title: Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection.
abstract: BACKGROUND
  Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity.
  
  
  RESULTS
  This was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n = 135), HRV (n = 30), and influenza (n = 16) LRTI, and healthy age- and sex-matched controls (n = 39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n = 45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n = 46, Dallas, Texas, US; validation cohort A, n = 16, Turku, Finland; validation cohort B, n = 28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%-98%]) and specificity (98% [95% CI 88%-99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2.
  
  
  CONCLUSIONS
  Blood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting. Please see later in the article for the Editors' Summary.
authors.affiliation: Division of Pediatric Infectious Disease, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio, United States of America ; Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Asuncion
authors.initials: A
authors.lastname: Mejias
authors.forename: Blerta
authors.initials: B
authors.lastname: Dimo
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Suarez
authors.forename: Carla
authors.initials: C
authors.lastname: Garcia
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Suarez-Arrabal
authors.forename: Tuomas
authors.initials: T
authors.lastname: Jartti
authors.forename: Derek
authors.initials: D
authors.lastname: Blankenship
authors.forename: Alejandro
authors.initials: A
authors.lastname: Jordan-Villegas
authors.forename: Monica I
authors.initials: MI
authors.lastname: Ardura
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xu
authors.forename: Jacques
authors.initials: J
authors.lastname: Banchereau
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Octavio
authors.initials: O
authors.lastname: Ramilo
mesh_terms: D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D005260:Female; D005387:Finland; D006801:Humans; D007223:Infant; D007902:Length of Stay; D008297:Male; D046228:Microarray Analysis; D009975:Orthomyxoviridae / Q000276:immunology; D010100:Oxygen / Q000627:therapeutic use; D011024:Pneumonia, Viral / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000821:virology*; D011446:Prospective Studies; D036301:Qualitative Research; D012313:RNA / Q000378:metabolism*; D018357:Respiratory Syncytial Virus Infections / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000821:virology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D012229:Rhinovirus / Q000276:immunology; D012720:Severity of Illness Index; D059467:Transcriptome; D014481:United States
chemical_list: D015415:Biomarkers; D012313:RNA; D010100:Oxygen