Application of Component-resolved Diagnostics(CRD) in Food Allergy


Introduction

Accurately diagnosing a patient with a possible food allergy is important to avoid unnecessary dietary restrictions and prevent life-threatening reactions. Routine testing modalities have limited accuracy, and an oral food challenge is often required to make a definitive diagnosis. Given that they are labour intensive and associated with risks of inducing an allergic reaction, several alternative diagnostic tests have been investigated. Component-resolved diagnostic (CRD) is a diagnostic test to detect specific IgE against individual allergen molecules or components using purified native or recombinant allergens. CRD has shown promise to improve diagnostics and has entered into clinical practice.

 

Advantages

One of the main advantages of CRD is to obtain information on the potential allergen cross-reactivity regarding inhalant allergens and food, which are exhibiting structural similarity within the epitopes. CRD explains at the molecular level allergens’ cross-reactivity. It allows distinguishing cross-reactions that occur after ingestion of food in patients with hypersensitivity primarily to pollen from the coexistence of inhaled and food allergies. It is also possible to use CRD for selected allergens to predict the severity of allergic reactions that may follow ingestion of those specific food in patients with food allergy. In addition, in small children, CRD can be helpful in predicting the likelihood of developing tolerance to certain allergens. Finally, CRD is useful in identifying specific allergens for immunotherapy in allergic patients.

 

Technical aspects

Measurement of specific IgE against allergen components can only be performed by blood tests at present and there are singleplex or multiplex systems. In the former one component is tested per assay and the techniques are similar to the those measuring sIgE to whole allergen extract. ImmunoCAP, CAP, radioallergosorbent test (RAST), sIgE and in vitro test are common terms of this laboratory technique. Multiplex systems measure more than one component in each assay and there is one commercially available kit, the immune-solid phase allergen chip (ISAC) which has > 100 allergen components from about 50 allergen sources coated on a biochip with several chips mounted on a slide.

 

Peanut

Not all peanut-sensitised children develop allergic reactions on exposure. In a population cohort, while 8-10 % children showed IgE measurement, only 1 in 5 of have clinical symptoms on challenge. The peanut component Ara h 2 was the most important predictor of clinical allergy. A cut-off of Ara h 2 > 1.63 kU/ l yielded a specificity of 100%, with a corresponding sensitivity of 70%. Symptom severity elicited during challenge correlated significantly with the levels of Ara h 2, but large individual variations were found. This cut-off would have reduced the necessary number of oral challenges by half. This result was reproduced by another group which also found the outcome of the food challenge could be predicted with sIgE to Ara h 2 in 50% of the patients. Using the same blood sample, a two-pronged blood test (with decision point at whole extract peanut IgE testing >15Kua/L and peanut Ara h2 >1 KUa/L) has reduced the need for oral food challenges four-fold in an Australian study.

Nonetheless, regional differences exist. In a study that compared patients with a peanut allergy from 3 countries (Spain, the United States, and Sweden), USA patients frequently had IgE against Ara h 1 to 3 that often manifested with severe symptoms, while sensitization to Ara h 9 and Ara h 8 were primarily found in Spanish and Swedish patients, respectively.

 

Shrimp allergy

One study that included 37 adults presented the accuracy of a specific IgE antibody toward rPen a 1 for shrimp allergy. Yang et al reported that sIgE antibodies to shrimp tropomyosin is more useful than a skin prick test to predict clinically relevant reactions in patients with shrimp allergy.

 

Egg allergy

A proportion of children with egg and milk allergies can tolerate cooked or the baked form of these foods. Such tolerance allows introduction of such foods and can greatly improve the ease of day to day management and quality of life of the patients and cares. However, a measurement of egg white-specific IgE level has been shown to be a poor predictor of clinical phenotypes of egg allergy, including to raw egg white, but particularly to baked or cooked egg. Egg white and yolk contain more than 20 different glycoproteins, including ovomucoid (Gal d 1), ovalbumin, ovotransferrin, alpha-livetin and the newly identified Gal d 6. CRD helps to diagnose the different clinical phenotypes of egg allergy. An Italian study showed that 94% of Gal d 1 negative patients tolerated boiled egg; however, 95% of Gal d 1 positive patients reacted to raw egg. Nevertheless in another study, sIgE against Gal d 1 has no better prediction than sIgE to egg white in assessing tolerance to baked egg.

 

Cow’s milk allergy

Cow’s milk protein allergens consist mainly of casein and whey proteins. The casein fraction (Bos d 8) accounts for 80%of total protein, while 20% is contained in whey protins such as β-lactalbumin (Bos d 4), β-lactalbumin (Bos d 5), bovine serum albumin (Bos d 6), immunoglobulin (Bos d 7), and lactoferrin. Cingolani et al. used CRD to compare the levels of specific IgE against nBos d 4, nBos d 5, and nBos d 8 between the anaphylaxis group and non-anaphylaxis group of patients with CMA. The level of IgE to nBos d 8 differentiated the “high anaphylaxis-risk” from the “milder-risk” group. However such results could not be consistently verified. Ott et al, evaluated the commercially available allergen microarray assay using Bos d 4,5,6, and 8 in patients with CMA. They found that no single allergen component could discriminate asymptomatic sensitization from clinically relevant allergy.

There have been more studies on diagnostic value of food allergies such as wheat, soybean, and hazelnut allergies.

 

Oral Allergy Syndrome (OAS)

OAS refers to a condition in patients who are sensitive to ragweed or birch pollens. When these patients eat certain fruits such as apples, cherries and melons they may rapidly develop an itchy, tingling sensation around the lips, with mild swelling. The tongue, palate and throat may also be involved. This is because the main allergen component in birch pollen, Bet v 1, is highly cross- reactive to many plant foods. For example, there is structural similarity between Bet v 1 and Ara h 8 in peanut or Cor a 1 in hazelnut. Fresh fruits, raw vegetables and nuts are common causes of OAS and the responsible allergen components are usually heat-labile. Hence cooked or processed forms of these foods are often tolerated.

 

Idiopathic anaphylaxis

A diagnosis of idiopathic anaphylaxis following a detailed clinical assessment remains very challenging if not frustrating assessment remains very challenging if not frustrating for patients and clinicians. Risk reduction strategies such as allergen avoidance are not possible without knowledge of the culprit allergen. Heaps et al T using ISAC allergen array with 103 allergens investigated 110 patients with a diagnosis of idiopathic anaphylaxis from five UK specialist centres. The ISAC array contributed to the diagnosis in 20% of patients with idiopathic anaphylaxis. A wide range of major allergens were identified, the most frequent being omega-5-gliadin and shrimp. The authors suggested that it may offer additional information where a careful allergy history and follow-on testing have not revealed the cause of the anaphylaxis.

 

Clinical utility

We often refer to the usefulness and cost-effectiveness for any new test. Antonicelli et al found only fair agreement between allergists’ risk assessment based on the current decision making process with that of allergen-oriented risk assessment through microarray-based immunoassay. Three main causes of discrepancy were the poor sensitivity of the allergen microarray-immunoassay, the differences in risk assessment established by the specialist and the microarray-immunoassay, and the non-inclusion of the causative allergen in the causative allergen in the microarray-immunoassay platform.

Allergy specialists want this test to be easy to use, easy to interpret and can reduce the need of oral challenge. In the current practice, CRD is an “add-on” test and it is not able to replace the whole extract IgE testing. The additional cost could be partially offset by reducing the need of food challenge which could ease an overwhelmingly busy allergy health service. Thus cost effectiveness has to be assessed against different practice situations.

 

Limitation

CRD does not replace clinical observation and double-blind placebo-controlled food challenge, which is still the gold standard in the diagnosis of food allergy. Due to the  geographic diversity in pollen exposure and dietary factors, researches on allergen components in populations living in different climatic zones give different results. CRD results should always be considered in the clinical context, especially when estimating the risk of severe allergic reactions. Practical conclusions and guidance derived from different populations should be drawn with caution.

 

Conclusion

Despite these limitations, the CRD method as a modern tool for the diagnosis of allergy deserves its increasing popularity. It provides information on allergenic components at the molecular level, allowing better understanding of the cause of symptoms and the introduction of individualized strategies for management. Validation for the local Hong Kong population is underway.

 

Dr Marco HK HO

MBBS, MRCP, MRCPCH, FHKCpaed, FHKAM

Consultant, Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital

 

Dr Eric YT CHAN

MBBS, FRCPath, FRCPA, FRCPath, FHKAM

Consultant, Department of pathology and Clinical Biochemistry, Queen Mary Hospital


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