Extra-respiratory spread of IAVs in birds Influenza A virus (IAV) inoculation of birds does not represent an ideal in vivo model to study the extra-respiratory systemic pathogenesis of influenza in humans. There are substantial differences in the pathogenesis of influenza between birds and mammals, and also among different bird species, which compromises comparison. However, this does not imply that studying the pathogenesis of influenza in birds cannot lead to findings that can be extrapolated to the mammalian situation. Intravenous inoculation in six-week-old chickens is still used for the determination of the intravenous pathogenicity index (IVPI) that categorizes the pathogenicity of IAVs. Here, we will in short describe the pathogenesis of IAV infections in birds to highlight the differences with humans and other mammals. Within birds, IAV infection is associated with a different pattern of disease in water birds compared to poultry. Wild ducks and geese are considered the main natural hosts of IAVs and typically do not show signs of disease [87]. Like in humans, epithelial cells are the main target of infection in these birds; however, the virus mainly infects the intestinal epithelium, and less frequently the respiratory epithelium [88]. Poultry, and several wild bird species, can be infected by low pathogenic avian influenza viruses (LPAIVs) and by highly pathogenic avian influenza viruses (HPAIVs) [89]. Infection with LPAIVs in poultry typically produces limited clinical signs, and the virus preferentially targets epithelium of the respiratory tract. Infection with HPAIVs of the H5 and H7 subtypes is associated with severe systemic disease in poultry. HPAIVs target endothelial cells of multiple organs, such as lung, liver, heart, kidney, spleen, pancreas, bursa, and brain. The endotheliotropism of HPAIVs in poultry, which is not observed in humans, is associated with oedema formation and hemorrhages, coagulation disturbances, and induction of acute pro-inflammatory cytokines (cytokine storm), which may lead to acute mortality [90]. In wild birds, HPAIVs predominantly infect epithelial cells of the respiratory tract but not endothelial cells. Infection may lead to infection of parenchymal cells of other organ systems as well, associated with multi-organ necrosis and inflammation [91]. Amongst wild birds, the black swan is an exception because HPAIVs target systemic endothelial cells [92].