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

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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 languageEnglish
Article numbere0131927
JournalPloS ONE
Volume10
Issue number7
DOIs
Publication statusPublished - 10 Jul 2015

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Respiratory Syncytial Virus Infections
Pediatrics
Viruses
disease severity
Gene expression
viruses
Blood
Genes
Biomarkers
Gene Expression
infection
gene expression
Genome
biomarkers
Common Cold
Pulse amplitude modulation
common cold
Virus Diseases
Natural Killer Cells
Respiratory Tract Infections

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

Cite this

Brand, H. K., Ahout, I. M. L., de Ridder, D., Warris, A., Li, Y., Zaalberg, M., ... 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), [e0131927]. https://doi.org/10.1371/journal.pone.0131927

Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection. / Brand, H K; Ahout, I M L; de Ridder, D; Warris, Adilia; Li, Y; Zaalberg, M; Andeweg, A; Roeleveld, N; de Groot, R; Warris, A; Hermans, P W M; Ferwerda, G; Staal, F J T.

In: PloS ONE, Vol. 10, No. 7, e0131927, 10.07.2015.

Research output: Contribution to journalArticle

Brand, HK, Ahout, IML, de Ridder, D, Warris, A, Li, Y, Zaalberg, M, Andeweg, A, Roeleveld, N, de Groot, R, Warris, A, Hermans, PWM, Ferwerda, G & Staal, FJT 2015, 'Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection', PloS ONE, vol. 10, no. 7, e0131927. https://doi.org/10.1371/journal.pone.0131927
Brand, H K ; Ahout, I M L ; de Ridder, D ; Warris, Adilia ; Li, Y ; Zaalberg, M ; Andeweg, A ; Roeleveld, N ; de Groot, R ; Warris, A ; Hermans, P W M ; Ferwerda, G ; Staal, F J T. / Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection. In: PloS ONE. 2015 ; Vol. 10, No. 7.
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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.",
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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.",
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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 - 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

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JO - PloS ONE

JF - PloS ONE

SN - 1932-6203

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