Review and Feature Article
Endotypes of Chronic Rhinosinusitis with Nasal Polyps: Pathology and Possible Therapeutic Implications

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Today, chronic rhinosinusitis (CRS) is a symptomatic disease diagnosed by nasal endoscopy and eventually computed tomography scan, and is treated by pharmacotherapy or, when unsuccessful, by sinus surgery. With the advent of biologics, the diagnostic approach needs to be adjusted to appreciate CRS endotypes, introducing biomarkers, and the therapeutic options will be extended by the application of biologics. Specifically, type 2 immune reactions moved into the focus, similar to asthma, involving innate and adaptive immunity pathways to establish an often severe, persistent disease. The role for endotyping of CRS became evident for biologics, but also turned out to be meaningful for the decision on the selection of pharmacotherapy and the specific surgical approach to choose. Furthermore, considerations on the role of surgery and biologics needed to be elaborated to develop decision-making processes for patients with moderate-to-severe CRS with nasal polyps, with or without comorbid asthma, allowing us to adjust the treatment for patient groups based on endotyping (precision medicine). We here aim to guide the decisions in a rational way based on the current knowledge of the efficacy and complications or side effects of the recently enlarged therapeutic options. Personal experience has been added where knowledge was lacking in this fast moving field.

Section snippets

The Rationale for Endotyping

Nasal polyps—also referred to as chronic rhinosinusitis with nasal polyps (CRSwNP)—may vary in their clinical expression from slowly to rapidly growing sinus disease, may appear early or late in life, may or may not be associated with late-onset asthma, and may or may not respond well to the currently established treatment modalities including topical glucocorticosteroids (GCSs), courses of oral GCSs, or conventional endoscopic sinus surgery (ESS). These clinical traits are different from the

Endotyping of CRS Based on Biomarkers and Clinical Traits: On the way to Precision Medicine

The currently most accepted endotyping approach was published in 2016,11 based on an unbiased cluster analysis of inflammatory cytokines and mediators such as eosinophilic cationic protein (ECP) and myeloperoxidase, and IgE. This resulted in 3 groups, a non–type 2 mostly chronic rhinosinusitis without (sine) nasal polyps (CRSsNP) (comprising type 1 and type 3 immune reactions), and a moderate and a severe type 2 mostly CRSwNP, with the severe type demonstrating significantly higher

Therapeutic Implications for Pharmacotherapy and Surgery

The treatment aim is the long-term management of patients with CRSwNP, reducing disease burden and risks of disease such as recurrence and asthma, by combining various strategies. Endotyping should guide the selection of treatments from pharmacotherapy over surgery to biologics. However, as this area is new and only partially established, only limited evidence is available and randomized trials comparing the current versus an endotype-based approach are lacking. The arguments for an

Biologics: State of the Art

It is evident that biologics targeting type 2 cytokines such as free IgE, IL-4, IL-5, and IL-13 or their receptors are only indicated in type 2 CRSwNP. We therefore need to identify indicators to increase the likelihood of type 2 immune reactions in an individual patient (Table I). Dupilumab phase 3 results in 2 studies with more than 700 patients over 24 and 52 weeks have recently been published43 after a successful proof-of-concept (PoC) study before.44 Approximately 2 of 3 patients had

Conclusion

It is obvious that the management of CRS, specifically severe CRSwNP, gets considerably more complex and asks additional skills, including the interpretation of endoscopy and CT scanning after former surgery, the indication for revision or possibly reboot surgery, and a good understanding of disease immunology and resulting indications for biologics. Often, patients do suffer from additional manifestations of type 2 immune reactions, including atopic dermatitis or eosinophil esophagitis, so

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      The underlying pathophysiology that mediates most cases of CRSwNP and asthma is characterized by eosinophilia and elevated levels of the proeosinophilic cytokines interleukin (IL)-4, IL-5, IL-13, and immunoglobulin E (IgE).6 This is termed type 2 pattern of inflammation, and is seen in 80% of Caucasian patients with CRSwNP, and up to 94% of patients with comorbid asthma7; a combination of nasal polyps, asthma, and a blood eosinophil greater than 300 cells/mm3 further increases the likelihood.7 Non-type 2 inflammation is more commonly linked with CRS without nasal polyps (CRSsNP), and in CRSwNP in patients from Asian countries,8 which is driven by neutrophils and IL-17 subunits, although this is changing over time.8–10

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    No funding was received for this work.

    Conflicts of interest: C. Bachert received speaker fees and is a member of advisory boards for Sanofi, Novartis, Astra-Zeneca, and GSK. The rest of the authors declare that they have no relevant conflicts of interest.

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