Clin Exp Otorhinolaryngol.  2023 Nov;16(4):359-368. 10.21053/ceo.2023.00542.

Differences in Clinical and Immunological Characteristics According to the Various Criteria for Tissue Eosinophilia in Chronic Rhinosinusitis With Nasal Polyps

• Yang SK
• Kim JW
• Won TB
• Rhee CS
• Han YB
• Cho SW

• KMID: 2548364
• DOI: http://doi.org/10.21053/ceo.2023.00542

Abstract

Objectives
Several criteria exist for classifying chronic rhinosinusitis with nasal polyps (CRSwNP) as eosinophilic or non-eosinophilic. This study attempted to evaluate several criteria for defining eosinophilic CRSwNP from clinical and immunological perspectives.
Methods
A cohort of 84 patients (73 patients with CRSwNP and 11 control patients) was retrospectively analyzed. Patients were divided into eosinophilic and non-eosinophilic CRSwNP based on four different criteria: eosinophils (EOS) accounting for more than 20% of the total inflammatory cells; ≥70 EOS per high-power field (HPF); >55 EOS/HPF; and ≥10 EOS/HPF. Preoperative clinical characteristics, the immunological profiles of 14 cytokines from nasal tissue, and postoperative outcomes were compared between eosinophilic and non-eosinophilic CRSwNP based on each criterion. These criteria were immunologically validated by using 14 cytokines to predict the performance of tissue eosinophilia with a random forest model.
Results
Patients with eosinophilic CRSwNP were significantly older when the criterion of ≥10 EOS/HPF or EOS >20% was used. The number of patients with aspirin intolerance was significantly higher in eosinophilic CRSwNP based on the criterion of EOS >20%. From an immunological perspective, non-type 2 inflammatory cytokines were significantly higher in non-eosinophilic CRSwNP with the criterion of EOS >20% of the total inflammatory cells. In addition, the criterion of EOS >20% of the total inflammatory cells resulted in the best prediction of eosinophilic CRSwNP, with an accuracy of 88.10% and area under the curve of 0.94.
Conclusion
Clinical and immunological characteristics were different between eosinophilic and non-eosinophilic CRSwNP depending on a variety of criteria, and the results of this study should be taken into account when choosing the criterion for defining eosinophilic CRSwNP and interpreting the data accordingly.

Keyword

Sinusitis; Nasal Polyp; Eosinophils; Classification

Figure

• 

  Fig. 1. Immunological comparison of eosinophilic and non-eosinophilic polyps based on different criteria. The level of interleukin (IL)-5 (A), a cytokine representative of type 2 inflammation, is significantly different between eosinophilic and non-eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) regardless of the diagnostic criteria. On the contrary, IL-1β (B), tumor necrosis factor (TNF)-α (C), IL-6 (D), IL-8 (E), and IL-12 (F) were significantly different between eosinophilic and non-eosinophilic CRSwNP only using the criterion of eosinophils (EOS) >20% of total inflammatory cells. E, eosinophilic; NE, non-eosinophilic; HPF, high-power field. *P<0.05, **P<0.01, ***P<0.001.

• 

  Fig. 2. Heatmaps of protein concentrations among the classes based on different criteria for eosinophilia. (A) ≥70 eosinophils (EOS)/highpower field (HPF), (B) >55 EOS/HPF, (C) ≥10 EOS/HPF, (D) EOS >20% of the total inflammatory cells. Color bars present Z-scores of tissue concentration for each measured cytokine. HNE, human neutrophil elastase; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; MIP, macrophage inflammatory protein; MPO, myeloperoxidase; TGF, tumor growth factor.

• 

  Fig. 3. Possible underestimation or overestimation of the expected characteristics of tissue eosinophilia depending on the criteria, as demonstrated by two samples of nasal polyps in hematoxylin and eosin sections (magnification, ×200). (A) 47 Eosinophils (EOS)/high-power field (HPF) may be classified as non-eosinophilic according to the criteria with high cut-off values, while the criterion of EOS >20% of total inflammatory cells classifies it as eosinophilic. (B) 11.66 EOS/HPF may be classified as eosinophilic according to the criterion of ≥10 EOS/HPF, while the criterion of EOS >20% of total inflammatory cells classifies it as non-eosinophilic. NE, non-eosinophilic; E, eosinophilic.

Reference

1. Ahn JC, Kim JW, Lee CH, Rhee CS. Prevalence and risk factors of chronic rhinosinusitus, allergic rhinitis, and nasal septal deviation: results of the Korean National Health and Nutrition Survey 2008- 2012. JAMA Otolaryngol Head Neck Surg. 2016; Feb. 142(2):162–7.

2. Larsen K, Tos M. The estimated incidence of symptomatic nasal polyps. Acta Otolaryngol. 2002; Mar. 122(2):179–82.

3. Calus L, Van Bruaene N, Bosteels C, Dejonckheere S, Van Zele T, Holtappels G, et al. Twelve-year follow-up study after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyposis. Clin Transl Allergy. 2019; 9:30.

4. Liao B, Liu JX, Li ZY, Zhen Z, Cao PP, Yao Y, et al. Multidimensional endotypes of chronic rhinosinusitis and their association with treatment outcomes. Allergy. 2018; Jul. 73(7):1459–69.

5. Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J Allergy Clin Immunol. 2016; May. 137(5):1449–56.

6. Yao Y, Zeng M, Liu Z. Revisiting Asian chronic rhinosinusitis in the era of type 2 biologics. Clin Exp Allergy. 2022; Feb. 52(2):231–43.

7. Kim JW, Huh G, Rhee CS, Lee CH, Lee J, Chung JH, et al. Unsupervised cluster analysis of chronic rhinosinusitis with nasal polyp using routinely available clinical markers and its implication in treatment outcomes. Int Forum Allergy Rhinol. 2019; Jan. 9(1):79–86.

8. Lou H, Zhang N, Bachert C, Zhang L. Highlights of eosinophilic chronic rhinosinusitis with nasal polyps in definition, prognosis, and advancement. Int Forum Allergy Rhinol. 2018; Nov. 8(11):1218–25.

9. Lou H, Meng Y, Piao Y, Wang C, Zhang L, Bachert C. Predictive significance of tissue eosinophilia for nasal polyp recurrence in the Chinese population. Am J Rhinol Allergy. 2015; 29(5):350–6.

10. Tokunaga T, Sakashita M, Haruna T, Asaka D, Takeno S, Ikeda H, et al. Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study. Allergy. 2015; Aug. 70(8):995–1003.

11. Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020; Feb. 58(Suppl S29):1–464.

12. Kim SY, Park JH, Rhee CS, Chung JH, Kim JW. Does eosinophilic inflammation affect the outcome of endoscopic sinus surgery in chronic rhinosinusitis in Koreans. Am J Rhinol Allergy. 2013; 27(6):e166–9.

13. Soler ZM, Sauer D, Mace J, Smith TL. Impact of mucosal eosinophilia and nasal polyposis on quality-of-life outcomes after sinus surgery. Otolaryngol Head Neck Surg. 2010; Jan. 142(1):64–71.

14. Lund VJ, Kennedy DW. Staging for rhinosinusitis. Otolaryngol Head Neck Surg. 1997; Sep. 117(3 Pt 2):S35–40.

15. Psaltis AJ, Li G, Vaezeafshar R, Cho KS, Hwang PH. Modification of the Lund-Kennedy endoscopic scoring system improves its reliability and correlation with patient-reported outcome measures. Laryngoscope. 2014; Oct. 124(10):2216–23.

16. Witten I, Frank E, Hall M, Pal C. Data mining. 4th ed. Morgan Kaufmann; 2016.

17. Kim JW, Won TB, Woo H, Yang SK, Phannikul C, Ko SA, et al. Age related non-type 2 inflammation and its association with treatment outcome in patients with chronic rhinosinusitis with nasal polyp in Korea. Sci Rep. 2022; Jan. 12(1):1671.

18. Gevaert P, Han JK, Smith SG, Sousa AR, Howarth PH, Yancey SW, et al. The roles of eosinophils and interleukin-5 in the pathophysiology of chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2022; Nov. 12(11):1413–23.

19. Meng Y, Lou H, Wang C, Zhang L. Predictive significance of computed tomography in eosinophilic chronic rhinosinusitis with nasal polyps. Int Forum Allergy Rhinol. 2016; Aug. 6(8):812–9.

20. Stevens WW, Schleimer RP. Aspirin-exacerbated respiratory disease as an endotype of chronic rhinosinusitis. Immunol Allergy Clin North Am. 2016; Nov. 36(4):669–80.

21. Rosati D, Rosato C, Pagliuca G, Cerbelli B, Della Rocca C, Di Cristofano C, et al. Predictive markers of long-term recurrence in chronic rhinosinusitis with nasal polyps. Am J Otolaryngol. 2020; 41(1):102286.

22. McHugh T, Snidvongs K, Xie M, Banglawala S, Sommer D. High tissue eosinophilia as a marker to predict recurrence for eosinophilic chronic rhinosinusitis: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2018; Dec. 8(12):1421–9.

23. Stevens WW, Ocampo CJ, Berdnikovs S, Sakashita M, Mahdavinia M, Suh L, et al. Cytokines in chronic rhinosinusitis. Role in eosinophilia and aspirin-exacerbated respiratory disease. Am J Respir Crit Care Med. 2015; Sep. 192(6):682–94.

24. Kim DK, Eun KM, Kim MK, Cho D, Han SA, Han SY, et al. Comparison between signature cytokines of nasal tissues in subtypes of chronic rhinosinusitis. Allergy Asthma Immunol Res. 2019; Mar. 11(2):201–11.

25. Ramezanpour M, Bolt H, Psaltis AJ, Wormald PJ, Vreugde S. Primary human nasal epithelial cells: a source of poly (I:C) LMW-induced IL-6 production. Sci Rep. 2018; Jul. 8(1):11325.

26. Wei B, Liu F, Zhang J, Liu Y, Du J, Liu S, et al. Multivariate analysis of inflammatory endotypes in recurrent nasal polyposis in a Chinese population. Rhinology. 2018; Sep. 56(3):216–26.

27. Xiao L, Jia L, Zhang Y, Yu S, Wu X, Yang B, et al. Human IL-21+IFN-γ+CD4+ T cells in nasal polyps are regulated by IL-12. Sci Rep. 2015; Aug. 5:12781.

28. Delemarre T, Holtappels G, De Ruyck N, Zhang N, Nauwynck H, Bachert C, et al. A substantial neutrophilic inflammation as regular part of severe type 2 chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2021; Jan. 147(1):179–88.

29. Kim DK, Kim JY, Han YE, Kim JK, Lim HS, Eun KM, et al. Elastase-positive neutrophils are associated with refractoriness of chronic rhinosinusitis with nasal polyps in an Asian population. Allergy Asthma Immunol Res. 2020; Jan. 12(1):42–55.

30. Kim DW. Can neutrophils be a cellular biomarker in asian chronic rhinosinusitis. Clin Exp Otorhinolaryngol. 2019; Nov. 12(4):325–6.

31. Cardell LO, Stjarne P, Jonstam K, Bachert C. Endotypes of chronic rhinosinusitis: impact on management. J Allergy Clin Immunol. 2020; Mar. 145(3):752–6.

32. Ryu G, Kim DK, Dhong HJ, Eun KM, Lee KE, Kong IG, et al. Immunological characteristics in refractory chronic rhinosinusitis with nasal polyps undergoing revision surgeries. Allergy Asthma Immunol Res. 2019; Sep. 11(5):664–76.

33. Burgel PR, Cardell LO, Ueki IF, Nadel JA. Intranasal steroids decrease eosinophils but not mucin expression in nasal polyps. Eur Respir J. 2004; Oct. 24(4):594–600.