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 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 archived issues, head over to college.acaai.org/publications/allergywatch. And make sure you check out the ACAAI community on DocMatter, where we can continue discussion about these articles.

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

Dr. Stan Fineman: Hello again. It's great to be here. I'm a past president of the college and adjunct faculty at Emory, and currently in practice at Atlanta Allergy.

Host: And for the third chair, we are excited to welcome Dr. Tim Chow. He is an Assistant Professor at UT Southwestern and Assistant Editor of Allergy Watch. Tim, welcome to Allergy Talk and tell the audience a little about yourself.

Dr. Timothy Chow: Yeah, thanks so much for having me. I'm down here in Dallas. I run our pediatric drug allergy program here, and so my clinical and research interests really revolve around drug allergy. But it's been fun being a part of Allergy Watch, where I mainly review respiratory journals, which is a nice change of pace from the usual literature I'm immersed in. And so, it's great to be here.

Host: Awesome. Well, Stan, I think we'll start with you. And I think we've all been trying to advocate for our food allergy patients, and they may see some new options for reactions in the future.

Dr. Stan Fineman: Yes. So, this article that we're going to talk about first, it was published in the Annals of Allergy, and it was published recently. And it was reviewed in the Allergy Watch by Dr. Otani, and it's entitled Pharmacokinetic and Pharmacodynamic Comparison of Epinephrine Administered Intranasally and Intramuscularly. It's an integrated analysis. So, as we know, a lot of people are very concerned about using an injectable or even a self-injectable epinephrine So, we're looking for different ways to treat anaphylaxis. And the concept of using intranasal, I think, is a great idea. So, this was an integrated analysis. It included data from adults who were participants in the studies. They were aged 19 to 55 years, and these were basically four randomized crossover phase I trials and the participants received epinephrine, 0.3 milligrams. It was given either by manually I.M. epinephrine injection, that's the old-fashioned way before we had auto-injectors, or it was given by an auto-injector, either the EpiPen or the Symjepi. And the other option was a one milligram dose that was given with an epinephrine nasal spray solution called Neffy. And then, they analyzed the PK and various biologic things like blood pressure and heart rate and things like that.

So interestingly, the maximum epinephrine concentration for the nasal spray, the Neffy, was 258, which is very similar to the 254, which was in the manual I.M. injection. The Symjepi and the EpiPen were both much higher. EpiPen was 503, which is the highest, and the Symjepi was 438. So, the four treatments also led to very similar increases in blood pressure. The maximum increase in systolic pressure was 16.4 with the Neffy, the nasal one, compared to 10.9 with the manual injection and 14.9 with Symjepi and 18.1 with the EpiPen. So, EpiPen had the highest change in systolic, and the nasal came in second. When you look at the diastolic pressure, there was a significant difference in those, mainly because the Neffy, which is the nasal, was a 9.32 increase versus a 5.5 in the manual, 5.78 in the Symjepi, and 5.93 in the EpiPen. So, the intranasal had interesting pharmacodynamic changes compared to the I.M. epinephrine, whether it's given by a manual injection or the auto-injectors.

And I think one of the most interesting parts of this analysis was the blood pressure differences. And the authors felt that the difference in the blood pressure changes may be related to the different affinities for the adrenergic receptors in the skeletal muscles. So, the beta 2 receptors in skeletal muscles have a high affinity for epinephrine. And they felt that this may contribute to the lower concentrations of epinephrine from promoting the vasodilatation of the skeletal muscles, which could cause a decrease in peripheral vascular resistance with an increased blood flow in the skeletal muscles, ultimately resulting in a decrease in the diastolic blood pressure. So, they tried to explain it that way. I mean, we don't exactly know why, you know, how can we account for the fact that the diastolic had such a great change with the nasal versus the others. But I think that bottom line is they all seem to get a good response.

And there was an editorial by Jay Lieberman who said that he's hoping that we'll have new options for treatment. And in fact, I know that we're not talking about this article today, but There was an article in one of our journals about a dry powder intranasal epinephrine spray. So, I think that we're going to hopefully see some changes in what we have. I know the FDA did not agree to have the Neffy product approved yet. They're going back to the drawing board. And anyway, I'm going to leave it right now that this is, I think, an interesting development. What Iris said, Iris Otani, in her comments were that the findings suggest that Neffy may be comparable, if not even better, than the manual I.M. epinephrine injection, but it must be noted that EpiPen, which is of course the most widely used epinephrine auto-injector, still had the highest concentration and it was the quickest to achieve the highest concentration with the maximum effect on the systolic blood pressure.

Dr. Timothy Chow: I echo your interest. I think that I'm also really interested to see, as they go back to the drawing board and kind of refine things, how the Neffy performs in other kind of circumstances. So, we know that when patients are having a systemic allergic reaction, they can get inferior turbinate edema, leading to anterior rhinorrhea, getting real stuffy. And I'm really curious to see if you get the same pharmacokinetic dynamic performance in that setting too, because that'd be a significant factor in terms of whether or not this would translate into an appropriate anaphylaxis treatment.

Host: Yeah, I know that was the major concern from the FDA. I think the only other thing I want to add and, obviously, this is implied, but anytime you make a new product like this, I'm totally curious how they're going to price this product. I mean, EpiPens and other similar auto-injector devices like the AUVI-Q have had very significant high prices for a life-saving medication.

And, you know, again, I think, it'd be great to have options for patients, but the affordability, I'd just love to see how they do it. I know there was that low copay plan for AUVI-Q earlier. But I've seen that kind of fade away into my patients, you know, that support. So, even the accessibility maybe initially you would have it, but then it could fade over time.

So, I think those are the other concern I always raise. Not saying we shouldn't do it, I'm just saying that this is going to be one thing. I think it's very important to make sure there's access with these sort of medications.

Dr. Stan Fineman: You both bring up really good points. If you have a deviated septum, is it going to work as well? Or if during pollen season and your nose is stuffy, or if your nose gets stuffy during an anaphylaxis. I mean, these are all questions. And of course, what the shelf life is going to be with the solution, as my understanding is, it does not need to be refrigerated. So that's a benefit, but who knows? And of course, I mean, everything's expensive now, so we have no idea.

Host: Well, we're looking forward to seeing the next trial. So, let's go to the next article. So Tim, you are going to tell us about, geez, climate change and how it's affecting our patients with allergies.

Dr. Timothy Chow: Yeah. So, I chose this article entitled, Wildfires and the Changing Landscape of Air Pollution-Related Health Burden in California. This was published in the American Journal of Respiratory and Critical Care Medicine in April 2023. And it came out of a group between the California Department of Public Health and the U.S. Environmental Protection Agency. And so, we all know, again, wildfires aren't new, but there definitely has been an increase in frequency and intensity of fires over recent decades, as just watching the news can tell us. And while wildfires, over time, as they've become more intense, they've contributed increasingly to fine particulate matter less than or equal to 2.5 microns. And so, I'm going to refer to that as PM 2.5 throughout this little blurb. And so, PM 2.5 has been decreasing actually, as efforts to improve air quality have been implemented over recent decades. But recent wildfires may be reversing that trend.

And so, the researchers wanted to look more globally at the trends of wildfire-driven changes in PM 2.5, and then looking at the associated PM 2.5-related cardiorespiratory health outcomes, because of wildfires in California. So in order to do that, the outcome of interest was really cardiorespiratory-related ER visits and hospital admissions between 2008 and 2016, and they used ICD-10 codes essentially to look at three categories of these. So, they looked at asthma, COPD, and then this bucket of cardiovascular disease, which included things like myocardial infarction, hypertension, and coronary artery disease. And then, what they did was they aggregated all that data by ZIP code, and then they used machine learning that was above my pay grade that combined satellite data, meteorological variables, something called smoke plume polygons, to essentially determine a wildfire smoke affected day and also their affected ZIP codes, while excluding, through modeling non-wildland sources of fire, so things like residential or commercial fires.

 They ended up finding 30 million cardiorespiratory ER visits and such admissions during this kind of their study period. And over that period, globally, total PM 2.5-related health burden declined from 2008 to 2016. And that's in line with other data that shows that, again, general PM 2.5 declined over that period. But the contribution of wildfires to total PM 2.5 actually varied by year, but contributed up to 15% of total PM 2.5. And when there was increased wildfire or smoke-affected days, it actually led to an increased risk of ER visits for all three of the cardiorespiratory outcomes. And certain populations were more affected by wildfire-related PM 2.5 than others. And so, those that are older than 65 had about a 3% increased risk of ER visit on those wildfire smoke-affected days. And while all races were affected by wildfire smoke, some were more than others, so Asian and Black populations had the greatest increase in those outcomes due to wildfire smoke.

Again, I'm sure all of our patients would be the first to tell us that air quality affects their respiratory health and that it's bad that, you know, things are acting up for them. But measuring, I think, the impacts of wildfire-related effects on health is the important first step because it's going to be a really complex conversation on how to best mitigate the detrimental impacts of wildfires across society, whether it be through the destruction of property and the health impact. And so having this additional data points, I think is important so that we can have nuanced conversations about this.

Dr. Stan Fineman: You're right. I saw a patient today who came in and was telling me how much trouble they had when they were visiting in New York this summer, where there were fires coming down from Canada. And it really impacted people visiting in that area. And she had asthma and, I mean, it really threw her for a loop. She had to take prednisone. So, these climate events like wildfires that are increasing in frequency because of the warming trends in our environment certainly have an impact on our patients, our respiratory patients. And you're right, I do agree with you. It's good to have this kind of information to help us understand it.

Host: And as we understand the health risks, we can certainly alert our patients about the precaution. I think, people are aware of the association but being more mindful about protective measures. I guess if it's PM 2.5, you're going to need to have either a significant mask quality if you're going outside, I suppose. Or, again, I hate to say it, but, you know, we try not to have people stay isolated indoors. But, again, for certain susceptible groups, you might have to do it. I think that's sort of our role to make sure we're educating our patients on how to take care of themselves, and of course, optimizing their care. So even if they are exposed, they're more resilient.

So, I'm going to wrap it up here with an article on ionidated contrast media. And the title of the article is Differences in Hypersensitivity Reactions in Contrast Media: Analysis of the U.S. Food and Drug Administration Adverse Event Reporting System Database. I've watched this from afar. I have to say that, I don't get consulted on this as much as other groups. But seeing how we've evolved from, "Oh, don't worry about it. They have allergy, just throw meds on it and just give it to them." You know, like the pre med, just pre med everyone thing, you know, like back in the day. Obviously, we've seen this change of the approach to hypersensitivity reactions. One of the most impactful articles I think came out a couple of years ago when the Mayo group found that changing the product was more effective in preventing reaction than pretreatment. And I think that that really raised everyone's attention that maybe there might be other approaches. And then, the Europeans, they recommend skin testing. They say, "Okay. Well, you got to skin test the different products." Oh, by the way, I've not skin tested to contrast, I guess. So, I need to be educated on that a little bit more.

And so, this article sort of furthers that sort of work. They looked at that FDA, Food and Drug Administration Adverse Event Reporting System, which records, obviously, voluntarily adverse events against different products and they were statistically looking at ionidated contrast media, trying to see is there any patterns in terms of immediate or non-immediate hypersensitivity reactions, which products, the frequency, and so on. So again, they were able to do this sort of data poll from 2013 to 2021. After combing through all the data, they found about 5,574 reactions during that period. And, you know, they found some pretty interesting findings. Number one, obviously, they saw some geographical differences. We don't need to really get into that. And so, they kind of looked at three major types of buckets. One was angioedema, the various odds ratios they found for angioedema of these products, so they calculated something called the reporting odds ratio. We're getting ranges of like 3.86 to 22, depending on the product. The one with the most common cause of angioedema is iopromide, and I hope there's no radiologists on there to kind of call me out on my pronunciation. But then for severe cutaneous adverse reactions, there's this one product called iomeprol, which had a reporting odds ratio of 127. So like, you see this graph here. And then, the force plot has all the contrast medias. There's this one outlier that just like shoots up. It's very dramatic to see that. And then, in terms of anaphylactic or anaphylactoid shock conditions, there was ranges of 8.6 to 31.1. So, the one that was 31, the highest one was iopamidol.

So, overall, even though we're seeing the general observation of hypersensitivity rather immediate or non-immediate with contrast media, which it doesn't surprise us. You know, it's a nonspecific mast cell activator. They are saying that different products have different relative frequencies depending on the subgroup. And so, I think this furthers our information when we're trying to make decisions. When someone does have a hypersensitive reaction, we're absolutely going to try to go after what product they have. And then, we're going to try to say, maybe based on the reaction, could we pick one in a category that's less likely to have a reaction, knowing that all of them have some sort of risk, but maybe the one with the lowest risk for that particular type of reaction.

I'm also going to call out that practice parameter from the European group. I thought it was very interesting. They actually have this nice table at the end that talks about which contrast medias have been reported to have high frequency of cross-reactivity or low. So, I encourage everyone to look at that. I think that was published about a few years ago. But it just furthers our understanding about our approach to these reactions. And, obviously, since we have someone familiar with drug allergy, I want to obviously all on you, Tim, to kind of share your approach and experience when you're approaching these sorts of consults.

Dr. Timothy Chow: I think this is a quite a valuable study, because I think the picture of contrast reactions has evolved over the last 30, 40 years where, you know, initially, as this kind of non-selective mast cell activator, especially with earlier ionic forms of contrast media, it was really prominent. And so, things like pre-medication were helpful with that. And that as we've shifted now, which this article kind of focuses on these newer contrast agents and non-ionic forms where we get much less of that. And so, the reactions, especially immediate reactions that we do see, may be more IgE-mediated. And so, I think that this adds to an important gap kind of in the literature.

Important to note just some of the limitations of using FAREs and just other retrospective that you definitely have some reporting bias there. Not that you were suggesting this, but the reactivity if you've reacted to one, reacted to another, it's hard to know how much we can really rely on that. But I think it's an important piece and really we'll need further study for us to more fully characterize like, what is the actual risk of, say, cross-reactivity across these different agents and how can we essentially ensure that patients can get the imaging procedures that they need to get optimal care.

Dr. Stan Fineman: So, as a community-based practitioner, we see patients who have reactions or history of reactions and we just tell them to pre-treat. I mean, is that still what we need to recommend? I mean, we don't do skin tests for these agents because we don't really have access to them.

Host: Obviously, the European perspective, they have a lot more resources and obviously are more academic in this approach. But I've just been interested in this sort of push to identify what is the exact product that they got, and then do we know, based on our experience, what are the potential cross-reactive products? Because it was a retrospective study, but it does seem like switching the product may be a more effective approach for future reactions.

Okay. Well, thanks for the discussion. There's some really interesting articles. If you really like what you've heard today, if you rate us on iTunes, that really helps out the podcast. But, again, we're always looking for ways to improve. If you have feedback, if you want to correct something that we said or you have a suggestion for a future podcast, our email is allergytalk@aacai.org. And that reminder about CME credit, if that interests you or you just want to see archived issues of Allergy Watch, our website is college.aacai.org/publication/allergywatch. Thanks everyone for your time. Thanks for listening. I hope you enjoy the rest of your day.

Disclaimer: The AACAI 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 might be referenced.

Today's speakers have the following disclosures. Drs. Lee and Chow have nothing disclosed. And Dr. Fineman has been a speaker for Takeda and has done research for AImmune, DBV, and BioCryst.