Gerald Lee, MD (Host): Hello, everyone, 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 reviewing more articles from Allergy Watch, a bi-monthly publication which provides research summaries to college members from the major journals of allergy and immunology.

And for those currently listening to the audio version, we have a video version as well. Please visit us at the ACAAI YouTube channel at youtube.com/allergist. And you can earn CME credit by listening or watching this podcast or vodcast. For information, go to education.acaai.org/allergytalk. And finally, we do have further conversations on the ACAAI community on Doc Matter. So, check us out where we can discuss these articles.

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

Shyam Joshi, MD: Thank you so much for having me. We are just wrapping up grass pollen season here in the Pacific Northwest. Did you all know that Oregon is the grass seed capital of the world? Which also means we are the grass pollen capital of the world. So, don't come up here in June. It is pretty brutal.

Gerald Lee, MD (Host): For the third chair, we're excited to be joined by Dr. Vivian Hernandez-Trujillo, the Division Director of Allergy and Immunology at Nicklaus Children's Hospital, a Clinical Professor of Pediatrics at the Herbert Wertheim School of Medicine, and Assistant Editor of Allergy Watch. Viv, welcome back to Allergy Talk. And now, I'd love to hear what's the pattern season in typical southern Florida.

Vivian P. Hernandez-Trujillo, MD, FACAAI: I will tell you that we have pollen year-round. And I think that whereas when I lived in the Northeast and the seasons were more defined, there's a lot more flux here in South Florida. And it's been an interesting summer as well with the grass pollen. And we still havesome tree pollen as well. So, it's kind of fluid. You know, it's constantly changing.

Host: Or it keeps us in business. Either way, you know, you can think about one side or the other. Okay. Well, again, we have three more really interesting articles to bring to you, and the first one is about potential new roles or not for the HPV vaccine. So, what do you have for us, Viv?

Vivian P. Hernandez-Trujillo, MD, FACAAI: So, I'm excited to talk about this article because in the age that we're living with vaccine hesitancy, I think any information that we can provide to patients that is accurate and true is really helpful. So, this actually is an article, it's called HPV Vaccination is Associated with a Lower Risk of Cancers Among Females. So in and of itself, the title tells you how important this is. It was by Dr. Hung and colleagues. They're from Taiwan. And it was published in the American Journal of Medicine.

And basically, HPV vaccine, we know prevents certain cancers, but the long-term effects are unclear. So really, the authors were looking at assessing whether HPV vaccine is associated with cancer risk, specifically in females ages nine to 26. This was a retrospective cohort study. So, it was from TriNetX, which is a US collaborative network. This is a network with information from 54 healthcare organizations. And what they looked at over a 10-year period was comparing HPV vaccinated versus unvaccinated females. And what they found was—which was very reassuring—HPV vaccine was significantly associated with overall cancer risk with greater reduction in those ages nine to 14.

Why is this important? As a pediatric allergist, and even as someone still board-certified in pediatrics, a lot of parents can be concerned and say, "Why does my daughter need this so early," right? I think there's a lot of misconceptions. The reality is we need to protect. And this is one of the reasons I thought it was important to talk about. In this age of vaccine hesitancy, if we have a vaccine that actually helps prevent cancer, that is huge. And when I've had different families say, "Well, you know, I don't know about the risks." And I'll say one of the problems with HPV is it can be silent. You don't know, right? And that's the problem.

So, they compared in ages nine to 14 versus 15 to 26, but both the 9 and the 4 HPV vaccines lowered cancer risk. And their bottom line, like their take-home, was that HPV vaccine was associated with lower risk of several cancers among women nine to 26. I think here it's a good opportunity to talk about, you know, what are some of the limitations.

So just today, I was made aware by Dr. Gerry Lee, it's true, something that brings to our attention that TriNetX actually is available to really, like, anybody within those 54 healthcare organizations. So, it's being used by medical students, and they're using tools that are available to perform statistical analysis.

And part of the problem with that is, A, you don't really know what the rigor in that statistical analysis. And B, more importantly, is how do you interpret it? So, I think, as excited as I was, and I still am, that this is important information that we can share, there's obviously limitations. And I welcome both of your comments on, you know, using certain databases like the TriNetX collaborative. There's always going to be some limitations. And please share your thoughts about that.

Host: Yeah, yeah. So, I'll try to put that science article in the show notes. Again, I'm going to be honest with you, I am not a biostatistician. There are definitely people way smarter than me. So, this science article was written by a blog author and scientist. He runs Retraction Watch. And Retraction Watch is a very interesting blog.

It talks about, you know, the story behind different retracted scientific articles and methodological issues. And TriNetX has built-in ways to try to account for certain biases when you do these sort of, you know, retrospective database-type studies. But there's sort of certain types of biases that can kind of creep in despite your best ways for adjustment.

Now, first one, as you know, is that obviously you can do something called a propensity score matching to try to even out the cohorts. You're going to try to, you know, balance it out demographics and comorbidities and so on. But unfortunately, there's no real way to ensure that the groups are equal. There may be something different with families who do complete a three-vaccine series that even though you tried to do propensity score matching, you couldn't really account for that type of individual who will actually commit to the three-dose series—you know what I mean—for an HPV.

I think the second thing that comes up, and this is a flaw for most TriNetX studies that they've not been able to account for, is something that they've broadly termed as the immortal time bias. And that means is you define the cohort by individuals who got the intervention. So, for you to get the HPV vaccine, that means you've had to survive a certain amount of years and then get the vaccine, and now you're in that group versus all-comers on the other group. What that means is that if you did not make it or had some sort of event that could have predisposed a cancer, then that obviously you are included versus the other one, the people who never got the event were excluded, if that makes sense.

So unfortunately, that does underestimate cancer incidence amongst vaccine recipients because the groups are inherently different from that variable. So, they call this immortal time bias. Okay. That's my broad understanding reading a blog article, right? But ultimately, you know, we could just like say, "Well, then forget about it."

But I love your message, Viv, right? We have to show patients data that there is potential benefit that, of course, we still need to do further research for, but that means we need more positive things than negative things when we talk about vaccination. So, I don't know. What side do you land on, Shyam, when we're trying to sort through all this? You know, there's obviously some positive news that we want to believe, but then we're concerned about the methods. What's your thought on that?

Shyam Joshi, MD: Yeah, I think this goes to the bigger question. It's not just TriNetX, right? There's methodology issues across the board. And so as practicing clinicians, it's our job to still dig through this information for our patients, right? Our patients were going to get the headliners. They're going to say they get the headline abstract, the flashy name, but it's our job to kind of help them understand, yes, that this is a very legitimate study, or there's some concerns here that maybe we can't make those conclusions that you're making.

I don't know how you guys, how your practice is, but I have patients bring me articles. And they're like, "Hey, I read this. Can we do this testing?" I'm like, "This article's not really addressing the specific question you're asking. Theres some issues here." And it's hard to do it on the fly, because they don't tell you ahead of time that they're bringing this article. You're reading it in the room with them. And sometimes you're like, "I'll get back to you." But I think this is a skill. This is a very important skill set to have, is to really evaluate articles and determine, is this something that is going to make a difference in my practice, or is this not going to make a difference in my practice?

And things like Allergy Watch and Allergy Talk bring these ideas to the forefront, and you have somebody else's opinion on is this article really meaningful or not? Or sometimes we have articles on Allergy Watch that are like, "Hey, this article came out. This is important to talk about, but this is really limited. Like, we shouldn't over-index on this single article." So, I hope we continue to use Allergy Watch and Allergy Talk to identify these deficiencies in some papers as well. I think it's as important to talk about negative studies or problems with certain studies as it is to talk about the great stuff that's happening in terms of new biologics and treatments that are coming out as well. So, I think this is a great conversation. I'm really happy you picked this article, Viv.

Vivian P. Hernandez-Trujillo, MD, FACAAI: No. And any information that will help us with vaccine hesitancy. Again, I think the same way that we're the experts in food allergy, we really should be the experts on immunizations as immunologists. So, I think that that's, like you said, like identifying flaws and just keeping that in mind, but being able to interpret that and talk to patients because it can provide very practical information.

Host: And take the hypothesis and run with it. Does that make sense? Now, we have evidence, can we build? I think that that's just how evidence-based medicine is born. So, we got to start somewhere. And so, hypothesis testing has to start with platforms like this.

Okay. Well, I continue to learn stuff. And another thing that I have just learned is the association with hereditary angioedema and muscles. So, Shyam, you got to tell me what's going on here.

Shyam Joshi, MD: Yeah. This was a really interesting article that was reviewed by Dr. Spriet, and it's called The Association of Muscle Instability and Long-Term Prophylaxis in Hereditary Angioedema. And this was published in the World Allergy Organization Journal back in February of this year.

And why I chose this article, well, first, it's just fascinating, but I have a specific patient that this perfectly hits home with. It's a young female. She was four-year-old when I diagnosed her with HAE, classic low C1 esterase inhibitor, confirmed SERPING1 mutation. But she would have these angioedema episodes on her hands, especially her extremities. She's a four-year-old. She's running into stuff. She's very active. But the biggest complaint that I would get from mom was she had tremendous muscle pain and weakness, especially in her legs, and that's usually the area where a lot of her HAE was taking place. And I'm like, "Yeah, maybe there's some association here." There are earlier studies that have shown patients with HAE have generally more weakness, more fatigue, reduced exercise tolerance, but these are all kind of survey information. So, this was just really interesting.

As we know in HAE, we have increased prekallikrein activity. We see increased bradykinin levels. And bradykinin has been known to be involved in muscle injury, muscle repair. And the theory is acting through the kinin B2 receptor, bradykinin induces prostaglandin E2 release from skeletal muscle-derived fibroblasts. And this potentially can lead to increased local inflammation, muscle damage. And we know that bradykinin can be associated with instability of skeletal muscle causing CK release potentially even from minor exercise or minor strain of the muscles.

These authors took data from the phase II and phase III studies of—I always mispronounce this—donidalorsenin, donidalorsen, which is a newer product on the market for HAE. And it's an antisense oligonucleotide that targets PKK mRNA activity and reduces the conversion of kallikrein and therefore reducing bradykinin levels. And it's FDA-approved. It's been shown to work. And so, their question was can we evaluate CK levels before somebody's on long-term prophylaxis therapy. And after they start long-term prophylaxis therapy and we're reducing bradykinin levels, does their CK get better?

In my patient, because she's so young, she's only a candidate for lanadelumab. So, I started her on lanadelumab, and her muscle pain went away completely, in addition to her HAE obviously getting better as well. So, I was like, "Hmm, this is interesting." So, they looked at the phase II and phase III data. And in the phase II trial, they looked at CK levels that were measured in 14 patients. It's phase II. It's a small study, 14 patients on the donidalorsen, they were getting every four weeks versus the placebo group. And they saw that CK levels dropped by 65 in the treatment group and only four in the placebo group. Because the numbers were so small, it wasn't statistically significant, but it was a clear trend that the majority of the patients on long-term prophylaxis did have this decrease in CK levels.

The phase III was a little bit larger, so they had 90 study participants, and they had the group that was on donidalorsen every four weeks, on every eight weeks, and the placebo group. And when they looked at the groups, the every four-week long-term prophylaxis therapy versus placebo, there was again a decrease in 88 by the donidalorsen group versus an increase in two in the placebo group. So again, a pretty notable difference.

The question is that clinically relevant enough to make a difference in these patients? Is that going to change long-term issues for these patients? A lot to be uncovered still, but it's still interesting to see that there seems to be a CK difference, when you put HAE patients on long-term prophylaxis, in reducing their overall bradykinin levels.

So, I think a lot more to still be understood, but this was exactly what you talked about, Gerry, a second ago, is this is the tip of the iceberg, that we have this question, we've proven there's something here to look into, and could we improve patients' quality of life significantly by really addressing the bradykinin instead of just looking at HAE attacks, which is obviously super important as well. But there could be more to it than just looking at HAE attack frequency or severity.

Host: Just all these things that are silently happening underneath the surface, I would've never thought about connecting. You know, peoples have so many non-specific things. But now, if you have data behind it, I don't know. Should I be checking CKs on my HAE? I mean, is that a routine test? Sorry, I'm a bad allergist.

Shyam Joshi, MD: I don't think so yet. No, I don't think it is. It isn't, and I don't think this article should change that just yet. But I do think it gives us a partial explanation if patients are experiencing muscle pain, weakness, just exercise-related fatigue. Like, we could give them, "Hey, we think this is a real thing. We validate your symptoms. We have some data suggesting this could be related to your HAE. But we still need more information to understand is this something worth testing for?" I think we're a long ways away from that, but it does give us something to think about.

Vivian P. Hernandez-Trujillo, MD, FACAAI: I mean, as you were talking about your patient, I've probably had two young boys where it was more upper extremity. There's pain and weakness even, you know, not in an acute attack, but when all appeared to be well. So, it's making me think as well. Yeah, I think I'm looking forward to hearing more about this because, to answer the question, yeah, Gerry, maybe we should be checking CKs. I don't think we're there yet, I know. But in those particular patients, that would be really interesting. So yeah, I look forward to hearing more about that.

Host: I'm just going to round it out with one more article, and I just get very excited about these breakthrough cures. I get thrilled about it. So, maybe a couple years ago, I went over the one where they corrected variant in CD3 receptor for causing SCID.

And this one was published in New England Journal in December of '25. It's called Prime Editing for P47phox-Deficient CGD. And this is, again, specifically addressing the one caused by the NCF GT deletion, which is about 25% of chronic granulomatous disease. And, you know, I don't know if any fellows listen to this podcast, but the boards love to test you on NCF1 because, number one, it is not on gene panels, like next-gen sequencing cannot distinguish between delta GT on a pseudogene, which is like adjacent to the real gene. And so, therefore, if you send like a typical PID panel, it's not even checking for this, right? And so, they kind of love to test you on that. But essentially, that's what's so unique about autosomal recessive p47phox, that like the incorrect transcript is next to the native one. And if the mistake happens or whatever, then you have no correct transcript.

And so, the reason this is important for CRISPR is the way CRISPR works is that the traditional CRISPR is that you would have this strand, this signal guide RNA that tells where to do the double-strand break But if like the pseudogene is the same as the regular gene, you're breaking all of them, right? And so, therefore, you get these big deletions. You cannot fix this. It's just not amenable to gene therapy. So, this group, this Prime Medicine group has sort of marketed and industrialized this different technique called prime editing.

And so, what prime editors do is they have the transcript that they want to insert. And what that does is they kind of put a reverse transcriptase next to it, next to this nickase that pokes the DNA exactly where you need to insert it. The - reverse transcript, it opens. The reverse transcriptase will put the native version in. And then, it will just sort of correct itself. It'll be like a flap, and then they cut out the opposite strand and keep the new strand, and then, you know, put in the other base pairs on the opposite side. And so, the nice thing about that is you're not doing a double strand break, right? You're just cutting one side and then healing it. It's very precise.

And in fact, if you're targeting delta GT, you're probably fixing the pseudogene copies as well as the real copy. You're fixing all of them, honestly. So, it's kind of neat, you know? And so, they kind of have this technique then where they would, again, mobilize stem cells. You know, you would take G-CSF and plerixafor, and then like you would do apheresis. You would take the CD4 cells. You would treat them with the prime editing transcript, repair the DNA, make sure that you have good conversion. And then, infuse it back to the patient, right? After obviously, you know, giving them chemo, right?

So, this is a study of two patients where they did underwent this treatment. It's called PM359, all right? And so, they have the two case reports. Number one is an eighteen-year-old. He had skin and soft tissue infections. He had B cell patient pulmonary infection. He had CG colitis. He was on mesalamine. So, they did the treatment. He had on-target editing of 68% of his colony-forming cells.

There was an editing frequency of 13% efficiency. So, you know, obviously, you know, when they initially gave him the conditioning, the busulfan, he did have some side effects from that. But after getting a platelet transfusion, he had neutrophils by day 16, platelets by day 19, and he was out of the hospital by day 24. And so when they do DHRs, they were able to get 69% positive neutrophils, with oxidative bursts after one month, and it persisted for six months after that single stem cell infusion. And so, they stopped the mesalamine before he started the treatment. He didn't have to go back on it. They stopped his long-term prophylaxis on day 181, and he was free of colitis.

Patient two. Patient two, 57-year-old with a history of invasive pulmonary fungal infections. He had a lobectomy, hepatic abscess, skin and soft tissue infections. He was having active colitis despite azathioprine. So, he undergoes the treatment on target editing of 91% of colony-forming cells, editing efficiency of 23%. He did again also have busulfan-related side effects, but neutrophil engraftment in two weeks, platelet engraftment at day 12, did not need blood factor or growth factor blood product support. Discharged day 19 after treatment. Eighty-three percent positive neutrophils DHR day 30 with sustained activity. Improvement in fecal calprotectin. No clinically significant illnesses.

I mean, amazing. fantastic. So, adverse events. Adverse events were attributed to the busulfan conditioning. But otherwise, the treatment was well-tolerated after that. And so, both of them had these amazing outcomes, and this was actually detailed in a New York Times article. The title of the article is, "These patients got the cure. Then, it went away." Okay. Why did it go away? Because this treatment to get FDA approved is immensely expensive.

So, Prime Medicine ran out of money with these two patients. They said to get FDA approval, they'd have to enroll six to 12 patients. The cost would be $20 to $30 million. They ran the numbers. There's about 200 patients with delta GT in the US, and 50 would be eligible. If they treat those patients, they're going to run out of patients. So, they actually decided not to continue it until the FDA allowed them to consider to go forward with FDA approval based on a two-patient study. And about a month ago, June 2026, they got the Regenerative Medicine Advanced Therapy designation to get priority review.

So, it has gone forward. We'll see what happens on a two-patient study. But this is where the economics of gene editing comes out. It's very expensive to develop these precision therapies. There's not a lot of patients, but these are life-changing treatments—like, life-changing treatments. And this is like what society and us are just grappling with. This story is very similar to the ADA-SCID story, where Dr. Kohn had to develop his own public benefit company, you know, Rarity, to try to get FDA approved on his own because the sponsor dropped him, right? Like, without that sort of, you know, passion to push it forward, it's going to be very difficult for pharma to do it by itself.

So, I wanted to talk about the article, but also the context. It's just the context is just so fascinating how we grapple about these rare diseases, where we're at the edge of technology with life-changing treatments that use a lot of resources and helps very few people. We see these people individually, .Ut then, like, we're balancing it with the whole idea about healthcare. Sorry to make it very big, but this is what all the issues I think about. I don't know. I mean, Viv, you've seen many of these patients. I don't know what you think about this.

Vivian P. Hernandez-Trujillo, MD, FACAAI: I mean, I totally agree with you. I think an important piece that you just brought up is actually Dr. Kohn was able to, right? Like, I think, again, it comes back to advocacy. Like, we continue to advocate for our patients. Sometimes we're able to get what we need, sometimes we're not. But actually, he's very inspirational. I think, you know, I would love to be able to have treatments for all the different types of inborn errors of immunity that we have. And realistically, is that going to happen? Maybe in the future. I won't live for that.

But I think I was super excited about the article as well, for the same reason as you were. And it is complicated. It is complex. There's a lot of economic factors that need to be considered. But when you take care of these patients, and you're talking to them, and you're speaking to the families, that's the part where, you know, my heart is always, "I want to do what I can." We're physicians. At the end of the day, we're here to help our patients.

And I think the piece of advocacy comes back yet again, that we need to, you know, be advocates for them in whatever sense it can be. Sometimes it's about education, sometimes it's about fundraising, sometimes it's about the research piece. But I think it is fascinating and it's exciting.

Like, In immunology, I always say, like, we're on the edge. We've already had somewhat of an increase in understanding, but this is going to explode. Like, the future of medicine is truly immunology. Because if you look at diseases across the board, especially chronic conditions, there's a lot of immunology there. So, I think it's fascinating. I'm so happy that you brought this up.

Shyam Joshi, MD: Yeah, we brought this up in journal club during our fellowship, and our fellows were just mind-blown, right? This is really great cutting-edge stuff. And yeah, hopefully, we'll be able to use it more freely, in the coming years or decades. But really having options for these patients.

I actually have a recent new diagnosis of p47PHOX, and this is something we had a really thorough discussion with my patient about, is there a possibility here for them to receive this because their life's been turned upside down with the new diagnosis. And if we have some options here going forward, it's really promising.

Host: Okay. Well, I mean, if you have thoughts about this conversation or any of the articles that we reviewed today, please reach out to us. The email is allergytalk, one word, @acaai.org. If you like what you're hearing, please leave a comment on YouTube or a rating. Please rate us on our podcast app. And again, don't forget about CME credit. That website is education.acaai.org/allergytalk. And of course, we didn't hit all the articles on the latest issue. So, please read the rest of these amazing, interesting things that make us better physicians. That website again is college.acaai.org/publications/allergywatch.

Well, again, another banger episode. Such interesting discussions. Such wonderful people. Thanks for joining us. And I hope you enjoy the rest of your day. Thanks, everybody.

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, or products or methods discussed in the podcast, and it does not approve or endorse any products, professionals, services, or methods that may be referenced.