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Food Allergy: Making an Accurate Diagnosis

  • Authors: Scott H. Sicherer, MD; Anna H. Nowak-Wegrzyn, MD; Matthew Greenhawt, MD, MBA
  • CME Released: 5/14/2012
  • Valid for credit through: 5/14/2013
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Target Audience and Goal Statement

This activity is intended for allergists, immunologists, pediatricians, and primary care physicians who care for patients with food sensitivity and allergy.

The goal of this activity is to educate physicians on what the various diagnostic tests measure, and how to appropriately use them to best diagnostic effect.

Upon completion of this activity, participants will be able to:

  1. Discuss recent guidelines for recognition, diagnosis and management of food allergy
  2. Assess testing options and the role of various tests in the diagnosis of food allergy
  3. Interpret the results of component allergy testing to assess patient risk of severe allergic reactions


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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


  • Scott H. Sicherer, MD

    Professor of Pediatrics and Chief of the Division of Pediatric Allergy and Immunology, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, New York, New York


    Disclosure: Dr Sicherer has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for the Food Allergy Initiative (FAI)
    Has received grants for clinical research from the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); FAI; and Food Allergy & Anaphylaxis Network

    Dr Sicherer does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Sicherer does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Anna H. Nowak-Wegrzyn, MD

    Associate Professor of Pediatrics and Clinical Researcher, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, New York, New York


    Disclosure: Dr Nowak-Wegrzyn has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for Merck & Co., Inc.
    Served as a member of the speaker bureau for Phadia
    Has received grants for clinical research from Nestle; HAL Allergy; and FAI

    Dr. Nowak Wegrzyn does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr. Nowak Wegrzyn does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Matthew Greenhawt, MD, MBA

    Assistant Professor, Division of Allergy and Clinical Immunology, Health Services Researcher and Clinician, University of Michigan Food Allergy Center, Ann Arbor, Michigan


    Disclosure: Dr Greenhawt has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for Thermo Fisher Scientific Inc.
    Served as a member of the speaker bureau for Thermo Fisher Scientific Inc; Nutrica; Sunovion
    Has received grants for clinical research from the American College of Allergy, Asthma & Immunology; NIH; private foundation

    Dr. Greenhawt does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Greenhawt does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Julia Muino

    Scientific Director, Medscape, LLC


    Disclosure: Julia Muino has disclosed no relevant financial relationships.

CME Reviewer

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

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Food Allergy: Making an Accurate Diagnosis

Authors: Scott H. Sicherer, MD; Anna H. Nowak-Wegrzyn, MD; Matthew Greenhawt, MD, MBAFaculty and Disclosures

CME Released: 5/14/2012

Valid for credit through: 5/14/2013


  • Scott H. Sicherer, MD: Hi, I'm Scott Sicherer, professor of pediatrics and chief of the Division of Pediatric Allergy and Immunology and a researcher at the Jaffe Food Allergy Institute at Mount Sinai School of Medicine in New York City.

  • Slide 1.

    Slide 1.

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  • I would like to welcome you to this program titled "Food Allergy: Making an Accurate Diagnosis." Joining me today are Dr Anna Nowak-Wegrzyn, who is associate professor and clinical researcher at the Jaffe Food Allergy Institute at Mount Sinai School of Medicine in New York City, and Dr Matthew Greenhawt, assistant professor in the Division of Allergy and Clinical Immunology and health services researcher and clinician in the University of Michigan Food Allergy Center. Welcome!

    Matthew Greenhawt, MD, MBA: Thank you.

    Anna H. Nowak-Wegrzyn, MD: Thank you.

    Dr Sicherer: Before we begin, I would like to note that this program will include discussions of investigational agents not yet approved by the US Food and Drug Administration (FDA). In addition, the program will include discussions of diagnostics not approved by the FDA. I also want you to be aware that are new National Institute of Allergy and Infectious Diseases guidelines for the diagnosis and management of food allergies in the United States, as well as a clinical report from the American Academy of Pediatrics, and I encourage you to read these papers as a supplement to this program.

  • Slide 2.

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  • So, Dr Nowak-Wegrzyn, let us get started. What is a food allergy?

    Dr Nowak-Wegrzyn: Food allergy is an adverse reaction to food that is mediated by the immune system. Food allergies are blamed for a number of adverse reactions, but only a subset of the adverse reactions to foods are fulfilling the criteria for a food allergy. Those have to be differentiated from the adverse reactions that are not mediated by the immune system, and those include metabolic problems such as enzyme deficiencies. For instance, a person can be intolerant of lactose because he is missing an enzyme to break down the sugar in milk. Other examples include fructose intolerance, galactosemia, and deficiencies of enzymes resulting from improper functioning of the pancreas or liver.

    There also could be adverse reactions that are due to the pharmacologic effects of active substances in the food, such as histamine in wine, tyramine in cheese, or caffeine and theobromine in coffee and tea, which can give you jitters or a skin reaction. Adverse reaction to foods also includes toxic reactions such as food poisonings. Scombroid fish poisoning and ciguatera fish poisoning also can masquerade as food allergy. Last is a group of adverse reactions that include anxiety, panic, and gastrointestinal (GI) tract manifestations such as reflux or hernia.

    I encourage the audience to visit the Website of The National Institute of Allergy and Infectious Diseases, which includes the guidelines for food allergy diagnosis and management. This is open access and it has the full guideline text, an executive summary, and helpful information for the patients. It is an excellent resource.

    Dr Sicherer: Okay. So, basically a food allergy is distinguished by being an immune system response to the food as opposed to all of these other illnesses that we can get from foods.

    Dr Nowak-Wegrzyn: That is correct.

    Dr Sicherer: Dr Greenhawt, the media frequently reports that food allergy is increasing in prevalence. What is the evidence for that?

  • Slide 3.

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  • Dr Greenhawt: We have seen a number of different markers that have been reported that seem to indicate that this is the case. When we look at the overall prevalence of the condition in children, estimates range between 4% and 8%. Some recent estimates have been on the higher side. Two years ago, the Centers for Disease Control reported that the prevalence of food allergy had increased some 18% over a 10-year period. We know a little bit less about the prevalence in adults. It is not as well studied, but we believe that the prevalence is between 2% and 4%. We need more studies to establish that.

    Let's look at the specific example of peanuts. We know that the rate of peanut allergy has been rising to epidemic proportions in the United States. One study in particular looked at the rate at 3 points over a 10-year period, and at each iteration the rate doubled.[1] It started at 0.4% in 1997, it doubled 5 years later to 0.8%, and it doubled again 5 years later to 1.4%. The rate more than tripled from when the original study began, and that is absolutely alarming.

    Some of the issues we have in measuring prevalence in the United States include the use of indirect measures, such as self-report estimates, which can be inaccurate. We are using things like discharge coding. We are using some of the Centers for Disease Control measures, which have some indirect properties to them. Some researchers outside the United States have gone for what we would consider more of a gold-standard type of study in which individuals in question are being tested to the food and then they are being challenged based on the response. I think that is what our studies should aim to do.

    Dr Sicherer: So food allergy is a big problem, and there is some evidence that the rate is actually increasing. I might add that for the clinician it is probably helpful to think about some of the foods that cause probably 90% of the more significant allergic reactions, what we call "major allergens." These include milk, egg, wheat, soy, peanuts, tree nuts, fish, and shellfish. Dr Nowak-Wegrzyn, what types of illnesses may we see that are due to food allergy?

  • Slide 4.

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  • Dr Nowak-Wegrzyn: Food allergies come in many different flavors, and one way of classifying food allergies is based on the involvement of the IgE antibody in the pathophysiology. If we look at this mechanism, IgE-mediated food allergies usually have an acute onset -- usually within minutes to an hour, and rarely past 2 hours. In their most dramatic form, these allergies manifest as a multisystem reaction, which is called anaphylaxis. Sometimes anaphylaxis occurs only in the setting of food ingestion and exercise, which is called food-associated exercise-induced anaphylaxis. Acute IgE-mediated reactions frequently affect the skin, manifesting as urticaria or angioedema. They also can produce immediate vomiting, nausea, and diarrhea.

    This category also includes a very common pollen-food allergy syndrome, which is associated with ingestion of raw fruits and vegetables in people who are allergic to pollen. Obviously, acute bronchospasm is also a manifestation of the IgE-mediated food allergy. The category of mixed pathophysiology disorders involves both IgE antibody and cell-mediated mechanisms with involvement of T cells, includes conditions that are more chronic in nature, and is characterized by relapses. Some examples are atopic dermatitis, eczema, and a growing group of eosinophilic GI tract disorders such as eosinophilic esophagitis or gastroenteritis. Chronic asthma could also be included in that category.

    Another category involves the non-IgE-mediated food allergies, in which there is no evidence of IgE antibody by either skin testing or blood testing, but there is evidence that the cell mechanisms are operational; so there are definitely T cells that are elaborating mediators. Those conditions have a variety of manifestations such as dermatitis herpetiformis with very itchy rashes, enteropathy, and celiac disease. They also include food protein-induced enterocolitis syndrome, which can manifest acutely or in a more chronic form, and allergic proctocolitis, which is quite common in breast-fed babies. We also have this unusual syndrome of pulmonary hemosiderosis, which is called Heiner syndrome.

    Dr Sicherer: So, there are a huge number of illnesses for us to consider. We are probably going to focus more on the IgE-mediated disorders during this discussion. Dr Greenhawt, it is important to think about the pathophysiology -- whether a reaction is IgE-, non-IgE-, or cell-mediated -- because this affects what you might expect from testing. What is your approach to food allergy diagnosis?

    Dr Greenhawt: I have a very simple approach, and it goes back to basic teaching in medical school: take a very sound history. I find that I can usually get most of what I need from the history. Some of the indicators that I look for include whether the symptoms are consistent with a reaction, and whether the reaction occurs within a couple of minutes to a couple of hours, or 3 or 4 days after a food is eaten. The latter is far less likely to be an IgE-mediated food reaction.

    Is the food typically an allergen? There is a big difference in the likelihood of a food allergy if the reaction was to something like a hypoallergenic formula vs something like a peanut. Then I consider the actual food that was eaten. Sometimes a person will report, "I was at a dinner party and I had a reaction." In this case, you need to look very carefully at what the foods were and what the individual likelihood is of those foods being an allergen. As you noted, there are 8 common foods that tend to be associated with about 90% of the reactivity, and then others that are far less likely to cause a reaction.

    Then you look at the nature of the reaction. Does this fit something that would be an IgE-mediated reaction or not? Are you seeing an eruption of hives? Are you seeing somebody start to wheeze? Are you seeing shock-like symptoms? Are you seeing things like headache or hyperactivity? The latter are far less likely to be explained by an IgE-mediated mechanism. Then you need to look at the person in general. What else is going on at that that time? Viral illness? Children may have unexplained hives, and an urticarial rash is a very common viral exanthem, and you must always exclude that possibility.

    The last major question is, "Have you tolerated this food previously?" Allergy is not likely in the presence of a long history of tolerance, although a new allergy can develop. The major question that I always ask is, "What has happened since you reported this reaction? Have you had further exposure to this?" When a person has more exposure to it after the associated event, then it becomes far less likely that it is an allergen. So, I try to incorporate all these things into my history.

    Dr Sicherer: So, history, epidemiology, pathophysiology, and some Sherlock Holmes questions to try to get an idea of what is really going on. Dr Nowak-Wegrzyn, can you give us more insights about how a clinician would use the medical history toward getting the right diagnosis?

    Dr Nowak-Wegrzyn: Well, Dr Greenhawt really gave an excellent run-through. I might add that I like to ask about the specific form of the food that has been eaten. Usually the more-raw foods are more allergenic; tolerance to, say, milk or egg in baked form does not necessarily prove that the person can tolerate liquid milk. It is also very important to know exactly how much food was eaten. The classic example is sesame seeds. Sesame seeds on a cracker or bagel are barely digested and do not prove that a person can tolerate sesame. When exposed to tahini or hummus, this person may well have an allergic reaction.

    Dr Sicherer: So, Dr Greenhawt, skin tests and serum tests are ways to measure food-specific IgE antibodies. What does the clinician need to know about these tests?

  • Slide 5.

    Slide 5.

    (Enlarge Slide)
  • Dr Greenhawt: We see a lot of confusion in the interpretation of these tests. The tests are designed to detect an antibody targeted against a particular food that you choose, and what it indicates is that you make IgE, which is the allergic antibody. We call that phenomenon sensitization; however, that is very distinct from having an allergy. There are lots of people who walk around sensitized to various foods for a number of different reasons. Allergy means that you are not only sensitized but that you have clinical manifestations when you eat that food that, as we have discussed, fit a certain pattern of illness. So, it is very important not to take the results of an allergy test too literally. You always have to incorporate the context from why you are testing that and what else might have been going on at the time. Again, the tests do not make the diagnosis. They also cannot tell you the complete story.

    Sometimes we tend to think of something like peanut being one protein but in fact it is several different proteins, and we are learning now that there are different parts to foods and some of these different parts might have different properties. So, at the level of the test that most people run, not all parts are equal. Sometimes you cannot determine the significance of cross-reactivity. We know that foods tend to derive from families and that among different families, there can be a whole litany of cross-reactivity that can come up on tests. It is very hard to determine how significant a skin or serum test is without further testing, such as an oral challenge.

    Most importantly, and this where I see the most confusion, the tests are never going to be a surrogate for how severely reactive you are. I hear a lot of parents say that their child is "class 5 to peanut" or "4-plus to shellfish." Those are markers that tell us how much IgE we are detecting, but there is no research that has ever shown that you can infer how severe someone's reaction will be based on this number. Some research shows that the larger the wheal on a skin test, the more likely you are to react.

    Dr Sicherer: I think a good example in this context is that about 8% of the general population will test positive to peanut, but clearly more than 95% of those people are able to eat peanut. As you said, it is really about likelihood of reactivity rate, so the larger the skin test, the stronger the blood serum IgE test to a particular food, maybe the more likely there is an allergy, but even the studies on those concepts have shown that different ages might have different exact values and that different foods behave differently on those types of studies. So, it is complicated.

    So, Dr Nowak-Wegrzyn, what are advantages or disadvantages of the 2 tests that we have available, the skin test vs the serum test?

  • Slide 6.

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  • Dr Nowak-Wegrzyn: Those are the 2 standard allergy tests we use in our clinical practice every day. Skin testing is less expensive. It is generally considered more sensitive than the blood test; although there are some caveats to it. Skin testing has a wide allergen selection available from the commercial providers, as well as from the fresh foods that we can test with the prick-by-prick technique. We get results immediately within 10 to 15 minutes and the positive reaction is like a little hive, like a mosquito bite, with some redness and wheal and it is semi-quantitative. We have some guidelines on how to interpret the size of the test based on the size of the wheal. I should point out that for the purpose of food allergy we do only perform skin prick testing as opposed to intradermal testing, which is not indicated for a food allergy. The serum immunoassay, which is also a standardized method of measuring food-specific IgE, is more convenient to the patient, and can be sent to different commercial laboratories. You have to stop the antihistamines for a skin test because otherwise the result could be falsely negative, whereas with the serum immunoassay test you do not have to stop the antihistamines.

    Blood tests give you very standardized quantitative results with a number you can take anywhere. They are not associated with any discomfort to the patient. There is no itching, there are no skin reactions. It is definitely preferable to skin testing when a patient has bad eczema or has extremely sensitive skin; it is dermatographic so you would expect a lot of false-positive tests. So, each of those tests has disadvantages and advantages, but each sort of complements the other.

    Dr Sicherer: I should probably mention there is a common misconception that you cannot test younger kids. Testing can be performed on children of just about any age, including infants, as long as you understand how to interpret those test results.

    So, Dr Greenhawt, how should a clinician, a pediatrician, for example, decide on testing?

  • Slide 7.

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  • Dr Greenhawt: It goes back to what we were talking about earlier with the history. The history will always determine the pretest probability, which is, how likely is it that this patient has an allergy? Tests are not supposed to be used for screening. Although there are panels available to do this, we generally do not support that practice. You need a clear indication for testing, because doing so will always give you the highest accuracy in terms of interpreting the test. It all comes back to context. If you do not have a supporting history, it is very, very difficult to interpret the results. Allergy tests have an odd property that the negative test result is actually more predictive than a positive test. These tests are so sensitive at picking up any antibody that is there when there is nothing to detect, we can have high confidence that this patient likely does not make the antibody and probably is not allergic. You can, however, get caught in traps with that.

    Dr Sicherer: Can you give us an example of how a blood test is interpreted?

  • Slide 8.

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  • Dr Greenhawt: Let's compare 2 patients. The first patient is a 2-year-old who develops hives and cough after the first exposure to peanut butter and visits the pediatrician. The pediatrician draws a sample for an IgE test, and the level is 5 kilounits of antibody per liter (kUA/L). This test is run on range from 0.35 to 100 kUA/L, and with this child's history, 5 kUA/L suggests that this child is allergic. The pediatrician appropriately recommends avoidance and refers to an allergist for further workup.

    Compare this with patient 2, another 2-year-old. This patient has no history of a reaction to anything he's eaten, but he has about 10 tests performed and all are positive. Investigating the history reveals that this child has actually tolerated, for a long time, 8 of the 10 foods, and the other 2 foods he has never been exposed to.

    Dr Sicherer: This doctor did a panel test, like a food panel, for example?

    Dr Greenhawt: Correct. The levels for peanut and shrimp suggest a positive result, but this child has never been exposed to either. If there was a supporting history, the levels would suggest that this child is likely allergic. However, when you do not have a clear history, it becomes very, very difficult to understand what those levels mean. So, in the case of Child 1 with the level of 5 and a strong history, we would say this child is unfortunately allergic to peanut and we would recommend the standard avoidance and anaphylaxis management. However, with Child 2, the same level is a lot harder to understand. It can mean something different in somebody else, and this is a child where we would need to do further workup, probably an oral challenge, to really understand what's happening.

    Dr Sicherer: Okay. So, that would be in the context of never having eaten peanut, so you just do not know.

    Dr Greenhawt: Correct.

    Dr Sicherer: If a child who had a level of 5 kU/L had eaten peanut without problems, you would say what? Keep eating peanut! You have a child with a 5 that means he is allergic, a 5 that means we do not know, or a 5 that means he is not allergic. So, you have to put the history together.

    Actually, Dr Nowak-Wegrzyn, you chaired a committee and developed the Work Group report on oral food challenge testing that Dr Greenhawt just mentioned. Can you tell us a little bit more about what is involved with an oral food challenge?

  • Slide 9.

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  • Dr Nowak-Wegrzyn: A food challenge is a medically-supervised procedure done in a very controlled environment with emergency medications immediately available. The gold standard in food challenge is a double-blind placebo controlled food challenge in which your allergen is masked, which eliminates bias or minimizes the bias in terms of anxiety and some subjective reactions. For clinical purposes, an open food challenge -- basically an age-appropriate serving of the food in a natural state, given over an hour or so -- is appropriate. A food challenge can induce allergic reactions and some of them could be severe, potentially anaphylaxis. We minimize this risk with incremental feeding. We start with a small dose and then 10 to 15 minutes later we re-examine the child, and if there are no symptoms we give another dose. So, this way we control for it. The food challenges are the standard against the blood test or skin test.

    Dr Sicherer: This is the "proof is in the pudding" test. If they can eat it, you tell them to keep eating it.

    Dr Nowak-Wegrzyn: Right.

    Dr Sicherer: So, Dr Greenhawt, how do you decide when it is time to do a food challenge? What are the major categories that you would say warrant a food challenge?

  • Slide 10.

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  • Dr Greenhawt: The first category is when you have a discrepancy between the history and the testing. Is there ambiguity? In the example that we just went through in Child 2, there is ambiguity. You have strongly positive results but you have a history that does not necessarily suggest risk. That is a perfect example. Another category involves cross-reactivity. There are data that support that certain peanut-allergic individuals may have tree nut co-allergy and if they have never eaten it, you need to understand that not everything that is positive on the test may have clinical significance. Then, there are cases in which you think that tolerance might have been regained. With some of these foods such as milk, egg, wheat, and soy, we expect the person will be able to tolerate this at some future point, so we serially track both the skin and the blood tests over time and when we start to see these levels decrease, that is usually an indication that the patient may be regaining tolerance. In some cases, we get lucky and when they come back for a visit we hear that they had an accidental exposure with no reaction, and that also might be an opportunity.

    Dr Sicherer: Or we get unlucky if they had a reaction.

    Dr Greenhawt: Correct. Then there are other extremes, and we are starting to learn more about some of the hidden costs of food allergy in terms of anxiety and quality of life and nutritional deficits, and these might be reasons why you may need to push for a challenge.

    Dr Sicherer: Let's move back a minute to testing before we would get to the oral food challenge. Dr Nowak-Wegrzyn, what do you suggest would be the role of the generalist or internist or pediatrician?

    Dr Nowak-Wegrzyn: Well, I think it is a crucial role because the primary care provider will determine whether the reaction fits the criteria for an immune system mediated reaction and whether it is likely to be a food allergy. Then, they can decide to send some confirmation blood tests. Obviously, they will advise the patient how to avoid the food and prescribe emergency medications, but when the situations are not straightforward, or where multiple foods are involved, or the reactions are extremely severe, then the generalist might consider referring to an allergy specialist.

    Dr Sicherer: What are some of the pitfalls that people might get into when they are sending these various tests?

    Dr Nowak-Wegrzyn: We touched on this earlier. For instance, testing large panels of foods, taking any positive result as an indication of a food allergy when in fact this is really just showing there is some IgE antibody. On the other hand, we have not really talked about it but the test could be falsely negative, which is rather unlikely. Preparing a food for the extract for skin test or for the serum assay could destroy or lose some of the ingredients that are important for that individual patient. If somebody comes to you with a history of anaphylaxis and one test is negative, you definitely are going to follow with an oral challenge test before you tell them, "okay you are fine with peanut."

    Dr Sicherer: So, there are pitfalls and you helped us identify how to avoid some of those. Dr Greenhawt, do you have some other pearls to avoid those pitfalls?

    Dr Greenhawt: Sure. What is the test that you are running and what can it tell you? Allergy is a mechanistic definition. You have sensitization and you have a clinical history of reactivity. You have to keep in mind that there are a number of different descriptions of adverse reactions to food. Allergy is a very, very small subset of that, and we are unfortunately limited in what we can test to. What we can test to is only defined by the presence or absence of IgE. There are other non-IgE mediated reactions such as food protein-induced enterocolitis or eosinophilic esophagitis that we cannot test for very well with those tests specifically. Then there might be a masquerader of allergy, something that looks very, very close but might not be. We talked about certain types of poisoning with spoiled fish or having a viral illness. There are some patients who just have chronic hives as a disease entity that can masquerade as having a chronic allergy to a food, and some people go through elimination diets, sort of in futility, trying to determine that.

    Dr Sicherer: We actually mentioned a little bit about this before, but the serum test -- does it tell you severity?

    Dr Nowak-Wegrzyn: I wish it did because it would make my life so much easier explaining those tests. We are just looking at a little piece, the level of the allergic antibody, but you do not really get any information. How well does antibody bind to the allergen? So the test does not tell you the affinity of the antibody. Obviously, antibody that has a high affinity will be much more efficient at producing allergic symptoms.

    Obviously, if you have asthma you are at risk of having more severe reactions. Also, if you have problems maintaining your blood pressure during an allergic reaction, this sets you up for more severe symptoms. The test also does not know what you were doing when you were eating the food. Were you exercising? Where you drinking alcohol? Were you taking aspirin or ibuprofen?

    Dr Sicherer: Looks like we are getting back to the importance of the history.

    Dr Greenhawt, earlier you mentioned cross-reactivity. Can you just briefly let the audience know some of the details about that?

  • Slide 11.

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  • Dr Greenhawt: We notice that for certain major allergens, there is some theoretic risk of cross-reacting on a test with other members of the allergen's family. An example of that is peanut, which is a legume. There is a theoretical risk that you may cross-react with things like soy, peas, or green beans. We find in clinical practice, however, that this is really not much of a risk. It is quite common to see both tests come up positive. We know that there is a high degree of cross-reactivity between different tree nuts. They are all very closely related, and there is a more realistic risk that if you are allergic to one tree nut that you probably have a stronger likelihood of reacting to another tree nut.

    This same thing happens with fish. The protein that you are allergic to is highly conserved among different species, so with one fish you tend to react to other fish; same thing with shellfish. Then it gets a little bit less risky with wheat and other grains, with a slightly elevated risk. With milk, there is a high conservation of the same milk proteins across a number of the different mammalian milks. A child who is allergic to cow's milk has a high risk for reaction to sheep or goat's milk, which are very, very similar to cow's milk. Anecdotally, I have seen a number of unfortunate reactions happen when the parents switched to that type of milk. Mare's milk, however, which may be more difficult to obtain, is associated with a very low risk of cross-reactivity.

  • Slide 12.

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  • D. Sicherer: The bottom line there is that there is a difference between true clinical reactivity and what you might see on a test. There are emerging tests where a food is not tested as a mixture of its many proteins, but rather as separate components. For example, if I am allergic to you, am I allergic to your eyeballs? Am I allergic to your nose, your liver? What part of you?

    As we see here, peanut is not just 1 protein; it is a collection of many different proteins, and there may be many different implications of being reactive to 1 protein or another. There are these new tests that are looking at allergy to different parts of the food. Dr Nowak-Wegrzyn, can you talk about that?

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  • Dr Nowak-Wegrzyn: This is the component-resolved diagnosis or molecular diagnosis, and I would like to illustrate it with the example of foods of plant origin, a classic example. We know that those foods will contain a number of proteins that are highly similar to pollen, and there are 2 different classes of pollen proteins, but in general those proteins that are pollen cross-reactive tend to be very unstable. They are very sensitive to heat or digestion, and do not survive in the harsh environment of the GI tract; they have minimal potential to cause any systemic reactions and do not get absorbed.

    In contrast, they are more likely to produce oral symptoms such as itching, swelling in the mouth, and discomfort. These are the proteins in our left column. Then we have the ingredients that are sort of intermediate. An example is lipid-transfer proteins. They are also present in pollen, nuts, legumes, and grains. By the way, the cross-reactivity with grains is mostly with the grass pollen, not with the tree pollen. They are sort of intermediate because they have a much more compact structure and are much more resistant to heating and digestion, so they have some potential to induce systemic reactions such as pain. Lipid transfer proteins in peach have been identified as a major cause of anaphylaxis. The last category is the proteins that have nothing to do with the pollen. They are called seed-storage proteins, and they are albumins and globulins that are classic food allergens. They are compact, they are highly resistant to digestion and heat, they sensitize through the GI tract, and they have high potential to produce systemic reactions, including anaphylaxis.

    Dr Sicherer: What is available now for this kind of testing?

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  • Dr Nowak-Wegrzyn: In terms of nuts, an example is peanut components. We can measure peanut components Ara h 1, 2, and 3, which are the stable components that tend to be associated with more systemic reactions. We can also measure Ara h 8 and 9, which are the pollen cross-reactive components and are usually associated with the more local oral symptoms. We also have components of hazelnut, which are tree pollen, cross-reactive Cor a 1, and the lipid transfer protein Cor a 8, which tend to be associated with more systemic reactions.

    Dr Sicherer: Dr Greenhawt, can you give us an example of where would you use this kind of approach?

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  • Dr Greenhawt: Take the case of a teenaged boy. This is an asthmatic child; he has a history of symptomatic food allergy to peanut from a very young age and has been tested for tree nut owing to the risk of cross-reactivity. We know that he had a positive skin test to hazelnut although he had never eaten it because of conservative management. This child lives in an area where there is lots of tree pollen, and he also has allergic rhinitis from trees. He had been successfully avoiding peanut up until about 3 years ago when a relative who had eaten a peanut butter sandwich gave him a kiss on the cheek, and he had an eruption of urticaria over the cheek. Present data suggest that less than 20% of people with peanut allergy will outgrow their allergy, and less than 10% will outgrow their tree nut allergy.

    Dr Sicherer: Depressing numbers.

    Dr Greenhawt: Very depressing numbers. Mom is noticing that her son is taking risks in other areas of life, as teenagers do, and because it has been 3 years since the last episode, she wants to know if he is still allergic. So, we had run IgE tests against peanut, hazelnut, and birch pollen. We know that birch pollen and hazelnut pollen are very, very common allergens. Actually, hazelnut is a derivative of birch and there can be cross-reactivity.

    Dr Sicherer: So there are some proteins in hazelnut that are similar to the birch pollen protein that we heard about before?

    Dr Greenhawt: Correct. We see that this child is still sensitized to all 3 agents. What we could do now is to run an additional test.

    Dr Sicherer: So the question here is, we know that they are strong to birch, is that accounting for their peanut test? Is that accounting for their hazelnut test?

    Dr Greenhawt: Correct.

    Dr Greenhawt: So, we run the component tests that are available now to both peanut and to hazelnut and we can see that when you start to break down the individual parts of peanut, there are different levels of reactivity.

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  • When we look specifically at 1 part of peanut, Ara h 2, that is a very, very strong sensitized marker in this child, and it is a marker of potential severity. Looking at hazelnut on this child, you can see that while the total number for hazelnut is quite high, the area that we think has the most attributable risk -- Cor a 8, there seems to be very little sensitization there.

    Now, contrast that to markers of cross reactivity looking at some of the shared proteins among tree pollen. In the case of peanut in this child, Ara h 8 is actually moderately elevated and Cor a 1, which is the corresponding or homologous area in hazelnut, is actually very elevated. So how would we synthesize this information? Sensitization to Ara h 2 tends to be a fairly ominous sign and probably an indicator of stable, lifelong, and possibly severe peanut allergy. However, there is a silver lining here. By running this test and looking at the relationship between hazelnut and birch, I think that in this child we are seeing enough information that shows that the positive test to hazelnut might be sort of an artifact of having strong birch-pollen sensitization.

    Dr Sicherer: So you might do a food challenge?

    Dr Greenhawt: Right.

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  • Dr Sicherer: Basically, what we have heard here is that these are the standard tests that we have. There have been studies looking at those tests, trying to correlate the level of IgE antibody with symptoms. For example, we have a size of skin test with outcomes, but there have been issues that are missing and some fine-tuning might be available through these component diagnostic tests.

    Now, as with everything else in medicine, there are some advantages and disadvantages, and it looks like the advantages include that it might help us with some additional diagnostic accuracy. It might reflect severity, which was one of the things you mentioned was missing before, and it could focus who might be a better candidate for a food challenge to particular foods and who might not be. We have some limitations here as well.

    There may be some issues in terms of having enough studies on this to be able to use the numbers. For example, there have been some studies from the UK now that have shown that measuring antibodies to Ara h 2, that part of peanut you mentioned before that tends to be associated with more severe reactions, might be a better test of who might be allergic to peanut or have a more significant reaction. But even then, what does the level of antibody to Ara h 2 mean? How high or low of a number means that there is going to be a problem? It is just some of the things we face with the regular tests as well, but it looks like we need more studies on that. So, would you agree, are there other issues that need to be sorted out with this? Where does this play a role in your activities now with diagnosis?

    Dr Nowak-Wegrzyn: Well, I think those tests have a huge potential to refine the diagnostic tools that we have available, but we still need many more studies to evaluate the utility of those tests in different patient populations. I do not know of any studies that have been done in older children or in adults; we do not really know what those numbers mean. We know that age plays a role in conventional allergy testing; you have to account for the age when you look at the numbers because you are going to interpret differently.

    Dr Sicherer: So a level 2 for a 2-year-old is different than a level 2 for a 7-year-old.

    Dr Nowak-Wegrzyn: Absolutely, they just sort of outgrow their numbers. Also, right now those tests are a little bit limited in their availability and more expensive than the other tests, but hopefully this will change in the near future.

    Dr Sicherer: A recent Australian study actually looked at placing an Ara h 2 type of test, if you are doing peanut diagnosis, after the history and the skin test or after the history and the standard peanut test if it sort of falls into an ambiguous category, to use it as one more test to do before deciding on a food challenge. So, Dr Nowak-Wegrzyn, what else is on the horizon for testing?

    Dr Nowak-Wegrzyn: We can take it a step farther. Instead of looking at the individual proteins, you can look at the spots on the protein that bind allergic antibody, or the epitope. You can define the epitope on those proteins, and a technology for doing this is the peptide microarray. The test uses a tiny amount of serum and it will give you this information. Some research data show that if people recognize a lot of allergen epitopes, their reactions tend to be more severe and more persistent. Some people are looking at patch testing. Unlike the prick test when it is sort of immediate, you put the food under an occlusion on the skin for 2 days, and then you look at eczema-like reactions. This is something that dermatologists are using routinely to define the allergens for contact dermatitis.

    Dr Sicherer: Like nickel allergy.

    Dr Nowak-Wegrzyn: Right. For the food allergy, those tests are being studied for conditions that are more chronic and they involve T cells, such as eosinophilic esophagitis or atopic dermatitis, but they are still non-standardized and works in progress.

    Dr Sicherer: So this is an exciting time for current diagnostics, emerging diagnostics, and future diagnostics, and it sounds like they all still need you to take a medical history. So, I think I would summarize that food allergy diagnosis is crucial because people need to know what they can eat or what they need to avoid and currently we have superb tests, namely the medical history, the skin and serum tests, and importantly the oral food challenge that can be a gold standard. It seems that the new tests might help us to further predict reactivity and perhaps severity, but more work does need to be done to best figure out where these tests play a role in our current tools.

    I know it sounds biased, being an allergist, but I have to suggest that, given the potential severity of food allergy and the need for oral food challenges, having a board certified allergist involved in the diagnosis and management seems very appropriate. In fact, I do not want to end without considering the management of the person who is diagnosed with food allergies. Dr Greenhawt, just briefly, what does the clinician need to do after making a diagnosis of food allergy for an individual?

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  • Dr Greenhawt: I think the first recommendation should be absolute avoidance, and the second recommendation should be planning for an unfortunate event. We try to counsel patients and parents on where you might find this food hidden in other foods, teach them how to read a label, but also very important is to instruct them on how to use an epinephrine self-injecting device, and when to use it. We go through very strict criteria about what types of symptoms are best treated with something like an antihistamine and when it becomes more severe and you absolutely need to use the epinephrine device, which can be lifesaving.

    Dr Sicherer: You did a great job summarizing that in about 30 seconds, but the reality is we might spend 45 minutes or longer trying to explain all of the nuances with all of this. Dr Nowak-Wegrzyn, what does the future hold for treatment?

    Dr Nowak-Wegrzyn: Right. The fact that there is no cure or effective treatment for food allergy at the time is an unmet medical need. There is a tremendous research effort devoted to coming up with therapy. Many potential treatments are being studied in test tubes, but those now in clinical trials are oral immunotherapy and sublingual immunotherapy. We will be testing patch immunotherapy as well as Chinese herbal medicines for a variety of food allergies using anti-IgE antibodies.

    We are also introducing milk and egg in the baked products because it turns out that the majority of children who are allergic to milk and egg can tolerate those foods when they are baked, and children seem to do better when these are added to the diet compared with strict avoidance.

    Dr Sicherer: We should probably remind the audience that a lot of these studies that are ongoing include things that potentially you do not want people to be trying at home, like the gradual introduction of foods.

    Dr Nowak-Wegrzyn: Right. Everything is under supervision and very controlled.

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  • Dr Sicherer: Well, that was great and I want to thank Dr Nowak-Wegrzyn and Dr Greenhawt, as well as our listeners. Thank you for participating in this activity. You may now take the CME posttest by clicking on the earned CME credit link and please also take a moment to complete the program evaluation that follows. Thank you.

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This transcript has been edited for style and clarity.

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