H5N1 virus related influenza remains a relatively novel disease with poorly understood pathology and pathogenesis, and only a limited number of reports describing pathological findings in human H5N1 cases have been published 
. Some studies have shown that H5N1 virus is found exclusively in the respiratory tract (mainly in the lung) 
. Other studies report the presence of H5N1 viruses in many extrapulmonary organs, such as intestine, liver, and brain 
. Viral RNA has been detected in nasopharyngeal aspirates ranging from 1 day up to 15 days after disease onset 
. Viral replication appears to be prolonged in H5N1 influenza because viral loads when plotted against time did not show a clear decline in a large group of H5N1 patients 
. Various animal studies indicate that aberrant production of proinflammatory cytokines and chemokines may play an important role in the pathogenesis of H5N1 influenza, which is consistent with abnormal regulation of cytokines and chemokines, including hemophagocytotic activity, that have been described in H5N1 autopsy cases 
. In many H5N1 patients elevated serum levels of proinflammatory cytokines and chemokines have been detected 
. Apoptosis in alveolar cells and infiltrating leukocytes are prominent findings 
. Lymphocyte depletion occurs in the spleen, lymph nodes, and tonsils; and reactive hemophagocytosis presumably result from host cytokine responses and viral infection.
Thus far, several hundred human infections with avian H5N1 viruses have been confirmed. The A/VN/1203/04 strain that we used in our study is a highly pathogenic isolate
. This viral strain caused viremia and was lethal to ferrets (). Viral sequences and antigens have been detected in lymphocytes in lymph node tissue, as well as in Hofbauer cells (macrophages of the placenta), Kupffer cells (macrophages of the liver), and mononuclear cells in the intestinal mucosa 
. Recently, it has been reported that viral RNA was found in the blood of humans with fatal outcomes while no viral RNA could be detected in the blood of surviving H5N1-infected individuals 
. This is consistent with the findings we report here in ferrets. Accordingly, extra-pulmonary dissemination may be the result of viremia or of infected immune cells transporting virus to other organs, although this remains to be demonstrated. Viremia was accompanied by low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels in humans infected with H5N1 viruses 
, suggesting that high viral load and the resulting acute inflammatory responses have interconnected roles in influenza H5N1 pathogenesis. Taken together, these findings highlight the need for further studies to examine the relevance of viremia in H5N1 pathogenesis and virus transmission.