In this issue of the Journal, Withers and colleagues present the results of a questionnaire follow-up of a cohort of 14–16-yr-old children who were first observed at ages 6–8 yr (1). The focus of the study is on the current status of the cohort with regard to asthma, wheezing, and cough in relation to the original report of cough, wheeze, and a doctor's diagnosis of asthma. Wheeze and cough each were classified based on the report of their presence in the 12 mo before the second survey (“current”), their persistence (“persistent,” if reported as present on both surveys), and the report of their first occurrence at the second survey (“late-onset”). A doctor's diagnosis of asthma (“ever”) also was reported by 94% of those with persistent, 69% of those with late-onset, and 80% of those with current wheeze.
The authors have investigated (1) a wide variety of factors that are frequently observed as risk factors for the occurrence and persistence of chronic respiratory symptoms and asthma in childhood and adolescence (Table 1 in Reference 1). Interpretation of their findings is made somewhat difficult by the large number of categories of conditions (n = 7) and risk factors (n = 21) that were evaluated and, particularly, by the fact that the classification of symptoms and asthma were not mutually exclusive. Maternal history of asthma and indicators of atopy in the child (eczema and hay fever) did show a consistent relationship to symptoms and a reported doctor's diagnosis of asthma across the classification scheme (Table 2 in Reference 1). These results are not surprising and would be expected in light of data from other population-based longitudinal studies (2, 3).
Of the other social, familial, and environmental factors that were evaluated, only the report of regular smoking by the child and the presence of a “smoker in the [child's] household” were associated with an increased risk across more than two of the seven symptom categories. Specifically, children's personal smoking was associated with persistent and late- onset wheeze and current and late-onset cough (70% and 64% with asthma and cough, respectively). If results for the three categories of passive exposure sources are combined, then only late-onset cough was not associated with passive exposure to tobacco smoke in the home. Because the categories of symptoms overlap, it is very difficult to interpret the implications of the observed relationships between tobacco smoke exposure and symptoms; however, it does appear that regular smoking by children contributed substantially to the persistence and new onset of symptoms. The effects associated with maternal smoking were limited to doctor-diagnosed asthma.
Consideration of other longitudinal studies that evaluate the relationships between exposure to tobacco smoke and childhood asthma or wheeze also present a somewhat confused picture of the effects of smoking. Relationships between passive exposure to tobacco smoke (especially maternal smoking) and the prevalence or new occurrence of asthma and wheeze are consistently seen in early childhood, i.e., age 5–6 or less (2-5). Such relationships often are not seen when children are evaluated later in childhood (6) or in the teenage years (2-4). The relatively few longitudinal data available about direct smoking in relation to asthma or wheeze show both decreased smoking in adolescent and young adult asthmatics (4), an observation that is attributed to the “healthy smoker” effect, and a slight increase in smoking in symptomatic asthmatics (7). In the latter case (7), bronchial responsiveness has been found to be lower in currently smoking asthmatics, which also is consistent with the healthy-smoker effect.
Can these inconsistent findings from longitudinal studies of asthma's natural history be reconciled? Because it is a given that smoking is detrimental to overall health as well as the health of the respiratory system, answers to this question relate more to an interest in understanding mechanisms through which nonantigenic, environmental factors influence the natural history of asthma in childhood than in any need to provide further justification for efforts to reduce cigarette smoking. Such a viewpoint is particularly relevant in light of the substantial current efforts to understand the genetic underpinnings of asthma. Examining the effects of cigarette smoking on pulmonary airways and on immunoglobulin E (IgE)–medicated responses can provide some useful insights into how exposure to tobacco smoke, and perhaps other environmental exposures (e.g., ambient oxidant air pollutants), could influence the natural history of childhood asthma and lead to results reported in epidemiologic studies of asthma.
Natural-history studies have indicated that lower levels of FEV1 in childhood asthmatics are associated with increased odds of more persistent and/or severe symptoms in adulthood (2, 7, 8). Thus, any factor that leads to decreased lung function in early childhood, in theory, could contribute to this more adverse prognosis or even to the phenotypic expression of asthma when it might not otherwise have occurred. Several studies have demonstrated that passive exposure to tobacco smoke influences the levels and development of lung function in early childhood (9). To the extent that impairment in airway development is altered by in utero exposure (10), in contrast to postnatal exposure, the process may be worsened by increasing the risk of childhood respiratory illness occurrence and severity (11). The inconsistent effects of passive smoke exposure in older children and adolescents are likely to result from several factors, all of which are consequences of the fact that tobacco exposure's effects on pulmonary function in childhood are small relative to other factors that affect lung function and, like the effects of direct exposure to tobacco smoke, probably have their earliest impact on the physiology of small, peripheral airways. As a result, variability among subjects that results from normal growth and development, especially during puberty, could obscure tobacco's effects in studies of asthma in adolescent youth. The wide variability in the magnitude of exposure by individuals within and between studies also may play a role—a possibility made more likely by the rather imprecise (or even inaccurate) estimates of exposure that are a feature of even the best epidemiologic studies. To the extent that early childhood exposure contributes to the physiologic abnormalities of small airways that have been reported in asthmatics (12), its effects would be unmeasured by the most widely reported measures of lung function, FEV1 and FVC, and to a lesser extent by FEF25–75. Moreover, any factor that leads to reductions of airway size would be expected to enhance the effects of airway narrowing (airway obstruction and/or hyperresponsiveness) that result from the chronic inflammation of asthma (13). Given the more dramatic effects of antigen exposure and respiratory viral infections, it is not surprising that a direct effect attributable to passive exposure to tobacco smoke would be difficult, if not impossible, to detect with any consistency.
All of these speculations about the effects of passive tobacco-smoke exposure on lung function also apply to the effects of direct smoking in adolescents. There is clear evidence that the relatively low total exposure to tobacco accrued by teenage smokers nonetheless has measurable effects on lung function level and growth, especially for measures that, in part, reflect small airway function (14). The apparent discrepancies among studies in terms of the direct effects of cigarette smoking on asthma's natural history cannot be pinpointed with any certitude, but they certainly must include all of the issues referred to above.
Immunoglobulin E–mediated immune responses are a hallmark of the immunopathology of asthma (15). Moreover, a strong relationship exists between levels of IgE and airway hyperresponsiveness, a physiological hallmark of asthma (16). Studies of occupational asthma (17) clearly indicate that cigarette smoke is capable of either enhancing responses to antigens that normally stimulate IgE responses (17) and/or modulating immune responses to favor the production of IgE antibodies (18). Although they are not consistent findings of all studies, elevated serum IgE levels in infants (19) and increased prevalence of skin-prick test responses in children (20) have been associated with maternal smoking. The failure to observe a consistent relationship between passive exposure to tobacco smoke and the expression of an atopic diathesis and asthma could indicate the importance of the time and intensity of smoke exposure as an influence on immune responsiveness in the infants and children. There is now evidence to suggest that the developing fetus is capable of making IgE-mediated immune responses to relevant antigenic stimuli (21), and that important steps in the maturation of adult immune response patterns occur in the first 2 yr of life (22). Therefore, prenatal exposure to products of tobacco smoke in conjunction with the mother's particular exposures to asthma-relevant environmental antigens (e.g., dust mites, pollen, etc.) may well constitute a critical exposure that is required for a more long-lasting effect of tobacco smoke exposure on IgE-mediated immune responses. Exposure during the prenatal period might be critical to a process by which postnatal antigen exposure, along with further early childhood exposure to environmental tobacco smoke and other relevant factors in the environment (specific antigens, respiratory viral infections, or direct smoking), leads to the Th2 lymphocyte cytokine profile that is now known to characterize asthma (15). If such a scenario is occurring, it is not likely that it would have been detected in the epidemiologic natural-history studies that have been performed to date.
These speculations are not meant to be exhaustive, since they do not consider other effects of tobacco smoke, such as those on the autonomic nervous system, that also could contribute to the natural history of asthma. They do point out the great difficulty and complexity involved in isolating the effects of complex environmental exposure on several intertwined pathways that can lead to the phenotypic expression of asthma. It is clear that, to understand better the ways in which environmental factors can interact with the genetic substrates of individuals, future epidemiologic studies of the natural history of asthma will have to (1) use better assessments of the time of exposure to tobacco smoke and its relationship to other relevant environmental exposures (antigen and nonantigen); (2) find better markers of the development of specific IgE-mediated immune response pathways; (3) report a wider spectrum of measures that can be derived from forced expiratory maneuvers (e.g., flows at the distal end of the flow-volume curve); and (4) evaluate appropriate markers of specific genetic predisposition as they become available. The study of Withers and colleagues (1) serves as a reminder that the issue of smoking remains important relative to asthma not only for scientific knowledge but for public health. Children's passive exposure to tobacco smoke remains widespread (23), and there is disturbing evidence that cigarette smoking in adolescents is increasing (24). Thus, it is quite likely that exposure to tobacco smoke will remain part of asthmatic's environment for some time to come.
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