Identifying the Biomarkers for the Treatment of Severe Asthma - Episode 4
Neal Jain, MD, FAAP, FAAAAI, FACAAI: In thinking about this, we’re hearing a lot about allergic asthma, and we’re hearing a lot about eosinophilic asthma. Is there a difference? Is it the same? What’s the overlap? What is the difference?
Nicola A. Hanania, MD, MS: There’s quite a bit of overlap. We know not all allergic asthmatics have high blood eosinophils, although many of them do. So I think in real life, just looking at eosinophils does not help you differentiate. You need to do more homework.
Bradley Chipps, MD: But it may be a marker of disease activity. As eosinophil counts go up, the incidence of exacerbation goes up too.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: As you see more inflammation, we see more exacerbations. That would be something that we all can agree on. We are dealing with a disease of the lungs, and we don’t have the ability to directly sample the lungs, right? We can’t biopsy all our patients for asthma with the prevalence of this disease as it is. And so we have to think about, how do we start to think about this? And I think we’ll get into a little bit more of that as we talk more about the biomarkers. But sort of thinking about that and moving forward, Brad, I’m going to pose a question to you. How do we diagnose asthma? How do we think about this disease, given this complexity of inflammation? We heard a little bit from Aidan about what this disease is, and what is happening. So then how do we diagnose it?
Bradley Chipps, MD: It’s tough sometimes, sort of like love. You know it when you see it, but you can’t really explain it. One of my mentors came up with that. But the point is, especially in Shawn Aaron’s paper published in JAMA and the follow-up in the Blue Journal that as many as many as 25% of patients treated both in primary care and specialty practices were undiagnosed with asthma when they went to a rigorous protocol that included bronchodilator reversibility, the presence or absence of airflow limitation, and a positive or negative methacholine test. And that Canadian study showed us that as much as 25% of patients are treated with asthma drugs when they don’t have an asthma diagnosis as their primary diagnosis. That just gives us a little bit of cause for concern and introspection, no matter where we sit in the cascade of asthma doctors, about making sure that we have the right diagnosis.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: So there’s both over and under diagnosis. Then how do we nail it down?
Nicola A. Hanania, MD, MS: That’s actually a very important issue you’re bringing up because we see this all the time. Patients are referred to us with uncontrolled or severe asthma on tons of medication. And we go really to square 1: Do they have asthma? And actually, some of these patients may have mimickers of asthma. Just the other day I had a patient referred with severe asthma. It turned out that she had glottic stenosis, or subglottal stenosis. She’s been previously intubated and she had fixed upper airway obstruction. She certainly had the inspiratory sounds on exam. So one has to go back to square 1: Is this asthma? Spirometry definitely is important to diagnose asthma. Many of my COPD [chronic obstructive pulmonary disease] patients are labeled with asthma. While both have airway obstruction, their response to therapy is different. And so, really the very first thing to know when we deal with an asthmatic [who] is very difficult to control is, is this asthma?
Bradley Chipps, MD: The important thing is that you’ve got to start with the upper airway and look all the way down into the alveolar air space to really decide: Is asthma the diagnosis? Is it interstitial lung disease? Is it another mimicker? Is it bronchiectasis? Is it smoking-related asthma?
Nicola A. Hanania, MD, MS: And at the same time, we also underdiagnose it. Many patients are referred to us with cough. We don’t think about asthma. We start looking at other causes. The triad of symptoms, the classic ones we learned about in medical school, are not always there. Cough, shortness of breath, wheezing—sure, if they’re there, there is a very high likelihood. Spirometry is important. And in those patients with normal spirometry, even a bronchial challenge should be done. Those usually detect mild asthma.
Bradley Chipps, MD: In children sometimes we have to, in fact, do a therapeutic trial of medication to make a diagnosis if they’re too young.
Nicola A. Hanania, MD, MS: Because you can’t do spirometry.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I think getting back to it, we had sort of heard a little bit about the pattern of symptoms. And so you saw someone who had symptoms that resembled asthma, in a way. I think getting that first medical history is great and is wonderful, but as you said, not all of our patients present with cough, wheezing, shortness of breath that’s worsened with activity or worsened at night, and a response to bronchodilators that can make it a challenge. But we do get that medical history, and then we use adjunct tests and our physical exam. And you had mentioned things like chest CT [computed tomography scan] and lung function. Brad, what are your thoughts on lung-function testing? How often is it helpful? Is it not helpful?
Bradley Chipps, MD: I think lung function test is extremely helpful, as it relates to airflow limitation, as it relates to bronchodilator responsiveness, and as it relates to airway constriction with a cholinergic agonist such as methacholine, or a histamine, or whatever you’re going to use as a marker of airway upper activity. And of course exhaled nitric oxide because that is a surrogate of eosinophilic airway inflammation.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Aidan, do you want to sort of build upon that?
Aidan A. Long, MD: Yeah, absolutely. We used to think that the process of airway inflammation would lead to what Brad was describing: Increased [bronchial] reactivity, or increased smooth muscle spasm due to stimuli such as methacholine. As that went untreated, then you would get what we call remodeling. These days we tend to think these things maybe go separately from one another. You can be very reactive without having a lot of inflammation. You can have a lot of inflammation without having much reactivity. And you have children who have significant remodeling, even early on—long before decades of untreated inflammation.
Bradley Chipps, MD: And it’s been shown that significant airway inflammation can occur with the positive symptoms.
Aidan A. Long, MD: So there’s that, and then, as Nic said, there are these masqueraders of asthma. So while, yes, it’s history, and it’s physical, and it’s lung function, you need to be fairly certain.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Yeah. I think there can be sort of different time courses for these different sort of pathways to be involved, right? You may have inflammation at 1 time that may lead to that airway hyperresponsiveness. Inflammation can disappear. The responsiveness in the airway reactivity remains, which can make it a challenge for us. In my practice, I say, “Let’s look at all these tools, and let’s look at them over a long period of time because we can be wrong.” And you have to always ask yourself the question, “Was I wrong about the diagnosis? Was I right?” And you have to constantly reassess, which I think is consistent with what the guidelines say.
Bradley Chipps, MD: And what is over all this is the fact that patients don’t take their medicine.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Absolutely.
Bradley Chipps, MD: As we try to look at patients that are referred to us who aren’t doing so well, that’s the main reason they’re not taking their medicine. That’s at least half the time.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I have a hard time believing that your patients don’t do everything you tell them to do.
Bradley Chipps, MD: They all do. I was talking about your patients, not mine.
Transcript edited for clarity.