Diseases / List of Viral Diseases / Disease description:

Rabbit Haemorrhagic Disease 

INFORMATION AVAILABLE

GENERAL INFORMATION

CLINICAL CHARACTERISTICS & PATHOLOGY

INVESTIGATION & DIAGNOSIS

TREATMENT & CONTROL

SUSCEPTIBILITY & TRANSMISSION

ENVIRONMENT & GEOGRAPHY

..

 

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General and References

Disease Summary

 
Lagomorphs Rabbit haemorrhagic disease causes an acute, fulminating, and frequently fatal disease in susceptible adult rabbits (Oryctolagus spp.). (B209.16.w16)

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Alternative Names (Synonyms)

Many of these synonyms originate from when the disease first emerged before the aetiology was identified.
  • RHD
  • Rabbit calicivirus disease
  • Hemorrhagic tracheitis of rabbits
  • Hemorrhagic pneumonia of rabbits
  • Infectious necrotic hepatitis of rabbits
  • Picornavirus haemorrhagic fever
  • Necrotic hepatitis of rabbits
  • Infectious hepatitis of rabbits
  • Rabbit plague (tuen in Chinese)
  • Rabbit X disease
  • Rabbit viral sudden death
  • Rabbit viral haemorrhagic disease
  • Rabbit viral haemorrhagic pneumonia
  • Viral haemorrhagic disease (VHD)
  • X disease of rabbits

(B209.16.w16, J29.9.w1, J64.10.w9, J484.24.w1, P18.3.w5)

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Disease Type

Viral Infection

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Infectious/Non-Infectious Agent associated with the Disease

Aetiology
  • Rabbit haemorrhagic disease virus (RHDV) is a Calicivirus (B209.16.w16, J64.10.w3, J80.64.w2, J83.31.w4, J484.24.w1) RHDV differs from the non-pathogenic but related calicivirus of European rabbits, "rabbit calicivirus" (RCV). (B209.16.w16)
  • Significant homology with feline calicivirus has been demonstrated by the comparison of nucleic acid sequences. (B614.9.w9)
  • RHD viruses from Korea, China and Europe all appear to be identical. (B614.9.w9)
History of the disease
  • 1984: Rabbit haemorrhagic disease first emerged in China in farmed domestic rabbits (Oryctolagus cuniculus domesticus). (B209.16.w16, B614.9.w9) The disease may have originated in rabbits that were imported from Europe. Tests of rabbit sera that had been stored in Czechoslovakia in 1978 revealed antibodies to RHDV. (B614.9.w9)
  • 1986: The disease suddenly emerged in Italy resulting in millions of farmed rabbits dying in a few months. The spread of RHD from China to Europe has proved difficult to trace. (B209.16.w16)
  • 1987: RHD was seen in France, Hungary, the Slovak and Czech Republics and the former U.S.S.R. (B209.16.w16)
  • 1988:
    • RHD was seen in Spain, Portugal, Switzerland and Egypt. (B209.16.w16)
    • RHD spread to the Americas with the disease reported in several locations in Mexico following imports of contaminated frozen rabbit carcasses. (B209.16.w16, B614.9.w9) RHD was then eradicated from Mexico by testing and slaughtering affected rabbits. (B209.16.w16)
  • RHD subsequently emerged in other areas of the Old World. (B209.16.w16)
  • 1991: Work began to determine the host range of RHDV. (B209.16.w16)
  • 1992: RHD first emerged in the UK following the return of rabbit owners who had been at at rabbit show in continental Europe. (B209.16.w16)
  • Early 1995: Field investigation of rabbit haemorrhagic disease "under contained conditions" begun on Wardung Island, Spencer Gulf, South Australia. (B209.16.w16)
  • By September 1995: RHDV had escaped from the study compound on Wardung Island. (B209.16.w16)
  • Early October 1995: Rabbit haemorrhagic disease was diagnosed on the adjacent mainland of Australia. (B209.16.w16)
  • 1996: RHDV progressively appeared in other regions of Australia even against the prevailing winds. Dissemination of the disease was legalised in Australia and (B209.16.w16)
  • January 1997: RHD reaches Tasmania before release was sanctioned. (B209.16.w16)
  • August 1997: RHD was detected in the South Island of New Zealand after it was surreptitiously introduction of the virus. The release of RHDV was subsequently legalised. (B209.16.w16)
  • Inevitably, rabbit haemorrhagic disease spread into wild rabbits (Oryctolagus cuniculus) in Europe with a dramatic impact equal to that seen in domestic rabbits. Recreational shooting groups exerted pressure for funding for research of the disease in order to preserve the wild rabbit populations for hunting use. (B209.16.w16)
  • The fact that European Brown Hare Syndrome is also caused by a Calicivirus and had been seen in hares since the 1970s, led to speculation that RHD and EBHS might have an identical cause. However it was subsequently shown that "There is 53%-71% homology between the genomes of EBHSV and RHDV isolates, with greater than 90% homology within each group". It is thought that the two viruses probably share a common ancestor rather than RHDV being a recent derivative of EBHSV. (B209.16.w16)
  • Origin of EBHSV and RHDV
    • It is difficult to trace the origins of these viruses. It is thought that they may either have arisen by mutation from a non-virulent calicivirus of Eurasian lagomorphs or by the introduction of a new virus that was not virulent in its natural host, e.g. South American rabbits (Sylvilagus spp.) or hares (Lepus spp.) that were imported in large numbers in the 1970s and 1980s into Europe for the purpose of recreational hunting. (B209.16.w16)
Pathogenesis
  • Rabbit haemorrhagic disease virus has a predilection for splenic histiocytes and hepatocytes, in which it induces apoptotic cell death. Procoagulant substances that are released by damaged cells are thought to initiate disseminated intravascular coagulation (DIC). It is this DIC and also the fulminant liver failure that causes the rapid death in rabbits that succumb to this disease. The reduced virulence of the virus seen in rabbits younger than eight weeks is thought to be due to their reduced capacity to support productive viral infection. (B209.16.w16)

Infective "Taxa"

Non-infective agents

--

Physical agents

-- Indirect / Secondary

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References

Disease Author

Nikki Fox BVSc MRCVS (V.w103); Dr Debra Bourne MA VetMB PhD MRCVS (V.w5
Click image for main Reference Section

Referees

William Lewis BVSc CertZooMed MRCVS (V.w129); Brigitte Reusch BVet Med (Hons) CertZooMed MRCVS (V.w127); Richard Saunders BVSc BSc CertZooMed MRCVS (V.w121)

Major References / Reviews

Code and Title List

B22.30.w17, B209.16.w16, B614.9.w9, J29.9.w1, J42.107.w1, J80.64.w2, J83.31.w4,  J484.24.w1, P18.3.w5

Other References

Code and Title List

J1.29.w20, J1.30.w9, J1.34.w13, J3.137.w9, J21.58.w2, J184.43.w, J484.28.w1 P2.47.w4

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Clinical Characteristics and Pathology

Detailed Clinical and Pathological Characteristics

General An acute, highly infectious disease of Oryctolagus cuniculus - European rabbit and Oryctolagus cuniculus domesticus - Domestic European rabbit. (B614.9.w9, J83.31.w4)

Clinical Characteristics

--
Lagomorphs "Malaise, pyrexia, anorexia, tachypnea, cyanosis, abdominal distension, and diarrhea, which rapidly progress to collapse, convulsions, epistaxis, and death, with hemorrhage from orifices. (J29.9.w1)

Clinical signs are usually brief and go unnoticed because the disease is often so acute. (B614.9.w9)

Peracute and acute disease

  • RHD is frequently peracute with adult rabbits found dying or dead with no or indistinct signs before death.
    • Epistaxis may occur as the only sign. (B22.30.w17)
    • Occasionally, foamy discharge from the nostrils and haematuria and/or vaginal haemorrhage are seen before death. (J64.10.w5)
  • In acute disease:
    • Inappetance, depression, lethargy and fever.
      • Fever 41 C or higher. (J83.31.w4).
    • Lateral recumbency. (J64.10.w5)
    • Tachypnoea or dyspnoea/respiratory distress. (B22.30.w17, B614.9.w9, J64.10.w5, J83.31.w4, J484.24.w1)
    • Excessive lacrimation, ocular haemorrhage. (J64.10.w5)
    • Abdominal distension (B614.9.w9)
    • Cyanosis of the eras, eyelids and mucous membranes. (B614.9.w9, J64.10.w5, J83.31.w4)
    • Diarrhoea or constipation (B22.30.w17, B614.9.w9, J83.31.w4)
    • Foamy bloody discharge at the nostrils in about 20%. (J83.31.w4)
    • Rarely, bloody vaginal discharge. (J83.31.w4)
    • Severe neurological signs - ataxia, posterior paralysis, peddling, opisthotonus, convulsions. (J64.10.w5)
    • Terminally
      • In the terminal stage, there are commonly clonic convulsions, lateral torsion of the body, paresis, sometimes epistaxis which may be foamy. Terminal hypothermia. (B614.9.w9, J484.24.w1)
      • "Frenetic" behavious and squealing/cries may occur terminally. (J64.10.w5, J83.31.w4)
      • Opisthotonus may occur. before death. (J83.31.w4)
      • Affected rabbits will become comatose a few hours before death and will usually die quietly. (B209.16.w16)
      • Unresponsive, recumbent and hypothermic; convulsions or paddling just before death. (B22.30.w17)
    • Death usually occurs in 2 - 3 days. (J83.31.w4)
    • Delayed mortality is sometimes seen: rabbits survive the acute stage, but are jaundiced. Just before death a few weeks after the initial illness, they show relaxation of the anal sphincter, distended abdomen with either constipation or diarrhoea and soiling of the perineum with faeces or mucous material. J64.10.w5

(B22.30.w17, B209.16.w16, B614.9.w9, J484.24.w1, J64.10.w5, J83.31.w4)

Other clinical signs include:

Subacute disease:

  • Signs similar to those of the acute disease, but much milder, or just anorexia, fever and depression/apathy.
  • Signs may last only two to three days or up to about a week before death or recovery.

(B22.30.w17, B209.16.w16, B614.9.w9, J64.10.w5)

Clinical pathology
  • Haematology
    • Lymphopenia (B614.9.w9)
    • Leucopaenia (low as 400/l) and transient lymphopaenia. (B22.30.w17)
    • A gradual decline in thrombocytes (B614.9.w9)
    • Prolonged prothrombin and thrombin times (B614.9.w9)
    • Fibrin degradation products may be detected in most moribund rabbits. (B614.9.w9)
  • Biochemistry
    • Serum bilirubin increased from 36 - 48 hours post inoculation and continuing to increase until death; can reach 7 mg/dL terminally. (B22.30.w17)
    • Aspartate aminotransferase (AST) may reach 45,240 IU/L and alanine aminotransferase (ALT) may reach 4680 IU/L. (B22.30.w17)
  • See: Clinical Pathology of Lagomorphs

Incubation

--
Lagomorphs
  • The incubation period of RHD ranges from one to two days. (B614.9.w9, J29.9.w1) 16 - 48 hours. (J83.31.w4)
  • Incubation period of one to two days, maximum three days. (J64.10.w5)
  • Death in usually 48 - 72 hours after inoculation, with some individuals dying after as long as eight days. (J484.24.w1)

Mortality / Morbidity

--
Lagomorphs RHD causes high morbidity and mortality. (B614.9.w9)
  • Morbidity rate: 70 to 80% (B614.9.w9, J29.9.w1)
  • Mortality rate: approaches 100% (B614.9.w9, J29.9.w1)
  • Morbidity and mortality can reach 90 - 100%. (J83.31.w4)
  • Mortality of 70 - 90% in adults and 30 - 50% in juveniles. (B22.30.w17)
  • During outbreaks of RHD, the number of rabbits affected often peaks in two to three days and lasts seven to thirteen days. (B614.9.w9)
  • Countries that have experienced epidemics with high morbidity and high mortality due to RHD include China, Korea, Germany, France, Spain and Mexico. (B614.9.w9)
  • Mortality rate of about 55% in adults in Donana National Park, Spain. (J1.30.w9)
  • Initial population reduction of 90% seen in arid areas of Australia. (P2.47.w4)
  • Rabbits under four weeks of age do not show clinical signs; they usually survive infection. (J484.24.w1)
  • Many rabbits that are younger than about six weeks of age will survive infection with this virus without apparent disease. However, a mortality rate of nearly 100% may be seen in rabbits that are older than eight weeks. (B209.16.w16)
  • In Italy, mainly peracute disease with 80-100% mortality, but in some cases after the preacute stage there were more chronic losses. (J64.10.w7)
  • Mortality is much lower with the subacute form, which appears later in an epidemic and presents with attenuated signs. (J64.10.w5)

Pathology

"The pathological changes apparently result from viraemia, with death attributable to an acute disseminated coagulopathy with deep venous thrombosis". (B614.9.w9)
Lagomorphs
Gross pathology
  • General:
    • Body condition is usually good but there may be moderate dehydration. (B209.16.w16, J83.31.w4)
    • In most fatal cases, death is due to a severe and massive intravascular coagulopathy. Congestion and haemorrhage occur in most organs but are most marked in the lungs. The disease consistently results in acute hepatic necrosis and this may be the only lesion found. (B614.9.w9)
    • Generalised congestion of blood vessels. Inhibited blood coagulation. (J484.24.w1)
    • Petechial haemorrhages in many organs, poor blood coagulation. (J1.30.w9, J64.10.w5)
      • Haemorrhages are characteristic but not always present. (J83.31.w4)
    • Sometimes jaundice. (J64.10.w5, J83.31.w4) - where present, immediately visible on the pinnae and in the subcutis. (J64.10.w5)
  • Upper respiratory tract:
    • Bloody discharge at the nares. (J64.10.w5)
    • Blood-stained froth at the nares if the rabbit has been dead for some time; deeply congested mucosa of the turbinates and the trachea. (B209.16.w16)
    • Tracheal mucosa congested (B22.30.w17), hyperaemic, (J1.30.w9, J64.10.w5) or haemorrhagic. (J83.31.w4)
    • Often blood foam in the trachea and bronchi. (J64.10.w5, J484.24.w1)
  • Lungs:
    • Congestion, oedema and multifocal haemorrhages. (B209.16.w16, J1.30.w9, J64.10.w5, J83.31.w4)
      • Varying haemorrhage. (J484.24.w1)
      • Petechiae and ecchymoses. (B22.30.w17)
  • Liver: 
    • Swollen and pale with an accentuated lobular pattern. (B209.16.w16)
    • The most consistent finding in RHD is a fine reticular pattern of periportal necrosis in a pale liver. (B614.9.w9)
    • Pale and fragile with an accentuated lobular pattern, or swollen and dark red. (J484.24.w1)
    • Yellow or pale, with an enhanced lobular pattern. (B22.30.w17)
    • Pale, yellow or greyish, friable, marked lobular pattern "or sometimes a finely granular surface." (J64.10.w5)
    • Pale, yellow or grey. Friable or congested with a lobular pattern. Multifocal petechiae. (J83.31.w4)
  • Spleen:
    • Sometimes enlarged. (J64.10.w5)
    • Dark and swollen due to acute infarction. (B209.16.w16, B614.9.w9)
      • Usually enlarged and dark reddish. (J83.31.w4, J484.24.w1)
  • Kidneys:
    • Dark and swollen due to acute infarction. (B209.16.w16, B614.9.w9)
    • Usually enlarged with red speckling; sometimes only a few petechiae. (J484.24.w1)
    • Petechiae. (J83.31.w4)
    • Occasionally "dull pale discolouration." (J64.10.w5)
  • Lymph nodes:
    • Mesenteric lymph nodes sometimes show hyperplastic enlargement. (J64.10.w5)
    • Oedematous and there may also be petechial haemorrhages. (B614.9.w9)
  • G.I. Tract:
    • There is frequently a segmental catarrhal enteritis. (B614.9.w9)
    • Catarrhal gastroenteritis. (J1.30.w9, J64.10.w5)
    • May be normal; sometimes enteritis. (J83.31.w4)
    • Small intestine may be hyperaemia with fluid or catarrhal contents. In the colon, thick, sticky, gelatinous mucus. (B22.30.w17)
  • Fat depots: Slight icteric. (B209.16.w16)
  • In pregnant does: focal haemorrhages may be seen in multiple organs of the fetuses. (J64.10.w5)
Histopathology
  • General:
    • Fibrin thrombi are common in the heart, lungs, spleen, liver, kidneys, and occasionally other organs of very recently deceased rabbits. Occasionally, there may be sequelae of ischaemia such as acute myocardial necrosis or small malacic foci in the brain. (B209.16.w16)
    • "Many tissues, especially the lungs, spleen, and kidneys, may have varying degrees of congestion and hemorrhage due to microinfarction or major venous thrombi. Acute coagulative necrosis due to micro infarction may be found in any organ". (B614.9.w9)
    • Fibrinous thrombi in capillaries of most organs. (J484.24.w1) Microthromi of any organ. (B22.30.w17)
  • Trachea:
    • Submucosal capillaries congested, sometimes infiltration of round cells. (J484.24.w1)
    • Usually hyperaemia (81%), with oedema in 22%, infiltration of leucocytes in 43% an tracheal cartilage calcification in 41%. (J64.10.w5)
  • Lungs:
    • Usually severe pulmonary congestion and oedema. (B209.16.w16)
    • Pulmonary venous thrombosis accounts for the serosanguinous frothy nasal discharge seen terminally. (B614.9.w9)
    • Alveolar oedema and haemorrhages; granulocyte infiltration. (J484.24.w1)
    • Disseminated alveolar haemorrhages. Occasionally in the interlobular and peribronchial interstitium, perivascular haemorrhages. Larger vessels obliterated by white thrombi. Also in alveolar capillaries, embolic megakaryocytes and neutrophils. Desquamation of bronchial epithelium and alveolar macrophages sometimes seen. (J42.107.w1)
  • Liver:
    • Necrotic hepatitis in all cases. (J64.10.w5)
    • Characteristic coagulation necrosis of the periportal hepatocytes; this may also extend to the midzonal areas or involve most of the liver lobule. (B209.16.w16, B22.30.w17, J42.107.w1, J64.10.w9, J83.31.w4)
      • Homogenous hyper-eosinophilia of hepatocytes; with high magnification, cytoplasm appearing slightly foamy due to tiny lipid droplets. (J42.107.w1)
      • Nuclei showing karyolysis and pyknosis, more rarely karyorrhexis. (J42.107.w1)
      • Individual cells sometimes shrunken, rounded off and hyalinised. (J42.107.w1)
      • Often neutrophils, usually karyorrhetic, around damaged hepatocytes, (J42.107.w1)
      • In the interlobular spaces, sometimes slight oedema and lymphocyte infiltration, with less frequent histiocytes and plasma cells. (J42.107.w1)
      • Usually not affecting the regions around the portal triads. (J42.107.w1)
      • Diffuse periportal hepatic necrosis that, when severe, may bridge acini. Degenerate hepatocytes may contain single or multiple small intranuclear bodies. There is usually little inflammation in necrotic areas. (B614.9.w9)
      • Early after infection, haemorrhages and local to diffuse granulocyte infiltrations, also "degenerative perilobular alterations in hepatocytes with strongly homogenous or pale vacuolized cytoplasm, nuclear pyknosis, karyorrhexis or karyolysis".  (J484.24.w1)
    • Calcification of hepatocytes in 8% of cases and fibrosis in 6%. (J64.10.w5)
  • Kidneys:
    • Focal haemorrhages, hyperaemia. Glomerular hyaline thrombosis seen sometimes, also dilated tubules and infiltration of lymphocytes. (J484.24.w1)
    • Glomerular tufts and medulla congested. Focal haemorrhages, red blood cells in tubules, interstitial haemorrhages in the cortex, hyaline thrombi in hyperaemic loops of glomerular tufts and small vessels, with white thrombi found sporadically in larger vessels. Sometimes hydropic degeneration of tubular epithelium. (J42.107.w1)
    • Comonly tubulonephrosis (65%), hyperaemia and haemorrhage (75), glomerular microthrombi (73%; tubular nephrosis and necrosis in 23% and epithelial calcification in 6%. (J64.10.w5)
  • G.I. Tract:
    • Segmental necrotising enteritis with severe necrosis of the crypts and villous atrophy. This is similar to that seen with feline or canine parvoviral infections. (B614.9.w9)
    • Lamina propria sometimes shows lymphocytic and granulocytic infiltration. Also submucosal oedema. (J42.107.w1)
  • Brain:
    • Microinfarcts which account for the terminal neurological signs. (B614.9.w9)
    • Low-grade inflammatory cell infiltration of the leptomeninges, hyaline thrombi and small isolated haemorrhages sometimes noted. (J42.107.w1)
  • Lymphoid tissues:
    • Necrosis or lymphoid depletion. (B22.30.w17)
    • There may be degeneration and karyorrhexis of lymphocytes. The thymus and spleen are usually more affected than the lymph nodes. (B614.9.w9)
    • Spleen:
      • Sinusoidal architecture is often obliterated by a coagulum of cell debris, erythrocytes and fibrin. The lymphoid follicles are usually spared, although they can be very depleted of lymphocytes. (B209.16.w16)
      • Hyperaemic; karyorrhexis of single follicles. (J484.24.w1)
      • Lymphocyte depletion, splenic nodules decreased size and number, soemtimes with accumulation of erythrocytes around the nodues. Occasionally homogenous eosinophilic material in nodule. . Eosinophilic and hyaline-like changes to splenic cords. (J42.107.w1)
      • In some remaining lymphocytes, karryorrhexis and sporadic pyknosis. (J42.107.w1)
      • Sometimes in the red pulp congestion and increased neutrophils. (J42.107.w1)
      • Follicular karyorrhexis in most (86%), hyaline necrosis of red pulp in 54%. (J64.10.w5)
  • Other tissues: in thymus, adrenal, urinary bladder, myocardium and skeletal muscles, sometimes small haemorrhages. (J42.107.w1)
  • Note: in rabbits that have recovered from RHD there are no residual lesions. Chronic respiratory, hepatic or splenic lesions are not recognised in RHD. (B209.16.w16)

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Human Health Considerations

RHD does not have zoonotic potential. No cases of infection have been decribed including in people with regular occupational exposure. ( In a study of 259 people that were occupationally exposed to the RHD virus, there was no serological or clinical evidence of RHDV infection. (B209.16.w16)

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Susceptibility / Transmission

General information on Susceptibility / Transmission

Susceptibility
Non-target species tested and found refractory to RHDV infection
  • Laboratory rodents (B209.16.w16)
    • Inoculation of mice, rats, hamsters or guinea pigs failed to induce disease. (B614.9.w9)
In Europe
  • Lepus europaeus - Brown hare: "inoculation of European hares and rabbits with doses of RHDV and EBHSV that are fatal in the homologous host produces no disease and only a low antibody response in the heterologous host". (B209.16.w16)
  • Vulpes vulpes - Red fox: this species has been shown to produce specific antibody to RHDV when fed livers of RHDV positive rabbits and also free-ranging foxes may produce an antibody response to RHDV. "This probably reflects a response to ingested antigen that has reached the peripheral circulation, rather than productive viral infection". (B209.16.w16)
    • In a study in Germany, 18 of 352 sera from red foxes were positive with a blocking ELISA; eight of these sera were also positive with a haemagglutination inhibition test. (J1.34.w14)
In Australia

The following species have been demonstrated to be refractory to infection with rabbit haemorrhagic disease virus after testing at the Australian Animal Health Laboratory:

(B209.16.w16)

In New Zealand
  • Apteryx australis - Kiwi (seroconversion occurred after inoculation with RHDV but there was no productive viral infection).
  • Mystacina tuberculata - Short-tailed bat (no antibody response or production of virus)

(B209.16.w16)

Lagomorphs
Susceptibility
  • Age: Rabbits approximately over the age of eight weeks are as susceptible to RHDV as adult rabbits. (B209.16.w16, J29.9.w1) However, only around 50% of rabbits five to six weeks old were found to be susceptible. Neonatal rabbits have been shown to be resistant to disease but support some viral replication. (B209.16.w16) "Outbreaks of disease have occurred mainly in rabbits 2 months of age and older, whereas younger rabbits were clinically unaffected". (B614.9.w9)
    • Rabbits under four weeks of age do not show clinical signs; they usually survive infection. (J484.24.w1)
    • Rabbits exposed at a young age do support some viral replication (B209.16.w16) and they develop life-long immunity. (B600.16.w16)
    • In an outbreak in Spain, rabbits less than four months old were not found affected. (J1.30.w9)
    • In a study, rabbits born to seronegative dams showed zero susceptibility at four weeks old but with a rapid increase to about 50% at 5 - 8 weeks and 70% at nine and ten weeks old. (J64.10.w2)
  • Breed: There is no apparent difference in the susceptibility to RHD infection among the different breeds of Oryctolagus cuniculus domesticus - Domestic European rabbit. (B614.9.w9)
  • Note: a study of wild rabbits in the UK found that 22/27 adults from southern England, before the introduction of RHD, were seropositive at titres > 1:10. These rabbit all survived inoculation with a fatal dose of RHDV, while three of five rabbits which were seronegative died.. (J484.28.w1)
  • No clinical signs in experimentally infected Sylvilagus floridanus - Eastern cottontail (although they possibly shed the virus for a short time), Romerolagus diazi - Volcano rabbit  or Lepus californicus - Black-tailed jackrabbit. (J64.10.w9)
  • Species: 
    • "Although O. cuniculus appears to be the only species susceptible to this disease, hares in China also appear to be infected and capable of transmitting the disease to rabbits experimentally". (B614.9.w9)
    • Cross-transmission experiments showed that hares could be infected with RHDV and developed low levels of antibodies, but were not then protected against challenge with EBHSV. Similarly, rabbits could be infected with EBHSV and developed low levels of antibodies, but these antibodies were not protective against RHDV. (J184.43.w1)
Immunity
  • Recovered rabbits are thought to have lifelong active immunity. (B209.16.w16)
  • Rabbit kittens will acquire passive immunity from their dams which will persist for up to twelve weeks after birth. However the insusceptibility of rabbits under the age of 6-8 weeks to RHDV is not antibody dependent. (B209.16.w16)
  • Vaccination: vaccinated rabbits are protected against the disease; commercially-available inactivated vaccines provide protection for at least 12 months. (B209.16.w16)
Transmission
  • The usual routes of entry are oral and respiratory. (J83.31.w4)
    • "Experimentally, the routes of entry, in order of importance, are oral, conjunctival, nasal and skin trauma". (B614.9.w9)
  • Note: rate of spread has varied in monitored situations from a few hundred metres per month in the UK to more than 400 km/month in Australia. (J1.34.w13)
  • Direct rabbit-to-rabbit (B22.30.w17, B209.16.w16, J83.31.w4)
    • "However, a fully susceptible rabbit could remain in immediate contact for up to 6 hours with one that had recently died of RHD, and not become infected". (B209.16.w16)
    • Direct contact with excretions and secretions of infected rabbits. (B614.9.w9)
  • Insect vectors may act as mechanical carriers of RHDV including:
    • Fleas
    • Flies:  the oral and anal excretions of flies have been shown to be infectious.
    • Mosquitoes
      (B209.16.w16, J1.34.w13, J83.31.w4)
    Mosquitoes
    (B209.16.w16, J1.34.w13, J83.31.w4)
  • On fomites
    • Spread of RHDV on fomites, in rabbit products and tissues or by people contaminated from infected rabbits, is an important mode of transmission.
    • Feed, water, utensils and animal attendants. 
    • (B22.30.w17, B614.9.w9, J83.31.w4)
    (B22.30.w17, B614.9.w9, J83.31.w4)

    Note: two outbreaks, in Mexico and on Reunion Island were associated with imports of frozen meat, although there was no indication of a possible route of infection from the frozen carcasses to rabbit farms in Mexico; the first affected farms were at least 200 m from where the meat was (correctly) stored. (J64.10.w2)

  • Other mechanical vectors
    • Scavenger birds: it is thought that birds feeding on infected dead rabbit carcases may have played a role in the spread of disease over long distances, e.g. over expanses of water, to the United Kingdom or Ireland. (B209.16.w16)
  • Faeco-oral route
    • Preferential mode of transmission. (J64.10.w2)
    • There are some reports of this route playing a role in the transmission of RHD, however, a study that was reported in 1996, found that rabbit urine rapidly degraded the RHDV and no virus was demonstrated in the faeces of infected rabbits. (B209.16.w16)
  • Vertical transmission/biological vectors
    • There is no evidence of biological vectors or vertical transmission in this disease. (B614.9.w9)
  • Note: indirect transmission can be very important, as indicated by infection and death of pet rabbits housed indoors and fed only commercial pellets. (B22.30.w17)

Persistance of infectious virus

  • Surviving rabbits can shed virus for at least one month. (B614.9.w9)
  • Infectious virus has been reported to only persist for up to a month in rabbit carcasses or in the experimental facility environment. However, virus suspensions have been reported to retain infectivity for at least nine months at 4 C. (B209.16.w16)
  • RHDV is highly stable in the environment. Infectivity is unaffected by exposure to pH 3, heating at 50 C or treatment with ether or chloroform. However, the virus is inactivated by 0.4 % formaldehyde or 1 % sodium hydroxide at ambient temperature, 4 C, or 37 C. (B209.16.w16)

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Disease has been reported in either the wild or in captivity in:

  • Oryctolagus cuniculus domesticus - Domestic European rabbit
    • Rabbit haemorrhagic disease first emerged in China in farmed domestic rabbits (Oryctolagus cuniculus domesticus). The disease has since spread around the world. (B209.16.w16, B614.9.w9)
    • In China. (J64.10.w6)
    • A serological survey (reported 1990) carried out on 1,461 rabbits from 43 farms in Czechoslovakia revealed that although the rabbits were apparently free of of RHD, 283 rabbits (19 %) had antibodies to RHDV. 33 of the 43 farms were affected. In another serological survey using a set of sera that were collected from laboratory-maintained rabbits between 1975 and 1987, antibodies were detected in 32 of the 42 sera (76 %). These results suggest that rabbit colonies in Czechoslovakia had subclinical carriers of a viral agent that had characterisitics similar to those of RHDV, but with a lower pathogenicity, several years before rabbit haemorrhagic disease was recognised in China. (B614.9.w9)
    • First diagnosed in domestic rabbits in the UK in 1992. (P18.3.w5)
    • Diagnosed in spring 2003 in domestic rabbits in Hungary. (P18.6.w2)
    • In Italy, the disease spread over the whole country in 1986-1988 in Oryctolagus cuniculus domesticus - Domestic European rabbit and continued in 1989-1990. (J64.10.w7)
    • In Mexico, following an import of rabbit meat from China in 1989. (J64.10.w9)
  • Oryctolagus cuniculus - European rabbit
    • Rabbit haemorrhagic disease spread into wild rabbits (Oryctolagus cuniculus) in Europe with a dramatic impact equal to that seen in domestic rabbits. (B209.16.w16)
    • In Italy, the disease spread over the whole country in 1986-1988 and was diagnosed in wild Oryctolagus cuniculus in 1988. (J64.10.w7)
    • First confirmed in wild rabbits in the UK in 1994, but it is probable that seropositive wild rabbits were present before clinical disease was detected. (P18.3.w5)
    • First diagnosed in wild rabbits in Hungary February 2004. Virus detected by antigen ELISA and PCR. (P18.6.w2)
    • In Sweden, first seen 1990. (J1.29.w20)
    • In Spain, RHD was first seen in the Iberian Peninsula in 1989 and rapidly spread across the country. At La Vera, Donana National Park, the disease was first detected 30th March 1990 and rabbit were found dead from the disease to 23rd May 1990. (J1.30.w9)
    • A study in Spain during 1993-1996 found RHD to be an endemic disease causing the deaths of both adult and juvenile rabbits. (J3.150.w5)
    • First seen in Ireland in 1995. (J3.137.w9)
    • In Germany, first recorded in 1988, with mortality of 5 - 90%; in wild rabbits, sporadic losses have been seen. (J64.10.w8)

Further information on Host species has only been incorporated for species groups for which a full Wildpro "Health and Management" module has been completed (i.e. for which a comprehensive literature review has been undertaken). Host species with further information available are listed below:

Host Species List

(List does not contain all other species groups affected by this disease)

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Disease has been specifically reported in Free-ranging populations of:

  • Oryctolagus cuniculus - European rabbit
    • Rabbit haemorrhagic disease spread into wild rabbits (Oryctolagus cuniculus) in Europe with a dramatic impact equal to that seen in domestic rabbits. (B209.16.w16)
    • First confirmed in wild rabbits in the UK in 1994, but it is probable that seropositive wild rabbits were present before clinical disease was detected. (P18.3.w5)
    • First diagnosed in wild rabbits in Hungary February 2004. Virus detected by antigen ELISA and PCR. (P18.6.w2)
    • In Sweden, first seen 1990. (J1.29.w20)
    • In Spain, RHD was first seen in the Iberian Peninsula in 1989 and rapidly spread across the country. At La Vera, Donana National Park, the disease was first detected 30th March 1990 and rabbit were found dead from the disease to 23rd May 1990. (J1.30.w9)
    • A study in Spain during 1993-1996 found RHD to be an endemic disease causing the deaths of both adult and juvenile rabbits. (J3.150.w5)
    • First seen in Ireland in 1995. (J3.137.w9)
    • In Germany, sporadic losses have been seen. (J64.10.w8)

Further information on Host species has only been incorporated for species groups for which a full Wildpro "Health and Management" module has been completed (i.e. for which a comprehensive literature review has been undertaken). Host species with further information available are listed below:

Host Species List

(List does not contain all other species groups affected by this disease)

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Environment/Geography

General Information on Environmental Factors/Events and Seasonality

  • Epidemics of rabbit haemorrhagic disease usually start in November and end in March. (B614.9.w9)
  • Seasonality of disease may be related to population characteristics: in the early part of the year, the majority of the rabbits are either adults which are already seropositive or kits which are under eight weeks of age and still [particularly under four weeks old] resistant to the virus. Later in the year more of the juveniles are old enough to be fully susceptible. (J64.10.w11)
  • Virus suspensions have been reported to retain infectivity for at least nine months at 4 C. (B209.16.w16)
  • RHDV is highly stable in the environment. Infectivity is unaffected by exposure to pH3, heating at 50 C or treatment with ether or chloroform. However, the virus is inactivated by 0.4 % formaldehyde or 1% sodium hydroxide at ambient temperature, 4 C, or 37 C. (B209.16.w16)
  • In Australia, outbreaks were seen mainly in spring and autumn, particularly when the daily maximum temperature was 15 - 32 C (optimum 23 C). (P2.47.w4)

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Regions / Countries where the Infectious Agent or Disease has been recorded

  • China (B209.16.w16, B614.9.w9)
  • Korea (B614.9.w9)
  • Most European countries (B209.16.w16, B614.9.w9)
    • Italy
    • Spain
    • Germany
    • France
    • UK (P18.3.w5)
    • Hungary (P18.6.w2)
    • Sweden (J1.29.w20)
    • Former USSR. (B209.16.w16)
  • Mexico (B614.9.w9)
  • India (B614.9.w9)
  • Middle East (B614.9.w9)
  • North Africa (B614.9.w9)
  • The Americas. (J1.34.w13)
    • Mexico. (B209.16.w16)
  • Australia, New Zealand. (B209.16.w16, J1.34.w13, P2.47.w4)
  • Asia: China and Korea; Africa and islands in the Indian Ocean: Egypt, Lebanon, Reunion Island, Tunisia; Americas: Mexico; Europe (Austria, Belgium, Czechoslovakia, Denmark, France, Germany, Greece, Hungary, Italy, Malta, Poland, Portugal, Romania, Spain, Switzerland and [former] USSR. (J64.10.w2)
  • EBHS has been reported in Europe (Austria, possibly Belgium, Denmark, France, Germany, Great Britain, Greece, Italy, Malta, Sweden. (J64.10.w2)

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Regions / Countries where the Infectious Agent or Disease has been recorded in Free-ranging populations

  • Europe. (B209.16.w16)
  • Australia, New Zealand. (B209.16.w16, J1.34.w13, P2.47.w4)

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General Investigation / Diagnosis

General Information on Investigation / Diagnosis

--
Lagomorphs
  • Clinical signs and pathological findings
    • Sudden death with high mortality in adult rabbits (Oryctolagus spp.) should arouse suspicion of rabbit haemorrhagic disease. (B22.30.w17, B209.16.w16)
    • Hepatic histopathological findings are typical. (B22.30.w17)

Virus detection for confirmation. (B22.30.w17)

  • Immunohistochemical stains
    • Specific stains will demonstrate RHDV antigen in splenic histiocytes and hepatocytes. (B209.16.w16)
  • Negative staining electron microscopy (J64.10.w4)
    • Typical calicivirus particles can be seen "in the supernatant of liver from rabbits that have died of RHD, and virions aggregate in homologous antiserum". (B209.16.w16)
    • Viral particles are often found in hepatocytes. (B22.30.w17, B614.9.w9, J83.31.w4)
  • Transmission electron microscopy. (J64.10.w9)
  • Antigen-detection ELISAs using the liver from disease suspects (B209.16.w16, J64.10.w4, J83.31.w4, P2.47.w4)
  • Antigen detection using monoclonal antibodies. These can distinguish between viral haemorrhagic disease virus and European brown hare syndrome virus. (J64.10.w4)
  • Polymerase chain reaction (PCR) (B209.16.w16, P2.47.w4)
    • RT-PCR. (J21.58.w2, J83.31.w4)
  • Haemagglutination test (J64.10.w4, J64.10.w9)
    • This test can be used with type O human erythrocytes to detect virus in suspensions of lungs, liver, kidneys and spleen from infected rabbits. (B614.9.w9)
  • Immunofluorescence tests and immunoenzyme assays
    • Monoclonal antibodies or antisera to the virus can be used to detect virus in hepatocytes of infected rabbits. (B614.9.w9, J83.31.w4)
Detection of antibodies
  • ELISA can be used for serologic investigation. (B209.16.w16, J64.10.w4, P2.47.w4)
  • The Haemagglutination inhibition (HI) test can also be used. (J64.10.w4, J64.10.w9)
  • "Serological tests include the hemagglutination inhibition test and enzyme-linked immunosorbent assay, the latter being preferable because of increased sensitivity and specificity". (B614.9.w9)
Related Techniques
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Similar Diseases (Differential Diagnosis)

--
Lagomorphs
  • Acute septicaemia. (B209.16.w16)
  • Rapidly acting poisons that are used for rabbit population control. (B209.16.w16)

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Treatment and Control

Specific Medical Treatment

--
Lagomorphs
  • Treatment of clinically affected rabbits is not likely to be ineffective. (B209.16.w16)
Related Techniques

 

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General Nursing and Surgical Techniques

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Lagomorphs --
Related Techniques
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Preventative Measures

Vaccination --
Lagomorphs Prevention of rabbit haemorrhagic disease in domestic rabbits can be achieved by instigating a vaccination program. (B209.16.w16)
  • Inactivated vaccines have been developed. (J64.10.w11)
  • Commercial inactivated virus vaccines can provide protection for up to twelve months after an initial dose. (B209.16.w16)
  • Vaccination against RHD has been shown to be safe and effective in preventing disease. Immunity develops within one to two weeks after vaccination and persists for five to fifteen months. (B614.9.w9)
  • "Although disease may be prevented in vaccinated rabbits, persistent infection may develop on exposure to the virus...Thus, vaccinated rabbits infected with virus should be considered infectious and should not be introduced into previously unexposed rabbitries". (B614.9.w9)

Vaccination of wild rabbits

  • In Spain, vaccination programmes have been carried out against both RHD/VHD and myxomatosis, aiming to protect wild populations of Oryctolagus cuniculus - European rabbit in order to maintain the populations as prey for a variety of endangered species. These programmes employ trap-vaccinate-release methods. (J3.155.w5, J40.68.w3)
    • In the three months following vaccination, radiotracked young rabbits (180 - 600 g) were 13.6 times more likely to die (from disease or predation) if they had not been vaccinated than if they had not been vaccinated. Adult rabbits were slightly less likely to die if they had been vaccinated. (J3.155.w5)
    • However, a study found that there were short-term negative effects on juvenile rabbits from such programmes, with deaths in the first three weeks mainly from disease (particularly RHD, also myxomatosis and Intestinal Coccidiosis) in young rabbits (less than 600g) and from predation in subadult rabbits (it was noted that some rabbits defined as predated might have died from disease an been taken as carrion). The negative effects were considered to be related to handling stress as well as possible adverse effects of the vaccinations. (J40.68.w3)
  • A recombinant combined myxomatosis-rabbit haemorrhagic disease vaccine has been produced, using a naturally attenuated field strain myxoma virus modified to give expression of the RHDV major capsid protein (VP60) (together with a "tag" of expression of nucleoprotein from transmissible gastroenteritis virus (TGEV). The vaccine was shown to be protective against VHD and myxomatosis in Oryctolagus cuniculus - European rabbit following either subcutaneous or oral vaccination, with limited horizontal transmission by direct contact or by fleas, producing immunisation of in-contact animals which had not themselves been vaccinated, and increased survival of such rabbits (about 50% protected, compared with no survivors on challenge of unvaccinated rabbits). Re-transmission from those rabbits to further individuals did not provide protection (no or minimal antibodies and no protection against challenge). (J80.74.w2)
    • The vaccine was shown to be safe even at 100 times vaccination dose, safe in pregnant and immunosuppressed rabbits (no undesirable effects) and to maintain its attenuated phenotype even after 10 passages in vivo. (J70.19.w1)
  • In a field trial on a 34 hectare island populated by about 300 rabbits, subcutaneous vaccination of 76 rabbits with recombinant attenuated myxoma virus expressing RHDV capsid protein VP60 elicited development of specific antibodies against both RHDV and myxomatosis in all the vaccinated rabbits and in about 50% of unvaccinated rabbits, indicating limited horizontal transmission. No adverse effects of the vaccine were detected. (J70.19.w2)
Prophylactic Treatment

--

Lagomorphs Short term protection of valuable rabbits can be achieved by using hyperimmune serum in the face of an outbreak. (B209.16.w16, B614.9.w9)
Related Techniques
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Environmental and Population Control Measures

General Environment Changes, Cleaning and Disinfection --

Lagomorphs

To prevent introduction of the virus:
  • "Commercial or research colonies and, desirably, pet rabbits, should be maintained on a sterilized, pelleted ration". (B209.16.w16)
  • Exclude flying insects by screening doors and windows. (B209.16.w16)
  • Restricted access and disinfection of any equipment that enters or leaves a facility. Equipment and cages can be disinfected with 1% formalin or 0.5% sodium hypochlorite. (B614.9.w9)
  • 1 - 2% formalin or 10% sodium hydroxide. (J83.31.w4)
  • Cleaning and disinfection of clothes, tools, hands etc., removal and disinfection of litter, destruction of carcasses, disinfection of facilities with e.g. hypochlorite, chloramine or sodium hydroxide, and control of rodents and arthropods. (J64.10.w7)
Population Control Measures --
Lagomorphs
  • Slaughter and disinfection, with repopulation after at least two months. (B22.30.w17)
  • Slaughter and disinfection to eliminate the disease from a commercial colony, with movement restrictions, then introduction of sentinels, followed by surveillance. (J83.31.w4)
  • Slaughter of diseased and in-contact animals and destruction of carcasses. (J64.10.w7)
  • Where possible, all-in, all-out policies in intensive facilities. (J64.10.w7)

Note: Use of RHDV as a biological control agent of wild rabbits 

Isolation, Quarantine and Screening --
Lagomorphs
  • If rabbits are physically separated by a minimum of 50 cm then RHD reportedly does not spread rapidly through a rabbitry, although contaminated insects will spread the virus in these circumstances. (B209.16.w16)
  • Colonies with RHD should be quarantined and depopulated since virus shedding from surviving rabbits occurs for at least one month. (B614.9.w9)
  • Quarantine of new animals: Rabbits from areas that have RHD should be quarantined for at least one month before introduction into a colony. (B614.9.w9)
  • Quarantine of new rabbits, avoiding contact between intensive establishments and more traditional farms, restrictions on visitors, and cancellation of rabbit markets in affected areas have all been used to prevent spread. (J64.10.w7)
Related Techniques
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