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FOOD ALLERGIES
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Food Allergies

Introduction

Background

Adverse food reactions can be broadly classified into 2 categories. The first category consists of immunologically-mediated adverse reactions to foods; these reactions are unrelated to any physiologic effect of the food or food additive. These reactions include disorders mediated by immunoglobulin E (IgE) antibodies (eg, IgE-mediated reaction to peanuts), which begin during or soon after exposure to the food, and others resulting from non–IgE-mediated mechanisms (eg, non–IgE-mediated reactions such as protein-induced enterocolitis syndrome), which generally take several hours to evolve.  

The second category is food intolerance. These reactions include any adverse physiologic response to a food or food additive that is not immunologically mediated (eg, lactose intolerance, bacterial food poisoning).

 

Pathophysiology

Allergic reactions to food are IgE-mediated or non–IgE-mediated. Immune responses mediated by specific IgE antibodies are the most widely recognized mechanism of food hypersensitivity. Patients with atopy produce IgE antibodies to specific epitopes of the food allergen. These antibodies bind to high-affinity IgE receptors on circulating basophils and tissue mast cells present in the skin, gastrointestinal tract, and respiratory tract. Subsequent allergen exposure binds two adjacent IgE antibodies, resulting in receptor cross-linking and intracellular signaling that initiates the release of numerous mediators, including histamine, prostaglandins, leukotrienes, chemotactic factors, and cytokines. The effects of these mediators on surrounding tissues result in vasodilatation, smooth muscle contraction, and mucus secretion, which, in turn, are responsible for the spectrum of clinical symptoms observed during allergic reactions to food.

Food allergens are typically water-soluble glycoproteins resistant to heating and proteolysis with molecular weights of 10-70 kd. These characteristics facilitate the absorption of these allergens across mucosal surfaces. Numerous food allergens are purified and well-characterized, such as peanut Ara h1, Ara h2, and Ara h3; chicken egg white Gal d1, Gal d2, and Gal d3; soybean-Gly m1; fish-Gad c1; and shrimp-Pen a1. Closely related foods frequently contain allergens that cross-react immunologically (ie, lead to the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less frequently cross-react clinically. Finally, cross-reactive allergens have been identified among certain foods and airborne pollens (see Pollen-food allergy syndrome). Conserved homologous proteins shared by pollens and foods likely account for this cross-reactivity.

 

Frequency

United States

General surveys report that as many as 25-30% of households consider at least 1 family member to have a food allergy. This high rate is not supported by controlled studies in which food challenges are used to confirm patient histories. The actual prevalence of food allergies is estimated to be approximately 6% in infants and children and 3.7 % in adults. Several published prospective investigations have determined the prevalence of certain common food allergies in children (eg, cow milk, 2.5%; eggs, 1.3%; peanuts, 0.8%; wheat, 0.4%; soy, 0.4%).

International

Prospective studies from several different countries indicate that approximately 2.5% of newborn infants experience hypersensitivity reactions to cow milk in the first year of life. A hypersensitivity reaction to peanuts occurs in approximately 0.5% of children in the United Kingdom. Surveys from the United Kingdom indicate that 1.4-1.8% of adults experience adverse food reactions and 0.01-0.23% of adults are affected by adverse reactions to food additives. Studies from the Netherlands demonstrate that approximately 2% of the adult Dutch population is affected.

Mortality/Morbidity

  • Severe anaphylactic reactions, including death, can occur following the ingestion of food. Typical symptoms observed in a food-induced anaphylactic reaction involve the skin, gastrointestinal tract, and respiratory tract. Frequently observed symptoms include oropharyngeal pruritus, angioedema (eg, laryngeal edema), stridor, dysphonia, cough, dyspnea, wheezing, nausea, vomiting, diarrhea, flushing, urticaria, and angioedema. Fatalities result from severe laryngeal edema, irreversible bronchospasm, refractory hypotension, or a combination thereof. Food allergy has been confirmed in approximately one third of the patients with anaphylaxis presenting to the emergency department at the Mayo Clinic.
  • Peanuts, tree nuts, and shellfish are the foods most often implicated in severe food-induced anaphylactic reactions, although anaphylactic reactions have been reported to a wide variety of foods.
  • Risk factors for fatal food-induced anaphylaxis include (1) the presence of asthma, especially in patients with poorly controlled disease; (2) previous episodes of anaphylaxis with the incriminated food; (3) a failure to recognize early symptoms of anaphylaxis; and (4) a delay or lack of immediate use of emergency medications (eg, epinephrine, antihistamines) to treat the allergic reaction.

Race

  • No predilection is known.

Sex

  • No predilection is known.

Age

  • In infants and children younger than 3 years, the prevalence of food allergy is approximately 6%.
  • The estimated prevalence in adults is approximately 3.7%.

Clinical

History

  • Necessary elements of a thorough medical history

    • Develop a complete list of all foods suspected to cause symptoms.
    • Discuss the manner of preparation of the food (cooked, raw, added spices or other ingredients).
    • Determine the minimum quantity of food exposure required to cause the symptoms.
    • Determine the reproducibility of symptoms upon exposure to the food.
    • Obtain a thorough description of each reaction, including the following:

      • The route of exposure (ingestion, skin contact, inhalation, injection) and dose
      • The timing of the onset of symptoms in relation to food exposure
      • All observed symptoms and each one’s severity
      • The duration of the reaction
      • The treatment provided and the clinical response to treatment
      • The most recent reaction
         
    • Inquire about a personal or family history of other allergic disease.
       
  • Cutaneous reactions

    • These are the most common clinical manifestations of an allergic reaction to a food or food additive.
    • Symptoms range from acute urticaria (most common) to flushing to angioedema to exacerbations of atopic dermatitis.
    • Food allergy is rarely the cause of chronic urticaria or angioedema.
       
  • Atopic dermatitis

    • Significant controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis. Studies show that of patients with moderate chronic atopic dermatitis, 35-40% have IgE-mediated food allergy contributing to their skin disease.
    • Both food-specific IgE-mediated and cellular mechanisms appear responsible for chronic eczematous inflammation.
    • Removal of a specific food allergen leads to reduction or resolution of clinical symptoms in affected patients; reintroduction of the food exacerbates the atopic dermatitis. Reintroduction of a suspected food allergen should be performed under medical supervision because, in some instances, initial reintroduction of the food after a period of dietary elimination has resulted in more significant symptoms than were observed when the food was regularly ingested.
    • Prophylactic studies show that avoiding particular foods (eg, cow milk, eggs, peanuts) helps delay the onset of atopic dermatitis.
       
  • Dermatitis herpetiformis

    • This is an unusual form of non-IgE cell-mediated hypersensitivity related to celiac disease. It manifests clinically with a chronic and intensely pruritic rash with a symmetrical distribution that has some similarities to the typical rash distribution of atopic dermatitis.
    • Elimination of gluten from the diet usually leads to resolution of skin symptoms.
       
  • IgE-mediated gastrointestinal food allergy

    • These food allergy reactions include immediate hypersensitivity reactions and the pollen-food allergy syndrome (oral allergy syndrome).
    • Specific gastrointestinal symptoms include nausea, vomiting, abdominal pain, and cramping. Diarrhea is found less frequently.
       
  • Pollen-food allergy syndrome (Oral allergy syndrome)

    • Patients with this syndrome develop itching or tingling of the lips, tongue, palate, and throat following the ingestion of certain foods. In addition, edema of the lips, tongue, and uvula and a sensation of tightness in the throat may be observed. In fewer than 3% of cases, symptoms progress to more systemic reactions, such as laryngeal edema or hypotension.
    • This syndrome is caused by cross-reactivity between certain pollen and food allergens. For example, individuals with ragweed allergy may experience oropharyngeal symptoms following the ingestion of bananas or melons, and patients with birch pollen allergy may experience these symptoms following the ingestion of raw carrots, celery, potato, apple, hazelnut, or kiwi.
       
  • Mixed IgE/non-IgE gastrointestinal food allergy (eosinophilic gastroenteritis)

    • Typical symptoms include postprandial nausea, abdominal pain, and a sensation of early satiety.
    • One of the hallmarks in children is weight loss or failure to thrive.
    • CBC count and differential findings may show eosinophilia in approximately 50% of patients; however, this is not diagnostic. Typically, endoscopy and biopsy must be performed in order to establish the presence of eosinophils in the intestinal wall. While a dense eosinophil infiltrate may be seen anywhere from the lower esophagus throughout the large bowel, involvement is patchy and variable.
    • Ultimately, an elemental or oligoantigenic diet is necessary to aid in the diagnosis.
    • If the patient does not respond to the elemental diet, a trial of systemic oral corticosteroids can be useful for resolving the clinical symptoms.
       
  • Non–IgE-mediated gastrointestinal food allergy

    • Dietary protein enterocolitis is a syndrome that typically manifests in the first few months of life in a child who has severe projectile vomiting, diarrhea, and failure to thrive.
    • Cow milk and soy protein formulas are usually responsible for these reactions, which occur 2 or more hours after food ingestion.
    • Infants typically appear lethargic, wasted, and dehydrated. To establish the diagnosis, an oral challenge study must be performed.
       
  • Upper and lower respiratory tract reactions

    • Upper respiratory reactions typically include nasal congestion, sneezing, nasal pruritus, or rhinorrhea. They are usually observed in conjunction with ocular, skin, or gastrointestinal symptoms.
    • IgE-mediated pulmonary symptoms may include laryngeal edema, cough, or bronchospasm.
       
  • Asthma

    • The role of food allergy in the pathogenesis of asthma is a controversial area of investigation.
    • At the National Jewish Center for Immunology and Respiratory Medicine, 67 of the 279 children (24%) with a history of food-induced asthma were documented to have a positive result after a blinded food challenge, which included wheezing. Interestingly, only 5 (2%) of these patients had wheezing as their only objective adverse symptom.
    • In a related report, 320 children with atopic dermatitis undergoing blinded food challenges at Johns Hopkins Hospital were monitored for respiratory reactions. Overall, 34 of 205 (17%) children with positive results from food challenges developed wheezing as part of their reaction. Therefore, a conservative estimate is that 5-10% of patients with asthma have food-induced allergy symptoms.
    • In a pediatric case-controlled study comparing 19 children who required ventilation for an exacerbation of asthma and 38 control subjects matched by sex, age, and ethnicity, coincident food allergy was found to be independently associated with life-threatening asthma.
    • Wheezing as the only manifestation of an allergic reaction to food is rare.
    • Children with atopic dermatitis, especially those with food reactions confirmed during blinded food challenges, appear to have a higher risk for developing food-induced asthma.
    • The primary clinical effect is not acute bronchopulmonary obstruction, but chronic asthma symptoms or difficulty in controlling the asthma.
       
  • Food-induced pulmonary hemosiderosis (Heiner syndrome)

    • This is a rare disorder characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates, hemosiderosis, gastrointestinal blood loss, iron deficiency anemia, and failure to thrive in infants.
    • While the precise immunologic mechanism is unknown, it is thought to be secondary to a non-IgE hypersensitivity process.
       
  • Food-induced anaphylaxis

    • Following the ingestion of food, severe anaphylactic reactions (ie, systemic allergic reactions), including death, can occur.
    • Symptoms may include the following:

      • Oropharyngeal pruritus
      • Angioedema (eg, laryngeal edema)
      • Urticaria
      • Ocular injection, ocular pruritus, conjunctival edema, periocular swelling
      • Nasal congestion, nasal pruritus, rhinorrhea, and sneezing
      • Stridor
      • Dysphonia
      • Cough
      • Dyspnea
      • Wheezing, bronchospasm
      • Nausea
      • Emesis
      • Abdominal pain
      • Diarrhea
      • A feeling of impending doom
      • Cardiovascular collapse
         
    • Risk factors for fatal reactions include the following:

      • The presence of asthma, especially in patients with poorly controlled disease
      • Previous episodes of anaphylaxis with the incriminated food
      • Failure to recognize early symptoms of anaphylaxis
      • Delay or lack of immediate use of emergency medications (eg, epinephrine, antihistamines)

Physical

  • The physical examination findings are most useful for assessing overall nutritional status, growth parameters, and signs of other allergic disease, such as atopic dermatitis, allergic rhinitis, or asthma.
  • Findings from a comprehensive physical examination can help rule out other conditions that may mimic food allergy.

Causes

  • Any food protein can trigger an allergic response, and allergic reactions to a large number of foods have been documented; however, only a small group of foods account for most of these reactions.
  • Eggs, milk, peanuts, soy, fish, shellfish, tree nuts, and wheat are the foods most often implicated in allergic reactions that have been confirmed in well-controlled blinded food challenges.
  • Investigations of near-fatal or fatal anaphylactic reactions following food ingestion reveal that most are caused by peanuts, tree nuts, and shellfish.
  • Differential Diagnoses

    Anorexia Nervosa
    Gastroesophageal Reflux Disease
    Bulimia
    Giardiasis
    Celiac Sprue
    Hiatal Hernia
    Clostridium Difficile Colitis
    Inflammatory Bowel Disease
    Constipation
    Intestinal Motility Disorders
    Diverticulitis
    Irritable Bowel Syndrome
    Dumping Syndrome
    Lactose Intolerance
    Esophageal Motility Disorders
    Trichosporon Infections
    Esophageal Spasm
    Urethral Diverticula
    Esophageal Stricture
    Urticaria
    Esophagitis
    VIPomas
    Factitious Disorder
    Vocal Cord Dysfunction
    Food Poisoning
    Wasp Stings
    Gastritis, Acute
    Whipple Disease
    Gastritis, Chronic
     
    Gastroenteritis, Bacterial
     
    Gastroenteritis, Viral
     

    Workup

    Laboratory Studies

    • Serum testing for specific IgE antibodies to foods

      • Specific IgE antibodies to foods can be measured by in vitro laboratory methods (eg, IgE radioallergosorbent testing), which offers advantages when dermatographism, generalized dermatitis, or a clinical history of severe anaphylactic reactions to a given food limit skin testing.
      • This form of testing provides information similar to prick skin tests, but it is more expensive and generally less specific.
      • The CAP System fluorescent-enzyme immunoassay (FEIA) (Pharmacia Diagnostics, Uppsala, Sweden) provides a more quantitative method of determining allergen-specific IgE to food allergens.
      • When compared with the outcome of well-controlled oral food challenges, results of the CAP system FEIA are generally similar to those of prick skin tests in predicting symptomatic food allergy.
      • Quantitating food-specific IgE antibodies with this automated system can help identify patients who are highly likely to have allergic reactions (>95% probability).
      • Published positive and negative predictive values using this system are available. These predictive values aid in making the diagnosis, thereby reducing the need for confirmatory food challenges in some patients.
      • Currently, the predictive values of CAP System FEIA results are limited to several major food allergens (ie, egg, milk, peanut, fish).
      • The predictive values developed using the CAP System FEIA are useful in predicting the likelihood of a reaction but do not predict the severity of a reaction  
    • Peripheral serum measurements of eosinophils or total IgE concentrations: Results from these tests support but do not confirm the diagnosis of food allergy. Likewise, normal values do not exclude diagnosis.
    • Basophil histamine-release assays: These tests are mainly limited to research settings and have not been shown conclusively to provide reproducible results useful for diagnostic testing in a clinical setting.

    Other Tests

    • Diet diary

      • This consists of keeping a chronological record of all foods eaten and any associated adverse symptoms. It is an inexpensive endeavor that documents the frequency of symptoms and their occurrence in relationship to food ingestion. In addition, it encourages patients to focus on their diet.
      • This record is occasionally helpful for identifying the food implicated in an adverse reaction; however, it is not usually diagnostic, especially when symptoms are delayed or infrequent.
      • Occasionally, review of the diet diary reveals that the patient is not experiencing a reaction even when eating, as an ingredient in other foods, a significant amount of a food to which they were thought to be allergic. 
         
    • Elimination diet

      • This is used in determining the diagnosis as well as in the treatment and prevention of food allergy.
      • When used as a diagnostic tool, the elimination diet requires complete avoidance of suspected foods or groups of foods for a given time period (usually 7-14 d) while monitoring for an associated decrease in symptoms.
      • Success depends on identifying the correct food allergen and completely eliminating it in all forms from the diet. These diets are increasingly difficult to develop and follow as more foods or foods that commonly occur in the diet are eliminated.
      • Additional limitations of this method include potential effects of patient or physician biases, variable patient compliance, and the time-consuming nature of the endeavor.
      • When the elimination diet is used as treatment, identified food allergens are removed from the diet indefinitely unless evidence exists that the food allergy has been outgrown.
         
    • Skin testing

      • Prick and puncture tests are the most common screening tests for food allergy and can even be performed on infants in the first few months of life. However, the reliability of the results depends on multiple factors, including use of the appropriate extracts and testing technique, accurate interpretation of the results, and avoidance of medications that might interfere with testing (eg, antihistamines).
      • When used in conjunction with a standard criterion of interpretation and appropriate controls (eg, histamine: positive, saline: negative), these tests provide useful and reproducible clinical information in a short period (ie, 15-20 min) with minimal expense and negligible risk to the patient.
      • This is a reliable method of excluding IgE-mediated food allergies. The negative predictive accuracy is greater than 95%; however, the positive predictive accuracy is generally less than 50%, which limits clinical interpretation of positive skin test results.
      • Positive skin test results, in addition to the suggestion of clinical reactivity based on the history, must often be confirmed by an oral food challenge unless the patient has a thoroughly convincing history of significant food allergy.
         
    • Intradermal skin testing

      • The risk of inducing a systemic reaction with this type of testing is increased in comparison to the prick or puncture method; as a result, intradermal skin testing should be avoided.
      • In addition, the results obtained by using this method are less specific compared to those obtained by using prick or puncture testing.
         
    • Tests with uncertain diagnostic value: The diagnostic value of performing the following tests is not currently supported by objective scientific evidence:

      • Results from food-specific immunoglobulin G (IgG) or IgG subclass antibody concentration testing have not been proven to be helpful with diagnosis.
      • Testing for food antigen-antibody complexes has no proven diagnostic value.
      • Performing leukocyte cytotoxic tests is not supported by objective scientific evidence.
      • Results from subcutaneous provocation and neutralization testing have not been proven to be helpful for diagnosis.
      • Kinesiology-based testing is not recommended because objective scientific evidence has indicated this type of testing does not aid in diagnosis.

    Procedures

    • Food challenge confirmation of food allergy

      • This includes properly conducted elimination of and subsequent oral challenge with foods suspected of causing allergic reactions based on the medical history, skin testing results, or in vitro testing results.
      • Of these procedures, the double-blind placebo-controlled food challenge (DBPCFC) is the most reliable method to help diagnose and confirm food allergy and other adverse food reactions because it eliminates both patient and observer bias. However, in a clinical setting where minimal bias is suspected, open food challenges may be preferable because blinding of the food is often not required.
      • Conduct any food challenge in a clinic or hospital setting with the personnel and equipment necessary to treat a systemic allergic reaction available at all times. Patients undergoing a food challenge should not be on beta-blocker medications or any medication that might interfere with the treatment of anaphylaxis. Obtain intravenous access in patients with history findings that indicate the potential for a systemic reaction.
      • If the history of the patient suggests an anaphylactic reaction is possible following food ingestion, do not perform an oral food challenge. 
         
    • Open food challenge

      • This test involves the patient ingesting the suspected food, prepared in its customary fashion (ie, the challenge food is not disguised in any way).
      • Both the patient and the observer (eg, physician, nurse) are aware of the food being ingested.
      • The open food challenge is best used in clinical practice when patient and physician bias is minimal.
      • This type of challenge is typically used when the skin test results for the suspect food are negative or if a specific food reaction is unlikely.
      • Whenever the results are equivocal, perform a blinded challenge.
      • Patients with histories of a previous reaction should never perform an open food challenge at home, even if the chance they will develop severe symptoms is remote.
         
    • Single blinded food challenge

      • This challenge involves the patient ingesting the suspected food disguised in a challenge food so the patient is unaware of the contents.
      • This type of challenge, which is suitable for clinical practice and some research investigations, is designed to reduce patient bias during the procedure. However, subjective attitudes regarding the outcome of the challenge cannot be completely eliminated.
      • This test is also useful for screening patients for entry into studies in which the findings will be unequivocally confirmed by DBPCFC results.
         
    • Double-blind placebo-controlled food challenge

      • DBPCFC involves ingestion of the suspected food disguised in another food so that both the patient and observer are unaware of the contents of the challenge.
      • This type of challenge is designed to reduce both patient and observer bias and subjective attitudes during the procedure.
      • Always perform this challenge in a clinic or hospital setting.
      • Consider this the criterion standard for diagnosing food allergy, especially in research investigations. Currently, it is the only completely objective method for determining the validity of the history of an adverse reaction to a food.
      • Do not perform a challenge if the patient has a clearly convincing history of a severe life-threatening anaphylactic reaction following the isolated ingestion of a specific food.
 
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