Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

H K Brand; I M L Ahout; D de Ridder; Adilia Warris; Y Li; M Zaalberg; A Andeweg; N Roeleveld; R de Groot; A Warris; P W M Hermans; G Ferwerda; F J T Staal

doi:10.1371/journal.pone.0131927

Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

H K Brand, I M L Ahout, D de Ridder, Adilia Warris, Y Li, M Zaalberg, A Andeweg, N Roeleveld, R de Groot, A Warris, P W M Hermans, G Ferwerda, F J T Staal

Applied Medicine

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

40 Citations (Scopus)

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Abstract

BACKGROUND: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making.

METHODS: In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort.

RESULTS: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age.

CONCLUSION: By combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.

Original language	English
Article number	e0131927
Journal	PloS ONE
Volume	10
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0131927
Publication status	Published - 10 Jul 2015

Bibliographical note

Funding: Statement of financial support: The study was financially supported by the VIRGO consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK 03012). The authors have indicated they have no personal financial relationships relevant to this article to disclose.
Data Availability Statement: The data is accessible at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69606.

Keywords

Biomarkers
Female
Gene Expression
Granulocyte Colony-Stimulating Factor
Hospitalization
Humans
Infant
Male
Prospective Studies
Respiration, Artificial
Respiratory Syncytial Virus Infections
Severity of Illness Index
Journal Article
Research Support, Non-U.S. Gov't

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10.1371/journal.pone.0131927Licence: CC BY

Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection
Copyright: © 2015 Brand et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
Final published version, 517 KBLicence: CC BY

Cite this

Brand, H. K., Ahout, I. M. L., de Ridder, D., Warris, A., Li, Y., Zaalberg, M., Andeweg, A., Roeleveld, N., de Groot, R., Warris, A., Hermans, P. W. M., Ferwerda, G., & Staal, F. J. T. (2015). Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection. PloS ONE, 10(7), Article e0131927. https://doi.org/10.1371/journal.pone.0131927

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title = "Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection",

abstract = "BACKGROUND: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making.METHODS: In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort.RESULTS: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age.CONCLUSION: By combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.",

keywords = "Biomarkers, Female, Gene Expression, Granulocyte Colony-Stimulating Factor, Hospitalization, Humans, Infant, Male, Prospective Studies, Respiration, Artificial, Respiratory Syncytial Virus Infections, Severity of Illness Index, Journal Article, Research Support, Non-U.S. Gov't",

author = "Brand, {H K} and Ahout, {I M L} and {de Ridder}, D and Adilia Warris and Y Li and M Zaalberg and A Andeweg and N Roeleveld and {de Groot}, R and A Warris and Hermans, {P W M} and G Ferwerda and Staal, {F J T}",

note = "Funding: Statement of financial support: The study was financially supported by the VIRGO consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK 03012). The authors have indicated they have no personal financial relationships relevant to this article to disclose. Data Availability Statement: The data is accessible at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69606.",

year = "2015",

month = jul,

day = "10",

doi = "10.1371/journal.pone.0131927",

language = "English",

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T1 - Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

AU - Brand, H K

AU - Ahout, I M L

AU - de Ridder, D

AU - Warris, Adilia

AU - Li, Y

AU - Zaalberg, M

AU - Andeweg, A

AU - Roeleveld, N

AU - de Groot, R

AU - Warris, A

AU - Hermans, P W M

AU - Ferwerda, G

AU - Staal, F J T

N1 - Funding: Statement of financial support: The study was financially supported by the VIRGO consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK 03012). The authors have indicated they have no personal financial relationships relevant to this article to disclose. Data Availability Statement: The data is accessible at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69606.

PY - 2015/7/10

Y1 - 2015/7/10

N2 - BACKGROUND: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making.METHODS: In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort.RESULTS: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age.CONCLUSION: By combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.

AB - BACKGROUND: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making.METHODS: In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort.RESULTS: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age.CONCLUSION: By combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.

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KW - Granulocyte Colony-Stimulating Factor

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KW - Humans

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KW - Prospective Studies

KW - Respiration, Artificial

KW - Respiratory Syncytial Virus Infections

KW - Severity of Illness Index

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1371/journal.pone.0131927

M3 - Article

C2 - 26162090

SN - 1932-6203

VL - 10

JO - PloS ONE

JF - PloS ONE

IS - 7

M1 - e0131927

ER -

Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

Abstract

Bibliographical note

Keywords

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