Food Allergies

Published on 23/06/2015 by admin

Filed under Complementary Medicine

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1504 times

Chapter 15 Food Allergies

image 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:

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,912 asthma,13,14 eosinophilic esophagitis,1517 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.2528 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.

image 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.2931 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 anaphylaxis3739 (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.4042 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 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.

image 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.

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

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.

Eliminate:

Reintroduction: (Caution: This type of testing should not be conducted with foods that are known to induce severe or anaphylactic responses in a person.)

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.

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

Advantages: APT offers a way to look at T-cell mediated reactions to foods. This type of test can be done in people taking antihistamines because it is not dependent on mast cell degranulation for a result.

Disadvantages: The research examining APT for atopic eczema is recent, yet the results appear promising.64,6668 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.

Method: RAST testing is performed using human serum to measure the amount of IgE antibodies present. In brief, the method involves binding a specific allergen to a solid substrate and adding human serum. Specific antibodies in the serum bind to the allergen. The serum is rinsed off, leaving the bound antibodies behind. A radioactive marker is added to bind to the IgE antibodies bound to the substrate. The radioactive signal can be measured and is proportional to the amount of allergen-specific IgE antibody in the serum. RAST identifies type I hypersensitivity reactions mediated by IgE antibodies.

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

Enzyme-Linked Immunosorbent Assay (ELISA) is a second generation, allergen-specific antibody test also known as a solid-phase immunoassay. The technology has advanced significantly since RAST was developed in 1961, allowing for a variety of changes in this type of testing. Most ELISA test results are reported qualitatively (positive or negative), or semi-qualitatively (values are assigned into different classes of reactivity).

Method: ELISA testing is similar to RAST in that an antigen (allergen) is bound to a solid substrate, and serum or whole blood is added to allow for antibodies to bind to the allergen being tested. The sample is rinsed to remove unbound antibodies and a fluorescent marker is added to bind to the desired antibody. ELISA tests can be used to identify IgE, IgG, IgA, and IgM antibodies depending on the fluorescent marker that is added. When measuring IgE antibodies, the test is looking at type I hypersensitivity responses. When measuring IgG, responses may be related to type II or type III hypersensitivity responses, although the significance of these responses to foods has not been fully elucidated. ELISA tests can be performed for whole blood (IgG, IgA, IgM), serum (IgE, IgG, IgA, IgM), saliva (IgA), and stool (IgA) samples.

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.71,8082 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

Method: The method is similar to RAST and ELISA testing but uses an automated machine and different solid substrates to increase sensitivity and specificity.

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.8991 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

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.101104 Cell size variability testing had random results with the same sample in a study examining reproducibility and reliability of this testing method.105

image Therapeutic Considerations for Food Allergy Testing

The list of food allergy symptoms is growing all the time. It ranges from traditionally accepted symptoms such as anaphylaxis and hives to less generally accepted symptoms such as headaches, diarrhea, fatigue, and joint pain. Food allergy tests can give clinicians good tools for developing a treatment plan for people with a wide variety of symptoms. Treatment of any type of food allergy or sensitivity is dependent on a variety of factors. A detailed medical history, physical examination, and laboratory tests must always be considered when choosing a food allergy test and interpreting the results.

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.107111 A person can have food sensitivity–related symptoms and not have any reactive foods on a test.

BOX 15-1 Food Sensitivity Reactions

This list is just a partial list of symptoms that may respond to eliminating food allergies or sensitivities. Many of these reactions have a variety of possible causes and should be evaluated according to the clinical picture presented. Some reactions may be nonimmune mediated and not test positive on a food sensitivity test.

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).

References

1. Sampson H.A. Update on food allergy. J Allergy Clin Immunol. 2004;113:805–819. quiz 820

2. Sicherer S., Sampson H. Food allergy. J Allergy Clin Immunol. 2006;117:S470–S475.

3. Osterballe M., et al. The prevalence of food hypersensitivity in an unselected population of children and adults. Pediatr Allergy Immunol. 2005;16:567–573.

4. Johansson S.G., et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56:813–824.

5. Johansson S.G., et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol, 2004;113:832–836.

6. Bernardi D., et al. Time to reconsider the clinical value of immunoglobulin G4 to foods? Clin Chem Lab Med. 2008;46:687–690.

7. Bock S., et al. Studies of hypersensitivity reactions to foods in infants and children. J Allergy Clin Immunol. 1978;62:327–334.

8. Sampson H.A., Burks A.W. Mechanisms of food allergy. Annu Rev Nutr. 1996;16:161–177.

9. Burks A.W., et al. Atopic dermatitis and food hypersensitivity reactions. J Pediatr. 1998;132:132–136.

10. Sampson H.A., McCaskill C.C. Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr. 1985;107:669–675.

11. Eigenmann P.A., et al. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics. 1998;101(3):E8.

12. Sicherer S.H. Manifestations of food allergy: evaluation and management. Am Fam Phys. 1999;59:415–424. 429-430

13. James J.M. Respiratory manifestations of food allergy. Pediatrics. 2003;111:1625–1630.

14. Toskala E., et al. Occupational asthma and rhinitis caused by milk proteins. J Occup Environ Med. 2004;46:1100–1101.

15. Liacouras C.A., et al. Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol. 2005;3:1198–1206.

16. Noel R.J., Putnam P.E., Rothenberg M.E. Eosinophilic esophagitis. N Engl J Med. 2004;351:940–941.

17. Fox V.L., Nurko S., Furuta G.T. Eosinophilic esophagitis: it’s not just kid’s stuff. Gastrointest Endoscop. 2002;56:260–270.

18. Talley N.J., et al. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Gut. 1990;31:54–58.

19. Hjorth N., Roed-Petersen J. Occupational protein contact dermatitis in food handlers. Contact Dermatitis. 1976;2:28–42.

20. Heiner D.C., Sears J.W., Kniker W.T. Multiple precipitins to cow’s milk in chronic respiratory disease. A syndrome including poor growth, gastrointestinal symptoms, evidence of allergy, iron deficiency anemia, and pulmonary hemosiderosis. Am J Dis Child. 1962;103:634–654.

21. Lee S.K., et al. Cow’s milk-induced pulmonary disease in children. Adv Pediatr. 1978;25:39–57.

22. Hill I.D. What are the sensitivity and specificity of serologic tests for celiac disease? Do sensitivity and specificity vary in different populations? Gastroenterol. 2005;128(4 suppl 1):S25–S32.

23. Sicherer S.H. Food protein-induced enterocolitis syndrome: case presentations and management lessons. J Allergy Clin Immunol. 2005;115:149–156.

24. Metcalfe D.D., Sampson H.A., Simon R.A. Food allergy: adverse reactions to foods and food additives, 4th ed., Malden, MA.: Blackwell Publishing; 2008:613. xv

25. Bentley S.J., Pearson D.J., Rix K.J. Food hypersensitivity in irritable bowel syndrome. Lancet. 1983;2:295–297.

26. Firer M.A., Hosking C.S., Hill D.J. Cow’s milk allergy and eczema: patterns of the antibody response to cow’s milk in allergic skin disease. Clin Allergy. 1982;12:385–390.

27. Jones V.A., et al. Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome. Lancet. 1982;2:1115–1117.

28. Vojdani A. Detection of IgE, IgG, IgA and IgM antibodies against raw and processed food antigens. Nutr Metab (Lond). 2009;6:22.

29. Mayer L., et al. Oral tolerance to protein antigens. Allergy. 2001;56(suppl 67):12–15.

30. Weiner H.L., Mayer L.F. Oral tolerance: mechanisms and applications. Introduction. Ann N Y Acad Sci. 778, 1996. xiii-xviii

31. Strober W., Kelsall B., Marth T. Oral tolerance. J Clin Immunol. 1998;18:1–30.

32. Garside P., Mowat A.M. Mechanisms of oral tolerance. Crit Rev Immunol. 1997;17(2):119–137.

33. Friedman A., Weiner H.L. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc Natl Acad Sci U S A. 1994;91:6688–6692.

34. Hafler D.A., et al. Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis. Ann N Y Acad Sci. 1997;835:120–131.

35. Strobel S. Neonatal oral tolerance. Ann N Y Acad Sci. 1996;778:88–102.

36. Kunimoto D.Y., Ritzel M., Tsang M. The roles of IL-4, TGF-beta and LPS in IgA switching. Eur Cytokine Netw. 1992;3:407–415.

37. Brandt E.B., et al. Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest. 2003;112(11):1666–1677.

38. Li X.M., et al. A murine model of IgE-mediated cow’s milk hypersensitivity. J Allergy Clin Immunol. 1999;103:206–214.

39. Berin M.C., et al. The influence of mast cells on pathways of transepithelial antigen transport in rat intestine. J Immunol. 1998;161:2561–2566.

40. Jakobsson I. Intestinal permeability in children of different ages and with different gastrointestinal diseases. Pediatr Allergy Immunol. 1993;4(3 suppl):33–39.

41. Troncone R., et al. Increased intestinal sugar permeability after challenge in children with cow’s milk allergy or intolerance. Allergy. 1994;49:142–146.

42. Laudat A., et al. The intestinal permeability test applied to the diagnosis of food allergy in paediatrics. West Indian Med J. 1994;43:87–88.

43. Larche M., Akdis C.A., Valenta R. Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol. 2006;6:761–771.

44. Akdis M. Healthy immune response to allergens: T regulatory cells and more. Curr Opin Immunol. 2006;18:738–744.

45. Umetsu D.T., DeKruyff R.H. A role for natural killer T cells in asthma. Nat Rev Immunol. 2006;6:953–958.

46. Golden D.B., et al. Outcomes of allergy to insect stings in children, with and without venom immunotherapy. N Engl J Med. 2004;351:668–674.

47. Mitre E., Nutman T.B. IgE memory: persistence of antigen-specific IgE responses years after treatment of human filarial infections. J Allergy Clin Immunol. 2006;117:939–945.

48. Murphy K.P., et al. Janeway’s immunobiology, 7th ed., New York: Garland Science; 2008:887. xxi

49. Hannuksela M., Lahti A. Immediate reactions to fruits and vegetables. Contact Dermatitis. 1977;3:79–84.

50. Amlot P.L., et al. Oral allergy syndrome (OAS): symptoms of IgE-mediated hypersensitivity to foods. Clin Allergy. 1987;17(1):33–342.

51. Isolauri E., Turjanmaa K. Combined skin prick and patch testing enhances identification of food allergy in infants with atopic dermatitis. J Allergy Clin Immunol. 1996;97:9–15.

52. Kekki O.M., Turjanmaa K., Isolauri E. Differences in skin-prick and patch-test reactivity are related to the heterogeneity of atopic eczema in infants. Allergy. 1997;52:755–759.

53. Mitchell E.B., et al. Basophils in allergen-induced patch test sites in atopic dermatitis. Lancet. 1982;1:127–130.

54. Turjanmaa K., et al. EAACI/GA2LEN position paper: present status of the atopy patch test. Allergy. 2006;61:1377–1384.

55. Bernstein M., Day J.H., Welsh A. Double-blind food challenge in the diagnosis of food sensitivity in the adult. J Allergy Clin Immunol. 1982;70:205–210.

56. Bock S.A., et al. Double-blind, placebo-controlled food challenge (DBPCFC) as an office procedure: a manual. J Allergy Clin Immunol. 1988;82:986–997.

57. Bock S.A., Atkins F.M. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges. J Pediatr. 1990;117:561–567.

58. Sampson H.A. Food allergy. Part 2: diagnosis and management. J Allergy Clin Immunol. 1999;103:981–989.

59. Position paper. Allergen standardization and skin tests. The European Academy of Allergology and Clinical Immunology. Allergy. 1993;48(14 suppl):48–82.

60. Hefle S.L., et al. Comparison of commercial peanut skin test extracts. J Allergy Clin Immunol. 1995;95:837–842.

61. Herian A.M., Bush R.K., Taylor S.L. Protein and allergen content of commercial skin test extracts for soybeans. Clin Exp Allergy. 1992;22:461–468.

62. Ortolani C., et al. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol. 1989;83:683–690.

63. Niggemann B., Ziegert M., Reibel S. Importance of chamber size for the outcome of atopy patch testing in children with atopic dermatitis and food allergy. J Allergy Clin Immunol. 2002;110:515–516.

64. Niggemann B., Reibel S., Wahn W. The atopy patch test (APT)– a useful tool for the diagnosis of food allergy in children with atopic dermatitis. Allergy. 2000;55:281–285.

65. Langeveld-Wildschut E.G., et al. Evaluation of the atopy patch test and the cutaneous late-phase reaction as relevant models for the study of allergic inflammation in patients with atopic eczema. J Allergy Clin Immunol. 1996;98:1019–1027.

66. Majamaa H., et al. Wheat allergy: diagnostic accuracy of skin prick and patch tests and specific IgE. Allergy. 1999;54:851–856.

67. Seidenari S., et al. Combined skin prick and patch testing enhances identification of peanut-allergic patients with atopic dermatitis. Allergy. 2003;58:495–499.

68. Vanto T., et al. The patch test, skin prick test, and serum milk-specific IgE as diagnostic tools in cow’s milk allergy in infants. Allergy. 1999;54:837–842.

69. De Boissieu D., Waguet J.C., Dupont C. The atopy patch tests for detection of cow’s milk allergy with digestive symptoms. J Pediatr. 2003;142:203–205.

70. Hamilton R.G., Adkinson N.F., Jr. In vitro assays for the diagnosis of IgE-mediated disorders. J Allergy Clin Immunol. 2004;114:213–225.

71. Hamilton R. Clinical laboratory assessment of IgE-dependent hypersensitivity. J Allergy Clin Immunol. 2003;111:687–701.

72. Adkinson N.F., Jr. The radioallergosorbent test in 1981–limitations and refinements. J Allergy Clin Immunol. 1981;67:87–89.

73. Steckelbroeck S., Ballmer-Weber B.K., Vieths S. Potential, pitfalls, and prospects of food allergy diagnostics with recombinant allergens or synthetic sequential epitopes. J Allergy Clin Immunol. 2008;121:1323–1330.

74. Niggemann B., Gruber C. Unproven diagnostic procedures in IgE-mediated allergic diseases. Allergy. 2004;59:806–808.

75. Stapel S.O., et al. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report*. Allergy. 2008;63:793–796.

76. Atkinson W. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004;53:1459–1464.

77. Lemon-Mule H., et al. Immunologic changes in children with egg allergy ingesting extensively heated egg. J Allergy Clin Immunol. 2008;122:977–983.

78. Vojdani A. Detection of IgE, IgG, IgA and IgM antibodies against raw and processed food antigens. Nutr Metab. 2009;6(1):22.

79. Ortolani C., et al. Diagnostic problems due to cross-reactions in food allergy. Allergy. 1998;53:58–61.

80. Biagini R.E., et al. Latex specific IgE: performance characteristics of the IMMULITE 2000 3gAllergy assay compared with skin testing. Ann Allergy Asthma Immunol. 2006;97:196–202.

81. Cox L., et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy Asthma Immunol. 2008;101:580–592.

82. Eckman J., Saini S.S., Hamilton R.G. Diagnostic evaluation of food-related allergic diseases. Allergy Asthma Clin Immunol. 2009;5(1):2.

83. Sampson H.A. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol. 2001;107:891–896.

84. Sampson H.A., Ho D.G. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol. 1997;100:444–451.

85. Paganelli R., et al. Specific IgE antibodies in the diagnosis of atopic disease. Clinical evaluation of a new in vitro test system, UniCAP, in six European allergy clinics. Allergy. 1998;53:763–768.

86. Li T.M., et al. Development and validation of a third generation allergen-specific IgE assay on the continuous random access IMMULITE 2000 analyzer. Ann Clin Lab Sci. 2004;34:67–74.

87. Hiller R., et al. Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment. FASEB J. 2002;16:414–416.

88. Harwanegg C., et al. Microarrayed recombinant allergens for diagnosis of allergy. Clin Exp Allergy. 2003;33:7–13.

89. Sicherer S.H. Clinical implications of cross-reactive food allergens. J Allergy Clin Immunol. 2001;108:881–890.

90. Jones S.M., et al. Immunologic cross-reactivity among cereal grains and grasses in children with food hypersensitivity. J Allergy Clin Immunol. 1995;96:341–351.

91. Soeria-Atmadja D., et al. Multivariate statistical analysis of large-scale IgE antibody measurements reveals allergen extract relationships in sensitized individuals. J Allergy Clin Immunol. 2007;120:1433–1440.

92. Steckelbroeck S., Ballmerweber B., Vieths S. Potential, pitfalls, and prospects of food allergy diagnostics with recombinant allergens or synthetic sequential epitopes. J Allergy Clin Immunol. 2008;121:1323–1330.

93. Jahn-Schmid B., et al. Allergen microarray: comparison of microarray using recombinant allergens with conventional diagnostic methods to detect allergen-specific serum immunoglobulin E. Clin Exp Allergy. 2003;33:1443–1449.

94. Lewith G.T., et al. Is electrodermal testing as effective as skin prick tests for diagnosing allergies? A double blind, randomised block design study. BMJ. 2001;322:131–134.

95. Semizzi M., et al. A double-blind, placebo-controlled study on the diagnostic accuracy of an electrodermal test in allergic subjects. Clin Exp Allergy. 2002;32:928–932.

96. Klinkoski B., Leboeuf C. A review of the research papers published by the international College of Applied Kinesiology from 1981 to 1987. J Manipulative Physiol Ther. 1990;13:190–194.

97. Deuster P.A. A Novel Treatment for Fibromyalgia Improves Clinical Outcomes in a Community-Based Study. J Musculoskeletal Pain. 1998;6(2):133–149.

98. Terwee C.B. Succesful treatment of food allergy with Nambudripad’s Allergy Elimination Techniques (NAET) in a 3-year old: A case report. Cases Journal. 2008;1:166.

99. Bindslev-Jensen C., Poulsen L.K. What do we at present know about the ALCAT test and what is lacking? Monogr Allergy. 1996;32:228–232.

100. Lieberman P., et al. Controlled study of the cytotoxic food test. JAMA. 1975;231(7):728–730.

101. Beyer K., Teuber S.S. Food allergy diagnostics: scientific and unproven procedures. Curr Opin Allergy Clin Immunol. 2005;5:261–266.

102. Gerez I.F., et al. Diagnostic tests for food allergy. Singapore Med J. 2010;51:4–9.

103. Teuber S.S., Porch-Curren C. Unproved diagnostic and therapeutic approaches to food allergy and intolerance. Curr Opin Allergy Clin Immunol. 2003;3:217–221.

104. Wuthrich B. Unproven techniques in allergy diagnosis. J Investig Allergol Clin Immunol. 2005;15:86–90.

105. Hodsdon W., Zwickey H. ., NMJ Original Research. Reproducibility and Reliability of Two Food Allergy Testing Methods. Natural Med J. 2010;2:8–13.

106. Aalberse R.C., et al. Immunoglobulin G4: an odd antibody. Clin Exp Allergy. 2009;39:469–477.

107. Lilja G., et al. Serum levels of IgG subclasses in relation to IgE and atopic disease in early infancy. Clin Exp Allergy. 1990;20(4):407–413.

108. Morgan J.E., Daul C.B., Lehrer S.B. The relationships among shrimp-specific IgG subclass antibodies and immediate adverse reactions to shrimp challenge. J Allergy Clin Immunol. 1990;86:387–392.

109. Barnes R.M. IgG and IgA antibodies to dietary antigens in food allergy and intolerance. Clin Exp Allergy. 1995;25(suppl 1):7–9.

110. Sletten G.B., et al. Changes in humoral responses to beta-lactoglobulin in tolerant patients suggest a particular role for IgG4 in delayed, non-IgE-mediated cow’s milk allergy. Pediatr Allergy Immunol. 2006;17:435–443.

111. Shek L.P., et al. Humoral and cellular responses to cow milk proteins in patients with milk-induced IgE-mediated and non-IgE-mediated disorders. Allergy. 2005;60:912–919.