Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma

Florence N. Schleich; Delphine Zanella; Pierre-Hugues Stefanuto; Kirill Bessonov; Agnieska Smolinska; Jan W. Dallinga; Monique Henket; Virginie Paulus; Francoise Guissard; Sophie Graff; Catherine Moermans; Emiel F. M. Wouters; Kristel Van Steen; Frederik-Jan van Schooten; Jean-Francois Focant; Renaud Louis

doi:10.1164/rccm.201811-2210OC

Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma

Florence N. Schleich^*, Delphine Zanella, Pierre-Hugues Stefanuto, Kirill Bessonov, Agnieska Smolinska, Jan W. Dallinga, Monique Henket, Virginie Paulus, Francoise Guissard, Sophie Graff, Catherine Moermans, Emiel F. M. Wouters, Kristel Van Steen, Frederik-Jan van Schooten, Jean-Francois Focant, Renaud Louis

^*Corresponding author for this work

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

Abstract

Rationale: Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking.

Objectives: To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes.

Methods: We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (FENO) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count.

Measurements and Main Results: In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study (n = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and FENO. Moreover, the combination of FENO, blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to FENO or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma.

Conclusions: Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma.

Original language	English
Pages (from-to)	444-453
Number of pages	10
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	200
Issue number	4
DOIs	https://doi.org/10.1164/rccm.201811-2210OC
Publication status	Published - 15 Aug 2019

Keywords

phenotype
biomarkers
inflammation
AIRWAY INFLAMMATION
ELECTRONIC NOSE
DIAGNOSTIC-TOOL
DOUBLE-BLIND
BREATH
IDENTIFICATION
EXACERBATIONS
AZITHROMYCIN
BIOMARKERS
ADULTS

Access to Document

10.1164/rccm.201811-2210OC

Cite this

Schleich, F. N., Zanella, D., Stefanuto, P.-H., Bessonov, K., Smolinska, A., Dallinga, J. W., Henket, M., Paulus, V., Guissard, F., Graff, S., Moermans, C., Wouters, E. F. M., Van Steen, K., van Schooten, F.-J., Focant, J.-F., & Louis, R. (2019). Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma. American Journal of Respiratory and Critical Care Medicine, 200(4), 444-453. https://doi.org/10.1164/rccm.201811-2210OC

@article{f9c5f5d2648e4337875a65b54271397c,

title = "Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma",

abstract = "Rationale: Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking.Objectives: To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes.Methods: We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (FENO) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count.Measurements and Main Results: In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study (n = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and FENO. Moreover, the combination of FENO, blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to FENO or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma.Conclusions: Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma.",

keywords = "phenotype, biomarkers, inflammation, AIRWAY INFLAMMATION, ELECTRONIC NOSE, DIAGNOSTIC-TOOL, DOUBLE-BLIND, BREATH, IDENTIFICATION, EXACERBATIONS, AZITHROMYCIN, BIOMARKERS, ADULTS",

author = "Schleich, {Florence N.} and Delphine Zanella and Pierre-Hugues Stefanuto and Kirill Bessonov and Agnieska Smolinska and Dallinga, {Jan W.} and Monique Henket and Virginie Paulus and Francoise Guissard and Sophie Graff and Catherine Moermans and Wouters, {Emiel F. M.} and {Van Steen}, Kristel and {van Schooten}, Frederik-Jan and Jean-Francois Focant and Renaud Louis",

note = "Funding Information: Supported by the European Respiratory Society, which provided the Fellowship (STRTF 80-2011) to perform the analysis of volatile organic compounds in the discovery study in Maastricht University; the Walloon Region, which provided the Maturation fund, financing the validation study in Liege University; and the Belgian federal government, which provided the EOS O013618F (ID EOS:30565447) for global financial support. Publisher Copyright: Copyright {\textcopyright} 2019 by the American Thoracic Society",

year = "2019",

month = aug,

day = "15",

doi = "10.1164/rccm.201811-2210OC",

language = "English",

volume = "200",

pages = "444--453",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "4",

}

Schleich, FN, Zanella, D, Stefanuto, P-H, Bessonov, K, Smolinska, A, Dallinga, JW, Henket, M, Paulus, V, Guissard, F, Graff, S, Moermans, C, Wouters, EFM, Van Steen, K, van Schooten, F-J, Focant, J-F & Louis, R 2019, 'Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma', American Journal of Respiratory and Critical Care Medicine, vol. 200, no. 4, pp. 444-453. https://doi.org/10.1164/rccm.201811-2210OC

TY - JOUR

T1 - Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma

AU - Schleich, Florence N.

AU - Zanella, Delphine

AU - Stefanuto, Pierre-Hugues

AU - Bessonov, Kirill

AU - Smolinska, Agnieska

AU - Dallinga, Jan W.

AU - Henket, Monique

AU - Paulus, Virginie

AU - Guissard, Francoise

AU - Graff, Sophie

AU - Moermans, Catherine

AU - Wouters, Emiel F. M.

AU - Van Steen, Kristel

AU - van Schooten, Frederik-Jan

AU - Focant, Jean-Francois

AU - Louis, Renaud

N1 - Funding Information: Supported by the European Respiratory Society, which provided the Fellowship (STRTF 80-2011) to perform the analysis of volatile organic compounds in the discovery study in Maastricht University; the Walloon Region, which provided the Maturation fund, financing the validation study in Liege University; and the Belgian federal government, which provided the EOS O013618F (ID EOS:30565447) for global financial support. Publisher Copyright: Copyright © 2019 by the American Thoracic Society

PY - 2019/8/15

Y1 - 2019/8/15

N2 - Rationale: Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking.Objectives: To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes.Methods: We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (FENO) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count.Measurements and Main Results: In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study (n = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and FENO. Moreover, the combination of FENO, blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to FENO or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma.Conclusions: Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma.

AB - Rationale: Analysis of exhaled breath for asthma phenotyping using endogenously generated volatile organic compounds (VOCs) offers the possibility of noninvasive diagnosis and therapeutic monitoring. Induced sputum is indeed not widely available and markers of neutrophilic asthma are still lacking.Objectives: To determine whether analysis of exhaled breath using endogenously generated VOCs can be a surrogate marker for recognition of sputum inflammatory phenotypes.Methods: We conducted a prospective study on 521 patients with asthma recruited from the University Asthma Clinic of Liege. Patients underwent VOC measurement, fraction of exhaled nitric oxide (FENO) spirometry, sputum induction, and gave a blood sample. Subjects with asthma were classified in three inflammatory phenotypes according to their sputum granulocytic cell count.Measurements and Main Results: In the discovery study, seven potential biomarkers were highlighted by gas chromatography-mass spectrometry in a training cohort of 276 patients with asthma. In the replication study (n = 245), we confirmed four VOCs of interest to discriminate among asthma inflammatory phenotypes using comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry. Hexane and 2-hexanone were identified as compounds with the highest classification performance in eosinophilic asthma with accuracy comparable to that of blood eosinophils and FENO. Moreover, the combination of FENO, blood eosinophils, and VOCs gave a very good prediction of eosinophilic asthma (area under the receiver operating characteristic curve, 0.9). For neutrophilic asthma, the combination of nonanal, 1-propanol, and hexane had a classification performance similar to FENO or blood eosinophils in eosinophilic asthma. Those compounds were found in higher levels in neutrophilic asthma.Conclusions: Our study is the first attempt to characterize VOCs according to sputum granulocytic profile in a large population of patients with asthma and provide surrogate markers for neutrophilic asthma.

KW - phenotype

KW - biomarkers

KW - inflammation

KW - AIRWAY INFLAMMATION

KW - ELECTRONIC NOSE

KW - DIAGNOSTIC-TOOL

KW - DOUBLE-BLIND

KW - BREATH

KW - IDENTIFICATION

KW - EXACERBATIONS

KW - AZITHROMYCIN

KW - BIOMARKERS

KW - ADULTS

U2 - 10.1164/rccm.201811-2210OC

DO - 10.1164/rccm.201811-2210OC

M3 - Article

C2 - 30973757

SN - 1073-449X

VL - 200

SP - 444

EP - 453

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 4

ER -