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RESPIRATORY SYMPTOMS IN THE CHILDREN OF SMOKERS: AN OVERVIEW Patrick G. Holt and Keven J. Turner EPIDEMIOLOGICAL FINDINGS Surveys on the association between parental smoking habits and respiratory symptoms amongst their offspring have produced the following claims. The relevant studies are summarized in Appendix Table 1: a) increased frequency of respiratory infections, particularly in the lower respiratory tract, is claimed in infants;; b) this effect is suggested to be age-related, being most marked in the first year of life; c) increased wheeze is reported in several surveys, separately or included amongst "respiratory symptoms"; d) reduced lung function detected via spirometry is reported in older children; e) exacerbation of asthma is claimed via hastening allergy development or effects related to bronchial reactivity; f).the claimed effects in some studies appear related more atrongly to maternal than to paternal smoking, especially when infants are involved. EXPOSURE OF CHILDREN TO ENVIRONMENTAL TOBACCO SMOKE: TOXICOLOGICAL EVALUATION While the effects of environmental tobacco smoke (ETS)

r~ exposure remain largely speculative, a detaile&literature exist upon the acute and chronic effects of active tobacco smoking on control systems which maintain homeostasis. In relation to the respiratory system, ETS has been shown to influence a variety of factors which contribute to the maintenance of health. These are discussed below in the context of the two major sets of symptoms claimed to be associated with ETS exposure in childhood. Infection Apart from immutable genetic factors associated with host infectivity, and frequency of contact with sources of infection, susceptibility to respiratory infection is determined by a collection of factors which display varying degrees of sensitivity to tobacco smoke exposure (see 1,2 for comprehensive reviews). The major factors in this category, summarized in Table 1, are as follows: respiratory mucosa itself has been suggested to break down in response to the, irritant effects of smoke (3) which may assist both in the penetration of invading microorganisms and (as discussed further beLow) allergenic material. Damage to the mucosa here has been suggested to result either from the direct irritant effect of smoke on the membrane, or from the toxic products of killed alveolar macrophages (3). This latter cell population has been shown experimentally to adapt to survival in the toxic to smoking. In the lower respiratory tract a similar function is fulfilled by the alveolar macrophages. The resident population in chronic smokers is recognized to be expanded in number and metabolic activity, and to exhibit a variety of malfunctions in in vivo and in vitro test systems. More recently, the physical integrity of the as as contributing factor in a number of diseases related Intrinsic exclusion mechanisms: Ciliostasis following brief exposure to tobacco smoke has for many years provided a sensitive index of acute toxicity, and defective ciliary clearance in the upper respiratory tract has been proposed I r environment of the lung chronically exposed to smoke (4) 2

via a process of biochemical activation (5). However, alveolar macrophages from lungs which have not previously encountered tobacco smoke exposure are highly susceptible to this agent, an6a sizeable proportion of the cells are kiLled:upon their first exposure (4). r I b) Immunological mechanisms: The first line of humoral immune defence against respiratory infection is provided by secretory IgA in the upper airways - reliable data is not available upon sufficiently large samples of smokers for firm concl~usions to be drawn regarding the susceptibility of local IgA response to smoke exposure. However, animal studies do indicate that local antibody responses within the lung are particularly sensitive to smoke in exposed animals (6). Systemic antibody response appear depressed both in man (1,2) and in chronically exposed animals,, whereas acute exposure appears stimulatory (1,6). Systemic cell mediated immunity (CMI) exhibits a biphasic pattern of change in animals during chronic smoke exposure, being initially stimulated and subsequently depressed as exposure continues (1,7), and comparable findings have been reported:for man (8,9). It has also recently been reported that T-lymphocytes isolated from lung lavage fluids from asymptomatic young smokers exhibit depressed in vitro CMI responses relative to those of age-matched non-smoking controls (10). Bronchial symptoms A number of the surveys listed in Table 1 report symptoms in smokers' children which involve narrowing of the small airways. These may be an indirect result of the excessive mucus production which may potentially be trigged by the irritant effect of ETS inhalation on bronchial tissue. The scheme proposed in Figure 11 presents a hypotheticaL framework for discussion of the interacting processes which may be .operative in these circumstances. 3

Firstly, respiratory infections per se may contribute to many of these symptoms, either as a direct result of excessive mucus production, or indirectly via a series of effects which stem from damage to the integrity of the respiratory epithelium. It has been observed that vagal sensory nerve endings lie beneath the tight junctions of the airway epithelium, and it has been proposed that damage to the junctions by a variety of agents "sensitizes" these receptors, and results in exaggerated reflex responses, i.e. bronchial hyperreactivity (reviewed in 11). Such agents include rhinovirus, influenza (12,13) and a variety_of other infections (14), and also a range of chemical irritants, such as ozone (15,16), S02 (17,18) No2 (19) and CO at levels approaching those encountered during:smoking (20). Epithelial damage of this nature may also cause airway hyperreactivity by increasing airway permeability, thereby allowing higher concentrations of inhaled irritant material (e.g. particulates) to reach "target" cells such as sensory nerves (11). Penetration of allergenic material may also increase in these circumstances. It is noteworthy in this regard that increased penetration of molecules such as horseradish peroxidase into the intercellular gaps of the respiratory epithelium has been observed in animals exposed to cigarette smoke (21,22,23), and a range of other irritants including histamine and methacholine (24), ozone (25) and N02 (26), the latter agent also promoting uptake via pinocytotic vesicuLar transport in the secretory cells of the airways. Experimentally induced chronic pulmonary inflammation in the rabbit is also associated with increased permeability to aerosolized protein (27). _ The recent development of a non-invasive procedure for assessing the permeability of the pulmonary epithelium has permitted preliminary studies on cigarette smoke effects of this nature in human smokers. Employing an aerosoL of 99M Tc-diethylenetriamine penta-acetate (particle size one micron)) to measure the rate of passage of inhaLed tracer into the blood, epithelial permeability has been shown to be W 0)

significantly increased amongst symptomless cigarette smokers (28), and to return to normal limits after cessation of the habit (3). The authors also reported a correlation between half-time lung clearance and carboxyhaemoglobin concentration (3) which suggests a role for CO in this process. stimulation of allergen-specific IgE synthesis; the latter would become fixed to local mucosal mast cells, and serve as a trigger for allergic responses to subsequent allergen penetration. Recent studies have shown that the passive deposition of allergen on the intact respiratory epithelium, protects against allergic sensitization via stimulation of specific suppressor T-Lymphocytes (29,30) wheras acute co-exposure to allergen and inflammatory agent(s) which affect mucosal permeability, such as ozone (31,32) or NO2 (31,33) or acid fumes (34) instead promotes IgE antibody production. The possibility that tobacco smoke may be capable of similar effects has not been tested directly. However, adult smokers exhibit higher overall levels of serum IgE than do non-smokers (35), and a recent study suggests that the age-related increase of serum IgE levels in high-risk groups of children (vriz. both parents atopics) is accelerated by the presence of adult smokers in the household (36). A further issue which must be considered in this context is the potential effect of increase& permeability of the respiratory epithelium to allergens. It is conceivable that such circumstances may promote allergic sensitization via the as a result of infection may promote IgE responses directly via accelerating penetration of allergens. Secondly, it is recognized that immune responses of the IgE class are tightly controlled by a subset of labile T-cells. Interference in overall T-cell function by the imposition of any form of exogenous immunosuppression may temporarily free IgE-B-cells from regulation and thus promote IgE production and subsequent allergic sensitization (reviewed in 37). Viral infections have Respiratory infection must also be considered in relation to this process, from two viewpoints. Firstly, epithelial damage been observed to depress T-lymphocyte function for several 5

weeks (38). The association of virus infections in children with the appeareance of immunologicaL evidence of allergic sensitization reported by Frick (39) may reflect either or both of these processes. EXTRAPOLATION OF FINDINGS TO CHILDREN EXPOSED TO ETS I L L The foregoing discussion draws upon data which, for the most part, pertain to high-dose tobacco smoke exposure in smoking adult humans and experimental animals. The implications of the published findings in relation to possible effects on children require consideration from two viewpoints. ETS dose levels encountered in the home The question of whether ETS components attain levels in the home environment which are capable of affecting the processes detailed above, cannot yet be answered directly. Few published studies are available which contain household measurements, and published dose-response experiments referred to above in the adult literature mainly pertain to high dose exposures. However, preliminary data obtained employing personal air sampling equipment have suggested:that an individual child's total respirable particulate load is largely determined by the indoor environment, exposures being higher amongst children who lived with smokers, where daily particulate loads often exceeded the primary air quality standard (40). Direct information on gas phase components such as carboxyhemoglobin levels in children exposed to ETS is not available; however, the data from adults (e.g. see 41) suggests that moderate CO exposure is likely in the home enviornment of smoking, families. Relative sensitivity of adults versus childrem A number of points summarized in Table 2 must be considered when assessing potential effects of ETS in children relative to their parents. Firstly, T-lymphocyte and macrophage function are not fully developed at birth, and the factor(s) 6

7 I C Secondly, a variety of factors may heighten the child's susceptibility (relative to the adult's) to sma1L airway obstruction. These (reviewed in 42) include increased which determine their rate of maturation in early life have not been defined. In the context of allergic sensitization, the early postnatal period is considered by many workers to be critical: in relation to the subsequent expression of genetic potential for allergic disease, and both immature T-ce1L function and defective mucosal exclusion mechanisms have been implicated. Consequently, exogenous factors which may contribute further to immune depression (Table 1) or increased mucosal permeability (Fig. 1) may be disproportionately injurious at this stage of life. susceptibility to infection as a result of comparatively immature immune defence mechanisms, the relatively small diameter of the airways, the high density of submucosal glands and their comparatively large size in relation to the bronchial wall, and perhaps reduced elastic properties. Thirdly, it has been suggested that changes in pulmonary function in children are especially sensitive to particulate pollution (43), which may be related to the relatively poor development of vibrissae on the epithelium lining the vestibule of the nose in children (42), the principal function of which is to filter out inhaled particles. It must also be remembered that such basic functions as temperature and humidity adjustment of inspired air are under more stress in the child than the adult, the conditioning mechanism of the infant's upper airway being called upon to handle a greater volume of air in proportion to lung size than that of the adult (42). In this context, increased airflow may also infer increased contact with air contaminants relative to an adult in the same room. one further inference may be drawn in relation to function which stems from the dimensional relationships of the lung,at different ages (44). It has been observed that the numbers of

alveoli and airways increase about 10-fold from infancy to adulthood, whereas lung surface area increases approximately 20-fold, in line with increases in body weight. Superficially, this wouLd appear to be a reasonable relationship, as area for gas exchange should theoretically bear some relationship to the mass of metabolizing cells. However, the metabolic rate of the infant is up to double that of adults when expressed on a per body weight basis. Therefore, the infant would:appear to have less reserve lung,surface area for added metabolism than the adult (44). Consequently, agents such as CO may exert deleterious effects at levels considerably below those toxic for adults, particularly under conditions of stress. Finally, the question of respiratory mucosal permeability in adults and children warrants consideration, as this appears at the focal point of the proposed effects of ETS (Fig. 1). Tracer molecules such as horseradish peroxidase are capable of broaching epithelial barriers in the fetal lung, as shown in studies of fluid resorption in newborn animals (44). However, studies on age-related changes in permeability during childhood are not available, but may now be feasible as appropriate technology becomes available (3,28). CONCLUSIONS AND RECOMMENDATIONS i The proposed effects of ETS exposure on the children of smokers, notably increased prevalence of respiratory infections and bronchial symptoms, are supported by a variety of epidemiological data and thus warrant more comprehensive investigation. In examining,the theoretical basis for these claims, an integrated pathway compri~sing a variety of interrelated immunological and inflammatory processes which are known to be sensitive to tobacco smoke exposure in adults andiwhich collectively result in increased permeability of the respiratory membrane, is proposed as a possible mechanism for the induction of respiratory symptoms in the child exposed to ETS. It should be stressed:that this scheme (Fig. 1) is 8

presented as a tool rather than a series of conclusions, and is intended to assist in focussing research upon specific control mechanisms with a view to obtaining more precise information on this question than is available in the current literature. In examine the relevance of the individual components of this pathway, it will be necessary to collect new data at three levels. Firstly, the existing,experimental literature pertains exclusively to adult animals; given the potential age-dependent variation in tobacco smoke sensitivity (Table 2), much of this work should be repeated employing younger animals. Secondly, both the experimental and human literature on mechanism(s) of tobacco smoke mediated effects is restricted to relatively high dose studies, which may not encompass the range relevant to the child exposed to ETS. Thirdly, there are no reported studies on actual absorption of ETS by children. Such studies should be performed as soon as possible to provide some form of baseline for future work. The recent development of non-invasive monitoring methods employing saliva and urine samples (see 45, this volume) have supplied convenient tools for this task. E

r Iocreased penetration of other irritants (e.g: particulates) . Immunosuppression ~ I .. igE synthesis Stimulation of irritant receptors L L !. Domage to,defenc! ~ na...~,.e ... 1 OOaCCO sfilOKe ... / PAM, ~ Enzyme release Infection ~ I Mucus Airway narrowing