Pathophysiology-Understanding Asthma Immunology, Phenotypes, & Biomarkers

Video Transcription

As a disease with significant heterogeneity, asthma is best managed when we take a precise approach to its evaluation and management.  But in order to do that, we must first understand its immunology, the phenotypes, and biomarkers, all of which will be the subject of today's discussion.  This is CME OnReachMD, and I'm Dr. Sandy Khurana. Here with me is Dr. Monica Kraft, professor and chair of the Department of Medicine at  the University of Arizona, and deputy director of the Asthma and Airways Disease Research Center at this institution. Dr. Kraft, welcome to the program.  Thank you so much for having me. So let's begin with an overview of current understanding of asthma and pathobiology, which has evolved significantly over the recent years.  Dr. Kraft, can you share some of your recent findings? Absolutely. I think, one, I think it's an amazing time to be caring for patients with asthma because  our understanding of the disease has evolved very dramatically really over the last, I would say, couple of decades to the point where we now have treatments that we can offer  patients that target specific inflammatory pathways. That's very exciting, and that we have a lot to offer our patients that we really didn't have before.  And it really is this concept of understanding what type of asthma does a patient have. And so one easy way to think of it is we have two major buckets, and we call those type  two and non-type two. And so when we think about type two, we think about allergy, we think about eosinophils, and there are many different kinds of type two asthma.  So it's not just one entity either. And it's not only a Th2 or T helper 2 disease, because we know that innate lymphoid cells also have a role in this type of type two asthma.  And so when I say type two, I'm referring to specific cytokines or a specific type of inflammation.  And those cytokines, I'll give examples, are going to be interleukin 4 and 13 and interleukin 5.  The non-type two, we would think about things like Th1 type of inflammation, Th17, very neutrophil predominant disease, interleukin 6, others.  So there's a whole different type of inflammation that we see in non-T2. And in fact, asthma can exist in either.  So our charge as clinicians is to figure out what kind of asthma does a patient have with this construct in mind, I would say. So that's sort of the start.  And then we can move forward from there and evaluate in the clinical arena. That's great. It sounds very complex, obviously.  And it's really hard to wrap our mind around some of this pathobiology. And we're hearing so much about phenotypes and endotypes. What is a phenotype? And what is an endotype?  And what has helped us understand the heterogeneity in asthma better? Great question. This is what I do every day when I'm seeing patients, but it's a different mindset to  understand that not all asthma is created equal. It's not all the same. And so to figure it out, we first start out with this concept of phenotypes, which are  basically observable characteristics, such as age of onset, lung function, exacerbation  history, family history, and aspirin sensitivity would be another one, exercise triggers, such  as exercise-induced asthma, menses-induced asthma, the goal of determining the endotype. And that's really the mechanism that's driving or the biological pathway that's driving that  phenotype.  And the challenge about this is there are many endotypes that can exist within a phenotype. So we often have several potential endotypes that we think about.  For instance, type 2 asthma, a good way to think about it is allergic and eosinophilic. Now they're not necessarily one and the same.  So we might want to be interested in age of onset. Early onset might suggest more of an IL-413 dominant or driven asthma.  Early onset asthma that has eosinophils may also be more IL-5 driven with less allergy. So 413 really drive IgE, allergic inflammation, IL-5 drives eosinophils.  Think about other triggers, such as I mentioned, exercise, aspirin would be others. And the presence of sinus disease, nasal polyps also help differentiate the type of asthma,  but that's all under this type 2 bucket. And so examples would be in the clinical arena that might help would be able to do  things such as using biomarkers, such as bloody eosinophils, exhaled nitric oxide, getting a sense of lung function, all those things that we can do to really better understand  and put the history together with the biomarkers that we have available to us to determine what kind of inflammation is driving a particular patient's asthma. This is great.  There are multiple endotypes that can give us the same phenotype or observable characteristic.  And it's really teasing out those more granular endotypes that really help us determine the pathway involved and then pave the way for future treatments.  In terms of severe asthma itself, what were some of the phenotypes or the cluster analysis work that you can share with us that has been pivotal in our understanding?  So in addition to these phenotypes that I mentioned, which would be sort of early onset allergic, you have the later onset with lots of eosinophils, sinus disease, less allergy,  exercise-induced asthma, aspirin-sensitive asthma, or aspirin-exacerbated respiratory disease. Those are examples of phenotypes.  But there's also clusters that the Severe Asthma Research Program has identified. And they went ahead and recruited a large number of patients with and without asthma,  looked at all of the characteristics that we think about. And really probably the major ones were age of onset, lung function, and the presence of bronchodilator reversibility.  And they did an unsupervised cluster analysis and identified five clusters, many that overlap a bit with what I've already said.  Some of the early onset asthma, really driven by allergy, IgE-mediated pathways, as opposed to the later onset asthma.  So even within an unsupervised cluster analysis, you can get these different clusters ranging  from very young, low healthcare utilization, steroid-responsive to very eosinophilic, presence of nasal polyps, no allergy to fixed air flow limitation, presence of eosinophils,  high healthcare utilization. It's sort of a spectrum across these five clusters. Now, obesity is interesting in that it can create its own phenotype that is more IL-6-driven  and is associated with metabolic syndrome, sometimes type 2 diabetes, and high serum IL-6 levels. And so that would be considered a non-type 2 phenotype.  And we didn't talk about the non-type 2 phenotypes as much. And so I'd like to do that for a minute. Obesity-induced asthma would be considered one of them.  Also there's an infection-induced phenotype. We all have seen these patients who have had upper respiratory and lower respiratory infections  that are left with paroxysmal wheezing that really looks a lot like asthma that then develops into a chronic illness.  So that's an infection-induced scenario that tends to have more of a neutrophilic type of inflammation.  There's also exposure to environmental irritants and pollutants that can produce also an asthma phenotype we think is associated less with the eosinophils, more with neutrophils.  And given that I live in Arizona and Phoenix in particular, especially this time of year, the air quality can be very poor there.  There can be high levels of particulates and ground level ozone. Patients have a very difficult time leaving their homes during the summer months because  of the presence of the air quality. And so that's another example of a type of asthma that can be caused by environmental exposure.  So back to the obesity question, I think obesity can create a separate phenotype, but it can also make type 2 asthma worse.  And so Anne Dixon has been very instrumental in really moving this field forward. And so she showed that if obesity occurs later in life associated with asthma, bariatric  surgery can be very beneficial. However, if obesity has been present a long time, especially in an early onset scenario  with allergy, bariatric surgery is less able to really change the course of asthma. So obesity can do a lot of different things with regard to asthma pathobiology.  Yeah, that is so fascinating. For those just joining us, this is CME Unreach MD, I'm Dr. Sandhya Khurana.  Today I'm speaking with Dr. Monica Kraft about some important updates to our molecular understandings of asthma. So, Dr. Kraft, let's focus on the subject of biomarkers.  I know you mentioned that briefly earlier. You could elaborate on what is currently clinically available and perhaps some research tools  that we hope to see utilized in the near future. I think we have a couple of biomarkers that we can use that give us a sense as to what  kind of an inflammation is driving a patient's asthma. And then we've got some on the horizon, so that's exciting.  So I think the blood eosinophil is the most common that we think about. And if it's elevated, usually we like to see levels above 150, ideally 250 to 300 and up  really gives us a sense that eosinophils are driving the asthma. Now with that, we have to remember that eosinophils have a circadian rhythm, so it depends on when they're drawn.  Also the presence of medications such as oral steroids and high-dose inhaled steroids can impact the value. So keep that in mind when measuring.  And so the take-home there would be to make sure you measure them more than once. And so the guidelines really suggest at least three times to get a good sense of how they vary.  And I often, depending on if the patient's asthma status changes, I will order it, especially  on if they're coming in for an exacerbation, I'd like to see if in fact blood eosinophils are elevated before they start their prednisone as an example.  And so along those lines and the sort of the type two arena, exhaled fraction of the exhaled nitric oxide or phenol is also a valuable biomarker.  It's not as widespread as I would like to see it used. It is more indicative of IL-13 driven inflammation, or that's at least the hypothesis.  It can suggest untreated inflammation or response to particular biologics where IL-13 is inhibited as examples.  It can also be decreased by oral steroids and by inhaled steroids in some patients as a measure of adherence and others really as a measure of untreated inflammation.  And so I like to measure it basically every visit for my patients with severe asthma, because again, I need to get a sense of how often it's elevated together with the bloody  is I think can be very helpful. And of course, in the T2 space, if you want to know if allergy is driving the asthma,  certainly IgE is a biomarker that helps us with that, but really allergen specific IgE is what I prefer to use.  Now I'm not an allergist, so I usually use the blood tests, the brass testing. And so I'll go ahead and order an allergen specific IgE and then I'll get a total with that as well.  We know that total IgE is really to be associated with asthma and the higher the level, there is some loose correlation with asthma, but I like a total IgE if I'm ever going to be  considering therapy that inhibits IgE directly like Omalizumab, but the allergen specific gives me a little bit more granular data on what types of allergens may be in fact driving  that person's asthma. So a couple of others on the horizon that I think are interesting to note, eosinophil  peroxidase, which is a granule that is from an activated eosinophil can actually be measured by throat swab or nasal swab.  And this is being investigated by the Mayo Clinic Scottsdale group. And in fact, the idea is to create a point of care biomarker for eosinophils in the clinic.  And as part of our precise network, we'll be validating this nasal swab in 800 patients.  So great to come back and talk about whether that can be a very useful point of care biomarker and you will know their eosinophil status right there in the clinic, we won't have to  wait for folks to go to the lab. So that's a nice option. RNA-bromotyrosine is also indicative of eosinophilic inflammation, and in fact, measured in urine.  And that's another biomarker that's being investigated, this one by the Cleveland Clinic group, and will also be incorporated into PRECISE.  So we've got two on the horizon that we're looking to validate. You know, induced butum is a great way of looking at airway inflammation, it's just  not as feasible in the clinical arena. So that's not used as often, we generally use it in the research setting.  And periostin used to be a very, I would say, a high-profile biomarker that's IL-13 driven. But due to the fact that it's not so easy to use in kids, because it's also produced  by bone and growth can affect it, it is not as robust a biomarker as we'd hoped it would be. So that's sort of fallen out of favor.  So at this point, the biomarkers we use the most would be bloody acinophils, XL nitric oxide, IgE and allergen-specific IgE, with the idea of measuring certainly the eos and  the pheno at multiple events, I usually get total IgE and allergen-specific usually on initial evaluation.  And between all of those, that can give me a very nice sense of whether T2 inflammation is really driving a patient's asthma, and really helps them with therapeutic choices as well.  Thank you so much, Monica. That is fascinating. And it really lays a great groundwork for our understanding of biomarkers and how to use them.  And if you'll just allow me to pick your brain and share a patient's story with you and see if you could walk us through how you would apply phenotyping, somebody like this  patient in clinical practice. So I have a 42-year-old female who has uncontrolled asthma, early onset, and she has had frequent  exacerbations despite regular use of an inhaled steroid and a long-acting beta agonist. If you were seeing somebody like that in your clinic, what would your first few steps  be in trying to understand her immunobiology a little bit better? That's a great question. These are the kinds of referrals I get all the time.  Patients aren't reading the textbook, so to speak. They're not responding to ICS-LABA, which for many asthmatic patients works very well.  The combination works very well, but not for everybody. I think before we jump in to phenotyping, I also like to look at comorbid conditions  because I think that adds to medication burden and can actually cause patients to be somewhat steroid resistant.  So certainly severe sinus disease, nasal polyps, or any association with exacerbation with aspirin, you'd want to absolutely know that. That's a little different pathway.  You'd certainly want to have your ENT colleagues involved, especially in the setting of nasal polyps.  Make sure they're on a good sinus regimen of nasal rinses, intranasal steroids, perhaps Stelazine, antihistamines, etc. So you'd want to make sure that's covered.  I also think about gastroesophageal reflux disease, both acid and non-acid, and patients may not have overt symptoms of GERD.  What I have noticed is those who do, I often see a nice response to muscarinic antagonists, interestingly, because I think they have high vagal tone, but that's just a little bit of  an aside. Therefore, GERD can exacerbate asthma and can also cause upper airway dysfunction and vocal cord dysfunction. So really important to identify whether GERD's present.  Sometimes that will take impedance testing because the patient's surrogate may be airway symptoms and not typical GI symptoms. So always need to sort of think about that.  And then obstructive sleep apnea, again, through vagal mechanisms, it can exacerbate asthma as well. And so that needs to be treated.  And with obesity also being an important factor to consider in asthma, obesity and OSA certainly go together. So you want to make sure all those entities are treated.  If patients are smoking, 20 to 40% of asthmatics smoke, depending on what part of the country you're in. And that can certainly add to a steroid resistant state.  So those are examples of comorbid conditions you want to certainly make sure are addressed being treated because they do go part and parcel with asthma.  I always get pulmonary function tests and I want to make sure that I'm dealing with what kind of air flow limitation am I dealing with.  I'm interested in knowing not only spirometry, I like a full set of pulmonary function tests. I like to look at lung volumes, look for any concerns about small airways disease as  well, which you can often glean by full PFTs. And so get a sense for that in addition to a really good history about exacerbation pattern  triggers the role of allergy and age of onset, all those characteristics we've been talking about for a while.  And then of course, moving on to using the biomarkers we just discussed. So certainly bloody acinophils, exhaled nitric oxide. I'm always amazed at how rare the biomarkers are used.  Oftentimes patients might come to me with a CBC, but not a differential. Phenol is really not done very often, at least in the referrals I've been seeing, which are  both in and out of state. So again, they can be very useful to assist you in understanding what kind of asthma patient has.  So I would absolutely measure exhaled nitric oxide, bloody acinophils, and then put the  history, comorbid conditions, biomarkers together to come up with a treatment plan at that point.  Those were great insights, Dr. Kraff. Thank you so much for enlightening us. We're almost out of time, so I'm just going to open the floor for what your call to action  would be going forward as it relates to understanding asthma mechanisms and the heterogeneity, the phenotyping going forward. Absolutely.  And thank you again for this opportunity to talk about the patients that we both see. I know you do a lot of this as well, Sandy, and you're right there with me on all the  areas that we've discussed today. And I think really just an appreciation of the heterogeneity of asthma, that if patients  are not responding to ICS-LAVA combination, they should have a deeper dive and a referral into what's causing their asthma if they're not responding to standard guideline-based  asthma medications before you refer. Think about using blood EOs, exhaled nitric oxide, if you can do that, to try to understand a patient's asthma as much as you can.  And then if you still need help, then certainly refer on to an asthma center where folks like Sandy and I do this every day. Thank you so much, Monica.  And with that call to action in mind, I want to thank you very much for joining us today and sharing your time and your expertise with our audience. Thank you again. Thank you.

Video Summary

In this video, Dr. Monica Kraft, professor and chair of the Department of Medicine at the University of Arizona, discusses the immunology, phenotypes, and biomarkers of asthma. Asthma is a disease with significant heterogeneity, and understanding its different subtypes is crucial for effective management. Dr. Kraft explains that there are two major categories of asthma: type two and non-type two. Type two asthma is characterized by allergy and eosinophilic inflammation, while non-type two asthma involves different types of inflammation, such as Th1, Th17, and neutrophil predominant inflammation. The understanding of asthma has evolved over the years, and there are now treatments available that target specific inflammatory pathways. Dr. Kraft emphasizes the importance of phenotyping patients with asthma, as there are various phenotypes and endotypes that can impact treatment decisions. She also discusses the use of biomarkers, such as blood eosinophils, exhaled nitric oxide, and allergen-specific IgE, to determine the type of inflammation driving a patient's asthma. Dr. Kraft also mentions some future biomarkers that are being investigated, such as eosinophil peroxidase and RNA-bromotyrosine. The video concludes with a call to action to better understand the heterogeneity of asthma and to use biomarkers to guide treatment decisions.

Asset Subtitle

Clinicians must be knowledgeable of the inflammatory, immunologic, and pathobiologic features leading to severe asthma, severe asthma phenotypes, and the implications for treating patients. This ReachMD podcast discusses various asthma phenotypes and the biomarkers used to identify the Th2 phenotype and also reviews the current understanding of asthma pathobiology.

Last Reviewed: September 2022

Asset Caption

Clinicians must be knowledgeable of the inflammatory, immunologic, and pathobiologic features leading to severe asthma, severe asthma phenotypes, and the implications for treating patients. This ReachMD podcast discusses various asthma phenotypes and the biomarkers used to identify the Th2 phenotype and also reviews the current understanding of asthma pathobiology.

Last Reviewed: September 2022

Keywords

asthma

phenotypes

biomarkers

inflammation

treatment decisions