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West Australia Sleep Disorders Research Institute, Queen Elizabeth II Medical Centre
School of Medicine and Pharmacology
University of Western Australia Centre for Medical Research, University of Western Australia and Laboratory for Genetic Epidemiology, Western Australian Institute for Medical Research
Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia
ABSTRACT
Asthma in adults may be associated with chronic airflow obstruction, possibly resulting from airway disease in early life and/or a greater rate of decline in lung function in adult life compared with those with asthma. Treatment and cigarette smoking may also influence the rate of decline of lung function. The aim of this analysis was to examine the level and rate of decline in lung function in relationship to asthma and cigarette smoking in adults. Subjects (n = 9,317) had participated as adults (> 18 years) in one or more of the cross-sectional Busselton Health Surveys between 1966 and 1981 or in the follow-up study of 1994/1995. The effects of sex, doctor-diagnosed asthma, smoking status, and anthropometric data on the level and rate of decline in FEV1 were examined in a linear mixed effects model. At the age of 19 years, FEV1 was reduced in subjects with asthma but was similar in smokers and nonsmokers. Males, taller subjects, smokers, and subjects with asthma had greater declines in FEV1 with age. Smoking and asthma had additive but not multiplicative effects on decline. Thus, asthma is associated with reduced lung function at the beginning of adult life as well as an increased rate of decline during adult life.
Key Words: asthma epidemiology lung function tests smoking
Asthma may be associated with fixed airflow obstruction (1, 2), which may result from airway remodeling from early life (3) and/or an increased rate of decline in lung function in patients with asthma (4eC7). Studies in children have shown that those with persistent symptoms (3), those with asthma of mild to moderate severity (8), and those with severe asthma (9) have abnormal lung function early in life. Birth cohort studies have suggested that abnormalities of lung function are not present in the first year of life but develop thereafter in those with persistent symptoms (10) or increased airway responsiveness measured in the first year of life (11).
In adults, it is difficult to determine the longitudinal effects of asthma on lung function because of the confounding effects of factors such as cigarette smoking (7, 12eC14), occupational exposures (15), raised white cell count (16eC18), and concomitant lung diseases such as bronchitis or emphysema (19). Treatment with inhaled corticosteroids improves or reverses airway inflammation (20) and airway remodeling (21, 22) and may reduce the rate of decline of lung function in subjects with asthma (23). Although many subjects with asthma continue to smoke cigarettes, there has only been one study that has reported the interaction of the effects of cigarette smoking and asthma on the rate of decline in lung function (7). It showed that compared with nonsmokers without asthma, the rate of decline in FEV1 was greater in those with asthma and in those who smoked and greatest in those with asthma who smoked: lung function at the age of 20 years was similar in the subjects with and without asthma (7).
Lung function, smoking habits, and the diagnosis of asthma have been recorded in the Busselton Health Surveys since 1966 (5). An earlier analysis of these data to 1983 showed a greater rate of decline in FEV1 in subjects with asthma (4). However, there were insufficient subjects with asthma who had smoked to examine validly the interaction of cigarette smoking and asthma. All subjects who attended any previous Busselton Health Survey from 1966 to 1983 were invited for further testing in 1994 and 1995. The greater numbers of observations in this study have allowed us to examine the separate and combined longitudinal effects of asthma and smoking in the Busselton population.
METHODS
Subjects
Cross-sectional, whole-population health surveys in Busselton, Western Australia, were undertaken at intervals of 3 years in adults (> 18 years of age) from 1966 to 1981 and in children from 1968 to 1983. In 1994, all traceable subjects who had participated (as a child or as an adult) in any previous survey were contacted for a follow-up study (Table 1). The studies were approved by the Human Rights Committee of the University of Western Australia and were performed in accordance with the Declaration of Helsinki, 1964.
Symptoms and Smoking
A self-administered questionnaire based on the British Medical Research Council questionnaire (24) was used. Doctor-diagnosed asthma was defined as a positive response to either of the following questions: "Has your doctor ever told you that you have asthma" or "Have you ever been treated for bronchial asthma or asthma" Subjects who gave a positive response to either question at one or more surveys were classified as "asthmatic." Smoking status at the time of the initial study attended as an adult was categorized as current smoker (smoking at the time of study: heavy 15 cigarettes per day and light < 15 cigarettes per day), ex-smoker (previous smoker but not smoking at the time of study), or never smoker. Medication use was recorded in 1981 and 1994.
Lung Function
From 1966 to 1978, FEV1 and FVC were measured using a McDermott dry spirometer (Pneumoconiosis Research Unit, Penarth, UK). Wedge spirometers (Vitalograph, Buckingham, UK) were used in 1981 and pneumotachograph spirometers (Welch Allyn, Skaneateles Falls, NY) in 1994/1995. Spirometers were calibrated daily using a 3-L syringe. All values obtained were corrected to body temperature and ambient pressure, saturated with water vapor (BTPS), with an assumed fixed room temperature and atmospheric pressure. FEV1 and FVC were measured in accordance with the American Thoracic Society guidelines, initially published in 1979 (25) and first revised in 1987 (26). Before the publication of guidelines, FEV1 and FVC were recorded as the highest values obtained from three maximum expiratory maneuvers, provided that two of the recordings were within 10% of each other. Predicted values derived from the Busselton population studies were used (18).
Statistical Analysis
Subjects who were more than 18 years old at the time of their first attendance at a survey were included in the analysis. All modeling was performed with males and females grouped separately. The primary response variables were the FEV1 and FEV1/FVC ratio measured at each survey. Explanatory variables included asthma status, current age, age at initial survey, height, weight, and smoking status. Initial modeling used a regression tree approach based on recursive partitioning (27), using standard residuals derived from a quadratic regression of FEV1 on age and height. A linear mixed effects modeling approach using restricted maximum likelihood (28) was used to investigate the longitudinal relationships of FEV1 levels with covariates. Subjects with one or more measurements were included. The rate of decline in FEV1 was investigated by inclusion of interaction terms with current age in the linear mixed effects models. Analysis and data management were performed using SPlus v2000 (Mathsoft Inc., Cambridge, MA). Statistical significance was defined at the 5% level.
RESULTS
Characteristics of Subjects
According to Shire records, over the period covered by this study, the adult population of the Busselton Shire increased from approximately 4,000 in 1966/1969 to 10,294 in 1993. Subjects attended on one to seven occasions (see Table E1 in the online supplement). Females were seen on average 3.4 times (SD = 1.8; range, 1eC7); males were seen on average 3.2 times (SD = 1.8; range, 1eC7). The number of new and previous attendees at each survey is shown in Table 1. The characteristics, categorized by asthma status, for adult (> 18 years) females (n = 4,796) and males (n = 4,521) who had spirometry assessed at the time of their first attendance at a survey showed that more males had ever smoked, were current heavy smokers, or had ceased smoking (Table 2). Similar numbers of women (14.9%) and men (13.0%) indicated that they had asthma. Slightly more men (8.2%) reported wheeze on most days compared with women (6.2%). Subjects with asthma were slightly younger, weighed less (males), reported more wheeze, and had lower levels of lung function. There were no significant differences in smoking habits between those with and those without doctor-diagnosed asthma (Table 2). In subjects with asthma, the reported current use of short-acting -adrenergic bronchodilators increased from 32% in 1981 to 55% in 1994, and reported current inhaled corticosteroid use increased from 11% in 1981 to 33% in 1994. Results for FEV1/FVC% gave identical patterns in the analyses, and therefore, data only for FEV1 are presented here.
Level of FEV1
In males and females, multivariate linear mixed effect modeling of FEV1 showed that current age, height, weight, age at initial survey, asthma, and smoking status were significant predictors of FEV1 level (Table 3). The negative association of smoking status with FEV1 level increased with increasing number of cigarettes smoked: FEV1 levels were highest in nonsmokers, lower in ex-smokers, lower still in current light smokers, and lowest in current heavy smokers.
Decline in FEV1 with Age
A multivariate linear mixed effects analysis showed that cigarette smoking and a diagnosis of asthma were significantly associated with an increased rate of decline in FEV1 in men and women (Table 4), as were increasing height (male, coefficient = eC0.003 ml/year/cm, SE = 0.001, p = 0.001; female, coefficient = eC0.002 ml/year/cm, SE = 0.001, p = 0.0001). A dose effect of smoking on rate of decline in FEV1 was present in both males and females. The average annual linear decline in FEV1 (ml/year) for males and females stratified as nonsmokers and smokers and as those with or without asthma showed that in each stratum males had a greater decline in FEV1 than females (Table 5 and Figures 1 and 2). In males and females, subjects with asthma had a greater decline in FEV1 than subjects without asthma, and male and female smokers had a greater decline in FEV1 than ex-smokers or nonsmokers. Although there are clearly additive effects of smoking and asthma (Table 5 and Figures 1 and 2), the modeling did not show any evidence of a significant multiplicative interaction between asthma and smoking on rate of decline in FEV1.
In a clinical context, the modeling suggests that, on average, a nonsmoking white male without asthma of average height (174 cm) and weight (77 kg) would have an FEV1 of approximately 3.20 L by the age of 60 years. A male subject with asthma with otherwise identical characteristics would have an FEV1 380 ml lower (2.82 L) by the age of 60 years. A male heavy smoker without asthma would have an FEV1 190 ml lower (3.01 L) by the age of 60 years, and a male who had asthma and was a heavy smoker would have an FEV1 560 ml lower (2.64 L) by the age of 60 years. A nonsmoking female without asthma of average height (161 cm) and weight (64.5 kg) would have, on average, an FEV1 of approximately 2.27 L by the age of 60 years. A female subject with asthma with otherwise identical characteristics would have an FEV1 200 ml lower (2.07 L) by the age of 60 years. A female heavy smoker without asthma would have an FEV1 130 ml lower (2.14 L) by the age of 60 years, and a female who had asthma and was a heavy smoker would have an FEV1 330 ml lower (1.94 L) by the age of 60 years.
For males without asthma, comparisons of the rates of decline in FEV1 before and after 1981 showed a small but significantly greater decline after 1981 of approximately 2.94 ml/year (SE = 1.51) (p = 0.05). There was no evidence of a significant change in the rate of decline in FEV1 in male subjects with asthma after 1981 (p = 0.54). In females (with or without asthma) there was no significant difference in the rate of decline in FEV1 before or after 1981 (data not shown).
DISCUSSION
Our study, designed to assess a sample of individuals followed longitudinally throughout adulthood and who were representative of a general white Australian population, has shown that the age-related decline in FEV1 is strongly associated with both asthma and cigarette smoking, which together have additive effects. At the age of 19 years, lung function levels were significantly lower in subjects with asthma but were similar in smokers and nonsmokers. Almost identical results were observed for FEV1/FVC.
The Busselton population studies from 1966 to 1987 were conducted as serial cross-sectional surveys. The 1994/1995 follow-up survey was of subjects who had attended any previous survey, either as a child or as an adult. For inclusion in this analysis, they may have appeared for the first time (as an adult) in the 1994 survey. Therefore, at each survey in this study, there were both new and repeat subjects so that each survey has both cross-sectional and longitudinal aspects. Potential sources of bias include survivor and selection biases. Survivor bias (and period and cohort effects) was reduced by the inclusion of new subjects at each survey. We investigated potential survivor biases affecting our longitudinal analyses by comparing mean FEV1 % predicted and current cigarette smoking (never + ex vs. light + heavy) measured at the time of first assessment in those men and women having different total numbers of assessments (from one to seven surveys; Table E1). FEV1 % predicted was significantly lower (p < 0.001) in men who attended only once (mean = 97.9%, SD = 21.7) versus more than once (mean = 99.4%, SD = 16.7). There was no significant difference between these groups among women. The proportion of current smokers was higher (p < 0.001) in both men (48.0%) and women (31.5%) who attended only once versus those who attended more than once (40.5% and 22.2%, respectively). However, there was no significant difference in either mean FEV1 % predicted or the proportion of current smokers among men or women who had between two and seven visits. Because the subjects with only one visit did not contribute to the longitudinal analysis, these results suggest that our study was relatively robust with regard to potential biases arising from differential survival. Selection bias is likely to be low, as all surveys were general health surveys without disease emphasis, and there was a very high participation rate in the earlier survey (70eC83% of eligible adult population). However, because men with lower lung function and men and women who were current smokers were more likely to attend only once, this suggests that the results at a minimum may underestimate the effects of smoking on asthma and lung function decline. For adult smokers and nonsmokers, a history of asthma was associated with lower levels of FEV1 from the age of 19 years and a more rapid rate of decline in FEV1 with age. Therefore, both a lower initial level of FEV1 and a more rapid decline in FEV1 with age in those with asthma are likely to contribute to lifelong lower levels of FEV1 in this group. As might be expected, the effects of smoking on levels of lung function are not evident at the age of 19 years but appear to contribute to reduced lung function in later life by increasing the rate of decline in FEV1 with age.
The overall "prevalence" of asthma in the study population was 12.7% for females and 11.4% for males. This does not represent a point or cumulative prevalence, as the times of entry into the study varied between subjects. Age-adjusted prevalence of asthma in adults in Busselton increased from 6% in 1966 to 11% in 1981 (29), with a further increase to 16% in a separate cross-sectional random sample of subjects from Busselton in 1990 (30). In the 1994/1995 follow-up study, the crude prevalence of doctor-diagnosed asthma (ever) was 18% (unpublished data). In this study, FEV1 and FEV1/FVC percent predicted values were lower in subjects with asthma. Smoking habits were similar in those with asthma and those without asthma, as has been observed elsewhere (7, 9).
The diagnosis of asthma used in this study was a positive response to the questionnaire item "Has your doctor ever told you that you had asthma (or bronchial asthma)" at any survey. This may underestimate the true prevalence of asthma. For analysis, subjects were categorized as having asthma if they gave a positive response at any survey. This is likely to increase the sensitivity of the questionnaire over the course of the study. Other definitions of asthma such as wheeze (ever) are likely to overestimate the prevalence of asthma, especially in older subjects, as the prevalence of wheeze steadily increases with age especially in smokers (31). Wheeze and airway hyperresponsiveness have also been used to define asthma (30); however, airway responsiveness was measured in all subjects only in the 1994/1995 follow-up study.
The findings from this study with regard to decline in lung function are consistent with those of Lange and colleagues (7) from the Copenhagen City Heart Study. They also found that both smoking and asthma were independently associated with a more rapid decline in FEV1 and had additive effects but did not report reduced lung function from approximately the age of 19 years. This study examined subjects over a greater adult age range and with a substantially longer follow-up than that previously reported (7). No other studies have reported these additive effects, although numerous studies have shown the separate effects of either smoking (5, 12, 13) or asthma (4, 6, 12). The use of a repeated measures analysis (28) in this study allowed inclusion of subjects with fewer observations so that the combined effects of smoking and asthma could be investigated more precisely than has previously been possible.
A more rapid decline in FEV1 such as that seen in smokers can result in chronic obstructive pulmonary disease (5, 12). It is also likely that the more rapid decline in FEV1 observed in those with asthma contributes to the development of reduced lung function (relative to age) and fixed airflow obstruction, and this study suggests that smoking and asthma are likely to have additive effects in this respect. Previous studies have shown that cessation of smoking results in a reduced rate of decline in FEV1 (4, 6, 12, 14); however, treatment with bronchodilators (13, 32) has no significant effect on the rate of decline in FEV1 in smokers or patients with chronic obstructive pulmonary disease. Finally, a recent study of 2,926 adult subjects over 20 years (19) has shown that compared with those without asthma, the rate of decline in FEV1 is not increased in those with asthma with questionnaire-diagnosed emphysema or chronic bronchitis. The differences between this study and that of Sherrill and colleagues (19) may be related to the increased numbers of subjects in the Busselton Health Studies or a more stringent diagnosis of asthma (19), which excluded subjects who also reported seeing a doctor for emphysema or chronic bronchitis.
In those with asthma, treatment with inhaled corticosteroids may reduce the rate of decline in FEV1 (23), although there are few prospective data to examine this thoroughly. We separately examined the rates of decline in FEV1 before and after 1981, a time point that coincided with the beginning of widespread use of inhaled corticosteroids in asthma treatment in Australia. In the Busselton population, the use of any inhaled corticosteroid increased threefold from 1981 to 1994, similar to that seen in a small group of well characterized people with asthma in Western Australia (1) followed over the same time period (33). Medication doses were not available. We did not observe a change in the rate of decline in subjects with asthma compared with those without asthma from before or after 1981. This does not, however, exclude a possible benefit of inhaled corticosteroids on the rate of decline in FEV1 because this analysis was retrospective and the study was not designed to test the effects of treatment on rate of decline in FEV1. A recent study (34) has also raised the possibility of an interaction between treatment and smoking, showing reduced effects of inhaled corticosteroids on lung function in patients with asthma who were current smokers.
In the Copenhagen study (7), there were more smokers in the groups with asthma compared with the groups without asthma, and in this study, the number of smokers were similar in those with and without asthma. This study shows that the well known deleterious effects of cigarette smoke on lung function and decline in lung function are even greater in males with asthma. This additive effect may result from the airway inflammation that is often present in smokers (35) and in those with asthma (36eC38). Our study shows that the detrimental effects of smoking on lung function are greater in those with asthma and that management of asthma should include persistent efforts to discourage smoking.
Finally, the reduced FEV1 observed from the age of 19 years in the subjects with asthma suggests that abnormalities of airway structure/function before this age contribute to impaired lung function in adulthood (3, 8, 9), probably beginning in early life (10, 11). Abnormalities in lung function appear to develop after the onset of symptoms (10) or in those with early airway hyperresponsiveness (11).
Acknowledgments
The authors thank the people of the Busselton Community for their participation in this study, the Busselton Population Medical Research Foundation, and the many colleagues, especially Ms. Davina Whittall, who assisted in the collection of this data. They also acknowledge the generous support for the 1994/1995 follow-up study from Healthway, Western Australia.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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