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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: H K
authors.initials: HK
authors.lastname: Brand
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: I M L
authors.initials: IM
authors.lastname: Ahout
authors.affiliation: Delft Bioinformatics Lab, Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: de Ridder
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Diepen
authors.affiliation: Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Zaalberg
authors.affiliation: Department of Virology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Andeweg
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Department for Health Evidence, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Roeleveld
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: de Groot
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Warris
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: P W M
authors.initials: PW
authors.lastname: Hermans
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud university medical center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Ferwerda
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: F J T
authors.initials: FJ
authors.lastname: Staal
mesh_terms: D015415:Biomarkers / Q000097:blood; D005260:Female; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood* / Q000235:genetics; D006760:Hospitalization; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D012121:Respiration, Artificial; D018357:Respiratory Syncytial Virus Infections / Q000097:blood* / Q000473:pathology / Q000628:therapy; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; C454127:OLFM4 protein, human; D016179:Granulocyte Colony-Stimulating Factor