title: Multiple influenza A (H3N2) mutations conferring resistance to neuraminidase inhibitors in a bone marrow transplant recipient.
abstract: Immunocompromised patients are predisposed to infections caused by influenza virus. Influenza virus may produce considerable morbidity, including protracted illness and prolonged viral shedding in these patients, thus prompting higher doses and prolonged courses of antiviral therapy. This approach may promote the emergence of resistant strains. Characterization of neuraminidase (NA) inhibitor (NAI)-resistant strains of influenza A virus is essential for documenting causes of resistance. In this study, using quantitative real-time PCR along with conventional Sanger sequencing, we identified an NAI-resistant strain of influenza A (H3N2) virus in an immunocompromised patient. In-depth analysis by deep gene sequencing revealed that various known markers of antiviral resistance, including transient R292K and Q136K substitutions and a sustained E119K (N2 numbering) substitution in the NA protein emerged during prolonged antiviral therapy. In addition, a combination of a 4-amino-acid deletion at residues 245 to 248 (Δ245-248) accompanied by the E119V substitution occurred, causing resistance to or reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir). Resistant variants within a pool of viral quasispecies arose during combined antiviral treatment. More research is needed to understand the interplay of drug resistance mutations, viral fitness, and transmission.
authors.affiliation: Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.
authors.forename: Alireza
authors.initials: A
authors.lastname: Eshaghi
authors.affiliation: Division of Infectious Diseases, University Health Network, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shalhoub
authors.affiliation: Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Rosenfeld
authors.affiliation: Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.affiliation: Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Higgins
authors.affiliation: University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stogios
authors.affiliation: University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alexei
authors.initials: A
authors.lastname: Savchenko
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bastien
authors.affiliation: National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Infectious Diseases, University Health Network, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada.
authors.forename: Coleman
authors.initials: C
authors.lastname: Rotstein
authors.affiliation: Ontario Agency for Health Protection and Promotion, Toronto, Ontario, Canada University of Toronto, Toronto, Ontario, Canada The Hospital for Sick Children, Toronto, Ontario, Canada jonathan.gubbay@oahpp.ca.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Gubbay
mesh_terms: D000146:Acids, Carbocyclic; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D017809:Fatal Outcome; D005260:Female; D006146:Guanidines / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000009:adverse effects; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics*; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation; D009439:Neuraminidase / Q000737:chemistry / Q000235:genetics*; D053139:Oseltamivir / Q000627:therapeutic use; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics*; D053243:Zanamivir / Q000627:therapeutic use
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D007166:Immunosuppressive Agents; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir; C414210:peramivir