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Allergic diseases among children: nutritional prevention and intervention

Allergic diseases comprise a genetically heterogeneous group of chronic, immunomediated diseases. It has been clearly reported that the prevalence of these diseases has been on the rise for the last few decades, but at different rates, in various areas of the world. This paper discusses the epidemiology of allergic diseases among children and their negative impact on affected patients, their families, and societies. These effects include the adverse effects on quality of life and economic costs. Medical interest has shifted from tertiary or secondary prevention to primary prevention of these chronic diseases among high-risk infants in early life. Being simple, practical, and cost-effective are mandatory features for any candidate methods delivering these strategies. Dietary therapy fits this model well, as it is simple, practical, and cost-effective, and involves diverse methods. The highest priority strategy is feeding these infants breast milk. For those who are not breast-fed, there should be a strategy to maintain beneficial gut flora that positively influences intestinal immunity. We review the current use of probiotics, prebiotics, and synbiotics, and safety and adverse effects. Other dietary modalities of possible potential in achieving this primary prevention, such as a Mediterranean diet, use of milk formula with modified (hydrolyzed) proteins, and the role of micronutrients, are also explored. Breast-feeding is effective in reducing the risk of asthma, allergic rhinitis, and atopic eczema among children. In addition, breast milk constitutes a major source of support for gut microbe colonization, due to its bifidobacteria and galactooligosaccharide content. The literature lacks consensus in recommending the addition of probiotics to foods for prevention and treatment of allergic diseases, while prebiotics may prove to be effective in reducing atopy in healthy children. There is insufficient evidence to support soy formulas or amino acid formulas for prevention of allergic disease. A healthy diet, such as the Mediterranean diet, may have a protective effect on the development of asthma and atopy in children. In children with asthma and allergic diseases, vitamin D deficiency correlates strongly with asthma, allergic rhinitis, and wheezing.


Background
Allergic diseases comprise a genetically heterogeneous group of chronic, immunomediated diseases 1,2 that mainly involve bronchial asthma, allergic rhinitis, atopic dermatitis, food allergy, and acute urticaria. They are more prevalent among children than adults. Worldwide, respiratory allergic diseases alone, namely asthma and allergic rhinitis, affect nearly 700 million subjects. 3 It has been clearly reported that the prevalence of these diseases has been on the rise for the last few decades, but at different rates, in various areas of the world. 3,4 Currently, bronchial asthma is considered the most common chronic, noninfectious condition among children. 4 In some industrialized countries, the prevalence of asthma is close to 35%-40%, whereas it is less than 5% in other communities; 5 furthermore, relatively new reports have shown that the prevalence of asthma is increasing in many low-and middle-income nations. 4 Hendaus et al The impact of allergic diseases is tremendous on affected individuals, their families, and societies. They adversely affect quality of life and increase the rate of comorbid conditions and risk of death, as noticed in asthma. 3,7 In addition, the economic burden of these diseases is considerable. This is usually related to the substantial direct medical cost (emergency department visits, physician's office visits, hospitalizations, diagnostic laboratory and radiological workup, and other modalities of therapy) and indirect medical costs (numerous absences from labor or school, reduced productivity, and diminished school performance). 3,[7][8][9] Allergic diseases are intricate diseases resulting from the interaction of genetic and environmental factors. 10 The latter include infectious agents (human rhinoviruses, respiratory syncytial virus, and mycoplasma), allergens (house dust mites, pollens, pets, and molds), pollutants, and medication exposure. [11][12][13] During the last 2 decades, primary prevention of allergic diseases and asthma (prevention of immunological sanitization, development of IgE antibodies) has proved to be a more effective strategy than secondary prevention (preventing the development of an allergic disease following sensitization) or tertiary prevention (treatment of asthma of allergic diseases). 14 As a strategy, primary prevention of allergic diseases includes 1) allergen avoidance, 2) restoration of gut microbiota-intestinal immunity relationship, 3) dietary pattern, 4) intake of modified dietary proteins in early life, and 5) micronutrients.
The Cochrane Library, Embase, Medline, and Google Scholar databases were searched in March 2015 (from inception to March 2015) for randomized controlled trials (RCTs), quasi-RCTs, and review articles that were published in English and Spanish. In addition, we searched the references of the identified articles for additional articles. We used a wide variety of different combinations of the following terms: allergy, primary, prevention, children, mothers, diet, milk, formula, breast-feeding, prebiotics, probiotics, synbiotics, Mediterranean, micronutrients, and fatty acids. We identified and reviewed 254 manuscripts, but filtered to 153 references ( Figure 1). This review paper focuses on primary prevention of allergic diseases in children.

Restoration of gut microbiotaintestinal immunity relationship
Since the allergy-high-risk infant (born to one or more allergic parent, and/or allergic sibling) is healthy, the strategy of preventing immunity alteration is aimed at the preservation of the "beneficial" gut microbiota in the newborn, and thus preventing deviations of the local intestinal immunity and consequently the systemic immunity to the proallergic side. To understand the rationale behind this preventive strategy, the bacterial colonization of gut, infant intestinal microbiota-intestinal immune interaction, and imbalances in the composition of the intestinal microbiota leading to allergic diseases have to be explored.

Gut microbiota, intestinal immunity, and allergic diseases
Microbial gut colonization typically commences at the time of birth, and is influenced by the load (inoculum) of the first maternal microbiota, type of delivery (cesarean section vs vaginal delivery), feeding practices (formula-feeding vs breast-feeding), and antimicrobial use. [15][16][17] The maternal intestinal microbiota clearly determines the type of infant's intestinal microbiota in the first few months of life. 18 Moreover, it takes a few months for the bacterial species to become steadily consistent, despite the early life complete colonization. 16,19 At the age of 1 month, infants born via cesarean section demonstrate similar numbers of gut bacteria to those who were vaginally delivered, but with higher rates of Clostridium spp., Klebsiella spp., Enterobacteriaceae, Bacteroides spp., Bifidobacterium spp., and Escherichia coli. 16,20,21 This effect extends

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Preventing allergies in children beyond the age of 6 months in infants born via cesarean section, 22 increasing the risk of atopy, asthma, and allergic rhinitis. 23 In normal breast-fed infants, Bifidobacterium spp. predominate the gut microbiota (60%-70%), compared to formula-fed infants, where Bacteroides and Clostridium spp. and Enterobacteriaceae prevail. 16,21 Perturbations in the intestinal microbial profile result in the reduction of the predominance of Bifidobacterium spp. or rise of unbeneficial microbiota, leading to increased risk of allergies, infections, 19 and other diseases. 24 In the newborn period, the gut microbiota plays a crucial role in promoting and maintaining the mucosal immune system, both in terms of its physical factors and function, and in maintaining a very well-balanced immune response. Gut-associated mucosal lymphoid tissue becomes reactive to pathogenic bacteria but tolerant to "beneficial" bacteria. Moreover, the intestinal microbiota plays an important role in the development of tolerogenic dendritic cells from the mesenteric lymph nodes of the gutassociated mucosal lymphoid tissue and in the production of secretory IgA. 25,26 The intestinal epithelia express various pathogenrecognition receptors, including Toll-like receptors and nucleotide-binding oligomerization domain-like receptors that activate immune response against pathogens. Since pathogenic bacteria and gut commensals express many of these pathogen-associated molecular patterns, there is tight control on the immune-response mechanisms so that it will recognize and specifically respond to pathogens, but at the same time remain tolerant to commensals. These mechanisms involve intestinal epithelial cells, Toll-like receptors, dendritic cells, and T-regulatory (T reg ) cells. 27 It is known that T-helper (Th)-2 cells are characterized by their production of IL-4, IL-5, IL-9, and IL-13, which contribute to the development of and maintenance of allergic inflammatory process, while Th1 cells produce TNFα and IFNγ, which contribute in the modulation of cell-mediated immunity. 27,28 T reg cells, however, maintain immunological tolerance due to their immunomodulatory or immunosuppressive capabilities, and are key players in regulating immune response in nondisease states. 27 Changes in T reg numbers or functions are usually associated with development of allergic disease ( Figure 2). Basic animal studies on germ-free mice revealed that in the absence of microbial colonization, T-cells produced more Th2 cytokines. This Th2-cell predominance was corrected with colonization of germ-free mice with Bacteroides fragilis alone, which promoted Th1 response and restored the Th1/Th2 imbalance. 28 Evidence from clinical studies also demonstrated that probiotic bacteria reduced Th2 cytokine patterns while promoting Th1 response. 29 The intestinal microbiota have marked immunomodulatory effects that are essential in maintaining immune tolerance. It has been proposed that certain diseases, such as eczema, asthma, allergic rhinitis, type 1 diabetes mellitus, and inflammatory bowel diseases, are linked to the dysregulation of the development of the intestinal mucosal defense system. 30 The composition of intestinal microflora differs between atopic and healthy infants. 20 Atopic children have lower counts of Lactobacillus, Bifidobacterium, and Bacteroides spp. 31 A recent systematic review by Melli et al 32 on the role of intestinal microbiota and allergic diseases among children revealed that in allergic children, early life microbiota was of lower diversity, predominantly Firmicutes; the same group of children also showed a higher amount of Bacteroidaceae and anaerobic bacteria, particularly B. fragilis, E. coli, Clostridium difficile, Bifidobacterium catenulatum, and B. bifidum, and fewer B. adolescentis, B. bifidum, and Lactobacillus. Well-conducted clinical trials have provided good data on the preventive benefit of probiotics (Lactobacillus or Bifidobacterium) in pregnant women and their infants in reducing the risk of allergic diseases, especially atopic dermatitis. 33,34 Breast milk constitutes a major source of support to gut colonization, due to its Bifidobacterium content and its composition of a large amount of galactooligosaccharides (GOS), which selectively accelerate the growth of bifidobacteria. 35,36 Multiple, recent, and large epidemiological studies confirmed the beneficial effects of breast-feeding in reducing the risk of asthma, allergic rhinitis, and atopic eczema among children. [37][38][39] Probiotics, prebiotics, and synbiotics Probiotics are defined as supplements that contain microorganisms (bacteria, yeast) and can change the microflora of the host. 40,41 The European Food and Feed Cultures Association and the International Life Sciences Institute defined probiotic as "a live microbial food ingredient that, when consumed in adequate amounts, confers health benefits on the consumers" and "live microorganisms that, when ingested or locally applied in sufficient numbers, provide the consumer with one or more proven health benefits". 42,43 Probiotics might be effective in preventing antibiotic-related diarrhea in healthy children and necrotizing enterocolitis in very low-birth-weight infants, as well as preventing childhood atopy and treating acute viral gastroenteritis; moreover, probiotics might be beneficial in the treatment of irritable bowel syndrome, chronic ulcerative colitis, infantile colic, and Helicobacter pylori gastritis. 41 The strains of probiotics most commonly used are Bifidobacterium and Lactobacillus spp., 44,45 which are also well known to have the capacity of resisting the physicochemical environment of the digestive tract. 46 On the other hand, prebiotics are aliments or supplements that contain a variety of molecules that stimulate the activity and/or growth of the native probiotic bacteria; a common component of prebiotics is fiber/oligosaccharides. 41 In the absence of fiber in the colon, anaerobic bacteria obtain their energy from protein fermentation, producing toxic metabolites, such as phenolic and ammoniac compounds. 47,48 By contrast, microbiota metabolites, such as short-chain fatty acids produce nontoxic material, such as propionate, butyrate, or acetate. 47,49 In a study conducted on rats, Gourgue-Jeannot et al 50 found that providing a fructan (inulin, fructooligosaccharide [FOS]) diet increased the synthesis of short-chain fatty acids. Currently, the most commonly used prebiotics are soybean oligosaccharides, FOS, GOS, and inulin. 51,52 Synbiotics are simply a mix of probiotic and prebiotic, which synergistically promote the growth of beneficial bacteria. 53,54 Use of probiotics in prevention of allergic diseases Asthma Several studies have been conducted using murine models to assess the effectiveness of probiotics in the treatment and prevention of asthma and hypersensitive airways. Blümer et al 55 studied the perinatal maternal administration of probiotics in mice. The study showed that application of Lactobacillus rhamnosus GG (LGG) suppressed significantly allergic airways and peribronchial inflammation in mouse offspring. In another murine model, Feleszko et al 56 found that application of either LGG or Bifidobacterium lactis (Bb12) significantly decreased pulmonary eosinophilia, airway reactivity, and antigen-specific IgE production. Moreover, the administration of a recombinant or wild-type Lactobacillus plantarum can effectively reduce airway eosinophilia following aerosolized allergen exposure. 57 Furthermore coadministration of L. plantarum and Lactococcus lactis has been shown to reduce allergen-induced basophil degranulation in a murine model of birch-pollen allergy. 58 Two different studies showed that oral administration of live Lactobacillus reuteri reduced hyperresponsiveness to methacholine, airway eosinophilia, and local cytokine responses. 59,60 There have also been several studies conducted on human beings, including children. Stockert et al 61 found that using laser acupuncture and probiotics in school-age children with asthma might prevent acute respiratory exacerbations and decrease bronchial hyperreactivity. However, two studies showed no efficacy of oral L. rhamnosus administration to adolescents suffering from pollen allergy. 62,63 Moreover, a systematic review of RCTs showed that the effectiveness of probiotics for the treatment of allergic rhinitis and asthma is questionable. 64 Therapeutics and Clinical Risk Management 2016:12 submit your manuscript | www.dovepress.com

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Preventing allergies in children Atopic dermatitis Management with LGG may ameliorate eczema/dermatitis syndrome symptoms in IgE-sensitized infants, but not in non-IgE-sensitized infants. 65 In IgE-sensitized children, treatment with L. rhamnosus results in tangible reduction in the prevalence of any IgE-associated eczema. 65, 66 Rosenfeldt et al 67 reported that the use of two Lactobacillus strains (rhamnosus and reuteri) in the treatment of allergic dermatitis was effective in children with increased IgE levels. In a review that included 13 RCTs, Betsi et al 68 concluded that regardless of IgE-sensitization, probiotics, especially LGG, can prevent atopic dermatitis. Vliagoftis et al 64 had the same conclusion in a meta-analysis of eleven studies. Furthermore, a meta-analysis showed that administration of probiotics during pregnancy reduced the risk of atopic eczema in children aged 2-7 years whose mothers received probiotics during pregnancy (reduction 5.7%, P=0.022). 69 Regardless of the timing of administration (pregnancy or early life), probiotics seem to prevent atopic dermatitis and IgE-associated atopic dermatitis in infants. 70 Han et al 71 mentioned that probiotic L. plantarum CJLP133 supplementation is of good value in the treatment of pediatric atopic dermatitis. The preventive effect of LGG on atopic eczema has been also described in infants during the first 6 months of life. 72 However, Kopp and Salfeld 73 presented a different opinion. In addition, Taylor et al 74 challenged the use of early probiotic supplementation with L. acidophilus, and found that it did not reduce the risk of atopic dermatitis in high-risk infants, but on the contrary was linked with increased allergen sensitization in infants receiving complements. In addition, Gore et al 75 found there was no usefulness from supplementation with B. lactis or Lactobacillus paracasei in the treatment of eczema, or benefits on the progression of allergic disease from age 1-3 years. Moreover, other authors found little evidence to support the idea of routine supplementation of probiotics to either infants or pregnant women to prevent allergic diseases in childhood. 76,77 Nonetheless, two major meta-analyses and one Cochrane study inferred that probiotics were not effective for the treatment for eczema. [78][79][80] Furthermore, RCT studies showed that the probiotic effect was not steady over the long term (4-7 years), 72,81 or even in the short term (6 months). 82 Dotterud et al 83 conducted an RCT to assess the effect of perinatal administration of probiotics on childhood asthma or atopic sensitization. A total of 415 pregnant women were randomized to receive probiotics (LGG, L. acidophilus La-5 and B. animalis subsp. lactis Bb12) or placebo. At 2 years, there were no substantial effects on asthma or atopic sensitization in the group that received probiotics compared to placebo. The heterogeneity in results in different studies is perhaps attributable to different probiotic strains used, environmental factors, such as diet or geographic region, and genetic liability. 76,84 Allergic rhinitis Probiotic treatment is beneficial in decreasing symptoms and reducing the use of relief medications in patients with seasonal and perennial allergic rhinitis. 64,73,85,86 Moreover, probiotic VSL3 ® (Sigma-Tau Pharmaceuticals, Inc. Gaithersburg, MD, USA) can prevent the development of Parietaria major allergen-specific local and systemic response when administered intranasally to mice. 87 In a double-blind RCT, Giovannini et al 88 reported that long-term (12 months) consumption of fermented milk containing L. casei may improve the health status of preschool children with allergic rhinitis. Kuitunen et al 89 showed that probiotics can prevent IgE-associated allergy until the age of 5 years in cesarean-delivered children. Moreover, L. rhamnosus HN001 can protect against eczema and rhinoconjunctivitis when given in the first 2 years of life. 90 Furthermore, studies have shown that fermented milk prepared with Lactobacillus gasseri-, LGG-, and B. longumsupplemented yogurt can ameliorate nasal blockage and hence be effective in seasonal allergic rhinitis, such as in Japanese cedar pollinosis. [91][92][93][94] However, a meta-analysis reported no benefits of probiotic use for allergic rhinitis. 77 In addition, Tamura et al 95 concluded in their study that fermented milk containing L. casei strain Shirota was futile in preventing allergic symptoms, including Japanese cedar pollinosis.

Food allergy
It has been reported that oral intake of Lactobacillus or Bifidobacterium strains could improve food allergy. 96 In a murine-based study, oral administration of L. acidophilus AD031 and B. lactis AD011 prevented ovalbumininduced food allergy in mice. 97 Other studies showed that administration of L. casei strain Shirota or VSL3 reduced anaphylaxis in a food-allergy model in mice. 87,97,98 Isolauri et al 99 mentioned in their study that supplementation of formulas with LGG ameliorated gastrointestinal symptoms in infants with eczema.
In contrast, administration of B. lactis Bb-12 and L. casei to extensively hydrolyzed formula did not improve cow's milk tolerance in infants with cow's milk allergy. 100 Moreover, other studies concluded that probiotics, specifically LGG or L. acidophilus, do not protect against cow's milk submit your manuscript | www.dovepress.com

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Hendaus et al allergy in infancy. 74,78,96,101 Finally, Osborn and Sinn 77 stated in their review involving 1,549 infants that the benefit of probiotics in improving food hypersensitivity is questionable.

Probiotic safety in disease prevention
Lactobacillus and Bifidobacterium as probiotics are considered to have a safe profile; however, there are limited data regarding the safety of other bacteria. 102 The rate of systemic infection with probiotic strains has been reported as 0.05%-0.4% in a large study conducted on adults, 103 but it is very rare in infants and children. [104][105][106] Allen et al 107 reported that lactobacilli and bifidobacteria are well tolerated with no adverse effects during pregnancy and in infants. Probiotic products may include hidden allergens of food, and might not be suitable for patients with allergies to cow's milk or hen's eggs. 108 Other side effects of probiotics on children have been restricted to case reports. For instance, Robin et al 109 reported L. rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation Moreover, Vahabnezhad et al 110 reported Lactobacillus bacteremia associated with probiotic use in a pediatric patient with ulcerative colitis receiving systemic corticosteroids and infliximab, while Luong et al 111 reported a case of Lactobacillus empyema in an HIV-infected immunodeficient patient with a lung transplant receiving a probiotic containing LGG. Bacteremia due to Lactobacillus supplementation was also reported in an immunocompetent infant and child without gastrointestinal diseases. 112 Finally, antibiotic resistance could emerge due to the long-term use of probiotics under antibiotic-selection pressure, and the resistance gene could be conveyed to other bacteria. 113

Use of prebiotics in prevention and treatment of allergic diseases
It has been postulated that prebiotics in infant formulas have the potential to prevent sensitization of infants to dietary allergens. In a 2-year follow-up RCT involving 132 infants at risk of atopy because of strong parental history, Arslanoglu et al 114 reported that the cumulative incidences for atopic dermatitis, recurrent wheezing, and allergic urticaria were lower in the group of infants fed with a formula with either an added mixture of FOS and GOS compared to the placebo group. Furthermore, in a prospective, double-blind, and placebo-controlled fashion, a mixture of neutral prebiotic oligosaccharides was evaluated for protective effect against allergy. A total of 92 healthy infants at risk of atopy were fed either a placebo-supplemented (0.8 g/100 mL maltodextrin) hypoallergenic formula or prebiotic-supplemented (0.8 g/100 mL short-chain GOS/ long-chain FOS) during the first 6 months of life. The authors concluded that feeding infants with oligosaccharide prebiotics (short-chain GOS/long-chain FOS) early in life protects against atopic dermatitis and allergic rhinoconjunctivitis. 115 However, in a Cochrane study, Osborn and Sinn 116 found that prebiotic supplementation in infant formula does not prevent food hypersensitivity or allergic disease. In addition, prebiotics alone are inferior to synbiotics in the treatment of moderate-to-severe childhood atopic dermatitis. 117 Combined prebiotics and probiotics in the prevention of allergic disease The effect of early intervention with synbiotics, a combination of probiotics and prebiotics, on the prevalence of asthma-like symptoms in infants with high risk of allergic diseases has been investigated. In a double-blind, placebocontrolled multicenter trial, 90 infants with atopic dermatitis, age ,7 months, were randomized to receive an infant formula with GOS/FOS and B. breve M16V mixture or formula without synbiotics; 75 children completed the 1-year follow-up, and the study showed that the prevalence of wheezing was substantially lower in the synbiotic than in the placebo group. 118 However, other studies showed that synbiotic has no benefit on the cumulative occurrence of allergic diseases, but was useful in reducing IgE-associated (atopic) diseases and the occurrence of atopic eczema. 41,119

Modified milk formulas during early life
Several health care practitioners recommend the use of soy-based formulas to treat infants with allergy or food intolerance. However, this is not currently recommended for prevention of allergy or food intolerance. 120 However, other formulas, such as hydrolyzed formulas, have been proposed for the prevention of allergy and food intolerance in infants. 121 Hydrolyzed formulas consist of cow's milk proteins that undergo enzymatic and chemical hydrolysis to decrease the peptide size, molecular weight, and allergenicity of the proteins. 122 It has been postulated that when breastfeeding alone is not feasible in high-risk infants, partially hydrolyzed (casein-or whey-based) formulas are effective in preventing allergic diseases, particularly atopic dermatitis. In a systematic review, Alexander and Cabana 123 reviewed 18 articles to study the role of partially hydrolyzed 100% whey (pHF-W) protein infant formula in reducing the risk of atopic dermatitis. The study showed that feeding with pHF-W statistically significantly decreased the risk of atopic manifestations (summary relative-risk estimate 0.56, 95%

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Preventing allergies in children confidence interval [CI]: 0.40-0.77). The authors concluded that exclusive breast-feeding should be the first choice of infant nutrition in the first 6 months of life. However, for infants who are not exclusively breast-fed, feeding with pHF-W instead of cow's milk formula reduces the risk of atopic dermatitis in those with a family history of allergy. Moreover, Szajewska and Horvath 124 conducted a metaanalysis to study the evidence of a pHF-W formula in the prevention of allergic diseases. The authors concluded that for all allergic diseases and atopic eczema/atopic dermatitis, the use of the pHF compared with standard formula decreased the risk of allergy in high-risk children. However, in a Cochrane systematic review, Osborn and Sinn 121 concluded that compared to exclusive breast-feeding, alimenting with hydrolyzed formula in the early days of infancy resulted in no significant difference in childhood cow's milk allergy or infant allergy. With regard to extensively hydrolyzed (caseinor whey-based) formulas, the literature indicates that they are effective for primary prevention of allergy in high-risk infants, but they are not cost-effective when compared with partially hydrolyzed formulas. 125

Dietary patterns (Mediterranean diet)
Changes in dietary customs play an important role in the prevalence of symptoms of allergic diseases. [126][127][128][129][130][131][132] The Western diet constitutes a high intake of processed and red meat, fast food, sugary drinks, and full-fat dairy products, with minimal vegetables. This diet pattern contains high levels of polyunsaturated fatty acids (PUFAs) and ω6 fatty acids, which are risk factors for some chronic and allergic diseases. 133,134 Meanwhile, the Mediterranean diet comprises increased use of unrefined grain, fruits, and vegetables, moderate utilization of dairy products and milk, and low meat intake. 135 Several studies have mentioned the protective role the Mediterranean diet plays in some chronic diseases and allergies, 133,[135][136][137][138] perhaps due to its antioxidant and immunoregulatory properties. 139 For instance, de Batlle et al 137 conducted a cross-sectional study that included 1,476 Mexican children (6-7 years old). Nutritional data of the children's intake in the previous 12 months and their mothers' intake during pregnancy were gathered. The study showed that maintaining a Mediterranean diet was inversely associated with wheezing ever (odds ratio  136 included in his study 700 children 10-12 years old from 18 schools located in Athens, Greece. The authors concluded that adherence to a Mediterranean diet was inversely linked to the likelihood of asthma symptoms. Moreover, in a study conducted on adults showed that adherence to the Mediterranean diet reduced the risk of uncontrolled asthma by 78% (OR =0.22, 95% CI: 0.05-0.85; P=0.028). 139 In a meta-analysis and systematic review, Garcia-Marcos et al 140 studied the influence of the Mediterranean diet on asthma in children. The outcomes measured were prevalence of "current wheeze", "current severe wheeze", or "asthma ever". The authors used ORs to compare the highest tertile of the scores with the lowest. In addition, random-effect meta-analyses for the whole group of studies were used and stratified by Mediterranean setting (centers ,100 km from the Mediterranean coast). The study concluded that following a Mediterranean diet is associated with lower prevalence of "asthma ever" (OR =0. 86

Micronutrients
As Hippocrates famously noted, "Let food be thy medicine". Perhaps the factors with the greatest effect on modulating atopic expression are nutritional in nature. For those at risk, exposure to certain foods may contribute to severe, lifelong asthma or food allergies. Other foods, rich in antiinflammatory antioxidants, may in fact ameliorate allergic responses to environmental stimuli. It is unlikely to be one factor that is solely responsible for unlocking genomic tendencies toward atopy. 142 An association between seasonal allergies and food allergies has been reported. In some individuals, allergic rhinitis due to specific pollens is connected to oral allergy symptoms due to certain fruits and vegetables. 143 Interestingly, organic versions of these same foods may be tolerated by patients who experience reactions with conventional submit your manuscript | www.dovepress.com

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Hendaus et al produce. It may be that the pesticide stimulation of the immune system is responsible for this difference, or it may be that the level of antioxidant nutrients in organic foods is more concentrated. 144 There is no clear evidence on the role of vitamins A or C in primary prevention of allergic diseases. However, vitamin D in particular is of increasing interest in atopic prevention and treatment. A growing number of studies have consistently demonstrated that a majority of children are vitamin D-insufficient or -deficient. In children with asthma and allergic diseases, vitamin D deficiency is a strong correlate for asthma, allergic rhinitis, and wheezing. 145 Furthermore, research indicates that vitamin D deficiency functions as a strong predictor of asthma in children. [146][147][148] In a Cochrane study conducted by Bath-Hextall et al, 149

essential fatty acids
More recent studies have looked at the role of essential fatty acids in reducing allergic disease. The evidence is very good for prenatal prevention of atopy when mothers ingest higher amounts of ω3 PUFAs. 150 It also appears that newborns who ingest breast milk relatively rich in ω3 are less likely to develop allergic symptoms. 151,152 This effect is most prominent in those babies at highest risk genetically for allergic diseases. Interestingly, the results of directly feeding infants PUFAs are not as clear. Studies of dietary modification with ω3 PUFAs in children at high risk demonstrated reduction in atopy. 153,154 Perhaps it is the balance of the two that is most important, and one must also take into account preexisting dietary deficiencies and genomic factors. More research is clearly needed in this realm before universal recommendations can be made.

Conclusion and recommendations
Multiple, recent, and large epidemiological studies have confirmed the beneficial effects of breast-feeding in reducing the risk of asthma, allergic rhinitis, and atopic eczema among children. Breast milk constitutes a major source of support to gut colonization, due to its bifidobacteria content and by providing a large amount of GOS, which selectively accelerate the growth of bifidobacteria. The literature lacks consensus in recommending the addition of probiotics to foods for prevention and treatment of allergic diseases. Moreover, probiotics must not be provided to immunocompromised children. Despite many studies portraying safety and efficacy in the use of probiotics during pregnancy and lactation, more evidence is required before a strong recommendation can be made. Probiotics in infant formula are safe. However, more RCTs are needed to compare human milk versus infant formula supplemented with probiotics.
Prebiotics may prove to be effective in reducing atopy in healthy children. Prebiotics in infant formula have been found to be safe, but clinical efficacy has to be investigated more, not to mention the high cost burden on families. There is insufficient evidence to support soy formulas or amino acid formulas for prevention of allergic disease. Partially hydrolyzed formulas are of use in infants at high risk of atopic dermatitis in the first 6 months of life instead of intact cow's milk protein formula. A healthy diet, such as the Mediterranean diet, may have a protective effect on the development of asthma and atopy in children. In children with asthma and allergic diseases, vitamin D deficiency is a strong correlate for asthma, allergic rhinitis, and wheezing. It is worth mentioning that the current deficiency of evidence of efficacy does not mean that future clinical investigations will not establish tangible health benefits for probiotics, prebiotics, diet, and vitamin supplementation. Therapeutics and Clinical Risk Management is an international, peerreviewed journal of clinical therapeutics and risk management, focusing on concise rapid reporting of clinical studies in all therapeutic areas, outcomes, safety, and programs for the effective, safe, and sustained use of medicines. This journal is indexed on PubMed Central, CAS, EMBase, Scopus and the Elsevier Bibliographic databases. The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.