Fast Facts on Rabbit Hemorrhagic Disease

Key Points

  • Rabbit hemorrhagic disease (RHD) is a highly infectious, fatal viral hepatitis affecting lagomorphs caused by a calicivirus.
  • There are three major pathogenic rabbit hemorrhagic disease virus (RHDV) genotypes: classical RHDV (RHDV1), RHDVa, which is closely related to RHDV1, and RHDV2.
  • RHDV type 2 has now become the dominant subtype in endemic countries, and sporadic cases have been confirmed in North America.
  • RHDV is easily transmitted through direct rabbit-to-rabbit contact with bodily fluids or hair through the oral, nasal, or conjunctival routes. Disease can also be transmitted through indirect contact with fomites or mechanical vectors.
  • The incubation period often ranges from 1 to 6 days.
  • Disease caused by RHDV1/RHDVa is restricted to wild and domestic European rabbits (Oryctolagus cuniculus). The host range is wider for RHDV2 and includes not only the European rabbit but species of wild rabbits and pikas.
  • Disease caused by RHDV1/RHDVa occurs primarily in adult rabbits, while disease caused by RHDV2 is seen in rabbits as young as 7-15 days old.
  • RHD is characterized by high morbidity and high mortality. Clinical signs associated with acute disease can include neurologic and respiratory signs, non-specific signs of illness, jaundice, and bleeding. Death usually occurs 12–36 hours after the onset of fever.
  • PCR and ELISA are most commonly used to identify the presence of virus. Viral loads are particularly high in the liver and spleen.
  • Prevention and control of disease relies upon isolation of rabbits confirmed or suspected to be infected, careful biosecurity protocols, and vaccination.

Introduction

Rabbit hemorrhagic disease (RHD) is a highly infectious, fatal viral hepatitis affecting lagomorphs (rabbits, hares and pikas), including the European rabbit (Oryctolagus cuniculus).7,20 RHD is considered a reportable disease of international concern by the World Organization for Animal Health (formerly OIE).7,17

Rabbit hemorrhagic disease virus (RHDV) is a non-enveloped, single-stranded, positive-sense RNA virus belonging to family Caliciviridae and genus Lagovirus.2,7,18 Historically, RHDV split into six highly pathogenic genotypes (G1-G6), however in 2010, a new, antigenically distinct genotype emerged:  rabbit hemorrhagic disease virus type 2 (RHDV2) (Box 1).6,20,21

Box 1. Rabbit hemorrhagic disease virus genotypes primarily seen today3,7-10,18

*RHDV1 and RHDVa are closely related
  • RHDV/RHDV1/classical RHDV/GI.1a-d/rabbit hemorrhagic disease virus type 1
  • RHDVa/G6*
  • RHDV2/RHDVb/GI.2/rabbit hemorrhagic disease virus type 2

The European brown hare syndrome virus is another lagovirus that causes RHD-like disease in hares (Lepus spp.).7,20

 

RHDV1

RHDV2

GEOGRAPHIC RANGERabbit hemorrhagic disease virus type 1 (RHDV1) was first reported in China in 1984, resulting in the loss of millions of rabbits in less than 1 year.6,8,11,22 Two years later, RHDV1 was first reported in Europe. In 2010, a new form of RHD, rabbit hemorrhagic disease virus type 2, emerged in France in wild and farmed rabbits.6-8,18
Since that time, RHD has been reported in over 40 countries, occurring regularly across parts of Europe, Asia, Africa, the Americas, and Oceania.21 Outbreaks have also occurred in the Middle East.21 Within 5 to 6 years, RHDV2 had spread across Europe and reached Africa, Israel, Australia, New Zealand, and North America.3,6,7,18 RHDV-2 has now become the dominant subtype of RHD in endemic countries.
Isolated cases have appeared intermittently in the US and Canada. The first confirmed case of RHDV2 reported in North America was seen in Quebec in 2016.18 The first case in the US was seen in 2018. Since then, RHVD2 outbreaks have been seen sporadically throughout the US and Canada.7,9,18
SIGNALMENT
SpeciesWild and domestic European rabbits (O. cuniculus)1,7,18Wider host range, including many species of wild rabbits, including hares (Lepus spp.) and cottontails (Sylvilagus spp.), pikas, and the domesticated European rabbit3,7,9,14,18

Since the emergence of RHDV2, viral RNA has been identified in a few rodent species, presumably through the ingestion of rabbit-infected tissues or feces during scavenging.1b, 5b, 15 Although virus was found in wild mice living near RHDV2 outbreaks, the mice did not show clinical signs of disease.15 The presence and replication of RHDV2 has also been identified in Eurasian badgers (Meles meles) found dead in Portugal between 2017 and 2020.1b This study showed that badgers are susceptible to RHDV2, developing systemic infection and excreting the virus in the feces.1b


RHD is not considered a food safety concern and is not associated with infection or disease in humans.12,21

AgeAdult rabbits 7,21Kits as young as 7 to 15 days old 20
TRANSMISSION

RHDV is extremely contagious. RHDV is easily transmitted through direct rabbit-to-rabbit contact with bodily fluids (urine, feces, respiratory secretions) or hair from an infected animal.7,21


Transmission mainly occurs by the oral route but nasal or conjunctival exposure is also possible.2,21


RHDV is extremely stable in the environment.2,7 Therefore exposure to fomites or mechanical vectors can transmit disease.7,21 Virus can also persist for months in decomposing carcasses in the environment as well as frozen infected rabbit meat.2,7,21 Importation of rabbit meat and by products may play an important role in the introduction of RHDV into new geographic regions.7,21

INCUBATIONShorter incubation periods of 1-3 days 2,7,21 Longer, more variable incubation period of 3-9 days 2,7,16
CLINICAL PICTURE
Mortality rate70-90% in adult rabbits 6,7,18,20RHDV2 strains have become progressively more virulent over time, ranging from 70-100%6,7,20
DurationDeath usually occurs 12–36 hours after the onset of fever 7,18,20,21More prolonged period of illness before death (up to 5 days)16
The clinical syndromes caused by RHDV and RHDV2 are similar.7, 6, 18 RHD often presents as peracute to acute disease.

In peracute cases, the only clinical signs may be sudden death without premonitory clinical signs except for vocalizations followed rapidly by collapse and death.7,18

The acute form of disease begins as fever (>40°C or 104°F) followed by a wide range of progressive clinical signs:2,7,8,18,20

  • Neurologic signs, such as loss of balance, ataxia, paralysis, or terminal seizure activity

  • Respiratory signs (dyspnea)

  • Conjunctivitis

  • Non-specific signs of illness, such as lethargy and hyporexia or anorexia

  • Jaundice

  • Fever can progress to hypothermia

  • Bleeding from the eyes, nose, mouth, and rectum, and hematochezia secondary to anemia and coagulopathies.

  • Death can occur within 12-36 (possibly up to 48) hours after clinical signs appear. Free-ranging lagomorphs may be found dead.


Approximately 5 to 10% of rabbits display a subacute to chronic clinical course.1,21 The clinical picture is often similar to that seen with the acute form, but with less severe clinical signs: 4,7,18,21

  • Non-specific signs of illness: lethargy, anorexia, weight loss

  • Jaundice

  • Gastrointestinal dilation

  • Cardiac arrhythmia, heart murmur

  • Neurologic deficits

  • Death can occur within 1–2 weeks, although some adult rabbits survive.

DIAGNOSISA presumptive diagnosis of RHD is often based on history, risk assessment, and clinical findings.

US veterinarians that suspect RHD should contact their state veterinarian to receive instructions on testing and reporting.
Minimum database 7,18Complete blood count

  • Leukopenia

  • Thrombocytopenia

Coagulation tests

  • Decreased fibrinogen

  • Prolonged prothrombin and activated partial thromboplastin times

Biochemistry panel

  • Elevated gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP)

  • Elevated bile acids

  • Hyperbilirubinemia

  • Decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity

  • Hypoglycemia

  • Hypocholesterolemia


Urinalysis

  • Bilirubinuria

  • Proteinuria

  • Elevated urinary GGT


Gross necropsy lesionsCommon necropsy lesions include pallor and necrosis of the liver, jaundice, and splenomegaly. There may also be evidence of disseminated intravascular coagulation , such as petechiation and hyperemia or hemorrhage of the trachea, lungs, heart, liver, spleen, and kidneys.2,7,21 It is also possible for there to be no gross necropsy findings in rabbits that die peracutely.14
HistopathologyThe most common histopathologic findings include extensive, multifocal hepatocellular necrosis and multifocal to diffuse splenic necrosis. 7,18 Bronchopneumonia, pulmonary hemorrhage or pulmonary edema, and cardiomyocyte necrosis, may be seen in some subacute to chronic cases.7
Laboratory testing

Reverse transcription (RT) PCR and enzyme-linked immunosorbent assay (ELISA) tests are commonly used to identify the presence of the virus.2,6,7,20,21 Test results typically take only 1-5 business days, but unfortunately, many animals have already succumbed to the virus. Therefore testing is most helpful in caring for other animals at risk of exposure and preventing viral spread.


PCR testing is best performed on fresh or frozen liver samples, but virus may also be detected in the spleen.2,7,20 A variety of additional tissues may be useful in rabbits suffering from subacute to chronic disease, including kidney, lung, heart, brain, bone marrow, muscle, spinal cord, thymus, or lymph.2 Although not ideal, formalin fixed tissue can also be tested.7,21 For antemortem testing, PCR can be performed on urine, feces, or serum collected from convalescent rabbits up to 15 weeks post-infection.7,20



Laboratories currently offering RHD testing:

Additional test methods that are used less commonly include electron microscopy, immunohistochemistry, Western blotting, in-situ hybridization, next-generation sequencing, and hemagglutination inhibition.2,7,20

Definitive diagnosis Like most caliciviruses, RHDV cannot be grown in cell culture. Therefore rabbit inoculation is necessary to isolate virus. This method is not used for routine diagnosis due to animal welfare concerns. 2,7,20,21
THERAPYThere is no specific treatment for RHDV, however supportive care can be rewarding, particularly in adult rabbits suffering from the subacute to chronic form of disease.7
PREVENTION AND CONTROL
Where RHD is absent...Prevent the introduction of virus through restrictions on importation of animals or products from endemic areas.7,19
When an outbreak occurs...Eradicate disease through strict quarantine, depopulation, disinfection, and serosurveillance.7 Vaccination of all animals is also recommended as successful post-exposure prophylaxis has been seen.7
Endemic disease

  1. Isolate infected rabbits


    • Any animal known or suspected to be infected should be immediately isolated; surviving rabbits can carry virus for up to 2 months. 7
    • Also strive to identify subclinical carriers that can shed virus for months without obvious signs of disease.7,21


  2. Practice proper biosecurity, such as hand washing, clothes changes between rabbit groups, etc.

  3. Disinfect and sanitize


    • RHDV can be inactivated using sodium hypochlorite (0.5%–1%), phenolics such as 1-Stroke Environ® (2%) (Vestal Lab Inc., St. Louis, MO, USA), chloramine, sodium hydroxide (1%), or formalin (1%–2%).7,21

    • Higher concentrations of formalin (3%) are recommended for disinfecting pelts.7,21

    • Incineration of infected material and cremation of carcasses is also recommended.7

    • Visit General Guidance for Cleaning and Disinfection of Rabbit Hemorrhagic Disease Virus (RHDV) Contaminated Premises by the United States Department of Agriculture, Animal Plant Health Inspection Services for additional information.


  4. Institute appropriate vaccination protocols


    • In many countries where RHD is endemic, vaccinations have been administered to susceptible rabbits and high-risk populations for many years.

    • In Europe, vaccines available include highly efficacious inactivated (killed), commercial vaccines available as well as recombinant vaccines:5-7,20

      • Eravac (Spain) is a monovalent RHDV2 vaccine primarily used in the rabbit-meat farming industry
      • Filavac (VHD K C+V, France) is a bivalent vaccine effective against both RHDV and RHDV2 that is widely used in pet rabbits in the United Kingdom and continental Western Europe.
      • Fatrovax RHD (Italy) RHDV1 and RHDV2
      • Nobivac Myxo-RHD (The Netherlands) is a recombinant vaccine that protects against RHDV1 and myxomatosis.

      • Nobivac Myxo-RHD Plus protects against RHDV1, RHDV2, and myxomatosis.
      • Visit the Frances Harcourt-Brown website for detailed information on vaccines against RHD available in the UK


      Cross protection between RHDV2 vaccines and RHDV/RHDVa vaccines is poor.6,7,20,21 Current recommendations in endemic countries is to vaccinate against both variants RHDVa and RHDV-2.



      The vaccines available in Europe are not licensed in the United States and are only available on a limited basis.5 In 2021, the US Department of Agriculture authorized emergency use of the Medgene RHDV2 vaccine (Medgene Labs, Brookings, SD, USA).5,13

      • In a challenge study, this inactivated, recombinant subunit vaccine was administered subcutaneously as a two-dose regimen (0.5-ml), administered 21 days apart.5,13

      • The vaccine proved effective in preventing mortality in 100% of rabbits challenged with live virus (n=9).5,13


 

References

References

  1. Abade Dos Santos FA, Carvalho C, et al. Detection of rabbit haemorrhagic disease virus 2 during the wild rabbit (Oryctolagus cuniculus) eradication from the Berlengas archipelago, Portugal. BMC Vet Res. 2017;13(1):336. doi: 10.1186/s12917-017-1257-3. PMID: 29141631; PMCID: PMC5688637.
  2. Abrantes J, Lopes AM. A review on the methods used for the detection and diagnosis of rabbit hemorrhagic disease virus (RHDV). Microorganisms. 2021;9(5):972. doi: 10.3390/microorganisms9050972. PMID: 33946292; PMCID: PMC8146303.
  3. Bell DJ, Davis JP, Gardner M, et al. Rabbit haemorrhagic disease virus type 2 in hares in England. Vet Rec. 2019;184(4):127-128. doi: 10.1136/vr.l337. PMID: 30683789.
  4. Bonvehí C, Ardiaca M, Montesinos A, et al. Clinicopathologic findings of naturally occurring rabbit hemorrhagic disease virus 2 infection in pet rabbits. Vet Clin Pathol. 2019;48(1):89-95. doi: 10.1111/vcp.12701. Epub 2019 Mar 12. PMID: 30861586.
  5. Bosco-Lauth AM, Cominsky B, Porter S, et al. A novel vaccine candidate against rabbit hemorrhagic disease virus 2 (RHDV2) confers protection in domestic rabbits. Am J Vet Res. 2022;83(12):ajvr.22.05.0095. doi: 10.2460/ajvr.22.05.0095. PMID: 36327167.
  6. Capucci L, Cavadini P, Schiavitto M, Lombardi G, Lavazza A. Increased pathogenicity in rabbit haemorrhagic disease virus type 2 (RHDV2). Vet Rec. 2017;180(17):426. doi: 10.1136/vr.104132. Epub 2017 Mar 24. PMID: 28341721.
  7. Gleeson M, Petritz OA. Emerging infectious diseases of rabbits. Vet Clin North Am Exot Anim Pract. 2020;23(2):249-261. doi: 10.1016/j.cvex.2020.01.008.
  8. Hänske GG, König P, Schuhmann B, Bertram CA, Müller K. Death in four RHDV2-vaccinated pet rabbits due to rabbit haemorrhagic disease virus 2 (RHDV2). J Small Anim Pract. 2021;62(8):700-703. doi: 10.1111/jsap.13333. Epub 2021 Apr 26. PMID: 33900627.
  9. Himsworth CG, Leung D, Byers K, et al. An outbreak of rabbit hemorrhagic disease in British Columbia, Canada. J Wildl Dis. 2021;57(4):983-986. doi: 10.7589/JWD-D-21-00061. PMID: 34516651.
  10. Le Pendu J, Abrantes J, Bertagnoli S, et al. Proposal for a unified classification system and nomenclature of lagoviruses. J Gen Virol. 2017;98(7):1658-1666. doi: 10.1099/jgv.0.000840. Epub 2017 Jul 17. PMID: 28714849.
  11. Liu SJ, Xue XP, Pu BQ, Quian NH. A new viral disease in rabbits. Animal Husbandry and Veterinary Medicine. 1984;16: 253–255.
  12. Mead C. Rabbit hemorrhagic disease. Emerg Infect Dis. 1998;4(2):344-5; author reply 345-6. doi: 10.3201/eid0402.980237. PMID: 9621219; PMCID: PMC2640127.
    Medgene Labs. Available at:  https://medgenelabs.com/rhdv2/. Accessed January 1, 2023.
  13. Rocchi M, Maley M, Dagleish M, Boag B. Rabbit haemorrhagic disease virus type 2 in hares in Scotland. Vet Rec. 2019;185(1):23. doi: 10.1136/vr.l4481. PMID: 31273141.
  14. Rocha G, Alda F, Pagés A, Merchán T. Experimental transmission of rabbit haemorrhagic disease virus (RHDV) from rabbit to wild mice (Mus spretus and Apodemus sylvaticus) under laboratory conditions. Infect Genet Evol. 2017;47:94-98. doi: 10.1016/j.meegid.2016.11.016. Epub 2016 Nov 19. PMID: 27871816.
  15. Saunders R. Vaccinating rabbits against RVHD-2. Vet Rec. 2016;178(4):100-1. doi: 10.1136/vr.i384. PMID: 26795863.
  16. United States Department of Agriculture, Animal Plant Health Inspection Services. WOAH and International Standards. Nov 22, 2022. Available at https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/nvap/NVAP-Reference-Guide/Animal-Health-Emergency-Management/OIE-and-International-Standards. Accessed January 23, 2023.
  17. Williams LBA, Edmonds SE, Kerr SR, Broughton-Neiswanger LE, Snekvik KR. Clinical and pathologic findings in an outbreak in rabbits of natural infection by rabbit hemorrhagic disease virus 2 in the northwestern United States. J Vet Diagn Invest. 2021;33(4):732-735. doi: 10.1177/10406387211022466. Epub 2021 Jun 7. PMID: 34092143; PMCID: PMC8229847.
  18. World Organisation for Animal Health. Terrestrial Animal Health Code. Chapter 13.2. Rabbit haemorrhagic disease. World Organisation for Animal Health website. March 8, 2022. Available at https://www.woah.org/fileadmin/Home/eng/Health_standards/tahc/current/chapitre_rabbit_haemorrhagic_disease.pdf. Accessed January 20, 2023.
  19. World Organisation for Animal Health. Chapter 3.7.2. Rabbit Haemorrhagic Disease. World Organisation for Animal Health Terrestrial Manual. 2021. Available at https://www.woah.org/fileadmin/Home/eng/Health_standards/tahm/3.07.02_RHD.pdf. Accessed December 23, 2022.
  20. World Organisation for Animal Health. Disease cards: Rabbit Hemorrhagic Disease. World Organisation for Animal Health website. January 2019. Available at:  https://www.woah.org/fileadmin/Home/eng/Animal_Health_in_the_World/docs/pdf/Disease_cards/RHD.pdf. Accessed August 3, 2022.
  21. Xu WY. Viral haemorrhagic disease of rabbits in the People’s Republic of China: epidemiology and virus characterisation. Rev Sci Tech. 1991 Jun;10(2):393-408. PMID: 1760583.

 

 

FURTHER READING

Le Gall-Reculé G, Lemaitre E, Bertagnoli S, et al. Large-scale lagovirus disease outbreaks in European brown hares (Lepus europaeus) in France caused by RHDV2 strains spatially shared with rabbits (Oryctolagus cuniculus). Vet Res 2017;48:70.

McGowan S, Choudhury B. Update on rabbit haemorrhagic disease virus 2-like variant in Great Britain. Vet Rec. 2016 Jun 25;178(26):662-3. doi: 10.1136/vr.i3449. PMID: 27339927.

McIntosh MT, Behan SC, Mohamed FM, Lu Z, Moran KE, Burrage TG, Neilan JG, Ward GB, Botti G, Capucci L, Metwally SA. A pandemic strain of calicivirus threatens rabbit industries in the Americas. Virol J. 2007 Oct 2;4:96. doi: 10.1186/1743-422X-4-96. PMID: 17910765; PMCID: PMC2147015.

Puggioni G, Cavadini P, Maestrale C, et al. The new French 2010 rabbit hemorrhagic disease virus causes an RHD-like disease in the Sardinian Cape hare (Lepus capensis mediterraneus). Vet Res 2013;44:96.

Rocchi M, Dagleish M. Diagnosis and prevention of RHVD2 infection. Vet Rec. 2018 May 26;182(21):604-605. doi: 10.1136/vr.k2313. PMID: 29794187.

Rouco C, Aguayo-Adán JA, Santoro S, Abrantes J, Delibes-Mateos M. Worldwide rapid spread of the novel rabbit haemorrhagic disease virus (GI.2/RHDV2/b). Transbound Emerg Dis. 2019 Jul;66(4):1762-1764. doi: 10.1111/tbed.13189. Epub 2019 Apr 17. PMID: 30924292.

United States Department of Agriculture, Animal Plant Health Inspection Services. General guidance for cleaning and disinfection of rabbit hemorrhagic disease virus (RHDV) contaminated premises. July 2020.

Available at https://www.aphis.usda.gov/animal_health/downloads/rhdv-cleaning-guidance.pdf. Accessed October 10, 2021.

United States Department of Agriculture, Animal Plant Health Inspection Services. https://www.aphis.usda.gov/publications/animal_health/fs-rhdv2.pdf. Accessed January 1, 2023.

United States Department of Agriculture, Animal Plant Health Inspection Services. https://www.aphis.usda.gov/publications/animal_health/fs-rhdv2.pdf. Accessed January 1, 2023.

Velarde R, Cavadini P, Neimanis, A, et al. Spillover events of infection of brown hares (Lepus europaeus) with rabbit haemorrhagic disease type 2 virus (RHDV2) caused sporadic cases of an European brown hare syndrome like-disease in Italy and Spain. Transbound Emerg Dis 2017;64:1750–61

Westcott DG, Choudhury B. Rabbit haemorrhagic disease virus 2-like variant in Great Britain. Vet Rec 2015;176:74

To cite this page:

Pollock CG, Murray J. Fast facts on rabbit hemorrhagic disease. LafeberVet website. Jan 23, 2023. Available at https://lafeber.com/vet/fast-facts-on-rabbit-hemorrhagic-disease/