This webinar was recorded on July 17, 2023

How is asthma impacted by allergies and immunotherapy? Join us as we explore the guidelines and implement them in patient care.


  • Désirée Larenas-Linnemann, MD, FAAAAI, Dist. Intl.FACAA, Clinic of Excellence in Allergy and Asthma, Mexico

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Transcript: While this transcript is believed to be accurate, errors sometimes occur. It remains your responsibility to evaluate the accuracy and completeness of the information in this transcript. This transcript is not intended to substitute for professional medical advice.

Andrea: Hello everyone. Thank you for joining us today. We will give everyone a few seconds. We know it takes a little while for you to connect. We will start in another 10-15 second. s.

Andrea: Hello everyone thank you for joining us and welcome to this afternoon’s webinar. We have a few housekeeping items before we start today’s program. I’m Andrea Jensen, I am the Education Specialist for Allergy & Asthma Network and a Certified Asthma Educator . All participants will be on mute for the webinar. We will record today’s webinar and post it on our website within a few days. You can find all of our recorded webinars on our website at Scroll to the bottom of the page to find our recorded webinars and any upcoming webinars — webinars. This webinar will be 1 hour and that includes time for questions. We will take those questions at the end of the webinar, but you can put your questions in the Q & A at any time. Sometimes I miss them during the session, so please be sure that you put them in the Q&A section. The Q & A box is at the bottom of your screen We have someone monitoring the chat if you have questions, or need help. We will get to as many questions as we can before we conclude today’s webinar. We DO offer CEU’s for this webinar. This webinar series is “Advances in Allergy & Asthma” in partnership with the American College of Allergy, Asthma, & Immunology. Allergy & Asthma Network offers CNE for nurses & CRCE for respiratory therapist American College of Allergy, Asthma, and Immunology offers CME’s. A few days after the webinar, so please be patient, you will receive an email a few days after the webinar with resources from the webinar, and a link to access continuing education credits. You will also have a link to a certificate of attendance We will also try to add the link to the certificate in the chat . So we How is asthma impacted by allergies and immunotherapy? Join us as we explore the guidelines and implement them in patient care. Allergy & Asthma Network is a grassroots organization that was started over 35 years ago by a mom who knew that other mothers like her needed resources and support. Our mission is to end the needless death and suffering due to allergies, asthma and related conditions through outreach, education, advocacy, and research. Today, it is my pleasure to introduce our speakers, Dr. Larenas-Linneman. She received her MD cum laude in 1992 at the Rijksuniversiteit Utrecht in the Netherlands. In 1995 she received her title as Pediatrician, and in 1997 as Pediatric Allergist at the National Institute of Pediatrics in Mexico City, Mexico. She has been working in private practice since 2001. That same year she founded the pro bono Allergy clinic in Pueblo Quieto. in March 2017, she was appointed Director of the Center of Excellence in Asthma and Allergy at the Hospital Médica Sur, Mexico City. Dr. Larenas-Linnemann is an internationally well-known and highly regarded expert in the field of allergy. Her special fields of interest are asthma, allergen immunotherapy, allergic rhinitis, and urticaria. She is National Advocate to GINA , ARIA Country Coordinator Mexico and coordinated the national ARIA México 2014 document. She chaired the National Urticaria Guidelines late 2014 . This resulted in over 90,000 downloads. In 2016, her center became a Center of Excellence UCARE. She forms part of the Global expert panel of the update of the Urticaria guideline 2017. In April 2017, the Mexican Guideline on Asthma was published under her leadership, co-authored by 58 experts from 12 national societies. Its content forms the basis for CME on asthma of CENAPRECE, from the Ministry of Health. Since Jan 2019 she chairs the — since January 2019 she chairs the International Severe Asthma Registry (ISAR)-Mexico. She co-chaired the Mexican Consensus on Atopic Dermatitis which ended in 2018 and chaired in 2019 the Renewal of the Mexican Guidelines on Immunotherapy. Dr. Larenas-Linnemann has lectured at National Allergy Congresses, at the American Academy of asthma and in meteorology, ACAAI and EAACI annual conference, and the World Allergy Congress. Dr. Larenas-Linnemann has published over 150 articles in peer-reviewed journals, written various book chapters, and is reviewer of 7 journals. She became member of the National System of Investigators, level II, in January 2016. Whew!

Dr. Larenas-Linneman: Yes, sorry. [LAUGHTER]

Andrea: No it is wonderful. We are happy to have you with us today. Feel free to go ahead with your slides.

Dr. Larenas-Linneman: That was a big background. It is all super. Thank you for such a sweet introduction. It is an honor definitely for me here sitting in my office in Mexico City to be able to work on this webinar together with you. Let’s get started, these are our disclosures. I received several grant and there are now nine national guidelines that I have chaired. We will speak a little further on that down the road and I am speaker of several industries. The learning objectives today are to discuss the place of AIT in asthma guidelines. To be acquainted with the results from recent AIT in asthma trials, specifically RWE. And at the end it is a very important to select the correct patient with the collect our June — correct allergen and the correct timing of when to start AIT in asthma so you can get the best benefit to the agent with — patient with asthma. These are the national guidelines I cochaired. This was in 2019, and very recently 2021 at the end of the year. The latest asthma one just got a check of 45,000 downloads. We really have been able to reach quite a lot of colleagues from the guidelines. That is the diffusion of those to the subject of my talk today with you.

At this moment, allergen immunotherapy has guidelines and evidence for this. I would like to show you one of the very earliest trials more than 50 years back of allergen immunotherapy. And the evidence will also be a method analysis in the central. And then whatever critical issues? What about allergic asthma and severe asthma? And what about the — what about for the future for those that have asthma and have been — allergen immunotherapy and asthma guidelines. I bumped into this recent article where it is explained why there might still be a problem and it is still of the — a bit of a holdback for regulators to approve asthma as an indication for allergen immunotherapy. Essential for licensure, they say that the allergen immunotherapy product has to remain comparable in quality and quantity of composition throughout the whole development. The most important part is the verification of efficacy now really showing to be of clinical relevance. That sometimes is slippery. what is of critical relevance to one is not so much to the other and vice versa. And speaking about clinical relevance, I think when we thought very deeply on this with some colleagues that helped me with the development of asthma guidelines two years back, we said what would be the main goal of asthma treatment? What do we really want to accomplish with the comprehensive management of asthma in our patients? Number one, sure, avoid depths –deaths. I know it is overlooked but this is finally the most important point. And then let me remind you that daily, this is data coming out recently, daily in the U.S. there are 10 deaths by asthma in the U.S. This is — I think it is 1.200 thousand inhabitants in the U.K. In Australia it was I think at .9 per 100,000 inhabitants. So it is still absolutely up-to-date to avoid asthma deaths. because they are still happening way, way too much. Avoiding some of the longer therapy at any level and early starting so that you can get down the information may be very important to avoid asthma death and avoid lung function on the long-term. This directly links to the quantity of excavations of asthma crisis that a patient has in his lifetime. Every crisis leaves a little scar, a little scar. It is very important to try to aboard — avoid severe excavations. And another point that’s very important is to reduce the side effects of medication. To keep it as low as possible in the doses. Those are the outcomes that we have to look for when we look for the trial and see how really yes or no important they are. Went to the guidelines say at this very moment? I would like to review with you those five guidelines.

I will start with GINA we know it is not really a guideline it is a strategy for asthma management. And GINNa officially put on the very first page that we cannot compare it with the quality that the guideline has to have because it is updated every year. Every year. So it might not have this super solid quality of evidence review that the guideline has, the good thing with GINA is that it’s very up-to-date. This is the 2023 slide of the two tracks of therapy. We can see here down under this figure is a gray box and we can see that already from 2022 onwards, GINA is now approving allergen immunotherapy . And it mentions sublingual allergen immunotherapy in step 2, 3, and four of asthma therapy. And then when we look at GINA text from 2023 contains this we have comparisons of SCIT in comparison to SLIT. — and there is insufficient evidence for mold. As for SLIT — there is modern — modest evidence in reducing that. The trial was lowering and then they were going to see how many patients were getting an excess ration — except for — exes to ration –exacerbation. — they advise potential been a bit too way against the risks inconvenience of having to go every time to an office to the shots — to get the shots and the cost. And for sublingual, they considered adding asymptomatic interesting HDM-sensitive adults with — controlled despite ICS. It is over 70%. Currently they are reviewing this. I asked them to put me on the committee that is reviewing, I was not excepted to be on the committee. So I really hope that there are allergist and not only moderate just on the committee now reviewing allergen — for the children. This is 2022. This is the same thing for 2023 as well. As for allergen immunotherapy no indication in children. That is GINA. Now let’s go to the asthma management guidelines in the U.S. Now here at the bottom of the figure we blow it up a little bit and it says four steps-2 — 2-4 says conditionally recommend the use of subcutaneous immunotherapy as an object — adjunct treatment to standard therapy for individuals that are less than five years of age whose asthma is controlled and the initiation and build up and maintenance phases of immunotherapy are. The patient has to be a controlled — to be able to start and continue the allergen therapy. When you look at the evidence, you see the different numbers of the recommendations and so forth, individuals ages five years and older with allergic asthma they recommend conditioning and subcutaneous allergen immunotherapy. And that goes more in favor of the sublingual.

Interestingly, there is one that goes against bears and additional recommendation against sublingual allergen immunotherapy are. It is conditional and it has a moderate level of evidence because there is not really enough evidence to support this. I think the good part of the NAE PP is a solid review of the evidence. It is so solid and it went through so many rounds of reviews and reviews and reviews the evidence was only up-to-date until October 2018. So everything that is been published almost over the past five years is not taken into account in that recommendation. The Spanish colleagues and what of a say? This is their treatment algorithm. As we can see in their text, they say that subcutaneous allergen vendor therapy — allergen immunotherapy is when it is well-controlled level eight of evidence. They can even start since esca lon 1, level one especially if there is rhinitis. They do not withhold until step two they make it possible already from step one to start allergen immunotherapy . Not in uncontrolled severe asthma though. And here but level of evidence is B. And in sublingual they stated as level B a little bit less. And this one is only guideline that clearly states, there is a lot of allergist from this guideline that it should be taken into account that allergen immunotherapy has a long-term benefit of clinical improvement even years after stopping the therapy. I think this is a special extra benefit that other guidelines have not taken into account. Again, I think it is very important the teams review that there are allergists and yes, there were quite a lot of colleagues there. So what doesS BTS/SIGN it is a little bit old. They hope in July of 2024 to have an updated version but right now I still have to show you the 2019 version. The subcutaneous immunotherapy or was one with two plus high level of review evidence of the benefit of allergen with therapy — allergen immunotherapy with the symptoms that improve heightened run curl activity. And it is a Level 1 double plus adverse reaction. You know in the U.K. immunotherapy is only light — license for rhinitis. They cannot come up with a recommendation. Very same for sublingual. There is good evidence, serious adverse event are very rare. The safety force is much higher but again, it is not licensed for asthma. Then we go to the last guideline and I cannot leave it out. This is our guideline. The MIA. we have an interesting outing therapy figure as we figured out that what you give — it depends what it would be the best rescue therapy. He made the little blocks together with the maintenance and the rescue. Just an interesting thing may be. Here on the right-hand side of our treatment figure, you can see that in allergic asthma step 2-4 allergen immunotherapy . This is the for 12 years and up. We do allow also allergen immunotherapy in children on the right-hand side from 4-11 years for the figure for kids. Yeah, I would like to add a little bit of some figures of — about pictures that we took in tequila. I think you all know about tequila, it is a very well-known drink here in Mexico. We went there and launched recently a guideline, but then we made nice pictures. We were sleeping in this hotel that was of, I don’t know how you called them the round when it — round wooden things.

Where they keep the tequila. It was nice pictures. What is the evidence for — and it takes you back to this publication probe the early 60’s from Johnston and his group — Johnstone and his group. This was not a nice trial in the sense that it was absolute the — absolutely flawed ethically. Nobody knew they were part of a clinical trial. The strong point is that nobody knew that they were part of a trial, so the bias of being part of a trial was not there because I didn’t even know. All children that arrived that had asthma, there was no informed consent and the parents did not know they were in a trial. All the children received SCIT until their 15th birthday. And randomly they were assigned to four groups there was a high dose group, the highest rated group. They push it to the highest dose that the kid could tolerate. I think that be more or less as good as allergen immunotherapy. And then there was the perceivable — placebo control group and another kind of placebo that was a hundred thousand times — no even more and million times diluted extract. This is also a controlled group. And then we look at the outcomes, there were several outcomes in this publication. I’ve been here besides of the original pictures of the original publication. If we look at — for kids have had as many or more asthma attacks is a previous year, in the highest dose group there were none of them anymore. When you look at no — severe exacerbation In the last year. There were hardly any in the highest dose group. And that is completely opposite in the control groupS but it was still almost year and 90% — 70% still having severe exacerbation The last year. The in between group was in between with those numbers. And unfortunately some 30 years after that the Atkinson trial really pushed allergen immunotherapy as being able to benefit in asthma way back. With his trial, this was a 1.5 year trial DBPC trial. With children with asthma and perennial symptoms. You can see 1.5 years later the black dots are allergen immunotherapy kids and the open dots are the placebo kids there is no difference at all between both groups as for medications in the last days. What are may be the flaws in this trial? Why was it completely negative? I think there are several. First, the median number of extracts, I know still in the U.S. you do makes quite a lot of allergens together. After the trial from [INDISCERNIBLE] sublingual allergen immunotherapy. We saw if you have one allergen and the rest is illegitimate and you do one allergen and any other allergens, it is not cross-reacted and has nothing to do with the patient, you add it to the vile in bile becomes much less effective. I do think that this also applies for subcutaneous allergen immunotherapy. So I think definitely six is probably a bit too many allergen, but more importantly, we all know that we do not have to mix highly — high content allergens which are cockroach and mold. Here there were two thirds of kids that receive mold mixed within the mix of bio — via l. So this affects severely the potency of the vial.

And when we look at the houses might, –mite, they made it from the home mite culture. It has a high quantity of one group, and the mites are all the stuff they are growing in. There is a high level of therapy one but the therapy to contact is almost 10 times less. Nowadays, the nice allergen immunotherapy extracts you have in the U.S. are highly — high quantity allergen access because it has just as much one and two in it within the trials and within the laboratory testing with the support of the — FDA and others. If you want to look those publications up, but now you have very good high-quality extracts. But for the ones using this trial that was not the case. So I think those probably made the trial come out negative. Then 20 years later, almost 20 years later, finally, with the group from alk was able to show that this is houses with sublingual allergen immunotherapy tablets. that if you Put the patients on sublingual allergen immunotherapy for house mites and you start after several months or reduction, a 50% reduction in the face — phase 3A that maintain the patients under control. And then in the phase3B you withdraw. Then you see surely the allergen — the asthmatic patient starting to get exacerbation. Severe exacerbationS. This was very clearly less than two active groups as compared to the placebo. Here it very clearly showed that the allergen immunotherapy partly protects against severe allergen im — exacerbations in a withdraw schedule. They say this is not a well-controlled asthmatic patient. Well we can discuss about that later. Then, now I would like to go a little bit further onto real-world evidence trials. First I did a small trial from Korea. I think it was interesting because they really gave it three years. Always, if you do and allergen immunotherapy trial at least you have to cover it in two years and prefer the three years — preferably three years. This takes a good while until the good effect gets in. This is a nice three year trial here. There was quite a high group of Korean patients that were able to completely discontinue the steroids. Two thirds of them at a low number percentage in the allergen immunotherapy not group. — the not allergen immunotherapy group. There were I will do — able to withdraw after three years. And only house dust mite and multi-allergen they did quite. e good. And in the different years of a trial you can see there is no different between old Jacinta size — mold desensitized patients.

And maybe here visiting point of which patients did better. Statistically, significantly better at least here and we see another strong trend. For those who have asthma with it more early onset. And the respondents were a little bit younger people and a little bit older in the numbers — in the nonresponders. We know the younger that starts it is really allergy asthma. Sure those that had allergic rhinitis did better in those that did not have allergy rhinitis. Then, here now these are the really large database studies which is very much evolved over the past couple years. We see here a large database in France, it was published four years back in allergy. And the therapy group reduced 40% while the matched control group — here is the matched control group and there is a rise of sin present in asthma medication. Then, three years later, Fogelberg and other base trials — they were eight and they decided to do a meta-analysis of 13 real-world evidence trials and database trials. There they concluded that it was not very clear. There were several trials that showed very nice effect as you can see on the left-hand side, but there were also some trials that did not show any effect at all. So they concluded that they cannot stray on saying that allergen immunotherapy’s really works in asthma. Results seem a little conflicting, but then we had after that — no, one of the trials was this one just think was quite solid. This is the database from Germany and they showed that there were allergen immunotherapy patients and non-exacerbation — non-allergen immunotherapy. And they look at those that were treating themselves with GINA step I, III, or IV. And they saw that being on allergen immunotherapy had a 30% reduction that they would go on from stage one until stage three. And then there was a 30% reduction for the risk of going from being at stage III to becoming stage IV GINA. compared to those who were not on allergen immunotherapy. And it was clear here that the children even had a stronger positive effect as opposed to adults. I think in general we know that allergen immunotherapy is normally tending to be more effective early — the earlier restart. Children do frequently better than the adult. At least that is what I see here is a pediatric allergist. And then, I think this is — yeah, well the best evidence for me coming from real-world evidence this was published after the meta-analysis of Vo gelberg and others. This was a retrospective cohort study. It was published in the Lancet in Europe. It was from 2000 7-2017. — 2007-2017. It is all registered there so you can do all the registries very nicely. Everything you buy in the pharmacy is registered on your name so you can really do a follow-up for many years. Here, it was clear reduction in the use of this of 34%. And also of moderate severe asthma exacerbations. And when you look here at the figures for those at 1, 2, 3, f nine years. And after a long follow-up and finishing allergen immunotherapy we can see a very clear, specifically the last 4-5 years a clear movement of reduced asthma treatment. More step down in asthma treatment, less severe exacerbations and less hospitalizations as we can see on the right hand of the panel. So I think this is quite strong real effect of the benefit of allergen immunotherapy of asthma in the long run. Then, systematic reviews bill and these are all the numbers here. This is with Abrams — A bramson. GINA did not like it because they said it was to head originates in the different doses and outcomes — had a rigidness –heterogenous. — we say the evidence for mold is very low. But a — Abramson said there was a number to already reduce the risk of deterioration of asthma symptoms with immunotherapy. And as medication, you see the reduction in asthma medication is this whole yellow group. And here again is four which is a strong effect in the benefit of this treated asthma group. Then the Cochrane sublingual pediatric asthma. One of my Mexican colleagues working with — a college since more than a decade back now. In 2008, they had a quite positive effect here for symptom score and a very clear and strong effect for reduction of medication. The flow of these meta-analysis both of them is very high heterogeneity again of the trials. Over 75% is high heterogeneity here you have 94% and here you have 95%. And we know the early sublingual allergen immunotherapy trials were many heterogeneities in many aspects. The total number of patients was low. Then, these were the — this is the latest one published by Rice now a little over five years back in pediatrics. He did already have now 40 studies. Rice and colleagues concluded with the latest systematic review of allergen immunotherapy in pediatric asthma that there was moderate strength evidence or — four SCIT for long-term and there was little to no evidence for sublingual. And a very strong group reviewing with a lot of help of methodologist was the EAACAI guidelines for this. I was happy to be part of this group. They had seven different subgroups.

Allergen immunotherapy asthma, and others. So the group that was with you more specifically on — into allergic asthma and here was house dust mite driven a G — allergy asthma. And the analysis came out and they recommended that add-on to the regular asthma therapy in adults with house dust mite allergic asthma partly controlled. This was a traditional recommendation of moderate quality of evidence. In house dust mite SCIT in children and liquid SLIT in children. And it was an add-on. I think it was a important point. It was not the sole medication but add-on at a — add-on medication for allergic asthma patients. For these conclusions they were solidly informed by systematic reviews done three years earlier. We always have to speak about safety, especially if you speak about allergen immunotherapy asthma. I would like to draw your attention here to a publication we did here in allergy asthma seedings in 2016. Here, we had a survey we sent out. It was pre-pandemic so people were still quite good replying to surveys. Now I think we get an ocean of surveys so it is really hard to get them back. But in those days, we get over 1000 responded back. We asked about do you give allergen immunotherapy in patients with pregnancy when they are already pregnant or continuing, hypertension, Kim — cancer, remission, autoimmune diseases, etc.. Among those many Russians we also ask sorry, this has gone — many questions sorry, this has gone one to the right. It is this one. Severe asthma patients. Two thirds of us said yes I am treating patients or I would treat. And only one third said, no, allergen immunotherapy is contradicted in asthma care. We are not speaking about control but the severity. And then we as physicians and colleagues in total more or less how many patients did you treat with this condition? You can see here that the severe asthma it is over 3500 patients in total. If you sum up all the different colleagues that replied. In total, over 3500 patients with severe asthma that have been treated in those days, in 2016, with allergen immunotherapy. And in the last question was, well, if you treated the patient with allergen immunotherapy, did you bump into major problems or minor problems or no problems at all? Again, we asked of all the different diseases, conditions that physicians treated patients with. You can see here that the number one with yes, definitely, we have a 12.5% of major problems was in the severe asthma patients. So, sure, this is probably — this is pre-Biologics now. This is still 2016 was this published. It was a pre-biology era, but with asthma and allergen immunotherapy this is a major caveat. Be very careful there. And then, yeah, the last slide is on — for sure have to come from the wonderful surveillance studies. David Bernstein started what was a decade ago with very strong help and then now it has almost been taken over by Tony Epstein. This was in 2008 where it started. I think it is wonderful data and so it is true data for us and what are the problems in the main issues with even — that is in allergen immunotherapy. In the latest publication is this one. Now we have — [LAUGHTER] The little one went down. We had 35 fatalities in the old days. 41 in the previous millennia. And fortunately all the safety issues being well in place, with the waiting period and not giving shots when the patients are uncontrolled. Lowering in the peak season, etc.. Those rate of death go nicely down until now the last report here in 2015-2018. Five and Ms. fortunately from 2018 through 2023 18 fatalities. Not doing well they are. As we look, those are the five patients. I am reviewing for you now. One by one patients of colleagues they come up with all the detailed descriptions of the patient and I put here a few of them up for you and they all had involved asthma. There was wheezing, in the reaction. You can see severe asthma, hospitalizations. And again, here, there was a low PEV one so it is still a high risk of giving allergy in therapy into uncontrolled or severe asthmatic patient if they are not under good control. These other fatalities have allergen immunotherapy. Now it is probably a little bit slower in its action — onset of action. At least I felt patients I will not tell you if you’re doing well or he virtually allergen immunotherapy — doing bad with your we have one year — with your allergen immunotherapy until we have one year. For sure, the safety part is wonderful. No fatalities at all to now. One of the interesting remarks surely that I cannot leave behind is on the prevention of asthma. Not treating but preventing asthma in patients that only have allergic rhinitis. We know the PAT trials. Jacobson working closely here and being employed by — and later working on his own. He did a very nice — this is open trial but a nice follow-up after giving three years of subcutaneous allergen immunotherapy therapy — two children with only allergic rhinitis and enrollment while at the end of allergen immunotherapy they were checked how much asthma symptoms medication was there. After five years or two years after finishing allergen immunotherapy and after 10 years or this was seven years after finishing the allergen immunotherapy. This was presented in Paris in 2003 as a poster and this was a solid publication in allergy 2007. If you look at how it did after three years, allergen immunotherapy does with no asthma and bows with asthma in red there is a clear difference between the allergen immunotherapy therapy group as compared to the controls.

Two years more two years after finishing allergen immunotherapy this still holds on very clearly. And even seven years after finishing allergen immunotherapy we can clearly see now that the percentage of the patient with only in the control group having asthma and those who have allergen immunotherapy for three years. And the ratios are really clearly significant. This was high-dose, subcutaneous, allergen immunotherapy. Most with house dust mite for pollens. And then was the sublingual trial done by –GAP trial. This was a European study of 11 different countries, 101 sites, 812 children. You see here all the different countries participating. And this was given sublingual allergen immunotherapy for three years and then they gave two years of follow-up. Here, you can see interestingly, how the kids, this was with grass pollen tablets, how to children after one year with the tablet they still had a little bit more symptoms, asthma symptoms during the winter. In the winter is not the pollen season. So those kids had a tendency to have more asthma shows an active group. But after the three years, and are already told you this takes time for to really kick in. After the three years, there you can see that even without outside of the pollen season in the winter months, the asthma symptoms are clearly less in the active group as compared to the placebo group. This still went on — there I go with my cursor here in the two years of follow-up. In the seasonal months, in the summer months during the pollen season, right from the start we see this very nice reduction and it still holds on also two years follow-up. Then, this was supposedly a negative trial. The solid primary efficacy outcome was very stringent definition of symptoms and spirometry and medications that had to go down. So the primary outcome was not met in the trial, but I think we can all very clearly see that the asthma symptoms reduced and advocate — asthma medication reduced. And the two combined together reduced. If you do symptom medication and spirometry together is still significantly in how it reduced. And then if you combine all of those plus — if you look at it in necessary doses, still a significant reduction in the active group, but the primary efficacy variable was not met. So, I think, yeah, although it is officially a negative trial I think it is very clearly showing us that there is — I’m sorry this is a bit of a neater picture. There is a bit of a clear tendency to reduce the going on to in children with only allergic rhinitis and also was sublingual allergen immunotherapy. And here it was with grass. Summing up now, vision that AIT it is a disease modifying therapy. I think this vision is very important. It should be taken into account if a guideline developerS are arguing if allergen immunotherapy should have a place in asthma guidelines for allergic asthma. And I think that is the important thing. Allergen immunotherapy in asthma only if it is allergic asthma and if there is better results in children. So I will not leave the children out. I do not like GINA leaves them out. And I think there is evidence in children as well and we know that children spun normally better than adults if there is. I think there is efficacy for S CIT and SLIT. the later trials are quite solid. And allergen immunotherapy subcutaneous is always part of the safety that really should only be listed strictly by experts in the office of the treating physician with a 30 minute rating period. Absolutely, then I do not have a slide on severe asthma. There, I would only like to share my thoughts. There is not solid evidence behind this yet, but my thoughts are that now in biologic era and what we have been living through here in my office is that once a patient is severe asthmatic patient, severe allergic asthmatic patient. We do the skin testing before we put them in biologic. We have to rule it out before we put them on the biologic. If they are really allergic asthma and flair when they are exposed to the allergen with asthma symptoms, once we have them for-six months on the biologic, we do start allergen immunotherapy and I normally start with sublingual at least for a year and eventually then go on with subcutaneous allergen immunotherapy. But having the patient well-controlled on a biologic therapy. And I think is a biologic, it is not a disease modifier.

I do think that allergen immunotherapy can add on their. But, sure, good solid trials. I need in this era and what I think about this — I think this is when I will open questions for all of us and I think we should definitely explore it. Yeah, and giving thanks to the big groups of colleagues, the core groups of guidelines and every guideline has also a large guideline developing group from 9, 10, 11 different societies collaborating with us and summing up to a total of normally 40-50 colleagues working on guidelines. But I would like to show you the faces of our allergen immunotherapy guideline groups of the ones pictured. This is where I originally come from, I am not Mexican I am not U.S. either. I have my English and Spanish accent that I have dodged. But I already told you, I did my pediatrics and the allergy degree here in Mexico City and I am now working on a big hospital in the south of Mexico City where I am giving this lecture from this moment. These are my my linked in, and if you have any more comments or questions I shall be here to very happily respond or discuss with you whenever you would like to tell me now. Thank you very much for your attention and I think we did the right thing to leave 5-6 minutes for questions or remarks. Really it is always very welcome. Thank you.

Andrea: Thank you that was a lot of information. I really like how you have all the data and it shows how effective it is. Thank you for helping old allergist out there know how to better treat their patients. We have a few questions in the chat let’s take a look at those. One says which allergy test is best for determining allergies? They may be referring to if it is a blood test or the skin brick test. How about people who test negative and will have reactions, what can they do?

Dr. Larenas-Linneman: Yeah there is the skin brick testing that allergists do and if you’re not an allergist that is not an option. To have the skin up Rick testing. But — skin creek testing — skin prink testing. it is possible that you can have cross-reactivity would urinate — which you are not able to have in skin testing is done in the whole allergen. Then there is blood testing. In the blood testing have two different types of blood testing. One is with the whole allergen. This is still the most sensitive test. And the other one is that complement diagnosis. The molecular allergen diagnosis.

And the good thing about the molecular allergen diagnosis is what it says, the molecules. Really, the different major allergens that you are testing through the blood with the serum of the patient, you can see then that the patient responds — or has a reaction for example to Philippi five but to another of the grasses and maybe some of the wheats to where it is cross-reacting. Sorry, I have very highly expert Mexican colleagues who just launched the molecular allergy gnosis guideline. It is banished, but there are tables which show the gross reaction. I do not know them by heart. I always have his guideline on my background while I am working, but there are several allergies that cross-react not only with families or a species, Regina’s, but also — or a genus, but in different families. Those are different conserved molecules in the world of plant s. So that you can pick up with molecular allergy diagnoses in the blood. The negative thing is it is quite pensive. Honestly, we have it here but I only do it in patients who have a lot of positive in skin testing and I think no, you have the cross activity of other allergens and then we do the blood diagnoses to be able to pick the real allergen and for cross-reactive ones.

Andrea: Thank you quite the science correct for. Thank you for so euro. That is very crew — very cool. Another one says — what effect does this have on cancer rates?

Dr. Larenas-Linneman: Yes it is very interesting. The ones on the survey — there was the other one for the indications, but then when we published, we also looked very much of the literature on cancer and allergen immunotherapy. And then there was one quite long study that showed it on the long run it was even a little bit less development of cancer. This was significant when patients got allergen immunotherapy as opposed to those who did not. So if there is any signal that it is a positive signal, it is a preventive signal. Of allergen immunotherapy against cancer.

Andrea: OK, thank you. Another question we have is doesn’t age have a lot to do with improvement? As the patient gets older?

Dr. Larenas-Linneman: Yes, OK. That is why you always need your control groups. Now on the long run of allergen immunotherapy, sure, there is a huge placebo effect linked to what you normally see specifically in the first 1-1.5 year. The patient gets it and they think — you can see it nice going on both of them but then after a while one or 1.5 years there is a clear separation of those really getting allergen immunotherapy and those who did not. So yeah, the best thing is yeah, that is why the control in the trial is always, if you do small groups I think it is best to say , yeah, there is a signal of the pure allergist allergen immunotherapy and not the compounder of the placebo effect. But in those long-term trials, it was really a difference between control group and the active group. It was not only allergen immunotherapy that I showed you. But it was the difference in vapor to allergen immunotherapy as opposed to the control group. So that is the way you should read those blocks I showed you.

Andrea: OK, thank you. And then, one question we have on here is that sometimes people have allergy shots when they are younger, they are children. Later on as adult they have to repeat this as an allergy shot. Do you see that to be like common customer — quite common?

Dr. Larenas-Linneman: Sure I will stop sharing if that is OK. Yes, sure, with my parents — with my patients I tell them I am not changing your genes allergic to several allergens I’m not taking that away I’m only teaching your immune system during the therapy. Luckily, that is why it has to be three years, two years is not enough. So that you really get your memory cells and they are we all know that it is the B memory in the follicular cells that are in — of importance. This was the hold on for several years, but your tendency to respond to several allergens with an allergic reaction, I am not taking that away. It is very possible after 10-teen years all of a sudden your allergies come back. Welcome back to me, we do have testing again. What generally has been shown — respond a little bit faster.

Andrea: Good to know. Thank you before we started I was sharing all of my three kids had allergy shots when they were younger and I worry that we have to repeat that later on like I am doing. So, think, a wealth of information. Thank you. We are just overtime. There are a couple more questions but we are a little over time. But thank you we are lucky to have you. You are doing great things there. The next Simmons will teach you. Stash will be July 25. — we also look for in email on Xing that will have the link to be able to review this as a recorded. — feel free to share it with anyone you would like to. And thank you again for the allergy network. Join us every day to be better together.

Dr. Larenas-Linneman: Thank you. Goodbye.