Issue 138 Food Allergy examined; where are we now? by NH Publishing Ltd

COVER STORY

FOOD ALLERGY EXAMINED: WHERE WE ARE NOW Jacqui Lowdon Paediatric Dietitian, Leeds Children’s Hospital

Food allergy (FA) is a dynamic area, with advances continuing to be made in the understanding, diagnosis, prevention and treatment. The following article includes updates on prevalence, incidence, causes, management and treatment.

Jacqui is a Clinical Specialist in paediatric cystic fibrosis at Leeds Children's Hospital. She previously specialised in gastroenterology and cystic fibrosis. Although her career to date has focused on the acute sector, Jacqui has a great interest in paediatric public health.

In 2010, an Expert Panel Report sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), defined FA as ‘an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food’, and food intolerance as ‘non immune reactions that include metabolic, toxic, pharmacologic and undefined mechanisms’.1 Any reaction to food that results in objectively reproducible signs or symptoms should be described as food hypersensitivity. If immunological mechanisms are involved, then it should be described as a FA. Where immunoglobulin E (IgE) is involved, then the terminology IgE mediated FA should be used and where immune mediated reactions not mediated by IgE, the term non-IgE mediated FA is the correct term.

REFERENCES Please visit the Subscriber zone at NHDmag.com

PREVALENCE AND INCIDENCE

This article has been peer reviewed by Dr Rosan Meyer, RD,PhD Paediatric Research Dietitian, Honorary Senior Lecturer, Imperial College, London.

Data suggests that FA is common, with the prevalence of clinically proven FA as high as 10%, in preschool children in developed countries.2 In countries such as Asia and China, where societies are large and rapidly increasing and there are documented increases in FA, the prevalence of oral food challenge (OFC) proven FA is now approximately 7% in preschoolers. This figure is comparable to European reported prevalence. It also appears to affect those in industrialised/westernised regions disproportionately, more common in children as opposed to adults and only a few foods accounting for most of the more serious reactions, namely peanut, tree nuts, fish, shellfish, egg, milk, wheat,

soy and seeds.1,3,4 In children, FA affects up to 6% to 8%5,6 and the incidence has increased significantly over the past 20 years.7 All prevalence data, outside of non-IgE mediated cow’s milk protein allergy (CMPA), is based on IgE mediated allergies. Determining prevalence statistics remains difficult, however, due to a number of reasons: many manifestations of FA with varying degrees of severity; different allergy definitions being used; evaluation of specific study populations; focus on specific foods; different methodologies; geographic variations; diet exposure effects; and differences according to age, race and ethnicity.8 Self-reported FA rates are substantially higher compared to those by medically supervised OFCs.9 The systematic review and meta-analysis of FA to ‘common foods’ in Europe, by Nwaru et al, looked at 42 studies, finding an overall lifetime self-reported prevalence of 6% (95% CI, 5.7% to 6.4%). A EuroPrevall birth cohort study involving nine countries enrolled 12,049 infants, with 77.5% followed to age two years and included OFCs to confirm diagnosis when possible.10,11 Results showed an adjusted mean incidence of egg allergy at 1.23% (95% CI, 0.98% to 1.51%), with the UK having the highest rate (2.18%). Compared to egg allergy, the rates were lower for milk allergy (0.54%; 95% CI, 0.41% to 0.70%), with the highest rates for milk allergy in the Netherlands and the UK (1%). Of all children with CMA, 23.6% had no cow’s milk-specific IgE in serum, especially those from the UK, the www.NHDmag.com October 2018 - Issue 138

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Learn more about our latest research and clinical trials: www.nestlehealthscience.co.uk/althera IMPORTANT NOTICE: Mothers should be encouraged to continue breastfeeding even when their infants have CMA. This usually requires qualified dietary counselling to completely exclude all sources of cows’ milk protein from the mothers’ diet. If a decision to use a special formula intended for infants is taken, it is important to give instructions on correct preparation methods, emphasising that unboiled water, unsterilised bottles or incorrect dilution can all lead to illness. Formula for special medical purposes intended for infants must be used under medical supervision. Althéra® and Alfamino® are for complete nutritional support from birth or supplementary feeding from 6 months and up to 3 years of age for the dietary management of CMA and/or multiple food protein allergies. Abbreviations: BLG, ß-lactoglobulin; CMA, cows’ milk allergy; Da, Daltons; eHF, extensively hydrolysed formula. References: 1. Dupont et al. BJN, 2012; 107(3): 325–338. 2. Chauveau et al. Pediatr Allergy Immunol, 2016; 27(5): 541–543. 3. Petrus, N.C. et al. Eur J Pediatr. 2015; 174(6): 759–765. 4. Kuslys M, et al. EMJ Allergy and Immunol. 2017; 2(1): 46–51. 5. Nutten S, et al. EMJ Allergy and Immunol. 2018; 3(1): 50–59. 6. Nutten S, et al. Abstract. EAACI Congress, 26-30 May, 2018. 7. Niggemann, B. et al. Pediatr Allergy Immunol. 2008; 194(4): 348–354. 8. Data on file. 9. Nowak-Węgrzyn A, et al. Clin Pediatr (Phila). 2015;54(3): 264–272. Version: ALLER51_August2018. For healthcare professionals only.

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PAEDIATRIC Netherlands, Poland and Italy. Of those children with CMA who were re-evaluated one year after diagnosis, 69% (22/32) tolerated cow’s milk, including all children with non-IgE-associated CMA and 57% of those children with IgEassociated CMA. A systematic review and meta-analysis on the prevalence of tree nut allergy included 36 studies, half from Europe and five from the USA, mostly about children (n=24). A prevalence rate of <2% for OFC-confirmed allergy and between 0.05% to 4.9% for probable allergy (including reported IgE-mediated reactions or a medical diagnosis). Hazelnut was the most common tree nut allergy in Europe, with walnut and cashew being the most common in the US.12 UK studies have also suggested an increase in peanut allergy.13,14 The prevalence of fish allergy in children is low (</= 0.2%). Although the prevalence of shellfish is also low, it is higher than fish allergy (</= 0.5%).15 However, with its high nutritive value and promotion of healthy eating, increased consumption of seafood may lead to more frequent reporting of adverse reactions in the future. Cow’s milk allergy (CMA) (also known as CMPA) is an abnormal response by the body’s immune system in which proteins in cow’s milk are recognised as a potential threat. This can cause the immune system to be ‘sensitised’. When this happens, there is the potential that when cow’s milk is consumed the immune system remembers this protein and may react to it by producing allergic symptoms. CMA remains one of the most common food allergies worldwide and is one of the most common food allergies to affect babies and young children in the UK, but it is still rare with a prevalence in the UK of 2-3% in one- to three-year-olds.70 CMA can present with immediate onset of symptoms or delayed symptoms. If cow’s milk continues to be consumed in the diet, the immune system will continue to produce such symptoms over days or weeks. CAUSES OF FOOD ALLERGY

Many hypotheses have been put forward to try to explain the increase in FA, including a diverse microbiota (the hygiene hypothesis), integration of vitamin D deﬁciency and the ‘dual-allergen exposure’ hypothesis. A reduced microbial diversity

and vitamin D deficiency are thought to interrupt the regulatory mechanisms of oral tolerance, with vitamin D deficiency also thought to contribute to decreased epidermal barrier function. The dual-allergen exposure hypothesis suggests that allergic sensitisation to food occurs through low-level skin exposure to food allergens, facilitated by an impaired skin barrier and inflammation, whereas oral exposure could potentially facilitate tolerance in children who have had early exposure to food protein.16 There is also emerging evidence that an increased diversity of food during the first year of life may have a protective effect on asthma, FA and food sensitisation. It is also associated with increased expression of a marker for regulatory T cells.69 The NAS report3 has considered the evidence behind a number of environmental factors and theories that have been put forward as influencers on FA outcomes. They considered the dual allergen exposure hypothesis to have limited but consistent evidence that an impaired skin barrier plays a role in sensitisation as a first step toward FA. Support for the hypothesis includes the efficacy of peanut early feeding in infants with eczema and the increased risk of FA in those with mutations in filaggrin, a protein responsible in part for maintaining the skin barrier.17,18 DIAGNOSIS

The most important, single test for diagnosing a FA is probably the clinical history. It needs to be reviewed within the context of knowledge about the clinical presentation and epidemiology of the FA, as well as having a good understanding of disorders with similar clinical presentations that might be misconstrued as food allergies. Some groups have proposed schematic diagnostic algorithms that take into consideration the history, epidemiology, pathophysiology, and test results leading to a diagnosis, including identification of the trigger food/s.20-23 A number of recommended diagnostic modalities have also been developed, through expert panels, practice parameters, systematic reviews and guidelines.8,23-27 Tests include medical history, physical examination, elimination diets, skin prick tests, sIgE tests and OFCs. However, diagnosis is not usually based on a single test. Instead, a stepped approach is www.NHDmag.com October 2018 - Issue 138

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References: 1. Arslanoglu S et al. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the ﬁ rst two years of life. J Nutr. 2008;138:1091-5. 2. Arslanoglu S et al. Early neutral prebiotic oligosaccharide supplementation reduces the incidence of some allergic manifestations in the ﬁ rst 5 years of life. J Biol Regul Homeost Agents. 2012;26:49-59. 3. Pampura AN et al. Ros Vestn Perinatol Paediat 2014;4:96-104

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PAEDIATRIC usually used, where the clinical history can lead to a test selection and the result can be used to determine whether an OFC is required. Nice guidelines on diagnosis and assessment of FA are key and Sicherer and Sampson provides a good summary on the pros and cons of different diagnostic testing.71,72,20 When the chances of tolerating the food item, based on clinical history and other tests, is probable for that individual based on their circumstances, e.g. age, dietary preference and nutritional requirement, then an OFC is offered for diagnostic purposes. Details for performing OFCs are available, with the gold standard being the doubleblind, placebo-controlled OFC.28-31 Although OFCs are time-consuming, resource intensive and carry an element of risk, they remain the gold standard and most data indicates that even when there is a risk, the impact on QoL is positive. If an OFC is indicated, families need to be counselled about the procedure even though it is generally safe. OFCs must be carried out with the required precautions by experienced clinicians.28-30,37 Severe and fatal reactions can and do occur. Also, for some families, fear of the procedure or lack of the potential benefits, result in them turning down the OFC38 and some families continue to exclude the previously avoided food, despite tolerance during an OFC. All of this needs to be included in the counselling,39 with benefits of a possibly improved quality of life40 and if a reaction does occur, it is not likely to result in an increase in sensitisation.41 Regarding CMA, the iMAP guidelines on mild to moderate non-IgE mediated CMA have contributed significantly towards improving diagnosis and management in the UK and now worldwide. The guidelines offer easy-to-use algorithms and newly added supporting material, as well as an updated milk ladder.70 The European Academy for Allergy and Clinical Immunology has published guidelines on IgE mediated allergy and is working on practice guidelines for non-IgE mediated allergies. ACTIVE MANAGEMENT

Active management of food allergies entails good knowledge and education. A systematic review confirmed concerns about labelling variations and errors, restaurant meals, eating at home and outside the home and risky behaviours leading to unexpected reactions.32 A more active approach to the management of FA is being adopted, 18

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which includes early introduction of potentially allergenic foods, anticipatory testing, active monitoring, desensitisation to food allergens and active risk management.75 Nutritional deficiencies can result from allergen avoidance diets and this is reported widely in the literature. In a recent study of 245 children (mean age four years) avoiding one to seven foods, those less than two years of age had a lower weightfor-length percentile, whilst those aged two years and older had lower body mass index profiles compared with healthy control subjects.33 These differences were especially noted in those avoiding milk and multiple foods. Other studies have also noted worse growth in those avoiding milk.34,35 A systematic review of six studies highlighted the risk of malnutrition and reduced height. They noted that children with food allergies who did not receive nutritional counselling were more likely to have inadequate calcium and vitamin D.36 It is essential then that children with FA receive nutritional counselling and growth monitoring.25 A recent article by Meyer discusses the nutritional disorders resulting from FA in children.73 Although strict avoidance is usually advised, approximately 70% of children with milk and egg allergy can tolerate these foods when extensively heated in bakery foods.42 However, this needs to be strictly and very carefully evaluated, such as using supervised OFCs, to determine whether the baked form can be tolerated, as severe allergic reactions are possible. It has been suggested that, for those who are able, ingestion of the baked form might result in faster resolution of the allergy,43,44 although the evidence is not conclusive.45 PREVENTION

There have been a number of recent reviews,46-48 detailing opportunities for prevention. Early peanut introduction in high-risk infants has the most convincing prevention approach data. In the Learning Early About Peanut (LEAP) trial, infants aged four to 11 months at high risk (severe eczema and/or egg allergy) for peanut allergy, but with peanut SPT wheals of 4mm or less, were randomised to eat or avoid peanut to age five years.17 Those sensitised to peanut and randomised to eating had a 10.6% rate of peanut allergy vs 35.3% in the avoidance group (P= 004; relative risk [RR] reduction, 70%). Among those infants not sensitised, 13.7% in the avoidance group

and 1.9% in the eating group had peanut allergy (P<001; relative reduction, 86.1%). Other studies that had the eating group avoid peanut for one year49 and evaluated nutritional outcomes,50 suggest that the protection was durable and did not result in reduced breastfeeding or nutritional concerns. Based on the results of this study, with evidence of possible protection in nonselected infants51 a NIAID expert panel has suggested applying the LEAP study results to highrisk infants and encouraging introduction of peanut early also for those at moderate risk.52 These new guidelines suggest that allergenic foods be introduced without any particular delay compared with non-allergenic foods.1,53,54 For high-risk infants, introducing peanut ‘as early as four to six months’ goes against the exclusive breastfeeding to around six months recommendation. However, the rationale to feed peanut earlier, so long as it is in a safe form to avoid choking and the infant has demonstrated an ability to manage solids, was to lessen the chance of the infant having increasing sensitisation over time.52,55 For high-risk infants, the guidelines suggest evaluation for sensitisation and possible OFCs, with dosing regimens that copy the LEAP study. Early introduction of other foods for allergy prevention have not been studied as much and so this area remains less certain. The Enquiring About Tolerance trial tried early introduction of six allergenic foods starting around four months of age.51 An intention-to-treat analysis did not demonstrate a preventative effect, but a per-protocol analysis suggested effectiveness for peanut and egg. A systematic review56 concluded that there was ‘moderate certainty’ of evidence for reduced egg allergy with introduction at four to six months (RR, 0.56; 95% CI, 0.36-0.87). However, this conclusion was mainly based on the results of the Natsume study.57 This study demonstrated greater sensitisation in the placebo group, produced low stepped cooked egg dosing and measured outcomes against the egg product used in prevention treatment, possibly enhancing the results or reflected the treatment rather than prevention. Currently, there is no recommendation to purposefully feed egg early, although there remains recommendations not to avoid including egg in the early infant diet.53,54

For more on the FA environmental risk factors from the NAS report,3 visit www.NHDmag.com/food-allergy.html Two studies58,59 noted high rates of reaction on raw egg introduction, raising questions of safety and the possibility that high-risk infants might already be allergic by four to six months. Data on milk is limited but also suggest delayed introduction can be associated with increased risk.60 Recommendations and guidance on the prevention of FA can be obtained from SACN, BASCI and the BDA.76-78 SACN recommends that advice on complementary feeding should state that foods containing peanut and hen’s egg can be introduced from around six months of age and need not be differentiated from other solid foods. The deliberate exclusion of peanut or hen’s egg beyond six to 12 months of age may increase the risk of allergy to the same foods. CONCLUSION

Whilst there are currently no approved treatments for FA,1,23,67 recent advances have made possible insights into the molecular mechanisms underlying FA, providing opportunities for the use of precision medicine to safely and effectively treat individual FA.68 Although some interventions (such as early introduction of dietary peanut) have demonstrated efficacy in a small number of well-conducted randomised clinical trials, evidence for broader effectiveness and successful implementation at a population level is still lacking, although epidemiological data suggests that such strategies are likely to be successful, at least for peanut. Finally, recent studies suggest that early allergen exposure may prevent FA. www.NHDmag.com October 2018 - Issue 138