| |
Controversial role of pets in the development of atopy in children
Andrew Fretzayas, Doxa Kotzia, Maria Moustaki
Athens, Greece
Author Affiliations: Third Department of Pediatrics, "Attikon" University Hospital, School of Medicine, University of Athens, Athens, Greece (Fretzayas A, Kotzia D, Moustaki M)
Corresponding Author: Andrew Fretzayas, MD, PhD, Professor of Pediatrics, 3rd Department of Pediatrics, "Attikon" University Hospital, Athens University School of Medicine, 1 Rimini str, Haidari, Athens 12462, Greece (Tel: 00302105832228; Fax: 00302105832229; Email: mar.moustaki@gmail.com)
doi: 10.1007/s12519-013-0412-6
Background: Exposure to environmental allergens originating from different sources has been implicated in the sensitization to the respective allergens and development of atopic diseases. Keeping domestic animals is associated with exposure to relevant allergens but there are controversial data whether this exposure promotes or protects from the development of atopy.
Data sources: We herein reviewed the literature regarding the available data for the exposure to pets (cats and/or dogs) and the development of atopy. For this purpose, we searched the PubMed database.
Results: This review attempts to answer the following questions that arise from the daily practice and the relevant studies, which are: a) is pet keeping associated with sensitization? b) is there an association between keeping pets and the development of asthma, allergic rhinitis and eczema, and, c) what is the underlying mechanism of any possible protective association? Despite the fact that several studies and meta-analyses have been conducted to explore the role of pets in the development of atopy, there are still conflicting pieces of evidence. It seems that there are different effects depending on the type of pets, the time and duration of exposure, and the genetic background of the individual.
Conclusion: Further appropriately designed birth cohort studies are needed to explore whether exposure to relevant allergens from pets promotes or protects from the development of atopy.
Key words: allergic rhinitis asthma; atopic dermatitis; atopy; pet keeping
World J Pediatr 2013;9(2):112-119
Introduction
Exposure to environmental allergens has been implicated in the sensitization to the respective allergens and development of atopic diseases, such as allergic rhinitis, asthma and atopic dermatitis. In particular, keeping domestic animals is associated with exposure to relevant allergens and therefore it is speculated that it may contribute to the development of atopy[1-3] or may aggravate the symptoms of atopic subjects.[4-6] However, there are also data deriving mainly from epidemiological studies, indicating that exposure to pets in early childhood may be a protective factor for the development of atopy.[7-9] As there are controversial data from different studies investigating a possible association of atopy with exposure to pets, meta-analyses[10-12] have been conducted in order to clarify this issue.
The questions that arised from this everyday practice and the respective studies are as follows: a) is keeping pets associated with sensitization? b) is there an association between pet keeping and the development of asthma, allergic rhinitis and eczema? c) what is the underlying mechanism of any possible protective association?
This review attempts to answer the abovementioned questions, based on relevant studies and meta-analyses, in order to clarify which questions are adequately answered and which need further investigation.
Is keeping cats or dogs associated with sensitization?
Cats and dogs are the most common domestic animals. Their main allergens are Felis domesticus allergen 1 and Felis domesticus allergen 4 (Fel d 1 and Fel d 4)[13] for cats and Canis familiaris allergen 1 and Canis familiaris allergen 2 (Can f 1 and Can f 2)[14] for dogs. They are disseminated by small particles, which remain in the air and adhere to surfaces and clothes. These properties result in widespread dissemination of the allergens, even in workplaces where there are no pets, i.e. in schools, where they are carried via clothes of children who keep a pet at home.[15] This is important in areas where pet keeping at home is a very common practice.
Several studies have been conducted[1,16-19] investigating the relationship between exposure to dogs and sensitization to the corresponding allergens, using either skin tests or levels of serum specific-immunoglobulin IgE (Table 1). Most studies concluded that there is no correlation between the two.[1,16-18] On the contrary, a limited number of studies suggested a lower risk of sensitization to dog allergens at the age of 7 years among children whose family used to keep a dog, particularly during infancy.[19] It was also recently shown that among males, those with a domestic dog in the first year of life had half the risk of being sensitized to dogs at the age of 18 years compared with those who did not have an indoor dog in the first year.[28]
However, results of exposure to cats are conflicting. This inconsistency can be justified, to some extent, by the fact that many studies have been conducted to explore sensitization to cats compared with dogs. At least six studies[16,18-20,25,27] failed to prove increased sensitization to cats in people who were living with a cat. Some studies[21,22] have shown a reduced risk of sensitization to cats among people who owned one as a pet. A recent study[28] showed half the risk of being sensitized to cats at 18 years of age among teens keeping an indoor cat in the first year of life.
On the other hand, studies[23,24,26] suggested an increased risk of sensitization to cats among owners. Furthermore, the European Community Respiratory Health Survey (ECRHS)[21] showed that the sensitization rate to cats among non-cat owners was higher in countries with higher rates of cat ownership. There was an increased risk of sensitization to cats among non-cat-owning school children who attended a school class with cat owners.[25]
A significant point underlined by Ownby et al[19] was that exposure to two or more cats or dogs during the first year of life was associated with reduced incidence of allergic sensitization to other allergens at the age of six to seven years. In a population, however, where at least one parent had an atopic history, only exposure to a dog during the first year of life was associated with the reduced risk of allergic sensitization to foods and air-borne allergens at the age of one year.
In 2005, a critical review[29] that studied the development of allergic sensitization in relation to pet keeping concluded that the results for cats are quite inconsistent. It seems, however, that there is no association between sensitization and dog keeping, whereas a protective role of dog ownership cannot be ruled out. A recent pooled analysis[30] from 11 European birth cohorts showed that dog ownership during the first two years of life reduced the odds of sensitization to more than one aeroallergen at the age of six to ten years [odds ratio (OR)=0.45-0.65]. For cat ownership there was a similar trend that was not statistically significant.
Further studies from different countries may clarify the situation, if data regarding outdoor or indoor pet keeping are taken into account as well as pet avoidance behaviour and the age and duration of exposure to cats.
It is obvious that the issue of sensitization in relation to cat ownership has not been resolved. It seems, however, that dog ownership in childhood may either be irrelevant or even protective against sensitization to dogs and/or other aeroallergens, whereas it has not been clarified how cat ownership contributes (as a risk or protective factor) to sensitization to cats and other aeroallergens in the future.
Is there an association between keeping pets and the development of asthma, allergic rhinitis and eczema?
Pet ownership by asthmatic individuals already sensitized to cat or dog allergens aggravates the severity of asthma,[31-33] as documented by the frequency of symptoms, use of medicines, reduced respiratory function and increased bronchial hyperactivity in asthmatic children and adults (Table 2).
However, a different field of research is whether pet ownership predisposes to the development of asthma or wheezing. It has been proven that people experiencing symptoms of asthma tend to eliminate pets from the home in order to control the symptoms of their diseases. This tendency of asthmatic people may cover a correlation between the occurrence of asthma and pets. A decade ago, a meta-analysis from Apelberg et al,[12] including studies containing data on exposure to pets (cats and/or dogs or other furry pets, before the onset of asthma), concluded that early exposure to pets increases the risk of asthma and wheezing in children over six years old. They also reached the conclusion of a lower risk of wheezing by exposed children under the age of six years, which may be interpreted as the result of the possibility of avoidance of maintaining domestic animals in families with an allergic history. However, it is impossible to extract conclusions for cats and dogs separately on the basis of this systematic review.
A more recent meta-analysis[10] concluded that exposure to dogs slightly increases the risk of asthma [OR=1.14, 95% confidence interval (CI)=1.01-1.29], while exposure to cats has a mild protective role (OR=0.79, 95% CI=0.68-0.93). A protective role of exposure to pets as a whole was also identified, regardless of their nature, for the manifestation of allergic rhinitis (OR=0.79, 95% CI=0.68-0.93). However, the previously mentioned pooled analysis of 11 birth cohorts[30] found no association between dog or cat ownership during the first two years of life and asthma or allergic rhinitis at school age.
The results of the different studies are summarized in Table 3. An interesting comment was made by the ECRHS.[39] This survey showed that among those who do not keep cats, while living in communities where cat ownership is common, there is no increased asthma risk. But for individuals who lived in areas with low public exposure to cats, cat ownership was associated with an increased risk of asthma.
In some studies, a family history of atopy seems to affect the association between exposure to pets and asthma. Exposure to cats reduces the risk of wheezing in children aged one to five years of age without a maternal atopic history, but increases the risk of wheezing in children aged three to five years with a positive maternal history of atopy.[35] Moreover, no association was found between dog ownership and wheezing development in toddlers, irrespective of the family history of atopy. Accordingly, the Asthma Multicenter Infants Cohort Study[41] found an interaction between amounts of the Fel d 1 in household dust, maternal asthma, and the occurrence of wheezing at four years of age [relative risk (RR)=2.77, 95% CI=1.19-6.46]. The Tucson study[9] also followed 1246 children from birth until the age of 13 years and concluded that only the presence of a dog as a pet was associated with a reduced risk of wheezing at the age of 13 years, and that there was no family history of asthma. All these studies converge on the conclusion that inheritance is likely to alter the effect of keeping pets with respect to the development of wheezing.
An interesting study[36] from Beijing, where the incidence of asthma is lower than that in Western countries, pointed out that simultaneous ownership of a cat and a dog increased the risk of asthma in children aged 6 to 10 years old (OR=1.5, 95% CI=1.0-2.3). Similar effect was not observed in families that had only a dog or a cat. This statement makes it likely that increased intensity of exposure to allergens by the simultaneous maintenance of a cat or a dog proliferates the risk of wheezing. However, these findings were in total contrast to those from a recent study[27] from New Zealand, the results of which showed that the simultaneous maintenance of a cat or a dog during childhood protects against the onset of atopy at the age of 13 years, while maintaining only a cat or a dog was not protective.
On the other hand, Remes et al[9] underscored the low risk of wheezing in children with continual exposure to dogs. Conversely, removal of the dog by the age of 3 or 6 years led to an increased chance of wheezing. The protective role of the continual presence of pets from birth until the age of 5 to 7 years against the development of wheezing in childhood has also been shown by Oberle et al,[40] who included all pets (cats, dogs, rabbits, guinea pigs, hamsters). When they analysed the impact of each type of domestic animals, they found that only continuous exposure to a cat entering a child's bedroom was associated with a reduced risk of wheezing. From these studies, it is likely that a possible protective role of domestic animals depends on early and constant exposure to them.
There were also studies, mostly birth cohorts, which investigated the impact of pets in more than one atopic disorder. In Norway,[34] monitoring of children from birth until the age of 4 years showed that the inclusion of any pet from birth reduced the risk of allergic rhinitis at the age of 4 years and atopic dermatitis for the first 6 months of life. In Sweden,[22] keeping pets from birth is associated with a lower incidence of allergic rhinitis at the age of 7 to 8 years (5.9% vs. 9.5%, P=0.016) and a lower frequency of asthma (3.3% vs. 10%, P<0.001) in children at the age of 12 to 13 years. In Germany,[37] school-aged children with continuous contact with a dog, but not with a cat, during the first year of life was associated with a reduction in allergic rhinitis (OR=0.61, 95% CI=0.39-0.95), eczema (OR=0.76, 95% CI=0.61-0.94) and sensitization to pollen (OR=0.56, 95% CI=0.38-0.80).
Several studies have shown an association between early exposure to pets and a reduced frequency of atopic dermatitis.[38,42] In Germany, Zirngibl et al[38] found that keeping any domestic animal, especially a dog, was linked to a low likelihood of developing atopic dermatitis during the first two years of life.
A recent meta-analysis[11] showed that the inclusion of a cat or a dog or any furry pet was associated with a lower risk of atopic dermatitis (OR=0.76, 0.62, 0.79, respectively). However, it also commented on the fact that the studies did not contain information about avoidance behaviour.
One of the latest birth cohort studies, exploring interactions between genetic and environmental factors that influence the risk of eczema, was published by Biagini Myers et al.[43] The CCAAPS study, after examining 762 high-risk children, assumed that specific genotypes and early food allergens favour the occurrence of eczema, whereas early dog ownership could work in an inverse way.
The largest cross-sectional population study[44] from Germany (17 641 children, from birth until 17 years old) determined factors that increase the risk of eczema. Among them, familial allergies (especially a history of eczema), breastfeeding, jaundice and perinatal infection as well as foreign nationality, male gender, and high socioeconomic status act in a positive way, but to a minor extent. Pet keeping was not significantly related to eczema.
Further birth cohort and cross sectional studies are needed to investigate the role of dogs and cats in development of wheezing in relation to its phenotype (transient or late onset), the period of first exposure to a pet, the duration of exposure, the family history of atopy and the possibility of avoidance behavior, as randomized control studies are not a plausible model for this investigation.
It seems that the role of pet ownership for the development of atopic symptoms is not consistent between different studies. There is evidence supporting that dogs may play either an indifferent or a protective role, whereas there are major inconsistencies in the results for pet cats.
What is the underlying mechanism of any protective association?
Data[45] support the idea that chronic exposure to high concentrations of cat allergens can promote a modified T-helper 2 (Th-2) response. This response consists of a reduction in specific IgE immunoglobulins and an increase in specific IgG immunoglobulins, especially IgG4. This modified response suggested a form of immunological tolerance, although no protective action of IgG4 has been proven against the onset of atopic disease.[45-48]
The existence of domestic pets, rural conditions, gas heating and breast-feeding also seem to tilt the balance between T-helper 1 (Th-1) and Th-2 dependent immune-responses toward the Th-1 side.[44] Duramad et al[49] found that exposure to pets and breast-feeding from birth increases the Th1 response using interferon-¦Ã and interleukin-4 as markers of Th-1 and Th-2 responses, respectively.
Many surveys have investigated the interaction between polymorphisms of CD14, TLR 4, CARD 4 and atopy after exposure to microbial molecules. Bottema et al,[50] after mingling findings from three Dutch cohort studies, detected important roles for interleukin-13 and CD14 polymorphisms, as well as exposure to environmental factors (smoking and animals), in the onset of allergic diseases by measuring IgE (total and specific) at certain ages. Eder et al[51] also found that the C allele of CD14/-260 was associated with higher values of total IgE and specific IgE to aeroallergens in children with exposure to pets, whereas the opposite association was found in children with exposure to stable animals. The investigators assumed that children in contact with pets were exposed to microbial products different from those to which children in contact with stable animals were exposed. The genotype at CD14 locus also seems to play a role in the development of atopic dermatitis in infancy,[52] as infants with the genotype -159TT were less likely to develop atopic dermatitis if they kept a dog at home.
Bisgaard et al,[53] using findings from two birth cohort studies in Denmark and the United Kingdom, demonstrated that children with deficient filaggrin function were more prone to develop eczema after contacting with a cat. The mechanism explaining this observation remains to be clarified.
It seems that although pet ownership as a contributing factor to the development of atopic symptoms is easily explicable through exposure to allergens, its possible protective role is not fully understood. Possibly, the type of the role of pet ownership in the development of atopy depends on genetic predisposition, which is, to some extent, reflected in the family's atopic history.
Conclusions
The role of cats or dogs in the development of atopic disorders needs further investigation in terms of the type of atopy, the genetic profile of the individual, the species of pet, and the period and duration of exposure to a pet. There are insufficient data to support either avoiding domestic pet ownership in order to prevent atopy, especially in non-atopic families, or beginning pet ownership in order to reduce the risk of atopy development.
Funding: Not needed.
Ethical approval: Not needed.
Competing interest: No conflict of interest to be disclosed.
Contributors: Fretzayas A was responsible for the concept and the structure of the review, and made critical revisions of the manuscript. Kotzia D and Moustaki M contributed to the literature searching and the drafting of the manuscript.
References
1 Brussee JE, Smit HA, van Strien RT, Corver K, Kerkhof M, Wijga AH, et al. Allergen exposure in infancy and the development of sensitization, wheeze, and asthma at 4 years. J Allergy Clin Immunol 2005;115:946-952.
2 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.
3 Heissenhuber A, Heinrich J, Fahlbusch B, Borte M, Wichmann HE, Bolte G, et al. Health impacts of second-hand exposure to cat allergen Fel d 1 in infants. Allergy 2003;58:154-157.
4 Gent JF, Belanger K, Triche EW, Bracken MB, Beckett WS, Leaderer BP. Association of pediatric asthma severity with exposure to common household dust allergens. Environ Res 2009;109:768-774.
5 Langley SJ, Goldthorpe S, Craven M, Morris J, Woodcock A, Custovic A. Exposure and sensitization to indoor allergens: association with lung function, bronchial reactivity, and exhaled nitric oxide measures in asthma. J Allergy Clin Immunol 2003;112:362-368.
6 Plaschke P, Janson C, Balder B, Löwhagen O, Järvholm B. Adult asthmatics sensitized to cats and dogs: symptoms, severity, and bronchial hyperresponsiveness in patients with furred animals at home and patients without these animals. Allergy 1999;54:843-850.
7 Anyo G, Brunekreef B, de Meer G, Aarts F, Janssen NA, van Vliet P. Early, current and past pet ownership: associations with sensitization, bronchial responsiveness and allergic symptoms in school children. Clin Exp Allergy 2002;32:361-366.
8 Almqvist C, Garden F, Kemp AS, Li Q, Crisafulli D, Tovey ER, et al. Effects of early cat or dog ownership on sensitisation and asthma in a high-risk cohort without disease-related modification of exposure. Paediatr Perinat Epidemiol 2010;24:171-178.
9 Remes ST, Castro-Rodriguez JA, Holberg CJ, Martinez FD, Wright AL. Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy. J Allergy Clin Immunol 2001;108:509-515.
10 Takkouche B, Gonz¨¢lez-Barcala FJ, Etminan M, Fitzgerald M. Exposure to furry pets and the risk of asthma and allergic rhinitis: a meta-analysis. Allergy 2008;63:857-864.
11 Langan SM, Flohr C, Williams HC. The role of furry pets in eczema: a systematic review. Arch Dermatol 2007;143:1570-1577.
12 Apelberg BJ, Aoki Y, Jaakkola JJ. Systematic review: Exposure to pets and risk of asthma and asthma-like symptoms. J Allergy Clin Immunol 2001;107:455-460.
13 Duffort OA, Carreira J, Nitti G, Polo F, Lombardero M. Studies on the biochemical structure of the major cat allergen Felis domesticus I. Mol Immunol 1991;28:301-309.
14 de Groot H, Goei KG, van Swieten P, Aalberse RC. Affinity purification of a major and a minor allergen from dog extract: serologic activity of affinity-purified Can f I and of Can f I-depleted extract. J Allergy Clin Immunol 1991;87:1056-1065.
15 Berge M, Munir AK, Dreborg S. Concentrations of cat (Fel d1), dog (Can f1) and mite (Der f1 and Der p1) allergens in the clothing and school environment of Swedish schoolchildren with and without pets at home. Pediatr Allergy Immunol 1998;9:25-30.
16 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.
17 Lindfors A, van Hage-Hamsten M, Rietz H, Wickman M, Nordvall SL. Influence of interaction of environmental risk factors and sensitization in young asthmatic children. J Allergy Clin Immunol 1999;104:755-762.
18 Lodge CJ, Lowe AJ, Gurrin LC, Matheson MC, Balloch A, Axelrad C, et al. Pets at birth do not increase allergic disease in at-risk children. Clin Exp Allergy 2012;42:1377-1385.
19 Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. JAMA 2002;288:963-972.
20 Munir AK, Kjellman NI, Björkst¨¦n B. Exposure to indoor allergens in early infancy and sensitization. J Allergy Clin Immunol 1997;100:177-181.
21 Roost HP, K¨¹nzli N, Schindler C, Jarvis D, Chinn S, Perruchoud AP, et al. Role of current and childhood exposure to cat and atopic sensitization. European Community Respiratory Health Survey. J Allergy Clin Immunol 1999;104:941-947.
22 Hesselmar B, Aberg N, Aberg B, Eriksson B, Björkst¨¦n B. Does early exposure to cat or dog protect against later allergy development? Clin Exp Allergy 1999;29:611-617.
23 Mel¨¦n E, Wickman M, Nordvall SL, van Hage-Hamsten M, Lindfors A. Influence of early and current environmental exposure factors on sensitization and outcome of asthma in pre-school children. Allergy 2001;56:646-652.
24 Custovic A, Simpson BM, Simpson A, Kissen P, Woodcock A; NAC Manchester Asthma and Allergy Study Group. Effect of environmental manipulation in pregnancy and early life on respiratory symptoms and atopy during first year of life: a randomised trial. Lancet 2001;358:188-193.
25 Ritz BR, Hoelscher B, Frye C, Meyer I, Heinrich J. Allergic sensitization owing to 'second-hand' cat exposure in schools. Allergy 2002;57:357-361.
26 Perzanowski MS, Chew GL, Divjan A, Johnson A, Goldstein IF, Garfinkel RS, et al. Cat ownership is a risk factor for the development of anti-cat IgE but not current wheeze at age 5 years in an inner-city cohort. J Allergy Clin Immunol 2008;121:1047-1052.
27 Mandhane PJ, Sears MR, Poulton R, Greene JM, Lou WY, Taylor DR, et al. Cats and dogs and the risk of atopy in childhood and adulthood. J Allergy Clin Immunol 2009;124:745-750.
28 Wegienka G, Johnson CC, Havstad S, Ownby DR, Nicholas C, Zoratti EM. Lifetime dog and cat exposure and dog- and cat-specific sensitization at age 18 years. Clin Exp Allergy 2011;41:979-986.
29 Simpson A, Custovic A. Pets and the development of allergic sensitization. Curr Allergy Asthma Rep 2005;5:212-220.
30 Lødrup Carlsen KC, Roll S, Carlsen KH, Mowinckel P, Wijga AH, Brunekreef B, et al. Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts. PLoS One 2012;7:e43214.
31 Gent JF, Belanger K, Triche EW, Bracken MB, Beckett WS, Leaderer BP. Association of pediatric asthma severity with exposure to common household dust allergens. Environ Res 2009;109:768-774.
32 Langley SJ, Goldthorpe S, Craven M, Morris J, Woodcock A, Custovic A. Exposure and sensitization to indoor allergens: association with lung function, bronchial reactivity, and exhaled nitric oxide measures in asthma. J Allergy Clin Immunol 2003;112:362-368.
33 Plaschke P, Janson C, Balder B, Löwhagen O, Järvholm B. Adult asthmatics sensitized to cats and dogs: symptoms, severity, and bronchial hyperresponsiveness in patients with furred animals at home and patients without these animals. Allergy 1999;54:843-850.
34 Nafstad P, Magnus P, Gaarder PI, Jaakkola JJ. Exposure to pets and atopy-related diseases in the first 4 years of life. Allergy 2001;56:307-312.
35 Celed¨®n JC, Litonjua AA, Ryan L, Platts-Mills T, Weiss ST, Gold DR. Exposure to cat allergen, maternal history of asthma, and wheezing in first 5 years of life. Lancet 2002;360:781-782.
36 Zheng T, Niu S, Lu B, Fan X, Sun F, Wang J, et al. Childhood asthma in Beijing, China: a population-based case-control study. Am J Epidemiol 2002;156:977-983.
37 Hölscher B, Frye C, Wichmann HE, Heinrich J. Exposure to pets and allergies in children. Pediatr Allergy Immunol 2002;13:334-341.
38 Zirngibl A, Franke K, Gehring U, von Berg A, Berdel D, Bauer CP, et al. Exposure to pets and atopic dermatitis during the first two years of life. A cohort study. Pediatr Allergy Immunol 2002;13:394-401.
39 Svanes C, Heinrich J, Jarvis D, Chinn S, Omenaas E, Gulsvik A, et al. Pet-keeping in childhood and adult asthma and hay fever: European community respiratory health survey. J Allergy Clin Immunol 2003;112:289-300.
40 Oberle D, von Mutius E, von Kries R. Childhood asthma and continuous exposure to cats since the first year of life with cats allowed in the child's bedroom. Allergy 2003;58:1033-1036.
41 Polk S, Sunyer J, Muñoz-Ortiz L, Torrent M, Figueroa C, Harris J, et al. A prospective study of Fel d1 and Der p1 exposure in infancy and childhood wheezing. Am J Respir Crit Care Med 2004;170:273-278.
42 Phipatanakul W, Celed¨®n JC, Raby BA, Litonjua AA, Milton DK, Sredl D, et al. Endotoxin exposure and eczema in the first year of life. Pediatrics 2004;114:13-18.
43 Biagini Myers JM, Wang N, LeMasters GK, Bernstein DI, Epstein TG, Lindsey MA, et al. Genetic and environmental risk factors for childhood eczema development and allergic sensitization in the CCAAPS cohort. J Invest Dermatol 2010;130:430-437.
44 Apfelbacher C, Diepgen TL, Schmitt J. Determinants of eczema: population-based cross-sectional study in Germany. Allergy 2011;66:206-213.
45 Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 2001;357:752-756.
46 Hesselmar B, Aberg B, Eriksson B, Björkst¨¦n B, Aberg N. High-dose exposure to cat is associated with clinical tolerance--a modified Th2 immune response? Clin Exp Allergy 2003;33:1681-1685.
47 Erwin EA, Wickens K, Custis NJ, Siebers R, Woodfolk J, Barry D, et al. Cat and dust mite sensitivity and tolerance in relation to wheezing among children raised with high exposure to both allergens. J Allergy Clin Immunol 2005;115:74-79.
48 Lau S, Illi S, Platts-Mills TA, Riposo D, Nickel R, Gr¨¹ber C, et al. Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood--report of the German Multicentre Allergy Study (MAS 90). Allergy 2005;60:766-773.
49 Duramad P, Harley K, Lipsett M, Bradman A, Eskenazi B, Holland NT, et al. Early environmental exposures and intracellular Th1/Th2 cytokine profiles in 24 month-old children living in an agricultural area. Environ Health Perspect 2006;114:1916-1922.
50 Bottema RW, Reijmerink NE, Kerkhof M, Koppelman GH, Stelma FF, Gerritsen J, et al. Interleukin 13, CD14, pet and tobacco smoke influence atopy in three Dutch cohorts: the allergenic study. Eur Respir J 2008;32:593-602.
51 Eder W, Klimecki W, Yu L, von Mutius E, Riedler J, Braun-Fahrländer C, et al. Opposite effects of CD 14/-260 on serum IgE levels in children raised in different environments. J Allergy Clin Immunol 2005;116:601-607.
52 Gern JE, Reardon CL, Hoffjan S, Nicolae D, Li Z, Roberg KA, et al. Effects of dog ownership and genotype on immune development and atopy in infancy. J Allergy Clin Immunol 2004;113:307-314.
53 Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, et al. Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 2008;5:e131.
Received September 22, 2012 Accepted after revision March 15, 2013
|
