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Immunocompromised patients are highly susceptible to influenza infection and can have prolonged viral shedding, which is a risk factor for the development of antiviral resistance.We investigated the emergence of oseltamivir-resistant influenza variants in children and young adults with cancer during the 2002–2008 influenza seasons. The demographic and clinical features of influenza infections in 12 patients who had viral isolates obtained before and after oseltamivir therapy was initiated were studied. Antiviral susceptibilities were determined by the fluorescence-based neuraminidase (NA) enzyme inhibition assay and by sequencing genes encoding NA and matrix M2 proteins.The mean age of patients was 10.5 (range, 1.1–23.0) years. Ten patients had hematologic malignancies, 4 were recipients of hematopoietic stem cell transplants, and all patients were receiving immunosuppressive therapy. Eleven patients had prolonged respiratory symptoms and 8 had prolonged viral shedding. Serial viral isolates were available for 8 of 12 patients. Oseltamivir-resistant influenza viruses were isolated from 4 children (3 influenza A [H3N2] and 1 influenza B virus): before the initiation of antiviral therapy in 2 patients and during therapy in the other 2 patients. Three resistant influenza A (H3N2) viruses shared a common E119V NA mutation. One patient was infected with oseltamivir-resistant influenza B virus (IC50, 731.86 ± 155.12 nM) that harbored a N294S NA mutation, the first report of this mutation in influenza B viruses.Oseltamivir-resistant influenza viruses can exist before or rapidly emerge during antiviral therapy in immunocompromised individuals, and this has important implications for therapy and infection control.