Molecular Diagnosis in Allergy
Development and progress made in the field of recombinant allergens have allowed for the development of a new concept in allergy diagnosis, molecular diagnosis (MD), which makes it possible to identify potential disease-eliciting molecules. Microarray-based testing performed with a small amount of serum sample enables clinicians to determine specific-IgE antibodies against multiple recombinants or purified natural allergen components. Performance characteristics of allergens so far tested are comparable with current diagnostic tests, but have to be confirmed in larger studies. The use of allergen components and the successful interpretation of test results in the clinic require some degree of knowledge about the basis of allergen components and their clinical implications.
Molecular-based allergy (MA) diagnostics is an approach used to map the allergen sensitization of a patient at a molecular level, using purified natural or recombinant allergenic molecules (allergen components) instead of allergen extracts. Since its introduction, MA diagnostics has increasingly entered routine care, with currently more than 130 allergenic molecules commercially available for in vitro specific IgE (sIgE) testing.
MA diagnostics allows for an increased accuracy in allergy diagnosis and prognosis and plays an important role in three key aspects of allergy diagnosis: (1) resolving genuine versus cross-reactive sensitization in poly-sensitized patients, thereby improving the understanding of triggering allergens; (2) assessing, in selected cases, the risk of severe, systemic versus mild, local reactions in food allergy, thereby reducing unnecessary anxiety for the patient and the need for food challenge testing; and (3) identifying patients and triggering allergens for specific immunotherapy (SIT).
Singleplex and multiplex measurement platforms are available for MA diagnostics. The Immuno-Solid phase Allergen Chip (ISAC) is the most comprehensive platform currently available, which involves a biochip technology to measure sIgE antibodies against more than one hundred allergenic molecules in a single assay. As the field of MA diagnostics advances, future work needs to focus on large-scale, population-based studies involving practical applications, elucidation and expansion of additional allergenic molecules, and support for appropriate test interpretation. With the rapidly expanding evidence-base for MA diagnosis, there is a need for allergists to keep abreast of the latest information.
Allergen components can be classified by protein families based on their function and structure. This review provides a brief overview of basic information on allergen components, recombinants or purified, currently available or soon to become commercially available in ImmunoCAP or ISAC systems, including names, protein family and function. Special consideration is given to primary or species-specific sensitization and possible cross-reactivity, because one of the most important clinical utility of MD is its ability to reveal whether the sensitization is genuine in nature (primary, species-specific) or if it is due to cross-reactivity to proteins with similar protein structures, which may help to evaluate the risk of reaction on exposure to different allergen sources. MD can be a support tool for choosing the right treatment for the right patient with the right timing. Such information will eventually give clinicians the possibility to individualize the actions taken, including an advice on targeted allergen exposure reduction, selection of suitable allergens for specific immunotherapy, or the need to perform food challenges. Nevertheless, all in vitro tests should be evaluated together with the clinical history, because allergen sensitization does not necessarily imply clinical responsiveness.
Correct identification of the culprit allergen is an essential part of diagnosis and treatment in immunoglobulin E (IgE)-mediated allergic diseases. In recent years, molecular biology has made important advances facilitating such identification and overcoming some of the drawbacks of natural allergen extracts, which consist of mixtures of various proteins that may be allergenic or not, specific for the allergen source or widely distributed (panallergens). New technologies offer the opportunity for a more accurate component-resolved diagnosis, of benefit especially to polysensitized allergic patients. The basic elements of molecular diagnostics with potential relevance to immunotherapy prescription with a focus on Southern European sensitization patterns to pollen allergens. The basic algorithm regarding component-resolved diagnostic work-up for pollen allergen-specific immunotherapy candidates in Southern Europe; this and similar algorithms can form the basis of improved patient management, conceptually a ‘Component-Resolved Allergy Management’.
Accurate diagnosis of peanut and legume allergy is challenging and essential. Measurement of IgE response to specific allergenic molecules may be more useful in predicting the presence and severity of clinical allergy than currently used skin or blood tests based on whole extracts. However, given the heterogeneity in component recognition patterns observed in different geographical areas, further studies are essential to identify and confirm potentially useful molecular diagnostic and prognostic markers. Until such markers are confirmed and replicated in different age groups, oral food challenge (OFC) remains the gold standard for accurate diagnosis.
MA diagnostics was developed more than a decade ago. The recent availability of a greater number of allergens has substantially modified the diagnostic approach used by many allergists. Currently, international guidelines recommend a thorough clinical case history as a first-line approach and allergen extract-based IgE tests (in vitro specific IgE or skin prick test) as a second-line investigation for the identification of the allergen source responsible for a patient’s symptoms. SPT and in vitro sIgE tests provide similar information and the associated advantages and disadvantages of both types of tests are dependent on the clinical case. For the majority of patients, first- and second-line investigation is sufficient to define the nature of a patient’s allergy. Molecular-based allergy (MA) diagnostics is considered a third-line approach to be used for select patients in whom first- and second-line investigations were inconclusive. For experienced users MA may be included in second-line testing.
Traditional diagnostic tests have been considered sufficient for the identification of the best SIT prescription in the majority of patients. With the identification of specific and cross-reacting allergens, a number of new diagnostic and therapeutic options are available to allergists, including the ability to choose the allergen composition for SIT.
MA diagnostics is relatively expensive compared with traditional tests, especially with regard to the microarray technology. Economic consideration or budget limitations may influence the decision in the individual patient, whether using a singleplex or multiplex approach. The number of allergens to be tested may influence this decision, both for economical reason, amount of information gained and for the overall serum volume required (especially in young children).
When making the choice to use the microarray diagnostics, it is important to consider the primary advantage which is that with a small serum or blood sample, a broad spectrum analysis of a patient’s IgE profile can be performed. However, a disadvantage is that patients may be at risk of revealing unanticipated sensitivities, possibly to potentially harmful molecules. Although this could also be considered as an advantage, the interpretation of such sensitization in clinically unresponsive patients is difficult or even impossible. Although MA diagnostics is a complex area, it provides novel and relevant information for the allergist and will soon become a standard tool in the allergist’s armamentarium. Educational programs training allergists on the use and interpretation of MA are highly needed.
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Douladiris N, Savvatianos S, Roumpedaki I, Skevaki C, Mitsias D, Papadopoulos NG: A molecular diagnostic algorithm to guide pollen immunotherapy in southern Europe: towards component-resolved management of allergic diseases.Int Arch Allergy Immunol 2013, 162:163-172.
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