Finding a Path to Safety in Food Allergy Assessment of the Global Burden, Causes, Prevention, Management, and Public Policy (2017) / Chapter Skim
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5 Potential Genetic and Environmental Determinants of Food Allergy Risk and Possible Prevention Strategies
5 Potential Genetic and Environmental Determinants of Food Allergy Risk and Possible Prevention Strategies
Pages 139-226
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From page 139... ...
The concept of atopic march1 is briefly introduced as potentially important when considering prevention strategies. Although other immune-related diseases, such as eczema 1 The atopic march refers to the idea that atopic disorders progress over time from eczema (i.e., atopic dermatitis)
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Also, the chapter concentrates on food allergy as an outcome except for a few risk determinants for which there are no data on food allergies. In these cases, the committee explored food sensitization2 as a potential surrogate outcome.
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The baby also produces antibodies. Infant feeding practices (i.e., use of formula versus breast milk)
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For instance, being at high risk of allergic disease could be a confounder when exploring the effects of breastfeeding in food allergies because high-risk families are more likely to follow guidelines, which might inform them about the putative protective effects of breastfeeding. If researchers do not adjust their analysis for family history of allergy (the main risk of allergy development)
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From page 143... ...
For example, the authors of a systematic review on the causal relationship between eczema and subsequent allergic disorders concluded that atopic dermatitis might contribute to the development of allergic rhinitis. However, they could not reach a similar conclusion for the relationship between atopic dermatitis and food allergies (Dharmage et al., 2014)
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, clinicians need to interpret emerging or less robust evidence and provide carefully framed information to individual patients and their families to inform health decisions. Until recently, food allergy has been less common than other allergic diseases.
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These studies do provide insights into the temporal trend changes in food allergy prevalence, but should be viewed with caution when assessing risk factors for predicting food allergy owing to the high false positive rate and low specificity of this method. Selfreported measures tend to overreport food allergy due to the inability of individuals to distinguish between symptoms of food intolerance and food allergy.
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. GENETIC AND EPIGENETIC RISK FACTORS The rise in the prevalence of allergic diseases has occurred more rapidly than can be accounted for by changes in genetic sequence (Tan et al., 2012b)
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. Epigenetic considerations for other environmental factors, for which there is evidence of involvement in allergic diseases, have not yet been considered.
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CoFAR2 Observational, Children with 515 After 3 years Peanut allergy What is the US egg and/or milk of age development of allergy, 3-15 mo peanut allergy in infants (3 to 15 months in age) with known milk or egg allergy?
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testing VITALITY RCT, Australia Infants 6-8 12 months Challenge- Vitamin D (400 Can vitamin D weeks proven food IU/day) versus supplementation in allergy in study placebo for 10 infants prevent food participants months allergy in the first with year of life?
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measured using fillagrin mutational status, skin barrier function, and vitamin D status and their effect on risk of eczema and food allergy in the first 2 years of life?
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Does food allergy; supplementation parental report with this probiotic of feeding reduce the chance of intolerance developing eczema and food allergies in enrolled infants? PROOM-3 RCT, Sweden Pregnant 6 and 12 IgE-associated Dietary Can supplementation women with at months disease supplementation with Lactobacillus least one parent measured by with L
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NOTE: AU = Australia; DBPCOFC = double-blind, placebo-controlled oral food challenge; FABP = fatty acid binding protein; GI = gastrointestinal; IgE = immunoglobulin E; sIgE = food-specific serum IgE; SPT = skin prick test; TB = tuberculosis; UK = United Kingdom; US = United States.
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From page 153... ...
However, the association studies performed to date that have aimed to uncover the genetic architecture of food allergies have faced similar challenges as for other complex human diseases to date. Specifically, the identified loci can explain only a very small fraction of the phenotypic variance and few of the loci examined have provided conclusive and consistent findings across populations (see Table 5-4)
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154 FINDING A PATH TO SAFETY IN FOOD ALLERGY TABLE 5-2 Current Guidelines on Food Allergy Prevention Guideline (reference) Year Country Breastfeeding Interim Guidance 2015 US, Australia, Regarding Peanut Japan, European Introduction from Union (EU)
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might benefit from evaluation by an allergist or physician to diagnose any food allergy and assist in implementing these suggestions of early peanut introduction. continued
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World Health 2003 Worldwide Breastfeed exclusively Organization and until 6 months. World Allergy Organization (WHO, 2003)
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Suggests that the use of hydrolyzed infant formulas, as opposed to cow milk formula, may be considered as a strategy for preventing the development of food allergy in at-risk infants who are not exclusively breastfed. Suggests that the introduction of solid foods should not be delayed beyond 4 to 6 months of age. Potentially allergenic foods may be introduced at this time as well.
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(Fleischer et al., 2013) European 2014 EU Exclusive breastfeeding Academy of for at least the first Allergy & Clinical 4-6 months of life is Immunology recommended.
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From page 159... ...
to infants who manifest signs of allergic disease shortly after birth, because treatment may, in some cases, involve dietary interventions during lactation. Introduction of For high-risk No special diet complementary foods infants: If a during pregnancy after the age of 4 supplement is or for the lactating months according needed during the mother.
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160 FINDING A PATH TO SAFETY IN FOOD ALLERGY TABLE 5-2 Continued Guideline (reference) Year Country Breastfeeding European Society 2008 Europe Exclusive or full of Pediatric Allergy breastfeeding for about and Clinical 6 months Immunology and is a desirable goal.
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POTENTIAL GENETIC AND ENVIRONMENTAL DETERMINANTS 161 Early Introduction of Prebiotics or Foods Infant Formula Diet of Mother Probiotics There is no convincing scientific evidence that avoidance or delayed introduction of potentially allergenic foods, such as fish and eggs, reduces allergies, either in infants considered at increased risk for the development of allergy or in those not considered to be at increased risk. Complementary foods should not be introduced before 17 weeks and foods should be added one at a time to allow detection of reactions to individual components.
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atopic disease, evidence suggests that exclusive breastfeeding for at least 4 months compared with feeding intact cow milk protein formula decreases the cumulative incidence of atopic dermatitis and cow milk allergy in the first 2 years of life.
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This hydrolyzed includes delaying the formulas, introduction of foods compared with that are considered cow milk formula, to be highly allergic, in early childhood. such as fish, eggs, and foods containing peanut Extensively protein.
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months. National Health 2012 Australia Exclusive breastfeeding and Medical until around 6 months Research Council of age.
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supervision. Soy-based formulas do not prevent or reduce the risk of developing allergies and are not a suitable alternative to cow milk–based formulas.
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a Australasian Society of Clinical Immunology and Allergy, Canadian Society of Allergy and Clinical Immunology, European Academy of Allergy & Clinical Immunology, Israel Association of Allergy and Clinical Immunology, Japanese Society for Allergology, Society for Pediatric Dermatology, and World Allergy Organization. b For all infants (not as a prevention for allergic diseases)
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From page 167... ...
convincing recommended. evidence to support a protective role for partially hydrolysed formulas or extensively hydrolyzed formulas for the prevention of food allergy in infants or children.
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From page 168... ...
However, as with other complex diseases that are polygenic, challenges remain to identify what contribute to the "missing heritability." The committee concludes that although some evidence from various lines of investigation suggests that genetics contribute to the development of food allergies, none of the studies on the association of food allergy with specific loci examined to date has provided conclusive and consistent findings across populations. Interaction Between Genetics and Environment: Migration Studies As mentioned above, environmental exposures, including lifestyle and diet, interact with genetic predisposition to modify the risk of disease.
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. Similar effects were seen for other food sensitizations and food allergies and for eczema.
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06:03P mean age 11 years 332 controls associated with peanut allergy Controls: mean age 4 years Hong et al., Observational, Participants in 1,315 children HLA Peanut allergy HLA-DR and -DQ 2015 US the Chicago Food 1,444 parents gene region at 6p21.32, Allergy Study tagged by rs7192 and rs9275596
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From page 171... ...
Woo et al., 2003 Observational, Food allergic 77 cases CD14 Food allergy The C-159T SNP US patients, mean age 61 controls associated with food 5.2 years, 74% allergy male, 83% white Non-atopic, non asthmatic adult controls Campos et al., Observational, Food-allergic 88 cases CD14 Food Allergy No association with the 2007 Japan children, mean age 101 controls C-159T or the C-550T 7.1 years Non-food-allergic controls, mean age 9.45 years Torgerson et al., Case series, Index case with 11 FOXP3 Severe food 1300-bp deletion could 2007 France IPEX syndrome allergy cause severe food and other family allergy members Siegel et al., Observational, Atopic patients: 65 patients STAT3 Food allergies Complex association 2013 US 40% female, mean with severe (egg, milk, or between this locus and age 14.8 years atopic disease peanut) allergic phenotypes Controls: 61% female, mean age 41 healthy 34.5 years controls continued 171
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UK Caucasian blood donors Negoro et al., Observational, Allergic children 220 STAT6 Food allergy No association of 2006 Japan G2964A and severity of food allergy Kusunoki et al., Observational, Children with 118 SPINK5 Food allergy The 1258AA or 2005 Japan atopic dermatitis, 1258AG carriers have >5 years of age higher prevalence of food allergy Negoro et al., Observational, Allergic children, 220 IL10 Food allergy No association with the 2006 Japan mean age 7.3 years C-627A SNP Campos et al., Observational, Food-allergic 111 cases IL10 Food allergy No association with the 2008 Japan children, mean age 115 controls C-627A SNP; but the 7.6 years, 63% male -1082AA genotype was associated with higher Atopic control risk children without food allergy, mean age 8.2 years, 64% male
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Chen et al., Observational, Food-allergic 37 cases IL10 Food allergy Both the -1082A/G and 2012 Taiwan patients, age range 52 controls the -592A/C SNPs were 1-32 years; 62% associated with food male allergies Non-food-allergic controls, age range 1-59 years, 40% male Liu et al., 2004 Observational, German children 823 IL13 Food C-1055T higher risk Germany who participated sensitization in the German Multicenter Allergy Study Gaudieri et al., Observational, Children recruited 35 allergic IL28B Food allergy The rs12979860 SNP 2012 Australia antenatally from 35 non-allergic associated positively healthy pregnant with food allergy mothers; followed from birth to age 5 years Venkataraman et Observational, Isle of Wight birth 1,456 FLG Food allergy FLG LOF mutations al., 2014 UK cohort; children associated with food ages 1-18 years allergy. Tan et al., 2012a Observational, HealthNuts Cohort 700 FLG Food FLG LOF mutations Australia study participants; sensitization/ do not increase the white infants, age allergy risk of food allergies 1 year beyond that of food sensitization 173 continued
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n levels are year or 10 years predictive factors for IgE food sensitization in childhood NOTE: FLG = filaggrin; HLA = human leukocyte antigen; IGHG = immunoglobulin heavy locus gene; IL = interleukin; LOF = loss of function; UK = United Kingdom; US = United States.
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, than for food allergies. In light of the
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on a birth cohort of 12 children with IgE-mediated food allergy diagnosed at 12 months; 12 individuals with no food allergies were controls (Martino et al., 2014)
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ENVIRONMENTAL RISK FACTORS Microbial Exposure Hypotheses As mentioned in Box 5-1, evidence increasingly suggests that the interaction between the host microbiome and the immune system is essential to the development of immune regulation and oral tolerance (Martin et al., 2010)
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Therefore, their use as potential risk factor for food allergies also is included. A systematic review of the evidence linking microbial exposure and food allergy was published by Marrs et al.
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From page 179... ...
Therefore, this ratio could potentially be used as a predictor of food sensitization, a potential surrogate for food allergies. Each quartile increase in richness at 3 months was associated with a 55 percent reduction in risk for food sensitization by 1 year (adjusted odds ratio [aOR]
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Additional research would be needed before recommending the use of prebiotics or probiotics to prevent the onset of food allergies. Route of Delivery The composition of the gut microbiota is influenced by route of delivery.
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Overall, these studies found no significant associations between cesarean delivery and a variety of food allergies. The age of the children in the studies ranged from 0 to 5 years, and most included physician-diagnosed food allergy.
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. Since 2012, two prospective cohort studies of food allergic children have been published that were not included in the Marrs systematic review (Marrs et al., 2013)
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However, additional studies are needed to conclusively demonstrate a link between antibiotic use in early life and food allergy risk. Only a few studies have explored the relationship between food allergies and antibiotic use.
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Two studies with a total of 350 children reported no association between pets in the home (Israel) and food sensitization (measured by specific IgE to cow milk)
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From page 185... ...
Further studies should be conducted on the nature of the association between exposure to farm animals or pet ownership and food allergies. Allergen Avoidance Hypothesis As mentioned in the introduction of this chapter, in considering the risk determinants for developing food allergies, the committee focused on the prenatal and early childhood developmental periods.
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. Its application to food allergies would suggest that consuming specific allergenic foods during this critical period might be associated with the development of the immune system in utero that may later manifest itself as food allergies over the life course, given specific childhood exposures.
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Another recent systematic review by de Silva et al. found seven highquality studies on maternal diets and also concluded that "overall, the evidence is not strong enough to recommend changing the diet or supplements of pregnant or breastfeeding women" to prevent food allergies in infants at normal or high risk of food allergies (de Silva et al., 2014)
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and food allergies among children (N=386) ages 0 to 18 years with atopic dermatitis.
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The committee concludes that due to inconsistencies in results from prospective studies, the evidence that breastfeeding is protective against food allergies is limited. Strong evidence is unlikely to be forthcoming because of the ethical inability to randomize a population to breastfeeding alternatives.
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study was a trial aimed at exploring the effect of hydrolyzed formulas (compared to cow milk formula) in preventing allergic diseases in infants at high risk of atopy.
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From page 191... ...
Therefore, evidence on the effect of PHF or EHF for the prevention of food allergies is limited. If this area were to be investigated, high-quality RCT studies on the effects of PHF and EHF to determine whether hydrolyzed infant formulas influence the onset of food allergies would be needed before the use of these formulas could be recommended for prevention.
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From page 192... ...
One human study demonstrated that peanut allergens can be found in the household environment and that higher exposure to environmental peanut antigens appears to increase the risk of peanut allergy in children with either filaggrin loss-of-function mutations or atopic dermatitis (Brough et al., 2014)
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From page 193... ...
. Recent data from the Isle of Wight birth cohort used path analysis to demonstrate that the effect of filaggrin loss-of-function mutations on food allergy at age 10 years occurred indirectly through an effect on eczema and food sensitization in early childhood (Venkataraman et al., 2014)
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. The EAACI systematic review includes three cohort studies that found that the concept of delaying solid foods or cow milk consumption until 4 months of age does not appear to confer any benefit in terms of food allergies (de Silva et al., 2014)
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From page 195... ...
from the original LEAP cohort, irrespective of whether they were in the original peanut consumer or avoidant group, were asked to completely avoid peanut consumption for 1 year and then their peanut allergy status was determined by OFC, SPT, and specific IgE. Despite high adherence to this protocol of avoidance, the protective effects of early consumption remained and the original peanut consuming group had a 74 percent reduction in peanut allergy at age 6 years compared to the original peanut avoid
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In contrast, the per protocol analysis did suggest that early introduction of other common allergenic foods into the diet of infants may protect against the development of food allergies in general (Perkin et al., 2016)
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A dose–response analysis revealed that 2 g of peanut protein or egg white protein per week appeared to be most protective against these food allergies. Interestingly 2 g of peanut protein per week is the dose that was observed in the Du Toit et al.
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. Limited evidence from observational studies also suggests that delaying the introduction of egg, cow milk, and wheat to decrease risk of those food allergies has no benefits.
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From page 199... ...
have recorded more pediatric admissions to the hospital for food allergy–related events, and more prescriptions of hypoallergenic formulas for the treatment of cow milk allergy and adrenaline auto injectors for the treatment of anaphylaxis in children, compared to countries closer to the Equator (Camargo et al., 2007; Mullins et al., 2009, 2010; Rudders et al., 2010)
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From page 200... ...
. A recent study from Australia described that infants with vitamin D insufficiency were three times more likely to have egg allergy than those who had adequate stores of the vitamin, with the odds increasing to 10-fold among those with two or more food allergies.
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From page 201... ...
increased the risk of food sensitization (defined as specific IgE ≥0.35 kUA/L to any common food allergen, that is, egg white, milk, peanut, walnut, soy, shrimp, cod fish, and wheat)
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. There was only one study where omega-3 supplementation reduced the incidence of IgE-mediated food allergies in children up to 12 months of age (Furuhjelm et al., 2009)
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From page 203... ...
In turn, this may influence the allergic predisposition in the neonate. To date, most human studies on this topic have focused on asthma, with very limited number of studies specific to food allergy or food sensitization.
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From page 204... ...
Thus, proper RCTs are required to determine the causal effect of the maternal diet on the etiology of food allergies in offspring. The committee concludes that evidence to assess the causal association between other nutrients and the development or prevention of food allergy is lacking.
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. Although the precise mechanism underlying the link between obesity and allergic disease including food allergies remains to be elucidated, the hypothesis is biologically plausible.
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. In a nested case-control within-cohort study of 41 infants using gold standard food challenge outcomes and 82 age-matched controls, the authors found that an infant diet with high levels of fruits, vegetables, and home-prepared foods is associated with less food allergy by 2 years of age.
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From page 207... ...
, although the evidence is inconsistent, it would be unethical to pursue RCTs; therefore, the evidence about their contribution to food allergies is derived solely from epidemiological studies. The review of the evidence by the committee neither confirmed nor rebutted current hypotheses related to any association between these factors and the increase in the prevalence of food allergies.
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From page 208... ...
RESEARCH NEEDS Considerations for Study Designs Studies on the etiological factors associated with food allergies frequently present methodological flaws due to various reasons, including lack of accounting for confounding factors (e.g., breastfeeding) , use of inaccurate food allergy measures (e.g., self-reporting)
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From page 209... ...
• Account for the potential influence of confounding factors, in addi tion to age, sex, and geography, such as breastfeeding, composition of breast milk, dietary intake, other allergic disorders in the patient or family history (particularly atopic dermatitis) , genetic suscepti bility, presence of dogs or cats in the household, number of siblings, history of antibiotic usage, and exposure to agents or practices that might impair skin barrier function.
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Prospective studies and behavioral research should be conducted to accomplish the following objectives: • Examine risk factors for food allergies in all populations (ages, sex, ethnicities, comorbidities, socioeconomic strata) , especially in those populations that might have been underrepresented in past research.
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From page 211... ...
with well-designed prospective studies and take into account the potential effect of differences in breast milk composition. • Determine, with RCTs, whether consuming or eliminating or avoid ing specific allergenic foods during pregnancy and lactation has any benefits.
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J Allergy Clin Immunol 131(4)
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J Allergy Clin Immunol 133(5)
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J Allergy Clin Immunol 131(3)
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J Allergy Clin Immunol 112(6)
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J Allergy Clin Immunol 138(4)
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J Allergy Clin Immunol 134(4)
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A population-based study. J Allergy Clin Immunol 126(4)
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J Allergy Clin Immunol 129(5)
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2014. Point prevalence and risk factors for food allergy in a cohort of 386 children with atopic dermatitis attending a multidisciplinary dermatology/paediatric allergy clinic.
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J Allergy Clin Immunol 127(5) :1097-1107; quiz 1108-1109.
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J Allergy Clin Immunol 129(3)
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J Allergy Clin Immunol 132(2)
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J Allergy Clin Immunol 106(1 Pt 1)
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J Allergy Clin Immunol 123(5)
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J Allergy Clin Immunol 105(2 Pt 1)
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