title: Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes.
abstract: Although avian H5N1 influenza virus has yet to develop the capacity for human-to-human spread, the severity of the rare cases of human infection has warranted intensive follow-up of potentially exposed individuals that may require antiviral prophylaxis. For countries where antiviral drugs are limited, the World Health Organization (WHO) has developed a risk categorization for different levels of exposure to environmental, poultry, or human sources of infection. While these take into account the infection source, they do not account for the likely mode of virus entry that the individual may have experienced from that source and how this could affect the disease outcome. Knowledge of the kinetics and spread of virus after natural routes of exposure may further inform the risk of infection, as well as the likely disease severity. Using the ferret model of H5N1 infection, we compared the commonly used but artificial inoculation method that saturates the total respiratory tract (TRT) with virus to upper respiratory tract (URT) and oral routes of delivery, those likely to be encountered by humans in nature. We show that there was no statistically significant difference in survival rate with the different routes of infection, but the disease characteristics were somewhat different. Following URT infection, viral spread to systemic organs was comparatively delayed and more focal than after TRT infection. By both routes, severe disease was associated with early viremia and central nervous system infection. After oral exposure to the virus, mild infections were common suggesting consumption of virus-contaminated liquids may be associated with seroconversion in the absence of severe disease.
  
  
  OBJECTIVE
  Risks for human H5N1 infection include direct contact with infected birds and frequenting contaminated environments. We used H5N1 ferret infection models to show that breathing in the virus was more likely to produce clinical infection than swallowing contaminated liquid. We also showed that virus could spread from the respiratory tract to the brain, which was associated with end-stage disease, and very early viremia provided a marker for this. With upper respiratory tract exposure, infection of the brain was common but hard to detect, suggesting that human neurological infections might be typically undetected at autopsy. However, viral spread to systemic sites was slower after exposure to virus by this route than when virus was additionally delivered to the lungs, providing a better therapeutic window. In addition to exposure history, early parameters of infection, such as viremia, could help prioritize antiviral treatments for patients most at risk of succumbing to infection.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Edenborough
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lowther
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: Laurie
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Manabu
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Fenella
authors.initials: F
authors.lastname: Long
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Bingham
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Jean
authors.initials: J
authors.lastname: Payne
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harper
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Haining
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Arkinstall
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
authors.forename: Brad
authors.initials: B
authors.lastname: Gilbertson
authors.affiliation: Australian Animal Health Laboratory, CSIRO, East Geelong, Australia.
authors.forename: Deborah
authors.initials: D
authors.lastname: Middleton
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia lorena@unimelb.edu.au.
authors.forename: Lorena E
authors.initials: LE
authors.lastname: Brown
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018562:Disease Transmission, Infectious; D005260:Female; D005289:Ferrets; D053124:Influenza A Virus, H5N1 Subtype / Q000502:physiology*; D008297:Male; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000473:pathology* / Q000635:transmission / Q000821:virology*; D018570:Risk Assessment; D016019:Survival Analysis