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

2016; Elsevier BV; Volume: 138; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2015.11.020

1097-6825

Timothy S.C. Hinks, Thomas Brown, Laurie C.K. Lau, Hitasha Rupani, Clair Barber, Scott Elliott, Jonathan Ward, Junya Ono, Shoichiro Ohta, Kenji Izuhara, Ratko Djukanović, Ramesh Kurukulaaratchy, Anoop Chauhan, Peter Howarth,

Eosinophilic Esophagitis

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.