Chapter 15 Food Allergies
Therapeutic Considerations for Food Allergy Testing
The percentage of people with food allergies or sensitivities is unknown because many people do not attribute their symptoms to the food they eat. In 2004, it was estimated that 6% of children and 4% of adults in America had immunoglobulin-E (IgE) mediated food allergies1 and that 20% of the population altered their diet due to adverse reactions to foods.2,3 It is clear that food reactions are common and the prevalence of food allergies specifically is rising.1 There are a variety of reactions a person can have to food including:
1. Psychological reactions to food (via exorphins or food aversions)
2. Toxic reactions to food (food poisoning or contaminated food)
3. Immune-mediated reactions to a food (type I, II, III, or IV hypersensitivity)
4. Food intolerance reaction (enzyme deficiency or hypersensitivity to a food component or additive)
This chapter focuses on the immune-mediated reactions to food, also referred to as food allergies.
The specific nomenclature used for food allergies has been defined in position statements written by the European Academy of Allergy and Clinical Immunology (EAACI) nomenclature review committee. Allergy reactions are defined as a “hypersensitivity reaction initiated by immunologic mechanisms.”4 This includes food reactions mediated by any antibody (IgE, IgG, IgA, or IgM), as well as cell-mediated reactions (as seen in contact dermatitis).5 Although this is the strict definition of food allergy, the same article also stated that, “Food-specific IgG antibodies in serum are not of clinical importance but merely indicate previous exposure to the food. If IgE is involved in the reaction, the term IgE-mediated food allergy is appropriate. All other reactions should be referred to as nonallergic food hypersensitivity.”5 Hypersensitivity is defined as a way to “describe objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal persons.”5 These definitions stated that food reactions mediated through IgG or IgA antibodies would strictly be defined as a “food sensitivity.” The clinical significance of IgG and IgA antibodies is still being debated in the scientific and medical communities.6 Most natural medicine practitioners call IgG- and IgA-mediated reactions “food allergies” because the reaction is associated with an antibody response. Food allergies will be defined here as any response to food that is immune mediated, including antibody responses (IgE, IgG, IgA, and IgM), as well as cell-mediated food reactions.
The discussion of definitions also extends into food allergy symptoms. The scientific community typically defines food allergy symptoms as IgE antibody mediated (type I or II hypersensitivity reactions). IgE associated disorders include immediate-type gastrointestinal hypersensitivity, oral allergy syndrome, acute urticaria and angioedema, allergic rhinitis, acute bronchospasm, and anaphylaxis. Symptoms include reddening of the skin; hives; pruritus of skin, mouth, or throat; swollen lips or eyelids; tightness of the throat; wheezing; difficulty breathing; coughing; vomiting; or diarrhea.7,8 Most of these symptoms happen right after eating the offending food. Mixed IgE- and cell-mediated food reactions cited in the literature include atopic dermatitis,9–12 asthma,13,14 eosinophilic esophagitis,15–17 and eosinophilic gastroenteritis.18 Food reactions mediated by cellular (non-IgE mechanisms) include contact dermatitis,19 food-induced pulmonary hemosiderosis,20,21 celiac disease,22 and food protein-induced enterocolitis syndrome.23,24 Many natural medicine practitioners recognize a wider array of food-related disorders and symptoms that can affect almost any system in the body. Symptoms may include diarrhea, constipation, abdominal bloating, gas, urinary irritation, rashes (including eczema and psoriasis), tinnitus, nasal congestion, chronic sinus or ear infections, joint pain, headaches, foggy thinking, fatigue, and mood disturbances.25–28 Many of these symptoms are delayed, sometimes taking a few days to appear. Because of the variety of symptoms and the time it takes people to show a reaction to some foods, food allergy testing can be useful.
Various types of food allergy testing methods are used as tools to identify a person’s reactive foods. Different tests are appropriate depending on the immunologic reaction a person is trying to discover. Food allergy or sensitivity testing can be a great motivational tool to encourage dietary changes, showing people in full color their specific reactive foods. People are often more willing to change their diet after a test provides “proof” that a particular food is reactive. Food allergy tests can also be useful when patients are unable or unwilling to do a full elimination diet, or when they are not aware of the food-related physical symptoms present in their body. Although an elimination diet is still the gold standard for food sensitivity testing, the time and diligence it takes to do a proper elimination diet is often overwhelming. An accurate and reproducible food allergy test allows nutritious foods to remain in a patient’s diet while eliminating reactive foods. This chapter provides a review of the immunology of food allergies and then specifically examines the different food allergy testing methods.
Immunology of Food Allergies
Healthy individuals do not have food allergies or sensitivities. Instead they eat foods, digest them well, absorb what they need, and their immune system develops “oral tolerance” to the food. Oral tolerance describes how the body learns not to react to an antigen (food) when it is delivered through the oral route.29–31 The factors that influence tolerance include the person’s genetics, digestive function, and the nature and form of the food when it is consumed. Proteins induce tolerance more than lipids and carbohydrates,32 and proteins given in a soluble form induce tolerance more than those that are aggregated.29 Low doses of antigen activate regulatory/suppressor T cells, generally described as TH3 cells (which can be both CD4 and CD8 T cells).33,34 The mucosal immune system consists of regulatory and suppressor T cells (TH3 cells) in Peyer’s patches and mesenteric lymph nodes that produce transforming growth factor-β (TGF-β). The role of TGF-β in the body is to promote B-cell class switching to IgA and to act as a general immunosuppressant for both T- and B-cell responses.35,36 In this way, we can accept food into the body while still fighting pathogens (bacteria, viruses, parasites, or toxins).
Increased intestinal permeability is related to increased aggressive inflammation and lack of tolerance. It appears that increased permeability throughout the intestine allows food antigens to pass through the disrupted tight junctions and, in animal models, induces anaphylaxis37–39 (see Chapter 20, Intestinal Permeability Assessment). When antigens are absorbed through the paracellular spaces, the mucosa-associated lymphoid tissue does not get the proper stimulation to induce a tolerance response. Data are conflicting regarding the integrity of the mucosal barrier in children with various gastrointestinal diseases.40–42 The role of intestinal permeability is critical for our understanding of food allergies and may play a role in a variety of types of immune-mediated food reactions. Natural medicine practitioners often talk about healing the intestines, leaky gut, and decreasing inflammation. These types of treatments are most likely aimed at increasing the tolerance response in the intestines.
Food allergies may develop when the regulatory system falters due to defects in TGF-β or when the intestinal epithelial barrier is breached. Both of these may contribute to a reactive individual developing an antibody-mediated food reaction. When a food is taken up by Peyer’s patches in a reactive individual, CD4 T cells specific for the food make TH2 cytokines, including IL-4 and IL-13. These cytokines cause B cells specific for the protein in the food to make IgE and induce mast cell activation and growth (IL-4 and IL-9).43,44 IgG is also produced in response to food antigens, although the mechanisms leading to the production of total IgG and its subclasses are not fully elucidated at this time. Allergic sensitization to allergens was originally attributed to a dysregulation of the Th1/Th2 balance. New subsets of T cells have been shown to induce allergies or have an effect on the immune regulatory balance. These cells include Th17 cells43 and nonclassical T cells such as natural killer T cells,45 γδ T cells, and subsets of CD8 T cells (Tc1 and Tc2 cells).43,44
For type I hypersensitivity reactions, antigen-specific IgE is produced by B cells. Elevated levels of antigen-specific IgE allergies are found in allergic people even with antigen avoidance for several years.46,47 Once IgE antibodies are made to a particular food, they attach to Fc receptors on mast cells and eosinophils. When the antibody binds to its triggering food, the cells degranulate, causing traditional allergy symptoms, including hives, diarrhea, and gastric distress.48
Types of Hypersensitivity Reactions
Type I hypersensitivity reactions involving IgE antibodies are the most commonly recognized type of food allergy.2 IgE antibodies are formed to soluble antigens that bind to antibodies, crosslink, and activate mast cell degranulation. Oral allergy syndrome is an IgE-mediated immune reaction; symptoms are usually limited to the oropharynx, which occurs upon ingestion of certain fresh fruits, nuts, or vegetables in pollen-sensitized individuals. The proteins in pollens and particular foods are similar in causing a reaction when particular raw fruits, nuts, or vegetables are eaten. Common symptoms include itching, tingling, erythema, and angioedema of the lips, mouth, and throat and usually occur within 5 minutes of eating the food. Cooked foods rarely induce the same response, because the protein shapes are changed when food is heated or digested.49,50
Type II sensitivity reactions involve IgG antibodies that are associated with cells or cell receptors. The antibodies alter signaling to the cell or affect the body through the complement system. Most often this reaction is seen in antibiotic or other drug reactions when IgG antibodies attach to red blood cells, causing destruction of red blood cells or platelets.48
Type III sensitivity reactions (Arthus reactions) involve IgG antibodies and soluble antigens. Normally, if an IgG antibody is produced and binds to its soluble antigen in large aggregates, the complement is fixed and the complex is readily cleared by the mononuclear phagocyte system. Small complexes are formed when there is a lot of antigen in the system; these complexes are often deposited in the blood vessels. These small complexes can bind to receptors on white blood cells, leading to white blood cell activation and tissue damage. A localized reaction is called an Arthus reaction and can be triggered in a sensitized individual who has IgG antibodies against a particular antigen. When that antigen is injected under the skin, IgG antibodies induce a local inflammatory response in the skin, causing swelling and redness. Mast cells induce this response in the skin and in the linings of joints (synovial). This process happens in the lung epithelium induced by macrophages in the alveoli.48 Pathologic immune-complex deposition is seen in situations where antigens persist, and when the body is not able to clear the complexes. This mechanism may be what occurs in subacute bacterial endocarditis or chronic viral hepatitis. The replicating pathogen continuously provides new antigens, and the body continues to form antibodies that result in these small complexes that deposit in blood vessels. Tissue damage can occur in a variety of tissues and organs, including skin, kidneys, and nerves.48 Research has not been done to study antibody–antigen complexes that are formed when food is eaten continually in people with persistent IgG antibodies. This could be a possible mechanism for the food sensitivity reactions seen affecting people in a variety of tissues.
Type IV hypersensitivity reactions are a delayed-type hypersensitivity (DTH) response that is mediated through T cells making TH1 cytokines (interferon-γ, tumor necrosis factor-α, and tumor necrosis factor-β) rather than antibodies. Generally, soluble antigens are presented by macrophages to antigen-specific effector T cells. These T cells respond like they would to any pathogen causing a TH1 cytokine reaction. The cytokines, chemokines, reactive oxygen species, prostaglandins, and leukotrienes formed by these T cells cause local and systemic tissue destruction. This type of reaction is being studied as a mechanism for atopic eczema.51–54
Food Allergy Testing Methods
The immune system has a variety of possible ways it can react that could induce a food allergy reaction. Different testing methods are best for specific food allergy reactions. There are variables within a testing method that may make its reliability and clinical relevance questionable. All of these factors need to be taken into consideration when selecting a food allergy testing method.
There are a variety of ways to test for food sensitivities, including elimination/challenge, skin testing, patch testing, enzyme-linked immunosorbent assay (ELISA) antibody tests for IgE, IgG, IgG4, and IgA antibodies, biochip technology, and energetic testing methods. As immunologic methods become more sophisticated, more specific and accurate tests are likely in the future. All methods look at a particular aspect of food reactions and have specific advantages and disadvantages. Clinical interpretation is required regardless of the type of testing used.
The most commonly used way of identifying and verifying food reactions is elimination and challenge of the specific foods. The double-blind, placebo-controlled food challenge is the gold standard for identification of food allergies and sensitivities for Western medicine.55,56 Often the food is disguised to eliminate potential bias on behalf of the patient and is used to identify type I hypersensitivity reactions.57 Many clinicians use food elimination and challenge as a way to confirm a food reaction. The basic design is to eliminate a suspect food for a period of time to see which symptoms subside. When the food is reintroduced to the diet, clinicians observe which symptoms reappear.12,56
Method: Eliminate test food or foods from the diet. This method depends on clinical presentation, ability of the person to adhere to a restricted diet, and preference of the clinician.
2. A group of commonly allergenic foods (dairy, eggs, gluten, citrus, nuts/seeds, and shellfish, etc.) or a group of identified allergenic foods.
3. Most foods except those generally thought to be “safe.” (Start eating one safe food only, add another if there is no reaction. Continue process.)
4. Water fast for a time to reduce allergenic symptom load before adding foods back to the diet.
Reintroduction: (Caution: This type of testing should not be conducted with foods that are known to induce severe or anaphylactic responses in a person.)
1. Add back one food every 3 days to diet.
2. Watch for any food sensitivity reactions to start.
3. If a reaction starts, wait until the symptoms resolve before trying a different food.
Type of reaction: This test has the potential to identify any type of food reaction causing physical symptoms, provided the person has the ability to recognize the physical symptoms when they occur. Because the test occurs in the person (in vivo) rather than with bodily fluid (in vitro), any type of immune response could show a reaction.
Advantages: This method identifies any type of reaction to foods and can be used to confirm a reaction and motivate food elimination compliance as well as identifying food sensitivities. The method is very adaptable and can accommodate a wide variety of people.
Disadvantages: This method is not appropriate for people with severe allergic reactions. People can influence the results based on their ideas rather than real reactions. The method can be time-consuming and requires the ability to be on a restricted diet. Also, some patients are not willing to stop eating favorite foods without an objective reason.
Clinical evaluation: Clinicians can consider the severity of the food allergy response, the timing and type of symptoms present, and past reactions when developing a specific, individualized protocol. The elimination/challenge diet can be used to confirm a food reaction as well as identify food allergies.
Skin Prick Testing
Skin prick testing (SPT) is the most common test performed by conventional allergists to confirm IgE-mediated allergies. This type of allergic response is typically seen in environmental allergic reactions, but can also be seen in food allergies.
Method: SPT is done by placing a drop of commercially prepared allergen on the skin and “pricking” or lightly lancing the skin. The person is allergic to the allergen when they have erythema or swelling greater than that of the control. This method identifies reactions to allergens that produce a type I, IgE-mediated allergy response.58,59 Immunologically, the IgE antibodies that the body made from past exposure to the allergen are bound to mast cells that degranulate when the allergen is encountered during the test.
Advantages: SPT is more sensitive than radioallergosorbent testing (RAST), which is an in vitro test looking specifically for IgE antibodies. The test is very accurate for identifying environmental allergies.
Disadvantages: SPT requires that a person be exposed to the allergen before being tested, so the body can produce IgE antibodies. A person cannot be taking antihistamines or other immune suppressants at the time of the test. Some food sensitivities are not IgE antibody mediated and therefore cannot be identified using this method. The commercial extracts used for SPT can degrade and vary by manufacturer.60,61 Although some people react to specifically cooked or raw foods, commercial extracts may lack the ability to display the labile proteins involved.62
Clinical Evaluation: This test is usually performed by a board-certified allergist. People who report being tested for food allergies already have had their IgE-mediated food allergies tested through SPT. If there is no reaction with SPT, then the food reaction is almost certainly not IgE mediated (excellent negative predictive value).24 Intradermal skin testing is a similar, more sensitive test and involves injecting the suspected allergen into the skin. This test is sometimes used by allergists when they suspect an allergy but had no response with SPT.