Peanut Allergy Diagnosis: As Simple as Ara h 1, 2, and 3

AUTHOR:
DEAN C. MITCHELL, MD

Dr Mitchell is an allergist and immunologist at Mitchell Medical Group Immunology and Integrative Medicine and an adjunct clinical assistant professor at Touro College of Osteopathic Medicine in New York, New York. He discloses that he has consulted for Thermo Fisher Scientific.

CITATION:
Mitchell DC. Peanut allergy diagnosis: as simple as Ara h 1, 2, and 3. Consultant for Pediatricians. 2013;12(8):347-351.

ABSTRACT: Peanut allergy can be life threatening, and its incidence recently has increased significantly in the United States. The growing incidence has placed increasing attention on finding better and more accurate ways of diagnosing and treating peanut allergy. Until recently, the diagnosis of peanut allergy depended on a thorough medical history in conjunction with allergy testing, either by skin prick testing (in vivo) or by laboratory testing (in vitro). Traditionally, this testing would be followed by a food challenge test to confirm the diagnosis. The relatively recent development of molecular allergy component testing for peanut allergy now allows the identification of the specific proteins that cause the most serious peanut allergy reactions.
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Food allergy is a major health issue in the United States, affecting almost 4% of children.¹ The U.S. Centers for Disease Control and Prevention has estimated that 3 million children and adolescents younger than 18 years of age in the United States had a reported food allergy in 2007, an increase of 18% from 10 years earlier.¹

Peanut allergy is one of the most common and dangerous food allergies affecting children.² Unlike cow’s milk or egg food allergy, peanut allergy tends to be lifelong, with only 20% of patients eventually outgrowing the allergy.³ The fear of accidental ingestion of peanuts in a peanut-allergic patient brings significant emotional distress to children and parents affected by this condition. Pediatricians are at the front line in caring for these patients. However, recent data show that pediatricians are only fair in their assessment of food allergies.⁴ Fewer than 30% of pediatricians felt comfortable interpreting food allergy laboratory tests, and only 22% felt their medical school education prepared them to care for food allergy patients.⁴ Supporting this finding is a study showing that allergists using only the history and physical examination to evaluate allergic disease had an accuracy of only 50%.⁵

Diagnosis is more difficult when the ingested allergen is unclear due to multiple ingredients in a food such as a cookie or cake, or when the child has never had a prior exposure or reaction. The commonly performed allergy skin and laboratory tests for peanut-specific immunoglobulin E (IgE) have a high sensitivity (greater than 80%) but a low specificity (between 30% and 50%). These characteristics result in many children who are not truly peanut-allergic testing positive for peanut allergy and being placed on dietary restriction.^6,7 Advances in molecular allergy component testing, however, now allow pediatricians to assess with a higher predictive value the risk of their patients having a peanut allergy.

Peanut Allergy Diagnosis

Peanut allergy, like other food allergies, can have typical and atypical presentations. The diagnosis of peanut allergy is straightforward when the history of ingestion is obvious and the reaction meets the criteria of type 1 hypersensitivity. The classic type 1 hypersensitivity reactions include signs and symptoms affecting the cutaneous, respiratory, gastrointestinal, cardiovascular, and central nervous systems, along with a number of atypical symptoms (Table).⁸

Among the challenges in using clinical testing for peanut and other food allergies is differentiating sensitizationto an allergen from a genuine allergy. Sensitization is when a patient has a positive skin test or blood test result for a specific allergen regardless of the clinical reaction. Genuine allergy is a positive allergy test with associated clinical signs or symptoms. There has been much debate and criticism of the overdiagnosis of food allergy in children based on only the positive result of a skin prick test or immunoassay.⁹

Peanut Allergy Testing Methods

Skin testing. Historically, the diagnosis of allergy to peanuts and other foods relied on skin testing. Originally, intradermal skin testing was performed for food allergy, but because this method presents a greater risk of systemic adverse allergic reactions than skin prick tests and other diagnostic methods, guidelines published by an expert panel of the National Institute of Health’s National Institute of Allergy and Infectious Diseases (NIAID) do not recommend its use.¹⁰

However, the NIAID panel guidelines do recommend skin prick testing to be done by clinicians who are trained to properly interpret the test results and to be prepared in the office to treat a potential adverse reaction from testing.¹⁰ Skin prick testing is regarded as generally safe for most allergy testing, but there are real risks, such as anaphylaxis, for highly sensitive patients. Other hindrances to testing include when a patient is taking certain medications, such as antihistamines, which can block testing analysis, or when patients have severe atopic dermatitis or dermatographism, which can lead to false-positive test results.

Laboratory testing. In the late 1960s, the discovery of IgE in the serum of allergic patients led to the better understanding of how the immune system responds to specific allergens. The earliest version of in vitro allergy testing was the radioallergosorbent test (RAST). The availability of RAST allowed physicians to test for sensitization to an allergen without introducing that allergen to the patient, obviating any potential adverse reaction.

The next evolutionary step in in vitro allergy testing was fluorometric enzyme immunoassay, better known by the trade names ImmunoCAP, Immulite, or HYTEC. These tests utilized better adherence of allergen to the polymer, and the false-negative value in testing decreased and approached the level of skin prick testing. The sensitivity of these laboratory assays ranges from 60% to 95%, and their specificity ranges from 30% to 95%.¹¹

Despite the popularity of these tests, questions have been raised about whether there is an overreliance on blood and skin testing for food allergy diagnosis; this is of particular concern in children with atopic dermatitis, whose elevated serum IgE levels can lead to multiple false-positive results, clouding the specific allergy diagnosis.¹²

Why are skin prick tests and specific IgE laboratory tests so limited in predictive value? Clinical research protocols call for the bar to be set high at 95% predictive value; however, in uncontrolled clinical practice, this range of 95% predictive value is not used, and this leaves positive test results with lower predictive values of clinical importance. Thus, the double-blind placebo-controlled food challenge (DBPCFC) is used to enhance the predictive value of test results for food allergy in patients whose results fall in the uncertain category. However, this test requires specialty access.

Double-blind placebo-controlled food challenge. The DBPCFC has been considered the gold standard test for diagnosing food allergy. However, a single-blinded or open food-challenge test may be considered diagnostic in certain circumstances. Before a person undergoes an oral food challenge, the suspected foods are eliminated from the diet for 2 to 8 weeks; after documenting significant improvement of allergic symptoms with dietary elimination, the challenge test is carried out while the person is on minimal or no medication. The oral food challenge begins with a low dose of the suspected allergen to test for a reaction; if no reaction occurs, a higher dose of the food is given until a cumulative dosage comparable with typical consumption is reached. When assessing allergy with the DBPCFC, only approximately one-third of the suspected foods are found to be truly allergic.

The expense and inconvenience of the DBPCFC usually make office-based use impractical, and so an open food challenge (OFC) is more common. Because of the dangers of an anaphylactic reaction, OFCs are to be done only by trained professionals in a facility equipped to treat such a reaction. No internationally accepted standardized protocols exist for performing and interpreting food challenges.¹⁰

Cross-reacting allergens

Multiple foods and environmental allergens naturally share homologous proteins. A variety of these allergens are conserved among plants and animals. For example, it is quite common for patients with a birch tree pollen allergy to also have a mild form of oral food allergy to apples, cherries, and hazelnuts, since these plants all share a common protein. Patients allergic to dust mites also may have positive allergy test results to shellfish, because the two share a common protein, tropomyosin.¹³

One of the best examples of differentiating cross-reactive proteins from true clinically significant proteins has been demonstrated in peanut molecular allergy. Whole peanut proteins have been shown to cross-react with proteins from tree pollens and grass pollens. This can cause confusion for clinicians interpreting these tests. Molecular allergy diagnostics has been shown to be valuable for differentiating these cross-reactions by providing specific protein analysis for the food allergen.

Molecular allergy testing

Molecular allergy component testing can sort out cross-reactivity among allergens as well as detect elevations of specific IgE to a particular allergen. This test method enables the identification of the specific proteins in food allergens or environmental allergens. In the near future, it no longer will be satisfactory to say that a patient’s test result is positive for allergy to egg, milk, or peanuts, but rather which protein components signify a higher risk of reaction. An apt analogy is that learning the individual proteins significant in peanut and other food allergies is equivalent to understanding that a patient’s total cholesterol is only one part of the laboratory evaluation, and that the high-density, low-density, and very low-density lipoprotein levels are other important components to explain to the patient. In general, IgE directed to a specific protein component is suggestive of a genuine allergy.

In peanut allergy, 5 proteins are associated with clinical reactions of varying severity: Ara h 1, Ara h 2, Ara h 3, Ara h 8, and Ara h 9. (The letters of the terminology correspond to the genus and species of the peanut plant, Arachis hypogaea, and the number distinguishes each discrete component.) Ara h 1, 2, and 3 are storage proteins that are heat-resistant and present in peanut-allergic persons with potentially severe reactions. As many as 95% of persons with a positive test result for Ara h 1, 2, or 3 reported symptoms after peanut intake.¹⁴

Ara h 9 also is associated with severe symptoms, but it mainly is identified in southern Europe.¹⁴ Ara h 8 is a pathogenesis-related class 10 (PR-10) protein that is heat-labile and typically is associated with cross-reactions to pollens; people with it generally have much milder reactions or no reaction at all to peanut ingestion. Only 18% of persons whose test results are positive for Ara h 8 alone report symptoms of peanut allergy.¹⁵

In May 2011, the U.S. Food and Drug Administration cleared the first practical molecular component test for specific peanut proteins, the uKnow Peanut ImmunoCAP molecular allergy test, manufactured by Thermo Fisher Scientific. This test analyzes a patient’s blood specimen and reports a quantitative assessment of the levels of the different Ara h proteins.

Sensitized or Allergic?

The task of identifying patients at risk for peanut allergy through conventional testing was elucidated by an analysis of a cohort of the Manchester Allergy and Asthma Study (MAAS),¹⁶ a prospective study of the development of asthma and allergies in 1,085 children in South Manchester and Cheshire, England, over an 8-year period. In their 2010 analysis, Nicolau et al¹⁷ assessed 933 of the 1,029 children who stayed in the MAAS until 8 years of age; they identified 110 (11.8%) children as peanut-sensitized based on a positive skin prick test result and/or a peanut-specific IgE level of 0.2 kIU/L or greater, in addition to a suggestive history.

Next, 91 of the 110 peanut-sensitized children were assessed for peanut allergy. The symptoms of 12 children were considered pathognomic for peanut allergy without oral food challenge; the other 79 underwent either DBPCFC or OFC. Of these 79 children, 66 had no symptoms, 7 had symptoms that categorized them as peanut-allergic, and 6 had inconclusive results and thus were excluded from further analysis.

All told, of the 85 peanut-sensitized children with an unequivocal outcome in Nicolau and colleagues’ study, only 19 (22.4%) were peanut-allergic. These results clearly demonstrate that neither skin prick testing nor radiosorbent testing is highly correlative with diagnosing or clarifying which patients are not truly peanut allergic. By using component allergy diagnostics, Nicolau et al were able to detect marked differences distinguishing peanut-tolerant children from peanut-allergic children. The peanut component Ara h 2 was the most important predictor of clinical allergy; it was significantly more specific than whole peanut extract, used in skin testing or in laboratory blood testing for specific peanut IgE, in identifying clinical peanut allergy.¹⁷

Klemans et al¹⁸ went a step further and analyzed the diagnostic value of specific IgE to Ara h 2 in predicting peanut allergy without an oral food challenge. Their findings demonstrated that Ara h 2 testing could discriminate peanut allergy almost equally as well as a prediction model combining testing for specific IgE to peanut, skin prick testing, and patient characteristics, and that it could reduce the need for food challenges by 50%.

Dang et al¹⁹ designed a study to validate the ability of Ara h 2 to predict peanut allergy and avoid the need for an oral food challenge in a population-based setting. They found Ara h 2 measurements to be more accurate in distinguishing true peanut allergy (correctly identifying 60% of study subjects with true peanut allergy confirmed by skin prick testing and oral food challenge) than whole-peanut specific IgE measurements (which correctly identified only 26% of subjects).

Peanut Allergy Prevention, TREATMENT

Education by a health care professional is essential for all parents of children with peanut allergy, so they can learn to avoid accidental peanut exposure. Well-trained supervision of label reading and avoiding foods outside the home, where ingredients are unclear, is of high priority in preventing serious peanut allergic reaction. The danger of hidden peanut proteins in food classically presents in such situations as eating at an Asian restaurant or eating ice cream or candy containing peanut proteins.²⁰ A common scenario is a young child with a peanut allergy attending a friend’s birthday party and being offered cake and ice cream without knowing whether peanuts were contained in any of the ingredients.

The unequivocal treatment for a child experiencing a type I hypersensitivity reaction to peanut is injectable epinephrine.²¹ Among the several available autoinjector products are the EpiPen, the Adrenaclick and Auvi-Q. All deliver epinephrine intramuscularly, which takes full effect in approximately 8 minutes and reverses more than 90% of systemic reactions. Each product is available loaded with a smaller epinephrine dose for children weighing less than 30 kg. Auvi-Q has the unique ability to voice-activate and instruct the user to deliver the medicine. Delivery of epinephrine via a sublingual tablet is now being studied for the treatment of type I hypersensitivity reaction.²²

Recent trials have shown the benefit of oral allergy immunotherapy²³ and sublingual allergy immunotherapy²⁴ in producing significant tolerance to peanuts in peanut-allergic individuals.

It is not unrealistic to hope that in the near future, children with peanut allergy and their parents no longer will have to fear accidental contact or ingestion of peanuts. While molecular allergy testing may not completely eliminate the need for office oral food challenges for patients with unclear peanut allergy, for now being able to diagnose and predict peanut allergy can be as simple as Ara h 1, 2, and 3.

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