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 reviewing more articles from Allergy Watch, our bi monthly publication which provides research summaries to college members from the major journals in allergy and immunology and you can earn CME credit by listening to this podcast.

For more information about CME credit, head over to education.acaai.org/ allergytalk and make sure you check out the ACAAI community on DocMatter where we can continue the discussion about these articles. Well, hello again. My name is Gerry Lee. I'm an Associate Professor at Emory University and Assistant Editor of Allergy Watch, and today, once again, I'm joined by the Editor in Chief of Allergy Watch, Dr. Stan Fineman.

Dr. Stan Fineman: Hello everybody and thank you for inviting me again. I'm a past president of the American College of Allergy. I'm retired from clinical practice here in Atlanta and a volunteer faculty at Emory.

Host: And for the third chair, we're excited to be joined once again by Dr. TIm Chow, Assistant Professor at UT Southwestern and Assistant Editor of Allergy Watch. Tim, welcome back and tell the audience a little about yourself.

Timothy Chow, MD: Yeah, so I'm down here in Dallas. I run the Pediatric Drug Allergy Program here, and so my clinical and research interests revolve around drug allergy, and that's one reason why I really enjoy being part of Allergy Watch, getting to keep track of all sorts of allergy literature, across the spectrum of our field.

Host: Yes, and I learn a lot. Like, a ton. So, I really appreciate all the hard work, Stan, you've put into it for years, and how the college has supported this for our membership. So, let's learn something! Stan, for this first article, when I think of IT, I think of immunotherapy, but I don't really think of intratonsillar, so why don't you explain what that means?

Dr. Stan Fineman: So, this was a study that was published in the Annals of Allergy in March of this past year, that was entitled, Efficacy and Safety of Intratonsillar Immunotherapy for Allergic Rhinitis, a randomized, double blind, placebo controlled clinical trial, and it's out of some allergy researchers out of China.

And we all know about immunotherapy and we know how effective it is and we just want to try to give it more safely and try to make sure that it's as efficacious as possible. And recently there have been some studies using intralymphatic type immunotherapy that reduce the dosages.

And these researchers decided to do it intratonsillar. So it was the first that I know of, it was a randomized double blind placebo controlled trial. They used the tonsils as a location for the injection of the immunotherapy, intralymphatic immunotherapy, and it was in adults. They had chronic, moderate to severe allergic rhinitis.

They all had positive dust mite skin testing and serum IGE. It was randomized, so the 40 patients in the active group received 6 injections, and the way they did this is they alternated the tonsil every 2 weeks, and the maintenance dose was up to 10,000 subcutaneous units, or SQ units, which is approximately one microgram of DERP1, the dust mite antigen, with the first injection, a tenth of the maintenance, then two injections a third of the maintenance, and basically they kind of have a built up schedule every two weeks.

And they've received a total of the six injections over this 12 weeks process. So the 40 patients, also received placebo injections. They received saline and the primary endpoint was a change in total symptom score from baseline, to a specified time point.

It was at completion of the therapy, and also 3, 6 and 12 months after the last injection. And there were also some secondary endpoints that included some of the immunologic parameters including size of the skin test, a specific IgE, and also IgG4, dust mite specific IgG4. So, with regard to the primary endpoint, three months after the intralymphatic intratonsular immunotherapy injections, six injections, the mean total symptoms were significantly lower in the treatment group compared with the placebo group.

Interestingly, the change did diminish over time and lost its significance at 6 and 12 months, after stopping the immunotherapy. So there seemed like a fall in the efficacy or the differential in the efficacy over time when they stopped using this technique. Now, interestingly, among the secondary endpoints, though, there was a rise in dust mite IgG4 was noted during the treatment and that did persist for the 12 months, but of course, clinically, it didn't seem to persist.

So, the conclusion for the study was that the clinical trial did reveal that intratonsular injections with dust mite extract was safe and effective, that optimizing the protocol, the allergen formulation, needs to be tweaked and probably increased.

The one thing I forgot to mention just now, and I wanted to, was the side effects, which, were really pretty minimal, and obviously, as most people would think, the main side effect was, injection discomfort, and people who didn't want to have the injection there, and, there was a little bit of drop off in the study.

There were about five discontinuations, but that was in both groups, and only 35 patients really did complete it till the end. But it looked like it was safe. Maybe not that efficacious long term, but in the short term, looked like it was efficacious. So maybe we'll be using other types of, intralymphatic immunotherapy.

I did want to mention one thing. If you go back to the March issue of Annals, there was an excellent editorial that did review the intralymphatic immunotherapy. It was a status update from Derek Smith and Kevin White at Lackland Air Force Base, which I thought was excellent.

Host: I guess in the era of sublingual immunotherapy to dust mite, I'm really weighing this and going after the tonsil with a needle. Obviously this is monosensitized patients. You have to do it with stenose extract. But, I don't know, big picture wise, is this something other than dust mite that they're looking into Stan? Because if it's dust mite, I'm going for the tablets. You know what I mean?

Dr. Stan Fineman: Well, that's a good point. This is the first study that I'm aware of using the intratonsillar. They've used intralymphatic for pollen before and that has shown efficacy even long term for both grass and Japanese cedar, and I think some other pollens as well. So, they decided on this one I'm not sure.

I think it is harder to study. I think the endpoints are a little more challenging. I think anytime I see an immunotherapy article with some kind of a new slant or somebody who's trying to make it safer and more effective, I think it's something that we should look at.

Host: Tim, any thoughts?

Timothy Chow, MD: Yeah, I think the first thing that came to my mind since I primarily care for pediatric patients is, just, wondering how tolerable this will be, and I don't know if this will ever be an option, for us. I can, just imagine trying to administer these into young kids. And as we kind of noted, this has been looked at for other air allergen prescriptions.

But I do wonder if the tolerability decreases as you start increasing to do multi allergen immunotherapy. So if you're getting, again, like three injections compared to just one, how does that impact patients acceptability, of this? I think that remains to be seen.

Host: And by the way, my previous comment wasn't that tablets are the solution for everything. I had a patient who just could not tolerate dust mite tablets. She felt awful on it. Like every day she was bothered by it. She ended up not being fully desensitized. So she stopped it on her own. So, obviously with shared decision making people do maybe want a shorter course and less visits. Absolutely. So, it's absolutely worth studying. I apologize. I didn't mean to say that, but that's the only way to skin a cat.

Dr. Stan Fineman: When I read this article, I was thinking, we have enough trouble trying to get patients to come in and show us their arms so we can give them a shot, to do an intratonsillar injection. I mean, I don't know. That seems like a big push.

Host: If you have big tonsils and you have a large target area, I guess, you know. Anyways, let's move on. Tim, you selected a great article that I've been hearing a lot about, but I actually have not thought about it as something I've integrated in labeling patients, and that is labeling them in remission. So, what do we know about remission in asthma?

Timothy Chow, MD: Yeah, so the article I chose is titled Clinical Remission in Severe Asthma with Biologic Therapy, an analysis from the United Kingdom Severe Asthma Registry. So this was published in the European Respiratory Journal, in October of 2023. And, we've all seen, biologic therapies for severe asthma have really been a significant game changer.

And now, clinical remission has entered the realm of possibility for many patients, including those with severe asthma. And so, the primary objective of this study was to characterize clinical remission within a cohort of patients with severe asthma. So to do that, the authors used data from the patient cohort in this United Kingdom Severe Asthma Registry.

They included adults who met ERS and ATS criteria for severe asthma, that they needed to be eligible for biologics using local criteria, and had at least one follow up visit as part of their registry protocol. And the primary outcome was clinical remission, which they defined as meeting four specific criteria.

So the first was that they had to have an asthma control questionnaire score of less than 1.5. Second, they had to have no oral corticosteroids for exacerbations for the last 12 months. Third, no maintenance oral corticosteroids for asthma over that 12 month period. And then fourth, an FEV1 above the lower limit of normal.

 The reason why I went over those in specific is I want to contrast that to some other definitions of clinical remission, later. So they included 1,111 patients. The mean age was 52, 60 percent were female. The majority, 87 percent identified as white. 85 percent had uncontrolled asthma with 60 percent on maintenance oral steroids.

981 commenced biologic therapy. The vast majority were on anti Io5 agents, so those were 84%. 15 percent were started on omalizumab, and 0.3 percent were started on dupilumab. And over the course of one year after being on biologic therapy, 18 percent achieved their definition of clinical remission. So, they then looked at, okay, what pre biologic initiation features were associated with remission.

And T2 high disease, was associated with an increased likelihood of achieving clinical remission. That's probably unsurprising since all the biologics targeted T2 endotypes of asthma. The odds ratio of having a high blood eosinophil count and a high pheno was 7.44. And then they kind of played around with their definition of remission, to see how that affected the number of patients that fell in that range, and they range between 12 to 21%. So, kind of in conclusion, in this real world patient cohort of severe asthma, again, 18 percent of patients achieved one definition of clinical remission through biologic therapy. I think it's important to note, though, that this definition's different from the ACAAI, the AAAI and ATS consensus workgroup definition of clinical remission in asthma on treatment. And so the workgroup defined clinical remission as meeting six criteria over a 12 month period. And so first, no exacerbations requiring a physician visit, ED visit, hospitalization, or systemic steroids for asthma.

Second, no missed work or school over the 12 month period for asthma symptoms. Third, stable PFTs, four continued use of controller therapies, apart from biologics, only at a low or medium dose of ICS. Five, having asthma well controlled on a validated measure, such as the ACT, the ARQ, or ACQ. And then six, symptoms requiring reliever therapy no more than once per month.

And you may be wondering, why did I just recount all that? But I think it really is important. As clinical remission becomes a potentially achievable outcome for patients with severe asthma, and there's further studies to investigate this, it's going to be important to be aware of how these definitions are being defined so that we can make sure we're comparing apples to apples.

But overall, this study, I think, supports that sustained, very well controlled asthma can be achieved by at least some patients with severe asthma.

Dr. Stan Fineman: So, Tim, were you concerned that it was 18 percent was the result?

Timothy Chow, MD: I think depending on the patients that we're taking care of, I think, many of us may see even higher levels of control on biologics. I think the issue here is that, again, this is a real world cohort, so we're not necessarily controlling for all these different things.

So while they are trying to apply maybe a more rigorous definition of clinical remission; there definitely may be some variations from patients with that. I think that another piece of this too, is that not everyone had T2 high disease, and as we know, our options for treating T2 low, severe asthma are much less robust.

But I think, again, further studies are needed to characterize this across other populations to see and really fully characterize, how many patients are able to fully achieve this.

Host: I'm just, in general noticing a change in attitude about what are we going to go after when we look at asthma outcomes and when are we going to be satisfied that we're achieving those outcomes. Just see what's happening to mild asthma. We actually are not accepting any exacerbation. And that's why we're really pushing anti inflammatory relievers, where again, even demonstrating one or two exaccerbations is a loss of lung function.

So, remission's, sort of like that same thing where now we're actually telling patients we shouldn't be normalizing that you're just going to have symptoms and you're going to go to the doctor because that's what asthma is and that's what it is. And I'm really excited about that because I think there was sort of this fatalism that takes over asthma patients that, yes, I have asthma and this is who I am and we're trying to get people to remission and we're trying to make sure they have as best quality of life as possible, that these sort of definitions may allow us to talk to patients about what their choices are as a choice that they actually can accept and not say I'm gonna always be short of breath, or always have to see the doctor.

We could actually give them choices. So I really like this shift. Obviously, I don't know if we can get everyone there. You're talking about low percentages, but it is a great way to talk to patients that, yes, we can achieve this. You don't have to accept that this is going to be what asthma is for you, if that makes sense.

Timothy Chow, MD: No, I completely agree. And I think, again, another thing to highlight was just that within this cohort, again, 60 percent were on maintenance oral steroids. And so, just having a framework for an even, like a mental model of that, oh, could it be possible that my asthma could be this well controlled? That, may not have really been something that they would have considered even possible, right? So, I completely agree.

Host: It's exciting to see that we can actually achieve these things, but obviously, as Stan has pointed out, we've got a long way to go. That's still the minority of patients. So I'm going to review one article that Iris Otani discussed, and this is looking at 11 years of data from Canada and Israel, cohort study looking at treatment for anaphylaxis pre hospital and in the emergency department. This is the Cross Canada Anaphylaxis Registry. And this was published in the annals December of 23. So essentially this was 11 years, some prospective data, some retrospective data looking at the Cross Canada Anaphylaxis Registry. And the questions are really about what are the treatment people are getting through emergency medical services or in the ED for anaphylaxis? As you know, we know epinephrine is underutilized. And then, when you do these real world studies, it allows you to examine the effects of these treatments on outcomes like multiple rounds of epi, getting admitted, ICU, because it's not ethical to do these in a controlled fashion. We can't give placebo steroid or placebo epi.

That is ridiculous, right? So there's gonna be some variation based on the patient characteristics. But ultimately we're going to answer these questions about what are some of the optimal treatments if we look at the outcomes after these treatments? So again, they got about 5,364 cases of anaphylaxis and about 44 percent of them got antihistamines in EMS, only 38 percent got epi by EMS, and about 6 percent saw about, steroid was like 3%.

And about 19 percent of the patients in EMS antihistamines was the only treatment for a moderate to severe anaphylactic reaction, which is remarkable. I mean, my goodness, just antihistamines alone. Now once they get to the ED, the number is a little bit better, about 51 percent were treated with antihistamines, still 43 percent treated with epi and 40 percent with corticosteroids.

Now if you look at both pre hospital and ED treatment for epi, the total cohort, about 76 percent got epi. So that means a quarter had anaphylaxis did not receive any epi before or in ED, like terrible, my goodness. In terms of admissions, about 5 percent were admitted in this 5,000 patient cohort, associated with admissions, older patients, severe reactions, and pre hospital steroids. So pre hospital steroids, you are more likely to get admitted to the hospital in this cohort. And then about 0.88 percent with the ICU, no fatalities.

So, about 4.6 percent needed two epinephrine doses, predictors of more likely receiving that was older patients, males, and having peanut allergy.

So, I have to say that the things that protected you from getting admitted, one of them was also noted to be pre hospital epinephrine and antihistamine, right? So, I think some of the take home points from this study, number one, 25 percent of these patients had anaphylaxis and didn't get epi. I mean, again, this continues to be an issue.

But also, this is very interesting, one of the associations with being hospitalized is pre hospital corticosteroids. Now that's kind of odd. It's possible that maybe corticosteroids was given in lieu of epi. There's maybe some hypothesis that corticosteroids is not helpful in the context of anaphylaxis and could actually cause harm.

This still needs to be worked out. But really it does, again, send the message that if we're really going to treat anaphylaxis, early epinephrine, ideally pre hospital; is going to be the best way to keep you well. And again, when we talk to people, we can talk to the patient, but we really should be talking about first responders.

They're going to be the ones that can have to really move the needle on preventing more severe outcomes in patients who are experiencing anaphylaxis.

Timothy Chow, MD: Two things that I thought of with this article were, one, as we have other forms of epinephrine that are now available for treatment of anaphylaxis, if that is going to increase the utilization of it pre hospital, either by EMS or by families, such as with like intranasal epinephrine. The other thing too that I think of is that I'm sure we've all experienced this where, we have patients with a peanut allergy who, had an accidental exposure, had symptoms, and then didn't want to give epinephrine because they didn't want to have to go to the ER. And now that, there's been this shift of saying, you know what, if you have shared decision making with the family, they have multiple epinephrine autoinjectors with them, they use it immediately, have complete resolution of symptoms, and feel comfortable waiting at home, that, right, we don't have to do that knee jerk trip to the ER. And it'll be interesting to see as that becomes more of a accepted approach kind of across our patients, if we'll also end up seeing increases in that pre hospital epinephrine use.

Dr. Stan Fineman: That's a good point, Tim. The other thing that struck me with this article is what's the role of corticosteroids in treating anaphylaxis? And I think we know over the last few years that there's really not a role for it. And I think most of the guidelines are now recommending against it, as far as I know.

Is that, your take as well? But the fact that the patients who did receive steroids before going to the ER, had required more fluids, means assuming that they must have had a tougher clinical time, shows that there's probably a detrimental effect if you use the steroids early.

Host: I don't have the anaphylaxis practice in front of me. I don't recall it saying recommend against

Timothy Chow, MD: That is one of the limitations too, where in order to have enough data to support the grade kind of assessment for this, I'm not aware of that data to be able to strongly recommend against using steroids. Because I think some of it comes down to, even like in this study, as a retrospective study, we don't know if there's confounders that patients were more likely to receive steroids if they developed or had a certain spectrum of anaphylaxis, compared to those who were maybe more likely just to receive antihistamines, which could be a contributing mixed signal.

Host: Yes. So the statement from the 2020 parameter, it says, quote, antihistamines and or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, but may be considered as secondary treatment. So really it was addressing the question, what is the efficacy for steroids for prevention of biphasic anaphylaxis?

We know the mechanism of steroids, decreasing gene transcription is not helping the patient during acute anaphylaxis. So really the question is, are you moving the needle on biphasic? And at least the data does not support that has a role there. But again, I told you about that language at the practice parameters.

They always do that. Well, maybe consider, they kind give you a little opening. If you have some variation in practice, you're not going to say anyone's going against the standard of care or something like that. So more studies would be needed to have more firm language, especially if they're using grade methodology as Tim mentioned.

So thanks, Stan. That's super important.

Dr. Stan Fineman: I was on that practice parameters committee years ago before they even used the grade and we did try to hedge a lot. We tried to make sure that the guidelines, were palatable for practitioners and they wouldn't get basically caught, which is, sometimes you don't want a medical legal problem with a guideline.

Host: We really want to be inclusive, but you also want to integrate evidence. So, I mean, that's how medicine works, evidence has a role, and then we have individualized situations. So I think that's appropriate. So I'm looking forward to more of these things. I do think it does make us reconsider more just protocols, give it to everyone sort of thing.

I think that's really important to discuss too. And I guess those are our articles for this episode. So if you like what you're hearing, please log in to the Apple podcast app or whatever podcast app you use and give us a good rating. If you have feedback for us; I'm always interested in your corrections, your further thoughts, any suggestions for future content.

The email for that is allergytalk one word@acaai.org And then again, that website for CME credit

Dr. Gerry Lee (Host): head over

to education.acaai.org/allergytalk.

Host: This is Gerry Lee. I really appreciate your time. And thanks again. Enjoy the rest of your day.

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. Feynman has nothing to disclose.

Dr. Chow has nothing to disclose.