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Rabbit haemorrhagic disease and its variants (Lagoviruses)

Page last updated August 20th 2017

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 that have been named (e.g. RHDV-K5,  RHDV1 and RHDVb). Non-pathogenic strains of the calicivirus (RCV or ‘rabbit calicivirus’) have also been discovered. Recently, a variant (RHDV2) has appeared that differs from the original strain (RHDV1).  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 of RHD

The virus that causes RHD is a calicivirus. Caliciviruses readily mutate. RHDV1 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. Several variants of RHD exist. 

RHDV1

RHDV1 is the original strain of RHD. Most of the information that is known about the virus that causes RHD relates to this strain. In the UK, this strain seems to have died out and been replaced by RHDV2.

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 analysed genetically 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.

RHDV-K5

RHDV-K5 is a variant of RHD that is more lethal than RHDV1 and appears to have less cross-immunity with non-pathogenic strains. It has been deliberately released in Australia to kill wild rabbits.  Vaccination against RHDV1 protects pet rabbits from this disease

Differences between RHDV1 and RHDV2

A feature of RHDV1 is that baby rabbits can have a natural immunity, which is not maternally derived.  Most rabbits under 4 weeks of age remain unaffected by RHDV1 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 and background infections with non-pathogenic strains of RHD could explain the decline in RHDV1 as the main cause of rabbit haemorrhagic disease. RHDV1 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.

Age immunity does not occur with RHDV2. Young and suckling rabbits may be affected. The variant can also affect hares. 

Transmission of RHD virus

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 dead rabbits can be a source of infection by spreading the virus via the faeces of scavengers, such as foxes or crows. Insects mechanically transmit the virus in viraemic blood from one animal to another. Fleas, blowflies and mosquitoes are known to spread the disease. Fly 'spots' (faeces) are infective and can contaminate pasture (Asgari et al, 1998). Cultivated vegetables may also be contaminated. Flies can travel long distances and be carried along by the wind and spread the disease far and wide. 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. It is believed that rabbits that have recovered from RHDV1 are potentially infectious to other rabbits for one month. It is not known how long the period is for RHDV2.

Vaccines against RHDV

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 not protective 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 are now available in the UK.  Filovac is the vaccine that is most commonly used in the UK. 

Clinical signs of 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 causing an acute necrotising hepatitis. 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 

Clinical signs of RHDV2

The clinical signs of RHDV2 are the same as RHDV1 although experimental infections suggest a lower mortality rate. Clinical signs develop after 3-9 days instead of 3-4 days with experimental RHDV infection (Le Call-Reculé, 2013). Subacute or chronic infections are more frequent so more rabbits can survive.  RHDV2 is more likely to cause a protracted disease with weight loss and jaundice. However, there is evidence that RHDV2 is becoming more virulent (Capucci et al, 2017).

Anecdotally, outbreaks in vaccinated pet rabbits show sporadic deaths, sometimes 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. 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. Apoptosis (extensive vacuolations, alterations in the mitochondrial structure, kryopyknosis and karoylysis) may be seen on electron microscopy. 

Confirmation of the diagnosis is made by PCR testing.  Although the clinical history and typical histopathological changes in the liver and/or spleen may be highly suggestive of RHDV infection, PCR testing confirms the diagnosis and determines the variant. Fresh or frozen liver is required by the laboratory. PCR testing on other samples, such as blood or faeces can give false negative results.

Frances Harcourt-Brown is currently running an investigation into sudden or unexpected death in rabbits and will pay for histopathology and, if hepatic necrosis is evident, PCR testing. Certain criteria apply.

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.

Current vaccination advice

Despite it's name, Nobivac Myxo-RHD is not protective against RHD. It only vaccinates rabbits against RHDV1, not RHDV2, which is the virus that is causing the current outbreak of RHD in the UK at the present time.

Vaccination with the bivalent vaccine (i.e. against RHDV and RHDV2) offers the best protection against RHD.  Vaccines have been developed to protect meat rabbits in other parts of Europe that are now available in UK.  Filavac is a brand that is licensed for use in the UK. Although it is available in multidose vials for vaccinating large numbers of rabbits, it is also available as single dose vials that are suitable for vaccinating individual pet rabbits

Filavac (and other RHDV2 vaccines) only offer protection against RHDV1 and RHDV2. They do not protect rabbits against myxomatosis so separate vaccinations against both diseases are be needed. At the moment, both Nobivac Myxo-RHD. It is recommended that both vaccines are given annually. 

Owners may voice concerns about over vaccinating against RHDV1. At the present time, there is no alternative if rabbits are to be protected against RHD and myxomatosis. There is no evidence that it is a problem

Early vaccination at 4 weeks of age is possible but the rabbits need to be revaccinated at 10 weeks and then 12 months later. 

Source of RHDV in outbreaks in domestic rabbits

It is believed that RHDV2 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 stockThe source of outbreaks and the spread of RHVD2 in pet rabbits are unclear. Infection may spread between rabbits at shows and introducing a new rabbit from a breeder into a pet shop or rescue centre can introduce infection that may be spread further when the rabbit and its contacts are rehomed.  Wild rabbits can act as a reservoir of infection so food, humans, insects and scavengers, such as foxes, may all be implicated in the spread of the disease. A survey is currently underway in order to gather and share information about RHDV outbreaks in somestic rabbits.

Lockdown

Once an outbreak has taken place in a place where there are rabbits, it can be difficult to know what to do. There is insufficient information at the present time to offer proven advice. Lockdown of infected premises is the most responsible way forward. 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. Ideally, no rabbits should go in or out of the premises and owners should take care not to spread infection. Separate clothing, especially footwear for dealing with the rabbits and going out is recommended. Footbaths containing disinfectants (Virkon 4%) may help. It is hard to know how long lockdown should continue. Four months from the date of the last death is recommended. Vaccination of surviving stock and a temporary halt in breeding programmes may be necessary for breeders to eliminate infection.

Veterinary premises

As with any disease, veterinary premises are a potential source of infection. They are where ill rabbits are brought for treatment and infected rabbits may be hospitalised. Ideally, all rabbits that are admitted for any type of treatment should be vaccinated against RHD, including RHDV2. Careful disinfection and vigilance to prevent cross infection are needed. 

Transmission from wild rabbits

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 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 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.