This study investigated the determinants of sex-specific maximally attained levels of FEV1, VC, and the ratio of FEV1 to VC. Subjects were between the ages of 15 and 35 years (1,818 males and 1,732 females), participating in the Vlagtwedde/Vlaardingen study in The Netherlands. The subjects were followed (3-year intervals) with questionnaire, spirometry, peripheral blood eosinophil counts, and testing for airway responsiveness to histamine. Skin tests were performed only at study onset. Regression splines were used to assess the effects of these variables on levels of FEV1, VC, and the ratio of FEV1 to VC, with adjustment for age, height, and area of residence. Current (−44 ml/pack/day) and cumulative (−85 ml/10 packs/year) cigarette smoking were significant predictors of reduced maximal level of FEV1 in males but not in females. The presence of respiratory symptoms (−114 ml in males, −106 ml in females), increased eosinophils (−128 ml [males], −53 ml [females]), and increased airway responsiveness (−225 ml [males], −213 ml [females]) were all significant predictors of reduced level of FEV1. To the degree that these factors diminished plateau phase pulmonary function, they may be important predictors of chronic obstructive pulmonary disease in later life.
Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death and contributes substantially to morbidity in the United States (1). Previous investigations on the natural history of COPD have focused on the decline of lung function measurements in adult subjects over the age of 40 (2). Cigarette smoking has been thought to be the most important cause of COPD in these studies (3, 4). However, it has long been recognized that only a small fraction of smokers, about 10 to 20%, go on to develop COPD, which suggests that there is considerable individual variation in disease susceptibility (5). Thus, investigations have focused extensively on the early childhood period, particularly on the effects of passive smoking (6) and early childhood asthma (7) on maximal level of lung function and their role in identifying the susceptible smoker.
Although a general picture has emerged of the overall pattern of growth and decline of pulmonary function over a person's lifetime (5, 8, 9), risk factors for reduced pulmonary function between the ages of 15 and 35 years have been infrequently explored in the epidemiology of COPD. The reasons for this are many and include difficulty in assembly of cohorts in this age range due to subject mobility and lack of data on relevant exposures. Understanding the determinants of maximal growth is critical as maximal lung growth is an important mediator of subsequent development of COPD. Knowledge about risk factors for maximal lung growth would provide new insights into the natural history of COPD and help guide intervention efforts. Using nonparametric curve-smoothing methods, two longitudinal studies (10, 11) recently examined the effects of smoking and respiratory symptoms on pulmonary function from childhood to late adulthood. The data suggest that reduced level and/or premature decline of pulmonary function during the plateau phase are alternative models for increased risk of COPD.
The Vlagtwedde/Vlaardingen study is unique in having an extensive follow-up of individuals initially between the ages of 15 and 54 years followed for a 24-year period, with pulmonary function measurements and relevant information on cigarette smoking, respiratory symptoms and diseases, airway responsiveness, and allergy markers. It offers an opportunity to study longitudinally the effects of these factors on pulmonary function during the plateau phase and on the subsequent decline of pulmonary function in later life. It also helps bridge the gap between recent epidemiologic studies of pulmonary function growth in children and adolescents (12, 13) and studies of pulmonary function decline in late adulthood (14–17).
The purpose of this study is to describe the sex-specific patterns of maximal level of FEV1, VC, and the ratio of FEV1 to VC between ages 15 and 35 years and to examine the associations of these pulmonary function measurements with various risk factors, including cigarette smoking, respiratory symptoms, airway responsiveness, eosinophilia, and positive skin tests, as well as possible interactions among these factors.
Detailed descriptions of the Vlagtwedde/Vlaardingen study have been published elsewhere (18–22). Since the baseline survey, the two cohorts have been reexamined every 3 years, beginning in 1970 in Vlagtwedde and 1972 in Vlaardingen.
At each survey, questionnaires on respiratory symptoms and smoking habits were administered by trained interviewers. Chronic cough or chronic phlegm, bronchitis, persistent wheeze, dyspnea (grade ⩾ 3), and asthma were defined as in previous reports (18–22). A subject was considered symptomatic if he/she had any of the six symptoms/diseases described previously.
Smoking was considered as both a categorical (never, ex, 1–4, 5–15, 15–24, 25+ cigarettes/day) and a continuous (packs/day) variable. Never-smokers were defined as subjects who never smoked cigarettes, and ex-smokers were those who had stopped smoking at least 1 month before each examination.
Pulmonary function was measured at each survey with a water-sealed spirometer (Lode Spirograph D53; Lode Instruments, Groningen, The Netherlands) while the subjects were seated and wearing nose clips. An inspiratory VC was measured after a deep expiration, followed by the measurement of FEV1.
Eosinophil counts were performed using methods described previously (21). Eosinophilia was considered to be present at a count greater than or equal to 275 (25 × 11) eosinophils per cubic millimeter of blood, as it provides the best correlation with both symptoms and level of lung function (21).
In this analysis, skin tests were coded on a six-point scale after subtracting positive controls and were considered to be positive at a score of 3 or more. This definition was chosen as it provides the best correlation with both symptoms (22) and level of lung function (21).
All the challenge tests (19, 20) used the method of Tiffeneau with some modification by De Vries and coworkers (23). This method meets standardization guidelines (24). In this analysis, a subject was classified as having increased histamine airway responsiveness if provocative concentration of histamine sufficient to produce a 10% drop in FEV1 was 16 mg/ml or less. This definition is equivalent to a provocative concentration of histamine sufficient to produce a 20% drop in FEV1 of less than 8 mg/ml, the upper limit of the asthmatic range (20).
All the observations of subjects between ages 15 and 35 years were included in the analysis. Neither models proposed for pulmonary function in children (12–14) nor in adults (15, 16) are adequate to describe pulmonary function during this age range. Tager and coworkers (10) and Sherrill and coworkers (11) used nonparametric smoothing methods to describe lung function growth and decline from childhood through adulthood. In this study, besides using a robust smoothing technique (25), we employed regression spline models (26, 27), which provide a flexible family of growth curve models, are fully parametric, and permit the use of familiar regression techniques for the assessment of covariates.
Our modeling approach for pulmonary function level used linear regression splines with age knots (14, 16, 18, 20, 22, 24, 29, 34). The regression coefficients are estimated assuming independence among all observations. All variables, including the symptoms and diseases, smoking, and airway responsiveness, are considered as time-dependent covariates, where subjects with and without the phenotypic trait are compared. The detailed statistical methods on parameter estimation can be found elsewhere (27). Robust variance estimates (28) were further calculated for the estimated regression coefficients to accommodate repeated measures on subjects. Graphic and residual analyses were performed to assess modeling assumptions. All predictor variables were evaluated individually and jointly as predictors of the level of VC, FEV1, and the ratio of FEV1 to VC. A subject's age, height, and area of residence were included in all models. All analyses were stratified by sex. Differences in the effect estimates between sexes were compared using two-tailed t tests. Because the stratified analyses (Table 5) suggested possible interactions, five of these were formally tested using cross-product terms in the sex-stratified regression models.
This analysis includes a total of 1,818 male and 1,732 female subjects who had at least one acceptable pulmonary function test between ages 15 and 35 years; they contributed 4,378 and 3,716 observations, respectively. Their characteristics are presented in Table 1
|No. of spirometry tests|
|Any of above|
Sex-specific mean FEV1 residuals and their 95% confidence intervals by personal smoking status, respiratory symptoms, eosinophil count, airway response, and skin tests are shown in Figure 2. The prediction models used to obtain the residuals included age, height, and area of residence. Current-smokers had a lower level of FEV1 than never-smokers. The data also suggested a dose–response relationship. The effects of smoking on FEV1 appear to be greater in males than in females. Presence of respiratory symptoms, high eosinophil count, and airway hyperresponsiveness, each was a significant predictor of lower level of FEV1. Skin tests, however, were not significantly associated with FEV1. Similar associations were observed for VC and the ratio of FEV1 to VC, but the magnitude of effects for VC was smaller than that for FEV1 (data not presented).
The associations between personal smoking status, respiratory symptoms, eosinophil count and airway responsiveness, and lower level of pulmonary function suggested by the residual analyses were further evaluated using the regression splines. As shown in Table 2
|Predictors||Effects* (ml)||SE||p Value||Effects* (ml)||SE||p Value|
|10 pack-years||−85||21||< 0.01||−40||30||0.18|
|Presence||−114||30||< 0.01||−106||25||< 0.01|
|< 275/mm3 (reference)|
|> 275/mm3||−128||28||< 0.01||−53||22||< 0.05|
|High||−225||48||< 0.01||−213||39||< 0.01|
|Unknown||−123||24||< 0.01||−85||18||< 0.01|
|Unknown|| 5||21||0.79|| 59||15||< 0.01|
As males did not reach their pulmonary function plateau until about 20 years of age, additional analyses were limited to male subjects aged 20 to 35 years so that they were comparable with female subjects in maturational stage. The results obtained from this male subgroup were similar to those from the whole male sample.
|Predictors||Effects* (ml)||SE||p Value||Effects* (ml)||SE||p Value|
|< 275/mm3 (reference)|
|> 275/mm3||−77||31||< 0.05||−13||24||0.57|
|High||−121||53||< 0.05||−122||43||< 0.01|
|Unknown||−6||22||0.80|| 56||18||< 0.01|
|Predictors||Effects* (%)||SE||p Value||Effects* (%)||SE||p Value|
|10 pack-years||−1.5||0.3||< 0.01||−0.1||0.5||0.92|
|Presence||−1.8||0.5||< 0.01||−2.6||0.4||< 0.01|
|< 275/mm3 (reference)|
|> 275/mm3||−1.4||0.4||< 0.01||−1.2||0.4||< 0.01|
|High||−2.6||0.7||< 0.01||−3.4||0.8||< 0.01|
|Not tested||2.0||0.3||< 0.01||−2.1||0.3||< 0.01|
Analyses stratified by smoking, respiratory symptoms, and eosinophil count were performed to evaluate the consistency of the associations across the strata (Table 5)
|Predictors||Effects* (%)||SE||p Value||Effects* (%)||SE||p Value|
|Stratifying by smoking status|
|Ever-smokers||−147||30||< 0.01||−99||30||< 0.01|
|Never-smokers||−290||101||< 0.01||−315||67||< 0.01|
|Ever-smokers||−220||55||< 0.01||−144||48||< 0.01|
|Positive skin test|
|Stratifying by respiratory symptoms|
|Cumulative, 10 pack-years|
|Current, 1 pack/d|
|Eosinophil > 275/mm3|
|Asymptomatic||−132||28||< 0.01||−47||23||< 0.05|
|Asymptomatic||−206||54||< 0.01||−217||42||< 0.01|
|Positive skin test|
|Symptomatic||−323||91||< 0.01||−148||63||< 0.02|
|Stratifying by eosinophil count|
|Cumulative, 10 pack-years|
|< 275/mm3||−78||22||< 0.01||−41||28||0.15|
|> 275/mm3||−142||57||< 0.05||28||84||0.74|
|Current, 1 pack/d|
|< 275/mm3||−61||23||< 0.01||−23||28||0.40|
|< 275/mm3||−107||31||< 0.01||−99||27||< 0.01|
|< 275/mm3||−235||52||< 0.01||−220||42||< 0.01|
|Positive skin test|
|> 275/mm3||−248||64||< 0.01||−30||56||0.59|
Due to the additive nature of the effects of smoking, respiratory symptoms, airway responsiveness, and eosinophil count, one can simply sum up a person's total deficit in pulmonary function on the basis of his/her risk factors. Figure 3illustrates six hypothetical cases who are all 25-year-old males (and females), with the same height and residence: (a) an asymptomatic never-smoker, without airway hyperresponsiveness or eosinophilia (reference); (b) a subject who has smoked 1 pack/day since 15 years of age but is asymptomatic, without airway hyperresponsiveness and eosinophilia; (c) a subject who is symptomatic but has never smoked, without airway hyperresponsiveness or eosinophilia; (d) a subject who has eosinophilia but has never smoked, is asymptomatic, and without airway hyperresponsiveness; (e) a subject who has airway hyperresponsiveness but has never smoked, is asymptomatic, and without eosinophilia; (f) a subject who combines all the risk factors of subjects b, c, d, and e. The projected deficits in FEV1 are 0, 129, 114, 128, 225, and 596 ml for subjects a, b, c, d, e, and f, respectively.
The relative importance of each individual symptom to pulmonary function was examined, with adjustment for personal smoking status, eosinophil count, airway responsiveness, and skin tests. In males, wheeze and dyspnea were much stronger predictors of VC than cough and phlegm, whereas all four symptoms were important predictors for FEV1. For females, all symptoms but phlegm were significant predictors of FEV1.
The effects of physician-diagnosed asthma and bronchitis on pulmonary function during the plateau phase were also investigated. Asthma was a significant predictor of all three pulmonary function measurements and was associated with 348 ml, 155 ml, and 5% deficits in FEV1, VC, and the ratio of FEV1 to VC, respectively, in males, after adjustment for cigarette smoking, eosinophil count, airway responsiveness, and skin tests. Similar effects were observed in females with deficits of 273, 165, and 4 ml for the three spirometric measures of pulmonary function. In comparison, bronchitis was a much weaker predictor in both sexes (data not shown).
This report focuses on factors that predict maximal level of prebronchodilator FEV1, VC, and FEV1 to VC ratio in the age range where pulmonary function is maximal, i.e., 15–35 years. Our results suggest that airway responsiveness, peripheral blood eosinophil count, respiratory symptoms, and cigarette smoking are all important predictors of maximal level of lung function. An additional finding is that skin test reactivity was a significant predictor of maximal level of FEV1 in individuals with respiratory symptoms and/or peripheral blood eosinophilia. Finally, we found sex differences in the length of the plateau period for the different measures of pulmonary function.
The graphic plots (Figure 1) suggest substantial sex differences in maximal level of lung function. In females, FEV1 has already peaked by age 15 years, whereas the peak in males does not occur until age 20 years. Decline in FEV1 occurred in both sexes at about the same age (25 years), which suggests that the plateau phase for FEV1 is longer in females than in males. The reasons for this are not known and may relate to differences in biology as well as potential differences in exposures. The maximal VC tended to lag behind the FEV1 for both sexes by 2–3 years. Males had consistently lower FEV1 to VC ratios than females throughout the age range. This finding may have prognostic significance in that Burrows and coworkers (29) have shown that the presence of a low ratio is a significant predictor of accelerated decline in lung function and hence a risk factor for COPD.
Precise data on the onset and the duration of the plateau phase are lacking. Tager and coworkers (10), using data from the East Boston Study, suggested a peak FEV1 for females at age 18 years and for males from ages 20–34 years. This study is not directly comparable with the current data as it was stratified by symptom status and included relatively sparse data in the age range of greatest interest, e.g., (15–35 years). Our data are consistent with the hypothesis that there are sex differences in the plateau phase of pulmonary function. To some extent these differences can be explained by differences in risk factors for less than maximal lung growth.
Our analysis suggests several important points about the risk factors: personal cigarette smoking, skin test reactivity, eosinophilia, respiratory symptoms, and airway responsiveness. Personal cigarette smoking was associated with a 5% reduction in maximally attained FEV1. The effect was independent of the other risk factors and approximately equal in magnitude to the effect of respiratory symptoms and eosinophilia. The magnitude of the smoking effect is greater than the effect of smoking seen in adults older than 35 years in three ways: the absolute effect is greater, the influence is on maximal growth, and possibly premature decline, not simply age-related decline after age 35 years. These results emphasize the importance of early intervention on cigarette smoking to prevent the development of COPD, as this is the only time in the life cycle that there can be actual preservation of lung function. Sex differences were observed for cigarette smoking; but, because of the small number of young female smokers, these were not significant. Thus, more recent data on this effect would be of value. Tager and coworkers found that cigarette smoking was associated both with a reduced level and a premature decline in FEV1. Although we did not study this latter phenomenon, our data are consistent with theirs on the effect on level of FEV1.
Previous investigators have found that respiratory symptoms in childhood are associated with a reduction in maximally attained level of pulmonary function (7, 30). In our investigation, the effects were approximately equal for males and females. The effects were of comparable magnitude with that seen for active cigarette smoking and for eosinophilia and were not due to asthma alone. However, the effect of an asthma diagnosis was greater than the effect of individual respiratory symptoms, and when examined separately, an asthma diagnosis was the only factor to approximate airway responsiveness in the magnitude of its effect on maximal lung growth. A variety of studies have noted an important effect of asthma on the maximal growth of lung function in children (7, 31). Asthma (symptoms plus airway responsiveness) was associated with a 10 to 15% reduction of maximal FEV1. The strength of our investigation is that it controls for all other known risk factors and separates the effect from that of allergy and airway responsiveness.
Airway responsiveness was the single most important risk factor for a reduced maximal level of lung function. In early adulthood, the effect (5%) was similar in males and females and was independent of all other risk factors most notably asthma, eosinophilia, and skin test reactivity. This result is consistent with the data of Redline and coworkers (32, 33) who found such an effect in a longitudinal study of children in East Boston, Massachusetts. It is also consistent with the concept that airway responsiveness is closely correlated with level of lung function at all ages (8). The importance of isolated airway responsiveness in the absence of asthma is twofold. A number of studies in children and young adults suggest that airway responsiveness antedates and predicts clinical asthma (34, 35). In addition, studies in older adults suggest that airway responsiveness predicts accelerated decline in FEV1 and hence the development of COPD (36–39). At the present time, it is unclear whether this represents subclinical inflammation and whether treatment can modify the effect on maximal lung growth. Further studies and confirmation of our results would add greatly to our knowledge in this area.
Although an independent effect of skin test reactivity on maximal lung growth could not be seen in these data, there was an independent effect of peripheral blood eosinophilia on maximal lung growth in both males and females. The effect was greater in males than in females, and this sex difference was statistically significant. This relates at least in part to the interaction between skin test reactivity and eosinophils in males but may be the result of sex differences in exposure or the biologic processing of antigen, differences in other exposures, or other factors requiring further investigation. Skin test reactivity was also a significant predictor of maximal lung growth in those with respiratory symptoms regardless of sex.
Using a stratified analysis, Robbins and coworkers (40) have shown that there is substantial individual variability in growth trajectories for FEV1 within sexes. Smokers were much more likely to begin to decline early in the plateau phase. These findings are consistent with our results. The host and environmental factors we assessed contribute to explaining this variation, but we cannot rule out the role of other as yet unidentified sources of variation. Although our analysis is the most comprehensive performed to date on the quantitation of risk factors influencing maximally attained level of lung function, certain limitations on exposures must be acknowledged. First, we have no data on indoor and outdoor air pollution, specifically we have no data on allergen-exposure levels, exposure to farm animals, and passive smoking. We did choose to include area of residence as a covariate in our models as we wanted to control for sampling differences in the two communities and any potential urban/rural differences in exposure. Second, we have no data on birth-related events, early-life respiratory illness, and passive-smoke exposure. Third, we have no data on total and specific IgE, and only two measures of skin test reactivity in comparison with the multiple measure of exposure are available for other risk factors. An additional concern is that maximum prebronchodilator FEV1 occurred in females before age 15 years at a time in the life cycle when we had no other data. Finally, by measuring pulmonary function at 3-year intervals we may have missed the maximum value. This latter concern is minimized as the majority of subjects had two or more values of pulmonary function in the interval 16–35 years.
Despite these deficiencies, these data confirm the independent and additive effects of respiratory symptoms and cigarette smoking and identify that asthma and airway responsiveness are the greatest risk factors for a reduced maximal level of lung function in early adult life. It remains to be seen whether treatment trials currently underway will be able to modify the deleterious effects of childhood asthma on lung growth. Prebronchodilator FEV1 has been the standard outcome variable in epidemiologic studies. To the extent that resting bronchometer tone due to airways responsiveness is an important predictor of maximal attained level of prebronchodilator FEV1, the effects observed here would tend to minimize what might be seen if postbronchodilator FEV1 was the outcome variable.
Maximally attained level of pulmonary function is important because it is the most important risk factor for the development of COPD potentially. This suggests that an understanding of the determinants of maximal lung growth is essential in designing intervention programs to prevent COPD.
Our investigation has several unique features. First, we have information on a large number of factors thought to be important in determining maximal lung growth: respiratory symptoms, skin test reactivity, airway responsiveness, eosinophilia, and cigarette smoking. Second, we used longitudinal data to predict maximally attained level of prebronchodilator FEV1 and VC. More than 50% of subjects had at least two values in the age interval. Third, our mathematical modeling of maximally attained level of lung function was not constrained to be linear.
Although differences in risk factors and body size can clearly contribute to sex differences in maximally attained level of pulmonary function, it is also worthwhile to consider the importance of absolute versus proportional differences in rate of decline in FEV1. Not only do women have lower absolute levels of FEV1 and VC, but proportionally, as a percent of VC, effects for symptoms and airway responsiveness seem to be greater, suggesting that both absolute and proportional differences may contribute to sex-specific differences in risk. This concept needs further exploration.
In summary, we have explored the relationship of cigarette smoking, respiratory symptoms, airway responsiveness, skin test reactivity, and eosinophilia on maximal levels of lung growth in a population-based cohort. Our results suggest that smoking, respiratory symptoms, and especially airway responsiveness are important determinants of maximal lung growth as measured by FEV and VC. Given the importance of maximally attained level of prebronchodilator FEV1 as a predictor of COPD, these findings target subjects at potentially high risk in whom intervention is justified.
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