IL-6 as a Biomarker for Asthma Exacerbations

In this podcast, Michael Peters, MD, talks about his team's cross-sectional analysis on the use of blood eosinophils and IL-6 as predictive biomarkers of the exacerbation-prone asthma phenotype over 3 years. 

Additional Resource:

• Peters MC, Mauger D, Ross KR, et al; NHLBI Severe Asthma Research Program. Evidence for exacerbation-prone asthma and predictive biomarkers of exacerbation frequency. Am J Respir Crit Care Med. 2020;202(7):973-982. https://doi.org/10.1164/rccm.201909-1813oc 

Michael C. Peters, MD, is an assistant professor of medicine in the Division of Pulmonary and Critical Care Medicine and the Department of Medicine at the University of California San Fransisco. 

TRANSCRIPT

Amanda Balbi: Hello everyone, and welcome to another installment of Podcasts360—your go-to resource for medical news and clinical updates. I’m your moderator, Amanda Balbi with Consultant360 Specialty Network.

Previous studies have suggested that eosinophils and IL-6 may be able to predict or identify exacerbation-prone asthma. However, longitudinal data is lacking.

To fill this need, a group of researchers conducted a trial to prospectively test for the exacerbation-prone asthma phenotype and utility of baseline blood measures of eosinophils and IL-6 as predictive biomarkers.

Today I’m joined by the lead study author, Dr Michael Peters, who is an assistant professor of medicine in the Division of Pulmonary and Critical Care Medicine and the Department of Medicine at the University of California San Francisco.

Thank you for joining me today, Dr Peters. To start, can you tell us more about how your study came about?

Michael Peters: In cross-sectional studies, there's been a pretty solid body of literature that suggests that some patients are exacerbation-prone or have higher rates of exacerbations, particularly severe asthma compared to another subgroup of patients, who's somewhat as exacerbation-resistant.

One of the first objectives of the study was to try and verify this or prospectively test whether or not an exacerbation-prone phenotype actually exists in asthma. And what that means is you can have a lot of exacerbations in one year, but it actually was somewhat unclear whether or not that people who have a lot of exacerbations one year are distinctly the same population of subjects over subsequent years. So that was the first objective.

Using transitional state modeling or some new methods for modeling prospectively, we’re able to pretty definitively show that there are a subgroup of patients—a relatively small subgroup at least in our cohort—that go on to experience exacerbations consistently over multiple years of follow-up. Our study was done over 3 years. So that was the first fundamental thing that we were looking to do.

Kind of interesting is that embedded in that is It also demonstrates that, even in the severe asthma population, which we were studying, there was also a subgroup of patients who actually didn't have exacerbations prospectively over multiple years.

And so, that implies that there's other things that we know that are keeping their disease ongoing, either it’s symptoms or persistently low lung function. But they're not actually having exacerbations. They seem to be somewhat exacerbation-resistant.

The next component of this trial was to prospectively look at 2 particular biomarkers that we believe to be associated with exacerbations in cross-sectional analysis. One was blood eosinophils in asthma. Blood eosinophils have been a pretty good predictive biomarker of TH2, or type-2 high asthma. That's an allergic asthma component.

There are now 4 FDA-approved drugs to treat the eosinophil-high or type-2 high patients. And mainly in preventing exacerbation. So we're interested in kind of seeing how that predicts the entire cohort of subjects.

And it does turn out that the blood eosinophils predicted the development of exacerbations prospectively, but equally somewhat interesting is that that effect size wasn't actually that large or at least was relatively inconsistent.

The other thing that we were interested in looking at was plasma IL-6. We had previously demonstrated that patients who had IL-6 levels or high plasma IL-6 levels tended to have more exacerbations in a cross-sectional analysis. This subgroup of patients tends to be obese, have metabolic diseases like hypertension and diabetes, and tended to have some of the other features a severe disease, such as low lung function and increased symptoms.

And what we found is that in the prospective data over 3 years that having high plasma IL-6 levels was actually pretty predictive of having exacerbations prospectively. And importantly, that so group of patients that I previously—the exacerbation-prone subgroup, a group that had exacerbations every year of the study—was characterized significantly by features of metabolic dysfunction, so high plasma IL-6 levels, a high body mass index, slightly older age, and significantly high comorbidities of hypertension and diabetes.

And so that was consistent with our hypothesis that metabolic disease or metabolic dysfunction may predispose a certain subgroup of patients with asthma to develop exacerbations over multiple years of follow-up. That's what we were kind of interested in at least determining and figuring out

Amanda Balbi: So, like you said, 3-year asthma exacerbation data were analyzed in 406 adults in the Severe Asthma Research program-3. Of whom, 83 participants had at least one exacerbation in each year and 168 participants had no exacerbations in any year. What patient characteristics contributed to a higher risk of exacerbation?

Michael Peters: The highest-risk patients were those who had features of metabolic dysfunction. For example, for each one picogram per microliter increase in plasma IL-6, which is a relative scale. Zero is basically no IL-6 levels; 10 is pretty high. So, for each one picogram increase on that scale, your risk of exacerbating or the incident rate ratio of exacerbating increased about 10%.

Given that range, a 3-picogram increase would increase your risk about 30% for a single exacerbation or the incidence of an exacerbation over 3 years. So, it was relatively significant. Other features of the disease where exacerbation-prone or other things that are associated with metabolic disease, diabetes, hypertension, and in high BMI.

Amanda Balbi: Your results also showed that the uninformed probability of an exacerbation in Year 3 was 40%, but the informed probability increased to 63% with an exacerbation in Year 2 and increased to 82% with an exacerbation in Years 1 and 2. The probability of a Year 3 exacerbation with no Year 1 or 2 exacerbations was 13%. What do these findings mean for clinical practice and how exacerbations should be managed in the future?

Michael Peters: Yeah, that's a great question. The 40% uninformed probability means generally in the cohort of patients we were studying, which was a pretty severe cohort, that in the annual about 40% of the patients had exacerbations randomly, if you didn't know anything about them outside of the fact that they were in the SARP cohort. But if you knew their exacerbation history just by one year, you significantly increase your ability to distinguish whether or not what the probability was that they would have an exacerbation over subsequent years.

And so that one year increased it about 40% to about 60%. And actually, if you knew their exacerbation history over 2 years, that increased probability was, as you said, 82%, so a significant increase in the probability that they would have an exacerbation of subsequent year.

And this means that you could potentially intervene, right? With either medications that prevent exacerbations, if they were eosinophil-high; if they had high eosinophil counts, you would consider giving them one of those anti-IL-5 or anti-IL-13 medications.

But conversely, what it also suggests is that patient population that we already have established as being associated with metabolic disease could be intervened upon with the disease modifiers that impact metabolic function—diabetes, hypertension, lifestyle modification, and potentially even an IL-6 antagonist.

That provides a new paradigm for potentially treating the patients that have these recurrent exacerbations. On the flip side of that is if someone didn't have an exacerbation over the subsequent prior years the likelihood that they go on to develop one is actually quite low.

You can be relieved and actually even consider stepping down therapies that are designed to prevent exacerbations with the thinking that that their likelihood of developing one is significantly lower than you may have received in the past.

So that that provides some context and confidence for clinicians to treat patients based on historical data prospectively.

Amanda Balbi: You and your team also evaluated baseline eosinophils and IL-6 as predictive biomarkers. What did your results show for these measures?

Michael Peters: Both of these are predictive exacerbations prospectively. The finding for eosinophils like I said is not super novel or new. That's been relatively well-described at eosinophils are associated with exacerbation risk. The somewhat new finding is that the plasma IL-6 levels for metabolic dysfunction was more or less equal.

Within this population, having metabolic dysfunction actually put your risk at the same level as having high blood eosinophil cell counts. That's important because we have drugs that are well established for treating eosinophil-high patients; that the medications to treat the IL-6-type subjects aren't as clear.

We would predispose that you might be able to improve their disease with treatments and metabolic dysfunction, but that actually has been proven and that's the next step of research—is to try and figure out how do we prevent exacerbations in this specific patient subgroup? Because drugs really don't exist that we know of that helped their disease.

And the other obvious context, just to mention it since we're in the middle of a pandemic, is that the same features have now been shown to be associated with COVID infection. This is something we didn't know when we were doing the trial or the study, which was long before COVID ever existed. But it's interesting that it came out around the same time that this association has now been appreciated in other viral illnesses such as COVID.

Amanda Balbi: That's very interesting. So, it'll be interesting to see your subsequent studies and see what kind of treatment options there are for people like that.

Michael Peters: This is a pretty new and exciting area of research that we've been working on for a while, but it just turns out that is now become much more hot and relevant to the world of respiratory illnesses, because of the obvious associations with COVID and metabolic dysfunction.

Amanda Balbi: Yeah, for sure. Overall, your analysis confirms an exacerbation-prone asthma phenotype characterized by features of metabolic dysfunction. How might clinicians use this information to better care for their patients with asthma?

Michael Peters: I think most clinicians, or I should say most pulmonologists, are well aware of the fact that metabolic disease causes diabetes, hypertension, cardiovascular disease, associations with depression, neurovascular illnesses.

But the thing that's been relatively underappreciated is that it causes lung diseases and particularly leads to, as we demonstrated, increased risk of viral induced or exacerbations in asthma. So pulmonologists are going to need to start paying attention a little bit more that the overall health of their patients and potentially intervening to prevent these downstream consequences—so better glucose control, better blood pressure control, generally better lifestyle modifications.

The thinking here, which is also important, is it wasn't simply a BMI effect. We controlled for body mass index in our analysis. So, pulmonologists a lot of times will say “lose weight” or “get your BMI lower.” And that's a pretty hard thing to do. The data to for interventions to lose weight are difficult.

But actually, the interventions in regard to improving metabolic disease are significantly easier. We have drugs that treat hypertension. We have pretty well-established lifestyle modifications that do decrease systemic inflammation and enable patients to get on a better scale in regard to metabolic diseases. It's a cognizant of pulmonologists now to be aware of this and to potentially treat their patients accordingly.

Amanda Balbi: Great. Thank you so much for joining me today and answering all my questions.

Michael Peters: Yeah. Thanks, Amanda. It's been great chatting with you and have a good day.