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About rabbit haemorrhagic disease and its variants (Lagoviruses)

Blood in the nares may be seen in rabbits that have died suddenly from RHD. A foamy blood stained exudate in the trachea is a feature of the diseases and the exudate may extend to the nostrils

Key Points

  • There are several variants of the virus that causes Rabbit (or Viral) Haemorrhagic Disease (RHD or VHD). Some variants do not cause disease but stimulate immunity.
  • The virus that causes RHD is a calicivirus. Caliciviruses readily mutate
  • The original strain of RHD causes sudden death and has a high mortality rate (up to 90%) in unvaccinated rabbits. Young rabbits (<4weeks) have natural immunity that wears off over 4-6 weeks
  • Vaccination is usually protective against RHD although problems with storing the vaccine at the correct temperature or underlying disease that can interfere with the rabbit's immune system may result in a few individuals not having full protection
  • A variant of the Rabbit Haemorrhagic Disease Virus (RHDV2) has appeared. There are confirmed cases in pet rabbits throughout the UK.
  • The RHDV2 is less virulent than the original strain.  It has a lower and variable mortality rate (5-70% with an average of 20%). It can also affect rabbits under 4 weeks old. 
    Although rabbits can die suddenly, some can recover and others may show no clinical signs at all.
  • The virus that causes RHD is very difficult to kill. It can survive outside the body and is resistant to temperature changes. It can survive at 50 degrees centigrade for an hour i.e some washing machine cycles. 
  • RHD and its variants are easily spread. The virus can survive in the digestive tract of animals that feed on carcasses of rabbits that have died. For example, faeces from crows, foxes and flying insects can infect rabbits
  • In the UK, definitive diagnosis of RHD is difficult in the live animal.  There is no blood test. Diagnosis is usually made after death . Post-mortem signs may or may not show definite signs. Microscopic examination of the liver and other organs will show signs that are highly suggestive.
  • Confirmation of the diagnosis is RHD or RHD2 is made from PCR testing on the liver
  • It is not known how long a rabbit that has recovered from RHD remains infectious. A period of 30 days has been suggested
  • In the UK, prevention of the new variant of RHD (RHDV2) is difficult. The only vaccine that is available (Nobivac Myxo-RHD) offers some protection against RHDV2 but some rabbits are still susceptible to infection. Vaccines against RHDV2 are available in other European countries and can be imported into UK if they are available. 
  • The imported vaccines are not effective against myxomatosis so, in the UK, rabbits will need to be vaccinated with both Nobivac Myxo-RHD and an imported RHD vaccine to be protected against both myxomatosis and both variants of RHD.

Terminology

In 1984 a highly lethal disease broke out in rabbits in China. The disease was characterised by haemorrhages around the body and a calicivirus was identified as the cause. The disease was named  ‘viral haemorrhagic disease’ (VHD)  or ‘rabbit haemorrhagic disease’ (RHD) and the latter name has become the standard term in recent years.  The acronym RHDV (‘rabbit haemorrhagic disease virus’) is used to describe the virus. Since the emergence of RHD, many variants of the virus have emerged (RHDVa and RHDVb). Non-pathogenic strains of the calicivirus (RCV or ‘rabbit calicivirus’) have also been discovered. Recently, the variant of RHDV that was previously called RHDVb has been shown to differ from RHDV in many of its characteristics so the virus was renamed  from RHDVb to RHDV2. There is a body of opinion that this is a new virus that is a distinct serotype from RHD.  The term ‘lagovirus’ encompasses all types of RHDV and its variants.

History of the infection

RHD was first identified in 1984 in the People’s Republic of China. It appeared to originate from a colony of Angora rabbits that were imported from Germany. Within a year, there was a loss of over 140 million rabbits and the disease was spread to Korea by rabbit fur (Abrantes et al, 2012).  RHD was diagnosed in Italy in 1986 and by 1988, the disease been reported throughout Europe and in many other countries worldwide where it was probably introduced through rabbit meat. The disease spread into the wild rabbit population and in 1990, RHD reached Scandinavia where wild rabbits in the densely populated island of Gotland became nearly extinct within 1 week (Gavier-Widén, 1996). Hundreds of rabbits were seen dead in the fields and many more died in their burrows. In 1997, in Australia, RHD was released onto Wardang Island as a means of biological control of the wild rabbit population. Infection spread to the mainland where it has killed millions of wild rabbits. The infection was also surreptitiously introduced into New Zealand.  The first confirmed case of RHD in the United States occurred in 2000 in a small breeding  colony of exhibition rabbits in Iowa. Twenty five of the 27 rabbits died with no indication of the source of the infection (Percy and Barhold, 2008).

Variants

Non-pathogenic rabbit calicivirus (RCV)

Although fatalities from RHD were first reported in 1994, antibodies to the virus were detected in sera collected before that time and it is believed that non-pathogenic strains (RCV) could have been responsible for protecting rabbits by stimulating antibody production.  In 1996, a non-pathogenic calicivirus was recovered from breeding rabbits in Italy that produced seroconversion and was found to protect rabbits against RHD.  Subsequent investigations in Australia and UK have also revealed the presence of non-pathogenic strains that may or may not confer some natural immunity.  Studies in Australia suggest that rabbits that live in areas of higher rainfall are more likely to be infected with RCV and therefore have some immunity to RHD (Liu et al. 2014).

New variant (RHDV2)

In 2010, an atypical outbreak of RHD occurred in a rabbitry in France in which 25% of the rabbits (that were vaccinated) died (Le Call-Reculé, 2013). Emergency vaccination appeared to stop the mortalities but in 7-15 days, compared with the usual 7-9 days. Similar outbreaks in wild rabbits with high mortality were also occurring. Samples from affected rabbits were genetically analysed and the virus that was causing the fatalities was found to be related to, but highly distinct from, the strains of RHD that were isolated from previous outbreaks. This variant is known as RHDV2. This new variant was identified in Italy in 2011 and in UK in 2013 although retrospective analysis of samples suggests that the infection has been in the British Isles since 2010.  (Westcott and Choudbury, 2015). The infection has potential to cause devastating effects on the wild rabbit population because it affects all ages. Unlike the original strain of RHD, rabbits under 4 weeks of age have no natural immunity to RHDV2. It also appears to affect hares.

Natural immunity to RHDV and RHDV2

Most young rabbits less than 4 weeks of age remain unaffected by RHD and develop a life-long immunity if they are exposed to the disease. Unexposed rabbits become increasingly susceptible until 6–10 weeks of age when physiological resistance to the virus disappears. This age resistance is an interesting feature of the disease and appears to be due to a rapid and effective inflammatory response by the liver, with a sustained elevation in local and systemic B macrophages and T lymphocytes (Marques, 2012). Subsequent exposure to the virus boosts immunity that protects these young rabbits when they reach adulthood (Ferreira, 2008). This age immunity does not occur with RHDV2. Young and suckling rabbits may be affected.

Vaccination

Due to the devastating effects of RHD in China, a vaccine was quickly developed from inactivated virus obtained from the liver and spleen of infected rabbits. Although the immunological response to inactivated vaccines (Cylap, Lapinject) was good, in the UK, they have been superseded by a bivalent vaccine that protects against both myxomatosis and RHD (Nobivac Myxo-RHD).  It is constructed from a laboratory-attenuated strain of myxoma virus and the capsid protein gene of RHDV. The vaccine is only partially effective against RHDV2 so some vaccinated rabbits can still succumb to the disease. Vaccines against RHDV2 have been developed in countries where rabbit meat is popular and can be imported into UK.  

Characteristics and transmission of the RHD virus

The RHD virus is a positive-sense, single-stranded RNA virus and the complete genomic sequence has been determined. It does not grow in tissue culture, which limits research.  RHDV is difficult to kill and can survive harsh environmental conditions. It can survive temperatures of 50 ο C for up to an hour and is not inactivated by freezing. The virus can survive in the environment for many months (Henning et al, 2005) and rabbit carcasses can be a source of infection by spreading the virus via the faeces of scavengers. Only a few virus particles are needed to infect a rabbit. Infection is also easily transmitted between infected rabbits by the oral, nasal or conjunctival routes. Food bowls and bedding can transmit infection. RHD only affects European rabbits (Oryctolagus cuniculus). It does not affect other lagomorphs, such as cottontails, or other small mammals such as chinchillas, guinea pigs, rats and mice.

It is believed that rabbits that have recovered from classic RHD are potentially infectious to other rabbits for one month. It is not known how long the period is for RHDV2.

Clinical signs of classical RHD

RHD has a short incubation period of 1–4 days. The virus replicates in many tissues, including the lung, liver and spleen with subsequent viraemia and haemorrhage. The RHD calicivirus has a predilection for hepatocytes and replicates within the cytoplasm of these cells and the disease it causes is essentially a necrotizing hepatitis, often associated with necrosis of the spleen. Disseminated intravascular coagulation produces fibrinous thrombi within small blood vessels in most organs, notably the lungs, heart and kidneys resulting in haemorrhages. Death is due to disseminated intravascular coagulopathy or to liver failure.

Three manifestations of the infection may be seen:

  1. Peracute with animals found dead within a few hours of eating and behaving normally.  This is the most common presentation.
  2. Acute with affected rabbits showing lethargy, pyrexia (>40οC)  with an increased respiratory rate. These animals usually die within 12h. Blood samples show leucopaenia, thrombocytopaenia, fibrin thrombi and markedly raised liver enzymes but a feature of the disease is a dramatic drop in blood pressure that makes it difficult to find a vein to take blood samples or set up intravenous fluids.  Dying rabbits are pallid, shocked and collapsed. Haematuria, haemorrhagic vaginal discharges or foamy exudate from the nostrils may be seen. Vascular infarcts can occur within the brain and occasionally convulsions or other neurological signs are seen just before death. The ‘classic’ picture is a dead rabbit in opisthotonus with a haemorrhagic nasal discharge. Rarely, a rabbit may recover from the acute phase, only to develop jaundice and die a few days later. Very occasionally, a rabbit can survive this period but with permanent liver damage.
  3. Subacute with rabbits showing mild or subclinical signs from which they recover and become immune to further RHDV infectionExploratory laparotomy is indicated for a number of conditions including jaundice, recurrent colic or the investigation of of palpable abdominal masses. In this case, the operation was performed to investigate a case of weight loss and jaundice. Areas of calcification could be seen on abdominal radiographs. Areas of hepatic necrosis were visible and histopathology confirmed the diagnosis of hepatocellular necrosis consistent with RHD. The rabbit recovered. The areas of calcification in the liver of this rabbit were caused by RHD.  Exploratory laparotomy confirmed the diagnosis. The companion rabbit died and this rabbit recovered after a period of jaundice, weight loss and anorexia..

 

Clinical signs of RHDV2

Experimental infections with RHDV2 have shown that mortalities occur later and over a longer period than classic RHD. Clinical signs developed after 3-9 days and lasted (on average) 5 days instead of 3-4 days with experimental RHD infection (Le Call-Reculé, 2013). Subacute or chronic infections were more frequent and more rabbits survived.  Clinically, RHDV2 was more likely to cause a protracted disease with weight loss and jaundice.  

Anecdotally, outbreaks in vaccinated pet rabbits show sporadic deaths,often with companion rabbits that survive with no obvious clinical signs. Sometimes other underlying diseases suddenly flare up (e.g rhinitis or treponematosis) in a short period of time. This can complicate the diagnosis. Systemic illness with weight loss and anorexia seems to be a feature.

Diagnosis

The diagnosis of RHD is usually made at post mortem examination. RHD is suspected in any sudden death especially if more than one rabbit in the household has died. The post-mortem picture may be of a healthy rabbit with non-impacted food in the stomach and hard faecal pellets in the distal colon, suggesting that death was sudden.

Gross post-mortem signs may be minimal or obvious. Suggestive findings include:

  • An enlarged pale, friable liver with a distinct lobular pattern. The liver is always affected, although the gross appearance may not reflect the severe histopathological changes.
  • An enlarged spleen. This is highly suggestive of RHD. There are few differential diagnoses
  • A trachea filled with foamy exudate that may or may not be blood stained
  • Haemorrhages in any part of the body may or may not be obvious. Free blood may be found in the abdomen or in the retroperitoneal spaces. Ecchymotic haemorrhages may be seen on the serosal surfaces or in the lungs. Petechiae may be seen in the muscles, including the heart.

Histopathology confirms acute hepatic necrosis. Apoptosis (extensive vacuolations, alterations in the mitochondrial structure, kryopyknosis and karoylysis) may be seen on electron microscopy. There may be many other changes such as pulmonary oedema, acute nephropathy or alveolar haemorrhage. Necrosis of lymphocytes in the splenic follicles and lymph nodes are typical findings. Fibrin thrombi are present in small vessels of multiple organs, including kidney, brain, adrenals, heart, testes and lung. Erythrophagocytosis may be evident in the spleen.

The typical histopathological changes in the liver and/or spleen are often suggestive. Confirmation of the diagnosis by PCR is performed at the Animal Plant and Health Agency. Fresh or frozen liver (or spleen) is required by the laboratory.

Treatment

There is no specific treatment for affected rabbits. The majority of them will die quickly. Generalised supportive care (fluid therapy, syringe feeding, warmth etc.) is indicated for rabbits that survive but it must be borne in mind that these rabbits can be infectious to others. Barrier nursing is required.

Prevention

Vaccination with the bivalent vaccine (i.e. against RHDV and RHDV2) offers the best protection. If no vaccine against RHDV2 is available, the vaccine against RHDV is the only option available and may provide some protection. Vaccines against RHDV2 can be imported into the UK, although the supply route is uncertain. Vaccines are available that should protect rabbits against both variants of RHD but it will not protect rabbits against myxomatosis so separate vaccinations against both diseases will be needed. It is recommended that vaccines are given at least annually and earlier if the rabbit is deemed to be ‘at risk’ e.g. going to boarding kennels, hospitalisation at a vets or a show where there is increased contact with other rabbits. Early vaccination (4 weeks) is recommended for young rabbits with a second vaccination 4-6 weeks later. 

The source of outbreaks and the spread of RHVD2 in pet rabbits is unclear. It is possible that the infection is spread between rabbits at shows and introducing a new rabbit from a breeder into a pet shop or rescue centre can also introduce infection that can be spread further when the rabbit and its contacts are rehomed. It is believed that RHD was originally introduced into the British Isles from exhibition rabbits from Europe that came to rabbit shows in the UK (Westcott, personal communication). The British Rabbit Council are presently monitoring the situation and offer breeders advice about how to protect their stock. Definitive diagnosis of RHD and RHDV2 is a major problem in identifying the source of infection. A post-mortem examination is needed on all rabbits that die and further laboratory investigations are required and these can prove to be expensive.

Once an outbreak has taken place, it can be difficult to know what to do and there is insufficient information at the present time to offer proven advice. The carrier status of surviving rabbits is unknown and it is probably impossible to eliminate cross infection in an infected premises. Any surviving rabbIts have already been exposed by the time a death occurs. It seems sensible that rabbits are not taken to shows, sold or rehomed from establishments where rabbits have inexplicably died unless the person that is taking on the rabbits is informed and accepts the risk. Vaccination of surviving stock and a temporary halt in breeding programmes may be necessary for breeders to eliminate infection. Veterinary premises are another potential source of infection. They are where ill rabbits are brought for treatment. Careful disinfection and vigilance to prevent cross infection are needed alongside recommendations that rabbits should be vaccinated even if it is only with the vaccine that is easily available. Nobivac Myxo-RHD could offer some protection.

There is also a risk of spreading RHDV2 into pet rabbits from outbreaks in wild rabbits. Recently, there has been a resurgence in popularity in picking wild plants to feed to pet rabbits (foraging) but many owners now worry about introducing infection. Theoretically, wild plants could be a source of RHDV2 but this has not been demonstrated. There is also the possibility of introducing infection from other sources, such as flying insects or on footwear. Even hay could be a source of infection as it could be contaminated by urine, faeces or tissues of rabbits were hiding in the hay before they died of VHD. Foraging has so many health benefits that it seems wise to continue but with some consideration to the possibility of introducing disease. Wild rabbits tend to graze locally and keep the plants short. Selecting tall plants from areas where rabbits do not graze is a good option. 

It is also possible that exposure to lagoviruses from the wild rabbit population is advantageous for a healthy, vaccinated pet rabbit. The rabbit may develop a stronger immunity if it is challenged.  Not all lagoviruses are pathogenic so natural exposure could be protective. The situation is not clear and more information should come to light over the next few months or years.