Prolonged Influenza Virus Shedding and Emergence of Antiviral Resistance in Immunocompromised Patients and Ferrets

Abstract

Immunocompromised individuals tend to suffer from influenza longer with more serious complications than otherwise healthy patients. Little is known about the impact of prolonged infection and the efficacy of antiviral therapy in these patients. Among all 189 influenza A virus infected immunocompromised patients admitted to ErasmusMC, 71 were hospitalized, since the start of the 2009 H1N1 pandemic. We identified 11 (15%) cases with prolonged 2009 pandemic virus replication (longer than 14 days), despite antiviral therapy. In 5 out of these 11 (45%) cases oseltamivir resistant H275Y viruses emerged. Given the inherent difficulties in studying antiviral efficacy in immunocompromised patients, we have infected immunocompromised ferrets with either wild-type, or oseltamivir-resistant (H275Y) 2009 pandemic virus. All ferrets showed prolonged virus shedding. In wild-type virus infected animals treated with oseltamivir, H275Y resistant variants emerged within a week after infection. Unexpectedly, oseltamivir therapy still proved to be partially protective in animals infected with resistant virus. Immunocompromised ferrets offer an attractive alternative to study efficacy of novel antiviral therapies. Immunocompromised patients, such as transplant recipients on immune suppressive therapy, are a substantial and gradually expanding patient group. Upon influenza virus infection, these patients clear the virus less efficiently and are more likely to develop severe pneumonia than immunocompetent individuals. Existing antiviral strategies are far from satisfactory for this patient group, as they show limited effectiveness with frequent emergence of antiviral resistance. For ethical and practical reasons antiviral efficacy studies are hard to conduct in these patients. Therefore, we developed an immunocompromised ferret, mimicking an immune suppressive regimen used for solid organ transplant recipients. Upon infection with 2009 pandemic influenza A/H1N1 virus these animals, like immunocompromised patients, develop severe respiratory disease with prolonged virus excretion. Interestingly, all immunocompromised ferrets on oseltamivir therapy excreted oseltamivir resistant viruses (H275Y) within one week after start of treatment. Furthermore, high dose oseltamivir therapy still proved to be partially effective against these oseltamivir resistant viruses. These immunocompromised ferrets provide a useful tool in the development of novel antiviral approaches for immunocompromised patients suffering from influenza.