Improving Outcomes of Severe Adult Asthma
In this episode, Dr Rizzo interviews Sally E. Wenzel, MD, to discuss her review titled “Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics,” examining comorbidities (including those that could mimic severe asthma) pulmonary function testing, and biomarker assessments.
- Wenzel SE. Severe adult asthmas: integrating clinical features, biology, and therapeutics to improve outcomes. Am J Respir Crit Care Med. 2021;203(7):809-821. doi:10.1164/rccm.202009-3631CI
- Nagasaki T, Schuyler AJ, Zhao J, et al. 15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation. J Clin Invest. 2022;132(1):e151685. doi:10.1172/JCI151685
- Zhao J, Dar HH, Deng Y, et al. PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells. Proc Natl Acad Sci U S A. 2020 Jun;117(25):14376-14385. doi:10.1073/pnas.1921618117
Sally E. Wenzel, MD, is a professor of medicine and immunology and acting director of the University of Pittsburgh Asthma and Environmental Lung Health Institute@UPMC.
Albert A. Rizzo, MD, is the chief medical officer of the American Lung Association and a member of ChristianaCare Pulmonary Associates in Newark, Delaware.
Moderator: Hello, and welcome to Critical Observations in Pulmonary Medicine, led by Chief Medical Officer of the American Lung Association, Dr Albert Rizzo, the views of the speakers are their own and do not reflect the views of their respective institutions.
Dr Albert Rizzo: Thank you for listening today, and welcome to this next episode of Critical Observations in Pulmonary Medicine. I am fortunate today to speak with Dr Sally Wenzel, who practices pulmonary allergy and critical care medicine. She is a professor of medicine in immunology and the Rachel Carson Chair in Environmental Health, as well as the chair in the Department of Environmental and Occupational Health. And she is also the acting director at the University of Pittsburgh Asthma and Environmental Lung Health Institute at UPMC.
So thank you for taking the time today to speak about an important topic, severe asthma, that by many estimates could include up to 5 to 10% of the patients with asthma. You have published extensively on this topic, and I would refer our listeners to your concise clinical review of this topic that was published in the American Journal of Respiratory and Critical Care Medicine back in April of 2021. To start off, would you please define what severe asthma should mean to a clinician?
Dr Sally Wenzel: Well, severe asthma is something that actually should probably concern a clinician. The first time they see a patient, these remain difficult to manage patients and very complex patients. And I think it's very important to go through multiple different steps to try to understand these folks who come in with an ostensible diagnosis of severe asthma. And so the first step is that you have to make sure that the patient has asthma. That sounds like such a simple thing, but it's really not. Patients can develop asthma anytime in their life. The concept that all asthma is a pediatric disease and just migrates into childhood, of course, is, is not correct. And there are people that can develop asthma after a respiratory infection. There are people that can develop asthma after a job change that they're exposed to various occupational threats. And, and of course, just for no reason at all, at least that we can identify.
And, and these are patients who, when you see them, it's really critical to do very well performed spirometry both before and after a bronchodilator. Asthma is still defined as reversible airflow limitation. Now that doesn't mean reversing back to normal. That's a common misperception, but they really need to have some element of reversibility of at least 12% or 200 MLS, or they cannot have a diagnosis of asthma. Now you can do it several times, but you still need to need to confirm at some point that they have a reversible component to the airway. And why is that important? That's really important because it helps to identify which treatments are appropriate for given patients. If a patient has truly has COPD, non-reversible, generally nonreversible airflow limitation, the responses to treatment are going to be very different than what might one might see in, in an asthmatic condition.
And then of course there are other things like bronchitis, even bronchiectasis that often masquerades as asthma, but really are not. And then of course, you've got vocal cord dysfunction on the other end, where you really have almost completely normal spirometry for the most part, but evidence of upper airway obstruction. So, all of those things can sometimes be labeled as severe asthma, but they're really not even asthma. So, let's get that first step out of the way and make sure that they have asthma. And then I think once you have determined that they have asthma, one has to identify whether this is really asthma, that if you, you address a few of the comorbid conditions that I know, we'll probably talk about later if you address things like current smoking if you address things like reflux disease if you address things like nasal congestion and postnasal drip that their asthma will in fact be manageable.
And certainly, I think that's the first piece of this. So to address those and then to if you've addressed those and the patient is still having symptoms, make sure that you're optimizing their asthma prescription medications. So again, are they on the the gold standard for the treatment of asthma, which is of course, high-dose inhaled corticosteroids in combination with a long-acting beta-agonist that is still the gold standard for the treatment of asthma and specifically severe asthma. And when you have a patient who you've addressed all those comorbid conditions, as best you can, you're convinced that they really have asthma, and when they are either still symptomatic on high dose, what we define is high-dose inhaled corticosteroids with a long-acting beta-agonist, or who really require that dose to maintain their asthma, then you have a patient who truly has severe asthma.
And that was the definition that was provided by the European Respiratory Society and the American Thoracic Society, now close to 10 years ago, actually, but I think is still pretty much the gold standard today. And, and again, it really does require a rather extensive evaluation to assess all of those things. And as part of that, we would even recommend that in these complex patients that they spend at least three months under the care of an asthma specialist, an allergist, a pulmonologist who can address all these things in, in detail before you actually give the person a diagnosis of severe asthma.
Dr Albert Rizzo: This is assuming that they're adherent to the regimen you want them to be on.
Dr Sally Wenzel: Absolutely.
Dr Albert Rizzo: And, and is that 5 to 10% of the asthmatics? Is that a good number to think?
Dr Sally Wenzel: I think it is a good number. I absolutely do think it's, it's a good number. You know, there have been some very rigorous studies that have been done in Europe that got to about 4%, but I think they actually probably eliminated some folks that they maybe should not have eliminated. So, I would say 5 to 10% is, is pretty close.
Dr Albert Rizzo: OK. Yeah. And you touched quite a bit on some of the, the comorbidities that I know many of these patients can have, and as you kind of mentioned, these comorbidities sometimes mimic asthma and you need to make sure you're not missing actually the underlying asthma when they have something else going on. I think you touched on that very nicely, and we know that the primary care physicians or the pediatricians are the ones who are frontline at this point and they have to be the ones then decide to move the patients on other than the spirometry that you mentioned, I think there are a number of other terms that are used looking at biomarkers, whether it's high-T2, low-T2, early-onset, late-onset, can you kind of break that down somewhat and tell us what biomarkers or other testing may be helpful to make some distinction among these patients?
Dr Sally Wenzel: Yeah, I think it's a very exciting time for asthma because we can start to think about asthma in the realm of precision medicine that we have directed treatments that will help certain people, and even non-specific treatments seem to help certain people better. And so, I think in 2022, any patient with asthma should be assessed at a minimum for whether they have a disease that is type 2 high, th2 high, or not. And the current gold standard for that is something that everyone, almost everyone, can measure in their clinical labs, whatever that supports them is just a complete blood count with a differential. It's one of the cheapest tests that you could even order today as a clinician. And so you want to look at the eosinophils, and for years, eosinophils have been completely ignored on a differential. It was like, well, you know, is there neutrophilia or not?
No, we're, we are really talking about are the eosinophils present? And in fact, are they elevated? And the threshold for what's high eosinophils has somewhat varied from study to study and, and the guidelines to guidelines, but in someone who's not on any inhaled corticosteroids, not on any systemic steroids like prednisone, then I think you would want to see the eosinophils be about 300 or above. Anything 300 or above is considered abnormally high eosinophils in an asthma population and qualifies them for a type 2 high asthma patient. And we say type 2 high, as opposed to th2 high, because other cells besides th2 cells can make these cytokines or these biochemicals that actually drive this type of inflammation that produces eosinophils, IL-4, 5, and 13. And those are important cytokines to actually remember because there are therapies targeted to them, but we now refer to it as type 2 high, as opposed to th2 high, because other cells can make them, besides th2 cells.
So in people that are on high doses of inhaled corticosteroids already, or even certainly people that are on prednisone on a daily basis, you cut that threshold a little bit lower, and it really goes more to around 150, but I think you still want to have at least 150 before you would call a person a truly a type 2 high asthmatic. There's a lot of overlap between eosinophilic asthma and type 2 high asthma. They're not completely the same thing. I think eosinophilic is a subset of type 2 high asthma that you can have people, because of their inhaled corticosteroids or their systemic corticosteroids, where you can't measure eosinophils in their blood. So you say, okay, they are eosinophil low, but if you look for other biomarkers of type-2 inflammation, you find that they're elevated. So eosinophilic high is a subset of type 2 high asthma.
And so that's the first thing that I think any clinician after you've seen a patient probably twice for asthma, I don't think you have to do it the first time you see an asthma patient, but once you've seen a patient because of follow up and maybe they're not doing quite as well as, as you would like a low dose inhaled corticosteroids, then I think it's time to get a CBC and just start phenotyping them, or assigning them to type 2 high or type-2 low asthma. And I think that we know that inhaled corticosteroids are again, gold standard for the treatment of all asthma patients for that matter, seem to work better in people that have evidence of type-2 inflammation. So, if you have elevated eosinophils in your blood, you're likely to respond to inhaled corticosteroids. If you have no eosinophils in your blood, and you've never been treated with corticosteroids before, chances are, you won't respond as well as if you had some measurable eosinophils in your blood. And that's, I think at the primary care level, that's really all you need to do to start characterizing the patients. I think once you get to the specialist level, then I think there are more things that should be done.
Dr Albert Rizzo: And where would the term allergic asthma come into play at this level?
Dr Sally Wenzel: Yeah, so again, that's a very excellent question. And it's another subset or umbrella under the big umbrella of type 2 high asthma for the most part. So allergic asthma is typically asthma that develops in childhood. It's typically associated with other allergic conditions like allergic rhinitis, hay fever, those sorts of things, sometimes with eczema. And it is typically associated with evidence for type-2 inflammation, so elevated blood eosinophils, but not always. There are people that have allergic asthma that you rarely see an eosinophil in the blood. And again, I think that's been a point of confusion for many people. It's, well, they're allergic, they must be type 2, but that doesn't always happen to be the case. And in fact, the drugs that we use to treat patients with this type 2 high asthma actually seem to work a little bit better in people with a disease that isn't necessarily characterized by allergic symptoms, and the less allergic asthma patients seem to do as well, if not better, than the allergic patients.
Dr Albert Rizzo: Before we talk about some of the other biomarkers, you mentioned spirometry being very important, obviously. What role at this point is the methacholine of the bronchoprovocation studies? Is that something that primary care physicians should be thinking about or is that really in the realm of the specialist?
Dr Sally Wenzel: Yeah, I would say that the methacholine challenges are generally going to be things that the specialist is going to use. I think a primary care physician can do repeated spirometry that I think is very easy. And one of the little tricks that I like to do is actually if a patient comes to me and they said “oh, you know, last week I was feeling terrible, and I got some prednisone from my brother or whatever, and now, you know, now I'm feeling good.” So, they come in with normal spirometry. I like to say, just, you know, let me know if you're having any increase in your symptoms. Give me a call, and then I'm going to order spirometry for you when you're having symptoms because spirometry is much more likely to be abnormal when someone's having symptoms and when they're not.
And you're much more likely to demonstrate that reversibility if a patient is having symptoms than when they're not, and most primary care offices can still call, you know, their local lab or whatever, and get a patient in within a window. And I don't know, everyone's very, every setting is different, obviously. And if it takes two weeks to get somebody spirometry, well, that may be too late, but certainly, I think that's a really nice way to demonstrate both obstruction and reversibility if you didn't demonstrate it when they first came into the office.
Dr Albert Rizzo: Very good. Talk about some of the other biologics. I know we have an older one that really dealt with the IgE antibody. And then as you mentioned, we have the, IL-4, IL-5 receptors. And now more recently, the thymic stromal lymphopoietin. Can you just kind of talk a little bit about the inflammatory cascade, where these biologics, where these cytokines and antibodies play a role and then how we get the targeted medications that help individuals?
Dr Sally Wenzel: Yeah. So again, all of this falls under the big umbrella as we've been talking about of type 2 high asthma. And type 2 high asthma seems to be associated with th2 cells, T-helper type-2 cells, and or some other cells, including maybe macrophages and monocytes that also seem to make these cytokines, as well as innate lymphoid cells, and maybe even mass cells. So, there's a range of different cell types that, under certain circumstances, may be related to allergies, may be related to viruses, may be related to family history, and environmental exposures that we don't even fully understand that causes cells to start making these cytokines, IL-4 and IL-13. And really, IL-4 is probably the first critical cytokine here, in that it's the one that actually develops th2 cells. And without IL-4, you can't have a th2cell.
So that starts the development of the th2cell. The th2 cells then make the cytokines, IL-4, IL-5, IL-13, these cytokines then can activate B cells. And by activating B cells, they make IgE, which is part of this cascade. IgE then combines to mass cells. Once it’s bound to mass cells, it serves as a receptor for various IgEs that are made to allergens– cats, dust, mites, cockroaches, etc., all those things– which the antibody binds to, and then binds to the mass cells on through the IgE receptor and activates the mass cell and that sort of the mass cell allergic cascade part of the paradigm. But then in addition, it's very complicated, these IL-4, certainly IL-5, and IL-13, we know can be made by these innate lymphoid cells.
So innate lymphoid cells are not th2 cells. They are a different type, what they call lineage negative lymphocytes, that make IL-5 and IL-13, maybe a little bit of IL-4, and they seem to be activated by viral-related pathways, maybe bacterial-related pathways, but they don't require T-helper cells to function. But once they start making IL-5 and IL-13, then you can start activating the same processes that you would if it was coming from a th2cell. It's just that it starts at a different level. And it, and at least there's some suggestion that it may start later in life and may be associated with people that have nasal polyposis as part of their asthma characteristics. They have nasal polyps as part of that. And the ILC-2 cells are also stimulated, of course, then by this new cytokine, this TSLP, thymic stromal lymphopoietin.
Dr Albert Rizzo: I had the same problem.
Dr Sally Wenzel: It’s a hard thing to say all at once but anyway, thymic stromal lymphopoietin, TSLP, that is felt to be generated primarily by epithelial cells and epithelial cells in response to virus. And so it may be that at some point in your life, you were exposed to a virus that caused your epithelium to produce this TSLP that then stimulated these innate lymphoid cells. And these innate lymphoid cells started making these cytokines that then drive an asthma reaction, with increases in mucus, with increases in these blood eosinophils, and another biomarker that we haven't talked about, which is of course, exhaled nitric oxide.
Dr Albert Rizzo: So, when you're presented with, or we have a patient with severe asthma who you now are starting to decide that a biologic may be for them, how do you start sorting out which the biologic is right for that particular patient?
Dr Sally Wenzel: Yeah. Again, this a is really an important question and one that there is not a black and white, yes and no answer on. And I think this is where it is important to have a specialist see a patient, because it's not an easy decision to make. I think the data would suggest that the anti-IL-5s and anti-IL-5 receptor antibodies, and there are three of them that are available in the US that those work better in people that don't have an allergic type of asthma. So, if you have someone who got their disease later in life, after the age of 18, maybe even 12 but later in life, specifically if they have nasal polyps, specifically if they have severe disease that requires corticosteroids, oral corticosteroids, prednisone a lot, those are the patients who seem to do pretty well with anti-IL-5, if you've had your disease your whole life.
And you're very allergic to, you know, the neighbor's cat, then anti-IL-5 is not likely the best treatment for you. And even the data in children is very limited with the anti-IL-5 and, of course, allergic asthma is typically the type of asthma that begins in childhood. So, if anti-IL-5 are only marginally effective in patients who are above the age of 12, and it’s Nucala, sorry, mepolizumab is approved for children, I believe above the age of 5 to 12, but it really was based, not on efficacy studies, it was based on safety studies. And so, it's really hard to know whether the anti-IL-5 in the younger allergic asthma population has any efficacy. So, if you get a whiff of allergies in the patients, I would consider another drug. And that's probably the first sort of cut point that I use.
If there are allergies, then I would consider an anti-IL-4 receptor antibody, especially if there's evidence of type-2 inflammation, especially if there's an elevated blood eosinophil count or an elevated exhaled nitric oxide, I would positively consider that before I would consider omalizumab. And the reason for that is even when you cut the data by the high type-2 biomarkers with omalizumab, the data on reduction in exacerbations and improvement in lung function is not as good as what you see with dupilumab with the IL-4 receptor antibody. So again, just based on published data, I would start with the IL-4 receptor antibody. Now, if you have somebody who has had asthma since their childhood, and they are allergic, but you can't find a type-2 biomarker anywhere, then I would probably start with omalizumab. I think that that's not an unreasonable choice at all.
And then finally, you know, the newest kid on the block is the anti-TSLP Tezepelumab, and I don't think we know really where that fits yet, to be quite honest with you. You know, the data in their oral corticosteroid sparing study was not as good as the data was for the anti-IL-5 or the anti-IL-5 receptor antibody or the anti-IL-4 receptor antibodies. And that would make me think that at least it's possible that if you have a very severe asthma patient, who's on a lot of oral steroids, anti-TSLP Tezepelumab may not be the first choice that you probably should go with an anti-IL-4 receptor antibody or an anti-IL-5. On the other hand, the data with the Tezepelumab would suggest that maybe it's also efficacious in people with very low levels of type-2 biomarkers. So maybe you can extend the biologics down a little bit lower with Tezepelumab than you can with the dupilumab or mepolizumab and benralizumab, and I think that's sort of the little niche where that might be the first drug that you would try in a patient with very difficult type of asthma. But again, with the caveat that being on prednisone right now, doesn't seem to make you have a better response. Unlike the IL-4 receptor antibodies and the anti-IL-5.
Dr Albert Rizzo: You mentioned the exhaled nitric oxide, and I don't think you specifically mentioned the IgE antibody level. Are those levels of those two biomarkers? Do they play a role in helping you decide which drug to use or not?
Dr Sally Wenzel: Certainly, exhaled nitric oxide does. I am a pretty strong proponent of exhaled nitric oxide. IgE doesn't seem to predict much of anything, although the companies that started to develop omalizumab thought that would be a good biomarker for them. It ended up not being a good biomarker for them. Now, I think it's helpful, can be helpful in more complicated patients to help me as an asthma specialist understand them. But I think routinely an IgE level by itself, doesn't do very much specific IgE testing. So again, IG-specific IgE to dust mites, to dogs, cats, etc., ragweed, that can be helpful, even from an avoidance perspective. If somebody finds out that indeed they're allergic to dogs and, you know, they're sleeping with their dog, well, that might be something to consider, maybe not sleeping with your dog. But beyond that, I don't think that it really predicts responses to biologics very well.
Exhale, nitric oxide is something that requires specific testing equipment for, but it's very simple equipment. And the cost probably to actually do the test is somewhere between $20 and $30. Now, obviously there are all sorts of other layers on hospitals and clinics, etc., that have to be paid for. But the actual price of doing the test is still quite reasonable. And it is a very nice biomarker measured in people's breath of enzyme that generates this nitric oxide that's produced by the airway epithelial cells. It's produced by the airway epithelial cells, primarily under the influence of IL-4 and IL-13, not IL-5. Only IL-4 and IL-13. And so, if you see elevated levels of this, you can pretty safely determine that there is IL-4 and IL-13 active in this person.
And, and it responds very nicely to treatment with dupilumab. So, it, if it's high, you treat with dupilumab, there's typically at least a 50% reduction in the exhaled nitric oxide. So again, you know you've hit your target when you're treating somebody with dupilumab. And the degree of drop actually correlates with the degree of improvement in lung function, the degree of improvement in FEV1. So, for those reasons, I actually think it's a pretty good biomarker. Some people would also suggest that it's a biomarker of adherence and that if you have somebody and you say you put them on inhaled corticosteroids… inhaled corticosteroids typically make the exhaled nitric oxide levels go down. In more severe patients, that's not always the case. But in your average asthma patient, when you put somebody on inhaled corticosteroids, that exhale nitric oxide should be reduced. And so, if you have that situation and you don't… and again, the patient is still symptomatic, and their exhale nitric oxide hasn't changed after you put them on inhaled corticosteroids, it’s worth of having a conversation with the patient regarding their adherence to therapy.
Dr Albert Rizzo: Aside from the science behind which drug should be used, I know in the real world we have to deal with a couple things, like making sure that coverage by insurance is available. And those biomarkers, you mentioned, certainly have to be ticked off to the right levels for that to happen. And then I also wonder, do you see much difference that the dosing schedules for these medications in-office vs at-home administration, does that help some of your patients decide which one they want to use or do you direct them more?
Dr Sally Wenzel: Yeah, they can certainly, if you're concerned that someone is going to have difficulty administering their medications, the home situation isn't ideal or whatever, then certainly the less frequent at-home dosing is probably the best way to go. I think most medications are now available as at-home dosing, including omalizumab, which for years you could not dose at home but now has become available. And so, there is a difference between having a medication that you dose every two weeks vs every two months there. There's no doubt about that, but to be quite honest with you, at least in the severe asthma patients that I take care of, their main concern is that they feel better. And if they feel better, they are willing to inject themselves every two weeks. And I almost never had anybody say “You know, that's too often.” If I could only be on an every two months drug, I would do this.
Dr Albert Rizzo: Just switching gears a little bit. You mentioned T2-low earlier. Do you see a role for bronchial thermoplasty in this population of T2-low? What been your experience with thermoplasty?
Dr Sally Wenzel: Yeah, that's a really good question. And I am certainly of the belief that if thermoplasty has any true indication, it would be in somebody who has type-2 low inflammation. And we haven't as a scientific community really sorted that out yet. I mean, there are some studies, none of which are placebo-controlled that really have suggested that “oh, maybe it's your T2 high people that actually respond better to thermoplasty.” And then, you know, even though it was set up initially as a way to ablate the smooth muscle in the airways, the data to actually support that is still pretty modest. And there are other data to suggest maybe it's a change in the epithelium. Well, if there's a change in the epithelium and the epithelium secretes all these things to drive mucus production and so on, then maybe it's a broader treatment than that.
I will say that the few people that I've had under my care are that have had bronchial thermoplasty, when it's successful… and it's successful a portion of the time, and I don't want to say because my sample size is too limited to actually speak to that, but people would say 50, 60% probably of people respond… is that it's not a long-term effect that after three to five years, there's evidence that the whatever effect was there in the first place has actually gone away. And I actually don't know of anyone who's doing repeat thermoplasty, not in my practice. I'm sure there are some somewhere that have done repeat thermoplasty, but I have not. And it would scare me a little bit because you are structurally changing the airways when you do this and to do this repeatedly over time, good safety data to support that, would certainly make me concerned. I think thermoplasty came on the market really before the, IL-4, IL-5, and IL-13 drugs came on. And, you know, at one point it was the only other option that we had besides omalizumab and oral corticosteroids. And I think now there are so many other options on the market that seem to work really, pretty well in many people that I think thermoplasty is used less now than it was in the past.
Dr Albert Rizzo: Where do you see the future development of drugs, for least severe asthmatics heading? Are we going to see more biologics or what do you think at this point in time based on your experience?
Dr Sally Wenzel: Yeah, again, really good question. I think the biologics, the combinations of IL-4 receptor antibodies in the anti-IL-5s have probably done a good to a great job of treating somewhere between 50 and 70% of the severe asthma population. And, you know, I think that these have been transformative drugs. There's no doubt about that, but there still remains again, 25 to 50%, depending on where you cut the improvement, who are still having some degree of symptoms and some many people who haven't responded at all. So, I think… and then those people who have very little evidence of type-2 inflammation… so, I think trying to understand what are the pathways that are driving the other 25%, that don't have any evidence of type-2 inflammation. And then those people that actually don't respond as well to the type-2 biologics, even though they make the biomarker criteria for a type-2 biologic.
And I think there's a some of the research that we've been doing suggests that even type 2 asthma is not the same in everyone. You can have a lymphocytic type of a type 2 high asthma. You can have a non-lymphocytic acidic type 2 high asthma. And obviously, we can kind of try to understand those pathways, maybe one of which is ILC-2 and the other of which is an adaptive th2 cell, better then we can target those elements of the immune system for treatment. And, you know, we've been very interested in type-1 inflammation, so interferon Gamma and the pathways that go along with that, I doubt that we'll ever block interferon Gamma in these patients, but there are many other downstream pathways, including jaks and stats that that could be, could be targeted. The jak inhibitors are, of course, being utilized in, in rheumatoid arthritis, but also in atopic dermatitis and showing efficacy in atopic dermatitis. So, there may be some overlap there.
And then we're very excited because of our precise network, which is an NHLBI-sponsored network, an adaptive trial design in patients with severe asthma. We're actually trialing five different treatments for patients with severe asthma, and they get enrolled and re-enrolled depending upon what their biomarkers show. We're actually studying an anti-IL-6 called clazakizumab in that study. And there's pretty good evidence that there's about a third of severe asthma patients that have pretty profound elevations in their IL-6 levels. Again, anti-IL-6 has been successful in the treatment of rheumatoid arthritis. So, we're actually hopeful that, you know, with the results from this study, we'll at least know whether we should explore anti-IL-6 further in asthma as well. I think the biologics one considers the biologics generally as intravenous or intramuscular or subcutaneous injections. And I think some of these other inhibitors, like the jack-inhibitors or oral medications. And so, you know, there are patients that I think would rather take an oral medication too. So that's sort of another kind of step in treatment.
Dr Albert Rizzo: You're certainly on the front line of the research it's going on in this population. So, thank you for that. And as you mentioned, it's a complicated and complex situation, but I would really recommend our listeners go back and look at your Blue Journal article last year. It's a very good review of the chemistry and all the cascade you mentioned. So again, I want to thank you for the time you took today. I really appreciate it.
Dr Sally Wenzel: Thank you very much, Dr Rizzo
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