Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 138, Issue 1, Pages 61-75Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2015.11.020
Keywords
Asthma; cytokines; eosinophils; neutrophils; phenotype; endotype; heterogeneity; matrix metalloproteinase; chitinase 3-like protein 1; topological data analysis
Categories
Funding
- Medical Research Council [G0800649]
- Wellcome Trust [088365/z/09/z]
- Academy of Medical Sciences
- National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit
- NIHR
- Wellcome Trust [088365/Z/09/Z] Funding Source: Wellcome Trust
- MRC [G0800649] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [16H05343, 15K15372, 15K09553] Funding Source: KAKEN
- Academy of Medical Sciences (AMS) [AMS-SGCL11-Hinks] Funding Source: researchfish
- Medical Research Council [G0800649] Funding Source: researchfish
- National Institute for Health Research [ACF-2006-26-005, NF-SI-0514-10085] Funding Source: researchfish
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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.
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