title: Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers.
abstract: 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.
  
  
  
  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.
  
  
  
  In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-β1, IgE, Staphylococcus aureus enterotoxin-specific IgE, and albumin. We used partition-based clustering.
  
  
  
  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 TH17 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.
  
  
  
  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.
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Tomassen
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Vandeplas
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent, Belgium.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Van Zele
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Arebro
authors.affiliation: Department of Otorhinolaryngology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Olze
authors.affiliation: Department of Otorhinolaryngology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Förster-Ruhrmann
authors.affiliation: Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, Poland.
authors.forename: Marek L
authors.initials: ML
authors.lastname: Kowalski
authors.affiliation: Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Olszewska-Ziąber
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent, Belgium.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Holtappels
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: De Ruyck
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Van Drunen
authors.affiliation: Clinical and Experimental Respiratory Immunoallergy, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Mullol
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Hellings
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Hox
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Temple University, School of Medicine, Philadelphia, Pa.
authors.forename: Elina
authors.initials: E
authors.lastname: Toskala
authors.affiliation: Royal National Throat, Nose and Ear Hospital, London, United Kingdom.
authors.forename: Glenis
authors.initials: G
authors.lastname: Scadding
authors.affiliation: Royal National Throat, Nose and Ear Hospital, London, United Kingdom.
authors.forename: Valerie
authors.initials: V
authors.lastname: Lund
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Luo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Otorhinolaryngology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Wytske
authors.initials: W
authors.lastname: Fokkens
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent, Belgium; Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden. Electronic address: claus.bachert@ugent.be.
authors.forename: Claus
authors.initials: C
authors.lastname: Bachert
mesh_terms: D000328:Adult; D001427:Bacterial Toxins / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002908:Chronic Disease; D016000:Cluster Analysis; D016207:Cytokines / Q000276:immunology; D004768:Enterotoxins / Q000276:immunology; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D008297:Male; D009195:Peroxidase / Q000276:immunology; D025341:Principal Component Analysis; D012220:Rhinitis / Q000276:immunology*; D012852:Sinusitis / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology
chemical_list: D001427:Bacterial Toxins; D015415:Biomarkers; D016207:Cytokines; D004768:Enterotoxins; D007073:Immunoglobulin E; D009195:Peroxidase
keywords: Chronic rhinosinusitis; asthma; cluster analysis; endotypes; inflammation; nasal polyps