C47a JeanCharlesClouet

The advent of molecular allergens heralds a new era in allergy diagnosis

Recent advances in the understanding of the compositions and structures of allergens now make it possible to use allergenic components instead of allergenic extracts in allergy testing.
In this interview, Jean-Charles Clouet, Director of Assay Business Development & Scientific Marketing at Siemens Healthcare Diagnostics, discusses the role of these molecular allergens in allergy diagnosis.

Q. What is the prevalence of allergies, and are there any geographical disparities?
Allergic diseases and asthma represent a growing and major healthcare challenge worldwide, as reported by the recent World Allergy Organization (WAO) White Book. [1] The authors confirm the steady increase of allergic diseases during the last decades that now affect approximately 30–40% of the industrialized world’s population, with an especially high percentage among the youngest subjects (40–50% of school-aged children are sensitized to one or more common allergens).

For example, allergic rhinitis is one of the most common allergic conditions, impacting roughly 500 million people of all social classes and ages globally. [2] In Europe, a study showed allergic rhinitis prevalence at approximately 25%. [3,4] It is important to note that, although direct costs induced by allergic rhinitis are limited, the condition affects subjects’ quality of life and has significant impact on performance at work or school. Therefore, its overall economic impact is probably underestimated. [2]

Another recent study, this one surveying more than 38,000 children (up to 18 years old) in the United States, reported that 8% had food allergy, including a rate of about 6% for those aged 0-2 years, and more than 8.5% for those aged 14-18 years. [5] Worldwide, it is estimated that 220–520 million people may suffer from food allergy. [1]

These statistics illustrate the high prevalence of allergy worldwide and why the World Health Organization (WHO) ranks allergy as the fourth most common global chronic disease. [6]

Q. What are the most common clinical manifestations of allergy that demand further testing?
Subjects suffering from allergic diseases tend to develop IgE-mediated immune reactions to normally harmless substances called allergens. These can include tree pollens, grasses and weeds; foods; mites; animal danders; molds; insects; and drugs. Associated clinical manifestations range from mild to severe and affect the upper and lower airways, gastrointestinal tract and skin. The consequent allergic diseases may include rhinitis, asthma, allergic conjunctivitis, atopic eczema, food allergy, insect allergy, drug allergy and anaphylaxis. Some can even be fatal, in the cases of allergic reactions to certain foods, insect venoms or drugs.

The model for the “Allergy March” published in the late 1990s emphasized that the most common forms of allergic diseases in early infancy are gastrointestinal symptoms and skin conditions (e.g., atopic dermatitis) caused by food proteins, such as hen’s egg and cow’s milk. [7] Additionally, IgE reactivity to food allergens in early infancy is a strong predictor for reactivity to respiratory allergens later in childhood. Other forms, such as allergic rhinitis and reactions to aeroallergens, happen later in life (1–10 years).

In 2003, the European Academy Of Allergy and Clinical Immunology (EAACI) published a position paper on allergy in children recommending testing for all subjects with severe, persistent or recurrent “allergic symptoms” (irrespective of age), along with those requiring a prophylactic treatment,. Proposals to select relevant allergens based on the subject’s age were provided. [8] Additional position papers are available for other forms of allergic reactions, such as drug allergy (causing 20% of deaths due to anaphylaxis) or insect allergy (fatal reactions in up to 50% of individuals with no documented history of reaction). [3]

Q. What are the current testing methods?
The objectives of allergy diagnosis are to identify both the symptoms’ origin (i.e., is the reaction IgE-mediated?) and the offending allergen(s). Allergy diagnosis is multi-factorial and includes a detailed case history and in vivo (i.e., skin tests) and/or in vitro (i.e., allergen-specific IgE measurements) testing. For some allergens (e.g., foods), oral challenges may also be performed to support diagnosis of food allergy.

Skin tests and blood tests, performed by allergists and laboratories respectively, present their own advantages and limitations. Skin tests are highly sensitive, with results immediately available for the patient. However, patients must discontinue medications (e.g., antihistamine) prior to testing, and interpretations of skin-test results are highly subjective and depend largely on operator skills. In vitro tests have the advantage of providing precise, quantitative results for each allergen, validated through extensive internal and external quality-control procedures and programs.

It is important to note that “allergens” used for in vivo and in vitro testing procedures are still primarily allergenic extracts. Obtained by extraction of proteins from crude allergenic sources, these extracts consist of a mixture of known and unknown proteins. Due to molecular-biology techniques and research begun in the 1980s, it is now possible to better understand compositions and structures of allergens, to classify them into families of proteins and to obtain for a significant number of them more qualified and standardized materials called “molecular allergens” or “allergenic components.” Whether highly purified in native form from the allergenic source or produced via recombinant protein expression techniques, molecular allergens have ushered in a new era in allergy diagnosis.

Q. What is the role of molecular allergens in allergy testing?

Allergenic extracts allow the detection of specific IgE directed against an allergenic source. In contrast, molecular allergens permit detection of precisely specific IgE directed against the disease-eliciting component(s) of the allergenic source. Therefore, measurements of specific IgE against molecular allergens yield additional key information that cannot be obtained by testing allergenic extracts. In particular, use of molecular allergens can help allergists define a more personalized and relevant sensitization profile for each patient.

For example, testing with molecular allergens makes it possible to determine if a patient’s sensitization is genuine (i.e., specific to one allergenic source) or comes from a cross-reactivity to proteins that have similar structures and are present in different sources. This is an important consideration when assessing a patient’s risk of reaction to some allergic sources and recommending appropriate avoidance measures. Allergenic molecules can also help clinicians assess the severity of a patient’s allergic reaction and, in the case of food allergy, decide whether or not to perform an oral food challenge. Finally, allergenic molecules can help clinicians identify patients who will benefit from immunotherapy treatment and decide which allergens should be used for treatment.

Q. Is this new technology likely to shift the burden of allergy testing towards the lab and away from in vivo (i.e., skin-based) testing?
In vitro testing is an accurate complement or alternative to skin testing for most allergens. However, despite their growing number, molecular allergens are not yet available for all types of allergens. Using allergenic extracts in conjunction with in vitro and/or skin testing is still the only option for a large number of
allergenic sources.

Q. In your view, what is the ideal sequence of tests to optimize the early diagnosis and treatment of allergy?
First of all, it’s important to raise awareness among the public and in the physician community of the importance of early diagnosis to better prevent and treat allergic diseases. Equally important is educating both clinicians and the public on the availability of new diagnostic tools, such as molecular allergens, along with the best way to leverage them to improve patient care.

An “ideal sequence” should begin with a careful and detailed case history taken by an allergist. This is critical in deciding whether further testing is necessary. Also, the results of specific IgE measurements should always be analysed in conjunction with the patient’s clinical history, since an allergen sensitization does not necessarily imply a clinical responsiveness.

If the clinical history suggests an allergic reaction, the clinician generally will request detection of specific IgE against the suspected allergens. Testing will then be performed using allergenic extracts in most cases. The reason is that allergen extracts are complex heterogeneous mixtures made of major and minor allergenic determinants. In some instances, a few molecular allergens will be enough to replace the corresponding allergenic extract. Unfortunately, this is not the case for sources with more complex compositions and in situations in which as-yet unidentified determinants (even minor ones) could be of clinical importance for particular patients. Also, as already mentioned, allergenic components have not yet been developed for a large number of allergenic extracts.

Therefore, in the majority of cases, testing allergenic extracts as a first step is the best or perhaps the only option to detect all sensitized patients. If specific IgE against the allergenic extract are found, relevant molecular allergens should then be tested to provide more information, as explained above.

1. World Health Organization. White Book on Allergy 2011-2012 Executive Summary. By Prof. Ruby Pawankar, MD, PhD, Prof. Giorgio Walkter Canonica, MD, Prof. Stephen T. Holgate, BSc, MD, DSc, FMed Sci, and Prof. Richard F. Lockey, MD.
2. Bousquet J, et al. Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63 Suppl 86:8-160.
3. Bauchau V, Durham SR. Prevalence and rate of diagnosis of allergic rhinitis in Europe. Eur Respir J. 2004;24:758–764.
4. Bauchau V, Durham SR. Epidemiological characterization of the intermittent and persistent types of allergic rhinitis. Allergy. 2005;60:350–353.
5. Gupta, R, et al. The prevalence, severity and distribution of childhood food allergy in the United States. Pediatrics. 2011;10.1542/ped.2011-0204.
6.I nternational classification of diseases (ICD). http://www.who.int/classifications/icd/en/.
7. Kulig M, Bergmann R, Klettke U, Wahn V, Tacke U, Wahn U. Natural course of sensitization to food and inhalant allergens during the first 6 years of life. J Allergy Clin Immunol. 1999;103:1173–1179.
8. Host, et al. Allergy testing in children: why, who, when and how? Allergy. 2003:58:1-11.