title: Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma.
abstract: BACKGROUND
  Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses.
  
  
  OBJECTIVE
  To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers.
  
  
  METHODS
  We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters.
  
  
  RESULTS
  Five clinical clusters were identified, including two characterized by high pack-year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later.
  
  
  CONCLUSIONS
  This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254).
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Konno
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Taniguchi
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Hironi
authors.initials: H
authors.lastname: Makita
authors.affiliation: 2 Otolaryngology Head & Neck Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamaru
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Kaoruko
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: 3 Department of Respiratory Medicine, JR Sapporo Hospital, Sapporo, Japan.
authors.forename: Noriharu
authors.initials: N
authors.lastname: Shijubo
authors.affiliation: 4 Department of Respiratory Medicine, KKR Sapporo Medical Center, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fuke
authors.affiliation: 5 Department of Respiratory Medicine, Otaru Kyokai Hospital, Otaru, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Takeyabu
authors.affiliation: 6 Department of Respiratory Medicine, Oji General Hospital, Tomakomai, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Oguri
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kimura
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Masaru
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Katsura
authors.initials: K
authors.lastname: Nagai
authors.affiliation: 7 Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japan; and.
authors.forename: Yoichi M
authors.initials: YM
authors.lastname: Ito
authors.affiliation: 8 University of Pittsburgh Asthma Institute at UPMC/University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.affiliation: 1 First Department of Medicine, and.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D016000:Cluster Analysis; D004804:Eosinophils / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics
keywords: cluster analysis; eosinophils; phenotypes; severe asthma; smoking