Bovine virus diarrhoea virus is related to border disease virus (BDV) in sheep and classical swine fever virus (CSFV) in pigs. The three viruses have been classified together as pestiviruses. CSFV infection is restricted to causing a serious acute haemorrhagic disease in pigs. The other two pestiviruses, the ruminant pestiviruses, infect cattle and sheep with a more subtle range of diseases. It is possible to infect artificially cattle with BDV and sheep with BVDV and produce disease in the foetus of both species. Under natural farming conditions BVD viruses from cattle are known to cause border disease in sheep; however BDV viruses from sheep have not yet been shown to cause natural disease in cattle.

As more and more BVD viruses from cattle have been analysed from around the world it has become apparent that two main groups can be identified. BVDV-1 viruses have a worldwide distribution including the UK. BVIDV-2 viruses mostly occur in North America where they have recently been associated with acute haemorrhagic disease outbreaks with high mortality rates.

BVDV is a small simple virus made up of 3 envelope proteins and an inner capsid protein surrounding a single strand of genetic material. The major envelope protein on the surface of the virus is the most variable protein and is the major target for neutralising antibody which confers protection following infection or vaccination. Another important property of BVD viruses is that they normally infect cells without killing them i.e. they are non-cytopathic. They do, however, grow quickly and spread easily to infect many cells. Only occasionally do BVD viruses arise that are cytopathic and kill cells.
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Acute BVD
Acute BVDV infections in calves frequently pass unnoticed. Mild clinical signs of depression, loss of appetite (anorexia) and diarrhoea may be apparent. There is raised temperature (pyrexia), lowered white blood cell counts (leukopaenia) and virus can be recovered from the blood (viraemia) and nasal secretions for 3 to 10 days after infection. Antibody to the virus is detectable by 3 weeks after infection and antibody levels peak one or two months later. Acute infections do occasionally result in severe disease and this seems more likely to occur when susceptible adult cattle are infected for the first time; milk drop (agalactia) and severe diarrhoea with fatalities up to 5% have been recorded. The acute haemorrhagic disease outbreaks with high mortality rates in calves associated with BVDV-2 have so far been restricted to North America.

Mixed BVD Infections
Mixed infections with BVDV and other viruses and bacteria are known to cause more severe disease than infections with single pathogens. Thus BVDV may exacerbate the complex syndromes of calf respiratory disease and neonatal diarrhoea. The immunosuppression following the transient leukopaenia is probably important in this process.

Foetal Infection
BVDV causes serious disease when it infects susceptible pregnant cattle. Infection first occurs in the nasal and oral mucosae. Viraemia follows within 3-4 days and the virus grows across the placenta to infect the foetus within 14 days. The effects on the foetus are very variable and depend on several factors, but the most important is the age of the foetus. The younger the foetus the more severe the infection.
Infection in the first trimester of gestation (0 to 110 days) can result in foetal deaths with subsequent resorption, abortion at any stage of pregnancy, mummification or stillbirth of the foetus. Foetuses that survive to full term may show congenital defects but many appear normal at birth. Surviving foetuses are always persistently infected (P1) with the virus and will remain so for the rest of their lives. They persistently excrete virus and are a constant source of infection. Their failure to produce detectable neutralising antibody suggests they are immunotolerant to the virus.
Infection in the second trimester (111-190 days) may result in any of the consequences of earlier infection but congenital defects such as cataracts and brain abnormalities are more likely at this stage of gestation. The immune system of the foetus starts to develop around 140 days of gestation after which foetuses surviving to term are born with neutralising antibody and are free of virus.
Infection in the third trimester usually results in the birth of a live calf with neutralising antibody and no virus.

Any bovine shown to have a generalised persistent infection with BVDV can only have acquired that infection in the first half of its foetal life.
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It is the birth of PI calves which is most important for the spread of BVDV. Such calves may die in the neonatal period or be recognised as 'poor-doers' early in life. However, many survive as immunotolerant excretors of virus for several years. If they reach sexual maturity they tend to have reduced fertility but PI cows will produce further PI calves.
At any age, but most commonly between 6 and 24 months of age, PI cattle can die from mucosal disease, a severe enteric disease characterised by erosive lesions in the oral/intestinal musoca. Mucosal disease can be acute with rapid death, or chronic lasting for several months. In chronic cases foot lesions causing lameness and skin thickening may occur. The non-cytopathic BVDV causing the persistent infection can still be recovered from animals dying of mucosal disease. In addition, a cytopathic BVDV very closely similar to the non-cytopathic virus can also be recovered. Comparisions of these 'pairs' of viruses recovered from mucosal disease cases has provided fascinating evidence of how the PI virus can change and cause sufficient cell death to kill its host. Because mucosal disease is the most dramatic manifestation of BVDV infection it may be the first indication that the virus is in the herd. However, it should be remembered that the events leading to the case started with infection of the dam, and will have occurred more than a year before.
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BVDV is one of the most widespread and successful animal viruses in the world. Virtually all cattle populations are infected, with antibody prevalence rates among adults exceeding 60%. The virus is too unstable to survive for long in the environment and its successful transmission is due to spread by PI cattle. Most body excretions and secretions contain infectious virus with nasal discharges and saliva being the most potent source. Thus, any husbandry system which increases nose to nose contact will hasten the spread of virus from P1 to susceptible animals. Intensive housing with trough feeding will ensure rapid virus spread in groups containing PI animals, whereas spread will be slower among cattle at grass.
Artifical breeding programmes aimed at synchronising the reproductive cycles of a large number of susceptible cattle have the potential for resulting in major outbreaks of BVDV disease. Persistently infected bulls excrete large amounts of infectious virus in semen and must be rigorously excluded from all breeding programmes. Donors, recipients and all fluids used in embryo transfer must be rigorously screened and shown to be free of BVDV. Similar vigilance is also needed during the exploitation of in vitro fertilisation.
Given levels of up to one million infectious virus particles per millilitre of blood in P1 cattle the potential exists for infection to be carried from such animals to others by needles or other contaminated veterinary instruments.
Virus levels in nasal secretions are also high and bull nose holders have been shown to be capable of spreading infection.
There are other potential but less likely sources of pestivirus infections of cattle. Infections of cattle from sheep or free living deer are possible, and in other countries BVD contaminated modified live virus vaccines have caused serious outbreaks of disease.
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The clinical diagnosis of the range of diseases caused by BVDV often requires confirmatory laboratory testing. The laboratory diagnosis of BVDV infection relies on the detection of the virus or viral components and/or the demonstration of an antibody response to the virus. Given the importance of viraemic PI cattle in the spread of infection, techniques which identify such animals from a single unclotted blood sample are of prime importance. The standard methods for assessing the BVD status of an individual animal are two separate enzyme linked immunosorbent assays (ELISA). One measures antibody levels in the plasma/serum and the other tests for the presence of viral antigen in the white blood cells. At birth PI calves have easily demonstrable virus in their blood. Once they have sucked, however, the high levels of antibody against BVDV in the dam's colostrum masks the virus. The virus may not be detectable for the next 4 months, making diagnosis difficult for this period.
In an infected herd many animals will be antibody positive and virus negative showing that they have suffered an acute infection and are now immune. Some will be antibody negative and virus negative showing they have not yet met the virus. Occasional animals will be antibody negative and virus positive. Such animals are most likely to be PI virus spreaders but to be sure they should be bled twice at least 3 weeks apart. True PI animals will be antibody negative and virus positive at both bleeds. Any animal undergoing an acute infection at the time of the first infection will be. antibody positive, virus negative at this second bleed.
Other methods used to detect virus are virus isolation from blood, nasal secretions and tissues and the immunoperoxidase (WX) test to measure live virus in serum or plasma. The nucleic acid of the virus can be detected by the reverse transcriptase polymerase chain reaction (RT-PCR); the test has been used to detect virus in bulk milk, pooled blood samples and in foetal tissues but needs further development to be robust enough for routine use.
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	33% naïve	Antibody negative Virus negative
	65% immune	Antibody positive Virus negative
	1% acutely infected	Antibody negative Virus positive
	1% persistently infected	Antibody negative Virus positive

 
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All breeding stock about to be purchased must be blood tested and proved not to be P1 virus carriers. This is now a standard requirement for international trade and should be adopted at the national and local level. Mandatory testing before bulls can enter artificial insemination centres has been practised for several years and sellers of high quality breeding stock are being urged to have their animals tested before sale. The introduction of some form of certification of breeding cattle to the effect that they are free of BVDV viraemia is inevitable.
The best way to prevent the introduction of BVDV into a herd is to use homebred replacement females and blood test all males before purchase, or in quarantine after arrival on the farm. When female breeding cattle have to be bought they must be blood tested, but beware of buying in pregnant females; antibody positive, virus negative dams may be carrying a P1 calf. Breeding stock can also be sourced directly from herds that are accredited free of BVD and certified as such through the Cattle Health Certification Standards.
All aspects of biosecurity on the farm need to be reviewed if BVDV is to be successfully excluded. Double fencing is essential to prevent nose to nose contact with neighbouring cattle.
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Any control of BVDV has 2 essential requirements:

• the identification of PI virus carrier cattle and
• the prevention of infection of susceptible pregnant dams especially during the first half of pregnancy

The requirement to control BVDV varies markedly from farm to farm. Cattle farmers with a high throughput of bought animals must expect trouble from BVDV. Losses can be reduced by never introducing new stock to pregnant animals and by mixing young stock thoroughly before they reach breeding age. This increases the chances of exposing stock to a PI virus excretor ensuring protective immunity before they become pregnant. Vaccination is likely to be useful on such farms. There are two vaccines currently available in the UK. Both are killed vaccines containing a single strain of BVDV-1. They are licensed to immunise cows and heifers to protect the foetus against transplacental infection with BVDV. It is recommended that 2 doses be given to females shortly before mating with an annual booster thereafter.
Among closed cattle herds, many have a high rate of BVDV antibody positive, immune animals without experiencing any apparent associated disease. Bulk milk samples and/or individual blood samples tested for antibody provide an indication of the level of exposure Within the herd. The antibody status of six animals from a group that have been reared together provide a good indication of the level of exposure within the whole group.
Any on-farm disease control programme requires considerable thought and will take a substantial commitment to achieve results. Given the current level of understanding of BVDV, the reliability of the diagnostic tests and the availability of vaccines BVDV can be controlled and eradicated. It is, however, a very successful widespread virus so any control programme should be clearly defined, realistic, constantly reviewed and sustainable.
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It is essential that BVDV-2 viruses are not imported into this country. Not only are some of them more virulent but currently available vaccines may not provide adequate protection against them. Constant surveillance of circulating viruses is essential to recognise any newly imported viruses. Diagnostic tests will continue to be developed. It is likely that the very sensitive RT-PCR will be used increasingly on pooled blood samples to detect PI cattle.

Current vaccines produce antibody in vaccinated animals that cannot be distinguished from antibody in cattle that have had a natural infection. 'Marker' vaccines are therefore being developed ' which will enable the antibody produced by the vaccinated animals to be distinguished from that produced following a natural infection.
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