A personalized approach to chronic rhinosinusitis with nasal polyps : based on biomarkers, phenotypes and new surgical thinking

Chronic rhinosinusitis (CRS) is a prevalent disease causing a substantial burden for the patient and the society. CRS is divided into CRS with (CRSwNP) and without nasal polyps (CRSsNP). Based on current knowledge on inflammatory markers, CRS can be further divided into endotypes, CRSsNP mainly being characterized by a neutrophilic type 1 inflammatory response and CRSwNP being characterized by an eosinophilic type 2 inflammation. With the increase of type 2 inflammation in CRSwNP patients, asthma comorbidity and relapse of disease becomes more frequent. In recent years, monoclonal antibodies (mAbs) directed towards the type 2 inflammatory response have been demonstrated to be efficacious in CRSwNP. The overall goal of this thesis was to investigate the pathophysiology of CRS and to evaluate effects of novel treatments.

Paper I and II focus on biomarkers and clinical characteristics to help identify type 2 CRSwNP. Serum periostin can, together with serum IgE and Staphylococcus aureus enterotoxin (SE)-IgE, identify formation of IL-5 and SE-IgE in nasal polyp tissue with a reasonable sensitivity and specificity. Eosinophilic blood count correlates poorly with inflammatory markers in nasal polyp tissue, but can, together with clinical history of asthma, allergy and/or aspirin exacerbated respiratory disease, help identify most type 2 CRSwNP patients in a clinical setting. Furthermore, in paper II we show that a shift towards an increase in type 2 inflammation is seen in CRS over recent years in Central Europe, measurable both as an increase in inflammatory markers and as a shift of endotype. This shift is seen in non-asthmatic, non-allergic patients and is more pronounced in patients with CRSwNP than in patients with CRSsNP. The results also indicate that polyp formation, at least in part, is driven by mechanisms not directly related to the type and extent of tissue inflammation. Paper III-V focus on novel treatment strategies. Paper III shows that treatment with dupilumab, a mAb directed to the IL-4Receptor a, reduces local type 2 inflammatory parameters in nasal secretions and nasal polyp tissue. Paper IV-V focus on reboot surgery. Reboot surgery appears to be favorable in terms of relapse in moderate to severe CRSwNP compared to conventional surgery, and it reduces type 2 inflammatory markers in nasal secretions, 12 months after surgery, in the same magnitude as dupilumab. The inflammation in CRSwNP appears to be wide-spread, involving not only polyps but also the seemingly healthy mucosa that lines the sinuses, a finding that strengthen the rationale for reboot surgery.

In summary, the described shift towards type 2 inflammation in CRS suggests that the disease is undergoing a continuous endotypic change towards a more severe state of disease. It is evident that carefully chosen biomarkers in combination with clinical characteristics can be used to identify type 2 CRSwNP. Reboot surgery is favorable compared to conventional surgery, and may, based on endotypes, as mAbs, be implemented in treatment for CRSwNP.

List of scientific papers

I. Jonstam K, Westman M, Holtappels G, Holweg CTJ, Bachert C. Serum periostin, IgE, and SE-IgE can be used as biomarkers to identify moderate to severe chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2017; 140:1705-8.e3.
https://doi.org/10.1016/j.jaci.2017.07.031

II. Jonstam K, Delemarre T, Holtappels G, Cardell L-O, Westman M, Bachert C. Type 2 inflammatory shift in nasal polyposis. [Manuscript]

III. Jonstam K, Swanson BN, Mannent LP, Cardell LO, Tian N, Wang Y, et al. Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. Allergy. 2019; 74:743-52.
https://doi.org/10.1111/all.13685

IV. Alsharif S, Jonstam K, van Zele T, Gevaert P, Holtappels G, Bachert C. Endoscopic Sinus Surgery for Type-2 CRS wNP: An Endotype-Based Retrospective Study. Laryngoscope. 2019; 129(6):1286-1292.
https://doi.org/10.1002/lary.27815

V. Jonstam K, Alsharif S, Bogaert S, Suchonos N, Holtappels G, Jae-Hyun Park J, Bachert C. Extensive type 2 inflammation in chronic rhinosinusitis with nasal polyps is suppressed by complete sinus mucosa removal (reboot surgery). [Manuscript]