Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1

作者：Hinks Timothy S C^*; Brown Tom; Lau Laurie C K; Rupani Hitasha; Barber Clair; Elliott Scott; Ward Jon A; Ono Junya; Ohta Shoichiro; Izuhara Kenji; Djukanovic Ratko; Kurukulaaratchy Ramesh J; Chauhan Anoop; Howarth Peter H

来源：Journal of Allergy and Clinical Immunology, 2016, 138(1): 61-75.

DOI：10.1016/j.jaci.2015.11.020

• Asthma
• cytokines
• eosinophils
• neutrophils
• phenotype
• endotype
• heterogeneity
• matrix metalloproteinase
• chitinase 3-like protein 1
• topological data analysis

Background: Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood.
Objective: We aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients.
Methods: 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.
Results: 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 T(H)2 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.
Conclusion: 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.

• 出版日期2016-7
• 单位test