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Title: Comparative pathology of select agent influenza A virus infections

Author
item KUIKEN, T - Erasmus Medical Center
item VAN DEN BRAND, J - Erasmus Medical Center
item VAN RIEL, D - Erasmus Medical Center
item Pantin Jackwood, Mary
item Swayne, David

Submitted to: Veterinary Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/23/2010
Publication Date: 9/1/2010
Citation: Kuiken, T., Van Den Brand, J., Van Riel, D., Pantin Jackwood, M.J., Swayne, D.E. 2010. Comparative pathology of select agent influenza A virus infections. Veterinary Pathology. 47(5):893-914.

Interpretive Summary: Influenza A viruses spread rapidly among humans causing sudden respiratory disease with variable death rate. Two of these influenza viruses are especially dangerous and are regulated by the U.S. government, allowing experimental studies only in high biocontainment laboratories: 1918 H1N1 "Spanish Influenza" and highly pathogenic avian influenza (HPAI) viruses. Influenza infections in humans can cause viral pneumonia, or often occurs together with or is followed by bacterial pneumonia. Experimental animals are used to study different aspects of influenza in humans. The most commonly used experimental animal species are laboratory mouse, domestic ferret, and cynomolgus macaque which produce pneumonia similar to that in humans. Each of these species has advantages and disadvantages that need to be assessed prior to choosing the most appropriate model for the development of more effective antiviral drugs and vaccines to protect humans.

Technical Abstract: Influenza A virus infections may spread rapidly in human populations and cause acute respiratory disease with variable mortality. Two of these influenza viruses have been designated as select agents because of the high case fatality rate: 1918 H1N1 virus and highly pathogenic avian influenza (HPAI) viruses. The 1957 H2N2 virus and the 2009 H1N1 virus are not select agents, but are considered of higher risk to public health than seasonal human influenza viruses. Knowledge of the pathology of these virus infections in humans, other naturally infected species, and experimental animals is important to understand the pathogenesis of influenza, to design appropriate models for evaluation of medical countermeasures, and to make correct diagnoses. The most important complication of influenza in humans from both human influenza and HPAI virus infections is viral pneumonia, categorized as diffuse alveolar damage. This viral lesion often occurs together with or is followed by bacterial pneumonia. Viremia and extra-respiratory disease are uncommon, and have been recorded more frequently in association with HPAI H5N1 virus infection than with human influenza virus infections. Besides in humans, HPAI H5N1 virus infection also causes severe disease in several species of carnivores after feeding on infected birds. In carnivores, virus infection and associated disease is not limited to the respiratory tract, but often extends to multiple extra-respiratory organs. HPAI viruses, including HPAI H5N1 virus, cause severe systemic disease in chickens, turkeys, and other galliform species. Anseriform species and bird species of other orders suffer similar severe disease from HPAI H5N1 viruses found in 2002 and later years. These infections involve virus replication in parenchymal cells of multiple organs and are associated with severe necrosis and inflammation. In galliforms and some swan species, virus replication also takes place in endothelial cells and is associated with widespread edema and hemorrhage. Experimental animals are used to model different aspects of influenza in humans, including uncomplicated influenza, pneumonia, and virus transmission. The most commonly used experimental animal species are laboratory mouse, domestic ferret, and cynomolgus macaque. Influenza viral pneumonia similar to that in humans can be induced in each of these species by intranasal or intratracheal inoculation of influenza virus. Each of these species has advantages and disadvantages that need to be assessed prior to choosing the most appropriate model to reach a particular goal. Experimental influenza virus infections are performed in various other species, including domestic pig and guinea pig. Animal models for influenza could be improved by better knowledge of the temporal progression of pulmonary lesions, better integration of pathology and cytokine data, standardardization of commonly used models, and development of aerosol exposure as a route of inoculation for select agent influenza viruses. Such animal models may be applied for the development of more effective antiviral drugs and vaccines to protect humans from the threat of these virus infections.