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Adult food allergy
tak Chin specialist registrar in allergy Medicine, southampton general Hospital
Carina venter Phd, rd senior Lecturer, University of Portsmouth
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dr tak Chin is a Specialist registrar in Allergy medicine at Southampton General hospital
As well as being a Senior Lecturer at the University of Portsmouth, Carina is an Allergy Specialist dietitian with the david hide Asthma and Allergy research Centre on the isle of Wight. She is also a food Allergy module Leader at the University of Southampton.
diAGNoSiS of ige-mediAted food ALLerGY iN AdULtS
Adult food allergy presents with a range of complex symptoms. A good diagnostic work-up is required, followed by appropriate dietetic advice.
In clinical practice, the offending food(s) causing IgE-mediated food allergy can often be identified by taking a careful clinical history. Important elements of the history include the type of food involved, quantity of food ingested, time between ingestion to reaction, symptoms/signs of the reaction, other occasions when similar reactions occurred, time since last reaction and other factors involved (e.g. exercise). In complex cases, a food-symptom diary may be required as an adjunct to the history.
The usual first-line diagnostic tests, routinely used in conjunction with the clinical history, to establish the diagnosis of IgE-mediated food allergy, are skin prick tests (SPT) (which can be performed with commercially-prepared standardised solutions of food allergen extracts, or with fresh foods (prick-toprick (PTP) testing) and serum specific IgE (sIgE) to food allergens.
SPT is generally preferred as it offers a quick and reproducible method for detecting IgE sensitisation. Although it is a safe procedure, severe and fatal anaphylactic reactions have been reported in those with highly severe allergies (1). It is, therefore, recommended that SPT is performed by experienced personnel in an appropriate setting with access to emergency medications and equipment. sIgE offers an in vitro method for quantifying IgE sensitisation and may be useful when SPT is not possible (e.g. limited skin surface for SPT, dermatographism, suppressed skin reactivity due to antihistamines, needlephobia).
Sensitivity and specificity varies depending on the food, as well as other factors (e.g. allergen extract, commercial test system, age of the patient). In general, a negative SPT result has an excellent negative predictive value, while a positive SPT result only indicates the possibility of symptomatic IgE-mediated food allergy. One exception to this is IgE-mediated food allergy to certain fruits/vegetables (particularly those associated with pollen-food allergy syndromes), which may sometimes not be detected using commercially-prepared extracts/reagents due to the labile nature of the allergenic epitope involved.
For some of the common major food allergens (e.g. hen’s egg, cows’ milk, peanut), decision points based on SPT size and also sIgE titre cut-off values have been described which have a >95 percent positive predictive value for IgE-mediated food allergy. However, decision points have not been successfully established for other major food allergens (e.g. soy, wheat) and the less common food allergens.
A potential issue with both SPT and sIgE is the possibility of cross-reactivity to common allergenic epitopes in related foods, unrelated foods and pollens which may result in false positives to food allergens that are not clinically relevant.
For certain foods - componentresolved diagnostics (CRD) - which involves the measurement of sIgE against purified individual proteins within the food - may be useful in determining the risk of severe allergic reactions. Numerous food proteins have been identified and knowledge of their allergenic significance continues to evolve.
In general, sensitisation to seed storage proteins and non-specific lipid transfer proteins (nsLTP) is usually associated with a higher risk of severe allergic reactions. In contrast, sensitisation to Bet v 1-related PR10 proteins is usually associated with mild allergic reactions to fruits and vegetables
due to cross-reactivity with birch pollen. For example, the seed storage protein Ara h 2 has a very high positive predictive value for severe allergic reactions to peanut (2). The other seed storage proteins Ara h 1 and Ara h 3 have also been associated with severe reactions - severe reactions, however, have been described in patients who are negative to these allergens (3). Exceptions have been reported where Bet v 1-related PR-10 proteins have been associated with severe allergic reactions (e.g. Gly m 4 in soy allergy) (4). Furthermore, sensitisation patterns may be different for populations in different countries - a study evaluating CRD in European patients with severe allergy to hazelnuts demonstrated that sensitisation was mainly to the major hazelnut allergen Cor a 1.04 (Bet v 1-related PR-10 protein) in Switzerland and Denmark, whereas it was mainly to Cor a 8 (nsLTP) in Spain (5). More recently, Cor a 9 and Cor a 14 (seed storage proteins) have been shown to be associated with severe allergy to hazelnuts in a Dutch population (6).
CRD appears to be useful in the more unusual clinical manifestations of IgE-mediated food allergy - such as when used in selected cases where wheatdependent exercise-induced anaphylaxis (WDEIA) is suspected (e.g. omega-5 gliadin (Tri a 19))(7) and in the evaluation of delayed anaphylaxis to red meat (e.g. galactose-α-1,3-galactose (α-gal)) (8). At the time of writing, a systematic review assessing the diagnostic accuracy of SPT, sIgE and CRD in supporting the clinical diagnosis of IgE-mediated food allergy is under way (9).
Oral food challenges (OFCs) may be necessary to establish the diagnosis of IgE-mediated food allergy or to determine the clinical relevance of SPT, sIgE and/or CRD results. The doubleblinded placebo-controlled food challenge (DBPCFC) is considered the ‘gold standard’ diagnostic test. OFCs can also be performed single-blinded or open. However, the potential risk of severe allergic reactions, as well as the time-consuming and resource-intensive nature of the procedure, limits their use. International consensus and standards have been developed to standardise various aspects of DBPCFCs to allow comparison between research studies (10). These variables include pre-challenge assessment, safety measures, type/quantity of the food allergen to be administered, timings between doses, intra-challenge assessment, managing subjective symptoms, objective criteria for a positive challenge, observation periods and outcome reporting.
Elimination diets are not usually diagnostic of food allergy on their own - while resolution of symptoms during an elimination diet supports a diagnosis of food allergy, this may be accounted for by other factors and so OFC should be performed to confirm the diagnosis. Elimination diets may be performed in several ways: (i) elimination of one or several suspected foods, (ii) elimination of all except a defined group of foods and (iii) elemental diet (e.g. hydrolysed formula, amino acid-based formulas).
The basophil activation test (BAT) appears to be a promising area of future development for diagnostic tests in food allergy with one recent study demonstrating that it can significantly reduce the requirement for OFC to peanut (11, 12, 13). However, this test is not yet routinely available in clinical practice.
A number of unproven tests are often used by complementary/alternative medicine practitioners (e.g. Vega testing, hair analysis, iridology, kinesiology, specific IgG/IgG4, cytotoxic test) and cannot be recommended for diagnosing food allergy.
diagnosis of non-ige-Mediated food aLLergy in aduLts The principles behind the diagnosis of non-IgEmediated food allergy do not significantly differ from those for IgE-mediated food allergy - the main difference is that clinical history, SPT and sIgE often do not correlate as well in non-IgE-mediated food allergy due to the immune mechanisms involved. As a result, elimination diets and modified OFCs (tailored to the individual and clinical reaction) are required more often in order to demonstrate if a suspected food is clinically relevant.
This is particularly the case in atopic eczema/ dermatitis (AE) where multiple IgE sensitisation without proven clinical relevance is commonly seen. Reactions to classical food allergens (e.g. hen’s egg, cows’ milk) in adulthood are not as common as in childhood (17) - adult studies have shown that foods cross-reactive to birch pollen can worsen AE (18, 19).
Three different reaction patterns may be seen in food-induced AE: (i) non-eczematous reactions (usually IgE-mediated causing pruritus, urticaria, flushing but also other immediate-type gastrointestinal, respiratory or anaphylactic symptoms); (ii) eczematous delayed reactions (usually after hours to
days) and (iii) combination of early non-eczematous and eczematous delayed reactions.
It is, therefore, recommended that the skin should be evaluated after 24 hours and later ideally using a validated score (e.g. SCORAD, EASI) following OFC for AE, as otherwise delayed reactions may be missed. It is also recommended that OFC is preceded by a diagnostic elimination diet of suspected food items over a period of up to four to six weeks (rather than the usual two to four weeks for IgE-mediated symptoms). Full details discussing the diagnostic approach in eczematous reactions to foods in AE are available in a position paper (20).
Atopy patch testing (APT) may be considered as an additional diagnostic test in suspected foodinduced AE. However, they are not in widespread clinical use since standardised reagents, methods for performing APTs and interpretation of their results have not been established. The use of APT has been evaluated (primarily in children), but did not result in a significant reduction in OFCs required where food-induced AE was suspected (21) - as a result, APT is not generally recommended for the routine diagnosis of food-induced AE.
For non-IgE-mediated gastrointestinal food allergies, a consensus diagnostic guideline is available for eosinophilic oesophagitis (EoE), which the most common form of eosinophilic gastrointestinal disease (EGID) (22). The diagnostic criteria for EoE includes: (i) clinical symptoms related to oesophageal dysfunction and exclusion of secondary causes of oesophageal eosinophilia, (ii) eosinophilpredominant inflammation on oesophageal biopsy (≥15 eosinophils per high-power field; two to four biopsies should be obtained from both the proximal and distal oesophagus), (iii) mucosal eosinophilia isolated to the oesophagus which persists after a proton pump inhibitor trial and (iv) a response to treatment such as dietary elimination or topical corticosteroids can further support the diagnosis.
The diagnostic approach to identifying the causative food(s) in patients with EoE is challenging. The usual strategy for this involves two phases: the elimination phase(s) of four to six weeks (rather than the usual two to four weeks for IgE-mediated symptoms) followed by the reintroduction phase(s). The general principle behind this is to initially induce resolution (of symptoms and ideally also oesophageal eosinophilic inflammation on histology) through the elimination phase, so that causative and non-causative food(s) can be identified when they are re-introduced - a food is considered causative if it results in recurrence of the above. The main elimination strategies may be broadly categorised as follows: (i) elemental diet free of food allergens (e.g. complete liquid amino-acid based formula); (ii) empiric food elimination diet which excludes the most common causative foods allergens (e.g. six food elimination diet: dairy, soya, eggs, wheat, peanuts, fish/shellfish) and (iii) targeted elimination which removes food allergens based on history and the results of allergy testing (e.g. SPT, sIgE, APT).
Food protein-induced enterocolitis syndrome (FPIES) was previously thought to occur primarily in infants and young children only - however, it has been reported to also occur in adults (with the predominant trigger being shellfish) (23).
As with the other non-IgE-mediated food allergies, SPT and sIgE are often negative and so OFC remains the only diagnostic test and is considered the gold standard. There is currently no standardised protocol for OFC for FPIES - however, this is usually done by experienced personnel as an open challenge with a long observation period after the last dose (minimum four to six hours) in a facility that can manage dehydration and allergic reactions. Pre- and post-challenge (six hours) blood samples for complete full blood count with differential counts can be taken to look for an increase in peripheral blood neutrophil counts - this has been proposed as
one of the major criteria for a positive challenge in acute FPIES.
However, in clinical practice, the diagnosis of FPIES is often made on the basis of a suggestive clinical history and resolution of symptoms on elimination of the causative food. APT in FPIES has been evaluated in children (24, 25) - at present APT is not recommended for routine diagnosis of FPIES.
For completeness, coeliac disease (CD) is technically classified as a non-IgE-mediated food allergy - the diagnosis of CD is primarily by serology (e.g. specific endomysial antibodies (EMA/ AEA), IgA anti-tissue transglutaminase antibodies (IgA-TG2/a-TTG/TTA), deamidated antigliadin antibodies (IgA-DGP or IgG-DGP); IgGTG2 is primarily useful in patients with known IgA deficiency) and duodenal biopsy when the patient is on a normal (gluten-containing) diet. It may also involve HLA testing (e.g. HLA-DQ2, HLA-DQ8 haplotype). The diagnostic algorithm for CD in adults is available in a guideline (26). Dermatitis herpetiformis is a related cutaneous condition associated with CD - diagnosis is by skin biopsy and demonstrating the presence of granular IgA deposits in the dermal papillae of uninvolved perilesional skin as shown by direct immunofluorescence (27).
ManageMent of aduLt food aLLergies The cornerstone in the management of food allergies in adults, requires avoidance of the offending food and prescription of emergency mediation when required.
Dietary avoidance issues Avoidance of allergenic foods can be complex, leading to nutritional deficiencies and can affect quality of life. Ideally, all adults presenting with a suspected or proven food allergy, should be referred for a dietetic consultation (28). A dietitian can provide individualised advice regarding the foods that should be avoided, the level of avoidance required and suitable substitute foods (29, 30). In addition, advice on required nutritional supplements can be provided. Advice on a range of lifestyle issues, such as shopping, eating at school or in the workplace, socialising and eating out and going on holiday will also be provided (31, 32).
A challenging factor in dealing with patients with FHS is to establish each patient’s tolerance level or degree of avoidance required. This will mainly be determined by the type of food allergy the patient is suffering from and the underlying mechanisms. Some people with food allergies, particularly those which are IgE mediated, need to completely avoid an allergic food - even in trace amounts. Others may be able to include small amounts of the food in their diet with no adverse effects. There are no clear guidelines for avoidance levels, but some patients may be aware of their own tolerance levels by trial and error. It is also known that some individuals become tolerant to baked forms of milk and egg, whilst they may still be allergic to less cooked forms. The level of avoidance required should, therefore, also be reviewed at regular intervals.
In terms of fruit of vegetables and nuts, it is also important to understand if the patient is suffering from a primary fruit, vegetable and nut allergy, or if the patient is suffering from a crossreaction to pollens such as birch and grass. For those with primary food allergies, strict avoid-
ance may be required, whereas those suffering from aero-allergen cross reactive reactions, often tolerate cooked versions of the food.
In terms of avoiding the major food allergens, EU labelling covers all the major food allergens, which, as from 12 December 2014, all need to be clearly identified on food labels in either bold, underlined or italic type. The major food allergens include: • Cereals containing gluten (i.e. wheat, rye, barley, oats, spelt, kamut or their hybridised strains) and products thereof • Crustaceans and products thereof • Eggs and products thereof • Fish and products thereof • Peanuts and products thereof • Soybeans and products thereof • Milk and products thereof (including lactose) • Nuts i.e. Almond (Amygdalus communis L.),
Hazelnut (Corylus avellana), Walnut (Juglans regia), Cashew (Anacardium occidentale),Pecan nut (Carya illinoiesis (Wangenh.) K. Koch),
Brazil nut (Bertholletia excelsa), Pistachio nut (Pistacia vera), Macadamia nut and Queensland nut (Macadamia ternifolia) and products thereof • Celery and products thereof • Mustard and products thereof • Sesame seeds and products thereof • Sulphur dioxide and sulphites at concentrations of more than 10mg/kg or 10mg/litre expressed as SO2. • lupin and products thereof • Molluscs and products thereof.
In the UK, The Food Standards Agency have information available on their website: www. food.gov.uk
May contain labelling Manufacturers often use phrases such as ‘may contain nut traces’ or ‘made on a production line using soya and milk’ or ‘produced on a line handling egg’ to show that there could be accidental traces of another food in a manufactured product, from the production process. This labelling is completely voluntary and, therefore, not legally binding, but many manufacturers choose to label their products in this way.
Current advice from the BDA Food Allergy and Intolerance Support group, regarding the management of precautionary labelling in those with more severe food allergies or nut allergies: (taken directly from the FAISG Nut avoidance diet sheet):
It is important to take these warnings seriously and consider the following points: • Just because a particular food with a nut warning has been eaten safely in the past, does not mean that it will always be safe; it may contain nut traces next time. Recipes and manufacturing processes can change. • All nut warnings should be treated with the same level of risk regardless of the wording used. • Patients may be more sensitive to nut protein if they are unwell, have been doing strenuous exercise or drinking alcohol, so having a nut trace during these times is more risky. • Chocolate and chocolate covered items pose a higher risk of nut contamination because chocolate dripping off one product may be used on another during manufacturing.
Therefore, chocolate with nut warnings should always be avoided (lists of peanut free or all nut free products are available from chocolate manufacturers).
The safest approach is to avoid all foods with ‘may contain’ nut warnings. However, if a food with a nut warning is to be eaten, the following advice should always be followed: 1. Always have in-date emergency medication to hand. 2. Be within easy reach of a phone or mobile that has charge and reception. 3. Only eat if someone is with you who can help if a reaction occurs. 4. Avoid if in a remote location, far from emergency services. 5. Avoid if unwell or asthma is not well controlled. 6. Avoid after strenuous exercise or drinking alcohol. 7. Avoid if previously had an anaphylactic reaction to nut traces or ‘may contain’ products.
Discuss your approach to managing ‘may contain nut’ products with your dietitian or allergy team, as they can give you specific advice.
suMMary In summary, the manifestations of food allergy in adults in varied diagnosis can be complex and any tests performed should be interpreted by a competent clinician. The management of adult food allergy will necessitate a referral to a dietitian in most cases. Important information can be provided during a dietary consultation such as foods to avoid, suitable foods to eat, supplementation of nutrients, label reading and lifestyle advice.
Sensitivity (‘true positive rate’) = the percentage of sick people who are correctly identified as having the condition
Specificity (‘true negative rate’) = the percentage of healthy people who are correctly identified as not having the condition
Positive predictive value (PPV) = probability that the disease is present when the test is positive
Negative predictive value (NPV) = probability that the disease is not present when the test is negative
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