The Use of Biologics for the Treatment of Asthma - Episode 3

Diagnosis and Biomarkers Tested

Peter L. Salgo, MD: What are the common ways now that you actually get on the diagnostic bandwagon here? If someone is in the office and says, “I wheeze,” now what do you do? Let me guess.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: You do pulmonary function tests.

Peter L. Salgo, MD: Wait a minute, stop with the pulmonary. Let me guess, you do a history first?

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: He probably has already done that.

Peter L. Salgo, MD: No, he didn’t.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: That’s because he’s babbling about cytokines.

Don A. Bukstein, MD: Their history is the most important part of diagnosis, and the most important part of the history in asthma or in any chronic disease is the part we probably don’t do as well as we should. [Sir William] Osler said it was the PPI. And I know you think PPI means something that we give when we have a little heartburn but no, it’s the patients perception of illness and their goals of what therapy they have. So that history of asthma has to start there, and then it includes the history. It gives you cough, or wheeze, or shortness of breath with the typical at night and, certainly, asthma is a night-time problem. Night. With exercise. With viral infections. You get the history.

You have to make a diagnosis. Especially some of the things that John and I encounter every day, and Linda, too, is that we have missed diagnoses. Some of the severe patients we see may not have asthma or may have asthma and another complicating thing like vocal cord dysfunction. So the very first thing we have to do is make the correct diagnosis. We do that by history, number 1. Number 2, we have objective tests. There’s the spirometry that Linda was talking about.

Peter L. Salgo, MD: Wait, before you get a spirometry, you listen to the lungs?

Don A. Bukstein, MD: No.

Peter L. Salgo, MD: Why not?

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Oh, come on, you listen to their lungs.

Don A. Bukstein, MD: An exam is…

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: It’s after history.

Don A. Bukstein, MD: No, exam in asthma oftentimes is very unrewarding.

Peter L. Salgo, MD: Why is that?

Don A. Bukstein, MD: Because oftentimes the most severe asthmatics with airflow obstruction, the

wheeze, they may cough a little bit, they may not do anything. You can get a little bit of abnormality in

the upper airway exam because it’s kind of 1 airway, 1 disease, but the truth is the exam, you do it and certainly it helps you rule out things but oftentimes is not real helpful in making that definitive diagnosis. So Linda is right. Making the definitive diagnosis is a diagnosis of spirometry and giving a bronchodilator. And I would say even no matter what that FEV1, the forced expiratory volume in 1 second is, you need to give a bronchodilator and see how much it improves. And then you do these ancillary tests to try to typify the asthma if you’re having a difficult time controlling.

Peter L. Salgo, MD: What about pulmonary function tests?

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Well, particularly in pediatrics because they can have normal FEV1s, but when you go to reverse them, you’ll see.

Don A. Bukstein, MD: Even in adults, we looked at several hundred patients—patients, athletes—at the University of Wisconsin, and what we found was when we measured their lung function, it was quite high, in the normal range. But many of them responded, by over 15%, 20%, to a bronchodilator, having super-normal lungs.

Peter L. Salgo, MD: Let me ask very quick questions now. They’re in the office. They are still in the office here. Pulmonary function tests. You were talking about them. What about a chest x-ray, sinus x-rays? Useful? Not useful?

Don A. Bukstein, MD: They can be if the history suggests. And that’s the thing, there are so many comorbidities.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Not sinus x-rays, sinus CT [computed tomography] scan. Nobody does x-rays.

Don A. Bukstein, MD: There are so many comorbidities involved here, a lot of them we should probably

talk about that really impact asthma and are super important for you as a payer. I know our HMO [health maintenance organization] wanted to know what factors predicted next year who would give us the most problem with asthma. And we looked at about 90 factors over a 2-year period, and what we found was it was a 2-question depression screen and PHQ-9 [Patient Health Questionnaire—9) that we did that predicted. So depression, that was one of the first studies to show that depression is really, really important in predicting asthma.

John J. Oppenheimer, MD: Another thing worth mentioning is that there’s a study by Shawn Aaron, MD, CM, and colleagues in Canada. They looked at a group of people with poorly controlled asthma. They went to a specialist. You know what they found?

Peter L. Salgo, MD: Tell me.

John J. Oppenheimer, MD: Thirty percent didn’t have asthma.

Don A. Bukstein, MD: Didn’t have asthma.

John J. Oppenheimer, MD: So I think some of the things we have to think about are, that we can get hoodwinked. People that really look like they have asthma. Or, more importantly, their comorbidity is driving their asthma symptoms.

Peter L. Salgo, MD: Are there biomarkers that help you make that diagnosis? Do they help identify that 30%?

Don A. Bukstein, MD: They only need to be used in those uncontrolled, difficult-to-control patients. They don’t need to be used in every single patient.

Peter L. Salgo, MD: So when do you use them? Who uses biomarkers? When do you use them? When do you get them?

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Which biomarker are we talking about?

Peter L. Salgo, MD: Take your pick. You’ve got cytokines, eosinophils, IL-4, IL-5, IL-13.

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: OK. Super-high eosinophils you start thinking about with a hypersensitivity pneumonitis or some of the other interstitial lung.

Peter L. Salgo, MD: But do you just get them on everybody? What triggers the...

Linda S. Cox, MD, FAAAAI, FACAAI, FACP: Almost everybody gets a CBC [complete blood count].

Don A. Bukstein, MD: The biomarkers we get are, we get skin testing to help us and, in a sense, that is a biomarker. It’s illuminating that Th2 [T-cell helper 2] phenotype. So we get skin testing. Then we get an eosinophil count. Everything has to be value. It’s got to be that quality over cost. So a CBC with differential, an eosinophil count, is very valuable. It is extremely valuable. IgE [immunoglobulin E] level, valuable. Exhaled nitric oxide, a test that’s relatively inexpensive, easy to do, reproducible. It isn’t always useful, but it’s useful a good bit of the time. And those are kind of the major biomarkers we’re kind of left with today. We can’t measure the cytokines, so those are the ones.

Louis Christos, RPh: What value were we measuring, and again I’m talking from a payer, before the biologics were approved for eosinophilic asthma? What was the benefit of measuring eosinophils?

John J. Oppenheimer, MD: Well, we didn’t have a stratifier. So, in the past, if you think about it, we approached all asthmatics all the same. And it’s really contrary to the syndrome we’ve talked about, asthmas, I like that. And we would just basically put people on ICS [inhaled corticosteroid] and dial up to ICS plus long-acting bronchodilators. And when they failed we would sort of scratch our head and figure out what comorbidity they had. Now, as we think about biologics, the present options we have in our armamentarium are a T2-high phenotype. So we’re looking at peripheral eosinophils. We’re looking at skin testing, which we always looked at because that’s a trigger. But we’re looking at that more carefully and we’re looking at ENO [exhaled nitric oxide], and putting it all together and trying to predict the right person for the right...

Don A. Bukstein, MD: In the old days we did eosinophil counts to see if the steroids were working. And I think that’s an important thing. We’re saying that eosinophil count is a biomarker. It really is more than that. It gives you the pharmacodynamics of the process that you’re trying to interrupt. So, if you give somebody an anti-eosinophilic treatment, whether it’s steroids or biologic, the very first thing you can see is that eosinophil count going down. So at least it tells you that you’re interrupting that physiologic process. Now, whether the patient gets better or not is something you have to say, but at least you know that you’re interrupting the process.