The Role of Biomarkers in the Evolution of Asthma

This is part of the MD Magazine^® Peer Exchange, “Precision Medicine in the Treatment of Severe Asthma.”Click here for Segment 6 and learn about considerations for diagnosing patients with asthma.

Peter Salgo, MD: When I was in medical school, the underlying mechanism of all of this was interleukins. I heard “interleukins” and I said, “I’ll never need that stuff.” But here we come—with IL-4, IL-5, IL-13, type 2 [T2]-high asthma. Can you put this together for me?

Raffi Tachdjian, MD: As we looked at asthma, we first alluded to the phenotypes. And then we got smarter and got into the lab and looked at genotypes. When we look at asthma in the span of about 15 to 20 years, and the prevalence which is doubling, that’s really an alarm. In any other disease state, that would be called an outbreak, right? An epidemic. And so, we got smarter and looked at endotypes.

In this era of precision medicine and personalized therapy, we need to understand the pathophysiologic mechanism for each person. And within each person, it’s now time to reassess control and all of the other things that we do phenotypically, taking it into this endotype and trying to get better at identifying triggers. Then we get predictive.

Peter Salgo, MD: OK. The interleukins that I hear about are IL-4, IL-5, and IL-13. And then we have biomarkers. What on earth do we do with the fractional exhaled nitric oxide [FeNO]? I am just used to using nitric oxide as a therapeutic agent. Now we’re looking at fractional exhaled nitric oxide.

Neal Jain, MD: This is an interesting story.

Peter Salgo, MD: It’s fascinating.

Neal Jain, MD: The individual who discovered this is in Sweden and was working in a lab. He was measuring exhaled nitric oxide in dogs and they had to calibrate this machine. One of his lab workers was allergic to dogs. The worker would come in and blow in this machine and his calibration was always off. It was always high. That led to the discovery of, “Hey, if you have allergic airway inflammation, that suggests that you’re going to produce more of this enzyme and this gas.”

And so, they ended up discovering these cytokines, or these interleukins. IL-4 and IL-13, particularly, drive up that enzyme to allow us to measure that gas in elevated levels if you have that pathway...

Peter Salgo, MD: Isn’t that interesting? Nitric oxide, as I understand it, is a tiny molecule that is actively involved in bronchodilation and pulmonary artery dilatation. It seems rational to me that everything structured down like that, you’re going to pump out nitric. Does that make sense?

Neal Jain, MD: We don’t really know the effects of nitric oxide on the airways. We know that it gets upregulated and how that has an effect, or if it does have an effect. If it’s just a bystander, we don’t know.

Peter Salgo, MD: It’s certainly an arterial active.

Neal Jain, MD: Right. An arterial active—absolutely. But if you look at the levels that are produced in the airways, it’s on orders of a magnitude that is higher than what you see in vascular endothelium or in neuronal tissue.

Peter Salgo, MD: Fascinating.

David Rosenstreich, MD: Many cells make nitric oxide in many different situations. They use it as a mediator for doing all kinds of things, but what we’re measuring is most of the nitric oxide that is coming from the airway eosinophils.

Neal Jain, MD: It’s from the airway epithelium.

David Rosenstreich, MD: And so, it’s like a surrogate marker for inflammation.

Peter Salgo, MD: Now we have serum periostin and blood and sputum eosinophils here. We’ve got immunoglobulin E [IgE]. This is all exploding. This is good stuff. Is the average practitioner expected to know all of this?

Raffi Tachdjian, MD: I don’t think so. Most allergists might not be getting into these details, but if we’re trying to achieve that type of personalization, we need to understand this. Going back to your point of innate versus adaptive immunity, certainly, on the innate side, we’ve got those pattern sensitizers, or pattern readers, in the innate immune system. When we look at our adaptive one, that’s where the IL-4 and IL-13 converge together on the IL-4 receptor. You’ve got eosinophils acting in the IL-5 patterns and IgE being produced in that adaptive immunity system. So, at any point, you might have a defect or an upregulation or downregulation. It helps to know where that problem is. The problem within the problem is biomarkers and having an easy set of readouts, kind of like a cardiologist could have for their EKG [electrocardiogram]. Now, we finally have our fractional exhaled nitric oxide.

Peter Salgo, MD: This is all exciting stuff.

Neal Jain, MD: It is. It’s complicated, and I don’t think we know the answers. Right now, what we’re looking for is, do you have T2-high asthma or not? And any of these—the IL-4, IL-5, and IL-13—tend to drive these biomarkers up.

Peter Salgo, MD: In T2-high asthma?

Neal Jain, MD: In T2-high asthma.

Peter Salgo, MD: So, T2 high is the stuff where we’re pointing at these biomarkers and the interleukins?

Neal Jain, MD: It’s a network. You have all of these different things that are out there, and you may have a source for this inflammation. But there’s a network and different sort of connections between that network.

Transcript edited for clarity.