Identifying the Biomarkers for the Treatment of Severe Asthma - Episode 5
Neal Jain, MD, FAAP, FAAAAI, FACAAI: So you mentioned exhaled nitric oxide. Thinking about that, what role do you see as far as biomarkers and testing for biomarkers? What are the primary biomarkers that we look at in evaluating our patients with asthma as we start to think about not only the diagnosis but sort of this idea of phenotyping as type 1, type 2, or type 2 high, type 2 low?
Nicola A. Hanania, MD, MS: Biomarkers are important. Unfortunately, we don’t have too many of them. As clinicians, we need tools to reflect what’s going on. What’s the mechanism of asthma that I’m dealing with? And really, biomarkers are supposed to help us with this. They’re supposed to tell us what’s going on with the patient’s airway. Right now, the biomarkers we have are limited to type 2-high asthma. Exhaled nitric oxide is an important biomarker, maybe not for diagnosis of asthma but simply for monitoring and titrating the inhaled steroid, also reflecting high-risk patients, with an increased risk of exacerbation. But also, it is a pharmacodynamic biomarker. It beautifully goes down with inhaled steroid therapy and some therapy with some biologics.
We have blood eosinophils. More recently, sputum eosinophil counts would be great, but it’s not very practical in every setting. There are some studies ongoing that look at point-of-care testing that reflect sputum eosinophils, looking at saliva and other things. Currently, blood eosinophil is the easiest way, and it certainly does correlate with sputum eosinophils, although there are some disagreements if you look at literature. But what is the cutoff above which you say this is an eosinophilic asthma? Some people say 200, others say 300. We can argue about this later on.
Bradley Chipps, MD: And the variability of eosinophils are important too.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Yeah, and especially with therapy. I mean all of these can change.
Nicola A. Hanania, MD, MS: Not only from day to day; there are changes even within the same day. There are some experimental biomarkers like serum periosteum. In our studies with anti—IL-13, it sounds like it is a promising biomarker. Right now, it’s still up in the air. It’s not approved. It does reflect IL-13 activity. And of course, IgE. IgE is not a predictor of response to therapy. More important is allergen-specific IgE. That’s more important. That usually helps identify allergic asthmatics, or at least in the presence of symptoms of allergy. So these are the ones we have now. People are looking at others. We certainly don’t have any biomarkers that reflect T2-low asthma at this point. We hope we will.
Bradley Chipps, MD: We sort of diagnose it in the absence of high type 2 biomarkers. We tend to think...
Nicola A. Hanania, MD, MS: And part of the problem is type 2-low asthma is so heterogeneous. It’s not just 1 type of disease, so it’s going to be very hard to have 1 biomarker for that.
Aidan A. Long, MD: It depends what you’re asking of the biomarkers. Are you asking for something that would help you diagnose asthma, that will help you monitor response to therapy, or will help you monitor adherence? And they seem to have different roles.
Bradley Chipps, MD: Or lead you to a different therapeutic option.
Aidan A. Long, MD: Or perhaps lead you to different therapeutics, based on the pathway.
Nicola A. Hanania, MD, MS: I think the ideal biomarker is one that is easy to measure. It’s producible. It’s done in the point of care, where we need it most. But also, it’s predictive and prognostic. That’s my Christmas wish. We don’t have 1 that fits all of these.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right. So right now we use many of them. What I’m hearing from all of you is that it’s helpful to use these. It doesn’t paint the entire picture, but it is helpful.
Aidan A. Long, MD: So the 3 big ones are serum IgE, peripheral blood eosinophil count, and exhaled nitric oxide level. The serum IgE is perhaps the least useful. It doesn’t diagnose asthma. It doesn’t predict the severity of asthma. It doesn’t really predict response to treatment. It points, perhaps, to 1 manifestation of a type 2-high phenotype. Whereas the other 2, eosinophils and exhaled nitric oxide, not always together, but generally they improve with decreasing type 2 inflammation.
Bradley Chipps, MD: Two things. One, as Nic said, specific IgE is probably more relevant, especially because it can be related historically to exposure-causing symptoms. And secondly, as seen in the inner-city studies, bronchodilator reversibility has been shown to be a major factor in predicting an adverse clinical outcome and response to therapy with long-acting beta agonists.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: One of the things that’s not mentioned here—I don’t know that we would think about it necessarily as a biomarker, but I think it’s worth at least bringing up, and maybe we’ll have more of a conversation as we move through this discussion—I like to think of exacerbations as a biomarker, right? In these patients who have this type 2 disease with a lot of inflammation, that is what tends to result in those exacerbations. I think the literature is starting to point this out, and that’s also what we think may lead to this loss of lung function over time. Given that we can’t test specifically for different cytokines, I think the things that we have, like eosinophils and feno [fractional exhaled nitric oxide], are as good as we get. Is there an ability to test for cytokines? Do you see that coming down the road? What are your thoughts?
Bradley Chipps, MD: No, but to get back to the point you made a moment ago, in the TENOR study, which I’ve been involved with for the last 19 years now, 2 things we show are, 1) a previous exacerbation and 2) very poorly controlled asthma all predict future exacerbations. So there are historical features that also predict exacerbations too.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right.
Bradley Chipps, MD: And remembering all these biologics that we currently have are approved on their ability to decrease exacerbations.
Nicola A. Hanania, MD, MS: We talk about these biomarkers. There’s actually a recent study from the UK that showed that a composite biomarker of feno [fractional exhaled nitric oxide] and blood eosinophil may actually be better than 1 by itself. I think in the future we may see, as you mentioned, clinical biomarkers. Exacerbation history is a very important one. We didn’t talk about radiological biomarkers. I know we are far advanced in the COPD [chronic obstructive pulmonary disease] world with that compared with asthma. But these biomarkers, such as CT [computed tomography]—type biomarkers, may actually help identify patients at high risk of remodeling, or they actually will have remodeling. These are not clinically applicable. They’re more in the research arena. So we really would like to see more biomarkers because, for a busy clinician, nobody is going to do a bronchoscopy to know what type of asthma we’re dealing with.
Aidan A. Long, MD: But there’s a big move afoot now to go, in an unbiased fashion, looking for biomarkers. Let’s not look for what we think we should be trying to identify, but let’s look very broadly through metabolomics or proteomics in the blood and in the urine. And there are some new things coming out—things we may never have thought about. The U-BIOPRED [unbiased biomarkers in prediction of respiratory disease outcomes] group in Europe and some big groups in the states are looking at this. Even at the American Academy meeting this month, there were some really exciting, promising potential future biomarkers.
Nicola A. Hanania, MD, MS: Proteomics.
Bradley Chipps, MD: And in the city, John Fahy is working on CT markers such as airway wall thickness and mucus plugging that help predict future bad outcomes.
Aidan A. Long, MD: Clinical biomarkers, yeah.
Transcript edited for clarity.