Type 2 chronic rhinosinusitis with nasal polyps: From phenotype to endotype

I read with great interest the report by Bachert et al.1Bachert C. Marple B. Hosemann W. Cavaliere C. Wen W. Zhang N.J. Endotypes of chronic rhinosinusitis with nasal polyps: pathology and possible therapeutic implications.J Allergy Clin Immunol Pract. 2020; 8: 1514-1519Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The authors reported current knowledge and personal opinions on the efficacy of therapeutic options, such as reboot surgery and biologics targeting type 2 (T2) cytokines in chronic rhinosinusitis with nasal polyps (CRSwNP). Another point the authors mentioned is that CRSwNP endotypes should be defined by clinical signs and/or biomarkers.1Bachert C. Marple B. Hosemann W. Cavaliere C. Wen W. Zhang N.J. Endotypes of chronic rhinosinusitis with nasal polyps: pathology and possible therapeutic implications.J Allergy Clin Immunol Pract. 2020; 8: 1514-1519Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar We thank Bachert et al for their contribution to literature with such a valuable review. We would like to share our opinions on this subject. We share the same view as the authors. It is very important to associate T2 CRSwNP subendotypes with T2 CRSwNP phenotypes (Figure 1). This will provide cost-effective use of biologics in T2 CRSwNP phenotypes. At this point, because there are no 1-to-1 comparative studies with these biologics, “What should be the most effective biological treatment for the T2 CRSwNP phenotype?” and “Which clinical and biological markers would be useful to select the appropriate biologics for this phenotype?” are remaining questions. To answer these questions, we need to know the subendotype (the dominant pathway of the T2 endotype) of the T2 endotype underlying the T2 CRSwNP phenotype. T2 CRSwNP endotype presents as T2-biased inflammation. T2 immune responses in CRSwNP are mediated mainly by TH2 cells, group 2 innate lymphoid cells (ILC2s), local IgE, and profound tissue eosinophilia. ILC2s are known to produce type 2 cytokines, especially IL-5 and IL-13, and TH2 cells secrete IL-4, IL-5, and IL-13. Both IL-4 and IL-13 induce IgE switching and IgE synthesis by B cells. Although IL-5 is the important driver of blood eosinophilia, IL-13 is strongly associated with airway eosinophlia and periostin. Periostin is a downstream molecule of IL-4 and IL-13, which potentially passes the IL-4 receptor α.2Fokkens W.J. Lund V.J. Hopkins C. Hellings P.W. Kern R. Reitsma S. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2020.Rhinology. 2020; 58: 1-464Crossref Scopus (0) Google Scholar, 3Schleimer R.P. Immunopathogenesis of chronic rhinosinusitis and nasal polyposis.Annu Rev Pathol. 2017; 12: 331-357Crossref PubMed Scopus (195) Google Scholar, 4Matsusaka M. Kabata H. Fukunaga K. Suzuki Y. Masaki K. Mochimaru T. et al.Phenotype of asthma related with high serum periostin levels.Allergol Int. 2015; 64: 175-180Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar IL-5 and IL-13 drive many features of the inflammation and eosinophil recruitment that is characteristic of the T2 CRSwNP.2Fokkens W.J. Lund V.J. Hopkins C. Hellings P.W. Kern R. Reitsma S. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2020.Rhinology. 2020; 58: 1-464Crossref Scopus (0) Google Scholar, 3Schleimer R.P. Immunopathogenesis of chronic rhinosinusitis and nasal polyposis.Annu Rev Pathol. 2017; 12: 331-357Crossref PubMed Scopus (195) Google Scholar, 4Matsusaka M. Kabata H. Fukunaga K. Suzuki Y. Masaki K. Mochimaru T. et al.Phenotype of asthma related with high serum periostin levels.Allergol Int. 2015; 64: 175-180Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 5Maxfield A.Z. Landegger L.D. Brook C.D. Lehmann A.E. Campbell A.P. Bergmark R.W. et al.Periostin as a biomarker for nasal polyps in chronic rhinosinusitis.Otolaryngol Head Neck Surg. 2018; 158: 181-186Crossref PubMed Scopus (33) Google Scholar Patients with a T2 CRSwNP phenotype have higher levels of serum periostin and blood eosinophils.2Fokkens W.J. Lund V.J. Hopkins C. Hellings P.W. Kern R. Reitsma S. et al.European Position Paper on Rhinosinusitis and Nasal Polyps 2020.Rhinology. 2020; 58: 1-464Crossref Scopus (0) Google Scholar, 3Schleimer R.P. Immunopathogenesis of chronic rhinosinusitis and nasal polyposis.Annu Rev Pathol. 2017; 12: 331-357Crossref PubMed Scopus (195) Google Scholar, 4Matsusaka M. Kabata H. Fukunaga K. Suzuki Y. Masaki K. Mochimaru T. et al.Phenotype of asthma related with high serum periostin levels.Allergol Int. 2015; 64: 175-180Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 5Maxfield A.Z. Landegger L.D. Brook C.D. Lehmann A.E. Campbell A.P. Bergmark R.W. et al.Periostin as a biomarker for nasal polyps in chronic rhinosinusitis.Otolaryngol Head Neck Surg. 2018; 158: 181-186Crossref PubMed Scopus (33) Google Scholar, 6Wenzel S. Castro M. Corren J. Maspero J. Wang L. Zhang B. et al.Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet. 2016; 388: 31-44Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar In conclusion, the ILC2 pathway and IL-5/IL-13 cytokines seem to be one of the dominant endotypes in the T2 CRSwNP phenotype. Therefore, higher blood eosinophil levels and higher serum periostin levels might be considered as biological markers reflecting the ILC2 subendotype. At this point, it is necessary to reduce the levels of eosinophils and periostin in sinonasal mucosa. Anti–IL-4Rα (dupilumab) therapy seems to be a bit more effective in the subendotype.7Ren L. Zhang N. Zhang L. Bachert C. Biologics for the treatment of chronic rhinosinusitis with nasal polyps – state of the art.World Allergy Organ J. 2019; 12: 100050Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar In the future, treatment regimens using combined biological agents, in which all pathways are suppressed, will be used to obtain better clinical results in this phenotype. We can think of this combined biologic agents concept (such as anti-IgE + anti–IL-4Rα + anti–IL-5/anti–IL-5R) as using systemic corticosteroids with minimal side effects because systemic corticosteroids suppress type 2 endotype regardless of their subgroups in the T2 CRSwNP phenotype. ReplyThe Journal of Allergy and Clinical Immunology: In PracticeVol. 9Issue 1PreviewI appreciate the comment by Yilmaz1 on our publication on type 2 chronic rhinosinusitis with nasal polyps (CRSwNP)2 and for supporting our view on the need of endotyping chronic rhinosinusitis for the selection of the most adequate treatment approach for an individual patient. We have recently further illustrated the currently available biomarkers for endotypes in uncontrolled severe CRSwNP in a patient group in whom the selection of adequate treatment is of utmost importance and in whom predictors for treatment approaches are particularly needed. Full-Text PDF