pISSN 0513-5796   eISSN 1976-2437
Open Access, Peer-reviewed, Monthly
    Yonsei Med J. 2016 May;57(3):542-548. English.
    Published online Mar 15, 2016.
    https://doi.org/10.3349/ymj.2016.57.3.542
    © Copyright: Yonsei University College of Medicine 2016
    Review

    Update on Early Nutrition and Food Allergy in Children

    Sun Eun Lee,1 and Hyeyoung Kim2
      • 1Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
      • 2Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul, Korea.
    • Corresponding author: Dr. Hyeyoung Kim. Department of Food and Nutrition, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: 82-2-2123-3125, Fax: 82-2-364-5781, Email: kim626@yonsei.ac.kr
    Received January 25, 2016.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    With growing evidence of an increase in the prevalence, food allergy has been emerged as a new public health problem. As treatment and management of food allergy remain challenging, more attention has been paid to the importance of prevention of food allergy. Although the exact mechanism of recent epidemic is not fully understood, it is suggested that nutritional exposure in early life may play an important role in food allergy development. The underlying hypothesis is that nutritional status or food exposure in the critical period of fetal development can affect the programming of immune system and modify the risk of immunologic reactions to foods in postnatal life. We review accumulating epidemiological studies to examine an association between nutritional exposure during pregnancy or early infancy and food allergy development in children. We also discuss recent advances in the studies of the genetic and epigenetic regulation of food allergy and evaluate the role of early nutrition in food allergy development to provide a new perspective on the prevention of food allergy.

    Keywords
    Food allergy; children; maternal nutrition; epidemiology; epigenetic regulation; immune tolerance

    INTRODUCTION

    Food allergy is defined as adverse health consequences mediated by abnormal immune reactions to innocuous food exposure. 1 It can be sometimes confused with food intolerance, which is different from food allergy. Food intolerance takes place in the digestive system without the body's immune response. 2 Prevalence of food allergy has not been accurately estimated due to lack of population-based data, especially from less developed countries. According to existing studies, the extent of prevalence varies considerably, depending on diagnostic methods such as self-report and oral food challenge (OFC) which is considered the gold standard test to confirm food allergy. 3 In addition, predictive diagnostic decision point (DDP) values for specific immunoglobulin E (sIgE) antibodies are also widely used in clinical settings.4, 5 A recent study based on OFC estimated that 1–10% of children under 5 years of age might have food allergy.6 Another comprehensive review showed that 8% of children and 5% of adults were affected by some types of food allergies.7 Among Korean patients under 4 years of age who had suspected peanut and tree nut allergy, 31% were sensitized to walnut and 8% experienced anaphylaxis due to a small amount of walnut exposure.8 The severity of symptoms of food allergy can range from mild, in most cases, to life threatening in rare cases. Importantly, food allergy can negatively affect perception of one's heath and limit family activities.9

    Genetic predisposition and lifestyle changes including hygiene, sun exposure, smoking, and environmental pollutants are proposed risk factors for allergy development.10, 11 As the development of immune system starts early gestation and the incidence of food allergy is highest during infancy or early childhood, 12 it has been hypothesized that nutritional exposure during the time of immune programming may play an important role in the development of food allergy. Although biological mechanisms remain to be explored, some studies have suggested that interaction between gene and nutrition may explain the increasing prevalence of food allergy. A limited but increasing number of studies attempted to find epigenetic evidence of food allergy in early life.

    In this review, we discuss epidemiological studies to examine evidence of food allergy in infants and children, possibly associated with prenatal or early postnatal nutritional exposure. We focus on selective common food allergens (peanuts and tree nuts, cow's milk, and egg) and nutrients (vitamin D and n-3 fatty acids) that have been rather widely studied. We also evaluate evidence of gene and nutrition interaction, and epigenetic regulation of food allergy by nutrients. Lastly, we discuss potential opportunities in the prevention and intervention strategies using immunotherapy.

    Allergic reaction and mechanisms of food allergy

    Food allergy refers to a series of complex immune reactions to food allergen, particularly mediated by an immunoglobulin E (IgE) antibody, which plays a critical role in allergic diseases.13 In individuals without food allergy, antigen-presenting immune cells such as dendritic cells, macrophages, and T regulatory cells (Treg) process food antigen and mediate suppression of further immune response of adaptive immune system.14, 15, 16 But, in individuals with food allergy, food allergen promotes exaggerated response of T helper cells (Th2) and Th2 cytokines,17 and these consequently stimulate the generation of food sIgE antibodies from allergen-stimulated B cells.18 When food allergen binds to IgE antibody-bound basophils and mast cells, this triggers release of histamine from basophils and mast cells. This causes various allergic symptoms such as eczema, hives, and gastrointestinal problems.2 In general, Treg prevent potentially dangerous hypersensitivity to harmless antigens and regulate immune homeostasis.19

    Genetic evidence of food allergy

    Genetic predisposition is a strong risk factor of food allergy. Family-based studies showed that the risk or prevalence of food allergy was greater in children with family history of allergy (parents, siblings, or relatives) than children without it.20, 21, 22 Twin studies from China and the USA showed that the concordance rate of food allergy was higher with identical twins than with dizygotic twins.23, 24 The familial aggregation and heritability of food allergy suggest that genetic factors may play a key role in developing susceptibility of food allergy. In addition, associations between genetic variants of nearly a dozen of candidate genes and food allergy were identified, although only few associations were reproduced by subsequent studies.25 A recent genome-wide association study confirmed that two loci in the human leukocyte antigen (HLA)-DR and -DQ regions were associated with peanut allergy in children of European ancestor.26 Collectively, the findings of familial aggregation, heritability and single nucleotide polymorphisms support the hypothesis that genes play a key role in the development of food allergy.

    Evidence from epidemiological studies

    Although evidence from genetic studies is compelling, genetic factors alone cannot fully explain the increasing prevalence of food allergy. This naturally led to a hypothesis that considerable extent of the risk may be attributable to non-genetic factors. An increasing number of epidemiological studies have examined associations between early nutrition or food exposure and the risk of food allergy development.

    Vitamin D

    The possible role of vitamin D in food allergy has been hypothesized because several observational studies reported varying food allergy incidence associated with geographic or seasonal variation (sun exposure). The prescription rate of epinephrine injection (anaphylaxis treatment) and the rate of hospital admission for food-induced anaphylaxis were higher in regions distant from equator in the USA and Australia.27, 28, 29 A study of multicenter medical records in the USA showed that children under 5 years of age born in fall or winter had 53% higher risk of food-related acute allergic reactions than children born in spring or summer. This study suggests that low sunlight and presumably suboptimal vitamin D status at birth is associated with food allergy development in childhood.30 A large scale population-based study in Australia showed that infants with low serum 25-hydroxyvitamin (OH) D3 levels (≤50 nmol/L) had almost 12 times and 4 times higher risk of developing peanut and egg allergies, respectively, in the first year of life than infants with adequate serum vitamin D level.31 However, another study conducted in Germany demonstrated that 25(OH)D3 concentration in pregnant women's serum and in cord blood were positively associated with increased risk of food allergy development among children in the first 2 years.32 A recent randomized double-blind controlled trial showed that maternal vitamin D3 supplementation for 6 weeks during lactation increased the risk of food allergy diagnosis by 3.42 times [95% confidence interval (CI)=1.02–11.77] among children of supplementation group compared to control group by 2 years of age.33 Due to lack of robustly designed studies, a causal association between vitamin D status during prenatal and neonatal period and food allergy development in children remains inconclusive.

    n-3 long chain polyunsaturated fatty acids

    Because n-3 polyunsaturated fatty acids (n-3 PUFA) have anti-inflammatory and immunomodulatory functions,34, 35 it is hypothesized that low fish intake or low n-3 PUFA exposure in early life may increase the risk of child allergic diseases.36 A birth cohort study reported that fish consumption in the first year of life was associated with reduced risk of food sensitization by 24% in children by age 4.37 In a randomized controlled trial of daily fish oil supplementation from birth to 6 months of postnatal period, fish oil supplementation in high-risk infants did not prevent allergy development, although the level of docosahexaenoic acid and eicosapentaenoic acid in erythrocytes of infants at 6 months was significantly higher in intervention than in control group.38 In addition, there were 3 randomized controlled studies of maternal fish oil supplementation. Dunstan, et al.39 reported that fish oil supplementation, from the 20 weeks of gestation until delivery, decreased risk of sensitization to egg [odds ratio (OR)=0.34; 95% CI=0.22–1.02], but not to peanut (OR=0.48; 95% CI=0.15–2.2) in Australian infants with high risk of allergy at 12 months of age. Maternal n-3 PUFA supplementation, from the 25 weeks of gestation to 3–4 months of lactation, reduced the risk of positive results from skin prick tests for egg, milk, and/or wheat (OR=0.36; 95% CI=0.14–0.95) and risk of food allergy with clinical symptoms (OR=0.09; 95% CI=0.01–0.74) among Swedish infants with high risk of allergy at 12 months of age.40 However, these two studies suffer from relatively small sample sizes (98 and 145, respectively). Maternal n-3 PUFA supplementation to more than 700 pregnant women during pregnancy in Southern Australia did not reduce clinical food allergy and peanut sensitization, but only egg sensitization [risk ratio (RR)=0.62; 95% CI=0.41–0.93] in one-year-old infants.41 Therefore, supplementation of n-3 fatty acids during pregnancy may protect specific food allergy development in children.

    Peanut or tree nut

    Peanut (ground nut) and tree nuts (i.e., almond, walnut, hazelnut, cashew, Brazil nut, and pecan) are common food allergens that can cause life-threatening anaphylaxis in severe cases.42 The prevalence of peanut and tree nut allergy ranges from 1–6% and 0.05–5%, respectively, according to population-based studies based on history of allergic reaction and clinical diagnosis, although these estimates are predominantly from industrialized western countries.43, 44, 45 In Korea, the parent-reported incidence of peanut allergy is 0.68% in infants and 0.34% in early childhood.46, 47 The peanut and tree nut allergies develop in early life and generally persist through adulthood.48 Because of the severity in clinical symptoms and a long natural history, peanut and tree nuts have been most frequently studied among food allergies. A study showed that frequent maternal consumption of peanuts during pregnancy increased the risk of peanut sensitization among atopic infants in a dose-dependent manner.49 On the other hand, some studies found no associations between maternal nut consumption during pregnancy or lactation and the risk of peanut sensitization among children, although these population-based studies may be underpowered due to a small number of infants with food allergy.50, 51 Du Toit, et al.52 reported that the risk of peanut allergy was nearly 10 times higher (RR=9.8; 95% CI=3.1–30.5) in Jewish children living in the UK where peanut consumption in the first year of life is not as frequent as Jewish children living in Israel where peanut is introduced early and consumed frequently. Frazier, et al.53 reported that the risk of peanut or tree nut allergy diagnosis was almost 70% lower (OR=0.31; 95% CI=0.13–0.75) among children born to non-allergic mothers who consume peanut or tree nuts more often during peri-pregnancy (≥5 times vs. <1 time per month). Recently, Kim, et al.54 showed that DDP of peanut-sIgE level may be useful predictor of the outcomes of OFC in Korean children suspected of peanut allergy. Ara h 2 is the most important allergen in Korean children with peanut allergy. They suggested the cutoff levels for peanut (10.3 kU/L) and Ara h 2 (4.0 kU/L) in the diagnosis of peanut allergy in Korean children. A randomized trial showed that the prevalence of peanut allergy among children assigned to consume at least 6 gram of peanut protein per week until 60 months of age was significantly lower than that of children assigned to avoid peanut consumption (1.9% vs. 13.7%, p<0.001) among 640 infants with severe eczema, egg allergy, or both.55 Although the results from observational studies are inconsistent, the result of the study with a robust experimental design suggest that early consumption of peanuts or tree nuts may prevent nut allergy development. Due to a long natural history, more randomized controlled trials with multiple long-term follow-ups need to validate this finding.

    Cow's milk, egg, and others

    Cow's milk and egg are relatively common food allergens.56 Because cow's milk is usually introduced to infants earlier than any other foods, it is the earliest food allergen among others.57, 58 The estimated incidence of cow's milk and egg allergies in infants and children are relatively high (0.3–3.5% and 0.5–8.0%, respectively), but most children (>80%) outgrow the allergies.59 A large prospective study showed that the average age of cow's milk introduction to infant feeding was significantly later among Israeli infants with cow's milk allergy than infants without it (116.1 days vs. 61.6 days, p<0.001).60 One randomized controlled trial showed that partially hydrolyzed whey formula and extensively hydrolyzed casein formula, as opposed to the standard cow's milk formula, reduced the risk of any allergic diseases by 13% (RR=0.87; 95% CI=0.77–0.99) and 17% (RR=0.83; 95% CI=0.72–0.95), respectively, among high-risk children aged 7–10 years.61 However, there is insufficient evidence of preventive effect of certain type of cow's milk formula on childhood food allergies.62 In a population-based study in Australia (HealthNuts), introduction of egg to egg-sensitized infants at 10–12 months and after 12 months of age increased the risk of egg allergy by 1.6 times (95% CI=1.0–2.6) and 3.4 times (95% CI=1.8–6.5), respectively. They suggested that introduction of cooked egg at 4 to 6 months of age might protect against egg allergy in these infants.63 Studies showed similar protective effects of early introduction of cereal, grain, and oligosaccharides against food allergy development.64, 65, 66

    Evidence of gene and nutrition interaction

    Few studies examined the modulatory effect of gene and nutrition interaction on food allergy development. In the Boston birth cohort study, cord blood vitamin D deficiency [25(OH)D concentration <11 ng/mL] was not found to be associated with food sensitization to eight common food allergen in children.67 However, when individual genetic variant of 4 candidate genes involved in IgE synthesis and vitamin D metabolism were jointly considered, there is a statistically strong gene-vitamin D interaction (Pinteraction=9×10-6) on food sensitization. In the same birth cohort study, children who were ever breast-fed had 1.5 times (95% CI=1.1–2.1) higher risk of food sensitization to any of 8 common food allergens than children who were never breast-fed.68 This association was significantly modified by individual or joint 3 single nucleotide polymorphism (SNP) in the IL12RB1, TLR9, and TSLP genes. These genes are related to innate immunity or Th1/Th2 balance. These studies identified functional genetic variants that could modulate the risk of food allergy in children related to early nutrition. Because there is an insufficient number of studies, more studies with a systemic approach are needed to support the effect of genetic variation on the associations between early nutrition and food allergy development in childhood.

    Evidence of epigenetic regulation of food allergy

    An increasing number of studies suggest that epigenetic regulation plays a critical role in the development of allergic diseases. 69 Syed, et al.70 found that CpG sties in forkhead box protein 3 in antigen-induced regulatory T-cells were differentially demethylated between children with immune tolerance of peanut allergy and children without tolerance. They suggested that modifications at the DNA level of antigen-induced T-cells may be predictive of clinical immune tolerance during peanut oral immunotherapy. In the HealthNuts study by Martino, et al.71 DNA methylation profiles in CD4+ T-cells were examined in 24 infants with and without IgE-mediated food allergy diagnosed at 12 months. The authors suggested that dysregulated DNA methylation at genes involved in mitogen-activated protein kinases (MAPK) cascade during early CD4+ T-cell development may affect T-cell response and IgE-mediated food allergy in early childhood.72 Hong, et al.26 conducted the genome-wide association study of food allergy in the USA population. They found that loci in the HLA-DR and -DQ gene regions were associated with peanut allergy in children. Differential DNA methylation might partially mediate the identified genetic risk factors of peanut allergy. The results of these studies suggest that differential DNA methylation in the regions of genes related to T-cell differentiation and balance between Th1 and Th2 during the critical period of early life may be potential mechanisms of allergic disease development.73

    Epigenetic regulation by nutrients

    Although possible roles of prenatal folate, n-3 PUFA, and vitamin D in immune programming have been suggested,34, 74 only a limited number of studies examined epigenetic regulation by these nutrients as a potential biological pathway of allergic diseases. An animal study showed that maternal methyl-rich diet taken during pregnancy changed methylation level at 82 gene-associated loci that are related to allergic airway disease in offspring mice.75 This study suggests that excessive DNA methylation by prenatal exposure to methyl donors reduces transcriptional activity of genes, which negatively regulate allergic airway disease. Lee, et al.76 showed that maternal docosahexaenoic acid supplementation (400 mg/day) during pregnancy changed DNA methylation levels of genes IFN-γ and IL-13 in mononuclear cells in the cord blood. Since IFN-γ and IL-13 are Th1 and Th2 cytokines respectively, the findings support the role of n-3 PUFA in T-cell differentiation. In a genome-wide study, a high level of 25(OH)D3 in the cord blood was associated with low DNA methylation in the enhancer region of TSLP. This study showed that prenatal vitamin D-mediated epigenetic regulation in TSLP increased the risk of wheezing in children.77 More human studies are needed to substantiate the role of epigenetic regulation by nutrients in the growing epidemic of food allergy.

    Induced immune tolerance

    Treatment of food allergy mainly relies on strict avoidance of specific food allergen, although complete avoidance of allergenic food can be hardly practiced. Recently, immunotherapy has been suggested as an emerging intervention that ameliorates allergic reactions or permanently desensitizes food allergen.78 Mechanisms of induced immune tolerance are not fully understood. The key idea is to induce immune tolerance by promoting non-responsiveness of adaptive immune system to innocuous food antigen through the activation of antigen-specific Treg cells or deletion of Th2 cells.18, 19 In oral immunotherapy, patients are gradually exposed to a small but steadily increasing amount of specific food allergen until they are desensitized to it and sustain non-responsiveness after discontinuation of the therapy. Recent meta-analysis of 18 randomized and 3 clinical controlled trials showed that oral immunotherapy showed a protective effect against food allergy (RR=0.21; 95% CI=0.12– 0.38).78 Oral immunotherapy also increased average risk of systemic adverse reactions although it was not statistically significant (RR=1.08; 95% CI=0.97–1.19). Although immunotherapy is not currently recommended for practice because of safety issue, more experimental studies with a larger sample size and longitudinal follow-ups are required to provide efficacy and safety of immunotherapy.

    CONCLUSIONS

    Based on accumulating evidence, prolonged avoidance of allergenic foods during pregnancy, lactation, and delayed introduction of allergenic foods in infant feeding are effective in preventing food allergy development. Epidemiological studies suggest that exposure to food allergens in early life may prevent food allergy development among high-risk individuals. Individual genetic variants and differentially methylated DNA at certain genes help us to understand potential biological pathways of food allergy. Epigenetic studies provide our knowledge of mechanisms of food allergy and insights into new approaches to the prevention and management of food allergy. As controlling food consumption during pregnancy and lactation is relatively possible, as opposed to controlling other environmental exposures, early nutrition deserves more attentions as a primary target of further food allergy research.

    Notes

    The authors have no financial conflicts of interest.

    ACKNOWLEDGEMENTS

    This work was supported by a grant from the NRF of Korea, which is funded by the Korean government (NRF-2015R1A2A2A01004855). Authors wish to express appreciation to Mr. Rin Park for language editing and proofreading and Dr. T. Morio (Tokyo Medical and Dental University) for valuable discussion.

    References

      1. Boyce JA, Assa'ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report. J Allergy Clin Immunol 2010;126:1105–1118.
      1. National Institute of Allergy and Infectious Diseases. Food allergy. 2012 [accessed on 2015 October 15].
        An overview.
        Available at: https://www.niaid.nih.gov/topics/foodAllergy/Documents/foodallergy.pdf.
      1. Allen KJ, Koplin JJ. The epidemiology of IgE-mediated food allergy and anaphylaxis. Immunol Allergy Clin North Am 2012;32:35–50.
      1. Sampson HA. Update on food allergy. J Allergy Clin Immunol 2004;113:805–819.
      1. Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol 2010;125 2 Suppl 2:S116–S125.
      1. Prescott SL, Pawankar R, Allen KJ, Campbell DE, Sinn JKh, Fiocchi A, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J 2013;6:21.
      1. Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol 2014;133:291–307.
      1. Lee SY. IgE mediated food allergy in Korean children: focused on plant food allergy. Asia Pac Allergy 2013;3:15–22.
      1. Sicherer SH, Noone SA, Muñoz-Furlong A. The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol 2001;87:461–464.
      1. Prescott S, Allen KJ. Food allergy: riding the second wave of the allergy epidemic. Pediatr Allergy Immunol 2011;22:155–160.
      1. Fogarty AW. What have studies of non-industrialized countries told us about the cause of allergic disease? Clin Exp Allergy 2015;45:87–93.
      1. Warner JO. Early life nutrition and allergy. Early Hum Dev 2007;83:777–783.
      1. Gould HJ, Sutton BJ, Beavil AJ, Beavil RL, McCloskey N, Coker HA, et al. The biology of IGE and the basis of allergic disease. Annu Rev Immunol 2003;21:579–628.
      1. Ruiter B, Shreffler WG. The role of dendritic cells in food allergy. J Allergy Clin Immunol 2012;129:921–928.
      1. Kumar S, Dwivedi PD, Das M, Tripathi A. Macrophages in food allergy: an enigma. Mol Immunol 2013;56:612–618.
      1. Palomares O. The role of regulatory T cells in IgE-mediated food allergy. J Investig Allergol Clin Immunol 2013;23:371–382.
      1. Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med 2001;344:30–37.
      1. Berin MC, Mayer L. Can we produce true tolerance in patients with food allergy? J Allergy Clin Immunol 2013;131:14–22.
      1. Pabst O, Mowat AM. Oral tolerance to food protein. Mucosal Immunol 2012;5:232–239.
      1. Hourihane JO, Dean TP, Warner JO. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ 1996;313:518–521.
      1. McKean M, Caughey AB, Leong RE, Wong A, Cabana MD. The timing of infant food introduction in families with a history of atopy. Clin Pediatr (Phila) 2015;54:745–751.
      1. Tsai HJ, Kumar R, Pongracic J, Liu X, Story R, Yu Y, et al. Familial aggregation of food allergy and sensitization to food allergens: a family-based study. Clin Exp Allergy 2009;39:101–109.
      1. Sicherer SH, Furlong TJ, Maes HH, Desnick RJ, Sampson HA, Gelb BD. Genetics of peanut allergy: a twin study. J Allergy Clin Immunol 2000;106(1 Pt 1):53–56.
      1. Liu X, Zhang S, Tsai HJ, Hong X, Wang B, Fang Y, et al. Genetic and environmental contributions to allergen sensitization in a Chinese twin study. Clin Exp Allergy 2009;39:991–998.
      1. Hong X, Tsai HJ, Wang X. Genetics of food allergy. Curr Opin Pediatr 2009;21:770–776.
      1. Hong X, Hao K, Ladd-Acosta C, Hansen KD, Tsai HJ, Liu X, et al. Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nat Commun 2015;6:6304.
      1. Camargo CA Jr, Clark S, Kaplan MS, Lieberman P, Wood RA. Regional differences in EpiPen prescriptions in the United States: the potential role of vitamin D. J Allergy Clin Immunol 2007;120:131–136.
      1. Mullins RJ, Clark S, Camargo CA Jr. Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis. Ann Allergy Asthma Immunol 2009;103:488–495.
      1. Sheehan WJ, Graham D, Ma L, Baxi S, Phipatanakul W. Higher incidence of pediatric anaphylaxis in northern areas of the United States. J Allergy Clin Immunol 2009;124:850–852.
      1. Vassallo MF, Banerji A, Rudders SA, Clark S, Mullins RJ, Camargo CA Jr. Season of birth and food allergy in children. Ann Allergy Asthma Immunol 2010;104:307–313.
      1. Allen KJ, Koplin JJ, Ponsonby AL, Gurrin LC, Wake M, Vuillermin P, et al. Vitamin D insufficiency is associated with challenge-proven food allergy in infants. J Allergy Clin Immunol 2013;131:1109–1116.
      1. Weisse K, Winkler S, Hirche F, Herberth G, Hinz D, Bauer M, et al. Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study. Allergy 2013;68:220–228.
      1. Norizoe C, Akiyama N, Segawa T, Tachimoto H, Mezawa H, Ida H, et al. Increased food allergy and vitamin D: randomized, double-blind, placebo-controlled trial. Pediatr Int 2014;56:6–12.
      1. Miles EA, Calder PC. Maternal diet and its influence on the development of allergic disease. Clin Exp Allergy 2015;45:63–74.
      1. Gottrand F. Long-chain polyunsaturated fatty acids influence the immune system of infants. J Nutr 2008;138:1807S–1812S.
      1. Black PN, Sharpe S. Dietary fat and asthma: is there a connection? Eur Respir J 1997;10:6–12.
      1. Kull I, Bergström A, Lilja G, Pershagen G, Wickman M. Fish consumption during the first year of life and development of allergic diseases during childhood. Allergy 2006;61:1009–1015.
      1. D'Vaz N, Meldrum SJ, Dunstan JA, Martino D, McCarthy S, Metcalfe J, et al. Postnatal fish oil supplementation in high-risk infants to prevent allergy: randomized controlled trial. Pediatrics 2012;130:674–682.
      1. Dunstan JA, Mori TA, Barden A, Beilin LJ, Taylor AL, Holt PG, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol 2003;112:1178–1184.
      1. Furuhjelm C, Warstedt K, Larsson J, Fredriksson M, Böttcher MF, Fälth-Magnusson K, et al. Fish oil supplementation in pregnancy and lactation may decrease the risk of infant allergy. Acta Paediatr 2009;98:1461–1467.
      1. Palmer DJ, Sullivan T, Gold MS, Prescott SL, Heddle R, Gibson RA, et al. Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants' allergies in first year of life: randomised controlled trial. BMJ 2012;344:e184.
      1. Crespo JF, James JM, Fernandez-Rodriguez C, Rodriguez J. Food allergy: nuts and tree nuts. Br J Nutr 2006;96 Suppl 2:S95–S102.
      1. Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol 2007;120:638–646.
      1. Osborne NJ, Koplin JJ, Martin PE, Gurrin LC, Lowe AJ, Matheson MC, et al. Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol 2011;127:668–676.
      1. McWilliam V, Koplin J, Lodge C, Tang M, Dharmage S, Allen K. The prevalence of tree nut allergy: a systematic review. Curr Allergy Asthma Rep 2015;15:54.
      1. Kim J, Chang E, Han Y, Ahn K, Lee SI. The incidence and risk factors of immediate type food allergy during the first year of life in Korean infants: a birth cohort study. Pediatr Allergy Immunol 2011;22:715–719.
      1. Park M, Kim D, Ahn K, Kim J, Han Y. Prevalence of immediate-type food allergy in early childhood in Seoul. Allergy Asthma Immunol Res 2014;6:131–136.
      1. Sicherer SH, Sampson HA. Peanut and tree nut allergy. Curr Opin Pediatr 2000;12:567–573.
      1. Sicherer SH, Wood RA, Stablein D, Lindblad R, Burks AW, Liu AH, et al. Maternal consumption of peanut during pregnancy is associated with peanut sensitization in atopic infants. J Allergy Clin Immunol 2010;126:1191–1197.
      1. Lack G, Fox D, Northstone K, Golding J. Avon Longitudinal Study of Parents and Children Study Team. Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348:977–985.
      1. Tariq SM, Stevens M, Matthews S, Ridout S, Twiselton R, Hide DW. Cohort study of peanut and tree nut sensitisation by age of 4 years. BMJ 1996;313:514–517.
      1. Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008;122:984–991.
      1. Frazier AL, Camargo CA Jr, Malspeis S, Willett WC, Young MC. Prospective study of peripregnancy consumption of peanuts or tree nuts by mothers and the risk of peanut or tree nut allergy in their offspring. JAMA Pediatr 2014;168:156–162.
      1. Kim HY, Han Y, Kim K, Lee JY, Kim MJ, Ahn K, et al. Diagnostic value of specific IgE to peanut and Ara h 2 in Korean children with peanut allergy. Allergy Asthma Immunol Res 2016;8:156–160.
      1. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 2015;372:803–813.
      1. Venter C, Pereira B, Voigt K, Grundy J, Clayton CB, Higgins B, et al. Prevalence and cumulative incidence of food hypersensitivity in the first 3 years of life. Allergy 2008;63:354–359.
      1. Host A, Halken S. Cow's milk allergy: where have we come from and where are we going? Endocr Metab Immune Disord Drug Targets 2014;14:2–8.
      1. Bock SA, Muñoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol 2007;119:1016–1018.
      1. Gray CL, Goddard E, Karabus S, Kriel M, Lang AC, Manjra AI, et al. Epidemiology of IgE-mediated food allergy. S Afr Med J 2015;105:68–69.
      1. Katz Y, Rajuan N, Goldberg MR, Eisenberg E, Heyman E, Cohen A, et al. Early exposure to cow's milk protein is protective against IgEmediated cow's milk protein allergy. J Allergy Clin Immunol 2010;126:77–82.
      1. von Berg A, Filipiak-Pittroff B, Krämer U, Hoffmann B, Link E, Beckmann C, et al. Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol 2013;131:1565–1573.
      1. Chan ES, Cummings C, Atkinson A, Chad Z, Francoeur MJ, Kirste L, et al. Dietary exposures and allergy prevention in high-risk infants: a joint position statement of the Canadian Society of Allergy and Clinical Immunology and the Canadian Paediatric Society. Allergy Asthma Clin Immunol 2014;10:45.
      1. Koplin JJ, Osborne NJ, Wake M, Martin PE, Gurrin LC, Robinson MN, et al. Can early introduction of egg prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol 2010;126:807–813.
      1. Arslanoglu S, Moro GE, Schmitt J, Tandoi L, Rizzardi S, Boehm G. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr 2008;138:1091–1095.
      1. Jeurink PV, van Esch BC, Rijnierse A, Garssen J, Knippels LM. Mechanisms underlying immune effects of dietary oligosaccharides. Am J Clin Nutr 2013;98:572S–577S.
      1. Poole JA, Barriga K, Leung DY, Hoffman M, Eisenbarth GS, Rewers M, et al. Timing of initial exposure to cereal grains and the risk of wheat allergy. Pediatrics 2006;117:2175–2182.
      1. Liu X, Wang G, Hong X, Wang D, Tsai HJ, Zhang S, et al. Gene-vitamin D interactions on food sensitization: a prospective birth cohort study. Allergy 2011;66:1442–1448.
      1. Hong X, Wang G, Liu X, Kumar R, Tsai HJ, Arguelles L, et al. Gene polymorphisms, breast-feeding, and development of food sensitization in early childhood. J Allergy Clin Immunol 2011;128:374–381.
      1. Hong X, Wang X. Epigenetics and development of food allergy (FA) in early childhood. Curr Allergy Asthma Rep 2014;14:460.
      1. Syed A, Garcia MA, Lyu SC, Bucayu R, Kohli A, Ishida S, et al. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol 2014;133:500–510.
      1. Martino D, Joo JE, Sexton-Oates A, Dang T, Allen K, Saffery R, et al. Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy. Epigenetics 2014;9:998–1006.
      1. Martino D, Dang T, Sexton-Oates A, Prescott S, Tang ML, Dharmage S, et al. Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants. J Allergy Clin Immunol 2015;135:1319–1328.
      1. Robinson JH, Delvig AA. Diversity in MHC class II antigen presentation. Immunology 2002;105:252–262.
      1. Zittermann A, Tenderich G, Koerfer R. Vitamin D and the adaptive immune system with special emphasis to allergic reactions and allograft rejection. Inflamm Allergy Drug Targets 2009;8:161–168.
      1. Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 2008;118:3462–3469.
      1. Lee HS, Barraza-Villarreal A, Hernandez-Vargas H, Sly PD, Biessy C, Ramakrishnan U, et al. Modulation of DNA methylation states and infant immune system by dietary supplementation with ω-3 PUFA during pregnancy in an intervention study. Am J Clin Nutr 2013;98:480–487.
      1. Junge KM, Bauer T, Geissler S, Hirche F, Thürmann L, Bauer M, et al. Increased vitamin D levels at birth and in early infancy increase offspring allergy risk-evidence for involvement of epigenetic mechanisms. J Allergy Clin Immunol 2016;137:610–613.
      1. Nurmatov U, Devereux G, Worth A, Healy L, Sheikh A. Effectiveness and safety of orally administered immunotherapy for food allergies: a systematic review and meta-analysis. Br J Nutr 2014;111:12–22.
    Cited by
    Crossref 9
    Google Scholar 
    PubMed Central 8
    Scopus 12
    Web of Science 10
    MeSH Terms
    Epigenesis, Genetic*
    Food Hypersensitivity*
    Nutritional Status*
    Allergens/immunology*
    Child
    Female
    Humans
    Immune System
    Infant
    Pregnancy
    Metrics
    Share
    Links to
    Funding Information
    PERMALINK