Practical aspects of allergy-testing

PAEDIATRIC RESPIRATORY REVIEWS (2003) 4, 312–318 doi: 10.1016/S1526–0542(03)00094-0

SERIES: ALLERGY

Practical aspects of allergy-testing Arne Høst1* and Susanne Halken2 1

Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark; 2Department of Pediatrics, Sønderborg Hospital, DK-6400 Sønderborg, Denmark KEYWORDS allergy; childhood; allergy-testing; specific IgE; skin prick test

Summary Allergy-testing is a prerequisite for specific allergy treatment, including specific allergen avoidance measures, relevant pharmacotherapy and specific allergy vaccination. All children with persisting, recurrent or severe possible ‘‘allergic symptoms’’ or those with a need for continuous treatment should be tested, irrespective of the child’s age. Allergy-testing includes a careful case history and a determination of IgE sensitisation by skin prick test or the measurement of allergen-specific IgE in serum by standardised and validated methods. The diagnosis of food allergy cannot usually be based solely on the case history and IgE sensitisation; the diagnosis has to be confirmed by controlled food elimination and food challenge procedures. The diagnosis of inhalant allergic disease requires only confirmatory nasal, conjunctival or bronchial challenges in equivocal cases or before specific allergy treatment such as extensive allergen avoidance measures or allergy vaccination. ß 2003 Elsevier Ltd. All rights reserved.

INTRODUCTION Over the past 20–30 years, the prevalence of allergic diseases in childhood (atopic dermatitis, asthma and allergic rhinoconjunctivitis) has increased considerably.1–3 Although several studies have demonstrated this increase, it has been argued that greater awareness and an improved ability to diagnose atopic diseases might account, at least in part, for this increase.4 Population-based studies using identical methods of ascertainment at intervals of 10–15 years have, however, also shown a significant increase in the prevalence of allergic diseases in children.3–5 In populationbased studies, a cumulative prevalence of allergic diseases in childhood of 25–30% has been reported, the prevalence of atopic dermatitis and allergic rhinoconjunctivitis being 15– 20%.1–7 Allergic diseases are thus one of the major causes of morbidity and the need for allergy-testing has, accordingly, increased.

THE ALLERGIC MARCH In infancy, the main diseases of a possible allergic nature are atopic dermatitis, gastrointestinal symptoms and recurrent *

Correspondence to: A. Høst. Fax: þ45 65 91 1862; E-mail: [email protected] 1526–0542/$ – see front matter

wheezing. The main problems later in childhood are bronchial asthma and allergic rhinoconjunctivitis.8,9 Adverse reactions to foods, mainly cow’s milk protein and hen’s eggs are most common in the first years of life, whereas allergy to inhalant allergens occurs later.9 Specific IgE antibodies against milk and eggs are most frequent during the first 2–3 years of life, whereas specific IgE against the inhalant allergens predominates later in childhood.9 IgE antibodies to hen’s eggs and cow’s milk in infants also predict sensitisation to inhalant allergens and allergy before the age of 7–10 years.10–14 Low levels of specific IgE to food and/or inhalant allergens are a normal phenomenon, especially in early childhood, and may have no clinical significance.10,14 Atopic dermatitis early in life may also be a predictor of asthma later in childhood. The phenomenon in which some allergic symptoms, or test positivity, predict other allergic diseases later in life is called the ‘‘allergic march’’.9

NOMENCLATURE In a revised nomenclature for allergic and related reactions,15 allergy is defined as a hypersensitivity reaction initiated by immunological mechanisms, whereas the term ‘‘non-allergic hypersensitivity’’ has been proposed when immunological mechanisms cannot be proven. In most ß 2003 Elsevier Ltd. All rights reserved.

PRACTICAL ASPECTS OF ALLERGY-TESTING

patients, the antibody typically responsible for an allergic reaction belongs to the IgE isotype and such patients may be said to suffer from IgE-mediated allergy. In non-IgEmediated allergy, different mechanisms (e.g. IgG, immune complexes or cell-mediated processes) may be responsible. In IgE-mediated allergic disease, exposure to a provoking allergen produces a biphasic response: an early response within 20 min characterised by a classic IgEmediated immediate type hypersensitivity and followed by a late response after 3–6 h. This late-phase response is characterised by the involvement of eosinophil inflammation and may be associated with prolonged hyperreactivity and, in the case of daily exposure to the allergen, persistent inflammation causing structural and functional changes.16,17 One or more immune mechanisms may act simultaneously in an allergic individual. A form of delayed hypersensitivity may therefore occur in individuals with atopic dermatitis and ‘‘atopy’’ patch tests have been used for the identification of cell-mediated reactions to foods.18,19

SPECIFIC ALLERGY TREATMENT Allergy-testing A correct diagnosis is the prerequisite for understanding the disease and commencing appropriate treatment – and since early treatment may have an influence on the severity of the condition, allergy-testing is one of the cornerstones of the management of allergic diseases. Allergy-testing is an important prerequisite for specific allergy treatment related to:  specific allergen avoidance measures;  appropriate pharmacotherapy;  specific allergy vaccination.

Allergen avoidance Allergen avoidance is a logical way to treat allergic diseases, for example allergic asthma, when the offending allergen can be identified and effective avoidance is feasible. Recent randomised-controlled studies have shown that measures to avoid house dust mite allergen are effective in reducing the level of allergens and may improve the control of disease, for example by reducing the need of pharmacotherapy.20,21 As pet allergens are ubiquitous,22 it may be impossible to avoid them. In pet-allergic patients, the first step should, however, be removal of the pet from the home.23,24

Appropriate pharmacotherapy Many non-allergic disorders may be misinterpreted as allergic and wrongly treated if correct allergy-testing is not performed, for example in patients with rhinoconjunctivitis or skin reactions. A specific allergy diagnosis is

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therefore also a prerequisite for instituting the appropriate treatment.24

Specific allergy vaccination In patients with allergic rhinoconjunctivitis, specific immunotherapy has been shown to be effective.24 Allergy vaccination with subcutaneous injections has been shown to be effective in allergic asthma in randomised-controlled trials using extracts of house dust mite, pollen and animal (cat) dander.25 A significant reduction in asthma symptoms and medication and a reduction in both non-specific and allergen-specific airway hyperresponsiveness have been documented.25 Allergy vaccination with extracts of birch and/or grass pollen in children with pure seasonal allergic rhinitis resulted in a significantly lower incidence of asthma than occurred in an untreated parallel control group.26 In some studies, sublingual–swallow immunotherapy has been reported to be effective in patients with allergic rhinitis caused by birch, grass or parietaria pollen or house dust mites.24 Further studies are, however, required to evaluate the effect of sublingual–swallow immunotherapy compared with traditional subcutaneous immunotherapy.

Early identification of infants at increased risk of developing allergic disease The early identification of children with atopic dermatitis and/or food allergy may provide an opportunity to prevent the development of the allergic march and diseases such as rhinoconjunctivitis and asthma. Pharmacological intervention with H1 antihistamines may reduce the onset of wheezing in those presenting with atopic dermatitis.27,28

INDICATIONS FOR ALLERGY TESTING Children with severe, persisting or recurrent ‘‘allergic symptoms’’ or anyone needing continuous prophylactic treatment should generally be tested for specific allergy, irrespective of how young they are. There is a widespread misunderstanding that infants and very young children cannot be tested but there is in fact no lower age limit. The limitation is more related to whether the test can provide the information that is required. The extent of the allergy tests will depend on the age of the child, the family history and the symptomatology, including possible seasonal or diurnal variations. Table 1 lists indications for allergytesting in children.8,23,24,29–41 Table 2 describes indications for allergy-testing in children with suspected specific allergies such as insect sting reactions, suspected penicillin/drug allergy and suspected latex allergy.40–43 A classification of the severity of insect sting reactions is given in Table 3.40 In Table 4, proposals for allergy-testing and relevant allergens at different ages are described.

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Table 1

A. HØST AND S. HALKEN

Indications for allergy-testing in children

Patient category

Symptom characteristics

Children with gastrointestinal symptoms: vomiting, diarrhoea, colic, failure to thrive

Persistent, severe symptoms without any other known reason, particularly in cases with other coexistent atopic symptoms

Children with atopic dermatitis

Persistent, severe symptoms or allergen-related symptoms, particularly in cases with other coexistent atopic symptoms

Children with urticaria/angioedema

Severe cases and/or at suspicion of specific allergy Chronic urticaria 6 weeks

Children <3–4 years old with recurrent wheezing/asthma

Persistent, severe symptoms and need for daily treatment Children with long-lasting cough/wheeze/dyspnoea, especially during play/physical activity and during the night, and children with a reduced level of activity or frequent pneumonia without any other known reason should be investigated for asthma

Children >3–4 years with asthma

Should always be tested for allergy to relevant allergens Should be investigated for rhinitis

Children with rhinoconjunctivitis

Treatment-resistant cases Should be tested for coexisting asthma

Children with anaphylaxis

Should always be evaluated for allergy by a specialist Testing performed under special observation

Suspected intolerance exclusively against known food additives is generally not an indication for allergy-testing.41 After pre-school age, a dermatologist should evaluate children with only skin symptoms.

Table 2

Indications for allergy-testing in children: special allergies

Patient category

Symptom characteristics

Children with insect sting reactions

Only severe, systemic reactions grade III–IV Local reactions/urticaria alone are not on indication

Children with suspected penicillin/drug allergy

Only with symptoms suspicious of a type I reaction: itching skin reactions, urticaria, angioedema, asthma or anaphylaxis

Children with suspected latex allergy

Symptoms of IgE-mediated allergy, primarily in children who belong to the risk groups for latex allergy (spina bifida, urogenital malformations, atopic symptoms and other patients with early exposure to latex)

Early childhood In infancy, food allergy with manifestations in the skin or in the gastrointestinal or respiratory tract is more common than inhalant allergy. The majority of children with food allergy simultaneously show symptoms from two or more organ systems, but some, for example those with atopic

Table 3

dermatitis, may show only one severe persisting symptom. Cow’s milk allergy is the most common food allergy in young children, followed by allergy to hen’s eggs, cereals and nuts. A few children, especially those with severe or recurrent wheezing or asthma, are already sensitised to indoor inhalant allergens during the first years of life.

Insect sting reactions: severity

Normal

Pain, small local swelling

Large local reaction Systemic grade I Systemic grade II Systemic grade III Systemic grade IV

Swelling >10 cm diameter after >24 h Indisposition, anxiety, generalised skin itching or urticaria Angioedema, vertigo, nausea, vomiting, diarrhoea, abdominal pain Dyspnoea, dysphagia, dysarthria, hoarseness, confusion, asthma Hypotension, incontinence, cyanosis, collapse, unconsciousness

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Table 4

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Allergy-testing according to age and symptoms

Disease/symptoms

Relevant allergens in relation to age

Atopic dermatitis

<3–4 years

>3–4 years

Foods:  cow’s milk  egg white  (peanuts, wheat, nuts, fish, etc.)

Foods:  cow’s milk  egg white  peanuts  (wheat, nuts, fish, etc.)

Possibly: Inhalant allergens:  house dust mites  cats, dogs and other furred animals

Inhalant allergens:  house dust mites  cats, dogs and other furred animals

   

house dust mites cats, dogs and other furred animals pollen others: relevant food allergens, e.g. cow’s milk and egg, especially in young children The allergens included in the test panel should be adjusted according to allergen-related symptomatology and allergen exposure, indoor as well as outdoor. Persistent and intermittent conjunctivitis, rhinitis and/or recurrent wheezing/asthma

Teenagers with atopic dermatitis (neck and face) should also be tested for pityrosporum ovale.

School age With increasing age, allergy to inhalant allergens develops, especially to indoor allergens (house dust mites, pets and cockroaches) and later to outdoor allergens (pollens and moulds). A high frequency of sensitisation is seen in both asthmatics and individuals with rhinitis and conjunctivitis. More than 70% of asthmatics also suffer from rhinitis and a high proportion of individuals with rhinitis (20–50%) also suffer from asthma, frequently undetected. In typical rhinitis and conjunctivitis in the spring and summer periods, symptomatic treatment can be instituted without allergy-testing, whereas allergy-testing should be performed with associated pollen asthma and/or treatment-resistant symptoms in order to prove or disprove the cause of the disease and institute adequate treatment. In asthmatics, allergy-testing should be performed where early intervention (the elimination of relevant allergens or treatment) may improve disease control and prevent disease progression.

seen to banana, avocado, kiwi, chestnut, papaya, figs, potato and tomato.

Cross-reactivities In general, cross-reactivities occur when two or more allergens share epitopes and thus bind to the same IgE antibodies. Patients sensitised to one allergen may therefore also react to the other without previous exposure and sensitisation. The most often reported cross-reactivities41 are shown in Table 5. Symptoms caused by pollen-related cross-reactivity to foods include swelling and itching of the mouth and oropharynx and such symptoms often lead to a Table 5

Cross-reactions

Symptom-related allergens

Frequently cross-reactive allergens

Birch

Apple, hazelnut, carrot, potato, celery, cherry, pear, others Celery, carrot, fennel, parsley, coriander, mustard Potato, tomato, wheat, peanut Goat’s milk, sheep’s milk, beef Tree nuts, soy beans, green beans, green peas, lentils Peanut, soy Banana, avocado, kiwi, chestnut, papaya, figs, potato, tomato, Ficus benjamina

Mugwort (artemissia)

Specific allergies Regarding specific allergies (see Table 2 above), children should only be tested against insect venoms if they have shown grade III–IV systemic reactions (see Table 3 above), for which specific immunotherapy/allergy vaccination may be indicated. Regarding allergy to drugs, maculopapulous exanthemata are not an indication for testing. The latter should only be performed following immediate-type (type I) reactions. In latex-allergic individuals, cross-reactions may be

Grass Cow’s milk Peanut Lentil Latex

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cessation of food intake (oral allergy syndrome). The diagnosis of oral allergy syndrome can be based on a typical case history in pollen-allergic individuals. In unclear cases, the demonstration of sensitisation by skin prick or specific IgE antibody-testing to the relevant allergen(s) may be helpful. Patients may rarely react to more than one member of a botanical family or animal species.41 ‘‘Serological crossreactivity’’ and/or cross-reactivity in the skin are not necessarily associated with clinical disease, which has to be confirmed by challenge.

PRACTICAL ALLERGY-TESTING Although a positive skin prick test and/or a positive specific IgE reading in the serum indicate that a person possesses antigen-specific IgE antibodies, these findings do not prove that exposure to the allergen in question causes clinical symptoms. Only a controlled allergen challenge can confirm the cause-and-effect relationship between allergen exposure and clinical symptoms. In routine allergy-testing, however, there is good agreement between clinical allergic disease and IgE sensitisation, as determined by a positive skin prick test (mean wheal diameter 3 mm larger than the negative control)44–46 and/or the presence in the serum of specific IgE class 2 (e.g. equivalent to 0.70 kU/l as measured by the Pharmacia CAP System)47–50 to the relevant environmental allergens. The reported frequency of IgE sensitisation may vary depending on age and type of allergic disease and may also reflect differences in the selection of patients and in study methodology.8,9 In preschool children, 40–60% of food-allergic children are sensitised to the offending food and 30–60% of recurrent wheezers are sensitised. In school-age children, 60–70% of food-allergic children are sensitised, as are 30–40% of individuals with atopic dermatitis and 60–90% of those with asthma and/or rhinitis or conjunctivitis. Allergy-testing may include the following elements:  Case history  Determination of IgE sensitisation – Skin prick test – Specific IgE in serum  Allergen challenges – Food allergy – Inhalant allergy  Other tests  Environmental investigations

Case history The case history should include age of onset, the frequency and severity of symptoms, atopic heredity, environmental factors such as housing conditions, school and leisure time environment, and exposure to pets, tobacco smoke and other possible irritants. The relationship to exposure to allergens and seasonal and diurnal variations should be registered.

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Determination of IgE sensitisation Skin prick test When performing a skin prick test, standardised extracts and methods should be used.44–46 When testing for food allergy, fresh food material and the prick-prick method can be useful. For practical performance, the guidelines for a skin prick test should be followed.44–46 A mean wheal diameter of 3 mm or more larger than the negative control defines a positive reaction. In infants and young children, the skin reactions may be smaller than in older children.51 The panel of allergens for skin prick testing will depend on the age of the child and the case history (see Table 4 above). Skin prick tests should not be performed if eczema is active at the test site or local treatment is being given with steroid or immunosuppressive creams. In addition, antihistamines should be avoided for at least 3 days before skin prick testing.

Specific IgE in serum Tests for specific IgE should be conducted using a validated method47–50 and can be performed at any age. Quantitative specific IgE results have a high reliability. Like the skin prick test, they must be used in association with the clinical case history. If there is any disagreement between the case history and the skin prick or specific IgE result, a supplementary investigation with specific IgE or a skin prick test should be conducted in order to document IgE-associated allergy.

Allergen challenges Food allergy The diagnosis of food allergy cannot in general be based solely on the results of the case history and specific IgE levels. The diagnosis is made using the controlled elimination of foods and food challenge procedures, except in children with severe systemic (anaphylactic) reactions confirmed by the results of the specific IgE sensitisation. The elimination period will usually last 1–4 weeks depending on the symptomatology and should abolish or at least markedly reduce symptoms. The challenge can be performed as an open controlled food challenge if objective reactions are expected. In children older than 2–3 years, a positive open food challenge may need a confirmatory double-blind, placebo-controlled food challenge in order to avoid false-positive reactions arising from psychological or other mechanisms or Mu¨ nchhausen by proxy syndrome. Negative double-blind, placebo-controlled challenges should be followed by open continued food challenge and then by a normal daily intake of the food in question. Food challenges should always be performed under controlled professional supervision. If there is a possibility

PRACTICAL ASPECTS OF ALLERGY-TESTING

of a systemic reaction, the challenge should be undertaken in hospital. Parental reports are not reliable. Because of the good prognosis of most food allergies in early childhood, rechallenges should be performed at intervals of 6 months to 1 year until 3 years of age and thereafter at intervals of 1–2 years until tolerance has developed.

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tested according to symptoms and age. For the majority of allergic individuals, one test on a single occasion may be enough. In individuals with established allergic disease, there are situations on which repeated testing must be considered necessary and can provide information regarding disease progression.

Inhalant allergy

PRACTICE POINTS

In inhalant allergic disease, there is no reason to perform allergen provocation in the target organ if there is full agreement between the case history and the results of testing for specific IgE sensitisation. In equivocal cases, a nasal, conjunctival or bronchial challenge may be necessary. Challenge procedures should be performed in specialist paediatric settings and may not be performed until the age of 5–6 years because of the need for co-operation and because of the inability of the child to perform lung function measurements with an acceptable reproducibility. Challenges should be performed according to standardised methods.52,53

 Indications for allergy-testing – Persisting, recurrent or severe ‘‘allergic symptoms’’ arising in the skin, gastrointestinal or respiratory tract. – Testing is required when there is a clinical need for continuous treatment. – There is no lower age limit. – Testing depends on the severity of the symptoms or disease.  Practical allergy-testing – The case history should include exposure to the relevant allergens. – A skin prick test or determination of specific IgE to relevant allergens is necessary. – A positive skin prick test with a mean wheal diameter of 3 mm or more larger than the negative control indicates a positive reaction. – A positive specific serum IgE class 2 indicates a positive reaction. – In equivocal cases with respiratory symptoms, confirmatory challenges should be performed. – In food allergy, controlled elimination or food challenge procedures are needed except in cases of anaphylactic reactions.

Other tests The histamine-release test measures histamine release from basophil granulocytes. The results of histaminerelease tests are similar to those of skin prick and specific IgE tests. The test is too complicated for daily clinical practice but may be helpful for infrequent allergies such as drug allergies or occupational allergies. Patch tests are used in delayed hypersensitivity and ‘‘atopy’’ patch tests have been used for the identification of cell-mediated reactions to foods in children with atopic dermatitis.18,19 Further confirmatory studies are awaited. There are also other test methods that are not validated and should not be used for allergy diagnosis.

REFERENCES Environmental investigations The determination of allergen content in house dust samples (house dust mites, cat, dog and others) may be useful to prove clinically important exposure to the allergens and to monitor avoidance measures.

What tests should be used? In daily clinical practice, skin prick testing or specific serum IgE measurement can be performed. Normally, few allergens are needed to get a good idea of the impact of true allergy underlying the child’s symptoms. This is because many allergens are biologically linked. For example, if the child reacts during the grass pollen season, it is usually enough to test with only one grass species. When using serum IgE tests, the appropriate allergens are available singly or in combination. Similarly, when performing the skin prick test, single allergens or a combination of allergens can be

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