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

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

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.
asthma, cytokines, eosinophils, neutrophils, phenotype, endotype, heterogeneity, matrix metalloproteinase, chitinase 3–like protein 1, topological data analysis
0091-6749
61-75
Hinks, Timothy
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Brown, T.
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Lau, L.C.
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Rupani, H.
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Barber, Clair
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Elliott, S.
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Ward, J.A.
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Ono, J.
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Ohta, S.
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Izuhara, K.
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Djukanovic, R.
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Kurukulaaratchy, R.J.
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Chauhan, A.
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Howarth, P.
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Hinks, Timothy
c7668ed3-f706-4038-8645-ee6cc6aef29f
Brown, T.
65b220ab-5839-4e03-b923-97694339baaf
Lau, L.C.
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Rupani, H.
cbc7068a-4279-4c8e-b83f-353210711062
Barber, Clair
ff31b460-34c3-466c-90e4-f70b3e954c82
Elliott, S.
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Ward, J.A.
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Ono, J.
273a8203-9863-47e5-ab8a-accdbfed334a
Ohta, S.
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Izuhara, K.
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Djukanovic, R.
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Kurukulaaratchy, R.J.
9c7b8105-2892-49f2-8775-54d4961e3e74
Chauhan, A.
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Howarth, P.
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Hinks, Timothy, Brown, T., Lau, L.C., Rupani, H., Barber, Clair, Elliott, S., Ward, J.A., Ono, J., Ohta, S., Izuhara, K., Djukanovic, R., Kurukulaaratchy, R.J., Chauhan, A. and Howarth, P. (2016) Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1. Journal of Allergy and Clinical Immunology, 138 (1), 61-75. (doi:10.1016/j.jaci.2015.11.020). (PMID:26851968)

Record type: Article

Abstract

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 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.

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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Accepted/In Press date: 20 November 2015
e-pub ahead of print date: 3 February 2016
Published date: July 2016
Keywords: asthma, cytokines, eosinophils, neutrophils, phenotype, endotype, heterogeneity, matrix metalloproteinase, chitinase 3–like protein 1, topological data analysis
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 390331
URI: https://eprints.soton.ac.uk/id/eprint/390331
ISSN: 0091-6749
PURE UUID: 737326d2-6b17-4a29-95a6-a6d0e1817f81
ORCID for Clair Barber: ORCID iD orcid.org/0000-0001-5335-5129
ORCID for R. Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

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Date deposited: 23 Mar 2016 16:46
Last modified: 09 Dec 2019 19:42

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Contributors

Author: Timothy Hinks
Author: T. Brown
Author: L.C. Lau
Author: H. Rupani
Author: Clair Barber ORCID iD
Author: S. Elliott
Author: J.A. Ward
Author: J. Ono
Author: S. Ohta
Author: K. Izuhara
Author: R. Djukanovic ORCID iD
Author: R.J. Kurukulaaratchy
Author: A. Chauhan
Author: P. Howarth

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