REVIEW URRENT C OPINION
Food allergy in children: what is new? Paul J. Turner a,b and Robert J. Boyle a
Purpose of review Food allergy affects up to 10% of preschool children, and continues to increase in prevalence in many countries, resulting in a major public health issue, with practical implications for the food industry, educational establishments and healthcare systems. Recent findings The need to distinguish between food allergen sensitization and true clinical reactivity remains crucial in diagnosis, often requiring formal food challenge to avoid unnecessary dietary elimination. Epicutaneous exposure in the absence of oral tolerance induction during infancy may be an important risk factor for food allergy. Mounting evidence suggests that for milk and egg allergens, many children are able to tolerate the food when heat-modified, and that this may hasten resolution of the allergy. Summary These developments will hopefully result in a lower adverse impact on quality of life for food-allergic individuals and their families. Keywords children, desensitization, food allergy, prevention
INTRODUCTION Food allergy affects up to 10% of preschool children, and continues to increase in prevalence in many countries [1 ]. Overdiagnosis by parents [1 ] and healthcare professionals [2] is common, resulting in unnecessary dietary exclusion, which can impair both nutrition and socialization [3]. The difficulty of establishing a clear diagnosis is compounded by a lack of understanding over the difference between allergy (involving an immune response to an otherwise innocuous food protein) and intolerance (which is often temporary in children, caused by nonprotein constituents which do not trigger an immune response, and thus does not result in life-threatening reactions). Food allergy is a major public health issue, with practical implications for the food industry, educational establishments and healthcare systems. The risk of fatal food-induced anaphylaxis is very low [4 ] but also unpredictable; this contributes to social restrictions and anxiety which result in the adverse impact of food allergy being comparable to that seen with other chronic illnesses, such as diabetes [5 ]. We review recent advances in the prevention, diagnosis and management of food allergy, including selected ongoing studies. The role of gut microbiota is discussed elsewhere in this issue. We discuss immunoglobulin E (IgE)-mediated and non-IgE-mediated food allergy under separate sections, due to the disparity in progress between &
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these food-allergic immunophenotypes. Non-IgE food allergy has different clinical features to IgEfood allergy, many of which overlap with common nonallergic gastrointestinal symptoms of infancy (Table 1). Limited availability of robust diagnostics (see later) makes this group of conditions hard to study. Non-IgE-mediated food allergy includes foodassociated atopic eczema, food protein-induced enterocolitis syndrome (FPIES), eosinophilic oesophagitis (EoE) and allergic proctocolitis.
PREVENTION: IMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY Until recently, public health advice was to delay the introduction of many potential food allergens
a Section of Paediatrics (Allergy and Infectious Diseases) and MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK and bDivision of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
Correspondence to Dr Paul J. Turner, Section of Paediatrics (Allergy and Infectious Diseases), Imperial College London, Norfolk Place, London W2 1PG, UK. Tel: +44 20 3312 7754; fax: +44 20 3312 7571; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:285–293 DOI:10.1097/MCO.0000000000000052 This is an open access article distributed under the Creative Commons Attribution-Non Commercial License, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially.
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KEY POINTS Up to 30% of 4-month-old infants with eczema already have egg allergy; thus any future strategy to prevent food allergy will need to start early in infancy. Component resolved diagnostics can be helpful for understanding a child’s food allergy, but a good clinical history supplemented by skin prick testing (SPT) using appropriate allergen extracts/whole foods is still the most reliable outpatient diagnostic test for food allergy. Introduction of baked egg or milk products should be considered in egg-allergic and milk-allergic children, but should be done by supervised food challenge due to the risk of anaphylaxis. Specific oral tolerance induction (SOTI) is a promising treatment, but is not yet ready for routine clinical use.
beyond infancy [6]. Despite this, the prevalence of food allergy has increased [1 ]. This advice has now been revised to reflect the lack of evidence for allergen avoidance during pregnancy, breast-feeding or &
in early childhood on the development of food allergy [7]. The studies in this area often have methodological limitations, including recall bias, limited power and short duration of follow-up. Allergen avoidance intervention trials and more recent large observational studies have overcome some of these shortcomings. For example, Frazier et al. [8] reported a 16-year prospective study of 10 907 infants and found a decreased risk of nut allergy associated with nut consumption during/ after pregnancy. Infant eczema is a significant risk factor for food allergy, and infants with egg allergy and severe eczema are at high risk of sensitization to peanut [9]. There is emerging evidence that initial exposure to food allergens through inflamed skin may result in sensitization, increasing later risk of food allergy [10]. Peanut is widely distributed throughout the homes of peanut-consuming families, in a form that is likely to be able to cause sensitization [11 ]. Early orogastric exposure to food allergen, in the context of concurrent breast-feeding, may be protective, and a number of randomized-controlled studies &
Table 1. Features of immunoglobulin E-mediated and nonimmunoglobulin E-mediated food allergy
Onset of symptoms
IgE-mediated FA
Mixed IgE/non-IgE and non-IgE-mediated FA
Usually within 30 min of ingestion, < 1–2 h
Mostly 2–72 h after consumption
Symptoms: Gastrointestinal
Vomiting
Vomiting
Diarrhoea
Excessive crying (‘colic’)
Abdominal cramps
Altered gut transit causing loose/ frequent stools/constipation Abdominal cramps Food refusal/aversion Blood/mucous in stools Faltering growth
Extra-gastrointestinal
Skin: erythema, urticaria and angioedema
Skin: eczema
Respiratory: rhinitis, wheeze and cough
Cardiovascular shock (FPIES) – pallor, lethargy (probably secondary to large fluid shifts within the gut)
Cardiovascular: hypotension/dizziness Diagnosis
Skin prick testing
Trial elimination of suspected food protein þ/–reintroduction
Serum specific IgE testing Oral food challenge Management
Dietary elimination of causative food protein
Dietary elimination of causative food protein
Dietetic support as needed
Dietetic support
Written management plan with rescue medication (nonsedating antihistamine þ/– adrenaline autoinjector) Prognosis
Often persist into late childhood and adulthood
Typically resolve in early childhood, although some forms persist into adulthood, for example, EoE
EoE, eosinophilic oesophagitis; FA, food allergy; FPIES, food protein-induced enterocolitis syndrome; IgE, immunoglobulin E.
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are underway to investigate this [12 ]. The first, assessing early introduction of egg in infants with moderate/severe eczema, was confounded by a high (31%) rate of clinical egg allergy at 4 months of age in those randomized to early introduction [13]. This highlights the very early development of food allergy even prior to weaning, and the need for primary prevention interventions to start in early infancy. At 1 year, infants exposed to egg from 4 months of age were less likely to have egg allergy than those in whom egg introduction was delayed until 8 months (33 vs. 51%), although the difference was not statistically significant. In this high-risk cohort, early egg introduction did not increase the risk of egg allergy.
PREVENTION: NONIMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY Little is known regarding the cause of most non-IgEmediated food allergy. Although coeliac disease is not generally thought of as a food allergy, it is caused by a protein-induced immune response. Early (under age 4 months) or delayed (after 7 months) introduction of gluten may increase the risk of coeliac disease; breast-feeding may be protective, although the effect may be limited to delaying onset of the disease rather than actual prevention [14]. A multicentre randomized-controlled trial is currently underway to clarify this in children with a first-degree relative with coeliac disease [15]. Anecdotally, children with FPIES often have a history of initial tolerance to the causative food, followed by a delay of several months before the next exposure, which triggers an FPIES event. Whether this lack of ongoing exposure allows for the development of the reaction is unclear, but it is for this reason that many specialists recommend ongoing regular exposure to a food once it has been introduced.
DIAGNOSIS: IMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY The gold standard for diagnosis remains the double blind, placebo-controlled food challenge (DBPCFC),
in which increasing doses of food (or placebo) are given under medical supervision, although in clinical practice, an unblinded food challenge is often a more pragmatic alternative. Food challenges are time-consuming and in practice, IgE-mediated food allergy is frequently diagnosed through the demonstration of specific IgE antibody to the food protein (‘sensitization’) as a surrogate. This is achieved through ‘SPT’ or measurement of circulating serum-specific IgE (ssIgE), as reviewed elsewhere [16]. However, sensitization frequently does not correlate with clinical reactivity. The frequency of sensitization without clinical reactivity was reported systematically in the HealthNuts survey, an unselected birth cohort of 2848 infants in Melbourne, Australia who underwent SPT and open food challenges [17]. The findings are summarized in Table 2 [17]: under 50% of infants sensitized to peanut or sesame were clinically reactive. This highlights the need to interpret the presence of sensitization with caution: in the absence of a prior history of clinical reaction, oral food challenge (OFC) under medical supervision remains necessary in order to avoid unnecessary food restriction [18]. One concern with OFC is the potential for reactions following discharge. The 2012 PRACTALL guidelines describe in detail the safe conduct of DBPCFC, and for the first time, set internationally agreed objective stopping criteria [19 ]. They recommend a 2-h observation following ingestion of the last dose. One specific safety issue is biphasic reactions, in which symptoms recur following initial resolution. Lee et al. [20] published a retrospective series of 614 positive food challenges, and found that 1.5% experienced biphasic reactions 2–24 h after challenge; six of nine biphasic reactions met criteria for anaphylaxis. Thus, although biphasic reactions are uncommon, it is important to counsel parents prior to discharge and ensure availability of rescue medication. Anecdotally, biphasic episodes sometimes occur when a child eats a meal following OFC; the consumption of food may lead to further allergen absorption from the gut. Some units, therefore, encourage a child to eat a light meal following OFC, prior to discharge. &&
Table 2. Rates of sensitization and challenge-positive clinical allergy in the HealthNuts cohort of 2848 unselected 1-year-old infants Food allergen
Sensitization rate on skin testing (95% CI)
Peanut Egg Sesame
6.4% (5.5–7.3%) 11.7% (10.6–13.0%) 1.6% (1.2–2.1%)
Weighted, challenge positive food allergy (95% CI) 3.0% (2.4–3.8%) 8.9% (7.8–10.1%) 0.8% (0.5–1.2%)
Data from [17]. CI, confidence interval.
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Many groups have investigated whether more recent diagnostic techniques may be able to distinguish between sensitization and true clinical reactivity. Component-resolved diagnostics (CRD) measures IgE directed to specific parts of the food allergen, rather than to the whole protein extract as is the case with SPT and conventional ssIgE testing. The role of CRD in allergy testing has been recently reviewed [21], and is most commonly utilized in the assessment of: (1) Peanut allergy: clinical reactivity has been shown to be associated with the presence of IgE to Ara h 1, Ara h 2 and Ara h 3, although significant geographical variations have been reported [22 ]. However, few studies have compared CRD with existing conventional testing; the HealthNuts study is one exception, in which IgE to Ara h 2 was a better predictor of clinical allergy than conventional ssIgE, but not superior to standard SPT; 19% of infants with challenge-proven peanut allergy had a negative IgE to Ara h 2 (0.35 kUA/l). Where locally derived cut-offs are available, Ara h 2 may be helpful in avoiding the need for diagnostic OFC in children with sensitization [23,24]. Children with isolated (or predominant) IgE to Ara h 8 may be tolerant to peanut [25], or have birch pollen-related ‘pollen-food syndrome’. (2) Wheat-dependent exercise-induced anaphylaxis: many cases have been associated with sensitization to omega-5-gliadin (Tri a 19) [21]. &&
DIAGNOSIS: NONIMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY These types of food allergy are usually diagnosed by empiric exclusion diets, supplemented by re-exposure and/or intestinal biopsies as needed. Guidelines have been published for the diagnosis and management of non-IgE-mediated food allergy to cow’s milk, highlighting the need to confirm recurrence of symptoms with re-exposure and avoid unnecessary dietary exclusion [26]. EoE is the best characterized non-IgE-mediated food allergy, but improved diagnostics are still needed. Studies have identified the mucosal gene expression profile of EoE; these data have been used to develop a diagnostic test which can reliably distinguish EoE from controls, and EoE in remission from active disease [27], although a biopsy is still 288
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required. Analysis of gene expression in other forms of non-IgE-mediated food allergy may allow for much improved characterization of these conditions. A new entity of non-IgE-mediated ‘nonceliac wheat sensitivity’ was described in a large retrospective series of patients assessed using DBPCFC by Carroccio et al. [28]. The authors report two separate phenotypes – one characterized by other food allergy and eosinophilic duodenal/colonic infiltration, and one characterized by histological features of coeliac disease, with no association with other food allergy. Brottveit et al. [29] demonstrated an increase in mRNA expression for g-interferon in a similar cohort of patients, all of whom were human leukocyte antigen – DQ2-positive. However, a subsequent prospective study found that in patients with symptoms previously attributed to wheat and other gluten, symptoms improved with a diet low in fermentable short-chain carbohydrates (FODMAPs); gluten reintroduction did not result in further symptoms, the implication being that the response to a gluten-free diet might be due to FODMAP exclusion [30]. These differences between studies may be explained by heterogeneity in patients with a diagnosis of nonceliac wheat sensitivity. This is a controversial area, but it does seem that non-IgE wheat sensitivity in the absence of coeliac disease is associated with an immune response in some patients, although this needs further characterization, particularly in children.
MANAGEMENT: IMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY The prognosis of IgE-mediated food allergy is variable: over 50% children with food allergy to cow’s milk [31] or egg [32] will outgrow their allergy prior to mainstream schooling while most (up to 80%) nut allergies persist into adulthood, with resolution uncommon after age 10 years [33]. The mainstay of management remains dietary avoidance, however, accidental/inadvertent reactions following diagnosis are common. Nguyen-Luu et al. [34] found that one in eight peanut-allergic children experienced at least one accidental reaction every year, whereas Fleischer et al. [35 ] prospectively collected similar data in 512 infants, of whom 52% had at least one reaction over 3 years of follow-up, equating to an annualized reaction rate of 0.81 per year. Cow’s milk was by far the most common trigger, accounting for 42% of reactions, compared with egg (21%) and peanut (8%); this may relate to the ubiquitous role of milk in the human diet. Avoidance is, therefore, an inadequate measure &
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on its own, and all food-allergic children should receive a personalized management plan together with provision of rescue medication (which may include adrenaline/epinephrine autoinjector devices) in the event of an accidental reaction [1 ]. The frequency of severe and fatal reactions for food-allergic children has been clarified by recent work. A systematic review by Umasunthar et al. [4 ] found the incidence of ‘self-reported food anaphylaxis’ in food-allergic people aged 0–19 is relatively high, estimated at 4.9 [95% confidence interval (CI) 2.8–8.7] episodes per 100 person years. Reassuringly, however, rates were significantly lower for medically coded food anaphylaxis [0.2 (95% CI 0.1–0.4) episodes per 100 person years], hospital admission for food anaphylaxis [0.2 (95% CI 0.1– 0.4) episodes per 1000 person years] and fatal food anaphylaxis [3.5 (95% CI 1.7–7.2) per million person years] (Fig. 1) [4 ]. Healthcare professionals and allergic individuals (or their parents) may understand the risk estimates in different ways: parents interpret the risks in a more emotion-led context, considering their child to be ‘the one in a million’ who will die from a food-triggered anaphylactic reaction, whereas healthcare professionals often take an objective, rationale approach to low risk [36]. It can be difficult for both healthcare professionals and families to ‘strike a balance’ allowing safe dietary practice while minimizing the impact on dietary choice, social activities and quality of life. &
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Food-allergic children and their families may benefit from peer-to-peer support, to address the emotional burden of living with food allergy [37]. For milk and egg allergy, strict dietary elimination is not required for many children. Up to 70% of children with allergy to cow’s milk or egg are able to tolerate the allergen when extensively heated in baked foods such as cake and biscuits, as reviewed in [38 ]. This significantly liberalizes the diet, with beneficial effects on socialization (e.g. being able to eat food at birthday parties). Furthermore, children who tolerate baked foods containing egg [39] or cow’s milk [40] outgrow their allergy to the native protein faster. It is unclear if these children are more likely to outgrow their allergy per se, irrespective of their actual consumption of the allergen in baked foods. However, children who eat regular baked egg/ cow’s milk exhibit similar immunological changes to those undergoing oral desensitization [38 ], and Peters et al. [41 ] recently reported that the rate of resolution of egg allergy is proportional to the frequency of baked egg ingestion. These observations suggest that consumption of extensively modified egg and cow’s milk in baked foods may, therefore, act as a form of immunotherapy. Unfortunately, it is not possible to predict those children who do not tolerate baked egg/cow’s milk, some of whom will experience potentially severe anaphylactic reactions at exposure [42,43]. It is, therefore, recommended that tolerance is determined at OFC under medical supervision.
1 in 10 million
1 in 100 million
FIGURE 1. Annual incidence rate for different events in food-allergic people aged 0–19 years. Data are estimated risk of self-reported/medically coded/fatal food anaphylaxis and hospital admission for food anaphylaxis. Continuous bars represent means with 95% CI, dotted bars represent the range of point estimates from individual studies, in a systematic review undertaken by Umasunthar et al. [4 ]. Wherein reference risks vary markedly between European and US populations, they are stated separately. Otherwise, reference risks are for the US population. Adapted with permission from [4 ]. &
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MANAGEMENT: NONIMMUNOGLOBULIN EMEDIATED FOOD ALLERGY Relatively few major innovations have been made in the management of non-IgE food allergy in the past 12–18 months, reflecting the general lack of knowledge and research into this area. In the same way that children with IgE-mediated food allergy to cow’s milk often tolerate baked milk, Leung et al. [44 ] demonstrated that most adults with EoE are able to tolerate baked milk, something that may be applicable to children. Updated guidelines for the management of EoE [45] and non-IgE-mediated food allergy to cow’s milk [26] have recently been published. Chronic spontaneous (idiopathic) urticaria is frequently misdiagnosed as food allergy, due to the occurrence of a similar rash to that seen in food allergy, although in practice, the rash is less responsive to antihistamine and frequently of longer duration. Gray et al. [46] recently reviewed the evidence for salicylate-free diets in the management of children with this condition. They found no evidence for the efficacy of this intervention, and of greater concern, report a high rate of adverse events most likely due to dietary elimination. These diets cannot, therefore, be currently recommended. &
ALLERGEN LABELLING Most countries in the developed world require mandatory disclosure of allergens present in prepacked foods (Allen K.J., Turner P.J., Pawankar R et al. unpublished data). From December 2014, mandatory disclosure will apply to all nonprepacked foods sold in countries, which make up the European Union, including those from catering outlets and
delicatessens [47]. This represents a significant change in current legislation, and challenge to the wider food industry. However, precautionary advisory labelling (PAL) (also referred to as ‘may contain’ labels) used by manufacturers to indicate possible allergen cross-contamination during production, will continue to remain a voluntary measure and not legislated for. The use of PAL by food manufacturers is variable: many use PAL after conducting a rigorous risk assessment for allergen contamination, whereas others may use such labelling as a means to avoid such an assessment. Some studies have found that foods without PAL may also have significant allergen contamination (Table 3) [48–50], thus the absence of PAL does not imply a food is safe for consumption by allergic individuals. Studies measuring allergen contamination in foods with PAL consistently demonstrated a low but not negligible risk associated with the consumption of foods with PAL [51,52 ]. This is not surprising, given that over 50% of allergic individuals eat foods with PAL, as reviewed elsewhere [53,54 ]. Indeed, the vast majority of allergic reactions occur to nonprepacked foods, with the minority due to consumption of prepacked foods with PAL (Brough H.A., Turner P.J., Wright T et al. unpublished data). The risk of reaction due to allergen contamination needs to be balanced against the adverse impact such avoidance may have on quality of life. A recent survey of health professionals found that only a third would advise patients with nut allergy to avoid all foods with PAL [55]. One concern is that children (and their families) may interpret ‘tolerance’ of products with PAL as a sign of a more ‘mild’ food allergy, which can result in increased risk &
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Table 3. Rates of undeclared allergen cross-contamination (assessed as detectable amounts of allergen not declared as an ingredient) in prepacked foods with and without precautionary allergen labelling Study and allergens
% (No.) of food products with PAL
% (No.) of food products without PAL
Peanut
33% (109/333)
25% (52/211)
Hazelnut
60% (175/291)
31% (64/209)
Europe, 2007a [48]
USA, 2010 [49] Peanut
4% (5/112)
0% (0/120)
Egg
2% (1/57)
3% (3/117)
10% (6/59)
3% (4/134)
Cow’s milk Eire, 2011 [50] Peanut
7% (5/75)
2% (2/106)
Egg
6% (1/18)
5% (5/106)
Soya
3% (1/30)
5% (5/106)
PAL, precautionary advisory labelling. a This study assessed contamination in biscuits and cookies, which may be at higher risk of nut cross-contamination than other food products.
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taking. It is, therefore, essential for healthcare professionals to provide allergic consumers with individualized advice with regards to PAL, and counsel that a personalized management plan with appropriate rescue medication should be available at all times.
VACCINATION Despite historical concerns, the measles and measles-mumps-rubella vaccines are produced in chick fibroblast cell lines, which contain negligible amounts of egg protein; egg-allergic children can be given these without any additional precautions. Three vaccines continue to be produced in chick embryos (and thus contain small amounts of ovalbumin): influenza, yellow fever and rabies. An egg-free rabies vaccine is available and recommended for use in egg-allergic individuals. Although a recombinant egg-free influenza vaccine is available, it is not licensed for use in children. Des Roches et al. [56 ] recently summarized the published data relating to influenza vaccination in egg-allergic individuals, and concluded that an individual with egg allergy is no more likely to experience anaphylaxis to influenza vaccine than someone without egg allergy. These data have yet to be incorporated into national guidelines [57], and may not be applicable to influenza vaccines with a higher ovalbumin content. A multicentre study is currently underway to assess the safety of the intranasal live attenuated influenza vaccine in egg-allergic individuals [58]. Allergic reactions in egg-allergic individuals are most likely to occur with yellow fever vaccine; a desensitization regime has been published, which is suitable for use in egg-allergic children [59]. &&
TOLERANCE INDUCTION Given the poor prognosis of some food allergy, much research is now directed towards desensitization, in a similar way that desensitization is used in clinical practice for drug allergies and hay fever. Clinical trials have been performed in children with allergies to cow’s milk, egg and peanut, among others. These studies tend to utilize the oral route [specific oral tolerance induction, (SOTI)] to induce short-term desensitization, with most studies demonstrating a positive effect. One notable gap in the literature is a shared aim of treatment, agreed by physicians and patients, and the use of appropriate outcome measures to assess this in clinical trials. Although many studies have focussed on ‘desensitization’, ‘partial desensitization’ or ‘immune tolerance’ as primary outcomes, it is unclear what value these hold for different
patient groups, and how to weigh up the different success rates with the adverse effect rates seen in these trials. There are currently two main limitations to SOTI: (1) Safety: Cochrane reviews of SOTI to cow’s milk [60] and peanut [61] were published in 2012. In both cases, while desensitization is achieved in most individuals, there was a high rate of adverse events during SOTI, causing withdrawals of up to 10% of patients. A subsequent study specifically assessing the safety of SOTI to cow’s milk in 81 children reported that only 5% did not experience allergic reactions whereas 25% suffered frequent reactions [62 ]. (2) Lack of long-term tolerance: Most studies of SOTI have not assessed whether short-term desensitization results in long-term tolerance. Those that have provide cause for concern, as it seems that tolerance is rapidly lost if ongoing exposure to the allergen is discontinued. In a multicentre, randomized trial of SOTI in 55 egg-allergic or egg-sensitized children, 40 children completed the protocol, and desensitization was successful in 75% [63]. However, only 11 of 40 children continued to exhibit tolerance 2 months after stopping egg exposure. A similar lack of long-term tolerance induction has been reported in children undergoing SOTI or sublingual immunotherapy to cow’s milk [64 ] and peanut [65 ]. Further research is needed before oral immunotherapy can be considered a therapeutic option for routine clinical practice [60,61]. &
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Other groups are investigating alternative methods of desensitization to overcome some of these limitations. Trials assessing desensitization via the sublingual route (sublingual immunotherapy) in children with peanut [66] and cow’s milk allergy [67] have been published, and while the rate of adverse events is lower via this route, the amount of food protein which can be tolerated is lower than with SOTI. Other routes of allergen administration (e.g. epicutaneous/transdermal) are also being investigated, although the published reports to date indicate a lack of treatment effect [68]. One group in the USA is investigating the concomitant use of anti-IgE therapy during SOTI to multiple food allergens [69], and has found a significant reduction in adverse events: this strategy may represent the best option for future food desensitization, although the cost and availability of anti-IgE therapy within public healthcare systems are likely to be significant limiting factors. Alternative strategies using tolerogenic peptides (which can
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induce desensitization via T-cells without activating an IgE-mediated allergic response) are currently being investigated [70–72].
CONCLUSION The management of food allergy continues to be challenging, with data demonstrating the need to distinguish between a positive ‘allergy test’ and true clinical reactivity. Non-IgE-mediated food allergy is poorly understood, and there is much scope for further research into this area. Evidence is mounting for transcutaneous sensitization, perhaps in the absence of gut exposure, being a major risk factor in IgE-mediated food allergy and possible other types of food allergy too. Potentially, this may lead to new preventive strategies. Finally, there is a need to investigate ways of improving outcome in those with food allergy and/or their carers, using both medical and nonmedical interventions, to alleviate the adverse impact of food allergy on quality of life measures. Acknowledgements The authors would like to acknowledge the contributions of Dr Thisayanagam Umasunthar and Dr Jo LeonardiBee who assisted with the analysis presented in Fig. 1. Conflicts of interest The authors are supported by a NIHR Biomedical Research Centre, and the MRC Asthma UK Centre in Allergic Mechanisms of Asthma. P.J.T. is in receipt of a Clinician Scientist award funded by the UK Medical Research Council. R.J.B. has received a grant for conference attendance from Meda Pharmaceuticals, and research support from Lincoln Medical and Danone Research. The authors otherwise have no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Prescott SL, Pawankar R, Allen KJ, et al. A global survey of changing & patterns of food allergy burden in children. World Allergy Organ J 2013; 6:21. A worldwide survey and review of published prevalence data for food allergy, which also addresses differences in prevalence between regions. 2. Elizur A, Cohen M, Goldberg MR, et al. Mislabelled cow’s milk allergy in infants: a prospective cohort study. Arch Dis Child 2013; 98:408– 412. 3. Alvares M, Kao L, Mittal V, et al. Misdiagnosed food allergy resulting in severe malnutrition in an infant. Pediatrics 2013; 132:e229–e232. 4. Umasunthar T, Leonardi-Bee J, Hodes M, et al. Incidence of fatal & food anaphylaxis in people with food allergy: a systematic review and meta-analysis. Clin Exp Allergy 2013; 43:1333–1341. A comprehensive review of the likelihood of fatal food-allergic reactions compared with other causes of death.
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5. van der Velde JL, Dubois AE, Flokstra-de Blok BM. Food allergy and quality of & life: what have we learned? Curr Allergy Asthma Rep 2013; 13:651–661. This review provides a valuable update on both methodology and the available literature on the effect of food allergy on quality of life measures. 6. American Academy of Pediatrics, Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000; 106:346–349. 7. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract 2013; 1:29–36. 8. Frazier AL, Camargo CA Jr, Malspeis S, et al. 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. 9. Du Toit G, Roberts G, Sayre PH, et al. Identifying infants at high risk of peanut allergy: the Learning Early About Peanut Allergy (LEAP) screening study. J Allergy Clin Immunol 2013; 131:135–143. 10. Flohr C, Perkin M, Logan K, et al. Atopic dermatitis and disease severity are the main risk factors for food sensitization in exclusively breastfed infants. J Invest Dermatol 2014; 134:345–350. 11. Brough HA, Santos AF, Makinson K, et al. Peanut protein in household dust is & related to household peanut consumption and is biologically active. J Allergy Clin Immunol 2013; 132:630–638. This study demonstrated the widespread distribution of peanut protein in households where peanut is consumed, and that the protein in house dust is capable of triggering an immune response in basophils obtained from peanut-allergic individuals. 12. Metcalfe J, Prescott SL, Palmer DJ. Randomized controlled trials investigating && the role of allergen exposure in food allergy: where are we now? Curr Opin Allergy Clin Immunol 2013; 13:296–305. A review of published data relating to allergen exposure in both the treatment and prevention of food allergy, including intervention studies currently underway throughout the world. 13. Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: a randomized controlled trial. J Allergy Clin Immunol 2013; 132:387–392. 14. Szajewska H, Chmielewska A, Pies´cik-Lech M, et al. Systematic review: early infant feeding and the prevention of coeliac disease. Aliment Pharmacol Ther 2012; 36:607–618. 15. Influence of the dietary history in the PREVENTion of Coeliac Disease: possibilities of induction of tolerance for gluten in genetic predisposed children. http://www.controlled-trials.com/ISRCTN74582487. [Accessed on 7 January 2014] 16. Longo G, Berti I, Burks AW, et al. IgE-mediated food allergy in children. Lancet 2013; 382:1656–1664. 17. Osborne NJ, Koplin JJ, Martin PE, 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; e1-2. 18. Dambacher WM, de Kort EH, Blom WM, et al. Double-blind placebocontrolled food challenges in children with alleged cow’s milk allergy: prevention of unnecessary elimination diets and determination of eliciting doses. Nutr J 2013; 12:22. 19. Sampson HA, Gerth van Wijk R, Bindslev-Jensen C, et al. Standardizing && double-blind, placebo-controlled oral food challenges: American Academy of Allergy, Asthma Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol 2012; 130:1260–1274. Essential guidance on the conduct of food challenges, written by international experts from the perspective of standardizing OFC in research but applicable to all challenges conducted in routine allergy practice. Includes safety considerations, food dosing schedules and stopping criteria. 20. Lee J, Garrett JP, Brown-Whitehorn T, Spergel JM. Biphasic reactions in children undergoing oral food challenges. Allergy Asthma Proc 2013; 34:220–226. 21. Canonica GW, Ansotegui IJ, Pawankar R, et al. A WAO - ARIA - GA2LEN consensus document on molecular-based allergy diagnostics. World Allergy Organ J 2013; 6:17. 22. Sicherer SH, Wood RA. Advances in diagnosing peanut allergy. J Allergy Clin && Immunol Pract 2013; 1:1–13. A recent review of the techniques available for the diagnosis of peanut allergy, and the benefits and limitations of each, including component testing. The authors also review data demonstrating that sensitization to peanut is far more common than clinical peanut allergy. 23. Dang TD, Tang M, Choo S, et al. Increasing the accuracy of peanut allergy diagnosis by using Ara h 2. J Allergy Clin Immunol 2012; 129:1056–1063. 24. Eller E, Bindslev-Jensen C. Clinical value of component-resolved diagnostics in peanut-allergic patients. Allergy 2013; 68:190–194. 25. Asarnoj A, Nilsson C, Lidholm J, et al. Peanut component Ara h 8 sensitization and tolerance to peanut. J Allergy Clin Immunol 2012; 130:468–472. 26. Venter C, Brown T, Shah N, et al. Diagnosis and management of non-IgEmediated cow’s milk allergy in infancy: a UK primary care practical guide. Clin Transl Allergy 2013; 3:23. 27. Wen T, Stucke EM, Grotjan TM, et al. Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology 2013; 145: 1289–1299.
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Food allergy in children: what is new? Turner and Boyle 28. Carroccio A, Mansueto P, Iacono G, et al. Nonceliac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol 2012; 107:1898–1906. 29. Brottveit M, Beitnes AC, Tollefsen S, et al. Mucosal cytokine response after short-term gluten challenge in celiac disease and nonceliac gluten sensitivity. Am J Gastroenterol 2013; 108:842–850. 30. Biesiekierski JR, Peters SL, Newnham ED, et al. No effects of gluten in patients with self-reported nonceliac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology 2013; 145:320–328; e1-3. 31. Wood RA, Sicherer SH, Vickery BP, et al. The natural history of milk allergy in an observational cohort. J Allergy Clin Immunol 2013; 131:805–812. 32. Clark A, Islam S, King Y, et al. A longitudinal study of resolution of allergy to well cooked and uncooked egg. Clin Exp Allergy 2011; 41:706–712. 33. Begin P, Paradis L, Paradis J, et al. Natural resolution of peanut allergy: a 12-year longitudinal follow-up study. J Allergy Clin Immunol Pract 2013; 1:528–530; e4. 34. Nguyen-Luu NU, Ben-Shoshan M, Alizadehfar R, et al. Inadvertent exposures in children with peanut allergy. Pediatr Allergy Immunol 2012; 23:133–139. 35. Fleischer DM, Perry TT, Atkins D, et al. Allergic reactions to foods in & preschool-aged children in a prospective observational food allergy study. Pediatrics 2012; 130:e25–32. An analysis of the frequency of accidental reactions in preschool children with food allergies over a 3-year period. Reactions were common; less than one-third of severe reactions were treated appropriately. 36. Hu W, Grbich C, Kemp A. When doctors disagree: a qualitative study of doctors’ and parents’ views on the risks of childhood food allergy. Health Expect 2008; 11:208–219. 37. Knibb RC, Hourihane JO. The psychosocial impact of an activity holiday for young children with severe food allergy: a longitudinal study. Pediatr Allergy Immunol 2013; 24:368–375. 38. Huang F, Nowak-We˛grzyn A. Extensively heated milk and egg as oral & immunotherapy. Curr Opin Allergy Clin Immunol 2012; 12:283–292. A summary of the evidence for introducing baked foods containing egg and milk into the diets of egg-allergic and milk-allergic children, once tolerance to the baked allergen has been confirmed. 39. Leonard SA, Sampson HA, Sicherer SH, et al. Dietary baked egg accelerates resolution of egg allergy in children. J Allergy Clin Immunol 2012; 130:473– 480; e1. 40. Kim JS, Nowak-We˛grzyn A, Sicherer SH, et al. Dietary baked milk accelerates the resolution of cow’s milk allergy in children. J Allergy Clin Immunol 2011; 128:125–131; e2. 41. Peters RL, Dharmage SC, Gurrin LC, et al. The natural history and clinical & predictors of egg allergy in the first 2 years of life: A prospective, populationbased cohort study. J Allergy Clin Immunol 2013. [Epub ahead of print]. doi:10.1016/j.jaci.2013.11.032. This study reports 1-year follow-up in egg-allergic children in the HealthNUTS cohort. Those infants found to tolerate baked egg at 1 year of age had over 50% chance of outgrowing their allergy by age 2 years (compared with just 13% resolution rate in those allergic to baked egg), an effect linked to the frequency of baked egg ingestion. 42. Turner PJ, Mehr S, Joshi P, et al. Safety of food challenges to extensively heated egg in egg-allergic children: a prospective cohort study. Pediatr Allergy Immunol 2013; 24:450–455. 43. Mehr S, Turner PJ, Joshi P, et al. Review of baked milk challenges at a tertiary paediatric allergy centre. Intern Med J 2013; 43 (S4):6. 44. Leung J, Hundal NV, Katz AJ, et al. Tolerance of baked milk in patients with & cow’s milk-mediated eosinophilic esophagitis. J Allergy Clin Immunol 2013; 132:1215–1216; e1. A retrospective analysis of 15 patients with EoE triggered by cow’s milk, 11 (73%) of whom could tolerate cakes and biscuits containing cow’s milk. 45. Papadopoulou A, Koletzko S, Heuschkel R, et al., ESPGHAN Eosinophilic Esophagitis Working Group and the Gastroenterology Committee. Management guidelines of eosinophilic esophagitis in childhood. J Pediatr Gastroenterol Nutr 2014; 58:107–118. 46. Gray PE, Mehr S, Katelaris CH, et al. Salicylate elimination diets in children: is food restriction supported by the evidence? Med J Aust 2013; 198:600–602. 47. European Commission. New EU law on food information to consumers. http:// ec.europa.eu/food/food/labellingnutrition/foodlabelling/proposed_legislation_ en.htm. [Accessed on 7 January 2014] 48. Pele M, Brohee M, Anklam E, van Hengel AJ. Peanut and hazelnut traces in cookies and chocolates: relationship between analytical results and declaration of food allergens on product labels. Food Add Contam 2007; 24:1334–1344. 49. Ford LS, Taylor SL, Pacenza R, et al. Food allergen advisory labeling and product contamination with egg, milk, and peanut. J Allergy Clin Immunol 2010; 126:384–385. 50. Food Safety Authority of Ireland (FSAI). Food Allergens & Labelling Survey 2011. www.fsai.ie/resources_publications/allergen_labelling_2011.html. html. [Accessed on 7 January 2014] 51. Robertson ON, Hourihane JO, Remington BC, Taylor SL. Survey of peanut levels in selected Irish food products bearing peanut allergen advisory labels. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013; 30:1467–1472.
52. Remington BC, Baumert JL, Marx DB, Taylor SL. Quantitative risk assessment of foods containing peanut advisory labeling. Food Chem Toxicol 2013; 62:179–187. This article demonstrates how cross-contamination data can be used in conjunction with consumption patterns and allergen threshold data to provide a model as to the population risk of an allergic reaction when consuming foods with a precautionary allergen label. 53. Zurzolo GA, Koplin JJ, Mathai ML, et al. Perceptions of precautionary labelling among parents of children with food allergy and anaphylaxis. Med J Aust 2013; 198:621–623. 54. Cochrane SA, Gowland MH, Sheffield D, Crevel RW. Characteristics and & purchasing behaviours of food-allergic consumers and those who buy food for them in Great Britain. Clin Transl Allergy 2013; 3:31. A useful insight into the process by which food-allergic patients and their carers decide what food products are safe for consumption. 55. Turner PJ, Skypala IJ, Fox AT. Advice recommended by health professionals regarding precautionary allergen labelling on prepacked foods. Pediatr Allergy Immunol 2013. [Epub ahead of print]. doi: 10.1111/pai.12178. 56. Des Roches A, Paradis L, Gagnon R, et al. Egg-allergic patients can be && safely vaccinated against influenza. J Allergy Clin Immunol 2012; 130:1213– 1216; e1. A summary of the published data to date relating to 4729 doses of influenza vaccine in 4172 egg-allergic individuals; no systemic reactions were recorded. The authors state that these data demonstrate the safety of influenza vaccination in egg-allergic individuals without the need for additional safety precautions beyond that which should be available in routine vaccination clinics, including in primary care. 57. Kelso JM, Greenhawt MJ, Li JY, et al. The Joint Task Force on Practice Parameters (JTFPP). Update on influenza vaccination of egg allergic patients. Ann Allergy Asthma Immunol 2013; 111:301–302. 58. Safety of Nasal Influenza Immunisation in Egg Allergic Children (SNIFFLE) Study. http://clinicaltrials.gov/show/NCT01859039. [Accessed on 7 January 2014] 59. Rutkowski K, Ewan PW, Nasser SM. Administration of yellow fever vaccine in patients with egg allergy. Int Arch Allergy Immunol 2013; 161:274–278. 60. Yeung JP, Kloda LA, McDevitt J, et al. Oral immunotherapy for milk allergy. Cochrane Database Syst Rev 2012; 11:CD009542. 61. Nurmatov U, Venderbosch I, Devereux G, et al. Allergen-specific oral immunotherapy for peanut allergy. Cochrane Database Syst Rev 2012; 9:CD009014. 62. Va´zquez-Ortiz M, Alvaro-Lozano M, Alsina L, et al. Safety and predictors of & adverse events during oral immunotherapy for milk allergy: severity of reaction at oral challenge, specific IgE and prick test. Clin Exp Allergy 2013; 43:92– 102. An analysis of safety data in 81 children undergoing SOTI to cow’s milk. Ninety-five percent of children suffered reactions, 78% of which occurred in a higher risk cohort of 20 children. The authors propose risk factors to identify children at higher risk of severe reactions during SOTI to milk. 63. Burks AW, Jones SM, Wood RA, et al. Oral immunotherapy for treatment of egg allergy in children. N Engl J Med 2012; 367:233–243. 64. Keet CA, Seopaul S, Knorr S, et al. Long-term follow-up of oral immunotherapy && for cow’s milk allergy. J Allergy Clin Immunol 2013; 132:737–739; e6. A summary of long-term tolerance data in children undergoing SOTI to cow’s milk. Although SOTI was initially successful, desensitization was lost with time, and only 31% children were able to tolerate a serving of milk at follow-up of 1–5 years after SOTI induction. 65. Vickery BP, Scurlock AM, Kulis M, et al. Sustained unresponsiveness to && peanut in subjects who have completed peanut oral immunotherapy. J Allergy Clin Immunol 2013. [Epub ahead of print]. doi: 10.1016/j.jaci.2013.11.007. In this study of 24 children who successfully completely a SOTI protocol to peanut, only 50% remained tolerant 1 month after stopping peanut consumption. 66. Fleischer DM, Burks AW, Vickery BP, et al. Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial. J Allergy Clin Immunol 2013; 131:119–127; e1-7. 67. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, et al. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol 2012; 129:448–455; 455.e1-5. 68. Dupont C, Kalach N, Soulaines P, et al. Cow’s milk epicutaneous immunotherapy in children: a pilot trial of safety, acceptability, and impact on allergic reactivity. J Allergy Clin Immunol 2010; 125:1165–1167. 69. Dominguez TLR, Mehrotra A, Wilson S, et al. The safety of multiple oral immunotherapy in phase one studies at a single center. Clin Transl Allergy 2013; 3 (Suppl 3):O25. 70. Meulenbroek LA, van Esch BC, Hofman GA, et al. Oral treatment with b-lactoglobulin peptides prevents clinical symptoms in a mouse model for cow’s milk allergy. Pediatr Allergy Immunol 2013; 24:656–664. 71. Rupa P, Mine Y. Oral immunotherapy with immunodominant T-cell epitope peptides alleviates allergic reactions in a Balb/c mouse model of egg allergy. Allergy 2012; 67:74–82. 72. Wood RA, Sicherer SH, Burks AW, et al. A phase 1 study of heat/phenolkilled, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy. Allergy 2013; 68:803–808. &
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Food allergy in children: what is new? Paul J. Turner a,b and Robert J. Boyle a
Purpose of review Food allergy affects up to 10% of preschool children, and continues to increase in prevalence in many countries, resulting in a major public health issue, with practical implications for the food industry, educational establishments and healthcare systems. Recent findings The need to distinguish between food allergen sensitization and true clinical reactivity remains crucial in diagnosis, often requiring formal food challenge to avoid unnecessary dietary elimination. Epicutaneous exposure in the absence of oral tolerance induction during infancy may be an important risk factor for food allergy. Mounting evidence suggests that for milk and egg allergens, many children are able to tolerate the food when heat-modified, and that this may hasten resolution of the allergy. Summary These developments will hopefully result in a lower adverse impact on quality of life for food-allergic individuals and their families. Keywords children, desensitization, food allergy, prevention
INTRODUCTION Food allergy affects up to 10% of preschool children, and continues to increase in prevalence in many countries [1 ]. Overdiagnosis by parents [1 ] and healthcare professionals [2] is common, resulting in unnecessary dietary exclusion, which can impair both nutrition and socialization [3]. The difficulty of establishing a clear diagnosis is compounded by a lack of understanding over the difference between allergy (involving an immune response to an otherwise innocuous food protein) and intolerance (which is often temporary in children, caused by nonprotein constituents which do not trigger an immune response, and thus does not result in life-threatening reactions). Food allergy is a major public health issue, with practical implications for the food industry, educational establishments and healthcare systems. The risk of fatal food-induced anaphylaxis is very low [4 ] but also unpredictable; this contributes to social restrictions and anxiety which result in the adverse impact of food allergy being comparable to that seen with other chronic illnesses, such as diabetes [5 ]. We review recent advances in the prevention, diagnosis and management of food allergy, including selected ongoing studies. The role of gut microbiota is discussed elsewhere in this issue. We discuss immunoglobulin E (IgE)-mediated and non-IgE-mediated food allergy under separate sections, due to the disparity in progress between &
&
&
&
these food-allergic immunophenotypes. Non-IgE food allergy has different clinical features to IgEfood allergy, many of which overlap with common nonallergic gastrointestinal symptoms of infancy (Table 1). Limited availability of robust diagnostics (see later) makes this group of conditions hard to study. Non-IgE-mediated food allergy includes foodassociated atopic eczema, food protein-induced enterocolitis syndrome (FPIES), eosinophilic oesophagitis (EoE) and allergic proctocolitis.
PREVENTION: IMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY Until recently, public health advice was to delay the introduction of many potential food allergens
a Section of Paediatrics (Allergy and Infectious Diseases) and MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK and bDivision of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
Correspondence to Dr Paul J. Turner, Section of Paediatrics (Allergy and Infectious Diseases), Imperial College London, Norfolk Place, London W2 1PG, UK. Tel: +44 20 3312 7754; fax: +44 20 3312 7571; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:285–293 DOI:10.1097/MCO.0000000000000052 This is an open access article distributed under the Creative Commons Attribution-Non Commercial License, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially.
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KEY POINTS Up to 30% of 4-month-old infants with eczema already have egg allergy; thus any future strategy to prevent food allergy will need to start early in infancy. Component resolved diagnostics can be helpful for understanding a child’s food allergy, but a good clinical history supplemented by skin prick testing (SPT) using appropriate allergen extracts/whole foods is still the most reliable outpatient diagnostic test for food allergy. Introduction of baked egg or milk products should be considered in egg-allergic and milk-allergic children, but should be done by supervised food challenge due to the risk of anaphylaxis. Specific oral tolerance induction (SOTI) is a promising treatment, but is not yet ready for routine clinical use.
beyond infancy [6]. Despite this, the prevalence of food allergy has increased [1 ]. This advice has now been revised to reflect the lack of evidence for allergen avoidance during pregnancy, breast-feeding or &
in early childhood on the development of food allergy [7]. The studies in this area often have methodological limitations, including recall bias, limited power and short duration of follow-up. Allergen avoidance intervention trials and more recent large observational studies have overcome some of these shortcomings. For example, Frazier et al. [8] reported a 16-year prospective study of 10 907 infants and found a decreased risk of nut allergy associated with nut consumption during/ after pregnancy. Infant eczema is a significant risk factor for food allergy, and infants with egg allergy and severe eczema are at high risk of sensitization to peanut [9]. There is emerging evidence that initial exposure to food allergens through inflamed skin may result in sensitization, increasing later risk of food allergy [10]. Peanut is widely distributed throughout the homes of peanut-consuming families, in a form that is likely to be able to cause sensitization [11 ]. Early orogastric exposure to food allergen, in the context of concurrent breast-feeding, may be protective, and a number of randomized-controlled studies &
Table 1. Features of immunoglobulin E-mediated and nonimmunoglobulin E-mediated food allergy
Onset of symptoms
IgE-mediated FA
Mixed IgE/non-IgE and non-IgE-mediated FA
Usually within 30 min of ingestion, < 1–2 h
Mostly 2–72 h after consumption
Symptoms: Gastrointestinal
Vomiting
Vomiting
Diarrhoea
Excessive crying (‘colic’)
Abdominal cramps
Altered gut transit causing loose/ frequent stools/constipation Abdominal cramps Food refusal/aversion Blood/mucous in stools Faltering growth
Extra-gastrointestinal
Skin: erythema, urticaria and angioedema
Skin: eczema
Respiratory: rhinitis, wheeze and cough
Cardiovascular shock (FPIES) – pallor, lethargy (probably secondary to large fluid shifts within the gut)
Cardiovascular: hypotension/dizziness Diagnosis
Skin prick testing
Trial elimination of suspected food protein þ/–reintroduction
Serum specific IgE testing Oral food challenge Management
Dietary elimination of causative food protein
Dietary elimination of causative food protein
Dietetic support as needed
Dietetic support
Written management plan with rescue medication (nonsedating antihistamine þ/– adrenaline autoinjector) Prognosis
Often persist into late childhood and adulthood
Typically resolve in early childhood, although some forms persist into adulthood, for example, EoE
EoE, eosinophilic oesophagitis; FA, food allergy; FPIES, food protein-induced enterocolitis syndrome; IgE, immunoglobulin E.
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Food allergy in children: what is new? Turner and Boyle &&
are underway to investigate this [12 ]. The first, assessing early introduction of egg in infants with moderate/severe eczema, was confounded by a high (31%) rate of clinical egg allergy at 4 months of age in those randomized to early introduction [13]. This highlights the very early development of food allergy even prior to weaning, and the need for primary prevention interventions to start in early infancy. At 1 year, infants exposed to egg from 4 months of age were less likely to have egg allergy than those in whom egg introduction was delayed until 8 months (33 vs. 51%), although the difference was not statistically significant. In this high-risk cohort, early egg introduction did not increase the risk of egg allergy.
PREVENTION: NONIMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY Little is known regarding the cause of most non-IgEmediated food allergy. Although coeliac disease is not generally thought of as a food allergy, it is caused by a protein-induced immune response. Early (under age 4 months) or delayed (after 7 months) introduction of gluten may increase the risk of coeliac disease; breast-feeding may be protective, although the effect may be limited to delaying onset of the disease rather than actual prevention [14]. A multicentre randomized-controlled trial is currently underway to clarify this in children with a first-degree relative with coeliac disease [15]. Anecdotally, children with FPIES often have a history of initial tolerance to the causative food, followed by a delay of several months before the next exposure, which triggers an FPIES event. Whether this lack of ongoing exposure allows for the development of the reaction is unclear, but it is for this reason that many specialists recommend ongoing regular exposure to a food once it has been introduced.
DIAGNOSIS: IMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY The gold standard for diagnosis remains the double blind, placebo-controlled food challenge (DBPCFC),
in which increasing doses of food (or placebo) are given under medical supervision, although in clinical practice, an unblinded food challenge is often a more pragmatic alternative. Food challenges are time-consuming and in practice, IgE-mediated food allergy is frequently diagnosed through the demonstration of specific IgE antibody to the food protein (‘sensitization’) as a surrogate. This is achieved through ‘SPT’ or measurement of circulating serum-specific IgE (ssIgE), as reviewed elsewhere [16]. However, sensitization frequently does not correlate with clinical reactivity. The frequency of sensitization without clinical reactivity was reported systematically in the HealthNuts survey, an unselected birth cohort of 2848 infants in Melbourne, Australia who underwent SPT and open food challenges [17]. The findings are summarized in Table 2 [17]: under 50% of infants sensitized to peanut or sesame were clinically reactive. This highlights the need to interpret the presence of sensitization with caution: in the absence of a prior history of clinical reaction, oral food challenge (OFC) under medical supervision remains necessary in order to avoid unnecessary food restriction [18]. One concern with OFC is the potential for reactions following discharge. The 2012 PRACTALL guidelines describe in detail the safe conduct of DBPCFC, and for the first time, set internationally agreed objective stopping criteria [19 ]. They recommend a 2-h observation following ingestion of the last dose. One specific safety issue is biphasic reactions, in which symptoms recur following initial resolution. Lee et al. [20] published a retrospective series of 614 positive food challenges, and found that 1.5% experienced biphasic reactions 2–24 h after challenge; six of nine biphasic reactions met criteria for anaphylaxis. Thus, although biphasic reactions are uncommon, it is important to counsel parents prior to discharge and ensure availability of rescue medication. Anecdotally, biphasic episodes sometimes occur when a child eats a meal following OFC; the consumption of food may lead to further allergen absorption from the gut. Some units, therefore, encourage a child to eat a light meal following OFC, prior to discharge. &&
Table 2. Rates of sensitization and challenge-positive clinical allergy in the HealthNuts cohort of 2848 unselected 1-year-old infants Food allergen
Sensitization rate on skin testing (95% CI)
Peanut Egg Sesame
6.4% (5.5–7.3%) 11.7% (10.6–13.0%) 1.6% (1.2–2.1%)
Weighted, challenge positive food allergy (95% CI) 3.0% (2.4–3.8%) 8.9% (7.8–10.1%) 0.8% (0.5–1.2%)
Data from [17]. CI, confidence interval.
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Many groups have investigated whether more recent diagnostic techniques may be able to distinguish between sensitization and true clinical reactivity. Component-resolved diagnostics (CRD) measures IgE directed to specific parts of the food allergen, rather than to the whole protein extract as is the case with SPT and conventional ssIgE testing. The role of CRD in allergy testing has been recently reviewed [21], and is most commonly utilized in the assessment of: (1) Peanut allergy: clinical reactivity has been shown to be associated with the presence of IgE to Ara h 1, Ara h 2 and Ara h 3, although significant geographical variations have been reported [22 ]. However, few studies have compared CRD with existing conventional testing; the HealthNuts study is one exception, in which IgE to Ara h 2 was a better predictor of clinical allergy than conventional ssIgE, but not superior to standard SPT; 19% of infants with challenge-proven peanut allergy had a negative IgE to Ara h 2 (0.35 kUA/l). Where locally derived cut-offs are available, Ara h 2 may be helpful in avoiding the need for diagnostic OFC in children with sensitization [23,24]. Children with isolated (or predominant) IgE to Ara h 8 may be tolerant to peanut [25], or have birch pollen-related ‘pollen-food syndrome’. (2) Wheat-dependent exercise-induced anaphylaxis: many cases have been associated with sensitization to omega-5-gliadin (Tri a 19) [21]. &&
DIAGNOSIS: NONIMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY These types of food allergy are usually diagnosed by empiric exclusion diets, supplemented by re-exposure and/or intestinal biopsies as needed. Guidelines have been published for the diagnosis and management of non-IgE-mediated food allergy to cow’s milk, highlighting the need to confirm recurrence of symptoms with re-exposure and avoid unnecessary dietary exclusion [26]. EoE is the best characterized non-IgE-mediated food allergy, but improved diagnostics are still needed. Studies have identified the mucosal gene expression profile of EoE; these data have been used to develop a diagnostic test which can reliably distinguish EoE from controls, and EoE in remission from active disease [27], although a biopsy is still 288
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required. Analysis of gene expression in other forms of non-IgE-mediated food allergy may allow for much improved characterization of these conditions. A new entity of non-IgE-mediated ‘nonceliac wheat sensitivity’ was described in a large retrospective series of patients assessed using DBPCFC by Carroccio et al. [28]. The authors report two separate phenotypes – one characterized by other food allergy and eosinophilic duodenal/colonic infiltration, and one characterized by histological features of coeliac disease, with no association with other food allergy. Brottveit et al. [29] demonstrated an increase in mRNA expression for g-interferon in a similar cohort of patients, all of whom were human leukocyte antigen – DQ2-positive. However, a subsequent prospective study found that in patients with symptoms previously attributed to wheat and other gluten, symptoms improved with a diet low in fermentable short-chain carbohydrates (FODMAPs); gluten reintroduction did not result in further symptoms, the implication being that the response to a gluten-free diet might be due to FODMAP exclusion [30]. These differences between studies may be explained by heterogeneity in patients with a diagnosis of nonceliac wheat sensitivity. This is a controversial area, but it does seem that non-IgE wheat sensitivity in the absence of coeliac disease is associated with an immune response in some patients, although this needs further characterization, particularly in children.
MANAGEMENT: IMMUNOGLOBULIN E-MEDIATED FOOD ALLERGY The prognosis of IgE-mediated food allergy is variable: over 50% children with food allergy to cow’s milk [31] or egg [32] will outgrow their allergy prior to mainstream schooling while most (up to 80%) nut allergies persist into adulthood, with resolution uncommon after age 10 years [33]. The mainstay of management remains dietary avoidance, however, accidental/inadvertent reactions following diagnosis are common. Nguyen-Luu et al. [34] found that one in eight peanut-allergic children experienced at least one accidental reaction every year, whereas Fleischer et al. [35 ] prospectively collected similar data in 512 infants, of whom 52% had at least one reaction over 3 years of follow-up, equating to an annualized reaction rate of 0.81 per year. Cow’s milk was by far the most common trigger, accounting for 42% of reactions, compared with egg (21%) and peanut (8%); this may relate to the ubiquitous role of milk in the human diet. Avoidance is, therefore, an inadequate measure &
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Food allergy in children: what is new? Turner and Boyle
on its own, and all food-allergic children should receive a personalized management plan together with provision of rescue medication (which may include adrenaline/epinephrine autoinjector devices) in the event of an accidental reaction [1 ]. The frequency of severe and fatal reactions for food-allergic children has been clarified by recent work. A systematic review by Umasunthar et al. [4 ] found the incidence of ‘self-reported food anaphylaxis’ in food-allergic people aged 0–19 is relatively high, estimated at 4.9 [95% confidence interval (CI) 2.8–8.7] episodes per 100 person years. Reassuringly, however, rates were significantly lower for medically coded food anaphylaxis [0.2 (95% CI 0.1–0.4) episodes per 100 person years], hospital admission for food anaphylaxis [0.2 (95% CI 0.1– 0.4) episodes per 1000 person years] and fatal food anaphylaxis [3.5 (95% CI 1.7–7.2) per million person years] (Fig. 1) [4 ]. Healthcare professionals and allergic individuals (or their parents) may understand the risk estimates in different ways: parents interpret the risks in a more emotion-led context, considering their child to be ‘the one in a million’ who will die from a food-triggered anaphylactic reaction, whereas healthcare professionals often take an objective, rationale approach to low risk [36]. It can be difficult for both healthcare professionals and families to ‘strike a balance’ allowing safe dietary practice while minimizing the impact on dietary choice, social activities and quality of life. &
&
&
1 in 100
1 in 1000
1 in 10 000
1 in 100 000
1 in 1 million
ligh tnin g due to a th De
a th De
a th
due to fi re due to m urd er (
Eur ope )
Fatal food anaphylaxis
f ro ma ny cau f ro se ma (US ny A) cau se De ( Eur a th ope due ) to a De na a th cci den due t (U to a De SA na a th ) cci due den to m t (E u urd rop er ( e) US A)
a th
a th
De
De
Em e due rgenc to m y ro oto om a r ve t hic t enda le a n cci ce den t
t t en dan ce
t t en dan ce
Em e due rgenc y to i nju room ry a
Em
erg
enc y ro om a
1 in 10
&
&
Hospital admission for food anaphylaxis
Medically coded food anaphylaxis
Definite
&
De
Self-reported food anaphylaxis
Food-allergic children and their families may benefit from peer-to-peer support, to address the emotional burden of living with food allergy [37]. For milk and egg allergy, strict dietary elimination is not required for many children. Up to 70% of children with allergy to cow’s milk or egg are able to tolerate the allergen when extensively heated in baked foods such as cake and biscuits, as reviewed in [38 ]. This significantly liberalizes the diet, with beneficial effects on socialization (e.g. being able to eat food at birthday parties). Furthermore, children who tolerate baked foods containing egg [39] or cow’s milk [40] outgrow their allergy to the native protein faster. It is unclear if these children are more likely to outgrow their allergy per se, irrespective of their actual consumption of the allergen in baked foods. However, children who eat regular baked egg/ cow’s milk exhibit similar immunological changes to those undergoing oral desensitization [38 ], and Peters et al. [41 ] recently reported that the rate of resolution of egg allergy is proportional to the frequency of baked egg ingestion. These observations suggest that consumption of extensively modified egg and cow’s milk in baked foods may, therefore, act as a form of immunotherapy. Unfortunately, it is not possible to predict those children who do not tolerate baked egg/cow’s milk, some of whom will experience potentially severe anaphylactic reactions at exposure [42,43]. It is, therefore, recommended that tolerance is determined at OFC under medical supervision.
1 in 10 million
1 in 100 million
FIGURE 1. Annual incidence rate for different events in food-allergic people aged 0–19 years. Data are estimated risk of self-reported/medically coded/fatal food anaphylaxis and hospital admission for food anaphylaxis. Continuous bars represent means with 95% CI, dotted bars represent the range of point estimates from individual studies, in a systematic review undertaken by Umasunthar et al. [4 ]. Wherein reference risks vary markedly between European and US populations, they are stated separately. Otherwise, reference risks are for the US population. Adapted with permission from [4 ]. &
&
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MANAGEMENT: NONIMMUNOGLOBULIN EMEDIATED FOOD ALLERGY Relatively few major innovations have been made in the management of non-IgE food allergy in the past 12–18 months, reflecting the general lack of knowledge and research into this area. In the same way that children with IgE-mediated food allergy to cow’s milk often tolerate baked milk, Leung et al. [44 ] demonstrated that most adults with EoE are able to tolerate baked milk, something that may be applicable to children. Updated guidelines for the management of EoE [45] and non-IgE-mediated food allergy to cow’s milk [26] have recently been published. Chronic spontaneous (idiopathic) urticaria is frequently misdiagnosed as food allergy, due to the occurrence of a similar rash to that seen in food allergy, although in practice, the rash is less responsive to antihistamine and frequently of longer duration. Gray et al. [46] recently reviewed the evidence for salicylate-free diets in the management of children with this condition. They found no evidence for the efficacy of this intervention, and of greater concern, report a high rate of adverse events most likely due to dietary elimination. These diets cannot, therefore, be currently recommended. &
ALLERGEN LABELLING Most countries in the developed world require mandatory disclosure of allergens present in prepacked foods (Allen K.J., Turner P.J., Pawankar R et al. unpublished data). From December 2014, mandatory disclosure will apply to all nonprepacked foods sold in countries, which make up the European Union, including those from catering outlets and
delicatessens [47]. This represents a significant change in current legislation, and challenge to the wider food industry. However, precautionary advisory labelling (PAL) (also referred to as ‘may contain’ labels) used by manufacturers to indicate possible allergen cross-contamination during production, will continue to remain a voluntary measure and not legislated for. The use of PAL by food manufacturers is variable: many use PAL after conducting a rigorous risk assessment for allergen contamination, whereas others may use such labelling as a means to avoid such an assessment. Some studies have found that foods without PAL may also have significant allergen contamination (Table 3) [48–50], thus the absence of PAL does not imply a food is safe for consumption by allergic individuals. Studies measuring allergen contamination in foods with PAL consistently demonstrated a low but not negligible risk associated with the consumption of foods with PAL [51,52 ]. This is not surprising, given that over 50% of allergic individuals eat foods with PAL, as reviewed elsewhere [53,54 ]. Indeed, the vast majority of allergic reactions occur to nonprepacked foods, with the minority due to consumption of prepacked foods with PAL (Brough H.A., Turner P.J., Wright T et al. unpublished data). The risk of reaction due to allergen contamination needs to be balanced against the adverse impact such avoidance may have on quality of life. A recent survey of health professionals found that only a third would advise patients with nut allergy to avoid all foods with PAL [55]. One concern is that children (and their families) may interpret ‘tolerance’ of products with PAL as a sign of a more ‘mild’ food allergy, which can result in increased risk &
&
Table 3. Rates of undeclared allergen cross-contamination (assessed as detectable amounts of allergen not declared as an ingredient) in prepacked foods with and without precautionary allergen labelling Study and allergens
% (No.) of food products with PAL
% (No.) of food products without PAL
Peanut
33% (109/333)
25% (52/211)
Hazelnut
60% (175/291)
31% (64/209)
Europe, 2007a [48]
USA, 2010 [49] Peanut
4% (5/112)
0% (0/120)
Egg
2% (1/57)
3% (3/117)
10% (6/59)
3% (4/134)
Cow’s milk Eire, 2011 [50] Peanut
7% (5/75)
2% (2/106)
Egg
6% (1/18)
5% (5/106)
Soya
3% (1/30)
5% (5/106)
PAL, precautionary advisory labelling. a This study assessed contamination in biscuits and cookies, which may be at higher risk of nut cross-contamination than other food products.
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taking. It is, therefore, essential for healthcare professionals to provide allergic consumers with individualized advice with regards to PAL, and counsel that a personalized management plan with appropriate rescue medication should be available at all times.
VACCINATION Despite historical concerns, the measles and measles-mumps-rubella vaccines are produced in chick fibroblast cell lines, which contain negligible amounts of egg protein; egg-allergic children can be given these without any additional precautions. Three vaccines continue to be produced in chick embryos (and thus contain small amounts of ovalbumin): influenza, yellow fever and rabies. An egg-free rabies vaccine is available and recommended for use in egg-allergic individuals. Although a recombinant egg-free influenza vaccine is available, it is not licensed for use in children. Des Roches et al. [56 ] recently summarized the published data relating to influenza vaccination in egg-allergic individuals, and concluded that an individual with egg allergy is no more likely to experience anaphylaxis to influenza vaccine than someone without egg allergy. These data have yet to be incorporated into national guidelines [57], and may not be applicable to influenza vaccines with a higher ovalbumin content. A multicentre study is currently underway to assess the safety of the intranasal live attenuated influenza vaccine in egg-allergic individuals [58]. Allergic reactions in egg-allergic individuals are most likely to occur with yellow fever vaccine; a desensitization regime has been published, which is suitable for use in egg-allergic children [59]. &&
TOLERANCE INDUCTION Given the poor prognosis of some food allergy, much research is now directed towards desensitization, in a similar way that desensitization is used in clinical practice for drug allergies and hay fever. Clinical trials have been performed in children with allergies to cow’s milk, egg and peanut, among others. These studies tend to utilize the oral route [specific oral tolerance induction, (SOTI)] to induce short-term desensitization, with most studies demonstrating a positive effect. One notable gap in the literature is a shared aim of treatment, agreed by physicians and patients, and the use of appropriate outcome measures to assess this in clinical trials. Although many studies have focussed on ‘desensitization’, ‘partial desensitization’ or ‘immune tolerance’ as primary outcomes, it is unclear what value these hold for different
patient groups, and how to weigh up the different success rates with the adverse effect rates seen in these trials. There are currently two main limitations to SOTI: (1) Safety: Cochrane reviews of SOTI to cow’s milk [60] and peanut [61] were published in 2012. In both cases, while desensitization is achieved in most individuals, there was a high rate of adverse events during SOTI, causing withdrawals of up to 10% of patients. A subsequent study specifically assessing the safety of SOTI to cow’s milk in 81 children reported that only 5% did not experience allergic reactions whereas 25% suffered frequent reactions [62 ]. (2) Lack of long-term tolerance: Most studies of SOTI have not assessed whether short-term desensitization results in long-term tolerance. Those that have provide cause for concern, as it seems that tolerance is rapidly lost if ongoing exposure to the allergen is discontinued. In a multicentre, randomized trial of SOTI in 55 egg-allergic or egg-sensitized children, 40 children completed the protocol, and desensitization was successful in 75% [63]. However, only 11 of 40 children continued to exhibit tolerance 2 months after stopping egg exposure. A similar lack of long-term tolerance induction has been reported in children undergoing SOTI or sublingual immunotherapy to cow’s milk [64 ] and peanut [65 ]. Further research is needed before oral immunotherapy can be considered a therapeutic option for routine clinical practice [60,61]. &
&&
&&
Other groups are investigating alternative methods of desensitization to overcome some of these limitations. Trials assessing desensitization via the sublingual route (sublingual immunotherapy) in children with peanut [66] and cow’s milk allergy [67] have been published, and while the rate of adverse events is lower via this route, the amount of food protein which can be tolerated is lower than with SOTI. Other routes of allergen administration (e.g. epicutaneous/transdermal) are also being investigated, although the published reports to date indicate a lack of treatment effect [68]. One group in the USA is investigating the concomitant use of anti-IgE therapy during SOTI to multiple food allergens [69], and has found a significant reduction in adverse events: this strategy may represent the best option for future food desensitization, although the cost and availability of anti-IgE therapy within public healthcare systems are likely to be significant limiting factors. Alternative strategies using tolerogenic peptides (which can
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induce desensitization via T-cells without activating an IgE-mediated allergic response) are currently being investigated [70–72].
CONCLUSION The management of food allergy continues to be challenging, with data demonstrating the need to distinguish between a positive ‘allergy test’ and true clinical reactivity. Non-IgE-mediated food allergy is poorly understood, and there is much scope for further research into this area. Evidence is mounting for transcutaneous sensitization, perhaps in the absence of gut exposure, being a major risk factor in IgE-mediated food allergy and possible other types of food allergy too. Potentially, this may lead to new preventive strategies. Finally, there is a need to investigate ways of improving outcome in those with food allergy and/or their carers, using both medical and nonmedical interventions, to alleviate the adverse impact of food allergy on quality of life measures. Acknowledgements The authors would like to acknowledge the contributions of Dr Thisayanagam Umasunthar and Dr Jo LeonardiBee who assisted with the analysis presented in Fig. 1. Conflicts of interest The authors are supported by a NIHR Biomedical Research Centre, and the MRC Asthma UK Centre in Allergic Mechanisms of Asthma. P.J.T. is in receipt of a Clinician Scientist award funded by the UK Medical Research Council. R.J.B. has received a grant for conference attendance from Meda Pharmaceuticals, and research support from Lincoln Medical and Danone Research. The authors otherwise have no conflicts of interest to declare.
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5. van der Velde JL, Dubois AE, Flokstra-de Blok BM. Food allergy and quality of & life: what have we learned? Curr Allergy Asthma Rep 2013; 13:651–661. This review provides a valuable update on both methodology and the available literature on the effect of food allergy on quality of life measures. 6. American Academy of Pediatrics, Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000; 106:346–349. 7. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract 2013; 1:29–36. 8. Frazier AL, Camargo CA Jr, Malspeis S, et al. 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. 9. Du Toit G, Roberts G, Sayre PH, et al. Identifying infants at high risk of peanut allergy: the Learning Early About Peanut Allergy (LEAP) screening study. 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Peanut and hazelnut traces in cookies and chocolates: relationship between analytical results and declaration of food allergens on product labels. Food Add Contam 2007; 24:1334–1344. 49. Ford LS, Taylor SL, Pacenza R, et al. Food allergen advisory labeling and product contamination with egg, milk, and peanut. J Allergy Clin Immunol 2010; 126:384–385. 50. Food Safety Authority of Ireland (FSAI). Food Allergens & Labelling Survey 2011. www.fsai.ie/resources_publications/allergen_labelling_2011.html. html. [Accessed on 7 January 2014] 51. Robertson ON, Hourihane JO, Remington BC, Taylor SL. Survey of peanut levels in selected Irish food products bearing peanut allergen advisory labels. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013; 30:1467–1472.
52. Remington BC, Baumert JL, Marx DB, Taylor SL. Quantitative risk assessment of foods containing peanut advisory labeling. Food Chem Toxicol 2013; 62:179–187. This article demonstrates how cross-contamination data can be used in conjunction with consumption patterns and allergen threshold data to provide a model as to the population risk of an allergic reaction when consuming foods with a precautionary allergen label. 53. Zurzolo GA, Koplin JJ, Mathai ML, et al. Perceptions of precautionary labelling among parents of children with food allergy and anaphylaxis. Med J Aust 2013; 198:621–623. 54. Cochrane SA, Gowland MH, Sheffield D, Crevel RW. Characteristics and & purchasing behaviours of food-allergic consumers and those who buy food for them in Great Britain. Clin Transl Allergy 2013; 3:31. A useful insight into the process by which food-allergic patients and their carers decide what food products are safe for consumption. 55. Turner PJ, Skypala IJ, Fox AT. 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Safety of Nasal Influenza Immunisation in Egg Allergic Children (SNIFFLE) Study. http://clinicaltrials.gov/show/NCT01859039. [Accessed on 7 January 2014] 59. Rutkowski K, Ewan PW, Nasser SM. Administration of yellow fever vaccine in patients with egg allergy. Int Arch Allergy Immunol 2013; 161:274–278. 60. Yeung JP, Kloda LA, McDevitt J, et al. Oral immunotherapy for milk allergy. Cochrane Database Syst Rev 2012; 11:CD009542. 61. Nurmatov U, Venderbosch I, Devereux G, et al. Allergen-specific oral immunotherapy for peanut allergy. Cochrane Database Syst Rev 2012; 9:CD009014. 62. Va´zquez-Ortiz M, Alvaro-Lozano M, Alsina L, et al. Safety and predictors of & adverse events during oral immunotherapy for milk allergy: severity of reaction at oral challenge, specific IgE and prick test. Clin Exp Allergy 2013; 43:92– 102. An analysis of safety data in 81 children undergoing SOTI to cow’s milk. 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