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 by the American College of Allergy, Asthma and Immunology. For today's episode, we'll be reviewing more articles from AllergyWatch, a bimonthly publication, which provides research summaries for college members from the major journals in Allergy and Immunology. And you can earn CME credit by listening to this podcast. If you'd like more information about CME, head over to education.acaai.org/allergytalk. And we also have the ACAAI community on DocMatter, where we can continue the discussions about these articles.

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

Dr. Stan Fineman: Hello everybody, and thanks again for having me. I'm currently retired from a clinical practice here in Atlanta, but I still am on the clinical faculty at Emory and active in the college, certainly as editor-in-chief of the AllergyWatch publication.

Host: All right. And for the third chair, we're welcoming again Dr. Tim Chow, Assistant Professor at UT Southwestern and another Assistant Editor of AllergyWatch. Tim, welcome back to AllergyTalk.

Dr. Tim Chow: Hey, thanks for having me. Yep, I'm down here in Dallas. I run the Pediatric Drug Allergy Program down here. And I love all things drug allergy. I also love keeping up with the literature. I Really enjoyed being a part of AllergyWatch. So, thanks for having me.

Host: All right. Well, we got three really interesting articles to discuss. Stan, you're talking about a potential future cure for hereditary angioedema. So, I'd love to hear all about it.

Dr. Stan Fineman: So, yes, I mean, that's what struck me with this article, which was published in February of this year in the New England Journal of Medicine, and it was using CRISPR. And the title of the article is CRISPR-Cas9 in Vivo Gene Editing of the KLKB1 for Hereditary Angioedema. We all know hereditary angioedema. We've seen patients with it. It's a terrible hereditary condition, you know, life-threatening. Fortunately, over the last few years, we've had some more therapies, both for acute treatment and for prophylaxis that have been fairly successful. But if we could do something like do some sort of gene editing, and then the patient may not even have to take anything after that, I mean, to really "cure" as you mentioned.

So, some of us know about CRISPR. I read the book Code Breaker, and that sort of goes along how it was developed, but the CRISPR is clustered, regularly interspaced, short palindromic repeats, that's what CRISPR stands for. And CRISPR is associated with protein 9. And the product that we're talking about here, the NTLA-2002, targeted the gene that encodes the kallikrein B1. Of course, kallikrein, we know is one of the proteins that causes these angioedema episodes that are so severe and life-threatening. You know, that's really how it works. So, what happens is that this complex, it blocks the production of the plasma pre-kallikrein, and then it uses this lipid nanoparticle. So, the lipid nanoparticle, it fits in with what they call a liver tropism to encapsulate two gene editing components, a messenger RNA, which encodes for the Cas9 and a single guide RNA, which is a 20 nucleotide sequence. And that it becomes then permanently expressed in the liver. And this complex then translocates and directs this KLKB locus to then change the precise double-stranded breaks in this kallikrein gene and repair of these double-stranded breaks by this non-homologous end joining pathway.

So, that's kind of a long explanation of how it works so it was very complicated. Quite frankly, I don't understand exactly how it works. But the interesting thing is with just one dose of this treatment, they were able to see effects. They did a dose-ranging study. So, these all were patients with hereditary angioedema, either type 1 or type 2. Three received the 25 milligram, four received the 50 milligram and three received 75 milligram. And they looked for some adverse events, maybe some relatively mild infusion-type reactions. Some of the patients got a little bit drowsy. But there were really no significant toxic effects or serious adverse events. So, what they found was that the dose-dependent reductions, and the total plasma kallikrein protein level were observed between the baseline and then the latest assessment. And so, there was a mean percentage change of 76% in the 25 mg group. So, what they found was that there was a 76% change in the reduction, change in the 25 mg group. There was a 84% change reduction in the 50 mg group. And a 95% change reduction in the 75 mg group. So, it was a dose-dependent type of change. And the percentage change of the number of angioedema attacks per month from week one through 16 was a 91% reduction in the 25 milligram, 97% reduction in 50 and 80% in the 75 mg, which I'm not sure I can explain that.

But the bottom line was that just one dose of this CRISPR, they called it the NTLA-2002, it did lead to a very robust dose-dependent and a very durable reduction in the total plasma kallikrein levels with no significant or severe adverse effects were observed. But this is obviously exploratory analysis. We stepped to look for the reductions in attacks. There were some reductions in the attacks, but they need to do the study longer and to see if it could be potentially used in the future. As we all know, CRISPR just recently got approved by the FDA for treatment of sickle cell disease. So, I think we're going to see more of these genetic diseases hopefully can respond to these new technologies such as CRISPR and give more hope to these patients with these terrible conditions.

Dr. Tim Chow: Yeah. These results are just super exciting. I think for all of us who've cared for patients with HAE, it is not only a disease that has significant morbidity, but has just a dramatic impact on quality of life where, you know, families have to may be on preventive therapy, but, you know, carrying their on-demand therapy in case they develop any symptoms, having the stress around dental procedures or surgical procedures and the unknown of that. And having sort of a definitive treatment that has, again, something on perhaps the horizon that now we're finally seeing the results for, which is super exciting.

I think also just putting my drug allergy hat on, as gene therapy becomes more and more prevalent, these infusion reactions are quite common. Fortunately, in this study all of them were fairly mild. But we have had both here at our local institution times where patients have had their infusion stopped because of an infusion reaction. And in the setting of kind of a life-altering definitive treatment for disease, that seems heartbreaking to me. And I'm trying to find out ways that we can optimize those infusions so that we can facilitate Patients receiving the full dose of the drug so that they can receive those benefits. I think it will be an important role for me and other folks in drug allergy to come.

Host: Yeah, Stan, I really appreciate you presenting this article. Just so exciting now, that we can get to the root cause by manipulating DNA. You know, and I think, allergists are all in on getting to the root cause. I mean, I always say that immunotherapy is one of the few things where we're trying to get people off medicine. There's a treatment where we get to the underlying mechanism of the disease, and we're trying to get people off the continuous prophylactic drugs, the hundreds of thousands of dollars that it costs. And again, really changing and transforming the quality of life. So, I'm really looking forward to these things.

Tim, I appreciate you talking about the barriers. Obviously, we're allergists. We're going to try to figure out a way to get around fusion reactions. That's what we do. So again, super exciting things, and I can't wait to see the next steps. So, our next article, Tim, you've selected something about the longer term knowledge we've gained about peanut allergy, and especially with introduction. So, what have we learned?

Dr. Tim Chow: Yeah. So, this article is titled, Rates of New Peanut Allergy and Discontinuation Following Introduction in High-Risk Infants. So, this was published in the Journal of Allergy and Clinical Immunology in Practice in March 2024 by a research group out of Johns Hopkins. And so, following really that seminal LEAP trial that was published in 2015, our guidelines have recommended that infants with severe eczema or egg allergy introduce peanut between ages four to six months of age and to then regularly consume at least 6 grams of peanut protein per week. And so in the LEAP trial, adherence to that protocol was really high, but the real world experience of, you know, when you tell a family, "Yeah, you go ahead and just keep giving your child the peanut," we really don't know what are barriers to that, how is the real world experience in terms of how much peanut parents give.

And so, the authors really sought to characterize this better. And so, they performed a prospective cohort study that enrolled infants four to 11 months in age. And they had to meet two criteria. So essentially, they had to have one of the following that would define them as high risk, which they defined as either having moderate to severe eczema, or a physician-diagnosed food allergy other than peanut, or a first-degree relative with peanut allergy. And so if they had one of those and they had never previously eaten peanut before, nor had testing for peanut, then they were eligible to be included. And so, infants who were enrolled would undergo a baseline visit where they underwent peanut skin testing as well as serum testing to total peanut IgE and components. And they had a subsequent protocol. So, infants with less than 3mm wheal underwent an observed feeding. Infants with a 3 to 10 millimeter wheal underwent a graded food challenge. And then, infants with a greater ten millimeter wheal were told to avoid. And so, patients who had no reactions with the observed feeding or the graded food challenge were then advised to go home and eat 2 grams of peanut protein three times per week. And these patients were then followed up monthly via phone call or smartphone app to assess any interval reactions, also to assess their monthly peanut consumption. And then, they had in person followup visits at 18 and 30 months. And the outcome data that they were primarily looking at was essentially reported peanut consumption, interval reactions to peanuts, barriers to introduction, and parental perceptions of introduction, and then the history of reactions to peanut and family members who are peanut-allergic within the household.

So in terms of their results, they enrolled 317 infants. Two-hundred seventy-seven were not peanut-allergic at baseline and entered that longitudinal followup where they were told to keep the peanut in their diet. So, the median followup for these infants was 24 months. And over the followup period, the median amount of peanut protein consumed was 3 grams per week, so about half of what was done in the LEAP trial. At the last followup, 88% reported that they were still consuming at least some amount of peanut protein.

In terms of the difficulty of introducing and keeping peanut in the diet, close to two-thirds of families reported peanut introduction to either be easy or very easy. But about a quarter of patients found peanut introduction to be difficult or very difficult. And for those families, the main reasons then for discontinuing keeping peanut in the diet, 35% reported a fear of reaction in another household member. And it's interesting, because in the study, as I mentioned before, one of their outcomes was looking at reactions in peanut-allergic siblings. And these were actually quite rare. So, out of 184 peanut-allergic siblings, only three had reactions, which was a rate of 1.6%. Interestingly, reactions were more frequently seen in peanut-allergic parents, and that occurred in about 18%. Another frequent reason for discontinuing the peanut was the infant refusing to take peanuts. And over the course of this longitudinal followup cohort study, only four of the infants or 1.5% developed new Ig-mediated peanut allergy.

So, I think there are a few important points from this study. One, it's notable that a similar rate of new peanut allergy was observed in this study compared to the LEAP trial, even though there was a lower median peanut protein weekly consumption, again, about half parent report compared to the LEAP trial. And while the majority of families found peanut introduction to be easy. Again, about a quarter found it difficult with two primary barriers, including the fear of reaction in a sibling. Although I think this study is really nice in that it provides reassuring data that with proper modifications, the risk to peanut-allergic siblings appears to be very low. I've definitely heard that as a concern when I've counseled families. But then, I think this gives another piece of data to help reassure families about that, that if they take again proper precautions that that can be helpful. I

I think there's some important limitations there to consider. So, peanut consumption was based on parent report, and so that certainly is potentially vulnerable to recall bias. Also, not all patients who discontinued peanut then underwent kind of a subsequent challenge to see if they developed a new peanut allergy. And so, that estimate of new Ig-mediated peanut allergy might be somewhat low. And then, finally there might be some selection bias, and I think that the ease of introduction of peanut potentially could be higher in a population who's motivated and has the resources to participate in a peanut allergy research study. And so, whether or not this is generalizable to all populations I think remains to be seen.

Host: Well, we've seen those population studies. And as you know, the earlier of that study showed early introduction didn't do a lot. It actually was extremely disappointing. And I know a lot of people have speculated why that is. Certainly, you bring up the point about consumption. Introducing is one thing, regular consuming is another. I know that that is something that's been discussed. Obviously, eczema prior to peanut consumption has been sort of suggested by that paper. But I don't know, Tim, how are you thinking about this in terms of reconciling these small studies that continue to look pretty good and then like the population level data from Australia, which doesn't seem to show that we're moving the needle on peanut allergy with early introduction

Dr. Tim Chow: Yeah, that's a great point, and I think really comes down to when we're thinking about things from like public health measures and thinking about what populations are going to either see the most benefit or perhaps not as much of a benefit. So, I feel like, again, the factors going into that are likely multifactorial. I think when it comes down to when you're sitting across from a patient in your clinic, trying to help even coming alongside families and acknowledging that, "Hey, you know what? I'm telling you this, and there might be challenges. So, normalizing that, I think, is helpful because it provides space for them, hopefully, then, to have some rapport with you to be able to work through that and to reassure them with that. And then, again, trying to identify within your particular patient what barriers may there be to keeping these in the diet? And can there be things that we address such as fear of a reaction in the sibling?

Dr. Stan Fineman: No, I was just going to agree that, I mean, I think this is a challenge in the clinic, especially in family members. And I think that's where we've seen the biggest problem is trying to encourage family members to give the sibling the peanut. It sounds like you guys have had that same problem.

Dr. Tim Chow: Yeah, yeah. Anecdotally, I would say, yeah, there's a lot of hesitancy around that.

Host: And then, it's just so critical. Like once it's in their system, they have to keep on eating it. And I think we're just highlighting us maybe making that extra effort to continually follow up and checking in on those patients. I'm not sure there's a lot of benefit of doing early introduction if they don't continue eating it. I mean, that's not really going to help the patient either. And potentially, as you're exposing it, you know, there's some data on milk of just one-time introduction of formula as a newborn and then stopping may potentially increase drug allergy. So, these are the sorts of things where continuous exposure seems to be the common theme for a lot of these things, if we decide to pull the trigger on early introduction. So, definitely great points that you're bringing up with this article.

So, I have one more. And I thought this article was super provocative and interesting. This was the article that's titled, IgE to Common Food Allergens is Associated With cardiovascular Mortality in the National Health Examination Survey and the Multi-Ethnic Study of Atherosclerosis. So, the association between allergies and heart disease, I think the one that comes to mind for a lot of us is Kounis syndrome. You know, if you had an anaphylactic reaction, acute coronary syndrome has been reported in the literature, and there has been some hypotheses about how mast cells are involved in cardiovascular disease.

But I think one of the intriguing observations that led to this study was a lot of the data from Tom Platt-Mills' Group investigating alpha-Gal and trying to figure out why is it delayed? Is it something to do with lipid processing? And noticing this association between alpha-Gal IgE and coronary artery disease and unstable characteristics of plaques. So, if you look at a large data set, you can sort of validate what is this association between coronary artery disease and cardiovascular outcomes and IgE to food?

And so, I think they looked at these two data sets, the NHANES, National Health and Nutrition Survey, and then this second data set, the Multi-Ethnic Study of Atherosclerosis. And so, you know, the NHANES survey, you know, that's that national CDC survey where they get a lot of questionnaire data, but they also have a lot of data from testing. And so, they were able to get allergen-specific IgE data of these patients. Now, the MESA study is a little bit smaller study. It's sort of a cohort study looking at risk factors for heart disease. So, it is a smaller population, but again, they were able to also examine the association between heart disease and blood testing. And so, they're looking at cardiovascular mortality based on ICD-10 codes, questionnaires, National Death Index, and there's a lot of confounders for cardiovascular mortality. So, they really try to control for all of them. Race, ethnicity, gender, age, smoking, asthma, obesity, hypertension, diabetes. And then, they also looked at like asthma and atopic dermatitis too. So, there's just multiple ways they try to strip out the confounders and really, to the best of their ability, narrow it down to IgE sensitization to food and cardiovascular outcomes. And so, what's remarkable? So, what this means is that if you look at the top level results after adjustment for all the stuff you're talking about, and they call this Model 3 in the paper. If you have IgE to milk, the odds ratio of a cardiovascular-related death was 2.1,1, all right? So, let's put that in perspective. The hazard ratio for smoking is 1.7. And the hazard ratio for diabetes is 1.9. So, that's greater than smoking and diabetes, which is quite a remarkable observation.

Similarly, if you had higher level sensitization, let's say not any Ig, but like Ig over 2 units per liter, that milk hazard ratio goes to 2.7, right, from 2. And if you do adjustments in the MESA cohort, so they're looking at a different cohort, different study on cardiovascular risk in the MESA cohort, after adjustment, that milk IgE sensitization goes to 3.5 on the odds ratio. And, you know, they were able to show Kaplan–Meier curves to show that over time, that presence of sensitization to milk and the cumulative risk over the years, right? And this is a questionnaire study from NHANES. So, they got diet history. So, they were able to correlate diet consumption history with the sensitization and separate out consumers and non-consumers. And absolutely, consumers of the food were more likely to have that increased risk of cardiovascular death.

So, they didn't see any association with aeroallergens, you know, obviously you're not exposed to as much. And of course, we have to talk about all the limitations, right? Self report, questionnaire data, misclassifications, you're just pulling ICD-10 codes, and they had to find the patients through like this national death index. They can't clarify baked goods, baked milk versus regular milk, and recall bias, non-response bias, and so on. This is a strong association.

Now, I thought about this, and association, as you know, is not causation. And so, obviously, we think about reverse causation, and I was thinking about this, and one possible cause of reverse causation is the fact that patients with cardiovascular risk take aspirin. And so, if you have an NSAID, is it possible that NSAID consumption increases gut permeability and increased sensitization? I'm not saying that's the reason, but you know, there may be a potential reverse causation happening here as well. So, I don't mean to suggest that all your food allergy patients need to get a heart cath. But, you know, certainly, that's a very intriguing association that needs further study. And I thought it was very provocative.

Dr. Stan Fineman: You know, it's Interesting that you brought up that reverse causation, this big data, and I'm always amazed by some of these studies that really you crunch so much big data, you get so many data points and can come up with all kinds of conclusions, you know, what's the real cause? And I don't know, this is kind of baffling to me. I just still can't put my hands around exactly why, you know, you'd see this. But maybe it is a reverse causation thing. But I'm glad you brought the study up. I think it's interesting for sure, especially the fact that the hazard ratio is so high just for food allergy.

Dr. Tim Chow: I agree. I guess the challenge is that, because in this study we didn't really have necessarily a gold standard, sort of a definition of confirmed Ig-mediated food allergy. And so, I think, it's somewhat of the challenge, where it's like, you know, in my main mantra to families who don't have, again, an index history of an immediate reaction consistent with mast cell degranulation to a specific food, is that this is just not clinically relevant.

And so, the question of how many of those patients are here, we won't know. But it'll be interesting to see if that's replicated in patients who, again, as we have longer term follow up with confirmed food allergy patients, if that's something that's seen, because I agree, this seems somewhat surprising.

Host: Yeah. It's just unexpected and you just look at it and the data speaks for itself. But then, the why question really comes out. So, I'm so fascinated how they'll further investigate this. So, if you have a thought on why this may be, I'd love your opinion. The email for me to send your thoughts would be allergytalk-- one word-- @acai.org. We have a lot of smart people who listen to this. Obviously, if you like what you hear and want to give us a rating please log into Apple Podcast. It does help the podcast. And then, of course, to get CME credit for this episode, just go

Dr. Gerry Lee (Host): to education.acaai.org/allergytalk.

Host: One more time, thank you so much for listening. I immensely enjoy doing this. I hope you enjoyed it as well. I hope you all enjoy the rest of your day. Thanks for listening.

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, professional services, or methods that might be referenced.

Today's speakers have the following disclosures. Dr. Lee has been a speaker for Novartis. Dr. Fineman has nothing to disclose. Dr. Chow has nothing to disclose.