INTRODUCTION — Advances in the identification of clinically relevant allergens and the development of recombinant proteins allow for assessment of immunoglobulin E (IgE) binding to individual proteins within an allergenic food. This type of testing is known as component-resolved diagnosis (CRD). Increased sensitivity and specificity can be achieved by assessing IgE binding to separate proteins, either purified native or recombinant, thereby providing improved diagnostic accuracy in terms of predicting clinical reactivity. CRD may also provide additional prognostic information regarding the severity or persistence of food allergies.
CRD is available for plant-derived and animal-derived foods. While CRD has shown to be informative for pollen-related food allergies, the usefulness of CRD for animal-derived food allergens is not as well defined.
CRD testing for animal-derived food allergies is reviewed here. Component testing for pollen-related, plant-derived food allergies is discussed separately, including an overview of CRD and the types of assays available. An overview of testing for food allergies is also presented separately. (See "Component testing for pollen-related, plant-derived food allergies" and "Diagnostic evaluation of IgE-mediated food allergy".)
ALLERGEN-SPECIFIC USE/INTERPRETATION — For milk and egg allergies, component-resolved diagnosis (CRD) allows identification of IgE binding to specific proteins, which may be informative to distinguish between different phenotypes of cow's milk (hereafter referred to in this topic as "milk") and hen's egg (hereafter referred to in this topic as "egg") allergy. For shrimp allergy, cross-reactive proteins with other arthropods (dust mite and cockroach) can result in positive tests that may not be clinically relevant, similar to what is seen in pollen-related, plant-derived food allergies. However, no single test result taken in isolation is reliable enough to negate the need for oral food challenges. Further studies are needed to determine the utility of IgE testing to individual proteins for these foods. (See "Component testing for pollen-related, plant-derived food allergies".)
Milk — Casein (Bos domesticus [Bos d] 8) is the major allergen present in milk, accounting for 75 to 80 percent of all cow's milk proteins [1]. Beta-lactoglobulin (Bos d 5) forms a large portion of whey, accounting for approximately 10 percent of proteins in milk. Alpha-lactalbumin (Bos d 4) represents 25 percent of the whey fraction and comprises 5 percent of cow's milk proteins. Sensitization to other minor components that can be measured include serum albumin (Bos d 6) and transferrin (Bos d lactoferrin). Additional studies are needed to determine the utility of component testing for milk allergy.
Studies have shown that serum specific IgE (sIgE) to caseins (Bos d 8) are associated with more persistent milk allergy [2,3] and more severe reactions to milk [4]. An Italian study found that assessing IgE reactivity to casein using a component-based allergen microarray provided improved positive and negative predictive values in the diagnosis of cow's milk allergy when compared with standard sIgE testing to milk [5]. However, a German study reported that sIgE to individual components was not superior to IgE to milk in differentiating clinically reactive individuals from those who were sensitized but tolerant to milk [6].
The majority of milk-allergic children have specific IgE that binds to conformational epitopes and are therefore able to tolerate baked or extensively heated milk [7]. This finding has led to studies assessing the utility of component testing to predict baked milk tolerance. In a United States study, receiver-operating characteristic (ROC) analysis showed that sIgE to casein, sIgE to whole milk, and skin prick testing (SPT) with whole milk extract were comparable in predicting baked milk tolerance, with casein IgE performing somewhat better than milk IgE or SPT [8]. Diagnostic cutoff levels were determined, and the optimal level giving equal weight to sensitivity and specificity was 4.95 kUA/L for casein (sensitivity 74 percent and specificity 77 percent) and 9.97 kUA/L for cow's milk (sensitivity 62 percent and specificity 85 percent). In order to achieve >95 percent specificity, the levels would be 20.2 kUA/L for casein and 24.5 kUA/L for cow's milk. However, another smaller study from the United States found differing results. In this study, SPT was reported to be the best predictor of baked milk tolerance [9]. Specific IgE to casein had poor sensitivity and specificity for predicting food challenge outcomes to baked milk. (See "Milk allergy: Clinical features and diagnosis".)
Egg — Ovomucoid (Gallus domesticus [Gal d] 1), ovalbumin (Gal d 2), ovotransferrin (Gal d 3), and lysozyme (Gal d 4) are major allergens in hen's egg [10]. Similar to milk allergy, the majority of individuals with egg allergy have IgE that primarily bind to conformational epitopes. Thus, many can tolerate extensively heated or baked egg [11]. Given the significant differences in patient populations and varying preparations of egg used in oral food challenges in the different studies, further investigation is warranted to explore the diagnostic value of sIgE testing to individual egg proteins. (See "Egg allergy: Clinical features and diagnosis".)
An Italian study reported that IgE reactivity to Gal d 1 is a good predictor of egg allergy. In this study, 95 percent of Gal d 1 IgE-positive patients reacted to raw egg at food challenge, whereas 94 percent of Gal d 1 IgE-negative patients tolerated heated egg (boiled for 10 minutes) [12].
In a study from Japan of 108 egg-allergic children, IgE to Gal d 1 was the best predictor for reactivity to heated egg (90°C for 60 minutes), with the optimal cutpoint for Gal d 1 IgE being 4.4 kUA/L (76 percent sensitivity, 81 percent specificity) [13]. In regard to determining reactivity to raw egg, IgE to Gal d 1 and Gal d 2 were not superior to IgE to egg white.
The utility of measuring IgE to individual egg proteins for predicting tolerance to baked egg (within a wheat matrix: 350°F x 30 minutes for muffin and 500°F x 3 minutes for waffle) has been investigated in a few United States studies. In a cohort of 117 children, IgE to Gal d 2 was a better predictor of baked egg challenge outcome compared with IgE to egg white and Gal d 1 [14]. However, a different United States study reported that IgE to Gal d 1 was not superior to egg white SPT or sIgE in predicting outcome of baked egg challenges [15].
Shrimp — Tropomyosin (Pen m 1 [Penaeus monodon, brown shrimp] and Pen a 1 [Penaeus aztecus, black tiger shrimp]) is considered the primary allergen in shrimp, with over 80 percent of shrimp-allergic individuals having IgE specific for this allergen [16,17]. Other allergens identified include arginine kinase (Pen m 2) and sarcoplasmic calcium-binding protein (Pen m 4).
Tropomyosin is an important muscle protein in arthropods and other animals, which results in crossreactivity between proteins found in shrimp, cockroach, and dust mites [18,19]. Studies have shown that individuals who have never ingested shellfish can have detectable IgE levels to shrimp due to primary sensitization to the environmental allergens [20]. (See "Seafood allergies: Fish and shellfish", section on 'Shellfish'.)
In two studies of patients from Brazil and Spain, measurement of sIgE to shrimp tropomyosin had similar sensitivity to SPT and shrimp-specific IgE but improved specificity [21,22].
Similar to the other allergens, no single test is reliable enough to negate the need for oral food challenges.
Red meat allergy — Delayed reactions to red meat are mediated by IgE to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate moiety that is abundantly expressed in most mammalian animals. Symptom onset typically begins three to six hours after ingestion. IgE immunoassays to alpha-gal are commercially available. However, the sensitivity and specificity of this test are relatively poor, so other diagnostic tests such as fresh meat testing and food challenge may be needed to confirm the diagnosis. (See "Allergy to meats".)
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
●The role of component-resolved diagnosis (CRD) in the diagnosis of immunoglobulin E (IgE) mediated allergies to animal-derived foods is not well established. (See 'Introduction' above.)
●CRD may offer increased specificity, but sensitivity is lacking when compared with traditional skin prick testing (SPT) and serum specific IgE (sIgE) testing for milk, egg, and shrimp. (See 'Milk' above and 'Egg' above and 'Shrimp' above.)
●Specific IgE galactose-alpha-1,3-galactose (alpha-gal) testing may be informative for delayed red meat allergy, but sensitivity and specificity are poor. (See 'Red meat allergy' above and "Allergy to meats".)
●CRD for these foods may be used as an adjunct to standard allergy tests, but oral food challenges remain the gold standard for food allergy diagnosis. (See 'Allergen-specific use/interpretation' above.)
