What is the clinical utility of anti-C3d and IgG4 (Immunoglobulin G4) food sensitivity testing in diagnosing food sensitivities?

From the Guidelines

Anti-C3d and IgG4 food sensitivity testing has limited clinical utility in diagnosing food sensitivities and is not recommended for routine clinical use. These tests lack sufficient scientific validation and standardization to reliably identify food sensitivities in patients, as noted in the guidelines for the diagnosis and management of food allergy in the United States 1. Traditional methods such as elimination diets followed by controlled food challenges remain the gold standard for diagnosing food sensitivities, with the double-blind, placebo-controlled food challenge (DBPCFC) being the most specific test for diagnosing food allergy 1.

Key Points to Consider

• IgE-mediated allergies can be reliably tested through skin prick tests or serum-specific IgE testing, but non-IgE-mediated sensitivities are more challenging to diagnose 1.
• The presence of IgG4 antibodies to foods often represents normal immune exposure rather than pathology, as IgG4 production can actually indicate tolerance development 1.
• Complement activation (measured by anti-C3d) has not been consistently linked to food sensitivity symptoms, making its use in diagnosis questionable 1.
• Patients experiencing suspected food sensitivities should work with healthcare providers to implement structured elimination diets, followed by systematic reintroduction of foods while monitoring symptoms, as this approach provides more reliable information about individual food triggers than unvalidated laboratory tests 1.

Clinical Recommendations

• Avoid using anti-C3d and IgG4 food sensitivity testing for routine diagnosis of food sensitivities due to their limited clinical utility and potential for misleading results 1.
• Utilize medical history and physical examination to aid in the diagnosis of food allergy, focusing on symptoms and potential causative foods 1.
• Consider oral food challenges, particularly DBPCFC, for diagnosing food allergy, especially when other tests are inconclusive or when verifying clinical reactivity is necessary 1.

From the Research

Clinical Utility of Anti-C3d and IgG4 Food Sensitivity Testing

• The clinical utility of anti-C3d and IgG4 food sensitivity testing in diagnosing food sensitivities is a topic of ongoing debate, with some studies suggesting that these tests may not be reliable indicators of food allergy or intolerance 2.
• IgG4 testing, in particular, has been shown to indicate immunological tolerance rather than hypersensitivity, and its presence should not be considered a factor that induces hypersensitivity 2.
• The use of IgG4 testing as a diagnostic tool for food allergy or intolerance is not recommended, as it may lead to overdiagnosis and unnecessary food avoidance 2, 3.

Limitations of Food Sensitivity Testing

• The diagnosis of food allergy is based on clinical history, skin prick tests, and laboratory tests to detect serum-food specific IgE, elimination diets, and challenges 4.
• Alternative diagnostic tests, such as cytotoxic tests, provocation/neutralization sublingual or subcutaneous tests, and immunological tests, have not been shown to be reliable or useful for the diagnosis of food allergy or intolerance 5.
• The use of broad panels to assess sensitization to multiple foods often leads to overdiagnosis and unnecessary food avoidance, resulting in unintended consequences such as physical harm, psychological harm, and financial cost 3.

Recommendations for Food Allergy Diagnosis

• The primary therapy for food allergy is to avoid the responsible food, and antihistamines, systemic corticosteroids, and epinephrine may be used to treat symptoms 4.
• Current guidelines recommend against the use of s-IgE food panel testing, and further work is needed to effectively spread the message that these food panels may cause unintended harm to patients and families 3.
• A systematic review of the literature evaluating the validity of tests and procedures used in food reactions is necessary to provide an evidence-based review of the tests and procedures currently used for patients with suspected food allergy 6.