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Seeking IgE—Know the allergen, improve the careRICHARD G. ROBERTS, MD, JD Professor, Department of Family Medicine, University of Wisconsin Medical School, Madison, Wis.More accurate and sensitive blood tests for specific IgE allow primary care clinicians to approach the precision of allergists in diagnosing allergy. With improved test results, atopy can be addressed in the primary care setting.Primary care clinicians are likely to encounter at least one patient affected by allergies every day.1 Yet sneezing, rhinorrhea, and ocular and nasal congestion, the hallmark symptoms of allergic rhinitis, also characterize numerous other upper respiratory tract diseases that have no atopic component. Being able to differentiate allergic from nonallergic conditions and make a definitive diagnosis from the patient's history and physical examination alone is not always the most consistent nor the most accurate approach.2 The strictest standard for diagnosis of upper respiratory tract disease due to allergy requires several components, including a supporting history, confirmation of the presence of specific IgE, allergen exposure of the concentration and duration known to cause sensitization, and clinical disease that either appears or worsens with allergen exposure.3
IMAGES: TOP: DR. P. MARAZZI/PHOTO RESEARCHERS INC.; BOTTOM: © SIU BIOMED/CMSP Establishing IgE sensitizationMost allergy-like nasal symptoms are treated empirically without objective confirmation of IgE sensitization, based on the patient's symptoms, history, and physical examination. Empiric treatment persists, in part, because testing for IgE sensitization has not always been practical in the primary care setting. Before the introduction of radioallergosorbent (RAST) tests in the 1970s, in vivo skin testing was the only method to confirm IgE-mediated allergy, and usually required referral to an allergist. The first-generation RAST technology brought testing into the primary care practice, but a high number of false-negative results limited its clinical application. With the advent of today's third-generation in vitro blood tests for specific IgE, primary care clinicians can approximate allergists in diagnostic precision.4 Both skin testing and specific IgE blood testing can be used to identify an atopic individual, determine the offending allergens, and monitor the risk for the evolution of allergic disease in the patient. Allergists who have performed skin testing for decades find the procedure safe, sensitive and economical. Skin testing accuracy is determined by both the quality of the allergen extracts and the testing technique. Results depend on complex interactions between IgE antibodies, activated immune system cells, the responsiveness of the skin, and irritation to the skin.5 Several commercially available multitest epicutaneous systems introduce allergens into the skin through pinpricks. Skin testing cannot be used• In patients with generalized skin disorders (atopic dermatitis, dermatographism, or urticaria) • In patients who cannot discontinue antihistamines or tricyclic antidepressants • When there is a risk of anaphylaxis. Intradermal skin testing is another form of in vivo testing. Intradermal testing results in a greater number of false-positive results than blood testing. Thus, results should correlate with a positive history of symptoms before treatment begins.6 Current allergen-specific blood testing is an easy alternative to skin testing that provides at least equivalent efficacy and can be performed in the primary care office.7 Blood testing also eliminates the risk of anaphylaxis. In ImmunoCAP IgE testing, serum collected from a patient is incubated with various allergens bound to a solid support. If IgE for a specific allergen is present, it forms a complex with the support-bound allergen. IgE that is not specific for that allergen is washed away. The complex, consisting of the attached allergen and antibody, is detected by binding to labeled antibodies specific for human IgE. Acceptable blood testing is calibrated to World Health Organization reference preparations to give reproducible results over time, with numerous allergens and in different laboratories. A review of the scientific literature found that results from blood and skin testing were highly correlated.8 The authors concluded, however, that without an independent standard for detecting inhalant allergens, results from the 2 types of tests could not be directly compared. They also found that blood testing offered more standardization than skin testing at a comparable per-patient cost. On a per-allergen basis, blood testing cost more than skin testing, but skin testing typically used many more allergen extracts. Another study compared in vivo skin tests (skin prick and intradermal) with specific IgE testing, evaluating their relative sensitivity, specificity, positive and negative predictive value, and efficiency (a measure that combines sensitivity and specificity) in the diagnosis of cat allergy.9 The blood and skin-prick tests were found to be comparable, exhibiting high levels on all measures (see Table 1). According to these investigators, intradermal testing added little to the diagnostic evaluation.
The typical childhood panel includes 11 specific IgE tests for food and inhalant allergens. The typical panel for adults combines common indoor allergens, such as Dermatophagoides farinae and cat and dog dander, with outdoor allergens characteristic for the geographic region. Each panel is performed on a 1.5 mL sample of blood serum. A positive test result indicates the presence of antigen-specific concentrations of antibodies in the blood, and means that there is a high likelihood that symptoms are caused by sensitization to the tested allergens. After specific allergens have been identified, the patient can be counseled regarding avoidance, and appropriate medication can be prescribed. A negative result means symptoms are probably not caused by the tested allergens, and the search for other causes should continue. A recent study analyzed the accuracy and precision of specific IgE tests on 26 masked serum samples that were sent to 6 laboratories which used 5 testing procedures for 17 aeroallergens.10 Analysis of 12,708 test results showed extensive variability among laboratories, testing technologies, and allergens. The third-generation ImmunoCAP technology used in 2 different laboratories performed closest to the ideal standard, and proved consistently superior to other assays. The study found that only ImmunoCAP technology was capable of measuring specific IgE antibodies over a large range with precision and accuracy, and supported its use as the current standard for quantitative measurements of specific IgE antibodies.11 Recent technological developments have yielded new IgE protocols that focus on automation to improve the quality of allergen-specific IgE assays. One automated enzyme immunoassay system, the HYTEC, was shown to yield results that parallel ImmunoCAP testing in its sensitivity for detecting allergen-specific IgE for 4 different allergens in 54 test subjects.12 Automation has the added benefit of allowing multiple assays to be performed simultaneously with less technician involvement. Skin-prick testing is compared with specific IgE blood testing in Table 2. Results from these tests, interpreted in the light of history and physical examination, serve as the basis for formulating a treatment plan.
Interpreting test resultsQuantitative results for specific IgE testing are measured in kilo-units per liter (kUA/L), but most laboratories report results using a simplified class scoring system (see Table 3). Reactions can range from class 0 (no reaction) to class VI, representing very high specific IgE levels. More than 90% of atopic patients react to fewer than 10 allergens, so testing for more allergens is rarely required.13 An example of test results from a typical specific IgE adult panel includes D farinae, animal danders, and a selection of outdoor allergens found in the geographic region where the patient lives (see Table 4). The patient in this example had a positive class III response to 2 types of grass.
Inaccurate diagnosis can lead to ineffective, unnecessary, or costly treatment. In 1998, 28.9 million office visits were coded for upper respiratory tract diseases: 8.8 million for allergic rhinitis, 4.7 million for rhinitis, and 15.4 million for sinusitis. During the same year, 33 million new prescriptions were written for nonsedating antihistamines, although the primary indication for these medications is allergic rhinitis.14 The results of specific IgE testing according to clinical relevance and suggested management options are also found in Table 3. For patients sensitized to indoor allergens, environmental controls should be instituted, because reduction of any part of the cumulative allergen load can help alleviate symptoms. Sensitivity to outdoor allergens, which are often not easily avoided, warrants a trial of pharmacotherapy. Intranasal corticosteroids are considered first-line therapy in patients with rhinitis due to atopy. Decongestants and OTC or prescription antihistamines are also appropriate choices. Nonsedating antihistamines effectively reduce itching, sneezing and rhinorrhea, but not nasal congestion. Prophylaxis with cromolyn can be helpful in patients with seasonal allergies.15 The many patients who present with allergy-like symptoms but whose test results are negative for atopy pose a different challenge. Their nasal symptoms may be due to the following: infections (colds, sinusitis); nonallergic rhinitis (vasomotor rhinitis, nonallergic rhinitis and eosinophilia; tumors; CSF rhinorrhea; rhinitis medicamentosa; anatomical abnormalities; atrophic rhinitis or rhinitis secondary to pregnancy; hypothyroidism; Horner's syndrome; Wegener's granulomatosis.16 The search for the cause of nasal symptoms should continue, so that patients can be accurately diagnosed and appropriately treated. Patients with nonallergic rhinitis can be managed with medication (such as decongestants, intranasal corticosteroids, and antibiotics) or surgery, depending on the nonallergic diagnosis. Intranasal corticosteroids are preferred for the management of inflammation associated with nonallergic nasal symptoms.17 Antihistamines are not thought to be helpful in nonatopic patients. Specific IgE testing can also play a role in helping to diagnose and manage patients with asthma. As many as 95% of children and young adults, and more than 50% of older adults with asthma, may have sensitivities that contribute to their condition.18 Specific IgE testing can help detect contributing allergens, such as house dust mite, mold, cat dander, cockroach, common ragweed, and grass. This knowledge, in turn, helps patients practice effective avoidance. Guidelines for asthma management published by the National Asthma Education and Prevention Program recommend that all patients with persistent asthma be tested for sensitization to indoor allergens.7 Specific IgE concentrations can also be used to predict the course of atopic disease. In small children, the correlation of specific IgE antibody levels and allergic symptoms is high. The formation of IgE antibodies starts early in life. It can be measured by 3 months of age, even before clinical symptoms appear. Sensitivity occurs first to food allergens, predominantly egg white and cow's milk.19 Evidence from several studies suggests that early avoidance of food and inhalant allergens, combined with aggressive treatment, can halt the progression of allergic disease.20, 21 In the Early Treatment of the Atopic Child (ETAC) trial, a total of 817 infants aged 1 to 2 years with a parent or sibling who had a history of atopic dermatitis were randomly assigned to receive the antihistamine cetirizine 0.25 mg/kg bid or placebo.21 The infants were treated for 18 months, and the number whose atopic disease progressed to asthma was monitored. The relative risk for asthma was greater (1.4-1.7) in placebo-treated patients with specific IgE of 0.35 kUA/L or more for grass pollen, house dust mite, or cat dander than in cetirizine-treated patients. Cetirizine significantly reduced the incidence of asthma in patients sensitized to grass pollen or the house dust mite. The rising prevalence of asthma, coupled with the related "march" of IgE-mediated disease in children from ingested, to indoor, to outdoor inhalant allergens, have resulted in the recent launch of a major campaign in Europe to identify and intervene in childhood allergic disease.22 While it is tempting to speculate that such interventions will reduce the burden of suffering from asthma and allergic disease, much remains to be learned.23 The need to better understand and define the nature and extent of allergic disease serves as the most powerful reminder of the importance of improved allergy diagnosis.
PRODUCED BY KRISTEN GEORGIDr Roberts discloses that he is a consultant for Pharmacia Diagnostics.
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