Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma

Paul Brinkman; Ariane H. Wagener; Pieter-Paul Hekking; Aruna T. Bansal; Anke-Hilse Maitland-van der Zee; Yuanyue Wang; Hans Weda; Hugo H. Knobel; Teunis J. Vink; Nicholas J. Rattray; Arnaldo D'Amico; Giorgio Pennazza; Marco Santonico; Diane Lefaudeux; Bertrand De Meulder; Charles Auffray; Per S. Bakke; Massimo Caruso; Pascal Chanez; Kian F. Chung; Julie Corfield; Sven-Erik Dahlén; Ratko Djukanovic; Thomas Geiser; Ildiko Horvath; Nobert Krug; Jacek Musial; Kai Sun; John H. Riley; Dominic E. Shaw; Thomas Sandström; Ana R. Sousa; Paolo Montuschi; Stephen J. Fowler; Peter J. Sterk

doi:10.1016/j.jaci.2018.10.058

Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma

Paul Brinkman^*, Ariane H. Wagener, Pieter-Paul Hekking, Aruna T. Bansal, Anke-Hilse Maitland-van der Zee, Yuanyue Wang, Hans Weda, Hugo H. Knobel, Teunis J. Vink, Nicholas J. Rattray, Arnaldo D'Amico, Giorgio Pennazza, Marco Santonico, Diane Lefaudeux, Bertrand De Meulder, Charles Auffray, Per S. Bakke, Massimo Caruso, Pascal Chanez, Kian F. ChungJulie Corfield, Sven-Erik Dahlén, Ratko Djukanovic, Thomas Geiser, Ildiko Horvath, Nobert Krug, Jacek Musial, Kai Sun, John H. Riley, Dominic E. Shaw, Thomas Sandström, Ana R. Sousa, Paolo Montuschi, Stephen J. Fowler, Peter J. Sterk

^*Corresponding author for this work

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes. Objectives: We aimed (1)to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses)and (2)to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes. Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability. Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19)were revealed, showing differences in circulating eosinophil (P =.045)and neutrophil (P =.017)percentages and ratios of patients using oral corticosteroids (P =.035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P =.045). Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.

Original language	English
Pages (from-to)	1811-1820.e7
Number of pages	17
Journal	Journal of Allergy and Clinical Immunology
Volume	143
Issue number	5
Early online date	6 Dec 2018
DOIs	https://doi.org/10.1016/j.jaci.2018.10.058
Publication status	Published - 31 May 2019

Funding

U-BIOPRED has received funding from the Innovative Medicines Initiative (IMI)Joint Undertaking under grant agreement no. 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007?2013)and European Federation of Pharmaceutical Industries and Associations (EFPIA)companies' in-kind contributions (www.imi.europa.eu). U-BIOPRED has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007–2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions (www.imi.europa.eu).

Keywords

electronic nose technology
eosinophils
exhaled breath
follow-up
neutrophils
oral corticosteroids
severe asthma
unbiased clustering
volatile organic compound

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10.1016/j.jaci.2018.10.058

Brinkman-etal-JACI-2018-Identification-and-prospective-stability-of-electronic-nose-derived-inflammatory-phenotypesAccepted author manuscript, 2.46 MBLicence: CC BY-NC-ND 4.0

https://eprints.soton.ac.uk/428269/Licence: CC BY-NC-ND 4.0

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Brinkman, P., Wagener, A. H., Hekking, P.-P., Bansal, A. T., Maitland-van der Zee, A.-H., Wang, Y., Weda, H., Knobel, H. H., Vink, T. J., Rattray, N. J., D'Amico, A., Pennazza, G., Santonico, M., Lefaudeux, D., De Meulder, B., Auffray, C., Bakke, P. S., Caruso, M., Chanez, P., ... Sterk, P. J. (2019). Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma. Journal of Allergy and Clinical Immunology, 143(5), 1811-1820.e7. https://doi.org/10.1016/j.jaci.2018.10.058

@article{71a1066f467344dd83ffd128779836ad,

title = "Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma",

abstract = "Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes. Objectives: We aimed (1)to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses)and (2)to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes. Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability. Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19)were revealed, showing differences in circulating eosinophil (P =.045)and neutrophil (P =.017)percentages and ratios of patients using oral corticosteroids (P =.035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P =.045). Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.",

keywords = "electronic nose technology, eosinophils, exhaled breath, follow-up, neutrophils, oral corticosteroids, severe asthma, unbiased clustering, volatile organic compound",

author = "Paul Brinkman and Wagener, {Ariane H.} and Pieter-Paul Hekking and Bansal, {Aruna T.} and {Maitland-van der Zee}, Anke-Hilse and Yuanyue Wang and Hans Weda and Knobel, {Hugo H.} and Vink, {Teunis J.} and Rattray, {Nicholas J.} and Arnaldo D'Amico and Giorgio Pennazza and Marco Santonico and Diane Lefaudeux and {De Meulder}, Bertrand and Charles Auffray and Bakke, {Per S.} and Massimo Caruso and Pascal Chanez and Chung, {Kian F.} and Julie Corfield and Sven-Erik Dahl{\'e}n and Ratko Djukanovic and Thomas Geiser and Ildiko Horvath and Nobert Krug and Jacek Musial and Kai Sun and Riley, {John H.} and Shaw, {Dominic E.} and Thomas Sandstr{\"o}m and Sousa, {Ana R.} and Paolo Montuschi and Fowler, {Stephen J.} and Sterk, {Peter J.}",

year = "2019",

month = may,

day = "31",

doi = "10.1016/j.jaci.2018.10.058",

language = "English",

volume = "143",

pages = "1811--1820.e7",

number = "5",

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Brinkman, P, Wagener, AH, Hekking, P-P, Bansal, AT, Maitland-van der Zee, A-H, Wang, Y, Weda, H, Knobel, HH, Vink, TJ, Rattray, NJ, D'Amico, A, Pennazza, G, Santonico, M, Lefaudeux, D, De Meulder, B, Auffray, C, Bakke, PS, Caruso, M, Chanez, P, Chung, KF, Corfield, J, Dahlén, S-E, Djukanovic, R, Geiser, T, Horvath, I, Krug, N, Musial, J, Sun, K, Riley, JH, Shaw, DE, Sandström, T, Sousa, AR, Montuschi, P, Fowler, SJ & Sterk, PJ 2019, 'Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma', Journal of Allergy and Clinical Immunology, vol. 143, no. 5, pp. 1811-1820.e7. https://doi.org/10.1016/j.jaci.2018.10.058

TY - JOUR

T1 - Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma

AU - Brinkman, Paul

AU - Wagener, Ariane H.

AU - Hekking, Pieter-Paul

AU - Bansal, Aruna T.

AU - Maitland-van der Zee, Anke-Hilse

AU - Wang, Yuanyue

AU - Weda, Hans

AU - Knobel, Hugo H.

AU - Vink, Teunis J.

AU - Rattray, Nicholas J.

AU - D'Amico, Arnaldo

AU - Pennazza, Giorgio

AU - Santonico, Marco

AU - Lefaudeux, Diane

AU - De Meulder, Bertrand

AU - Auffray, Charles

AU - Bakke, Per S.

AU - Caruso, Massimo

AU - Chanez, Pascal

AU - Chung, Kian F.

AU - Corfield, Julie

AU - Dahlén, Sven-Erik

AU - Djukanovic, Ratko

AU - Geiser, Thomas

AU - Horvath, Ildiko

AU - Krug, Nobert

AU - Musial, Jacek

AU - Sun, Kai

AU - Riley, John H.

AU - Shaw, Dominic E.

AU - Sandström, Thomas

AU - Sousa, Ana R.

AU - Montuschi, Paolo

AU - Fowler, Stephen J.

AU - Sterk, Peter J.

PY - 2019/5/31

Y1 - 2019/5/31

N2 - Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes. Objectives: We aimed (1)to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses)and (2)to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes. Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability. Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19)were revealed, showing differences in circulating eosinophil (P =.045)and neutrophil (P =.017)percentages and ratios of patients using oral corticosteroids (P =.035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P =.045). Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.

AB - Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes. Objectives: We aimed (1)to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses)and (2)to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes. Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability. Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19)were revealed, showing differences in circulating eosinophil (P =.045)and neutrophil (P =.017)percentages and ratios of patients using oral corticosteroids (P =.035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P =.045). Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.

KW - electronic nose technology

KW - eosinophils

KW - exhaled breath

KW - follow-up

KW - neutrophils

KW - oral corticosteroids

KW - severe asthma

KW - unbiased clustering

KW - volatile organic compound

UR - http://www.scopus.com/inward/record.url?scp=85059453249&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2018.10.058

DO - 10.1016/j.jaci.2018.10.058

M3 - Article

C2 - 30529449

AN - SCOPUS:85059453249

SN - 0091-6749

VL - 143

SP - 1811-1820.e7

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

Identification and prospective stability of electronic nose (eNose)–derived inflammatory phenotypes in patients with severe asthma

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