Shifting the Treatment Paradigm of Severe Asthma With Novel Biologics - Episode 3

TH2-High and TH2-Low Phenotypes in Severe Asthma

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Nicola Hanania, MD, MS, explains the pathophysiology of type 2 inflammation in patients with severe asthma and the importance of differentiating TH1-high and TH2-low phenotypes.

Reynold Panettieri Jr, MD: Let’s move on to the third question. Nic, could you take the lead on this? We’re going to be talking about T2 vs low T2, high T2 vs low T2. This is a big topic, so we want to really get it down to what we need to know. Nic, for our colleagues listening today, how do you differentiate high T2 from low T2? What are the cell types and maybe some of the mediators?

Nicola Hanania, MD, MS: For many years, we’ve known that asthma is caused by airway inflammation, but we always thought that it’s 1 type of inflammation. More recently, it was important to realize that it’s not a 1-phase disease. It’s based not on phenotypes but also on endotypes and the mechanism of the disease. Right now, our thought is—and this is an evolving field—that we have at least 2 large subsegments of asthma but only 1 inflammatory-wise. One is a T2-high asthma, and then another is T2-low, or non-T2 asthma. T2-high asthma is usually characterized by eosinophils in the periphery or in the sputum, and highly FeNO [exhaled nitric oxide]–allergen driven, so there could be allergen driven by TH2 cells. But it also could be driven by the innate immune system by certain cells, called ILC2 [group 2 innate lymphoid] cells, which drive very similar mediator release. These mediators include interleukin-5, interleukin-13, and interleukin-4, and this type of asthma is definitely characterized by eosinophilic inflammation. 

The recommendations for labeling someone with T2-high asthma are high peripheral eosinophils, high FeNO allergic-driven disease, or dependent on oral steroids. That may be controversial, but it’s listed as 1 of the criteria for labeling somebody with T2-high asthma. It is biomarker driven but also allergen driven or triggered—but it’s also dependent on oral steroids. Those groups of patients are thought to have T2-high asthma. This obviously has implications on response to therapy, particularly when it comes to inhaled steroids or even targeted therapies. The simple thing is that there’s really no 1 answer or 1 test you can do. It’s taking a good history, looking at triggers, checking IgE levels, allergen-specific IgE or skin testing, and checking peripheral blood eosinophil levels. If you have the capability to look at sputum eosinophil, and if you can measure the FeNO in adults, 25 parts per million or higher suggests a T2-high asthma. Somebody who is dependent on oral steroid is thought to have T2-high asthma.

Reynold Panettieri Jr, MD: You hit all the points. The biomarkers are critical, right? They really are critical. Why even care about T2-high, T2-low? Because they’re specific therapies, right Nic? That’s where the rubber meets the road. We have therapy and biomarkers to find the therapeutic approach. Sid, anything to add? How about the case definition for low T2s and the absence of T2-high?

Sidney Braman, MD: Unfortunately, there’s no specific definition. We know that the biomarkers are a very different thing. You’ve got IL-6, TNF [tumor necrosis factor] alpha, and IL-8, so you’re not dealing with the same immunologic milieu as you would. But in terms of the absolute definition, we don’t have it. We certainly know that it’s predominantly neutrophilic or paucigranulocytic, so those are some of the markers of this non-T2. But regarding a specific definition, I don’t think anybody has created 1 yet.

Reynold Panettieri Jr, MD: Thank you for watching this HCP Live® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. It comes to you wherever you’re at: on your phone, in your office, or in your home. I want to thank everyone and our sponsors for this wonderful opportunity. Have a wonderful day, and be safe. Thank you.

Transcript Edited for Clarity