title: Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1.
abstract: Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood.
  
  
  
  We aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients.
  
  
  
  One hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis.
  
  
  
  Severe asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3-like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels.
  
  
  
  In 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma.
authors: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom. Electronic address: t.hinks@soton.ac.uk.
authors: Timothy S C
authors: TSC
authors: Hinks
authors: Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom.
authors: Tom
authors: T
authors: Brown
authors: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
authors: Laurie C K
authors: LCK
authors: Lau
authors: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
authors: Hitasha
authors: H
authors: Rupani
authors: NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
authors: Clair
authors: C
authors: Barber
authors: Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom.
authors: Scott
authors: S
authors: Elliott
authors: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
authors: Jon A
authors: JA
authors: Ward
authors: Shino-Test Corporation, Kanagawa, Japan.
authors: Junya
authors: J
authors: Ono
authors: Department of Laboratory Medicine, Saga Medical School, Saga, Japan.
authors: Shoichiro
authors: S
authors: Ohta
authors: Department of Biomolecular Sciences, Saga Medical School, Saga, Japan.
authors: Kenji
authors: K
authors: Izuhara
authors: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
authors: Ratko
authors: R
authors: Djukanović
authors: Department of Respiratory Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors: Ramesh J
authors: RJ
authors: Kurukulaaratchy
authors: Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom.
authors: Anoop
authors: A
authors: Chauhan
authors: Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital, Southampton, United Kingdom; NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital, Southampton, United Kingdom.
authors: Peter H
authors: PH
authors: Howarth
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism*; D001499:Bayes Theorem; D015415:Biomarkers; D016022:Case-Control Studies; D000071451:Chitinase-3-Like Protein 1 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D012129:Respiratory Function Tests; D012307:Risk Factors; D012720:Severity of Illness Index; D013183:Sputum / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D000071451:Chitinase-3-Like Protein 1; D016207:Cytokines; D018836:Inflammation Mediators; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases
keywords: Asthma; chitinase 3–like protein 1; cytokines; endotype; eosinophils; heterogeneity; matrix metalloproteinase; neutrophils; phenotype; topological data analysis