Chapter 15 Food Allergies
Introduction
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.
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
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
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
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
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
Elimination/Challenge
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
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.
Skin Prick Testing
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.
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.
Atopy Patch Test
Atopy patch test (APT) is most commonly used to distinguish irritant contact dermatitis from allergic contact dermatitis. APT is used to identify allergies that take a few days to show up, also know as late-phase clinical reactions.54 Irritant contact dermatitis does not have an immune response and is seen when a person is in contact with skin irritants such as household cleaners, paints, oils, adhesives, and cement.
Method: APT is performed by using adhesive tape to adhere particular potential allergens on the skin. The patches are left in place for 48 hours, and the skin is examined at 48 and 72 hours for a response. If the skin develops redness or blisters, the person is allergic to the substance.63,64 This testing method identifies type IV hypersensitivity reaction, also known as DTH response. This type of immune response is mediated through T cells rather than antibodies and takes 2 to 3 days to show a response. APT is beginning to be explored in infants with atopic eczema as a way to discover food sensitivities missed by SPT and RAST testing.65
Disadvantages: The research examining APT for atopic eczema is recent, yet the results appear promising.64,66–68 Studies examining gastrointestinal diseases have had mixed results.67,69 The patch test is performed most often with cosmetics, cleaning products, jewelry, and metals that come in contact with skin. Although most clinicians will use commercially prepared extracts, it is possible to make food extracts from fresh foods. This can be time-consuming and make interpretation more challenging. The test requires some skin that is not affected with a rash or eczema, and at least three visits to the doctor for application and interpretation.
Clinical Evaluation: APT is being used experimentally for atopic eczema, and is usually used in conjunction with other tests. A controlled, oral food challenge is still necessary to verify symptoms in reactive foods.24
Radioallergosorbent Testing
Radioallergosorbent Testing (RAST) was the first test reported in the literature for identification of IgE antibodies to specific allergens.70 This test allowed the in vitro testing of allergies. Through the years, the specificity of allergens has changed and the method has developed considerably. The basic method of the RAST test is followed in different forms as the technology of antibody testing has evolved.
Advantages: This type of testing allows for identification of allergens in the blood rather than using an SPT. RAST sets the stage for second-generation, allergen-specific antibody tests using the same basic method.71 The newer antibody tests can measure different types of antibodies, use higher quality allergen extracts, and use different matrix substrates that improve the test accuracy and sensitivity.
Disadvantages: Antibody testing is limiting in that a person needs to be exposed to an allergen to have antibodies and a positive result. This type of testing specifically looks at only IgE antibodies and is hampered by cross-reactive proteins and low-quality test agents.72,73
Clinical Evaluation: RAST testing in its original form is not used currently. It has been replaced by quantitative, automated technology, bringing more accuracy and precision to this type of testing.70
Enzyme-Linked Immunosorbent Assay
Advantages: ELISA testing is versatile, relatively inexpensive, and readily available, making it a useful screening tool for food allergies. The clinical relevance of IgG antibodies to food is still being debated.74,75 IgG testing is generally accepted in the literature for celiac disease and irritable bowel syndrome,76 but not for other diseases.
Disadvantages: A person must be eating the food in question for it to come up positive on an antibody test. Without exposure to the food, the white blood cells do not get activated and make antibodies. More frequent exposure to specific food sensitivities induces higher antibody levels in reactive individuals. If a person stops eating the reactive food, the antibody response will initially increase, because the antibodies are still being produced, but not utilized. The amounts of antibodies will decrease over time as long as the immune system is not reactivated by the food. Cross reactions between specific food antigens and other agents can cause a positive test reaction even when a person has never eaten the food. The significance of these types of cross reactions is generally unknown.
The quality and form of the antigen (food) being tested greatly affects the results. One research study looking at the differences between raw versus processed food allergens showed higher reactivity in processed foods.77,78 Most commercially available antigens are made from raw foods, highlighting the importance of the type and quality of food antigen being used in testing.
Allergy shots are given specifically to induce an IgG antibody response to a food. If a person has received allergy shots as a treatment for an IgE-mediated allergy, the IgG antibody may be protecting them from a more severe anaphylactic response to that food.70
Clinical Evaluation: ELISA tests for IgG or IgA antibodies are often used by alternative medicine practitioners to identify food allergies that have not been identified with more conventional, but limited, methods examining IgE antibodies. People with a history of allergy shots or anaphylactic responses in the past should be monitored closely for an increase in IgE antibodies after food elimination, because IgG antibodies can increase as a protective mechanism in these people. If a person has multiple extremely high reactions to a variety of foods, it may be a nonspecific reaction to a test reagent rather than reactions to specific foods.79 Testing total antibody levels can be instrumental in determining whether the person has a high antibody load or a nonspecific reaction to the test reagents.
Third Generation ELISA Assays
Third generation ELISA assays ImmunoCAP (Phadia, Uppsala, Sweden), Immulite (Deerfield, Ill.), and Turbo RAST (Hycor, Garden Grove, Calif.) are automated systems utilizing solid-phase immunoassay technology to identify IgE antibodies.71,80–82 These systems are more sensitive and specific for IgE antibody tests than ELISA or RAST, although most of the research performed examined latex and other environmental allergens. Technologic advances have allowed quantification of IgE antibodies and calibration, so different tests could be compared.70
Advantages and Disadvantages: This technology improves on ELISA technology, but is more expensive and generally only available for IgE antibodies. These third generation of IgE ELISA tests improved on RAST by developing a dose–response curve of IgE. This allowed clinicians to study how the quantity of serum IgE antibody was related to clinical sensitivity by relating amounts of IgE antibody to the results of double-blind, placebo-controlled food challenges.83,84 Dose–response curves have not been created for IgG, IgA, or IgM antibodies. The relationship between amount of non-IgE antibodies and clinical symptoms has not been correlated in research studies. Different systems cannot be accurately compared directly,81 although, unlike IgG and IgA testing, there is literature comparing the different methods.85,86
Clinical Evaluation: For identifying specific IgE allergens, these methods are less sensitive than skin testing, but more sensitive and specific than ELISA testing. Serologic IgE antibody tests can aid in predicting the presence of clinically significant food allergies and can therefore decrease the need for food challenges.84
Microarray Chip Technology
Microarray chip technology (ImmunoCAP-ISAC [Phadia, Uppsala, Sweden]) is an IgE antibody technology that utilizes serum to identify IgE antibodies.87 Recombinant proteins are used as a purified source of allergic proteins, allowing for specific identification of allergens.88
Method: Allergens are bound in triplicate to a microarray chip. Serum is added to the chip and antibodies specific for the allergens attach to the chip surface. IgE is detected with a fluorescently-labeled IgE and read to give a semi-quantitative estimate of amounts of IgE.88
Advantages and Disadvantages: This technology is being utilized to identify specific proteins in foods that a person reacts to. This may allow clinicians to correlate clinical reactivity with IgE antibodies to specific proteins in foods,73 or identify them if cross reactivity occurs with foods carrying homologous proteins.89–91 This type of testing could be easily adapted to identify IgE, IgG, IgA, and IgM antibodies in parallel.88 More studies are required to fully understand the role of specific proteins in the severity and persistence of an allergy response.92 Microarray tests are not considered as sensitive as the third generation ELISA tests (ImmunoCAP) tests when the same allergens are used.82
Clinical Evaluation: Identification of specific allergic proteins in foods could allow for greater correlation between antibody responses and clinical responses, and could allow for more specific immunotherapy.92,93
Energetic Methods
Advantages and Disadvantages: Some practitioners have reported good success with these types of devices in identifying food sensitivities. Clinical trials using Vega testing and EDS have not shown them to be reliable compared with traditional allergy testing.94,95 A review of applied kinesiology literature showed the studies to be unreliable, although many of the studies quoted in a review showed favorable results.96
Other Testing Methods
Other testing methods, including lymphocyte response testing (ELISA/ACT), cell size variability testing (ALCAT), provocation–neutralization testing, cytotoxic food allergy testing, and Nambudripad’s allergy elimination techniques (NAET), have been used for food sensitivity testing and treatment. Anecdotal evidence is positive for many of these testing methods,97,98 but systematic scientific studies have either not been done to verify the clinical relevance of these methods, or have shown the tests to be unreliable and clinically questionable.74,99,100 Four review articles suggested that these methods lack scientific rationale, standardization, and reproducibility.101–104 Cell size variability testing had random results with the same sample in a study examining reproducibility and reliability of this testing method.105
Therapeutic Considerations for Food Allergy Testing
When choosing which type of food allergy test to perform, consider the types of reactions the patient has had in the past. If there is any history of anaphylaxis or difficulty breathing associated with foods, then a test that evaluates a type I sensitivity response should be considered. ELISA testing for IgG antibodies (and possibly IgA and IgM) can be useful for a wide variety of symptoms. See Box 15-1 for a list of possible reactions. IgG antibody responses to foods are seen clinically,6,106 but the relevance is still being debated in the scientific literature.107–111 A person can have food sensitivity–related symptoms and not have any reactive foods on a test.
BOX 15-1 Food Sensitivity Reactions
• Skin reactions: Itching, burning, hives, red spots, sweating, eczema, psoriasis, other rashes.
• Ear, nose, and throat: Sneezing, runny nose, sore or dry throat, hoarseness, ringing in the ears, dizziness.
• Eyes: Blurring, spots before eyes, watering, pain, twitching, sensitivity to light, redness, swelling of eyelids.
• Respiratory: Wheezing, mucus formation, shortness of breath, tightness of chest, asthma.
• Cardiovascular: Pounding heart, increased heart rate, flushing, tingling, faintness.
• Gastrointestinal: Increased salivation, canker sores, indigestion, bloating, stomachache, heartburn, colic, constipation, abdominal pain, diarrhea, gas, itching, or burning of rectum or anus. One may also experience weight gain from food sensitivities.
• Genitourinary: Frequent, urgent, or painful urination; inability to control bladder; itching; discharge; pain; water retention.
• Musculoskeletal: Fatigue, weakness, pain, swelling, stiffness of joints, backache.
• Nervous System: Headache, migraine, drowsiness, inability to concentrate, depression, irritability, restlessness, hyperactivity, dizziness, numbness, tremors.
Many of the food allergy tests available are not standardized by the Clinical and Laboratory Standards Institute, so results between companies cannot be compared. Some tests are not internally consistent as well as not comparable to other laboratories, as shown in a small study that examined multiple samples sent to two different laboratories.105 A clinician can test if a laboratory is internally consistent by sending to the same laboratory two samples from the same person and same blood draw, but under different names. The results should be nearly identical. This can also be done to test the accuracy of some of the energetic methods of food sensitivity testing. This can help the clinician be more confident in the reproducibility and consistency of the test results.
The relationship between non-IgE testing methods and disease is not well represented in the research literature. Clinicians are starting to recognize the importance of addressing food allergies when treating a variety of complaints. Food has a role in decreasing inflammation in the body and can be used to treat inflammatory diseases. The immune system has an extensive presence in the intestines, and by working with how the body accepts food, oral tolerance could be restored with implications in many disease processes (see Box 15-1).
Conclusions
Food allergy tests should be used in clinical practice to confirm or exclude a suspected diagnosis of food allergies and as a tool to motivate dietary changes. Selection of allergy diagnostic tests and interpretation of the results must be directed by the person’s clinical history. Future research studies should address the clinical significance of IgG, IgA, and IgM antibodies to specific foods and correlate physical symptoms with food allergy elimination. Food can be medicine in chronic illnesses when food causing inflammation is eliminated from the diet. Diagnosing food-related illness will become easier as food allergy diagnostic methods continue to improve.
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