Mixed Type 1/3 Inflammation Linked to Faster Polyp Recurrence in CRSwNP

A recent study revealed distinct disease trajectories among endotypes in chronic rhinosinusitis with nasal polyps (CRSwNP), showing that patients with mixed type 1 and type 3 inflammation tend to have more recalcitrant disease.1

“These findings suggest that therapies beyond traditional type 2 inflammation treatments may be needed to effectively reduce CRSwNP disease recurrence,” wrote investigators led by Christina Dorismond, MD, MPH, from the department of otolaryngology-head and neck surgery at Vanderbilt University Medical Center in Nashville.

Traditionally, chronic rhinosinusitis (CRS) treatment has been guided by phenotypic features, but recent research suggests that inflammatory endotypes may offer more guidance. Emerging therapies for CRSwNP, such as dupilumab, omalizumab, and mepolizumab, target type 2 inflammation.2 However, despite growing interest in endotype-based classification, studies linking specific endotypes to clinical outcomes remain limited.

Investigators sought to compare the disease trajectory, specifically the time-to-polyp recurrence, between CRSwNP endotypes.1 They collected data, such as cytokine levels measured using a multiplex bead assay, on patients with CRSwNP undergoing surgery between 2015 and 2025. The team conducted a principal component analysis and hierarchical cluster analysis to identify endotype clusters.

Dorismond and colleagues identified 6 CRSwNP disease clusters:

• Cluster 1: Relatively low inflammation (46.5%)
• Cluster 2: Mixed type 1/3 inflammatory endotype (IFN-γHigh/IL-4High/IL-17AHigh) (4.5%)
• Cluster 3: Innate, proinflammatory responses (IL-1βHigh/IL-6High/IL-8High) (10%)
• Cluster 4: Low inflammation but elevated levels of interleukin (IL)-12/IL21 (13.3%)
• Cluster 5: Type 2 dominant inflammation (IL-5High/IL-9High/IL-13High) (18.9%)
• Cluster 6: Low inflammation but elevated levels of CCL5 (7.1%)

All disease clusters were characterized by some kind of type 2 inflammatory burden, but only cluster 5 was characterized by homogenous type 2 inflammation. Patients in cluster 5 had the greatest levels of IL-5 and IL-13, the largest numbers of tissue eosinophils on pathology, and the greatest proportion of patients with AFRS.

The analysis showed clusters 2 and 4 had the shortest time-to-polyp recurrence, and cluster 3 had the longest time-to-recurrence (P < .001). The clusters had similar time-to-oral steroids (P = .13) and time-to-biologic therapy (P = .43), which could be attributed to the low number of patients prescribed biologics (n = 64).

These findings indicate that patients with mixed type 1 and 3 inflammation dominant endotype (cluster 2) have more rapid polyp recurrence and worse disease outcomes compared to patients with a type 2 dominant inflammatory endotype (cluster 5). Polyp-free survival was similar between cluster 5 and clusters 1 (low inflammation and 6 (low inflammation and high CCL6 levels).

“This suggests that while type 2 inflammation is a key player in the inflammatory pathway for CRSwNP, a purely type 2 predominant endotype does not necessarily portend worse outcomes,” investigators explained.

Investigators noted these findings differed from the results of a recent cluster analysis that found the type 2 inflammation cluster had the greatest polyp recurrence. The other analysis included patients with both CRSsNP and CRSwNP, and Dorismond and colleagues theorized that including patients with CRSsNP in the study could have impacted patient distributions within each cluster and may have limited the generalizability of the findings to only patients with CRSwNP.

“…our analysis benefited from focused analysis of phenotypically similar CRSwNP patients and allowed us to identify nuanced outcome differences between clusters,” investigators wrote.

Investigators highlighted a common characteristic in endotypes that may be linked to poorer outcomes: the abundance of inflammatory cytokines associated with mixed type 1 and 3 inflammation.

“This potential association warrants further investigation because biologics currently used in the treatment of CRSwNP all target type 2 inflammation,” investigators wrote. “Our study suggests that therapeutic alternatives for CRSwNP that target type 1 and 3 inflammation may be needed given the association of mixed inflammation with polyp recurrence in our study, though further studies investigating this relationship are needed.”

References

1. Dorismond C, Trivedi Y, Krysinski MR, Lubner RJ, Huang LC, Goswami S, Sheng Q, Chandra RK, Chowdhury NI, Turner JH. Effects of Inflammatory Endotypes on Disease Trajectory in Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol. 2025 Apr 10:S0091-6749(25)00379-3. doi: 10.1016/j.jaci.2025.03.029. Epub ahead of print. PMID: 40220908.

2. Lelegren MJ, Son SY, Han JK, Lam KK. A review of phase III clinical trials of US FDA-approved biologic therapies for chronic rhinosinusitis with nasal polyposis. Immunotherapy. Jun 2022;14(8):655-662. doi:10.2217/imt-2021-0310