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Allergy: an overview of diagnosis and testing

Samantha Walker
RGN PhD
Head of Research and Allergy Course Leader
National Respiratory Training Centre
Warwick
Allergy Specialist Nurse Chest and Allergy Clinic
St Mary's Hospital
London

The prevalence of allergic disease is increasing in the UK and throughout the Western world, such that approximately 25% of the UK population now suffers with some form of allergic condition (eg, hayfever, allergic asthma or eczema).(1) The first port of call for the majority of patients is their general practitioner, although facilities for diagnosing and managing allergy in primary care are limited.
Allergy diagnosis, according to guidelines from the British Society for Allergy and Clinical Immunology, should include identification of allergic triggers from the clinical history, together with some form of objective confirmation of allergic status.(2) 
This has resulted in the development of reliable, reproducible diagnostic tests which are able to confirm the presence or absence of specific allergic antibodies, such as allergy skin prick tests (SPT) and specific immunoglobulin E (sIgE) blood tests. However, these tests are often interpreted inappropriately.
To understand the importance of the relationship between the test results and the clinical history, it is necessary to understand the basic principles of allergic sensitisation and the cellular interaction that leads to the expression of symptoms.

Allergic mechanisms
A significant proportion of allergic disease is inherited, so that people with one or two allergic parents are predisposed to develop allergic sensitivities.(3) In patients who have this inherited predisposition, initial exposure to allergen (whether inhaled, swallowed or injected) results in allergen being taken up and processed by antigen-presenting cells, which then present the allergen to B-cells.(4) B-cells are then switched on to manufacture antibodies against that particular allergen.
These allergen-specific antibodies (called sIgE antibodies) then attach themselves to the surface of mast cells. Mast cells are ubiquitous in the peripheral circulation and tissues and contain granules. These granules contain histamine, a potent chemical which causes itching due to irritation of nerve endings, redness due to vasodilatation of blood vessels, and swelling due to increased vascular permeability. The mast cells, the surfaces of which are now covered in allergen-specific IgE antibodies, are now ready to release their contents and cause the next stage of the allergic process: symptoms.
The process, up to this point, is called allergic sensitisation, and the patient is described as being "atopic": that is, they have IgE antibodies to a particular allergen but may not necessarily have any symptoms on exposure to that allergen. Clinically, atopy is defined as one or more positive skin prick tests or sIgE blood tests to common aeroallergens. It is not yet understood why some patients who become sensitised to an allergen go on to develop symptoms on exposure and others do not. The important point to remember is that allergen sensitivity as measured by positive skin prick tests or sIgE blood tests does not mean that that allergen is causing the patient's symptoms.
In susceptible individuals, however, subsequent allergen exposure leads to a complex chain of events culminating in symptoms.(4) Allergic reactions such as the sneezing, itching and watery rhinorrhoea seen in summer hayfever; the immediate generalised rash (urticaria) and subsequent anaphylaxis observed in severe peanut allergy are classic examples of Type 1 hypersensitivity, first described by Gell and Coombs in 1963.(5)
The inhalation (via the nose or mouth), ingestion or injection of allergen results in a classic sequence of events: allergen quickly forms a bridge between two allergen-specific IgE antibody molecules and mast cells, which then degranulate (break open) and release their contents. Histamine, amongst other chemicals such as leukotrienes, prostaglandins, heparin and platelet-activating factor (PAF), is released into the local and general circulation, causing the characteristic symptoms of allergy in one or more organ systems.
The classic signs of allergy (itching, redness and swelling) and its classic time course (immediate symptoms, usually occurring within 15 minutes of exposure) mark the cornerstone of allergy diagnosis, and, at a simplistic level, allow the health professional to quickly differentiate between allergic and nonallergic symptoms.

Allergy diagnosis
For accurate allergy diagnosis, it is vital to differentiate between patients with measurable specific IgE (positive skin prick tests or specific IgE blood tests) without symptoms and those with measurable IgE with symptoms. Only in patients with specific IgE and symptoms should rigorous allergen avoidance be recommended, as avoidance is often costly and time-consuming. For example, avoiding common foods in the absence of any measurable link between symptoms and exposure is stressful and associated with considerable morbidity. Similarly, avoiding penicillin to prevent anaphylaxis in a child with repeated chest infections because of an isolated childhood rash and no evidence of an IgE-mediated cause is costly and may have severe cost implications during hospital admissions in later life.
Accurate history taking is of primary importance in establishing the role of allergy, and it is important to question patients closely. Particular questions to ask include:

  • Do the symptoms seem to fit the pattern of histamine release: that is, do symptoms include redness, itching or swelling?
  • What is the relationship between allergen exposure and symptoms? Typical IgE-mediated allergic symptoms occur within 15 minutes of allergen exposure.
  • Is there more than one organ system involved? Because mast cells are present at many different sites throughout the body, IgE-mediated allergy tends to occur in more than one organ system. Patients are also likely to present with symptoms in more than one organ system during their lifetimes.
  • Is there an obvious allergic trigger? In a situation where the history points to an obvious allergic trigger, a test for specific IgE may not be ­necessary.
  • Is there a past history of allergic disease? True (IgE-mediated) food or drug allergy is more likely in patients who have seasonal or perennial hayfever.
  • Other questions should include family history (allergy is more common in children of an atopic parent), environmental history (exposure to furry animals, house dust mites) and occupation/hobbies.

The information should be collected, ideally on a standardised record card (available from the National Respiratory Training Centre, Warwick), and considered, if necessary, with the results of an objective allergy ­diagnostic test (skin prick test or sIgE blood test).

Diagnostic tests
Skin prick tests and sIgE blood tests essentially both measure the presence or absence of IgE antibodies to a particular allergen. They are equally reliable when used to test for aeroallergens. There is controversy in the UK about the need for objective tests as the treatment for the commonly presenting problems (asthma and rhinitis) is rarely allergen-specific and usually consists of a combination of bronchodilator and inhaled anti-inflammatory drugs (asthma) and antihistamines and nasal anti-inflammatory drugs (rhinitis). However, patients often wish to develop some degree of nonpharmacological control of their symptoms and are keen to identify potential triggers and to institute avoidance measures where possible.
Positive skin prick tests and blood tests demonstrate sensitisation to a particular allergen, although the magnitude of the response does not necessarily correlate with disease severity. As a rough guide, however, skin test responses greater than 6mm in diameter and specific IgE levels of approximately 11kU/l (to seasonal and perennial allergens) are more likely to be associated with clinical symptoms on exposure to the relevant allergen.(6) There is a relatively good correlation between skin prick tests and blood tests, and so the choice of test is likely to be based on the nature of the symptoms, safety, availability of extracts, cost and operator expertise in the interpretation of results. Patients in whom there is a discrepancy between the clinical history and results of an objective test may benefit from referral to a clinical allergist.

Skin prick tests
Skin prick tests can be performed quickly and easily and have been shown to be well tolerated by patients and by nurses performing the tests.(7) The test involves placing of drops of several allergens on the inner aspect of the forearm and pricking through the droplet with a sterile lancet. Results can be measured 10-15 minutes later; a positive result is defined as a skin wheal 2mm bigger than the negative control. Skin prick tests are useful to diagnose atopy, which can be done by performing a panel of tests to common aeroallergens (eg, grass pollen, house dust mite, cat and dog). Confirmation of atopic status is vital when investigating any type of allergic symptoms, as an IgE-mediated cause is significantly more likely in patients who are atopic. It is therefore important to know the atopic status of any patient attending for investigation of potentially allergic symptoms. Skin prick testing solutions are available from several manufacturers. When considering which one to choose, take into consideration cost, shelf-life, standardisation of allergen content (biological standardisation) and availability.

Specific IgE blood tests
Measurement of allergen-specific IgE antibodies present in the serum is an alternative and comparably reliable way of diagnosing atopy when skin prick tests are not available. They are particularly useful for measuring IgE to venom, food or drug allergens prior to referral to an allergist. They are also useful in patients who are on regular antihistamine tablets which are known to ­interfere with skin prick test results.
They are performed by adding patients' serum to an allergen-soaked sponge in a test tube; any specific IgE present will bind to the allergen in the sponge; excess allergen is then washed off and fluorescent-labelled anti-IgE added. This attaches to the bound IgE, and it is then possible to measure the amount of a IgE in the sample by immunofluorescence.
Testing should be arranged via the local pathology laboratory and requests made on a locally available request form. Most laboratories have access to specific IgE testing. It is important to make sure that you have requested a specific allergen to be measured: for example, you should write on the request form "specific IgE to house dust mite, grass and cat". It is not helpful to request a total IgE as this is not a reliable indicator of atopic status. Requests should be accompanied by clinical information to allow the laboratory to offer appropriate advice on interpretation. Results are generally available within two weeks.

Choosing between tests
Advantages of skin prick tests include the immediate availability of results and the visibility of the result to patients. They are low in cost, although the cost of the tests has to be covered by the practice as it is not possible to claim reimbursement for materials or allergens.
One bottle of standardised aeroallergen skin prick testing solution (ALK-Abelló UK Ltd, February 2002) costs £29, and the positive and negative controls cost £6 each, making a total of £186 for an atopy screening kit containing grass pollen, house dust mite, cat, dog and the two controls. A box of 100 sterile lancets costs £10. Each bottle contains 3ml of allergen/control solution, and 3ml is roughly equivalent to 150 drops. Therefore each set of six solutions will be sufficient for 150 tests. This works out at £1.31 per set of six tests per patient (22p per allergen).
This is slightly higher if one considers the nurse time taken to do the test - 15 minutes of an average-earning practice nurse (£24,000 a year) costs approximately £3.07, bringing the total cost of six tests per patient to £4.38.
Specific IgE blood testing for a panel of common aeroallergens is relatively costly in comparison, although costs are reimbursable. Tests for individual allergens cost £10-15 per allergen, making a total of £40-60 per set of four tests required to screen for atopy. The sIgE blood tests become more cost-effective compared with skin prick tests when testing for allergens such as foods, venoms or drugs which are used less frequently and so substantially increase the skin prick testing cost per test. For many health professionals, sIgE blood tests are preferable due to the concerns about the safety of skin prick tests. Despite the large body of evidence that skin prick tests to aeroallergens are safe for use in general practice,8 there continues to be distrust of the procedure. In these cases, sIgE blood tests may be a more acceptable test for use in primary care.

Conclusion
Approximately 25% of the population have allergic disease, the symptoms of which range from mild seasonal hayfever to severe life-threatening anaphylaxis. Many more patients suffer with atypical, nonspecific symptoms which are not attributable to an immunological mechanism.
The ability to distinguish between true IgE-mediated allergy, with its potentially serious and sometimes life-threatening implications, and intolerance, which, though less serious, is associated with a high level of morbidity, is a great challenge facing those working in primary care today. Diagnostic tests to confirm the presence or absence of specific IgE are available in primary care and should be used and interpreted appropriately.
Basic training in the diagnosis and management of allergic disease is recommended to ensure that patients receive the highest standards of care and to prevent the movement towards costly and sometimes dubious alternative allergy practice.

Reference

  1. Sibbald B, Rink E, D'Souza M. Is the prevalence of atopy increasing? Br J Gen Pract 1990:40;338-40.
  2. Rusznak C, Davies RJ. Diagnosing allergy. In: Durham SR, editor. ABC of Allergies. London: BMJ Books; 1998.p. 8-11.
  3. Cookson WO, Hopkin JM. Dominant inheritance of atopic immunoglobulin responsiveness.Lancet 1988;1:86-8.
  4. Sompayrac L. How the Immune System Works. Oxford: Blackwell Science; 1999.
  5. Coombs RRA, Gell PGH. The ­classification of allergic reactions underlying disease. In: Gell PGH, Coombs RRA, editors. Clinical Aspects of Immunology. Oxford: Blackwell Scientific Productions; 1963. p. 317-37.
  6. Pastorello EA, et al. Studies on the relationship between the level of specific IgE antibodies and the clinical expression of allergy: I. Definition of levels distinguishing patients with symptomatic from patients with asymptomatic allergy to common aeroallergens. J Allergy Clin Immunol 1995;96:580-7.
  7. Sibbald B, Barnes G, Durham SR. Skin prick testing in general practice: a pilot study. J Adv Nurs 1997;26:537-42.
  8. Reid MJ, et al. Survey of fatalities from skin testing and immunotherapy. J Allergy Clin Immunol 1993;92:6-15.

Resources
National Respiratory Training Centre
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nrtc.org.uk
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The Anaphylaxis Campaign
T:01252 542029
W:www.
anaphylaxis.org.uk
British Allergy Foundation
T:020 8303 8583
F:020 8303 8792
E:info@allergy
foundation.com
W:www.allergy
foundation.com
British Society for Allergy and Clinical Immunology
T:020 8398 9240
F:020 8398 2766

Events
British Society for Allergy and Clinical Immunology Meeting
July 2003
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