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Breaking New Ground in CRSwNP: Type 2 Inflammatory Pathways in CRSwNP and the Critical Function of Airway Epithelial Cytokines Roundtable Module 1
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Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

Nurse Practitioners/Nurses: 0.25 Nursing contact hour

Released: June 20, 2025

Expiration: June 19, 2026

Kathleen Buchheit
Kathleen Buchheit, MD
Anju Peters
Anju Peters, MD, MSCI
Stephanie S. Smith
Stephanie S. Smith, MD, MS

Breaking New Ground in Chronic Rhinosinusitis with Nasal Polyps

 

Katie: We are going to start by discussing inflammation in chronic rhinosinusitis with nasal polyps, specifically type 2 pathways.

 

First off, what is chronic rhinosinusitis with nasal polyps or CRSwNP? This is predominantly a type 2 inflammatory disease. Patients develop chronic inflammation of the perinasal sinuses and they can develop nasal polyp formation that leads to symptoms including rhinorrhea. Patients can get thick nasal discharge, postnasal drip, nasal congestion, hyposmia, or even complete anosmia and sometimes facial pain and pressure.

 

There may be a slight male predominance, and this is actually very common in patients with asthma. There are estimated to be about 25% to 50% of patients with chronic rhinosinusitis with nasal polyps also have asthma.

 

In terms of the inflammation driving chronic rhinosinusitis with nasal polyps in the polyp tissue itself, we will see dense eosinophilic infiltration, type two inflammation predominates. Th2 cells, ILC2s are producing type 2 cytokines such as IL-4, IL-5, IL-13.

 

Looking in more detail at this type 2 inflammatory cascade, we often think about type 2  inflammation starting in the epithelium. Patients with chronic rhinosinusitis with nasal polyps have really profound dysregulation of the nasal epithelium and the sinonasal epithelium. This damaged epithelium can release alarmin or innate type 2 cytokines such as interleukin-25, IL-33 or TSLP.

 

These cytokines can lead to activation of ILC2s, Th2 cells, to really propagate type 2 inflammation, leading to downstream further release of the adaptive type 2 cytokines such as IL-4, IL-5, IL-13, leading to all of the players that we see in type 2 inflammation including class switching to IgE, eosinophilic inflammation, activation of mast cells and mast cell mediators being released and basophil activation.

 

Now we are going to watch a short video that goes into this inflammation in further detail.

 

Speaker: Alarmins are released by epithelial cells in response to environmental insults like allergens, microbes and pollutants. They help to shape the immune response. The alarmins include interleukin-33, interleukin-25, and thymic stromal lymphopoietin, also known as TSLP.

 

TSLP promotes the differentiation of naive T cells into Th2 cells. It also enhances group 2 innate lymphoid cells known as ILC2s to produce IL-5 and IL-13. These are key cytokines in type 2 inflammation. Interleukin-33 acts on ILC2s and Th2 cells to stimulate production of IL-5 and IL-13. This can promote eosinophilic infiltration, mucosal edema, and polyp formation.

 

Interleukin-25 enhances ILC2 activity and Th2 cytokine production. It works with IL-33 and TSLP to amplify type 2 inflammation. These alarmins play a central role in the pathogenesis of chronic rhinosinusitis with nasal polyps by orchestrating a type 2 immune response. This contributes to eosinophilic inflammation, tissue remodeling, mucus hypersecretion and the formation of nasal polyps.

 

Katie: There are multiple different molecular endotypes that can drive chronic rhinosinusitis with nasal polyps. We have talked a lot about type 2 inflammation already, but there are patients who have predominantly type 1 endotypes in chronic rhinosinusitis. This is thought to be driven primarily by interferon gamma released by Th1 cells, NK cells and type 1 innate lymphoid cells.

 

There are type 2 molecular endotypes, which we have talked a lot about already, and this is actually really what we see as the predominant endotype of most patients in western countries. That is again driven by the canonical type 2 cytokines, IL-4, IL-5, IL-13, driven primarily by Th2 cells, mast cells, ILC2s.

 

Then some patients have what we call a type 3 endotype, which we think is driven by IL-17 released by Th-17 cells and ILC3 cells. These patients predominantly develop neutrophilic inflammation.

 

In the United States, we see type 2 endotypes as the most common endotype. In parts of Eastern Asia, all three endotypes can be prevalent in different patients. Then we do see a lot of patients who have mixed inflammatory endotypes, so they may have evidence of more than one of these predominant endotypes present in the same patient.

 

There are specific rules for cytokines, leukocytes and tissue inflammation in chronic rhinosinusitis with nasal polyps. We already talked about type 2 cytokines. It is very well established that interleukin-5 can sustain and lead to further tissue eosinophilic inflammation, IL-4 and IL-13 have a variety of different roles, including B cell class switching to IgE producing cells, mucus production, macrophage polarization, and it has effects on remodeling of epithelial tissue.

 

Then immune cells can really further propagate this inflammation. Eosinophils can release toxic granules leading to tissue damage, furthering mucus production. B cells can produce IgE which can activate mast cells and basophils further. Then the cytokines can actually feed back onto the epithelium leading to further epithelial dysregulation impacts on cell test cell adhesion in the epithelium so it becomes leakier. Then leading to further release of alarmins such as TSLP, IL-33 and IL-25.

 

Clinically, type 2 inflammation is important. We see this as a strong driver of sinonasal inflammation in patients with chronic rhinosinusitis with nasal polyps. It is associated with symptoms such as loss of smell. It is associated with asthma comorbidity and it is a target for biologic therapies. There are biologics available that can target IgE, IL-5 and IL-4 receptor alpha, which can block IL-4 and IL-13 signaling.

 

We are going to have a panel discussion here with my colleagues. I would love to hear from Anju and Stephanie[?], do you use specific tests like biomarkers to characterize inflammation in patients who are presenting with symptoms of chronic rhinosinusitis with nasal polyps?

 

Dr. Anju Peters (Northwestern Feinberg School of Medicine): Alright. Katie[?], thank you very much for sharing type 2 inflammation in nasal polyps. As you know, I take care of patients with asthma and CRS with nasal polyps. Unlike asthma, where I feel like we have better biomarkers with CRSwNP, we do not really have good biomarkers to tell us a patient with nasal polyp will respond to which type of medication.

 

However, we do have some biomarkers I feel in CRSwNP that do give us an idea of disease recurrence, especially if they had surgery and disease severity. Those I think help me a lot if I see patients who have had surgery for nasal polyps, which is I feel every patient with nasal polyps should be evaluated for surgery and consider at least one surgery. The one I do use is look at the pathology, and if they have increase in eosinophils and what do call increases different throughout the world, but if they have eosinophilic inflammation on their surgical pathology, it gives us a pretty good idea that disease can recur based on quite a bit of literature. That to me is one of my favorites to use as a biomarker, clinical history sometimes.

 

So you take care of a lot of patients with AERD, the aspirin-exacerbated respiratory disease, which we know those patients have such severe disease recur patients with asthma recur. Those are what I would consider clinical biomarkers to me.

 

Stephanie, what do you think as a surgeon?

 

Stephanie: Yeah, I would agree with Anju. I think that sort of pathology demonstrating more than 10 EOs per high power field suggests that type 2 inflammatory response to me. Whereas lower EO count and more neutrophil predominant might suggest more of a type 1 or type 3 or mixed inflammatory pattern, but it is not just a black and white situation here. We rely on that surgical path.

 

I think sometimes whole blood eosinophils or total serum IgE may be helpful as well. Or if I know the patient has allergies, has tested positive skin prick or serum tests, sometimes we will take that into consideration. It can clue us into more allergic or type 2 picture.

 

Katie: Yeah, those are really good points. I think I do something very similar. Often when I meet a patient who, I have a sense that they have pretty severe disease and are going to likely need interventions such as surgery or biologic therapy, I will often check at least the biomarkers I can check, which would be peripheral eosinophil count and serum IgE levels before doing anything because we know that our interventions like oral steroids, biologic therapy and even surgery can impact these biomarkers.

 

I find it helpful just to get some baseline information for patients when I have a feeling that they have quite severe symptoms and are likely going to lead pretty intensive therapy down the line. That is great.

 

Next question is what are the benefits of early mitigation of inflammatory pathways with biologics?

 

Dr. Peters: I think that is a difficult question. I am sure Stephanie, you have your view on it. I feel like you and I probably share similar view. I mean you mentioned it, both Katie and Stephanie, we can check to see if they have type 2 inflammation and euphoria gives us a pretty good guidelines on it.

 

In someone who has significant asthma, the way I am thinking of it, if you are asking me should we consider biologics to avoid surgery, I do think most patients should probably get one surgery. Biologics are really expensive and most people need to be on it long term. However, there is subgroup of people who we know disease recurs after surgery. I may consider using a biologic either with surgery or even ahead of surgery to decrease inflammation that coexists with nasal polyps often in their asthma.

 

In terms of using it with surgery, we really have one study that was recently published that did not really show that much difference because it was small study, whether they got biologic surgery or without surgery. Their polyps, all of them went down. The people who got biologics with surgery had dupilumab, they had some improvement in smell more than the group that just got surgery.

 

I am not so sure in most patients with nasal polyps, but I would start them with biologics just to get rid of their inflammation. I think most should get an evaluation with a surgeon too. I really feel that it should be a multidisciplinary and then we can decide. I think if they do well just with one surgery, which many do unless there is some other need for biologic, I am not sure I would go that route.

 

Stephanie: I think the question of what are the benefits of early mitigation with biologics, is difficult to answer at this time with the evidence we have. We may find that biologic therapy concurrently with surgery or potentially before surgery can help us avoid it or reduce bleeding or operative time. But right now the evidence for that, we do not have.

 

I think early treatment of inflammatory pathways and polyps can potentially reduce systemic steroid use and just over utilization of healthcare in general. But right now we still have that question there of biologics before surgery or going straight to surgery and using biologics as a rescue.

 

Katie: Yeah. I agree with both of you. I think that this is an area where there is not strong evidence to really guide when to use it very early or not. Even in the asthma world, where we have been using biologics a lot longer, this is still an area of active investigation. I think it is going to take some really some time to understand how and when timing wise to really utilize this.

 

I do exactly what Anju does. Unless patient has really severe comorbid asthma or another indication where they really need a biologic, I often will send them for at least one surgery before initiating biologic therapy.

 

Our last question is, what are advantages of targeting airway epithelial cytokines like TSLP versus downstream cytokines?

 

Stephanie: I think that Anju and you are more of an expert than I am. But to me just the most obvious answer is broader disease coverage for our mixed endotypes or type 1, 2 and 3 endotypes potentially. That is the big answer to me.

 

Dr. Peters: I think I totally agree with what you are saying, Stephanie, especially because we have always said in western population nasal polyps 87-some-percent are type 2. However, work done by actually one of our colleagues at, Atsushi Kato, who I think is just a genius and from other places it looks like there is a lot more mixed inflammation than we used to think and that having the neutrophilic inflammation with the eosinophilic inflammation, potentially maybe more severe disease.

 

There is a study done at Vanderbilt where they took people with actually chronic rhinosinusitis and those that had both eosinophilic inflammation on their pathology and neutrophilic inflammation had more severe disease in terms of SNOT-22. So their symptoms, they had worse CT scans.

 

Even Atsushi recently has shown that if you have neutrophilic inflammation, you may get more disease recurrence after surgery. I think targeting broader inflammatory pathways by targeting TSLP, which is more upstream makes sense because our immune system is so complex. Just blocking one or two cytokines potentially may not target all the inflammation. However, I think we still need to learn a lot because dupilumab works very well for nasal polyps and targets.

 

We think only IL-4 receptor alpha, which shares the signaling for both IL-4 and IL-13. However, in targeting IL-5, we do see benefit and there are proof of polyps, but potentially we are not seeing as much benefit.

 

Katie: Yeah, I think that is all really good point. This is a very heterogeneous disease. Even in AERD, which we think of as one of the most type 2 phenotypes, we are learning again from some good work that was done at Vanderbilt, that indeed there is much more inflammatory heterogeneity even in patients who have AERD specifically, and that there are certainly different post endoscopic sinus surgery outcomes, post aspirin desensitization outcomes, and really targeting something more upstream may take some of the guesswork out of which patient is going to respond to this specific type 2 markery. It is really upstream of all of them. That I think is certainly attractive from that standpoint.

 

That is great. Thank you so much for your excellent thoughts and for joining us today.

 

[END OF TRANSCRIPT]