intro: Please stay tuned to the end of this program or see the show notes for important information regarding today's speakers and the content of this podcast.

Dr. Gerry Lee (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 will be reviewing more articles from Allergy Watch, a bimonthly publication, which provides research summaries to college members from the major journals in Allergy and Immunology. And you can also earn CME credit by listening to this podcast. For information about CME credit, or to read archive issues of Allergy Watch, head over to college.acaai.org/publications/allergywatch. And we also have discussions on the ACAAI community on DocMatter, where we can continue conversations about these articles.

Well, hi everyone. My name is Gerry Lee. I'm an Associate Professor at Emory University and an Assistant Editor of Allergy Watch. Today, I'm once again joined by the Editor-in-Chief of Allergy Watch, Dr. Stan Fineman.

Dr. Stan Fineman: Hello again, everybody, and thanks for having me. I'm, as Gerry said, the Editor-in-Chief of Allergy Watch. I'm a past president of the college and also in private practice at Atlanta Allergy and Asthma and an adjunct faculty at Emory.

Host: And for the third chair, we are very excited to be joined by Dr. Melinda Rathkopf. Dr. Rathkopf has just joined me as a colleague as an Associate Professor at Emory University, and has had multiple leadership positions with the college in the past. She was on the Board of Regents. She chairs the Practice Management Committee. We are so fortunate to have her expertise, experience, and opinion. So, Melinda, thank you so much for joining us on Allergy Talk.

Dr. Melinda Rathkopf: Thanks, Gerry. I'm excited to be here with you and Stan this evening, and thanks for having me. As Gerry said, I am an Associate Provisional Professor here at Emory and at Children's Healthcare of Atlanta and a colleague of Gerry's here in the Pediatric Clinic. And thanks for having me on my first Allergy Talk podcast.

Host: Well, we're, again, super grateful that you joined me in Atlanta. Oh, you're coming back home too, so that's in our favor, that's great. And also, to talk about some really interesting articles. Stan, let's get started and let's talk about biologics and allergy shots.

Dr. Stan Fineman: Yes this is an article that was reviewed in the Allergy Watch in the May/June 2023 issue. And the article is from the Journal of Allergy, Clinical Immunology, January 2023. And it's entitled, Effects of Combination Treatment with Tezepelumab and Allergen Immunotherapy on Nasal Responses to Allergen: A Randomized Controlled Trial, and John Corren was the first author and there's several other authors. This is a whole research network that studied this. And it's an interesting study because, as you know, we're always trying to find ways that help our patients improve their symptoms with allergies. And allergy immunotherapy is a very, very effective tried and true way for us to use for patients. We always want to try to make it better and more effective and also obviously safer.

So, what these researchers did is they took anti-TSLP or anti-thymic stromal lymphopoietin. And we all know that TSLP is an epithelial-derived cytokine that promotes the development of antigen-specific Th2 cells among other of its effects. So, an anti-TSLP biologic product such as the tezepelumab reduces the interleukins of 4, 5, and even IL-13 as well as total IGE in patients with asthma. And of course, it's indicated here in the U.S. for patients with persistent asthma that's not controlled.

So, what these researchers were trying to figure out is could this be used as an adjuvant to allergen immunotherapy? And so, it evaluated the effects of our subcutaneous immunotherapy for patients who have cat dander allergy. And the study was called the CATNIP trial, which I thought was kind of a cute name. So, they enrolled 121 patients with moderate to severe cat allergy-related allergic rhinitis. So, these patients didn't have asthma, they just had cat dander allergy, and they were assigned to four treatment groups. One was allergy shots alone. One was the tezepelumab alone, one was the shots plus tezepelumab, and one was a placebo arm. And the treatment was continued for 52 weeks and then everything was discontinued, and they were studied again over the next year. And so, the secondary endpoint was at 104 weeks, which is year two. So, the tezepelumab plus the subcutaneous immunotherapy was associated with a greater efficacy at 52 weeks with significant reductions in the total nasal symptom score, which was calculated area under the curve in response to a nasal allergen challenge. And this was their primary endpoint. So, this was a nasal allergen challenge, looking at the total area under the curve. And they also looked at the peak nasal symptom scores in the first hour. So, that's only in zero to one hour reduction in just the first hour. And what they found was statistically significant changes in both, the one in the first hour and also the area under the curve at 52 weeks. But at 104 weeks, only the area under the curve analysis was statistically significant. And so, there was a difference in the patients who had the tezepelumab before the shots.

Now, the way it was administered was kind of interesting. It's not our usual subcutaneous administration. This was given IV. It was given one to three days before they started the subcutaneous immunotherapy and the subcutaneous immunotherapy was administered by a cluster program, which was built up to maintenance in about 12 weeks, and then every four weeks was their maintenance after that, continued for the full year. And then, they stopped it, of course, and then they did their analysis. They also looked at some transcriptomic analysis of epithelial samples looking at genomes, and they felt that the shots plus the tezepelumab associated with a lasting downregulation of mass cell gene signature compared to the shots alone.

So, you know, there was a couple of different findings I thought that was sort of interesting. The shots, of course, whether they had tezepelumab or not, you could see a rise in IgG4, which we know occurs in shots. Cat dander-specific IgE tended to fall in all the groups really, but especially the ones that had the immunotherapy. And of course, the IgE and IgG4 ratios seem to do much better in the group that had the tezepelumab and the shots. So, the main difference was this endpoint, which was peak total nasal symptom scores, there was a statistical significance with the group that got tezepelumab and shots, and the area under the curve endpoint and those after the two years, really there wasn't statistical significance, although there was improvement overall.

So, the bottom line is they did show efficacy that the tezepelumab may improve both the magnitude and the duration of immunologic response to shots. And Gerry, who basically made a comment on this article in Allergy Watch, and I think his comment was very cogent, stated, "Unanswered questions include whether the clinical symptoms were also improved and whether the cost of the tezepelumab is justified if there are no other medical indication." So, this was the study.

Host: Yeah. So, you know, the reason I made that comment was I completely agree that you know, optimizing immunotherapy by shortening its duration and improving its efficacy as a pilot study, obviously in a very mechanistic, in a chamber exposure model sort of thing, not real world, is really intriguing. But tezepelumab is really expensive. I mean, we certainly have allergic asthma patients who could fail standard therapy and may need tezepelumab. So, that would be your real world exploration. You know, we're giving, what, I guess a third of the dose, 200 milligrams instead of 700 or something like that? But just to do it with immunotherapy, I was thinking about the real world. I don't know, Melinda, what do you think?

Dr. Melinda Rathkopf: Wasn't this previously looked at with ragweed and omalizumab? And there have been some studies at looking at response. But again, I don't know clinically of any of us that are doing it, mostly related to cost. Although, you know, I don't think it was set up to look at this. I could see a case of a patient with moderate to severe asthma that immunotherapy may be helpful and you might not be as comfortable doing immunotherapy on them, but you might if they were on the tezepelumab. But yeah, I don't think using it just in the setting for allergic rhinitis to justify shortening the duration. Could it be improved adherence? By a shorter duration potentially. But I think costs would be the biggest thing and, of course, the dictation of that cost from the payers.

Dr. Stan Fineman: Right. And of course, this was only given one time. There was only one dose of tezepelumab. But still, I don't know what it costs. It's probably at least several hundred dollars, maybe a thousand. So, who knows what the benefit would be I do recall some of the studies that you mentioned about using omalizumab with immunotherapy. And I think a lot of those reduce the risk for reactions. But I'm not sure they showed a lot of increased efficacy.

Dr. Melinda Rathkopf: Yeah, I think that's what I recall, was seeing if it could be used to put people on immunotherapy that previously were failing immunotherapy due to reactions. Am I recalling that correctly?

Host: Or a bridge, right? Like, we know that omalizumab is not disease-modifying. And so, you know, you could put someone on omalizumab and control their asthma. But as you know, we're very interested in treating the underlying condition. And so, this is where immunotherapy offers a disease-modifying effect. So, converting someone from a control effect that's not disease-modifying and then bridging them by controlling their asthma to allow them to get immunotherapy, I mean, many of us have used that strategy before. So, I think that's sort of the background I'm aware of, but it is intriguing to maybe think of ways where you can hit two birds with one stone, which we know what we do with biologics, and maybe entering immunotherapy in the conversation regarding that. This seems to seem like there's a role for that.

Dr. Melinda Rathkopf: Although it would be intriguing to look at it from a cost perspective if you're looking at a single dose of the biologic, and a year of immunotherapy with that single dose, what would the cost of that be compared to a three to five-year regimen of immunotherapy, but also the cost of missing work or school, the cost of coming to the appointment, the cost of gas? There's a lot of other factors that are spread out over three to five years of immunotherapy. Would the relative costs kind of pan out that it wouldn't be as disfavorable as we think it would be just from the dollar standpoint?

Dr. Stan Fineman: I love that you brought that up. I think that's a great comment. We do know the studies seem to indicate that you need three years at least of immunotherapy to have a sustained benefit. So, I think you're right. I think they have to look at the whole picture.

Host: All right. Well, let's talk about the next article. I also reviewed this in Allergy Watch and the title of the article is Allergen Immunotherapy for Atopic Dermatitis: Systematic Review and Meta Analys-s of Benefits and Harms. And this was a study that actually was sponsored by the Joint Task Force for Practice Parameters, to lead to their eventual publication of the revision to the Atopic Dermatitis Guidelines, which I think, as of this recording, is still under comment.

So, immunotherapy, we've just talked about it for rhinitis, we do it for asthma. But atopic dermatitis, I looked it up, the last major recommendation was 2010 for subcutaneous and it said potential indication and that was, based on a few selected studies potentially inconsistent. So, I think when they wanted to revise the atopic dermatitis guidelines, the Joint Task Force was very interested in the update. What have we learned now since that recommendation, gosh, like 13 years ago?

So, what they did is they, again, commissioned this systematic review looking at all the studies that looked at subcutaneous and sublingual immunotherapy, and looked at atopic dermatitis outcomes, severity, so, you know, caregiver scores like SCORAD and EASI score. They talked about patient-reported outcomes, itching, sleepiness, sleep disturbance, and quality of life. And, of course, it's immunotherapy, so they had to look at adverse events. And, you know, they use the GRADE approach, they use the PRISMA framework, the typical things you would expect with a systematic meta-analysis type study. So, they were able to identify 23 randomized controlled trials, this is almost 2, 000 patients, 1,957. It had adults and children. And you could expect this, but the majority of studies focused on house dust mite, some included some pollens as well, but house dust mite was the major allergen they were desensitizing against. The mean duration of the therapy was about 12 months. And as you can imagine there was some bias, because it's really hard to do placebo control that's blinded with immunotherapy. So, there may have been some lack of blinding in some of the studies as well.

But when you look at the actual outcomes, and so you're really comparing these outcomes I mentioned before for atopic dermatitis severity, they considered a significant improvement of a 50% from baseline. So, without immunotherapy, it was 26%. With immunotherapy, 40%. That's a 14% more patients in the treatment group. achieved a significant improvement with moderate certainty. So, pretty impressive. They had similar improvements in quality of life, 17% more had improvement in quality of life. And unfortunately, they didn't really see a strong effect in flares, reduction of flares leading to systemic steroid therapy. That was pretty uncertain to be very different. But as you can imagine, we can talk about efficacy, but we also have to think about adverse events. So, I don't need to tell you that subcutaneous immunotherapy over placebo has more adverse events.

In this particular study, they found that there was about 3% more systemic reactions versus placebo. Overall, it was an 11% rate for systemic reactions. And then, about a 10% rate for adverse events causing therapy discontinuation for subcutaneous. Now for sublingual, immensely small, 0.14% systemic reaction rate, only, 1.2% had some sort of adverse event leading to discontinuation in that group.

Oh, one thing I forgot to mention, median time to effect in the improvement of outcomes was about five months. So, the Joint Task Force looked at that systematic review, they did a very thorough analysis, and the draft of the practice parameter states that they will be in favor conditionally for the treatment of moderate to severe atopic dermatitis where benefits outweigh the risks, but you know, because of the potential for systemic reactions, they have a conditional recommendation against that for mild atopic dermatitis.

Clearly, it's still under comment. I think different stakeholders will be weighing in on this. I think if we think about sublingual dust mite immunotherapy being, you know, available, and actually being studied in children down to five, I'm not sure when we'll get the results of that, I think the MATIC study, like phase III study it is potential that we have another option to offer our patients. And I'm going to tell you, if it's sublingual, then it's going to help multiple allergic diseases, and the adverse event rate wouldn't be so bad. So then, we got to our earlier conversation is, will it get covered? That's another discussion. But I don't know, I think this is a promising direction for our patients who are suffering with atopic dermatitis.

Dr. Stan Fineman: You know, it's very, very exciting to me having trained-- well, I don't want to even say how many years ago. When I trained, it was contraindicated to use subcutaneous immunotherapy for atypic dermatitis because it was current knowledge, or at least at that time, we felt that it made it worse. And through the years, of course, I've used it for rhinitis, respiratory allergy, and patients had concomitant atopic dermatitis, and they got better, their atopic dermatitis got better. And parents would bring the kids in and said, "Wow, this is terrific." So, I'm glad to see that they've got some good hard data and that, hopefully, they'll change some of the recommendations and guidelines. And, you know, if the guidelines are changed, then hopefully the third party payers will follow suit and enable us to be able to use it for our patients.

Dr. Melinda Rathkopf: So funny, Stan, you beat me to the punch there with that comment, because I was going to say how long ago I trained, but that it was somewhere between you and Gerry. And when I trained, it was more the, "Well, we used to say it made it worse, but it may not make it worse. It may make it better, but we're really not sure." So, I was in that transition time, I guess. But yeah, this was exciting to see because I too don't think I've tried it solely for atopic dermatitis, but have definitely seen patients' atopic derm improve, you know, when they're on immunotherapy for their other allergic asthma or allergic rhinitis. So Gerry, so in this, I'm assuming this was with the commercially available FDA-approved dust mite tablets

Host: Oh, gosh. No, many of the studies were on drops, dust mite drops. So, I'm sorry I didn't mention that.

Dr. Melinda Rathkopf: It was all types of dust mites sublingual that are given around in allergist's office?

Host: That's right.

Dr. Melinda Rathkopf: Okay. Thank for clarifying that. no,

Host: I should have mentioned that. I apologize. But yeah, many of the sublingual studies were actually drops and not tablets. And then, yeah, as you know, subcutaneous is pretty straightforward for subcutaneous.

Dr. Melinda Rathkopf: Yeah, the biggest barrier I see is coverage. I've not had success in any of the sublingual FDA-approved products getting covered.

Host: Again, I have no financial relationship. There are some ways to reduce that cost by getting it directly through certain pharmacies and so on. But yeah, it could be a significant cost. I mean, something like $7,500 a month uninsured. So yeah, there's going to be some barriers.

But there's a benefit and it goes back to my early point of disease-modifying. I would make the argument that depilumab is not disease-modifying either. So, I'm not saying that this study proves that this is disease-modifying, but that's sort of our intent with these treatments, to actually change the course of the disease to modify the immune system.

Dr. Melinda Rathkopf: And although rarely done, it would be great to see a head-to-head comparison, allergen immunotherapy versus a biologic, if you want to talk about cost effectiveness.

Host: There you go.

Dr. Stan Fineman: Now, the only other comment I wanted to make was I really want to recognize that the task force of practice parameters for doing this, because as a clinical practitioner, we rely on the Joint Task Force of practice parameters for helping give us guidelines with the latest information and evidence-based and here is just a good example that they are really on top of their game and looking out for patients and the clinical practitioners. So, I think we should give kudos to the Joint Task Force for this.

Host: No, absolutely, Stan. We need studies like this to move this practice forward and help convince payers and other stakeholders of the role of Allergy and Immunology in the care of these conditions. So, a hundred percent agree. So Melinda, let's wrap it up with you. And I think it's the age old debate about, is it good to have dogs or not good to have dogs? And I think we have more data for dogs.

Dr. Melinda Rathkopf: Yes. Okay, here it goes. So, my first article being presented on Allergy Talk. So, this article is the Impact of prenatal dog-keeping on Infant Gut Microbiota Development. And it was published in May of this year in Clinical and Experimental Allergy, and it came out of the Allergy Immunology Department at Henry Ford Health System in Detroit. So, you know, most of our listeners know, we know that there has been this debate over the years. And we could go back to, depending on when we trained, what did we learn, but between prenatal and early life dog exposures linked to reduced childhood allergy and asthma. But the mechanism has never been fully elucidated. And there's some theory about gut microbiome among dog-exposed infants.

We know vertical transfer of maternal microbes during the environmental exposure can shape the bacterial community of the neonatal GI tract and looking at those profiles. So, what they did is they looked at 141 maternal-child pairs from Southern Michigan and they recruited women while they were pregnant who planned to stay in the area at least 2 years and they had had a dog for at least a year prior and agreed to try to keep that dog for at least 2 more years, or they were pet-free and intended to stay pet-free. So, that's how they were originally divided up. They did questionnaires prenatally and, again, at the first week, six months, and 18 months after delivery. In a subset, they looked at maternal, vaginal and rectal swabs, and maternal stool and infant stool were collected. And then, that's where they looked at the microbiota.

So for those that are interested, there's a very complicated procedure with a lot of words you don't want me to try to pronounce on this podcast on how they extracted the DNA, how they sequenced it, and What they found in the microbiome. And then, they went on to see if they were sensitized at 18 months of age. So, meaning, did they have a specific IGE over a certain level to common indoor? They looked at dust mite, cat, dog, mold, and they also checked grass and looked at those in the homes. And they found of 141 children at 18 months of age 81 in dog homes and 60 in pet-free, seven were sensitized to common inhalants. They looked at those that developed asthma and eczema. Then, they looked at those divided on which home they lived in.

And, you know, to kind of just cut to the chase here, what was interesting is that what they found was that prenatal dog-keeping associates with altered gut microbial community trajectories. So basically, there was more biodiversity and it was interesting they looked at the children, those frequent visits in early infancy, and saw initially the gut microbiome was very similar to the maternal gut microbiome, but diversified as the child got older, so that's kind of expected, and showing that diversity. But then, they also found in homes with dogs versus not dogs that they were more diverse if there was dog exposure. And this showed out, it was most evident in the three-month visit and the six-month visit and in those that did not receive breast milk and those that were formula-fed.

So, the overall conclusion was that prenatal dog-keeping may have this beneficial effect, especially in formula-fed infants. So, is having a dog a way to enhance the immune system in someone, especially if they're not able or choose not to breastfeed? I thought that was an interesting conclusion there. And Dr. Joshi reviewed this for Allergy Watch and he concluded that the study again showed early dog exposure had a more diverse microbiome at three and six months of age and it was most prominent in formula-fed infants. So, can dog exposure provide an alternative source of environmental microbes in the absence of breast milk?

Dr. Stan Fineman: Go dogs.

Host: Dogs are all over the place. Makes sense to me. Those buggers are all over the place. They'll bring everything, the whole world to you and lick it all over you.

Dr. Stan Fineman: Well, these guys, I mean, Dennis Ownby was one of the folks down in Michigan. He was even cited as an author in this study. And they've done phenomenal stuff up there in Michigan, following these moms and these kids, in homes that have animals. And I remember at one point they came out with an article that basically supported the hygiene hypothesis and said, if you had animals in your home, you reduced your risk for developing asthma. And this is almost the same type of story in terms of supporting your suppression of Th2 and because of your exposure to these microbiomes change.

Dr. Melinda Rathkopf: Yeah. I think this was trying to look for a potential mechanism to explain the prior studies that showed it helped, and is that related to the gut microbiome?

Host: So yeah, good news for dogs, I guess. If we want to stop allergies in America, I guess, everyone should get a dog if you're expecting a kid. I guess that would be your standard baby shower gift.

Dr. Melinda Rathkopf: Oh, but they had them a year prior. So in this study, they had them a year prior.

Host: Oh, you're right. Oh, too late.

Dr. Melinda Rathkopf: Yeah. So, I do have to relay a personal story. My husband says my mom gave us the worst wedding present you could give a couple, which is a puppy. So, maybe, you know, you get the dog, you get the dog as a wedding gift, and then, you know, when you have the baby down the road, you've had the dog in the home for a while.

Host: There you go.

Dr. Stan Fineman: And your kids didn't have any allergies either, did they, Melinda?

Dr. Melinda Rathkopf: They did not, but, you know, I might not be the best--

Host: It was the dog. It was the dog.

Dr. Melinda Rathkopf: And we had multiple dogs and dad is atopic. So maybe, you know, we got past that atopic tendency.

Host: We got an N-of-1 right here. All right. So, okay. So, I apologize. If you want a wedding gift, just say you're doing it for the allergies.

Dr. Melinda Rathkopf: There you go.

Host: Okay. Very good. All right. Well, I had a lot of fun. Thank you so much for listening. Melinda, thanks for joining us. If you did enjoy what you heard, if you'll rate us on iTunes, that really helps us out. I also do want your feedback if we made a mistake, you want to make a correction or a suggestion for a new episode, just email us. Our email is allergytalk@acaai.org. And remember about CME credit, you just go to our website, college.acaai.org/publication/allergywatch. My name is Gerry Lee. Thank you for listening. I hope you enjoy the rest of your day. We'll see you next time.

Dr. Melinda Rathkopf: Thank you.

Outro: 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 may be referenced. Today's speakers have the following disclosures. Drs. Lee and Rathkopf have nothing to disclose, and Dr. Fineman has been a speaker for Takeda and has done research for AImmune, DBV, and BioCryst.