title: Emergence of oseltamivir-resistant influenza A/H3N2 virus with altered hemagglutination pattern in a hematopoietic stem cell transplant recipient.
abstract: BACKGROUND
  Persistent influenza virus replication during antiviral therapy in patients undergoing hematopoietic stem cell transplantation (HSCT) could promote the emergence of antiviral drug resistance.
  
  
  OBJECTIVE
  To follow the viral genotypic and drug susceptibility changes in a patient who developed progressive influenza A/H3N2 pneumonia despite oseltamivir therapy after haploidentical HSCT.
  
  
  METHODS
  Direct genotypic analysis of the neuraminidase (NA) and hemagglutinin (HA) genes in successive bronchoalveolar lavage specimens was employed in combination with hemagglutination and NA enzymatic activity assays of the corresponding viral isolates.
  
  
  RESULTS
  The emergence of NA oseltamivir-resistance mutation R292K was detected by 12 days of oseltamivir treatment with 44,286-fold increase in oseltamivir IC50. Resurgence of wild type viral population was identified by 7 days after cessation of oseltamivir. Sequential HA mutations R228S and A138S were identified and associated with a shift in the HA receptor binding pattern reflected by loss of the ability to agglutinate chicken erythrocytes.
  
  
  CONCLUSIONS
  These rapid evolutionary changes warrant close virologic monitoring of immunocompromised patients treated for influenza infection, and raise concern about the efficacy of mono-drug therapy for influenza-associated disease in HSCT recipients.
authors.affiliation: Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Leonor
authors.initials: L
authors.lastname: Cohen-Daniel
authors.forename: Zichria
authors.initials: Z
authors.lastname: Zakay-Rones
authors.forename: Igor B
authors.initials: IB
authors.lastname: Resnick
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Shapira
authors.forename: Marina
authors.initials: M
authors.lastname: Dorozhko
authors.forename: Nurith
authors.initials: N
authors.lastname: Mador
authors.forename: Evgenia
authors.initials: E
authors.lastname: Greenbaum
authors.forename: Dana G
authors.initials: DG
authors.lastname: Wolf
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000821:virology; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D006385:Hemagglutination Inhibition Tests; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000302:isolation & purification*; D007251:Influenza, Human / Q000821:virology*; D020128:Inhibitory Concentration 50; D020125:Mutation, Missense; D053139:Oseltamivir / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D053139:Oseltamivir