Introduction to Allergy and Diagnosis

Learning objectives

By the end of this chapter, participants will be able to:

• list the tests available to support allergy diagnosis
• know what guidelines recommend for allergy diagnosis
• recall the main concepts and applications of molecular allergology that can be used to support clinical diagnosis of allergy.

A brief introduction to allergy

• Allergy is an adverse immunological hypersensitivity to harmless foreign substances that can lead to several types of disease.¹
  • These triggering foreign substances, mostly proteins, are called allergens and can be found in various tissues, particles, foods and organisms.²
• Manifestations of allergy range from relatively mild symptoms, including urticaria, wheezing and sneezing, to severe and life-threatening symptoms, including anaphylaxis.¹
• The European Academy of Allergy and Clinical Immunology (EAACI) has called for improvements in the prevention, diagnosis and treatment of allergy.³

Burden of disease³

Allergy is the most common chronic disease in Europe.
150 million EU citizens suffer from chronic allergic diseases and, by 2025, more than 50% of all Europeans will suffer from allergy.

• There is wide variation across Europe in terms of allergy services provided and access to specialised healthcare professionals.
• Around half of all identified allergy patients in Europe are managed in primary care, but there are recognised variations in the level of training received.
• Allergies should not be underestimated, especially where there is risk of anaphylaxis; they hold the potential to impact significantly on quality of life, education performance, career progression and personal development.
• Further, estimates for the avoidable indirect costs of failure to properly treat allergy in the EU are in the range of €55–151 billion every year.
• With proper treatment, which relies on an accurate diagnosis, an estimated €142 billion per year could be saved.

How does allergy develop?^4–6

Cross-reactivity versus co-sensitivity

• Most allergens are proteins that belong to a select number of protein families owing to similarities within their amino acid sequences and structures, including polcalcin, profilin, serum albumin, lipocalin, parvalbumin, pathogenesis-related and the non-specific lipid transfer protein families.⁷
• Cross-reactive immune responses can occur with proteins from the same protein family. This is because antibodies raised against one protein can also bind to other structurally related proteins and induce an immune reaction.⁸
  • An example of this is the allergenic birch pollen protein Bet v 1, which has structurally related proteins in apples, cherries, peaches, tree nuts, carrots and soybean.⁸
• Cross-reactivities can often confound results from conventional allergen sensitisation tests. This can make identification of the triggering allergen a challenge.⁹
• Patients can be sensitised to multiple allergens (where sensitisation is not due to cross-reactivity) – this is defined as co-sensitisation.¹⁰

Antibodies can cross-react with unrelated antigens in proteins if they share identical or similar epitopes.

What is the best practice approach to achieve an accurate diagnosis?

• Since the recognition in the 1960s of immunoglobulin E (IgE) as a major mediator of allergic response, efforts have been focused on achieving “allergen- specific” diagnoses, to help inform management.^2,8
• However, the first step in diagnosing allergy should always be the acquisition of a detailed patient history and physical examination. This will help to direct the choice of diagnostic test.^11,12
• A patient history should include:¹³
  • type, severity and duration of symptoms
  • timing of onset
  • relationship of symptom with time, place, hobbies, work etc.
  • family and personal history of atopy
  • any new exposures i.e. food, pets, medicines.
• Physical examinations are often specific to the patient’s symptoms and suspected allergy,^12,14 but it should be considered that symptoms may have resolved by the time a patient presents at a consultation, which is why obtaining the history is key.
• An allergen sensitisation test can further aid the diagnostic process, informing decisions relating to a patient’s treatment pathway.¹²

Conventional sensitisation testing

• Conventional allergen sensitisation tests include those for allergen reactivity or identification of IgE in the blood:⁸
  • Skin prick testing: a small, disposable plastic device coated with diluted allergen is used to prick the skin and observe any reactivity.¹⁵
  • Oral challenge testing: food containing the suspected allergen is slowly fed to a patient in a controlled environment and reactivity is observed.^2,16
  • Serum-specific IgE (sIgE) testing: a blood sample is taken and used to test for the presence of specific IgE antibodies to allergen source extracts, following exposure.¹¹
• Consideration of available facilities is key:
• Although skin prick testing may seem simple, it must be carried out by trained practitioners with an understanding of the variables and risks of the testing procedure.^12,15
• There is a small but unpredictable risk of anaphylaxis; therefore, the right facilities (e.g. oxygen, cannulation equipment, adrenaline injectors) and personnel trained in their use should be present.^2,16–18
• There is variation in how it is performed, interpreted and documented.¹²
• Results can vary with the season, location on the body, device and extract.¹²
• In vitro tests:
  • sIgE testing, for example,  may be more readily accessible to primary care providers, as they require a single venipuncture; office staff do not need to be trained to perform them; there is no risk to the patient since direct exposure to the allergen is avoided, and the tests are not affected if the patient has taken an antihistamine.¹²

Advances in allergy diagnostics: molecular allergology

• Conventional allergen sensitisation tests including skin prick and serum-specific IgE tests are dependent on the detection of specific IgE antibodies to allergen source extracts containing both allergic and non-allergic components.⁸
• Methodological and technological advances in protein biochemistry and molecular biology have led to the production of recombinant and purified natural allergens for diagnosis, hereafter referred to as allergen components.⁸
• In comparison to traditional techniques, the use of allergen components provides higher specificity and sensitivity and the ability to distinguish primary sensitisation from cross-reactivity.⁸
  • Cross-reactivity can lead to false-positive results which may lead to ineffective treatment strategies.
• Commercial availability of over 130 allergen components has led to the emergence of a novel diagnostic tool called component-resolved diagnostics (CRD).²
• CRD involves the implementation of single allergen component in a diagnostic assay to determine IgE specific to the allergen component.
  • This can be with either a singleplex or multiplex assay:^7,8
    • Singleplex assay – with one allergen component per sample
    • Multiplex assay – with concurrent testing of several allergen components per sample

Diagnostic algorithms including CRD

Benefits of component-resolved diagnostics

• For example, CRD can be used to:
  • provide information on the patient’s specific allergen sensitisation profile including primary (genuine) sensitisations and cross-reactivities^19,20
  • predict a patient’s reaction to an allergen source – this is dependent on the patient’s level of sensitisation to the allergen and abundance and/or stability of the specific allergen in the allergen source^8,21,22
  • aid decisions on providing patients with the correct allergen immunotherapy^22,23
  • potentially avoid the immediate need for provocation testing^24,25
  • test patients against allergens of low abundance and/or weak stability that are missing in allergen extracts ⁸

Key considerations when using CRD

CRD offers additional benefits to the use of allergen extract-based diagnostics. However, interpretation of data should include several considerations:

• The patient’s clinical history and symptoms should be used to select the correct allergen components for singleplex assays.^12,18
  • This will ensure that interpretations are made in the context of the patient’s clinical history.
• A positive result for IgE sensitisation against a component does not causally imply that this allergen is clinically relevant.
  • Relevant symptoms and a reflective medical history must also be present.¹²
• Results obtained from one patient cannot be projected onto the rest of the population – this is a personalised diagnostic tool.¹⁸
• If specific IgE is not detected in the serum, this rules out sensitisation.⁸
  • However, the following factors must be met: serum total IgE levels (>20 kU/I), tested suitability of the allergen component in diagnosis and sensitivity of the IgE testing method.
• Multiplex assays can be less sensitive than singleplex assays at low serum IgE levels.¹⁹

References

1. Akdis CA, Agache I. (Editors). Global Atlas of Allergy. 2014. Zurich: European Academy of Allergy and Clinical Immunology.
2. Canonica GW et al. World Allergy Organ J. 2013;6(1):17.
3. European Academy of Allergy and Clinical Immunology. https://www.eaaci.org/documents/EAACI_Advocacy_Manifesto.pdf (accessed May 2019)
4. Yoo Y et al. Curr Allergy Asthma Rep. 2014;14(10):465.
5. Actor J. Elsevier’s Integrated Review Immunology and Microbiology. 2011. Adaptive Immune Response and Hypersensitivity. Saunders
6. Simpson EL et al. N Engl J Med. 2017;376(11):1090–1.
7. Matricardi PM et al. (Editors). Molecular Allergology User’s Guide. 2016. Zurich: European Academy of Allergy and Clinical Immunology.
8. Kleine-Tebbe J, Jakob T. (Editors). Molecular Allergy Diagnostics. 2015. Cham: Springer International Publishing.
9. Sicherer S. J Allergy Clin Immunol. 2001;108(6):881–90.
10. Migueres M et al. Clin Transl Allergy. 2014;4:16.
11. Mahmoudi M (Editor). Allergy and Asthma. 2016. Cham: Springer International Publishing.
12. Portnoy JM. Mo Med. 2011;108(5):339–43.
13. Royal College of Paediatrics and Child Health. https://www.rcpch.ac.uk/sites/default/files/Taking_an_Allergy_Focused_Clinical_History_-_Allergy_Care_Pathways_Project.pdf (accessed May 2018).
14. Quillen DM, Feller DB.  Am Fam Physician. 2006;73(9):1583–90. http://www.pulsetoday.co.uk/clinical/sponsored-information/how-can-identifying-and-managing-allergic-disease-help-you-care-for-your-patients
15. American College of Allergy, Asthma and Immunology. https://acaai.org/allergies/treatment/allergy-testing/skin-test (accessed May 2019).
16. Lancashire Teaching Hospitals. https://www.lancsteachinghospitals.nhs.uk/download.cfm?doc=docm93jijm4n3853.pdf&ver=7772 (accessed May 2019).
17. Liccardi G et al. J Investig Allergol Clin Immunol. 2006;16(2):75–8.
18. Australasian Society of Clinical Immunology and Allergy. https://www.allergy.org.au/images/stories/pospapers/ASCIA_SPT_Manual_March_2016.pdf (accessed May 2019).
19. Dodig S, Cepelak I. Biochemia Medica. 2018;28(2):020501
20. Jakob T et al. Allergo J Int. 2015;24:320–32.
21. Hong X et al. Allergy. 2012;67(12):1538–46.
22. Kukkonen AK et al. Allergy. 2015;70(10):1239–45.
23. Stringari G. J Allergy Clin Immunol. 2014;134(1):75–81.
24. Dang TD et al. J Allergy Clin Immunol. 2012;129(4):1056–63.
25. Rajput S et al. J Allergy Clin Immunol. 2018;141(1):457–8.