Version June 2024
INTRODUCTION — There are several validated, standardized, and accepted tests for the evaluation of food allergy and intolerance. However, there are also a large number of other tests for these conditions that are promoted by various laboratories and practitioners who are not allergy specialists [1]. These tests are either performed by the practitioner, or, in some instances, blood or hair samples are collected at home and mailed in to a laboratory. The most widely used of the unproven or disproven food allergy tests are described here. Standardized, validated food allergy testing methods are reviewed in detail separately, as are investigational diagnostic methods. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Future diagnostic tools for food allergy".)
TERMINOLOGY — "Adverse food reaction" is the general term used for any untoward response to the ingestion of a food. Adverse food reactions can be divided into those that are immunologically mediated and those that are not. The term "food allergy" generally refers to an immunologic process whereby genetically predisposed persons produce immunoglobulin E (IgE) antibody to food proteins to which they have been exposed and, with sufficient subsequent exposures, develop a clinical reaction (eg, urticaria, anaphylaxis) [2]. For IgE-mediated food allergy, the presence of IgE antibody to the suspect food is necessary but not sufficient for the diagnosis (ie, a person cannot have IgE-mediated food allergy without IgE antibody; however, a person can have IgE antibody to a food but no clinical reaction, termed "sensitization"). (See "History and physical examination in the patient with possible food allergy", section on 'Overview' and "Clinical manifestations of food allergy: An overview".)
The term "food allergy" can also more broadly refer to immunologic, but non-IgE-mediated, reactions to food such as celiac disease [3]. Although the term "food allergy" is sometimes also used to describe nonimmunologic adverse reactions to foods, such reactions are better termed "food intolerance" (table 1) [2]. Food intolerances may be related to a patient's inability to digest or metabolize certain food substances, as in the case of lactose intolerance [4].
STANDARD DIAGNOSTIC TESTING — Well-standardized and validated methods to demonstrate IgE antibody to food include skin prick testing and serum-specific IgE antibody testing [2]. Other diagnostic tools include the oral food challenge. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Oral food challenges for diagnosis and management of food allergies".)
Immunologic assays are available to aid in the diagnosis of immunologically mediated, but non-IgE-mediated, conditions (eg, immunoglobulin A [IgA] anti-tissue transglutaminase [tTG] in celiac disease) [3]. Endoscopy with biopsies is typically performed to confirm the diagnosis for celiac disease and the eosinophilic gastrointestinal disorders. Validated tests are also available for some nonimmunologically mediated conditions as well (eg, the lactose hydrogen breath test for lactose intolerance) [4]. (See "Diagnosis of celiac disease in children" and "Diagnosis of celiac disease in adults" and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Eosinophilic gastrointestinal diseases", section on 'Diagnosis' and "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management".)
UNPROVEN/DISPROVEN TESTS — The unproven/disproven tests reviewed here are promoted as methods to determine often unsuspected intolerance to foods that may be causing a wide variety of adverse reactions in patients. The practice parameter on allergy diagnostic testing from the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) concluded that there was no evidence of diagnostic validity for any of these tests [5], and guidelines on the diagnosis and management of food allergy from the Expert Panel sponsored by the US National Institute of Allergy and Infectious Diseases specifically recommended against using them [2].
These tests are purported to identify a food-related cause for various maladies including gastrointestinal symptoms such as nausea, bloating, stomach cramps, diarrhea, or constipation; dermatologic conditions such as acne and eczema; neurologic symptoms such as headaches, fatigue, or "brain fog"; rheumatologic conditions such as joint pain; and propensity to infections such as ear infections or sinusitis, among others. Some involve the collection of blood samples for evaluation of cellular or antibody responses, while others involve analysis of hair or reactions to skin testing. Still other tests involve the interpretation of electrodermal responses or muscle strength. These tests have not been validated or standardized. In most cases, the pathophysiologic mechanism explaining how a positive test result leads to symptoms is unknown and/or lacks biologic plausibility. Most have been subjected to scientifically rigorous evaluation and specifically failed to demonstrate reproducibility or any association with disease [1].
IgG food tests — Just as immunologic assays can quantitate IgE antibody to foods, they can also quantitate immunoglobulin G (IgG) and IgG subclass antibodies (eg, IgG4) to foods. The methodology used for these assays is standardized, and there is no reason to believe that they do not provide accurate measurements. However, the clinical utility of food-specific IgG tests has not been established, a fact that even some laboratories performing these assays acknowledge. Nonetheless, websites of various practitioners and laboratories promote IgG food testing as diagnostic for the multitude of maladies described above. Patients are provided with a long list of foods to which they have generated IgG antibodies and told that the ingestion of these foods is the cause of their symptoms. They are advised to either eliminate or reduce the ingestion of these foods or to consume them on some sort of rotating diet.
A position statement from the European Academy of Allergy and Clinical Immunology (EAACI) concludes "food-specific IgG4 does not indicate (imminent) food allergy or intolerance, but rather a physiological response of the immune system after exposition to food components. Therefore, testing of IgG4 to foods is considered as irrelevant for the laboratory work-up of food allergy or intolerance and should not be performed in case of food-related complaints" [6]. This position paper was endorsed by the AAAAI [7]. A similar position statement from the Canadian Society of Allergy and Clinical Immunology (CSACI) also concludes that "the presence of specific IgG to food is a marker of exposure and tolerance to food… expected in normal, healthy adults and children" and "the inappropriate use of this test only increases the likelihood of false diagnoses being made, resulting in unnecessary dietary restrictions" [8].
Some authors have proposed that the presence of food-specific IgG or IgG4 antibodies could lead to immune complex formation and type III hypersensitivity reactions [9] or that some patients may be more sensitive to the inflammatory process caused by these antibodies, even though they are also present in healthy individuals [10]. However, unlike IgE antibodies, which have been definitively shown to lead to aberrant responses to foods such as urticarial or anaphylactic reactions through the well-characterized mechanism of mast cell degranulation, the production of IgG antibodies to foods is a normal and universal immune response to the ingestion of food [11]. Not only are such antibodies without adverse clinical consequence, they are associated with food tolerance [12-20].
One observational study described 55 patients who "complained of symptoms suggestive of adverse reactions to foods" including "malaise/prostration, fever, rash, arthritis, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), neurologic symptoms (headache, cerebral, neuritic), lymphadenopathy, myocardial ischemia, and transient renal disease" [9]. Elimination diets were recommended based upon specific IgG antibody test for foods. Twenty-eight of 31 patients (90 percent) who followed the diet reported an improvement versus 7 of 24 (29 percent) who chose not to follow the diet. Patients who followed the diet also showed a drop in their IgG food antibodies. However, definitive conclusions cannot be drawn from this study, due to significant limitations, including lack of randomization and blinding and assessment of primary outcome by patient report.
A blinded trial evaluated 150 patients with irritable bowel syndrome (IBS) who were randomly assigned to receive either a "true" diet excluding foods to which they had elevated IgG antibodies or a "sham" diet that eliminated foods to which patients did not have such antibodies (each patient eliminated approximately six to seven foods) [10]. After 12 weeks, those on the true diet had a 10 percent greater improvement in their IBS symptom scores. Although this study is scientifically more rigorous, very different foods were eliminated from the diets in the two groups, including much higher rates of elimination in the true diet of foods such as milk and wheat that have been shown to reduce symptoms in patients with IBS, which could explain the small difference found [21].
Flow cytometry — The two most common unproven tests that use flow cytometry are the antigen leukocyte antibody test (ALCAT) and the mediator release test (MRT). It is not clear how the claimed alterations in leukocyte morphology after food exposure would lead to the broad array of diseases for which these tests are supposed to be helpful. Most of the literature presented in company literature in support of these tests is in abstract form or obscure medical journals and often authored by persons associated with the companies. An independent review of the ALCAT methodology concluded that, while the apparatus used to measure cell volumes may be validated, there are no data available regarding analytical precision or accuracy or clinical sensitivity, specificity, or predictive values to diagnose specific disorders [22]. Several reviews have concluded that there is no scientific basis for these tests and have recommended against their use [23-25].
●ALCAT – In the ALCAT, a patient's white blood cells are incubated with food extracts. The number and distribution of cell sizes after the food exposure are compared with baseline values. The percent change is then compared with values obtained from a healthy control population, and values above a certain percentage are considered positive [26]. Patients are told to strictly or partially avoid certain foods depending upon how strongly positive the results are. The company's website indicates that the test would be appropriate for patients with gastrointestinal disorders, skin symptoms, neurologic symptoms, respiratory disease, metabolic/endocrine disorders, muscular/skeletal disorders, immune system disorders, and other comorbidities.
A company-sponsored study published in 2017 describes a trial of 58 adults with IBS who were randomly assigned to a four-week diet that eliminated foods positive on the ALCAT and allowed foods that were negative (intervention group) or a diet that allowed foods with positive results and eliminated those with negative results (control group) [27]. The intervention group had a statistically greater improvement in two outcome measures, the global improvement scale (GIS) and symptom severity score (SSS) but no difference in two other outcome measures, the IBS adequate relief (AR) and quality of life (QOL) scores. It is unclear whether or not a difference of 0.86 on a seven-point scale for GIS or a difference of 61.78 on a 500-point scale for SSS is clinically meaningful. Most of the foods eliminated during the diet are foods that would be unlikely to have been consumed on a regular basis prior to the diet, and, therefore, "eliminating" them would seem to be an unlikely explanation for the "success" of the diet. Sufficient data on the specific foods avoided in the groups are not provided to assess whether there are other explanations for the questionable improvements seen in the intervention group, for example, avoidance of dairy foods could account for the difference due to lactose intolerance. No explanation or speculation is provided regarding how the mechanism of the leukocyte activation test identifies clinically relevant foods.
MRT – Another assay, the MRT, is described as being from the same inventor as the ALCAT but is offered by a different company. Although the name of the assay implies measurement of mediators, it reportedly uses a proprietary flow cytometry instrument to evaluate volumetric changes in various cell types (including neutrophils, monocytes, eosinophils, and lymphocytes) after incubation with foods [28]. It is claimed that these cells become smaller after releasing mediators and that this change in cell volumes is being measured as an indication of a reaction to the food, regardless of the type of reaction or underlying mechanisms (eg, immediate or delayed, subclinical or symptomatic, dose dependent or independent, cell or humorally mediated, innate or adaptive immunity). The company's website indicates that an elimination diet based on the test would be appropriate for patients with a broad array of disorders including gastrointestinal, endocrine, neurologic, urologic, gynecologic, musculoskeletal, and dermatologic.
Provocation/neutralization testing — In this technique, patients who report various symptoms are tested to determine whether food may be the cause [29]. Food extracts are injected intradermally or placed as drops under the tongue in increasing concentrations until the symptoms (usually subjective or behavioral) are induced. Subsequent intradermal injection or sublingual drops of the same food extract at a lower or higher dose is purported to relieve the symptoms. Although exposure to a food substance in this manner could possibly provoke symptoms, it is not clear how subsequent exposure to a lower or higher concentration of the same substance would alleviate the symptoms. In addition, intradermal testing for foods is not recommended, because of the increased risk of triggering a systemic reaction. (See "Diagnostic evaluation of IgE-mediated food allergy", section on 'Intradermal skin tests'.)
A study of 18 patients who had previously been evaluated by this technique and found to have reactions to injections of certain concentrations of foods were reevaluated in a double-blind fashion [30]. The concentrations for injection were chosen based upon prior reactions reported by the practitioners as provoking or neutralizing doses. Various concentrations of the food extracts and control injections of saline were given in random order, and patients were asked whether or not symptoms were provoked. Twenty-seven percent of the active injections were reported to provoke symptoms, as were 24 percent of the saline injections. When neutralizing doses were administered, they were equally effective whether the "provoking" dose had been the active substance or saline. The authors concluded that this technique lacks scientific validity and that positive responses were due to suggestion or chance.
In another study, 132 patients felt to have food or chemical sensitivities underwent intradermal skin testing with various concentrations of foods and chemicals as well as placebo injections of normal saline in a double-blind, randomized fashion [31]. Seventy percent of patients reported symptoms in response to saline injections. Symptoms reported by patients to injections of foods, chemicals, or saline showed a random pattern. The authors concluded that this test should not be used to make diagnostic or therapeutic decisions.
Hair analysis — Hair analysis is promoted as a method to identify food intolerance. Patients submit a hair sample to a laboratory where it is tested against 600 different food and nonfood items to identify the cause of unexplained skin, respiratory, or digestive problems [32]. The testing methodology is not described. In a study of the reliability of hair testing, samples from nine healthy subjects who were not aware of any sensitivities to any foods or other substances were submitted in duplicate to three different laboratories performing hair analysis. A large number of positive test results were obtained in these asymptomatic patients, and there was a lack of reproducibility with the duplicate samples, leading the authors to conclude that "the results gave clear evidence of diagnostic failure" [33].
Electrodermal testing — In this technique, a low-voltage electrical circuit is created by having patients hold an electrode in one hand while another is placed on a toe. Food substances contained in glass ampules are inserted into a holding chamber in the circuit, and any change in voltage measured by a galvanometer is taken as a positive test [34]. It is not clear how having any sort of sensitivity to a food would alter an electrical circuit in this way. A study was carried out in 30 subjects to evaluate the effectiveness of this test in a double-blind, randomized manner [35]. The test was performed by experienced operators using their own testing machines. The same number of positive test results (25 percent) were returned whether the vials contained allergens or distilled water. Another study evaluated patients in a double-blind, placebo-controlled trial [36]. Both the subjects and the operator were blinded as to whether the test vial contained allergens or saline. There was no consistent relationship between the results and the contents of the vials and no reproducibility of observations with the same stimulus in the same subject.
Kinesiology — Kinesiology for evaluation of food allergy involves having the patient hold a glass vial containing a possible food allergen in one hand while muscle strength is assessed in the contralateral arm, a decrease of which is taken to indicate a food sensitivity [37]. It is not clear how any sort of food intolerance would alter muscle strength in this way. In a study of four kinesiology examiners who had rated patients as having positive test results in open testing, the results could not be reproduced when the testing was performed in a blinded manner, and placebo vials yielded positive results as often as allergen-containing vials [37]. The authors concluded that kinesiology was not reproducible and was not an indicator of food allergy. In another study, the technique was evaluated in 51 subjects who were tested randomly to vials containing either saline or hydroxylamine hydrochloride as a toxic test substance [38]. Two different kinesiologists evaluated the muscle responses, which were also assessed objectively with a hand dynamometer. The rate of results determined as positive by any method were what would be expected by chance alone. The authors concluded that applied kinesiology is not a useful or reliable diagnostic tool upon which health decisions can be based.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)
SUMMARY AND RECOMMENDATIONS
●Validated and standardized tests – Validated and standardized tests are available to assist in the evaluation of patients with adverse reactions to foods (eg, skin tests or serum specific immunoglobulin E [IgE] antibody assays for the evaluation of IgE-mediated food allergy). (See 'Standard diagnostic testing' above and "History and physical examination in the patient with possible food allergy", section on 'Overview' and "Clinical manifestations of food allergy: An overview".)
●Unproven or disproven tests – Many other tests are promoted to patients to identify food intolerance as a cause of a wide variety of symptoms and diseases. Most of these tests lack biologic plausibility. When subjected to appropriate scientific evaluation in controlled, blinded, randomized trials, all have demonstrated a lack of reproducibility and a lack of any association with disease. As such, these tests should not be used for the diagnosis of food allergy. (See 'Unproven/disproven tests' above.)
These tests include:
•Immunoglobulin G (IgG) food tests (see 'IgG food tests' above)
•Flow cytometry food tests (see 'Flow cytometry' above)
•Intradermal or sublingual provocation/neutralization (see 'Provocation/neutralization testing' above)
•Hair analysis (see 'Hair analysis' above)
•Electrodermal testing (see 'Electrodermal testing' above)
•Kinesiology (see 'Kinesiology' above)
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