Approach

Diagnosis of a food allergy relies critically on the history. This should focus on the specific symptoms a patient has in order to classify the patient as having a disorder mediated by IgE, T cells, or both. Testing for specific food allergens will depend critically on this differentiation.

Diagnosis of food intolerance and sensitivity also relies critically on the history. The timing of symptoms in response to ingestion of particular foods often leads to suspicion of a food intolerance or sensitivity.[53]

History

All patients, regardless of age, who have symptoms of hoarseness, urticaria, angio-oedema, pruritus, throat tightness, wheezing, vomiting, or cardiovascular collapse within 2 hours of food ingestion should be evaluated for possible food allergy following treatment with intramuscular adrenaline. Key information to accurately identify a possible food trigger for anaphylaxis includes the following:

  • A list of all food items ingested within 2 hours preceding the reaction

  • Length of time between food ingestion and reaction

  • Quantity of food consumed

  • History of any symptoms upon prior ingestion of the food

  • Other factors associated with the allergic reaction, such as exercise or aspirin ingestion.[16][31]

Typically the history narrows the focus of the diagnostic evaluation from a long list of many possible foods to a shortlist of several more likely foods. The most common food allergens in adults are peanuts, tree nuts, shellfish, and fish. In younger children, the usual culprits are milk, eggs, wheat, soya, peanuts, and tree nuts.[1]

Galactose-alpha-1,3-galactose (alpha-gal) allergy (tick borne) results in non-specific symptoms, such as abdominal pain, diarrhoea, nausea, or vomiting, one to several hours after eating mammalian-derived products.[54]​ Skin symptoms such as urticaria and angio-oedema may or may not be present.[54]​ Tick bites or parasitic infection appear to result in sensitisation.[54]​ The tick species most commonly implicated in the US is the lone star tick (Amblyomma americanum).[54]​ Other species have been implicated in other parts of the world (Ixodes ricinus, Isoces holocyclus, Amblyomma cajennense, Amblyomma sculptum, Ixodes (Endopalpiger) australiensis, and Haemaphysalis longicornis).[55]

Food allergy in infants

  • Infants may have anaphylaxis in response to either food they ingested directly or food ingested by breastfeeding mothers. A careful history can focus the evaluation for potential food allergens.

  • Infants with moderate to severe eczema should undergo a diagnostic evaluation for food allergy. This begins with a careful clinical history to identify underlying food triggers of immediate reactions and worsening eczema. Often a parent may not be able to identify a particular food associated with the eczema. If an underlying food allergy cannot be identified by history, then testing should be conducted to evaluate for the common food allergens of milk, eggs, wheat, soya, peanuts, tree nuts, and possibly shellfish.[22][23][56][57]

  • Often infants present with failure to thrive and vomiting. These two features are common in infants who have either eosinophilic oesophagitis or coeliac disease. In addition, infants with coeliac disease often have steatorrhoea.​​[34][58]​ Presence of these symptoms warrants further investigation. Identification of the inciting food allergen is not possible through history alone, and requires further testing.

  • Infants with profuse vomiting, diarrhoea, irritability, and lethargy may have food protein-induced enterocolitis.[28][29] Healthy, thriving infants with blood-streaked stools may have food protein-induced proctocolitis.[1] History is key to the diagnosis and identification of the food trigger in both these conditions. Often the inciting food is ingested about 2 hours prior to the onset of symptoms. A careful dietary history is crucial to determine the causative agent. There is no diagnostic testing to identify the causative foods in these 2 disorders; diagnosis of the food allergy is based solely on history. Milk and soya are the two most common food triggers.[1][21][28] Once a suspect food is identified based on history, it should be removed from the diet. Diagnosis is confirmed if symptoms resolve once the food is removed.[28][29]

Food allergy in children

  • Children may experience the symptoms of anaphylaxis in response to ingestion of a particular food. Identification of the causative food relies critically on history. Exercise, in addition to food ingestion, may be an important component of inducing anaphylaxis, so the history should include questions regarding the timing of anaphylaxis in relation to any exercise.[17]

  • Children with moderate to severe eczema may have an underlying food allergy that worsens their skin disease. If a parent can recall a food that seems to worsen the eczema, further testing to confirm the food allergy can be performed. However, often parents are unable to identify a food that triggers a reaction. In this circumstance, a general evaluation for allergy to the common food allergens including peanuts, tree nuts, milk, soya, eggs, and wheat should be performed.[11][12][56][57]

  • Children and adolescents with eosinophilic oesophagitis often suffer from heartburn, abdominal pain, and dysphagia.[19][59] An oesophageal biopsy is necessary to confirm this diagnosis. The specific food allergens exacerbating eosinophilic oesophagitis cannot be determined from history alone, but are often the same foods that cause IgE-mediated anaphylaxis.[19][59]

  • Coeliac disease (sprue) can cause vomiting, steatorrhoea, and failure to thrive in children. Further evaluation with antibody testing and small bowel biopsy is warranted in children with this symptom complex.​​[34][58]

Food allergy in adults

  • Symptoms of urticaria, angio-oedema, vomiting, wheezing, pruritus, throat tightness, or cardiovascular collapse indicate anaphylaxis, and require prompt administration of intramuscular adrenaline. Following this, patients require a careful history for possible food triggers of the event. Common causes in adults are an allergy to peanuts, tree nuts, shellfish, or fish. Potential food allergens identified should be further evaluated with skin prick tests and/or in vitro IgE tests.

  • Adults with pollen or latex allergies may experience oral symptoms (classically localised to the oropharynx and possibly including pruritus and angio-oedema of the lips, oral mucosa, and soft palate) following ingestion of particular fruits, vegetables, and spices.[21][60] These patients should undergo evaluation for pollen or latex allergy with skin prick tests.

  • Adults with eczema do not warrant evaluation for food allergy unless a history of anaphylaxis is obtained. Any adult with food impaction, dysphagia, or failure to respond to anti-reflux therapy should undergo investigation for eosinophilic oesophagitis by oesophageal biopsy.[12] Once the diagnosis of eosinophilic oesophagitis is made, then further evaluation for food allergies with skin prick testing should be performed.[61][62]

  • Adult patients with diarrhoea, weight loss, abdominal discomfort, fatigue, nutritional deficiencies, anaemia, or osteoporosis should undergo further evaluation with antibody testing and biopsy for coeliac disease.​​[34][58]​ In addition, any patient with the skin rash of dermatitis herpetiformis should also be evaluated for coeliac disease.

Food intolerance in infants, children, and adults

  • Infants with congenital enzyme deficiencies may present with diarrhoea, failure to thrive, and abdominal distension within the first year of life. Any infant presenting with these symptoms should undergo evaluation for gastrointestinal enzyme deficiencies.[11][38]

  • Children and adults who experience flatulence, diarrhoea, and abdominal pain after ingesting dairy products should undergo evaluation for lactose intolerance.

Food sensitivities in infants, children, and adults

  • Patients on monoamine oxidase inhibitors who develop migraines should be evaluated for food sensitivities.[39] However, the association between food ingestion and migraines is very controversial. The literature suggests that there is no correlation between ingestion of foods with tyramine and other biogenic amines and migraines.[8]

  • Patients with asthma who report exacerbations after ingestion of products such as wine and dried fruit should be evaluated for potential sulfite sensitivity.[10]

  • The association between monosodium glutamate (MSG) and sensitivity reactions has not been demonstrated in clinical trials.[7][40]

Physical exam

Significant physical examination findings in patients who present acutely with food-induced anaphylaxis include urticaria, angio-oedema of the oropharynx, hoarseness, sweating, sneezing, wheezing, and low blood pressure. However, patients often present for evaluation after the anaphylactic event and therefore do not have any signs of anaphylaxis at time of exam. Occasionally, patients have features of atopic conditions, such as signs of allergic rhinitis (darkened areas of skin around the eye sockets, pale boggy nasal mucosa, injected conjunctiva) or signs of eczema (rough, red, raised plaques and patches in the flexor surfaces of joints in children/adults, or in the extensor surfaces of joints and faces of infants). Signs of allergic rhinitis may also occur in patients with oral allergy syndrome.

Patients with coeliac disease may have dermatitis herpetiformis: a rash located on the extensor surfaces of the elbows, knees, buttocks, and back consisting of erythematous plaques, papules, and vesicles that are grouped together.[63] Often the rash appears excoriated due to patient scratching.​​[34][64]

[Figure caption and citation for the preceding image starts]: Dermatitis herpetiformis: typical lesions on extensor surface of forearmFrom the collection of Adam Reich MD, PhD [Citation ends].com.bmj.content.model.assessment.Caption@5d86162a

Patients with food protein-induced enterocolitis, food protein-induced proctocolitis, or eosinophilic oesophagitis usually have normal physical examination findings. Some infants and children with eosinophilic oesophagitis or coeliac disease may have low weight and failure to thrive.

Investigations for food allergy with anaphylaxis

If a patient has symptoms of anaphylaxis, a careful history should identify the likely foods responsible. Once several candidate foods have been identified by history, skin prick tests and in vitro IgE assays (e.g., immunoCAP hydrophilic carrier polymer fluoroenzyme immunoassay) can be used to further evaluate for a potential food allergy. IgE testing may be preferred over, or in addition to, a skin prick test in patients with severe dermatitis or dark skin, patients using antihistamines, or patients who exhibit dermatographism. Allergy testing may be performed at all ages, including in infants.

Skin prick tests

  • A minuscule amount of food antigen is introduced into the skin through pricking or puncturing.[16]

  • Food allergen binds to IgE on the surface of mast cells, thereby causing mast-cell degranulation, which results in the formation of a wheal.[6]

  • Allergens that result in a wheal 3 mm greater in diameter than the saline control are considered positive.[6]

  • Negative predictive value of an allergen skin prick test is 95%, meaning that a negative skin prick test indicates a lack of a response to that particular allergen.[12]

  • Generally, the positive predictive value of a skin test is 50%.[12] This means a positive skin prick test may or may not indicate a true allergy to the particular allergen. However, several studies have established 95% positive predictive values for skin prick test wheal diameters and yielded differing results based on a number of factors. In general, the greater the wheal diameter, the more likely the individual is to have an immediate reaction to the food following ingestion.[65] Further investigation with in vitro IgE and oral food challenges may be warranted in some situations.

  • Many people are sensitised to a particular allergen but fail to have a clinical reaction when exposed to the allergen.[12]

In vitro quantitative specific-IgE capsulated hydrophilic carrier polymer fluorescent enzyme immunoassay (CAP-FEIA)

  • Used to detect whether a patient has been sensitised to a particular food.[6][66]

  • A positive result does not necessarily mean that the patient is allergic to the particular food.

  • If the patient is tolerating the food in question in his or her diet, then he or she is only sensitised and not allergic.

  • Studies have shown that very high concentrations of food-specific IgE may be predictive of clinical reactions to food.[67]

  • In young children with atopic dermatitis, values of specific IgE concentrations for egg, milk, peanuts, and cod using a particular assay have been identified that are 95% predictive of a reaction.[67]

Oral food challenges[68][69][70]

  • The double-blinded, placebo-controlled oral food challenge is considered the definitive standard for the diagnosis of food allergy.[12]

  • If the diagnosis of a food allergy remains uncertain after skin prick testing and IgE antibody measurement, then the patient may need to undergo an oral food challenge with the suspected food.

  • Open food challenges can be used to screen for reactivity.[66][71]​​

  • All food challenges should occur under physician supervision with emergency medications, including adrenaline, readily available.[22]

  • During a food challenge, the patient gradually ingests increasing amounts of the food in question until he or she either reacts or tolerates a full serving of the food.[23]

Skin prick testing and in vitro IgE testing should be performed only for food allergens identified by history as possible culprits in an anaphylactic reaction. A panel of positive in vitro IgE test results to multiple food allergens is useless unless the foods have been identified as possible causes by history. A positive skin prick test or IgE test does not indicate that a patient has a food allergy; it means only that they are sensitised to a food. Only the history or an oral food challenge can identify true food allergens.

Serum tryptase

  • The UK National Institute for Health and Care Excellence (NICE) recommends that serum tryptase samples should be taken from children <16 years during or soon after resuscitation.[45]

  • In adults, NICE recommends that blood should be taken to assess mast cell tryptase levels as soon as possible after emergency treatment has started, with a second sample ideally within 1 to 2 hours (but no later than 4 hours) from the onset of symptoms. A third sample should be taken during a follow up appointment.[45]

  • ​The American Academy of Allergy, Asthma & Immunology recommends obtaining a baseline serum tryptase in patients presenting with a history of recurrent, idiopathic, or severe anaphylaxis, particularly those presenting with hypotension.[47]

  • Note that in clinically obvious food-induced anaphylaxis, tryptase levels are seldom elevated, even if serum was collected in a timely manner.[72]

Investigations for food allergy with oral symptoms only

Adults with oral symptoms of itching, or angio-oedema upon ingestion of fruits, vegetable, or spices, should be evaluated for oral allergy syndrome.

  • Patients with oral allergy syndrome have either pollen-food syndrome (the most common form) or latex-food syndrome.

  • History should focus on identifying the symptoms of allergic rhinoconjunctivitis (runny nose, sneezing, and itchy, watery eyes) as well as the season of symptoms.

  • History should include foods causing reactions.

  • Specific pollen allergies are associated with oral symptoms to particular fruits and vegetables. For example, birch pollen allergy is often associated with oral symptoms to stone fruits, nuts, or certain vegetables.[73]

  • Latex allergy is often associated with oral symptoms to avocados, kiwis, bananas, or chestnuts, although other fruits and vegetables may also be involved.

  • Skin prick tests can be used to identify pollen or latex allergy.

  • Knowledge of the pollen/food associations and latex/food associations can help patients avoid foods to which they react.

Investigations for food allergy with atopic dermatitis

In patients with severe eczema:

  • A careful clinical history is required to identify underlying food triggers of immediate reactions and worsening eczema

  • If there is no history of a food allergy, children with moderate to severe eczema may be screened by skin prick test or in vitro IgE against the common food allergens (milk, eggs, wheat, soya, peanuts, and tree nuts)

  • If a screening test is positive, then the suspected food should be eliminated from the diet for at least 1 month

    • If the eczema improves on the elimination diet or clinical reactivity is uncertain, perform oral food challenge

    • If no symptoms are immediately apparent after the challenge, the food should be consumed for several days and the patient re-evaluated for worsening eczema[22][23]

    • If the patient has symptoms or worsening eczema after food challenge, the food should continue to be eliminated

    • If there are no symptoms and the eczema is unchanged after food challenge, the food can be reintroduced.[22][23]

Investigations for food allergy with eosinophilic oesophagitis

The following should be considered for any patient with food impaction, dysphagia, or failure to respond to anti-reflux therapy; for any infants and young children with failure to thrive, vomiting, or regurgitation; or for any children and adolescents with heartburn, abdominal pain, or dysphagia:

  • Upper endoscopy with oesophageal biopsy (positive biopsy shows >15 eosinophils per high-power field)[60][74]

  • Food allergy evaluation

    • Skin prick test and in vitro IgE testing for food-specific IgE

    • Atopy patch testing (controversy exists over the role of atopy patch testing in identifying food allergens causing a delayed cell-mediated response)[62]

    • Empirical diets based on removal of the most common food allergens[20][61]

    • Trial of elemental diet.

Investigations for food allergy in infants with enterocolitis or proctocolitis

Enterocolitis or proctocolitis can be suspected in infants with a history of profuse vomiting, diarrhoea, and irritability after food ingestion, or in healthy, thriving young infants presenting with intermittent blood-streaked, loose stools.[1][28][29][75][76]

  • Diagnosis is based primarily on history.

  • Milk and soya are the foods most commonly responsible.

  • Occasionally, other foods such as grains, vegetables, and poultry have been reported as inciting agents in food protein-induced enterocolitis.[29]

  • About 50% of infants with proctocolitis are breastfed and may be responding to a food antigen in the maternal diet.[16]

  • Once the inciting food is removed from the infant or maternal diet, symptoms resolve.[61]

Investigations for suspected coeliac disease

Features that would suggest possible coeliac disease include a history of diarrhoea, bloating, abdominal pain, anaemia, and dermatitis herpetiformis (intensely pruritic papulovesicular lesions that occur symmetrically over the extensor surfaces of the arms and legs, as well as on the buttocks, trunk, neck, and scalp).

Work-up for suspected coeliac disease may include serological and genetic tests, and biopsy; serological tests should be performed while the patient is still on a gluten-containing diet.[58][64]

  • Immunoglobulin A-tissue transglutaminase (IgA-tTG): ordered first in all patients on a gluten-containing diet, including in individuals less than 2 years who are not IgA deficient. This would show a titre above normal reference range, with higher titres having increased positive predictive value.​​​ Note that antigliadin antibodies are non-specific and not useful.​

  • Quantitative (total) IgA: routinely requested to assess for IgA deficiency, since the presence of IgA deficiency renders IgA-tTG insensitive.[77]​ IgA deficiency is more common in people with coeliac disease than in the general population.[78]

  • Immunoglobulin G-tissue transglutaminase (IgG-tTG) and deamidated gliadin peptide (IgG-DGP): performed in all patients with low IgA levels or IgA deficiency.

  • Endomysial antibody (EMA): an alternative to IgA-tTG, with greater specificity but lower sensitivity. A combination of high-level IgA-tTG (>10 times upper limit of normal) with a positive EMA in a second blood sample can be used to diagnose coeliac disease in children. In symptomatic adults unwilling or unable to undergo upper gastrointestinal endoscopy, the same criteria may be considered as a diagnosis of likely coeliac disease.

  • Duodenal biopsy: ordered in adults and children who have suspected coeliac disease. This should be considered, even if serologies are negative, in patients with high pre-test probability.

  • HLA haplotype: genetic testing for coeliac disease-compatible haplotype is not required for diagnosis in all cases, but may be helpful in selected situations, such as in serology-histology discrepancy. If negative, coeliac disease is ruled out. HLA testing is central to the approach to coeliac disease testing for individuals who have started a gluten-free diet before evaluation; in the presence of a coeliac disease-compatible haplotype, a gluten challenge can be offered.

  • FBC: frequently shows low Hb and microcytic red cells; iron deficiency anaemia is the most common clinical presentation in adults; folate (and, rarely, vitamin B12) deficiency may lead to a macrocytic anaemia.

  • Biopsy of dermatitis herpetiformis skin lesions: will show granular deposits of IgA at the dermal papillae of lesional and perilesional skin by direct immunofluorescence.

Investigations for suspected lactose intolerance

Children, adolescents, and adults who develop loose stools, flatulence, or abdominal pain after ingestion of milk products should undergo investigation for lactase deficiency.[7][13] Investigations include:

  • Dietary exclusion of milk and milk products with symptom diary to determine if symptoms improve while lactose is excluded from the diet. Challenge with milk and milk products after exclusion to determine if symptoms return upon re-introduction of dairy into the diet.[7]

  • Lactose hydrogen breath test, in which the patient ingests a standardised amount of lactose (2 g/kg, maximum 25 g) after an overnight fast with measurement of exhaled hydrogen over a 2- to 3-hour period. A positive test is an increase of >20 ppm of exhaled hydrogen after approximately 60 minutes.[7][13][79]

  • Biopsy of small intestine with measurement of lactase levels.

Investigations for suspected congenital sucrase isomaltase deficiency

Infants who develop diarrhoea, abdominal pain, or poor growth when non-lactose-based infant formula or solid food is introduced should be evaluated for sucrase isomaltase deficiency.[38][80] This is a very rare condition and can be difficult to diagnose. Investigations include:

  • Sucrose hydrogen breath test, in which the patient ingests a standardised amount of sucrose with measurement of exhaled hydrogen over a 2- to 3-hour period. A positive test is an increase of >20 ppm of exhaled hydrogen after approximately 60 minutes.[38]

  • Biopsy of the small intestine with assay of sucrase and isomaltase levels.[38]

Investigations for food sensitivities

The diagnosis of food sensitivities is determined by elicitation of symptoms upon challenge with the presumed causative food. Double-blind placebo-controlled trials are the best way to diagnose food sensitivities.

Numerous studies have failed to elicit symptoms upon challenge with MSG and tyramine.[8][40]

Sulfite sensitivity has been clearly documented with double-blind placebo-controlled trials in asthmatic patients.[41] Pulmonary function testing should be performed prior to sulfite challenge and after challenge at defined intervals. A positive challenge occurs when the forced expiratory volume (FEV1) decreases by 20% from baseline.[10][41]

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