Component Resolved Diagnosis Future Concept in Diagnosis Allergic Disease.
The diagnosis of food allergy, as assessed by skin tests or in vitro tests with allergen extracts, has insufficient diagnostic performance and needs to be confirmed by food challenges. However, the availability of molecular allergens (recombinant or highly purified) for laboratory methods has profoundly changed the diagnostic approach to food allergy. In fact, the allergy diagnosis conducted at the molecular level, which is defined internationally as component resolved diagnosis (CRD), allows to characterize more precisely the sensitization profile of the individual patient, distinguishing the sensitizations to allergens that are strongly associated with a given source (genuine sensitizers) from those to molecules that are common to many sources (panallergens) or cross-react with other components from the same family or from other families.
Traditionally, diagnosis of pediatric allergic disease is based on a careful and thorough history, skin prick testing, and assessment of specific IgE antibodies to allergens in the blood, and on provocation or elimination-provocation-elimination tests. Skin prick testing (SPT) and serum food-specific IgE (sIgE) levels are extremely sensitive testing options, but positive test results to tolerated foods are not uncommon. By means of molecular methods over the last few years, it has become possible to measure IgE antibodies to specific components of allergens. The methods are designated as component-resolved diagnosis. The molecular structures of many allergens have been characterized and are commercially available as recombinant products. This has focused attention on the need for assessment of the clinical application of the methods in pediatric populations; however, guidelines or consensus on their use have not been defined.
The vast information provided by molecular allergy needs a structured approach in order to be adequately interpreted. There is a need to evaluate single positivities and negativities, but also to appraise “the big picture” with perspective. When making decisions on this information, one has to bear in mind what is included in the tests and what is missing. It is needed that we understand that not all allergenic sources are present in the available arrays, but that the most important allergenic protein families are. This is relevant both when searching for a culprit allergen as when ruling out possible causes of certain reactions.
The concept of component resolved diagnosis, to identify conditions in which the new diagnostic tool may be helpful in pediatric allergic disease, and to discuss conditions in which more evidence should be provided before large-scale use of the methods may be warranted. Allergen component-resolved diagnostics (CRD) have the potential to provide a more accurate assessment in diagnosing food allergies. Recently, a number of studies have demonstrated that CRD may improve the specificity of allergy testing to a variety of foods including peanut, milk, and egg. While it may be a helpful adjunct to current diagnostic testing, CRD is not ready to replace existing methods of allergy testing, as it not as sensitive, is not widely available, and evaluations of component testing for a number of major food allergens are lacking.
Component resolved diagnosis is a new concept in the investigation of pediatric allergic disease. Component resolved diagnosis with respect to implications for investigation of children with allergic disease. In most conditions head-to-head comparisons of component resolved diagnosis with traditional IgE testing have not been performed. Rather than alternatives the molecular methods should be seen as adjuncts to the cheaper traditional specific IgE tests. It may be appropriate to determine IgE antibodies to components as part of the diagnostic work-up in selected cases of peanut and birch pollen allergy and in hymenoptera allergy. However, cost benefit analyses of component resolved diagnosis compared with traditional work-up of allergy are needed. Prospectively planned protocols for assessment of the extent to which component resolved diagnosis may be able to improve the selection of children to immunotherapy and, thus, the efficacy of immunotherapy, are needed. Finally, studies of component resolved diagnosis with microarray technology in screening panels with hundreds of components should be undertaken before it can be determined to which extent such panel screening, if at all, may be helpful in children.
Component-resolved diagnostics (CRD) utilize purified native or recombinant allergens to detect IgE sensitivity to individual allergen molecules and have become of growing importance in clinical investigation of IgE-mediated allergies. This overview updates current developments of CRD, including multiarray test systems. Cross-reactions between allergens of known allergen families (i.e. to Bet v 1 homologues) are emphasised. In pollinosis as well as in allergy to hymenoptera venoms or to food, CRD allows to some extent discrimination between clinically significant and irrelevant sIgE results and the establishing of sensitisation patterns with particular prognostic outcomes (i.e. sensitisations to storage proteins which correlate with clinically severe reactions in peanut allergy). Further promising improvements in diagnostics are expected from additional, not yet commercially available, recombinant allergen diagnostics identifying particular molecules of risk. Overall, CRD may decrease the need for provocation testing and may also improve the specificity of allergen-specific immunotherapy.
In several IgE-mediated conditions in children, the use of component resolved diagnosis in the hands of trained clinicians will offer improved diagnosis and therapy. There is evidence for investigating selected cases of suspected peanut allergy, birch pollen allergy, and associated cross-reactivity by means of component analyses. More than 95% of patients with IgE antibodies to Ara h 2 in combination with Ara h 1 or Ara h 3 have symptoms when ingesting peanuts. Whether there may be a threshold level of IgE to Ara h 2, however, above which peanut allergy may be diagnosed with a sufficient clinically sensitivity and specificity which may abandon the need for oral provocation remains to be evaluated. If it is important to know the degree of severity of the allergic reaction to peanut, oral provocation should still be considered.
The allergen molecules from foods, including plant foods and animal foods, and on the techniques to detect them, by means of a single reagent (singleplex) or an array of molecules tested at the same time (multiplex). Such testing offers detailed information on the sensitization profile of patients and enables the physician to suitably manage their allergy. Moreover, identifying the real causative allergens will be crucial when allergen immunotherapy for food allergy will be introduced in the near future.
Component resolved diagnosis has a place in the investigation of children with insect allergy. For the frequent cases of an unclear history and increased IgE to both bee and wasp assessment of IgE to Api m 1 and Ves v 5 is helpful for the decision of whether immunotherapy to both allergens should be recommended or not. Component resolved diagnosis may also be indicated in the investigation of rare, anaphylactic reactions in patients with suspected wheat or soy allergy. Prospectively planned protocols for clarification of the extent to which component resolved diagnosis will be able to improve selection of patients to immunotherapy and, thus, the efficacy of immunotherapy, are needed.
Risk Assessment Food Allergy
Since the first study on CRD in apple allergy across Europe, where it was demonstrated that sensitization to apple nsLTP (Mal d 3) was associated with a 7 fold risk of anaphylaxis compared to sensitization apple Bet v 1 homologue (Mal d 1), nsLTP have been considered markers of severe allergic reactions. However, studies on patterns of nsLTP sensitization in Mediterranean patients have shown that the clinical expression is variable, ranging from asymptomatic sensitization to severe anaphylaxis, possibly modulated by pollen allergen co-sensitization and the presence of cofactors . A predictive pattern of clinical expression in nsLTP-sensitized patients has not yet been elucidated.
Bet v 1 homologues are considered markers of mild allergic reactions to fruits and vegetables due to cross-reactivity with birch pollen. However, although not frequent, some anaphylactic reactions to apple in patients sensitized to PR10-proteins have been reported. In the particular case of soya allergy, Gly m 4 (the Bet v 1 related allergen in soya) has been related to severe, generalized symptoms.
Seed storage proteins from nuts and soya have been associated with higher risk of severe allergic reactions. In the case of peanut, Ara h 2 seems to be the best predictor of peanut allergy, reducing the need for peanut challenges by at least 50%. Altogether, Ara h 1, Ara h 2 and Ara h 3 have been associated with severe symptoms, although anaphylactic reactions have been described in patients negative for these allergens.
Sensitization to Cor a 9 and Cor a 14 have been reported to be highly specific for hazelnut allergic patients with objective symptoms in DBPCFCs and proposed as markers for a more severe hazelnut allergic phenotype. Similarly, in patients with soybean allergy, Gly m 5 and Gly m 6 have been proposed as potential markers for severe allergic reactions. Altogether, CRD may be a useful tool for stratifying patient’s risk for severe reactions but it is important to bear in mind that the risk of developing anaphylaxis depends not only on the allergen sensitization pattern, but also on the avidity and affinity of immunoglobulins to bind the allergen, the route of application, characteristics of the allergen and the presence of cofactors depicts those allergens that have been associated to higher versus lower risk of anaphylaxis.
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