Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis
Whitney W Stevens, Anju T Peters, Bruce K Tan, Aiko I Klingler, Julie A Poposki, Kathryn E Hulse, Leslie C Grammer, Kevin C Welch, Stephanie S Smith, David B Conley, Robert C Kern, Robert P Schleimer, Atsushi Kato, Whitney W Stevens, Anju T Peters, Bruce K Tan, Aiko I Klingler, Julie A Poposki, Kathryn E Hulse, Leslie C Grammer, Kevin C Welch, Stephanie S Smith, David B Conley, Robert C Kern, Robert P Schleimer, Atsushi Kato
Abstract
Background: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by mucosal inflammation in the nose and paranasal sinuses. Inflammation in CRS is also heterogeneous and is mainly characterized by type 2 (T2) inflammation, but subsets of patients show type 1 (T1) and type 3 (T3) inflammation. Whether inflammatory endotypes are associated with clinical phenotypes has yet to be explored in detail.
Objective: To identify associations between inflammatory endotypes and clinical presentations in CRS.
Methods: We compared 121 patients with nonpolypoid CRS (CRSsNP) and 134 patients with polypoid CRS (CRSwNP) and identified inflammatory endotypes using markers including IFN-γ (T1), eosinophil cationic protein (T2), Charcot-Leyden crystal galectin (T2), and IL-17A (T3). We collected clinical parameters from medical and surgical records and examined whether there were any associations between endotype and clinical features.
Results: The presence of nasal polyps, asthma comorbidity, smell loss, and allergic mucin was significantly associated with the presence of T2 endotype in all patients with CRS. The T1 endotype was significantly more common in females, and the presence of pus was significantly associated with T3 endotype in all patients with CRS. We further analyzed these associations in CRSsNP and CRSwNP separately and found that smell loss was still associated with T2 endotype and pus with the T3 endotype in both CRSsNP and CRSwNP. Importantly, patients with CRS with T2 and T3 mixed endotype tended to have clinical presentations shared by both T2 and T3 endotypes.
Conclusions: Clinical presentations are directly associated with inflammatory endotypes in CRS. Identification of inflammatory endotypes may allow for more precise and personalized medical treatments in CRS.
Keywords: Chronic rhinosinusitis; Clinical presentation; Endotype-phenotype association; Inflammatory endotype.
Conflict of interest statement
Competing interests: The authors declare no conflict of interest as to the interpretation and presentation of this manuscript.
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6842686/bin/nihms-1530074-f0001.jpg)
![Figure 2.. Odds ratio for clinical presentations…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6842686/bin/nihms-1530074-f0002.jpg)
Figure 3.. Endotype-phenotype associations in CRSsNP and…
Figure 3.. Endotype-phenotype associations in CRSsNP and CRSwNP.
Association of clinical presentations with the absence…
Figure 4.. Endotype-phenotype association in single, mixed…
Figure 4.. Endotype-phenotype association in single, mixed and untypeable endotypes of CRSsNP and CRSwNP.
Comparison…
- Endotype-Phenotype Correlation in Chronic Rhinosinusitis: Is It Time to Think Beyond Polyposis?Borish L, Hamilos DL. Borish L, et al. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2821-2822. doi: 10.1016/j.jaip.2019.07.024. J Allergy Clin Immunol Pract. 2019. PMID: 31706495 No abstract available.
- Mechanisms and biomarkers of inflammatory endotypes in chronic rhinosinusitis without nasal polyps.Klingler AI, Stevens WW, Tan BK, Peters AT, Poposki JA, Grammer LC, Welch KC, Smith SS, Conley DB, Kern RC, Schleimer RP, Kato A. Klingler AI, et al. J Allergy Clin Immunol. 2021 Apr;147(4):1306-1317. doi: 10.1016/j.jaci.2020.11.037. Epub 2020 Dec 14. J Allergy Clin Immunol. 2021. PMID: 33326802 Free PMC article.
- An Integrated Analysis of Inflammatory Endotypes and Clinical Characteristics in Chronic Rhinosinusitis with Nasal Polyps.Hao D, Wu Y, Li P, Li C, Jiang T, Zhang Q, Liu S, Shi L. Hao D, et al. J Inflamm Res. 2022 Sep 24;15:5557-5565. doi: 10.2147/JIR.S377301. eCollection 2022. J Inflamm Res. 2022. PMID: 36185639 Free PMC article.
- Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers.Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, Förster-Ruhrmann U, Kowalski ML, Olszewska-Ziąber A, Holtappels G, De Ruyck N, Wang X, Van Drunen C, Mullol J, Hellings P, Hox V, Toskala E, Scadding G, Lund V, Zhang L, Fokkens W, Bachert C. Tomassen P, et al. J Allergy Clin Immunol. 2016 May;137(5):1449-1456.e4. doi: 10.1016/j.jaci.2015.12.1324. Epub 2016 Mar 4. J Allergy Clin Immunol. 2016. PMID: 26949058
- A real-world assessment of asthma with chronic rhinosinusitis.Ricciardolo FLM, Levra S, Sprio AE, Bertolini F, Carriero V, Gallo F, Ciprandi G. Ricciardolo FLM, et al. Ann Allergy Asthma Immunol. 2020 Jul;125(1):65-71. doi: 10.1016/j.anai.2020.03.004. Epub 2020 Mar 30. Ann Allergy Asthma Immunol. 2020. PMID: 32171930
- Endotype-driven precision medicine in chronic rhinosinusitis.Lou H, Wang C, Zhang L. Lou H, et al. Expert Rev Clin Immunol. 2019 Nov;15(11):1171-1183. doi: 10.1080/1744666X.2020.1679626. Epub 2019 Oct 22. Expert Rev Clin Immunol. 2019. PMID: 31600458 Review.
- Diagnostic value of myeloperoxidase and eosinophil cationic protein in nasal secretions for endotypes of chronic rhinosinusitis.Jin J, Guo B, Zhang W, Chen JJ, Deng YQ, Xiang R, Tan L, Qin DX, Zheng L, Chen Z, Tao ZZ, Xu Y. Jin J, et al. Eur Arch Otorhinolaryngol. 2023 Mar 20. doi: 10.1007/s00405-023-07903-3. Online ahead of print. Eur Arch Otorhinolaryngol. 2023. PMID: 36939907
- Subjective symptoms as predictors for eosinophilic chronic rhinosinusitis with nasal polyps in the Chinese population.Zhang C, Wang H, Zhang Q, Chen J, Yu H, Li W, Xu H, Hu L, Wang D, Sun X. Zhang C, et al. Eur Arch Otorhinolaryngol. 2023 Mar 14. doi: 10.1007/s00405-023-07905-1. Online ahead of print. Eur Arch Otorhinolaryngol. 2023. PMID: 36917251
- Treatment Strategy of Uncontrolled Chronic Rhinosinusitis with Nasal Polyps: A Review of Recent Evidence.Kim SD, Cho KS. Kim SD, et al. Int J Mol Sci. 2023 Mar 6;24(5):5015. doi: 10.3390/ijms24055015. Int J Mol Sci. 2023. PMID: 36902445 Free PMC article. Review.
- Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease.Schneider S, Poglitsch K, Morgenstern C, Quint T, Gangl K, Sinz C, Bartosik T, Campion NJ, Liu DT, Landegger LD, Tu A, Stanek V, Rocha-Hasler M, Bangert C, Eckl-Dorna J. Schneider S, et al. Eur Respir J. 2023 Mar 16;61(3):2201335. doi: 10.1183/13993003.01335-2022. Print 2023 Mar. Eur Respir J. 2023. PMID: 36549708 Free PMC article.
- Chronic rhinosinusitis with nasal polyps management in the biologic therapy era: an international YO-IFOS survey.Maza-Solano J, Biadsee A, Sowerby LJ, Calvo-Hernández C, Tucciarone M, Rocha T, Maniaci A, Saibene AM, Chiesa-Estomba CM, Radulesco T, Metwaly O, Lechien JR, Alobid I, Locatello LG. Maza-Solano J, et al. Eur Arch Otorhinolaryngol. 2022 Dec 1. doi: 10.1007/s00405-022-07762-4. Online ahead of print. Eur Arch Otorhinolaryngol. 2022. PMID: 36454385
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Asthma / epidemiology
- Asthma / immunology
- Chronic Disease
- Comorbidity
- Eosinophil Cationic Protein / immunology
- Female
- Glycoproteins / immunology
- Humans
- Interferon-gamma / immunology
- Interleukin-17 / immunology
- Lysophospholipase / immunology
- Male
- Middle Aged
- Nasal Polyps* / epidemiology
- Nasal Polyps* / immunology
- Olfaction Disorders / epidemiology
- Olfaction Disorders / immunology
- Phenotype
- Rhinitis* / epidemiology
- Rhinitis* / immunology
- Sinusitis* / epidemiology
- Sinusitis* / immunology
- Young Adult
- Glycoproteins
- IL17A protein, human
- Interleukin-17
- Interferon-gamma
- Lysophospholipase
- lysolecithin acylhydrolase
- Eosinophil Cationic Protein
- RNASE3 protein, human
- Full Text Sources
- Medical
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![Figure 3.. Endotype-phenotype associations in CRSsNP and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6842686/bin/nihms-1530074-f0003.jpg)
Figure 4.. Endotype-phenotype association in single, mixed…
Figure 4.. Endotype-phenotype association in single, mixed and untypeable endotypes of CRSsNP and CRSwNP.
Comparison…
- Endotype-Phenotype Correlation in Chronic Rhinosinusitis: Is It Time to Think Beyond Polyposis?Borish L, Hamilos DL. Borish L, et al. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2821-2822. doi: 10.1016/j.jaip.2019.07.024. J Allergy Clin Immunol Pract. 2019. PMID: 31706495 No abstract available.
- Mechanisms and biomarkers of inflammatory endotypes in chronic rhinosinusitis without nasal polyps.Klingler AI, Stevens WW, Tan BK, Peters AT, Poposki JA, Grammer LC, Welch KC, Smith SS, Conley DB, Kern RC, Schleimer RP, Kato A. Klingler AI, et al. J Allergy Clin Immunol. 2021 Apr;147(4):1306-1317. doi: 10.1016/j.jaci.2020.11.037. Epub 2020 Dec 14. J Allergy Clin Immunol. 2021. PMID: 33326802 Free PMC article.
- An Integrated Analysis of Inflammatory Endotypes and Clinical Characteristics in Chronic Rhinosinusitis with Nasal Polyps.Hao D, Wu Y, Li P, Li C, Jiang T, Zhang Q, Liu S, Shi L. Hao D, et al. J Inflamm Res. 2022 Sep 24;15:5557-5565. doi: 10.2147/JIR.S377301. eCollection 2022. J Inflamm Res. 2022. PMID: 36185639 Free PMC article.
- Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers.Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, Förster-Ruhrmann U, Kowalski ML, Olszewska-Ziąber A, Holtappels G, De Ruyck N, Wang X, Van Drunen C, Mullol J, Hellings P, Hox V, Toskala E, Scadding G, Lund V, Zhang L, Fokkens W, Bachert C. Tomassen P, et al. J Allergy Clin Immunol. 2016 May;137(5):1449-1456.e4. doi: 10.1016/j.jaci.2015.12.1324. Epub 2016 Mar 4. J Allergy Clin Immunol. 2016. PMID: 26949058
- A real-world assessment of asthma with chronic rhinosinusitis.Ricciardolo FLM, Levra S, Sprio AE, Bertolini F, Carriero V, Gallo F, Ciprandi G. Ricciardolo FLM, et al. Ann Allergy Asthma Immunol. 2020 Jul;125(1):65-71. doi: 10.1016/j.anai.2020.03.004. Epub 2020 Mar 30. Ann Allergy Asthma Immunol. 2020. PMID: 32171930
- Endotype-driven precision medicine in chronic rhinosinusitis.Lou H, Wang C, Zhang L. Lou H, et al. Expert Rev Clin Immunol. 2019 Nov;15(11):1171-1183. doi: 10.1080/1744666X.2020.1679626. Epub 2019 Oct 22. Expert Rev Clin Immunol. 2019. PMID: 31600458 Review.
- Diagnostic value of myeloperoxidase and eosinophil cationic protein in nasal secretions for endotypes of chronic rhinosinusitis.Jin J, Guo B, Zhang W, Chen JJ, Deng YQ, Xiang R, Tan L, Qin DX, Zheng L, Chen Z, Tao ZZ, Xu Y. Jin J, et al. Eur Arch Otorhinolaryngol. 2023 Mar 20. doi: 10.1007/s00405-023-07903-3. Online ahead of print. Eur Arch Otorhinolaryngol. 2023. PMID: 36939907
- Subjective symptoms as predictors for eosinophilic chronic rhinosinusitis with nasal polyps in the Chinese population.Zhang C, Wang H, Zhang Q, Chen J, Yu H, Li W, Xu H, Hu L, Wang D, Sun X. Zhang C, et al. Eur Arch Otorhinolaryngol. 2023 Mar 14. doi: 10.1007/s00405-023-07905-1. Online ahead of print. Eur Arch Otorhinolaryngol. 2023. PMID: 36917251
- Treatment Strategy of Uncontrolled Chronic Rhinosinusitis with Nasal Polyps: A Review of Recent Evidence.Kim SD, Cho KS. Kim SD, et al. Int J Mol Sci. 2023 Mar 6;24(5):5015. doi: 10.3390/ijms24055015. Int J Mol Sci. 2023. PMID: 36902445 Free PMC article. Review.
- Dupilumab increases aspirin tolerance in NSAID-exacerbated respiratory disease.Schneider S, Poglitsch K, Morgenstern C, Quint T, Gangl K, Sinz C, Bartosik T, Campion NJ, Liu DT, Landegger LD, Tu A, Stanek V, Rocha-Hasler M, Bangert C, Eckl-Dorna J. Schneider S, et al. Eur Respir J. 2023 Mar 16;61(3):2201335. doi: 10.1183/13993003.01335-2022. Print 2023 Mar. Eur Respir J. 2023. PMID: 36549708 Free PMC article.
- Chronic rhinosinusitis with nasal polyps management in the biologic therapy era: an international YO-IFOS survey.Maza-Solano J, Biadsee A, Sowerby LJ, Calvo-Hernández C, Tucciarone M, Rocha T, Maniaci A, Saibene AM, Chiesa-Estomba CM, Radulesco T, Metwaly O, Lechien JR, Alobid I, Locatello LG. Maza-Solano J, et al. Eur Arch Otorhinolaryngol. 2022 Dec 1. doi: 10.1007/s00405-022-07762-4. Online ahead of print. Eur Arch Otorhinolaryngol. 2022. PMID: 36454385
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Asthma / epidemiology
- Asthma / immunology
- Chronic Disease
- Comorbidity
- Eosinophil Cationic Protein / immunology
- Female
- Glycoproteins / immunology
- Humans
- Interferon-gamma / immunology
- Interleukin-17 / immunology
- Lysophospholipase / immunology
- Male
- Middle Aged
- Nasal Polyps* / epidemiology
- Nasal Polyps* / immunology
- Olfaction Disorders / epidemiology
- Olfaction Disorders / immunology
- Phenotype
- Rhinitis* / epidemiology
- Rhinitis* / immunology
- Sinusitis* / epidemiology
- Sinusitis* / immunology
- Young Adult
- Glycoproteins
- IL17A protein, human
- Interleukin-17
- Interferon-gamma
- Lysophospholipase
- lysolecithin acylhydrolase
- Eosinophil Cationic Protein
- RNASE3 protein, human
- Full Text Sources
- Medical
![Figure 4.. Endotype-phenotype association in single, mixed…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6842686/bin/nihms-1530074-f0004.jpg)
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