Epizootic HPAIV, H5N6, and H5N8 infections produced severe loss in poultry and wild birds in the Republic of Korea from 2016 to 2017. But pathological lesions and antigen distribution of the novel HPAIV H5N6 clade 2.3.4.4 in natural cases have been rarely reported. Herein, we describe the pathological lesions and antigen localization in chickens (layer and Korean native), ducks, and Japanese quail naturally infected by HPAIV H5N6. Grossly, severe reddening, swelling, and some necrotic foci, which were similar to septicemia or viremia, were observed in skin and many visceral organs including trachea, lung, liver, spleen, and pancreas. Histopathologically, pulmonary congestion and edema, as well as necrotizing hepatitis, splenitis, pancreatitis, myocarditis, and encephalitis were observed. Immunohistochemically, numerous HPAIV antigens were detected in necrotic parenchymal cells and in blood vessels of the respiratory, lymphoid, digestive, urinary, nervous, and cardiovascular systems. The results indicate that HPAIV H5N6 spread to the entire body via blood and caused severe damage throughout the entire body. The HPAI H5N6 clade 2.3.4.4 virus was isolated from samples of all four cases.

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