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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 for predicting clinical reactivity. CRD may also provide additional prognostic information regarding the severity or persistence of food allergies.
CRD testing for pollen-related, plant-derived food allergies is reviewed here. Component testing for animal-derived food allergies is discussed separately. An overview of testing for food allergies is also presented separately. (See "Component testing for animal-derived food allergies" and "Diagnostic evaluation of food allergy".)
OVERVIEW — Allergies to plant-derived foods may occur in pollen-sensitized individuals due to pollen allergens that cross-react with food allergens, such as profilins or pathogenesis-related class 10 (PR-10) proteins that are homologues of the major white birch pollen antigen (Betula verrucosa 1 [Bet v 1]). This type of allergy is associated with symptoms that are generally limited to the oropharyngeal area (oral allergy syndrome/pollen-food allergy syndrome). In the absence of sensitization to pollens, allergies to plant-derived foods are the result of sensitization to more stable proteins, such as the seed storage or lipid transfer proteins (LTPs). In these cases, reactions are more often systemic, and there is a higher risk for anaphylaxis . (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)" and "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food allergy syndrome)".)
Component-resolved diagnosis (CRD) entails measurement of specific immunoglobulin E (IgE) responses to individual allergens as opposed to measuring IgE responses to allergen extracts that contain a mixture of proteins, including ones that may have greater or less clinical relevance. The pattern of specific IgE reactivity to defined allergens can help determine which patients are at higher risk for allergic reactions versus those who are sensitized but clinically tolerant. It may also help distinguish between those who are at risk for more severe reactions versus those or who are likely to have milder symptoms.
The prime example of the utility of CRD in the management of food allergy is peanut allergy . Several studies have noted that having detectable levels of specific IgE to the seed storage proteins are associated with more severe, persistent peanut allergy [3-7], whereas exclusive sensitization to a Bet v 1 homologue is more often associated with a low risk of reactivity to peanut [8,9]. (See "Peanut, tree nut, and seed allergy: Diagnosis" and 'Peanut' below.)
ASSAY SYSTEMS — Two different types of immunoassays are commercially available for the measurement of immunoglobulin E (IgE) levels to individual allergens:
●Measurement of specific IgE to individual allergens or components – Quantitative results of specific IgE levels to purified native or recombinant allergens can be obtained using a fluorescent enzyme immunoassay, such as the ImmunoCAP. Components may be selected for individual allergens with ImmunoCAP, allowing for individualized testing to further characterize a patient's allergies.
●Measurement of specific IgE to multiple allergen components in one test panel simultaneously – A microarray-based immunoassay such as the ImmunoCAP ISAC (Immuno Solid-phase Allergy Chip) provides results for multiple components from different allergen sources that cover a wide spectrum of food and environmental allergens using a small quantity of blood. This is a semiquantitative assay and, as such, may be better suited as a screening tool rather than a test for diagnosis and management of allergies .
Technical differences in fixing allergen to the assay platforms result in variability of specific IgE binding. Thus, IgE values obtained with ImmunoCAP are not equivalent to the corresponding values obtained with the ISAC microarray system [11,12]. Different units of measurement are used in the two assays (kUA/L for ImmunoCAP versus ISAC standardized units [ISU] for ISAC).
In the United States, several of the individual component tests are approved by the US Food and Drug Administration (FDA), whereas others are not. This can impact the likelihood that the test will be covered by third-party payers. Thus, patients and/or clinicians may wish to determine if the tests are covered before they are ordered.
Peanut — Several peanut (Arachis hypogaea, Ara h) proteins have been characterized and are US Food and Drug Administration (FDA) approved and commercially available for component testing (table 1). Immunoglobulin E (IgE) levels to components, similar to whole peanut IgE, provide a likelihood of clinical reactivity but, on their own, are not diagnostic of allergy or severity of reactions. Guidelines on when to use component testing for peanut allergy are available and are reviewed below (table 2) . (See 'Peanut testing approach' below.)
Ara h 1, 2, and 3 are seed storage proteins and are the major allergens for peanut. Ara h 6 is closely related to Ara h 2. Ara h 8 is a birch allergen (Bet v 1) homologue associated mainly with milder symptoms localized to the oropharyngeal area. Ara h 9 is a nonspecific lipid transfer protein (LTP). Sensitization to this peanut protein is predominantly seen in the Mediterranean area [14-16]. Ara h 10 and 11 are oleosins, and small studies have shown that some peanut-allergic patients have detectable IgE directed towards these proteins . However, their clinical relevance is unclear. Ara h 12 and 13 are defensins that have antifungal activity. In one small series, they were associated with severe anaphylactic reactions .
IgE binding to Ara h 2 outperforms whole peanut extract and other components in predicting clinical allergy [3-7], although optimal cutoff values for Ara h 2 with high positive-predictive values have not yet been determined. A range of cutoffs with varying sensitivities and specificities have been reported in several studies, probably due at least in part to differing patient selection criteria and geographic locations, reflecting inherent differences in patient characteristics such as genetics, diet, and environmental exposures [3-6,9].
Component-resolved diagnosis (CRD) testing can facilitate patient selection of oral food challenges. A stepwise approach for peanut IgE and Ara h 2 component testing can significantly reduce the need for oral food challenges in patients who are highly likely to be allergic [5,6]. Data also suggest the utility of measuring IgE levels to other peanut components. Isolated sensitization to Ara h 8, for example, is associated with a high likelihood of tolerance to peanut [8,9]. Thus, this testing can also increase the selection of patients who are likely to pass a diagnostic food challenge.
The following studies are illustrative:
●A 2010 study using a population-based birth cohort of 933 children in the United Kingdom demonstrated a high rate of false-positive test results when using skin prick tests (SPTs) and specific IgE testing to whole peanut . One hundred ten (110) children (11.8 percent) had positive testing to peanut at eight years of age. Approximately two-thirds of these children (n = 66) had no reaction at oral food challenge to peanut; approximately one-fifth were allergic (12 by convincing history without challenge, 7 by challenge); and the remainder (n = 6) were deemed inconclusive.
Approximately 15 percent were misclassified when a peanut-specific IgE level of ≥15 kUA/L or a SPT wheal size of ≥8 mm was used for a cutoff, whereas the misclassification rate was reduced to approximately 7 percent when results from a microarray that included multiple recombinant allergens from peanut, tree pollens, grass pollens, and cross-reactive carbohydrate determinants (CCDs) were used. Subjects with peanut allergy tended to have higher fold change values (calculated expression level estimates of the sample against the negative controls) to the major peanut components Ara h 1 to 3, whereas the peanut-tolerant subjects had higher values to CCDs and grass components (Phl p 1, Phl p 4, and Phl p 5). This study concluded that assessing IgE binding to Ara h 2 had higher accuracy than whole peanut extract and other components in predicting clinical reactivity to peanut.
●A study from Denmark reported that 2 percent of positive challenges had undetectable Ara h 2 , whereas another European study found that 26 percent of subjects who were tolerant to peanut showed IgE binding to Ara h 2 . In addition, isolated sensitization to Ara h 8 is sometimes associated with positive challenges with systemic symptoms [8,20]. As an example, a case was reported of a child with undetectable IgE to Ara h 2 and elevated IgE to Ara h 8 who experienced anaphylaxis at oral food challenge to peanut. After performing additional testing, he was found to have an elevated IgE to Ara h 6, a homologue of Ara h 2 . This suggests that additional peanut components not routinely included in test panels may play important roles for certain individuals.
●One study has examined whether IgE levels to peanut components have prognostic value for persistence of disease. Sensitization to Ara h 1 to 3 at one year of age was associated with persistent peanut allergy at 13 years of age, but it did not provide independent predictive value in addition to the information provided by IgE levels to whole peanut .
●A United States study examined threshold levels of Ara h 2 in the diagnosis of symptomatic peanut allergy in a general pediatric allergy referral population . Measurement of specific IgE to Ara h 2 had a diagnostic sensitivity of 96 percent and specificity of 54 percent when sensitization was defined as >0.1 kUA/L (sensitivity 88.5 percent and specificity 71.4 percent using a threshold of 0.35 kUA/L).
Peanut testing approach — In a patient with a history consistent with IgE-mediated allergy to peanut, we suggest first testing peanut-specific IgE.
●Component testing can be informative for those with low peanut IgE levels (<25 kUA/L), known birch pollen sensitization, and/or mild or no history of reaction to peanut. Having detectable IgE to Ara h 1, 2, or 3 is associated with higher risk of systemic reactions to peanut, and these patients would be advised to continue peanut avoidance.
●Peanut component testing is probably useful in adults with seasonal allergies who had tolerated peanuts earlier in life but later reported mild symptoms with peanut ingestion. Isolated Ara h 8 sensitization (without detectable IgE to Ara h 1, 2, or 3) suggests low risk for systemic reactions to peanut. The risk of a reaction on oral food challenge is decreased in this population, but a challenge is probably still warranted to confirm lack of systemic reactivity.
●For a young child who has experienced immediate systemic symptoms upon peanut ingestion, component testing is unlikely to provide additional information that would influence management.
Hazelnut — Several hazelnut (Corylus avellana, Cor a) allergens have been characterized. Cor a 1 is a heat labile protein that is homologous with the major birch pollen allergen, Bet v 1. Sensitization to Cor a 1 is generally associated with tolerance to hazelnut or mild oropharyngeal symptoms [23,24]. Sensitization to Cor a 8, an LTP, has been linked with more severe symptoms in patients from the Mediterranean area [24,25]. Cor a 9 is an 11S globulin, and data have implicated sensitization to Cor a 9 in severe reactions in children in the United States and Europe [23,26,27]. Sensitization to Cor a 14, a 2S albumin, is also highly specific for more severe reactions at food challenge .
In a study of 26 children from a birch-endemic area (Spain) who had positive hazelnut IgE and underwent double-blind, placebo-controlled food challenge (DBPCFC), sensitization to Cor a 8 was found to be a good discriminator of severe allergic reactions to hazelnut .
A 2013 Dutch study investigated specific IgE binding to hazelnut components Cor a 9 and Cor a 14 as indicators for a more severe hazelnut allergy phenotype . Diagnostic cutoffs of IgE levels ≥1 kUA/L to native Cor a 9 in children and adults or ≥5 kUA/L to recombinant Cor a 14 in children and ≥1 kUA/L in adults had a specificity of >90 percent. This association was confirmed in a 2014 United States study of 116 patients who underwent hazelnut oral food challenge. Cor a 9 and 14 were highly sensitive and specific for predicting clinical reactivity to hazelnut.
Component testing for hazelnut is commercially available and can be informative for patients who test positive to hazelnut but have known birch pollen sensitization and/or mild or no history of reaction to hazelnut. Having detectable IgE to Cor a 8, 9, and/or 14 is associated with a higher likelihood of clinical reactivity to hazelnut, and these patients would be advised to continue hazelnut avoidance.
Wheat — Several groups of allergens have been described for wheat (Triticum aestivum, Tri a). Some of these allergens are associated with specific forms of wheat allergy, such as baker's asthma or wheat-dependent, exercise-induced anaphylaxis. Others are associated with severe allergic reactions. However, detection of multiple wheat allergens concurrently does not identify all patients with wheat allergy . Thus, further research is needed to confirm the relevance of these proteins in larger populations and to assess the utility of measuring IgE to these individual allergens in the diagnosis of wheat allergy. These allergens are discussed in greater detail separately. (See "Grain allergy: Allergens and grain classification", section on 'Wheat'.)
Soy — Several soy (Glycine max, Gly m) allergens have been characterized . However, sensitization to these specific allergens is not consistently associated with the diagnosis of clinical allergy or severity of reactions. Thus, further studies are needed to determine the clinical utility of measuring IgE to these components.
Birch pollen-related soy allergy is attributed to sensitization to Gly m 4, a Bet v 1 homologue . Gly m 5 (beta-conglycinin) and Gly m 6 (glycinin) are storage proteins that are associated with severe reactions to soybean [31,32]. However, IgE levels to these allergens are not diagnostic for soy allergy, since nonsymptomatic individuals also have detectable IgE to these proteins. Although Gly m 4 sensitization is generally associated with milder symptoms or oral allergy, it is also related to severe, generalized symptoms in the absence of sensitization to Gly m 5 and 6 .
The storage protein 2S albumin (Gly m 2S albumin or Gly m 8) was reported to be an important allergen in Japanese children . In this study, symptomatic children had significantly higher levels of IgE to Gly m 2S albumin than nonsymptomatic children. A study from the Netherlands also demonstrated that IgE to Gly m 2S albumin is important in adults with soy allergy. However, the diagnostic value of IgE to Gly m 2S albumin was comparable with SPT or IgE to soy extract . In another study, the sensitivity of IgE to Gly m 8 was better than IgE to soy extract (78 versus 44 percent), but the specificity was lower (78 versus 87 percent) .
Fruits — Fruits more commonly cause oral allergy syndrome (pollen-food allergy syndrome) than systemic allergic reactions. A number of fruit allergens have been identified that cross-react with pollen allergens such as Bet v 1. Sensitization to other allergens, particularly nonspecific LTPs, is seen patients with fruit allergy who do not also have pollen allergy. Testing for most of these allergens is not available outside of the research setting. In addition, the utility of testing is generally not clear. Fruit and vegetable allergens are discussed in greater detail separately. (See "Pathogenesis of oral allergy syndrome (pollen-food allergy syndrome)".)
Measurement of IgE to specific kiwi (Actinidia deliciosa) allergens (Act d 1, 2, 5, and 8) is available on microarray testing. Act d 5 is homologous with Bet v 1. Thus, determination of IgE reactivity to these proteins may distinguish those who have primary kiwi allergy and are at high risk for systemic reactions from those with secondary kiwi allergy due to pollen cross-reactivity .
Testing for IgE to several peach (Prunus persica) allergens is available. Pru p 1 is a Bet v 1 homologue, Pru p 3 is an LTP, and Pru p 4 is a profilin. Some studies suggest utility in measuring IgE to these proteins in the characterization of peach reactions [38,39], but one study noted that sensitization to Pru p 3 was not associated with systemic symptoms nor was there an association with severity of reactions .
●Advances in the identification of 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). (See 'Introduction' above.)
●CRD holds promise for distinguishing patients with clinical allergy as opposed to those sensitized, but tolerant to, plant-derived foods. It also has the potential to provide additional information regarding the severity of symptoms that may occur in clinically reactive individuals, with those sensitized to pollen-related proteins having a lower risk of severe systemic reactions with exposure. (See 'Overview' above.)
●Two different types of immunoassays are commercially available: those that measure specific IgE to individual allergens (components) and those that measure specific IgE to multiple components simultaneously (microarrays). (See 'Assay systems' above.)
●For peanut allergy, data indicate that CRD can provide useful information for discriminating between pollen-related symptoms as opposed to primary peanut allergy, particularly in older individuals. This information can be used to facilitate patient selection of oral food challenges (table 2). (See 'Peanut' above.)
●Further studies in larger populations are needed to determine the clinical utility of CRD for each different food. Oral food challenge remains the gold standard for food allergy diagnosis. (See 'Allergen-specific use/interpretation' above.)
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