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, MD: 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 just by listening to this podcast. For information about CME credit or to read archive issues of Allergy Watch, head over to college.acaai.org/publications/allergywatch. And also, make sure you also check out the ACAAI community on DocMatter, where we can continue the discussion about the articles we discussed today.

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

Stan Fineman, MD: Hi everybody. I'm glad to be here. As Gerry said, I'm Editor in Chief of Allergy Watch and past president of the college and an adjunct faculty at Emory Medical School as well.

Host: And for the third chair, we are once again joined by another Assistant Editor for Allergy Watch, Dr. Sarah Spriet.

Sarah Spriet, MD: Hi guys, thanks for having me on today. I am an allergist clinical immunologist at A.T. Augusta Military Medical Center in Northern Virginia. I'm also the Associate Program Director for the Allergy Fellowship Training Program at Walter Reed.

Host: All right, so we have a really interesting slate for you today. Stan, I'd love for you to kick it off. I know we think of allergy shots helping with allergic disease, but now you're saying it could maybe boost our viral immunity?

Stan Fineman, MD: That's very intriguing. That's why I picked this article that was reviewed by Tim Chow in our Allergy Watch issue. And the article is entitled Allergen Immunotherapy Enhances Airway Epithelial Antiviral Immunity in Patients with Allergic Asthma. It was called the Vital, V-I-T-A-L study, mostly from Denmark.

So what these researchers did as part of this Vital V-I-T-A-L study is they take patients who had allergic asthma and were house dust mite allergic and they did bronchoscopy and took their bronchial epithelial cells at baseline. And then after 24 weeks of sublingual immunotherapy to house dust mite, half the patients got the sublingual, half got placebo.

And then they analyzed this simulating a virus type response in vitro. And they did this through a tried and true technique that's, fairly complicated. But the bottom line is that they could induce this expression of the interferon beta with this polyinosinic and polycytidylic acid, induction technique that they use in vitro.

So what they say, of course, is that we do know that the immunotherapy does enhance our immune tolerance, in several ways. It does direct desensitization of mast cells and basophils. It does suppress the submucosal T2 inflammatory response with induction through the TGF beta. That's a transforming growth factor beta.

Also tolerogenic IL 10 and regulatory T cells. And of course it induces the IgE blocking IgG4 antibodies as well. And there have been a variety of studies looking at immunotherapy and the benefit, besides of course, improving outcomes in allergic asthma, it also seems to reduce certain types of infections.

So they were trying to figure out exactly the reasons for that with this study. Twenty got the sublingual immunotherapy, 19 got the placebo, and what they found was that there was a increase of this acid expression of IF and beta in both the gene and also the protein levels, and that the IFN lambda gene expression was also increased.

Evidently, the interferon lambda is associated with viral infections as well, whereas the IL 33 and interleukin tended to be decreased. The bottom line is it's very complicated, and they had a very detailed analysis of the different, studies that they did in vitro on these cells. But the bottom line was they felt that it was clear cut evidence that the sublingual immunotherapy with house dust mite did improve the bronchial epithelial antiviral resistance in viral infection situations.

And they felt that this could potentially explain the efficacy of the house dust mite sublingual immunotherapy in helping to reduce exacerbations of allergic asthma. And in terms of reviewing comments, this was Dr. Cho, who presented this article in Allergy Watch and stated that this prompts many further interesting questions regarding the effects of longer term allergy immunotherapy treatment and persistence of observed effects with different immunotherapy administration modalities.

Host: When you tell me about this study, Stan, I always think about the previous evidence for omeluzumab and the antiviral effects, they have that increase of seasonal peak of exacerbations that when you give omalizumab before they start school, kids don't have that viral peak associated with school attendance.

 You know, it's so interesting also that they make this comment that the patients who received immunotherapy didn't really have any changes in TSLP 4 and 13. And so there's just something unique about IgE, I think, and just your susceptibility to viral infection. I can't tell you how many parents, we see, and they just want to know why their kid's sick all the time, and it ain't some rare immune deficiency, they got allergies, you know, like, let's just be honest.

 And so, we're well positioned to fix that, and that's what's so great about immunotherapy. This is a great validation of all the work that we do to really improve a very common quality of life affecting trigger for children. All these darn infections.

Sarah Spriet, MD: Well, and I'm so glad they looked at dust mites specifically too, because you get that revving or activation of the innate immune system along with the adaptive cells with dust mite allergen. So it's a really a cool study design and to see those immune effects in this case. And I may have missed this, Stan, but are these monosensitized dust mite allergic patients? Did it?

Stan Fineman, MD: That's a good point, Sarah, because they were not all monosensitized. Some of them were polysensitized and the authors commented about that in the study, that that was one of the limitations and it could also explain why some of their responses were not as rigorous.

And, the other thing of course is the fact that they only treat them for 24 weeks. I mean, we know that optimal immunotherapy is three years. So if you get this effect just after a few months, my goodness, you know, I agree with Gerry. I mean, we need to be telling patients that immunotherapy is very helpful and can really improve the patient's, reducing their exacerbations, maybe improving some of their ability to fight infections.

 One of the beauties of Allergy Watch was the fact that this was a study from the American Journal of Respiratory Disease Critical Care Medicine, which is not one of the usual journals, that I read certainly on a monthly basis.

So it does, present interesting information that really is pertinent to our patients in terms of how immunotherapy can enhance our viral immunity as well and help our patients in a variety of ways.

Host: Just being a, an assistant editor of Allergy Watch, I learned a lot. And this podcast too, very helpful. Okay. So, Sarah, I think you were going to tell us how are we going to grapple with omalizumab dosing in our hives patients.

Sarah Spriet, MD: Yeah. So I'm bringing you guys another real world experience study to talk about this evening. And I'll be curious to hear your input on this one as well. So I reviewed this article for Allergy Watch. The title is Omalizumab in Chronic Spontaneous Urticaria, Real Life Experience in Dose Interval Adjustments and Treatment Discontinuation.

And this was published in JACI in Practice last year. And so as our listeners know, approximately 30 percent of our chronic spontaneous urticaria patients don't respond to our standard omalizumab dosing, and they continue to have bothersome refractory symptoms. So the authors of this study are in a specialty practice that manages chronic urticaria in Portugal.

And they described their experience from 2009 to 2021, and they did refine their approach with dose adjustments and interval adjustments over time. And so they described over 130 patients in their study, and by using the Urticaria Activity Score 7 and Urticaria Control Test, they rated what the treatment response was, if it was a full response, if it was a partial response, or a non response.

And so they found that 70 percent of patients in their patient population responded to the 300 milligrams of omalizumab every four weeks, while 21 percent had a partial response and 9 percent were unresponsive. And after updosing up to a max of 600 milligrams every two weeks, they were able to increase that response rate to 78%, and they found that this was well tolerated.

 And while it can be really challenging for us as clinicians to get these higher than licensed doses of omalizumab approved, the study did support that updosing can result in disease control in a portion of patients that otherwise wouldn't have responded to the dosing that's currently licensed.

Now, what I also really appreciate about this study is many of us struggle about when to stop our patients and to determine are there predictive factors of either who's likely to relapse if you stop them or who may not respond to the standard dosing of omalizumab. And so I really appreciate that not only did they describe their experience, but they give us a really practical algorithm about how to assess the outcomes and then how to either increase your dose or in the responders, how to go about lengthening the interval and then trialing off.

And I'll just offer that the predictive factors that they found for those who were more likely to need omalizumab updosing in their patient population was presence of angioedema, a body mass index over 30 kilograms per meter squared, positive basophil activation test, and a positive autologous serum test. And so I'm curious what you guys thought of this one.

Stan Fineman, MD: Well, I thought it was just really fascinating as well. And, we certainly don't do all these ancillary tests that they talked about, but I haven't seen that many patients that are not responding to a routine omalizumab dosing, initially, although after a year or two, sometimes we see people breaking through there. And sometimes that's when I'll change from a monthly administration to a every two week administration. So I guess I sort of do increase the dose, like that, but I, I don't go up to 600 milligrams every two weeks, like they talked about here.

But, everybody doesn't respond to omalizumab who has chronic spontaneous urticaria. So we need some other types of strategies.

Host: We just need things to cite, if you want to submit a rebuttal or appeal I think these studies really help us so much as you know, it's a fight. You know, people are suffering when they have uncontrolled hives and it's a fixable thing. It's just convincing someone who's looking at an algorithm to go beyond what's written on the paper for the best interest of the patient. I think that that's really what it's all about.

Sarah Spriet, MD: I was interested that the BMI over 30 kilograms per meter squared, right, we adjust dosing based on weight for asthma for patients who are on omalizumab. Can that be a next step with us and does it matter? We clearly need more studies, but just as you said, Gerry, I think studies like this help add to that body of evidence that will help guide some of our practice guidelines in the future, I hope.

Host: Anyways, we're throwing it into my template for my preauthorization. This is going into the letter. So hopefully it works. I'll print it out. Thanks for sharing this one, Sarah. Okay, let's wrap it up. I got one other article. We're just going to change gears a little bit.

This was published in JACI. And the title of the article is, Prevalence of CFTR Variants in Primary Immunodeficiency Patients With Bronchiectasis is an Important Modifying Cofactor. And, Dylan Lawless is the lead author. This is, multiple locations, but mainly this is a UK study. So, you know, CFTR, the Cystic Fibrosis Transmembrane Regulator, we know that is the chloride channel important for cystic fibrosis. Some general statistics, in European populations, it's been reported as common as one in 2,500, though, again, it's not limited to Europeans.

There's about 2,000 variants. The one that gets the most recognition is the Delta F508 deletion. And I didn't know this, some studies suggest that some sort of those 2,000 variants, a variant could be as common as 1 in 25 in certain European populations. I did not know that. That seems really common.

Now, again, some of these variants I'm not saying are like pathogenic, but again, it's just very interesting. So when you've looked at just carrier status, I'm not saying they have cystic fibrosis, but if you just look at carrier status, there are previous studies that show some associations with chronic bronchitis and bronchiectasis.

And so, we know we have bronchiectasis in our primary immunodeficiency patients. These investigators want to look at their PID cohort that they had genomic testing, they had genome wide testing on, and just see, is there any association between their lung phenotype and some of the CFTR variants?

Very interesting study. So this is called the UK National Institute for Health Research Bioresource for Rare Diseases. And again, they have over a thousand patients that they have whole genome sequencing. And obviously they have clinical information, so they looked at that cohort and especially the association of lung disease.

And just for fun, they also looked at immunoglobulins in some of the cystic fibrosis patients they have in this genomic database. And so when you look at just general population allele frequencies and then allele frequencies associated with primary immune deficiency, they actually did find that Delta F508 deletion was enriched in patients with PID with lung disease.

Very interesting. There was actually some other CFTR variants. I'm actually not going to list them there, but they're actually in the summary, but there are three other variants they found were associated with PID and lung disease. There was also ones that were just associated with PID in general and not specific to lung disease. The clinical significance of that is not clear. But, it's intriguing to think about which of your patients with primary immune deficiency may need potentially higher IgG trough levels or maybe more frequent monitoring, and that maybe CFTR genetics should be routine just to do some sort of prognostic measurement or biomarker of future disease risk.

Now, I told you they did that flip side where they looked at IgG levels in cystic fibrosis. Now, on the flip side, they're not really saying that IgG levels seem to make a difference in terms of CF outcomes, but I do think the take home message is that we should consider CFTR sequencing in some of our primary immune deficiency patients.

Now, this is interesting. The next thing I did was I just went to some of the major websites and I said, Hey, What's in this panel anyways? So, I went to a bunch of different popular PID panels that look at the 400 plus known primary deficiency disorders, and wouldn't you know it, the one panel that does not currently, as of the recording of this podcast, contain CFTR is the Invitae panel.

I thought that was very surprising. That was like the one that did not have CFTR routinely in the PID panel. So just something for your consideration, when we order the Invitae panel, especially if your patient has lung disease, maybe you just want to throw it in there, you know, just add that in.

Stan Fineman, MD: So do you do this testing on your patients? Do you do genetic testing for your PID patients?

Gerry Lee, MD: Oh my goodness, absolutely. I think, we have now learned that there is precision therapies for certain phenotypes. Now, again, I would say that we're probably not going to find much for like infection only CVID. Maybe I'm being naive about that, but the patients I'm thinking about have significant non infectious manifestations.

They got lymphoproliferation or something and autoimmunity. You're going to be more enriched to find something. But if you have a clinical suspicion of a genetic monogenic PID, if you order the panel, you're going to find something 25 percent of the time.

That was very interesting statistic. So you're really not, shotgunning things if you have a high clinical suspicion. And, that information has significant implications for the patient's central prognosis, potentially the use of precision therapies. There's some really nice reviews on the role of genetic testing in the patients with confirmed immune deficiency. But again, outside of just looking at the immune system, I think these co factors are sort of open my eyes up about other things to consider about the comorbidities, I mean.

Sarah Spriet, MD: Well, and as you pointed out, I think the panel that many of us use most commonly apparently doesn't have the major variant in question, and it makes me wonder, you know, a lot of the pediatric patients I may be working up have already had a negative sweat test. So how far do you chase it down? I'm not sure of the answer to that, but it's definitely a good article to review.

Host: Well, I thought that was an interesting one. If you learned something and you enjoyed what you're listening to, please rate our podcast. It really helps us out on iTunes. We really welcome your feedback, corrections, and suggestions. The email address is allergytalk one word, at ACAAI.org.

And remember you did earn CME credit by listening. So all you got to do is go to our website, it's college.acaai.org/publication/allergywatch. You can reach other issues of Allergy Watch. And again, we welcome your time and your participation. Thank you so much for listening.

I hope you all have a wonderful day and learn something new. Thank you so much. Have a good one.

 The ACAAI is presenting this podcast for educational purposes only. It is not medical advice or intended to replace the judgment of a licensed physician. The college is not responsible for any claims related to the procedures, professionals, products, or methods discussed in the podcast, and it does not approve or endorse any products, professional services, or methods that might be referenced.

Today's speakers have the following disclosures. Drs. Lee and Dr. Spreit have nothing to disclose. Dr. Fineman has been a speaker for Takeda and has done research for A. Immune, DBVU, and BioQuest.