Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study

SysPharmPediA and U-BIOPRED Consortia

doi:10.1164/rccm.202312-2270OC

Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study

SysPharmPediA and U-BIOPRED Consortia

Faculty of Science

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

Abstract

Rationale: The early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. Objectives: To assess the accuracy of gas chromatography-mass spectrometry-based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. Methods: This study encompassed discovery (SysPharmPediA [Systems Pharmacology Approach to Uncontrolled Paediatric Asthma]) and validation (U-BIOPRED [Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes] and PANDA [Paediatric-Asthma-Non-Invasive-Diagnostic-Approaches]) phases. First, exhaled VOCs that discriminated degrees of asthma control were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled on the basis of asthma control test scores and the number of severe attacks in the past year. In addition, the potential of VOCs to predict two or more future severe asthma attacks in SysPharmPediA was evaluated. Measurements and Main Results: Complete data were available for 196 children (SysPharmPediA, n = 100; U-BIOPRED, n = 49; PANDA, n = 47). In SysPharmPediA, after randomly splitting the population into training ( n = 51) and test ( n = 49) sets, three compounds (acetophenone, ethylbenzene, and styrene) distinguished between patients with uncontrolled and controlled asthma. The areas under the receiver operating characteristic curves (AUROCCs) for training and test sets were, respectively, 0.83 (95% confidence interval [CI], 0.65-1.00) and 0.77 (95% CI, 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ± 0.06 (U-BIOPRED) and 0.68 ± 0.05 (PANDA). Attack prediction tests resulted in AUROCCs of 0.71 (95% CI, 0.51-0.91) and 0.71 (95% CI, 0.52-0.90) for the training and test sets. Conclusions: Exhaled metabolite analysis might enable asthma control classification in children. This should stimulate the further development of exhaled metabolite-based point-of-care tests in asthma.

Original language	English
Pages (from-to)	1091-1100
Number of pages	10
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	210
Issue number	9
DOIs	https://doi.org/10.1164/rccm.202312-2270OC
Publication status	Published - 1 Nov 2024

Funding

The SysPharmPediA Consortium is supported by ZonMw (project 9003035001); the Ministry of Higher Education, Science and Innovation of the Republic of Slovenia (contract C330-16-500106); the German Ministry of Education and Research (project FKZ 031L0088); and Instituto de Salud Carlos III through Strategic Action for Health Research and the European Community within the Active and Assisted Living Program framework (awards AC15/00015 and AC15/00058) under the frame of the ERACoSysMed JTC-1 Call. U-BIOPRED is supported by the Innovative Medicines Initiative Joint Undertaking under FP7 Health grant agreement 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and in-kind contributions from European Federation of Pharmaceutical Industries and Associations companies (www.imi.europa.eu). The PANDA study is supported by a Junior Investigator research grant from Lung Foundation Netherlands (6.2.18.244JO). The authors thank all the participating children and their families. The authors acknowledge the contributions of the SysPharmPediA and U-BIOPRED Consortia and express their gratitude to the individuals and groups involved. The names of these contributors are listed in the online supplement of the research paper. *These authors contributed equally to this work. A complete list of SysPharmPediA and U-BIOPRED Consortia members may be found in the supplement. The SysPharmPediA Consortium is supported by ZonMw (project 9003035001); the Ministry of Higher Education, Science and Innovation of the Republic of Slovenia (contract C330-16-500106); the German Ministry of Education and Research (project FKZ 031 L0088); and Instituto de Salud Carlos III through Strategic Action for Health Research and the European Community within the Active and Assisted Living Program framework (awards AC15/00015 and AC15/00058) under the frame of the ERACoSysMed JTC-1 Call. U-BIOPRED is supported by the Innovative Medicines Initiative Joint Undertaking under FP7 Health grant agreement 115010, resources of which are composed of financial contributions from the European Union\u2019s Seventh Framework Programme (FP7/2007-2013) and in-kind contributions from European Federation of Pharmaceutical Industries and Associations companies (www.imi.europa.eu). The PANDA study is supported by a Junior Investigator research grant from Lung Foundation Netherlands (6.2.18.244JO).

Funders	Funder number
Seventh Framework Programme
Instituto de Salud Carlos III
European Union's Seventh Framework Programme
U-BIOPRED Consortia
Innovative Medicines Initiative
Active and Assisted Living Program framework	AC15/00015, AC15/00058
Bundesministerium für Bildung und Forschung	FKZ 031 L0088
Bundesministerium für Bildung und Forschung
Ministry of Higher Education, Science and Innovation of the Republic of Slovenia	C330-16-500106
ZonMw	9003035001
ZonMw
FP7 Health	115010
FP7 Health
Lung Foundation Netherlands	6.2.18.244JO
Lung Foundation Netherlands

Keywords

Humans
Asthma/metabolism
Volatile Organic Compounds/analysis
Child
Male
Female
Breath Tests/methods
Biomarkers/analysis
Adolescent
Exhalation
Gas Chromatography-Mass Spectrometry
Severity of Illness Index
Child, Preschool

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@article{85386243108349df86a5ce0548ba9deb,

title = "Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study",

abstract = " Rationale: The early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. Objectives: To assess the accuracy of gas chromatography-mass spectrometry-based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. Methods: This study encompassed discovery (SysPharmPediA [Systems Pharmacology Approach to Uncontrolled Paediatric Asthma]) and validation (U-BIOPRED [Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes] and PANDA [Paediatric-Asthma-Non-Invasive-Diagnostic-Approaches]) phases. First, exhaled VOCs that discriminated degrees of asthma control were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled on the basis of asthma control test scores and the number of severe attacks in the past year. In addition, the potential of VOCs to predict two or more future severe asthma attacks in SysPharmPediA was evaluated. Measurements and Main Results: Complete data were available for 196 children (SysPharmPediA, n = 100; U-BIOPRED, n = 49; PANDA, n = 47). In SysPharmPediA, after randomly splitting the population into training ( n = 51) and test ( n = 49) sets, three compounds (acetophenone, ethylbenzene, and styrene) distinguished between patients with uncontrolled and controlled asthma. The areas under the receiver operating characteristic curves (AUROCCs) for training and test sets were, respectively, 0.83 (95% confidence interval [CI], 0.65-1.00) and 0.77 (95% CI, 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ± 0.06 (U-BIOPRED) and 0.68 ± 0.05 (PANDA). Attack prediction tests resulted in AUROCCs of 0.71 (95% CI, 0.51-0.91) and 0.71 (95% CI, 0.52-0.90) for the training and test sets. Conclusions: Exhaled metabolite analysis might enable asthma control classification in children. This should stimulate the further development of exhaled metabolite-based point-of-care tests in asthma. ",

keywords = "Humans, Asthma/metabolism, Volatile Organic Compounds/analysis, Child, Male, Female, Breath Tests/methods, Biomarkers/analysis, Adolescent, Exhalation, Gas Chromatography-Mass Spectrometry, Severity of Illness Index, Child, Preschool",

author = "{Shahbazi Khamas}, Shahriyar and {Van Dijk}, Yoni and Abdel-Aziz, {Mahmoud I} and Neerincx, {Anne H} and {Maarten Blankestijn}, Jelle and Vijverberg, {Susanne J H} and Simone Hashimoto and Andrew Bush and Kraneveld, {Aletta D} and Hedman, {Anna M} and Toncheva, {Antoaneta A} and Catarina Almqvist and Christine Wolff and Murray, {Clare S} and Gunilla Hedlin and Graham Roberts and Adcock, {Ian M} and Javier Korta-Murua and Klaus B{\o}nnelykke and Fleming, {Louise J} and Maria Pino-Yanes and Mario Gorenjak and Michael Kabesch and Olaia Sard{\'o}n-Prado and Paolo Montuschi and Florian Singer and Elosegui, {Paula Corcuera} and Fowler, {Stephen J} and Susanne Brandstetter and Susanne Harner and Sven-Erik Dahl{\'e}n and Uro{\v s} Poto{\v c}nik and Urs Frey and {van Aalderen}, Wim and Paul Brinkman and {Maitland-van der Zee}, Anke-Hilse and {SysPharmPediA and U-BIOPRED Consortia}",

year = "2024",

month = nov,

day = "1",

doi = "10.1164/rccm.202312-2270OC",

language = "English",

volume = "210",

pages = "1091--1100",

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

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "9",

}

Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study. / SysPharmPediA and U-BIOPRED Consortia.
In: American Journal of Respiratory and Critical Care Medicine, Vol. 210, No. 9, 01.11.2024, p. 1091-1100.

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

TY - JOUR

T1 - Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma

T2 - Results from the SysPharmPediA Study

AU - Shahbazi Khamas, Shahriyar

AU - Van Dijk, Yoni

AU - Abdel-Aziz, Mahmoud I

AU - Neerincx, Anne H

AU - Maarten Blankestijn, Jelle

AU - Vijverberg, Susanne J H

AU - Hashimoto, Simone

AU - Bush, Andrew

AU - Kraneveld, Aletta D

AU - Hedman, Anna M

AU - Toncheva, Antoaneta A

AU - Almqvist, Catarina

AU - Wolff, Christine

AU - Murray, Clare S

AU - Hedlin, Gunilla

AU - Roberts, Graham

AU - Adcock, Ian M

AU - Korta-Murua, Javier

AU - Bønnelykke, Klaus

AU - Fleming, Louise J

AU - Pino-Yanes, Maria

AU - Gorenjak, Mario

AU - Kabesch, Michael

AU - Sardón-Prado, Olaia

AU - Montuschi, Paolo

AU - Singer, Florian

AU - Elosegui, Paula Corcuera

AU - Fowler, Stephen J

AU - Brandstetter, Susanne

AU - Harner, Susanne

AU - Dahlén, Sven-Erik

AU - Potočnik, Uroš

AU - Frey, Urs

AU - van Aalderen, Wim

AU - Brinkman, Paul

AU - Maitland-van der Zee, Anke-Hilse

AU - SysPharmPediA and U-BIOPRED Consortia

PY - 2024/11/1

Y1 - 2024/11/1

N2 - Rationale: The early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. Objectives: To assess the accuracy of gas chromatography-mass spectrometry-based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. Methods: This study encompassed discovery (SysPharmPediA [Systems Pharmacology Approach to Uncontrolled Paediatric Asthma]) and validation (U-BIOPRED [Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes] and PANDA [Paediatric-Asthma-Non-Invasive-Diagnostic-Approaches]) phases. First, exhaled VOCs that discriminated degrees of asthma control were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled on the basis of asthma control test scores and the number of severe attacks in the past year. In addition, the potential of VOCs to predict two or more future severe asthma attacks in SysPharmPediA was evaluated. Measurements and Main Results: Complete data were available for 196 children (SysPharmPediA, n = 100; U-BIOPRED, n = 49; PANDA, n = 47). In SysPharmPediA, after randomly splitting the population into training ( n = 51) and test ( n = 49) sets, three compounds (acetophenone, ethylbenzene, and styrene) distinguished between patients with uncontrolled and controlled asthma. The areas under the receiver operating characteristic curves (AUROCCs) for training and test sets were, respectively, 0.83 (95% confidence interval [CI], 0.65-1.00) and 0.77 (95% CI, 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ± 0.06 (U-BIOPRED) and 0.68 ± 0.05 (PANDA). Attack prediction tests resulted in AUROCCs of 0.71 (95% CI, 0.51-0.91) and 0.71 (95% CI, 0.52-0.90) for the training and test sets. Conclusions: Exhaled metabolite analysis might enable asthma control classification in children. This should stimulate the further development of exhaled metabolite-based point-of-care tests in asthma.

AB - Rationale: The early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. Objectives: To assess the accuracy of gas chromatography-mass spectrometry-based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. Methods: This study encompassed discovery (SysPharmPediA [Systems Pharmacology Approach to Uncontrolled Paediatric Asthma]) and validation (U-BIOPRED [Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes] and PANDA [Paediatric-Asthma-Non-Invasive-Diagnostic-Approaches]) phases. First, exhaled VOCs that discriminated degrees of asthma control were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled on the basis of asthma control test scores and the number of severe attacks in the past year. In addition, the potential of VOCs to predict two or more future severe asthma attacks in SysPharmPediA was evaluated. Measurements and Main Results: Complete data were available for 196 children (SysPharmPediA, n = 100; U-BIOPRED, n = 49; PANDA, n = 47). In SysPharmPediA, after randomly splitting the population into training ( n = 51) and test ( n = 49) sets, three compounds (acetophenone, ethylbenzene, and styrene) distinguished between patients with uncontrolled and controlled asthma. The areas under the receiver operating characteristic curves (AUROCCs) for training and test sets were, respectively, 0.83 (95% confidence interval [CI], 0.65-1.00) and 0.77 (95% CI, 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ± 0.06 (U-BIOPRED) and 0.68 ± 0.05 (PANDA). Attack prediction tests resulted in AUROCCs of 0.71 (95% CI, 0.51-0.91) and 0.71 (95% CI, 0.52-0.90) for the training and test sets. Conclusions: Exhaled metabolite analysis might enable asthma control classification in children. This should stimulate the further development of exhaled metabolite-based point-of-care tests in asthma.

KW - Humans

KW - Asthma/metabolism

KW - Volatile Organic Compounds/analysis

KW - Child

KW - Male

KW - Female

KW - Breath Tests/methods

KW - Biomarkers/analysis

KW - Adolescent

KW - Exhalation

KW - Gas Chromatography-Mass Spectrometry

KW - Severity of Illness Index

KW - Child, Preschool

U2 - 10.1164/rccm.202312-2270OC

DO - 10.1164/rccm.202312-2270OC

M3 - Article

C2 - 38648186

SN - 1073-449X

VL - 210

SP - 1091

EP - 1100

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 9

ER -

Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study

Abstract

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Keywords

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