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Messages from the Aalst Allergy Study
Dirk Van Gysel, Elke Govaere, Katia M.C. Verhamme, Erenik Doli, Frans De Baets
Aalst, Belgium
Author Affiliations: Department of Pediatrics (Van Gysel D, Govaere E, Doli E) and Department of Epidemiology (Verhamme KMC), O.L.Vrouw Hospital, Aalst, Belgium; Department of Pediatric Pulmonology, University of Ghent, Belgium (De Baets F)
Corresponding Author: Dirk Van Gysel, MD, Department of Pediatrics, O.L.Vrouw Hospital, Moorselbaan 164, B-9300 Aalst, Belgium (Tel: 00 32 53 724155; Fax: 00 32 53 724645; Email: dirk.van.gysel@olvz-aalst.be)
doi:10.1007/s12519-009-0035-0
Background: The prevalence of sensitization and allergic disease has increased significantly worldwide. The aim of the "Aalst Allergy Study" was to document prevalences of sensitization and allergic symptoms, and to evaluate the effect of personal and environmental influences on these prevalences in an unbiased Belgian pediatric population.
Methods: A cross-sectional study was performed in an unbiased population of 2021 Belgian schoolchildren (3.4-14.8 years). Skin prick testing with the most common aeroallergens was performed. Allergic symptoms as well as potential risk factors for sensitization and allergic disease were documented by a parental questionnaire.
Results: The prevalence of sensitization to the most common aeroallergens and the prevalence of allergic diseases (eczema, asthma and rhinoconjunctivitis) were in line with the data in the literature. The association of current allergic symptoms with sensitization was only significant in the children aged ¡Ý6 years. Age, gender, body mass index, bedroom environment and exposure to pets were the factors significantly associated with sensitization and allergic symptoms.
Conclusions: Our study corroborates the reported prevalences of sensitization and allergic diseases. Moreover the study illustrates the complexity of the search for factors involved in the process of sensitization and allergic disease. The impact of different potential causative factors is not only influenced by mutual interactions of these factors, but also by the existence of distinct subtypes of disease.
Key words: Aalst Allergy Study; allergic symptoms; risk factors; sensitization; skin prick test
World J Pediatr 2009;5(3):182-190
Introduction
he prevalence of allergic sensitization has increased dramatically worldwide during the recent years.[1-3] Recent Australian data suggest that this increase may now be levelling off.[4] Allergen exposure in childhood is a risk factor for sensitization and allergic sensitization is generally agreed to be an important risk factor of allergic diseases.[5-7] On the other hand it has been hypothesized that allergen exposure in early childhood may induce tolerance and may have a protective effect on sensitization.[8,9] Early life events seem to have a major impact on the development of sensitization or tolerance.[9-11] Besides environmental factors, however, personal factors such as genetic predisposition and gender also influence atopy.[12,13]
In order to evaluate the prevalences of sensitization and allergic symptoms and the effect of personal and environmental influences in an unbiased Belgian pediatric population we performed the "Aalst Allergy Study" (AAS).
Methods
The AAS is a cross-sectional study that was performed from January 2004 to June 2005 in an unselected sample of children aged 3.4 to 14.8 years (mean age, 9.3 years) attending randomly selected nursery, primary and secondary schools in the city of Aalst and the surrounding area. Aalst is a Belgian municipality, 19 miles northwest from Brussels. Aalst has a total population of 76 852 for a total area of 78.12 square kilometers, which gives a population density of 983.83 inhabitants per square kilometers.
The parents of all 2674 children of the 2nd grade of nursery school, the 1st, 3rd and 5th grade of primary school and the 1st grade of secondary school were contacted, received a questionnaire (see below) and were invited to participate in this study. The parents of 2021 children (75%) returned a completed questionnaire and gave permission by written consent to perform skin prick testing in their children. The baseline characteristics of the study population are summarized in Table 1.
The questionnaire included questions on rhinoconjunctivitis and asthma, that were adapted and translated from the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire.[1] The presence of eczema, as well as the time of occurrence, was documented by parentally reported eczema. We defined current allergic symptoms as the presence of wheezing, dyspnea, airway hyperreactivity, rhinitis, conjunctivitis or eczema in the last 12 months. A positive family history of allergy was defined as the presence of one of the allergic symptoms in one of the parents or siblings.
The questionnaire further included questions about demographic characteristics (age, gender, nationality, maternal and paternal profession) and potential risk factors for sensitization, such as prematurity, feeding practices in the neonatal period, family history of allergy, number of siblings, frequency of childhood infections, vaccinations, place of residence (urban or rural), housing characteristics (age of building, heating, dampness, bedroom conditions, etc), animal contacts and tobacco smoke exposure (pre- and postnatal).
The allergen panel (Stallergenes, Waterloo, Belgium) consisted of the most common aeroallergens¡ªDermatophagoides pteronyssinus, Alternaria tenuis, cat, dog, mixed grass pollens [Dactylis glomerata (orchardgrass), Poa pratensis (Kentucky bluegrass), Lolium perenne (perennial ryegrass), Anthoxanthum odoratum (Gramineae) and Phleum pratense (Timothy)], tree pollens [Alnus glutinosa (Common Alder), Betula alba (Common Birch), Corylus avellana (Hazel) and Carpinus betulus (European hornbeam)], and Blatella germanica (cockroach). Atopy was defined as at least one positive skin test to any of the seven allergens tested.[14]
The Chi-square test or Fisher's exact test was used to study the differences in prevalence according to age and gender. Differences in mean BMI for the different age categories were tested by ANOVA. Logistic regression analysis was used to study the association between co-variates and the different outcomes of interest. In a univariate analysis, the association between each covariate and the outcome of interest was studied. We then added one by one all risk factors for the outcome into the model. If any of these factors changed the estimate with more than 5%, these risk factors were entered into the final model. A P value <0.05 was considered statistically significant. All statistical analyses were done using SPSS 13.0 (SPSS Inc., Chicago, IL, USA).[15-22]
Results
Prevalence of sensitization and allergic symptoms
A total of 483 children (23.9%, 95% CI 22.1-25.8%) had evidence of allergic sensitization.[15] The age standardized prevalence rate was 20.5% (95% CI 17.9-23.2%).
The prevalence rates of sensitization to the most common allergens were as follows: Dermatophagoides pteronyssinus 291 (14.4%), mixed grass pollens 205 (10.1%), tree pollens 67 (3.3%), cat 97 (4.8%), dog 54 (2.7%) and Alternaria tenuis 58 (2.9%). Sensitization to Blatella germanica was present in only 11 (0.5%) children.[15,18] The AAS prevalence rates of eczema, respiratory symptoms and rhinoconjunctivitis for the whole study population are shown in Table 2.
In our study, all investigated current allergic symptoms were positively associated with sensitization.[17] The association was strongest for rhinoconjunctivitis and stronger for respiratory allergic symptoms than for eczema. After stratification of the whole study population into children younger than or older than 6 years, we found that the associations of any of the investigated allergy symptoms with overall sensitization were limited to the children older than 6 years. No significant association could be documented in the group of children younger than 6 years.
Association of personal and environmental factors with the prevalence of sensitization and allergic symptoms
Age and gender[15]
Overall sensitization to at least one allergen increased significantly with age from 15.9% (95%CI: 12.4-20.0%) for the younger age group up to 30.5% (95%CI: 26.2-35.0%) for the older age group (Fig. A). The increase with age was gradual, but a marked increase was observed at the age of 8 to10 years.
A significant association with increasing age was also seen for the individual allergens D. pteronyssinus, mixed grass pollens, and tree pollens. For cat, dog, Alternaria tenuis and Blatella germanica, no statistically significant increase of sensitization with age could be documented (Fig. A and B).
When studying sensitization in relation to gender, we observed that the prevalence of sensitization was much higher in boys than in girls; 293 (29.6%) of the 990 boys were sensitized compared to 190 (18.4%) of the 1031 girls. The male predominance was present in all age categories, but was more obvious in the categories of children under 8 years. In the categories of children older than 8 years, the male predominance remained, but the ratio of male to female decreased.
When stratifying into boys and girls, it was observed that sensitization increased with age for both boys and girls with a steep increase after the age of 8 years for girls (ORadj 4.0) and after the age of 10 years for boys (ORadj 3.3).
Body mass index (BMI)[22]
Our study showed an increased prevalence of sensitization in underweight girls only, not in underweight boys, nor in overweight or obese children. We also found a strong positive association between obesity and exercise induced respiratory symptoms in both boys and girls.
Indoor allergen exposure[19]
Allergen exposure in childhood is a risk factor for sensitization. On the other hand it has been hypothesised that allergen exposure in early childhood may induce tolerance and may have a protective effect on sensitization. In the AAS we focused on the influence of bedroom conditions on sensitization and allergic symptoms.
The presence of stuffed toys in the bedroom correlated with a lower prevalence of overall sensitization and a lower prevalence of conjunctivitis and allergic respiratory symptoms. This effect was almost exclusively present in children with a positive family history of allergy and was more pronounced as the number of stuffed toys increased.
A significantly lower prevalence of overall sensitization, sensitization to house dust mite and wheezing was documented in children with non-synthetic bedding materials. That effect was exclusive to children with a positive family history of allergy.
The type of flooring was not associated with sensitization or allergic symptoms.
Pets[21]
Dog ownership at birth and dog ownership at present were not associated with sensitization whereas the presence of a domestic dog both at birth and at present seemed to protect against overall sensitization (ORadj 0.6 [95%CI: 0.5-0.9]). None of the categories of cat ownership (at birth and/or at the time of the study) were associated with overall sensitization.
No significant association was found in pet ownership with sensitization for one of the individual allergens or with current allergic symptoms.
Other risk factors
Preterm birth seemed to be protective in the development of eczema, whereas birthweight did not.[16]
The other analyzed risk factors such as month of birth, vaccinations, breastfeeding, day-care attendance, frequency of childhood infections, pre- and/or postnatal passive smoke exposure, housing conditions, growing up in a farming environment, number of siblings and birth order showed no association with the prevalence of sensitization and allergic symptoms in children.
Discussion
The prevalences of skin sensitization for the most common aeroallergens in the AAS are in line with the data in the literature from neighbouring European countries.[3,23-31] As for cockroach only two European studies described cockroach sensitization in a non-selected pediatric population. A study of German school children aged 5-11 years living in Dresden showed a prevalence of 4.2%;[32] a study of Italian preschool children showed 0.45% sensitization.[33] The sensitization rate in our study group was much lower than that in the German study,[32] and comparable with the findings in Italian preschool children.[33] Differences may be explained by differences in age range of the study population and by differences in cockroach allergen exposure,[34] due to differences in socio-economic conditions and indoor environments.
The prevalence rates of allergic symptoms in the AAS are in line with the data of the ISAAC.[1,35] However, comparison of prevalence data remains difficult due to differences in definitions, study population, and others.
When sensitization is presumed to be the cause of allergic diseases in the vast majority of children, similar "allergic" symptoms occur in non-atopic individuals. On the other hand, we know from daily practice that many subjects sensitized to aeroallergens do not always experience allergic symptoms.[36,37] In our study, all investigated current allergic symptoms were positively associated with sensitization.[17] After stratification of the whole study population into children younger than or older than 6 years, we found that the associations of any of the investigated allergic symptoms with overall sensitization were limited to the children older than 6 years. No significant association could be documented in the group of children younger than 6 years. This might be due to the overlap of the "allergic" symptoms (such as sneezing, runny or blocked nose, cough and wheezing) with viral induced symptoms, which have a high prevalence in the younger age group. On the other hand, our data also illustrate that many children without sensitization still had identifiable "allergic" symptoms, confirming the observation that the development of allergic symptoms is not solely attributable to allergic sensitization and highlighting the need to further investigate the role of allergic sensitization in "allergic" symptoms.[30,38-41]
The personal and environmental factors significantly associated with the prevalence of sensitization and allergic symptoms in the AAS were age, gender, BMI, bedroom environment and exposure to pets.
Overall sensitization is significantly associated with increasing age. The significant association of sensitization with increasing age for individual allergens such as D. pteronyssinus, mixed grass pollens and tree pollens does correlate with the hypothesis that allergen exposure in childhood is a risk factor for sensitization.[1,5] For cat, dog, Alternaria tenuis and Blatella germanica, no statistically significant increase of sensitization with age could be documented. This might be due to the small numbers of subjects in the different age groups rather than a real lack of effect, or might be suggestive for induction of tolerance, as has been hypothesized previously by others for cat and dog.[4,8,9,11]
Gender, especially male sex, is a known risk factor for sensitization and allergy.[42] Boys suffer more often from asthma than girls, while in adults the gender ratio is reversed.[43,44] The exact timing and underlying mechanism of this change in gender ratio and disease severity is not clear. Some studies suggest that an increase in sensitization alone can not explain this observation.[45] Data from our study show that children under the age of 8 years have a significantly higher male/female ratio of sensitization than children older than 8. This is prominent for all tested allergens. After the age of 8 years, male predominance persists, but a significant increase in percentage of sensitized females occurs. Our data showed, for the first time ever, the age of 8 to 10 years to be a pivotal time for the atopic child with a significant increase in prevalence of sensitization and a significant decrease in the male/female ratio. The observed gender differences and age-related changes may be related to differences in the hormonal environment.[15,46]
In the literature there are conflicting reports about the influence of BMI on the allergic status. A review confined to studies in children and adolescents on the possible association between obesity and asthma or asthma-like symptoms concluded that no study in a Western society has found objective evidence for the association, and results of some studies suggesting a possible association might be due to increased reporting of symptoms in obese children or to diagnostic bias.[47] Similar contradictory results were found for BMI and sensitization.[48-55] Our study showed an increased prevalence of sensitization in underweight girls only, not in underweight boys, nor in overweight or obese children. Reasons for the association of underweight and sensitization in girls are not clear. Nutritional status with nutritional deficiencies in certain nutrients or undernourishment might explain the higher degree of sensitization in underweight children, as a recent study by Chatzi et al[56] showed a potential protective effect of fruity vegetables and fish intake on childhood atopy. However this does not explain the gender difference in the relation between underweight and sensitization.
The strong positive association between obesity and exercise induced respiratory symptoms in both boys and girls is unlikely to be related to atopy, because neither association of obesity with sensitization nor association with other allergic respiratory symptoms, eczema or rhinoconjunctivitis could be found. Mechanical properties of the respiratory system[57,58] and poor physical fitness[51,57-60] may account for this result.
The protective effect of bedroom exposure to stuffed toys and non-synthetic bedding material could encompass several factors. Stuffed toys and non-synthetic bedding materials can be considered not only as reservoirs of house dust mites (HDM), but also as a reservoir of microbes and endotoxins. Several studies demonstrated a higher degree of sensitization (especially with exposure in infancy and early childhood)[61,62] and/or more allergic symptoms in persons who are more often exposed to allergens such as HDM.[63-65] On the other hand, the presence of microbes and endotoxins may be responsible for a lower prevalence of sensitization and allergic symptoms, as stated in the "hygiene hypothesis"[66] and as reported before.[67,68]
The reported data on the effect of pet ownership on the development of sensitization and allergic disease in children are conflicting.[69-71] The data on the effect of cat ownership are equivocal, with some studies suggesting an increase and others a decrease in risk of sensitization or allergic disease. For dogs, results are more consistent, generally suggesting that owning a dog has no effect or may be protective against the development of specific sensitization to dog and overall sensitization. Our results suggest that domestic cat exposure neither at birth nor at present has any effect on the subsequent development of sensitization and allergic disease. For dogs, the inverse association of sustained dog ownership (both at birth and at present) with overall sensitization, but not with allergic disease, suggests that only prolonged domestic dog allergen exposure, from birth on, may protect against sensitization. A number of interesting hypotheses to explain the relationship between dogs, immune development and atopic outcomes in childhood have been developed, but prove difficult to test.[72] It seems likely that the effect is mediated through stimulation of innate immune responses, although endotoxin levels by themselves do not always explain the relationship between dog ownership and atopic outcomes.[71,73-75]
As for all observational research, our data need to be interpreted with caution. First of all, we conducted a cross-sectional study implicating that we only measured sensitization, allergic symptoms and covariates at a single moment in time. Secondly, there might have been the potential of selection bias, recall bias and confounding. This has been discussed earlier.[15-22]
In conclusion, we studied the prevalence of sensitization to aeroallergens and allergic symptoms in a community population of schoolchildren, aged 3.4 to 14.8 years and found that 23.9% had evidence of allergic sensitization to aeroallergens. Our sensitization data are the first published data ever in unselected Belgian schoolchildren. The personal and environmental factors significantly associated with the prevalence of sensitization and allergic symptoms in the AAS were age, gender, BMI, the bedroom environment and exposure to pets.
The results of our study illustrate the complexity of the search for factors involved in the process of sensitization and allergic disease. Further large, prospective, population-based studies with accurate documentation of the coexisting genetic and environmental subtext and identification of the temporal "windows" are required to further elucidate any individual effect on sensitization and development of allergic disorders, in order to propose a strategy for the primary or secondary prevention of allergic diseases.
Acknowledgements
We thank the collaborators of the AAS (Patrick De Weert, Anne-Marie Van Heesvelde, Trees Evenepoel, Hedwige Creus, their colleagues and the nurses of the participating medical school centers, the colleagues and medical school students of the Department of Pediatrics of the O.L.Vrouw Hospital Aalst) for their support in realizing this project.
Funding: The Aalst Allergy Study was supported by an unrestricted grant from Numico, Stallerg¨¨nes and UCB.
Ethical approval: This study was approved by the Ethical Committee of the University of Ghent. Informed consent was obtained from the parents of all participants.
Competing interest: None.
Contributors: Van Gysel D and Govaere E equally contributed to this paper. Van Gysel D, Govaere E and De Baets F wrote the protocol. Van Gysel D, Govaere E and Doli E performed the study. Van Gysel D and Govaere E analyzed the data and Verhamme KMC supervised the statistical analysis. Van Gysel D and Govaere E wrote the first draft of the paper and all contributors participated in the revision and final approval of the paper.
References
1 Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998;351:1225-1232.
2 Isolauri E, Huurre A, Salminen S, Impivaara O. The allergy epidemic extends beyond the past few decades. Clin Exp Allergy 2004;34:1007-1010.
3 von Mutius E, Weiland SK, Fritzsch C, Duhme H, Keil U. Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. Lancet 1998;351:862-866.
4 Nowak D, Suppli Ulrik C, von Mutius E. Asthma and atopy: has peak prevalence been reached? Eur Respir J 2004;23:359-360.
5 Kuyucu S, Saraçlar Y, Tuncer A, Saçkesen C, Adalioglu G, S¨¹mb¨¹loglu V, et al. Determinants of atopic sensitization in Turkish school children: effects of pre- and post-natal events and maternal atopy. Pediatr Allergy Immunol 2004;15:62-71.
6 Wahn U, Bergmann R, Kulig M, Forster J, Bauer CP. The natural course of sensitisation and atopic disease in infancy and childhood. Pediatr Allergy Immunol 1997;8:16-20.
7 Nickel R, Lau S, Niggemann B, Gr¨¹ber C, von Mutius E, Illi S, et al. Messages from the German Multicentre Allergy Study. Pediatr Allergy Immunol 2002;13:7-10.
8 Riedler J, Braun-Fahrländer C, Eder W, Schreuer M, Waser M, Maisch S, et al. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129-1133.
9 Upham JW, Holt PG. Environment and development of atopy. Curr Opin Allergy Clin Immunol 2005;5:167-172.
10 Warner JO, Jones CA, Kilburn SA, Vance GH, Warner JA. Pre-natal sensitization in humans. Pediatr Allergy Immunol 2000;11:6-8.
11 Kemp A, Björkst¨¦n B. Immune deviation and the hygiene hypothesis: a review of the epidemiological evidence. Pediatr Allergy Immunol 2003;14:74-80.
12 Lichtenstein P, Svartengren M. Genes, environments, and sex: factors of importance in atopic diseases in 7-9-year-old Swedish twins. Allergy 1997;52:1079-1086.
13 Arriba-Mendez S, Sanz C, Isidoro-Garcia M, Davild I, Laffond E, Horeno E, et al. 927T>C polymorphism of the cysteinyl-leukotriene type-1 receptor (CYSLTR1) gene in children with asthma and atopic dermatitis. Pediatr Allergy Immunol 2006;17:323-328.
14 Dreborg S, Frew A. Position paper: allergen standardization and skin tests. The European Academy of Allergology and Clinical Immunology. Allergy 1993;48:48-82.
15 Govaere E, Van Gysel D, Massa G, Verhamme KM, Doli E, De Baets F. The influence of age and gender on sensitization to aero-allergens. Pediatr Allergy Immunol 2007;18:671-678.
16 Govaere E, Van Gysel D, Verhamme KMC, Doli E, De Baets F. The prevalence, characteristics of and risk factors for eczema in Belgian schoolchildren. Pediatr Dermatol 2009;26: 129-138.
17 Govaere E, Van Gysel D, Verhamme KMC, Doli E, De Baets F. The association of allergic symptoms with sensitization to inhalant allergens in infancy and childhood. Pediatr Allergy Immunol 2008. DOI: 10.1111/j.1399-3038.2008.00805.x
18 Van Gysel D, Govaere E, Doli E, De Baets F. Cockroach sensitisation in Belgian children. Eur J Pediatr 2006;165:662-664.
19 Van Gysel D, Govaere E, Verhamme K, Doli E, De Baets F. The influence of bedroom environment on sensitization and allergic symptoms in schoolchildren. J Investig Allergol Clin Immunol 2007;17:227-235.
20 Van Gysel D, Govaere E, Verhamme K, Doli E, De Baets F. The influence of atopic status and potential risk factors for sensitization on histamine skin reactivity in unselected Belgian children. Pediatr Dermatol 2007;24:363-368.
21 Van Gysel D, Govaere E, Verhamme KMC, Doli E, De Baets F. Exposure to pets and the association with sensitization and allergic disease in Belgian schoolchildren. Allergy 2009;64:663-664.
22 Van Gysel D, Govaere E, Verhamme KMC, Doli E, De Baets F. Body mass index in Belgian schoolchildren and its relationship with sensitization and allergic symptoms. Pediatr Allergy Immunol 2009;20:246-253.
23 Ronmark E, Lundback B, Jonsson E, Platts-Mills T. Asthma, type-1 allergy and related conditions in 7- and 8-year-old children in northern Sweden: prevalence rates and risk factor pattern. Respir Med 1998;92:316-324.
24 Norrman E, Rosenhall L, Nystrom L, Jonsson E, Stjernberg N. Prevalence of positive skin prick tests, allergic asthma, and rhinoconjunctivitis in teenagers in northern Sweden. Allergy 1994;49:808-815.
25 Haahtela T, Bjorksten F, Heiskala M, Suoniemi I. Skin prick test reactivity to common allergens in Finnish adolescents. Allergy 1980;35:425-431.
26 Ronchetti R, Haluszka J, Martella S, Falasca C, Guglielmi F, Parmiani S, et al. Skin reactivity to histamine and to allergens in unselected 9-year-old children living in Poland and Italy. Pediatr Allergy Immunol 2003;14:201-206.
27 Weinmayr G, Weiland SK, Björkst¨¦n B, Brunekreef B, B¨¹chele G, Cookson WO, et al. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med 2007;176:565-574.
28 van Amsterdam JG, Janssen NA, de Meer G, Fischer PH, Nierkens S, van Loveren H, et al. The relationship between exhaled nitric oxide and allergic sensitization in a random sample of school children. Clin Exp Allergy 2003;33:187-191.
29 Schäfer T, Vieluf D, Behrendt H, Krämer U, Ring J. Atopic eczema and other manifestations of atopy: results of a study in East and West Germany. Allergy 1996;51:532-539.
30 Arshad SH, Tariq SM, Matthews S, Hakim E. Sensitization to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. Pediatrics 2001;108:E33.
31 Heinzerling L, Frew AJ, Bindslev-Jensen C, Bonini S, Bousquet J, Bresciani M, et al. Standard skin prick testing and sensitization to inhalant allergens across Europe¡ªa survey from the GALEN network. Allergy 2005;60:1287-1300.
32 Hirsch T, Stappenbeck C, Neumeister V, Weiland SK, Von Mutius E, Keil U, et al. Exposure and allergic sensitization to cockroach allergen in East Germany. Clin Exp Allergy 2000;30:529-537.
33 Peroni DG, Alfonsi L, Ress M, Milanesi E, Piacentini GL, Boner AL. Low rate of cockroach sensitivity in Italian pre-school children. Allergy 2003;58:531.
34 Chew GL, Perzanowski MS, Canfield SM, Goldstein IF, Mellins RB, Hoepner LA, et al. Cockroach allergen levels and associations with cockroach-specific IgE. J Allergy Clin Immunol 2008;121:240-245.
35 Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368:733-743.
36 Baldacci S, Modena P, Carrozzi L, Pedreschi M, Vellutini M, Biavati P, et al. Skin prick test reactivity to common aeroallergens in relation to total IgE, respiratory symptoms, and smoking in a general population sample of northern Italy. Allergy 1996;51:149-156.
37 Ernst P, Cormier Y. Relative scarcity of asthma and atopy among rural adolescents raised on a farm. Am J Respir Crit Care Med 2000;161:1563-1566.
38 Kurukulaaratchy RJ, Matthews S, Arshad SH. Defining childhood atopic phenotypes to investigate the association of atopic sensitization with allergic disease. Allergy 2005;60:1280-1286.
39 Arshad SH, Karmaus W, Matthews S, Mealy B, Dean T, Frischer T, et al. Association of allergy-related symptoms with sensitization to common allergens in an adult European population. J Investig Allergol Clin Immunol 2001;11:94-102.
40 Prasarnphanich T, Sindhurat S. Sensitization to common indoor allergens and its association with allergic diseases in Thai female high-school students. Pediatr Allergy Immunol 2005;16:402-407.
41 Turner SW, Devereux G. Early life influences on the development of allergy and asthma¡ªhow early is early? Clin Exp Allergy 2007;37:163-165.
42 Arruda LK, Sole D, Baena-Cagnani CE, Naspitz CK. Risk factors for asthma and atopy. Curr Opin Allergy Clin Immunol 2005;5:153-159.
43 de Marco R, Locatelli F, Sunyer J, Burney P. Differences in incidence of reported asthma related to age in men and women. A retrospective analysis of the data of the European Respiratory Health Survey. Am J Respir Crit Care Med 2000;162:68-74.
44 Nicolai T, Pereszlenyiova-Bliznakova L, Illi S, Reinhardt D, von Mutius E. Longitudinal follow-up of the changing gender ratio in asthma from childhood to adulthood: role of delayed manifestation in girls. Pediatr Allergy Immunol 2003;14:280-283.
45 Kjellman B, Gustafsson PM. Asthma from childhood to adulthood: asthma severity, allergies, sensitization, living conditions, gender influence and social consequences. Respir Med 2000;94:454-465.
46 Chen W, Mempel M, Schober W, Behrendt H, Ring J. Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy 2008;63:1418-1427.
47 Chinn S. Obesity and asthma. Paediatr Respir Rev 2006;7:223-228.
48 Xu B, Pekkanen J, Laitinen J, Jarvelin MR. Body build from birth to adulthood and risk of asthma. Eur J Public Health 2002;12:166-170.
49 Hancox RJ, Milne BJ, Poulton R, Taylor DR, Greene JM, McLachlan CR, et al. Sex differences in the relation between body mass index and asthma and atopy in a birth cohort. Am J Respir Crit Care Med 2005;171:440-445.
50 von Mutius E, Schwartz J, Neas LM, Dockery D, Weiss ST. Relation of body mass index to asthma and atopy in children: the National Health and Nutrition Examination Study III. Thorax 2001;56:835-838.
51 Jarvis D, Chinn S, Potts J, Burney P; European Community Respiratory Health Survey. Association of body mass index with respiratory symptoms and atopy: results from the European Community Respiratory Health Survey. Clin Exp Allergy 2002;32:831-837.
52 Oddy WH, Sherriff JL, de Klerk NH, Kendall GE. Breastfeeding, body mass index, and asthma and atopy in children. Adv Exp Med Biol 2004;554:387-390.
53 Mai XM, Nilsson L, Axelson O, Braback L, Sandin A, Kjellman NI, et al. High body mass index, asthma and allergy in Swedish schoolchildren participating in the International Study of Asthma and Allergies in Childhood: Phase II. Acta Paediatr 2003;92:1144-1148.
54 Huang SL, Shiao G, Chou P. Association between body mass index and allergy in teenage girls in Taiwan. Clin Exp Allergy 1999;29:323-329.
55 Schachter LM, Peat JK, Salome CM. Asthma and atopy in overweight children. Thorax 2003;58:1031-1035.
56 Chatzi L, Torrent M, Romieu I, Garcia-Esteban R, Ferrer C, Vioque J, et al. Diet, wheeze, and atopy in school children in Menorca, Spain. Pediatr Allergy Immunol 2007;18:480-485.
57 Unterborn J. Pulmonary function testing in obesity, pregnancy, and extremes of body habitus. Clin Chest Med 2001;22:759-767.
58 del R¨ªo-Navarro B, Cisneros-Rivero M, Berber-Eslava A, Esp¨ªnola-Reyna G, Sienra-Monge J. Exercise induced bronchospasm in asthmatic and non-asthmatic obese children. Allergol Immunopathol (Madr) 2000;28:5-11.
59 King GG, Brown NJ, Diba C, Thorpe CW, Muñoz P, Marks GB, et al. The effects of body weight on airway calibre. Eur Respir J 2005;25:896-901.
60 Platts-Mills TA, Erwin E, Heymann P, Woodfolk J. Is the hygiene hypothesis still a viable explanation for the increased prevalence of asthma? Allergy 2005;60 Suppl 79:25-31.
61 Custovic A, Simpson BM, Simpson A, Hallam CL, Marolia H, Walsh D, et al. Current mite, cat, and dog allergen exposure, pet ownership, and sensitization to inhalant allergens in adults. J Allergy Clin Immunol 2003;111:402-407.
62 Huss K, Adkinson NF Jr, Eggleston PA, Dawson C, Van Natta ML, Hamilton RG. House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program. J Allergy Clin Immunol 2001;107:48-54.
63 Wahn U, Lau S, Bergmann R, Kulig M, Forster J, Bergmann K, et al. Indoor allergen exposure is a risk factor for sensitization during the first three years of life. J Allergy Clin Immunol 1997;99:763-769.
64 Kuehr J, Frischer T, Meinert R, Barth R, Forster J, Schraub S, et al. Mite allergen exposure is a risk for the incidence of specific sensitization. J Allergy Clin Immunol 1994;94:44-52.
65 Lau S, Illi S, Sommerfeld C, Niggemann B, Bergmann R, von Mutius E, et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet 2000;356:1392-1397.
66 Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J. Too clean, or not too clean: the Hygiene Hypothesis and home hygiene. Clin Exp Allergy 2006;36:402-425.
67 Gehring U, Bischof W, Fahlbusch B, Wichmann HE, Heinrich J. House dust endotoxin and allergic sensitization in children. Am J Respir Crit Care Med 2002;166:939-944.
68 Niven R. The endotoxin paradigm: a note of caution. Clin Exp Allergy 2003;33:273-276.
69 Simpson A, Custovic A. Pets and the development of allergic sensitization. Curr Allergy Asthma Rep 2005;5:212-220.
70 Chen CM, Rzehak P, Zutavern A, Fahlbusch B, Bischof W, Herbarth O, et al. Longitudinal study on cat allergen exposure and the development of allergy in young children. J Allergy Clin Immunol 2007;119:1148-1155.
71 Chen CM, Morgenstern V, Bischof W, Herbarth O, Borte M, Behrendt H, et al. Dog ownership and contact during childhood and later allergy development. Eur Respir J 2008;31:963-973.
72 Rigotti E, De Luca G, Boner AL. Dog ownership might exert a protective effect on wheezing and atopy independently by endotoxin exposure. Clin Exp Allergy 2009;39:299.
73 Bufford JD, Reardon CL, Li Z, Roberg KA, DaSilva D, Eggleston PA, et al. Effects of dog ownership in early childhood on immune development and atopic diseases. Clin Exp Allergy 2008;38:1635-1643.
74 Litonjua AA, Milton DK, Celedon JC, Ryan L, Weiss ST, Gold DR. A longitudinal analysis of wheezing in young children: the independent effects of early life exposure to house dust endotoxin, allergens, and pets. J Allergy Clin Immunol 2002;110:736-742.
75 Wright AL. Early dog exposure: potential pathways to allergic disease. Clin Exp Allergy 2008;38:1568-1571.
Received December 22, 2008 Accepted after revision February 26, 2009
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