title: Enterovirus D68 in Hospitalized Children: Sequence Variation, Viral Loads and Clinical Outcomes.
abstract: BACKGROUND
  An outbreak of enterovirus D68 (EV-D68) caused severe respiratory illness in 2014. The disease spectrum of EV-D68 infections in children with underlying medical conditions other than asthma, the role of EV-D68 loads on clinical illness, and the variation of EV-D68 strains within the same institution over time have not been described. We sought to define the association between EV-D68 loads and sequence variation, and the clinical characteristic in hospitalized children at our institution from 2011 to 2014.
  
  
  METHODS
  May through November 2014, and August to September 2011 to 2013, a convenience sample of nasopharyngeal specimens from children with rhinovirus (RV)/EV respiratory infections were tested for EV-D68 by RT-PCR. Clinical data were compared between children with RV/EV-non-EV-D68 and EV-D68 infections, and among children with EV-D68 infections categorized as healthy, asthmatics, and chronic medical conditions. EV-D68 loads were analyzed in relation to disease severity parameters and sequence variability characterized over time.
  
  
  RESULTS
  In 2014, 44% (192/438) of samples tested positive for EV-D68 vs. 10% (13/130) in 2011-13 (p<0.0001). PICU admissions (p<0.0001) and non-invasive ventilation (p<0.0001) were more common in children with EV-D68 vs. RV/EV-non-EV-D68 infections. Asthmatic EV-D68+ children, required supplemental oxygen administration (p = 0.03) and PICU admissions (p <0.001) more frequently than healthy children or those with chronic medical conditions; however oxygen duration (p<0.0001), and both PICU and total hospital stay (p<0.01) were greater in children with underlying medical conditions, irrespective of viral burden. By phylogenetic analysis, the 2014 EV-D68 strains clustered into a new sublineage within clade B.
  
  
  CONCLUSIONS
  This is one of the largest pediatric cohorts described from the EV-D68 outbreak. Irrespective of viral loads, EV-D68 was associated with high morbidity in children with asthma and co-morbidities. While EV-D68 circulated before 2014, the outbreak isolates clustered differently than those from prior years.
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Moyer
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Salamon
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Leber
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio, United States of America.|Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Asuncion
authors.initials: A
authors.lastname: Mejias
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000453:epidemiology / Q000821:virology; D002648:Child; D002675:Child, Preschool; D004196:Disease Outbreaks; D030016:Enterovirus D, Human / Q000235:genetics*; D004769:Enterovirus Infections / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007902:Length of Stay; D008297:Male; D009820:Ohio / Q000453:epidemiology; D012189:Retrospective Studies; D019562:Viral Load / Q000235:genetics*