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 remember, you can earn CME credit by listening to this podcast. For information about CME credit, or to read archived issues of Allergy Watch, head over to college.acaai.org/publications/allergywatch. And there also will be discussion of the articles on the ACAAI Community on DocMatter where we can talk about these articles.

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

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

Host: And for the third chair, we are once again so pleased to have Dr. Melinda Rathkopf, a provisional Associate Professor at Emory and Chair of the practice Management Committee for the college, join us for the podcast. Melinda, welcome back to Allergy Talk.

Melinda Rathkopf: Thank you. Thanks for having me back. I feel like an old pro now. As Gerry mentioned, I'm an Associate Professor Provisional here at Emory and working as his colleague in the Allergy and Immunology Clinic at Children's Healthcare of Atlanta and excited to be back home in Atlanta.

Host: Yes, and we are excited as well. So, we got three more really interesting articles. Hopefully, we spark some Interesting discussion. The first article, Stan, I think we are always struggling with adolescence and maybe you might have the solution for us?

Dr. Stan Fineman: Well, this article was studying a potential solution and it was published in the Journal of Pediatrics in February of this year. And it's entitled Food Allergy Management for Adolescents Using Behavioral Incentives. It was a randomized trial and it was reviewed by Samantha Knox for the Allergy Watch.

So, what they did here, which I think is really interesting, was that they took-- as we know, everybody knows that food allergies are a challenge and adolescents are probably the worst at carrying their epinephrine auto-injectors. It puts them at higher risk. They do more of the risk-taking behaviors and things like that. So you know, we always try to figure out how can we incentivize our adolescents to carry their epinephrine auto-injectors. So, this study included 131 patients who were between ages of 15 to 19. They had food allergies and they were all prescribed an epinephrine auto-injector and they were assigned to two different intervention groups and two control groups.

So, both of the intervention groups received frequent automated text messages or nudges reminding them to carry their epinephrine auto-injector. In addition to the text messages, the other group also had a modest financial incentive based on something called the low aversion principle. I'm going to explain that in just a minute. So basically, this intervention development, there are several different types of interventions that can affect behavior: availability, feedback, general financial incentives, loss aversion, and presence. Anyway, this is a whole another psychological type of area that I'm really not that familiar with. But the bottom line was this study, they looked at all these different interventions. And the Intervention 2 group used all five principles. The Intervention 1 just used the feedback and then simple nudges, just the text messages. But the second intervention group also had a financial incentive. And the way they did this was the group was notified that they had $100 placed in a virtual account for them and that they would lose $10 every time they failed to successfully demonstrate that they were carrying their epinephrine auto-injector at each of the 10 random checkpoints. So, they'd get a nudge on their phone, a text message that said, "Are you carrying your epi?" And what they had to do was they had to take a picture of their epi, and they had to put it with a code word. So in other words, the nudge said, "Are you carrying your epi? Your code word is computer." They had to take a picture of their epi with the code word so that they wouldn't get docked 10 bucks. So, that was their financial incentive.

So, interestingly, when you look at the results, the text messages themselves didn't really significantly affect the carriage rates of the epinephrine auto-injectors. There was only about 28% compared to 38% of the control group, in fact. But the financial incentive, those really did increase the consistency of carriage 45% versus 23%. So, it almost doubled the carriage rate when you had a financial incentive in these teenagers. So, they felt that the text messages were not that useful, but the financial incentives were, "highly motivating." So, they said that this obviously shows it's highly motivating. But in spite of all that, the overall carriage rates were still less than 50%. So, part of the problems that they cited, the authors cited, were the fact that a lot of times people overestimate their carriage of the epinephrine auto-injectors. And I recall a few years ago when we asked patients in the office, we did a little survey to see, you know, did you have your epi there? And we basically gave them a coupon for one of the local fast food restaurants if they had it there. And interestingly, a number of patients, I think it was like 70% said that they had it, and I made them show it that they had it. And then, there was another percentage that said they had it, but they didn't really have it with them. In other words, they couldn't show it. They had to show me their epi. So, this is a chronic problem, not just for adolescents, but it's for all patients who require epinephrine, because they're at risk for anaphylaxis. But I thought this was an interesting way, and I guess it shows that if you're dealing with teenagers and you want to incentivize them, that money talks.

Host: Wait, wait, Dr. Fineman. Just based on what you told me, your population's carriage rate is 70%. This study is 50%. Is that what you just said?

Dr. Stan Fineman: So, we had warned them. In other words, they were notified. But yes, it was higher than group, but it was also, you know, all-comers.

Host: You've got to give me your secret, Dr. Fineman. You are like the gold standard for epinephrine carriage.

Dr. Stan Fineman: No, I'm not because it also included moms with young children. And if you want to get a high percentage, it's the moms with young children who are always going to have it there. They are highly, highly motivated.

Host: The adolescents are hopeless, you're saying.

Melinda Rathkopf: Yeah. So if you break it down by age in your post hoc analysis, what would the teens be doing?

Dr. Stan Fineman: Yes.

Host: Well, that's depressing, like less than 50% in the best case scenario where they're bribing them with actual money. I mean, I think what that tells us that that's not the reason. I think the adolescents are rushing to school, and the last thing they're thinking about is their EpiPen or, you know, AUVI-Q, or I have no any auto-injector.

But, essentially, I wonder, if you talk to adolescents, and you ask them about the barriers, I think there is just so much they're responsible for. And especially if it's been a long time since they've had anything serious, so it's not on their mind. It's very easy, just like out of sight, out of mind, especially something that's not a common allergen. I'm not saying that's the only reason, but there has to be some sort of recency or some sort of reinforcement. And some of my food allergy patients I see, like, once a year. So, I'm not saying that I'm making excuses, I'm just saying we have a lot of challenges to address this.

Melinda Rathkopf: Agree. You know, and I think as Stan said, the moms of these children when they were younger were very vigilant about it, so you do end up with a significant number who probably never recall having had a reaction, if they ever did. We definitely see plenty labeled with allergies have high testing and have high numbers that they never get challenged. So if they ever even truly had an anaphylactic reaction as part of their initial diagnosis, when was the last time do they recall it? So, I bet you, you know, in those conversations, they just don't think they need it. I found that a lot. At least with inhalers, I think I've discussed more than carrying epi auto-injectors, is they really just don't think they need it. And with food allergies, they have no intention of eating the food, so why would they need to carry the epi auto-injector? I think that very concrete thinking comes out in those teenage years of, "I don't need it because I'm not going to eat the food."

Host: You know, another thing to think about is adolescence is this time where you're magically responsible for everything. And I think a lot of caregivers are in the driver's seat when it comes to food allergy in terms of setting the conditions to protect them and also the responsibility for carrying the auto-injector. And now, suddenly, adolescents are supposed to do everything. They've never had to have that responsibility. We see a lot of children where they've never had to do anything. And so, I do the best I can to engage children at every visit, as developmentally appropriate. And, again, maybe I should be doing more about asking them specifically about EpiPen and getting them involved. I think engagement is something that, you know, it's the quickest thing to do. The parent wants to talk over their kid, you know, they want to take over the visit, but setting that participation and ownership of food allergy might also be something we should be doing from day one since diagnosis. And a quick intervention after years of not addressing it may not be enough. It's like a long-term investment, I guess, I'm trying to say.

Melinda Rathkopf: It would be interesting, and I apologize if you mentioned this, tan, did it break it down by gender? Because I would think there might be a little higher carriage rate in females who carry a purse or a bag, whereas you might have a harder time in males if they are less likely to carry a bag on them regularly.

Dr. Stan Fineman: That's a great point, but it's not mentioned here. They did, have 50% males, 50% females in each of the groups, but it didn't really break down the carriage rate by gender. But I just wanted to throw out, you know, we're going to be having some alternatives to an epinephrine auto-injector for administration of epinephrine and for patients at risk for anaphylaxis. There's nasal sprays coming out. People are studying little strips like they use for breath strips that you can put in your mouth. So, you kind of wonder, maybe part of the reluctance might be the fact that they don't want to give a shot. So, maybe that'll improve with some of these newer modalities of ways to administer epinephrine. So, we're hopeful that we'll see these in the future.

Melinda Rathkopf: Although I think refill rates and carriage with inhalers, while maybe a little better, probably isn't as robust as we'd like it to be. That would be interesting to see down the road.

Dr Gerry Lee (Host): This may be a situation where everything helps. It's not going to be one thing. It's going to be attacking the problem through all different ways. So, thanks, Stan, for bringing attention to something we should all be thinking about.

So Melinda, you have a very interesting article about infant feeding, which I know is a really big issue. What should I be feeding my kid, what do we know about that, and milk allergy?

Melinda Rathkopf: Yeah. So, we're going to look at early continuing exposure to cow's milk formula and cow's milk allergy, or the COMEET study, which is a single-center perspective interventional study out of Israel. And what's interesting with this is we already lament when we're giving guidance on peanut and egg that we often aren't seeing these children early enough. Well, this is very early because here we're talking about formula feeding versus breast milk. So, we're talking immediately after birth.

So, this study as we all know, we have seen peanut and egg being discussed and that early introduction of peanut and egg decreases risk of subsequent IgE-mediated allergy. However, the value of early exposure to cow's milk is a little more debated. So, the authors here hypothesize that early continuous exposure to cow's milk formula could lower the chance of an IgE-mediated cow's milk allergy. And what was kind of different in this study is they recruited pregnant mothers shortly before labor and followed up monthly by phone or email. And they let the parent choose the feeding method, which could also be a limitation. It wasn't purely randomized, but it's more practical, right? So if parents wanted to breastfeed, parents were breastfeeding, if parents wanted to do formula... And they divided them into exclusive breastfeeding or exposure to cow's milk formula. Exposure to cow's milk formula could be breastfed with as little as one bottle of cow's milk formula a day versus those that were just on cow's milk formula.

The primary outcome was looking at the presence of an IgE-mediated reaction to cow's milk or cow's milk allergy in the first year of life. And secondary outcomes, they looked at non-IgE and talked specifically about FPIES and milk protein-induced allergic proctocolitis. They did a post hoc analysis where they subdivided the group, the breastfed group, based on how many protocol deviations. So, if you're talking about the whole first year of life, how many breastfed infants maybe got formula in the hospital in the first 48 hours or in another setting, or they got intermittent exposure to formula but did not meet that criteria of getting it at least once a day.

So when they looked at 12 months of age, 97% who had been exposed routinely did not have any suspected allergic reactions. So, they ended up with 46 infants with the cow's milk allergy, both IgE-mediated allergy or non-IgE. And then when they looked at those, there was no significant difference, so this is interesting. There was no significant difference if they were atopic from an atopic family, had other atopic comorbidities. And there was no significant difference in the prevalence of FPIES of allergic proctocolitis with a study group. However, with IgE-mediated reaction, they did find those who had exclusively breastfed had higher rates than those who were given some exposure to cow's milk. And then when they looked at it further, those who had just random, very intermittent exposure were the highest risk.

So, the message being, in families, to try to prevent cow's milk allergy, there should be early and continuous exposure to cow's milk formula. It could be a single serving of cow's milk formula a day. But those at the highest risk were those that may have received very intermittent or very early exposure, but then were predominantly breastfed and there wasn't routine continuous exposure. And that only played out for IgE-mediated allergy, not for the non-IgE-mediated. And this was also a little different than extrapolating from peanut and egg, and that these were not kids that were considered previously high risk. So, these were not in kids who, you know, already had atopic dermatitis or other high-risk atopic abnormalities.

So, this was reviewed in Allergy Watch by Dr. Vivian Hernandez-Trujillo. And her conclusion is that the authors recommended starting cow's milk formula early in infancy and feeding it continuously, even if only one feeding per day. They caution against occasional or infrequent use, which actually was higher risk than if they didn't expose them at all. And the authors, you know, I think the authors did a good job of noting this goes totally against what the World Health Organization and what the AAP recommends, which is exclusive breastfeeding in the first six months of life.

So, more studies are needed, needs to be discussed on a societal level. Would you just implement this in the higher risk patient where the risk versus benefit? Although this study was not done in high risk. So, I welcome your thoughts on this.

Host: Well, Melinda, there's this whole culture about how breast milk is the perfect food that, you know, has evidence. But at the same time, there's clear evidence for early introduction. And one concern I think that does come up is how much does formula interfere with breastfeeding? Would it lead to, again, early termination, or potentially that you may hear things like nipple confusion those are terms that are thrown about.

And I wanted to reference another article I remember reviewing from Japan, where they did it between one to two months of age. And the continuous exposure was 10 mL. Like, all they did was like 10 mL, and they had an effect. So, it seems like you could do continuous exposure. But if you did have concern that it was going to interfere with the success of long-term breastfeeding, it doesn't sound like it takes much. But it does mean that you're going to have to be very consistent. That intermittent exposure seems like what parents would do. Like, they're in a pinch. They need some formula. Like I can imagine that happening. And so like, maybe cautioning parents about that. It's just knowledge they need to know so they could be more mindful about it.

Dr. Stan Fineman: Echoing what Gerry said, I know there've been studies looking at giving milk like in the first week like a formula in the first week to supplement breastfeeding and seeing if that changed the outcome or the potential for a cow's milk allergy. We know about tolerance for all the allergens. So, I mean, I guess, it'll be interesting to see how this article is received and how it might change our standards or practices and whether or not other allergens should be included in their supplement. And that's another good question.

Melinda Rathkopf: Yeah. And I found this interesting because, as a mom, we hear breast is best, breastfeeding is best. None of us are debating that. But it is interesting how successive breastfeeding and especially exclusively breastfeeding is worn like a badge of honor. And even having read this article and prepared over the last couple of days, today, talking to a mom, and when I asked how long breastfeeding, and she added in, "Exclusively." So, that breastfeeding exclusively is worn like a badge of honor among breastfeeding moms.

And so, this will be interesting to see, because there is some thought of feeling like you haven't succeeded as a mom if you're not successfully breastfeeding and having to reach for that bottle of formula. As a mom, when I was a resident and a fellow and having times where I did have to reach for that formula, it would be interesting. The scientific basis, the allergy prevention, all the medical part. But I think the implications, that bond and that culture of breastfeeding, it would be very interesting to see how this is received, like Stan said.

Host: By the way, I support moms. Being a mom is very tough. I do see some moms feeling extremely guilty, you know, like judgmental information or they heard something and they didn't do that so they feel like they're a terrible mom. I just want to say to the moms out there, you're a great mom, all right? Don't feel bad. Don't let someone make you feel bad about yourself. Sorry for that soapbox, I'm just thinking about all the information my wife got from all directions when she was raising our kids. It's tough.

Melinda Rathkopf: It's tough. I'm having a little flashback to my oldest. Her first introduction of formula was when I was on call. My husband had brought her in. I was nursing her and I get called to an emergency C-section and literally have to interrupt her. And you know what? Right there on the shelf in the NICU was a little bottle of formula sample. And that was her first bottle of formula. So, yeah, it happens.

Host: And you're not a bad mom.

Melinda Rathkopf: Well, thank you. I hope my kids are listening to this.

Host: Okay, there you go. Listen, kids. Okay. So, let's do the last article here. And this is talking about other concerns we have about children. And this is looking at lung function in our asthmatics. And through the CAMP study or in other longitudinal studies, we looked at the future of the patients we see with asthma. We do know that they're at higher risk for loss of lung function compared to people without asthma, but particularly COPD, the conversion from asthma to something not reversible. And the CAMP study showed that you could have mild to moderate asthma, and about 17% of those patients will develop stage I COPD. So, you know, there's a vested interest to see, while a child is developing in school age, what can we look out for? What can we do to preserve as much lung function as possible? You know, that's the sort of the cornerstone of pediatrics to prevention.

So, the Severe Asthma Research Program is well positioned to look at this. They do these very large observational studies looking at mobile parameters, looking at severe asthma patients and patients without severe asthma to really understand the factors that lead to severe asthma. And certainly, loss of lung function is one of those outcomes. So, they looked at SARP3 where they had 111 severe asthma patients and 77 non-severe. And they had different parameters they looked at, as you expect, demographics. They also looked at steroid responsiveness by administering intramuscular triamcinolone to look at changing FEV1. Obviously, they have annual spirometry to measure lung function over time. They were able to do about a medium of five visits in the cohort with these patients. And essentially, they're looking at all the parameters.

And so when they look at what are some of the parameters that are going to increase the risk of this loss of lung function, predictors of lower FEV1, include what I mentioned before, steroid responsiveness, exhaled nitric oxide, bronchodilator reversibility, obesity, and what was not surprising, because this has been described before, is exacerbation frequency. But what was most interesting is that exacerbation frequency was more specifically in boys and not girls. So, multiple exacerbation in girls did not lead to the loss of lung function in a dose response, dose-dependent manner, versus boys. Where in boys, one to two events per year was a 20 mL reduction in FEV1 in each successive year, and three plus exacerbations per year, was a loss of 34 mLs of lung function each successive year. Pretty significant if you add that up over time.

So, I think this sort of underlies this common theme of inflammation. I would imagine that exhaled nitric oxide and steroid responses would suggest that they are having untreated inflammation over time. And certainly, I don't have a good explanation for the gender difference. And unfortunately, the study didn't address that. But the overlying message is we should be really thinking about are we completely controlling inflammation in our children and, again, minimizing exacerbations? You know, GINA has taken the stance that any exacerbation is unacceptable. And so, they recommend that you're preferred reliever should have steroid in it. They are using this anti inflammatory reliever strategy now to reduce exacerbations that not a single person should-- well, I mean, I guess let's qualify that statement. They're really not talking about under five, but at least adolescents, based on the SIGMA trial and so on, there's strong evidence that intermittent inhaled steroid with your reliever significantly reduces exacerbations just as good as low dose daily steroid.

So ultimately, as we think about what patients are willing to accept, I accept that maybe once a year, you know, I'm going to have a flare up and that's fine. Well, I think maybe we should sort of emphasize that there is some risk over time that even though we know that this is what happens in asthma, there is now very good strategies to minimize exacerbations. And that's going to really have long-term implications in your child's future health. So, at least, it's just sort of awareness to me that talking about future of your child's health, and then also use that as further messaging to emphasize the importance of medication. Because, you know, I think a lot of parents are gun shy about giving daily medicines to their children. They worry about side effects, and they're thinking about one sort of consequence, but we have to talk about the other side as well.

Dr. Stan Fineman: So, you brought up a very good point, Gerry, which I always struggle with my patients. Because I have many come in and they say", Well, I don't want to use this inhaled steroid because of all the steroid side effects." And I keep trying to explain to them, well, it's going to prevent them from needing systemic steroids, fewer exacerbations.

 This study, you know, we're able to tell the patients, "Look, there's data now to support the fact that there's a 20 milliliter reduction in lung function with exacerbations. So, I think this is just something we can talk about with our patients that controller steroid is much, much safer in the long run than any potential steroid side effect, which we all know is really minimal.

Melinda Rathkopf: Yeah, I find that interesting too, because talking about those who may just want to PRN use their inhaled steroid without the controller, well, they're already exacerbating by the time they need it. So, it'd be interesting if there was enough data to be able to get granular. Is it a prolonged exacerbation? If you have someone that waits until they get the cold? When we were looking in the guidelines the younger age group who would just use PRN inhaled steroids when they got sick, is that adequate, or is that already an exacerbation, and it counts? Or is it exacerbations that last longer than a certain number of days, or exacerbations that require systemic steroids? It'd be interesting to see over time if there's more data that can be found in this subgroup, including why it's less so in females. When you look at the age group, the average age was 11 and a half years. So, hormones of course stick out in all of our minds of hormonal differences in that age group. So yeah, it'd be interesting to be able to get down further into this. What is the definition of an exacerbation? What about a mild versus moderate versus severe exacerbation? Can you extrapolate that? But yeah, going back to what Stan said, you need to take it way before you have the exacerbation to prevent it.

Host: Great point, Melinda. I think it's so interesting how that ratio between boys and girls flips in puberty, right? And then in adulthood, women are more common than men in terms of severity and frequency. So, I think that does explain part of it, of this difference in the childhood susceptibility.

But overall, my take-home is really me integrating this in the conversation when we're trying to persuade caregivers to be very consistent about asthma therapy, even when they're well. If you can convince someone who feels fine to take a medicine every day, you are probably the top 5% of medical clinicians in the world. Very difficult. We struggle with it every time. So, we use everything we can to be persuasive, and this is another thing.

Well, again, I appreciate the discussion. So many interesting things I learned today. If you learned something and you enjoyed the podcast, if you rate us on iTunes, that's super helpful. If you'd like any feedback for us, like to make any corrections, you have personal thoughts or suggestions for the podcast, just email us. The email is allergytalk,@acaai.org. Remember to go to our website if you're interested in earning CME credit. That's college.acaai.org/publication/allergywatch.

Thank you, Stan. Thank you, Melinda. I had a great time. I hope everyone is enjoying their day. And I'll talk to you next time. Have a good one.

Melinda Rathkopf: Thanks.

Host: 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.