Abstract
BackgroundDisease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood.ObjectiveWe aimed to identify and replicate clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients.MethodsOne 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.ResultsSevere 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.ConclusionIn 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.
Highlights
Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood
First, we investigated which of the 103 clinical, physiologic, and pathobiologic parameters measured were associated with severe asthma (Global Initiative for Asthma [Global Initiative for Asthma Hospital Anxiety and Depression (HAD) (GINA)] step 4 and 5)
Pathobiologic parameters associated with a diagnosis of severe asthma were neutrophilic sputum; an increase in peripheral blood neutrophil counts; serum and sputum chitinase 3–like protein 1 (YKL-40) levels; sputum matrix metalloproteinase (MMP) 1, MMP3, MMP8, and MMP12 levels (P < .0001 each, Fig 1); vascular endothelial growth factor, IL-5, IL-6, IL-8, and IL-6 soluble receptor levels; and a decrease in sputum macrophage counts and levels of tissue inhibitor of metalloproteinases 1, fibroblast growth factor, IL-1 receptor antagonist, and IL-2
Summary
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. From aClinical and Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton University Hospital; bthe NIHR Southampton Respiratory Biomedical Research Unit, Southampton University Hospital; cPortsmouth Hospitals NHS Trust; dShino-Test Corporation, Kanagawa; ethe Department of Laboratory Medicine and fthe Department of Biomolecular Sciences, Saga Medical School; and gthe Department of Respiratory Medicine, Southampton General Hospital. Supported by the Medical Research Council (G0800649).
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