Rabbit Hemorrhagic Disease Virus Type 1 and Type 2 (RHDV1 / RHDV2)

Rabbit Hemorrhagic Disease (RHD) is a highly contagious, often fatal viral disease affecting lagomorphs, primarily European rabbits (Oryctolagus cuniculus). It is caused by Rabbit Hemorrhagic Disease Virus (RHDV), a calicivirus in the genus Lagovirus. Two major genotypes are recognized: RHDV1 (classic) and RHDV2 (emerging variant). RHDV1 emerged in China in 1984 and spread globally, causing high mortality in adult rabbits. RHDV2 was first identified in France in 2010 and has since become endemic in many regions, affecting both domestic and wild rabbits, including young kits and other lagomorph species (e.g., hares). The disease is characterized by acute necrotizing hepatitis, disseminated intravascular coagulation (DIC), and hemorrhagic lesions in multiple organs. The virus is highly resistant in the environment, facilitating rapid spread. In veterinary exotic practice, RHD is a critical differential for sudden death in rabbits, and vaccination is essential for prevention.

The primary causative agents are Rabbit Hemorrhagic Disease Virus Type 1 (RHDV1) and Type 2 (RHDV2), both belonging to the family Caliciviridae, genus Lagovirus. RHDV1 is the classic strain, while RHDV2 is a distinct genotype with antigenic differences. The virus is a non-enveloped, single-stranded positive-sense RNA virus with an icosahedral capsid. It is extremely stable in the environment, resistant to heat (survives 60°C for 30 minutes), freezing, and many disinfectants (e.g., ether, chloroform). It can persist in contaminated environments for months. Transmission occurs via direct contact with infected rabbits, their excretions (urine, feces, respiratory secretions), contaminated fomites (feed, water, bedding, equipment), and vectors such as insects (flies, mosquitoes) and rodents. The virus can also be spread by birds and humans via contaminated clothing or shoes. The incubation period is typically 1-3 days. The virus primarily targets hepatocytes, causing massive hepatic necrosis, leading to fulminant liver failure and coagulopathy.

RHDV1 affects mainly European rabbits (Oryctolagus cuniculus), both domestic and wild. It causes high morbidity and mortality (up to 90-100%) in adult rabbits (>2 months of age), while young kits (<4-6 weeks) are often resistant to clinical disease. RHDV2 has a broader host range, affecting rabbits of all ages, including young kits, and also infects other lagomorphs such as hares (Lepus spp.) and cottontail rabbits (Sylvilagus spp.). The disease is endemic in many parts of Europe, Australia, New Zealand, and has been reported in North America, Africa, and Asia. In captive populations, outbreaks are often associated with introduction of new rabbits, poor biosecurity, and lack of vaccination. The virus is highly contagious and can spread rapidly within a rabbitry. Wild rabbit populations serve as reservoirs. The incidence varies seasonally, with peaks in spring and autumn. In veterinary practice, RHD should be suspected in any unvaccinated rabbit presenting with sudden death or acute hepatic failure.

After ingestion or inhalation, RHDV replicates in the upper respiratory tract and then spreads via the bloodstream to the liver, where it infects hepatocytes. The virus causes severe cytolytic necrosis of hepatocytes, leading to acute liver failure. This results in a cascade of metabolic derangements: hypoglycemia, hyperbilirubinemia, elevated liver enzymes (AST, ALT, GGT), and coagulopathy due to decreased synthesis of clotting factors (II, V, VII, IX, X) and disseminated intravascular coagulation (DIC). DIC is triggered by massive tissue necrosis and endothelial damage, leading to microthrombi formation, consumption of platelets and clotting factors, and subsequent hemorrhagic diathesis. Clinically, this manifests as petechiae, ecchymoses, and bleeding from orifices. The liver necrosis also causes release of pro-inflammatory cytokines, contributing to systemic inflammatory response syndrome (SIRS) and multi-organ failure. In peracute cases, death may occur within 12-24 hours before clinical signs are observed. In subacute cases, rabbits may show depression, anorexia, and respiratory distress. The virus also causes splenic necrosis, pulmonary edema, and renal tubular necrosis. The exact mechanism of age resistance in young kits is not fully understood but may involve immature hepatocyte receptors or maternal immunity.

Intrinsic factors include species susceptibility (European rabbits are highly susceptible; other lagomorphs may be less so), age (RHDV1 affects adults >2 months, RHDV2 affects all ages), and immune status (unvaccinated rabbits are at high risk). Extrinsic factors include poor biosecurity (introduction of new rabbits without quarantine), contaminated housing (cages, hutches), inadequate disinfection protocols, and environmental contamination (virus persists in soil, bedding, and feed). Stress factors such as overcrowding, poor nutrition, concurrent diseases, and transportation can increase susceptibility. In outdoor hutches, exposure to wild rabbits and insects increases risk. Lack of vaccination is the most significant preventable risk factor.

Clinical signs vary depending on the viral strain and rabbit age. In peracute cases, rabbits may be found dead without premonitory signs. Acute cases may show fever (rectal temperature >40°C), lethargy, anorexia, and reluctance to move. Neurological signs such as ataxia, opisthotonos, and convulsions may occur due to hepatic encephalopathy or cerebral hemorrhage. Respiratory signs include tachypnea, dyspnea, and nasal discharge (sometimes blood-tinged). Gastrointestinal signs include anorexia, constipation or diarrhea, and abdominal pain. Hemorrhagic signs include petechiae and ecchymoses on the skin and mucous membranes, epistaxis, hematuria, and bleeding from the anus. Icterus may be evident in subacute cases. In RHDV2 infections, clinical signs may be milder, with some rabbits surviving, but mortality can still be high. Young kits may show only mild depression or no signs. Physical examination may reveal dehydration, pale mucous membranes, and a palpable enlarged liver (hepatomegaly).

Differential diagnoses for RHD include: 1) Tularemia (Francisella tularensis) - causes fever, hepatosplenomegaly, and sudden death; diagnosis via serology or PCR. 2) Myxomatosis - causes skin lesions (myxomas), conjunctivitis, and immunosuppression; less acute than RHD. 3) Pasteurellosis (Pasteurella multocida) - causes respiratory disease, abscesses, and septicemia; often chronic. 4) Hepatic coccidiosis (Eimeria stiedae) - causes hepatomegaly, icterus, and diarrhea; diagnosed by fecal floatation and histopathology. 5) Toxemia of pregnancy (in does) - causes sudden death and hepatic lipidosis; history of pregnancy. 6) Acute toxicosis (e.g., plant toxins, heavy metals) - can cause hepatic necrosis and hemorrhage; history of exposure. 7) Bacterial septicemia (e.g., E. coli, Clostridium spp.) - can cause sudden death and hemorrhagic lesions; blood cultures and necropsy. 8) Heat stroke - causes sudden death, but no hepatic necrosis; environmental history. 9) Trauma - can cause internal hemorrhage and sudden death; necropsy findings. 10) Other viral infections (e.g., RHDV variants) - differentiate via PCR and antigenic testing.

1) Clinical triage: Isolate any rabbit suspected of RHD immediately. Use strict biosecurity (gloves, disposable gowns, footbaths). 2) Physical examination: Assess vital signs, hydration, mucous membranes, and presence of hemorrhages. 3) Blood sampling: Collect blood for hematology, biochemistry, and PCR. Venipuncture sites: lateral saphenous vein, jugular vein, or cephalic vein. Use a 25-gauge needle and 1-3 mL syringe. 4) Point-of-care testing: Check blood glucose (may be low), liver enzymes (AST, ALT), and coagulation parameters (if available). 5) Molecular diagnosis: Submit whole blood (EDTA) or liver tissue (from necropsy) for RHDV1/RHDV2 PCR. This is the definitive diagnostic test. 6) Serology: Detect antibodies via ELISA, but this is less useful in acute cases. 7) Necropsy: If the rabbit dies, perform a necropsy to observe characteristic lesions: pale, enlarged liver with necrosis; splenomegaly; hemorrhages in lungs, kidneys, and intestines. Collect liver, spleen, and lung samples for histopathology and PCR. 8) Histopathology: Liver shows massive hepatocellular necrosis with intracytoplasmic inclusion bodies. 9) Rule out other causes: Perform bacterial culture, fecal floatation, and toxicology as needed. 10) Report to authorities: RHD is a notifiable disease in many countries; contact veterinary authorities.

Hematology: Leukopenia (lymphopenia and neutropenia) may be seen in acute cases. Thrombocytopenia is common due to DIC. PCV may be normal or elevated due to dehydration. Biochemistry: Marked elevation of liver enzymes (AST, ALT, GGT, ALP) and bilirubin. Hypoglycemia is common. BUN and creatinine may be elevated due to renal involvement. Electrolyte imbalances (hyperkalemia, hyponatremia) may occur. Coagulation profile: Prolonged PT and aPTT, elevated D-dimer, decreased fibrinogen. PCR: Positive for RHDV1 or RHDV2 RNA in blood, liver, or other tissues. Serology: IgM and IgG antibodies may be detected in surviving rabbits, but not in peracute cases. Urinalysis: Hematuria, proteinuria, and bilirubinuria may be present. Fecal analysis: No specific findings, but may be normal.

Radiography: Thoracic radiographs may show pulmonary edema (interstitial pattern) and cardiomegaly. Abdominal radiographs may reveal hepatomegaly (enlarged liver silhouette) and gas-filled intestines. Ultrasonography: Abdominal ultrasound can assess liver size and echotexture (diffuse hyperechoic or hypoechoic areas), splenomegaly, and free abdominal fluid (ascites). Echocardiography may be performed if cardiac involvement is suspected. CT and MRI are rarely used in clinical practice but can provide detailed images of hepatic necrosis and hemorrhage. Endoscopy is not typically used for diagnosis of RHD, but if performed, may show gastric or intestinal hemorrhages.

Cytology: Fine-needle aspiration of the liver may show necrotic hepatocytes, but is rarely performed due to risk of hemorrhage. Histopathology: Liver: Diffuse severe hepatocellular necrosis with acidophilic degeneration, karyorrhexis, and intracytoplasmic inclusion bodies (eosinophilic, round to oval). There is often massive hemorrhage and sinusoidal congestion. Spleen: Necrosis of lymphoid follicles and red pulp. Lungs: Pulmonary edema, alveolar hemorrhage, and hyaline membrane formation. Kidneys: Tubular necrosis and hemorrhage. Intestines: Hemorrhage and necrosis of the mucosa. Immunohistochemistry can confirm the presence of RHDV antigen in tissues.

There is no specific antiviral treatment for RHD. Treatment is primarily supportive and aimed at managing complications. 1) Emergency stabilization: Isolate the rabbit, provide a quiet, warm environment. Administer oxygen if dyspneic. 2) Fluid therapy: Correct dehydration and electrolyte imbalances. Use isotonic crystalloids (e.g., Lactated Ringer's solution) at 10-20 mL/kg IV or IO bolus, then 100-150 mL/kg/day IV or SC. Monitor for fluid overload. 3) Nutritional support: If the rabbit is anorexic, provide syringe feeding with a critical care formula (e.g., Oxbow Critical Care) at 10-15 mL/kg every 4-6 hours. 4) Hepatoprotectants: Consider using silymarin (milk thistle) at 10-20 mg/kg PO q12h, or SAMe (S-adenosylmethionine) at 20-50 mg/kg PO q24h, though evidence is limited. 5) Coagulopathy management: Administer vitamin K1 (phytonadione) at 2-5 mg/kg SC q24h, but this is unlikely to reverse DIC. 6) Antibiotics: To prevent secondary bacterial infections, use broad-spectrum antibiotics such as enrofloxacin (10 mg/kg PO q12h) or trimethoprim-sulfamethoxazole (30 mg/kg PO q12h). Avoid penicillins and cephalosporins due to risk of enterotoxemia. 7) Analgesics: Provide pain relief with meloxicam (0.3-0.6 mg/kg PO q24h) or buprenorphine (0.01-0.05 mg/kg SC q8-12h). 8) Vaccination: In the face of an outbreak, vaccinate all in-contact rabbits with an inactivated RHDV1/RHDV2 vaccine if available. 9) Biosecurity: Strict quarantine, disinfection with 10% bleach or 1% sodium hydroxide, and control of insects and rodents. 10) Euthanasia: In severe cases with poor prognosis, euthanasia may be recommended to prevent suffering.

The prognosis for RHD is generally poor to grave. Mortality rates can reach 90-100% in unvaccinated adult rabbits infected with RHDV1. RHDV2 has a slightly lower mortality (up to 80%) and some rabbits may survive with supportive care. Factors indicating a poor prognosis include peracute death, severe coagulopathy, marked hypoglycemia, and multi-organ failure. Rabbits that survive the acute phase may take several weeks to recover and may have chronic liver damage. Early diagnosis and aggressive supportive care may improve survival in some cases, but the disease is often fatal. Vaccination is the most effective way to prevent RHD.

For rabbits that survive RHD, follow-up should include: 1) Recheck examination at 1, 2, and 4 weeks post-infection. 2) Serial blood work (liver enzymes, bilirubin, glucose) every 1-2 weeks until normalized. 3) Monitor weight and appetite daily; adjust nutritional support as needed. 4) Assess for chronic liver disease (e.g., hepatic fibrosis) via ultrasound or biopsy if indicated. 5) Vaccinate surviving rabbits after recovery (if not already vaccinated) to boost immunity. 6) For the rabbitry, implement strict biosecurity measures, including quarantine of new rabbits for at least 2 weeks, disinfection protocols, and insect control. 7) Consider vaccination of all rabbits in the facility with RHDV1/RHDV2 vaccine. 8) Educate owners on preventing introduction of the virus via fomites and wildlife.

Pearls: 1) Always consider RHD in any unvaccinated rabbit with sudden death or acute hepatic failure. 2) Use PCR on blood or liver tissue for definitive diagnosis; it is highly sensitive and specific. 3) In an outbreak, vaccinate all in-contact rabbits immediately with a killed vaccine. 4) Use strict biosecurity to prevent spread; RHDV is highly resistant to many disinfectants, but 10% bleach or 1% sodium hydroxide is effective. 5) Supportive care with fluids, nutrition, and hepatoprotectants may help some rabbits survive. Pitfalls: 1) Do not use live vaccines in rabbits that are already infected; they can cause disease. 2) Avoid using corticosteroids in rabbits with RHD; they can exacerbate immunosuppression and viral replication. 3) Do not administer penicillins or cephalosporins; they can cause fatal enterotoxemia. 4) Do not overlook the possibility of RHDV2 in young kits; it can affect them. 5) Do not rely solely on clinical signs; many diseases mimic RHD. 6) Do not forget to report RHD to veterinary authorities; it is a notifiable disease in many countries.

Based on Carpenter's Exotic Animal Formulary (6th edition) and current literature: 1) Fluid therapy: Lactated Ringer's solution (LRS) or Normosol-R, 10-20 mL/kg IV/IO bolus, then 100-150 mL/kg/day IV or SC. 2) Enrofloxacin: 10 mg/kg PO or SC q12h (dilute for SC). 3) Trimethoprim-sulfamethoxazole: 30 mg/kg PO q12h. 4) Metronidazole: 20 mg/kg PO q12h (if anaerobic infection suspected). 5) Meloxicam: 0.3-0.6 mg/kg PO q24h (use with caution in renal/hepatic disease). 6) Buprenorphine: 0.01-0.05 mg/kg SC q8-12h. 7) Vitamin K1 (phytonadione): 2-5 mg/kg SC q24h. 8) Silymarin (milk thistle): 10-20 mg/kg PO q12h. 9) SAMe (S-adenosylmethionine): 20-50 mg/kg PO q24h. 10) Syringe feeding: Oxbow Critical Care, 10-15 mL/kg every 4-6 hours. 11) Vaccination: Inactivated RHDV1/RHDV2 vaccine, 1 mL SC, boosters as per manufacturer (e.g., annually). Note: Always check for drug interactions and contraindications.

Key literature: 1) Abrantes et al. (2012) 'Rabbit haemorrhagic disease (RHD) and rabbit haemorrhagic disease virus (RHDV): a review' - comprehensive review of virology, epidemiology, and control. 2) Dalton et al. (2012) 'Variant rabbit hemorrhagic disease virus in young rabbits, Spain' - describes RHDV2 affecting young kits. 3) Le Gall-Reculé et al. (2013) 'Emergence of a new lagovirus related to Rabbit Haemorrhagic Disease Virus' - first description of RHDV2 in France. 4) Spibey et al. (2012) 'Development of a vaccine against RHDV2' - vaccine efficacy studies. 5) BSAVA Manual of Rabbit Medicine (2014) - clinical guidelines for diagnosis and management. 6) ABVP and ECZM consensus statements on rabbit vaccination and biosecurity. 7) Carpenter's Exotic Animal Formulary (6th ed., 2018) - drug dosages. 8) Recent studies on environmental persistence of RHDV and disinfection protocols. 9) Studies on cross-protection between RHDV1 and RHDV2 vaccines. 10) Meta-analyses on mortality rates and risk factors. These sources provide evidence-based recommendations for diagnosis, treatment, and prevention.