Gerry Lee, MD (Host): Hello, everyone, and welcome to another episode of Allergy Talk, a roundup of the latest in the field of allergy and immunology by the American College of Allergy, Asthma, and Immunology. For today's episode, we'll be viewing more articles from Allergy Watch, a bi-monthly publication which provides research summaries to college members from the major journals in allergy and immunology.

And for those listening to the audio version, we are now having a vodcast on YouTube. So, go to the ACAAI YouTube channel at www.youtube.com/allergist. And just by listening to this podcast, you can earn CME credit. For information about CME, head over to education.acaai.org/allergytalk. And we do have the Doc Matter community where you can log in and discuss the articles we talk about today.

Well, hello again. My name is Gerry Lee. I'm an Associate Professor at Emory University and Assistant Editor at Allergy Watch. And once again, I'm joined by Dr. Shyam Joshi, the Editor-in-Chief of Allergy Watch and Associate Professor and Section Chief at Oregon Health & Science University. Shyam, welcome back to Allergy Talk.

Shyam Joshi, MD: Thanks so much for having me again, Gerry. Really excited to talk about some awesome articles this time.

Host: As always. And for the third chair, we are so excited to be joined by one of the new associate editors of Allergy Watch, Dr. Karla Adams, a professor of pediatrics, the program director for the Allergy and Immunology Fellowship at Wilmer Hall. And so, welcome to your first episode of Allergy Talk. Just introduce yourself to the audience.

Karla Adams, MD: Thanks. So excited to be here and excited to join the Allergy Watch team, and excited to review some articles with you too as well.

Host: Okay. Well, let's let it rip. I think I'll get the ball rolling. This article is entitled Epidemiology and Management of Malignancies in Patients with Inborn Errors of Immunity: An ESID Registry Study of 19,959 Patients.

Before we go to this article, I think we should do a story time. I finished fellowship at Cincinnati Children's. I went to my first faculty position, and one of my earliest consults, as, like, a junior faculty member who didn't know anything, was, you know, a hem-onc consults me, and it was a boy who had the second recurrence of Burkitt's lymphoma in the exact same place. So, like, he had Burkitt's, like, ileocecal Burkitt's. It was treated. He was in remission. Margins were clear. Like, you could see the anastomosis site, and he had cancer in the exact same place. And they're like, "Well, this seems very odd. We're going to consult you." And I'm like, "Oh, goodness. I'm just a new attending. Oh my gosh." And I was like, "Well, the only thing I know that does this is X-linked lymphoproliferative syndrome. We should send, like, a SAP protein expression." And the patient had, like, zero expression. The patient ended up having XLP.

Fast-forward to, like, a few years ago, I saw a patient who was referred to us for eosinophilic gastrointestinal disease, and he was, like, very failure to thrive. Like, his growth chart was really low. And all I got on the referral—and the fellow says, "Oh, by the way, he has a history of Burkitt's lymphoma." I was like, "Where's Burkitt's lymphoma?" He's like, "Oh, ileocecal Burkitt lymphoma." Like, okay, we should absolutely test this person for XLP. Guess what? It was XLP.

So, that's sort of, like, the motivation that this article caught my view because malignancy is the second most common cause of death for inborn errors of immunity, and we absolutely should be thinking about it. And so, what do we know about malignancies in IEI? And so, what this article reviews is the prevalence and the status of 20,000 patients in the European ESID registry, which is a fantastic data set with multiple centers across that continent.

And what they find i is that the general prevalence of malignancy in their cohort was 8.9%. But the most important thing, and that was sort of the motivation of me telling the story, is that 27% of the patients' malignancy was the first manifestation. And if you take children, that was 39% malignancy, the first manifestation.

And so, what kind of malignancies do these patients report? Well, B-cell non-Hodgkin's lymphoma exerting Burkitt's was number one. That was 20%. Then, Hodgkin's, then T-cell non-Hodgkin's lymphoma, and then Burkitt's with 3.6%. Now, they did have solid tumors. That was skin cancer 8%, breast cancer 7.9%, leukemias was about 8%.

But, you know, essentially, when you think lymphoma, that's got to be one of the things you're going to ask the question, there's something else going on. Now, certainly, primary antibody deficiencies predominated this registry, so that was probably the most prevalent group, but that's just general prevalence of that IEI. But as you can imagine, there are certain inborn errors of immunity that are more enriched with developing malignancy, and you can guess what those are. They're probably going to be your DNA, repair defects. So for example, ataxia telangiectasia, 8.8 to 13.4. Nijmegen breakage syndrome was 28% to 42%. And then, they had activated PI3 kinase delta, 15% to 24%. Wiskott-Aldrich was about 3.4%. Good syndrome, 40% to 60%, right? So, oh, yeah, ALPS. ALPS was, you know, about 3% to 4%. CVID was 6% to 9.3%.

So, just taken together, I thought this was a very good insight on what we should be thinking about. It's a good reminder. Number one, you know, patients are not going to follow the order we think that is. You know, we think of infection, okay, inborn errors of immunity. Well, they don't have to follow the order, and sometimes cancer malignancy was going to be that early sign, especially lymphoma, is something we should raise our antenna.

And then, certainly once we have a patient diagnosed with an inborn errors of immunity, we have to tell them about the signs and symptoms of malignancy. Potentially, we have to do cancer screening. Obviously, we're going to avoid anything that's going to make it worse, like ionizing radiation if possible.

And if you went to our previous episodes, Dr. Vivian Hernandez-Trujillo talked about the benefit of vaccination, like the HPV vaccine, right? We can actually immunize against cancer. So anyways, I thought it was a good take-home message for me, and I'm not sure how many of you all have seen this experience of malignancy as a presenting manifestation. What have you all seen?

Shyam Joshi, MD: I think from a pediatric side, that's exactly it, especially the lymphomas in these early kiddos, that hematology is starting to think more about it as well, or oncology. So, they are referring to us sooner in those situations, especially if it's something atypical or definitely recurrence of malignancy despite appropriate chemotherapy and looked like the outcome was looking pretty well.

So, I think this is going to be something oncology, especially pediatric oncology, is going to start looking at a little bit more in detail as well, doing genetic testing at an earlier age, at an earlier period, and hopefully making these diagnoses a little bit earlier and getting us involved sooner rather than later, right? We don't have access to these patients right off the bat. It really has to come from our colleagues over in hem-onc to make that connection a lot of times, especially if this is their presenting symptom.

Karla Adams, MD: Yeah, I was going to add also the autoimmune kind of initial presentation for these patients, right? And then, subsequently, when they get treatment for their cancer or their autoimmunity, I feel like a lot of the patients that I see, they come in to see me because they're worried about the secondary kind of, you know, complications from that treatment.

But unfortunately, without having that evaluation done before that treatment, it's hard to know what came first. So, it sounds, you know, like definitely, and that data set, like you said, like the fact that so many patients that they included is great, because obviously we're talking zebras, right, when it comes to these populations at smaller centers. So, it sounds like we're going in the right direction, at least with early identification and referral.

Host: Yeah. So again, we absolutely should engage with our hematology oncology colleagues. And again, hopefully we'll learn more about this and get built-in protocols that we're asking these questions about what else could be going on. Is this the tip of the iceberg?

Okay. Well, let's continue the inborn errors immunity theme. I think when we see common variable immunodeficiency, we check the big three, IgG, IgA, and IgM. But Dr. Adams, what about IgE? Tell us about IgE in common variable immunodeficiency.

Karla Adams, MD: Yeah. Thanks for that segue. It's perfect lead in with that first review. So, the second article, this is undetectable IgE association with non-infectious complications for CVID. It was published in Annals this year. It was previously reviewed for Allergy Watch by Dr. Vivian Hernandez-Trujillo, who's also one of our assistant editors.

So, the big question they're trying to ask for this paper is, in a patient with CVID, does an undetectable IgE level tell you anything? Does it prognosticate whether or not that patient is headed for non-infectious complications, so cytopenias, malignancy, granulomatous disease?

And as we all know, kind of like the name implies, CVID presents in a very variable fashion, right? So, these patients can present with infections. They can present with kind of that autoimmunity or even the cancer kind of phenotype as well. And we know that those non-infectious complications are associated with significant morbidity and mortality. So, anything that we could do to help prognosticate, like, we want that, right?

So, what they did is this was a retrospective chart review. It was a single tertiary academic center at University of Virginia. They looked at their adults with CVID and the diagnosis was using the international consensus criteria. And they looked at patients who had an IgE level drawn at diagnosis. They ended up recruiting about 150 patients total. They defined a total IgE as less than two, so It was not detectable or very minimally detectable, which was roughly about 60% of their cohort.

I will point out that demographics, I think, are important for this study just because I think, you know, the generalizability might be impacted. So, most of their cohort was white, about 95%, and they did have a little bit of difference between the undetectable IgE and detectable IgE group in that the undetectable group was mostly female, and they were older, about 63 years old, versus the detectable IgE group that was a little bit younger, so 53.

And I think that's really important, because the study authors ended up doing two sets of analysis. So one, they corrected because of those differences in age and gender, so they looked at their data after correction for those two things. And then, they also noted that absence of IgE was also predictive of having a low IgG and an IgA. So, they did run subsequent, like, covariate analysis just to make sure that they adjusted for those levels.

And then, when it comes to the results, I kind of split them in two different buckets. So, the first one is immunophenotyping. So, what did they find? What did the lab values show? And what they found was that undetectable IgE was associated with having a lower IgG, IgA, fewer CD4 T cells, fewer memory B cells, fewer plasmablasts. And the one lab that definitely stood out was they had lower amounts of class-switched memory B cells, so I think the difference was kind of striking. It was, like, 0.6% versus, like, 5% for the detectable IgE group, which I think, obviously, I think we all know that that's pretty significant since other studies have shown that those low class-switched memory B cells are associated with increased non-infectious complications. So, that kind of confirmed other studies as well. After they adjusted for low IgG and IgA, they did see that there was a persistently low, CD4 T cell count, CD19 B cell count, and then the switched memory cells persistently remained low.

The other bucket of results is the clinical outcomes, right? So, what happened to these patients that they have those non-infectious complications? And interestingly, before they adjusted for the low IgG and A, they did see a difference in autoimmune hematologic disease that was about tripled between the undetectable and the detectable IgE group, and then lymphoma was also different as well.

The interesting thing was that when they adjusted for the IgG and IgA levels, those differences, like, were nonexistent. So, it looked like at least the lymphoma risk seemed to track better with the low IgG level. And then, the autoimmune cytopenia risk seems to be murky at best, right? Like, it's not just the low IgE that is associated, which I think just speaks to the complexity of CVID, right? Like, it's complex. It's not just the one lab value that's going to lead to these other complications.

And then, the last thing they did was they actually looked to see if having a low IgE could be a diagnostic classifier for the low switched memory B cell. And the practical thing here was, well, if I get an IgE, do I also need to get the expanded B-cell panel, which I thought was super interesting. They found that, like, the odds ratio for having low switched memory B cells in undetectable IgE was about six. So, it looked great, except for the sensitivity and specificity were about 20% to 30%, which is less than optimal.

So, my takeaway from this study was that this is great news. It means I should pay attention to my total IgE when I'm evaluating these patients. I should be getting a total IgE if I'm not already getting it. But it doesn't mean I don't get the expanded B-cell panel. Like, you still need to consider getting that test because I think it's going to help you in the long run in terms of the prognostication.

But just from a cost standpoint, right, and an E standpoint, that total IgE is probably easier to reach for, at least initially while you're getting the rest of your workup before you press to do the more advanced testing, if you will.

So, I thought it was a great study. I think it confirms a lot of thoughts that we had seen in our CVID population as well. And again,I'm all for low-cost, easy tests to get

Host: You know, I've had a couple fellows show me absent IgE and they're like, "What should we do?" I'm like, "Well, wait. Whoa, whoa, whoa, whoa, whoa. We're talking about CVID here." I mean, just recognize people without allergies, they don't have to make IgE. You know, it's not a requirement. But yes, I think if you do have CVID, it's absolutely why not? Why not send it? I think sometimes just getting that patient in the right thing to get the blood shipped out overnight, you know, could be difficult. And you've seen a immunologist patient on Friday, you didn't predict it.

So clearly, anything we can do that's done in-house, unfortunately, we don't have the expanded B cell panel in-house, is going to help us get the most information we need to, again, risk stratify patients and do what we need to do. I love biomarkers. I think ideally, you know, we're going to want the information though. Other than the switched memory B cells, I think I've also been doing the naive,T cells. I hope I'm not missing anything. I don't know. What are the other ones that are out there? Just to jog my memory.

Karla Adams, MD: Yeah, I think those are the ones I've covered in the past. And again, some of this is just like you were speaking about, like just the ease of testing, right? Like, you know, insurance companies may not cover the more specialized testing and whatnot. So, we want to get as much information from the tests that we do have available.

Shyam Joshi, MD: The one that I've started ordering more recently is CD21 low. So, that has some association with immune dysregulation, autoimmunity, non-infectious complications as an independent risk factor. It's a little bit harder to get. It's not available through all expanded B-cell panels. But there are some national labs that do have that present. And so, that's one I've been keeping a little bit closer eye on.

Going back to the article specifically, I think where I find this interesting as well is when you have referrals that come in for low IgE now, right? There are primary care providers ordering these allergy panels that come with a total IgE, and the total IgE comes back absent. Previously, I was like, "That's probably not a big deal. It's just their IgE is really low." But now, knowing that these CVID specifically in those patients with absent IgE, they have a little bit of a different presentation that I'm paying more attention to when we're getting these absent IgEs because it could be part of a much bigger picture here.

Host: So again, another tool in our toolbox and a lot cheaper to get to. So, I really appreciate reviewing the article. Let's do one more. And Shyam, I'm really glad you chose this article because I thought it was fascinating, and it's what RoCHE talked about. The topic of neuroimmunology comes up more and more about how these two systems just interface together. So, what else have we learned about atopic dermatitis and the nervous system?

Shyam Joshi, MD: Yeah. This is a really interesting, but also really dense article. And so, I'm not going to be able to go through all the nitty-gritty here on the podcast. I don't think people want me to go through all the nitty-gritty on the podcast.

Host: They like the details. Come on.

Shyam Joshi, MD: Yes, we're going to hit it a little bit on a higher level of kind of what the implications are. But I do recommend reading through this article. It's heavy, but there's a lot of really interesting material here.

So, the article is called Sympathetic Nerve Dysfunction Exacerbates Skin Inflammation in Atopic Dermatitis. And this was by Yu et al. Reviewed by Gerry Lee, so our very own Gerry Lee here on the Allergy Watch, published in JACI back in March 2026. And so, we already know that pruritus itchiness plays a major role in atopic derm. It leads to a lot of decline in quality of life, including mental health issues like depression, anxiety, suicidal ideation.

And we also know that the sympathetic nervous system has been shown to modulate inflammatory responses. We know in AD, so previous studies have showed patients with AD, you see in the skin biopsies that there is some impairment in the sympathetic nervous system. We also know that the sympathetic nervous system overactivity happens when patients are scratching a lot or there's increased stress. And we know that pro-inflammatory cytokines sensitize sensory neurons and alter their excitability of the sympathetic nerves. And it leads to increased sympathetic outflow and other nervous changes.

And I think it's important to know there that the nervous system influences the inflammatory system, and it goes the other way. The inflammatory system interacts with the or influences the nervous system, and we call that the neuroinflammatory crosstalk, right? That's the buzz term right now.

And so, this study was really looking at what is exactly happening there. What's the exact destructive effects of atopic dermatitis skin inflammation on the sympathetic nervous system? So, they went about it with kind of two different approaches. They did kind of a human approach and a mouse approach. And there's things to learn from each of these.

One of the really interesting methods that they use, which I found fascinating, is in their human subjects, they use something called impression mold technique. And so, what they do is they use a Silasoft, which is when you go to the dentist and you bite into that and it creates a mold of your teeth. They use that same material and applied it to different areas of the bodies. They applied it to the abdomen, back, bilateral cubital fossa, bilateral forearms, and the facial regions. And after they applied it, they had patients, these are patients with AD, exercise. And what they were measuring was how much of their sweat came out, and they can count the number of bubbles that formed when the sweat was pushing up into the mold itself, and that was their measure of sympathetic nervous activity. They also used some other techniques with the mice as well, which we'll talk about in a second.

And so, I think the big takeaways that I found in this study for from the human side of things, they did this impression mold technique, and they found that in the patients that had atopic dermatitis versus the controls, there was a decrease in the sweat bubble formation in the molds for those that had atopic dermatitis. So, you're already seeing this change in the nervous system, especially in the areas that are more problematic. They have more lesional lesions of AD in those areas. They took a survey of their atopic dermatitis patients and self-reported, 21% of them reported a decline in sweating across the board. So, this is something I haven't really asked my patients before. They always complain that the sweating makes their atopic derm burn or flare sometimes. But a lot of these patients just sweat less. And it also correlated with the severity of the atopic disease. So if they had really severe atopic derm, they sweat considerably less.

And interestingly, of those that already had dysfunction, 29% of those patients, it reversed when they were started on dupilumab. So, we think of dupilumab as more of an inflammatory mediator, kind of changing the inflammation, but it's clearly having effects on the neuronal system, whether that's through the inflammatory process or directly on the neurons themselves. That's something still to be determined.

They found a reduction in neuroelectric responses in patients with AD when they asked them to do the Valsalva maneuver. And so, this should activate the sympathetic nervous system by increasing iintrathoracic pressure during forced exhalation. And they found that this was reduced in those with AD. So again, another sign of changes in the neuronal system. And then, when these patients were put on dupilumab, that went away. It went back to kind of the normal population.

And finally on the mouse side, they used more histologic studies, and they showed that the ganglia were enlarged in atopic dermatitis mice. Neurotransmitter norepinephrine was reduced in these skin lesions. And we know that norepinephrine and dopamine actually reduce type 2 inflammation. So, that kind of makes sense here.

And they used these special type of mice called Foxp2b mice, and they found that activation of Foxp2b, which is really important in the sympathetic nervous system development. So when they activated that, it actually reduced skin inflammation and pruritus in those mice with atopic derm. So again, we're enhancing parts of the neuronal system and leading to improvements in the inflammation we see on the skin and the symptoms that you see from it.

So, is there a major takeaway from here for our patients? It's important to understand this changes in the immune system as well as the neuronal system. But I think it's just really fascinating to understand that this connection is real and that we're learning more and more about it. There could be a future where we're actually using medications to enhance the neuronal system, which indirectly will actually improve their AD or directly improve their AD. So, a lot more to know here and also a little sneak peek that dupilumab may be doing more than just decreasing inflammation.

Host: You know, I think in the study they also, like, applied norepinephrine and it's helping the AD. And I'm not saying they're going to have, like, a norepinephrine drug. But essentially, it's just so fascinating that interface. You know, you can imagine why this may occur. I'm not suggesting I know why, but the pruritus in atopic dermatitis is so stressful.

Imagine this, you know, hyperactive stressed state you are. Your body's going to adjust to that and then potentially it's going to try to bring that down. And so, you know, when we think about treating the whole patient, you know, we're always focused on, you know, what's causing the AD and how we're going to treat it.

But, you know, from a holistic standpoint, addressing the stress response and sympathetic is something I think is just less appreciated, but certainly is in the toolbox in assessing patients and potentially a burden that could exacerbate this sympathetic dysfunction down the line. You know, theoretical, but I think it's worth reminding ourselves of that part of atopic disease, especially something so distressing like atopic dermatitis.

Karla Adams, MD: Yeah, I was thinking of some of the other conditions that we treat that are very similar, right? So, not just chronic itch and atopic dermatitis, chronic itch as well as chronic cough in terms of that neural response, like that connection seems to exist. And, you know, talking about treating the whole, like, individual, right?

Like, you know, I think we try medications and we hope for the best, but it's hard sometimes to understand why not every patient responds the same. And I think this is a potential reason for why, like, that connection may be stronger in some than others. So yeah, it's exciting to think about potential treatment options down the line that might cover both.

Host: So, I just love that perspective as we learn on the mechanisms of disease, we find new avenues for treatment, things to remind us when we see a patient in front of us of to address the potential sympathetic activation or stress in our patients.

So if that's something that you've had good experiences or other commentary on the other articles you've seen, just please send us an email. The email is allergytalk, one word, @acaai.org. If you appreciate what you've heard, we would appreciate a strong rating either on Apple Podcasts or on YouTube. And of course, if you want to get that CME credit, just to remind you, that website is education.acaai.org/allergytalk. And this is just a sample of all the wonderful articles that we review on Allergy Watch. So, the website for that is college.acaai.org/publications/allergywatch.

Well, I have fun every time I do this. I learn a lot. I hope you do too. And I hope you all have a wonderful day. Thanks for joining in.



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.