Activity Transcript

William W. Busse, MD: Hello, I'm Dr William Busse, Professor of Medicine and Division of Allergy, Pulmonary, and Critical Care Medicine at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin.

Welcome to this program: "Foundations of Asthma: Expanding the Role of Biomarkers in Managing Therapy." Please, also see other activities in this series: "Foundations of Asthma: Exploring the Allergic Component of Management," and "When to Consider Biologic Therapies."

I'm joined today by Dr Stephen Peters, the Davis Professor and Chief, Section on Pulmonary, Critical Care, Allergy, and Immunologic Diseases at Wake Forest School of Medicine and Wake Forest Baptist Health in Winston-Salem, North Carolina. Welcome Steve.

Stephen Peters, MD, PhD: Thanks Bill, it's a pleasure to be here with you and our listeners.

Dr Busse: In the previous segment we defined severe vs uncontrolled asthma, reviewed the clinical and cellular characteristics of allergic eosinophilic asthma, and discussed how patients with symptoms of asthma should be investigated to determine asthma severity, asthma phenotype, risks for exacerbation, and appropriate next steps in management.

In this segment, we will discuss the role of biological markers in asthma and, specifically, how they can be used to help identify which patients may derive the greatest benefit from biologic therapies, and which biologic may be most helpful.

First, let's briefly review the available biologic therapies for asthma and their mechanisms of action. We currently have 5 agents that are FDA-approved. These are depicted on this slide. We have omalizumab, which is anti-immunoglobulin (Ig) E, and then we have 3 products that are directed toward anti-interleukin (IL) 5. There's mepolizumab and reslizumab, which are anti-IL5 cytokine monoclonal antibodies (mAb). There's benralizumab, which is an anti-IL5 receptor antibody. And finally, the newest biologic recently approved for asthma is dupilumab, and this is an anti-IL4 receptor mAb which also affects IL-13 function.

Steve, would you please describe the 3 main types of biomarkers and how they could be used in the management of patients with severe asthma?

Dr Peters: Potentially, biomarkers can be used in several different ways. They can be used diagnostically, or in a predictive manner, or in a prognostic matter. First, while they can be helpful in making the diagnosis or confirming it, they're most valuable in defining a phenotype or an endotype of asthma. And then, we can use predictive or prognostic data. These can help us define the natural history of the disease; that is its severity, exacerbations frequency, and perhaps other long-term effects like loss of lung function and, importantly, the potential response to therapies.

So, Bill, if you could create the ideal biomarker, what characteristic would it have?

Dr Busse: Well, I think there are a number of properties of an ideal biomarker that we'd like to see. First, we'd like it to be high in its sensitivity and specificity. We would like it to be reliable and reproducible. We'd like it to be easy to collect, and that's why blood samples are very helpful in this regard. We'd also like it to provide biologically relevant information that can aid in the clinical decision making. Measuring disease progression, response to therapy; we'd also like it to be cost effective.

Steve, there are 3 primary asthma biomarkers that can be used today in the clinic: serum IgE, fractional exhaled nitric oxide (FeNO), and blood eosinophils. What can these biomarkers tell us in terms of the underlying disease?

Dr Peters: First, is total serum IgE, which is a general marker of atopy and a qualifying agent for the use of omalizumab. Second, we have blood eosinophils which are used to look at and describe eosinophilic phenotype, a type 2 (T2) inflammatory state. And third, we have FeNO, which is a different marker of T2 inflammation, and which is really is related not to the IL-5 pathway like the eosinophils, but to the IL-4 and IL-13 pathway.

The first one, serum IgE is really a general marker of atopy and atopic airway inflammation. It's also associated with a risk for developing asthma, and it is associated with greater asthma severity and airway remodeling. FeNO, or expired nitric oxide, is again a T2 inflammatory marker; it's related to asthma severity and early onset allergic disease, and exclusively related to eosinophilic asthma. It's also predictive of a risk for asthma exacerbations, and again, is most closely relinked to the IL-4 and IL-13 pathways. Finally, blood eosinophils, the second T2 inflammatory marker, can help define patients with that phenotype who is a potential candidate for anti-IL5 therapies and, again, these are predictive of increased asthma exacerbations.

It's important to note that while FeNO and eosinophils are both T2 inflammatory markers, they are not equivalent. Again, FeNO is more of a marker of activity in the IL-4, IL-13 pathway, and blood eosinophils relates to the IL-5 pathway.

Bill, can these biomarkers predict which patients will respond to corticosteroids or biological therapies? What does the evidence tell us?

Dr Busse: So, in answer to your question, can these biomarkers predict response or adherence to therapy -- with IgE, as you indicated, it is a marker of a presence of disease, disease severity, but it doesn't necessarily tell us whether patients are going to respond to omalizumab or not. We need the serum IgE level for dosing, but FeNO and eosinophils are far better predictors of response to omalizumab. FeNO is effective in predicting the response to inhaled corticosteroids (ICS). Its increase may also indicate a lack of adherence to ICS or the presence of the severe asthma phenotype. FeNO will increase if patients tend to pull back on their dose of ICS. There are multiple confounders with the presence of FeNO that need to be considered. It's reduced in the presence of smoking, and again, it's reduced in response to therapy. It's been very effective as you indicated in predicting the response to dupilumab, which is the anti-IL4 receptor, IL-13 blockade.

With blood eosinophils, they also predict a positive response to corticosteroids, IL-5 inhibitors, and dupilumab. We also note that different levels of eosinophils, or cut points, are very helpful in predicting the likelihood of response to anti-IL5 therapy. The higher the level of blood eosinophils, the greater the likelihood of response to anti-IL5 treatment. They (eosinophils) can be elevated in response to other causes, such as parasitic diseases, underlying neoplasms, or other systemic diseases.

So, if we look at blood-based biomarkers with IgE, it's usually associated with the allergic phenotype of asthma, early onset disease. The associated biologic for IgE is omalizumab. Eosinophils are found to be elevated in both early onset asthma, late onset asthma, and allergic and nonallergic asthma. As we mentioned before, IL-5 is a driving cytokine for the presence of eosinophils. But the presence of IL-4 and IL-13 can also reflect the level of peripheral blood eosinophilia; therefore, mepolizumab, reslizumab, benralizumab, and dupilumab are all effective biologics in the presence of elevated eosinophils.

Periostin is a product of IL-13. It marks the T2 inflammation, though it is not currently used for clinical monitoring of asthma or response to therapy.

Steve, how do you use biomarkers in your practice? Would you walk us through how available biomarkers can aid in clinical decision making for the asthmatic patient?

Dr Peters: So, Bill, let's look at this patient Maria. She's a 39-year-old female, diagnosed with asthma at age 19, has a history of wheezing with viral respiratory infections. She also has atopic dermatitis but no other current morbidities. Asthma has become more severe in the last 3 years. She's had prednisolone bursts on 4 occasions and had an emergency department (ED) visit for an acute attack 6 months ago. Her current asthma medications are, initially, low dose ICS, long acting beta-agonists; but currently high-dose ICS long, acting beta agonists. She did not use or benefit from the use of a long acting anti muscarinic agent. So, on this basis, with this history, this patient appears to have severe refractory asthma. Of course, like in any patient with potentially severe asthma we have to first confirm the diagnosis. Secondly, we have to address comorbidities, such as gastroesophageal reflux and upper airway disease and, make sure she has her medication and can use her inhaler correctly.

Now, let's look at her biomarkers. Her total IgE level was 125; that's really in the normal level. So, she may be mildly atopic, but not greatly so. The importance of this value to me is that it's not extremely high, that is over 1,000, to suggest another diagnosis such as allergic bronchopulmonary aspergillosis. Her blood eosinophil levels, however, are high at 365 cells per microliter. Again, she might be a candidate for anti-IL5 therapies. And, finally, her FeNO expired nitric oxide is also elevated at 75 parts per billion. Again, suggesting activity through the IL-4/IL-13 pathway, and she might be a candidate for dupilumab. Also, note in her history she has atopic dermatitis and that drug [dupilumab] is also shown to be useful in that indication.

Bill, how do you think about this patient in terms of these biomarkers?

Dr Busse: I would interpret these data to indicate that Maria has T2 inflammation. But I am more impressed by the increase in eosinophils and the increase in FeNO. And these tell me that the IL-5 pathway and the IL-4/-13 pathway are no doubt activated and driving her disease process.

Dr Peters: Bill, what are you most excited about in terms of developments in biomarkers for asthma in the next few years?

Dr Busse: Well, I think there are a number of potential advances that are coming down the road. First, greater ability to identify T2 inflammation. Second, to be more effective in directing our intervention. Third, we also have begun to identify specific biomarkers for specific interventions. We'd like to have a biomarker to direct us towards the right treatment, and I think the advance that's going to be the most important is determining a response to a specific treatment. To tell early in the course of management that the measurement of a biomarker tells you that your patient is responding to your intervention -- that would be a very important step forward.

So, Steve, in summarizing our discussions for today, when you are seeing a patient with severe asthma, what biomarkers do you routinely get on virtually all of these patients?

Dr Peters: Bill, I always measure the 3 biomarkers we have discussed today. That is total IgE, blood eosinophils, and FeNO, simply, to be able to categorize that patient as well as we can with the currently available methods. I'm most excited about those patients who have elevated markers of either eosinophils or FeNO as a marker of T2 inflammation and, as we discussed, if the eosinophils are high and FeNO is low, again that points me towards the IL-5 pathway and the anti-IL5 agents. While, if the eosinophils happen to be low and FeNO is high, that points me towards the IL-4, IL-13 pathway and, perhaps, dupilumab as the therapeutic option. While not every patient with these biomarkers responds to these therapeutic approaches, a large number do -- probably on the order of 40% to 60%. We're making tremendous progress, but we still have a way to go.

Dr Busse: Steve, I'd like to thank you for joining me in this discussion. I also want to thank our audience for listening. Please proceed to answer the post activity questions and complete the evaluation. Thank you.

This transcript has been edited for style and clarity.