AAAAI Podcast: Conversations from the World of Allergy
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AAAAI Podcast: Conversations from the World of Allergy
Making Sense of Component Testing in Food Allergy
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In this episode Amanda Cox, MD, FAAAAI, walks us through component-resolved diagnostics, why it’s important, and how it helps distinguish primary food allergy from pollen sensitization. We will talk about where it fits alongside the history, skin testing and oral food challenge as we make decisions about our food allergy patients.
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Hello, and welcome to Conversations on the World of Allergy, the podcast of the American Academy of Allergy, Asthma & immunology. I'm your host, Rebecca Staff. Allergy and Immunology is a field that's involving an incredible pace, and staying current isn't just important, it's essential. In this podcast, we'll talk with leading experts about the latest advances, challenge how we think about core topics, and explore how we can put what we learn into practice to provide the best care for our patients. Component resolved diagnostics can help us put together a patient's food allergy story and put their clinical symptoms and testing into better context. It helps us to understand which proteins our IgE recognizes and why that matters clinically. In this episode, we'll explore the immunology behind component testing and how it can help distinguish true allergy from cross-reactivity. We'll also talk about where it fits alongside the history, skin testing, and oral food challenges as we make decisions about our food allergy patients. Today we welcome Dr. Amanda Cox. Dr. Cox is an assistant professor of pediatrics in the division of pediatric allergy and immunology at Mount Sinai. She specializes in food allergy and has been involved in research in oral immunotherapy and has written about cross-teractivity and food allergy, which is where component-resolved diagnostics become so important. Dr. Cox, thank you so much for taking the time to join us today.
Amanda Cox, MD, FAAAAIThank you so much for having me. This is a very exciting opportunity and my first foray into podcasting. So thank you again. So I wanted to just like say a little bit about myself. So you know where I'm coming from, and um I'm sort of thinking about it because we're in the midst of doing fellowship interviews right now, and it's just it's really interesting to see how young people are ending up in the field. So I like to think about how I ended up here. So I've been at uh Mount Sinai since 2008, um, except for two years that I actually worked in private practice, and I did my training at what was Schneider Children's Hospital, is now Cohen Children's Hospital in part of Northwell in Long Island. For my medical school days, I was at Einstein in the Bronx, and I was really you know interested and struck by asthma affecting children. I knew I was going to do pediatrics, but as pediatric asthma care was just like front and center on all of our ER shifts, our inpatients. It really was like a lot of our inpatients were affected by asthma, and then just the community in the Bronx was you know affected by asthma because of environmental causes. So it's sort of like where I thought I was going. And then during my residency at what's not Northwell, the we actually had a lot of inpatients that were taken care of by the AI service, but it wasn't us just asthma, it was um primary immunodeficiency and the adolescent HIV AIDS at that point, and not even really very much food allergy anaphylaxis. It really wasn't a huge need at that point, or there. So I but I had a lot of interaction with the the faculty in the AI division, and I just sort of got excited by how like how they conducted the consults and all the sort of investigation and how much of that was so clever, and um, and then how you know their findings and treatments and and really diagnosis really made a big difference in quality of life, um, and such a diversity of conditions. It wasn't just asthma. So I just sort of got hooked on it in that way. And then when I came to Sinai, which is really my first like full-time job after fellowship, I actually kind of had a second fellowship in the food allergy niche with Dr. Q Sampson, Scott Sisher, Anya Noah, Vegdran. So we're all with sort of my my sort of mentor in the greats, and we got exposed to food allergy trials and therapeutics, and this is now sort of what I'm working in. So it's not what I expected when I started my residency or even my fellowship, um, but I'm really happy and thankful for these opportunities and the direction things have gone in, and like especially for all of the brilliant colleagues and friends that I made. So I highly recommend this field for anyone who's interested.
Rebecca Saff, MD, PhD, FAAAAIThat's an amazing mentorship team. Those are some of the greats in food allergy to train under.
Amanda Cox, MD, FAAAAII have to pinch myself. I'm very lucky, yeah.
Rebecca Saff, MD, PhD, FAAAAIWell, I wanted to start with just what is component resolve diagnostic testing and what information does it give it, give us that we don't get from the skin testing or just a specific IgE to the whole allergen.
Amanda Cox, MD, FAAAAIOkay, so so I'm not a molecular biologist, so I'm gonna try to explain this in terms of you know, from the perspective of a clinician, you know, someone who's seeing patients and using tests, um, but not so much in like really detailed molecular composition terms, but there is a lot of information about that available to read. But essentially the component resolved or molecular diagnostic testing or CRD is allergy testing using serum IgE assays to specific proteins and an allergen source. So this might be plant or animal-derived foods, arrow allergens, and it's different from conventional serum testing, which measures an IgE response to the whole allergen, which has a mix of proteins. So in the CRD or component testing, we're looking at IgE response to very specific proteins within an whole allergen. So when somebody is allergic to something, whether it's a food or a drug or a venom or an inhalant allergen, their IgE is actually recognizing and binding to specific proteins within that. And this is what sets off the allergic response and the whole cascade of an allergic reaction. So the CRD actually allows us to look at that a person's binding to those specific proteins where we know which ones they are, and those proteins also are associated with like different biologic functions within the plant or the or the animal. So I think we know that they're with conventional serum testing, looking at IgE levels for for a whole food, such as like peanut or milk or egg, we see a lot of false positive testing because because the IgE is binding to the whole allergen, and it's it's not necessarily binding to the clinically relevant allergens within the within the whole protein, and maybe giving you a sensitization uh result that's not actually clinically relevant. So I'll sort of talk about there's like there's two kinds of uh component result uh diagnostic testing assays, the one that we use more than the other. One gives us a quantitative measurement of IgE concentration to individual allergens using like the immunocap methodology, is really just like our conventional serum IgE testing. And there's also an Isaac test, which is the immunosolid phase allergy chip, and that gives you results for IgE binding to multiple components at once from different allergen sources, and it gives you more of a semi-quantitative result. And both of these assays can use native proteins that have been isolated and identified, um, or recombinant proteins that have been developed. And these have really been like identified and purified and developed over the last 30 years. So, sort of when I was finishing fellowship, I think we maybe had access to testing for you know proteins, component proteins in milk and egg, and really not much else. Peanuts started to be available during my or after my fellowship, and now we have you know many more within our commercial labs that we can actually order to order. And some of these tests are approved by the FDA and some are not or may not be yet. Um, and we know that these different proteins can be, even though we have access and identified many, not all of them are equally clinically relevant, which we'll go through sort of different foods, I think, some of the later questions. But CRD testing might hopefully improve diagnostic accuracy for food allergy testing, and maybe in some cases, maybe better than just skim prick testing or the conventional IgE testing. And the CRD may actually be identifying the proteins that trigger the allergic reactions rather than giving us a false positive sensitization result. And we're hoping we're looking at, you know, we're looking at whether it can be used in their ongoing, and there have been studies of whether that the CRD testing can give us information not just about like clinical reactivity, but maybe prognosis or like persistence of a food allergy, severity of a reaction or potential for severe reactions, and maybe even like how someone will respond to a therapy. Um so this is sort of where we, you know, there may be a lot of applications for component testing that we aren't even using yet. So we would love to have like cutoffs and know the you know clinical importance of every single allergen. I don't think we're really there yet. And obviously, this is like an area of pretty active research. So everybody needs to stay tuned.
Rebecca Saff, MD, PhD, FAAAAIIs the Isaac test does it is it much different than the the testing that you would get from a conventional laboratory with components?
Amanda Cox, MD, FAAAAIUm it's gonna give you semi-quantitative results. You're not you're not gonna be able to look at like concentrations of IgE. So I think it's gonna be more like positive, negative, relative, but and it's it's probably good for screening to see if there's sensitization to to like important allergens. I I think um I've seen it commercially at points I've seen it available commercially where you're looking uh like cat and dog sensitization patterns because it's sometimes it's useful, useful for that as well. But I haven't we really haven't used it. I haven't used it in clinical practice and no.
Rebecca Saff, MD, PhD, FAAAAII think that's primarily a European test. They we don't use it as much in the US, I think.
Amanda Cox, MD, FAAAAIYeah, that sounds right.
Rebecca Saff, MD, PhD, FAAAAITell us a little bit about the epitopes of the different proteins.
Amanda Cox, MD, FAAAAIOkay, so first I should explain what an epitope is. So an epitope is actually a sequence of proteins and it can be linear or conformational. A linear epitope is a row or a continuous chain of amino acids. Conformational epitope is the 3D structure that forms when this when a group of protein folds up. So IgE can be specific for linear or conformational epitopes. This is this comes into play with uh milk and egg allergy and also for peanut. Generally, the conformational epitope can be disentangled or unfolded or denatured when with heat or enzymatic digestion. So it's considered more labile or unstable. The linear epitopes, however, may not be denatured or destroyed by heating and are more stable. In our example, IgE sensitization to linear epitopes may confer allergy to baked forms of milk or egg because baking doesn't break up those the epitopes or the major allergens in casein. But if you're only allergic to the conformational epitope, baking may destroy the that structure, and then your IgE doesn't recognize the um sort of milk in there, and you may be able to tolerate baked a baked milk product. So somebody who's only sensitized to confirmational epitope in particular for egg or milk may be able to tolerate baked forms of those. So that's sort of where the epitopes come into play. There's also you know evidence that people may their IgE may attach to different multiple epitopes. And if you have a if there's a diversity of epitopes within an allergen that you recognize, you'd be maybe more likely to be clinically reactive versus if you don't have a diversity of epitopes that your IgE recognize. So this has been looked at for peanut in terms of threshold, sort of threshold for reacting to peanut. People with more epitope binding are more likely to be reactive to smaller amounts or lower doses of peanut or trace amounts, whereas those who are not don't have that diversity of epitope binding may not be quite as sensitive and might not might not react to the smallest amount of peanut. So epitope testing in particular for peanut is commercially available uh in a private lab. We unfortunately are not not able to do it in New York, so I don't actually run that test, but it is it is out there and you it does come with that particular threshold interpretation when you get the result.
Rebecca Saff, MD, PhD, FAAAAISomething that if you have access to maybe worth exploring. And then what are the major protein families that we see in pollen and foods? And what particular proteins are they recognizing, and why does that matter to our food allergy?
Amanda Cox, MD, FAAAAISo the allergen protein families, like from my reading, they're really based on the structural, structural and functional properties of you know these amino acid sequences. There's actually an a World Health Organization and an international union of immunological societies that has established like a whole nomenclature and the subcommittee that standardizes these names for allergenic proteins as they're also being sort of, I guess, purified or identified. And these are sort of these are based on biochemical analysis. I don't really know all of the details about that, but there's also sometimes the names are based on homology to other ones that we also recognize where there's probably cross-reactivity. And so this is an you know evolving process and more and more being identified. Within the plant-based, you know, plant-based food allergens, the major allergens uh are there's the cupin superfamily. So these are the stable seed storage proteins, and we're pretty familiar with these from peanut. Uh, the biselins, uh, RH1 and Jugar II are cupons, and the in um peanut also and he's let RH3 and chori9, these are cupons, these are major allergens in peanut. There's also the prolamin superfamily, and this includes the the 2S albumins, which includes the Brazil nut, bear E1 and Cessite 2, Jugar 1, these and sorry, and sesame and walnut, and these are major seed storage proteins, and they're stable and they actually do confer like clinical reactivity. Within the prolamin superfamily, there's also the nonspecific lipid transfer proteins or the NSLTPs. These are also resistant to enzymatic destruction or pH changes and heating, and they there actually there's a lot of cross-reactivity within the NSLTPs. Some of the more well-known ones are um PRUP3 in peach, MALD3 in apple, Cori8 and hazelnut. There's also amylase and trypsin inhibitors, and then there are serial prolamins. There's also the pathogenesis related, pathogenesis-related proteins are the PRs, and this is actually a family that has 14 different heterogeneous family of 14 different families. So, like all of the sort of classification is can be a little bit nebulous if you're not a sort of molecular biologist. But these are uh proteins that are involved in plants' resistance to pathogens and and harsh environmental conditions. And these are the ones that are that we know well as being responsible for pollen fruit or the old what we used to call oral allergy syndrome, but pollen fruit allergy syndrome and latex cross-reactivity. So those are some of the protein families in plant-based food allergy that we're familiar with that we can test for. Within the animal-based food allergy, um, I like wanted to focus sort of on milk and egg, because we know the most about them. And again, like milk is one of the ones that we have had component testing, although it wasn't called that necessarily back then, 30 years ago, but we have had uh access to testing for casein and and whey and large albumin for a while. But so within milk, the casein family, the major one in there is the VAST8, which is casein. This is a major allergen milk, it's accounts for about 80% of all of the milk proteins. And and that and sensitization to casein or BOS T8 is associated with more persistent milk milk allergy and maybe more severe reactions and even reactivity to like baked forms of milk and suggested. And there are other caseins as well. Within milk, we also have the whey family, and the whey family allergens are more sensitive to heating. They lose their binding after boiling for a little while, so they're not as not as stable as the caseins, and they are not as important in milk allergy, but there is you know there is some sensitization to these too. But the beta-lactoglobulin, alpha lactalbumin, these are most, these are major allergens within the whey fraction. Um, there are also minor components like ovine serum albumin and lactoferin uh within milk. So, sort of how milk can be sort of separated into casein and whey, and within those, there's there's individual allergens that we can look at. And for egg, the sort of important one to know is ovamucoid, which is also galdy one. And this is a very good predictor of all forms of egg allergy. So it's in henzeg, or this is one to know. Ovalbumin, which is gal D2, is actually the most abundant protein in egg white, but not the most allergenic. And there's lysozyme, uh, which is actually, I believe it's responsible for the sort of unusual uh egg feather syndrome, because it's found in hen yolk, chicken meat, um, and then galdi three is conalbumin, which I I haven't really tested for that. So this is those are for milk and egg, those are the the major allergens that at least I'm familiar with or I'm used to seeing there are also proteins within like shrimp and some other foods that have been identified.
Rebecca Saff, MD, PhD, FAAAAIAnd do you think we should always order this component testing? I mean, do you think that this is something that's always worthwhile, or should we only order it in certain cases?
Amanda Cox, MD, FAAAAISo it's interesting, like when we're seeing a patient for food allergy, like I think we are interested in you know determining as accurately as possible what they're actually allergic to. We don't want, we don't want people to be on overly restricted diets. We don't want them to worry about severe allergic reactions if there's little to no risk of that. We also want to avoid having to do food challenges if there's a really high certainty that there'll there will be a reaction or risk of a severe reaction. So, like when we're looking at allergy testing, these are the kind of things I'm thinking about. And we want tests with very high sensitivity and high specificity, and obviously in a perfect world, we would have that. But no test that we have is perfect. And I would say I don't think that we should just be doing component testing for everyone, for everything. If we had like really high quality data and predictive cutoff values for these in terms of predictor, then I'd say, yeah, we'd I would use that test 100%. But you want to look maybe at the individual food and see what the evidence is for that component to be used for evaluating that particular food. So I I think we have uh probably good evidence for, and we can talk about those for the for molecular diagnosis being part of diagnosis for peanut or dog you for cashew and hazelnut, and then some evidence for milk and egg as well, but it's the the testing is not perfect predictors. But I I think it can be part of your armamentarium. It wouldn't be the only thing I would do. Um, I think the the clinical history is important, your sort of pre-test probability, or like if the patient coming in there with the history of a very recent reaction to the food, it couldn't have been anything else. Like, how you think about whether you need to order, you know, extraneous tests if it's already quite certain that that allergy is present. Although the caveat would be is if someone's going to be doing a therapy or doing some other intervention, you may be looking at these components as sort of a baseline, baseline measurement. So, yeah, I think I think it's not necessarily for everyone for every food, but I think it's like a really useful tool for some foods.
Rebecca Saff, MD, PhD, FAAAAIAnd you've already alluded to some of the different classes. I thought we could talk about some different foods and kind of that way really get a good idea of how we can use it. And starting with, you know, peanut is probably the component testing that a lot of people are are familiar with. Um, and how should we interpret? So we get these call these components, you mentioned one, three, or one, two, three, six, eight, nine are kind of the usual ones. How should we interpret those? So a positive RH2 versus an eight versus let's say a six.
Amanda Cox, MD, FAAAAISo I think this peanut is a good example because we do have probably the most evidence for the utility of this type of testing. I think this there are six that we can quite widely have tested, at least in the US. That's that's one, two, three, six, eight, and nine. There are other allergens within peanut that have some clinical relevance, but I don't think the studies are as big or wider that we know. But there's like also RH4, five, seven, ten, eleven, twelve, thirteen. And these have been identified, and you know, they may have some clinical relevance as well, but I don't I don't think we're there yet to, and they may actually have cross-reactivity with ones that we already know about. The RH1, two, and three, these are the seed storage proteins, and these are major allergens in in peanut. So I think they have like very high clinical relevance. RH6 is a is called a congloten and is very closely related to RH2. Both, so RH6 is also important and associated with clinical reactivity. Both RH2 and RH6 may be associated with more severe reactions to peanut. So I think these are sort of our our starts. Major allergens. RH8 is goes back to our family our food allergen or plant-based allergens. So this is actually a Bet B1 homologue. It's related to birch pollen. RH8 is heat label, so it like breaks apart in heating with heat or with digestion from digestive enzymes. And it's the one that's associated with the pollen food syndrome in some people. So if you have an isolated sensitization to RH8, this is generally associated with probably being able to tolerate peanut and andor just having mild symptoms that are like oral allergy symptoms with peanut, usually raw peanut ingestion. RH9 is interesting. So this is a an SLTP. It is a stable protein, so think of it as being important. But we sensitization to RH9 is predominantly seen in in Mediterranean areas, but it can be associated with very severe reactions. So it isn't it isn't one to ignore if you if you have a positive result for RH9. So I say like RH2 seems to be the best for predicting like clinical allergy to peanut, but we don't have like absolute cutoffs for that have a high predictive value. And we even see like at different ages and different geographic regions that the the value of RH2 may have a different predicted value or a different implication.
Rebecca Saff, MD, PhD, FAAAAIYeah, no, the different areas that it might be different re related to their geographic region.
Amanda Cox, MD, FAAAAIRight. I would say go back and say that if you have you know multiple of these allergens positive, that's also a like if you have RH1, two, three, six, all positive or significant, this indicates a like a greater chance of reactivity as well.
Rebecca Saff, MD, PhD, FAAAAIOne thing that comes up pretty commonly is someone comes in and they have had positive testing in the past, someone sent it because they had some kind of symptoms. And if someone has had pretty mild symptoms, but they have a positive ARH2 versus a positive ARH eight, would you how would that change your decision about whether you should challenge them if their ARH2 is positive, but their symptoms have been very mild versus an RH eight with mild symptoms?
Amanda Cox, MD, FAAAAIOh, it's interesting. You're talking to someone who we do a lot of food challenges for other reasons. So not just to determine if someone's allergic or not, but sometimes a determined threshold, sometimes to determine uh like readiness for a certain therapy. So so my my decision making is a little bit skewed by that. Yeah, but if in the regular clinical office, I I would take into account like, okay, when when was this test ordered? Like what I mean, when was the test first obtained? Um, and when was the the reaction history? So if if it was a remote history of reaction and you have a test now and and RH2 is positive, I I would actually look at probably the absolute level of the RH2, compare it to the other components and whether they're positive or not. I would use skin testing as well to help decide, you know, look look again for clinical reactivity. I think a large skin test for peanut over eight millimeters can be suggestive of a risk of reaction. And I guess like any history of tolerating the food before, you know, before having had any type of reaction. And then, of course, obviously severity reaction. Like what were the symptoms? Did the patient complain of oral itching and or hives around the mouth or a little congestion, or did they have respiratory distress and generalized hives and hypotension? You know, so severity of reaction is also really important when you're deciding whether to offer a food challenge. So I'd say, like, if if testing really skews towards RH8 being the only positive test and maybe a mild, a history of mild reaction, I would go ahead and challenge that that person. If the RH2 is positive but relatively low and compared to other components, I might also challenge them. But I'd say like an RH2 that is positive is a pr is more sensitive than nothing. And I would probably use that as a predictor and defer food challenge if it seems like the clinical history and that test is positive. You probably don't need to do a food challenge. You have your you probably have your diagnosis, but I think that clinical history, yeah.
Rebecca Saff, MD, PhD, FAAAAII think that clinical history plays so much into it because if it was very mild, you want to take that into in the context of the testing, you can't use the testing alone. Absolutely.
Amanda Cox, MD, FAAAAIAnd the age is important too. I think you know, if this is if the reaction happened when they were a baby or a toddler or they still are a toddler, we do see we do see transient peanut allergy. We know that the natural resolution rate for peanut allergy is probably around 10 to 15 percent. So you're gonna see patients who really do react who actually really outgrow it without any intervention. So I think using using any testing is helpful for that. I think the RH2 testing is not as not as useful in the younger patients, for but in like a teenager, they had a reaction as a toddler, and you have a you do testing, even negative RH2, they may really well have outgrown their peanut allergy, and it would be very worth doing a challenge and um probably getting rid of that label of peanut allergy for them.
Rebecca Saff, MD, PhD, FAAAAIBesides the kind of two and eight that we think about kind of most commonly, is there are there certain components that are more likely to be outgrown than others from you know, especially the one, three, six, nine families, or not, we don't really know that yet.
Amanda Cox, MD, FAAAAII don't know exactly how RH6 behaves over time, like sort of the natural history of that. I think if you have a positive test for one N3 by the age of one, there's been at least one study that shows that this may be associated with persistent peanut allergy. And I think having multiple allergens that are significant also probably predicts more persistent peanut allergy.
Rebecca Saff, MD, PhD, FAAAAII think tree nuts have become more complicated because we used people used to be told that they're just allergic to all the tree nuts, and now we're kind of thinking about them more much more individually. And so, which of the components of tree nuts are you most useful clinically? Things like ANO3, um, jugar one, you know, what where is it that we want to use those with the tree nuts?
Amanda Cox, MD, FAAAAISo we do we don't have component testing for every tree nut available, at least not in the US. So um the only tree nuts that that I am aware of and that that I that I use in my sort of my clinical evaluation are component testing for Brazil nuts, so berry one, component test and for cashew and O3, component testing for hazelnut, so we have four components there: one, eight, nine, and fourteen, and walnut. We have jugger one and jugar three. So I will use those in clinic. I think the the ones that are sort of the full the best predictors are the cashew and o3 and the hazelnut, in particular Cori 14. These are these are predictors of of true like clinical allergy and sensitization to those, like may predict more severe reactions too. So I think those are very important. I I think the data for walnut jugar one we is the seed storage protein, we would think that that is probably associated with more persistent or severe reactions and maybe helpful in diagnosis, but I don't really have cutoffs or numbers that I feel are that useful yet. And the Brazil nut, I think the berry one is okay. I get there's just there's not very much data on Brazil nut. But I would say for cashew and hazelnut, the component testing can be pretty clinically useful. Similar to peanut with hazelnut, you know, there is the there is the sort of bet B1 homologue in that cluster of allergens of components in hazelnut. So core A1 is like RH8, is a Bet B1 homologue. And if you're if you've isolated sensitization to Core A1 with hazelnut, then that may be associated with being able to tolerate hazelnut or just having like mild oral allergy type symptoms with that.
Rebecca Saff, MD, PhD, FAAAAII'll say I've definitely had people with uh very positive component testing to what I think is, you know, all Core A1, for example, but they ate a lot of it, um, their numbers are very high, and they exercised. And I feel like, you know, you have to take into account all of those factors too. Um, and then they have bigger reactions because they have all those kind of things stacked against them going into it, even though it seems like one of the ones they would tolerate better.
Amanda Cox, MD, FAAAAII I've actually seen that also with soy, um, that people that are highly birch allergic have had soy, like concentrated forms of soy, either like soy protein shakes or soy milk. And I think the bet via homologue, they have symptoms and exercise. And I've actually seen some some more significant reactions. It's probably related to this cross-reactivity.
Rebecca Saff, MD, PhD, FAAAAIYeah. So what about soy? There's soy components, and so why is soy frequently positive, at least the whole allergen in patients who tell her soy, and do the components help us?
Amanda Cox, MD, FAAAAII couldn't find a lot of great data on on soy. So I think there have been there are a lot of allergens that have been identified and characterized, but I don't think the sensitization patterns are really well worked out yet. Um, and they haven't they haven't been very useful yet in predicting clinical allergy or severe reactions to soy. I I think we need more data, but again, yeah, the Gly M4 is that B1 homologue, and that can count for soy like a total soy IgE being positive or soy skin test being positive even without a soy allergy, if if a patient is also very birch allergic, but it also could be associated with a real allergy. So I I think not quite sure if we're there yet with soy components being like extremely useful, but I think it would be it would be good if we do know more. I think I did find, you know, in sort of preparing for this, there is there are some other sort of regional findings with soy. Um there was a study of soy allergy in Japanese children, they found Gly M2S and Gly M8 to be important in this population, and then there was another study of adults with soy allergy in the Netherlands who also found that same allergen to be significant. So I think there may be regional age differences as well with soy, and again, the sort of the birch, the birch pollen allergy is another you know factor in cross-reactivity and probably some false positive testing.
Rebecca Saff, MD, PhD, FAAAAIAnd I wonder if it's the form of soy in the local diet, you know, the versus what we eat here in the US versus in the Netherlands versus in Japan is probably quite different in terms of the form of soy that's most common.
Amanda Cox, MD, FAAAAIAbsolutely true. Yeah, the different way things are manufactured and that sort of concentration, and I guess probably even the concentration of the individual allergens within those products makes makes sense.
Rebecca Saff, MD, PhD, FAAAAIYeah. And then what about sesame? Um, that we have a component for sesame now. How reliable is that?
Amanda Cox, MD, FAAAAISo for sesame, we do have sesite one as a component that's available to available to us to to evaluate overall sesame testing isn't highly, isn't predictive or as good as some other foods. Um in this one study that was sort of a meta-analysis of a of component testing for all different uh food allergens, they looked at, they found nine studies that fit their criteria to look at that had pulled data of sesame allergy. And in this, the the sesame one had like a 77% sensitivity profile and 87% specificity. And it wasn't really clear from looking at these nine-pole studies that that was any better than looking at the skin test or the sesame IgE. And even those are only around 70% sensitive, the skin test and the sesame IgE, the sort of standard IgE testing for that. So I think again with sesame, we need more, we need more information for about that too. I don't know that's the first one that I would that I would run to test when you're evaluating salemity from sesame allergy because it doesn't, it's not clear that it that it performs better than the skin test or the blood test, the normal blood test.
Rebecca Saff, MD, PhD, FAAAAISo that one it may be worth getting the skin testing, getting the blood testing and the clinical history and putting it all together, the component isn't as useful there.
Amanda Cox, MD, FAAAAIYeah. I would say sesame overall is an emerging allergy in pediatrics, and there is more information about it, and I think we'll have we will have more uh because it's just it has sort of become more prevalent in the last like 10-15 years. And so we will know more if it affects more people, we will we will learn more about it.
Rebecca Saff, MD, PhD, FAAAAINow the ninth allergen on our list, so that so then we'll be able to kind of pick it up probably better because we'll know which foods actually have it and what people are reacting to. So it's useful. Yeah. Yeah. Um, so it sounds like kind of in summary in the tree nuts, it sounds like cashew, the ANO1 is a useful component. The Brazil nut, uh, the hazelnut, maybe we're still working on the data for walnut and kind of how we should use that in our in our clinical kind of judgment.
Amanda Cox, MD, FAAAAIYeah, Ana O3 for cashew. But I and then we don't really I we don't have a component test that I'm aware of has been published for almonds. And uh we know pecans are related to walnuts, so I I generally assess that allergy together kind of as one walnut pecan, and pistachio is closely related to uh cashews, so similar, and they're they're homologous tree nuts, and then there are some other tree nuts we don't I macadamia, pine nut, like those are ones I don't think we have any. I have not seen any data on that, but probably because they're less common tree nut allergies, I think you know, we see more cashew, pistachio, walnut, pecan, hazelnut allergies, those are definitely the more common ones, at least in the US.
Rebecca Saff, MD, PhD, FAAAAIYeah. Oh, definitely. So one of the most common misconceptions in allergy testing, especially with our patients, is that the number reflects how severe their allergy is. And so um, how do you explain to patients, you know, how that relationship between the number that they're seeing, oh no, it's you know, take a number, it's 90 versus it's 20. And does that predict severity or threshold, or is it more just about whether or not they'll react?
Amanda Cox, MD, FAAAAII don't think it's at this point reflects severity. I think it reflects like likelihood of reactivity. Looking at the sort of meta-analysis that I was reading last night, their thresholds for it being predictive of uh reactivity were actually quite low numbers, like for the different um peanut and tree nut allergens, like ranging from like 0.3 to 1.2 or something for the different foods. So pretty low numbers just like essentially being positive or predictive of clinical reactivity. So it really didn't see anything about even even higher levels and and what they mean. I think it's it's more going to be predictive of true reactivity versus no reactivity rather than like severity of reaction, with the exception that if if you're suspecting, if you're trying to rule out sort of a pond food allergy syndrome and we're considering that a mild reaction versus like a more systemic allergic reaction potential, like that's so that's a difference. Obviously, those those are less severe, but otherwise, in terms of the potential for systemic reaction to food, I I haven't seen that there's a correlation yet.
Rebecca Saff, MD, PhD, FAAAAISo and how much should other patient characteristics play in things like age? You mentioned that younger, you know, that sometimes we should take caution with younger kids versus older kids. Um, how should we think about that?
Amanda Cox, MD, FAAAAIWell, one thing is like the clinical history that you are able to get from a get from those different ages. So, you know, obviously um just the fact that they are a younger child and they probably if you're seeing them in their one or two, and their history of reaction is pretty recent, most likely, because they haven't had the decades to be eating or not eating a food. So you have a more like more recent reaction history, which already sort of increases your pretest probability if you're looking at if you're evaluating somebody who has a clinical reaction history. If you're looking at the I at least with RH2, if if there's no reaction history and you're just evaluating component tests, the testing isn't as good in in the toddler or baby age. So a negative RH2 in a one or two-year-old isn't as helpful as as it would be in a 15-year-old. Whereas in a 15-year-old, a negative RH2 would be pretty helpful at letting you know that that person does not have a peanut allergy, it's probably safe if everything else is negative, of course. But it wouldn't necessarily be predictive for for a younger age.
Rebecca Saff, MD, PhD, FAAAAII was in in when I was trained, I was always taught to send a total IgE with it. And then it turns out some of my colleagues that were trained at other places do not send total IgEs with it. Um, I know that there's probably no perfect answer to this, but um, do you think that's a useful number to have kind of the overall IgE burden, or we don't have enough information to really know?
Amanda Cox, MD, FAAAAII do use, I wouldn't necessarily associate that with component testing, but I do use the total IgE in general in my evaluations to sort of look at atopic status, also for you know our patients that have like pretty extensive eczema, especially at a young age. Sometimes the elevation of the total IgE is skewing everything. Um, so it would skew the the whole protein um you know Ig levels for foods as well as skew the components if you happen to get those too. Um, so I I would say I the total IgE is is still a useful thing to look at. Um and seeing it change over time in you know a child who's getting older, you you would sort of are following an expected pattern of it sort of increasing and plateauing. And you know, so that's I think that's probably important. And also, you know, we don't I don't really use ratios or or numerical ratios at this point, um, but there's some evidence that it may be helpful in in determining like response to therapies, in particular food allergy, oral immunotherapy or you know, other immunotherapy, those those ratios might be helpful in determining like how someone's responding. So I don't think of it as necessarily a component per se, but uh I think there's a there's a place for doing total IgE.
Rebecca Saff, MD, PhD, FAAAAIWhere do you think component testing fits into kind of our modern diagnostic algorithm? How should we kind of weigh the different factors? The history, the skin testing, the blood testing, the component testing, um, and how do we kind of put it together for the patient in front of us?
Amanda Cox, MD, FAAAAISo I sort of repeat that we always want to consider like pretest probability, so likelihood of the patient having a food allergy based solely on like the clinical history they're presenting, and also comorbidities like like potentially asthma, um asthma, hate fever, eczema, EOE, or an isinophilic uh gastrointestinal diseases. So I think that skim prick testing, sort of standard skim prick testing with commercial extracts and the serum IgE that we've been doing standardly are still favored for supporting a diagnosis of food allergy, in particular for peanut egg, milk, hazel, and cashews. We sort of talked about those foods. They're they're still highly sensitive, and a negative test of a negative skin test or serum IgE for any of these foods is really does help you rule out food allergy. I mean, there may be a food challenge involved in there too, but it does help with that process. These tests, the skin prick testing, IgE, standard IgE, are are less accurate for sesame, soy wheat, shrimp, and other food allergens. And the component resolved testing, I think, seems to perform the best after looking at all these meta-analyses. It seems to be the best for RH2 and peanut, the Cori14 in hazelnut, and the NO3 in cashew. So I think it's it's useful if you have a question about these allergies being present or real or you know clinically important to a patient. Ovomucoid will support a diagnosis if you have a positive ovomucoid IGE. This supports the diagnosis of likely being allergic to raw and cooked egg. And casein can support the diagnosis of milk allergy, including allergy to baked milk, but it doesn't look like the component testing is like is much better than whole extracts for milk and egg. Doesn't mean you can't look at them and gather more information, but it just may not perform in a more predictive way, I guess. And we we do, but we do know that the testing for whole extracts for milk or egg doesn't really help you with baked milk or baked egg allergy or determining that at all. So for peanut in particular, it you know, doing component testing is not going to be so informative. Again, if we've talked about it, there's been a recent convincing reaction and you're trying to determine if they're allergic. You had a recent convincing reaction, you probably still are allergic. If it was yesterday. If the you know, if it's a remote history but of reaction to peanut but the total peanut IgE is over 15 or 20, the component test is probably not also going to be that helpful. And if the patient, if the child is younger, one or two, and their total peanut IgE is um is already low, then the component test may not, the RH2 isn't going to be so helpful. But again, like if you have a mild history or no reaction history, or the reaction was a while ago, and the patient has developed in the meantime a birch pollen allergy, and if the peanut IgE is somewhere you know positive but less than 15 to 25, it might be a really useful test as an example.
Rebecca Saff, MD, PhD, FAAAAISo I wanted to kind of actually kind of have a little case that we kind of talk through maybe as we think about the components. So let's say we have a teenager around 15 with seasonal allergic rhinitis, mild eczema, and was told when they were very young that they were allergic to peanuts and tree nuts. Um, because of testing that was performed, no history of reaction, um, but um a sibling had a food allergy and they got tested. So he avoids all nuts. And he accidentally ate a small amount of a hazelnut containing candy several years ago, had some itching. That was it, took some antihistamines. So the history is not, we don't have a lot of history, you know, probably just tested. And this is true with a lot of kids, I think with particularly coming in the teenage years, they didn't grow up in this necessarily introduce all the nuts era that we're now in since the LEAP study. So they have this, you know, history that's hanging over their heads. Um, we let's do the skin testing. Um, let's say that they're positive to peanut, hazelnut, cashew, pistachio, and they have this low ARH2, but a strongly positive ARH eight, which goes with this history of allergic rhinitis. So just starting with peanut. Um, how would you use those numbers to kind of decide whether or not you should go forward with a food challenge in this kid?
Amanda Cox, MD, FAAAAISo I mean, I think the relative number of the RH2 is important there if it's relatively low in the less than less than one range and the other, and the total peanut IgE is a reflection of the high IRRH eight, then this would be someone who it probably would be useful to do a food challenge. Um, again, they did not have a history of peanut reaction, and I guess uh yeah, just to emphasize that somebody missed may have missed the sort of critical window for um introducing peanut early um and a kid who was at higher risk for developing peanut allergy with no exposure, but that's uh that's like Monday morning quarterbacking, as they say. But that is too bad that it didn't, but hopefully it hasn't become true peanut allergy. It's it is possible that they could actually be allergic to peanut, but I do think that the challenge is warranted there.
Rebecca Saff, MD, PhD, FAAAAIYeah, sure. And then what about core their low positive Core A14, but a strongly positive Core A1? What do you think about that in terms of hazelnut? And they had this history of having some itching in their mouth with when they ate hazelnut.
Amanda Cox, MD, FAAAAIYeah, so similarly, like the it's the the Bet V1 homologue there that's um that's positive, the the Cori1, and and the Cori 14 is is a is a pretty strong predictor of of real hazelnut allergy. We're seeing it's low positive. So I think this one it might be worth challenging the hazelnut. They did have some symptoms with the hazelnut containing chocolate. Generally, like generally, if it's chocolate, it's pretty highly processed. So you shouldn't be having oral allergy symptoms with the with the processed hazelnut in a chocolate. Um, so it's a little bit of a question, this may be real hazelnut allergies. So I would approach that challenge with caution because there is a possibility that's that's a true hazelnut allergy, even though he it does seem like he is probably also strongly birch allergic. And then with cashew, I'm more worried that that is a true cashew allergy. NO3 is not a BEP1 homologue. Cashew isn't as cross-reactive with tree pond in general, and it's definitely possible that in 15 years he could have developed a cashew allergy or had it even from the beginning if the testing was done, was when he was pretty young and just sounds like he did a good job of avoiding avoiding the foods, like maybe too good of a job, but he did a good job, so he didn't have a reaction to cashew. So that one I would be hesitant to challenge.
Rebecca Saff, MD, PhD, FAAAAIYeah, no, fair enough. Cashew is definitely one that can cause reactions. Sounds like an three is a better component than some. And he may be allergic to pistachio too, most likely.
Amanda Cox, MD, FAAAAIYes.
Rebecca Saff, MD, PhD, FAAAAIExactly. Well, that's great. Do you have take-home messages you want people to remember about component testing?
Amanda Cox, MD, FAAAAIWell, I think the take-home messages, yes, it can be, it can be very useful and helpful. It does give you a more granular picture of an individual food allergy. I think like understand that this, the testing will, I guess the utility of it and the sort of understanding of it, it's it's gonna grow because we we will have more studies where we have correlation between these actual values and double-blind placebo-controlled food challenge uh results. So I think we may have we may end up having scales or more predictive, positive predictive values for these levels. So that's something to look out for. And we may even identify um important allergens in some of the foods that we don't have them for yet. So I absolutely think we should be staying tuned and this is like a growing, a growing area, not just in food allergy, but in I think in venom and environmental allergy and for sure.
Rebecca Saff, MD, PhD, FAAAAISo it's great to be in a field that's continuing to grow so rapidly, like in Lurky.
Amanda Cox, MD, FAAAAIIt keeps us on our toes and keeps us engaged.
Rebecca Saff, MD, PhD, FAAAAISo totally. Well, thank you so much.
Amanda Cox, MD, FAAAAIThank you very much.
Rebecca Saff, MD, PhD, FAAAAIWe hope you enjoyed listening to today's episode. Please visit aaaai.org for show notes and any pertinent links from today's conversation. If you like the show, please take a moment to rate and subscribe through wherever you download your podcast. As a reminder, this podcast is not intended to provide any individual medical advice to our listeners. We do hope that our conversations provide evidence-based information. Any question pertaining to one's own health should always be discussed with their personal physician. To find an allergist search engine on the Academy website is a useful tool to locate a listing of board-certified allergists in your area. Use of this audio program is subject to the American Academy of Allergy Asthma & Immunology terms of use agreement, which you can find at aaaai.org.