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Original Contribution
April 4, 2007

Emergence of Influenza B Viruses With Reduced Sensitivity to Neuraminidase Inhibitors

Author Affiliations

Author Affiliations: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science (Drs Hatakeyama, Ito, Kiso, and Kawaoka), Department of Infectious Diseases, Graduate School of Medicine (Drs Hatakeyama and Koike), and International Research Center for Infectious Diseases, Institute of Medical Science (Dr Kawaoka), University of Tokyo, Tokyo, Japan; Department of Pediatrics, Keiyu Hospital, Kanagawa, Japan (Dr Sugaya); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama (Drs Ito, Kiso, and Kawaoka); Zama Children's Clinic, Kanagawa (Dr Yamazaki); Department of Pediatrics, Isehara Kyodo Hospital, Kanagawa (Drs Ichikawa and Kimura); Kawasaki City Institute of Public Health, Kanagawa (Mr Shimizu); Yokohama City Institute of Health, Kanagawa (Ms Kawakami); Department of Pediatrics, Eiju General Hospital, Tokyo (Dr Mitamura); and Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison (Dr Kawaoka).

JAMA. 2007;297(13):1435-1442. doi:10.1001/jama.297.13.1435

Context Very little is known about the frequency of generation and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. Furthermore, transmission of resistant virus, whether influenza A or B, has not been recognized to date.

Objective To assess the prevalence and transmissibility of influenza B viruses with reduced sensitivity to neuraminidase inhibitors.

Design, Setting, and Patients Investigation of the neuraminidase inhibitor sensitivity of influenza B isolates from 74 children before and after oseltamivir therapy and from 348 untreated patients with influenza (including 66 adults) seen at 4 community hospitals in Japan during the 2004-2005 influenza season. Four hundred twenty-two viruses from untreated patients and 74 samples from patients after oseltamivir therapy were analyzed.

Main Outcome Measure Sialidase inhibition assay was used to test the drug sensitivities of influenza B viruses. The neuraminidase and hemagglutinin genes of viruses showing reduced sensitivity to neuraminidase inhibitors were sequenced to identify mutations that have the potential to confer reduced sensitivity to these drugs.

Results In 1 (1.4%) of the 74 children who had received oseltamivir, we identified a variant with reduced drug sensitivity possessing a Gly402Ser neuraminidase substitution. We also identified variants with reduced sensitivity carrying an Asp198Asn, Ile222Thr, or Ser250Gly mutation in 7 (1.7%) of the 422 viruses from untreated patients. Review of the clinical and viral genetic information available on these 7 patients indicated that 4 were likely infected in a community setting, while the remaining 3 were probably infected through contact with siblings shedding the mutant viruses.

Conclusions In this population, influenza B viruses with reduced sensitivity to neuraminidase inhibitors do not arise as frequently as resistant influenza A viruses. However, they appear to be transmitted within communities and families, requiring continued close monitoring.