This webinar was recorded on April 16, 2024

Type 2 inflammation is a systemic allergic response that is known to play a role in moderate-to-severe asthma, atopic dermatitis, and nasal allergies. In this webinar, learn what Type 2 inflammation is, how it affects certain conditions and how it is treated.

Speaker:

  • Warner Carr, MD, FACAAI, FAAAAI, FACP

Dr. Carr is board-certified in Allergy and Clinical Immunology as well as Internal Medicine.  He has a busy clinical practice at Allergy & Asthma Associates of Southern California and has been the Principal Investigator for numerous clinical trials. He has served on several boards, including the American College of Allergy Asthma and Immunology (ACAAI), a national organization for over 6,000 allergists.  He served 17 years in the United States Army and has served as a Medical Officer at the Food and Drug Administration.  Dr. Carr has authored several scientific articles and a book on lung function testing.  Dr. Carr has been invited to present scientific lectures around the world.

CE is not available for this webinar.


Special thanks to Sanofi/Regeneron who has provided funding support to make this webinar possible.

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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.

Lynda Mitchell:  Why don’t we get started. Thank you for joining us today, welcome to this afternoon’s webinar, we are in for a very interesting session. We have a few housekeeping items to go over. All participants will be on mute, we will be recording it. You can find all of our recorded webinars on the website. This webinar will be one hour in length. We will take questions after the presentation is finished. We will be monitoring the chat so if you have questions, we will go over them. We will not be offering continuing education credits, but we do have a certificate of attendance. A few days later we will have an email with a list of resources and a link to download the session. We were also tried to link a certificate in the chat. Let’s get started.

Today’s topic is the role of Type 2 Inflammation in Asthma, Allergy and Immunologic Diseases. Type 2 inflammation is a systemic allergic response that is known to play a role in moderate-to-severe asthma, atopic dermatitis, and nasal allergies. In this webinar, learn what Type 2 inflammation is, how it affects certain conditions and how it is treated.

It is my pleasure to introduce our speaker, Dr. Warner Carr. Dr. Carr is board-certified in Allergy and Clinical Immunology as well as Internal Medicine.  He has a busy clinical practice at Allergy & Asthma Associates of Southern California and has been the Principal Investigator for numerous clinical trials. He has served on several boards, including the American College of Allergy Asthma and Immunology (ACAAI), a national organization for over 6,000 allergists.  He served 17 years in the United States Army and has served as a Medical Officer at the Food and Drug Administration.  Dr. Carr has authored several scientific articles and a book on lung function testing.  Dr. Carr has been invited to give scientific lectures around the world.

Special thanks to Sanofi/Regeneron who has provided funding support to make this webinar possible today.

Thank you for being here today, Dr. Carr. I’ll turn it over to you.

Dr. Warner Carr: Thank you so much. It really is my pleasure. While you were speaking, I brought up the mission statement. This organization and the tireless work you will have done to advocate for our patients is very important and I want to recognize that. Today, I’m giving a talk on type two inflammation. I gave this talk at the College meeting, and for those of you who were not able to make it, hopefully I can share some valuable information with you. If you were there, this would be a good refresher. I want to extend thanks and gratitude for our sponsors in helping advance diseases.

These are my learning objectives. The epithelium can serve as a barrier. We’re going to talk more about allergic inflammation. How neuro-immune dysregulation plays in amplifying and perpetuating diseases, we are going to discuss the contributions of asthma, historically AERD, atopic dermatitis. Finally we will discuss the frequency of how these things coexist. These are systemic issues, and we treat patients that have more than one simultaneously. Type two inflammation may involve an interplay between triggers, the epithelium, innate immune components. You see in the diagram that historically people ask if it is nature or nurture. The answer is, yes. It’s both. How genes interact with environmental factors are the key components that play into the development of type two inflammation. Type two inflammation is classic allergic inflammation with typical mast cell D granulation. See the barrier dysfunction whether it is in the nose or lungs and this can lead to irreversible tissue damage. As part of this, separate and distinct. One of the key white blood cells activates and is produced in the bone marrow and becomes active and survives there. Then, there is a neuro-immune dysfunction. Itching is a great example. This is a non-histamine driven itch with sensory nerve fibers.

These are some key components of type two inflammation. Unfortunately, the slide got cut off but the point is type two inflammation is systemic. It can drive multiple things simultaneously. In other words, many of these coexist. You can have a patient with all of these conditions or it’s one or many of them. What this is showing is a grid of how frequently these coexist, but the key factor is type two inflammation. The systemic component as well as the local component. You see the primary diagnosis and how frequently it coexists with secondary diagnosis. Long-term effects not only affect immune cells but structural as well. They contribute to the tissue remodeling.

If you are looking at tissue remodeling, you see it in asthma patients. See it in the nasal passageway. See it in the skin and then in the esophagus you see structural changes. So, it’s not just immune cells, it is structural as well. You can see the epithelial morphology barrier is disrupted. In the skin there are junctions that hold skin cells together, and one of the key proteins is called filaggrin. We know these mutations increase the permeability. That can play into irritants and dryness, then you get the synthesis of the major proteins which ultimately lead to tissue remodeling. When this happens at the level of the epithelium, it sends a signal downstream. Everything that’s underneath, there is a problem. There are three alarm ends. TSLP, this barrier gets disrupted and sends an alarm downstream and that triggers the inflammation. That causes progressive inflammation. I’m going to go over the cytokines. I just mentioned a couple of them. What I’m going to do is downstream and you get generation, there are some signatures that are part of this cascade. What we know is when these levels go high, you get a decrease in the integrity of those junctions between cells. With this, you see more permeability.

A clinical application would be in babies with eczema. We think kids can get a food allergy through the eczema skin and it creates an avenue for halogens to get into the cells. On the left side, we are looking at a lower airway biopsy and you can see the disruption. You can see the control on top is intact and down on the bottom, so you have lost that. We can inhale these things and it’s easier to get into the respiratory epithelium, activate the alarm ends and then he keeps going on. Look up in the upper airway and see the effects where you are getting this disruption and then again it needs back and starts the cycle. When this feeds back, it can cause fibrosis or thickening. It also drives inflammation through the induction of nitric oxide.

There is a test we do that goes up because of the effect of IL-13. Again, damage, inflammation. On the left see at the bottom a lot of scar tissue. They will lay down in the airway and that will cause thickening. On the right side of the screen you see the same process going on in the esophagus. This is in a mouse model. Essentially the same process would go on in humans. One of the key cytokines in inflammation.

Tissue remodeling is important. What I want you to look at is the right side of the slide. You will see at the very top, someone who does not have eczema. This is a person who does not have eczema. You see normal characteristics. The middle image is a patient that has eczema but where they did the biopsy, there is no rash. Then at the bottom see the biopsy of the rash and eczema patient. What I want you to notice is even in non-rash skin, you will see disruption of the epithelium and all of the tissue remodeling that is occurring downstream. So downstream inflammation is very important that we understand that. If you look at the left side of the panel, you will see what is driving it. You will see the classic lesions. Interleukin four. Interleukin 13.

Type two inflammation and asthma. I think we should break it down and talk about some disease states and how it applies specifically to each one of these. The type to profile includes allergic and eosinophilic. You can be eosinophilic with no allergy, but you can also have both. When you look at the immune pathways, you see high expression. The tissue remodeling. Patients that are more allergic tend to have early-onset. It’s more allergen specific. They can have a lot more comorbidities with things like eczema and allergic rhinitis. It’s affecting the upper respiratory. This is more in adulthood, it’s usually nonspecific. We see a little more on those that are purely driven but realize the allergic and eosinophilic can occur in the same patient. Interleukin four and interleukin 13 drive that production. To some degree IL-5 is a key that is causing differentiation in bone marrow. Driving that out and into the target tissue promotes survival. When you look at allergic inflammation. When you’re allergic to, that mass-based cell and releases all of those chemicals. That causes the symptoms downstream. Again, it’s primarily driven by differentiation of the survival once he gets into the target tissue. Eosinophils perpetuates and provides. You can see how they are two separate things that interact. You can be allergic or both can happen. Type two inflammation is reflected and defined by different types of biomarkers.

On the left is called the fractional nitric oxide. It’s a biomarker of inflammation in the airway area people who are allergic tend to have more. Serum IgE is another biomarker. These three things plus the asthma control test is what I like to call the asthma vital sign. I get these in every one of my patients and helps me direct my therapy. These are key markers.

When you look at the guidelines, there are a couple we use. The American driven guidelines and the Global Initiative for Asthma. When you look at the GINA guidelines, we should be thinking about this. Type two should be considered or I should say recurring doses. If it’s greater than 150, if you have induced sputum, if you have a nitric oxide of 20 or greater or out, that is driven by allergies, and the patient requires maintenance for frequent steroids may have underlying type 2 inflammation.

Low-dose cumulative exposure of steroids, we know there are problems. You get significant adverse effects. I saw patients all morning and we tried to talk about how to use therapies to decrease exasperation and we are decreasing the need for the steroids. Patients will ask me about steroids. I will say you had three rounds of oral steroids. That is a big footprint of steroids. By using the inhaler, you can have much less exposure to steroids. We know cumulatively you’re seeing increased risks of metabolic disturbances as well as cardiovascular disease. Even with these bursts we see, it can be a patient to has had a couple of doses per year. We need to be better with the steroid stewardship.

Type two inflammation can really self-perpetuate the cycle of exacerbation, more information, and this is exemplified by this diagram when we are talking about corticosteroids and hospital care. We really need to attack the source of the inflammation. If you look at the right side, changes in airflow and you look at patients that have a correlation with the rate of a severe exacerbation, in the light blue, you will see the more exacerbation they are having, the more remodeling they are having and more impairment they have in the lung function. It is important for us to identify the target this inflammation.

We know that if you can improve the lung function, it decreases the need for steroids, we can have better steroid stewardship, but it also correlates with improved health. I don’t think I ever had a patient who asked if I could increase that area they say, can you make me feel better. When a patient says I feel sick, I asked him if we could explain it. It’s very important that we don’t forget this. This is critical in our patients. There is a correlation between lung function symptoms and quality of life issues, and they all overlap.

Now, let’s talk about the upper airway. There is a united airway hypothesis that I subscribe to. How many times have you been sick in the upper airway and it settles into the chest. We know that there is a correlation between the upper and lower airway. When you look at the pathophysiological evidence that supports this united airway, we can look at inflammatory responses and it makes sense. We see the coexistence of all of these diseases. Neither with or without the polyps. Asthma, Aspirin Exacerbated Respiratory Disease. I think there should be a tiny overlap because there are patients that have comorbid diseases. When you look at patients that get their care primarily from ENT, you are seeing a need for repeated surgery, especially with nasal polyps process. You will see an increase in coexisting diseases.

You will see it with or without asthma and how it correlates to more surgery, you see it in patients with Aspirin Exacerbated Respiratory Disease. I almost look at that as a separate syndrome. Especially when I have asthma. In the old days, we called it Samter’s Triad. Those patients have a higher coexistence of type two disease. With these patients, you see these comorbidities. When you see that, they are more likely to have oral steroid use. I don’t know how many times I’ve had patients who told me they got oral steroids, went to the ENT and had multiple courses of oral steroids. We have to think about the risk of long-term steroid use or even systemic use.

A special thing we need to consider is the aggregates. Remember what I talked about nasal polyps are little bags of aggregates. These are associated with recurrent when they are sensitive to prednisone so what ends up happening is the doctors noticed the patient gets better, but it is short-term. Ultimately this type of patient ends up having more surgery. In the big scheme of things, all you do is this cycle of prednisone and surgery. You see an 85% recurrence rate. We need to be better at controlling type two inflammation versus constantly dealing with the consequences.

That is the key thing for us to think about. I’m going to focus on this slide. These two are driving this inflammation. You start seeing a thickening and then at some point a section just pops up and now you have the polyp. You see activity, cross-linking. We call it a matrix. You get this driven by type two cytokines. When you are looking at fibrin degradation, that is what helps this. When it is degraded, you have less protection in these patients, and the higher, the more you see that. In your mind’s eye, you can see it. IL-4, IL-13, then it just perpetuates. Then they do surgery, and it starts all over. We need to be better at targeting type two inflammation.

Let’s move onto another syndrome, NSAID-ERD. This can be with more than just aspirin. This is characterized by comorbid asthma. It’s almost a subset of disease. When you look at hypersensitivity, these patients where you can give it to, that’s nonspecific. There is a prevalence in about 9% of these patients, and if you throw in asthma goes up to 30%. You can’t just give them the inhibitor drugs. This is probably underdiagnosed in the U.S.. It’s probably not recognized. This subgroup of patients contributes a lot to the cost of health care as well as quality of life is significantly impaired. There is a lot higher morbidity. More frequent exacerbations which tend to be more severe. They end up in the emergency room more often. They end up being hospitalized more often, they end up in the intensive care unit more often, and integrated care more often. Those patients tend to have a higher death rate. Worsening lung function compared to just aspirin intolerance. We can desensitize some of these patients but it is complex and it needs to be done with a specialist who understands how to do it. It’s often associated with higher revision surgery.

Now let’s move from the airway to the skin. Atopic dermatitis is characterized by the same general process. We see a lot of epidermal abnormalities. Six times the number of T cells. They are the ones telling them what to do. 86% increase of non-lesion on skin you see it increase, a significant decrease in barrier proteins. It’s defective in the barrier function as well as proteins. Big problem with sleep disturbance. This is an interesting survey. This itch is a big problem. 91% experience daily itching. You will see it in babies sometimes. Non-has many contributions and you will see this on the left. Stimulation. You get a decrease, so you have lots of the barrier, you have more itching, and this starts the type to include mandatory process and that it involves multiple self types. Then you have interleukin, lymphoid cells and you see activated cells and issues with the cells themselves.

Eosinophilic esophagitis is a chronic disease driven by type two inflammation. We see this allergic sensitization which tend to be in young ones, there tends to be more food allergy. And older populations, there tends to be more environmental. We always check for food allergy and environmental allergy and retreat it when we see it. Obviously, it’s in the name. Becomes activated and increases secretion of some of the chemicals. On the right side of the panel, we are reinforcing the point. When you look at the number of patients asthma, allergic rhinitis. Even food allergy. Especially in the younger age groups. This is a systemic process we are seeing. Tissue remodeling and fibrosis really is a hallmark feature. Some of the inflammation is in the name. They will do a biopsy and sometimes you see the micro abscess. You will see disruption and see it, grading with a significant thickening of that laser thatch layer. Again, immune cells and non-immune cells just like we see in the lungs and skin all being activated. This is all driven let’s talk a little bit we think about it more driven by neutrophils.

If you look when you look at COPD patients, you see the exacerbation. The higher the exacerbation rate. The risk for severe exacerbation goes up and you see that on the right panel. Looking at the phenotype can help. Those are the ones that are a higher risk for exacerbating. You treat them a little bit differently then you would with no signs of type two inflammation. Even in COPD. Now, it makes sense that you are more likely to exacerbate. Patients with type two inflammation with more exacerbations will see more utilization of health care and a shorter time until the exacerbation. So sooner, more frequently. There is a distinct subset. When they get hospitalized, compounds the risk in these patients and adds to the cost. Elevated, more exacerbation, more frequently, they end up getting hospitalized more, higher utilization, not only focusing in normal respiratory self, these are much rarer, under IL-13 you get much more shift to the mucus secreting cell. There is a shift of the stem cell like cells in that layer. They then grow into a mucus cell , this is through an expression. Messager RNA, more mucus secretion. When you look at this in a mouse model, a kind of mirrors it. We see overexpression and you see much higher mucus production in this animal model.

This was my learning objective today. Transitioning to disease states and how important it is to have early identification. We have a few minutes left and I would like to open it up for any questions we may have.

Lynda: Thank you. Really wonderful presentation. It’s a complex topic, that usually means we don’t get as much questions as usual. This is just a comment. You said in the old days today that AERD has changed to NSAID-ERD. When did that change?

Dr. Carr: We changed the terminology several years ago. It is essentially the same thing. First we call it a try, then we realize it can occur with ibuprofen. It’s all the same disease with different nomenclature. I appreciate you asked writing that. Regarding that. Is it something else going on mostly related to asthma. When patients have the triad of having hypersensitivity to aspirin and they have a really robust airway inflammation. And that manifests in sinuses via polyps, the same process goes on in the lungs. Kind of like at the end of the spectrum. If you can imagine type two inflammation like a forest fire, this forest fire is raging. Just a little extra fuel sets these people off. They tend to and they have to rapidly compensate. It’s because of how severe the airway disease is.

Lynda: The next question is not really about type two. If the patient has allergies, is a beneficial to treat with allergen immunotherapy or is there another way?

Dr. Carr: I will answer the specific question. The answer is yes. You may say how does it help? When you have environmental allergies and the pollen counts are high, what happens is start getting priming. You become more sensitive but you are getting more. You were getting worse. When you are primed, the bucket is full. When you get your exposure, your reaction is worse. If you can get immunotherapy, you remove that to extrapolate on the question with cases which you can only do his desensitized the people. Doing that really significantly decreases the risk in these patients.

Lynda: Back to asthma. Can people help get their airways back to where they should be?

Dr. Carr: I wish I could give you my business card. Yes. That is what we do. We are experts in type two inflammation. It just depends. In this case, the question was asthma. There is much better therapy today than 30 years ago. I am not sure who asked the question. My recommendation would be to find a board-certified allergist in your community and that is who you should be seeing. We can help you. You can see a registry and look up a local allergist and only people who are board-certified are on the registry.

Lynda: This is a question about oral steroids. Before you were talking about the long-term side effects. Can you comment on that?

Dr. Warner Carr: The answer is yes. Let me explain myself. The biological equivalent is about prednisone. Not only have you shut down you increase cataract, glaucoma, diabetes, heart attack, stroke, even small amounts over a long period of time. If you do the math, if you are just generally speaking, if you do it every day, it will take three to five years of a daily dose of an asthma inhaler to equal one five day course of prednisone. We always want to use and health therapy. Topical, targeted Darby and look for alternatives. Hopefully that answers the question.

Today — there is a very good study that I have been a part of called Chronicle and the study is sponsored by a pharmaceutical study that is looking at severe asthma patients in different therapies they have been on. As part of the study will look for who they are seeing. You can look it up and see the publications. Pulmonologist. Allergist. Even primary care. It’s regional, you will see it in your communities and the use of steroids is regional. To answer the questions in my community most that most of the day refer to me that there are a lot of communities where they do it all on their own or where the allergist refers to the pulmonologist, and there are a lot of systems where they are working together.

Lynda: Thank you. That is going to be the last question we have for today. I want to thank you so much for making this complicated topic easy to understand. I want to thank you for being here. We have several webinars coming up. First is food allergy and individualized management. I hope you join us for that. Then, we have another one in our expert with a topic dermatitis to talk about the complex relationship between atopic dermatitis and allergies. You will receive any mail with a link to this recording as well as additional resources. With that, thank you very much for all of you who have remained until the end. I learned a lot. With that, have a good night, take care, and we will see you next time. Goodbye.