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World Allergy Organization
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Disease Summaries

Food Allergy

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Posted: May 2004

Professor Cassim Motala, South Africa

Definition and Classification

Adverse reactions can be subdivided into non-toxic or toxic reactions. The term food allergy is used when an immunological mechanism has been defined or is suspected. The two broad groups of immune reactions are IgE-mediated and non-IgE-mediated. The IgE-mediated reactions are usually divided into immediate onset reactions (immediate in time) and immediate plus late-phase (in which the immediate onset symptoms are followed by prolonged or on-going symptoms). Non-IgE-mediated reactions, which are poorly defined both clinically and scientifically, are believed to be T-cell-mediated. They are typically delayed in onset, and occur 4 to 28 hours after ingestion of the offending food(s). Non-immune or non-allergic adverse reactions are termed food intolerance, for example, pharmacological reactions or intolerance to lactose.

Pharmacological reactions to foods are due to chemicals normally present in the foods, e.g., theobromine in chocolate or tyramine in aged cheeses. So too are adverse reactions to food additives such as sodium and potassium sulfites, metabisufites, monosodium glutamate and gaseous sulphur dioxides. Such agents are added to foods and drinks to prevent discoloration and are also used as preservatives in a variety of medications. Sulfites are converted in the acid environment of the stomach to SO2 and H2SO3. They are then inhaled and may cause non-allergic irritant reactions and asthma in susceptible individuals. Host factors such as lactase deficiency, which are associated with lactose intolerance, or idiosyncratic responses may be responsible for other non-allergic reactions to foods.

Toxic reactions to food can occur in anyone provided a sufficient amount of the food is ingested; they are due to toxins in the food, e.g., to histamine in scombroid fish or bacterial toxins in food.

A severe generalised allergic reaction to a food is classified as anaphylaxis.

Underlying Mechanisms of Food Allergy

The gastrointestinal tract processes ingested food for absorption. It neutralizes foreign antigens and blocks them from entering the circulation. Enzymes from salivary, gastric, pancreatic and intestinal secretions, combined with mastication, gastric acid, and peristalsis, reduce ingested substances to small sugars, peptides and fats. Non-specific (mucin coat) and specific (secretory IgA) mechanisms ‘hold up' and/or block potentially harmful antigenic substances from penetrating the intestinal barrier. Many of the immunological and mechanical barriers involved in this process are immature at birth, leaving the infant at risk. Large amounts of immunologically intact food proteins penetrate the gut barrier in children and adults and enter into the circulation, but clinical tolerance prevents pathologic reactions. A failure to develop tolerance or a breakdown in tolerance results in excessive production of food-specific IgE antibodies.

Mast cells line the GI tract from the lips to the rectum. Food antigens are most rapidly absorbed from the small intestine, colon and rectum and more slowly from the oesophagus and stomach. When food allergens penetrate mucosal barriers and reach specific IgE antibodies bound to mast cells, mediators such as histamine, leukotrienes and prostaglandins are released inducing an immediate hypersensitivity reaction manifested by vasodilatation, smooth muscle contraction and other alterations in normal physiology.

Epidemiology

Food hypersensitivity reactions affect approximately 2.5% of the general population. Up to 8% of children under 3 years may be affected and in children with eczema, the prevalence may be as high as 30%. About 2.5% of newborn infants have hypersensitivity reactions to cow's milk in the first year of life with approximately 80% outgrowing the allergy by the fifth birthday; about 60% of milk allergic reactions are IgE-mediated. Approximately 25% of these infants retain their sensitivity into the second decade of life, and 35% may acquire other food allergies. Studies suggest that 1.3 -1.5% and 0.5% of young children are allergic to eggs and peanuts, respectively. Food allergy is more common in children with other allergic diseases, with about 35% of children with severe allergic eczema experiencing IgE-mediated food allergy, and 6% of children with asthma experiencing food-induced wheezing. Approximately 2% of adults are affected by food allergies.

Common Food Allergens

Food
Infants/Young children
Older Children And Adults
Anaphylaxis
Milk (cow/goat)
 
Chicken egg
 
Soy
 
 
Peanut
Tree nuts (walnut, hazel/filbert, cashew, pistachio, Brazil , pine nut, almond)
 
Wheat
 
 
Fish
 
 
Shellfish (shrimp, crab, lobster, oyster, scallops)
 
Fruit
 
Vegetables
 
Seeds (cotton, sesame, psyllium, mustard)
 
Spices
 
 

Food sensitivity occasionally can be so severe that a systemic reaction can occur caused by inhalation of aerosols containing the food allergen, for example from odors of cooking fish or shellfish.

Cross-Reactivity of Pollen and Food Allergens

A severe allergy to pollen can indicate that an individual may be susceptible to developing the oral allergy syndrome or anaphylaxis when eating certain foods. Such reactions are due to profilins, homologous proteins found both in pollens and plants and fruits. Oral allergy syndrome also has been reported following ingestion of crustaceans by individuals who are sensitive to house dust mites.

Typical cross reactivity associations include:

Inhalant Allergen

Food Allergens

Birch pollen Apple, raw potato, carrot, celery, hazelnut, pear, peach, plum, cherry
Mugwort pollen Celery, apple, peanut, kiwi fruit, carrot, parsley, spices (fennel, coriander, aniseed, cumin)
Ragweed pollen Melons, e.g., watermelon, cantaloupe, and honeydew, bananas
Latex Avocado, kiwi fruit, chestnut, papaya, banana
Chironomidae Crustaceans (shellfish)

IgE-Mediated Food-Related Disorders

Skin Manifestations

Acute urticaria and angioedema frequently occur secondary to food allergy. The onset of symptoms may be rapid, within minutes, following the ingestion of the offending food Foods most often implicated include raw meats, fish, vegetables and fruits. Acute contact urticaria, secondary to coming into contact with the offending food allergen also occurs but the prevalence is unknown.

Chronic urticaria is rarely due to food allergy.

Eczema
About one-third of infants and young children with atopic eczema have IgE-mediated food allergy. Egg allergy is the most common food hypersensitivity in children with eczema. Appropriate diagnosis of food allergy and elimination of the offending allergen leads to significant clearing or improvement of eczematous lesions in many young children with eczema and food allergy. Food allergens may be triggers for some acute exacerbations.

Gastrointestinal Tract

Symptoms caused by immediate sensitivity in the gastrointestinal tract typically develop within minutes to 2 hours of ingesting the offending food. Symptoms can include lip, tongue and palatal pruritus and swelling, laryngeal oedema, nausea, abdominal cramping, vomiting and diarrhoea. Severe reactions can result in most or all symptoms associated with angioedema.

Oral allergy syndrome (OAS), a form of contact urticaria confined to the lips and oropharynx, most commonly occurs patients with allergic pollenosis. Symptoms include oropharyngeal itching, with or without facial angioedema, and/or tingling of the lips, tongue, palate and throat.  

Infantile colic presents in the first 2-4 weeks of life. Symptoms include crying, abdominal distension and belching. The child in distress may assume the fetal position. Symptoms may persist through to the third of fourth month of life. IgE-mediated food allergy may be a factor in 10-15% of infants with colic.

Allergic eosinophilic oesophagitis, gastritis or gastroenteritis: The exact cause of these disorders remains unknown although both IgE-mediated and T-cell-mediated reactions have been implicated. These conditions are characterized by infiltration of eosinophils in the mucosal, muscular and/or serosal layers of the stomach or small intestines. Patients present with postprandial nausea and vomiting, abdominal pain, diarrhoea (occasionally steatorrhoea) and weight loss in adults and failure to thrive in young infants. Eighty percent of patients with eosinophilic oesophagitis have symptoms similar to gastroesophageal reflux, which are refractory to anti-reflux therapy. In the case of infants, the vomitus often contains stringy mucus (similar to egg albumen). Patients may also present with food refusal, dysphagia, food impaction or abdominal pain. Food induced IgE-mediated allergy has been implicated in the pathogenesis in some patients.

Respiratory Reactions

Allergic rhinoconjunctivitis and asthma can also occur following food challenge testing, however, respiratory symptoms, in the absence of skin or gastrointestinal symptoms are rare. Two patients in a survey of 323 patients with chronic rhinitis had reproducible symptoms during blinded food challenge. When respiratory symptoms occur following food challenge, both early- and late-phase IgE-mediated mechanisms are probably involved. Only 0.08% to 0.2% of infants in three epidemiological surveys were found to have nasal symptoms following milk challenge.

Anaphylaxis

Food allergy is one of the most common causes of anaphylaxis. In addition to gastrointestinal symptoms, individuals may experience urticaria, angioedema, asthma, rhinitis, conjunctivitis, hypotension, shock and cardiac arrhythmias, caused by the massive release of mediators from mast cells and basophils.

Food-associated, exercise-induced anaphylaxis occurs when exercise takes place 2-4 hours after ingestion of a food to which the individual is allergic. Food or exercise alone will not cause this reaction. Risk factors for food-induced anaphylaxis include asthma and previous allergic reactions to the causative food.

Non-IgE-Mediated Food Allergic Disorders (some appear to be T-cell-mediated)

Gastrointestinal

Dietary protein enterocolitis syndrome
Affected group:
Early infancy.
Symptoms: Irritability, protracted vomiting 1 to 3 hours after feeding, bloody diarrhoea (may result in dehydration) anaemia, abdominal distension, failure to thrive.
Implicated food: Cow's milk and soy
Affected group: Older infants and children.
Symptoms: As above.
Implicated foods: Egg, wheat, rice, oat, peanut, nut, chicken, turkey, and fish.
Affected group: Adults.
Symptoms: Severe nausea, abdominal cramps, protracted vomiting.
Implicated foods: Crustaceans e.g., shrimp, crab, and lobster.
Pathology: Negative skin prick test responses to the suspected foods. Jejunal biopsy specimens reveal flattened villi, oedema, increased numbers of lymphocytes, eosinophils, and mast cells. Increased numbers of IgM-and IgA-containing plasma cells are present in the jejunal mucosa.

Dietary protein proctitis
Affected group: Early infancy
Symptoms: Blood-streaked stools in otherwise healthy infants. Blood loss usually modest but can be severe enough to cause anaemia.
Implicated foods: About 60% of cases occur in breast-fed babies, the remainder in infants fed cow's milk or soy protein-based formulas.
Pathology: Mild hypoalbuminaemia and peripheral eosinophilia occur rarely. Bowel lesions usually confined to distal large bowel; endoscopy reveals linear erosions and mucosal oedema with infiltration of eosinophils in the epithelium and lamina propria.

Dietary protein enteropathy
Affected group: Early infancy.
Symptoms: Protracted diarrhoea, vomiting, failure to thrive, abdominal distension, early satiety, and malabsorption. Anaemia, oedema, and hypoproteinaemia are occasionally present.
Implicated foods: Cow's milk sensitivity is the most frequent cause of this syndrome.
Affected group: Older children.
Symptoms: As above
Implicated foods: Soy, egg, wheat, rice, chicken, fish
Pathology: Patchy villous atrophy with cellular infiltrate on biopsy. Serum IgA and IgG antibodies to cow's milk proteins are usually elevated in cow's milk-induced enteropathy.

Coeliac disease
Affected group: All ages.
Symptoms: Malabsorption, chronic diarrhoea, steatorrhoea, abdominal distension, flatulence, weight loss or failure to thrive.
Implicated foods: Patients with coeliac disease are sensitive to gliadin, the alcohol-soluble portion of gluten found in wheat, oat, rye and barley.
Pathology: A dietary protein enteropathy characterized by villous atrophy and inflammatory cell infiltrate. Coeliac disease is associated with the HLA-DQ2 (and DQ8) haplotype. About 90% of patients with coeliac disease ingesting gliadin possess IgA anti-gliadin and antiendomysium antibodies. Endoscopy typically reveals profound villous atrophy and extensive cellular infiltrate.

Cutaneous

Dermatitis herpetiformis
Affected group: All ages.
Symptoms: Chronic, intensely pruritic papulovesicular rash symmetrically distributed over the extensor surfaces and buttocks, sometimes mistaken for atopic dermatitis.
Implicated foods: Associated with gluten-sensitive enteropathy.
Pathology: Like coeliac disease, 80% to 90% of patients with dermatitis herpetiformis have the HLA-DQ2 (or DQ8) haplotype.

Respiratory

Food induced pulmonary haemosiderosis (Heiner's Syndrome)
Affected group: Infants and young children.
Symptoms: Very rare syndrome characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates, haemosiderosis, gastrointestinal blood loss, iron deficiency anaemia, failure to thrive.
Implicated foods: Cow's milk; reactions to egg and pork have also been reported.
Pathology:
Peripheral blood eosinophilia and multiple serum IgG precipitating antibodies to cow's milk are a relatively constant feature; the immunologic mechanisms responsible for this disorder are unknown.

Diagnosis of Food Allergy

Low concentrations of IgG, IgM and IgE food specific antibodies are commonly found in sera of normal individuals; high levels of IgE and IgA are most likely to be indicative of a pathological process, e.g., food allergy and coeliac disease, respectively.

A double-blind, placebo controlled food challenge (DBPCFC) is the preferred test to diagnose food allergy. DBPCFC should be performed in specialist centres with close supervision. Resuscitation facilities, and overnight admission can be offered in severe cases. Results of skin prick tests (SPT), radio-allergosorbent testing for IgE antibodies, and patient histories are not predictive of true food allergy. The negative predictive accuracy of a skin prick test weal of < 3mm greater than the negative control is high, usually > 95%, and is strong evidence that the food may be safely consumed. A positive SPT, even a weal of 3 mm or more, may be clinically irrelevant, as the patient may tolerate the ingested food. Therefore, such results are not necessarily indicative of allergy to a particular food (a so-called false-positive test). Highly positive reactions, evidenced by SPT weals of 7mm-8mm to cow's milk, egg or peanut, are predictive of clinical reactivity, since such results are usually associated with positive challenge tests to these foods. Therefore, subjects who have highly positive skin prick tests can assume that they are allergic to a given food and need not be food challenged, reducing both costs and potential hazard to the patient.

Infants typically lose food sensitivity over time, but SPTs may still be positive even after the patient has developed tolerance to the food.

A concentration of specific IgE = 0.35 kU/l is regarded as the cut-off level for a positive in-vitro test of specific IgE. While this may be appropriate for airborne allergens, it is a poor predictor of clinical reactivity to food allergens. Higher levels of specific IgE (decision points) for food allergens may correlate with clinical reactivity as evidenced by challenge testing (see table below).

Table:

Food-specific IgE concentration (kU/L) clinical decision points
  Egg Milk Peanut Fish Soya Wheat
Reactive if equal to or greater than: 7 15 14 20 65 80

(From Sampson HA; J Allergy Clin Immunol 2001; 107: 891-896)

decision point is the concentration of specific IgE for a particular food allergen that is 90% predictive of a clinical reaction to the food (note: these concentrations vary for different foods). Decision points for infants appear to be lower (e.g., for infants, a concentration equal to or over 2 k/U/L to egg and 5 kU/L to milk is predictive of a reaction*). No challenge testing is needed if the concentrations are equal to or greater than the decision points. In patients with a strong history of an IgE-mediated food allergic reaction, food challenges should be performed with physician supervision, regardless of food-specific IgE value.

(* Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, et al. Specific IgE levels in the diagnosis of immediate hypersensitivity to cow's milk protein in the infant. J Allergy Clin Immunol 2001: 107 :195-190. Boyano MT, Garcia-Ara, Diaz-Pena JM et al. Prediction of tolerance on the basis of quantification of egg-white specific IgE antibodies in children with egg allergy. J Allergy Clin Immunol 2002; 110 : 304-309)

Identification of cross reactive allergens between pollen and certain foods, and foods and latex, are caused by common lipid transfer proteins (LTPs) and profilins. Profilin is an important protein which is responsible for IgE cross-reactivity between pollen and certain fruits. Skin prick/puncture tests using commercial extracts to the implicated fruit, are often negative, but a positive test may be obtained using a drop of fresh juice from the incriminated fruit.

The in-vitro test for diagnosing cell-mediated food hypersensitivities is an enzyme linked immunosorbent assay. The sensitivity of this test is uncertain.

The atopy patch test (APT) is an epicutaneous skin test in which allergens commonly associated with IgE reactions can be used, although the test is more commonly performed for metals such as nickel, which causes a positive patch test in nickel sensitive subjects. Although the pathogenic mechanisms of the APT have not been fully elucidated, a positive APT can predict a late phase reaction following oral food challenge. A positive APT may detect clinically relevant late phase eczematous reactions in infants and children. This test is not useful for IgE-mediated food allergy. It is considered experimental in most parts of the world.

Prevention and Treatment

The World Allergy Organization/World Health Organization evidence-based document, Prevention of Allergy and Allergic Asthma, recommends breast-feeding only for the newborn infant until 4-6 months and no special diet for the lactating mother. The report recommends that infants who have cow's milk allergy should avoid cow's milk proteins, and if a supplement is needed, hypoallergenic formula, if available, should be given to improve symptom control.

Treatment

Food Allergen Avoidance
The foods to which an individual is allergic should be avoided. Where avoidance of the implicated food may result in nutritional deficiency, dietary supplementation is necessary.

Processed foods may contain hidden proteins, e.g., milk, egg and soy proteins may be added to increase the protein content or enhance flavour. Peanuts and nut products are added to thicken and flavour sauces. Patients can be taught to identify hidden food components in processed foods. Commonly used ‘hidden' proteins are casein and lactose, derived from milk, and albumin from egg. The name arachis is frequently used to describe peanut products, both in foods and in cosmetics.

In some countries major supermarket chains provide lists of the allergen-free products suitable for individuals with a specific food allergy. Some manufacturers include information when processed foods are produced in food preparation areas where nut or milk proteins may be present and could be contaminates.

Individuals with food allergies should alert restaurant personnel about their food allergy and ask whether ingredients are contained in menu dishes or whether there is possible contamination of foods due to shared preparation areas or equipment. Allergen avoidance cards for travellers are available in a number of translations (e.g., Allergy UK and Food Allergy and Anaphylaxis Network websites).

Individuals allergic to egg should not be given influenza vaccines without prior consultation with their physician. Egg allergy is not generally a contraindication for administration of measles and MMR vaccine.

Pharmacotherapy
A number of medications have been prescribed for the treatment of food allergy. These include H1 and H2 antihistamines, ketotifen, corticosteroids and prostaglandin synthetase inhibitors. These drugs may modify allergic symptoms but, in general, are minimally effective and sometimes have unacceptable side effects. Oral sodium cromoglycate has been used but conflicting results are reported. Patients receiving immunotherapy for pollen allergy may lose their oral allergy syndrome. Anti-IgE therapy is licensed for use in some countries, and studies are under way to determine if it has a role in the management of serious food allergies.

Course and Prognosis

Individuals may lose their allergies over time, and after challenge, careful re-introduction of the implicated food can be attempted.

Younger children are more likely to outgrow IgE-mediated food allergy. Older children and adults will lose their hypersensitivity if the allergen can be identified and is completely eliminated from the diet, although SPT and RAST results often remain positive and do not necessarily reflect clinical reactivity. Patients allergic to nuts, peanut, fish and shellfish rarely lose clinical sensitivity. Children with milk, soy and wheat allergy can be challenged every 1-2 years, and children with egg allergy can be challenged every 2-3 years to determine if their allergy still exists.

Food-induced enterocolitis and allergic eosinophilic gastroenteritis in older children and adults appears to persist for prolonged periods. Coeliac disease is a life-long sensitivity and gluten must be avoided for life.

Source Documents

Motala, C: New perspectives in the diagnosis of food allergy. Current Allergy and Clinical Immunology, September/October 2002, Vol 15, No. 3: 96-100

Motala C. Food Allergy - Current issues. Current Allergy and Clinical Immunology 2000;13(4):8-12.

Sampson H A: Food Allergy. Journal of Allergy and Clinical Immunology, 2003; Vol 111, No 2, S540-S547

Sampson H: Food Allergy. In Allergy and Allergic Diseases, Ed. AB Kay, Blackwell Scientific, 1997

Helpful Links

Coelic Disease

www.coeliac.co.uk
www.celiac.org
www.csaceliacs.org

Professional and Patient information on food allergies

www.allergyuk.org/auk_transcards.html
www.aaaai.org/patients/allergic_conditions/food_allergy.stm
www.allergysa.org
www.anaphylaxis.org.uk/mainpage_info.html
www.anafylaxis.nl (Dutch Anaphylaxis Network)
www.astmafonds.nl
www.foodallergy.org
www.allergyfoundation.ca/public_information.html#Food
www.mayoclinic.com/
www.foodallergyinitiative.org
www.allergy.org.au/aer/infobulletins/hp_allergy_milk.htm