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Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers

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Abstract
Background: Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS. Objective: We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes. Methods: In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-gamma, IL-17A, TNF-alpha, IL-22, IL-1 beta, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-beta 1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering. Results: Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5-negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a T(H)17 profile and had mixed CRSsNP/CRSwNP. The IL-5-positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin-specific IgE. Conclusion: Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only.
Keywords
nasal polyps, Chronic rhinosinusitis, endotypes, cluster analysis, inflammation, asthma, NASAL POLYPS, SINUS DISEASE, TH22 CELLS, ASTHMA, PHENOTYPES, EUROPE, IDENTIFICATION, ASSOCIATION, IGE

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Chicago
Tomassen, Peter, GRIET VANDEPLAS, Thibaut Van Zele, Lars-Olaf Cardell, Julia Arebro, Heidi Olze, Ulrike Förster-Ruhrmann, et al. 2016. “Inflammatory Endotypes of Chronic Rhinosinusitis Based on Cluster Analysis of Biomarkers.” Journal of Allergy and Clinical Immunology 137 (4): 1449–1456.
APA
Tomassen, P., VANDEPLAS, G., Van Zele, T., Cardell, L.-O., Arebro, J., Olze, H., Förster-Ruhrmann, U., et al. (2016). Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 137(4), 1449–1456.
Vancouver
1.
Tomassen P, VANDEPLAS G, Van Zele T, Cardell L-O, Arebro J, Olze H, et al. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. 2016;137(4):1449–56.
MLA
Tomassen, Peter, GRIET VANDEPLAS, Thibaut Van Zele, et al. “Inflammatory Endotypes of Chronic Rhinosinusitis Based on Cluster Analysis of Biomarkers.” JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 137.4 (2016): 1449–1456. Print.
@article{7145200,
  abstract     = {Background: Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS. 
Objective: We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes. 
Methods: In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-gamma, IL-17A, TNF-alpha, IL-22, IL-1 beta, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-beta 1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering. 
Results: Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5-negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a T(H)17 profile and had mixed CRSsNP/CRSwNP. The IL-5-positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin-specific IgE. 
Conclusion: Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only.},
  author       = {Tomassen, Peter and VANDEPLAS, GRIET and Van Zele, Thibaut and Cardell, Lars-Olaf and Arebro, Julia and Olze, Heidi and F{\"o}rster-Ruhrmann, Ulrike and Kowalski, Marek L and Olszewska-Zi\k{a}ber, Agnieszka and Holtappels, Gabri{\"e}le and De Ruyck, Natalie and Wang, Xiangdong and Van Drunen, Cornelis and Mullol, Joaquim and Hellings, Peter and Hox, Valerie and Toskala, Elina and Scadding, Glenis and Lund, Valerie and Zhang, Luo and Fokkens, Wytske and Bachert, Claus},
  issn         = {0091-6749},
  journal      = {JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY},
  language     = {eng},
  number       = {4},
  pages        = {1449--1456},
  title        = {Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers},
  url          = {http://dx.doi.org/10.1016/j.jaci.2015.12.1324},
  volume       = {137},
  year         = {2016},
}

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