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 Jerry Lee: Hi 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 three more articles from the July, August, 2022 issue of Allergy Watch a bimonthly publication which provides research summaries to college members from the major journals of algae and immunology.

And you could 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.acai.org/publication/allergy watch. And also make sure you check out the Acaai community on Doc matter, where we can continue the discussion about these articles.

Well, hi, my name is Jerry Lee. I'm an associate professor at Emory University and an assistant editor in Allergy Watch. And once again, I'm joined by the editor, chief of Allergy Watch, Dr. Stan Feynman.

Dr Stan Fineman: Hello again, it's great to be here. Jerry said, I'm the editor in chief of Allergy Watch and I'm in practice here in Atlanta at Atlanta Allergy and Asthma and I'm on the clinical faculty at

Dr Jerry Lee: Emory.

And for the third chair, we are once again joined by another Allergy Watch assistant editor, Dr. Vivian Hernandez Trujillo.

Dr Vivian Hernandez-Trjillo: , hi Jerry, it's great to be back. I am the fellowship training program director and division director of allergy immunology at Nicholas Children's Hospital and clinical professor at the Herbert Wertheim School of Medicine.

Dr Jerry Lee: Okay, well, again, we got another three really interesting articles for this episode. So, Stan, we'll start with you, and this is very interesting. You're saying we're testing for venom allergy wrong?

Dr Stan Fineman: Well, the article says that. this is an article that was published in the Journal of Allergy, Clinical Immunology and Practice in March of 22.

It's entitled Combining Discordant Serum IgE. and skin testing improves diagnostic and therapeutic accuracy for hominoptera venom hypersensitivity immunotherapy. And this is a study out of, Walter Reed, in fact, is where the researchers and, what they did is, they basically, as everyone knows, Typically in the, the practice parameters, the ones that were published, I think it was in 17 is the most recent ones, suggested doing intradermal skin testing as a standard approach for the diagnosis of hominoptera venom hypersensitivity.

then you do a serum IgE immunocab, If you see a negative, skin test and you, suspect maybe the patient is still sensitized. So this study evaluated the concordance between these two tests, intradermal skin tests and Immunocab. in patients who, have suspected hymenoptera hypersensitivity and they assess the implications for venom immunotherapy.

So this is a pretty practical study because they're looking at how these tests impact our treatment. It's a prospective study. They enrolled 70 patients. All of them had a history of a probable systemic reaction to hymenoptera venom. They also had a control group. which were 51 patients who did not have systemic reactions.

And they all had intradermal skin testing, according to the protocol, and also Immunocab testing. And they tested for the big five. insects that we test for, including honeybee, wasp, yellowjacket, yellow hornet, and white faced hornet. They tested for all those venoms. And the results showed that there was a significant discordance between the positive results in the two tests.

Patient cases had discordance in the wasp. Yellowjacket and white faced hornet venom. And in a pooled analysis of all individual results, all discordance, there was 27. 5%. You know, so in patients who had systemic reactions versus 8. 2 percent in control. So in both groups, about 80 percent of discordances were immunocap positive and intradermal skin test negative.

So that means in nearly half the patients, the venom immunotherapy prescription would have been different. If the initial testing had included both the intradermal testing and the immunocab compared to the intradermal testing alone. So, based on these discordant results, the researchers propose that the immunocab should be done first.

for a diagnosis of suspected hymenoptera venom hypersensitivity, then you do the intradermal for those patients who have a negative immunocab that you still suspect have a problem. And they suggest that this approach would reduce the likelihood of missed sensitizations as well as fewer intradermal tests and fewer venom immunotherapy prescription changes.

So, I thought this was really interesting. And what, John Oppenheimer, who, made comments on this for Allergy Watch stated in his comments was that the authors suggest that the order of our testing be switched. So the immunocap be performed first and intradermal performed on all the negative tests.

So, he said that, obviously that's something that we should consider. And, quite frankly, I think that the Practice Parameter Committee needs to look at these types of data do that. Anyway, let me open it up for comments and then let's talk about, what you're doing in your practice.

Well, I'm going to,

Dr Jerry Lee: make a huge confession. And so, so Stan, you can tell me if I'm off base here, but, we actually don't see a lot of venom enough to keep the skin test extract around cause it goes bad pretty quickly. So we actually do a lot of serum testing and then when the testing is normal and we're still worried.

We refer to your office for the skin test, Stan. You help us out. So, I don't know if you, if we're abusing your clinic that way. But, obviously, your office is awesome. But, that's what we're doing. I don't know how we feel about

Dr Stan Fineman: that, Stan. You know, it's interesting. I'm fine with it, obviously, because we do keep the venoms.

But you are correct, Jerry. Venoms are very expensive and they're getting more expensive. We just found out there's about a 20 percent plus, higher fees for some of our extracts, for next year, beginning next year. and, so a lot of people do exactly what you do.

They, do the testing with Immunocap and some of them don't do skin testing at all. And interestingly, I've started doing the Immunocap first. on some of my patients and found that in a lot of cases I don't even need to do the intradermal testing because you clearly get these huge positive reactions.

I had one who had a yellow jacket immunocab result was over 25 just. yesterday, so I think that the test, is very specific and, certainly sensitive. They felt that the immunocap had a higher sensitivity, but a lower specificity than the intradermal skin testing.

But still you get that higher sensitivity, that's significant. And

Dr Vivian Hernandez-Trjillo: I think, especially if we have pediatric patients, it really does make a difference to not have to do, right? so I, actually don't send a lot of immunocap, but because I do primarily pediatrics, we also don't have that many patients that are on venom immunotherapy.

But when we do it, it's intradermal. So this was kind of music to my ears, to be honest with you, because is a big deal. As a mom, I always say it's a big deal when we have to put, children through a lot of these, intradermal tests. and for venoms, we often do.

Dr Jerry Lee: Okay, well, good. Now this gets me off the hook. So I feel a lot better. And again, Stan, I really thank you so much for supporting patients and so on. well, Viv, you also have a really important issue relevant to children and that is Vaccination against flu. So Dr., why don't you tell us about your

Dr Vivian Hernandez-Trjillo: study?

so I'm excited to talk about this one because, in this day of vaccine hesitancy, any research or any, papers that actually So, to support the use of non needle vaccines, I think, very refreshing. So, this is actually an article published in Pediatrics in April of 2022. It was called, The Safety of Live Attenuated Influenza Vaccine in Children with Asthma.

we've always thought that this was a contraindication, but this is a paper by Socolow et al. that looked at this. And this was a prospective open label clinical trial. I compared the proportion of participants with asthma exacerbations post immunization in children. This was 5 to 17 years of age.

So the contraindication still exists in children below 5, but this is in children 5 to 17 that received the live attenuated influenza vaccine. Quadrivalent versus the inactivated influenza vaccine, the quadrivalent. And here study participants were enrolled over a two year period at three academic centers, which included Vanderbilt, Duke and Cincinnati Children's.

And the children again, 5 to 17, but they had a diagnosis of persistent asthma. in the 2018 to 2019 season, only children 5 to 11 years were enrolled, and then in the 2019 to 2020 children, children 5 to 17 were enrolled. And really, the primary outcome, really, they were just looking at asthma exacerbations, in these kids.

There were 151 Participants, 52 in the first time period, and then 99 from, 2019 to 2020, which I thought was incredible considering, this was right before the pandemic. So it's, important timing within 42 days of post vaccination, 12.7% of the participants. Overall had an asthma exacerbation and in the live attenuated, it was 10.

8 percent versus 14. 7 percent in the inactivated vaccine. So really what they talked about was that, the live attenuated really remains non inferior, to the, inactivated. And, I think, again, in this day and age of vaccine hesitancy, and, and I'll go to, it was Dr.

Samantha Knox is actually the one who reviewed it, who did remind us that the contraindication still remains for children under five with a history of asthma, but being able to offer a safe and effective alternative is essential. and having, a non needle option, I think, is really important.

What do you, both think about? This recent study.

Dr Jerry Lee: Oh man, I would love to have this for our kids. I actually don't have that available in my office, but I do feel lucky that Children's Health of Atlanta does allow me to do it at point of care. So we could just, talk to them and then while they're still interested, we could just like vaccinate them right there.

I mean, that conversion same day is helpful. So if if the vaccine hesitancy is due to, oh, I promised them they wouldn't get a shot. I don't know how often you hear that. You know, I promised them they wouldn't get a shot. Like, okay, well, we can fix that with the live attenuated.

I guess I have to convince the administration to get it. But, at least I got some ammunition. Stan, how about you? Do you ever use the

Dr Stan Fineman: live? No, we just do the regular injection. in fact, we don't even have the high dose, for people over 65.

I think this is, pediatricians are the ones who usually use the intranasal but I think this, data really does support, them being able to use that even in our asthmatics. And, think that hopefully we'll see some changes in practice patterns.

Dr Jerry Lee: Yeah, absolutely. let's run it on with something I thought was a little interesting. I always like to challenge myself. So did a journal club on this also. I reviewed an algae wash. This was published in Nature. And the title of the article is Obesity Alters Pathology and Treatment Response in Inflammatory Disease.

And so, we know about the relationship between obesity and atopy. We know that they have higher IgE levels, they're more likely to have a positive test. We know that obesity is a risk factor for asthma, whether it's that late onset phenotype or just nutrition. Influencing airway inflammation or lung function.

And, if you actually look at obese individuals, they do actually have immunologic changes. we know that obesity is pro inflammatory. They've seen increased IL 6 and TNF alpha. And there's been alterations in subucosal eosinophil content and so on. But I think they really wanted to look at AD for this.

So they were looking at atypic dermatitis and they used a mouse model. for this to really understand if you compare lean and obese mice, what is the effect on two models of atopic dermatitis? So they have like this, vitamin D3 model where if you put that repetitively on a mouse, you can induce atopic dermatitis.

And interestingly, they actually get worse AD if they have a high fat diet and develop obesity in this model. And, they also did it with a second model, which was for a tape stripping model using egg. protein, but then they did something very interesting. They actually, only did the high fat diet for nine weeks, and then they went to a normal diet, so they actually had high body mass index that went down, but they still had the exacerbation, sort of suggesting that Any history of obesity just seemed to alter your immunologic reaction to AD, and they also found increased inflammation and asthmas, too, so they did like a egg exposure to do sort of, an asthma bottle, and so, you know, when you look at the immunology of these mice on the high fat diet, they actually have a mixed inflammatory, profile where they both have Th2 and Th17 populations, so it's sort of like The Th17 contribution from the obesity seems to be what's exacerbating the Th2 phenotype.

And this has actually been demonstrated in obese patients. You can see increased Th17, Th2 signatures, the higher body mass index increases. You get more of these IL 17 induced signature proteins and so on. and so, if you do RNA seq, which is just trying to understand the expression profiles of these mice, you actually see this Th17 population, occur there.

Now, this is the wild part. They actually gave sort of like a dupilumab equivalent. They gave like this IL 413 treatment in these mice. It actually worsened their AD. So, if you had obesity and a high fat diet And yet, in this atypic dermatitis model, when you treated them with 13 blockade, it worsened their AT, so, why is that?

Why would an anti T2 therapy in this sort of obese, Mixed Th2 Th17 model, inflammation, worsened AD, and so one of the hypotheses they developed was, you may were aware of these group of receptors called Le PPARs, Paroxysome Proliferator Active Receptors, and we use this in diabetes.

There's like these TDZ drugs that we use for reduce insulin resistance. And interestingly, these drugs reduce Th17 differentiation. So they wanted to understand the relationship of these PPARs. So they actually knocked it out in the mice. And interestingly, it reproduces that exacerbated AD phenotype.

So like, if you compare control mice to those who did knock out this PPAR, gamma, receptor, they actually have similar exacerbations in AD and this sort of non TH2 signature. And, I mentioned that worsening with that IL 413 blockade like dipilomab. In these PPAR knockouts, when you give them dipilomab in an AD model, it actually worsens them like the obesity.

So if we think that that's related to that, and perhaps the contribution is this deficiency. In this PPAR Gamma, what they did was they gave Rosaglitazone, which is a agonist for PPAR Gamma. and what that did was it actually seemed to improve the AD in these obese mice. which I thought was really interesting.

Now, again, this is a mouse model. I'm not sure if that is what's happening in real life, but sort of the hypothesis they're suggesting here is that if we think about atopy in obese patients, And they have this mixed Th2 and Th17 signature. Is it possible then that it may be a lack of response to traditional high T2 targeted drugs is because of this untreated Th17?

Inflammation present, and therefore we need to address that as well. And again, I'm not saying that we should start rosiglitazone on all those patients, but again, maybe further investigation of that could maybe understand differential responses to these drugs. So again, very exploratory study.

Obviously, they kind of have to follow up. But, we're just trying to, nail down the mechanisms of, what's the differences in atopy, in these different populations.

Dr Vivian Hernandez-Trjillo: I wonder if at some point we'll be measuring PPARs in our patients that are non responders to certain medications.

Dr Stan Fineman: You know, that's interesting that you said that because, for the last few years, we've been looking at the different endotypes of asthma and, obesity is one of the endotypes that they describe, as very difficult to treat, but not necessarily always associated with allergy.

In fact, rarely associated with allergy. and, terms of response to our normal biologics and, typical, treatment regimen with combos, they're much more difficult to treat. And you may be right. I think it's fascinating. and I don't understand all the physiologic mechanisms of these things, but, I'm always fascinated the fact that, the more we learn about biologic mechanisms and the pathophysiology of this, the more we realize that there's different opportunities to really target the treatment for these patients.

So, this is just probably another example of potential, targeted therapy.

Dr Jerry Lee: recall a few papers coming out, during my fellowship. from Cincinnati, where they were also looking at mixed Th2, Th17 populations in asthma as well, right? So again, I know this is an AD model, but at least we've seen these sort of co expressors of Th2 and Th17 in some of the severe asthma patients.

So I do think this is happening. not sure what to do about it in terms of treatment or so on. But we do see people who are treatment resistant they seem to follow the profile. We do the usual stuff, but they just don't respond as well. And I think there's something we're missing and this might be the key to get more patients under control.

I'm really looking forward to more research in this, direction. All right. Well, I think those are our three articles. if you really liked what you heard today, please rate our podcast on iTunes. It really helps us out. we do want your feedback, corrections, or suggestions for future episodes to email us that feedback.

You go to AllergyTalk at ACAAI. org and we'll just, send you a reply. We appreciate that. And remember, you can earn CME credit for listening to this podcast. for that information, the website is college. acaai. org slash publication slash Allergy Watch. thank you so much for listening. I had a really great time.

Viv, thank you again for joining us, and, hope everyone enjoy the rest of their day.

Host: the ACAAI is presenting this podcast for educational purposes only. It is not medical advice or intended to place 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 may be referenced.

Today's speakers have the following disclosures. Dr. Lee has nothing to disclose. Dr. Hernando Trujillo has been a Takeda and CSL. He's been on the advising board for Takeda, Regeneron, and Sanofi. He has been a consultant for Clio Farming, Enzovit, National Peanut Board, and the Algae and Asthma Network.

Dr. Feynman has been a speaker for Takeda and has done research with AI MUNE, DVV, and BioQuest.