Review and Feature Article
Diagnosing Peanut Allergy with Fewer Oral Food Challenges

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Diagnosis of peanut allergy presents a significant clinical challenge. Accurate diagnosis is critical for patient management and prevention of allergic reactions, whereas overdiagnosis or failure to diagnose tolerance in a previously allergic patient can lead to unnecessary dietary restrictions and impaired quality of life. Oral food challenges, the criterion standard for diagnosis, pose a risk of potentially severe allergic reactions, and are time- and resource- intensive. In this article, we review other currently available tests for peanut allergy and present the strengths and weaknesses of each to assist the clinician in determining which test might be appropriate for their patients, as well as highlighting emerging tests currently in development. Traditional tests for peanut-specific IgE (skin prick testing and specific IgE) remain useful as first-line tests—a negative test result is useful for excluding peanut allergy and a high positive result has a high specificity for peanut allergy. For those with an intermediate positive test result, Ara h 2 testing might be useful as a second step. Basophil activation tests and peanut protein epitope-specific IgE analyses appear promising in recent studies; however, further research is required into standardization, validation, and cost-effectiveness. Given the limitations of existing tests for peanut allergy, there remains a clear need for improvement. Finding a safe and affordable method for peanut allergy diagnosis that is both sensitive and specific remains an active area of research.

Introduction

Accurate diagnosis of peanut allergy, critical for patient management and prevention of allergic reactions, presents a significant clinical challenge. Oral food challenges (OFCs), particularly double-blind placebo-controlled OFCs, are the criterion standard for diagnosis of peanut as well as other food allergies. However, food challenges pose a risk of potentially severe allergic reactions, and are time- and resource- intensive.

Diagnosis of IgE-mediated peanut allergy may be straightforward in the context of a clear clinical history of reaction following known peanut exposure and evidence of peanut-specific IgE. However, for patients who present with an unclear history of peanut ingestion or reaction, or infants without a clear history of tolerating age-appropriate portions of peanut, but who are at high risk due to history of early severe eczema or egg allergy, an accurate diagnostic test is vital. Similarly, accurate diagnostic tests are needed to determine resolution of allergy (development of tolerance) in patients with a history of peanut allergy.

In this article, we review currently available tests for peanut allergy and present the strengths and weaknesses of each to assist the clinician in determining which test might be appropriate for their patients. We also highlight emerging tests currently in development.

Section snippets

Definitions

The ability of a diagnostic test to correctly classify individuals into 2 categories (allergic or not allergic) is assessed by 2 parameters, sensitivity and specificity.

Sensitivity is defined as the proportion of true positives (peanut-allergic individuals) correctly identified as peanut allergic by the diagnostic test. In other words, for a test with high sensitivity, very few truly allergic patients will have a false-negative test result.

Specificity is defined as the proportion of true

A note about study designs

Many of the early studies investigating the accuracy of diagnostic tests such as SPTs and measurement of peanut sIgE in serum used data from patients presenting to allergy clinics for peanut OFC. Several issues need to be considered when interpreting the results of these studies: OFCs are typically offered clinically to only those patients deemed by the allergist to be at low risk of reacting (eg, because of recent history of accidental exposure without reaction); patients seen in allergy

Skin prick testing

In Australia, most pediatric allergy clinics use SPTs in preference to sIgE testing because results are immediately available. SPT has consistently been shown to have high sensitivity; in other words, peanut allergy is highly unlikely in an individual with a negative SPT result (usually defined as a wheal size of <3 mm). In a systematic review and meta-analysis, Soares-Weiser et al3 calculated a pooled sensitivity of 94.7% (95% CI, 87.9-97.8) for an SPT with a wheal size of greater than or

Peanut sIgE (whole peanut)

Measurement of serum peanut sIgE levels is common as a first-line test for peanut sensitization in US pediatric allergy clinics. Like SPT, sIgE measurement has a high sensitivity but a relatively low specificity. In a systematic review and meta-analysis, Soares-Weiser et al3 calculated a pooled sensitivity of 96.3% (95% CI, 91.6-98.4) and a specificity of 59.3% (95% CI, 45.4-72.0) for peanut sIgE (mixed cutoffs) using data from 5 studies with a combined total of 817 participants and 452 cases

sIgE to peanut components

In the past 5 to 10 years, more studies have focused on measuring IgE to specific peanut components (component-resolved diagnosis) rather than to whole peanut in an attempt to improve on the high rate of false-positive results for SPT and sIgE levels. These test are now commercially available and in widespread clinical use.

Peanut components that have been tested in clinical studies include Ara h 1, 2, 3, 6, 8, and 9. A systematic review by Klemans et al10 of 22 studies, 21 in pediatric

Basophil activation test

Basophils, like mast cells, express a high-affinity IgE receptor. Cross-linking of IgE bound to FcεRI receptors on the cell surface results in rapid release of granule-stored inflammatory mediators (eg, histamine) and upregulation of cell surface receptors such as CD63 and CD203c. The basophil activation test (BAT) is an in vitro functional assay that assesses the expression of these activation markers on the surface of live basophils in whole fresh blood by flow cytometry following stimulation

Mast cell activation test

Mast cells have traditionally been considered the main effector cells in patients with allergic reactions (activated through IgE cross-linking of FcεRI on the cell surface, resulting in de nuovo synthesis and release of inflammatory mediators) and it therefore makes sense that a test to measure their activation might make a good in vitro diagnostic test. Recently, this novel test has been validated against existing tools.15, 19 In the mast cell activation test (MAT), the function of the

Histamine release assays

Another new in vitro assay, the histamine release (HR) assay, measures the amount of histamine released from activated basophils. In this version of the basophil diagnostic test, whole blood (collected < 24 hours from sampling) is incubated with peanut extract or anti-IgE, released histamine binds to a solid glass fiber phase, and unbound blood is removed with repeated washing. Trapped histamine is obtained from the solid phase by increasing pH and quantified flurometrically. A modified passive

Other emerging diagnostic tests

Given the limitations of existing tests for peanut allergy, there remains a clear need for improvement. Finding a safe and affordable method for peanut allergy diagnosis that is both sensitive and specific remains an active area of research. Two decades ago it was shown that IgE antibodies to sequential (linear) epitopes of food proteins correlated closely with reactivity to specific foods.21 Subsequently, IgE to allergenic (IgE-binding) epitopes were evaluated using short sequential peptides

Conclusions

Forty-eight years ago the double-blind placebo-controlled food challenge was shown to be the “criterion standard” for diagnosing food allergy. Over the past 4 decades diagnostic testing has progressed from the SPT to crude measurements of serum IgE to whole peanut protein (radioallergosorbent test) to quantitative measurement of IgE to whole peanut protein, component proteins comprising peanut, and most recently to allergenic epitopes of Ara h 1, 2, 3, and 6. With this evolution, the clinician

References (26)

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    The BAT measures markers of basophil activation, cluster of differentiation (CD) 63 and CD203c expression, by flow cytometry following allergen stimulation of a patient’s basophils in vitro. This testing might be useful in the future as an intermediate step before proceeding with an oral food challenge if the SPT and sIgE are equivocal.39,40 The mast cell activation test is another promising diagnostic tool currently used in research.

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K.P.P. is supported by a Melbourne Children's Clinician-Scientist Fellowship. Research at the Murdoch Children's Research Institute is supported by the Victorian Government's Operational Infrastructure Program.

Conflicts of interest: H. A. Sampson reports being a part-time employee of DBV Technologies; receiving consultant fees from N-Fold, LLC, and UCB SA, and royalties from UpToDate and Elsevier; holding stock options in DBV Technologies and N-FOLD; and receiving grants to his institution from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Food Allergy Research & Education. The rest of the authors declare that they have no relevant conflicts of interest.

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