Positive allergy test results are more common than clinically bothersome allergic symptoms.

The Center for Disease Control evaluated a sample of 10,508 individuals selected to represent the U.S. population with skin prick tests (SPT) as part of the Third National Health and Nutrition Survey. Common aeroallergens were used with appropriate positive and negative controls. They reported at least one positive test in 53.9% of subjects (2). However, a 2009 national survey by the Center for Disease Control found that 11.8% reported “respiratory allergies.”(3) Similarly, a positive SPT for food has a reported unacceptable specificity of about 50% (4). In venom allergy, 3% of the population has systemic allergic reactions to bees, while 20% have positive skin or specific IgE (sIgE) tests (5). Thus allergy testing should only be performed in individuals with symptoms of allergic disease, and test results must be interpreted in the context of the patient’s history.

Allergic disease, including anaphylaxis, can be seen after negative allergy tests.

Rhinitis symptoms in patients with negative allergy testing are designated as nonallergic rhinitis. However, in food and venom anaphylaxis, there is no designation of nonallergic anaphylaxis. In food allergy, a negative sIgE test for peanut in a child suspected of peanut allergy occurs in about 10% to 20% of children who will have an allergic response on double-blinded placebo-controlled peanut challenge (6). In venom allergy, there are reports of sting anaphylaxis after negative tests, but these events are rare and less likely to be fatal (5). While negative tests are useful, they do not always exclude clinical allergic disease.

There are at least four possible reasons for false negative tests. First, some individuals test positive only during a certain window after exposure, so testing may be negative outside that time frame. Second, allergen extract material used in testing does not always match an individual’s “real world” exposures. Third, some hypersensitivity reactions, even anaphylaxis, are not IgE mediated (e.g., contrast dye anaphylactoid reactions are not IgE mediated [7]). Fourth, there is a theory of local allergy in which the immunologic process in the nose may not be mirrored by mast cells in the skin (8).

Testing sensitivities and clinical tolerance can change over time.

Since positive allergy tests do not always correlate with clinical symptoms, having a positive allergy test is termed an “allergic sensitivity.” Those who suffer from IgE-mediated ragweed allergy, should produce sIgE to ragweed, and have bound sIgE to ragweed on their mast cells and basophils. However, it should be noted that when they are treated with immunotherapy for their allergy, the sIgE does not become undetectable (or even consistently reduce) (9). Despite this, their allergy symptoms improve or may resolve. This suggests that the mechanism of developing tolerance does not require a reversal of the sensitization process. Rather, tolerance has a distinct mechanism that likely involves specialized T cell lymphocytes that regulate inflammation, called T-regs (10). Although semantically paradoxical, sensitization and tolerance can coexist.

Studies that have investigated the natural history or development of allergic disease demonstrate that sensitization and tolerance can vary over time (11). The controlling factors in this are not well understood, but exposure to allergen likely plays a role.

All allergy testing relies on source allergen extracts that have significant biologic variability.

Both allergy skin and laboratory testing require use of raw biologic material. For example, testing for ragweed pollen requires the collection, purification, and sterilization of ragweed pollen (12). Creating an allergen extract is an inexact process and biologic diversity exists between different extract manufactures and even different lots of extract from the same manufacturer. Several common allergens are standardized; however, most allergen extracts are not standardized (13). Along with variation in allergen extract, allergic individuals express diversity not only to what source they are allergic to, but differ in the specific molecular epitopes their sIgE binds (14). Most allergenic sources, such as cat, have multiple molecular proteins to which human IgE can bind. This leads to confusion with terminology as an “allergen” can refer to a source (i.e., cat), a particle (dander), a protein (Fel d 1), or a molecular epitope. The allergens defined by the molecule are named by a convention, the first three letters of the genus, first letter of the species, and sequential number of the identified molecule. For cat, Felis domesticus, the first molecular allergen was Fel d 1. Cat has eight identified allergens, Fel d 1-8 (15). If more than 50% of the clinically allergic population produces IgE to a specific molecular allergen, it is termed a “major allergen.” Fel d 1 is a major allergen shared by more than 80% of the cat allergic population. As such, cat allergen extracts are standardized by their Fel d 1 content (13). If a person allergic to cat was sensitized only to Fel d 4, they could test negative if the extract, standardized to Fel d 1, did not have an adequate concentration of Fel d 4. This is especially problematic for sources without major allergens, with multiple allergens, or with nonstandardized extracts (many of the molds, tree pollens, and nonragweed weed pollens). Individuals sensitized only to the minor allergens are at risk for false negative tests. In conclusion, all allergy testing is only as good as the allergen extract.

If these four concerns are valid, the diagnosis of allergic rhinitis is primarily a clinical diagnosis. In individuals with a clinical history suggestive of allergy, allergy testing is useful and can direct use of medication, guide environmental control strategies, and identify candidates for immunotherapy.