This transcript has been edited for clarity.
Michael Wechsler, MD: Hi. I’m Dr Mike Wechsler and welcome to Medscape’s InDiscussion series on moderate to severe asthma. This is episode one of the first season. Today, we’ll be discussing developing a precision medicine approach to asthma control with my good friend and colleague, Dr Geoffrey Chupp. Geoff is professor of medicine in the Division of Pulmonary, Critical Care & Sleep Medicine at Yale, and director of the Pulmonary Function Lab at the Yale Center for Asthma and Airway Disease. Welcome to InDiscussion, Geoff. How are you today?
Geoffrey Chupp, MD: Great, Mike. It’s great to be here and thanks for having me. I’m looking forward to a great discussion.
Wechsler: I’m excited to have you, Geoff. What can you share with listeners that not many people know about you?
Chupp: Well, people might not know that one of my favorite hobbies is cooking. And it was born from working in Sicilian seafood restaurants before I went to medical school and while I was in medical school in the north end of Boston.
Wechsler: Nice. So why did you leave cooking to go into medicine? What is it about this specialty that first drew you in?
Chupp: I’ve been trying to figure that out, but one of the things about cooking is that you get to take care of people and you get to make them happy. And that’s something I felt like I wanted to do in medicine as well. Now I get to do both.
Wechsler: That’s so great. You and I both work in the field of asthma. I’ve noticed that asthma has changed so much over the last 25 years that I’ve been working in it. Tell me, how do you feel that asthma has evolved over the last 25 years, particularly in the management of patients with severe asthma?
Chupp: One of the reasons I became interested in asthma is that many years ago and when I was training, we used to see a lot of patients in the intensive care unit who were in respiratory distress and often required intubation. The therapies we had to treat them with were pretty limited. We gave them a lot of beta-agonists, of course, and aminophylline drips to try to release the bronchospasm, and systemic steroids. But there were still a lot of challenges in getting these patients better because we didn’t have any chronic controller therapies to keep them from developing these exacerbations. We would use really massive doses of inhaled steroids. The addition of bronchodilators and combination therapy has incrementally improved outcomes for these patients. In the turn of the decade, the new millennium, we had the development of biologic therapies, which has, again, been another game changer. Alongside this has been our improved understanding of the biology of the disease. We are always looking at who we’ve been able to improve and recognizing that there are patients who haven’t responded to therapies. This has allowed us to study aspects of the disease that are underlying the inflammatory airway disease that is central to asthma.
Wechsler: I think it’s been really exciting to see this evolution from a one-size-fits-all approach now that we have developed more of a precision medicine approach. What does precision medicine mean to you?
Chupp: I think President Obama described it quite well in one of his speeches when he says it is choosing the right drug for the right patient at the right time. This requires you to have an adequate understanding of the patient’s biology. I think the challenge, of course, for us in chronic lung diseases, and particularly in asthma, is that we’re dealing with a complex disease that’s occurring at the intersection of the patient’s genetic background, their environmental exposures, and time in their life. This creates a lot of subtleties to the biology that’s driving each patient’s disease and has made it challenging for us to solve.
Wechsler: It’s so complex. I think about the interaction between the environment where people have allergies, and then that people can get exposed to viruses, and people can get exposed to different irritants like smoke or pollution. All of this complicates things because it’s on top of the genetic scaffold we all have, and we’re all a little bit different. It’s likely that we’re all going to respond a little bit differently. We’ve seen this with our patients. We’ve seen this in our clinical trials, whereby patients respond differently to different therapies at different times. One of the concepts we talk about in asthma that’s evolved a little bit are the concepts of phenotype and endotype. This has led to our appreciation that everyone’s a little bit different. Can you talk about phenotype and endotype and what these terms mean to you?
Chupp: I think it’s a somewhat personal opinion because there is some grayness around the definitions of these terms. In general, I think most people accept that a phenotype is a constellation of symptoms and clinical characteristics that describe a subgroup of patients. When you move toward endotype, you’re talking about a patient’s subtype where there is a very clear biology driving that patient’s disease. I think the Src clusters are a good example of phenotypes. They were generated based on clustering analyses of clinical characteristics.
Wechsler: To me, I think phenotype is the outward manifestation of a disease characteristic that results from the interaction between the environment and the individual’s underlying genotype. I think we can describe phenotype in many different ways. It’s usually something a patient can describe to you. Are you Black or White? Are you short? Are you tall? Are you fat or thin? That’s one type of phenotype. Another might be your exposure history. Do you get asthma when you’re exposed to allergies or to exercise? Another might be describing the characteristics of your asthma. Do you have exacerbation-prone asthma? I think endotype is the underlying mechanism of disease that a patient can’t really describe to you unless they know their biomarkers. I think of two broad categories, type 2 asthma and non–type 2 asthma. Maybe you can talk a little bit about defining type 2 and non–type 2 asthma, and also how to use type 2 and non–type 2 asthma and their subcategories in terms of selecting precision medicine approaches for your patients.
Chupp: I think you’ve nicely highlighted some of the complexity of these concepts of phenotype and endotype. Some of us would consider a third term that’s actually emerged, which is called endophenotype. This is where we are between the clinical characteristics as you describe them and an actual underlying biology that’s driving these phenotypes. Type 2 asthma is probably, in my estimation, what I would consider an endophenotype of disease because we understand some of the biologic mechanisms, but it’s still really quite complicated. Within the type 2 asthma space, we have the classic allergic subtype of disease that is driven by Th2 responses and adaptive immune responses. That’s probably the closest thing to a real endotype in asthma that’s very well accepted because we understand the immunologic mechanisms that drive this adaptive immune response. The other subtype within there that we recognize would be the eosinophilic inflammatory process, or eosinophilic subtype, where you can see patients who have eosinophilic inflammation. They have many of the features of asthma, and classic features of asthma but don’t have the adaptive immune response — an IgE response. So, they can be eosinophilic and nonallergic. Of course you can also see many patients with both features because these phenomena overlap in any given patient. The third subtype would be the non–type 2 disease, which is something we understand the least how to define because of all the things that we’ve talked about.
Wechsler: First of all, the non–type 2 asthma patients — usually, we refer to them as having an absence of type 2 signaling, meaning, they don’t have the key biomarkers of type 2 inflammation. They lack eosinophilia, they lack nitric oxide, and they lack allergic components or IgE-mediated disease. These are more challenging patients. They’re often associated with smoking history or obesity or infections. These patients can be quite challenging because we don’t have precision medicine–targeted approaches for them. When I think about type 2 asthma, I think about, as you said, the key mechanisms involved. Type 2 asthma is really derived from the concepts of both Th2 cells and ILC2 cells. That’s why it’s called type 2 cells producing the type 2 cytokines, IL-4, IL-5, and IL-13, which result in all of the key manifestations of asthma. Patients can all get to the same endpoint of having asthma symptoms, cough, shortness of breath, wheezing, and chest tightness, whether or not they have type 2 or non–type 2 asthma. But the designation of type 2 vs non–type 2 asthma plus the subgroups of IL-5 mediated, IL-13 mediated, and IgE mediated asthma has allowed us to target these patients with appropriate therapies for their dominant or likely dominant pathways. So, tell me, how do you use biomarkers? When do you check biomarkers? Which biomarkers are you checking, and are there any biomarkers in the future that may be useful?
Chupp: Right now, the way we approach evaluating patients with asthma, and in particular moderate to severe uncontrolled asthma — because these are the patients most commonly seen in an asthma center by pulmonologists who specialize in asthma — is that virtually all these patients get phenotyped and their biomarkers get checked. It has evolved over the last 20 years based on an increase in understanding of asthma and the options we have to treat it. Twenty years ago when I was a pulmonary fellow, we would check pulmonary function tests, we would do spirometry and bronchodilator response, and we might do allergy testing on these patients, or I could check a total IgE. Now we do that testing of course, and we always check allergy tests in these patients — usually ImmunoCAP testing by blood. We’ve also added a CBC count to check for eosinophil levels because we recognize now that this is a very important factor to identify a type 2 asthma patient who has the ILC2 activation but not the adaptive response. You could see a significant proportion of these patients have this, and it’s been shown to be an important factor to define therapeutic options. The other thing we check now is an exhaled nitric oxide level, which is somewhat controversial as to how it changes management of a patient compared to the other things we test for. But in our center, we find it very valuable to evaluate patients who have chronic respiratory symptoms, such as chronic cough and severe asthma, because it gives us some reading on the inflammation that’s going on in the airway. You have to understand how to interpret it because of the limitations of the test and how it can be affected by inhaled steroids and things patients eat. But it’s the fourth biomarker we check. It is these four biomarkers or tests that we do.
Wechsler: Yeah. I think that nitric oxide is woefully underutilized by most practitioners. We use it in our practice. It used to be thought to be reflective of eosinophilic inflammation because oftentimes it is associated with high eosinophils. But what we now realize is that high nitric oxide is just a manifestation of type 2 inflammation and generally Th2 mediated or ILC2 mediated disease. It’s really brought forth by IL-13. We know this because when we block the IL-5 pathway, which blocks eosinophils, we don’t see any reduction in nitric oxide levels in many of our patients. It tells us that maybe we should be targeting the IL-13 pathway in these patients. I said before that I think nitric oxide is woefully underutilized, and it’s not such an expensive test to do. The test itself is about $20. The device is about $1000, which is peanuts compared to most biomarkers and most things we do in medicine. I think it gives a fair amount of information and useful information, and if you don’t do it, you’re really not getting the full picture of asthma in your patients. So when do you check these biomarkers? Do you check them the first time you meet a patient? Do you check them serially? Do you check them only when they’re severe and you’re thinking about biologics? When do you check these kinds of biomarkers?
Chupp: I think the proper answer is all of the above. But I don’t check them every time a patient comes in. Certainly, our initial evaluation of any patient who gets referred to our center includes these tests — spirometry with a bronchodilator, exhaled nitric oxide level, CBC, total IgE, and then immunoCAP testing. And if we have these from another source, it often is adequate. We also make sure we have imaging on the patient because the first thing you have to do when you evaluate a patient with severe asthma is make sure you’re not missing another diagnosis. Chest imaging is critical for that. Often, a CT scan of the chest is done to evaluate the patient for bronchiectasis. Once the patient’s had that, depending on their disease severity and how things go in terms of their response to treatments we prescribe, I think the follow-up testing is variable. If you see the patient every 6 months, we don’t necessarily check their lung function every 6 months, especially if it’s in the normal range initially. But if it is low, I’d say below 70%, we would probably routinely check their lung function more frequently to see if we can see improvements. When we do any spirometry, we always do exhaled nitric oxide testing. I think CBCs for eosinophils are similar. If we are confident the patient’s a type 2–high asthma patient, and we have an eosinophil level that’s maybe 300 or 350 cells/mcL on multiple occasions in the patient’s record or when we first see them, then we might not need to check it again. But if it’s bouncing around at the lower end of values in the 100-200 cells/mcL range, and we want to ensure we have an understanding of the patient’s endophenotype, then we will recheck it more frequently. Sometimes we even give a patient a standing order for a CBC, telling them that if they start having symptoms or their disease activity changes, they should go to the lab and get their CBC checked so we can see what happens to the eosinophil counts.
Wechsler: I think these are really important strategies we also utilize in our practice here at National Jewish. You mentioned the key biomarkers that are currently available. Are there any biomarkers in development that you’ve either worked with or that people are studying that you’re aware of? What’s the future of biomarkers in asthma?
Chupp: I think that there’s a tremendous opportunity here because we know that these biomarkers we check have gotten us a long way, but they overlap a lot in terms of selecting biologic therapies for patients. And now that we have half a dozen biologics available, we really need better strategies to choose the right drug at the right time for the patient. We then don’t have to take a guess and predict the response as much as we do now. The other things that have been looked at recently have been the periostin levels. Of course, as everybody knows, we thought this was going to be a great biomarker for IL-13 activation based on Prescott Woodruff’s paper early on, describing Th2-high and Th2-low asthma. But unfortunately, it didn’t pan out in the trials looking at a soluble anti–IL-13 blockade, and so it wasn’t adequately predictive in a prospective trial. That test never came to the clinic. The other one that was looked at was dipeptidyl peptidase–4 (DPP-4). This is another serum biomarker that can be checked that relates to other inflammatory conditions. But again, it was looked at retrospectively in a phase 2 trial as a predictor of response, but it really hasn’t gained any traction. The other biomarkers that have been looked at that are popular in other countries are sputum cell counts. Both sputum eosinophil and neutrophil counts have been popular in Canada at McMaster University, as well as in some places in Europe where they’re done routinely on patients. This hasn’t developed in the United States because it’s not practical, it takes time, it’s expensive, and you need a lot of infrastructures to do it. But there are pretty good data showing that both sputum eosinophils and neutrophil counts can help you manage patients and determine when they have refractory inflammation that might respond to a specific type of drug. Then, of course, the pivotal trials pilot studies that were published in The New England Journal of Medicine by Parameswaran Nair and Pranabashis Haldar that are looking at mepolizumab treatment based on sputum yield counts of 2% or more showing a reduction in exacerbations opened up our new era of biologics. Recently, the AMAZES study out of Australia that looked at sputum neutrophils subtyping patients with neutrophilic asthma as a marker for patients who might respond to chronic macrolide therapy was published in The Lancet and has been successful as well. So, I think there’s some opportunity there, but it is not necessarily that practical. I think the future is still in the blood — a liquid biopsy approach with a transcriptomic analysis of the blood. In order to do this, we have to do studies of biologics and look at the transcriptomics before and after treatment to see if we can identify a signature associated with response.
Wechsler: I think you’ve highlighted a lot of the key biomarkers we’re currently using and that maybe we will be using in the future. Other ones I think of that might have some role include eosinophilic peroxidase. Urinary bromotyrosine has been studied. I do like your comment about using more genetic biomarkers to help profile the disease, and I think we’re still a ways away there. We’ve tried to use pharmacogenetic approaches to offer a more precision medicine approach. With beta-agonists, the B16 locus was thought to potentially predict responsiveness. I think we need biomarkers to be both predictive of response to therapies and also be a good response biomarker — meaning that if a patient has a high level of a biomarker, they’re going to respond to therapy, and you can then evaluate that biomarker to see whether or not it pharmacodynamically changes. Can you talk a little bit about the future of precision medicine in the last couple of minutes we have?
Chupp: Yeah. I think we’ve focused a lot on the classic approach with blood tests and biomarkers and office-based care. But I think that precision medicine in the future is also going to have a lot to do with internet technology, monitoring patients appropriately when they’re not in front of you, and having access to data on them. I think it will be a digital health approach with monitoring of rescue inhaler use and some number of actuation symptoms that patients may be having outside of the hospital outside of your office. In addition, there has been this new approach of SMART (single maintenance and reliever therapy), as well as PARTICS (patient-activated reliever-triggered inhaled corticosteroid), as published by Elliott Israel and Juan Cardet. This looks at rescue inhaler use in addition to inhaled corticosteroid use by recognizing that we’re dealing with an inflammatory condition, and that the patient who has symptoms likely has inflammation that also needs to be treated. We’re getting more precise in how we approach patients.
Wechsler: I think we’d be remiss, Geoff, if we didn’t talk about the PrecISE network, which is the network that you and I are part of, funded by the National Institutes of Health (NIH). PrecISE stands for Precision Interventions for Severe and/or Exacerbation-Prone Asthma. And this is really an exciting project sponsored by the NIH that is really trying to help us identify novel approaches, novel biomarkers, and novel therapies for our patients with asthma. Let’s finish up on that note. Geoff, I want to thank you so much today for joining me. We’ve had a great discussion about precision medicines for severe asthma. And I want to thank you, the listeners, for joining us as well. Today, we’ve had the opportunity to have national expert Dr Geoff Chupp discuss precision medicine approaches to asthma control. Thank you all for joining us today for episode one. We look forward to another great discussion in episode two. This is Dr Mike Wechsler for InDiscussion.
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Cite this: Challenges and Opportunities: Precision Medicine in Asthma - Medscape - Aug 04, 2022.