A Comparison of Pulmonary Function in Male Smokers and Nonsmokers ,_ 4

M. TOCKMAN, 5 H. MENKES, B. COHEN, S. PERMUTT, J. BENJAMIN, W. C. BALL, JR., and J. TONASCIA

SUMMARY __________________________________________ _________ Results of certain tests of pulmonary function, including a questionnaire, single-breath N 2 test of closing capacity, forced expiration, and diffusing capacity were significantly different in groups of male smokers and nonsmokers. The influence of age on these smoking-related changes of pulmonary function was evaluated. The analyses indicated that (I) some tests including number of symptoms; closing capacity, i.e., closing volume plus residual volume as a percentage of total lung capacity; residual volume as a percentage of total lung capacity; Phase III of the singlebreath N 2 test, and steady-state diffusing capacity (ml of CO(mm Hg • min) revealed significant differences between adjusted mean smoker and nonsmoker values but did not reveal differences a~sociated with age. (2) Tests of forced expiration (1-sec forced expiratory volume(vital capacity, reciprocal of the maximal mid-expiratory flow, maximal flow at 50 per cent of vital capacity; and moments) however, revealed differences between smoker and nonsmoker means (adjusted and unadjusted), as well as increasing smoker-nonsmoker differences with increasing age. It is suggested that the first group of tests probably measured an ali-or-none response that occurred with the onset of smoking and was not affected by duration of smoking. The second group of tests probably measured the effects of continued smoking and indicated increasing abnormality associated with longer exposure (years of smoking). Tests showing age-related differences between smokers and non· smokers may reflect cumulative, irreversible changes in pulmonary function to a greater extent than tests that do not.

Introduction Smokers develop abnormalities in pulmonary function more frequently than nonsmokers. They are more likely to exhibit frequency dependence of compliance (1 ), increased closing capacity (2), abnormal spirograms (3), and decreased diffusing capacity (4). The present com(Received in original form january 27, 1975 and in revised form july 2, 1976) 1 From the Johns Hopkins Medical Institutions, Baltimore, Md. 2 Supported by NIH grant no. 14153 from the National Heart and Lung Institute. 3 Requests for reprints should be addressed to Dr. Melvyn S. Tockman, Respiratory Division, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Md. 21205.

munication reports a comparison of tests of pulmonary function designed to determine how well those tests detect smoking-related changes of pulmonary function, and the influence of age on those changes. The smoker and nonsmoker populations used were well defined and similar, except for smoking habits. Therefore, direct smoker-nonsmoker comparisons could be made without resorting to indirect comparisons between smokers and "normal" values obtained from 4 Because of a miscalculation, the numbers reported for MMEF-1 should be exactly twice as large. The MMEF-1 (in vital capacity per sec) equals twice the time, in seconds, required for the expiration of the middle half of the vital capacity (t50 ). 2 (t 50). (MMEF (FVC)-1 5 Dr. Tockman has received support from NCI grant no. NOl-CN-45037.

AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 114, 1976

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TOCKMAN, MENKES, COHEN, PERMUTT, BEXJAMIX, BALL, AND TONASCIA

control populations, which might have differed from ours. Materials and Methods Stud,, 'ubvcts. Two groups of subjects not known to ha\e disease were selected from the Baltimore metropolitan area. One group (series I) had been chosen a; neighborhood control subjects for an epi· demiologic study of obstructive pulmonary disease. The other (series 2) consisted of professional emplo)ees of the Baltimo1e public school system, primarily teachers, who volunteered for a study of health and disease. From the 2 series, men who eithel cmrently were smoking at least I package of cigatettes dail) at the time of the study, or currently did not smoke and had smoked less than 5 packages of cigarettes in their lhes, were selected to comprise the "smokers" and "nonsmokers" of the study, re'pcctivcly. Of the 149 subjects, 16 were rejected because of unsatisfactory spirograms (not reproducible or not continuing for at least 6 sec). The distribution of the remaining 133 subjects (78 smoke• s and 55 nonsmokers) by age, series, race, and smoking status is shown in table 1. Serie;. Of the 133 subjects, 98 (73.7 per cent) were derived from series 1; 35 (26.3 per cent), from series ~. with smokers having a significantly larger percentage hom series 1 than nonsmokers (82 versus 62

per cent, respectively). To determine whether this difference was meaningful, smokers and nonsmokers were compared by race, age, and socioeconomic status, as well as by series. Race. Slightly more than one fourth of both smokcts and nonsmokers were black (25.6 and 27.3 per Lent, respectively). These subjects were distributed similarly among series 1 and series 2 smokers, but there was a somewhat larger, although not significantly larger, percentage of blacks among series 1 nonsmokers (32.4 per cent) than among series 2 non· smokers (19.0 per cent). Age. The age distributions by smoking habits are also shown in table I. Comparisons of the distribution of total smokers to those for nonsmokers in the age categories, IS to 34, 35 to 44, 45 to 54, and 55-65 years; revealed no significant differences among them. Despite a slight excess of middle-aged smokers, not only was there no significant difference between smokers and nonsmokers in distribution among the 4 age categories with races and series pooled, but also considered separately by series with races pooled, and by race with series pooled, the differences were not significant. Even when the 8 classes of seriesrace-smoking combinations were compared with one another, no significant age difference was observed. Finally, comparing the distributions of smokers and nonsmokers by age and series in a 2 X 8 table, a chi

TABLE 1 DISTRIBUTION OF NONSMOKERS AND SMOKERS BY SERIES, RACE, AGE, AND SOCIOECONOMIC STATUS Smokers

Nonsmokers

(no.) Total no.

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(no.)

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55

100.0

78

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34 21

61.8 38.2

64 14

82.0 17.9

40 15

72.7 27.3

58 20

74.4 25.6

9 14 18 14

16.4 25.4 32.7 25.4

6 17 40 15

7.7 21.8 51.3 19.2

14 9 6 9 9

29.8*. 19.1 •• 12.8** 19.1 •• 19.1*.

22 17 7 14 6

33.3** 25.8** 10.6*. 21.2** 9.1*.

47 8

85.4 14.5

66 12

84.6 15.4

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*Includes 1 subject 65 years of age. tclassification based on 1970 census data for the Baltimore Standard Metropolitan Statistical Area, from the lowest 20 per cent, classified as "1," through the highest 20 per cent, classified as

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TABLE 2 PARAMETERS OF THE AGE REGRESSIONS* OF PULMONARY FUNCTION IN SMOKERS AND NONSMOKERS (WHERE y = a + bx) a

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(r) for (FEV l/VC, 1jVC, %); (7) the mean transit time (r) flow out of the lungs (see Appendix) during a forced vital capacity maneuver; (8) the root mean (al/2); (9) reciprocal of square of the transit times (al/2); maximal mid-expiratory flow in vital capacity per (MMEF-1); (10) maximal flow at 50 per cent of sec (MMEF-l); vital capacity, in liter per sec ('Vmax 50); (11) maximal flow at 25 per cent of vital capacity, in liter per sec (Vmax25 ); (12) forced vital capacity (FVC); and (13) TLC. The FEV11 and FVC were calculated for each of 5 spirograms. The 2 highest values of FEV11 and FVC obtained were averaged and recorded. The >pirogram with the highest FEV 11 alld and a reprodu.pirogram cible ::'VC was selected for the moments calculation. The forced expiratory volumes were measured on a Cardio-Pulmonary Instruments electronic spiromHewleu eter (model 220) and were recorded on a Hewletr Packa1d Packald X-Y recorder (Model 7046A). Volumes to RTPS. BrPs. J'or }'or the CC, Phase III, were then conccted to DLco, and lung volumes, the mean of 2 trials was DLCO, used. Nitrogen measurements were made on a HewN 2 analyzer and recorded on the Hewlett-Packard N2 lett-Packard X-Y X-V recorder. The CO measurements were made on a Beckman CO analyzer (Model IR215-B) and recorded on a Rikadenki multipen recorder (KA series). Helium measurements were made with a Collins helium meter. The associations of each pulmonary function test with age were compared for smokers and nonsmokers. The parameters of each regression were calculated (slope, standard error of the slope, intercept, standard error of the intercept, mean squared error, and correlation coefficient), and arc are shown in table 2. Both smoker and nonsmoker populations were then divided into 4 age groups (18 to 34, 35 to 44, 45 to 54, and 55 to 65 years of age). A Bartlett's test of variance homogeneity was performed over the variances of the age groups, and an analysis of variance (with residual variance partitioned) was conducted to test the significance of the slope (difference from zero) and the linearity assumption. The regression equations of each pulmonary function on age were compared by an analysis of covariance. Slopes of the age regressions were compared directly by an F test. Next, a pooled slope and adjusted intercepts were calculated. Where no difference could be demonstrated between slopes, adjusted intercepts were compared to eliminate any potential bias due to smoker-nonsmoker differences in age distribution.

Results Results are summarized in tables 2, 3, and 44 and figures 1I to 10. The TLC and VC (figure 10) decreased significantly with age among both smokers and nonsmokers. The mean values of the 22 groups were not significantly different from each other, and the slopes of the age regression did not differ significantly, indicating that smokers smokers and and nonsmokers nonsmokers were closely closely matched matched by lung volumes in addition to age and height

(table 3). Five tests (figures 1I to 5) showed significant differences between the group means of the smokers and nonsmokers, but showed no difference between the slopes of the age regression. These tests were symptoms (number of affirmative responses) (figure 1), RV (figure 2), CC (figure 3), slope of Phase III of the single-breath N2 N 2 test (AN 2 /liter) fliter) (figure 4), and the steadystate DLco (figure 5). Tests of forced expiration, on the other hand, showed significant differences

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regressions with age, reflected reversible changes associated with smoking, and that tests that showed different regressions with age reflected irreversible changes associated with smoking. All of the pulmonary function tests we used are reported to be alterable. 'With cessation ot smoking, symptoms and frequency dependence of compliance tend to reverse (1). l\Iecho1yl challenge and acute infections can increase the CC, at least in smokers (14, 15). Spirometric indices can change acutely and reversibly in asthmatics. Even the DLco has been shown to improve with the cessation of smoking (16). Yet; clinical experience has demonstrated that these same indices become irreversibly altered in patients with advanced lung disease, despite therapeutic intervention. In a cross sectional study such as this, we had no way of estimating how much of a pulmonary function test abnormality was reversible and how much was not reversible. Nevertheless, one may speculate that irreversible pulmonary function differences are better shown by tests with a greater age-related component, and reversible differences are shown by the other tests. With the passage of time, therefore, one might expect to observe a greater cumulation of irreversible change in the pul-

COMPARISON OF PUUJO:\ARY FUr-;CTIOX 11\ ~!ALE SMOKERS A:-10 :\OXS~IOKERS

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Fig. 10. Vital capacitY as a function of age in years (yrs). The regression shown is for subjects 178 em tall. Regression lines for smokers (S) and non smokers (:\IS) are shown.

monary function of older persons compared to younger ones. If smoking contributes to these irreversible changes, then with increased duration of smoking, one might expect to observe a greater difference in pulmonary function between older smokers and nonsmokers, compared to the difference between younger smokers and nonsmokers. Tests that fail to show a greater smoker-nonsmoker difference in older persons, i.e., fail to accumulate change with increased duration of smoking, are possibly more likely to result from an acute, but temporary change in ventilation. The importance of detecting reversible changes has not been demonstrated. Reversible changes might coexist with irreversible abnormalities, and might even lend some protection to the subject. For example, acute changes may provide for a more efficient cough mechanism by narrowing affected airways. Thus, although smokers as a group had poorer pulmonary function than nonsmokers when almost any test was used, it is suspected that only some of these tests may be helpful for detection of smokers at greatest risk of ventilatory deterioration. In fact, it may be more important to follow subjects in a prospective study with measurements of spirometry than tests that are more likely to reflect acute reversible changes, e.g., frequency dependence of compliance or other tests that are believed to detect early abnormalities. An interesting crossover phenomenon was seen at younger ages in tests of forced expiration

721

and Phase III of the N 2 washout. In these tests, young smokers seemed to have better pulmonary function than young nonsmokers; but a steeper downward trend in the age regression suggested a more rapid deterioration among smokers with increasing age. A similar crossover was noted by Ferris and associates (17) in a community survey of prevalence of chronic obstructive pulmonary disease. If this finding can be substantiated in longitudinal follow-up, it might indicate that persons with poorer lung function are Jess likely to choose to smoke. On the other hand, this crossover phenomenon might represent an artifact. It is possible that the linear model based on the entire group was inappropriate for younger age groups; however, specific examination of the youngest age group showed that the forced expiration (FEV 1 / VC, i\Il\fEF·I, Vmax_, 0 , Vmax 2:J, T, and a 21/2) age group means were better for young (18 to 34 years of age) smokers than for nonsmokers. Thus, the crossover could, in fact, be valid. Although it is possible that a cohort effect might be responsible for a more rapid functional deterioration among the young, it would be difficult to explain why such a cohort effect should occur among young smokers and not among young nonsmokers, again suggesting that the observation may be valid. In conclusion, a word of caution is needed, because the findings reported here are based on cross sectional data. Nevertheless, the implications regarding changes with age and irreversible versus reversible alterations, strongly suggested by the observed variation in different age groups, remain very provocative as they await the necessary confirmation in longitudinal investigations. Appendix

The mean forced expiratory transit time (T) is a con· cept derived directly hom dye-dilution studies of vascular circulation times (18). The vital capacity volume, expired over a period of seconds, is usually considered as a cumulative dis· tribution of volumes of expirate over time; however, this same volume-time relationship can be expressed as a distribution of times on volume by a 90° rota· tion of the axis. Thus, any increment of the expired volume, dvi' is composed of all the expired gas that was initially present in the lung at time 0 and had transit times between ti and ti + dt. Considering the spirogram as a distribution of transit times over the vital capacity, one may look into some statistical functions of that distribution, namely, the first· 2 moments. The first moment (T),

722

TOCKMAN, MENKES, COHE:'i, PER:\ICTT,

or mean, is the mean time required for the incremental volumes to leave the lung. The second moment (a 2 ) is the mean square of the times and is a function of dispersion about the onset of expiration. This function, because of its higher order, lends more weight to the longer times. Thus, for a given mean expiratory time, a curve with a larger a 2 will be found to have more of its volume a function of longer (Outlying) transit times. This situation is found in spirograms that have a substantial slope to the terminal portion. The magnitude of (a 2)1/2 in relation to -r is a function of the dispersion of transit times. To determine -rand (a 2)1/2, our laboratory has used the following procedure. (1) The steepest slope (greatest flow) of the spirogram is extrapolated back to time 0. (2) The terminal flow of the spirogram is arbitrarily concluded at 6 sec to give uniformity to the index. (3) The spirogram is digitized. Currently, this is being done by hand, whereby at every 100-m! increment of volume, the distance from the origin is recorded in millimeters. (4) These raw data points are interpolated in the computer, and the vital capacity is divided into 50 equal divisions by volume. (5) The midpoint volume of each division is recorded. (6) The corresponding times for these 50 volumes are averaged. The average of these 50 times is the mean transit time, -,. (7) The mean square of these 50 times is the second moment about the origin, a 2 .

Acknowledgment The writers wish to acknowledge the advice of Dr. George Comstock, Professor of Epidemiology, and the assistance of Shirley Brashears of the Epidemiology Staff, The Johns Hopkins University, in the preparation of this manuscript.

References 1. Ingram, R. H., Jr., and O'Cain, C. F.: Frequency dependence of compliance in apparently health) smokers versus nonsmokers, Bull Pathophysiol Respir (Nancy), 1971, 7, 195. 2. Buist, A. S., Van Fleet, D. L., and Ross, B. B.: A comparison of conventional spirometric tests and the test of closing volume in an emphysema screening center, Am Rev Respir Dis, 1973, 107, 735. 3. Grimes, C. A., and Hanes, B.: Influence of cigarette smoking on the spirometric evaluation of employees of a large insurance company, Am Rev Respir Dis, 1973, 108,273. 4. Van Ganse, W. F., Ferris, B. G., Jr., and Cotes, J. E.: Cigarette smoking and pulmonary diffusing capacity (transfer factor), Am Rev Respir

BE:-\JA~II:-.1,

BALL, A:-.ID TO:-\ASCIA

Dis, 1972, 105, 30. 5. Anthonisen, R. R., Dawson, J., Robertson, P. C., and Ross, W. R. D.: Airway closure as a function of age, Respir Physiol, 1969-70,8,58. 6. Bates, D. V., Woolf, C. R., and Paul, G. J.: Chronic bronchitis: A report on the first two stages of the coordinated study of chronic bronchitis in the Department of Veterans Affairs, Canada, Med Serv J Canada, !962, 18, 211. 7. Woolcock, A. J., Colman, M. H., and Blackburn, C. R. B.: Factors affecting normal values for ventilatory lung function, Am Rev Respir Dis. I 972, 106, 692. 8. Stebbings, J. H.: A survey of respiratory disease among New York City postal and transit workers, Environ Res, 1973,6, 147. 9. Doll, R., and Hill, A. B.: Mortality in relation to smoking: Ten years' observation of British doctors. Part I, Br Med J, !964, 1, 1399. 10. Hammond, E. C.: Smoking in relation to the death rates of one million men and women, in Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases, ,N. Haenszel, ed., U. S. Public Health Service, National Cancer Institute Monograph No. !9, Bethesda, Md., January, 1966, pp. 127-204. 11. Snedecor, G. W., and Cochran, W. G.: Statistical Methods, Iowa State Univcrsitv Press, Ames, 1968, p. 141. 12. Ibid., p. 296. 13. Hogg, J. C., Macklem, P. T., and Thurlbeck, W. M.: Site and nature of airway obstruction in chronic obstructive lung disease, N Eng! J Med, 1968,278, 1355. 14. Auerbach, 0. A., Stout, R., Hammond, E. C., and Garfinkel, L.: Smoking habits and age in relation to pulmonary changes, N Engl J Med, 1962, 269, 1045. 15. Ingram, R. H., Jr., O'Cain, C. F., and Friday, W. \V., Jr.: Simultaneous quasistatic lung pressurevolume curves and "closing volume" measurements, J Appl Physiol, 1974,36, 135. 16. Friday, W., Ingram, R. H., Jr., Hierholzer, J., and Coleman, M.: Airway function during mild viral respiratory illnesses, Ann Intern Med, 1974, 80, 150. Ii. :Ferris, B. G., Jr., Anderson, D. 0., and Zickmantel, R.: Prediction values for screening tests of pulmonary function, Am Rev Respir Dis, 1965, 91' 252. 18. Zierler, L. L.: Circulation times and the theory of indicator-dilution methods for determining blood flow and volume, in Handbook of Physiology, sec. 2, Circulatio11, vol. I, W. 0. Fenn and H. Rahn, eel., American Physiological Society, Washington, D. C., 1962, p. 585.