Changes in Smoking Status Affect Women More than Men: Results of the Lung Health Study

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1 American Journal of Epidemiology Copyright 2003 by the Johns Hopkins Bloomberg School of Public Health All rights reserved Vol. 157, No. 11 Printed in U.S.A. DOI: /aje/kwg083 Changes in Smoking Status Affect Women More than Men: Results of the Lung Health Study John E. Connett*,1, Robert P. Murray 2, A. Sonia Buist 3, Robert A. Wise 4, William C. Bailey 5, Paula G. Lindgren 1, and Gregory R. Owens,6 for the Lung Health Study Research Group 1 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN. 2 Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. 3 Division of Pulmonary and Critical Care Medicine, Oregon Health Sciences University, Portland, OR. 4 School of Medicine, Johns Hopkins University, Baltimore, MD. 5 Pulmonary Division, University of Alabama at Birmingham, Birmingham, AL. 6 School of Medicine, University of Pittsburgh, Pittsburgh, PA. Received for publication August 7, 2002; accepted for publication December 18, Lung Health Study participants were smokers aged years with mild lung function impairment who participated in a 5-year, 10-center (nine in the United States, one in Canada) clinical trial in The authors compared the relation of randomized treatment assignments and of smoking history during the study with changes in lung function between men and women. Spirometry was performed annually, and 3,348 men and 1,998 women attended the follow-up clinic visit that included spirometry at year 5. This paper reports on an analysis of changes in lung function by gender, treatment group, and three smoking history categories: sustained quitters, intermittent quitters, and continuing smokers. Among participants who quit smoking in the first year, mean forced expiratory volume in 1 second (FEV 1 ) expressed as a percentage of the predicted value of FEV 1 given the person s age, height, gender, and race (FEV 1 %) increased more in women (3.7% of predicted) than in men (1.6% of predicted) (p < 0.001). Across the 5-year follow-up period, among sustained quitters, women gained more in FEV 1 % of predicted than did men. Methacholine reactivity was more strongly related to rates of decline in women than in men (p < 0.001). Therefore, among persons at risk for chronic obstructive pulmonary disease, smoking cessation has an even clearer advantage for women than it does for men. clinical trials; lung diseases, obstructive; sex; smoking cessation; spirometry Abbreviations: COPD, chronic obstructive pulmonary disease; FEV 1, forced expiratory volume in 1 second; FEV 1 %, forced expiratory volume in 1 second expressed as a percentage of the predicted value of FEV 1 given the person s age, height, gender, and race. Chronic obstructive pulmonary disease (COPD) has been the fourth leading cause of death in the United States since at least 1978 (1). It is an insidious disease, with many years intervening between development of pulmonary function abnormalities and onset of serious respiratory symptoms. Age-adjusted rates of death from COPD among men have leveled off since the early 1980s, while those among women have doubled (2). Previous studies indicate that smoking cessation leads to a slowing of the accelerated rate of decline in pulmonary function noted in smokers susceptible to cigarette smoke (3, 4). Although gender differences have been explored in some studies, few have commented on differences between men and women in the rates of pulmonary function change as they relate to smoking history (5 7). The Lung Health Study was a randomized 10-center (nine in the United States, one in Canada) intervention trial conducted from October 1986 to April 1994 and was designed to test whether intervention with a bronchodilator and a smoking cessation program could reduce the rate of decline in pulmonary function among middle-aged smokers with mild to * Reprint requests to Dr. John E. Connett, Coordinating Centers for Biometric Research, 2221 University Avenue SE, Room 200, Minneapolis, MN ( john-c@ccbr.umn.edu). Deceased. 973

2 974 Connett et al. moderate airflow limitation. The primary endpoint was the rate of decline in postbronchodilator forced expiratory volume in 1 second (FEV 1 ) over a 5-year follow-up period. The intention-to-treat analysis of Lung Health Study data has been reported previously (8). Smoking cessation was found to have important effects on pulmonary function, particularly in the first year of the study, with a substantial improvement in FEV 1 and forced expiratory volume in 1 second expressed as a percentage of the predicted value of FEV 1 given the person s age, height, gender, and race (FEV 1 %) of predicted. In subsequent years, FEV 1 declined considerably less in the quitters than in those who continued to smoke. This paper focuses on differences between men and women in pulmonary function changes as they relate to randomized group assignment in the intention-to-treat analysis and also in a retrospective analysis as they relate to quitting smoking or continuing to smoke. MATERIALS AND METHODS The study population was 5,887 men and women participants in the Lung Health Study, a clinical trial of ipratropium and smoking intervention in patients with early COPD who were studied over 5 years. Of these persons, 149 died during the study period; of those surviving, 5,346 (93 percent) underwent pre- and postbronchodilator lung function measurements at year 5. Protocols were approved by the institutional review board for human studies at each clinical center, and written informed consent was obtained from each participant. Details of the study design, participant characteristics, smoking intervention program, and main outcomes have been published previously (8 11). Spirometry was performed at study entry and annually, with values for FEV 1 and forced vital capacity selected as the highest of the preand postbronchodilator measures (12). Data are presented as absolute and percent predicted values (13). Baseline airways reactivity was quantified by using the O Connor two-point slope, defined as the percentage change in FEV 1 from diluent to the last attained dose of methacholine, divided by the cumulative dose of methacholine (14). We used mean change in postbronchodilator FEV 1 between baseline and year 5 to indicate overall change in lung function. Because quitters typically showed an initial increase in FEV 1 followed by a linear decline, we also analyzed changes between years 1 and 5. In the intention-to-treat analysis, participants were categorized by their randomized assignments: 1) smoking intervention with either ipratropium bromide (an anticholinergic bronchodilator) or placebo inhaler or 2) usual care. In the analysis, participants were categorized as continuous smokers, intermittent quitters, or sustained quitters on the basis of their annual, biochemically confirmed smoking status (15). They were classified as smokers if their salivary cotinine levels were higher than 20 ng/ml. In those who used nicotine gum or other nicotine substitutes that invalidated cotinine measurement, compliance with smoking cessation was checked by measuring exhaled carbon monoxide concentrations; values of less than 10 parts per million defined successful compliance. Participants who did not attend follow-up visits for validation of smoking status were assumed to be smokers. Continuous smokers were defined as those biochemically verified as smokers at each annual clinic visit. Intermittent quitters were biochemically verified as smoking at between one and four annual follow-up visits, and sustained quitters were biochemically verified as nonsmokers at all annual clinic visits. Because ipratropium bromide had only a small and transient effect on lung function (8), in this analysis we combined both intervention groups as smoking intervention to focus on the effects of smoking changes and gender. Statistical methods included the following: Descriptive statistics are presented in this paper as counts for categorical data and as means and standard deviations for continuous variables. Bivariate comparisons were made by using chisquare or t-test statistics, as appropriate. Graphic data are presented as mean ±2 standard errors. Linear regression and analysis of covariance were used to adjust changes in FEV 1 (or percent predicted) for baseline values, body mass index, number of cigarettes smoked per day, and methacholine reactivity. Terms for interaction of randomized treatment assignment and of smoking status with gender were used to evaluate gender differences in lung-function response to smoking intervention. Statistical significance was inferred when p < 0.05 (two sided). RESULTS Baseline characteristics Baseline characteristics of study participants, by gender and by treatment group, are shown in table 1 (also refer to Buist et al. (10)). Men and women did not differ significantly in age, percentage with physician-diagnosed asthma, or FEV 1 % predicted. However, men and women did differ regarding number of cigarettes smoked per day, pack-years of smoking, salivary cotinine level, exposure to dust or fumes, years of education, married status, and O Connor slope. The percentage of both genders married at baseline was higher in the smoking intervention group than in the usual care group (p = 0.004). Because group assignment was random, this was a chance finding. Smoking intervention participants, as described in table 1, differed from usual care participants regarding only the percentage married: a higher percentage of men were married. No significant interactions were found between gender and the smoking intervention versus usual care groups. Intention-to-treat analysis The rate of change per year in postbronchodilator FEV 1 % of predicted is shown by gender and by treatment group in figure 1 and in table 2. In the unadjusted analysis, there was a greater spread between treatment groups in women s FEV 1 % predicted change data ( vs ) than in those for men ( vs ). We found significant effects for gender, treatment group, and the interaction of gender with treatment group in this analysis. When mean FEV 1 % predicted change values were adjusted for baseline age, number of cigarettes smoked per day, cotinine level, postbronchodilator FEV 1 % predicted, exposure to dust or fumes, body mass index, percentage

3 Gender and Effects of Smoking Changes 975 TABLE 1. Baseline characteristics, by gender and randomization group, of participants for whom 5-year pulmonary function data were available, Lung Health Study, United States and Canada, Variable Men (n = 2,211) SI* UC* p value for effects Women (n = 1,365) Men (n = 1,137) Women (n = 633) Gender SI vs. UC Interaction Non-White race (%) Age (years) 48.3 (7.0) 48.4 (6.5) 48.2 (6.9) 48.6 (6.6) No. of cigarettes smoked/day 32.6 (13.3) 29.0 (11.9) 32.3 (13.2) 28.6 (11.5) No. of pack-years of smoking 42.5 (20.2) 35.7 (16.1) 42.5 (19.0) 36.3 (16.9) Salivary cotinine level (ng/ml) (209.2) (186.3) (200.1) (203.3) Physician-diagnosed asthma (%) Exposure to dust or fumes (%) Education (no. of years) 13.8 (3.0) 13.3 (2.5) 13.9 (2.8) 13.2 (2.7) Married status (%) FEV 1 * % of predicted (post-bd*) 78.4 (9.2) 78.3 (8.8) 78.6 (8.9) 78.0 (9.3) O Connor slope 9.3 (18.7) 17.8 (27.9) 9.5 (20.6) 18.5 (28.4) * SI, smoking intervention; UC, usual care; FEV 1, forced expiratory volume in 1 second; BD, bronchodilator (isoproteronol). Between gender and randomization group as determinants of the variable. Values in parentheses, standard deviations. Defined as the percentage change in FEV 1 from diluent to the last concentration of methacholine tested, divided by the cumulative concentration of methacholine; units are percentage change in FEV 1 per mg/ml change in concentration of methacholine. FIGURE 1. Mean forced expiratory volume in 1 second (FEV 1 ) % of predicted, by year of follow-up, in men and women assigned to smoking intervention (SI) or usual care (UC), Lung Health Study, United States and Canada, Vertical bars, ±2 standard errors. bronchodilator response, and O Connor slope, the results for men and women in the usual care group were slightly closer (table 2). (A separate analysis indicated that baseline number of cigarettes smoked per day was a more significant predictor of change than pack-years.) In both the unadjusted and adjusted analyses, women assigned to the smoking intervention group lost less lung function than men did, whereas women in the usual care group lost more. This interaction of gender and treatment group was significant (p = 0.012). The mean FEV 1 % predicted values for smoking intervention participants increased notably in the first year: approximately 1.5 percent predicted for women and 0.5 percent predicted for men. Thereafter, the values declined and converged to approximately the same value for both genders at year 5. The values for men and women in the usual care group decreased steadily during the 5 years, with mean lung function loss for women being greater than that for men. The net effect of intervention after 5 years of follow-up was clearly greater for women than for men. Retrospective analysis of smoking history Men in the Lung Health Study were more likely than women to achieve sustained smoking cessation (18.3 percent vs percent, p = 0.016). However, the genders did not differ significantly regarding the proportions of intermittent quitters or continuing smokers. The rates of change per year in postbronchodilator FEV 1 % of predicted are shown in table 3 by gender and by categories of smoking history. In the unadjusted analysis, women sustained quitters actually gained lung function on average across the study years compared with men, whose status remained essentially the same across the 5 study years. Even women intermittent quitters lost less lung function than men did. Women intermittent quitters averaged slightly more years of smoking in the trial than did men intermittent quitters: 2.81 (standard error, 1.18) years for women versus 2.75 (standard error, 1.18) years for men. Men and women who were verified at each annual visit as continuing to smoke were approximately equivalent in their percent predicted lung function loss. Although this analysis was unadjusted, FEV 1 % of predicted effectively adjusts for gender, height, race, and age so that results for men and women can be compared.

4 976 Connett et al. TABLE 2. Mean rate of change per year (standard error) in postbronchodilator FEV 1 * % of predicted, by gender and randomized assignment group, Lung Health Study, United States and Canada, Unadjusted analysis Men Women Gender p value for effects SI* vs. UC* Interaction SI (0.034) (0.043) UC (0.047) (0.063) Adjusted analysis SI (0.034) (0.044) UC (0.046) (0.063) * FEV 1, forced expiratory volume in 1 second; SI, smoking intervention; UC, usual care. Restricted to participants for whom year 5 pulmonary function data were available. Refers to the hypothesized difference between the genders in the effects of randomization group on changes in lung function. Adjusted for baseline age, number of cigarettes smoked/day, salivary cotinine level, previous exposure to dust or fumes, postbronchodilator FEV 1 % of predicted, body mass index, bronchodilator response percentage, and O Connor slope. As shown in the adjusted analysis in table 3, the gender, smoking history, and interaction effects were more noticeable. For men and women continuing smokers, values for lung function change (loss) were very similar. Women intermittent quitters lost less lung function than men did, and women sustained quitters gained a striking percentage of lung function when compared with men. In this analysis, the interaction of gender with smoking history was again significant (p = 0.001). Figure 2 presents longitudinal data on FEV 1 % predicted for men and women verified as being either sustained quitters or continuing smokers during follow-up. Although much of the difference between smoking categories occurred during the first year, differences for both genders continued to increase across subsequent annual visits. For male sustained quitters, mean FEV 1 % predicted increased from 79.1 to 80.7 during the first year, with a smaller increase through the second year. During the remainder of the study, FEV 1 % predicted decreased slightly in men; the final mean value was 79.6 and was not significantly different from the value at baseline (p > 0.10). TABLE 3. Mean rate of change per year (standard error) in postbronchodilator FEV 1 * % of predicted, by gender and smoking history group, Lung Health Study, United States and Canada, Unadjusted analysis Men Women Gender p value for effects Smoking Interaction history Sustained quitter (611 men; < < women) (0.060) (0.085) Intermittent quitter (916 men; 592 women (0.050) (0.062) Continuing smoker (1,821 men; 1,093 women) (0.035) (0.045) Adjusted analysis Sustained quitter (0.060) (0.085) < < Intermittent quitter (0.049) (0.062) Continuing smoker (0.036) (0.046) * FEV 1, forced expiratory volume in 1 second. Restricted to participants for whom year 5 pulmonary function data were available. Refers to the hypothesized difference between the genders in the effects of smoking history on changes in lung function. Adjusted for baseline age, number of cigarettes smoked/day, salivary cotinine level, prior exposure to dust or fumes, postbronchodilator FEV 1 % of predicted, body mass index, bronchodilator response percentage, and O Connor slope.

5 Gender and Effects of Smoking Changes 977 FIGURE 2. Mean forced expiratory volume in 1 second (FEV 1 ) % of predicted, by year of follow-up, in men and women sustained quitters (SQ) and continuing smokers (CS), Lung Health Study, United States and Canada, Vertical bars, ±2 standard errors. Female sustained quitters showed about a 2.3-fold larger improvement in FEV 1 % predicted in the first year, increasing from 78.3 to 82.0, than was noted in men (p < 0.001). This increase was sustained through the second year of the trial and then decreased slightly. At year 5, pulmonary function in female sustained quitters was still better than that noted at baseline: a net increase of 1.9 percent (standard error, 0.4 percent) in FEV 1 % predicted versus a net increase of 0.4 percent (standard error, 0.3 percent) in men. The difference in response to smoking cessation among men and women was significant and was due largely to differing increases in the first year of smoking cessation. After year 1, no difference was found in mean change in FEV 1 % predicted between men and women who quit smoking. Among continuing smokers, the mean pattern of decline was quite similar for both genders, with women losing slightly more FEV 1 % predicted by year 5 than men did (5.4 percent predicted vs. 5.0 percent predicted). DISCUSSION This analysis of longitudinal data on pulmonary function from the Lung Health Study indicated that, among smokers with mild to moderate lung function impairment, women tended to have greater improvement in lung function in response to smoking cessation than did men. In the first year, the improvement in FEV 1 % predicted in women sustained quitters was 2.3 times higher than in men who quit. Similar, but less extreme differences were seen in the 5-year data. The Lung Health Study had a number of strengths that enabled us to detect the gender/smoking intervention interaction described here, including a large sample size, a relatively high proportion of women, an aggressive smoking cessation program with high rates of initial quitting and low relapse rates (16), a 5-year period of follow-up with followup rates at the fifth annual visit in excess of 94 percent, and high-quality measurement of pulmonary function. The study focused on smokers of both genders who already had mild to moderate COPD, for whom relatively high rates of decline in FEV 1 could be expected. Note that participants recruited for the study were selfselected and were not a random sample of middle-aged smokers. As in most clinical trials, this factor might limit generalizability of our findings. Many Lung Health Study participants were found to be reactive to methacholine (11, 14). Reactivity was closely related to FEV 1 and FEV 1 % predicted and was substantially more common in women (87 percent) than in men (63 percent) (17). Airways reactivity, as suggested by the Dutch hypothesis (18), was a strong determinant of lung function decline, particularly in continuing smokers. However, our multivariate analyses indicated that the greater response of Lung Health Study women to quitting smoking was only partially explained by gender differences in airways reactivity. Both differences and similarities exist between the Lung Health Study and other longitudinal studies of pulmonary function and smoking cessation. Lange et al. (19), who followed a cohort of 7,764 men and women aged 20 years or older in the Copenhagen, Denmark, population, noted that, among women smokers older than age 55 years, the rate of decline in FEV 1 was greater for heavy smokers than for light smokers. No such relation was seen among men. Xu et al. (20), in a study of 3,287 men and women aged years in China, found that women smokers had a greater decrease in pulmonary function than men did. The Chen et al. (21) study of 1,149 adults aged years in Saskatchewan, Canada, noted that gender and smoking intensity affected FEV 1 and maximal midexpiratory flow and that women were more affected than men. The observed interaction of gender and smoking intensity was independent of age, height, and weight. Langhammer et al. (22), in a survey of more than 65,000 men and women in Norway, noted that, of current and previous smokers, women were significantly more likely than men to report respiratory symptoms and asthma, even after the authors controlled for pack-years of smoking and current levels of cigarette smoking per day. Their conclusion that women seemed to be more susceptible to the effect of tobacco smoking than men (22, p. 917) parallels our findings on lung function. The explanation for an apparent heightened sensitivity to cigarette smoke in women is unknown. It is possible that, since women s lungs tend to be smaller than men s, cigarette smoke is more concentrated in the airways. Thus, pack-years or reported number of cigarettes smoked per day could underrepresent the effective smoke exposure to the lungs of women. If so, women could be expected to have higher levels of cotinine than men do. However, mean levels of salivary cotinine in our study were lower in women than in men, consistent with the baseline difference in number of cigarettes smoked per day. A second possible explanation might be that, because the FEV 1 of women is lower than that of men, the effect might be related to airways caliber. Our analyses of covariance suggest that that is not the complete explanation. After we

6 978 Connett et al. controlled for covariates including baseline FEV 1, gender remained a powerful predictor of response to smoking cessation. In the present analysis, FEV 1 and FEV 1 % predicted were postbronchodilator values and were presumably less subject to day-to-day environmental exposures that may differ by gender. To summarize, our three most important findings were the following: 1. Among participants who quit smoking in year 1, women showed greater improvements in both FEV 1 and FEV 1 % predicted. Among sustained quitters, 5-year losses in FEV 1 and FEV 1 % predicted were smaller in women than in men. 2. Among participants who continued to smoke, declines in FEV 1 % predicted were about equivalent in women and in men. 3. Evidence of an interaction exists between gender and smoking behavior as determinants of changes in lung function. The observed gender effects persisted even after adjustment for such potentially confounding factors as baseline lung function, airways reactivity, smoking level, age, and body mass index. Our results should serve as an impetus for more emphasis on smoking cessation among women, especially as the number of women with COPD continues to increase. For women at risk of COPD, there is a clear healthpromotion message here. ACKNOWLEDGMENTS Supported by contract NO1 HR from the Division of Lung Disease; National Heart, Lung, and Blood Institute; National Institutes of Health, Bethesda, Maryland. Atrovent and placebo inhalers were supplied by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut. Nicorette was supplied by Marion Merrell Dow, Inc., Kansas City, Missouri. The initial primary author of this manuscript was Dr. Gregory R. Owens, who died in September The principal investigators and senior staff of the clinical and coordinating centers and of the National Heart, Lung, and Blood Institute, as well as members of the Safety and Data Monitoring Board and the Morbidity and Mortality Review Board, are as follows: Case Western Reserve University, Cleveland, Ohio Dr. M. D. Altose (Principal Investigator), Dr. A. F. Connors (Co-Principal Investigator), Dr. S. Redline (Co-Principal Investigator), Dr. C. D. Deitz, and Dr. R. F. Rakos; Henry Ford Hospital, Detroit, Michigan Dr. W. A. Conway, Jr. (Principal Investigator), Dr. M. Eichenhorn (Principal Investigator), Dr. A. DeHorn (Co- Principal Investigator), Dr. J. C. Ward (former Co-Principal Investigator), C. S. Hoppe-Ryan, R. L. Jentons, J. A. Reddick, and C. Sawicki; Johns Hopkins University School of Medicine, Baltimore, Maryland Dr. R. A. Wise (Principal Investigator), Dr. S. Permutt (Co-Principal Investigator), and Dr. C. S. Rand (Co-Principal Investigator); Mayo Clinic, Rochester, Minnesota Dr. P. D. Scanlon (Principal Investigator), Dr. L. J. Davis (Co-Principal Investigator), Dr. R. D. Hurt (Co-Principal Investigator), Dr. R. D. Miller (Co- Principal Investigator), Dr. D. E. Williams (Co-Principal Investigator), G. M. Caron, G. G. Lauger, and S. M. Toogood (Pulmonary Function Quality Control Manager); Oregon Health Sciences University, Portland, Oregon Dr. A. S. Buist (Principal Investigator), W. M. Bjornson (Co-Principal Investigator), and Dr. L. R. Johnson (Lung Health Study Pulmonary Function Coordinator); University of Alabama at Birmingham, Birmingham, Alabama Dr. W. C. Bailey (Principal Investigator and Associate Chief of Staff for Education, Department of Veterans Affairs Medical Center, Birmingham), Dr. C. M. Brooks (Co-Principal Investigator), Dr. J. J. Dolce, D. M. Higgins, M. A. Johnson, and B. A. Martin; University of California, Los Angeles, Los Angeles, California Dr. D. P. Tashkin (Principal Investigator), Dr. A. H. Coulson (Co-Principal Investigator), Dr. H. Gong (former Co-Principal Investigator), Dr. P. I. Harber (Co- Principal Investigator), Dr. V. C. Li, (Co-Principal Investigator), Dr. M. A. Nides, M. S. Simmons, and I. P. Zuniga; University of Manitoba, Winnipeg, Manitoba, Canada Dr. N. R. Anthonisen (Principal Investigator, Steering Committee Chair), Dr. J. Manfreda (Co-Principal Investigator), Dr. R. P. Murray (Co-Principal Investigator), S. C. Rempel- Rossum, and J. M. Stoyko; University of Minnesota Coordinating Center, Minneapolis, Minnesota Dr. J. E. Connett (Principal Investigator), Dr. M. O. Kjelsberg (Co-Principal Investigator), Dr. M. K. Cowles, D. A. Durkin, Dr. P. L. Enright, K. J. Kurnow, W. W. Lee, P. G. Lindgren, S. Mongin, Dr. P. O Hara (Lung Health Study Intervention Coordinator), H. T. Voelker, and Dr. L. Waller; University of Pittsburgh, Pittsburgh, Pennsylvania Dr. G. R. Owens (Principal Investigator (deceased)), Dr. R. M. 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