Alimentary Pharmacology and Therapeutics

Review article: the diagnosis and management of food allergy and food intolerances J. L. Turnbull*, H. N. Adams† & D. A. Gorard†

*Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford, UK. † Department of Gastroenterology, Wycombe Hospital, High Wycombe, Bucks, UK.

SUMMARY

Correspondence to: Dr D. A. Gorard, Wycombe Hospital, Queen Alexandra Road, High Wycombe, Bucks HP11 2TT, UK. E-mail: david.gorard@buckshealthcare. nhs.uk

Aim To critically review the data relating to diagnosis and management of food allergy and food intolerance in adults and children.

Publication data Submitted 11 May 2014 First decision 23 May 2014 Resubmitted 7 September 2014 Resubmitted 14 September 2014 Accepted 16 September 2014 EV Pub Online 14 October 2014 This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.

Background Adverse reactions to food include immune mediated food allergies and nonimmune mediated food intolerances. Food allergies and intolerances are often confused by health professionals, patients and the public.

Methods MEDLINE, EMBASE and the Cochrane Database were searched up until May 2014, using search terms related to food allergy and intolerance. Results An estimated one-fifth of the population believe that they have adverse reactions to food. Estimates of true IgE-mediated food allergy vary, but in some countries it may be as prevalent as 4–7% of preschool children. The most common food allergens are cow’s milk, egg, peanut, tree nuts, soy, shellfish and finned fish. Reactions vary from urticaria to anaphylaxis and death. Tolerance for many foods including milk and egg develops with age, but is far less likely with peanut allergy. Estimates of IgE-mediated food allergy in adults are closer to 1–2%. Non-IgE-mediated food allergies such as Food Protein-Induced Enterocolitis Syndrome are rarer and predominantly recognised in childhood. Eosinophilic gastrointestinal disorders including eosinophilic oesophagitis are mixed IgE- and non-IgE-mediated food allergic conditions, and are improved by dietary exclusions. By contrast food intolerances are nonspecific, and the resultant symptoms resemble other common medically unexplained complaints, often overlapping with symptoms found in functional disorders such as irritable bowel syndrome. Improved dietary treatments for the irritable bowel syndrome have recently been described. Conclusions Food allergies are more common in children, can be life-threatening and are distinct from food intolerances. Food intolerances may pose little risk but since functional disorders are so prevalent, greater efforts to understand adverse effects of foods in functional disorders are warranted. Aliment Pharmacol Ther 2015; 41: 3–25

ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12984

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J. L. Turnbull et al. INTRODUCTION Although food allergies are commonly encountered by paediatricians, and although the public and lay press demonstrate a marked interest in food allergies and intolerances, this diagnostic arena is little regarded by most gastroenterologists dealing with adult patients. Adverse reactions to foods vary in clinical presentation, severity and underlying aetiology. Patients, the public, doctors and other health professionals frequently confuse non-allergic food reactions with food allergy. Adverse reactions to foods can be broadly divided in to those with an immune basis – food allergies and coeliac disease, or those without an immune basis – termed food intolerances (Figure 1). Although coeliac disease is a T-cell mediated (type 4 hypersensitivity) immune response to gluten, it is not usually classified as a food allergy and is not discussed further. Acute toxic reactions to food contaminated by bacteria or by aflatoxins, or to food containing excess histamine such as spoilt fish (scombroid food poisoning), are not reviewed here. Furthermore, adverse reactions to foods arising from metabolic errors (usually autosomal-recessively inherited enzyme deficiencies) and culminating in serious disease such as phenylketonuria, tyrosinaemia, organic acidaemias, homocystinuria, Refsum’s disease,

galactossaemia are not discussed. Malabsorptive problems such as abetalipoproteinaemia and pancreatic insufficiency in which fats aggravate bowel symptoms are similarly not included. Although dietary intervention can influence Crohn’s disease1–3 and orofacial granulomatosis,4 the role of food in these inflammatory illnesses is also beyond this article’s scope.

METHODS A literature search was performed, using OVID MEDLINE, EMBASE and the Cochrane library, up until May 2014. Search terms included ‘food allergy’ ‘food intolerance’, ‘IgE-mediated’, ‘non-IgE mediated’, ‘cow’s milk protein allergy’, ‘Protein-induced enterocolitis syndrome’, ‘anaphylaxis’, ‘immunotherapy’, ‘eosinophilic oesophagitis’, ‘eosinophilic gastroenteritis’, ‘lactose intolerance’, ‘fructose intolerance’, ‘gluten sensitivity’. The articles returned by the search were selected based on English language and relevance to this review. Important articles identified in the most recent published reviews were also then appraised. What is food allergy? Food allergy is an adverse immune-mediated response, which occurs reproducibly on exposure to a given food

Adverse reactions to foods

Immune mediated

Non-immune mediated

Toxic reactions Toxins

Food allergy

Food intolerance

Pathophysiology explained

IgE-mediated Urticaria Angioedema Bronchospasm Rhinitis Laryngospasm Diarrhoea/ vomiting Anaphylaxis Oral Allergy

Non-IgEmediated Food protein -induced enterocolitis syndrome Food protein -induced proctocolitis Food protein -induced enteropathies

Mixed IgE- and non-IgE-mediated

Enzyme Coeliac Pharmacological deficiencies Disease lactose/

Cow’s Milk Protein Allergy Eosiniphilic Oesophagitis Eosinophilic Gastroenteritis

caffeine

tyramine

fructose malabsorption

Bacterial toxins Aflatoxins Scombroid poisoning

unexplained

Non specific gut and non-gut reactions to food includes Irritable Bowel Syndrome & other functional GI disorders: -luminal distension -heightened gastrocolic reflex -altered perception Behavioural factors: -expectation/conditioning Psychological factors

Figure 1 | Classification of adverse reactions to foods. 4

Aliment Pharmacol Ther 2015; 41: 3-25 ª 2014 John Wiley & Sons Ltd

Review: food allergies and intolerances and is absent during avoidance. A diagnosis of food allergy requires evidence of sensitisation and specific symptoms on exposure to a particular food. The immune response in food allergy can be classified into IgE-mediated, non-IgE-mediated or a mixture of both (Figure 1). IgE-mediated food allergy requires food allergen sensitisation (with the development of serum specific IgE antibody to a food allergen), and secondly the development of signs and symptoms on exposure to that food. In non-IgE-mediated food allergy, T-cell-mediated processes predominate and there may be histological evidence of an underlying immune process such as eosinophilic inflammation of the gastrointestinal tract.

What is food intolerance? Other types of undesirable reactions to food are termed food intolerances. These non-allergic food reactions do not involve the immune system. Some food intolerances involve an organic pathophysiological process, e.g. lactose intolerance occurs as a consequence of deficiency in the enzyme that breaks down lactose. However, some food intolerances cannot be readily explained by currently understood organic processes, e.g. many of the food intolerances reported in irritable bowel syndrome (IBS) patients. Prevalence of food allergy and other adverse reactions to food Perceptions of adverse reactions to food, whether allergy or intolerance are common. In a United Kingdom household survey, 20% of the population reported food intolerances. However when double-blind placebo-controlled food challenges were performed, the prevalence of true reactions to food was less than 2%.5 In a German study, one-third of respondents to a postal questionnaire reported reactions to food, but subsequent double-blind placebo-controlled food challenges identified a true prevalence of adverse food reactions of 3.6%, of which more than two thirds were IgE-mediated.6 Women were more likely to have both self-reported symptoms and blind challenge-confirmed adverse food reactions.7 The prevalence of true immunologically mediated food allergy is difficult to measure. There are large variations in study methodology, from those relying on self-reporting questionnaires that tend to vastly exceed the true prevalence due to their reliance on lay perceptions of allergy, to studies using more rigorous double-blind placebo-controlled food challenges but only including small numbers of patients. What is clear is that food allergy is more common in children than adults, and Aliment Pharmacol Ther 2015; 41: 3-25 ª 2014 John Wiley & Sons Ltd

seems to be increasing in prevalence in many countries.8–11 The prevalence of food allergy across the whole US population is approximately 2.5–3% when objective measures, such as serological testing and food challenges, are used.11, 12 While prone to overestimation, population surveys of US children yield self-reported prevalences of food allergy that vary from 4% in the 2007 National Health Interview Survey,13 to 8% in another population survey of US children.14 More objective serological data from the 2005 National Health and Nutrition Examination Survey, established that 4.2% of US children aged 1–5 years had positive food-specific serum IgE serology results for peanut, milk, egg white or seafood. The prevalence of elevated specific IgE reduced with age to 3.8% in 6–19 year olds, and 1.3% in those over 60 years.12 Since relatively few epidemiological studies have used the gold standard of diagnosis – the double-blind placebo-controlled food challenge, the true prevalence of food allergy remains elusive, and a US-based metaanalysis from 2010 was forced to give a range from 1–10%.9, 15 The ongoing European Union-commissioned birth cohort study EuroPrevall will provide important epidemiological data on allergy in Europe.16

IgE-MEDIATED FOOD ALLERGY The very nature of the gut requires that its large mucosal surface is continually vulnerable to foreign substances, from food proteins to commensal bacteria and pathogens. The mucosal immune system is required to mount protective responses against pathogenic organisms and toxins, whilst not responding excessively to harmless commensal bacteria and food components. In health, the physical properties of the gut, including gastric acid, digestive enzymes, mucosal integrity and mucus secretion, reduce the penetration of ingested pathogens and food proteins. The innate immune system targets molecules common to many pathogens. There are also targeted responses from the adaptive immune system to either tolerate or react to specific proteins, utilising lymphocytes, cytokines, secreted IgA and Gut Associated Lymphoid Tissue.17, 18 This immune exclusion minimises the amount of potentially allergenic protein taken up from the gastrointestinal tract, but nonetheless more than 100 g of immunologically recognisable dietary protein can still be absorbed by those following North American diets.19 The interaction of this protein load with the gastrointestinal immune system, particularly in early life, is key in determining the response to individual proteins in future. An interplay of factors determines whether there 5

J. L. Turnbull et al. will be a mucosal IgA secretion response, a systemic immune response, or local and systemic tolerance upon re-exposure. The mechanisms leading to food protein tolerance are not fully understood but tolerance involves an active regulatory response mediated by regulator T (T Reg) cells, and clonal deletion which removes T cells with undesirable targets. Antigen-presenting macrophages and dendritic cells may be modulated by commensal bacteria, so they more readily secrete cytokines encouraging T Reg cell amplification and tolerance. Current theories behind tolerance and hypersensitivity are more thoroughly detailed by Brandtzaeg.18 IgE-mediated food allergy results when an adaptive immune response that is effective in targeting parasites is instead mounted against food proteins. Food and other proteins enter the body by ingestion, inhalation and skin penetration. They are taken up by antigen presenting cells and presented to THelper cells. The resulting cytokine release determines whether there is a predominant TH1 or TH2 response. The TH1 response is the cell-mediated response, effective against intracellular bacteria and protozoa. In contrast the TH2 response targets parasites such as helminths with stimulation of eosinophils, basophils and mast cells, along with IgE-producing B cells. When food proteins inappropriately trigger a TH2 predominant response the result is Type 1 hypersensitivity and IgE-mediated food allergy. In IgE-mediated allergy, exposure to a trigger food brings about immediate and consistently reproducible effects on the gut, skin or respiratory system. Any protein can theoretically cause sensitisation, but the vast majority of these hypersensitivity reactions occur to the same most common allergens. The common allergen proteins tend to be water-soluble glycopeptides with greater resistance to proteolytic enzymes, acid and heat. In children, cow’s milk, egg, peanut, soy, tree nuts, fish, shellfish and wheat account for 85% of all food allergies (Table 1). However, many of these early onset allergies are associated with the eventual development of tolerance and this leads to a different spectrum of allergies in adults. The most common allergens in adults are peanuts, tree nuts and seafood. Tree nuts include pistachio, pecan, Brazil, cashew, hazel and walnut, and many others. Although some individuals are allergic to just one tree nut type, there is much cross-reactivity so individuals tend to be allergic to multiple varieties of tree nut. Symptoms of food allergy usually start within minutes of exposure to the trigger food and must occur within 2 hours to classify as an IgE-mediated response. Any combination of local oral, dermatological, gastrointestinal 6

Table 1 | Prevalence of food allergies in adults and children30 Food Young children Cow’s milk Egg Peanut Soy Tree nut Shellfish Adults Shellfish Peanut Tree nut Fish

Prevalence (%) 2.5 1.3 0.8 0.4 0.2 0.1 2 0.6 0.5 0.4

and respiratory symptoms can occur (Table 2). The most severe reactions have systemic effects leading to potentially fatal anaphylaxis. Cutaneous effects are the most common, found in 80% of cases.20, 21 Respiratory symptoms usually occur only as part of a generalised reaction and isolated respiratory symptoms should prompt a reconsideration of the diagnosis of food allergy. Gastrointestinal symptoms can occur through immediate gastrointestinal hypersensitivity.

Oral allergy syndrome (pollen food allergy) Oral allergy syndrome, or pollen food allergy, is a localised IgE-mediated food allergy triggered by certain fruits and vegetables. Symptoms affecting the lips, mouth and throat are usually mild without any associated systemic reaction. The phenomenon results from the similarity between epitopes present in fruit and vegetables and in common pollens such as birch and ragweed. Pollensensitised individuals, often with clear symptoms of seasonal rhinitis, can therefore mount an IgE response to structurally similar fruit and vegetable allergens upon oral contact. Their food allergy symptoms tend to be worse during times of high pollen counts. Associated systemic symptoms can occasionally occur, and anaphylaxis has been reported in around 2%.22 Oral allergy syndrome affects around 2% of the UK population and 50–90% of those with birch pollen allergy.23 It is more common in adults than children. Exposure to trigger foods causes an immediate contact-related urticaria, with associated itching and tingling of the lips, tongue and throat. Occasionally there are more severe features such as frank angioedema or blistering. Common triggers are melon, banana, apple, kiwi, tomato and celery. Reactions usually occur only with the raw food Aliment Pharmacol Ther 2015; 41: 3-25 ª 2014 John Wiley & Sons Ltd

Review: food allergies and intolerances Table 2 | Clinical features of IgE-mediated food allergy Local oral & orbital

Dermatological

Gastrointestinal

Respiratory

Systemic

Itching of palate/lips Swelling of lips/ tongue

Acute urticaria Flushing

Nausea Abdominal pain

Hypotension

Eye itching, redness and watering Periorbital oedema

Angioedema

Vomiting

Nasal itching Rhinorrhoea & nasal obstruction Sneezing

Exacerbation of existing eczema Morbiliform rash

Diarrhoea

Laryngospasm

and not to cooked or processed forms, since heating attenuates the culprit allergens.20 Particular pollen allergies are associated with a corresponding group of food allergies (Table 3). Examples of identified overlapping antigens include the Bet v 1-cross reactive antigens that have a role in the food allergies commonly associated with birch pollen allergy. Bet v 1 comprises a plant defense protein, but there are homologous proteins found in apple (Mal d 1), cherry (Pru av 1) and celery (Api g 1).24 In contrast, where oral allergy syndrome occurs in the absence of pollen allergy the culprit allergens are more likely nonspecific lipid transfer proteins. These are often concentrated in the peel of, for example, apple (Mal d 3), cherry (Pru av 3) and orange (Cit s 3).25, 26 IgE-mediated allergy testing can be performed in oral allergy syndrome, preferably using raw foods in skin prick testing. Managing oral allergy syndrome involves avoidance of raw trigger foods alongside antihistamine treatment of seasonal allergic rhinitis. Since many of the more immunogenic proteins are found within a fruit/vegetable’s skin, peeling the offending fruit/vegetable may diminish the reaction. Those with solely mild oral symptoms may choose to continue consuming culprit foods. The minority of individuals who experience systemic reactions should strictly avoid trigger foods and carry adrenaline (epinephrine) autoinjector pens. Cross-reactivity also occurs in latex allergy. 30–50% of individuals who have allergic reactions on contact with

Dyspnoea, wheeze

latex have an increased likelihood of being allergic to banana, avocado, chestnut, kiwi, tomato, bell pepper and often to some other fruits too. Hevein is a latex protein with cross-reactive epitopes shared by some fruits. Cross reacting epitopes include those of the Hev b class including Hev b 2 (beta-1,3-glucanase).27, 28

Anaphylaxis Anaphylaxis is a systemic response initiated by binding of antigen to membrane-associated IgE on mast cells and basophils. This causes the release of inflammatory mediators, including histamine, tryptase and chemo-attractants. Injected histamine can reproduce most of the features of anaphylaxis in animals, where it leads to smooth muscle spasm, eosinophil activation and increased vascular permeability.29 Food anaphylaxis can occur after ingestion and also after exposure via other routes such as skin contact with vomit, or inhalation of minute food particles released during cooking. Food anaphylaxis presents differently to drug- or venom-induced anaphylaxis in that the mechanism for fatal reactions is almost always respiratory arrest, with isolated cardiovascular collapse being rare. Gastrointestinal features are more common in food anaphylaxis and occur in 41% episodes, compared to 3.7% of anaphylaxis episodes induced by drugs/venoms.29 Biphasic or protracted reactions are more common in food anaphylaxis.30

Table 3 | Food groups cross reacting with pollens in Oral Allergy Syndrome (adapted from ref 22) Pollen

Allergen

Associated cross-reacting Oral Allergy Syndrome triggers

Birch

Bet v 1

Ragweed Mugwort Orchard Grass Timothy Grass

amb a allergen group art v 1 dac g allergen group Phl p allergen group

Apple, peach, plum, cherry, apricot, almond, carrot, celery, parsley, hazelnut (also possible soy and peanut systemic allergy) Melon, cucumber, zucchini, banana, kiwi Celery, carrot, parsley, peppers, mustard, cauliflower, broccoli, garlic, onion Melon, peanut, potato, tomato Swiss chard, orange

Aliment Pharmacol Ther 2015; 41: 3-25 ª 2014 John Wiley & Sons Ltd

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J. L. Turnbull et al. Sampson et al. have drawn up three sets of clinical criteria for the diagnosis of food allergy-induced anaphylaxis (Table 4).30 An elevated serum tryptase soon after a suspected reaction can identify anaphylaxis. However tryptase levels are less commonly elevated in anaphylaxis when it is caused by food than when triggered by drugs or venoms. This may be because basophils play more of a role than mast cells in food anaphylaxis. Although there are increasing numbers of emergency hospital attendances for food-induced anaphylaxis31 deaths from food-induced anaphylaxis are uncommon. A meta-analysis concluded that the incidence of death due to food-induced anaphylaxis was 1.8 per million person-years in food-allergic individuals.32 In these fatalities, peanut is the most common food allergen, and there is invariably a history of asthma.

Food dependent exercise-induced anaphylaxis Exercise-induced anaphylaxis is a rare disorder affecting adults and children, in which allergic symptoms occur during or after exercise. Symptoms range from urticaria, angioedema, respiratory and gastrointestinal signs to anaphylactic shock.33 In one-third of patients there is an association with certain food allergens,34 and the condition is then termed food dependent exercise-induced anaphylaxis (FDEIA). In FDEIA, allergic symptoms typically occur two hours after ingestion of allergen food and with subsequent exercise.35 FDEIA may also rarely occur if the food is ingested soon after the completion of exercise.36 Shellfish and wheat are the most common causative foods in both children and adults. Alcohol, tomatoes, cheese, peanuts and celery are also often implicated.33, 34, 37, 38 Food processing and the presence of undigested protein allergens in the digestive tract at the time of exercise may be a prerequisite for the develop-

ment of FDEIA. This has been suggested after studying a patient with FDEIA who could safely exercise after soy milk, but not after tofu – a coagulated form of soy milk that is more slowly digested.39 Other factors linked to FDEIA include nonsteroidal anti-inflammatory 40, 41 drugs, a history of atopy and consumption of alcohol with the food allergen.41 The pathophysiological mechanisms leading to a temporary loss of immune tolerance in FDEIA have not been established. The Transient Receptor Potential channel, TRPV1, functions as an ion channel in neurones. TRPV1 regulates the cellular influx of calcium, and can be activated by heat, acidosis and various chemical stimuli. Mast cells are closely anatomically related to neurones bearing TRPV1 receptors, and anaphylaxis is associated with TRPV1 activation. Exercise increases temperature and metabolic acidosis which lower the threshold for TRPV1 activation, and may provide an explanation for exercise-induced anaphylaxis.42 Furthermore exercise increases gut permeability,43 and food allergens may more easily permeate the gut wall during exercise gaining greater access to the gut-associated immune system.44 NSAIDs and alcohol also increase gut permeability, explaining why they can exacerbate FDEIA.41, 45 Additionally, exercise diverts blood from inactive tissue to active tissue. Food-sensitised, gut-associated immune cells may redistribute to the skin and skeletal muscles during exercise. The increased amount of food allergen presented to the mast cells and basophils precipitates histamine release and the allergic reaction of FDEIA.46 The diagnosis of FDEIA is extremely challenging since prior food allergy may not be suspected and food challenge in the absence of exercise is usually negative. Once a responsible food allergen is identified, it should be

Table 4 | Diagnostic criteria for anaphylaxis (adapted from ref 30) Anaphylaxis is highly likely when any 1 of the following three criteria sets is fulfilled: 1. Onset of illness in minutes to several hours with involvement of the skin or mucosa (urticaria, itching or flushing, swollen lips-tongue-uvula) and one of: a Respiratory compromise (dyspnoea, wheeze, stridor, reduced peak expiratory flow, hypoxia) b Reduced blood pressure or associated symptoms of end organ dysfunction (eg syncope, incontinence) 2.

Known allergy and likely exposure to allergen for that patient and with rapid symptoms including two of: a Skin/mucosa involvement (urticarial, itching/flushing, swollen lips-tongue-uvula) b Respiratory compromise (dyspnoea, wheeze, stridor, hypoxia) c Reduced blood pressure or associated symptoms (collapse, syncope, incontinence) d Persistent gastrointestinal symptoms (cramping, abdominal pain, vomiting)

3.

Reduced blood pressure after exposure to known allergen for the patient: Adult: systolic pressure 30% lower than patient’s baseline Child: refer to age-specific centile charts

8

Aliment Pharmacol Ther 2015; 41: 3-25 ª 2014 John Wiley & Sons Ltd

Review: food allergies and intolerances avoided for at least 4–6 h before exercise and also for a period after exercise.33, 36 If the food allergen is not identifiable then avoiding all foods, nonsteroidal anti-inflammatory drugs, aspirin and alcoholic beverages for 4–6 h before and a period after exercise is advisable. Prophylactic agents such as cetirizine combined with montelukast,47 and mast cell degranulation inhibitors such as sodium cromoglycate48 and ketotifen49 may provide some protection. Exercise should be terminated immediately if allergic symptoms develop.

Diagnosis of IgE-mediated food allergy In confirming a diagnosis of a food allergy, the history is key, with tests playing a supportive role. Performing allergy tests and interpreting their results in the context of the history, requires specialist knowledge. Furthermore in vivo allergy tests can be hazardous. Thus in most cases, a diagnosis of food allergy is best made by a specialist clinic. However, a recent UK guideline is recommending primary care based diagnosis for cow’s milk allergy in children.21 A detailed history is essential, but is not sufficient alone to diagnose food allergy.9 The goal of the history is to identify a likely cause for symptoms, decide whether any allergy is likely to be IgE-mediated and then guide appropriate testing of this allergen and its likely cross-reactive foods. It is important to be focussed with testing, as most tests in allergy are sensitive but not specific. Therefore indiscriminately testing for large batteries of allergens will yield many false positive results. It is important to consider reactions to cooked and uncooked forms of food.9, 21 The history should also address any personal and family history of asthma, eczema or allergic rhinitis, and family history of food allergies. There is a strong link between atopic eczema and food allergy. The development of atopic eczema before 6 months of age, and severe eczema within the first year of life are associated with the development of egg, milk and peanut allergies.50 Finally the response to any dietary restrictions and medications should be explored. Testing for IgE-mediated food allergy. Approved tests of value in diagnosing IgE-mediated food allergy are the skin prick test, and measuring food-specific IgE antibody levels. The double-blind placebo-controlled food challenge remains the gold standard in food allergy testing, but is not frequently performed due to its inherent risks, inconvenience and cost. Alternative tests, some of which are readily available to the public, are specifically not recommended. These include Vega (electrodermal) testAliment Pharmacol Ther 2015; 41: 3-25 ª 2014 John Wiley & Sons Ltd

ing, hair analysis, applied kinesiology, serum-specific IgG4, lymphocyte stimulation, facial thermography, gastric juice analysis, endoscopic allergen provocation, cytotoxicity assays and the Mediator Release Test. In addition atopy patch tests are not helpful in the diagnosis of IgE-mediated food allergy,9, 21 but may have a role in testing for T cell mediated immune responses. The main difficulty with both specific IgE (sIgE) testing and skin prick tests is that they cannot distinguish between an individual who is merely sensitised to the allergen (has detectable circulating sIgE) and one who is clinically allergic (has mast cell-bound IgE leading to immediate mediator release). This is why it is essential to target allergy testing based on leads in the patient’s history, and it is ideal to complement the tests with a definitive food challenge.51 Skin prick tests are usually first line, but sIgE tests are preferable where there is a significant anaphylaxis risk, in pregnancy, in severe skin disease and dermatographism and in patients unable to stop taking medications such as b-blockers and antihistamines.

Food allergen specific serum IgE. The measurement of sIgE antibodies in serum was originally done by radioallergosorbent test (RAST) assay. However, more accurate methods including fluorescence enzyme-labelled tests are available for measuring sIgE. Thus, other assays such as ImmunoCap, Immunlite and HYTEC-288 systems are now in use.51 The assays involve a surface-fixed allergen which is incubated with the patient’s serum. Any sIgE antibody to the antigen will bind to the fixed allergen and remain after washing. Bound IgE is then identified by the binding of labelled anti-IgE. The methods in common use are all reliable, but require different reference ranges for clinical decision points.51 The level of sIgE correlates with the likelihood of a clinically significant reaction to that food trigger, but does not indicate its likely severity. Sampson et al. originally drew up values of sIgE to the most common allergens that had a 95% positive predictive value in the diagnosis of food allergy, based on a study of more than 100 children where tests were correlated with the gold standard food challenge (Table 5).52 SIgEs are not helpful if the history is not supportive of IgE-mediated allergy as there is a reasonably high chance of a false positive result. Conversely, sIgE testing cannot rule out allergy where the history is suggestive since its sensitivity is low and between 10% and 25% of significant reactions, including anaphylaxis, may be missed. Individuals with a strong history for IgE-mediated allergy and negative sIgE testing should undergo an oral food challenge.53 9

J. L. Turnbull et al. Table 5 | Predictive value of food allergen-specific IgE levels (from ref 52) Allergen Egg Milk Peanut Fish Tree nuts Soybean Wheat Egg

Review article: the diagnosis and management of food allergy and food intolerances.

Adverse reactions to food include immune mediated food allergies and non-immune mediated food intolerances. Food allergies and intolerances are often ...
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