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.

Gerry Lee: 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 three articles from the July, August, 2021 Issue of Allergy Watch a bi-monthly publication, which provide research summaries to college members from the major journals in allergy and immunology.

also, make sure you check out our ACAAI community on Doc Matter, where we will make an article post where we can continue discussion about this article.

Well, again, my name is Jerry Lee. I'm one of the co hosts of Allergy Talk. I'm an Associate Professor of Allergy Immunology at Emory University, and I'm joined by my two co hosts. First, Dr. Stan Feynman.

Stan Fineman: Hi, everybody. Yes thank you. It's great to be here. I'm an allergist in practice here in Atlanta, at Atlanta Allergy. I'm a past president of the college and currently the editor in chief of Allergy Watch.

Gerry Lee: And the third co host is Dr. Merin Kuruvilla.

Kuravilla: Hi, everyone. Thank you for having me again on the show, Jerry. And I am an assistant professor of allergy and immunology at Emory University in Atlanta.

Gerry Lee: Well, we have three really interesting articles to go over today, so let's just get started. First, Stan, I'm really glad that you're telling us more about these biologics. We just can't get enough about learning how to manage our asthma patients.

Stan Fineman: Well, as a matter of fact, this is an article that John Oppenheimer reviewed for Allergy Watch, the July August issue, and the article comes from the Journal of Allergy, Clinical Immunology, and Practice, the March 2021 issue, and it's titled Dupilumab Improves Asthma Control and Lung Function in Patients with Insufficient Outcome During Previous Antibody therapy.

And it's from Germany. And as far as I can tell, it's not sponsored by a pharmaceutical, but what they did is what basically we all know is that patients who have severe TH2 high asthma anti IgE or an anti biologic therapies have been shown to improve clinical outcomes in their asthmatic patients, but some patients may not achieve optimal treatment response to these agents.

And the newer anti IL 4 uh, receptor, uh, receptor antibody, the dipilomab was evaluated in this study for use in patients who had an insufficient response. To a previous treatment with biologics. So what they did is they had 38 patients who had severe asthma who had been treated. So 32 of them were treated with anti IL five or anti IL five, or, you know, the, receptor therapy either benralizumab mepolizumab or reslizumab.

And then there were six patients. who had received anti IgE, that's a melizomab treatment, and they were switched because they felt that they did not have an adequate response. And then after three to six months on the dupilumab, the treatment response were assessed, and the main criteria that they were looking for was either an increase in asthma control test score of three or more, or a 50 percent reduction in oral steroid use, or FEV on an improvement, greater than or equal to 150 milliliters.

And they classify the response, the patients as either responding to the Dupilumab or not responding to it based on, what are those three criteria? So, Interestingly, there was a mean for overall cohort. Let's just look at the overall cohort first. The of 2. 9 points with significant reductions in exacerbations and the number of oral corticosteroid dependent patients from 15 ruled it.

to There was also a mean milliliter increase in FEV1 and part per billion decrease in the median exhaled nitric oxide, which we're going to talk about in just a minute. So with this with a 0. 17 grams per liter, increased in eosinophil count. So the eosinophil count went up somewhat.

Patients who had exhaled nitric oxide of 25 parts per billion or greater during their previous biologic therapy had an even greater response to dopilumab. 23 of the 27 compared to those who had lower, Feno levels in three of the eight in the responders versus non responders. So, uh, among the things that I think is important besides the fact that the Feno seemed to predict the response was that interestingly, when you look at the clinical characteristics of the patients. 74 percent of these 38 patients had ENT problems, comorbidities, and almost half of them had nasal polyposis. So 18 of the 38 patients also had nasal polyposis. So you kind of wonder if that may be a contributing factor here, in terms of, knowing our we've already talked previously about dipilumab with nasal polyposis, but the authors.

were suggesting that many patients in the cohort had a mixed phenotype at baseline and the presence of allergens as well as eosinophilia, and they felt that dupilumab may have what they called pleiotropic effects on Th2 inflammation acting on the eosinophil and also reducing IgE response, as well as So, they felt that maybe that was one of the reasons, but the demo, the study did demonstrate it.

And one of the other problems with the study was that it was retrospective. So it was a design. It was not prospective. So they looked at patients who had already been treated, already been switched. But, the fact that they found these changes. Changes with increases in lung function, reduction in residual volume, improvement in FEV1 also a change in the asthma control score.

And even the reduction in oral steroid dose, I think is important. And when you look at Dr. Oppenheimer's comment, he said that this retrospective study indicates there may be hope in switching to a different class of biologic. when the first one fails.

Kuravilla: So, Stan I think sort of very similar data has been reproduced in other real world cohorts and there are several that come to mind. One of them was published last year out of a group in Canada, sort of demonstrating that of one of the risk factors for non responsiveness to mepolizumab and reslizumab was in fact the presence of nasal polyps.

And there were two others, one from Brigham. And another from, scripts that was published very recently in Jackie in Practice. And both of these looked at cohorts of ARD patients, and essentially what they found was that patients who were initially on anti IL 5 therapies and then subsequently switched to diplomab tended to have better outcomes with The caveat that both of these, again, were retrospective trials with their own sort of inherent limitations., In the study out of Brigham, the only distinguishing feature between non responders to anti IL 5 agents, who subsequently did better on dupilumab, was the presence of an elevated serum IgE, and they didn't necessarily make any mention of the phenol. wIth the phenol, again, we don't... routinely monitor pheno in patients on anti IL 5 therapy, as in, in the sense that it's long been known to be dissociated from responsiveness or non responsiveness.

We published a small study in the annals a few years ago, looking at a small cohort of about 50 patients, and this has been reproduced subsequently, sort of just demonstrating that pheno doesn't predict responsiveness. And pheno doesn't necessarily change during therapy, independent of clinical improvement.

Gerry Lee: But it's interesting, that latest 2020 asthma guideline has sort of now, proposed... Obviously not in isolation, but amongst clinical characteristics that pheno is in our toolbox to monitor patients. So that's where we struggle with I would say that obviously we're not gonna hang our hat on it, but I'm just curious Stan, mayor, how are we using pheno to monitor? we're not talking about like, is this. be a synophilic or not. We're talking like, monitoring over time, is this a useful thing? Like, on top of clinical? Or is it just correlate together? You know, I'm just curious what your thoughts

Kuravilla: no that's, a really great point, Jerry. And in fact, like there was actually another paper in Jackie in practice, published recently of, patients who were on And to IL 5 agents, and they looked at a cohort of more than 200 patients actually, and the clinical efficacy of both mepolizumab and benrolizumab was completely independent of the baseline phenol levels, even very high levels.

And so it's hard for me to that incongruity between clinical response parameters as well as this pheno number that's essentially unchanged, but that's just sort of what the data, even going back to the DREAM study, right? That

there's equivalent effectiveness and the pheno doesn't change over time.

So that's what I sort of try to tell myself when I'm monitoring these patients.

Gerry Lee: mean, Stan, do you find it helpful?

Stan Fineman: Well, it may not be that helpful for monitoring the biologics, but I find it still helpful for the patients who are just on inhaled steroids. So, and that's been shown before as well. And I tend to use it. So when I see an elevation in the in the pheno, then I can go back to the patient and say, are you really using your inhaled steroid every day, or maybe that's a reason to consider even starting to use it on a daily basis if the patient's not on it. So I kind of still use it. Maybe I'm an older school person, using it that way, but haven't really used it. monitoring our biologics, but I do for the persistent asthmatics.

Gerry Lee: Well, I'm just gonna throw it out there. These are retrospective studies and not clinical research studies. Are they just saying that Depilumab is better for monotherapy? I'm just, again, that's, I didn't mean to be provocative, but like, maybe the rise of, you know, in those patients and being responders is that, they're just not taking their inhaler and then they're just taking the biologic by itself. Again, there's so many things that influence that number that it's just hard to wrap your head around it. And there's, a whole bazillion reasons I'm sure why that could be occurring.

Stan Fineman: But we see patients who are on dipilomab, their ears tend to, sometimes they'll go up. I mean, it does vary, although it, obviously with the IL 5s, they always go down.

Gerry Lee: Alright, well, again, I think we are still learning more about these biologics, so I'm glad, Mered, you're talking about a different biologic and maybe a new reason to use it.

Kuravilla: That's right, so I'm talking about the oldest biologic uh, omelizumab, and this was a paper that was published in Jackie in practice this year and also reviewed in Allergy Watch by John Oppenheimer, and it looked at the relationship between omelizumab and lung function, but a different angle as opposed to just whether there was a straightforward improvement in FEV1, which we Although it does increase by a little bit, but rather it actually looked at whether omelizumab could prevent the loss of lung function over time, which is characteristic of patients with frequent exacerbations they looked at lots of different sort of endpoints, but what really stood out to me were their findings in the pediatric population. in particular, The benefits with omelizumab were seen only in exacerbators in the pediatric population, but among both exacerbators as well as non exacerbators in adolescents and adults.

And this is sort of reminiscent, as the authors referenced, to the inner city pro study that was published several years ago of asthmatics aged 6 to 17 years. And in this study, those with a history of exacerbations received greater benefit from omalizumab as compared to children who did not have recent exacerbations.

Omalizumab in the pro study was shown to decrease the duration, as well as the severity of rhinovirus infections. And the authors theorized that maybe the prevention of severe infection was another mechanism through which omelizumab prevented lung function decline in pediatric asthmatics. And the reason I found this interesting is because, and I'm sure both of you have also seen this particular phenotype of inner city asthma frequently, wherein undertreatment and underdiagnosis of severe asthma, have reduced adolescent related growth in their FEV1, and By the time they reach adulthood have a low maximal FEV1 and I see them in their 20s and 30s where they have pretty significant advanced and chronic airflow obstruction that is often irreversible and this was interesting because it suggested that maybe using omalizumab for the purposes of preventing this lung function decline may be helpful in pediatric patients to prevent the development of irreversible airway obstruction.

And the bottom line was, as John Oppenheimer stated, was that omelizumab may give us some protection against lung function decline, not only among children, but also among adolescents and adults, especially in patients who experience frequent acid exacerbations while on therapy.

Gerry Lee: So, just to clarify, just so I'm understanding the article, you know, was always drilled into me that omeluzumab is effective for exacerbations, but doesn't modify FEV1 or lung function. But I guess this is a little bit different. You're saying that it just doesn't, we're not improving lung function, but we're keeping the lung function that they have?

Kuravilla: Exactly. So it was sort of a different angle. So there was a very mild, perhaps even negligible improvement in FEV1 that was noted across the different pediatric as well as adolescent and adult populations. But the purpose of the study was not necessarily to look for improvement in lung function, but rather to make sure that they did not, the severe asthmatics did not lose their lung function over time.

Gerry Lee: Hmm, okay. see difference now then.

Stan Fineman: tHat's an interesting point. And I mean, obviously that's the nirvana we all try to have for our asthma patients because we do know that over time when they're not controlled they do tend to have loss of lung function that sometimes may not even come back. And we always, I guess it was, I was taught that it was from steroids.

Steroids were the ultimate, medication that would prevent this from happening. So, it looks like maybe other things, maybe this omelizumab can do it as well, or maybe it's just that the patients are under better control.

Kuravilla: Right. So it could be multiple different factors. So as you said, it's probably just. the direct anti IgE and thereby anti inflammatory effect. As they suggested in this paper, it may also be due to the prevention of lung function decline in the setting of a rhinovirus infection and related viral inflammation.

So it could be several different things that are contributing, but it's interesting that it was just so prominent in pediatric exacerbators.

Gerry Lee: Just as a side note, inspired by this article, I just refreshed my memory about allergen immunotherapy and lung function, and apparently it's completely inconsistent. Like, there's complete variability on the effects of maintaining lung function on allergen immunotherapy. But maybe I shouldn't be thinking of them in the same league, you know, thinking very, very dense about inhalant allergy and IgE and how we're just trying to mito mutate.

But I shouldn't be trying to compare the two. I mean, maybe Zolair's direct effect on, mast cells is unique, I guess. I'm just hand waving there, I guess.

Well, let's round up the article with just a little something a little bit different. anyone who's listened to this podcast probably realizes I pick a lot of food allergy articles. I think, that's Brian Vickery's influence on me anyways. this is a very interesting study about something that comes up a lot. And that is patients worried about airborne exposure to peanut.

And so this was a very interesting article that came out of Sweden.

That's called peanuts in the air, clinical and experimental studies. And really they just want to put the bed. the whole concern about airborne exposure to peanut and the risk of severe allergic reactions. And they have this very interesting statistic that I didn't know. There's a study from 2009 that said 48.

6 percent of the self reported allergic reactions to peanuts and tree nuts on commercial flights were reported to be inhalation triggered. I Mean, almost half of them, they say are inhalation triggered. So like, this is definitely comes up a lot on flights and, gives a lot of anxiety and concern to patients.

And I, and we all have patients who come to us and say that they had a inhal inhalational trigger. due to peanut. And so they investigated this question two different ways. First way is they found children who had or had a history of allergic reaction to peanut or just had a positive test to peanut but never eaten it before.

And they actually did airborne peanut challenges to either roasted salted nuts or dry roasted peanuts. Second thing, They constructed this sort of container that contained nuts in it, and they had this filter device that collected airborne peanut at different distances. Like, one was, like, right on top of the container, and then they sort of go, like, 0.

5 meters, 1 meter, 1. 5 meters, 2 meters, so were looking at different distances. And, you know, they're disturbing the peanuts, they're shaking it up. They got this filter and this sort of air pump to like get some airflow and they collect the airborne peanut protein on the filter and they do an ELISA to detect for peanut, right?

And so, with these airborne challenges and obviously direct ELISAs to detect peanut protein, they're really want to know, what is the clinical or just the actual. Exposure, quantity of exposure through the airborne route. So let's start with the challenges, all right? So, when they challenged the children, none of the children had a severe reaction, but there were two patients who had some mild symptoms.

One had a history of anaphylaxis after peanut, and he had rhinoconjunctivitis. Right? Now, there was another one who never actually ate peanut before, but just had a history of reported reactions to airborne peanuts. And she had itching of the mouth and mild rhinoconjunctivitis, but none of them required medical treatment, and the other 82 children had zero signs or reported symptoms, like zero, right?

Okay. Okay. So, that's the challenges. Let's talk about the experimental setup. Okay, so, they do, like, peanut, sampling right above the container, and at different, distances. So, if you're right by the container, and you do an ELISA, the concentration of peanut maximally found was 166 nanograms per ml, all right?

So, let's put that into context. The ED05, the eliciting dose for 5 percent of the lowest 5 percent of peanut allergic population, sort of like what we think as part of The minimum safe threshold for 95 percent of penile allergic patients is 1. 5 milligrams, right? So again, ELISA showed 166 nanograms per ml, and the listening dose at the 5th percentile is 1.

5 milligrams. Milligrams, right? So, once you take the detector, like, 0. 5 meters or longer away from the container, it just drops precipitously, it, the majority of the samples drop to, like, undetectable. So, interestingly, we learned two things from the study. Number one, if you actually do an airborne challenge, To allergic patients, 98 percent of them feel nothing.

And then if they do feel something, it's going to be like rhino conjunctivitis symptoms, right? No one had anaphylaxis and I'm using our patients with very significant IgE history of anaphylaxis, whole nine yards. Number two, the actual detected amount of peanut is immensely low, and that's inside the container.

Right? So, like, if you even try to do air sampling, a decent distance away from the canine ear, you detect nothing. Right? So, again, this is just another way we can educate our patients with data. They even suggest that you could replicate this challenge on... In the clinic, if you'd want it to, again, provide additional reassurance, I do note that there's actually cutaneous challenges as well, where people have directly placed peanut butter on the skin just to show that an intact skin barrier protects you from anaphylaxis, right? We, it's a skin test, we have to break the skin, right? So if you get intact skin, the mast cells are never going to see the protein. Again, I just think it's just something that comes up that it's really helpful to have something we can cite when we talk to our patients.

Stan Fineman: I think you're right. I think this patients do need to have data and to be able to support it with data is very important because, I can't explain why a patient on an airplane who smells somebody eating a peanut, two rows away is going to cause a problem. I think that most of us have said that the Biggest problem on the planes is peanut dust and pieces of peanut that is in the cha in the chair.

And so I've always instructed my families to make sure they get on board and clean the area really well. To make sure there's no residual peanuts there, because I think that's probably a bigger problem than just the smell. And this study obviously shows that the smell is really not a major factor.

Kuravilla: right. No, and obviously, like, I feel like the smell can create that, like aversion, but not necessarily. Allergy, right? But as Stan said, I agree that that's something we've known for a long time, but it's nice to have this objective, really, like, nicely, elegantly done data.

Gerry Lee: Yeah, so not doubting the fact that no one likes to smell peanut if it's a life threatening event. I'm not going to disagree that that's going to cause discomfort and anxiety, but we want to just reassure them it won't lead to anaphylaxis, again, want to let you know that the discomfort will be present, but it won't be dangerous.

I think that that's really, what we're just trying to improve the quality of life of our patients and just make sure that they can. Not avoid going on air travel and all these things, try to live the most full unrestricted life as possible. just do that advocacy.

Absolutely.

Kuravilla: No, I mean, in fact, I had a mom of a food allergic child tell me recently that her daycare has constructed a plexiglass chamber for her, during mealtimes to prevent any sort of contact reactions or inhalational reactions. And I just find it a little extremist.

And its approaches.

Gerry Lee: think, the thing is, is that everything has side effects, right? So that may improve your anxiety about a reaction. But the impact on the child, I mean, there's pretty interesting data about that sort of obvious attention placed on food allergy leads to bullying, like, it's not, it not doesn't create an inclusive environment.

And it's interesting, a lot of the major food allergy experts at national meetings are really against peanut free schools and, these peanut free environments because of the possible impact of on the child, not allergic reactions because the risk is low, but we're talking about the social aspects of food allergy. So I think that that's just very insightful and this is further evidence that we, these things intended to be helpful may not be necessary and therefore you're only getting the harm that's, again, potentially, so anyways, great discussion. If you like what you're hearing, please rate this podcast on iTunes.

I think we're at 38 reviews as the time of this recording. We want your feedback. If we said something wrong, if you wanted to contribute something, please email us. Our email is AllergyTalkOneWord at ACAAI. org. So again, thanks for listening and we'll Talk to you next time.