Key Points
- Rabbit hemorrhagic disease (RHD) is a highly infectious, fatal viral hepatitis caused by a calicivirus that affects lagomorphs.
- 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 outbreaks affecting both domestic and wild rabbits have occurred in North America. Disease is now considered endemic in some parts of the US.
- 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 domestic European rabbits (Oryctolagus cuniculus). The host range is wider for RHDV2 and includes not only the European rabbit but several species of wild lagomorphs.
- Disease caused by RHDV1/RHDVa occurs primarily in adult rabbits, while disease caused by RHDV2 is seen in adults as well as 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 is most commonly used to identify the presence of virus. Viral loads are particularly high in the liver and spleen. At this time, antemortem PCR is not a reliable diagnostic test.
- Prevention and control of disease relies upon strict biosecurity protocols, stringent disinfection, 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).10,24 RHD is considered a reportable disease of international concern by the World Organization for Animal Health (formerly OIE).10,20
Rabbit hemorrhagic disease virus (RHDV) is a non-enveloped, single-stranded, positive-sense RNA virus belonging to family Caliciviridae and genus Lagovirus.2,10,22 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).9,24,25
| *RHDV1 and RHDVa are closely related |
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The European brown hare syndrome virus is another lagovirus that causes RHD-like disease in hares (Lepus spp.).10,24
RHDV1 | RHDV2 |
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GEOGRAPHIC RANGE | Rabbit 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. 6,7,8,18 |
| 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 |
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| Species | Wild and domestic European rabbits (O. cuniculus)1,7,18 | Wider host range, including many species of wild rabbits, such as 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.1, 5, 15 Although virus was found in wild mice living near RHDV2 outbreaks, the mice did not show clinical signs of disease.15 |
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| Age | Adult rabbits 7,21 | Adults as well as kits as young as 7 to 15 days old 20 |
| Zoonotic potential | RHD is not considered a food safety concern and is not associated with infection or disease in humans.12,21 |
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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 byproducts may play an important role in the introduction of RHDV into new geographic regions.7,21 |
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INCUBATION | ||
CLINICAL PICTURE |
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| Mortality rate | 70-90% in adult rabbits 6,7,18,20 | RHDV2 strains have become progressively more virulent over time, ranging from 70-100%6,7,20 |
| Duration | Death usually occurs 12–36 hours after the onset of fever 7,18,20,21 | More prolonged period of illness before death (up to 5 days)16 |
| The clinical syndromes caused by RHDV and RHDV2 are similar.6,7,18 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 often begins as fever (>40°C or 104°F) followed by a wide range of progressive clinical signs related to circulatory shock, liver failure, and disseminated intravascular coagulation or DIC: 2,7,8,18,20
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
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DIAGNOSIS | A presumptive diagnosis of RHD is often based on history, risk assessment, and clinical findings. American veterinarians that suspect RHD should contact their state veterinarian to receive instructions on testing and reporting. |
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Minimum database 7,18 | Complete blood count |
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Coagulation tests |
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Biochemistry panel |
*Liver enzymes can be decreased 6 or elevated (M. Gleeson, written communication, Mar 18, 2023). |
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Urinalysis |
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| Gross necropsy lesions | Common necropsy lesions include pallor and a friable liver due to necrosis, splenomegaly, and epistaxis. 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 |
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| Histopathology | The most common histopathologic findings include extensive, multifocal to massive 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 |
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| Laboratory testing | Reverse transcription (RT) PCR and antigen ELISA are the most commonly used tests to identify the presence of 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. Most animals will also die before an antibody response can be detected by Ab ELISA. 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 Formalin fixed tissue can also be submitted for histopathology.7,21 For antemortem testing, PCR can be performed on urine, feces, or serum collected from convalescent rabbits up to 15 weeks post-infection but results can be inconsistent.7,20 Laboratories currently offering RHD testing include (but are not limited to):
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 **Plum Island currently does not offer antemortem testing because of inconsistent test results; Ab ELISA is performed for export purposes. |
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| 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 When sudden deaths of multiple rabbits occur within a household or collection, the most useful diagnostic test is necropsy and testing of samples from deceased rabbits. |
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THERAPY | There 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 |
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PREVENTION AND CONTROL |
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| Where RHD is absent... | Prevent the introduction of virus through restrictions on importation of animals or products from endemic areas.7,19 |
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| 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 |
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When disease is endemic... |
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. |
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SUMMARY
Rabbit hemorrhagic disease is a highly infectious, fatal viral hepatitis of lagomorphs caused by a calicivirus. There are three major pathogenic rabbit hemorrhagic disease virus genotypes: classical RHDV, RHDVa, and RHDV2. Rabbit hemorrhagic disease virus type 2 has now become the dominant subtype in endemic countries, and outbreaks affecting both domestic and wild rabbits have occurred in North America. Virus 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. While disease caused by RHDV1/RHDVa is restricted to domestic European rabbits, the host range is wider for RHDV2 and includes not only the European rabbit but several species of wild lagomorphs. Also, disease caused by RHDV1/RHDVa occurs primarily in adult rabbits, while disease caused by RHDV2 is seen in rabbits of all ages as young as 7-15 days old.
Rabbit hemorrhagic disease 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. A presumptive diagnosis of RHD is often based on history, risk assessment, and clinical findings. When sudden deaths of multiple rabbits occur within a household or collection, the most useful diagnostic test is necropsy and testing of samples from deceased rabbits. Viral loads are particularly high in the liver and spleen. PCR is most commonly used to identify the presence of virus. Prevention and control of disease relies upon strict biosecurity protocols, stringent disinfection, and vaccination.
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
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/