Dr. Gerry Lee (Host): Hello, everyone, and welcome to another episode of AllergyTalk, a roundup of the latest in the field of Allergy and Immunology from the American College of Allergy, Asthma, and Immunology. For today's episode, we'll be reviewing more article from AllergyWatch, a bi-monthly publication which provides research summaries to college members from the major journals of Allergy and Immunology. And you could also earn CME credit by listening to this podcast. If you want more information about CME, head over to education.acaai.org/allergytalk. And we also have that community on DocMatter where we can continue the discussion about these articles.

Well, hello again. My name is Gerry Lee. I'm an Associate Professor at Emory, an Assistant Editor of AllergyWatch. And once again, I'm joined by the Editor-in-Chief of AllergyWatch, Dr. Stan Fineman.

Dr. Stan Fineman: Hi. And thanks for having me again and looking forward to a good discussion. I'm retired from active practice, but still active at Emory as an adjunct faculty. And I'm a past President of the College of Allergy.

Host: And for the third chair, we are so excited again to be joined by Dr. Vivian Hernandez-Trujillo. She is the Division Director of Allergy and Immunology at Nicklaus Children's Hospital, an Assistant Editor of AllergyWatch. Viv, So glad you could come back to AllergyTalk. Tell the audience a little about yourself.

Dr. Vivian Hernandes-Trujillo: Thank you so much. So, I'm excited that I am a Fellowship Training Program Director in A&I. And I'm also a Clinical Professor of Pediatrics at Herbert Wertheim School of Medicine, and very excited to be with both of you today.

Host: All right. Well, we got an interesting slate. I am so excited to get started. Stan, tell me a little about the grass pollen allergy testing. You have something to tell us about its accuracy and considerations.

Dr. Stan Fineman: Right. Well, it was presented in AllergyWatch and commented by Dr. Joshi. And the article is entitled IgE to Cross Reactive Carbohydrate Determinants, or CCDs, in Childhood: the Prevalence, Risk Factors, and Putative Origins. And it was published in Clinical Experimental Allergy earlier this year.

Just another plug for AllergyWatch, I mean, this journal is definitely not on my radar screen, but the fact that AllergyWatch looks at these journals to look for interesting articles, I think that's very important for us as we try to keep up with all the new developments in our specialty.

So, this study was basically looking at cross-reacting carbohydrate determinants, or CCDs. And usually, they're really irrelevant clinically, but they can cause a false positive outcome on an IgE test, mainly in vitro, not really in skin testing, but in vitro they can. So, it's not clear exactly what types of patients you see these in. But theoretically, you could get a false-positive serum IgE, you know, specific IgE when you do a screening.

What these researchers did was to look at children from Italy, it was 1263 Italian children who had pollen allergies, and then there were six hundred and twelve patients from Germany, these were children in a German study. And they used the basically serum that had been stored in these children who had been studied for other things previously. So, this was really sort of a panel, and they looked for the presence and the levels of IgE to these CCDs, they were examined in the serum and they used a special kind of bromelain as a reagent, and it gave it a novel chemoluminescence detection system operating in a solid phase of ______ labeled. Anyway, it's way over my head, but they use these particular microparticles to pick the CCDs up in the serum that had been collected from these patients. And what they found was that the IgE to these cross-reacting carbohydrate determinants were found in 22% of the Italian pollen-allergic children, mainly those who had Timothy grass pollen allergy. The more allergic they were, in other words, the higher their levels of specific IgE to the Timothy grass, the more likely they were to have these CCDs. Again, this is a lab study. It's not really clinical. But that was significant because they felt that the level of their severity of the disease was probably higher, or at least their sensitivity was higher.

The other thing that they found, which I thought was interesting, was the fact that most of these, they can develop early, these CCDs, they can develop early in life. And if they do develop, they tend to linger and they can last for quite some time. And in terms of characteristics of the patients, if some of them had asthma, I was a little surprised to see that almost half the parents smoked in this group of patients. Of course, it is from Italy and Germany, but still I don't think we would see that in our patients.

And the other thing, of course, to note is that the labs were done between 2009 and 2011. So, the studies were really older studies. The German study was done in the 1990s. So, it was collected a long time ago. But yeah, I think the interesting thing for us is the fact that these cross-reacting carbohydrate determinants can cause a false positive specific IgE test, not really a skin test, but specific IgE.

So when we do our diagnostics, I think we need to just keep this in mind and realize that maybe they did speculate. By the way, before I stop and we could talk about a little bit, they did speculate that the start of this was in the first two decades in life. And they did suggest that it was related to some type of a long living plasma cell that produces the IgE to these cross-reacting carbohydrate determinants. So, it may be B cell epitope-related. But anyway, it's just something that we need to look at, especially, or think about rather when we're making diagnosis, especially using labs in vitro or ImmunoCAP.

Host: So Stan, I know these carbohydrate determinants in this study was looking at pollen, but I think these determinants are in a lot of things, including food. So, did they comment about that? Because my perception is that we see these big, multi-positive Ig panels, and I think for some patients CCDs are driving that.

Dr. Stan Fineman: You know, they didn't really specifically talk about food. Again, they really were looking just at inhalants. They looked at grass pollen and tree pollens and they were not looking at food. But I think you're correct.

Dr. Vivian Hernandes-Trujillo: It's super important, Gerry, because we know like the use of these food panels for no really clinical reason is very dangerous. It leads to restriction of foods that patients could otherwise tolerate and can actually lead to food allergy if there is strict avoidance. So, I think this was really fascinating.

Host: Yeah. And it just shows you it's just so important to do skin testing. It's like the in vivo test of what's really going on in the mass cell. And so, you know, I know we do a lot of blood testing, it's convenient for certain patients, or now we have direct-to-consumer stuff. But there's no substitute to the actual in vivo test that you're telling us is more accurate. I completely agree with that. I have definitely seen discordant blood testing and skin testing, makes sense that these sort of false positive CCDs could be driving some of that.

All right. Well, that was super interesting. Let's go to the next article. So, Viv, you are going to tell us a little bit about a possible cause for transfusion reactions. That is a little unexpected.

Dr. Vivian Hernandes-Trujillo: So, I honestly was excited when I read this article because my question has always been Why do some patients react? And then. Why do some allergic patients react, right? But it doesn't happen with every transfusion. So, this was actually an article that appeared in Allergy in June of 2024. And Gerry, you were the reviewer in AllergyWatch. And basically, just some things for us to think about. In many cases of allergic transfusion reactants, we really don't know what caused it. Blood products can contain food allergens. So, we may not think about that, but they can. And then allergic transfusion reactions are more common in children than in adults.

So, here, the authors were actually interested in studying whether food allergens in blood products can actually trigger the allergic transfusion reaction in kids. And they conducted basophil activation tests. And using the basophils collected from children with allergy to egg, milk, or wheat, and then sera from healthy donors collected two and four hours after the donors consumed three raw eggs, 500 mLs of milk, or three slices of bread. I really thought that it was interesting the way they came up with their methods and how they studied this.

Kids with egg allergy did have increased BAT scores when the donor serum collected after egg ingestion was used. And the increased BAT levels were associated with increased levels of IgE to egg white and a history of anaphylaxis in the patients. And then, children with milk and wheat allergies showed response to only one of the donor sera. So, BAT responses here varied according to the time that actually passed between the consumption of the food by the blood donor, and then the blood collection and obviously the type of food. But they didn't verify the concentration of allergens in the donor blood, so I think that's something that would be important to look at. And then, obviously, further studies are needed. And so, one of the comments you made, Gerry, was that the study found that healthy donors who consume these foods four hours prior can induce basophil activation. So, we really need to have a better understanding, especially, you know, it almost makes you think, with time, if we study it more, there may be a box people check for patients who have food allergy. It sounds crazy to ask a donor, "What have you consumed?" But it might be something that's relevant and important to our patients. So, I really thought it was fascinating.

Dr. Stan Fineman: Yeah. That's a fascinating story, but have you ever seen anybody that had that kind of reaction?

Host: We never thought about it.

Dr. Vivian Hernandes-Trujillo: I know. I've had patients with food allergy who let's say also have a malignancy and needed transfusions and had reactions, but I never thought, "Could there be food allergens that are causing IT?" I know now it's something to think about.

Host: Yeah. It's just something to think about, right? We know we do like blood typing, right? We like cross match or whatever. Should we be looking at food allergens in certain patients? I know that's kind of silly. But it would be interesting if, as part of the compatibility process, we assess for mass activation. I'm not saying we can do that right now. But those are the sorts of interesting questions I'd never thought of, but it kind of makes sense.

Dr. Vivian Hernandes-Trujillo: It does. Because I always wonder why is this patient reacting today and has never reacted or is reacting multiple times. I really think it's important. It will be interesting to see what the technology, how we can address this in the future.

Dr. Stan Fineman: I mean, it's been a long time since I treated a patient who needed a blood transfusion, but I vaguely remember we used to say that histamine release was a factor. They would get the unit of blood, and then they might have a rash or they'd have something. And we would say, "Oh, that's probably just histamine release," give an antihistamine." But maybe there was something more to it.

Host: It was something in the blood. Maybe it was the egg sandwich, I guess, with milk. No, thanks for sharing that, Viv. I think it's something for us to at least think outside the box when we're asked to consult on a transfusion reaction. So, I got one more, and this one came out of the New England Journal from Steve Holland's group in the NIH, and we have moved the needle on the evaluation of immunodeficiency.

A lot of us are doing genetic testing to look for inborn errors of immunity. But this is going to the other side, which is the secondary immunodeficiency. And this is the concept of a phenocopy, where you have an autoantibody affecting immune function that looks like a primary immunodeficiency. You know, one, we always think about is acquired ______, you know, antibodies against C1 inhibitor. But this is actually talking about blocking cytokines that's going to cause an immunodeficiency-like disease.

And so, the title of this article in the New England Journal was Anti-IL-23 Autoantibodies in Adult-Onset Immunodeficiency. And it all started with a case. So, they had this case of a woman who had severe Burkholderia gladioli suppurative lymphadenitis. And when they evaluated why this was happening, they found these neutralizing anti-IL-12 p70 autoantibodies. And so, they published this in JCI, this is in 2013. . And after that article, what they realized was is that these anti-IL-12 auto-antibodies are actually not uncommon. So, there's a group of thymoma patients who actually have these auto-antibodies that this patient had, but they were fine. And so, they were wondering like, "Well, what? Maybe that can't be it if a lot of patients have these autoimmunities and don't have these severe infections." And so, that raised the question about could there be something else going on?

Well, the interesting thing about IL-12 is it has this subunit p40 that is actually shared with another cytokine called IL-23. We have a biologic called ustekinumab that exploits this, right? If you give anti-p40 subunit that targets both IL-12 and IL-23, we can treat IBD or psoriasis. And so, then they know this, so they're saying, "Okay, well, maybe the patient didn't have IL-12 antibodies as the pathophysiology, but had IL-23." And wouldn't you know it? They investigated this and they did find the presence of IL-23 autoantibodies that inhibited IL-23 induction of STAT3 phosphorylation. It inhibited the function of IL-23. But you know, again, that's one patient. So, they went through an intensive validation process with multiple cohorts to try to see is this real or not, and this just shows you the thoroughness of what the NIH goes through.

So, the first thing is they did a cohort of looking at other patients other than their index patient with IL-23 autoantibodies. And wouldn't you know it, two-thirds of them had invasive infections with fungal mycobacterial or bacterial pathogens. And those patients with the biggest potency, so again, they were able to measure the inhibition potential of these autoantibodies. The ones with the stickiest or most potent anti-23 antibodies had the most severe infections, and those who had maybe some binding but less potency had more localized infections. So, the potency of the autoantibody mirrored the severity of the phenotype. They also did a validation cohort where they looked at thymoma patients who have a tendency to make these antibodies. They did find 24 out of 91 with the anti-IL23 antibodies, and those patients were more likely to have infections. And the patients who did not have those anti-L23 antibodies were not sick. And they actually again expanded the cohort again and found two patients in their cohort just looking with unusual infections, and they were able to find IL-23 antibodies. But then, they looked at a healthy population and this is not common. It was very uncommon in donors with COVID-19 or Chronic mucocutaneous candidiasis with these antibodies. It's like less than 2% in the healthy controls. So, taken together, they have this evidence that there's a possibility of patients who take out IL-23 and these severe infections. You know, a lot of the things would be like intracellular fungal infections, mycobacteria, candida, pneumocystis, pseudomonas that resemble IL-12 receptor deficiency.

Now, here's the other thing that's very important. With that index patient, when they found that the patient had anti-IL-23 antibodies, they treated the patient with rituximab, with B-cell depleting therapy, and the patient had improvement in their infections and remission of their disease. And actually, that patient rebounded when they stopped ritux, so they kept it going. And so, when we think about how are we going to help our patients, certainly we could treat them like we normally do with prophylaxis. But in the patients with an autoimmune mechanism for their immunodeficiency, if we identify these patients, then if we do B-cell depleting therapy, counterintuitively, we actually could help them.

We actually could fix the online calls, reduce autoantibody, and that is another treatment in our armamentarium to help patients with these rare disorders. Now, clearly, this is not like we go to Labcorp and order these sorts of things. This is a collaboration with our colleagues in the NIH and other immunologists. But this just opens our idea of, like, when we are challenged with patients with current infections, other than genetics, we should be thinking outside the box of these phenocopies. And I thought it was very eye-opening.

Dr. Vivian Hernandes-Trujillo: We take care of these patients with different inborn errors of immunity, and sometimes we want them to fit a box, but they don't. And so, this is another reminder that when something isn't exactly what you're expecting, think outside the box and reach out to those colleagues because there's more to the story. I mean, that's one thing I talk with the fellows about all the time, right? We have to remember that not everybody reads the book and they don't present that way. And sometimes it's not what you initially thought the diagnosis was.

Dr. Stan Fineman: Yeah. This is definitely counterintuitive. I mean, I had some patients who had Good's syndrome, which is the patients with thymoma who have no B cells, and they, you know, get immunodeficiency. This looks like it's a thymoma, but it's different.

Host: Yeah. And again, that's what keeps things interesting. We have all these spectrums of disease. And then, once we understand what's going on, i really like how it drives our therapy. Now, we have precision medicine for a lot of the inborn errors or immunities. And now, the precision medicine for this type of immunodeficiency is actually potentially B cell depletion. So, again, this is sort of how we understand the disease, and then it informs our practice. I just think it's great. It's a great example of why immunology is so interesting.

Well, I love the discussion. Thank you for presenting all these great articles. If you like what you hear, please help us out. Rate us on Apple podcasts. And of course, we do want your feedback. We want to hear from our audience. If you have a correction, if you saw an interesting patient you want to discuss, email us at AllergyTalk, one word, at acaai.org. And then, don't forget about CME credit. The website is education.acaai.org/allergytalk. And then, you can also get AllergyWatch episodes at the main college website. Anyways, thank you for your time. I enjoyed this immensely. Enjoy the rest of your day.

DISCLAIMER: The ACAAI is presenting this podcast for educational purposes only. It is not medical advice or intended to replace the judgment of a licensed physician. The college is not responsible for any claims related to the procedures, professionals, products, or methods discussed in the podcast, and it does not approve or endorse any products, professionals, services, or methods that might be referenced.