Pandemic 2009 H1N1 isolates containing the neuraminidase inhibitor resistance mutation H275Y have been reported. We describe rapid selection for the H275Y resistance mutation during therapy in two immunocompromised individuals in 9 and 14 days respectively, and the first described case of clinically significant resistance to peramivir.

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Background The overall impact of influenza virus infection in immunocompromised patients is largely unknown. Antigenic drift and genetic variations during prolonged influenza infection have been demonstrated. In this report we describe a multi-drug resistant H3N2 influenza virus isolated from an immunocompromised patient after 5 days of therapy. Methods Multiple nasal washes were collected from an infected patient and viral isolates characterized. Sensitivity to antiviral agents was evaluated. Fitness and transmissibility was assessed in ferrets and tissue culture. Results An in-frame 4 amino acid deletion emerged in the neuraminidase gene of an H3N2 virus after 5 days of oseltamivir therapy. No other changes in the NA or HA genes were noted. Drug sensitivity assays revealed resistance to oseltamivir (>10-fold increase in IC50) and reduction of sensitivity to zanamivir (3 to 7-fold increase in IC50/EC50). No change in fitness or transmissibility was observed. Conclusions An in-frame NA gene deletion was rapidly selected for in an immunocompromised patient, resulting in decreased sensitivity of the isolate to available neuraminidase inhibitors without a change in fitness or transmissibility. This carries implications for our understanding of the emergence of antiviral resistance and treatment of patients with influenza A infection, especially those who are immunocompromised.

Antivirals with specificity for a broad range of targets are easily identified in an accelerated viral inhibition assay that uses NA as a read-out of replication. This assay is suitable for high throughput screening to identify potential antivirals or can be used to identify drug-resistant influenza strains.

SummaryEpidemiological studies show an association between early exposure to respiratory syncytial virus (RSV) and the development or exacerbation of asthma. This idea is supported by studies in mice that demonstrate worsened airway hyper-reactivity (AHR) when RSV-infected animals are exposed to allergen. The effect of allergen on RSV disease, however, has not been reported. Cotton rats (Sigmodon hispidus) that have been used as a model to study RSV pathogenesis were sensitized to extracts of Aspergillus fumigatus (Af ), a common household mould. The allergic response to Af included eosinophilia, formation of granulomas and induction of Th2 type cytokines. RSV infection prior to allergen challenge resulted in exacerbation of the inflammatory response as well as increased airway responsiveness to methacholine. The exacerbated response was indeed dependent on virus replication. Virus replication in turn was influenced by the allergic response, with persistence in the noses for 2 days longer in animals challenged with allergen. This diminished clearance corresponded to decreased induction of mRNA for IFN-g, a Th1-type cytokine that is characteristic of viral infection. Treatment of RSV-infected Af-challenged animals with recombinant IFN-g reduced the allergic inflammatory response as well as the relative levels of Th1 and Th2 cytokine mRNA. However, this treatment did not reduce airway reactivity, showing that these pathologic and physiologic measures of exacerbated disease are independent. We speculate that the reciprocal effect of the allergic response on viral immunity may benefit the host by limiting exacerbation of physiologic responses that are IFN-g-dependent.