Phenotypes, Endotypes of Allergic Asthma
In this podcast, Wanda Phipatanakul, MD, MS, speaks about allergic phenotypes and endotypes of asthma, including biomarkers that distinguish patients with allergic asthma and how patients should be managed.
- Investigating dupliumab's effect in asthma by genotype. Boston Children's Hospital. Accessed February 2, 2022. https://ideaasthma.org/
- Precision interventions for severe asthma. Collaborative Studies Coordinating Center. Accessed February 2, 2022. https://preciseasthma.org/preciseweb/
- Asthma clinical research center. Boston Children's Hospital. Accessed February 2, 2022. https://www.childrenshospital.org/research/centers-departmental-programs/asthma-clinical-research-center
- Preventing asthma in high-risk kids. Boston Children's Hospital. Accessed February 2, 2022. https://parkstudy.org/
- Fliesler N. Can asthma be nipped in the bud? Boston Children's Hospital. August 2, 2016. Accessed February 2, 2022. https://answers.childrenshospital.org/asthma-prevention-xolair/
- Fliesler N. Trial for severe asthma targets a mutation common in children of color. Boston Children's Hospital. September 7, 2021. Accessed February 2, 2022. https://answers.childrenshospital.org/duplimab-asthma/
Wanda Phipatanakul, MD, MS, is a professor of pediatrics at Harvard Medical School and the research center director in the division of asthma, allergy, dermatology, rhematology, and Immunology at Boston Children’s Hospital in Boston, MA. You can contact her at firstname.lastname@example.org.
Jessica Bard: Hello everyone and welcome to another installment of Podcast360, your go‑to resource for medical news and clinical updates. I'm your moderator, Jessica Bard, with Consultant360 Specialty Network.
According to the Cleveland Clinic, allergic asthma is the most common type of asthma. In the United States, 25 million people have asthma, and 60 percent of people in that group have asthma caused by allergies.
Dr Wanda Phipatanakul is here to speak with us about her team's research, allergic endotypes, and phenotypes of asthma.
Dr Phipatanakul is a Professor of Pediatrics at Harvard Medical School, and the research center director in the Division of Asthma, Allergy, Dermatology, Rheumatology, and Immunology at Boston Children's Hospital in Boston, Massachusetts.
Thank you for joining us today Dr Phipatanakul. Can you please give us an overview of this study?
Dr Wanda Phipatanakul: A lot of my work in the lab is related towards understanding certain phenotypes and endotypes and how they may have their trajectory for predicting response to different types of therapies based on many different characteristics.
We look at cohorts of children and adults and get potential biomarkers, we characterize them by their phenotypes, looking at whether they have certain characteristics; race, ethnicity.
Whether their body mass index is a certain level, how they breathe, how their lung function test goes. That's some of their phenotypes, which is a picture of what they look like.
Then there, we also look at endotypes. We're starting to look at some of certain genotypes and things like that, that might predict how somebody may respond to certain types of therapies based on that genotype.
In the lab, we found that there's certain individuals that have a genotype or mutant allele in the IL‑4 receptor, which seems to be much more associated with significantly bad asthma. This genotype or mutant allele seems to be much more common in minority populations.
For instance, blacks and Hispanics tend to have this more commonly. It is seen in whites as well. Those who have this genotype, their asthma is worse.
There seems to be this dose‑response relationship with more inflammation, inflammatory markers, and they seem to have a mixed TH17 response as opposed to an allergic‑type 2 response. It's kind of a novel type of pathway that seems to explain why these patients seem to have more significant asthma. That was published in a couple of journals. Relatively recently, we had a paper "Nature Medicine" that described this genotype.
Then in "Nature Immunology" we also found that patients with these genotypes seems to have more markers on the Notch4 T regulatory cells that also seems to be licensed to more inflammation in asthma. That's what some of the research is.
We also look at the standard biomarkers that people have. They are not great biomarkers that are readily available, but looking to see whether they are allergic, whether they are IgE levels elevated, whether they have high eosinophils and things like that.
That might get us into the second question of what types of biomarkers distinguish allergic asthma and so we look at that as well.
Jessica: Absolutely. Let's delve a little bit deeper into that if you don't mind explaining a little bit more. What biomarkers distinguish patients with allergic asthma?
Dr Phipatanakul: Allergic asthma is one phenotype that's really...We call more this type 2 inflammatory asthma. They seem to be triggered by allergens. It tends to have patients who have a high IgE or lots of allergens specific IgE which is in biomarker than then help distinguish that these patients are type 2.
Also, patients who have elevated FeNO or fractional screening nitric oxide also tend to be more allergic if the levels are greater than 20, 25 or 30. Those tend to be in that phenotype. Then patients who have high eosinophil count which is obtained by cell blood count, CBC with differential, they may have lots of eosinophils.
They tend to also be allergic as well. IgE, FeNO and eosinophils seem to be these biomarkers. Then, we're trying to understand a little bit more through some of our studies that there are even other genotypes that can help predict response, but they are not ones that are readily available.
One of the studies that we are looking at is building from what these research showed where they have the phenotype that's more common in the minority populations and then we are trying to treat them in a genotype‑stratified approach to see if they would respond more favorable to a medication that works on that IL‑4 receptor.
The study is called the IDEA Study. You can do, ideaasthma.org and it talks a little bit about the study. It's NIH funded. We're recruiting patients and genotyping them upfront and then treating them with Dupilumab which locks an IL‑4.
Receptor works on that pathway to see if patients with this genotype respond more favorable to a biology that works directly on that phenotype.
Jessica: I know you mentioned some of these already, but let's get a little bit deeper into it. What are the allergic endotypes of asthma?
Dr Phipatanakul: I had mentioned this type 2 inflammatory cells, cytokines, such as IL‑4, IL‑13, and IL‑5 are important. There's other ones as well. The eosinophil is elevated and IL‑5 seems to rev up the eosinophils. There are immune‑based therapies that block these cytokines. Some of them block the receptors, so that it blocks the production of eosinophil counts.
That's something that we see in allergic asthma. That's why there are therapies now. There are now five FDA‑approved biologics that work on reducing type 2 or allergic type of asthma. There are three that work on IL‑5. They blocked, two of them block IL‑5, one blocks the IL‑5 receptor and in turn, that reduces the eosinophil count.
Then there is immune‑based therapy that blocks IgE, which is one and that IGE is also important in allergic asthma as well. Then that other biologic that blocks both IL‑4 and IL‑13, works on the IL‑4 receptor. Those are some of the endotypes in allergic asthma. By phenotypically, you'll see these are patients who tend to have type 2 inflammation.
They have allergic triggers. They respond to type 2 medications with based on their phenotype. There is also non‑allergic asthma to not forget about as well. Until recently, there have been no immune‑based therapies that work on the non type 2, which is more...
It can be pollutants and other types of exposures that might trigger these tend to be or maybe those with a high BMI or body mass index or obese.
There is now a new anti‑TSLP biologic that has just been approved for adults that actually works on the non type 2 asthma, as well as type 2. That is one of the first work on the non‑type 2. I'm using the word type 2, type 2 mean goes along with allergic, non‑type 2 is non‑allergic as well. I talked a little bit about the endotypes, and then I spilled into a bit about the phenotypes as well.
Jessica: Is there anything else you'd like to add about the allergic phenotypes of asthma or do you think you've covered it?
Dr Phipatanakul: In children, most of the children are this allergic phenotype, while an adult there is maybe 50‑50. There's a significant portion that's not allergic. There's a lot of adults that until recently didn't even have any good therapies. That work on the non‑allergic type of asthma and corticosteroids and the five biologics, I mentioned.
There's omalizumab that blocks that works on IgE. There is reslizumab, benro and mepolizumab. They work on the IL‑5 cytokine, and that reduces eosinophils. Then there is benralizumab, which works on IL‑5 receptor and by doing that it reduces eosinophils and reduces the allergic phenotype.
Then dupilomab, which is one of the studies I mentioned before, is working on the IL‑4 receptor and blocks IL‑4and IL‑13. Those are all important in that type two inflammatory pathway.
They tend to work better in patients who seem to be allergic and have allergic triggers and things like that. I'm also doing some work looking at IgE in young children. Treating them with anti‑IgE in little kids to see if we can prevent this allergic asthma march by modifying the progression of the disease. That's called the Park Study.
That's parkstudy.org, has a video and has information on it as well. That is what I would say the phenotypes I view is the picture, or how you see the patient. The endotypes are biomarkers and things that you can get through blood or sampling sputum and things like that. That talk about some of the characteristics involved in allergic asthma.
Jessica: To sum it up, really how should patients with allergic asthma be managed?
Dr Phipatanakul: The first thing is to identify what are some allergic triggers. That is often helpful by going to see an allergist and getting allergy skin tested, or getting IgE and looking to see whether they have allergen specific IgE to certain types of allergens.
Then working with someone to work with their environment and reduce some of the exposures to things that are triggering these allergic responses. Then, of course the mainstay is inhaled corticosteroids that blocks a lot of the pathways of allergic asthma. Sometimes patients are treated with oral corticosteroids, when they have exacerbations and things like that.
Maybe with just inhaled corticosteroids that's all they need, if their asthma is relatively mild or doesn't need a lot of other therapies.
They also often now the guidelines recommend these inhaled corticosteroids and a long‑acting Beta agonist, which comes in a combination therapy and sometimes, we use them when they have an exacerbation.
There are other therapies as well, some of the leukotriene modifiers that work as well on type 2 allergic asthma, montelukast and zafirlucast, Zileuton or some oral medications that are used.
Then those who significantly still have trouble after you've worked on the environment and you've given them inhaled corticosteroids. They may be the ones that are eligible for some of these immune‑based therapies that I mentioned.
Those that work on the type 2 inflammatory endotypes and biologics such as the anti‑IgE, or omalizumab, benralizumab, reslizumab, and mepolizumab which work on IL‑5, and then dupilimab which works on IL‑4 and IL‑13.
Those are the five biologics that are for allergic asthma. Now we have the anti‑TSLP or tezepelumab, it just came out, and that might help also the non‑type 2 asthma. That's what I would say in a stepwise approach, working globally with the patient.
The other thing to think about as well is to make sure that they know how to use the medications properly, adherence and proper use of the inhalers is also super important as well. If they aren't adherent, trying to understand why and a shared decision‑making model. Why do you not want to use the merit medications that are being prescribed by your physician.
That's also important in the landscape as well as to look at adherence and knowledge on how they know, if they know how to use the medication properly as part of the management.
Jessica: It sounds like there would be some challenges as well. What are some other challenges associated with treating patients with allergic asthma?
Dr Phipatanakul: Sometimes despite trying all therapies available, their asthma is still not well controlled. Then there are some interest in thinking about other novel therapies. I'm also part of the PrecISE Network, which is an NHLBI initiative where we're looking at precision‑based biomarker driven therapy, looking at novel therapies that haven't been used in asthma before.
That is some of the challenges that despite...We've got five biologics. We've got inhaled corticosteroids. We have all these different medications. Some of them are not triple therapies, where you have an inhaled costeroid, a long‑acting Beta agonist, and a long‑acting muscarinic antagonists. All in one inhaler, and their asthma is still not controlled and they tried biologics.
We're looking at some other novel therapies. In the PrecISE Network, some of them that we're looking at in the teens. We're looking at an oil like an MCT oil, which is a nutritional supplement that might induce ketogenesis that might help with as bad asthma. There's a medication we're trying called Bronco‑vaxom, which is a kill bacteria lysate that we're trying to see as a novel therapy for asthma.
In the adults, the one I'm really interested in is the anti‑IL‑6 tocilizumab. Because of that is being used...It's used in rheumatologic disorders. There's a lot of evidence on some of the work I mentioned before that IL‑6 is really critical in this Notch four pathway and all this inflammation in type 17. That's a biologic.
We're also looking at imatinib, which is a c‑kit inhibitor used in cancer and something called [inaudible 13:32] , which is used with mucus in cystic fibrosis. There was discussion on looking at JAK inhibitors as well, but I don't think we're looking at that right away.
We're doing this adaptive trial where you take a biomarker and take patients and try them on different therapies, and adapt to what they respond into and a precision‑based approach. That network is on preciseasthma.org. That's also another type of thing.
That's what is something with the challenges that despite all the therapies out there, we still have patients who are still suffering and in difficult to control asthma.
Jessica: What would you say are the overall take‑home messages from your study?
Dr Phipatanakul: I would say I mentioned the body of work when it comes to endotypes and phenotypes of asthma. That right now, we've come a long way in our understanding of asthma. We've understood the basic pathophysiology of asthma and certain phenotypes and endotypes that point to certain types of asthma.
We have figured out certain endotypes and biomarkers that are predictive really bad asthma and then developed therapies to act on those as well. Besides nonspecific with corticosteroids, we also have immune‑based biologics that really act on these bio to reduce biomarkers that are associated with significant disease.
There's some more in the pipeline that we're looking at as well. As we further our understanding of why patients have significant asthma, then we'll be able to better care for our patients. The landscape of position‑based therapy is really here.
We're trying to have personalized therapy where a patient comes into clinic and you see that potentially they have a certain phenotype or characteristic or endotype. That may point to a certain therapy that may work better for that patient. Because that's one of the challenge.
It's not like a one size fits all. It's not that the same therapy can be used for everyone and everyone get the same response. That was in the old days.
We just had a few therapies, and everybody with asthma just got put into the bucket of asthma. They all got treated the same way, though. We're now in more of a personalized approach. We're making a lot of headway in that area. That's what I would say is the overall messages on this body of work when it comes to endotypes and phenotypes of asthma.
Jessica: Thank you so much for joining us on the podcast. Is there anything else you'd like to add?
Dr Phipatanakul: No, thanks for your time. I hope that if you have any questions, just reach out.
Jessica: We'll do. Thank you again and thanks for all your work on this.