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PASSIVE SMOKING AND RESPIRATORY DISORDERS OTHER THAN CANCER ă 7.1. INTRODUCTION In 1984, a report of the Surgeon General identified cigarette smoking as the major cause of chronic obstructive lung disease in the United States (U.S. DHHS, 1984). The same report stated that there is conclusive evidence showing that smokers are at increased risk of developing respiratory symptoms such as chronic cough, chronic phlegm production, and wheezing (U.S. DHHS, 1984). More recently, longitudinal studies have demonstrated accelerated decline in lung function in smoking adults (Camilli et al., 1987). In children and adolescents who have recently taken up smoking, several cross-sectional studies have found statistically significant increases in the prevalence of respiratory symptoms (cough, phlegm production, and dyspnea [i.e., shortness of breath]) (Seely et al., 1971; Bewley et al., 1973). Longitudinal studies also have demonstrated that, among young teenagers, functional impairment attributable to smoking may be found after as little as 1 year of smoking 10 or more cigarettes per week (Woolcock et al., 1984). From a pathophysiologic point of view, smoking is associated with significant structural changes in both the airways and the pulmonary parenchyma (U.S. DHHS, 1984). These changes include hypertrophy and hyperplasia of the upper airway mucus glands, leading to an increase in mucus production, with an accompanying increased prevalence of cough and phlegm. Chronic inflammation of the smaller airways leads to bronchial obstruction. However, airway narrowing also may be due to the destruction of the alveolar walls and the consequent decrease in lung elasticity and development of centrilobular emphysema (Bellofiore et al., 1989). Smoking also may increase mucosal permeability to allergens. This may result in increased total and specific IgE levels (Zetterstrom et al., 1981) and increased blood eosinophil counts (Halonen et al., 1982). The ascertained consequences of active smoking on respiratory health, and the fact that significant effects have been observed at relatively low-dose exposures, lead to an examination for similar effects with environmental tobacco smoke (ETS). Unlike active smoking, involuntary exposure to ETS (or "passive smoking") affects individuals of all ages, particularly infants and children. An extensive analysis of respiratory effects of ETS in children suggests that the lung of the young child may be particularly susceptible to environmental insults (NRC, 1986). Exposures in early periods of life during which the lung is undergoing significant growth and remodeling may alter the pattern of lung development and increase the risk for both acute and chronic respiratory illnesses. Acute respiratory illnesses are one of the leading causes of morbidity and mortality during infancy and childhood. Onethird of all infants have at least one lower respiratory tract illness (bronchitis, bronchiolitis, croup, or pneumonia) during the first year of life (Wright et al., 1989), whereas approximately onefourth have these same illnesses during the second and third years of life (Gwinn et al., 1991). The high incidence of these potentially severe illnesses has an important consequence from a public health viewpoint: Even small increases in risk due to passive exposure to ETS would considerably increase the absolute number of cases in the first 3 years of life (see Chapter 8). In addition, several studies have shown that lower respiratory tract illnesses occurring early in life are associated with a significantly higher prevalence of asthma and other chronic respiratory diseases and with lower levels of respiratory function later in life (reviewed extensively by Samet and collaborators [1983]). This chapter reviews and analyzes epidemiologic studies of noncancer respiratory system effects of passive smoking, starting with possible biological mechanisms (Section 7.2). The evidence indicating a relationship between exposure to ETS during childhood and acute respiratory illnesses (Section 7.3), middle ear diseases (Section 7.4), chronic respiratory symptoms (Section 7.5), asthma (Section 7.6), sudden infant death syndrome (Section 7.7), and lung function impairment (Section 7.8) is evaluated. Passive smoking as a risk factor for noncancer respiratory illnesses and lower lung function in adults also is analyzed (Section 7.9). A health hazard assessment and population impact is presented in the next chapter. 7.2. BIOLOGICAL MECHANISMS 7.2.1. Plausibility It is plausible that passive smoking may produce effects similar to those known to be elicited by active smoking. However, several differences both between active and passive forms of exposure and among the individuals exposed to them need to be considered. The concentration of smoke components inhaled by subjects exposed to ETS is small compared with that from active smoking. Therefore, effect will be highly dependent on the nature of the dose-response curve (NRC, 1986). It is likely that there is a distribution of susceptibility to the effects of ETS that may depend on, among other factors, age, gender, genetic predisposition, respiratory history, and concomitant exposure to other risk factors for the particular outcome being studied. The ability to ascertain responses to very low concentrations also depends on the reliability and sensitivity of the instruments utilized. Breathing patterns for the inhalation of mainstream smoke (MS) and ETS differ considerably; active smokers inhale intensely and intermittently and usually hold their breath for some time at the end of inspiration. This increases the amount of smoke components that are deposited and absorbed (U.S. DHHS, 1986). Passive smokers inhale with tidal breaths and continuously. Therefore, patterns of particle deposition and gas diffusion and absorption differ considerably for these two types of inhalation. There are also important differences in the physicochemical properties of ETS and MS (see Chapter 3). These have been extensively reviewed earlier by the National Research Council (NRC, 1986) and the Surgeon General (U.S. DHHS, 1986). ETS is a combination of exhaled MS, sidestream smoke (that is, the aerosol that is emitted from the burning cone between puffs), smoke emitted from the burning side of the cigarette during puffs, and gases that diffuse through the cigarette paper into the environment. This mixture may be modified by reactions that occur in the air before involuntary inhalation. This "aging" process includes volatilization of nicotine, which is present in the particulate phase in MS but is almost exclusively a component of the vapor phase of ETS. Aging of ETS also entails a decrease in the mean diameter of its particles from 0.32 m to 0.1-0.14 m, compared to a mean particle diameter for MS of 0.4 m (NRC, 1986). Individual and socioeconomic susceptibility may be important determinants of possible effects of ETS on respiratory health. A self-selection process almost certainly occurs among subjects who experiment with cigarettes, whereby those more susceptible to the irritant or sensitizing effects of tobacco smoke either never start or quit smoking (the so-called "healthy smoker" effect). Infants, children, and nonsmoking adults thus may include a disproportionate number of susceptible subjects when compared with smoking adults. In addition, recent studies clearly have shown that, as incidence and prevalence of cigarette smoking has decreased, the socioeconomic characteristics of smokers also have changed. Among smokers, the proportion of subjects of lower educational level has increased in the past 20 years (Pierce et al., 1989). The femaletomale ratio also has increased (Fiore et al., 1989), and this is particularly true for young, poor women, in whom incidence and prevalence of smoking has increased (Williamson et al., 1989). It is thus possible that exposure to ETS may be most prevalent today among precisely those infants and children who are known to be at a high risk of developing respiratory illnesses early in life. 7.2.2. Effects of Exposure In Utero and During the First Months of Life A factor that may significantly modify the effect of passive smoking (particularly in children) is exposure to tobacco smoke components by the fetus during pregnancy. This type of exposure differs considerably from passive smoking; in fact, the fetus (including its lungs) is exposed to components of tobacco smoke that are absorbed by the mother and that cross the placental barrier, whereas passive smoking directly affects the bronchial mucosa and the alveolus. It is difficult to distinguish between the possible effects of smoking during pregnancy and those of ETS exposure after birth. Some women may quit smoking during pregnancy, only to resume after pregnancy is over. Most mothers who smoke during pregnancy continue smoking after the birth of their child (Wright et al., 1991), and among those who stop smoking after birth, the influence on that decision of events occurring shortly after birth (such as respiratory illnesses in their child) cannot be excluded. Recall bias also may influence the results of retrospective studies claiming differential effects on lung function of prenatal and postnatal maternal smoking habits (Yarnell and St. Leger, 1979). To attempt to circumvent these problems, researchers have studied infant lung function shortly after birth (the youngest group of infants reported was 2 weeks old [Neddenriep et al., 1990]), with the implication that subsequent changes encountered could be attributed mainly to ETS exposure. However, the possibility that even brief exposure to ETS may affect the lungs at a highly susceptible age may not be discarded. Maternal smoking during pregnancy needs to be considered, therefore, as a potential modifier of the effect of passive smoking on respiratory health, particularly in children. Exposure to compounds present in tobacco smoke may affect the fetal and neonatal lung and alter lung structure much like these same compounds do in smoking adults. Neddenriep and coworkers (1990) studied 31 newborns and reported that those whose mothers smoked during pregnancy had significant increases in specific lung compliance (i.e., lung compliance/lung volume) at 2 weeks of age when compared with infants of nonsmoking mothers. The authors concluded that exposure to tobacco products detrimentally affects the elastic properties of the fetal lung. Although these effects also could be attributed to postnatal exposure to ETS, it is unlikely that such a brief period of postnatal exposure would be responsible for these changes affecting the lung parenchyma (U.S. DHHS, 1986). There is evidence for similar effects of prenatal lung development in animal models. Collins and associates (1985) exposed pregnant rats to MS during day 5 to day 20 of gestation. They found that pups of exposed rats showed reduced lung volume, reduced number of lung saccules, and reduced length of elastin fibers in the lung interstitium. This apparently resulted in a decrease in lung elasticity: For the same inflation pressure, pups of exposed mothers had significantly higher weight-corrected lung volumes than did pups of unexposed mothers. Vidic and coworkers (1989) exposed female rats for 6 months (including mating and gestation) to MS. They found that lungs of their 15-day-old pups had less parenchymal tissue, less extracellular matrix, less collagen, and less elastin than found in lungs of control animals. This may explain the increased lung compliance observed by Collins et al. (1985) in pups exposed to tobacco smoke products in utero. Hanrahan and coworkers (1990) reported that infants born to smoking mothers had significantly reduced levels of forced expiratory flows. The researchers studied 80 mother/child pairs and found significant correlations between the cotinine/creatinine ratio in urine specimens obtained during pregnancy in the mother and maximal expiratory flows and tidal volumes at a postconceptional age of 50 weeks or younger in their children. The investigators concluded that exposure due to prenatal smoking diminishes infant pulmonary function at birth and, by inference, airway size. These authors also measured maximal flows during tidal breathing in their subjects. At rather low lung volumes, such as those present during tidal breathing, airway size and maximal flows are both a function of lung elasticity. These results thus may be due to both a specific alteration of the infant's airways and an increased lung compliance in infants whose lungs are small relative to the infant's length. It also has been suggested that the increased IgE levels observed in adult smokers also may be present in fetuses whose mothers smoke during pregnancy. Magnusson (1986) reported that cord serum levels of IgE and IgD were significantly higher for neonates whose mothers smoked during pregnancy, particularly if the neonates had no parental history of allergic disorders. Cord serum levels of IgD (but not of IgE) were increased for neonates whose fathers smoked, and this effect was independent of maternal smoking. A more recent study on a larger sample (more than 1,000 neonates) failed to find any significant difference in cord serum IgE levels between infants (N = 193) of mothers who smoked during pregnancy and those (N = 881) of mothers who did not (Halonen et al., 1991). It also has been reported recently that the pulmonary neuroendocrine system may be altered in infants whose mothers smoke during pregnancy. The pulmonary neuroendocrine system, located in the tracheobronchial tree, consists of specialized cells (isolated or in clusters called "neuroepithelial bodies") that are closely related to nerves. In humans, these cells increase in number significantly during intrauterine development, reach a maximum around birth, and then rapidly decline during the first 2 years of life. Their function is not well understood, but the presence of potent growth factors and bronchoconstrictive substances in their granules suggests that they play an important role in growth regulation and airway tone control during this period of lung development (Stahlman and Gray, 1984). Chen and coworkers (1987) reported that maternal smoking during pregnancy increases the size of infant lung neuroepithelial bodies and decreases the amount of core granules present in them. Wang and coworkers (1984) had reported previously that mother mice receiving tap water with nicotine during pregnancy and during lactation had offspring with increased numbers of neuroepithelial bodies at 5 days of age when compared with baby mice whose mothers were not exposed. Baby mice exposed to nicotine only during pregnancy had neuroepithelial bodies of intermediate size with respect to these two groups, whereas those exposed only during lactation had neuroepithelial bodies of normal size. By age 30 days, only baby mice exposed to nicotine during both pregnancy and lactation had neuroepithelial bodies that were larger than those of control animals. Activation of the pulmonary neuroendocrine system is not limited to ETS exposure; it is activated by active smoking as well. Aguayo and collaborators (1989) reported that bronchoalveolar lavage fluids obtained from healthy smokers have increased levels of bombesin-like peptides, which are a normal component and a secretion product of human lung neuroendocrine cells (Cutz et al., 1981). In summary, effects of maternal smoking during pregnancy on the fetus are difficult to distinguish from those elicited by early postnatal exposure to ETS. Animal studies suggest that postnatal exposure to tobacco products enhances the effects of in utero exposure to these same products. 7.2.3. LongTerm Significance of Early Effects on Airway Function By altering the structural and functional properties of the lung, prenatal exposure to tobacco smoke products and early postnatal exposure to ETS increase the likelihood of more severe complications during viral respiratory infections early in life. Martinez and collaborators (1988a) measured lung function before 6 months of age and before any lower respiratory illness in 124 infants. They found that infants with the lowest levels for various indices of airway size were three to nine times more likely to develop wheezing respiratory illnesses during the first year of life than the rest of the population. The same authors (Martinez et al., 1991) subsequently showed that, in these same infants with lower initial levels of lung function, recurrent wheezing illnesses also were more likely to occur during the first 3 years of life. A similar study performed in Australia (Young et al., 1990) confirmed that infants who present episodes of coughing and wheezing during the first 6months of life have lower maximal expiratory flows before any such illnesses develop. The increased likelihood of pulmonary complications during viral respiratory infections in infants of smoking parents has important longterm consequences for the affected individual. There is considerable evidence suggesting that subjects with chronic obstructive lung diseases have a history of childhood respiratory illnesses more often than subjects without such diseases (reviewed by Samet and coworkers [1983]). Burrows and collaborators (1988) found that active smokers without asthma (N = 41) who had a history of respiratory troubles before age 16 years showed significantly steeper declines in FEV1 (as a percentage of predicted) after the age of 40 than did nonasthmatic smokers without such a history (N = 396). Although these results may have been influenced by recall bias, they suggest that lower respiratory tract illnesses during a period of rapid lung development may damage the lung and increase the susceptibility to potentially harmful environmental stimuli. There is no information available on the degree of reversibility of changes induced by exposure to ETS during early life. Longitudinal studies of lung function in older children have shown, however, that diminished levels of lung function are found in children of smoking parents at least until the adolescent years. 7.2.4. Exposure to ETS and Bronchial Hyperresponsiveness Bronchial hyperresponsiveness consists of an enhanced sensitivity of the airways to pharmacologic or physical stimuli that normally produce no changes or only small decreases in lung function in normal individuals. Subjects with bronchial hyperresponsiveness have significant drops in airway conductance and maximal expiratory flows after inhalation of stimuli such as cold air, hypertonic saline, nebulized distilled water, methacholine, or histamine. Bronchial hyperresponsiveness is regarded as characteristic of asthma (O'Connor et al., 1989) and may precede the development of this disease in children (Hopp et al., 1990). It has also been considered as a predisposing factor for chronic airflow limitation in adult life (O'Connor et al., 1989). Recent studies of large population samples have shown that active smokers have increased prevalence of bronchial hyperresponsiveness (Woolcock et al., 1987; Sparrow et al., 1987; Burney et al., 1987) when compared with nonsmokers. This relationship seems to be independent of other possible determinants of bronchial hyperresponsiveness (O'Connor et al., 1989). However, one large study of almost 2,000 subjects from a general population sample failed to find a significant relationship between smoking and prevalence of bronchial hyperresponsiveness (Rijcken et al., 1987). The subjects involved in the latter study were younger and were therefore exposed to a smaller average cumulative pack-years of smoking than were the subjects of studies in which a positive relationship was found. This suggests that the relationship may be evident only among individuals with a high cumulative exposure. Epidemiologic studies have demonstrated that exposure to ETS is associated with an increased prevalence of bronchial hyperresponsiveness in children. Murray and Morrison (1986), in a cross-sectional study, reported that asthmatic children of smoking mothers were four times more likely to show increased responsiveness to histamine than were asthmatic children of nonsmoking mothers. O'Connor and coworkers (1987), in a study of a general population sample, found a significant association between maternal smoking and bronchial hyperresponsiveness (as assessed with eucapnic hyperpnea with subfreezing air) among asthmatic children, but not among nonasthmatic children (Weiss et al., 1985). Martinez and coworkers (1988b) reported a fourfold increase in bronchial responsiveness to carbachol among male children of smoking parents when compared with male children of parents who were both nonsmokers. A smaller (and statistically not significant) increase in bronchial responsiveness was reported in girls. These authors also found that the effect of parental smoking was stronger in asthmatic children, and results were still significant after controlling for this factor in a multivariable analysis. Because only a small proportion of mothers in this population smoked during pregnancy, the effect was considered to be associated mainly with exposure to ETS in these children. Lebowitz and Quackenboss (1990) showed that odds of having bronchial reactivity (as assessed by the diurnal variability in maximal expiratory flow rate) were 3.6 times as high among 18 children aged 15 years and younger who lived with persons who smoked more than 20 cigarettes per day than among 62 children of the same age who lived with nonsmokers (95% C.I. = 1.2, 10.6). Children living with smokers of 1 to 20 cigarettes per day had a prevalence of bronchial reactivity that was similar to that of children living with nonsmokers. Therefore, there is evidence indicating that parental smoking enhances bronchial responsiveness in children. The mechanism for this effect and the possible role of atopy in it are unknown. The doses required to enhance bronchial responsiveness in children exposed to ETS are apparently much lower than those required to elicit similar effects among adult active smokers. A process of self-selection, by which adults who are more sensitive to the effects of tobacco smoke do not start smoking or quit smoking earlier, may explain this finding. Variations in bronchial responsiveness with age also may be involved (Hopp et al., 1985). Increased bronchial responsiveness may be an important predisposing factor for the development of asthma in childhood (Hopp et al., 1990). Moreover, it has been suggested that bronchial hyperresponsiveness may have effects on the developing respiratory system that predispose to chronic obstructive lung disease in later life (O'Connor et al., 1989). Redline et al. (1989) examined bronchial responsiveness to hyperventilation with cold air and its association with growth of lung function over a 12year period in 184 children and young adults (aged 8 to 23 years) over a maximum span of 12 years. Among subjects with persistent positive responses to cold air during followup, forced vital capacity grew faster, but forced expiratory flows grew more slowly, than among subjects who consistently did not respond to cold air. Among subjects with intermittently positive cold air responses, forced expiratory flows also grew more slowly than in controls, but growth of forced vital capacity was not changed. Although this study needs confirmation, its results suggest that bronchial hyperresponsiveness may have significant effects on the rate of growth of airway function and lung size in children. 7.2.5. ETS Exposure and Atopy Atopy has been defined epidemiologically as the presence of immediate hypersensitivity to at least one potential allergen administered by skin prick test. Atopy is an immediate form of hypersensitivity to antigens (called allergens) that is mediated by IgE immunoglobulin. Allergy (as indicated by positive skin test reactivity to allergens, high levels of circulating IgE, or both) is known to be present in almost all cases of childhood asthma. Recent epidemiologic studies have indicated that an IgE-mediated reaction may be necessary for the occurrence of almost all cases of asthma at any age (Burrows et al., 1989). Although genetic factors appear to play a major role in the regulation of IgE production (Meyers et al., 1987; Hanson et al., 1991), several reports have indicated that active smoking significantly increases total serum IgE concentrations and may thus influence the occurrence of allergy (Gerrard et al., 1980; Burrows et al., 1981; Zetterstrom et al., 1981; Taylor et al., 1985). Active smokers also have been found to have higher eosinophil counts and increased prevalence of eosinophilia when compared with nonsmokers (Kauffmann et al., 1986; Halonen et al., 1982; Taylor et al., 1985). The physical and chemical similarities between MS and ETS have prompted the investigation of a possible role of passive smoking in allergic sensitization in children. Weiss and collaborators (1985) first reported a 2.2-fold increased risk of being atopic in children of smoking mothers. Martinez and coworkers (1988b) confirmed that children of smoking parents were significantly more likely to be atopic than were children of nonsmoking parents, and the researchers reported that this association was stronger for male children. They also found a rough dose-response relationship between the number of cigarettes smoked by parents and the intensity of the skin reactions to a battery of allergens. Ronchetti and collaborators (1990) extended these findings in the same population sample of Martinez and coworkers. They found that total serum IgE levels and eosinophil counts were significantly increased in children of smoking parents, and the effect was related to both maternal and paternal smoking. It is relevant to note that, due to the so-called "healthy smoker effect," children of smokers should be genetically less sensitive than children of nonsmokers, because the latter are likely to include a disproportionate number of allergic subjects who are very sensitive to the irritant effects of smoke. As a consequence, the atopy-inducing effects of ETS may be substantially underestimated. In summary, there is convincing evidence that both maternal smoking during pregnancy and postnatal exposure to ETS alter lung function and structure, increase bronchial responsiveness, and enhance the process of allergic sensitization. These changes elicited by exposure to tobacco products may predispose children to lower respiratory tract illnesses early in life and to asthma, lower levels of lung function, and chronic airflow limitation later in life. Most of these same effects have been described for active smoking in adults. These smokeinduced changes are, therefore, known biological mechanisms for the increased prevalence of respiratory diseases associated with ETS exposure described later in this chapter. Exposure to tobacco smoke products during pregnancy and to ETS soon after birth may be the most important preventable cause of early lung and airway damage leading to both lower respiratory illness in early childhood and chronic airflow limitation later in life. Xr 7.3.rrrEFFECT OF PASSIVE SMOKING ON ACUTE RESPIRATORY ILLNESSES IN CHILDREN X` hp x (#%'0*,.8135@8:x7 , .!X` hp x (#%'0*,.8135@8:5 cig./day vs. none) LRI controls vs. nonLRI controls OR = 2.7 (1.3, 5.7)Cases matched to controls for age, sex, race, month of admission, form of payment; selection bias not ruled out&  &Chen et al. (1986)1,058 infants born in Shanghai, ChinaParental self administered questionnaire; number of cigarettes smoked by household membersAdmissions to hospital for respiratory illness as reported by parentsCig./day OR 19 1.2 (0.6, 2.3) >9  $ 1.9 (1.1, 3.4) Controlling for crowding, paternal education, feeding practices, birthweight, family history of chronic respiratory illness  `&.Q(continued on the following page)  ,   X` hp x (#%'0*,.8135@8: 19 cig./day), whereas the same risk was 3.4 times as high among non-breast-fed infants of smoking families. The studies by Chen (1989) and Chen and coworkers (1986, 1988) were retrospective in nature and thus not immune to possible biases generated by the fact that the occurrence of the outcome event may enhance reporting or recall of the conditions considered as risk factors. However, conclusions are strengthened by the finding that admissions for nonrespiratory illnesses were unrelated to passive smoking in the study in which the relationship was assessed (Chen et al., 1986) and by the fact that the finding remained significant after adjusting for known confounders. BreeseHall and coworkers (1984) studied 29 infants hospitalized with confirmed RSV bronchiolitis before age 2, 58 controls hospitalized for acute nonrespiratory conditions, and 58 controls hospitalized for acute lower respiratory illnesses from causes other than RSV. Cases and controls were matched for age, sex, race, month of admission, and form of payment for hospitalization. Information on smoking habits in the family was obtained at the time of each patient's admission. Cases were 4.8 times as likely as controls (95% C.I.=1.8, 13.0) to have one or more household members who smoked five or more cigarettes per day. However, there was no significant difference in the prevalence of cigarette smoking in the households of subjects with respiratory illnesses caused by RSV and those not caused by RSV. This was attributable to the fact that the controls with respiratory illnesses not caused by RSV were also much more likely to live with smokers of five or more cigarettes per day than were controls with nonrespiratory illnesses (OR = 2.7, 95% C.I. = 1.3, 5.7). Little information is given about enrollment and refusals; thus, it is not possible to know if selection bias may have influenced the results. Also, other possible confounders such as socioeconomic level were not taken into account when matching cases to controls or when data were analyzed. McConnochie and Roghmann (1986a) compared 53 infants drawn from the patient population of a group practice in Rochester, New York, who had physician-diagnosed bronchiolitis before age 2 years, with 106 controls from the same practice who did not have lower respiratory illnesses during the first 2 years of life and who were matched with cases for sex and age. Parental interviews were conducted when the child had a mean age of 8.4 years. Parents were asked about family history of respiratory conditions and allergy, socioeconomic status, passive smoking, home cooking fuel, home heating methods, and household pets. Passive smoking was defined as current and former smoking of "at least 20 packs of cigarettes or 12 ounces of tobacco while living in the home with the subject." Current and former smoking was scored equally, based on the assumption that the report of either reflected passive smoking in the first 2years of life. Frequency of paternal smoking was not increased among children who had bronchiolitis. Cases were 2.4 times (95% C.I. = 1.2, 4.8) as likely to have smoking mothers as were controls. The association was stronger in families with older siblings (OR = 8.9); however, a multiplicative test for this interaction did not reach statistical significance. The authors studied 63% of eligible cases and 34% of eligible controls. Although the reasons for exclusion from both groups are detailed, selection bias cannot be excluded completely, and the authors give no information about maternal smoking habits among excluded subjects. Also, overreporting of smoking by parents who were aware of their child's history of bronchiolitis may have introduced biases due to differential misclassification. However, the results were consistent across groups classified according to family history of asthma or allergy, social status, presence of older siblings, and crowding. Ogston and coworkers (1987) conducted a prospective study of 1,565 infants of primigravidae enrolled antenatally in the Tayside Morbidity and Mortality Study in New Zealand. Information on the father's smoking habits and on the mother's smoking habits during pregnancy was obtained at the first antenatal interview and from a postnatal questionnaire. A summary record was completed when the child was 1 year of age and included a report of the child's respiratory illnesses (defined as "infections of the upper or lower respiratory tract") during the first year of life derived from observations made by health visitors during scheduled visits to see the child. The authors used a multiple logistic regression to control for the possible effects of maternal age, feeding practices, heating type, and father's social class on the relationship between parental smoking and child health. Of the 588 children of nonsmokers in this sample, 146 (24.8%) had respiratory illnesses during the first year of life. Paternal smoking was associated with a 43% increase (95% C.I. = 4.7, 96.1) in the risk of having respiratory illnesses in the first year of life, and this was independent of maternal smoking. The risk of having a respiratory illness was 82% higher (95% C.I. = 25.6, 264.4) in infants of smoking mothers than in infants of nonsmoking parents. Smoking by both parents did not increase the risk of having respiratory illnesses beyond the level observed in infants with smoking mothers and nonsmoking fathers. It is difficult to compare this study with other reports on the same issue because the authors could not distinguish between upper and lower respiratory tract illnesses.Anderson and coworkers (1988) performed a case-control study of 102 infants and young children hospitalized in Atlanta, Georgia, for lower respiratory tract illnesses before age 2 and 199 age- and sex-matched controls. The unadjusted relative odds of having any family member smoking cigarettes were 2.0 times as high (p < 0.05) among cases as among controls (confidence interval was not calculable from the reported data). The effect disappeared, however, after controlling for other factors (prematurity, history of allergy in the child, feeding practices, number of persons sleeping in the same room with the child, immunization of the child in the last month) in a multivariable logistic regression analysis. No information is provided in this report about maternal and paternal smoking separately, and the number of cigarettes smoked at home by each family member was not recorded either. Also, almost 30% of all target cases declined participation in the study, and no information was available on smoking habits in the families of these children. No information is given about number of refusals among controls. Woodward and collaborators (1990) obtained information about the history of acute respiratory illnesses in the previous 12 months on 2,125 children aged 18 months to 3 years whose parents answered a questionnaire mailed to 4,985 eligible families in Adelaide, Australia. A "respiratory score" was calculated from responses to questions regarding 13 different upper and lower respiratory illnesses. A total of 1,218 parents (57%) gave further consent for a home interview. From this total, parents of 258 cases (children whose respiratory score fell in the top 20% of scores) and 231 "controls" (children whose scores were within the bottom 20% of scores) were interviewed at home. When compared with controls, cases were twice as likely to have a mother who smoked during the first year of life (95% C.I. = 1.3, 3.4). This effect was independent of parental history of respiratory illnesses, other smokers in the home, use of group child care, parental occupation, and level of maternal stress and social support. The authors found no differences in the way smokers and nonsmokers perceived or managed acute respiratory illnesses in their children. Based on this finding, they ruled out that such differences could explain their findings. They also reported that feeding practices strongly modified the effect of maternal smoking; among breast-fed infants, cases were 1.8 times as likely to have smoking mothers as were controls (95% C.I. = 1.2, 2.8), whereas among non-breastfed infants, cases were 11.5 times as likely to have smoking mothers as were controls (95% C.I. = 3.4, 38.5). Wright and collaborators (1991) studied the relationship between parental smoking and incidence of lower respiratory tract illnesses in the first year of life in a cohort of 847 white non-Hispanic infants from Tucson, Arizona, who were enrolled at birth and followed prospectively. Lower respiratory illnesses were diagnosed by the infants' pediatricians. Maternal and paternal smoking was ascertained by questionnaire. For verification of smoking habits, the researchers measured cotinine in umbilical cord serum of a sample of 133 newborns who were representative of the population as a whole. Cotinine was detectable in umbilical cord sera of all infants whose mothers reported smoking during pregnancy and in 7 of 100 cord specimens of infants whose mothers said they had not smoked during pregnancy. There was a strong relationship between cotinine level at birth and the amount that the mother reported having smoked during pregnancy. Children whose fathers smoked were no more likely to have a lower respiratory tract illness in the first year of life than were children of nonsmoking fathers (31.3% vs. 32.2%, respectively). The incidence of lower respiratory tract illnesses was 1.5 times higher (95% C.I.=1.1, 2.2) in infants whose mothers smoked as in infants whose mothers were nonsmokers. This relationship became stronger when mothers who were heavy smokers were separated from light smokers; 45.0% of children born to mothers who smoked more than 20 cigarettes per day had a lower respiratory illness, compared with 32.1% of children whose mothers smoked 1 to 19 cigarettes per day and 30.5% of children of nonsmoking mothers (p < 0.05). The authors tried to differentiate the effects of maternal smoking during pregnancy from those of postnatal exposure to ETS but concluded that the amount smoked contributed more to lower respiratory tract illness rates than did the time of exposure. The authors also found that maternal smoking had a significant effect on the incidence of lower respiratory tract illnesses only for the first 6 months of life; the risk of having a first lower respiratory illness between 6 and 12 months was independent of maternal smoking habits. A logistic regression showed that the effect of maternal smoking was independent of parental childhood respiratory troubles, season of birth, day-care use, and room sharing. Feeding practices, maternal education, and child's gender were unrelated to incidence of lower respiratory illnesses in this sample and were not included in the regression. The analysis also showed a significant interaction between maternal smoking and day-care use; the effects of maternal smoking were significant when the child did not use day care (OR = 2.7; 95% C.I. = 1.2, 5.8) but were weaker and did not reach significance among infants who used day care (OR = 1.9; 95% C.I. = 0.9, 4.0). The authors suggested that day-care use may protect against lower respiratory illnesses by reducing exposure to ETS. Reese et al. (1992) studied urinary cotinine levels in 491 children, aged 1 month to 17 years, on admission to hospital. Children admitted for bronchiolitis had higher urinary cotinine levels than a group of children of similar age admitted for nonrespiratory illnesses (p < 0.02). The researchers concluded that there are objective data linking passive smoking to hospital admission for bronchiolitis in infants. 7.3.2. Summary and Discussion on Acute Respiratory Illnesses Both the literature referenced in the Surgeon General's report (U.S. DHHS, 1986) and the NRC report (1986) and the additional, more recent studies considered in this report provide strong evidence that children who are exposed to ETS in their home environment are at considerably higher risk of having acute lower respiratory tract illnesses than are unexposed children. Increased risk associated with ETS exposure has been found in different locales, using different methodologies, and in both inpatient and outpatient settings. The effects are biologically plausible (see Section 7.2). Several studies also have reported a dose-response relationship between degree of exposure (as measured by number of cigarettes smoked in the household) and risk of acute respiratory illnesses. This also supports the existence of a causal explanation for the association. The majority of studies found that the effect was stronger among children whose mothers smoked than among those whose fathers smoked. This is further evidence in favor of a causal explanation, because infants are generally in closer and more frequent contact with their mothers. There are now also fairly convincing data showing that the increased incidence of acute respiratory illnesses cannot be attributed exclusively to in utero exposure to maternal smoke. In fact, Chen (1989) and Chen and coworkers (1986, 1988) reported increased risk of acute respiratory illnesses in Chinese children living with smoking fathers and in the total absence of smoking mothers. This effect also could be attributed either to in utero exposure to the father's smoke or to an effect on the father's sperm. This seems unlikely, however, because no such effects of parental smoking during pregnancy have been described in similar studies performed in Western countries. Furthermore, Woodward and coworkers (1990) found that children of smoking mothers were significantly more prone to acute respiratory illnesses even after mothers who   smoked during pregnancy were excluded from the analysis. This clearly suggests the existence of direct effects of ETS exposure on the young child's respiratory health that are independent of in utero exposure to tobacco smoke products. There is also convincing evidence that the risk is inversely correlated with age; infants aged 3 months or less are reported to be 3.3 times more likely to have lower respiratory illnesses if their mothers smoke 20 or more cigarettes per day than are infants of nonsmoking mothers (Wright et al., 1991). Increases in incidence of 50% to 100% (relative risks of 1.5-2.0) have been reported in older infants and young children. The evidence for an effect of ETS is less persuasive for school-age children, although trends go in the same direction as those reported for younger children. This may be due to a decrease in illness frequency, to physiological development of the respiratory tract or immune system with age, or to a decreased contact between mother and child with age. Reasonable attempts have been made in most studies to adjust for a wide spectrum of possible confounders. The analyses indicate that the effects are independent of race, parental respiratory symptoms, presence of other siblings, socioeconomic status or parental education, crowding, maternal age, child's sex, and source of energy for cooking. One study (Graham et al., 1990) also showed that the effect of ETS exposure on proneness to acute respiratory illnesses in infancy and early childhood was also independent of several indices of maternal stress, lack of maternal social support, and family dysfunction. Other factors, such as breastfeeding, decreased birthweight, and day-care attendance, have been shown to modify the risk. Some sources of bias may have influenced the results, but it is highly unlikely that they explain the consistent association between acute lower respiratory illness and ETS exposure. With one exception (Wright et al., 1991), all studies relied exclusively on questionnaires or interviews to assess exposure. Although questions tend to be very specific, overreporting or more accurate reporting of smoking habits by parents of affected children is possible, particularly in case-control and retrospective studies. However, such a bias should affect both respiratory and nonrespiratory outcomes, and at least two studies have shown no association between nonrespiratory outcomes and ETS exposure (Chen et al., 1988; Breese-Hall et al., 1984). Selection bias could not be excluded in some case-control studies, but satisfactory efforts were made to avoid this source of bias in most studies. 7.4. PASSIVE SMOKING AND ACUTE AND CHRONIC MIDDLE EAR DISEASES ČThe Surgeon General's report (U.S. DHHS, 1986) and the NRC report (1986) reviewed five studies demonstrating an excess of chronic middle ear disease in children exposed to parental cigarette smoke (Table 73X` hp x (#%'0*,.8135@8: onefourth of subjects lost to followup&&Toyoshima et al. (1987)48 wheezy children <3 yr. followed in Osaka, JapanParental questionnaireNumber of children still wheezing at end of followupOR = 11.8 (1.3, 105.0) for children living in smoking householdsSelection bias cannot be ruled out &XX&Tsimoyianis et al. (1987)193 12 to 17yearold high school athletesQuestionnaire to the child on household smoking habitsSelfreport of cough, bronchitis, wheeze, and shortness of breathNo effect on bronchitis, wheeze, shortness of breath. Increased frequency of cough (p=0.08) Reporting bias cannot be ruled out `&.Q(continued on the following page)  , xxX` hp x (#%'0*,.8135@8:24 cig./dayIndependent of sex, allergy, smoking during pregnancy, paternal smoking, crowding, dampness, feeding practices, gas cooking, social status, and maternal respiratory symptoms&xx&Chan et al. (1989a)134 children 7 yr. of age in London, England, <2,000 g birthweight; 123 controls with normal birthweightParental questionnaireWheeze and coughOR = 2.7 (1.3, 5.5) of having wheeze at age 7 in children of smoking mothers, OR = 2.4 (1.3, 4.6) of having coughEffects on wheeze independent of confounders; effects on cough disappeared after controlling for confounders XF195% confidence intervals in parentheses.  3'   X` hp x (#%'0*,.8135@8: 3 nights in the past month) was more likely to occur in children living with one smoker (OR = 1.6; 95% C.I. = 1.1, 2.6) or two smokers (OR = 2.5; 95% C.I. = 1.5, 4.0) than in children living with nonsmokers. Occurrence of "chesty colds" in children was also more frequent in households with one (OR = 1.3; 95% C.I. = 0.9, 1.9) or two smokers (OR = 1.9; 95% C.I. = 1.3, 3.0). A subsequent report (Strachan et al., 1990) based on the same population sample studied the relationship between salivary cotinine levels and respiratory symptomatology in a subset of 770 children (see also Strachan et al. [1989], Section 7.4.1). The authors found no relationship between cotinine levels and wheezing or frequent night cough. Frequency of chesty colds was significantly correlated with quintals of salivary cotinine (p < 0.01). The authors noted that objective markers of recent exposure to ETS may not adequately reflect exposure at some critical period in the past. They also noted that there may be different ways of understanding the concept of "wheezing" and proposed that this could explain the lack of association between this symptom and both questionnaire-based and cotinine-based assessment of exposure to ETS in their sample. Lewis and coworkers (1989) performed a case-control study of risk factors for chronic cough in children under 6 years in Salford, United Kingdom. They enrolled 60 children referred to a pediatric outpatient clinic with cough lasting more than 2 months or frequent episodes of cough without wheeze. These 60 subjects were compared with controls admitted for routine surgical procedures. Children with chronic cough were 1.7 times (95