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Component resolved diagnostics in allergology

Component resolved diagnostics (CRD) is a novel method of allergy testing, moving beyond the classical concept of patient approach by providing new information for clinical decision making.1,2 All the previously applied diagnostic methods for atopic diseases, such as skin prick tests and in vitro immunoassays, are directed at detecting specific immunoglobulin E (sIgE) against a crude mixture of allergens (usually poorly standardised allergenic extract).1,2 An allergenic extract consists of various allergenic and non-allergenic proteins (components) containing antigenic determinants (linear or conformational epitopes), which are recognised by the immune system. sIgE bound to an epitope triggers an allergic response in a sensitised patient. CRD tests are directed at detecting sIgE against recombinant allergenic proteins or eventually pure components derived from natural products. The components can be species-specific (for example, peanut) or can cross-react between different species (for example, pollens, fruits). CRD provides more precise information about the patient sensitisation, supporting the management of an allergic patient including dietary restrictions, allergen-specific immunotherapy and further treatment modalities.2
The nomenclature of components
Allergen components are named after their Latin name (the first three letters of the genus name), followed by a first letter for the species and an Arabic number (1, 2, 3 etc). For example: hazelnut – Corylus avellana (Cor a 1); egg – Gallus domesticus (Gal d1). By contrast, many allergens still retain their biochemical names: for example, Gal d1 – ovomucoid; Gal d2 – ovalbumin; Gal d3 – conalbumin; Gal d4 – lysozyme.2
Clinical applications of CRD
CRD enables establishing of an individual IgE profile and can improve management of an allergic patient by:
  • Providing individual sensitisation profiles
  • Prognosis and understanding of cross-reactivity, discriminating between primary allergen sensitisation and reaction to cross-reacting components
  • Predicting the risk and severity of allergy symptoms (anaphylaxis)
  • Diagnostics of oral allergy syndrome
  • Providing recommendations for elimination diet 
  • Monitoring of long-term tolerance development 
  • Qualification for specific immuno-therapy
  • Monitoring response to specific immunotherapy
  • Optimising the decision process of 
  • food challenge tests
  • Differentiating between asymptomatic sensitisation and true allergy.1–4
CRD in food allergy testing
CRD is especially beneficial for patients with food allergy.2,3 (The gold standard for diagnosing food allergy is a double-blind, placebo-controlled food challenge, a complicated, expensive and potentially dangerous procedure. CRD can be considered as an easy and accurate alternative to predict allergic reaction to food. CRD allows for detection of food specific-IgE with the potential to overcome limitations of currently applied diagnostic methods.2,4 The major components (panallergens), widely distributed in natural products and associated with food allergy include: 
  • Carbohydrate determinants (CCDs) 
  • Profilins 
  • Pathogenesis-related proteins 10 (PR-10) 
  • Non-specific lipid transfer proteins (nsLTPs)  
  • Storage proteins (see Table 1). 
These components differ in terms of heat and digestion stability, cross-reactivity among species and severity of induced allergic reactions. The detection of sIgE against food components may also explain cross-sensitisation between different allergens and particular pollen–food or latex–food syndromes.2,5,6
The interpretation of CRD test results requires specific knowledge about the properties of the different protein families and their role in the development of specific symptoms, especially in terms of predicting the severity of clinical reactions.
The severity of allergic reaction grades from CCD < profilin < PR-10 < nsLTP < storage proteins. IgE against CCDs may cause positive reactions in an immunoassay detecting antibodies against crude extract of an allergen that is not usually clinically relevant (see Table 1). At the other extreme, patients sensitised to storage proteins are at high risk for anaphylaxis/severe systemic reactions. Severity of the allergic reaction to a component is related to its resistance to heat and digestion in the gastrointestinal tract.2 Specific properties of various families of food allergenic components are summarised in Table 1.
Allergen components as severity markers
The components that are heat-stable and digestion-resistant are associated with the highest risk of serious clinical reactions in the sensitised patient when exposed to the allergen.2 Therefore, the sensitisation to those components has prognostically significant implications (Table 2).
Ara h 1, Ara h 2, Ara h 3 are storage proteins of peanuts (Arachis hypogaea), major allergens responsible for sensitisation of peanut-allergic patients. These proteins were identified as potent allergen, causing severe systemic/anaphylactic reactions.8
Omega-5 gliadin (Tri a 19) is a major allergen of wheat, responsible for wheat food allergy in children and immediate wheat exercise-induced anaphylaxis.9
Bos d 8 (casein) is a major component causing cow’s milk allergy, including severe systemic reactions. Cow’s milk is the third most common food after peanuts and tree nuts that causes food-induced anaphylactic reactions. The level of IgE antibodies to Bos d 8 decreases along with the development of the tolerance to cow’s milk.10
Gal d 1 (ovomucoid), the major egg allergen, is dominant and responsible for severe adverse reactions to  egg. The reaction to Gal d 1 are also associated with persistent egg white allergy. The concentration of IgE antibodies to Gal d decreases along with the development of the tolerance to baked eggs.11
Gly m 5 (beta-conglycinin) and Gly m 6 (glycinin) are potential diagnostic markers for severe allergic reactions (including anaphylaxis) to soybean (Glycine max). Both components are soybean major storage proteins considered as potential biomarkers for severe allergic reactions to soybean.12 
CRD in specific immunotherapy
The information regarding sensitisation to specific components of pollens (birch and timothy grass) as well as of hymenoptera venoms (honeybee and common yellow jacket) may support the decision about specific immunotherapy of an allergic patient.13
Sensitised patients exhibit differing reactivity profiles to the major components of allergenic extracts, present in immunotherapeutic vaccines. Recombinant birch pollen (rBet v 1, rBet v 2) and timothy grass (rPhl p 1, rPhl p 2, rPhl p 5) components can help to establish the patients’ pollen reactivity profile.14 Accordingly, CRD increased the specificity of diagnostic tests for hymenoptera venom allergy (Api m 1 – phospholipase A2; Api m 2 – hyaluronidase; Api m 3 – acid phosphatase; Api m 4 – melittin; Ves v 1 – phospholipase A1; Ves v 2 – hyaluronidase).15 The accurate diagnosis of an individual patient’s sensitisation profile may be helpful for the selection of patients for specific immunotherapy for birch and grass pollen as well as for hymenoptera venoms.16
Specific immunotherapy seems to be most effective in patients sensitised to Bet v 1 (major birch component) or a combination of the two major timothy grass pollen allergens, Phl p 1 and Phl p 5 (major grass pollen allergens).17 It is probable that a patient not sensitised to the major components of birch or timothy grass will not benefit from specific immunotherapy.18 A future challenge might be personalised, specific immunotherapy according to individual sensitisation profiles of a patient, that is, ‘component-resolved immunotherapy’.19,20
1 Treudler R, Simon JC. Overview of component resolved diagnostics. Curr Allergy Asthma Rep 2013;13:110–17.
2 Canonica GW et al. A WAO – ARIA – GA2LEN consensus document on molecular-based allergy diagnostics. World Allergy Organ J 2013;6:17.
3 Tuano KS, Davis CM. Utility of component-resolved diagnostics in food allergy. Curr Allergy Asthma Rep 2015;15:32.
4 Borres MP et al. Recent advances in component resolved diagnosis in food allergy. Allergology Int 2016;65:378–87.
5 Ahn K. The usefulness of component-resolved diagnostics in food allergy. Allergy Asthma Immunol Res 2014;6:103–4. 
6 Hofmann A, Burks AW. Pollen food syndrome: update on the allergens. Curr Allergy Asthma Rep 2008;8:413–7.
7 Chinthrajah RS et al. Molecular and cellular mechanisms of food allergy and food tolerance. J Allergy Clin Immunol 2016;137:984–97.
8 Nicolaou N. Allergy or tolerance in children sensitized to peanut: Prevalence and differentiation using component-resolved diagnostics J Allergy Clin Immunol 2010;125:191–7.
9 Morita E, Chinuki Y, Takahashi H. Recent advances of in vitro tests for the diagnosis of food-dependent exercise-induced anaphylaxis. J Dermatol Sci 2013;71:155–9.
10 Restani P et al. Molecular aspects of milk allergens and their role in clinical events. Anal Bioanal Chem 2009;395:47–56. 
11 Alessandri C et al. Ovomucoid (Gal d 1) specific IgE detected by microarray system predict tolerability to boiled hen’s egg and an increased risk to progress to multiple environmental allergen sensitisation. Clin Exp Allergy 2012;42:441–50.
12 Holzhauser T et al. Soybean (Glycine max) allergy in Europe: Gly m 5 (beta-conglycinin) and Gly m 6 (glycinin) are potential diagnostic markers for severe allergic reactions to soy. J Allergy Clin Immunol 2009;123:452–8.
13 Darsow U et al. Heterogeneity of molecular sensitization profiles in grass pollen allergy-implications for immunotherapy? Clin Exp Allergy 2014;44:778–86.
14 Tripodi S et al. Molecular profiles of IgE to Phleum pratense in children with grass pollen allergy: implications for specific immunotherapy. J Allergy Clin Immunol 2012;129:834–9 e8.
15 Ebo DG et al. In vitro diagnosis of Hymenoptera venom allergy and further development of component resolved diagnostics. Expert Rev Immunol 2014;10:375–84. 
16 Douladiris N et al. A molecular diagnostic algorithm to guide pollen immunotherapy in southern Europe: towards component-resolved management of allergic diseases. Int Arch Allergy Immunol 2013;162:163–72. 
17 Melioli G et al. Potential of molecular based diagnostics and its impact on allergen immunotherapy. Asthma Res Pract 2016;2:9.
18 Focke M et al. Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity. Clin Exp Allergy 2010;40:385–97. 
19 Heiss S et al. Component-resolved diagnosis (CRD) of type I allergy with recombinant grass and tree pollen allergens by skin testing J Invest Dermatol 1999;113:830–7. 
20 Sastre J et al. How molecular diagnosis can change allergen-specific immunotherapy prescription in a complex pollen area. Allergy 2012;67(5):709–11.