduction have demonstrated that counseling on individual specific risk factors and exposure to smoking cessation techniques can be effective. These trials have been discussed in detail in the 1983 Report of the Surgeon General The Health Consequences of Smoking (USDHHS 1983). Rose and Hamil- ton and their colleagues (Rose 1977; Rose and Hamilton 1978; Rose et al. 1982) have found higher abstinence levels in a group given intense advice and education as compared with a control group. The Multiple Risk Intervention Trial (MRFIT) (Ockene et al. 1982b), with 12,866 high risk men, reported 40 percent abstinence in the special intervention group and 21 percent in the usual care group. Similar results were found in Britain (Rose et al. 1980) as part of the WHO multifactorial trial (WHO European Collaborative Group 1982). Other smaller scale studies have generally found that high risk men are susceptible to risk-reduction interventions (Cooper et al. 1982; Malotte et al. 1981; Powell and Arnold 1982). For the most part, these studies have been well designed and many have included objective validation of verbal reports. The Use of Nicotine Chewing Gum A pharmacological aid to smoking cessation designed to decrease the smoker’s desire for nicotine and to relieve withdrawal symptoms has recently become available as a prescription product in the United States after development in Europe; current information and research has been summarized (Grabowski and Hall, in press; Hughes and Miller, unpublished manuscript). The new aid is a chewing gum containing 2 mg nicotine bound to an ion exchange resin for controlled release and buffered for rapid absorption through the buccal mucosa. Compared with the rapid elevation of blood nicotine levels achieved after smoking a cigarette, peak blood levels with 2 mg gum are lower and are achieved more slowly (Russell et al. 1976a; McNabb et al. 1982). Although blood levels may peak within minutes following smoking, peak levels occur after 20 to 30 minutes of chewing the gum, presumably not reproducing the pleasure of smoking because of the slower, nonbolus release of nicotine (Russell et al. 1980). Nicotine chewing gum is indicated as a temporary aid to the cigarette smoker seeking to give up his or her smoking habit while participating in a behavioral modification program under medical supervision. The efficacy of nicotine chewing gum use without concomitant participation in a behavioral modifica- tion program has not been established. Thus, nicotine gum could aid 476 in the cessation process by allowing the smoker to break the smoking habit with abrupt cigarette cessation, while gradually withdrawing from nicotine. In controlled studies, evidence has been offered that nicotine gum can relieve withdrawal symptoms (Jarvis et al. 1982; Schneider and Jarvik 1984; Schneider et al. 1983; Hughes et al. 1984; West et al. 1984). According to Hughes and Miller (unpublished manuscript), con- traindications include recent MIs or life-threatening arrythmias, severe or worsening angina, or active temporomandibular joint disease. Nicotine may aggravate coronary heart disease, vasospastic diseases, hypertension, diabetes, and hyperthyroidism. Because nicotine is swallowed during use of the gum, people with peptic ulcer or esophagitis may be particularly at risk. These contraindications are based on known or presumed relationships between nicotine and these conditions, and not upon direct tests of nicotine gum use. Women who are pregnant or nursing should also avoid gum use because nicotine decreases fetal breathing movements and is secret- ed in maternal milk (USDHHS 1980). Common side effects of use include air swallowing, belching, jaw ache, sore mouth or throat, upset stomach, hiccups, nausea, and mouth ulceration (Fagerstrom 1982; Jarvis et al. 1982; Russell et al. 1980; Schneider et al. 1983). Most side effects can be diminished by proper instruction on mode of chewing. The percentage of subjects who may become dependent upon gum use is not well known. In two studies, 3 to 7 percent of all subjects were considered dependent by the investigators (Jarvis et al. 1982; Raw et al. 1980). Given that nicotine gum does appear to alleviate withdrawal symptoms, to what extent has it been efficacious in cessation? Early studies of cessation were confounded by allowing smokers to simultaneously smoke and chew the gum (Brantmark et al. 1973; Puska et al. 1979; Russell et al. 1976b). More recently, controlled clinic-support studies have shown enhancement of both short- and long-term success rates with nicotine gum (Fagerstrom 1982; Jarvis et al. 1982; Schneider et al. 1983). Success has been attributed to an interaction between the active gum and the support systems in ways not yet understood. Schneider et al. (1983) compared nicotine and placebo gum in both dispensary and clinic settings. There was no effect of active gum in the dispensary setting; subjects chewed the gum for a very short time period and resumed smoking quickly. In the clinic conditions, the nicotine gum produced significantly higher success rates than placebo, with a peak difference achieved at 6 months (48 percent versus 20 percent). In other studies with followups of from 3 to 12 months, cessation rates were higher for groups receiving active gum than for placebo gum groups or groups receiving other treatments (Fee and Stewart 1982; Hjalmarson 1983; Jarvis 1983; Malcolm et al. 1980; Raw et al. 1980). Fagerstrom’s 477 (1982) work suggests that highly nicotine-dependent smokers may be the best candidates for gum use. Studies conducted in physicians’ offices have produced mixed results. In a study using over 1,500 patients with smoking-related diseases attending a hospital or chest clinic, there was no reported superiority of nicotine gum compared with several conditions involving usual physician advice to quit and a booklet (British Thoracic Society 1983). Overall, 9.7 percent of patients were absti- nent at 1 year, but approximately one-fourth of patients claiming abstinence had carboxyhemoglobin and plasma thiocyanate concen- trations typical of smokers. This study has been criticized for the manner in which the gum was administered to the patients (Jarvis and Russell 1983). On the other hand, Fagerstrom (1983) found . nicotine gum use to be statistically superior to a no-gum condition at — l-year followup in a 13-physician study involving 145 patients. Similarly, Russell and his colleagues (Russell et al. 1983a,b), in a well-designed study involving 1,938 general practice patients, ob- served a difference for the same time period. Success rates in the nicotine gum plus advice group were about double those in the nonintervention and advice-only groups (8.8 percent versus 4 percent not smoking at 4 months and at 1 year). These results are based on all smokers who saw their physician regardless of desire to quit. The higher success rate of the group offered the nicotine gum was achieved even though only 53 percent tried the gum. The self- selected subgroup who used more than one box of gum (105 pieces) had an adjusted long-term success rate of 24 percent. Reasons for the inconsistent results may relate to differences in (1) instructions on gum use given to the patient, (2) distribution of the gum (whether it was provided directly to the patient or offered in the form of a prescription), (3) patient personality characteristics or motivation for smoking, (4) support .or followup in addition to providing the gum, and (5) sample sizes and duration of followup. The first four of these factors can all affect compliance, which is deemed critical for effective use of the gum in physician practice. Key questions remaining to be systematically tested relate to what constitutes optimal gum use, such as dose, frequency, and duration (Schneider et al. 1983). Future research should resolve the general usefulness of this pharmacologic treatment as well as the appropri- ate adjunct treatment strategies. Discussion and Synthesis Methodological Considerations There is marked variation in the methodology and presentation of results from the studies included in this review, posing problems for comparison. To begin with, interventions are not always well 478 specified, making it difficult to categorize or to evaluate any given technique. This is particularly true in studies in which the interven- tion consisted of a very brief warning to quit delivered in the physician’s own style. Any accompanying written material is often only vaguely described. There are, of course, studies in which interventions are well detailed, such as the MRFIT trial (Ockene et al. 1982b). In this relatively new area of smoking cessation research, it is particularly important to researchers to report as much detail as possible on their intervention and control methods. In evaluating the success of interventions, standard definitions of outcome need to be agreed upon. These include total abstinence from tobacco use, not just cessation of cigarette smoking or reduction in total amount smoked. If multiple measures are preferred, abstinence should always be reported. Objective validation of self-report is critically important, especially when at-risk or patently ill patients may be biased to report abstinence. Followup periods should optimally be at least 1 year. When subjects are lost to followup, the method of calculating success rates should be clearly specified. For example, the most conservative criterion would dictate classifying as smokers subjects who refuse measurement. Other problems may include incomplete data because of nonsurvivors, especially in medical populations. If results are based only on those successfully followed, as much information on lost subjects as is possible should be provided. In retrospective studies, memory bias may also influ- ence results. Other problems common to smoking cessation research include inadequate sample sizes, which reduce statistical power; lack of comparison or control groups; and the failure to select an appropriate design, such as randomization or a quasi-experimental model. Design, methodology, and interpretation issues in smoking research have been treated in other sources in greater detail (Pederson 1982; USDHEW 1979; USDHHS 1982, 1983). Trends in the Literature When considering quit rates among the various patient groups discussed in this review, it is important to keep two considerations in mind. First, quit rates can vary as a function of the type of intervention, not only by patient group. For example, the highest quit rate among controlled pregnancy interventions (Sexton and Hebel 1984) was found in the study with the largest subject sample and strongest design, and consisted of a multiple contact interven- tion. Second, of the four classes of patient considered, persons with pulmonary and cardiac disease differ qualitatively from general practice and pregnant patients. The first two categories of patients have diseases directly related to their smoking behavior; risks and consequences of continued smoking can be personalized and detailed. On the other hand, general practice patients may not be coming in 479 for a problem directly related to their smoking. Battista (1983) reported that antismoking counseling was delivered by 99 percent of primary care physicians in his survey sample when the reason for the medical visit was related to smoking, but by only 52 percent when the medical problem was unrelated and a mere 11 percent when the visit was for a minor problem. Finally, pregnant patients seen routinely for prenatal care are usually not ill, and may have difficulty personalizing the risks to the fetus and to themselves, especially if they have smoked through previous pregnancies and borne healthy babies. Notwithstanding these limitations, some trends are evident in the literature: the quit rates in recent research appear lower than in older studies, and a positive association between severity of disease and quit rate can be noted. There are exceptions to these generaliza- tions, but the intention in presenting them is to bring some order to the results. The series of studies examining quit rates among pulmonary patients indicate a decrease in success over time, with more recent studies reporting lower rates. The same general trend appears among post-MI patient groups when data from groups receiving treatment in addition to physician advice are excluded. This apparent decline in effectiveness may be attributable to higher spontaneous quit rates in the population of smokers. Because more people are quitting on their own, fewer current smokers and more ex-smokers are presenting themselves to physicians. Included in the group of ex-smokers are those who a decade or two ago would have stopped on the advice of their physician, but who have quit because of media educational campaigns. Physicians specializing in pulmo- nary or cardiac disease are then left to deal with the more recalcitrant, hard-core group. In addition, current patients may be more honest in reporting failure to quit, and there are measures for objectively verifying verbal reports (e.g., expired air carbon monox- ide, carvoxyhemoglobin, saliva or blood thiocyanate, saliva or blood cotinine). | Although there are comparatively few studies with general practice patients and pregnant women, these two groups show fairly low abstinence rates. As mentioned above, when attending for routine visits, these patients are generally healthier than those with chronic pulmonary disease or cardiac disease. They are also less likely to be visiting the physician for an illness related to smoking. When treated with a powerful intervention, however, high cessation rates (over 40 percent) have been reported (Sexton and Hebel 1984). The quit rates among patients with pulmonary disease vary from 12.5 to 76 percent. The highest rates are found in studies including patients who have ever smoked in the past, as well as those who are smoking at the time of treatment (Daughton et al. 1980; Dudley et al. 480 1977; Mausner 1970). When these studies are excluded, the between- study rates cluster more closely between 20 and 40 percent. In general, it appears that patients with MI, especially those receiving strong advice, are much more likely to quit smoking than are other patient groups, with 40 to 50 percent abstinence levels being the rule rather than the exception. This finding matches the most successful behavioral interventions reported in the general smoking cessation literature—those programs with strong maintenance as well as cessation components (USDHHS 1982). The potential effect of continued smoking on future health status for cardiac patients has an immediacy that appears to motivate positive action. Six studies investigating severity of diagnosis (Baile et al. 1982; Campbell et al. 1983; Dudley et al. 1977; Mausner et al. 1970; Sillett et al. 1978; Wilhelmsson et al. 1975) support this relationship; one does not (Weinblatt et al. 1971). It is possible that the health benefits of cessation have been underestimated to date, if the most severely ill patients are the most likely to quit. Although this discussion implies a causal relationship between severity of disease and compliance, other explanations are possible. Factors such as personality characteristics that are differentially related to diagnosis and ease of quitting may influence results. In _ addition, physician involvement may be much more intense with patients who have more severe diagnoses and may be causally related to differential outcome. Patient Variables Related to Abstinence There have been a number of attempts to relate variables to successful quitting among patient groups. The underlying rationale of these attempts can be conceived as a search for possible causal factors. Multivariate statistical procedures have been used to generate predictive models, which may serve as the basis for theorizing about mechanics involved in explaining why some pa- tients quit smoking and others do not. The results with respiratory patients of Dudley et al. (1977) and Pederson and her colleagues (Pederson et al. 1980, 1982; Pederson and Baskerville 1983) were described earlier. Examining the psychological and behavioral variables, the retrospective study of Dudley et al. (1977) identified good adjustment variables as predictors of success, and the prospec- tive studies (Pederson et al. 1982; Pederson and Baskerville 1983) found that prediction of quitting and desire for quitting were positively associated with success, but addiction was negatively associated. In the MRFIT program (Ockene et al. 1982a), men at high risk for CHD who were classified as Continuing Successes (stopped smoking and maintained abstinence) were characterized as having, in combination (and in decreasing order of importance), a high expectation of success, few cigarettes smoked upon entry, low stress, 481 ease of prior cessation attempts, a long period of prior abstinence, and a high degree of personal security. Together, the combination of high stress and low psychosocial assets acted as barriers to long-term smoking cessation, characterizing the “problem smokers” (the combined group of nonstoppers and recidivists). The congruency of these findings suggests the need to “develop systematic and conve- nient ways to collect and use data regarding a participant’s experiences of stress and psychological assets,” according to Ockene et al. (1982a, p. 26). As studies of self-attribution of change related to positive outcome (self-efficacy) in smoking ceesation have shown (USDHHS 1982), these and related psychosocial variables may be critical predictors for all persons attempting smoking cessation. Thus, this approach should be expanded and tested on other patient populations. Physician Variables Related to Effectiveness Success rates in physician intervention studies have been shown to vary as a function of the participating physicians as well as of the interventions they employ (Ewart et al. 1983; Pincherle and Wright 1970; Rose and Hamilton 1978; Russell et al. 1979). While most smoking cessation studies using behavior modification techniques attempt to standardize the intervention and to eliminate differ- ences among those delivering it, physician intervention studies often involve advice delivered in the doctor’s own style and hope to capitalize on the personal interaction with the patient, e.g., Russell et al. (1979). As this stage of research it is sometimes difficult to separate out the various factors contributing to the degree of success of a particular intervention. Both types of intervention and physician factors were found to be important in determining success rates in two studies reported by Ewart et al. (1983), using two very different patient populations, asbestos-exposed shipyard workers (n=871) and low-income women attending family planning clinics (n=1,179). Physicians saw all patients only once; assignment to group was random in the shipyard study and controlled by clinic in the family planning population (quasi-experimental design). In both studies, the more detailed advice effort consisted of a physician’s warning to stop smoking with up to 5 minutes of individually focused cessation counseling. The comparison technique consisted of a simple warning by the physician (shipyard workers) or viewing an educational film (low-income | women). Cessation rates at 1 year in the detailed advice group were double those in the comparison group in both studies. Mean quit rates were not reported, but variability in physician success was examined. In the shipyard study, success rates were defined as the proportion of patients counseled by the physician who quit smoking 482 within 3 months. Among the four participating physicians, success rates ranged from 6 to 14 percent at the 1-year followup. Success rates were examined by types of patients assigned to each physician and by differences in physician behavior. Patient charac- teristics did not explain the variable rates of success between different physicians. These included medical symptoms, demograph- ics, physiological characteristics, and a number of behavioral vari- ables that have been found to predict smoking cessation (number of cigarettes smoked daily, motivation to quit, and length of past nonsmoking periods). On the other hand, physician motivation and effort in patient counseling emerged as important factors. When physician success rates were examined as a function of time since the continuing medical education (CME) training program over a 9- month period, all physicians were shown to become less effective as time passed, but two of the four had dramatic drop-offs in effective- ness. Declining rates of success were associated with lack of compliance with the protocol by failing to have the patient select a target date for quitting smoking. (Both patient and physician had been asked specifically about this in an exit interview. The propor- tion of patients who reported agreeing on such a target date was treated as an indirect marker of compliance.) Target date setting in noncompliant physicians decreased from 23 percent of patients counseled in the first 3-month period to 3 percent in the final 3- month period, with a concomitant decrease in success from 15 to 2.0 percent. In comparison, the two more successful physicians set target dates with 57 and 49 percent of their patients in the first and final 3- month study periods, and achieved 15 and 9 percent success rates, respectively. Furthermore, with the passage of time, the two less compliant physicians altered their pattern of target date setting with patients, providing such advice to many fewer lighter smokers (under 20 cigarettes per day) but maintaining the rate of advice with heavier smokers. The authors interpreted this as a selective shift of effort, but it can be seen also as a simple diminution of effort with the former group of patients because the proportion of heavy smokers advised did not actually increase over time. In the family planning clinic study, maintenance of physician performance was influenced by a feedback intervention. Perfor- mance was monitored by asking patients who had just seen the physician whether they had been counseled to quit smoking; when the percentage of patients reporting advice declined, a private personal communication was made with the physician. For both physicians involved in this study, the percentage of patients coun- seled to quit smoking rose after each feedback session. Although physicians may adequately learn antismoking interventions with training, these two studies show that their application of such skills may decline with time and their own modifications of the interven- 483 tions, two sources of variability that are potentially controllable with regular feedback sessions. Ewart et al. (1983) suggest that experi- mental designs include collecting continuous time series data that can be analyzed for individual and group performance trends. Such analyses will also provide a means of testing the generalizability of these findings. Conclusions Recommendations for Physicians Patients, particularly those who are not experiencing life and death decisions in which continuation of smoking is relevant, find it difficult to comply with their physicians’ advice to quit. Griffiths has observed, however, “Physicians frequently get discouraged with their rate of success, about one out of five, in helping patients to stop smoking. They forget, however, that their rate of success in curing lung cancer is much lower” (Griffiths 1981). As we have seen, a 20 percent cure rate would indeed be high for a truly minimal intervention. What are some of the actions that the physician who is interested in preventive action can take to assist his or her patients to stop smoking? Some suggestions come from a theoretical formulation known as the Health Belief Model (Becker 1974, 1976; Becker et al. 1979). According to the model, the following elements are hypothesized to determine behavior: the individual’s readiness to take action, determined by perceived susceptibility to the illness and perceived severity of the consequences of the illness; the individual’s evalu- ation of the feasibility and efficacy of health behavior; the individu- al’s evaluation of barriers to the health behavior; and a cue to action that triggers the behavior. On several of these elements, patients who are experiencing respiratory and cardiac problems have much more clearly defined reasons to be compliant with the request to quit smoking than patients seen in general practice. Thus, they would be seen as having stronger health beliefs. Women who are pregnant fall somewhere in between, depending on just how harmful they perceive their smoking to be to themselves and the fetus (Dalton et al. 1981). The clinician may succeed in motivating the members of the latter two groups by intensifying the message. Support for this position is found in studies that have compared more intense with less intense advice (Burt 1974; Ockene et al. 1982b; Raw 1976; Rose 1977). Other models with a more social learning and social psychological _ orientation pose as central concepts the belief in personal control (Bandura 1973) and the need for relearning to change the condi- tioned emotional schema that contribute to maintaining smoking (Leventhal and Cleary 1980). Social support has also been raised as an important theoretical variable (Ockene et al. 1982a; USDHHS 484 1980). Practical applications of such approaches might be assessing and bolstering the self-confidence of a patient wishing to quit smoking and involving a spouse in the cessation effort. The physician’s message must be tempered with other factors, such as the strength of already existing beliefs and the mechanisms for continued smoking. Work by Leventhal (1968, 1970) on the communication of fear messages suggests that such messages may interfere with adoption of a recommended health-facilitating behav- ior. For example, he found that smokers are less likely to undergo a chest X-ray after viewing a filmed lung cancer operation than smokers who do not view the film, because the experience produces an increased fear that interferes with the goal of the advice. The extent of the interference is probably related to the purpose that smoking serves for the person (whether it is arousal reducing or habitual). Physicians should also appreciate the importance of both physio- logical and personality variables that lead to the initiation and maintenance of smoking (USDHEW 1979; USDHHS 1982). Likewise, they should consider both the habitual and the addictive components of smoking behavior and the consequent difficulty in producing extinction (APA 1980; NIDA 1979). When these factors are consid- ered, it is not surprising that a brief warning to a “healthy” patient is not effective. In this context, “healthy” relates to the lack of current major symptoms that the smoker relates to smoking. Physicians do not need to assume full responsibility for helping patients quit smoking, however. Lichtenstein and Danaher’s (1978) model suggests that the physician can become involved with patients at a variety of levels, although Wilson et al. (1982) indicate that continuing contact with the patient can be useful. Chu and Day (1981), Ewart et al. (1983), and Spencer (1983) have shown that awareness of smoking and providing antismoking materials for clinical use can motivate physicians toward increased effort with smoking patients. Wechsler et al. (1983) found that 81 percent of primary care physicians surveyed personally provided patient educa- tion as opposed to having a nurse or other health professional deliver it. They were more likely to want to learn about a specific area (e.g., smoking cessation techniques) in CME classes if they believed in the importance of changing behavior in that area and had confidence in their chances of success in helping patients. Thus, physician self- efficacy is an important concept in delivering smoking cessation advice. The most valuable types of assistance identified by the physicians in this study were information on referral sources, financial reimbursement for health-promotion services and staffing, literature for distribution to patients, and training for physicians, support staff, or both. The direct provider role, as well as other roles for the physician (such as referral to treatment), has been described, 485 and practical guides that cover the physician’s involvement on a number of levels do exist (Pechacek and Grimm 1983; Shipley and Orleans 1982). Smoking cessation materials prepared especially for the physician are available from the National Cancer Institute—the Helping Smokers Quit Kit—and from the American Cancer Soci- ety—the Physician’s Help Quit Kit. These kits have not yet been formally evaluated for efficacy. Future Research A number of salient issues for future research in the area of physician intervention emerge from this review. First of all, the interventions that will work best for physician providers have yet to be identified. For example, is a minimal intervention like simple advice to quit the optimal use of a physician’s time, or can physicians successfully integrate a multicomponent or multistage intervention into their practice and achieve substantially higher quit rates? What techniques supplementary to physician advice will yield maximum return in cessation? What are the differential effects of advice alone and of the offer of treatment on the likelihood of cessation? How does one improve the communication skills of physicians practicing health education with patients? Second, will different interventions work best for different pa- tients classified according to disease status? Will tailoring treat- ments according to patient group or to individual patient character- istics be useful (Best 1975; Best and Steffy 1975; Eiser 1982)? Can the physician employ a sequential model of smoking behavior (Prochas- ka and DiClemente 1983) so that interventions can be staged according to the patient’s readiness to quit smoking? Third, what kind of training in smoking cessation will be most effective for physicians? Training formats range from noninteractive materials such as printed matter and audio or video cassettes to formal programs such as CME classes or other instructor-led workshops or programs. Should role modeling and direct practice under supervision be used to help teach skills? What educational (or other) efforts will be needed to sustain physician counseling efforts and success? Fourth, what are the variables controlling differential success rates among physicians? Are they personal variables, like smoking status (American Cancer Society 1981; Danaher 1978), or training- influenced performance factors such as consistency of applied effort over time (Ewart et al. 1983)? How can physician motivation to counsel patients be increased and maintained? How can physicians best be delivered feedback about their counseling performance as well as the efficacy of their efforts? Fifth, future research needs to pay closer attention to methodologi- cal considerations that will facilitate testing hypotheses and evaluat- 486 ing outcomes. These have been summarized earlier and involve design considerations, assignment of patients to groups, followup of outcome, and objective verification of self-report. Sufficient evidence has been presented here to support an effective role for the physician, as the leading and most credible figure in the health care world, in smoking cessation efforts. As Cullen and Gritz (1983) stated, “The most effective technique to be employed, as well as when and with what specific group, can await further research. But given the importance of smoking as the most potent, preventable pathogen still responsible for a substantial amount of premature mortality, morbidity, and health care costs, there is no longer an excuse for physicians to leave this effort solely to other health professionals” (p. 224). Summary and Conclusions 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. j 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 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, 487 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. 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COMMUNITY STUDIES OF SMOKING CESSATION AND PREVENTION - ' > i-@ 4 ‘ “ ‘ ’ nd , , ‘ : oe «=? s > ; ¥ an] ‘ - ' 42 - ) \ we » r i <7 yer? t rly ‘7 iw wr) on? eondto®, ASD Whe 4 i Me theetrn st = * eto RARE lone Sie 4 CONTENTS Introduction Characteristics of a Controlled Community Study Theoretical Background Mass Communication Community Organization Environmental Change Cessation Studies Stanford Three-Community Study Australian North Coast Program Swiss National Research Program The North Karelia Project Other Large-Scale Studies Related Studies of Cessation Prevention Studies Stanford Study The North Karelia Youth Project Other Prevention Studies Methodological Issues Directions for Future Studies Summary and Conclusions References An seco) fwiiesingD « 26 OO Age, ey ee : cd y Ps > Ws; ou “a é » uh i = hn d 5m et | ge oi ; -—< +9 —— . . ——« bad qi - a ~s —e sus o.2) ii ae] b~ o —_ n oe ~ ~ é j \) - ’ ee oo iio ' cin . 1 ra y Bi “RAS ‘ 5 -” -t pawl Ue (s Pteted 4!» te § Introduction Community studies of smoking cessation and prevention are defined as research in which geographically defined populations or age cohorts are selected for experimental intervention or as control or comparison groups. In this chapter, four major studies of cessation are described, and related research findings are briefly considered. Three major studies of prevention are also reviewed, with less extensive presentations of other recent research. The theoretical background for these studies is outlined, methodological issues are discussed, and directions for future research are suggested. It is concluded that community studies represent a significant emerging paradigm for public health research. The first public health “revolution,” the recently achieved control of major infectious disease, evolved in two phases: (1) recognition that certain aspects of the environment are associated with disease, and (2) establishment of sanitation facilities and services, such as refuse collection and plumbing systems, for entire communities of people. Basic public health engineering that was revolutionary a century ago is now taken for granted by society. Today we emphasize the second public health “revolution,” the current efforts to control chronic disease through behavior change. This development has also evolved in two stages: (1) recognition of behaviors, such as cigarette smoking, as being associated with disease, and (2) development of new services to change those behaviors (Wynder and Hoffman 1979). As might be expected, this most recent history of public health is no less turbulent than that which preceded it. Various factors have hindered progress. After the basic causes of smoking-related diseases were recognized, there has been a tendency to invest scarce resources in increasingly intricate studies of disease causation processes. In addition, once funding is secured for inter- vention to reduce smoking, efforts often focus on individual-level, clinically oriented interventions (Lichtenstein 1982). If these inter- ventions do not succeed, society is inclined to “blame the victim,” much as the poor were held responsible for the microbes in their water by 19th century social conservatives. The socioeconomic gradient in rates of smoking and smoking-related disease may also slow society’s response at a community level to this modern, noncommunicable disease epidemic. The greatest factor inhibiting progress, however, is the cost of prevention. Such costs are com- pounded by political obstacles stemming from the tremendous influence of the tobacco industry, which employs thousands of people and regularly delivers a substantial portion of tax revenues (Breslow 1982; Fritschler 1975; Sapolsky 1980). On a national scale, dramatic changes in tobacco consumption have occurred in response to successive measures (Warner 1977; Warner and Murt 1982), but these have been limited largely to higher income groups. Few 503 examples of bold community or regional efforts comparable to those involved in the control of infectious disease have been witnessed, and the prevalence of smoking has declined much less dramatically among women and has even increased in some minorities. Characteristics of a Controlled Community Study For this discussion, a controlled community study is defined according to the scope of intervention and quality of research design, with the essential feature being identification of natural, location- based aggregations of individuals as well as formal and informal social systems. In a community study, the entire population of a geographic area is considered, so that a church or worksite is not a community itself, but one of many systems constituting the total network of interactions. The term “community” originally referred to small systems numbering no more than several thousand persons. This discussion, however, includes research on towns, counties, or other relatively independent zones with up to several hundred thousand inhabitants. Because educational systems represent all age cohorts of youth, school-based studies are also reported. Studies of entire States or nations are only briefly considered. Because the population size to be addressed is a limiting factor in any social program, the large numbers of people involved in a community study dictate selection of intervention methods. Clinical or other people-oriented approaches that typify behavioral research on smoking cessation and prevention (Bernstein 1969; Bernstein and McAlister 1976; Pechacek and McAlister 1980; Lando and McGovern 1982; Lichtenstein 1982) are not feasible for programs directed toward many thousands of people. Community studies instead emphasize large-scale delivery systems such as the mass communica- tion media. Because community participation is now considered essential for success, such studies also include community organiza- tion programs seeking to stimulate interpersonal communication in ways that are feasible on a large-scale basis. Community studies also may involve environmental change, such as programs to modify the purchase price or availability of consumer products or to sanction public behaviors. | Because the emphasis herein is on controlled community research, attention is limited to studies in which valid inferences can be made ~ concerning the effects of intervention on smoking rates in an entire population. The essential elements are use of adequate measures of smoking behavior applied over time in order to estimate long-term trends, and equally important, the inclusion of control or reference areas for the purpose of comparison. There are, of course, many questions and controversies regarding the usefulness and validity of large-scale experimental or quasi-experimental research (Campbell 504 and Cook 1979). Social policies such as those needed to sharply reduce smoking are not likely to be introduced without experimental trials, however, and the studies reported herein probably represent the best currently attainable compromise between external and internal validity. Given the very small number of studies meeting even the minimal methodological criteria, it would be unwise to restrict this review to the standards required by laboratory or clinical studies. Theoretical Background Effective mass communication, community organization, and environmental change require a theoretical basis for planning. Most community studies of health promotion and disease prevention are based on fundamental theories and concepts from the behavioral sciences. The most important of these are briefly outlined below. Mass Communication Theories on mass media effect have changed during the recent history of communication research, and several clear stages have been identified (Klapper 1960; Griffiths and Knutson 1960; Atkin 1979; Flay et al. 1980; Wallack 1981). Media were initially considered nearly omnipotent in directly altering behavior, but it was later discovered that they are incapable of producing effects independent of other, more powerful social forces. The most recent view is that mass media may have effects, but that they are small and largely dependent on facilitation from interpersonal influences and favor- able environmental circumstances. Notwithstanding these limita- tions, shifts of a few percentage points in consumer preferences may be very significant in product marketing, while similar reductions in chronic disease-promoting behaviors may have enormous absolute significance in a population of several millions. One mass media effect that is agreed upon by most communication scientists is termed the “agenda-setting function” (McCombs and Shaw 1972), in which the media powerfully influence topics generated in formal and informal social gatherings. Media communication can also inform and teach simple skills (Bandura 1977). But the manner in which people actually behave with regard to a particular topic of discus- sion, and whether or not information or skills are actually used, depends more upon interpersonal forces than upon the media messages themselves. Community Organization The theories and concepts that underlie community organization are less well developed than those applied to media planning. Although there is broad agreement that the effects of the media are 505 enhanced by interpersonal factors, there is no clear consensus on the exact identity of those factors or how they can be feasibly modified in entire communities. A useful principle is derived from Bandura’s (1977) distinction between factors influencing acquisition of new behaviors and those influencing performance of new behaviors. Media communications can model new behaviors so that they are learned (acquired) on a cognitive level (the person knows how to perform the behavior). However, cueing and feedback (direct social reinforcement) are usually needed for behavioral learning, or actual performance of the new behavior. Numerous studies of learning via media communication show that when a complex behavior is being learned, effectiveness is sharply enhanced by providing supplemen- tary interpersonal communication for encouragement, feedback, and reinforcement (Bandura 1977). To create feedback and reinforce- ment in a community setting, organizations must be involved to provide roles and structure for interpersonal communication. Where formal sociai networks are not involved, communication and influ- ence will be diffused through families and other informal systems (Meyer et al. 1977). The effectiveness of interpersonal communica- tion can be greatly enhanced, however, by organizing formal or semiformal structures, such as learning groups using leaders trained to lead discussions, answer questions, and provide encouragement and followup. Various campaigns in agricultural development illus- trate these principles (Green 1970; Rogers and Shoemaker 1971). A related factor is the notion of generalized social support (Caplan et al. 1975), which refers not to the differential social reinforcement of specific behaviors, but to the general extent and quality of interpersonal relationships. Social relations appear to be generally helpful, probably because of their “stress-buffering” effects. Social ties within the family probably enhance cessation and prevention of tobacco use. For example, spousal support leads to higher successful quit rates (West et al. 1977; Mermelstein et al. 1983), and lower rates of teenage smoking occur in families in which neither parent smokes (National Institute on Education 1979). The general enhancement of interpersona! support networks is, of course, a primary objective of religious groups and social work and most other helping professions. Environmental Change There are also theories and concepts from which environmental changes can be planned (Bandura 1977; Craik 1973), the basic principle of which is to modify the availability and cost of products or behaviors (such as by limiting supply or prohibiting behaviors in public settings). Not all such measures can be applied by communi- ties as defined herein. For example, regulations on mass media advertising can probably be controlled in most cases only at the Federal level, although billboard advertising may be amenabie to 506 more local control. Other promising interventions such as taxation (Lewit et al. 1981; Fugi 1980) can be applied within fairly small localities, but the risk of “black market” competition is lessened when economic controls are fairly uniform across larger geographic units. Product availability and regulation of behavior can be achieved by towns or countries, but restrictive regulations almost invariably arouse opposition unless the public is willing to self- enforce the restrictions. Therefore, it is legitimate to favor voluntary restraints over those that require formal policing. Syme and Alcalay (1982) call for intervention and prevention efforts at the community level using a public education agenda. Such programs will seek to increase public awareness of the health consequences of smoking, create an atmosphere in which smoking is recognized as a minority behavior, influence public policy, and increase antismoking adver- tisements. Breslow (1982) has recently reviewed the environmental and public policy approaches to smoking control and calls for a “compre- hensive strategy that will mobilize all available resources most effectively” (p. 149). He advocates Federal, State, and local legisla- tion as the most important forms of social action directed toward action alternatives as well as research. He states that “protection and advancement of economic interests will generally follow prevail- ing ideology. Finding ways of cutting through the economic barriers, as always, will pose a challenge to public health. While compromises will be necessary, the objective of steady movement toward the goal now seems attainable” (p. 149). | Cessation Studies Controlled community studies on smoking cessation are still relatively scarce. However, community trials for cardiovascular disease prevention, in which cigarette smoking is the major risk factor, are providing some of the best examples of research in this area. These studies have tended to focus on cessation among adults because primary outcomes of the trials include possible short-term (5- to 10-year) effects on cardiovascular mortality and morbidity rates that could hypothetically result from widespread adult cessa- tion. These studies were reviewed in depth in the 1983 Report of the Surgeon General The Health Consequences of Smoking (USDHHS 1983). Stanford Three-Community Study The most well known U.S. cardiovascular community study was conducted in California by Farquhar, Maccoby, and colleagues at Stanford University (Farquhar et al. 1977; Maccoby and Alexander 1980; Meyer et al. 1980). Beginning in 1972 and ending in 1976, the 507 study was supported threugh the National Institutes of Health research grant program and involved three small communities (population of each was approximately 20,000) nonrandomly as- signed to control, media-only, or media and face-to-face programs. The three towns are all within 100 miles of Stanford University. The control town, Tracy, is located in an inner valley and not exposed to media sources common to the other two towns, Gilroy and Watson- ville. Gilroy, assigned to the media-only condition, is situated in a coastal valley, and Watsonville, receiving a small additional inter- personal communication program, is on the coast. In Watsonville, a cardiovascular high risk group including many smokers (n=169) was identified, and 113 cases were randomly assigned at a 2:1 ratio for face-to-face intervention. The three towns are demographically similar, although the proximity of Watsonville and Gilroy to the larger cities of Santa Cruz and San Jose gives them more cosmopoli- tan features than Tracy. Nevertheless, the research design was probably the best balance of feasibility and external and internal validity that could have been achieved in that setting given the limited available resources. In each town, multistage probability samples of households were contacted and invited to a survey station where questionnaires and physiological measures were administered. These surveys were applied in the autumn months, beginning in Watsonville in Septem- ber and ending in Tracy in November. Approximately 600 persons aged 35 to 59 were sampled at each location. The measurements included questions about smoking, and serum samples from high risk participants were analyzed to estimate thiocyanate concentrations as a check on inaccurate reporting of smoking status (Meyer et al. 1980). These measurements were taken annually for 4 years, yielding a picture of 3-year smoking trends among the survey participants in the three communities. | The program of media communication was conducted over 3 years (1973 to 1975), with greatest intensity in the first and second years of work. Television, newspapers, radio, billboards, and direct mail advertising were designed to provide information and to model attitudes and skills that would promote behavioral changes associ- ated with lowered cardiovascular risk, such as weight reduction, lowered fat consumption, and increased exercise. To encourage cessation of smoking, information about its harmful effects was given, along with advice on how to stop smoking. In booklets mailed to the sampled households in Gilroy and Watsonville, instructions were provided for simple self-control skills (Meyer et al. 1980). In brief television and radio communications, actors were shown recommending or modeling cessation of smoking in a variety of authoritative and entertaining ways. 508 The face-to-face, intensive instruction program was provided for 113 randomly assigned high risk participants in Watsonville, of whom 107 started treatment, and 77 continued for the second annual examination. Activities were based on principles of behavioral psychology and group dynamics and were designed to reinforce and train skills for behavior change (Meyer et al. 1980). The first-year program consisted of classes and home visits, mostly during the summer of 1973. During the summer of the following year, aggres- sive followup activities were conducted to reinforce smokers who reported cessation and to encourage and train those who were not yet able to quit. This maintenance program included training in stress management and other intensive, individual counseling for those who consented to continuing contact. In the third year, the activities were gradually reduced to telephone contacts and a small “reunion” in the summer of 1975. The results of the program among high risk participants in each of the four surveys are displayed in Figure 1. Over the 3 years of study, the prevalence of smoking decreased markedly among the group receiving media and face-to-face communication. The group receiv- ing media intervention showed an initial decline as compared with the control group, but the change did not differ from the modest reduction observed in Tracy over the entire 3-year period. Because the high risk samples included most of the older smokers in the survey samples from each community, the data on cessation in the complete samples corresponded closely to that of the high risk group. The serum thiocyanate tests indicated very slight overreporting of cessation (Farquhar et al. 1977), but self-reported cessation rates were not adjusted for thiocyanate findings (Kasl 1980). There was some attrition in this longitudinal study, but not enough to account for the clear differences in cessation rates between the intensively instructed and the other participants. Adjusting for attrition, 32 percent reported sustained cessation in the intensive intervention group (Meyer et al. 1980). This research supports the hypothesis that face-to-face communication is a necessary part of a successful community program to reduce smoking. Farquhar and his colleagues (Farquhar et al. 1981) conclude that the question of how such communication can be feasibly and cost-effectively provided on a widespread basis remains to be answered by further studies, and this conclusion will be noted in a later section. A number of critical comments can be made in regard to the Stanford three-community study, and these have been thoroughly discussed in numerous publications (Leventhal and Cleary 1980; Meyer et al. 1980). The primary shortcomings concern the quasi-experimental research design and the inability to generalize from the longitudinally followed study group to the entire community. 509 Gilroy—media only Watsonville—intensive instruction plus media Percent change in smokers Survey FIGURE 1.—Comparison of cessation rates among smokers in communities subjected to varied intensities of education, the Stanford three-community study SOURCE: Farquhar et al. (1981). Australian North Coast Program A trial very similar to the Stanford three-community study was conducted by the regional Health Department of New South Wales, Australia (Egger et al. 1983), beginning in 1978 and, as in the Stanford study, using small community populations of 12,000 to 27,000 persons. The towns of Tamworth, Coff’s Harbor, and Lismore were assigned to one of three conditions: control, media only, or combined media and community programs. The three towns were all between 300 and 400 miles from the research center in Sydney. Coff’s Harbor, the media-only town, was approximately half the size of the other two communities. Tamworth was not served by the regional administrative center in Sydney. In each town, a series of random sample surveys was conducted. Interviews and physiological examinations were requested from up to two adults in randomly sampled households. Those who refused appointments were given self-report questionnaires to be completed at home. Separate samples were drawn in 1978, 1980, and 1981 with the objective of measuring 600, 1,200, and 1,200 different persons in the 3 respective years. Smoking behavior, attitudes, and knowledge 510 regarding smoking were measured, and in 1980 and 1981, serum thiocyanate values were determined for a randomly selected 5 percent subsample. Measures were also made of other cardiovascular disease risk factors in accordance with the program’s primary goal. The media program included output from a television station, a radio station, and several small newspapers, supplemented by other materials such as stickers, posters, T-shirts, and balloons. The three stages of the media campaign were designed to sequentially raise awareness, provide information, and stimulate action. Advertising time was purchased to insure presentation of television commercials during peak viewing periods. Beginning in October 1979, the print advertisements were suspended for several months because of a complaint to the Media Council of Australia. The overall campaign continued for approximately 1 year. The community program ‘that was applied in Lismore was varied. Several different kinds of groups, clinics, workshops, and other interpersonal support systems were organized; physicians were also involved. A total of 386 smokers participated in these activities, most (150) joining a 1-day workshop. The 3-month success rate in smoking cessation, measured by telephone interview, was 16 percent for the workshop participants. The highest success rate (48 percent) was found for the 40 persons who received help kits from physicians. The community program also included other programs (e.g., for physical fitness and stress management), which may have facilitated the cessation of smoking. The results of the project were based on the three independent sample surveys. The authors point out that “there was substantial confounding owing to age and sex differences between towns” (p. 1127). Analyzing results according to a multiple logistic model controlling for age and sex differences, a significant treatment effect (p=0.05) was observed. Thiocyanate analyses showed no difference between towns in the small estimated invalidity of self-reports (3 percent). Among men and women in various age groups, consistently different rates of change in prevalence of smoking were found. In Lismore, absolute percentage reductions ranged from 6 to 15 percent. In the media-only town (Coff’s Harbor) absolute 6 to 11 percent reductions were estimated. In Tamworth (the control) absolute reductions of only 2 to 5 percent were found. The research- ers found no evidence of effects on knowledge or attitudes. Many criticisms can be made from the standpoint of a clinical scientist accustomed to dealing with individual subjects in highly controlled settings. If limitations to inference are clearly acknowl- edged, however, the Australian study provides a practical illustra- tion of what may be achieved through community intervention. The findings are based on independent samples, and thus represent changes that seem to have occurred on a communitywide basis. The magnitude of the apparent effect was particularly encouraging 511 among the youngest age groups (18 to 25) where absolute reductions in prevalence of smoking showed a threefold difference between the maximum intervention (15.6 percent) and control towns (5.0 per- cent). The most significant limitation arises out of the nonrandom assignment of communities and problems with their comparability. Swiss National Research Program Another important community study was conducted in Switzer- land (Autorengruppe Nationales Forschungsprogramm 1984; Gutz- willer and Schweizer 1983). Four communities of 12,000 to 16,000 inhabitants were selected, two each from the German-speaking and the French-speaking parts of the country. A fifth community in the Italian-speaking region was also studied, but only for epidemiological purposes. French-speaking and German-speaking pairs were ran- domly assigned to intervention (Nyon) or regular care (Solothurn and Vevey) conditions. This project was conducted over a 4-year period with research support from the Swiss National Science Foundation. A baseline assessment was made in late 1977 and early 1978 by stratified random sampling and examination of 2,000 persons aged 16 to 69 in each community. With attrition of approximately 30 percent, this sample was resurveyed at the end of 1980, at which time another independent sample was drawn and surveyed. A questionnaire was used to determine smoking behavior, and plasma thiocyanate was measured on a subsample of respon- dents. Other health-related factors such as blood pressure, lipid fractions, exercise tolerance, and psychosocial adjustment were also measured. The community interventions were conducted over 2.5 years in Nyon, with guiding principles of “active local participation” and “integration into existing local health and social services.” The central feature was the establishment of a Citizen Health Action Committee in each of the two towns, with a coordinator assigned to guide local planning and implementation. Media and community organizations were combined to promote a variety of programs in each location, including classes, self-help groups, and meetings to discuss topics such as environmental regulation via public non- smoking areas. The results of this study are moderately encouraging. Within the sample population surveyed at baseline and followup, 26 percent of the regular smokers in the intervention communities reported cessation. In the control areas, 18 percent of the corresponding group reported cessation. The investigators also report effects on other cardiovascular disease risk factors, although plasma cholesterol reductions were significant only for women in the German-speaking region. A cost-benefit estimation model has been applied to the data and results indicate a twofold cost-benefit ratio. The use of indepen- 512 dent surveys and the random assignment of communities represent significant methodological strengths as compared with the Stanford and Australian studies. However, the rural communities in this study were very small, and only four were included. The final report has been presented to formal decisionmakers to determine whether broader national efforts are warranted. The North Karelia Project The best documented long-term community study is being conduct- ed in Finland by Puska and colleagues (Puska et al. 1979, 1981, 1983a; Puska and Koskela 1983; McAlister et al. 1982). Also beginning in 1972 and continuing to the present, the research is comparing changes in cardiovascular disease risk factors in two neighboring counties of eastern Finland, Kuopio and North Karelia. Both are large rural areas with numerous small farming, lumber, or mining communities and a single major town. North Karelia is representative of eastern Finland as a whole in having one of the world’s highest rates of cardiovascular disease (Pyérala 1974; World Health Organization 1975). Financial support for the intervention came from the Finnish Ministry of Health, following a formal request from leaders in North Karelia for help in reducing the high mortality and morbidity levels. Research funds were awarded by the Academy of Finland. The neighboring county of Kuopio was selected as a reference or control location. In North Karelia, a broad program was implemented to provide new services, education, and training through community health centers, the mass media, and a variety of community organizations. During the second 5 years of the project, media programs were carried out on a national level, with special organizing and support for activities in North Karelia. In both counties, independent samples of households were drawn in 1972, 1977, and 1982, with approximately 5,000 persons aged 25 to 59 in 1972 sampled in each area in the first two surveys and about 4,000 aged 25 to 64 sampled in the 1982 measurement. Response rates were generally excellent, and nearly 90 percent of the sample participated by attending local survey centers in the spring of each of the survey years (1972, 1977, 1982). Self-reported cigarette-smok- ing behavior was measured in all three surveys. In the 1977 survey, serum thiocyanate values were estimated for a subsample, and in the 1982 survey, for all participants. For the 1977 sample, there was 99 percent agreement in smoking status (smoker/nonsmoker), and when classified by intervals of 5 or 10 cigarettes, the agreement between results was 93 and 97 percent, respectively (Puska et al. 1979). The age-adjusted partial correlation between daily reported number of cigarettes and serum thiocyanate in 1982 was approxi- mately 0.7 among men and women in both areas. In the years when the larger surveys were not conducted, smaller samples (1,200 to 513 3,500) were selected yearly for a postal survey of North Karelia. Together, these measurements provide a comparative view of trends over 10 years in the populations of both counties and a year-to-year picture of the changes in North Karelia. | The program of service, education, and training was very broad in scope. Initially, an intensive educational campaign was conducted for reduction of cigarette smoking with cooperation from the news media. Physicians and public health nurses staffing community health centers were provided special training and were encouraged to recommend cessation to all patients visiting the centers. Tens of thousands of leaflets and posters were distributed to encourage nonsmoking. With assistance from Heart Association volunteers in each small community, informal restrictions on smoking and point- of-purchase advertising were adopted. During 1976 and 1977, these measures became part of a package of national legislation that increased cigarette tax revenue, directed health services to provide information services, limited public smoking, and banned tobacco advertising. During the second 5-year period, an effort was made to provide nationwide applications, while maintaining intensive community work in North Karelia. A series of programs was broadcast national- ly on television to demonstration how “average” people stop smoking (Puska et al. 1981). In association with these broadcasts, special organizing campaigns were conducted in North Karelia to increase social support for people attempting to quit. These activities occurred in the winters of 1978, 1979, 1980, and 1982 and were seen nationally by a majority of the population, with higher viewership in North Karelia. During the first broadcast series, an effort was made to encourage the formation of informal volunteer-led self-help groups to view the broadcasts together. Very few volunteers succeed- ed in establishing groups, however, and focus in subsequent years has been on training volunteers to provide even less formal cueing, reinforcement, and support in their incidental, day-to-day contacts with cigarette smokers (Puska et al. 1981). The results to date (Puska and Koskela 1983) are presented in Table 1. Over the 10-year period, self-reported numbers of cigarettes smoked per day fell by more than one-third among men in North Karelia. In the control or reference area, a less than 10 percent reduction was observed. Changes in prevalence of smoking account for most of this difference. No evidence of an effect occurred among women, with rates of smoking going up in both areas. In Figure 2, the year-to-year data for 25- to 29-year-old men and women in North Karelia show an interesting pattern, with the sharpest declines among men associated with the first year of work and with the television broadcasts and associated activities in 1978 to 1980 and in 1982. Since 1978, when new antismoking laws were passed, the 514 proportion of male smokers aged 15 to 64 has changed from 44 to 31 percent in North Karelia, and from 39 to 35 percent in the rest of the country, a difference of 9 percent in absolute rates of change over that 4-year period. Although the effect of changes in smoking cannot be separated from the effects of new hypertension services and other measures to prevent cardiovascular disease, there is some early indication that mortality rates may have been influenced by the program: a 24 percent decline in cardiovascular deaths has been observed in North Karelia, compared with a 12 percent decline nationally in Finland (Puska et al. 1983a, b). The North Karelia Project has received much attention, and various points of controversy have been widely discussed. The methodology of the study does not compare with that achieved in controlled clinical trials, but it may have been the optimal design that was feasible in the circumstances. Puska and his colleagues point out that “it is easy to say that the North Karelia Project was successful because of the unique historical background and because the conditions in North Karelia were favorable for the program. However, at the planning stage, great concern was expressed because the area was rural, of low socioeconomic status with high unemployment, and so forth.” Because a large number of indepen- dent units were not randomly assigned to experimental and control conditions, the Finnish study cannot be taken as a conclusive test of the effects of community programs, but it does provide a promising illustration and evaluation of what can be achieved through broad and vigorous intervention to reduce smoking behavior. Its major strengths are the relatively large number of different communities that were studied and the 10-year followup interval. Other Large-Scale Studies There have been a number of other large-scale controlled studies, single and multifactor clinical trials, and worksite trials that provide a context for the consideration of the community-level intervention studies described above. These studies were discussed in the 1983 Report of the Surgeon General The Health Consequences of Smoking and include the London Civil Servants Smoking Trial (Rose and Hamilton 1978; Rose et al. 1980, 1982), the Goteborg (Sweden) study (Werko 1979; Wilhelmsen 1981; Wilhelmsen et al. 1972), the Oslo (Norway) study (Hjermann et al. 1981; Holme et al. 1981), the World Health Organization European Collaborative Trials (WHO European Collaborative Group 1974; Kornitzer et al. 1980a, b) and the Multiple Risk Factor Intervention Trial (MRFIT) (Hughes et al. 1981; MRFIRG 1982). In the sole American study (MRFIT), 12,866 men, 35 to 57 years old and at high risk for coronary heart disease (CHD), were entered into a randomized clinical trial designed to test the effect of a multifactor intervention program on CHD morbidity and 515 ‘E86T) B[24s0y pue BysNg “AOUNOS “SOUBLIBA Jo siskTeuy = VY AONV s ‘(SLET-LLET/Z86T “Bere soussajey) — (Z/61-LLET/Z86I “BteIey YON) , nnn nnn nnn rr SSS SSS Too'0>d so'o>d xos-OUll}-Boly Too'0>d Too>d oull}-Bely 1000 >d 1000 >d WouIOM Too'0>d ‘su oul], ‘s'U 100'0>d ueW ‘su co'o>d Bely BIB BOUsIIjayY BIeIey YWON C86T “LLET ‘SLET puer} C86I-ZL6T LL6I-ZL6T z VAONV 4eM-In0J Teoul] 10} VAONV _—_— SSS Ss SSS iat 8 To + 61 br FET sé + ZT Ly FLT ov F+TT sé +IT TBO], Th €F OF FCT ce + 80 § +01 98 + 60 ve +10 cé + L0 63-0 9€ €% 6h FLT Ue Ras ea | ce FOOT Tyee oy + TI OF + ZT 6F-0F j ST 9 + 8Z 8h + 02 cy + GT sg + 9% To +91 oy FFT 6&-0€ waul0M 8 €T TIl + SL VIL + G8 90T + G8 COT + 99 61I + 98 STt + OOT TROL €Z 9T 96 +99 GOT + LL 66 FLL L6 FL GIT + 6L LOT + 06 6S-0S 1Z OT LIl + 08 VIT + 98 LOl + 06 Ol + OL OTT + G8 ol + 201 6-07 €€ 91 cIl + 98 6TT + 06 OTT + G8 LOT + GL G2I + 06 LIL + 9OT 6E-0€ ua, —_—_—_——————————————————————— C86I-CL6T LLEI-ZLET o86T LL6T oLét o86T LL6T oL6l (sree) , e8ejUs0Jed ‘souslajJIp 49N Bale sOUalIjayY BYaIVy YVION ee pus xag e386 pues xos Aq ‘sojdures Aoams dnmojjoy (Zg6l) 1804-9] pus (L261) 1eah-g pues (ZZ6]) CUT[eseq yUopuadepuT Ul “BaIB BdUdIJoI 94} PUB BIAIVyY YON ul (Gg+) Suryous Ajrep poziodei Jo yunowe uveaW—T] WIAVL 516 Men Women 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 EOT2 50 40 oO oO oO N 10 Percentage of smokers FIGURE 2.—Prevalence of smoking among men and women, aged 25-29, North Karelia, 1972-1982 SOURCE: Puska and Koskela (1983). mortality. They were followed for an average of 7 years. At intake, 517 TABLE 2.—Results of community studies compared with other large-scale studies Years of Net percent reduction Study study in smoking? Strengths - Weaknesses Stanford Three- Matched Panel study Community study 3 15-20 communities only - Australian Independent Problems with North Coast 3 15 samples comparability study of groups Swiss National Randomization, Small size and Research 3 8 independent number of program samples study sites North Karelia Numerous Nonrandom project 10 25? communities, assignment independent samples Other large- Internal External scale studies * 2-10 5-25 validity validity ' Difference between percent reduction in proportion of smokers in the maximum intervention versus control condiiions. ? Difference between percent reduction in the mean number of cigarettes smoked per day among men. *Clinical and work-site trials: the London Civi! Servants Smoking Trial, the Géteborg study, the Oslo study, the WHO Collaborative Trial, and the Multiple Risk Factor Intervention Trial. the self-reported prevalence of smoking was 64 percent. The 6,428 men randomized into the Special Intervention (SI) group received intensive group sessions, personal instruction, and other followup to encourage and support cessation of smoking, as well as intensive assistance to alter other CHD risk factors. There were 6,438 men in the group randomly assigned to Usual Care (UC). At 6-year followup, self-reported cessation rates were 43 percent in the SI group and 25 percent in the UC group. Thiocyanate analyses showed a necessity for small adjustments in these figures to 42 percent and 24 percent, respectively, a statistically significant difference (p< 0.01). Compari- son of the results from the four community studies with those from the iarge-scale studies, as shown in Table 2, indicates distinct similarities. The individual studies each have somewhat different weaknesses, but all indicate that absolute reductions in smoking prevalence in intervention communities are about 12 percent greater than reductions in comparison communities. Several ambitious community studies of cardiovascular disease prevention are currently in progress with support from the National Heart, Lung, and Blood Institute, but no additional data on community-level intervention are available. At Stanford University, a large study of two intervention and three control towns with several hundred thousand residents has been in progress since 1978 and is projected to continue for at least 10 years (Farquhar 1978). A 518 similar study, with three matched pairs of variously-sized towns and cities, has been in progress in Minnesota since 1979 (Blackburn et al., in press; Blackburn, in press; Blackburn and Pechacek, in press). A smaller study of one Rhode Island town aid one town in a neighboring State began in 1980 (Lasater 1983). Because it has become clear that community studies are the most natural and cost- effective method fcr testing new public health services to reduce chronic disease (Farquhar 1978; Puska et al. 1983a, b), more of these efforts may be useful, particularly if costs can be reduced and, where possible, absorbed into existing services. Related Studies of Cessation A number of recent efforts have increased understanding of and confidence in the methods employed in large-scale community studies. Research on methods of stimulating interpersonal support for mass media programming is particularly relevant (Colletti and Brownell 1982). In quasi-experimental studies, McAlister et al. (1980) and Puska et al. (1981) have reported methods for facilitating the effectiveness of televised smoking cessation classes in Finland. Formal self-help groups appear difficult to organize, but reorganiza- tion of less formal social reinforcement in natural interaction settings appears feasible and effective. Related studies of television and other media-based methods are described by Danaher et al. (1983), Best (1980), Leathar (1981), and others. Dubren (1977a, b), Brengelmann (1976), and the American Cancer Society (1981) found that effects of media programs may be enhanced if a telephone hotline is offered. Flay et al. (1983b) used a school-based, family- oriented prevention program that included a five-segment television component to be aired the foilowing week to encourage participation of cigarette-smoking parenis. Overall, parents of students in experi- mental groups were over three times more likely to view the cessation segment than parents of control students, with similar differences observed for the proportions of successful parental attempts to quit. Within the experimental groups, teacher training had a significant effect (p<.C1) on raising participation rates by parents of program students. Considering only homes with smokers, 51 percent of the students with trained teachers reported that at least one cigarette smoking adult viewed one or more cessation segments, compared with 37 percent of students with untrained teachers. Furthermore, 38 percent of parents with trained teachers attempted to quit smoking, compared with 24 percent of parents of students with untrained teachers (p< .001). At 1-year followup, the cessation rates in the two groups were 19 and 13 percent, respective- ly, according to children’s reports of parental behavior. The validity of the indicators of adult smoking behavior is at issue; student reports could contain bias, which will be estimated in further 519 analyses. Nevertheless, these results suggest that children can enhance the effectiveness of a media program in encouraging parents to stop smoking, and that organized social reinforcement is important in mass media smoking cessation programming (Flay et al. 1983b). More research is needed on these and other methods of large-scale social reinforcement and support for cessation of smok- ing. Some attention has been given to environmental changes that might contribute to the cessation of cigarette smoking. Evidence indicates that smoking can be regulated by counteradvertising, restrictions on advertising, warning labels, and symbolic or govern- mental actions such as the Surgeon General’s Report of 1964 (Warner 1977). Complete prohibition of smoking is not an acceptable - alternative, but restrictions on smoking locations may be helpful for people attempting to quit voluntarily (Horwitz et al. 1982). Taxation of cigarettes has provided an effective deterrent in some population groups, particularly among younger men (Lewit et al. 1981). In Finland, cigarette taxes have been increased and a portion (0.5 percent) of the funds are dedicated to support services to reduce the prevalence of smoking (Puska and Koskela 1983). Similarly, integrat- ed environmental and educational interventions may be useful in further large-scale efforts. Prevention Studies Although evidence increasingly indicates that it is more cost effective to prevent the onset of smoking among young people than to change the dependent behavior of adults, smoking prevention has received far less attention than cessation in controlled community research. This can be attributed to the complex processes involved in the onset of smoking (e.g., Evans 1976; Leventhal and Cleary 1980), to the extended timespan required for proper evaluation of preven- tion studies, and to the overall tendency of the health sciences to focus more on individual-level research than on primary prevention studies in which whole populations must be followed: Research on the prevention of smoking onset was considered in detail in the 1982 Report of the Surgeon General The Health Consequences of Smoking: Cancer (USDHHS 1982), and only selective studies are reviewed herein. Although there are no currently available published reports on controlled community studies of smoking onset prevention in whole populations, a number of school-based studies have been conducted recently that involve large proportions of particular age- grade cohorts in discrete communities. 520 Stanford Study In one such study McAlister et al. (1979, 1980b) assigned the 1978 seventh grade cohorts in two similar suburban California towns to control (receiving Usual Care health education) or to a special peer prevention program to deter the onset of smoking. The special intervention program consisted of 7 classroom hours distributed over the school year in which 15- to 17-year-old peer leaders led Socratic dialogues, role plays, and simple contests to reinforce smoking avoidance behavior among 12-year-old students and to promote the social desirability of nonsmoking. Role plays and simple contests were used to help students learn assertive ways of declining offers to smoke, emphasizing counterarguments to the kinds of perceived peer social pressures that may be associated with the onset of smoking (McAlister et al. 1979). Several followup sessions were conducted when the study cohort reached the eighth grade. At baseline and three followup points, students in the control and the environmental groups provided anonymous self-reports of smok- ing through classroom surveys. Participation rates were close to 100 percent in all surveys, and the measures were supplemented by collecting samples of exhaled breath at followup. These repeated surveys provided good measures of smoking prevalence in the age- grades studied in the two similar suburban communities, and although attrition and replacement may have threatened inference, the findings in Figure 3 indicate that the special intervention may have had a preventive effect. Note that the dependent variable is the percentage of participants who reported smoking during the previ- ous week. Definitions of smoking in adolescents often differ, making results difficult to compare. Over 2 years of initial followup, the rate of self-reported smoking onset diverged sharply in the two age-grade cohorts, and differences persisted over an additional year of followup (Telch et al. 1982). The North Karelia Youth Project Stemming from the North Karelian project described in an early section, a youth program was initiated in six rural communities in eastern Finland (Vartiainen et al. 1983). Two urban and two rural communities were assigned to intensive (direct contact with the experimenter) or countywide (teacher-led) intervention programs in North Karelia. Two matched communities were selected as controls in the neighboring province of Kuopio, and subjects were seventh grade students (average age of 13 years) in the autumn of 1978. From a population of 897 available students, nearly all participated in the baseline survey; 95 percent participated in a 2-year followup; and 88 percent participated in a second followup 30 months after the program began. The survey included measurements of self-reported smoking and related variables as well as serum thiocyanate levels. 521 480-144 0 - 85 - 18 / Control school rd (N=217) Pw Experimental school (N=353) Percentage reporting smoking during previous week 0 4 9°42, AGI T 223 33 Months of study FIGURE 3.—Long-term effects of a peer group training course on smoking behavior of 13-year-old students SOURCE: Telch et al. (1981). The special intervention spanned the seventh and eighth grade years and included 10 hours of instruction in the intensive program and 5 hours in the countywide program. The methods were based on those employed by McAlister et al. (1980), as reported in the preceding study. Peer leaders, students 1 to 2 years older than the subjects, were the primary agents used to deliver the antismoking message. The program used role play and other active learning techniques to teach skills for resisting the social and psychological pressures to smoke and to reinforce negative attitudes toward smoking. The results indicated a preventive effect from the special interven- tion, as shown in Figure 4. Among boys, the followup rates of smoking at least once a month were significantly lower in the four intervention schools (21 to 24 percent) than in the reference area communities (39 percent). Results for girls were less conclusive, but the overall difference between groups at followup was significant: a 17 percent rate of smoking at followup in intervention schools and a 24 percent rate in control schools. Analysis of the serum thiocyanate samples showed that 2 to 3 percent of the professed nonsmokers gave inaccurate self-reports, but the slight underreporting was greater in the control schools—indicating that inferences from the reported findings were not significantly threatened by self-report biases. Other Prevention Studies In a more rigorous study, Flay et al. (1983a) assigned 22 schools in Canada, some randomly, to receive special interventions or to serve as controls. The smoking prevention curriculum consisted of three major components, using the social psychological model delivered in 522 Reference area Intensive intervention ES Dea ae a“ & a“ “Countywide a ee intervention Percentage of children smoking Autumn Autumn = Spring 1978 1980 1981 FIGURE 4.—Percentage of children who reported smoking at least once a month in baseline survey (1978) and two followup surveys (1980 and 1981) SOURCE: Vartiainen et al. (1983). six 1-hour weekly sessions during grade six. The social psychological model aims at developing future attitude and behavior changes and acquiring social skills, and involves eliciting information from children rather than providing it for them. The three components focused on smoking consequences and reasons for smoking, social influences promoting smoking, and decisionmaking and public commitment. Two booster sessions were delivered in both grades seven and eight. Short-term findings show a preventive effect, manifested in grade seven by an increased level of experimental smoking in the control group compared with the experimental group. In another study, Worden et al. (1983) tracked changes in smoking rates in two towns receiving a mass media campaign and a high-intensity program of adult communication skills related to adolescent smoking prevention. Over 1 year of followup, onset rates were markedly greater among a set of comparison towns receiving only the media campaign and some low-intensity community inter- vention. 523 McAlister (1983) randomly assigned members of five matched pairs of community and neighborhood schools to serve as controls or to receive an experimental prevention program. The study included students in the first year of secondary school (sixth or seventh grade) in 1979 in coastal and inland California towns and inner-city and suburban locations near Boston, Massachusetts. Over 2 school years of initial followup, sharply lower smoking onset rates were observed in some of the schools receiving the experimental programs. The findings are difficult to interpret and suggest that variability among highly diverse community age-grade cohorts, inconsistent implemen- tation, and other related factors threaten inferences that may be drawn from studies of relatively small numbers of unique age-grade cohorts. Preventive effects on smoking onset have been reported by other investigators in Houston (Evans 1976), Minnesota (Hurd et al. 1980), New York (Botvin et al. 1980), and elsewhere; they were reviewed extensively in the 1982 Report of the Surgeon General The Health Consequences of Smoking (USDHHS 1982). These studies have tended to show positive results for the nontraditional health education methods, particularly those using peer teaching and role plays of saying no or resisting social pressures toward smoking. Currently, large-scale research on the prevention of smoking is in progress in the community studies of cardiovascular disease preven- tion that were cited in a previous section, as well as in other research centers in the United States and abroad. Internationally, Sweden has declared the creation of a “Smoke-Free Generation,” and other countries have taken various steps to deter the onset of smoking (Wake et al. 1982). Although studies were not sufficient to confirm the hypothesis, it is probable that young people not strongly dependent on tobacco are most sensitive to the various “environmental” policy options for smoking reduction. For example, the price elasticity of decisions to smoke regularly (smoking status) is -1.4 for males aged 20 to 25, but lower for older men (Lewit et al. 1981). This indicates that a 9 percent increase in the price of cigarettes might yield a 15 percent decrease in the proportion of male smokers in the younger age group. Environmental changes related to the marketing, price, or availabili- ty of cigarettes tend to be implemented in whole States or nations and are not amenable to controlled demonstration research. How- ever, as local authorities play an increasing role in various matters, opportunities for innovative community level research may be available. | Methodological issues In view of the high costs of clinical trials, such as those incurred by the Multiple Risk Factor Intervention Trial, a strong argument can 524 be made for the cost effectiveness and generalizability of community studies of chronic disease prevention (e.g., Farquhar 1978). However, there are methodological problems with the community studies that deserve careful consideration. In order to ensure strict adherence to assumptions of the statistical theories supporting experimental inference, independent units of observation must be sampled. Because the behavior and disease rates of people within a communi- ty are obviously not independent, the data from geographic units must be aggregated at various levels, such as family, neighborhood, community, and region. Thus, for example, smoking rates in three communities assigned to three different experimental conditions must be treated as three discrete observations, but having only one observation per condition does not permit use of traditional statisti- cal procedures for hypothesis testing. By assigning more than one community to each condition, between-community variance can be estimated to provide more valid tests of program effect. As the statistical theory guiding community studies becomes more devel- oped (Flay and Cook 1981), future research may be expected to involve more sites, with fewer cases sampled in each site. Another problem concerns the comparability of groups. Unless a large number of communities are randomly assigned to conditions, the strict methodologist can identify obvious threats to experimental validity. For example, it might be natural to expect a bias toward the application of experimental programs in settings favorable to the adoption of innovation, while using “less interested’? communities for the control group. This inevitably raises questions about the comparability of communities with regard to socioeconomic status, cosmopolitan features, or other hard-to-measure social characteris- tics. If the experimental group has a favorable predisposition at baseline, inferences about changes in health-related variables are severely threatened. When a high degree of demographic similarity between communities can be demonstrated, confidence in inferential statistics is enhanced. If possible, the communities to be compared should be assigned randomly to experimental groups or to control groups. Problems with comparability are also introduced by the possibili- ties of experimental contamination or confounding effects of compet- ing experimental programs. This issue must be thoroughly analyzed with respect to the North Karelia Project, where it appears that program results for dietary change and control of hypertension have been diluted by program spillover and the establishment of new health services in the reference (control) area. Related to the issue of comparability of groups within a study is the problem of generalization to broader populations. For example, some groups that fall into the lower socioeconomic strata have not followed the general population trend toward smoking cessation and 525 may also be at increased risk for smoking-related disease from concurrent industrial exposures. Results of trials involving such populations (WHO European Collaborative Trials) should be exam- ined for overall outcome as well as evaluation of programmatic elements wherever possible. Differential effectiveness of interven- tion techniques with varying populations remains to be established. Another methodological question is raised by studies that rely primarily on self-reports that may be biased by intervention programs (Evans et al. 1977; Benfari et al. 1977; Pechacek et al., in press). Physiological indicators of cigarette smoking are expensive in studies involving large numbers of individual measurements. Most researchers take physiological measurements from a subsample of the group providing self-reports. If there is no evidence of self-report bias between groups, experimental comparisons can be based on the self-report data. However, the usefulness of this procedure depends upon the statistical power of the test comparing relationships between self-reports and physiological measures in the different experimental groups. Tests based on very small subsamples will almost certainly show no statistically significant evidence of self- report bias, but only because they lack the statistical power to detect the relatively small differences that might confound inference. Numerous other methodological points are pertinent to the review of community studies. For example, cohort studies that track individu- als over time may be much less generalizable than those that involve repeated independent surveys, but are critical for studying develop- ment of certain behaviors, such as smoking onset. A great need exists, therefore, for more focused awareness on the various method- ological concerns that limit the interpretation of community studies. Directions for Future Studies There is a clear need for further research on community-level intervention to reduce smoking. The challenge is to develop relative- ly inexpensive methods that can be easily implemented on a large- scale basis. This will involve refinements in three broad activity categories: (1) education and instruction related to smoking, smoking cessation, and smoking prevention; (2) social reinforcement in support for nonsmoking behavior; and (3) environmental changes related to cigarettes and cigarette smoking. Education and instruction methods are needed to convey informa- tion, attitudes, and skills more effectively as they relate to the cessation and prevention of smoking. For example, as the factors contributing to the process of smoking cessation and prevention are identified (DiClemente and Prochaska 1982; McAlister 1983; Leven- thal et al. 1980), they can be modeled via television or other forms of mass communication. Although the schools have an obvious role in 526 smoking prevention, the kinds of educational activities that appear to produce results are not easily adopted by traditional educators. Innovative education and training programs can be marketed to those willing to pay for therapeutic or consultative services related to smoking cessation and prevention, but less costly methods need to be developed for communitywide application. The establishment of smoking cessation programs within existing health services and the integration of chronic disease prevention with mental health promo- tion are also needed to effect broad-scale societal education and change. Growing evidence indicates that the social reinforcement and support provided in formal therapies can be effectively evoked at far less expense by self-help groups and natural helping networks. In the North Karelia Project, community volunteers were taught to rein- force learning of smoking cessation skills from television (Puska et al. 1981). Children may also be powerful, natural sources of social reinforcement (Flay et al. 1983b). Related methods are being applied in other ongoing community studies to harness the influence of natural social networks for antismoking campaigns (Pechacek et al., in press). In addition to reinforcing specific behaviors and attitudes related to smoking prevention and cessation, social environments can give more general support and assistance to people trying to cope with stress, strain, and conflict. Given the relationship between chronic smoking, stress, and alienation, it is reasonable to expect a positive effect from interventions that reduce stress, improve coping, and increase social support (Colletti and Brownell 1982). Other community efforts are being made in noncontrolled con- texts, as in the following examples. First, the American Cancer Society has introduced an “Adopt A Smoker” program to involve ex- smokers in the annual Great American Smokeout Day. Second, community physicians are being urged to increase the frequency and intensity of cessation advice given to smokers. Finally, the television and newspaper media have become involved in the antismoking campaign, frequently including programming and articles that feature behavioral scientists discussing smoking behavior and the techniques of quitting. Options for environmental change and public policy are varied and complex (Farquhar et al. 1981). The outright prohibition of smoking is not feasible, but limited prohibitions on smoking in public and some private places can have desirable effects in shifting negative attitudes. Restrictions on marketing are difficult on a local level, but constraints on advertising or availability may have a powerful effect. As indicated in a previous section, new taxes or other broad environmental changes are more likely to affect young smokers among whom dependence is not firmly established. Thus, they may be expected to have cumulative, long-term effects on future smoking 527 rates. There is a role for research in clarifying optimal forms of restriction, but is has not been implemented, even in worksites where the effects of restrictions could be evaluated (Orleans and Shipley 1982). Future studies must also develop an integrated model for combin- ing cessation and prevention activities. Although the processes involved in the adoption of smoking are clearly different from those involved in its discontinuance, there are commonalities to be explored to find more efficient strategies for smoking reduction. The research of Flay et al. (1983a) is particularly promising in this regard. Any program that changes perceptions of social norms or other environmental factors may influence nonadoption or discon- tinuance of cigarette smoking, but effects will probably be greatest on young people not dependent on tobacco or on older age groups where the adverse health effects of smoking are already becoming apparent. | Summary and Conclusions 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. 528 _ References AMERICAN CANCER SOCIETY. A Study of the Impact of the 1980 Great American Smokeout. Summary Report. National program sponsored by Gallup Organization, Inc., and analyzed by Lieberman Research, Inc., January 1981, 7 pp. ATKIN, C. 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Stockholm, Sweden, Almquist and Wiksell International, 1981, pp. 73— 88. 533 WILHELMSEN, L., TIBBLIN, G., WERKO, L. A primary preventive study in Gothenburg, Sweden. Preventive Medicine 1(1-2): 153-160, March 1972. WORDEN, J.K., FLYNN, B.S., BRISSON, S.F., McCAULIFFE, T.L. Adult Communi- cation Skills Training to Prevent Adolescent Smoking. Paper presented at the Annual Meeting of the American Public Health Association, Dallas, November 15, 1983. WORLD HEALTH ORGANIZATION. Vital Statistics and Causes of Death. 1972, Volume 1. Geneva, 1975. WORLD HEALTH ORGANIZATION EUROPEAN COLLABORATIVE GROUP. An international controlled trial in the multifactorial prevention of coronary heart disease. International Journal of Epidemiology 3(3): 219-224, September 1974. WYNDER, E.L., HOFFMANN, D. Tobacco and health: A societal challenge. New England Journal of Medicine 300(16): 894-903, 1979. 534 INDEX Chronic ™ ..uctive Lung Disease is abbreviated as COLD throughout this index. ACROLEIN alpha,-antitrypsin effect, 436 alveolar macrophage effects, 432 cilioinhibitory effect, 295 gas phase component, 294, 417 ADDICTION cessation of smoking, relationship, 468, 481, 485 ADDITIVES (See alco MENTHOL; PHENOL) low yield cigarettes, increasing use, 13, 352, 354 ADOLESCENTS (See also CHILDREN) increased cough in smokers, 6 prevalence of cough and amount smoked, 64 sex differences in prevalence of respiratory symptoms, 66 small airways dysfunction in smok- ers, 37, 427 smoking rates with smoking and nonsmoking parents, 506 ADVERTISING (See also MASS MEDIA) government regulation of tobacco advertising, 506-507, 514, 520, 527 promotion of cardiovascular risk re- duction, 508 smoking cessation or reduction ef- fects, 457 AGE DIFFERENCES airflow obstruction incidence, 103 cessation rates in post-MI patients, 475 cessation success, 468 chronic airflow obstruction, preva- lence, 78 chronic bronchitis, prevalence, 46- 47 COLD mortality, 191-192, 197, 203-205 AGE DIFFERENCES—Contd. cough and phlegm, prevalence, 48, 65-68 emphysema, severity in smokers and nonsmokers, 126, 241-242 initiation of smoking and COLD mortality, 209 lung pathology in smokers, 124- 125, 231 mucociliary transport, 283 pulmonary function, 6 pulmonary function in children of smoking parents, 398 pulmonary function, rate of de- cline, 9, 137 reductions in smoking with commu- nity intervention studies, 511- 512 small airways dysfunction, 9, 29- 30, 32-35, 37-39, 136-137 AIR POLLUTION (See also PASSIVE SMOKING) airflow obstruction relationship, 105 bronchitis morbidity factor, 212 COLD mortality factor, 192 lung clearance effect, 424 particulates exposure compared with smoking, 417 workplace levels and pulmonary function, 31 ALCOHOL CONSUMPTION abstinence in pregnancy, 462 airflow obstruction relationship, 105-106 ALLERGY atopy and pulmonary function, 106 lung hypersensitivity and airflow obstruction, 104-105, 118 skin test reactivity and incidence of airflow obstruction, 103 535 INDEX Alpha,-antiprotease See ALPHA,- ANTITRYPSIN ALPHA,-ANTITRYPSIN antiprotease activity, 262-264 deficiency in panacinar emphyse- ma, 234-235 elastase inhibition, 8, 11, 301 genetic deficiency, 9-10, 83, 104, 118, 129-137, 261-262, 275 oxidants and decreased inhibitory capacity, 273-274, 435 papain elastolysis, inhibitor, 265 tar and nicotine content effect on elastase inhibition, 340 tobacco smoke effects, 434—437 Alpha,-proteinase inhibitor See ALPHA,-ANTITRYPSIN ALVEOLAR MACROPHAGES changes in smokers, 255-257, 259, 261, 278-279 changes induced by tobacco smoke, 431-434 emphysema pathogenesis, role, 268- 270 increased numbers in smokers, 11, 270-271, 301 increased numbers with nitrogen dioxide, 276 lung clearance mechanisms, role, 423-424 neutrophil chemotaxis, role, 258 toxicity of cigarette smoke, 279-280 ALVEOLITIS smoking relationship, 255 AMISH COLD mortality, 213 AMMONIA gas phase component, 294, 417 ANGINA contraindication for nicotine chew- ing gum, 477 Antibodies See IMMUNE SYSTEM ANTISMOKING CAMPAIGNS (See also SMOKING INTERVEN- TION STUDIES) smoking behavior, effect, 457 smoking cessation at prenatal clin- ics, effect, 462-463 ASBESTOS cessation success in exposed ship- yard workers, 482-483 536 ASTHMA bronchoconstrictive effect of smoke inhalation in asthmatics, 428- 429 children of smoking parents, 389, 392-393, 403 mortality in California physicians, Ly i | nonsmokers exposed to tobacco smoke, 403, 405-406 reversibility of airflow obstruction, 75 ATROPINE cilioinhibitory effect, 295 AVERSIVE SMOKING cessation effectiveness, 469 BACTERIA clearance from respiratory tract, 281 macrophage bactericidal capacity in smokers and nonsmokers, 278— 279 reduced resistance to infection in smoke-exposed animals, 280 BEHAVIOR MODIFICATION physicians’ efforts to get patients to quit, 455 social reinforcement in community intervention trials, 506 BIRTHWEIGHT maternal smoking relationship, 461, 464-465 BRONCHIOLITIS childhood, association with subse- quent panacinar emphysema, 236 COLD, role in pathogenesis, 11 pathology, 223, 230-231 smoking relationship, 242, 255-256 BRONCHITIS (See alco MUCUS HYPERSECRE- TION) abnormalities in regional gas ex- change, 22 aerosol clearance effects, 292-293 childhood, association with panaci- nar emphysema, 236 . children of smoking parents, 13, 393, 405 definition, 45-46, 224 excessive morbidity in Britain, 212 mortality and age of smoking initi- ation, 209-210 INDEX BRONCHITIS—Contd. mortality and depth of inhalation, 208 mortality and smoking habit, 201 mortality in physicians, 211 mucociliary dysfunction, 12, 283, 297-302 natural history, 115 particulate phase components, role, 426 pathology, 227, 229 prevalence, 46 smoking relationship, 48, 255 BRONCHOCONSTRICTION dogs exposed to cigarette smoke, 429 ‘ induction by cigarette smoke, 428, 430 inhalation pattern relationship, 349-350 low yield cigarettes effect, 341 CADMIUM induction of emphysematous lesions in animals, 276 tobacco smoke component, 426 CARBON DIOXIDE gas phase component, 417 CARBON MONOXIDE breath test to demonstrate smoking effects in pregnant women, 464 breath test to validate self-reported cessation, 460, 463 gas phase component, 417 increased alveolar epithelial perme- ability, role, 430 indoor air pollutant, 366, 383 low-tar and low-nicotine cigarettes, yields, 345-346 CARBOXYHEMOGLOBIN asthmatics exposed to tobacco smoke, levels, 403 inhalation pattern relationship, 345, 349 measure of carbon monoxide ab- sorption, 366, 383 nonsmokers exposed to tobacco smoke, levels, 384 CARCINOGENESIS consequence of mucociliary dysfunc- tion, 301 CASEIN chemotaxis of polymorphonuclear leukocytes, effect, 433. 480-144 0 - 85 - 19 CATALASE reduction of smoke effects on al- pha,-protease inhibitor, 436 CERULOPLASMIN prevention of alpha,-antitrypsin ox- idation, 274 CESSATION OF SMOKING (See also REDUCTION OF SMOKING) cardiopulmonary function improve- ment, 465 COLD incidence and progression ef- fects, 7-8 COLD mortality relationship, 10, 210-211, 214 community intervention studies, 15, 503-528 cough and phlegm reduction, 9, 48, 137 emphysema morbidity and mortali- ty, 126 emphysema severity in ex-smokers, 241-242 emphysematous changes, effect, 127-129 lung clearance effects, 430 mechanical properties of lungs, ef- fect, 123 morbidity and mortality reduction, 465 mucociliary transport effects, 293, 300 parents, effect on children’s asth- ma, 403 physicians, 456 pulmonary function effects, 9, 227, 232, 242 pulmonary function effects, rate of decline, 9, 116-118, 137 reasons given by ex-smokers, 457 respiratory symptoms in ex-smok- ers, 67 role of physicians, 14, 455-488 sex differences in pulmonary func- tion effects, 104 small airways function effects, 11, 40-42, 44, 137 CHEST INFECTIONS airflow obstruction, role in etiology, 83, 107 CHILDREN (See also ADOLESCENTS) influence on parental smoking ces- sation, 468 537 INDEX CHILDREN—Contd. pulmonary function effects of smoking, 398 respiratory illnesses and subsequent airflow obstruction, 104, 106, 118 respiratory infections and COLD susceptibility, 7 respiratory symptoms, parental smoking relationship, 13, 388- 389, 392-393, 397-398, 402-403, 405 school-based prevention programs, 519-524 CHLORAMINE-T inhibitory capacity of alpha,-anti- trypsin, effect, 273-274, 436 Chronic airflow obstruction See PULMONARY FUNCTION CIGAR SMOKERS COLD mortality, 10, 211-212, 214 cough and phlegm prevalence, 48 — emphysema incidence at autopsy, 240 former cigarette smokers, 460 Cilia See MUCOCILIARY TRANS- PORT CORONARY HEART DISEASE contraindication for nicotine chew- ing gum, 477 COTININE nicotine exposure in nonsmokers, measure, 13, 383, 405 urinary levels in children of smok- ing mothers, 397 COUGH (See alco MUCUS HYPERSECRE- TION) children of smoking parents, 388 contribution to pulmonary clear- ance, 300: increase in smokers, 6 low yield cigarettes effect, 336-339, 354 prevalence in smokers vs. nonsmok- ers, 9 tobacco smoke exposure as factor, 386 CREATININE urinary levels in children of smok- ing mothers, 397 CROSS-CULTURAL STUDIES COLD mortality, 10-11, 212-214 538 CYSTIC FIBROSIS impairment of mucociliary trans- port, 283 submucosal gland enlargement, 225 DIABETES contraindication for nicotine chew- ing gum, 477 EDUCATIONAL ATTAINMENT cessation of smoking, relationship, 462, 468 ELASTASE experimental induction of emphyse- ma, 8, 122-123, 134, 266-270 increase in people deficient in al- pha,-antitrypsin, 262 increased activity in smokers, 271, 301 inhibition by alpha,-antitrypsin, 301 inhibition by protease inhibitors, 434-435, 437 low yield cigarettes effects, 340 pathogenesis of COLD, role, 11 physiochemical conditions that modify kinetics, 272-273 proximity in elastin degradation, role, 272 release by macrophages and neu- trophils, 257-258, 271-272, 301, 432-434 ELASTIN chemoattractant for blood mono- cytes, 258 degradation by elastase, 8 degradation by elastase, role of proximity, 272 degradation by papain, 265 synthesis and repair, cigarette smoke effect, 14, 438-439 EMPHYSEMA age of smoking initiation and mor- tality, 209-210 amount smoked and severity, 11, 137 animal models, 275-278, 433 bronchiolitis as precursor, 256 COLD disease process, 21 definition and characterization, 119-120 detection, 120 gas phase components, role, 426 irreversibility, 75 INDEX EMPHYSEMA—Contd. lung clearance mechanisms effect, 424 mechanical properties of lungs in etiology, 122-123 mortality in physicians, 211 oxidants in pathogenesis, 426-427 pathogenic mechanisms, 11-12, 261, 275-301, 431, 435, 437 pathology, 223, 226, 230-242 peripheral airway resistance, 22 protease-antiprotease imbalances in pathogenesis, 11, 262, 270-278, 301, 339-340 pulmonary function, 26, 121-122 quantification, 120-121 smoking relationship, 8, 10, 125— 135, 255 ESOPHAGITIS contraindication for nicotine chew- ing gum, 477 EXERCISE cessation in post-MI patients, ef- fect, 475 lung deposition of aerosols, effect, 421 promotion in community interven- tion studies, 508 EYES irritation following acute exposure to tobacco smoke, 13, 386—387, 405 FAMILY influence of support on smoking cessation, 457, 485, 506 recidivism prevention in post-MI patients, 475 FIBROBLASTS membrane damage caused by to- bacco smoke, 438 FIBROSIS lung clearance mechanisms, effect, 424 FILTER CIGARETTES (See also LOW YIELD CIGAR- ETTES) amount smoked and prevalence of mucus hypersecretion, 65 cilioinhibitory capacity, 287 filter use and cessation probability, 469 mucociliary transport effects, 296- 297 FILTER CIGARETTES—Contd. pulmonary function effects, 116 GENETIC FACTORS alpha,-antitrypsin deficiency, 9-10, 83, 104, 118, 129-137, 261-262, 275 development of airflow obstruction, 104, 106-107 GROUP COUNSELING cessation rates in post-MI patients, effect, 475 HEADACHE after acute exposure to tobacco smoke, 386 HEXAMETHONIUM cilioinhibitory effect, 295 HISTAMINE involvement in bronchoconstrictive response to smoking, 428 reactivity in smokers and nonsmok- ers, 430 ' release in animals exposed to to- bacco smoke, 429 HYDROGEN CYANIDE ciliotoxicity, 283, 295 HYDROGEN PEROXIDE alpha,-protease inhibition, effect, 436 enhanced production in alveolar macrophages in smokers, 432 inactivation of alpha,-antitrypsin, 274 HYPERKINESIS maternal smoking relationship, 461 HYPERTENSION cardiovascular risk reduction pro- gram, factor, 515 contraindication for nicotine chew- ing gum, 477 pulmonary artery, association with chronic airflow obstruction, 232 HYPERTHYROIDISM contraindication for nicotine chew- ing gum, 477 IMMUNE SYSTEM ABH antigens and airflow obstruc- tion, 105 COLD susceptibility, factor, 7 smoking effects, 12, 255, 279-281, 301 539 INDEX INFLUENZA increased susceptibility in smokers, 12, 280, 301 Involuntary smoking See PASSIVE SMOKING ISOPRENE mucociliary transport effects, 295 ISOPROTERENOL reversal of airways reactivity, 105 LACTATION inhibition by maternal smoking, 461 LEAD particulate phase component, 417 LEGISLATION restrictions on smoking in public places, 507, 514, 520, 527 LOBELINE nicotine substitute, 458 LOW YIELD CIGARETTES (See also FILTER CIGARETTES) additives, 13, 352-354 cessation success and tar yield, 461 COLD mortality, 198, 201, 203 COLD risk, 12-13, 336-341, 354 lung cancer mortality relationship, 339 mucociliary transport effects, 294 particulate concentrations and size, 418-419 research recommendations, 353 respiratory symptoms, 66 smoking behavior effects, 341-348, 354 tar yield and respiratory symp- toms, 65 LUNG CANCER aerosol deposition at bronchogenic carcinoma sites, 422 low yield cigarettes relationship, 339 mortality in smokers, 336 polonium deposition and site of bronchogenic carcinoma, 424 smoking behavior relationship, 333 smoking relationship, 255 LUNGS cigarette-induced disease, pathology, 11 growth in children of smoking mothers, 398 localization of emphysematous le- sions, 275 540 LUNGS—Contd. . pulmonary epithelial permeability and smoking, 430-431, 439 tissue repair, cigarette smoking ef- fects, 437 Macrophages See ALVEOLAR MACROPHAGES MARITAL STATUS cessation of smoking, relationship, 468-469 MASS MEDIA (See also ADVERTISING) antismoking educational campaigns, 480 community intervention studies, 15, 505-506, 508-514, 523, 526, 528 televised smoking cessation classes, 519 MATERNAL SMOKING (See allo PARENTAL SMOKING; PREGNANCY) fetal and childhood effects, 461 prenatal smoking and respiratory infections in children, 393 METHACHOLINE responsiveness and airways reactiv- ity, 105 responsiveness and smoking, 428— 429 METHOL mucociliary transport effects, 295 Minority groups See RACIAL/ ETHNIC DIFFERENCES MORBIDITY bronchitis in Britain, 212 chronic airflow obstruction, 68-118 chronic mucus hypersecretion, 45- 73 COLD prevalence and inhalation practices, 209 emphysema, 119-135 improvement following cessation of smoking, 465 small airways dysfunction, 22-44 smoking and COLD morbidity, 8-10 MORTALITY . cardiovascular diseases, declines re- lated to risk factor reduction program, 515 cessation of smoking relationship, 465 COLD, airflow obstruction relation- ship, 339 INDEX MORTALITY—Contd. N-CHLORSUCCINIMIDE COLD, mucus hypersecretion rela- reduction of activity of alpha,-anti- tionship, 339 trypsin, 436 COLD, smoking relationship, 8, 10- NEUTROPHILS 11, 189-214, 336 fetal and neonatal, maternal smok- ing effect, 461 myocardial infarction patients who quit smoking, 470 predictive effectiveness of FEV,, 72 MUCOCILIARY TRANSPORT chronic bronchitis, 297-301 filters, effect, 296-297 lung clearance of deposited particu- lates, 423-424 normal function, 283-286 smoke constituents, effect, 293-296, 426 tobacco smoke, effect, 12, 290-296, 301-302, 418, 431 MUCUS HYPERSECRETION cigarette smoke effects, 11, 107, 292, 302 COLD disease process, 21 COLD mortality relationship, 339 cough and phlegm, relationship to airflow obstruction, 68-73 cough and phlegm, relationship to sex and age, 65-68 cough and phlegm, relationship to smoking, 47-48, 63-65 inhalation depth relationship, 349 low yield cigarettes, effect, 336-339, 354 measurement of cough and phlegm, 45-46 phlegm in smokers vs. nonsmokers, 9 prevalence and amount smoked, 137 prevalence of cough and phlegm, 46-47 MYELOPEROXIDAS inactivation of alpha,-antitrypsin, 274, 436-437 MYOCARDIAL INFARCTION cessation of smoking in post-MI pa- tients, 15, 470, 475-476, 480-481, 487 contraindication for nicotine chew- ing gum, 477 changes induced by tobacco smoke, 255-261, 432-434 chemotaxis inhibition by cigarette smoke, 269-270 decrease following elastase instilla- tion, 266 elastase source, 257-258, 267-268, 271-272 increased numbers in smokers, 11, 256-257, 270-271, 301 increased numbers with nitrogen dioxide, 276 migration in response to macro- phage chemotactic factor, 258 toxicity of cigarette smoke, 279-280 NICOTINE alpha,-protease inhibitor effect, 436 alveolar epithelial permeability ef- fect, 430 blood levels with nicotine chewing gum, 476 bronchial reactivity effect in ba- boons, 430 bronchoconstriction effect, 428 chemokinetic factor for neutrophils, 258, 432-433 compensatory behavior in smokers of low nicotine cigarettes, 421 DNA synthesis effect, 280 indoor air pollutant, 366 machine-determined yields and ac- tual intake, 335-336, 346-347 mucociliary transport effects, 295 nonsmokers exposed to tobacco smoke, levels, 383 particulate phase component, 417 reinforcer of smoking behavior, 13 saliva levels to validate cessation reports, 459 NICOTINE CHEWING GUM cessation aid, 14, 460, 476-478, 487 NITRIC OXIDE mucociliary transport effects, 295 NITROGEN DIOXIDE effect on macrophages, 279 emphysematous lesions in animals, role in induction, 276 gas phase component, 294 mucociliary transport effects, 295 541 INDEX NITROGEN OXIDES acute bronchospasm effects, 428 epithelial permeability effects, 430- 431 gas phase component, 417 indoor air pollutant, 366 lung clearance mechanisms, toxic effects, 424 NITROSAMINES indoor air pollutants, 366 Nonsmokers See PASSIVE SMOKING NOSE irritation following acute exposure to tobacco smoke, 386 NURSES involvement in community inter- vention studies, 514 OCCUPATIONS (See also WORKPLACE) coal miners, 230, 234, 240 grain elevator workers, 31 industrial workers, 277 iron foundry workers, 42 physicians, 14-15, 194, 198, 206, 208, 210-211, 455-488, 511, 514, 527 shipyard workers, 482-483 steelworkers, 30, 43 textile workers, 225, 242 OZONE lung clearance mechanisms, toxic effects, 424 preexposure and cigarette smoke effects in animals, 437 PAPAIN emphysema pathogenesis, role, 265- 266 PARENTAL SMOKING (See allo MATERNAL SMOKING) children’s encouragement to quit, effect, 519-520 influence on adolescent smoking rates, 506 pulmonary function in children, 397-398, 405 respiratory infections in children, 393, 397, 405 respiratory symptoms in children, 13, 388-389, 392, 403, 405 PARTICULATES (See also TARS, TOBACCO) BRAD PARTICULATES—Contd. - aerodynamic diameter, 418-420, 438 exposure measurement, 383 indoor air pollutants, 366 ingestion by pulmonary macro- phages, 259 lung deposition, 420-422, 425, 438 lung retention, 423-424 PASSIVE SMOKING acute airway response, 384, 386 children, respiratory infections re- lated to parental smoking, 393, 397 children, subsequent susceptibility to COLD, 7 COLD risk effect, 13 deposition of particulates in lungs, 425 exposure measurement, 316, 383— 384 patients with preexisting pulmo- nary disease, 403-405 prevalence of respiratory symp- toms, 66 pulmonary function in children, pa- rental smoking relationship, 397-402 pulmonary function relationship, 402-403 sidestream vs. mainstream smoke, 365-366 symptomatic responses, 386-392 PEPSIN emphysema induction in experi- mental animals, 123 PEPTIC ULCER contraindication for nicotine chew- ing gum, 477 PEROXIDASE transfer across tracheal epithelium, 431 PERSONALITY cessation of smoking factor, 469, 481-482, 485 ) PHENOL mucociliary transport effects, 295- 296 ; PHENYLMETHYLOXADIOZOLE anticiliotoxic effects, 296 PHENYLVINYLOXADIOZOLE anticiliotoxic effects, 296 INDEX Phlegm See MUCUS HYPER- SECRETION PHYSICIANS cessation of smoking and COLD mortality, 210-211 COLD mortality, 194, 198, 206, 208 involvement in community inter- vention studies, 511, 514, 527 smoking cessation in patients, role, 14-15, 455-488 smoking prevalence, 14, 456 PIPE SMOKERS COLD mortality, 10, 211-212, 214 cough and phlegm prevalence, 48 emphysema incidence at autopsy, 240 former cigarette smokers, 460 PNEUMOCONIOSIS pathology, 225, 234 PNEUMONIA children of smoking parents, 13, 393, 405 POLONIUM deposition at site of bronchogenic carcinoma, 424 particulate phase component, 417 POLYCYCLIC AROMATIC HYDROCARBONS fibroblast membrane effects, 438 Polymorphonuclear leukocytes See NEUTROPHILS PREGNANCY (See allo MATERNAL SMOKING) antibody production in pregnant smokers, 280 cessation of smoking, 14, 479-480, 487 motivation for quitting, 484 physician intervention and cessa- tion of smoking, 461-465 PREVENTION OF SMOKING community intervention studies, 15, 520-524 PROTEASE-ANTIPROTEASE IMBALANCE alpha,-antitrypsin deficiency, 130 effect of oxidants, 275 emphysema pathogenesis, 11, 262, 270-278, 301, 339-340 smoke exposure effect, 277-278 PULMONARY FUNCTION airway lesions relationship, 227, 229 asthma patients, 13, 403, 405-406 PULMONARY FUNCTION—Contd. children of smoking parents, 13, 393, 397-398, 405 chronic airflow obstruction, 42-44, 68-118, 223-232 cigarette smoke effects, 6, 9, 191, 427-430, 438 emphysema, 121-122 expiratory airflow obstruction as COLD disease process, 21 inflammation and small airways dysfunction, 11 inhalation depth relationship, 349 low yield cigarettes relationship, 337-338, 354 occupational exposure relationship, 107 passive smoking effects, 13, 384— 386, 402-403, 405 people deficient in alpha,-antitryp- sin, 262 small airways dysfunction, 22-44, 136-137, 227 RACIAL/ETHNIC DIFFERENCES cessation of smoking during preg- nancy, 462 chronic airflow obstruction, preva- lence, 78 COLD mortality, 11, 191, 214 COLD risk, 212-213 serum concentrations of alpha,-an- titrypsin, 263 smoking prevalence trends, 504 RECIDIVISM post-MI patients, environmental factors, 475 pregnant smokers, before end of pregnancy, 463 REDUCTION OF SMOKING (See also CESSATION OF SMOKING) physician intervention, effec- tiveness, 458-459 pregnant women, 463-465 psychologist’s advice, effectiveness, 468-469 RESPIRATORY SYNCYTIAL VIRUS INFECTION children of smoking mothers, 393, 397 SEX DIFFERENCES airflow obstruction prevalence, 78, 83 5A INDEX SMOKING INTERVENTION STUDIES—Cont SEX DIFFERENCES—Contd. cessation of smoking, 468 cessation rates in post-MI patients, 475 cholesterol reduction, 512 chronic bronchitis mortality, 210 chronic bronchitis prevalence, 46— 47 COLD mortality, 10, 189, 192, 203- 207, 213-214 community intervention effec- tiveness, 511, 514 cough and phlegm prevalence, 48, 65-68 emphysema incidence at autopsy, 240-241 emphysema severity at autopsy, 241-242 particulates deposition, 423 preventive effect of school-based smoking interventions, 522 pulmonary function after passive smoking, 384-386 reduction of smoking following phy- sician intervention, 458-459 small airways dysfunction, 9, 28, 37-40, 137 smoking patterns and pulmonary function, 32-33, 35, 104 smoking prevalence, 504 Small airways disease See PULMO- NARY FUNCTION SMOKING BEHAVIOR cigarette yields, effect, 13, 64, 334- 335 inhalation pattern and cessation probability, 469 inhalation pattern and COLD mor- tality, 208-209, 214 inhalation pattern and COLD sus- ceptibility, 7, 348-352, 354 low yield cigarettes relationship, 12-13, 341-348, 354 lung deposition of particulates, ef- fect, 420-423, 425 lung injury relationship, 341 SMOKING INTERVENTION STUDIES (See also ANTISMOKING CAM- PAIGNS) cessation and prevention effects, 15 community cessation studies, 504— 505, 507-520, 528 544 community prevention studies, 520— 524, 528 methodological issues, 524-526, 528 research needs, 526-528 theoretical basis, 505-507 SMOKING-MACHINES comparability to actual smoking be- havior, 12, 64, 333-336, 341, 354, 420-421 SMOKING PATTERNS age of initiation and COLD mortal- ity, 209-210 alveolar macrophage changes and amount smoked, 256 cessation probability and amount smoked, 459, 469, 481 COLD morbidity relationship, 9 COLD mortality and amount smoked, 10, 198, 201, 203, 205- 208, 210-211, 213-214 COLD severity relationship, 336 cough and phlegm prevalence, 9, 47-48, 137 determinants of airflow obstruction, 92, 103-104 emphysema at autopsy and amount smoked, 240-241 emphysema severity, 10, 137 emphysematous changes and amount smoked, 126-127 mucus hypersecretion and amount smoked, 63-65 pulmonary function and amount smoked, 6-7, 9, 69, 115, 117, 131, 137 respiratory symptoms prevalence, 73 small airways dysfunction and amount smoked, 32-35, 39, 43, 136-137 SMOKING PREVALENCE physicians, 456, 487 trends in various demographic groups, 503-504 SOCIOECONOMIC STATUS cessation of smoking, relationship, 468-469 pulmonary function relationship, 108 reduction in tobacco consumption in higher income groups, 503 smoking prevalence, 525-526, 528 trend toward reduced smoking, 15 ——— INDEX Sputum See MUCUS HYPER- SECRETION STRESS cessation success relationship, 481- - 482 chronic smoking relationship, 527 management training to maintain nonsmoking, 509 SUPEROXIDE DISMUTASE activity depression by tobacco smoke, 434 reduction of smoke effects on al- pha,-protease inhibitor, 436 SUPEROXIDE RADICALS alpha,-protease inhibitor activity, effect, 436 generation by alveolar macrophages in smokers, 259, 432 release from neutrophils in smok- ers, 433 TARS, TOBACCO (See also PARTICULATES) ciliotoxic effect, 295 cough and phlegm production rela- tionship, 337 exposure in nonsmokers, 384 mucus hypersecretion relationship 12, 339 pulmonary function relationship, 338 . respiratory symptoms effect, 65 smoking behavior relationship, 13, 347-348, 354 TAXES increases as part of community in- tervention trials, 514 TAXES—Contd. revenues contributed by tobacco in- dustry, 503 smoking deterrent effectiveness, 457, 507, 520, 527 THIOCYANATE plasma levels to validate self-re- ports of cessation, 512 saliva levels to validate self-reports of cessation, 464 serum levels to validate self-reports of cessation, 508-509, 511, 513, 518, 521-522 TOBACCO SMOKE aerosol characterization, 417-420, 438 deposition and toxicity, 14 mainstream vs. sidestream smoke, 365-366 toxicology, 426-439 TRACHEA epithelial permeability in smoke-ex- posed animals, 430-431 WHEEZING children of smoking parents, 388- 389, 392-393 WOOD SMOKE airflow obstruction, etiologic factor, 83 WORKPLACE (See also OCCUPATIONS) air pollution and pulmonary func- tion, 31 smoking prohibitions and cessation, 457 545 + dae SEAT sere ey é ‘ 4 ’ ‘ *, e be e _ “at i - = ee : * on Awe ntact oily © A dace “¢ ree? oP 6) na 412, Caan ~ 4 a) J res i ag 7 i re ¥ nr JA , 37 OM hig 7 ; yy ‘ fine x pas en , e Ney "4 P TT 43 i i i G03 att '’ f * tt AT: 7 ‘ ’ ’ »& * A es 7 (pas 4 ‘ 4 7 ? s an : ih OV UE (Fi mone.’ a ] ' A ‘a hi - * r ae rvyy . - 7 1 on ‘ ; b Sw { > 4 : 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Te a9 _ ~~ SR. af 5. i] _— F oad e bP ha ® 7 $ ‘ rl P 9 - | ic mi % ? ~~ 7200-529 PB-3) C BT U.S. DEPARTMENT OF HEALTH AND HUMAN ahi cel Public Health Service Office on Smoking and Health Rockville, Maryland 20857 UNIVERSITY OF ILLINOIS-URBANA 616.865H34 492 C001 THE HEALTH CONSEQUENCES OF SMOKING : CHR wu un 0112 SPECIAL FOURTH CLASS OCS5793N Illinois BOOK Univ of Illincis at Urbana-Chempaicgn Library Documents Civision Urbana It 6180f, DHHS (PHS) 84-50205 30942