On-line version ISSN 2078-5135
SAMJ, S. Afr. med. j. vol.99 n.7 Cape Town Jul. 2009
Diagnostic testing in allergy
C Motala; D Hawarden
Allergy Society of South Africa
Atopy. Atopy is a personal and/or familial tendency, usually in childhood or adolescence, to become sensitised and produce IgE antibodies in response to ordinary exposure to allergens, usually proteins. As a consequence, such individuals can develop the typical symptoms of asthma, rhinoconjunctivitis or eczema.1
Allergy. Allergy is a hypersensitivity reaction initiated by immunological mechanisms. Allergy can be antibody- or cell-mediated. In the majority of cases the antibody typically responsible for an allergic reaction belongs to the IgE isotype, and these individuals may be referred to as suffering from an IgE-mediated allergy.1
Atopic individuals must have clinical symptoms. Some 30 - 40% of individuals in developed countries are allergic, but only a proportion of these have atopic diseases, which include asthma (5 - 10%), rhinitis (10 - 20%) and food allergy (1 - 3%). In population studies allergic diseases peak at different ages. Food allergy and atopic eczema are predominant in early childhood, whereas asthma shows a biphasic peak and rhinitis peaks in the second or third decade.
Atopic diseases manifest as hyper-responsiveness in the target organ, whether skin, nose, lung or gastrointestinal tract. This hyper-responsiveness (allergy) may have both IgE-mediated and non-IgE-mediated components. The situation is further complicated because allergen exposure in allergic subjects may increase target organ hyper-responsiveness, which results in exaggerated symptoms on exposure to nonspecific irritants (tobacco smoke, changes in temperature, etc.) in allergic subjects. Only a proportion of atopic subjects develop disease, and atopic individuals may have casual factors in their disease independent of their atopic status. Furthermore, increased nonspecific responsiveness lowers the threshold for symptoms on subsequent allergen exposure.
2. Diagnostic approach
Allergy diagnosis depends primarily on the clinical history. The history, aided by a physical examination, guides objective tests of IgE sensitivity. Either skin tests or allergen-specific serum IgE measurements (RAST) are used to focus on the following questions:
Is the patient allergic?
Does allergy contribute to the patient's symptoms?
What are the clinically relevant allergens?
There should be a high index of suspicion of allergy in patients presenting with symptoms of asthma, rhinitis or eczema, particularly if there is an associated personal or family history of other atopic disease. On the basis of a positive initial history, a limited number of skin-prick tests (SPTs) and possibly specific IgE measurements (radio-allergosorbent tests RASTs) to commonly prevailing aero-allergens (Table I) or foods should be performed to confirm or exclude atopy. Few foods commonly provoke allergic reactions; they include cow's milk, egg and peanut in infants and young children, and fish, shellfish, peanuts, tree nuts, fruit and spices in older children and adults. Physical examination may determine which organ or organs is or are involved. When both the clinical history and results of SPTs (or specific IgE) are negative, one can exclude allergy with a high degree of confidence and no specific treatment for allergy is indicated. A positive history and positive tests help in rationalising treatment, initiating specific allergen avoidance measures and selecting appropriate immunotherapy.
2.1 Skin-prick testing
SPTs with allergen extracts are the favoured method of in vivo testing for IgE-mediated sensitivity. Testing for a limited number of common allergens (Table I) may confirm or exclude atopy. The quality of extracts is important for reliable results. Standardised extracts are currently available for most common inhalant allergens and for some food allergens. Many patients with documented food allergy fail to react to commercial extracts but react to fresh extracts of the food,2,3 e.g. fruits,3 celery,4 shellfish and fish.5,6 Interpretation of SPTs may also be difficult in children younger than 2 years because of reduced reactivity to histamine in this age group.7 Results of SPTs must always be expressed in a quantitative manner that can be interpreted by other practitioners. SPTs must be performed in a setting where personnel and equipment are available for resuscitation (because of a very low but definite risk of anaphylaxis8).
2.2 Blood tests (in vitro)
Total IgE was initially used as a diagnostic marker of allergic disease, but it has limitations: IgE is elevated in allergic diseases and in non-allergic conditions, e.g. parasitic infestation, and half of IgE-mediated allergic patients have a total IgE within the normal range.9 The predictive value of this test is therefore rather limited in allergy diagnosis.
Specific IgE (RAST) measures allergen-specific IgE to allergens in patient serum. In the case of inhalant allergens a level of >0.35 kU/l is considered positive (sensitivity 60 - 80%, specificity 90%); for food allergy, the cut-off values for positive (indicating clinical reactivity) appear to be much higher (Fig. 1).10 The respective advantages of SPTs and specific IgE are shown in Table II.
2.3 Multi-allergen IgE antibody screening assays
These are useful when a patient provides an equivocal history for allergic disease (making it difficult to pinpoint with reasonable certainty the appropriate allergens to test for). The multi-allergen screen for aero-allergens is the Phadiatop12 (Phadia, Uppsala) and for foods the Fx5 (Phadia, Uppsala). Phadiatop is usually reported as positive or negative. A positive test indicates that the patient may be sensitive to one or more of the following inhalants: house-dust mites, grass, mould, cat, dog. The laboratory should then contact the doctor to discuss testing for the relevant allergen(s). The Fx5E is a quantitative test; a level of >0.35 kU/l is considered positive and indicates that the patient may be sensitive to one or more of the following foods: cow's milk, egg white, fish, wheat, peanut, soya. The laboratory should contact the referring doctor to discuss further testing. A negative multi-allergen screen reduces the probability that IgE-mediated allergic disease is the cause of the patient's clinical problems.
2.4 Mast cell tryptase
The serum level of β-tryptase can be useful as a marker of mast cell activation in the definitive diagnosis of anaphylaxis.13 Tryptase levels peak at 45 - 60 minutes and may remain elevated for several hours (up to 24 hours).14 Ideally, three serial measurements should be performed: the first soon after the reaction, the second a few hours later, and a baseline level 24 hours later.
2.5 CAST testing
Some patients may develop symptoms due to sensitivity to various food additives (colourants, flavourants or preservatives) or medications, which are not IgE mediated. These chemical sensitivities may be confirmed by CAST testing (cellular antigen stimulation test) and should be discussed with a specialist.
2.6 Unproven diagnostic tests
There are many allergy 'diagnostic' tests performed by ecologists and alternative practitioners. These tests are of unproven value, are often time-consuming and expensive, and are not to be recommended (Table III).15-17
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