Allergy Testing



Allergy Testing


James W. Mims



Allergic rhinitis is one of the most common conditions that otolaryngologists treat (1). While the diagnosis of allergic rhinitis is founded on clinical impression, allergy testing plays an important role in distinguishing allergic rhinitis from nonallergic inflammation. Inhalant allergies may also play a role in comorbidities that are disproportionately represented in otolaryngology patients including allergic asthma, atopic dermatitis, allergic conjunctivitis, sinusitis, allergic ear disease, and allergic laryngeal manifestations. While history and physical exam provides the clinical suspicion of hypersensitivity, allergy testing is necessary to determine which allergens are most likely causing the allergic symptoms.


INFLUENCES ON ALLERGY TESTING ACCURACY

Before discussing different types of allergy testing, there are four principles that help to understand and interpret allergy test results. Each complicates our tendency to interpret allergy testing as a “black/white” decision where a positive test represents clinical disease and a negative test removes allergy from the differential diagnosis. We also look at research from food and venom allergy to clarify these points. The four principles are as follows:


Positive Tests Prevalence and Allergic Disease Prevalence

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.


Negative Allergy Tests and Allergic Reactions

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).



Sensitivity and Tolerance

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.


Variability in Allergen Extract

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.


SELECTING ALLERGENS FOR TESTING

Inhalant allergens are generally divided into groups by source. The main groups are pollens, molds, epidermals, and arthropods (16). Allergen qualities that effect their selection in testing include cross-reactivity, potency, and abundance. An example of cross-reactivity is demonstrated in pollens. Timothy and fescue grass pollens come from different plants but are antigenically very similar (17). A sensitized person who tests positive for one will reliably test positive for the other as they bind the same sIgE sites that can be proved through competitive inhibition. As such, it is not necessary to test an individual for both (16). However, many of the molds are antigenically distinct and testing for Alternaria may not cross-react with other regionally antigenic mold spores (16). Potency, or antigenicity, refers to the strength of reaction produced by the exposure. While grass pollen is less abundant than tree pollen, grass pollen is more potent. Generally, if a sensitized person were tested to an equal amount of grass and tree pollen, they would likely develop a larger reaction from the grass pollen. Pine pollen is an example of a pollen that can be very abundant but not potent and tends not to cause symptoms (18). However, small quantities of cat dander can elicit symptoms because it is potent (19). As such small quantities of cat allergen, such as found in dust collected from a school, may be clinically significant. Abundance is obviously important and explains the seasonal and regional allergies to different pollens.

Pollen allergens are subdivided into trees, grasses, and weeds. Allergenic pollens are typically spread by wind rather than by insects (bees). Pollens are relatively large airborne particles that tend to impact in the nose and conjunctiva rather than the lower airways due to size. For this reason, pollens tend to clinically exacerbate allergic rhinitis and conjunctivitis, while smaller mite, dander, and mold allergens play a larger role in asthma. Pollen allergy tends to be intermittent or seasonal (20,21,22).

Tree pollens tend to be released in the spring and the abundance causes significant clinical allergy (22). Most tree pollen exhibits modest cross-reactivity and usually testing
one allergenic tree from each family is sufficient. The local variety of trees differs across North America. Thus practitioners will need to gather information about their local pollens. Allergen extract providers, publications, botanists, and environmental agencies are often reasonable sources of information. Common allergenic trees include oak, cedar, and birch. Grass pollens exhibit high potency and high cross-reactivity (21). Selecting one grass from each family represented in the region is sufficient. In most areas, three representative grass pollens will suffice. Grass pollen is most prevalent in the summer. Weed pollen is present in the summer and fall. Ragweed is a potent, abundant, and widely distributed pollen that tends to be released in the late summer and early fall. Weed pollens have less crossreactivity than grass and vary significantly by region (20). It is sensible to research local antigenic weeds and create a panel that accounts for cross-reactivity.

Inhalant mold allergy is produced by the air-borne mold spores. Spore counts typically range between 5,000 and 50,000 spores/m3 of air (23). A person typically breaths around 3 m3 daily. (For reference, a moderate grass pollen level would be 5 grains/m3.) Multiple factors make testing for mold allergy problematic. There are over one million species of mold that have been identified, but less than 80 are known to play a role in respiratory pathology (24). Multiple factors including poor resources to obtain regional mold data, changing taxonomy, and the sheer quantity of routine exposure further complicate mold allergy. Additionally, spores collected from the single mold strain can vary substantially in antigenicity. And, crossreactivity between molds varies. Molds within the same genus can be antigenically distinct and molds of different families sometimes display significant cross-reactivity. Despite this, mold is a commonly identified sensitivity and immunotherapy for some molds has been shown to be effective (24).

Proteins on animal dander are frequently antigenic. As such, common household pets like cats and dogs are frequently included on testing panels for persistent allergy symptoms. Fel d 1 is the major allergen found in cat saliva and dander but the function of the protein is unknown (19). Cat allergen has been identified in dust collected from schools, and living with a cat is not required to become sensitized (19). Dander tends to be a small particle and is frequently a trigger for allergic asthma. Beyond dog and cat, the patient’s history should be used to guide testing. Guinea pigs, laboratory animals, farm animals, and pet birds are other frequent sources of allergic sensitization in exposed atopic individuals (25).

Arthropod allergy mostly encompasses dust mites (26) and cockroach. However, sometimes a careful history can lead to other concerns; an obscure example would be Asian ladybug sensitization for those living in log cabins (27). Dust mite allergy is very common. Dust mites thrive in humid temperate regions and feed on the gram of human skin each person sheds daily. They are found in high quantity in pillows and mattresses but also found in furniture used frequently. They are microscopic and do not cause symptoms in nonsensitized individuals. There are two common dust mite species in the United States, Dermatophagoides farinae and Dermatophagoides pteronyssinus. Blomia tropicalis can be found in southern regions approaching tropical climates. Cockroach allergy is especially problematic for childhood asthma in urban settings (28).


ANTIGEN SCREENS

Smaller panels of 9 to 15 selected allergens have been shown to correlate well with larger batteries of allergy tests (29,30). Regional antigenically distinct trees and weeds along with a grass from each family represented in the region are commonly selected pollens. Most screening panels would also include dog, cat, D. farinae, and D. pteronyssinus. Common allergenic molds including Alternaria, Aspergillus, Hormodendrum, Helminthosporium, and Penicillium are frequently tested. Sometimes with skin or sIgE screening, several allergens are combined as a mix, for example, tree mix, grass mix, or mold mix.


ALLERGY SKIN TESTING

In 1865, Charles Blackley suspected he had allergic rhinitis, abraded his skin, and bandaged grass pollen grains over the wound. An intense cutaneous response developed and allergy skin testing was discovered (31). Blackley had performed a version of a scratch test, which is today discouraged because of inconsistencies with the technique (32,33

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May 24, 2016 | Posted by in OTOLARYNGOLOGY | Comments Off on Allergy Testing
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