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Viral diseases of ferrets

      With the continually growing popularity of ferrets, practitioners will encounter individuals that suffer from viral disease more frequently. Ferrets have been used extensively as animal models to study a variety of viral diseases, many of which only occur following experimental infection. This article provides a review of viral diseases that occur naturally in ferrets (Table 1). The etiology, transmission, and pathogenesis of each virus is discussed. There is special emphasis on clinical signs, diagnostic tests, and methods to control and prevent these conditions.
      Table 1List of naturally occurring viruses of domestic ferrets
      VirusesFamilyNucleic acidEnvelopeSize (nm)
      Distemper virusParamyxoviridaessRNAyes150–300
      CoronavirusCoronaviridaessRNAyes60–220
      Influenza virusOrthomyxoviridaessRNAyes90–120
      Rabies virusRhabdoviridaessRNAyes70–85 × 130–380
      RotavirusReoviridaedsRNAno80–130
      ParvovirusParvoviridaessDNAno18–26
      Infectious bovine rhinotracheitis virusHerpesviridaedsDNAyes46–48
      Abbreviations: ds, double stranded; ss, single stranded.

      Distemper

      Distemper is caused by an RNA virus of the genus Morbillivirus in the Paramyxoviridae family. There is one serotype of canine distemper virus (CDV) with several strains that produce different clinical presentations [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Distemper probably is the most serious infectious disease of ferrets; mortality rates approach 100%. Infection of ferrets with CDV is uncommon because of the availability of effective vaccines and client education on the importance of vaccination. Unvaccinated dogs and wild Canidae, Mustelidae and Procyonidae may serve as reservoirs of the disease [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. A CDV epizootic was reported in a black-footed ferret (Mustela nigripes) colony in the fall of 1985 in Wyoming. The source of infection was not identified, but several badgers and coyotes in the area had CDV-neutralizing antibodies [
      • Williams E.S.
      • Thorne E.T.
      • Appel M.J.G.
      • et al.
      Canine distemper in black-footed ferrets (Mustela nigripes) from Wyoming.
      ].

      Pathogenesis

      CDV is transmitted by aerosol exposure to infected body fluids and by direct contact with infected animals and contaminated fomites. The virus is shed in ocular and nasal secretions, saliva, urine, and feces [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Viral shedding begins approximately 7 days postinfection [
      • Appel M.J.G.
      • Summers B.A.
      Pathogenicity of morbilliviruses for terrestrial carnivores.
      ]. The primary site of viral replication is the respiratory epithelium and lymphoid tissue of the nasopharynx [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Von Messling V.
      • Springfeld C.
      • Devaux P.
      • et al.
      A ferret model of canine distemper virus virulence and immunosuppression.
      ]. The virus disseminates by way of peripheral blood leukocytes to the liver, kidneys, gastrointestinal tract, urinary bladder, and brain. Viremia has been documented 2 days postinoculation or infection and persists until the virus is neutralized by antibodies or the animal dies [
      • Crook E.
      • Gorham J.R.
      • McNutt S.H.
      Experimental distemper in mink and ferrets. I. Pathogenesis.
      ]. Gastric hypochlorhydria has been associated with CDV infection in ferrets [
      • Pfeiffer C.J.
      Gastric hypochlorhydria in ferret distemper.
      ]. The lack of gastric acid was hypothesized to be due to direct action of the virus on gastric mucosa or was secondary to the viral effect on the central nervous system.

      Clinical signs

      Infected ferrets become symptomatic after an incubation period of 7 to 10 days [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Ryland L.M.
      A clinical guide to the pet ferret.
      ,
      • Ryland L.M.
      • Bernard S.L.
      • Gorham J.R.
      A clinical guide to the pet ferret.
      ]. In ferrets, natural CDV infection most often consists of a catarrhal phase followed by a fatal neurotropic phase [
      • Davidson M.
      Canine distemper virus infection in the domestic ferret.
      ]. The initial phase is characterized by anorexia, pyrexia, conjunctivitis, and serous nasal discharge. An erythematous, pruritic rash appears on the chin (Fig. 1) and eventually spreads to the inguinal area [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Davidson M.
      Canine distemper virus infection in the domestic ferret.
      ]. Hyperkeratosis of the footpads (Fig. 2) occurs inconsistently in ferrets [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Melena may be observed early in the course of the disease [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Davidson M.
      Canine distemper virus infection in the domestic ferret.
      ]. Some ferrets die during the catarrhal phase secondary to bacterial infections, such as pneumonia. Clinical signs that are seen in the neurotropic phase include hyperexcitability, muscle tremors, hypersalivation, seizures, and coma. Ferrets die 12 to 16 days after being infected with ferret-adapted CDV [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Ryland L.M.
      • Bernard S.L.
      • Gorham J.R.
      A clinical guide to the pet ferret.
      ]. The disease has a longer course when ferrets are infected with a wild canine strain; death occurs 21 to 35 days postinfection [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Sometimes a decrease in temperature is observed by the time the animals become moribund [
      • Von Messling V.
      • Springfeld C.
      • Devaux P.
      • et al.
      A ferret model of canine distemper virus virulence and immunosuppression.
      ].
      Figure thumbnail gr1
      Fig. 1An erythematous, cutaneous rash on the chin of a ferret with canine distemper virus infection. (From Blair EM, Chambers MA, King HA. Treating distemper in a young ferret. Vet Med 1998;98(7):656; with permission.)
      Figure thumbnail gr2
      Fig. 2Hyperkeratosis on the footpads of a ferret with canine distemper virus infection. (From Blair EM, Chambers MA, King HA. Treating distemper in a young ferret. Vet Med 1998;98(7):657; with permission.)

      Diagnosis

      A tentative diagnosis of canine distemper is based on the presence of typical clinical signs, severe leukopenia, a history of potential exposure to the virus, and questionable vaccination. A study demonstrated that virulent and attenuated CDV strains caused a severe leukopenia 1 week after infection [
      • Von Messling V.
      • Springfeld C.
      • Devaux P.
      • et al.
      A ferret model of canine distemper virus virulence and immunosuppression.
      ]. Leukocyte counts from animals that were infected with virulent strains remained low, whereas those of animals that received attenuated strains progressively increased to reach preinfection, or near preinfection, values 35 days postinfection.
      The diagnosis of canine distemper is confirmed routinely by an immunofluorescence test on peripheral blood smear, buffy coat, or conjunctival scrapings in live animals. In experimentally-infected ferrets, a reverse transcriptase–polymerase chain reaction (RT-PCR) has been used to detect the virus in peripheral blood [
      • Stephenson C.B.
      • Welter J.
      • Thaker S.R.
      • et al.
      Canine distemper virus (CDV) infection of ferrets as a model for testing Morbillivirus vaccine strategies: NYVAC- and ALVAC-based CDV recombinants protect against symptomatic infection.
      ]. Recently, nested-PCR was found to be a sensitive and specific method for diagnosis of CDV infection [
      • Rzezutka A.
      • Mizak B.
      Application of N-PCR for diagnosis of distemper in dogs and fur animals.
      ].
      On postmortem examination, the gross lesions correspond to the aforementioned clinical signs. On hematoxylin and eosin–stained sections, round eosinophilic intracytoplasmic and occasional intranuclear inclusion bodies are present in epithelial cells of the trachea, bronchi, and urinary tract [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Other tissues, such as skin, gastrointestinal tract, salivary and adrenal glands, spleen, lymph nodes and brain, have been reported to contain inclusions [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ].

      Treatment and prevention

      Ferrets that have signs that are suggestive of canine distemper infection should be placed in isolation. Supportive care, including fluid therapy, systemic and ophthalmic antibiotics, gavage feeding, and bathing with antipruritic shampoo, may be initiated. Administration of immune anti-CDV serum also may be considered. Thorough daily disinfection of the environment is indicated. In all cases, prognosis is grave. The virus is inactivated by heat, visible light, and commonly used disinfectants (0.75% phenol, 0.2% roccal, 2%–5% sodium hydroxide, and 0.1% formalin) [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Appel M.J.G.
      • Summers B.A.
      Pathogenicity of morbilliviruses for terrestrial carnivores.
      ]. Some investigators reported that out of more than 1000 cases of distemper, not a single ferret survived the infection [
      • Ryland L.M.
      • Bernard S.L.
      • Gorham J.R.
      A clinical guide to the pet ferret.
      ]. Blair et al [
      • Blair E.M.
      • Chambers M.A.
      • King H.A.
      Treating distemper in a young ferret.
      ] treated distemper in a 7-month-old ferret while in the catarrhal phase. The ferret's life span and quality of life were improved with treatments, but the neurotropic phase could not be prevented and the animal was euthanized. When faced with an outbreak of canine distemper in a ferret colony, euthanasia and repopulation following disinfection is recommended.
      Distemper is prevented best by vaccination. Two vaccines are approved for use in ferrets in North America—Fervac-D Canine Distemper Vaccine (United Vaccines Inc., Madison, Wisconsin) and Purevax Ferret Distemper Vaccine (Merial, Athens, Georgia and Montréal, Quebec, Canada). Fervac-D is a modified-live virus vaccine of chick cell origin. A 5.9% incidence of anaphylactic reaction has been reported with this vaccine [
      • Greenacre C.B.
      Incidence of adverse events in ferrets vaccinated with distemper or rabies vaccine:143 cases(1995–2001).
      ]. Adverse events developed within 25 minutes and were characterized by hyperemia, hypersalivation, and vomiting. Purevax is a lyophilized vaccine of a recombinant canary pox vector that expresses the HA and F glycoproteins of CDV. The manufacturer uses the term “ferret distemper” vaccine on the product label to prevent confusion with their canine products; however, there is no such thing as a “ferret distemper virus” and ferrets are infected by CDV. The absence of adjuvant or entire distemper virus decreased postvaccination risks and the manufacturer reports an incidence of 0.3% reversible anaphylactic reactions in its field safety trials. Another modified-live canine distemper vaccine attenuated in primate cell line (Galaxy D, Schering Plough Animal Health, Omaha, Nebraska) has been studied in ferrets. This vaccine was effective in preventing canine distemper in young ferrets that were challenged with virulent CDV after two vaccine inoculations [
      • Winsatt J.
      • Jay M.T.
      • Innes K.E.
      • et al.
      Serologic evaluation, efficacy, and safety of a commercial modified-live canine distemper vaccine in domestic ferrets.
      ]; however, the duration of immunity and the incidence of vaccine reactions are unknown. Clinical use of this vaccine is extra label (not approved for use in ferrets by USDA) and requires informed owner consent. Postvaccinal distemper infections were reported in black-footed ferrets that were vaccinated with chicken embryo–tissue culture–origin CDV vaccine and in domestic ferrets that were vaccinated with canine cell products [
      • Carpenter J.W.
      • Appel M.J.
      • Erickson R.C.
      • et al.
      Fatal vaccine-induced canine distemper virus infection in black-footed ferrets.
      ,
      • Kauffman C.A.
      • Bergman A.G.
      • O'Connor R.P.
      Distemper virus infection in ferrets: an animal model of measles-induced immunosuppression.
      ]. Therefore, vaccination of ferrets with these products must not be performed.
      Most ferrets that are obtained from pet stores at a young age received only one dose of CDV vaccine before leaving the breeding facility. Repeated inoculations are required because maternal antibodies may interfere with proper immune response to CDV vaccine antigens. Ferret kits should be vaccinated at 8 weeks of age and every 3 weeks for a total of 3 vaccinations [
      • Rosenthal K.L.
      Respiratory diseases.
      ,
      • Quesenberry K.E.
      • Orcutt C.
      Basic approach to veterinary care.
      ]. Yearly booster vaccines are recommended [
      • Rosenthal K.L.
      Respiratory diseases.
      ]. Observation of the ferret for 25 minutes following vaccination is advisable. In the event that a vaccine reaction occurs, administration of fluids, oxygen, antihistamine, and epinephrine may be indicated.

      Parvovirus

      Parvovirus strains of varying virulence and immunogenicity cause Aleutian disease. The disease was first reported in mink in the 1940s and got its name because mink that were homozygous for the Aleutian (blue) gene were affected most severely [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. The infection was documented in ferrets in the late 1960s [
      • Kenyon A.J.
      • Howard E.
      • Buko L.
      Hyperglobulinemia in ferrets with lymphoproliferative lesions (Aleutian disease).
      ]. At least three separate strains of Aleutian disease virus (ADV)—distinct from the mink strains—have been identified in ferrets [
      • Murakami M.
      • Matsuba C.
      • Une Y.
      • et al.
      Nucleotide sequence and polymerase chain reaction/restriction fragment length polymorphism analyses of Aleutian disease virus in ferrets in Japan.
      ,
      • Porter H.C.
      • Porter D.D.
      • Larsen A.F.
      Aleutian disease in ferrets.
      ]. The ferret strains are believed to be mutant strains of the mink parvovirus; the hypervariable capsid region of the ferret strains of ADV is similar to that of the mink parvovirus [
      • Saifuddin M.
      • Fox J.G.
      Identification of a DNA segment in ferret Aleutian disease virus similar to a hypervariable capsid region in mink Aleutian disease parvovirus.
      ]. Ferrets can be infected with the mink virus [
      • Murakami M.
      • Matsuba C.
      • Une Y.
      • et al.
      Nucleotide sequence and polymerase chain reaction/restriction fragment length polymorphism analyses of Aleutian disease virus in ferrets in Japan.
      ,
      • Porter H.C.
      • Porter D.D.
      • Larsen A.F.
      Aleutian disease in ferrets.
      ] and ferret ADV can infect mink; however, the virulence is lower compared with mink that are infected with mink strains [
      • Porter H.C.
      • Porter D.D.
      • Larsen A.F.
      Aleutian disease in ferrets.
      ,
      • Ohshima K.
      • Shen D.T.
      • Henson J.B.
      • et al.
      Comparison of the lesions of Aleutian disease in mink and hypergammaglobulinemia in ferrets.
      ,
      • Daoust P.Y.
      • Hunter D.B.
      Spontaneous Aleutian disease in ferrets.
      ].

      Pathogenesis

      Transmission of the virus may occur by aerosolization; by direct contact with urine, feces, saliva, and blood; or by contact with fomites [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Daoust P.Y.
      • Hunter D.B.
      Spontaneous Aleutian disease in ferrets.
      ]. Vertical transmission of ADV occurs in mink [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ]. The lesions that are caused by ADV infection are immune mediated, but the mechanism by which ADV interferes with the immune system is unknown. The severity of disease depends on the origin (mink or ferret) of the ADV strain that is involved as well as the immune status and genotype of the infected individual [
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ].
      Minks that are infected with mink ADV strains deposit immune complexes in various organs that result in glomerulonephritis, bile duct proliferation, and arteritis [
      • Morrisey J.K.
      Part II. Other diseases.
      ]. Mink kits from antibody-free jills die from acute interstitial pneumonia when infected with virulent ADV [
      • Alexandersen S.
      • Bloom M.E.
      Studies on the sequential development of acute interstitial pneumonia caused by Aleutian disease virus in mink kits.
      ]. Affected individuals are immunosuppressed, and therefore, are more susceptible to influenza, viral enteritis, and distemper [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Morrisey J.K.
      Part II. Other diseases.
      ]. Ferrets that are inoculated with ferret-adapted ADV exhibit marked, persistent hyperglobulinemia and periportal lymphocytic infiltrates of the liver [
      • Porter H.C.
      • Porter D.D.
      • Larsen A.F.
      Aleutian disease in ferrets.
      ]; however, immunocompetent adult ferrets that are infected experimentally can develop a persistent infection without clinical disease [
      • Porter H.C.
      • Porter D.D.
      • Larsen A.F.
      Aleutian disease in ferrets.
      ]. Mink strains cause milder lesions and only a moderate elevation in gamma globulins in ferrets [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ].

      Clinical signs

      Most ferrets that show clinical signs are between 2 and 4 years old. Ferrets can be infected for years before clinical symptoms are noted [
      • Morrisey J.K.
      Part II. Other diseases.
      ]. Any situation that leads to immunosuppression may play a role in the development of clinical disease. The clinical presentation of infected ferrets varies. Some ferrets that are infected with ADV die without clinical signs in good body condition [
      • Daoust P.Y.
      • Hunter D.B.
      Spontaneous Aleutian disease in ferrets.
      ]. Generally, ferrets show signs of a chronic wasting disease with progressive weight loss, malaise, and melena [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Acute dyspnea was described in one report [
      • Une Y.
      • Wakimoto Y.
      • Nakano Y.
      • et al.
      Spontaneous Aleutian disease in a ferret.
      ]. Central nervous system signs, such as tremors, ataxia, paralysis, and convulsions, also have been reported [
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ,
      • Oxenham M.
      Aleutian disease in the ferret.
      ,
      • Stewart J.D.
      • Rozengurt N.
      Aleutian disease in the ferret.
      ,
      • Welchman D de B.
      • Oxenham M.
      • Done S.H.
      Aleutian disease in domestic ferrets: diagnostic findings and survey results.
      ,
      • Wolfensohn H.H.L.
      Aleutian disease in laboratory ferrets.
      ]. Affected animal also may present with fecal and urinary incontinence [
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ,
      • Oxenham M.
      Aleutian disease in the ferret.
      ].

      Diagnosis

      A presumptive diagnosis can be made based on a high gamma globulin concentration, the history, and clinical signs. Although hypergammaglobulinemia is considered to be pathognomonic in mink, this feature is not always present in infected ferrets [
      • Une Y.
      • Wakimoto Y.
      • Nakano Y.
      • et al.
      Spontaneous Aleutian disease in a ferret.
      ,
      • Oxenham M.
      Aleutian disease in the ferret.
      ]. Serum protein electrophoresis often shows that gamma globulins account for more than 20% of the total protein concentration [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Porter H.C.
      • Porter D.D.
      • Larsen A.F.
      Aleutian disease in ferrets.
      ].
      Other clinical pathologic findings of infected ferrets are variable. Anemia, possibly attributable to hemolysis and decreased erythrocyte production, may be present [
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ]. Biochemical abnormalities, such as azotemia and elevated liver enzymes, may be seen according to damage that results from immune complex deposition. Proteinuria and urinary casts that are secondary to kidney damage also may be observed [
      • Une Y.
      • Wakimoto Y.
      • Nakano Y.
      • et al.
      Spontaneous Aleutian disease in a ferret.
      ].
      Diagnosis of Aleutian disease is confirmed antemortem with a positive serum titer coupled with hypergammaglobulinemia or lymphoplasmacytic inflammation in tissue biopsy samples. Two serologic tests are available for ADV testing—counterimmunoelectrophoresis (CEP or CIEP) (United Vaccines, Madison, Wisconsin) and ELISA (Avecon Diagnostics, Bath, Pennsylvania). The specificity and sensitivity of the ELISA test has not been investigated in ferrets. Therefore, results must be interpreted with caution. The CEP test is used routinely in ferrets and is an effective method for identifying ferrets that have ADV antibodies [
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ,
      • Stewart J.D.
      • Rozengurt N.
      Aleutian disease in the ferret.
      ,
      • Welchman D de B.
      • Oxenham M.
      • Done S.H.
      Aleutian disease in domestic ferrets: diagnostic findings and survey results.
      ,
      • Wolfensohn H.H.L.
      Aleutian disease in laboratory ferrets.
      ,
      • Oxenham M.
      Aleutian disease in ferrets.
      ]. Presence of antibodies without clinical disease for extended periods is possible [
      • Kenyon A.J.
      • Kenyon B.J.
      • Hahn E.C.
      Protides of the Mustelidae immunoresponse of mustelids to Aleutian mink disease virus.
      ]. Ferrets probably develop persistent and nonpersistent, nonprogressive forms of ADV infection similar to mink [
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ,
      • Bloom M.E.
      • Race R.E.
      • Wolfinbarger J.B.
      Identification of a non-virion protein of Aleutian disease virus: mink with Aleutian disease have antibody to both virion and nonvirion proteins.
      ].
      Detection of ADV DNA by in situ hybridization has been performed, but this method is not practical to screen for this condition [
      • Haas L.
      • Lochelt M.
      • Kaaden O.R.
      Detection of Aleutian disease virus DNA in tissues of naturally infected mink.
      ]. Recently, polymerase chain reaction amplification of part of the capsid gene that is specific to ADV and restriction fragment length polymorphism to distinguish the ferret types of ADV from the mink types of ADV are valuable, time-saving assets for diagnosis of this infection in ferrets [
      • Murakami M.
      • Matsuba C.
      • Une Y.
      • et al.
      Nucleotide sequence and polymerase chain reaction/restriction fragment length polymorphism analyses of Aleutian disease virus in ferrets in Japan.
      ].
      At necropsy, infected ferrets may have few or no gross lesions. Hepatosplenomegaly, splenomegaly, and mesenteric lymphadenopathy have been reported [
      • Ohshima K.
      • Shen D.T.
      • Henson J.B.
      • et al.
      Comparison of the lesions of Aleutian disease in mink and hypergammaglobulinemia in ferrets.
      ,
      • Daoust P.Y.
      • Hunter D.B.
      Spontaneous Aleutian disease in ferrets.
      ]. The most consistent histologic findings of ADV infection in ferrets are periportal infiltration of the liver by plasma cells, lymphocytes, and macrophages with stimulated lymphoid tissues [
      • Ohshima K.
      • Shen D.T.
      • Henson J.B.
      • et al.
      Comparison of the lesions of Aleutian disease in mink and hypergammaglobulinemia in ferrets.
      ,
      • Daoust P.Y.
      • Hunter D.B.
      Spontaneous Aleutian disease in ferrets.
      ]. Bile duct hyperplasia, periportal fibrosis, and membranous glomerulonephrosis have been documented [
      • Ohshima K.
      • Shen D.T.
      • Henson J.B.
      • et al.
      Comparison of the lesions of Aleutian disease in mink and hypergammaglobulinemia in ferrets.
      ,
      • Daoust P.Y.
      • Hunter D.B.
      Spontaneous Aleutian disease in ferrets.
      ,
      • Une Y.
      • Wakimoto Y.
      • Nakano Y.
      • et al.
      Spontaneous Aleutian disease in a ferret.
      ]. In individuals that present with neurologic signs, perivascular lymphocytic cuffing in the brain and spinal cord (Fig. 3) and lymphoplasmacytic meningitis may be observed [
      • Palley L.S.
      • Corning B.F.
      • Fox J.C.
      • et al.
      Parvovirus-associated syndrome (Aleutian disease) in two ferrets.
      ,
      • Stewart J.D.
      • Rozengurt N.
      Aleutian disease in the ferret.
      ,
      • Welchman D de B.
      • Oxenham M.
      • Done S.H.
      Aleutian disease in domestic ferrets: diagnostic findings and survey results.
      ].
      Figure thumbnail gr3
      Fig. 3Severe perivascular cuffing with mononuclear cells in the spinal cord of a ferret with Aleutian disease. (From Welchman D de B, Oxenham M, Done SH. Aleutian disease in domestic ferrets: diagnostic findings and survey results. Vet Rec 1993;132:481; with permission.)

      Treatment and control

      There is no definitive treatment of Aleutian disease in ferrets. Symptomatic ferrets may benefit from use of anti-inflammatory medication or immunosuppressive drugs, such as prednisone and cyclophosphamide. In mink, treatment with cyclophosphamide has been used to control infections for up to 16 weeks, but virus titers did not decrease [
      • Cheema A.
      • Henson J.B.
      • Gorham J.R.
      Aleutian disease of mink: prevention of lesions by immunosuppression.
      ]. Administration of gamma globulin–containing ADV antibody may be considered because it contributed to decreased mortality rates in mink kits [
      • Aasted B.
      • Alexandersen S.
      • Hansen M.
      Treatment of neonatally Aleutian disease virus (ADV) infected mink kits with gamma-globulin containing antibodies to ADV reduces death rate of mink kits.
      ].
      Control of Aleutian disease is dependent on testing, cessation of breeding, and isolation of seropositive ferrets. All seropositive ferrets should be considered to be potential sources of ADV and should be isolated from seronegative ferrets [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. In mink farms, testing by CIEP and removing all individuals that have ADV antibodies has been an efficient method to eradicate the disease [
      • Cho H.J.
      • Greenfield J.
      Eradication of Aleutian disease of mink by eliminating positive counter immunoelectrophoresis reactors.
      ]. This approach, coupled with thorough disinfection, should be considered in any facility with a large number of ferrets. Formalin, sodium hydroxide, and a phenolic disinfectant were efficacious against ADV in the presence of organic material [
      • Shen D.T.
      • Leendertsen L.W.
      • Gorham J.R.
      Evaluation of chemical disinfectants for Aleutian disease virus of mink.
      ].
      There is no vaccine to prevent Aleutian disease and vaccination probably is contraindicated because of the immune-mediated nature of this condition. In mink, vaccination exacerbated the severity of Aleutian disease [
      • Porter D.D.
      • Larsen A.E.
      • Porter H.G.
      The pathogenesis of Aleutian disease of mink. II. Response of mink to formalin treated diseased tissue and to subsequent challenge with virulent inoculum.
      ].

      Coronavirus

      In the late 1980s, a novel diarrheal disease that affected domestic ferrets was reported by pet owners and ferret breeders in the mid-Atlantic area of the United States. Since that time, this condition has been diagnosed throughout North America and in several other countries. The disease was named epizootic catarrhal enteritis (ECE) on the basis of similarities to the epizootic catarrhal gastroenteritis of mink [
      • Gorham J.R.
      • Evermann J.F.
      • Ward A.
      Detection of coronavirus-like particles from mink.
      ]. ECE of mink is caused by a coronavirus that is related to transmissible gastroenteritis virus of pigs [
      • Have P.
      • Moving V.
      • Svansson V.
      • et al.
      Coronavirus infection in mink (Mustela vison). Serological evidence of infection with a coronavirus related to transmissible gastroenteritis virus and porcine epidemic diarrhea virus.
      ]. Research strongly implicates a coronavirus as the causative agent of ECE because: (1) microscopic lesions that were consistent with intestinal coronavirus infection were detected consistently in diseased ferrets; (2) coronavirus particles were identified in the feces and enterocytes, but no other viruses could be identified; and (3) immunohistochemical staining of jejunum showed coronavirus antigens in affected ferrets, but not in healthy individuals [
      • Williams B.H.
      • Kiupel M.
      • West K.H.
      • et al.
      Coronavirus-associated epizootic catarrhal enteritis in ferrets.
      ].

      Clinical presentation

      The disease is characterized by high transmissibility, high morbidity, and a low mortality rate. Ferrets show signs of lethargy and anorexia within 48 to 72 hours postinfection. Vomiting is the first sign of gastrointestinal disease in most ferrets, but it may go unnoticed by some owners because it subsides within hours [
      • Williams B.H.
      • Kiupel M.
      • West K.H.
      • et al.
      Coronavirus-associated epizootic catarrhal enteritis in ferrets.
      ]. Subsequently, profuse green, bile-tinged diarrhea with a variable amount of mucus develops (Fig. 4). The stool's appearance is responsible for the term “green slime disease” that also is used to describe this condition [
      • Hoefer H.L.
      Gastrointestinal diseases.
      ].
      Figure thumbnail gr4a
      Fig. 4(A, B) A. Profuse green bile-tinged diarrhea from the young ferret with epizootic catarrhal enteritis shown in Fig. B. (Courtesy of C. Greenacre, DVM, Knoxville, Tennessee.)
      Figure thumbnail gr4b
      Fig. 4(A, B) A. Profuse green bile-tinged diarrhea from the young ferret with epizootic catarrhal enteritis shown in Fig. B. (Courtesy of C. Greenacre, DVM, Knoxville, Tennessee.)
      The severity of clinical signs is highly variable; older ferrets that have concurrent diseases, such as insulinoma, long-standing infection with Helicobacter mustelae, or adrenal neoplasia, are prone to develop severe clinical signs. Ulcerations of the intestinal wall may occur which leads to the presence of blood in the feces. Young ferrets tend to have mild or subclinical infection. The hypersecretory phase of uncomplicated ECE often resolves within 5 to 7 days in healthy young animals. In some ferrets, this phase may be followed by a period of maldigestion or malabsorption of variable duration secondary to persistent lymphocytic inflammation of the intestinal wall. The feces become yellowish in color and contain grainy material that resembles bird seed.

      Diagnosis

      ECE often can be diagnosed solely on the basis of characteristic historical findings and clinical signs [
      • Williams B.H.
      • Kiupel M.
      • West K.H.
      • et al.
      Coronavirus-associated epizootic catarrhal enteritis in ferrets.
      ]. Thorough collection of the history data often reveals exposure to an asymptomatic ferret 48 to 72 hours before the onset of clinical signs. Generally, clinicopathologic findings are nonspecific. Inanition may cause increased serum activity of alanine aminotransferase and alkaline phosphatase secondary to mobilization of peripheral fat stores to the liver, with resultant hepatocellular swelling [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Williams B.H.
      • Kiupel M.
      • West K.H.
      • et al.
      Coronavirus-associated epizootic catarrhal enteritis in ferrets.
      ,
      • Hoefer H.L.
      Gastrointestinal diseases.
      ]. Hypoalbuminemia may develop as a result of enteritis and malabsorption in chronically affected individuals. Leukocytosis may be present in ferrets that have concurrent bacterial infection or gastric ulcers. Definitive diagnosis of coronavirus infection often is difficult. Coronavirus-like particles may be identified in the feces by electron microscopy during the acute phase of the disease process. Characteristic histologic lesions that are seen in intestinal coronavirus infection, such as lymphocytic enteritis with villus atrophy, fusion, blunting and vacuolar degeneration or necrosis of the apical epithelium, may be identified on intestinal biopsy or necropsy specimens [
      • Williams B.H.
      • Kiupel M.
      • West K.H.
      • et al.
      Coronavirus-associated epizootic catarrhal enteritis in ferrets.
      ].

      Treatment

      Ferrets may become dehydrated rapidly during the hypersecretory phase of infection. Dehydration and electrolyte imbalances need to be addressed. Fluids that are supplemented with dextrose and electrolytes may be administered orally, subcutaneously, or intravenously, according to the degree of dehydration. Antibiotic may be indicated to prevent secondary bacterial infection, particularly in cases with suspected intestinal ulcerations. In these cases, administration of sucralfate and an H2 antagonist (eg, cimetidine) also are beneficial. Sucralfate requires an acidic environment to be effective, so it should be given at least 30 minutes before an H2 antagonist. Syringe feeding with a highly digestible diet (Science Diet A/D, Hill's Prescription Diet) may be indicated if anorexia persists. If clinical signs that are suggestive of maldigestion develop, oral administration of prednisone may be indicated. Use of an anti-inflammatory dose of prednisone for 1 to 4 weeks, was followed by gradual tapering of the dose successfully.

      Influenza virus

      Influenza viruses belong to the class Orthomyxoviridae. Human influenza types A and B are pathogenic to ferrets [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Ferrets also are susceptible to avian, seal, equine, and swine influenza A viruses, although only human, avian, and swine strains induce clinical signs [
      • Doggart L.
      Viral disease of pet ferrets: part II. Aleutian disease, influenza, and rabies.
      ,
      • Marois P.
      • Boudreault A.
      • DiFranco E.
      • et al.
      Response of ferrets and monkeys to intranasal infection with human, equine, and avian influenza viruses.
      ,
      • Shope R.E.
      The infection of ferrets with swine influenza virus.
      ,
      • Zitzow L.A.
      • Rowe T.
      • Morken T.
      • et al.
      Pathogenesis of avian influenza A (H5N1) viruses in ferrets.
      ,
      • Smith W.
      • Andrews D.H.
      • Laidlow P.O.
      The virus obtained from influenza patients.
      ]. Infection with influenza B virus less frequently results in illness and is associated with a milder clinical course [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Transmission of influenza virus from human to ferrets and from ferrets to humans was documented in the 1930s [
      • Smith W.
      • Stuart-Harris C.H.
      Influenza infection of man from the ferret.
      ,
      • Smith H.
      • Sweet C.
      Lessons for human influenza from pathogenicity studies in ferrets.
      ]. Ferrets are used extensively as an animal model for influenza virus pathogenesis and immunity studies because their biologic response to influenza infection is similar to that of humans [
      • Sweet C.
      • Fenton R.J.
      • Price G.E.
      The ferret as an animal model of influenza virus infection.
      ,
      • Basarab O.
      • Smith H.
      Quantitative studies on the tissue localization of influenza virus in ferrets after intranasal and intravenous or extracordial inoculation.
      ].

      Pathogenesis and clinical signs

      Influenza virus is transmitted by aerosol droplets from an infected individual, either to a human or a ferret. After intranasal inoculation, the virus localizes and replicates in great numbers within the nasal mucosa [
      • Marini R.P.
      • Adkins J.A.
      • Fox J.G.
      Proven and potential zoonotic diseases of ferrets.
      ]. Following a short incubation period, the body temperature increases and then decreases approximately 48 hours later [
      • Collie M.H.
      • Rushton D.I.
      • Sweet C.
      • et al.
      Studies of influenza infection in newborn ferrets.
      ]. Transmission of the virus begins at the height of pyrexia and continues for 3 to 4 days [
      • Sweet C.
      • Fenton R.J.
      • Price G.E.
      The ferret as an animal model of influenza virus infection.
      ]. As in humans, the disease is characterized by upper respiratory signs. Clinical signs appear 48 hours postinfection and include anorexia, malaise, fever, sneezing, and serous nasal discharge [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Collie M.H.
      • Rushton D.I.
      • Sweet C.
      • et al.
      Studies of influenza infection in newborn ferrets.
      ]. Infection usually is mild in adult ferrets compared with neonates who can be severely ill [
      • Buchman C.A.
      • Swarts J.D.
      • Seroky J.T.
      • et al.
      Otologic and systemic manifestations of experimental influenza A virus infection in the ferret.
      ]. Conjunctivitis, photosensitivity, and unilateral otitis also may be seen [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Rosenthal K.L.
      Respiratory disease.
      ].
      Influenza infection may involve the lower respiratory tract in some susceptible animals [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Sweet C.
      • Macartney J.C.
      • Bird R.A.
      • et al.
      Differential distribution of virus and histological damage in the lower respiratory tract of ferrets infected with influenza viruses of differing virulence.
      ]. Usually, influenza virus is confined to the bronchial and bronchiolar tissues [
      • Sweet C.
      • Fenton R.J.
      • Price G.E.
      The ferret as an animal model of influenza virus infection.
      ,
      • Coates D.M.
      • Husseini R.H.
      • Rushton D.I.
      • et al.
      The role of lung development in the age-related susceptibility of ferrets to influenza virus.
      ]. The disease may be fatal in 1- to 2-day-old ferret kits secondary to bronchiolitis, pneumonia, and aspiration of material from the upper respiratory tract [
      • Buchman C.A.
      • Swarts J.D.
      • Seroky J.T.
      • et al.
      Otologic and systemic manifestations of experimental influenza A virus infection in the ferret.
      ,
      • Sweet O.
      • Jakeman K.J.
      • Rushton I.
      • et al.
      Role of upper respiratory tract infection in the deaths occurring in neonatal ferrets infected with influenza virus.
      ,
      • Glathe H.
      • Lebhardt A.
      • Hilgenfeld M.
      • et al.
      Intestinal influenza infection in ferrets (in German).
      ]. Lancefield group C hemolytic streptococci have been involved in secondary bacterial pneumonia [
      • Collie M.H.
      • Rushton D.I.
      • Sweet C.
      • et al.
      Studies of influenza infection in newborn ferrets.
      ].
      Influenza virus may infect the intestinal epithelium and cause limited enteritis [
      • Smith W.
      • Andrews D.H.
      • Laidlow P.O.
      The virus obtained from influenza patients.
      ,
      • Kang E.S.
      • Lee H.J.
      • Boulet J.
      • et al.
      Potential for hepatic and renal dysfunction during influenza B infection, convalescence, and after induction of secondary viremia.
      ]. Hepatic dysfunction also has been reported in ferrets that were infected experimentally with influenza [
      • Rowe T.
      • Cho D.S.
      • Bright R.A.
      • et al.
      Neurological manifestations of avian influenza viruses in mammals.
      ]. Neurologic symptoms, including ataxia, hind-limb paresis, and torticollis, were reported in ferrets that were infected experimentally with avian influenza A (H5N1) viruses that were isolated from the 1997 outbreaks of disease in domestic poultry markets in Hong Kong [
      • Smith W.
      • Andrews D.H.
      • Laidlow P.O.
      The virus obtained from influenza patients.
      ,
      • De Boer G.F.
      • Back W.
      • Osterhaus A.D.
      An ELISA for detection of antibodies against influenza A nucleoprotein in humans and various animal species.
      ].

      Diagnosis

      Generally, the diagnosis of influenza infection is based on the presence of compatible clinical signs, a history of exposure to infected individuals, and recovery from illness within 7 to 10 days. The differential diagnosis of any ferrets that has upper respiratory signs should include canine distemper. The usually mild and brief nature of influenza infections help to distinguish it from distemper. The use of virus isolation or hemagglutinin-inhibiting antibody titers on acute and convalescent serum samples rarely is needed for a diagnosis [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. An enzyme-linked immunosorbent assay has been used to detect antibodies against influenza A and may be used to obtain a diagnosis rapidly [
      • Sweet C.
      • Bird R.A.
      • Cavanah D.
      • et al.
      The local origin of the febrile response induced in ferrets during respiratory infection with a virulent influenza virus.
      ].
      Clinical pathologic findings may present abnormalities. Studies demonstrated an elevation in the neutrophil:lymphocyte ratio in the peripheral blood [
      • Smith W.
      • Andrews D.H.
      • Laidlow P.O.
      The virus obtained from influenza patients.
      ,
      • Chen K.S.
      • Bharaj S.S.
      • King E.C.
      Induction and relief of nasal congestion in ferrets infected with influenza virus.
      ]. Transient lymphopenia, with a loss of 60% to 65% of peripheral blood lymphocytes 3 days postinfection was reported experimentally with avian influenza A (H5N1) [
      • Smith W.
      • Andrews D.H.
      • Laidlow P.O.
      The virus obtained from influenza patients.
      ]. Plasma biochemical values generally are within reference ranges, but increases in concentrations of creatinine, blood urea nitrogen, potassium, albumin, and alanine aminotransferase were reported in some infected ferrets [
      • Rowe T.
      • Cho D.S.
      • Bright R.A.
      • et al.
      Neurological manifestations of avian influenza viruses in mammals.
      ].

      Treatment

      In most cases, infected ferrets can be treated at home. Owners should be instructed to let their ferret rest until fully recovered. Offering affected animals their favorite diet, highly palatable food (chicken baby food, beef baby food), or a highly energetic diet (Science Diet A/D, Hill's Prescription Diet) is indicated. Force feeding and offering water by syringe can be performed as needed. Treatments to relieve clinical symptoms should be done on a case by case basis. If coughing is persistent, a pediatric cough suppressant without alcohol (at the pediatric dosage on a per weight basis) has been used [
      • Sweet C.
      • Macartney J.C.
      • Bird R.A.
      • et al.
      Differential distribution of virus and histological damage in the lower respiratory tract of ferrets infected with influenza viruses of differing virulence.
      ]. To alleviate nasal congestion, the use of an antihistamine, such as diphenhydramine (2–4 mg/kg, by mouth, every 8 to 12 hours) [
      • Ryland L.M.
      • Bernard S.L.
      • Gorham J.R.
      A clinical guide to the pet ferret.
      ,
      • Sweet C.
      • Macartney J.C.
      • Bird R.A.
      • et al.
      Differential distribution of virus and histological damage in the lower respiratory tract of ferrets infected with influenza viruses of differing virulence.
      ], or intranasal delivery of phenylephrine may help [
      • Husseini R.H.
      • Collie M.H.
      • Rushton D.I.
      • et al.
      The role of naturally-acquired bacterial infection in influenza-related death in neonatal ferrets.
      ]. Antibiotics may be indicated to control secondary bacterial infections of the respiratory tract. Neonates typically succumb to secondary bacterial infections. Therefore, antibiotics may be useful in these patients to reduce mortality [
      • Husseini R.H.
      • Sweet C.
      • Overton H.
      • et al.
      Role of maternal immunity in the protection of newborn ferrets against infection with a virulent influenza virus.
      ].
      The use of non steroidal anti-inflammatory drugs to control fever is of questionable benefit because fever seems to be important in restricting the severity of infection [
      • Fenton R.J.
      • Bessell C.
      • Spilling C.R.
      • et al.
      The effects of per oral or local aerosol administration of 1-aminoadamantane hydrochloride (amantadine hydrochloride) on influenza infections of the ferret.
      ]. Experimentally, ferrets who received aspirin had cooler body temperature, but they shed more virus and their viral levels decreased less rapidly compared with ferrets that were not treated with an antipyretic.
      Administration of antiviral medication has been studied in ferrets. Amantadine hydrochloride (6 mg/kg, by mouth, every 12 hours) (Symmetrel, Bristol-Myers Squibb Canada, Montreal, Quebec, Canada) has been effective in treating ferrets that have influenza [
      • Fenton R.J.
      • Morley P.J.
      • Owens I.J.
      • et al.
      Chemoprophylaxis of influenza A virus infections, with single doses of zanamivir, demonstrates that zanamivir is cleared slowly from the respiratory tract.
      ]. Zanamivir (12.5 mg/kg) (Relenza, Glaxo Wellcome, Mississauga, Ontario, Canada), given as a one-time intranasal dose was able to prevent influenza infection [
      • Herlocher M.L.
      • Truscon R.
      • Fenton R.
      • et al.
      Assessment of development of resistance to antivirals in the ferret model of influenza virus infection.
      ]. Administration of amantadine in ferrets rapidly produces antiviral resistance, but use of zanamivir does not [
      • Potter C.W.
      • Oxford J.S.
      • Shore S.L.
      • et al.
      Immunity to influenza infection in ferrets. I. Response to live and killed virus.
      ].

      Prevention and control

      Vaccination of ferrets against influenza virus generally is not recommended because it is usually a mild disease and the antigenic variation of the virus complicates vaccination [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Sweet C.
      • Macartney J.C.
      • Bird R.A.
      • et al.
      Differential distribution of virus and histological damage in the lower respiratory tract of ferrets infected with influenza viruses of differing virulence.
      ]. Experimentally, ferrets who recovered from influenza infection remained resistant to infection with the same strain for 5 weeks following initial infection [
      • Husseini R.H.
      • Sweet C.
      • Collie M.H.
      • et al.
      Elevation of nasal viral levels by suppression of fever in ferrets infected with influenza viruses of differing virulence.
      ]. Ferret kits are protected from disease by milk-derived antibodies in immunized females [
      • Paisley J.W.
      • Lauer B.A.
      Severe facial injuries to infants due to unprovoked attacks by pet ferrets.
      ].
      Controlling influenza infection resides in avoiding exposure of susceptible ferrets to infected individuals, either ferret or human. Owners should be advised to minimize contact with their ferrets if they have a respiratory infection and should be sure to wash their hands thoroughly before changing the animal's cage, food, and water. Veterinarians who have respiratory infections may consider wearing a mask and gloves.

      Rhabdovirus

      Rhabdovirus causes rabies, an acute and almost invariably fatal disease that affects many mammals and humans. Over the past several years, there have been numerous reports of ferret bite injuries, including unprovoked attacks on infants and small children [
      • Diesch S.L.
      Reported human injuries or health threats attributed to wild and exotic animals kept as pets (1971–1981).
      ,
      • Applegate J.A.
      • Walhout M.F.
      Childhood risks from the ferret.
      ,
      National Association of State Public Health Veterinarians. Compendium of animal rabies control.
      ]. These reports brought great controversy over the acceptability of keeping ferrets as pets with regard to the potential risk for rabies. This was because the period of viral shedding in the animal's saliva—before the onset of recognizable signs—was unknown at that time [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Jenkins S.R.
      • Osterholm M.T.
      Epidemiologists and public health veterinarians issue statement on ferrets.
      ,
      • Centers for Disease Control
      Viral diseases: ferret rabies. Rabies surveillance, annual summary.
      ]. To the author's knowledge, there is no reported case of human rabies secondary to a ferret bite. Since 1958, less than 30 cases of rabies in domestic ferrets have been reported to the U.S. Centers for Disease Control [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ]. One of theses cases was attributed to vaccinating a ferret with modified-live virus rabies vaccine [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ].

      Pathogenesis

      Rabies virus must contact nerve endings and enter nerve fibers before infection occurs. Exposure to rabies virus does not always lead to productive infection [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Host response to rabies virus is influenced by the rabies virus variant, the viral dose, the route of transmission, the host species, and individual variations [
      • Charlton K.M.
      The pathogenesis of rabies and other lyssaviral infections: recent studies.
      ]. Infection occurs primarily by contact of nerve endings with infected saliva from a rabid animal as a result of a bite wound. Contact with the conjunctiva or olfactory mucosa also can result in transmission [
      • Charlton K.M.
      The pathogenesis of rabies and other lyssaviral infections: recent studies.
      ]. Transmission of rabies through ingestion of an infected mouse was unsuccessful [
      • Bell J.F.
      • Moore G.J.
      Susceptibility of carnivore to rabies virus administered orally.
      ].
      The pathogenesis of rabies in ferrets has been studied using European red fox rabies variant, North Central skunk rabies variant, and raccoon rabies variant [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. The mean incubation period is approximately 1 month [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Clinical signs reported include ascending paralysis, ataxia, tremors, paresthesia, hyperactivity, anorexia, cachexia, bladder atony, constipation, fever, and hypothermia [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Two of 19 rabid ferrets that were inoculated with raccoon rabies variant showed aggressive behavior [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Signs were reported to be mild in ferrets that were inoculated with the European red fox rabies variant [
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ]. Mean morbidity period was 4 to 5 days [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Mortality in ferrets that were inoculated with the European red fox variant was dose dependent [
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ]. In the study that used skunk variant, ferret susceptibility was dose dependent and the incubation period was inversely proportional to dose [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ]. In contrast, ferrets that were inoculated with raccoon variant were only moderately susceptible—regardless of dose—and there was no correlation found between viral dose and incubation period [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Ferrets who survived experimental infection remained clinically normal except for one ferret that was given skunk rabies variant and had severe paralytic sequelae [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ].
      The immunologic response of ferrets to rabies virus infection seems to vary depending on the rabies virus variant that was inoculated. Virus neutralizing antibodies were demonstrated in 14 of 33 (42.4%) rabid ferrets that were inoculated with skunk rabies variant compared with only 2 of 19 (10.5%) rabid ferrets that were given raccoon rabies variant [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Also, among ferrets that survived the infection, the proportion of seropositive cases was greater in ferrets that were given skunk rabies variant [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ].
      Ferrets may or may not excrete rabies virus in their saliva depending on the virus variant to which they have been exposed. Viral shedding was not documented in the saliva 120 days postinoculation with European red fox variant [
      • Blancou J.
      • Aubert J.F.A.
      • Artois M.
      Rage expérimentale du furet [Mustela (putorius) furo] [Experimental rabies in the ferret (Mustela (putorius) furo)].
      ]. Rabies virus was not detected in the saliva of any ferrets that were given skunk rabies variant, but it was isolated from the submaxillary salivary gland of one rabid ferret that was euthanized [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ]. Shedding of rabies virus in the saliva was documented in ferrets that were inoculated with the raccoon rabies variant [
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Rabies virus was isolated from the salivary glands of 63% of rabid ferrets and 47% shed rabies virus in their saliva. Initial viral excretion ranged from 2 days before the onset of clinical signs to 6 days after the onset. Viral shedding also was documented in 1 of 23 ferrets that were inoculated with a rodent strain of rabies virus [
      • Förster U.
      Zur frage der adaptationsfähigkeit von zwei in Mitteleuropa isolierten tollwutvirusstâmmen an eine domestizierte und zwei wildlebende spezies. Ein beitrag zur epidemiologic der tollwut 4. Mitteilung: übertragsversuche an frettchen mit einem nagerisolat. [The adaptability of two rabies virus strains isolated in central Europe to one domesticated and two wild-living species: a contribution to epidemiology of rabies. Part 4: transmission studies on ferret with rodent isolate].
      ].

      Diagnosis

      Rabies should be included in the differential diagnoses of any ferret that has an unexpected onset of paralysis or acute personality change, especially if the ferret is unvaccinated, has access to outdoors, or lives in an area that is experiencing an epizootic of rabies. A ferret that is suspected of having rabies should be euthanized and its head should be submitted to the appropriate laboratory. Generally, the diagnosis is based on direct immunofluorescent antibody testing of brain tissue [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Pathogenesis of experimentally induced rabies in domestic ferrets.
      ,
      • Niezgoda M.
      • Briggs D.J.
      • Shaddock J.
      • et al.
      Viral excretion in domestic ferrets (Mustela putorius furo) inoculated with a raccoon rabies isolate.
      ]. Confirmation may be established by intracerebral inoculation of suckling mice or inoculation of tissue culture with homogenized brain tissue [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ].

      Prevention and control

      The protective efficacy of killed rabies vaccine was demonstrated in ferrets that were vaccinated once subcutaneously with an inactivated rabies virus and were challenged 1 year later with street virus of fox origin. Vaccinated ferrets had a survival rate of 89% compared with less than 6% for unvaccinated controls [
      • Rupprecht C.E.
      • Gilbert J.
      • Pitts R.
      • et al.
      Evaluation of an inactivated rabies virus vaccine in domestic ferrets.
      ]. Domestic ferrets that were vaccinated with a commercially inactivated rabies vaccine showed rapid induction of virus-neutralizing antibody—a seroconversion that persisted at least 7 months [
      • Hoover J.P.
      • Baldwin C.A.
      • Rupprecht C.E.
      Serologic response of domestic ferrets (Mustela putorius furo) to canine distemper and rabies virus vaccines.
      ]. Based on these studies, killed rabies vaccines were approved for immunizing ferrets [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ,

      Rabies vaccines licensed in Canada. Canadian Food Inspection Agency, Animal Health and Production Division, Veterinary biologics section. Available at: http://www.inspection.gc.ca/english/anima/vetbio/prod/rabrage.shtml. Accessed October 2004.

      ] (Table 2). Ferrets should be vaccinated once at 3 months of age or older and then annually thereafter [
      • Rupprecht C.E.
      • Gilbert J.
      • Pitts R.
      • et al.
      Evaluation of an inactivated rabies virus vaccine in domestic ferrets.
      ]. An animal is considered to be immunized if the primary vaccination was administered at least 28 days previously [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ]. Because a rapid anamnestic response is expected, an animal is considered to be vaccinated currently immediately after booster vaccination [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ].
      Table 2Killed rabies vaccines licensed for use in ferrets in the United States and Canada
      Trade nameCountry where licensedManufacturerDosageRouteRecommended schedule
      Imrab 3 TFCanada United StatesMerial1 mLSubcutaneous3 months, then annually
      Imrab 3Canada United StatesMerial1 mLSubcutaneous3 months, then annually
      ProrabCanadaIntervet Canada1 mLSubcutaneous3 months, then annually
      Data from National Association of State Public Health Veterinarians. Compendium of animal rabies prevention and control, 2003. Morb Mortal Wkly Rep 2003;52(RR-5):14; Rabies Vaccines licensed in Canada. Canadian Food Inspection Agency, Animal Health and Production Division, Veterinary Biologics Section. Available at: http://www.inspection.gc.ca/english/anima/vetbio/prod/rabrage.shtml. Accessed October 2004.
      Local injection site reactions were reported to develop frequently with rabies vaccine [
      • Murray J.
      Vaccine injection-site sarcoma in a ferret.
      ]. Studies in cats showed that rabies vaccines more consistently produce granulomatous inflammation at vaccine sites, although leukemia virus vaccines are incriminated more often in the pathogenesis of vaccine-associated sarcomas [
      • Hendrick M.J.
      Historical review and current knowledge of risk factors involved in feline vaccine-associated sarcomas.
      ,
      • Hendrick M.J.
      Feline vaccine-associated sarcomas.
      ,
      • Hendrick M.J.
      • Dunagan C.A.
      Focal necrotizing granulomatous panniculitis associated with subcutaneous injection of rabies vaccine in cats and dogs: 10 cases (1988–1989).
      ]. There is only one report of vaccine-associated sarcoma in a ferret [
      • Murray J.
      Vaccine injection-site sarcoma in a ferret.
      ]. The ferret had been vaccinated for distemper and rabies on an annual basis in the dorsal area of the neck or interscapular area, so it is impossible to determine from which vaccine the tumor arose. Practitioners should consider establishing a protocol in regard to the site of administration of rabies and distemper vaccines. This would allow the determination of which vaccine may be involved in the event that a tumor develops.
      A study demonstrated that the cellular response to the canary pox–vectored rabies vaccine in ferrets was much milder than to the adjuvanted rabies vaccines [
      • Carroll E.E.
      • Dubielzig R.R.
      • Schultz R.D.
      Cats differ from mink and ferrets in their response to commercial vaccines: A histologic comparison of early vaccine reactions.
      ]. Consequently, its future use may be associated with a decreasing number of local vaccine reactions. Also, because persistence of lymphocytes and macrophages has been suggested to play a role in the pathogenesis of vaccine-associated sarcomas, the canary pox–vectored vaccine would be less likely to be involved in the oncogenesis of these tumors. Although it shows great promise, practitioners should remember that canary pox–vectored rabies vaccine is not approved for use in ferrets in North America at this time.
      To the author's knowledge, there is only one report of anaphylactic reaction in a ferret following administration of an inactivated rabies vaccine [
      • Greenacre C.B.
      Incidence of adverse events in ferrets vaccinated with distemper or rabies vaccine:143 cases(1995–2001).
      ,
      • Lincoln J.
      Another interpretation of ferret's reaction to vaccination.
      ]. This ferret previously had an anaphylactic reaction after receiving a distemper and rabies vaccine simultaneously. Observation of ferrets for 25 minutes following rabies vaccination is advisable.
      Unvaccinated ferrets that are exposed to a rabid animal should be euthanized immediately [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ,
      • Fearneyhough M.G.
      Rabies postexposure prophylaxis.
      ]. If the owner refuses, the animal should be quarantined strictly for 6 months and vaccinated 1 month before being released [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ,
      • Fearneyhough M.G.
      Rabies postexposure prophylaxis.
      ]. Ferrets that are vaccinated currently should be revaccinated immediately [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ,
      • Fearneyhough M.G.
      Rabies postexposure prophylaxis.
      ].
      If a healthy ferret bites a person, it should be confined and observed for 10 days [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ,
      • Fearneyhough M.G.
      Rabies postexposure prophylaxis.
      ]. The animal needs to be evaluated by a veterinarian at the first sign of illness during confinement. If signs that are suggestive of rabies develop, the animal should be euthanized and tested for rabies [
      • National Association of State Public Health Veterinarians
      Compendium of animal rabies prevention and control, 2003.
      ,
      • Fearneyhough M.G.
      Rabies postexposure prophylaxis.
      ].

      Rotavirus

      Rotavirus belongs to the family Reoviridae. All rotaviruses are unique because they possess double-stranded RNA genome. Generally, these viruses cause diarrhea in young animals and children, but they also can occur in older individuals [
      • Torres-Medina A.
      Isolation of an atypical rotavirus causing diarrhea in neonatal ferrets.
      ]. An atypical rotavirus was isolated from neonatal ferrets (Mustela putorius furo) that had diarrhea at a large commercial farm in the United States. The disease was recognized at the ferret farm for several years and was referred as “ferret kit disease” [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. Partial characterization identified this virus as an atypical rotavirus, based on the lack of rotavirus group A common antigen and on its distinct double-stranded RNA electropherotype pattern in polyacrylamide gels. In Finland, a rotavirus outbreak in ferret kits had a mortality rate that approached 100% [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ].

      Clinical presentation

      Clinical signs of rotavirus infection occur in 2- to 6-week-old ferrets. Soft yellow to green diarrhea is present with associated fecal staining or matted hair on their bodies. Erythema of the anus and perineum also is reported [
      • Torres-Medina A.
      Isolation of an atypical rotavirus causing diarrhea in neonatal ferrets.
      ]. The disease was prevalent throughout the year at the American commercial farm, with a increased incidence in colder months. Morbidity among primiparous jills was high (up to 90%); the morbidity rate decreased with each gestation to range between 10% to 25% in multiparous jills [
      • Torres-Medina A.
      Isolation of an atypical rotavirus causing diarrhea in neonatal ferrets.
      ]. The condition could be reproduced in 2- to 3-week-old ferret kits that were inoculated orally with viral preparations that were obtained from diarrheic ferrets; however, mortalities nor histologic lesions were observed in individuals that were infected experimentally [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Torres-Medina A.
      Isolation of an atypical rotavirus causing diarrhea in neonatal ferrets.
      ].

      Diagnosis

      Antemortem diagnosis is difficult. Viral particles may be detected by electron microscopy in clarified, ultracentrifuged fecal suspensions, following negative staining in symptomatic ferrets. In a study, 58% of diarrheic ferrets that were infected naturally were positive for rotavirus particles in their feces. The ferret atypical rotavirus does not react with the Rotazyme test (Abbott Laboratory, Chicago, Illinois), a commercially available enzyme immunoassay [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ,
      • Torres-Medina A.
      Isolation of an atypical rotavirus causing diarrhea in neonatal ferrets.
      ]. The prevalence of this viral infection is unknown in ferrets because of the absence of reliable serologic tests. On postmortem examination, gross lesions are limited to the gastrointestinal tract. Subtle histologic lesions that consist of mild blunting of the tips of the intestinal villi of the small intestine with enterocyte metaplasia to cuboidal cells may be observed.

      Treatment/prevention

      Secondary bacterial infections may be a significant factor in the severity of the diarrhea. Therefore, antibiotics are indicated and may contribute to accelerated recovery and decreased mortality rates. Additional supportive care, including appropriate fluid therapy and force feeding, are indicated in most cases.
      In piglets, colostral antibodies play a key role in the protection against rotavirus [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. This also may be true for ferrets. Ferret kits acquire most of their passive immune globulins from their mothers by intestinal transmucosal absorption from colostrum and milk; they acquire all of their IgA from their mother's milk [
      • Suffin S.C.
      • Prince G.A.
      • Murk K.B.
      • et al.
      Ontogeny of the ferret humoral response.
      ]. The observed decrease in morbidity from ferrets of primiparous jills to ferrets of multiparous jills may be secondary to build-up of colony immunity with increasing age and exposure to the virus [
      • Torres-Medina A.
      Isolation of an atypical rotavirus causing diarrhea in neonatal ferrets.
      ].
      Oral vaccination of primiparous jills was attempted at a ferret breeding farm; however, this procedure was ineffective. Atypical rotaviruses have not been cultivated successfully in cell culture [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ]. The ability to propagate the virus in cell culture in sufficient numbers will play a key role in the development of a vaccine.

      Infectious bovine rhinotracheitis virus

      The infectious bovine rhinotracheitis virus (IBR) belongs to the family Herpesviridae. There is only one published case report of spontaneous IBR infection in a ferret [
      • Porter D.D.
      • Larsen A.E.
      • Cox N.A.
      Isolation of infectious bovine rhinotracheitis virus from Mustelidae.
      ]. The virus was isolated from the liver, the spleen, and the lungs of a clinically normal ferret. Its diet consisted of 5% raw beef by-products; it was hypothesized that virus-laden raw beef was the source of infection. The pathogenesis by which the virus disseminated to the liver, spleen, and lung tissue has not been elucidated. In contrast to naturally-occurring infection, experimental infection of ferrets with IBR virus by intranasal and intraperitoneal inoculations induced acute and chronic respiratory disease [
      • Smith P.C.
      Experimental infectious bovine rhinotracheitis virus infection of English ferrets (Mustela putorius furo L).
      ]. Considering that IBR virus can cause pathology in ferrets, these animals should not be fed raw meat or meat products [
      • Fox J.G.
      • Pearson R.C.
      • Gorham J.R.
      Viral diseases.
      ].

      Summary

      Distemper and rabies vaccination are highly recommended because of the almost invariable fatal outcome of these conditions. Vaccination should constitute an important part of a ferret's preventative medicine program. With the current and anticipated development and licensing of new vaccines, practitioners are invited to gain awareness of the latest vaccine information. Establishment of a practice vaccination protocol with regards to the site of administration of rabies and distemper vaccines is paramount to document any future abnormal tissue reactions.
      Influenza is the most common zoonotic disease that is seen in ferrets. Although it generally is benign in most ferrets, veterinarians must take this condition seriously. The characteristic continuous antigenic variation of this virus may lead to more virulent strains; the recent emergence of avian influenza virus outbreaks; and the increased susceptibility of elderly, young, and immunosuppressed individuals.

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