Whole Blood Gene Expression Profiles to Assess Pathogenesis and Disease Severity in Infants with Respiratory Syncytial Virus Infection

Asuncion Mejias, Blerta Dimo, Nicolas M. Suarez, Carla Garcia, M. Carmen Suarez-Arrabal, Tuomas Jartti, Derek Blankenship, Alejandro Jordan-Villegas, Monica I. Ardura, Zhaohui Xu, Jacques Banchereau, Damien Chaussabel, Octavio Ramilo

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159 Scopus citations

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.Methods and Findings: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.

Original languageEnglish (US)
Article numbere1001549
JournalPLoS Medicine
Volume10
Issue number11
DOIs
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Mejias, A., Dimo, B., Suarez, N. M., Garcia, C., Suarez-Arrabal, M. C., Jartti, T., Blankenship, D., Jordan-Villegas, A., Ardura, M. I., Xu, Z., Banchereau, J., Chaussabel, D., & Ramilo, O. (2013). Whole Blood Gene Expression Profiles to Assess Pathogenesis and Disease Severity in Infants with Respiratory Syncytial Virus Infection. PLoS Medicine, 10(11), [e1001549]. https://doi.org/10.1371/journal.pmed.1001549