Highly Pathogenic Avian Influenza Virus (H5N1) Infection in Red Foxes Fed Infected Bird Carcasses

Leslie A. Reperant; Geert van Amerongen; Marco W.G. van de Bildt; Guus F. Rimmelzwaan; Andrew P. Dobson; Albert D.M.E. Osterhaus; Thijs Kuiken


Emerging Infectious Diseases. 2008;14(12):1835-1841. 

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This study demonstrates that red foxes are susceptible to infection with a wild bird isolate of HPAI virus (H5N1) from clade 2.2. Red foxes can become infected after eating infected bird carcasses, and they can excrete the virus for as many as 5 days in the absence of severe disease. Therefore, naturally infected red foxes may potentially survive infection in the wild and excrete and disperse HPAI viruses (H5N1) within their home ranges. The size of foxes' home ranges depends on the environmental conditions and availability of food resources, but typically it varies between 1 km2 and 10 km2.[34] Red foxes are highly mobile and may travel 5-20 km within their home range during a night.[35] A juvenile fox traveled 90 km in 1 direction within 5 days during fall dispersal from its place of birth.[35] Furthermore, red foxes have colonized most urbanized areas in Europe, resulting in increased contact with domestic and peridomestic animals.[23] They may transmit the virus to domestic species, such as poultry. Therefore, we propose that this abundant and widespread carnivorous species be surveyed for exposure to or infection with HPAI viruses (H5N1) in influenza-endemic areas or in areas experiencing outbreaks of HPAI virus (H5N1) infections in wild bird populations. Where foxes are hunted, carcasses may be routinely sampled and tested. Where foxes are protected or not hunted, live trapping, bleeding, and pharyngeal swabbing of anesthetized foxes may be implemented.

Although red foxes fed infected bird carcasses may survive infection, severe pneumonia, myocarditis, and encephalitis may develop in those inoculated intratracheally. Frequent findings of HPAI virus (H5N1) infections in naturally infected carnivores were pneumonia associated with respiratory distress and encephalitis (in some cases associated with neurologic signs).[12,13,14,16,18,19,20,21] In most instances, the animals were either euthanized because of the severity of the disease or were found dead. Surprisingly, foxes with severe respiratory and cerebral lesions did not show any visible clinical signs. Foxes, being wild animals, were wary in the presence of humans and changed their behavior even when observed from a distance. This behavior may have prevented us from observing subtle clinical signs, notably abnormal breathing. A cat that died of HPAI virus (H5N1) infection in Germany did not show visible clinical signs 24 hours before death, despite marked respiratory lesions,[16] which suggests that even severe respiratory lesions may not be noticed clinically. Clinical manifestations of neurologic lesions in infected foxes may have gone unnoticed because the lesions were in the cerebrum rather than in the cerebellum. Although cerebellar lesions may cause conspicuous neurologic signs, e.g., ataxia and loss of balance, cerebral lesions may cause more subtle clinical signs, e.g., altered mental attitude, which were not noticed under these experimental conditions.[36]

Foxes may exhibit more severe disease after eating infected birds under natural conditions than under the controlled conditions of our feeding experiments, because of poorer health, possible co-infections, and poorer nutritional status of wild animals. For instance, the cats that died of HPAI virus (H5N1) infection in Germany were all infected with Aelurostrongylus spp., and pulmonary aelurostrongylosis was considered to have contributed to the severity of the disease in these animals.[16] Fatal cases of HPAI virus (H5N1) infection in red foxes may have been missed after the spread of HPAI viruses (H5N1) in poultry and wild bird populations outside Asia because fox carcasses are difficult to locate and because those found may likely be routinely tested for rabies and canine distemper rather than for influenza virus infection. Therefore, we suggest that red foxes with neurologic signs or red foxes found moribund or dead in disease-endemic areas or in areas experiencing outbreaks of HPAI virus (H5N1) infections in wild bird populations be tested for HPAI virus (H5N1) infection.

Foxes infected intratracheally and those fed infected bird carcasses exhibited similar virus-shedding patterns despite the different routes of exposure and despite marked differences in the severity and extent of associated lesions. Foxes fed infected bird carcasses likely inhaled virus particles during mastication. The differences in the severity and extent of associated lesions may have thus resulted from a difference in the respiratory inoculum received by foxes infected intratracheally and those fed infected carcasses. We did not observe influenza antigen-positive neuronal cells in the submucosal or myenteric plexi of the small intestine of foxes fed infected bird carcasses. This contrasts with findings in cats infected in the same way; in the cats, these cells were positive, which suggests the intestine as a route of virus entry.[37] The fact that the viral shedding patterns were similar despite the marked differences in severity and extent of respiratory lesions is surprising and difficult to explain. On the basis of the absence of influenza antigen-positive cells in the respiratory tract, all but 1 fox appeared to have cleared the virus from this site by 7 dpi. Signs of regeneration in bronchiolar and alveolar epithelia were observed both in foxes infected intratracheally and in those fed infected bird carcasses.

In summary, we have shown that red foxes are susceptible to infection with a wild bird isolate of HPAI virus (H5N1) from clade 2.2, can become infected after feeding on infected bird carcasses, and can excrete the virus for as many as 5 days without severe disease developing. Surveillance and monitoring of HPAI virus (H5N1) infections may therefore be beneficially expanded to red foxes, and potentially to other free-living wild carnivores, in influenza-endemic areas and in areas experiencing outbreaks of HPAI virus (H5N1) infections in wild bird populations.


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