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Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review

Risk and Protective Factors for the Development of Childhood Asthma Guodong Ding 1,2, Ruoxu Ji 1, Yixiao Bao 1,* 1 2

Department of Pediatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China MOE and Shanghai Key Laboratory of Children’s Environment Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

EDUCATIONAL AIMS 1. Asthma, as a complex disease, has a broad spectrum of potential determinants ranging from genetics to environmental and lifestyle-related factors. 2. Despite evidence indicating that many factors are probably associated with the onset of childhood asthma, the relationships are not considered causal. 3. Only environmental tobacco smoke has been associated with an increased risk for the development of childhood asthma.

A R T I C L E I N F O

S U M M A R Y

Keywords: Childhood asthma Development Risk factor Protective factor Environment Lifestyle

Childhood asthma prevalence worldwide has been increasing markedly over several decades. Various theories have been proposed to account for this alarming trend. The disease has a broad spectrum of potential determinants ranging from genetics to lifestyle and environmental factors. Epidemiological observations have demonstrated that several important lifestyle and environmental factors including obesity, urban living, dietary patterns such as food low in antioxidants and fast food, non-breastfeeding, gut flora imbalance, cigarette smoking, air pollution, and viral infection are associated with asthma exacerbations in children. However, only environmental tobacco smoke has been associated with the development of asthma. Despite epidemiological studies indicating that many other factors are probably associated with the development of asthma, the relationships are not considered causal due to the inadequate evidence and inconsistent results from recent studies. This may highlight that sufficient data and exact mechanisms of causality are still in need of further study. ß 2014 Published by Elsevier Ltd.

INTRODUCTION Over recent decades, the prevalence of childhood asthma has been dramatically increasing globally, but the etiology of the disease is still not well understood. Asthma incidence among U.S. children increased from 3.6% in 1980 to 5.8% in 2003, and it is the third highest cause of hospitalization, exceeded only by pneumonia and injuries [1]. Increases in the prevalence of asthma with similar or even greater magnitude were also reported from

* Corresponding author. Department of Pediatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092 Shanghai, China. Tel.: +86-21-25078300. E-mail address: [email protected] (Y. Bao).

many other developed countries such as the U.K., Germany, Canada, and Australia [1]. Although asthma is generally less common in developing countries than in developed countries, the prevalence is increasing as they become more westernized or communities become urbanized. Such a transition is currently taking place in China at a much higher speed and during a shorter period than in many other countries [2]. The second nationwide survey in 2000 revealed that the prevalence of asthma among Chinese children 0 14 years old was 1.97%, nearly 2 times of that in 1990 (1.00%), suggesting an increasing trend [3]. Asthma, as a complex disease, has a broad spectrum of potential determinants ranging from genetics to environmental and lifestyle factors. However, this rapidly increasing incidence worldwide cannot be explained by genetic causes alone, as genetic changes require many generations for population-wide effects to occur. Evidence

http://dx.doi.org/10.1016/j.prrv.2014.07.004 1526-0542/ß 2014 Published by Elsevier Ltd.

Please cite this article in press as: Ding G, et al. Risk and Protective Factors for the Development of Childhood Asthma. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.07.004

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has shown that environmental and lifestyle factors are likely to be key events in explaining the overall increasing trend toward asthma prevalence [4]. In this report, we aimed to provide the data relating several important lifestyle and environmental factors, and to discuss their possible association with the development of childhood asthma.

in a rural or urban location [11]. These factors may partly explain why there were no differences in asthma prevalence in rural and urban areas from several studies [14,15]. However, not all farming environments are associated with protection against allergies. The multicenter PARSIFAL study revealed that exposure to sheep farming was associated with increased risk of allergies, but the explanation for this association remained to be explored [16].

Lifestyle Factors Overweight/obesity Recently, the prevalence of both asthma and obesity in children have increased substantially in many countries. The parallel rise in prevalence of both disorders and the coexistence of both asthma and obesity has led interest in the association between the two epidemics [5]. A number of epidemiological studies in children have examined the relationship of obesity or overweight with asthma, and many studies support a positive association between body mass index (BMI) and asthma. Chinn performed a comprehensive review and found that obesity increases the risk of subsequent asthma, although no evidence supports the hypothesis that asthma leads to increased obesity [6]. Flaherman and Rutherford conducted a meta-analysis and found that high birth weight had a pooled relative risk of 1.2 for the subsequent development of asthma, and further calculated a population attributable risk of 0.066 [7]. It should be noted that children and adolescents or boys and girls were considered together in many previous studies which did not divide children on age or gender. One problem exists here that does not exist in the adult studies, which is in the definition of weight for height in children and, more particularly, in the cut-off points used to define overweight and obesity [8]. In children, adult BMI cut-off points are not an accurate measure of body fatness because BMI changes with age, requiring age-specific cut-off points [5]. Unfortunately, until now there has been no standardized definition of overweight and obesity in children to correspond with the adult cut-off points. The other problem is that sex may be an important confounding factor in the study of obesity and asthma. However, the data is conflicting as to whether the association of BMI with asthma is affected by gender. A prospective study revealed that among overweight children, the risk of newonset asthma was evident among boys but not in girls [9]. In contrast, another birth cohort study showed that, girls, but not boys, who became overweight were seven times more likely to develop asthma [10]. Urban/rural area Many epidemiological studies in the past decade have consistently documented that children living in rural areas seem to be at lower risk of asthma than their urban counterparts; moreover, children living in a rural areas are at decreased risk of developing asthma [11]. For example, rural Chinese children had significantly lower prevalence of asthma and atopic sensitization than urban children, using the validated ISAAC (International Study of Asthma and Allergies in Childhood) questionnaire and objective skin-prick tests [12]. Another large study in the U.S. pediatric Medicaid population found that the rural children had increased asthma prevalence and similar asthma morbidity compared with urban children [13]. These results support the hygiene theory, early exposure to infection for children may confer an advantage by regulating the immune system to protect against allergies so as to reduce the future risk of asthma. Although the underlying mechanisms behind this apparent protective effect of rural/farm living are not well understood, the overall consensus is that environmental factors and socioeconomic issues predispose people to asthma. It appears that places that share similar environmental and socioeconomic risk factors may have comparable prevalence of asthma regardless of whether it is

Diet (antioxidants) The antioxidant hypothesis was first proposed in 1994 by Seaton et al., who suggested that alteration in diet associated with westernization may be responsible for the increase in asthma prevalence [17]. Observations showed that consumption of foods rich in antioxidants had decreased in the UK diet while asthma prevalence concurrently rose. The transition from a traditional diet to a modern diet appeared to have resulted in a decrease in antioxidant intake [17]. Subsequently, many observational studies have focused on vitamin C, vitamin E, carotenoids, flavonoids, and minerals such as selenium and zinc, and typically these have reported low antioxidant intake to be associated with an increased incidence of childhood asthma [18,19]. However, not all studies on the role of antioxidants have been positive. A meta-analysis concluded that dietary intake of antioxidant vitamins C and E and b–carotene does not significantly influence the risk of asthma [20]. In addition, the potential role of antioxidants as supplements has been explored, but a number of studies have been inconclusive. A Cochrane review of vitamin C supplementation in asthma showed that there is insufficient evidence to recommend vitamin C supplementation in the treatment of asthma [21]. It should be noted that overall the body of observational evidence is inherently weak because of the biases and limitations of cross-sectional and case-control studies that predominate. These limitations include the difficulties in quantifying dietary intake, reverse causation, and lack a temporal element. Unfortunately, longitudinal data are very limited for antioxidants highlighted in studies of asthma. There is an urgent need for longitudinal studies to fill the gaps of information on the association of antioxidants with asthma. Diet (lipids) Black and Sharpe in 1997 proposed that the rise of asthma prevalence may stem from increased consumption of polyunsaturated fatty acids (PUFAs) and decreased consumption of saturated fat [22]. The v-6 PUFAs may particularly have a role in regulating immune response and inflammation. These PUFAs are found largely as linoleic acid in foods such as margarine and vegetable oils, which have increased in consumption with westernization [23]. Linoleic acid is a precursor of prostaglandin E2 that inhibits interferon-g and promotes an inflammatory environment which favors the development of asthma. Meanwhile, v-3 PUFAs from oily fish may have an anti-inflammatory role [23]. Therefore, atopic sensitization and inflammation could be promoted by increasing dietary intake of v-6 PUFAs and decreasing intake of v-3 PUFAs. A small number of epidemiological studies have examined the lipid hypothesis, but they reported inconsistent results. For example, in children aged 12 to 15 years, atopic disease and atopic sensitization were associated with reduced v-3 PUFA and an increase in v-6/v-3 PUFA ratio. In addition, serum IgE levels were positively associated with v-6 PUFAs and negatively associated with serum eicosapentaenoic acids (EPAs) [24]. In contrast, Griese et al reported that plasma and mononuclear cell phospholipid EPA levels were positively associated with atopic asthma and serum IgE in children [25]. Although there is increasing interest in the use of dietary PUFA supplementation to prevent the development of asthma and atopic disease, it is disappointing that intervention studies have not found consistent results nor provided sufficient support for dietary supplementation with PUFAs [26,27].

Please cite this article in press as: Ding G, et al. Risk and Protective Factors for the Development of Childhood Asthma. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.07.004

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Early hypotheses analyzed population level trends and focused on major dietary factors such as antioxidants and lipids. More recently, larger dietary patterns beyond individual nutrients have been investigated such as fast foods and the Mediterranean diet [23]. A cross-sectional study of children aged 10 to 12 years in New Zealand revealed that hamburger consumption positively associated with asthma symptoms while takeaway consumption had a marginal effect on bronchial hyperresponsiveness [28]. On the other hand, the Mediterranean diet has been suggested as a healthy dietary pattern that may reduce the risk of asthma [29]. Despite the plethora of cross-sectional data about fast foods and the Mediterranean diet, there is a lack of longitudinal studies and analyses to form a causal link between these foods and asthma prevalence. Breastfeeding Many studies have demonstrated that breastfeeding, in addition to its nutritional and sociological benefits, provided a number of specific health benefits to the infant, including reduction of the incidence of allergy and childhood asthma [30]. A number of studies reported lower risks of asthma, atopic eczema, and positive allergy skin tests in breastfed children, or equivalently, higher risks in infants fed conventional cow milk- or soy-based formulas [31], and many of these studies reported a greater degree of protection with more exclusive and/or more prolonged breastfeeding [32,33]. The third NHANES study in the U.S. showed that compared with never breastfed children, ever breastfed children had significantly reduced odds of being diagnosed with asthma and of having recurrent wheeze before 24 months of age [34]. A multidisciplinary review from the Swedish National Institute of Public Health concluded that exclusive breastfeeding reduces the risk of developing asthma, and the protective effects increase with the duration of the breastfeeding up to at least 4 months of age [35]. Yet, several publications have challenged this view, particularly with respect to the long-term outcomes for asthma. Breastfeeding does not necessarily protect children against asthma and the magnitude of the effect is relatively modest, and may even increase the risk [36,37]. Sears et al. conducted a longitudinal study of children from New Zealand, and found an increased risk of asthma in children who were breastfed [38]. A total of 1037 children were recruited at birth and assessed at regular intervals from 9 years of age for the presence of asthma and atopy. Breastfeeding significantly increased the likelihood of current asthma at age 9 years (11% vs 5%), at 15 years (18% vs 11%), at 21 years (19% vs 13%), and at 26 years (23% vs 15%) [38]. These conclusions have been preeminent in raising concerns about the effects of breastfeeding on the development of asthma, and many scholars have raised several critical questions and challenged these conclusions [39]. First, the breastfeeding data were collected at age 3 years, which may indicate problems with the accuracy of recall. Second, individuals were classified as being breastfed if they had some breastfeeding for at least 4 weeks but most cohort studies classified as being breastfed had more than 12 weeks breastfeeding. Third, breastfeeding was not exclusive, as supplementation with formula at night was common in New Zealand. Evidence has shown that a beneficial effect of breastfeeding on allergic disease indicating that both the duration, and exclusivity are of importance. To date no plausible mechanism explains how breastfeeding could increase the risk of asthma. On the other hand, evidence has shown major benefits of breastfeeding for child neurodevelopment and chronic disease (e.g., obesity). It is thus important to consider that any decision not to breastfeed made in the light of possible adverse effects on the development of asthma is not well founded.

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Probiotics The human gastrointestinal tract is sterile at birth, rapidly undergoing colonization of the gut with subsequent development of the immune system. Variations in patterns of microbial colonization of the gastrointestinal tract, linked with lifestyle and geographic factors, may be important determinants of the heterogeneity in allergy prevalence throughout the world. Studies have shown that there are obvious differences in the composition of intestinal microbiota between healthy and allergic infants within the first week of life and before clinical symptoms for the latter group, suggesting that modifying microbiota composition may affect disease outcome [40]. Probiotics are increasingly marketed and used as health promoting agents, which mainly contain beneficial bacteria such as Lactobacilli and bifidobacteria. Several previous studies suggested that probiotics used as dietary supplements may be effective in preventing early atopy in children through the modulation of intestinal microbiota and the regulation of inflammatory response [41,42]. A recent cohort study shows that probiotic milk consumption in pregnancy is associated with a slightly reduced incidence of eczema and rhinoconjunctivitis, but not asthma, at 3 years of age [43]. Despite these findings indicating a beneficial effect of lactic acid-producing bacteria, many questions have been raised regarding optimal strains, dosages, timing and route of administration. Ongoing clinical trials are required before any recommendations can be given about the use of probiotics in the prevention or treatment of allergy. Environmental Exposure Environmental tobacco smoke/active smoking A number of epidemiological surveys support the role of environmental tobacco smoke (ETS) exposure in increasing the incidence of wheezing, airway hyperresponsiveness, and asthma in children [44,45]. In a population-based cohort study in Finland that included almost 60,000 children, the risk of developing asthma amongst children at 7 years of age increased in a dose-dependent manner with maternal smoking rates during pregnancy: OR 1.23 (95% CI 1 .07–1.42) for 10 cigarettes/day [44]. Consequently, a series of systematic reviews and meta-analyses provide compelling evidence of a causal relationship between parental smoking and the development of childhood asthma [46,47]. For example, Burke et al. identified over 70 studies examining the effect of exposure to pre- or post-natal passive smoke on the development of asthma, and reported a 21% to 85% increased risk of incident asthma. The strongest effect from prenatal maternal smoking on asthma in children aged  2 years had an OR of 1.85 (95% CI 1.3–2.5) [47]. It seems difficult to separate the effect of prenatal ETS exposure from the effect of postnatal ETS exposure because women who smoked during pregnancy are likely to continue smoking after delivery. Still, there is some evidence to indicate that the association between prenatal exposure to maternal smoking with wheeze and/ or asthma in children is stronger than that of postnatal exposure [48]. Among adolescents with asthma, exposure to tobacco smoke, not only by ETS but also by use of tobacco smoke products (active smoking), can cause increased asthma morbidity including reduced lung function and exacerbation of asthma symptoms [49,50]. Current asthma treatment guidelines recommend avoiding exposure to tobacco smoke, including both ETS and active smoking. However, most of previous studies have focused on active smoking and risk of developing asthma in adulthood. It is debated whether active smoking induces the development of asthma in adolescents. Few studies performed in adolescents have shown that active smoking increased the risk of new-onset of asthma

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during adolescence. In a prospective study including 2609 children with no lifetime history of asthma, Gilliland et al. found that children who were nonsmokers without any history of allergy and who became regular smokers later in life were 5.2 times more likely to develop asthma, but among those with a history of allergy there was little evidence of increased risk [51]. Building upon existing findings, exposure to passive smoking increases the risk of incident asthma in children. There is an need for more evidence to confirm whether active smoking in adolescents could increase the risk of developing asthma. Indoor air pollution Major categories of indoor pollutants include nitrogen dioxide (NO2), particulate matter (PM), and indoor allergens (e.g., dust mite, mouse, cockroach, and molds). NO2, a common air pollutant, is produced from high temperature combustion. Cooking with gas is by far the most important source of indoor NO2 levels in China and around the world [52]. Historically, several epidemiological studies evaluated the potential health effects of indoor NO2 exposure on childhood asthma by using the gas appliances as a surrogate for indoor NO2 levels, and many of these studies reported that the use of gas appliances was associated with an increased risk of asthma [53,54]. Recently, population-based studies with measured indoor NO2 and risk of developing asthma in children have emerged but produced inconsistent results, with some reporting a positive relationship [55] and others showing no association [56]. Despite recent indoor monitoring studies that have been performed to develop better exposure estimates for NO2, these approaches to quantifying exposure have severe limitations. Daily or weekly average exposures to NO2 were measured or estimated without error, but short term peak exposures were not adequately known. Indeed, the major sources of NO2 indoors are typically in use for only a few hours each day, and NO2 levels follow a spiked pattern with one hour maximum levels exceeding daily or weekly averages [57]. Animal studies suggested that repeated exposure to high NO2 levels for short periods of time is more harmful than continuous exposure to elevated NO2 levels at a lower level [58]. To sum up, populationbased studies in children observed less consistent results on the association between asthma and exposures to NO2, assessed by the presence of gas appliances or indoor nitrogen dioxide measurements. PM, consists of coarse PM10 and fine PM2.5, is a principal component of indoor air pollution. Indoor sources include cooking exhaust, wood-burning stoves and fireplaces, cleaning activities, and penetration of outdoor particles. Indoor PM differs from outdoor PM in source, composition, and concentration, and the health effects of indoor PM cannot be readily extrapolated from studies of outdoor air pollution. Previous studies and metaanalysis have indicated that exposure to high indoor (both coarse and fine) PM levels is associated with decreased lung function and respiratory symptoms in children with asthma [59,60]. However, few studies regarding indoor PM and the onset of asthma in children are available, and thus a causal link has not been established. Common indoor allergens include house dust mite, cockroach, animal dander, and certain molds. Evidence from epidemiological studies indicates that exposure to indoor allergen in sensitized individuals with asthma has clear implications on lung function and asthma severity [61,62]. The counterargument that reduction in indoor allergen exposure will result in improvement in asthma has been less convincing [63]. Although cross-sectional studies supported the hypothesis that allergen exposure causes asthma [64,65], the evidence is considered weak as confounder bias cannot be totally ruled out. Prospective studies may be better designed regarding the role of indoor allergens in the causation of asthma,

but many of them reported inconsistent results. In a large birth cohort from Germany, Lau et al. showed that no association was found between early indoor allergen exposure and the development of asthma or bronchial hyperresponsiveness in children observed up to 7 years of age [66]. In contrast, a recent study from the same cohort found that children who were sensitized and had high exposure to the relevant allergen were at high risk of persistent asthma and bronchial hyperresponsiveness in later childhood [67]. Therefore, evidence for the direct association between exposure to indoor allergens and the development of childhood asthma is available but not conclusive. Ambient air pollution With rapid urbanization in many communities, traffic (diesel) exhausts have become the major source of ambient/outdoor air pollution. Therefore, there have been a number of studies indicating that exposure to ambient air pollutants can exacerbate pre-existing asthma in children [68,69]. However, there are relatively few studies that address the issue of whether traffic exhausts may induce the development of asthma. Earlier studies have generally relied on simple measures of traffic proximity and density to estimate exposure and have not shown an association between air pollution and asthma incidence [70,71]. More recent studies have used modeling approaches that provide high-resolution estimates of neighborhood-scale variations in air pollution. Several studies using this approach have observed increases in asthma incidence for children exposed to higher levels of traffic-related air pollution [72,73]. However, not all such studies of this type have reported consistent associations [74]. For example, as part of an international collaborative research on the impact of Traffic-Related Air Pollution on Childhood Asthma, two cohort studies from Holland and Sweden showed a positive association [72,73], but another cohort study from Germany showed no association [74]. Thus, it may be accepted that ambient air pollution can exacerbate asthma in those who already have the condition. Whether air pollution can contribute to the development of asthma remains speculative due to the existing evidence for causal relationship being unconvincing. Viral infection Viral respiratory infections, particularly with respiratory syncytial virus (RSV) and human rhinovirus (HRV), are the most common causes of wheezing in infants and young children and are common triggers of asthma exacerbations in pediatric patients with preexisting asthma [75,76]. Whether these infections are causal in asthma development or simply identify predisposed children remains a controversial issue. Contrary to the concept that link infections in early life with subsequent wheezing, the hygiene hypothesis proposed that respiratory infections in early life were protective towards the development of asthma. However, this hypothesis has not been well supported by evidence, such as an increase of asthma in North American inner cities that are generally characterized by poor housing and dirty environments [77]. More recent studies indicate that exposure to non-pathogenic rather than pathogenic microbes would be more important in reducing the risk for asthma [78]. RSV lower respiratory tract illnesses in infancy, particularly those severe enough to lead to hospitalization, are associated with subsequent recurrent episodes of wheezing [79,80]. This association has prompted speculation that RSV lower respiratory illness may be causal in asthma development. In this regard, Sigurs et al. conducted a case-control study to examine the association between an RSV infection and the eventual development of asthma. They found that severe RSV bronchiolitis was associated with an increased risk of asthma at 13 years of age [81]. A large retrospective cohort study in Tennessee supported a causal role for RSV bronchiolitis during infancy on asthma inception [82].

Please cite this article in press as: Ding G, et al. Risk and Protective Factors for the Development of Childhood Asthma. Paediatr. Respir. Rev. (2014), http://dx.doi.org/10.1016/j.prrv.2014.07.004

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However, an association between RSV infection and asthma has not been seen in all investigations. A longitudinal data from the Tucson Children’s Respiratory Study suggested that RSV infections of the lower respiratory tract during the first 3 years of life were associated with subsequent wheezing and asthma in early childhood, but not beyond age 11 years [83]. Similarly, Thomsen et al. examined the relationship between severe RSV infection and development of asthma based on a registry-based twin study in Denmark, and found that severe RSV infection (enough to warrant hospitalization) does not cause asthma but is an indicator of the genetic predisposition to asthma [84]. With the development of molecular diagnostics, Human Rhinovirus (HRV) wheezing illnesses have been recognized more recently as a stronger predictor of developing asthma than RSV [85]. Several epidemiological observations have identified that infants hospitalized with HRV wheezing illnesses have a increased risk of developing asthma later in childhood. Kotaniemi-Syrja¨nen et al. conducted a long-term case-control study and found that HRV-induced wheezing episodes in infancy were highly predictive of subsequent asthma, and this relationship persisted at least through the late teen years [86]. This finding was subsequently confirmed by the results of one birth cohort study. The Childhood Origins of Asthma (COAST) study, a high-risk birth cohort examining the role of respiratory viruses in development of asthma, identified HRV wheezing illnesses during the first year of life as significant risk factors for wheezing in the third year of life [87] and asthma at age six years [88]. Collectively, early respiratory RSV infections such as RSV and HRV seem to be an important risk factor associated with shortterm recurrent wheeze, but whether RSV or HRV is causal in asthma inception is an open question. Despite existing evidence indicating that wheezing with HRV may be the most robust predictor of subsequent asthma, adequate data of causality are still in need of further study. Finally, it should be noted that asthma is a complex disease resulting from genetic and environmental interactions and epigenetic regulation is also a major contributor. It is well known that many individuals are predisposed to developing allergic reactions to substances that do not in general elicit an immune response, and these individuals are thought to be genetically predisposed to develop hypersensitivity to substances such as pollens and perfumes [89]. On the other hand, the environmental component is also critical, as supported by many studies documenting shifting asthma rates by geographical region and level of urbanization, and others documenting differences in disease incidence between monozygotic twins [90]. More and more emerging evidence suggests that epigenetic regulation following environmental exposures may underlie the interface between prenatal and early postnatal environmental exposure and the development of asthma [90]. Epigenetic changes can occur throughout life, but much of the epigenome is established during early development of the fetus. Several prenatal environmental exposures such as maternal smoking, dietary pattern, and microbial exposure have been shown to modify fetal immune function important to the later development of asthma and other allergic diseases [91–93]. How genes and environment exactly interact and then contribute to the development of allergic diseases is yet poorly understood, and the role of epigenetic regulation in asthma susceptibility is a new and promising area that needs further attention and better understanding. CONCLUSIONS Numerous risk and protective factors have been identified which could influence the likelihood of sensitization and trigger symptoms in already sensitized individuals. However, only one

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environmental factor (passive smoking) has been associated with an increased risk for the development of childhood asthma. Despite evidence indicates that many other factors are probably associated with the onset of asthma, the relationships are not considered causal due to the inadequate evidence and inconsistent results from current epidemiological studies. Childhood asthma probably has complex etiologies involving the interaction between the environment, genetic susceptibility, and chance (critical time windows). Equipped with this general understanding, a logical and essential step is to examine these factors simultaneously in an attempt to further elucidate the existing causal relationships for childhood asthma. As the development of asthma is probably multifactorial, there is a need for more large-scale studies that are capable of providing sufficient power to detect even modest associations with precision. References [1] Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006;355(21):2226–35. [2] Yang G, Kong L, Zhao W, Wan X, Zhai Y, Chen LC, Koplan JP. Emergence of chronic non-communicable diseases in China. Lancet 2008;372(9650):1697– 705. [3] National cooperation group on childhood asthma. A nationwide survey in China on prevalence of asthma in urban children [in Chinese]. Zhonghua Er Ke Za Zhi 2003;41(2):123–7. [4] Gern JE. The Urban Environment and Childhood Asthma study. J Allergy Clin Immunol 2010;125(3):545–9. [5] Story RE. Asthma and obesity in children. Curr Opin Pediatr 2007;19(6):680–4. [6] Chinn S. Obesity and asthma. Paediatr Respir Rev 2006;7(3):223–8. [7] Flaherman V, Rutherford GW. A meta-analysis of the effect of high weight on asthma. Arch Dis Child 2006;91(4):334–9. [8] Chinn S. Obesity and asthma: evidence for and against a causal relation. J Asthma 2003;40(1):1–16. [9] Gilliland FD, Berhane K, Islam T, McConnell R, Gauderman WJ, Gilliland SS, Avol E, Peters JM. Obesity and the risk of newly diagnosed asthma in schoolage children. Am J Epidemiol 2003;158(8):406–15. [10] Castro-Rodrı´guez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med 2001;163(6):1344–9. [11] Malik HU, Kumar K, Frieri M. Minimal difference in the prevalence of asthma in the urban and rural environment. Clin Med Insights Pediatr 2012;6:33–9. [12] Ma Y, Zhao J, Han ZR, Chen Y, Leung TF, Wong GW. Very low prevalence of asthma and allergies in schoolchildren from rural Beijing, China. Pediatr Pulmonol 2009;44(8):793–9. [13] Valet RS, Gebretsadik T, Carroll KN, Wu P, Dupont WD, Mitchel EF, Hartert TV. High asthma prevalence and increased morbidity among rural children in a Medicaid cohort. Ann Allergy Asthma Immunol 2011;106(6):467–73. [14] Priftis KN, Anthracopoulos MB, Nikolaou-Papanagiotou A, Matziou V, Paliatsos AG, Tzavelas G, Nicolaidou P, Mantzouranis E. Increased sensitization in urban vs. rural environment–rural protection or an urban living effect? Pediatr Allergy Immunol 2007;18(3):209–16. [15] Pesek RD, Vargas PA, Halterman JS, Jones SM, McCracken A, Perry TT. A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas. Ann Allergy Asthma Immunol 2010;104(2):125–31. [16] Ege MJ, Frei R, Bieli C, Schram-Bijkerk D, Waser M, Benz MR, Weiss G, Nyberg F, van Hage M, Pershagen G, Brunekreef B, Riedler J, Lauener R, Braun-Fahrla¨nder C, von Mutius E, PARSIFAL Study team. Not all farming environments protect against the development of asthma and wheeze in children. J Allergy Clin Immunol 2007;119(5):1140–7. [17] Seaton A, Godden DJ, Brown K. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994;49(2):171–4. [18] Harik-Khan RI, Muller DC, Wise RA. Serum vitamin levels and the risk of asthma in children. Am J Epidemiol 2004;159(4):351–7. [19] Rubin RN, Navon L, Cassano PA. Relationship of serum antioxidants to asthma prevalence in youth. Am J Respir Crit Care Med 2004;169(3):393–8. [20] Gao J, Gao X, Li W, Zhu Y, Thompson PJ. Observational studies on the effect of dietary antioxidants on asthma: a meta-analysis. Respirology 2008;13(4):528– 36. [21] Kaur B, Rowe BH, Arnold E. Vitamin C supplementation for asthma. Cochrane Database Syst Rev 2009;1:CD000993. [22] Black PN, Sharpe S. Dietary fat and asthma: is there a connection? Eur Respir J 1997;10(1):6–12. [23] Kim JH, Ellwood PE, Asher MI. Diet and asthma: looking back, moving forward. Respir Res 2009;10:49. [24] Yu G, Bjo¨rkste´n B. Polyunsaturated fatty acids in school children in relation to allergy and serum IgE levels. Pediatr Allergy Immunol 1998;9(3):133–8. [25] Griese M, Schur N, Laryea MD, Bremer HJ, Reinhardt D, Biggemann B. Fatty acid composition of phospholipids of plasma and of mononuclear blood cells in children with allergic asthma and the influence of glucocorticoids. Eur J Pediatr 1990;149(7):508–12.

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