Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study

Nina M Frerichs; Sofia El Manouni El Hassani; Nancy Deianova; Mirjam M van Weissenbruch; Anton H van Kaam; Daniel C Vijlbrief; Johannes B van Goudoever; Christian V Hulzebos; Boris W Kramer; Esther J d'Haens; Veerle Cossey; Willem P de Boode; Wouter J de Jonge; Alfian N Wicaksono; James A Covington; Marc A Benninga; Nanne K H de Boer; Hendrik J Niemarkt; Tim G J de Meij

doi:10.3390/microorganisms11030572

Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study

Nina M Frerichs, Sofia El Manouni El Hassani, Nancy Deianova, Mirjam M van Weissenbruch, Anton H van Kaam, Daniel C Vijlbrief, Johannes B van Goudoever, Christian V Hulzebos, Boris W Kramer, Esther J d'Haens, Veerle Cossey, Willem P de Boode, Wouter J de Jonge, Alfian N Wicaksono, James A Covington, Marc A Benninga, Nanne K H de Boer, Hendrik J Niemarkt, Tim G J de Meij

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Abstract

Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography-ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker.

Original language	English
Article number	572
Journal	Microorganisms
Volume	11
Issue number	3
DOIs	https://doi.org/10.3390/microorganisms11030572
Publication status	Published - Mar 2023

Keywords

fecal biomarker
gas chromatography—ion mobility spectrometry
gas chromatography—time of flight—mass spectrometry
microbiota
neonatology
volatile organic compounds

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Frerichs, N. M., El Manouni El Hassani, S., Deianova, N., van Weissenbruch, M. M., van Kaam, A. H., Vijlbrief, D. C., van Goudoever, J. B., Hulzebos, C. V., Kramer, B. W., d'Haens, E. J., Cossey, V., de Boode, W. P., de Jonge, W. J., Wicaksono, A. N., Covington, J. A., Benninga, M. A., de Boer, N. K. H., Niemarkt, H. J., & de Meij, T. G. J. (2023). Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study. Microorganisms, 11(3), Article 572. https://doi.org/10.3390/microorganisms11030572

@article{4adf0ea08b1c4d6491bb316bd3ce72c6,

title = "Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study",

abstract = "Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography-ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker. ",

keywords = "fecal biomarker, gas chromatography—ion mobility spectrometry, gas chromatography—time of flight—mass spectrometry, microbiota, neonatology, volatile organic compounds",

author = "Frerichs, {Nina M} and {El Manouni El Hassani}, Sofia and Nancy Deianova and {van Weissenbruch}, {Mirjam M} and {van Kaam}, {Anton H} and Vijlbrief, {Daniel C} and {van Goudoever}, {Johannes B} and Hulzebos, {Christian V} and Kramer, {Boris W} and d'Haens, {Esther J} and Veerle Cossey and {de Boode}, {Willem P} and {de Jonge}, {Wouter J} and Wicaksono, {Alfian N} and Covington, {James A} and Benninga, {Marc A} and {de Boer}, {Nanne K H} and Niemarkt, {Hendrik J} and {de Meij}, {Tim G J}",

note = "Funding Information: This work was supported by unrestricted grants from the Landelijke Vereniging van Crematoria (Dr. C.J. Vaillant Fonds); Zeldzame Ziekten Fonds and the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement [grant number 814168]. None of the funding sources had any role in the design or conduct of the study. Funding Information: None of the co-authors received a honorarium, grant, or other form of payment for the production of this manuscript. Outside the submitted work, N.K.H.d.B. has served as a speaker for AbbVie and MSD. He has also served as a consultant and/or principal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted) research grant from Dr Falk, TEVA Pharma BV, MLDS and Takeda. The other authors have nothing to declare. Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = mar,

doi = "10.3390/microorganisms11030572",

language = "English",

volume = "11",

journal = "Microorganisms",

issn = "2076-2607",

publisher = "MDPI AG",

number = "3",

}

Frerichs, NM, El Manouni El Hassani, S, Deianova, N, van Weissenbruch, MM, van Kaam, AH, Vijlbrief, DC, van Goudoever, JB, Hulzebos, CV, Kramer, BW, d'Haens, EJ, Cossey, V, de Boode, WP, de Jonge, WJ, Wicaksono, AN, Covington, JA, Benninga, MA, de Boer, NKH, Niemarkt, HJ & de Meij, TGJ 2023, 'Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study', Microorganisms, vol. 11, no. 3, 572. https://doi.org/10.3390/microorganisms11030572

TY - JOUR

T1 - Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants

T2 - A Nationwide Case-Control Study

AU - Frerichs, Nina M

AU - El Manouni El Hassani, Sofia

AU - Deianova, Nancy

AU - van Weissenbruch, Mirjam M

AU - van Kaam, Anton H

AU - Vijlbrief, Daniel C

AU - van Goudoever, Johannes B

AU - Hulzebos, Christian V

AU - Kramer, Boris W

AU - d'Haens, Esther J

AU - Cossey, Veerle

AU - de Boode, Willem P

AU - de Jonge, Wouter J

AU - Wicaksono, Alfian N

AU - Covington, James A

AU - Benninga, Marc A

AU - de Boer, Nanne K H

AU - Niemarkt, Hendrik J

AU - de Meij, Tim G J

N1 - Funding Information: This work was supported by unrestricted grants from the Landelijke Vereniging van Crematoria (Dr. C.J. Vaillant Fonds); Zeldzame Ziekten Fonds and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement [grant number 814168]. None of the funding sources had any role in the design or conduct of the study. Funding Information: None of the co-authors received a honorarium, grant, or other form of payment for the production of this manuscript. Outside the submitted work, N.K.H.d.B. has served as a speaker for AbbVie and MSD. He has also served as a consultant and/or principal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted) research grant from Dr Falk, TEVA Pharma BV, MLDS and Takeda. The other authors have nothing to declare. Publisher Copyright: © 2023 by the authors.

PY - 2023/3

Y1 - 2023/3

N2 - Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography-ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker.

AB - Early detection of late-onset sepsis (LOS) in preterm infants is crucial since timely treatment initiation is a key prognostic factor. We hypothesized that fecal volatile organic compounds (VOCs), reflecting microbiota composition and function, could serve as a non-invasive biomarker for preclinical pathogen-specific LOS detection. Fecal samples and clinical data of all preterm infants (≤30 weeks' gestation) admitted at nine neonatal intensive care units in the Netherlands and Belgium were collected daily. Samples from one to three days before LOS onset were analyzed by gas chromatography-ion mobility spectrometry (GC-IMS), a technique based on pattern recognition, and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), to identify unique metabolites. Fecal VOC profiles and metabolites from infants with LOS were compared with matched controls. Samples from 121 LOS infants and 121 matched controls were analyzed using GC-IMS, and from 34 LOS infants and 34 matched controls using GC-TOF-MS. Differences in fecal VOCs were most profound one and two days preceding Escherichia coli LOS (Area Under Curve; p-value: 0.73; p = 0.02, 0.83; p < 0.002, respectively) and two and three days before gram-negative LOS (0.81; p < 0.001, 0.85; p < 0.001, respectively). GC-TOF-MS identified pathogen-specific discriminative metabolites for LOS. This study underlines the potential for VOCs as a non-invasive preclinical diagnostic LOS biomarker.

KW - fecal biomarker

KW - gas chromatography—ion mobility spectrometry

KW - gas chromatography—time of flight—mass spectrometry

KW - microbiota

KW - neonatology

KW - volatile organic compounds

UR - http://www.scopus.com/inward/record.url?scp=85151481985&partnerID=8YFLogxK

U2 - 10.3390/microorganisms11030572

DO - 10.3390/microorganisms11030572

M3 - Article

C2 - 36985146

SN - 2076-2607

VL - 11

JO - Microorganisms

JF - Microorganisms

IS - 3

M1 - 572

ER -

Fecal Volatile Metabolomics Predict Gram-Negative Late-Onset Sepsis in Preterm Infants: A Nationwide Case-Control Study

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