Socioeconomic Status, Number of Siblings, and Respiratory Infections in Early Life As Determinants of Atopy in Children
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- Agabiti, N.
- Corbo, M.
- Dellorco, V.
- Forastiere, F.
- Levenstein, S.
- Perucci, C.A.
- Pistelli, R.
- Porta, D.
- PSCI, PUBLICATION SCIENTIFIC
- BIBL, BIBLIOGRAPHY
- EXTR, EXTRA
- MARG, MARGINALIA
- Named Organization
- Obsservatorio Epidemiologico Regionale
- Author (Organization)
- Catholic Univ
- Epidemiology Resources
- Lazio Regional Health Authority
- Williams Wilkins
- Named Person
- Bueti, P.
- Cento, G.
- Destefani, B.
- Elefante, A.
- Forastiere, F.
- Imigli, A.
- Pizzabioca, A.
- Schiano, G.
- Master ID
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Socioeconomic Status, Number of Siblings, and Respiratory Infections in Early Life as Determinants of Atopy in Children Francesco Forastiere ,t Nera Agabiti,~ Giuseppe M. Corbo ,~ Valerio Dell' Orco ,~ Daniela Porta,~ Riccardo Pistelli,z Susan Levenstein,~ and Carlo A. Peruccii Asthma and allergic disorders have been on the increase in recent decades, especially among children living in affluent countries; some aspects of the "Western" way of life may • explain this trend. We evaluated the relation of aeroallergen skin test reactivity with socioeconomic status, number of sib- lings, and respiratory infections in early life. We examined a total of 2,226 schoolchildren, ages 7-11 years, in three areas of Lazio, italy. Skin prick tests were performed to assess aropic status, and self-administered questionnaires were completed by the parents. The prevalence of prick test positivity was greater among children whose fathers were in the highest educational level than among those in the lowest [prevalence ratio (PR) = 1.58; 95% confidence interval (CI) = 1.21-2.06]. There was also a lower prevalence of atopy among larger sibships (PR = 0.38 for subjects with four or more siblings vs those without siblings; 95% CI = 0.14-0.99). A history of bronchitis or bronchiolitis before age 2 years was weakly associated with an increased risk of atopy, whereas a history of pertussis or pneu- monia was not. Both the effect of father's education and the influence of larger sibship size remained when we adjusted for several potential confounding factors, including respiratory infections in early life. We infer that higher socioeconomic status and lower sibling number are determinants of atopy in this Italian population. Protection arising from early severe respiratory infections does not explain this association, al- though we cannot exclude a role for other viral infections. (Epidemiology 1997;8:566-570) Keywords: allergy, asthma, children, respiratory tract infections, social class, viruses. A rising prevalence of allergies and asthma has recently been reported from several developed countries~-3; hos- pital admissions for asthma, for exampIe, increased by 21.5 per 10,000 between 1977 and 1990 in the United Kingdom.4 Various hypotheses have been postulated to explain this secular trend, including increased circula- tion of allergens, indoor and outdoor pollution, better diagnostic classification and treatment of asthma, and changes in dietary habits.~,6 Results from studies con- ducted in Germany indicate that allergic disorders and asthma may be diseases related to affluence: higher rates of skin prick test reactivity and wheezing symptoms were found in Munich, in western Germany, in comparison with Leipzig, in the East.~.s Facilitation of early circula- tion of viral infections among children attending day care centers in eastern Germany was suggested as a possible explanation for the difference? The recent find- From the IDel~artment of Epidemiology, Lazio Regional Health Authorit3,, Rome, and aRespiratoty Ph~'stology Department, Catholic Umversity, Rome, Italy. Address correspondence to: Fmncesco Forastiere, Ossetvatorio Epidemiologico Regionale, Via Santa Co~tanza, 53, 00198 Rome, Italy. Submitted July 1, 1996; final version accepted April 18, 1997. © 1997 by Epidemiolog,/Resoume~ Inc. ing of a lower prevalence of skin test positivity among children with multiple siblings supports this hypothesis.9 Although previous investigations have shown little 12 13 association1°'|1 or an inverse association • • between so- cioeconomic status and asthma prevalence, several re- cent epidemiologic studies of eczema and hay fever have linked such allergic disorders with wealthier social class- es.~4a5 Strachant6 has postulated that higher living stan- dards and improved personal hygiene lead to an in- creased risk of allergic sensitization. As a biological basis for this hypothesis, he suggested that a lower frequency of viral infections in childhood, due to a reduced oppor- tunity for contacts, may influence the mechanisms of dysregulation of the immune responseJ5'|6 Repeated vi- ral infections in early life can, in fact, inhibit the pro- liferation of Th2-1ike clones, with reduced production of specific immtmoglobulin E (IgE).~7 Such a mechanism has previously been postulated to explain the association of childhood leukemia with socioeconomic status and with sibling numberJs Aside from the above-cited German studies, no inves- tigator has examined the complex relation between fam- ily factors and the distribution of atopic status in chil- dren. We therefore used data collected in a cross- sectional study of children to examine the association of socioeconomic status and sibling number with skin test 566 This article is tbr individual use only and may not be tiarther reproduced or stored electronically vathout wTitten permission fi'om the copyright holder
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Epidemiology September 1997, Volume 8 Number 5 positiviry. We also examined the frequency of respire- tory infections early in life as a possible predictor of atopy, and thus as a potential intermediate factor to explain the links among social class, sibship size, and positive skin tests. Methods SUbJeCTS AND DATA COLLECTION Our survey of respiratory health among schoolchildren in three areas of the Lazio region of Italy was conducted in the periods of January-June 1987 and September- November 1987.tg'z° The areas included the center of Rome; Civitavecchia, a recently urbanized and industri- alized town 80 km north of Rome; and three rural communities (Canino, Montalto di Castro, and Tusca- nia) 130 km north of Rome in the province of Viterbo. The schools within each area were randomly sampled to select at least 900 children from the second to the fifth grades (7- to 11-year-olds). A total of 17 schools were. chosen (3 in Viterbo province, 10 in Rome, and 4 in Civitavecchia), and all 2,789 attending children were enrolled in the study. The children's parents were asked to complete a self-administered questionnaire, adapted from the American Thoracic Society children's instru- ment,zt and to give written consent for prick testing; 2,226 children (79.8% of target) underwent prick test- ing. Descriptive data on atopic status in this population, as well as a more detailed account of the sampling procedure, have been reported2z Skin prick tests were used to evaluate atopic status, using eight allergen extracts (Dermatophagoides pteronys- sinus, grass, mugwort, Parietaria, cat, o/ca, mixed trees, and Akernar/a) (Bayropharm, Milan, Italy), with hista- mine dihydrochloride (10 mg per ml) and diluent as positive and negative controls, respectively. After 15 minutes, the wheals were outlined, and the markings were transferred to mm2 paper by means of a tape. Wheal size was calculated by multiplying the long axis by its perpendicular, with size >4 mmz considered a positive result. We considered a subject with at least one positive result as atopic. We calculated an arbitrary atopy index by subtracting the size of the negative control (NC) from the size of the largest wheal of each subject (WZ), and then dividing by the size of the histamine control (HI). The resulting ratio [(WZ - NC)/HI] was catego- rized into grades of increasing atopic status as follows: grade 0 (nonmeasurable wheal size, non-atopic); grade 1 [(WZ - NC)/HI < 0.5]; grade 2 [(WZ - NC)/HI = 0.5-1.0]; grade 3 [(WZ - NC)/HI > 1.01. Results ob- tained with this method were validated in a pilot study of 48 children randomly chosen and tested twice at an interval of 1 month: a high level of agreement between test and re-test was found (crude agreement = 0.98; Cohen's kappa23 = 0.95; standard error = 0.04). VARIABLES AND DATA ANALYSIS Information regarding number of siblings, family history of respiratory disease, day care attendance during the first 5 years of life, and respiratory infections (pneumo- DETERMINANTS OF ATOPY IN CHILDREN 567 TABLE 1. Characteristics of Children Undergoing Prick Testing, Lazio Region, Italy, 1987 N % Subjects with prick tests 2,226 100.0 At least one positive prick test 469 21.1 Sex, male 1.126 50.6 Age (years) (mean ~ SD) 9.35 (-+1.24) Area of residence Rural (Viterbo province) 749 33.6 Industrial (Civitavecchia) 785 35.3 Urban (Rome) 692 31.1 Parental smoking No 624 28.0 Yes 1,512 67.9 Unknown 90 4.0 Familial respiratory diseases No 1,982 89.0 Yes 244 11.0 Father's education (years) <6 687 30.5 6-8 734 33.0 9-13 53O 23.8 >13 217 9-7 Unknown 67 3.0 Number of siblings 0 388 17.4 I 1,290 58.0 2 393 17.7 3 i01 4.5 :'4 54 2.4 ttousehold crowding (inhabitants/room) Low (<1) 310 13.9 Medium (I-2) 1,510 67.8 High (>2) 331 ,14.9 Unknown 75 3.4 Day care attendance No 156 7.0 Yes 2,021 90.8 Unknow'a 49 2.2 Respiratory refections in first 2 years of life Pneumonia No 1,842 82.7 Yes 28 1.3 Unknown 356 16.0 Bronchitis No 1,371 61.6 1 episode 436 19.6 2 episodes 149 6.7 >3 episodes 161 7.2 Unknown 109 4.9 Bronchioliris No 1,796 80.7 1 episode 41 1.8 ~'2 episodes 26 1.2 Unknown 363 16.3 Pertussis No 1,743 78.3 Yes 435 19.5 Unknown 58 2.6 nia, bronchitis, bronchiolitis, and pertussis) in the first 2 years of tile was derived from the parents' questionnaires. We assessed socioeconomic status on the basis of the
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568 FORASTIERE F_.T AL Epidemiology September 1997, Volume 8 Number 5 TABLE 2. Prevalence of Positive Skin Tests, Prevalence Ratios (PR), and 95% Confidence Intervals (95% CI) for Various Family Factors and Early Respiratory Infections Variable % PR 95% CI Father's education (years) <6* 17.8 1.00 6-8 21.1 1.18 0.96-1 A7 9-13 22.5 1.26 1.00-1.58 >13 28.1 1.58 1.21-2.06 Number of siblings 0* 19.6 1.00 1 22.5 1.15 0.92-1.44 2 21.1 1.08 0.82-1.42 3 15.8 0.81 0.49-1.32 :"4 7.4 0.38 0.14-0.99 Day care attendance No* 17.3 1.00 Yes 21.3 1.23 0.86-1.75 Household crowding (inhabitants/room) Low (<1)* 22.9 " 1.00 Medium (1-2) 21.8 0.95 High (>2) 22.7 0.99 Respiratory infection~ in first 2 years of hfe 0.62-1.52 0.61-1.60 No* 21.2 1.00 Yes 17.2 0.82 0.34-2.01 Bronchitis No* 21.0 1.00 l episode 18.3 0.87 0.70-1.09 2 ~ptsodes 25.5 1.21 0.91-1.63 ~'3 episodes 26.7 1.27 0.97-1.68 Bronchiolitis No* 20.9 1.00 1 episode 19.5 0.93 0.50-1.75 :~2 episodes 34.6 1.66 0.97-2.83 Pertussis No* 21.6 1.00 Yes 19.5 0.90 0.73-1.12 * Referent category. father's education (<6, 6-8, 9-13, and >13 years of education, corresponding to the Italian educational lev- els of primary school, secondary school, high school, and university, respectively). We had data on the number of inhabitants in the dwelling and the dwelling size (num- ber of rooms); we calculated household crowding by dividing the number of inhabitants by the number of rooms (low = <I, medium = 1-2, high = >2). Other factors potentially linked with a~opy were also collected: parental smoking, birthweight (<2,500 gin, ->2,500 gm), maternal age, .breast feeding (no, yes), presence of pets (no, yes), and season of testing (spring, other sea- sons). We compared the crude prevalence of positive skin tests across the categories of the explanatory variables of a pr/or/interest (father's education, number of siblings, household crowding, day care attendance, and respira- tory infections in the first 2 years of life), calculating the prevalenc.e' ratio (PR) and 95% confidence interval (CI).2a We also calculated an odds ratio (OR) from logistic regression to adiust for potential confounders. Results We found positive skin test results in 469 individuals (21.1%) of the 2,226 persons under study (Table 1); 717% of the cohort had atopygrade 1, 6.5% had grade 2, and 6.9% had grade 3. It may be noted that a relatively high proportion of responses was missing for the ques- tions regarding early respiratory infections (from 4.9% for bronchitis to 16.3% for bronchiolitis) (Table 1). Prevalence of positive skin tests and prevalence ratios for various family characteristics are reported in Table 2. The prevalence of atopy increased in families with a higher paternal educational level, from 17.8% in the lowest group (<6 years) to 28.1% in the highest group (>13 years) (PR = 1.58; 95% Ct = 1.21-2.06; P-value for trend = 0.001). Severity of aropic sensitization also increased with increasing educational levels: only 5.0% of children belonging to the lowest social class showed an atopy index grade 3 compared with 13.4% of children whose fathers had the highest level of education (PR = 2.70; 95% CI = 1.69-4.30). Prick test positivity de- creased with increasing number of siblings (from 19.6% for no siblings to 7.4% for four or more siblings; PR = 0.38; 95% C[ = 0.14-0.99). A similar pattern was present for atopy severity: the prevalence of grade 3 wheal size was 1.9% among those having four or more siblings and 6.7% among children without siblings (PR = 0.26; 95% CI =- 0.04-1.85). The association between atopy and day care attendance, household crowding, and a history of pertussis or pneumonia early in life were all close to unity. A history of 3 or more episodes of bronchitis or 2 or more episodes of bronchi- olitis before age 2 years was weakly associated with a higher probability of atopy (PR = 1.27, 95% C1 = 0.97-1.68 for bronchitis; PR -- 1.66, 95% CI = 0.97- 2.83 for bronchiolitis). Table 3 shows the crude and adjusted odds ratios (OR~ and ORz) for father's education and number of siblings. In a logistic regression model containing sex, age, area of residence, familial respiratory diseases, father's educa- tion, number of siblings, household crowding, and day care attendance, aropy remained associated with father's educational level (:>13 vs <6 years: ORz = 1.80; 95% CI = 1.25-2.60) and with number of siblings (four or more vs no siblings: ORz -- 0.36; 95% CI = 0.13-1.06). We found no substantial change when we included early respiratory infections (pneumonia, bronchitis, and bron- chiolitis) in the logistic model (OR~). In a further sen- sitivity analysis, we considered additional potential pre- dictors of aropy (parental smoking, birthweight, maternal age, breast feeding, pets, and season of testing), but again we found no substantial change in the regres- sion coefficients for the variables of interest (data not shown). Discussion This study indicates that atopic sensitization to common aeroallergens is positively associated with the level of socioeconomic status and negatively and independently associated with the number of siblings. The results con-
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Epidemiology September 1997, Volume 8 Number 5 DETERMINANTS OF ATOPY IN CHILDREN 569 TABLE 3. Association of Prick Test Positivity with Father's Education and Number of Siblings: Multivariate Analysis* Variable OR~ 95% CI ORZ 95% CI OR, 95% CI Father's education (yearn) <6~* 1.00 1.00 1.00 6-8 1.23 0.94-1.60 1.16 0.89-1.53 1.17 0.89-1.54 9-13 1.33 1.00-1.77 1.26 0.94-1.69 1.25 0.93-1.69 >13 1.79 1.26-2.57 1.80 1..25-2.60 1.84 1.26-2.69 Number of siblings 0t 1.00 1.00 1.00 ! 1.19 0.89-1.58 1.23 0.92-1.65 1.24 0.91-1.68 2 1.09 0.77-l.56 1.13 0.79-1.61 1.12 0.77-1.63 3 0.77 0.43-1.39 0.79 0.43-1.46 0.79 0.43-1.46 :"4 0.33 0.12-0.95 0.36 0.13-1.06 0.36 0.12-1.06 * OR, = crude odd.~ ratio and 95% cor~fldencc interval (CI); OR, - odds ratio adjusted in the lngisric model fi)r sex. age. area of residence, familial respiratory d~ea~e, 'mmsehold crowding, and day care attendance; OR~ ~ odds ratio adiusted in the logistic model for sex, age, area of residence, ~unilial ~spirato~/diseases, household cruwdm~, day care attead~ce, and reSl~iratory infections in the fi~t 2 year~ of life (pneumonia. bronchitis, hronchiol.ms). t Red'rent catego~. firm previous findings from Germany.s,° Multiple epi- sodes of bronchitis and bronchiolitis early in life may also have a role in the later development of ampy. Nevertheless, the associations of atopy with socioeco- no,nic status and sibling number appeared to be inde- pendent of, and thus not mediated by, these early respi- ratory infections. This is the first study to evaluate simultaneously the roles of socioeconomic status, number of siblings, and early respiratory infections in atopy. We obtained a high response rate and used an objective method to measure aropic sensitization. A limitation of the study is the possible inaccuracy of parental reporting of respiratory early infection, especially if inaccuracy is associated with number of siblings. Nevertheless, parental reporting of respiratory infections early in life had a good level of test-retest reliability in two separate studies that we conducted in the same population39 Several recent studies in addition to our own have found an excess of asthma or allergic diseases in higher socioeconomic classes,~as but others have reported no association~°,u or an association in the opposite direc- tion.u't3 These contrasting results may be due to dissim- ilar social structures, or sets of exposures, in different populations. For instance, exposure to mouse urine, Al- temar/a, and cockroaches in low-income families in the American inner city has been associated with excess risk of asthma and wheezing;, an effect of unmeasured factors associated with poverty has also been hypothesized in the American inner city.t3 It has similarly been sug- gested that Factors other than exposure to allergens may contribute to differences in skin test reactivity in West and East Germany.s An early study from England indi- cated social and life-style characteristics related to high parental educational level (a higher income, a larger home, less crowding, a smaller family) as determinants of asthma and allergic diseases)5 In our study, the social class effect was not explained by confounding due to the number of siblings, since both were independently present in the multivariate model. One may speculate that the true etiologic factors for which father's education and number of siblings are i~roxies Operate at cady -stages of life, possibly in- cluding the intrauterine period,z6 The fact that an effect was seen for number of siblings but not for household crowding or day care attendance similarly points to maternal and perinatal factors,a; It has recently been pos- tulated that viral infec- tions in early childhood might prevent allergic dis- eases; a low number of sib- lings may be associated with a reduced opportu- nity for cross-infections early in life.sa5 Strachan16 hy- pothesized that protection against allergic diseases could result from infections in early childhood, whether trans- mitted from siblings or acquired in utero from a mother infected by contact with her older children. Recent immunologic studies have also suggested a down-regula- tion of IgE production by viral and bacterial infec- tions37'z8 On the other hand, respiratory viruses have also been thought capable of promoting allergic sensiti- zation,z9 Although them is little evidence available in humans,s° damage to airways by respiratory syncytial virus infection (commonly, bronchiolitis) has been shown to alter the immune system, thus leading to allergic sensitization,n Our dataset permitted evaluation of the influence of selected respiratory infections on the development of allergic sensitization. We found that multiple episodes of bronchitis and bronchiolitis in the first 2 years of life were associated with an increased risk of atopy but that adjustment for such episodes did not abolish the associ- ation with a small sibling number. These findings do not exclude a protective effect of viral infections as a factor in the decreased rate of allergic sensitization among members of large sibships. Bronchitis and bronchiolitis are, as compared with most childhood respiratory infec- tions, relatively severe (possibly leaving structural dam- age that might have an allergy-promoting effect), rela- tively infrequent, and somewhat more likely to have a bacterial etiology, although the bulk of lower respiratory infections in developed countries is thought to be viral,n If viral infections do have a down-regulating effect on the allergic diathesis, the quantitative contribution of lower respiratory infections could be minor in compari- son with that of the much more frequent upper respira- tory infections, the viral gastroenteritides, and the clas- sic childhood infections such as measles, currently on the wane in the developed world.31 Interestingly, a co- hort study in Guinea-Bissau suggested that young adults who had experienced measles in childhood were less likely to be atopic than those who had not had measles.~ Our findings do, however, indicate a need to look be-
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570 FORASTIERE ET AL Epidemiology September 1997, Volume 8 Number 5 yond infection factors in explaining the lower rate of allergy among children from large sibships. Acknowledgments We thank Bibtana De Srefartis. Augusro Pi~zabiocca, Adalg~sa Elefance, Paola Bueti, Gienna Cenu~, and Giorgio Schiano of the Local Health Authorities RM/21, RM]2. and VT/2 for their coopcmrion in collecting the data, and Anna Emigli for typing the manuscript. References 1. Peat JK, van den t~erg RH, Green WF, Mellis CM, Laeder SR, Woolcock AJ. Changing prevalence of asthma in Australian children. BM.I 1994;308: 1591-1596. 2. Hyndman SJ, Wilharus DRR, Merrill SL, Lipscombe JM0 Palmer CIL Rates of admission to hospital for asthma. BMJ 1994;308:I596-1600. 3. Anderson HR, Burhnd BK, Strachan DP. Trends in prevalence and severity of childhood asthma. BMJ 1994;308:1600-1604. 4. Srmchan DP, Anderson HR. Trends in hospital admissiun rates for asthma in children. BMJ 1992;304:819-820. 5. Newman-Taylor A. 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