Identifying Allergic Asthma
MARCH 25, 2019
MD Magazine Staff
Neal Jain, MD, FAAP, FAAAAI, FACAAI: So we heard a little bit about allergic asthma. This is a conversation that I think we’re having oftentimes: What is an allergic asthmatic, and how does that differ from the other asthmatic? What is the overlap? So Aidan, I’m curious to hear your thoughts on how you would define an allergic asthmatic.
Aidan A. Long, MD: Clinically, they may not be that different from other asthmatics. Pathologically, allergy is a systemic disease in which people have an exaggerated immune response to everyday environmental proteins: pollen grains, dust mites, cat and dog allergens. And some of those people get disease in the nose, the eyes, and in the lungs.
Bradley Chipps, MD: And the skin.
Aidan A. Long, MD: And lung disease shows up as asthma. Clinically, in the mild and moderate forms, it doesn’t differentiate from other pathways of asthma. It still is the same process. Airway constriction, inflammation, and mucus production. But the triggers might be different. So it may be driven by specific exposures. Being in a dusty environment or a moldy environment or being around cats or dogs may worsen asthma. So they have that difference from the others. They’re still prone to viral-induced exacerbations like other people. So it’s not an exclusive pathway, but it’s a contributing pathway.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I think that’s a really important point. Exercise, those other factors, infections, etc, will oftentimes drive their disease. But this question is, is that sort of ongoing allergic exposure sort of predisposing them from the standpoint of driving that inflammation that you had discussed earlier?
Nicola A. Hanania, MD, MS: Yeah. As a pulmonologist, I find that allergic asthma is fascinating. Not only is it the most common type, but often these patients, as you mentioned, have other upper-airway comorbidities. If we miss the point that there are allergens driving these comorbidities, we may not be able to treat them well. I think it has now become very apparent, at least in the pulmonary community, that looking for allergic asthma—testing for IgE, or even skin testing, or doing RAS testing—is important, to see not only if the patient would be qualified for certain targeted therapies but actually what type of asthma you are dealing with. Do I treat these patients differently? I think it’s something that is very important, and we see it a lot.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Yeah. So you had touched on IgE earlier, Brad. You had mentioned some of the different inflammatory cells: Again, type 2 innate lymphoid cells, eosinophils, mast cells. Let’s talk a little bit more about the biology. We’re hearing more about the different cytokines that are involved as we learn more about these targeted therapies. What are those cytokines? What does the inflammation look like when we think about allergic asthma?
Bradley Chipps, MD: Well, with allergic asthma, especially since I’m the token pediatrician here, in younger children IgE, of course, is a major player as it relates to degranulation of mast cells and the downstream effects associated with mediated release, which are potentially blocked by omalizumab, which is anti-IgE treatment approved down to age 6 in children. I think it’s an important adjunct to our therapeutic armamentarium in younger children. Many of these children, of course, are treated quite nicely with the current pharmacologic therapy we have without having to use a biologic. But I think those are important conversations to have with the patients and caregivers in order to try to determine the best way forward for those patients.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Sure.
Aidan A. Long, MD: So I think in terms of the pathway, the allergic asthma is the classic T2 high. As Brad mentioned, IgE is formed. It tends not to stay in the bloodstream. It sits on top of specialized cells, such as mast cells and basophils, which then get activated release, a bunch of cytokines and chemicals, including those cytokines that we typically recognize as being the T2-high group: interleukin-4 [IL-4], interleukin-5, interleukin-13, there are some others, interleukin-9. They’re the key players. They then drive the other manifestations of the disease as far as we understand. They induce bronchospasm; they induce eosinophil infiltration; they increase mucus production. So many of what Nic described as the phenotypic characteristics can be related back to these cytokines that are produced in this very canonical T2 type of pathway that we call allergic asthma.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: What are the cytokines that lead to that IgE production in the first place? How does that develop?
Nicola A. Hanania, MD, MS: There are several. Interleukin-4 is a very important cytokine for the switching, in which B cells and formation of IgE is important. Of course the trigger is the allergen, right? And epithelial cells are very important there. There are several cytokines up in the cascade that may play a role. These are the alarmins at which we’re still trying to block now with novel therapies.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Tell me a little bit more about the alarmins, because I think that’s the first time we’re hearing about this.
Nicola A. Hanania, MD, MS: There are several, including IL-25, IL-33, and TSLP. These are cytokines that are up in the cascade that can actually drive both T2 high and T2 low asthma. They may play a role in allergic asthma but also in nonallergic asthma. We’re trying to figure this out, but certainly the cytokines we are more familiar with are downstream signals. IL-4 is certainly upstream, but IgE, IL-4, and IL-5 are the ones that we are more familiar with now and that we can target. But certainly, mast cells play a major role in the allergic asthma cascade, and circulating IgE, which is 1 thing that we try to tackle.
But another reason that it is important to look for allergic asthma—and I’m sitting here with 2 allergists—is the role of immune therapy. There’s an emerging role with a sublingual immune therapy injection. I don’t deal with this as a pulmonologist, but I think there are options for these patients, not only to identify allergic comorbidities but to identify the role of targeted therapy for IgE but also IL-4. Targeting IL-4 can lower the IgE levels but also immune therapy—in some patients it works. So I think that’s why it’s important to sort of split the pie and not just lump the whole asthma group in 1.
Aidan A. Long, MD: I actually think you asked a great question about the alarmins, and Nic described it well. He talked about them being higher up in the cascade. And schematically we think of it as the epithelium. The alarmins are those triggers that come from the damaged epithelium that drive the whole T2 cascade, whether it’s through the adaptive immune system with Th2 [T helper 2] cells or the innates through the ILC2s. But the allergenic exposure, the virus exposure, or the pollutant exposure at the epithelium sets this whole thing up.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Right. So that’s painting the picture. From up high, you start with this damage that you’re describing. That damage can come from a variety of different factors. That damage then leads to this downstream inflammatory cascade with things like the production of IgE and, again, stimulation of things like IL-5 and eosinophils.
Transcripts edited for clarity.