Changes

There are two antigenically distinct<ref name="nine">Paton, D J et al (1995) '''A proposed division of the pestivirus genus using monoclonal antibodies, supported by cross-neutralisation assays and genetic sequencing.''' ''Veterinary Research'', 26, 82-109.</ref> genotypes of BVDV, type 1 and type 2, which are most accurately characterised based on sequence variation.  BVDV-1 and BVDV-2 contain 11 and 3 subtypes respectively, which have been demonstrated by analysis of the 5’UTR<ref name="ten">Vilcek, S et al (2001) '''Bovine viral diarrhoea virus genotype 1 can be separated into at least eleven groups.''' ''Archives of Virology'', 146, 99-115. </ref>. Despite the large antigenic differences between the genotypes, some cross-protection against type 2 viruses is afforded by type 1 vaccines<ref name="eleven">Carman, S et al (1998) '''Severe acute bovine viral diarrhea in Ontario, 1993-1995.''' ''Journal of Veterinary Diagnostic Investigation'', 10, 27-35. </ref><ref name="twelve">Cortese, V S et al (1998) '''Clinical and immunologic responses of vaccinated and unvaccinated calves to infection with a virulent type-II isolate of bovine viral diarrhea virus.''' ''Journal of the American Veterinary Medical Association'', 213, 1312-1319. </ref><ref name="thirteen">Van Oirschot, J T et al (1999) '''Vaccination of cattle against bovine viral diarrhoea.''' ''Veterinary Microbiology'', 64, 169-183.</ref>.

There are two antigenically distinct<ref name="nine">Paton, D J et al (1995) '''A proposed division of the pestivirus genus using monoclonal antibodies, supported by cross-neutralisation assays and genetic sequencing.''' ''Veterinary Research'', 26, 82-109.</ref> genotypes of BVDV, type 1 and type 2, which are most accurately characterised based on sequence variation.  BVDV-1 and BVDV-2 contain 11 and 3 subtypes respectively, which have been demonstrated by analysis of the 5’UTR<ref name="ten">Vilcek, S et al (2001) '''Bovine viral diarrhoea virus genotype 1 can be separated into at least eleven groups.''' ''Archives of Virology'', 146, 99-115. </ref>. Despite the large antigenic differences between the genotypes, some cross-protection against type 2 viruses is afforded by type 1 vaccines<ref name="eleven">Carman, S et al (1998) '''Severe acute bovine viral diarrhea in Ontario, 1993-1995.''' ''Journal of Veterinary Diagnostic Investigation'', 10, 27-35. </ref><ref name="twelve">Cortese, V S et al (1998) '''Clinical and immunologic responses of vaccinated and unvaccinated calves to infection with a virulent type-II isolate of bovine viral diarrhea virus.''' ''Journal of the American Veterinary Medical Association'', 213, 1312-1319. </ref><ref name="thirteen">Van Oirschot, J T et al (1999) '''Vaccination of cattle against bovine viral diarrhoea.''' ''Veterinary Microbiology'', 64, 169-183.</ref>.

In general, the genotypes do not differ in virulence. It was, at one time, considered that BVDV-1 species which are found worldwide caused milder disease ¹⁴, whereas BVDV-2 isolates typically caused more severe disease which is often haemorrhagic and was associated with a high mortality rate^{11, 15}. This is no longer the case. The relationship between genotype and virulence is, however, not fixed: some type 2 strains cause mild or subclinical disease¹⁶, and the spectrum disease caused by type 1 viruses is broad. Type 2 viruses were first reported in Canada and the USA and have a more limited distribution than type 1 isolates.  

In general, the genotypes do not differ in virulence. It was, at one time, considered that BVDV-1 species which are found worldwide caused milder disease <ref name="fourteen">Deregt, D et al (2004) '''Attenuation of a virulent type 2 bovine viral diarrhea virus.''' ''Veterinary Microbiology'', 100, 151-161.</ref>, whereas BVDV-2 isolates typically caused more severe disease which is often haemorrhagic and was associated with a high mortality rate<ref name="eleven"/><ref name="fifteen">Corapi, W et al (1989) '''Severe Thrombocytopenia in Young Calves Experimentally Infected with Noncytopathic Bovine Viral Diarrhea Virus.''' ''Journal of Virology'', 63(9), 3934-3943. </ref>. This is no longer the case. The relationship between genotype and virulence is, however, not fixed: some type 2 strains cause mild or subclinical disease<ref name="sixteen">Ahn, B C et al (2005) '''Biotype, Genotype, and Clinical Presentation Associated With Bovine Viral Diarrhea Virus (BVDV) Isolates From Cattle.''' ''International Journal of Applied Research in Veterinary Medicine'', 3(4), 319-325.</ref>, and the spectrum disease caused by type 1 viruses is broad. Type 2 viruses were first reported in Canada and the USA and have a more limited distribution than type 1 isolates.  

===Virus Biotypes===

===Virus Biotypes===

BVDV isolates from either genotype can be of a cytopathic or non-cytopathic biotype. Non-cytopathic (ncp) viruses produce no visible effects in cell culture, whereas infection with cytopathic (cp) viruses gives cell vacuolation and death. Although non-cytopathic isolates are responsible for the majority of BVDV infections worldwide, cytopathogenicity gives no indication of disease-causing potential. Cytopathic biotypes of bovine viral diarrhoea virus are always isolated alongside non-cytopathic strains, and are found in cases of mucosal disease, a fatal BVD-associated condition⁴⁶.

BVDV isolates from either genotype can be of a cytopathic or non-cytopathic biotype. Non-cytopathic (ncp) viruses produce no visible effects in cell culture, whereas infection with cytopathic (cp) viruses gives cell vacuolation and death. Although non-cytopathic isolates are responsible for the majority of BVDV infections worldwide, cytopathogenicity gives no indication of disease-causing potential. Cytopathic biotypes of bovine viral diarrhoea virus are always isolated alongside non-cytopathic strains, and are found in cases of mucosal disease, a fatal BVD-associated condition<ref name="seventeen">Brownlie, J., Clarke, M. & Howard, C. (1984) '''Experimental production of fatal mucosal disease in cattle''' ''Veterinary Record'', 114, 535-536</ref>.

Cytopathic viruses originate from non-cytopathic strains by mutation, including viral gene rearrangements, duplications and deletions¹⁷, and insertions of cellular origin, such as ubiquitin sequences. Point mutations in the NS2 region and various RNA recombination events are also important¹⁸. Serologically, the two BVDV biotypes are indistinguishable, but on a molecular level cytopathic viruses produce an additional protein, NS3, not found in cells infected with non-cytopathic virus^{19, 20, 21}. This marker molecule arises from when NS2-3, expressed in non-cytopathic isolates, is cleaved at a site created by the mutations above²².

Cytopathic viruses originate from non-cytopathic strains by mutation, including viral gene rearrangements, duplications and deletions<ref name="eighteen">Deregt, D and Loewen, K G (1995) '''Bovine viral diarrhea virus: Biotypes and disease.''' ''Canadian Veterinary Journal'', 36, 371-378.</ref>, and insertions of cellular origin, such as ubiquitin sequences. Point mutations in the NS2 region and various RNA recombination events are also important<ref name="nineteen">Donis, R O and Dubovi, E J (1987) '''Differences in virus-induced polypeptides in cells infected by cytopathic and noncytopathic biotypes of bovine virus diarrhea-mucosal disease virus.''' ''Virology'', 158, 168-173.</ref>. Serologically, the two BVDV biotypes are indistinguishable, but on a molecular level cytopathic viruses produce an additional protein, NS3, not found in cells infected with non-cytopathic virus<ref name="twenty">Pocock, D H et al (1987) '''Variation in the intracellular polypeptide profiles from different isolates of bovine viral diarrhea virus.''' ''Archives of Virology'', 94, 43-53.</ref><ref name="twone">Magar, R et al (1988) '''Bovine viral diarrhea virus proteins: heterogeneity of cytopathogenic and noncytopathogenic strains and evidence of a 53K glycoprotein neutralization epitope.''' ''Veterinary Microbiology'', 16, 303-314.</ref><ref name="twtwo">Tautz, N et a; (1999) '''Establishment and Characterization of Cytopathogenic and Noncytopathogenic Pestivirus Replicons.''' ''Journal of Virology'', 73(11), 9422–9432.</ref>. This marker molecule arises from when NS2-3, expressed in non-cytopathic isolates, is cleaved at a site created by the mutations above<ref name="twthree">Meyers, G and Thiel, H J (1996) '''Molecular characterization of pestiviruses.''' ''Advances in Virus Research'', 47, 53-118.</ref>.

==Transmission and Epidemiology==

==Transmission and Epidemiology==

In most countries, BVDV is endemic and studies detecting antibody have estimated that between 70 and 100% of herds are either currently infected or have previously been infected with bovine viral diarrhoea virus²³.

In most countries, BVDV is endemic and studies detecting antibody have estimated that between 70 and 100% of herds are either currently infected or have previously been infected with bovine viral diarrhoea virus<ref name="twfour">Houe, H (1999) '''Epidemiological features and economical importance of bovine virus diarrhoea virus (BVDV) infections.''' ''Veterinary Microbiology'', 64, 89-107.</ref>.

BVDV can be transmitted from infected to susceptible cattle in several ways. Firstly, direct contact with an animal shedding BVDV in its secretions and excretions can cause disease. Virus is shed by both acutely and persistently infected (PI) animals but levels of shedding are much higher in persistently infected cattle, which are the natural reservoir for virus. It is estimated that the incidence of persistently infected animals is 1-2% of cattle less than one year of age and may be higher in infected herds. On a farm, PI cattle are often found in cohorts of similarly aged animals. This is because persistent infections arise when pregnant animals are acutely infected in early pregnancy, and so an outbreak of acute, possibly subclinical, BVD in pregnant cattle can later result in a "batch" of PI calves.

BVDV can be transmitted from infected to susceptible cattle in several ways. Firstly, direct contact with an animal shedding BVDV in its secretions and excretions can cause disease. Virus is shed by both acutely and persistently infected (PI) animals but levels of shedding are much higher in persistently infected cattle, which are the natural reservoir for virus. It is estimated that the incidence of persistently infected animals is 1-2% of cattle less than one year of age and may be higher in infected herds. On a farm, PI cattle are often found in cohorts of similarly aged animals. This is because persistent infections arise when pregnant animals are acutely infected in early pregnancy, and so an outbreak of acute, possibly subclinical, BVD in pregnant cattle can later result in a "batch" of PI calves.

Transmission to heifers and cows may also occur venereally, via artificial insemination or during embryo transfer, as acutely and persistently infected bulls shed bovine viral diarrhoea virus in their semen²⁴. The testes is an immunoprivileged site, and the virus can persist in this location despite otherwise systemic clearance²⁵. Indirect spread is possible: BVDV has been shown to spread through the re-use of needles, nose tongs²⁶ and rectal gloves²⁷, and blood feeding flies also give transmission.

Transmission to heifers and cows may also occur venereally, via artificial insemination or during embryo transfer, as acutely and persistently infected bulls shed bovine viral diarrhoea virus in their semen<ref name="twfive">Kirkland, P D et al (1991) '''Replication of bovine viral diarrhoea virus in the bovine reproductive tract and excretion of virus in semen during acute and chronic infections.''' ''Veterinary Record'', 128, 587–590.</ref>. The testes is an immunoprivileged site, and the virus can persist in this location despite otherwise systemic clearance<ref name="twsix">Gunn, H M (1993) '''Role of fomites and flies in the transmission of bovine viral diarrhoea virus.''' ''Veterinary Record'', 132, 584-585.</ref>. Indirect spread is possible: BVDV has been shown to spread through the re-use of needles, nose tongs<ref name="twseven">Lang-Ree, J R et al (1994) '''Transmission of bovine viral diarrhoea virus by rectal examination.''' ''Veterinary Record'', 135, 412-413.</ref> and rectal gloves<ref name="tweight">Tarry, D W et al (1991) '''Transmission of bovine virus diarrhoea virus by blood feeding flies.''' ''Veterinary Record'', 128(4), 82-84.</ref>, and blood feeding flies also give transmission.

==Pathogenesis==

==Pathogenesis==

Following entry and contact with the mucosa of the oral or nasal cavities or the reproductive tract, BVDV replicates in epithelial cells and has a predilection for the palatine tonsil and the nasal mucosa. From here, the virus spreads to regional lymph nodes before a viraemia becomes established. Virus can be disseminated free in the blood, or associated with leukocytes, particularly lymphocytes and monocytes²⁸. Bovine viral diarrhoea virus can then gain access to many tissues, but shows a preference for lymphoid tissue, reaching its highest concentrations in the tonsil, thymus and ileum. Bone marrow²⁹ and intestinal mucosa are often infected, and the lymphoid tissue of the Peyer's patches is frequently depleted. However, there is variation between strains as to which tissues are specifically infected and in general, a wider distribution is associated with higher virulence.

Following entry and contact with the mucosa of the oral or nasal cavities or the reproductive tract, BVDV replicates in epithelial cells and has a predilection for the palatine tonsil and the nasal mucosa. From here, the virus spreads to regional lymph nodes before a viraemia becomes established. Virus can be disseminated free in the blood, or associated with leukocytes, particularly lymphocytes and monocytes<ref name="twnine">Bruschke, C J M et al (1998) '''Distribution of bovine virus diarrhoea virus in tissues and white blood cells of cattle during acute infection.''' ''Veterinary Microbiology'', 64, 23-32.</ref>. Bovine viral diarrhoea virus can then gain access to many tissues, but shows a preference for lymphoid tissue, reaching its highest concentrations in the tonsil, thymus and ileum. Bone marrow<ref name="thirty">Spagnuolo, M et al (1997) '''Bovine Viral Diarrhoea Virus Infection in Bone Marrow of Experimentally Infected Calves.''' ''Journal of Comparative Pathology'', 116, 97-100.</ref> and intestinal mucosa are often infected, and the lymphoid tissue of the Peyer's patches is frequently depleted. However, there is variation between strains as to which tissues are specifically infected and in general, a wider distribution is associated with higher virulence.

==Diagnosis==

==Diagnosis==

===Clinical Signs===

===Clinical Signs===

It might be expected from the nomenclature (bovine viral diarrhoea virus) that diarrhoea is a key clinical feature in BVDV infection, but it is not a major clinical sign. The clinical presentation can actually manifest in a variety of ways ranging from subclinical disease to the fatal muscosal disease³⁴. Virulence factors related to genotype and strain are partially responsible for these variations, but host factors are also important. Pregnancy status, stage of gestation, immunity and the level of development of the foetal immune system all contribute to the outcome of BVDV infection.

It might be expected from the nomenclature (bovine viral diarrhoea virus) that diarrhoea is a key clinical feature in BVDV infection, but it is not a major clinical sign. The clinical presentation can actually manifest in a variety of ways ranging from subclinical disease to the fatal muscosal disease<ref name="thone">Brownlie, J (1985) '''Clinical aspects of the bovine virus diarrhoea/ mucosal disease complex in cattle.''' ''In Practice'', 7(6), 195-202.</ref>. Virulence factors related to genotype and strain are partially responsible for these variations, but host factors are also important. Pregnancy status, stage of gestation, immunity and the level of development of the foetal immune system all contribute to the outcome of BVDV infection.

====Acute Infections: Non-Pregnant Cattle====

====Acute Infections: Non-Pregnant Cattle====

In the naive, non-pregnant, immunocompetent animal, BVD is normally mild: it is estimated that 70 to 90% of BVDV infections cause no obvious clinical signs³⁰. If these subclinically affected cattle are observed closely, body temperature may marginally rise and mild leukopenia and agalactia may be seen ^{31, 32}. When clinical disease does occur in these animals, morbidity is high amongst cattle of 6-12 months of age. Following a 5-7 day incubation period, pyrexia and leukopenia is seen. Viraemia arises on days 4-5 days post-infection, and continues until around day 15³³. Although some cattle suffer diarrhoea in BVDV infection, the disease no longer seems to present as herd outbreaks of diarrhoea³⁴. Clinical signs more commonly include depression, anorexia, occulo-nasal discharge, decreased milk production and oral lesions³⁵, with a rapid respiratory rate resembling pneumonia sometimes apparent³¹. Acutely infected, non-pregnant animals shed low concentrations of virus compared to persistently infected cattle³³, and antibodies are produced 2-4 weeks post-infection which persist for many years³⁵.

In the naive, non-pregnant, immunocompetent animal, BVD is normally mild: it is estimated that 70 to 90% of BVDV infections cause no obvious clinical signs<ref name="thtwo">Ames, T R (1986) '''The causative agent of BVD: Its epidemiology and pathogenesis.''' ''Veterinarni Medicina'', 81, 848-869.</ref>. If these subclinically affected cattle are observed closely, body temperature may marginally rise and mild leukopenia and agalactia may be seen <ref name="ththree">Perdrizet, J A et al (1987) '''Bovine virus diarrhea – clinical syndromes in dairy herds.''' ''Cornell Veterinarian'', 77, 46-74.</ref><ref name="thfour">Moerman, A et al(1994) '''Clinical consequences of a bovine virus diarrhoea in a dairy herd: A longitudinal study.''' ''Veterinary Quarterly'', 16, 115-119.</ref>. When clinical disease does occur in these animals, morbidity is high amongst cattle of 6-12 months of age. Following a 5-7 day incubation period, pyrexia and leukopenia is seen. Viraemia arises on days 4-5 days post-infection, and continues until around day 15<ref name="thfive">Duffell, S J and Harkness, J W (1985) '''Bovine virus diarrhoea-mucosal disease infection in cattle.''' ''Veterinary Record'', 117, 240-245.</ref>. Although some cattle suffer diarrhoea in BVDV infection, the disease no longer seems to present as herd outbreaks of diarrhoea<ref name="thone"/>. Clinical signs more commonly include depression, anorexia, occulo-nasal discharge, decreased milk production and oral lesions<ref name="thsix">Baker, J (1995) '''The Clinical Manifestations of Bovine Viral Diarrhea Infection.''' ''The Veterinary Clinics of North America: Food Animal Practice'', 11(3), 425-445.</ref>, with a rapid respiratory rate resembling pneumonia sometimes apparent<ref name="ththree"/>. Acutely infected, non-pregnant animals shed low concentrations of virus compared to persistently infected cattle<ref name="thfive"/>, and antibodies are produced 2-4 weeks post-infection which persist for many years<ref name="thsix"/>.

Acute BVDV infection causes a significant leukopenia, hampering the host's defences against invading pathogens. This BVDV-associated immunosupression has a particularly important role in bovine respiratory disease: an association has been demonstrated between BVDV antibody titre and treatment for respiratory disease³⁶. BVDV is the virus most frequently isolated from pneumonic lungs and is often found in association with ''[[Pasteurella haemolytica]]''³⁵, causing severe fibrino-purulent bronchopneumonia and increasing the total lesion area by 35-60% compared to pasteurellosis alone³⁴. Synergism is also displayed with [[Bovine Parainfluenza - 3|parainfluenza]], bovine rhinotracheitis and [[Bovine Respiratory Syncytial Virus|respiratory syncitial viruses]].

Acute BVDV infection causes a significant leukopenia, hampering the host's defences against invading pathogens. This BVDV-associated immunosupression has a particularly important role in bovine respiratory disease: an association has been demonstrated between BVDV antibody titre and treatment for respiratory disease<ref name="thseven">Martin, S W and Bohac, J G (1986) '''The association between serologic titers in infectious bovine rhinotracheitis virus, bovine virus diarrhea virus, parainfluenza-3 virus, respiratory syncitial virus and the treatment for respiratory disease in Ontario feeder calves.''' ''Canadian Journal of Veterinary Research'', 50, 351-358.</ref>. BVDV is the virus most frequently isolated from pneumonic lungs and is often found in association with ''[[Pasteurella haemolytica]]''<ref name="thsix"/>, causing severe fibrino-purulent bronchopneumonia and increasing the total lesion area by 35-60% compared to pasteurellosis alone<ref name="thone"/>. Synergism is also displayed with [[Bovine Parainfluenza - 3|parainfluenza]], bovine rhinotracheitis and [[Bovine Respiratory Syncytial Virus|respiratory syncitial viruses]].

BVDV infections in naive, non-pregnant animals are usually mild; however outbreaks of a severe form of BVD became evident in the late 1980s in the USA and Canada^{11, 37}. These were characterised by the acute onset of diarrhoea, pyrexia and milk drop, with some cases proving fatal. These oubtreaks were associated with genotype 2 viruses, and it transpired vaccination with type 1 vaccines had afforded poor cross-protection in these instances due to non-compliance with instructions. Initially, BVDV-2 infection was seen less frequently than disease related to type 1 virus, but was associated with a haemorrhagic syndrome. The haemorrhagic syndrome is characterised by severe thrombocytopaenia leading to haematochezia, petechiation and epistaxis³⁸ and has now been described in both Europe and North America. Severe disease is also possible with virulent type 1 infection, presenting as high fever, oral ulcerations, eruptive lesions of the coronary band and interdigital cleft, diarrhoea, dehydration, leukopenia, and thrombocytopenia. Thrombocytopenia may give petechiation of  the conjunctiva, sclera, nictitating membrane and the mucosal surfaces of the mouth and vulva, as well as prolonged bleeding from injection sites³⁹.

BVDV infections in naive, non-pregnant animals are usually mild; however outbreaks of a severe form of BVD became evident in the late 1980s in the USA and Canada<ref name="eleven"/><ref name="theight">Hibberd, R C, Turkington, A & Brownlie, J.(1993) '''Fatal bovine viral diarrhoea virus infection of adult cattle.''' ''Veterinary Record'', 132, 227-228.</ref>. These were characterised by the acute onset of diarrhoea, pyrexia and milk drop, with some cases proving fatal. These oubtreaks were associated with genotype 2 viruses, and it transpired vaccination with type 1 vaccines had afforded poor cross-protection in these instances due to non-compliance with instructions. Initially, BVDV-2 infection was seen less frequently than disease related to type 1 virus, but was associated with a haemorrhagic syndrome. The haemorrhagic syndrome is characterised by severe thrombocytopaenia leading to haematochezia, petechiation and epistaxis<ref name="thnine">Rebhun, W C et al (1989) '''Thrombocytopenia associated with bovine viral diarrhoea infection in cattle.''' ''Journal of Veterinary Internal Medicine'', 3, 42-46.</ref> and has now been described in both Europe and North America. Severe disease is also possible with virulent type 1 infection, presenting as high fever, oral ulcerations, eruptive lesions of the coronary band and interdigital cleft, diarrhoea, dehydration, leukopenia, and thrombocytopenia. Thrombocytopenia may give petechiation of  the conjunctiva, sclera, nictitating membrane and the mucosal surfaces of the mouth and vulva, as well as prolonged bleeding from injection sites<ref name="forty">Merck & Co (2008) '''The Merck Veterinary Manual (Eighth Edition)''', ''Merial''.</ref>.

====Acute Infections: Pregnant Animals====

====Acute Infections: Pregnant Animals====

When acute BVDV infection occurs during pregnancy, the dam may show any of the clinical manifestations that are seen in non-pregnant animals. BVDV is able to cross the placenta and infect the developing foetus and so there may be additional outcomes of infection that depend on the stage of gestation. If infection becomes established at the time of insemination, conception rates may be reduced, and early embryonic death is increased when the virus is introduced at a slightly later stage<Sup>40, 41</sup>.  '''Foetal infection in the first trimester (50-100 days)''' may also result in '''death''', although expulsion of the foetus often does not occur until several months later. An additional effect of foetal infection before 120 days gestation is the birth of '''persistently infected (PI) calves'''.

When acute BVDV infection occurs during pregnancy, the dam may show any of the clinical manifestations that are seen in non-pregnant animals. BVDV is able to cross the placenta and infect the developing foetus and so there may be additional outcomes of infection that depend on the stage of gestation. If infection becomes established at the time of insemination, conception rates may be reduced, and early embryonic death is increased when the virus is introduced at a slightly later stage<ref name="foone">Carlsson, U et al (1989) '''Bovine virus diarrhoea virus: A cause of early pregnancy failure in the cow.''' ''Journal of Veterinary Medicine'', 36, 15-23.</ref><ref name="fotwo">Mc Gowan, M R et al (1993) '''Increased reproductive losses in cattle infected with bovine pestivirus aroung the time of insemination'''  ''Veterinary Record'', 133, 39-43.</ref>.  '''Foetal infection in the first trimester (50-100 days)''' may also result in '''death''', although expulsion of the foetus often does not occur until several months later. An additional effect of foetal infection before 120 days gestation is the birth of '''persistently infected (PI) calves'''.

'''Congenital defects''' can arise from transplacental infection '''between days 100 and 150'''. This is caused by an inappropriate inflammatory response mounted to BVDV by the immune system, which is undergoing the final phase of development at this stage³³. Examples of common congenital abnormalities include defects of the thymus, ocular changes and cerebellar hypoplasia³⁴. Calves with cerebellar hypoplasia ataxic, reluctant to stand and may suffer tremors³⁵, and ocular pathology often causes blindness and cataracts. Localisation of virus to the vascular endothelium gives vasculitis, leading to oedema, hypoxia and cellular degeneration. Weak, stunted calves may also be produced by BVDV infection in the second trimester.

'''Congenital defects''' can arise from transplacental infection '''between days 100 and 150'''. This is caused by an inappropriate inflammatory response mounted to BVDV by the immune system, which is undergoing the final phase of development at this stage<ref name="thfive"/>. Examples of common congenital abnormalities include defects of the thymus, ocular changes and cerebellar hypoplasia<ref name="thone"/>. Calves with cerebellar hypoplasia ataxic, reluctant to stand and may suffer tremors<ref name="thsix"/>, and ocular pathology often causes blindness and cataracts. Localisation of virus to the vascular endothelium gives vasculitis, leading to oedema, hypoxia and cellular degeneration. Weak, stunted calves may also be produced by BVDV infection in the second trimester.

Infection in the '''third trimester trimester (over 180-200 days)''' elicits a response from the fully-developed immune system, giving rise to '''normal but seropositive calves'''.

Infection in the '''third trimester trimester (over 180-200 days)''' elicits a response from the fully-developed immune system, giving rise to '''normal but seropositive calves'''.

====Persistent Infections====

====Persistent Infections====

Foetal infection with a non-cytopathic BVDV virus before 120 days gestation may result in the birth of calves persistently infected with and tolerant to bovine viral diarrhoea virus. At this stage in gestation, the immune system is partially competent and recognises the BVDV antigen as self, meaning that no response is mounted. The calf therefore becomes tolerant to the virus which persists into neonatal life⁴⁶. Persistently infected animals can be identified at birth as being antigen-positive but seronegative. However, colostral transfer of maternal immunity or infection with a heterologous strain of BVDV can make these animals seropostitive, so care must be taken when timing and interpreting tests⁴².

Foetal infection with a non-cytopathic BVDV virus before 120 days gestation may result in the birth of calves persistently infected with and tolerant to bovine viral diarrhoea virus. At this stage in gestation, the immune system is partially competent and recognises the BVDV antigen as self, meaning that no response is mounted. The calf therefore becomes tolerant to the virus which persists into neonatal life<ref name="seventeen"/>. Persistently infected animals can be identified at birth as being antigen-positive but seronegative. However, colostral transfer of maternal immunity or infection with a heterologous strain of BVDV can make these animals seropostitive, so care must be taken when timing and interpreting tests.<ref name="fothree">Bolin, S R et al (1985) '''Response of cattle persistently infected with noncytoparthic bovine viral diarrhea virus to vaccination for bovine viral diarrhea and subsequent challenge exposure who cytopathic bovine viral diarrhea virus.''' ''American Journal of Veterinary Research'', 46, 2467-2470.</ref>

Persistently infected animals continuously shed large amounts of virus throughout their lives, providing a major source of infection for naive cattle²³. Persistently infected dams produce persistently infected calves, resulting in family lines capable of maintaining the virus in a herd³⁵. It is estimated that 1-2% of the cattle population and up to 13% of foetal calves are persistently infected³⁴.

Persistently infected animals continuously shed large amounts of virus throughout their lives, providing a major source of infection for naive cattle<ref name="twfour"/>. Persistently infected dams produce persistently infected calves, resulting in family lines capable of maintaining the virus in a herd<ref name="thsix"/>. It is estimated that 1-2% of the cattle population and up to 13% of foetal calves are persistently infected<ref name="thone"/>.

50% of persistently infected cattle die within the first year of life<Sup>33</sup>. Animals may be undersized and slow-growing, and are predisposed to other diseases⁴³. Persistent infection with BVDV is the prerequisite for developing mucosal disease⁴⁶.

50% of persistently infected cattle die within the first year of life<ref name="thfive"/>. Animals may be undersized and slow-growing, and are predisposed to other diseases.<ref name="fofour">Houe, H (1993) '''Survivorship of animals persistently infected with bovine virus diarrhoea virus (BVDV)''' ''Preventative Veterinary Medicine'', 115, 275-283.</ref> Persistent infection with BVDV is the prerequisite for developing mucosal disease<ref name="seventeen"/>.

====Mucosal Disease====

====Mucosal Disease====

[[Image:Mucosal disease cartoon.jpg|right|thumb|150px|Cartoon depicting the development of mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]

[[Image:Mucosal disease cartoon.jpg|right|thumb|150px|Cartoon depicting the development of mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]

Mucosal disease is an invariably fatal condition of 6-18 month-old cattle⁴⁴. Disease follows a course of several days to weeks and intially presents as pyrexia, depression and weakness. Anorexia leads to emaciation, and animals suffer watery, foul-smelling and sometimes bloody diarrhoea. Dehydration ensues. As suggested by the name, lesions are localised to mucosal surfaces. These include the oral mucosa, tongue, external nares, nasal cavities and conjunctiva³⁴, where large lesions  cause excessive salivation, lacrimation, and oculo-nasal discharge. The coronet and interdigital surface are also affected, causing the animal to become disinclined to walk and eventually recumbent.

Mucosal disease is an invariably fatal condition of 6-18 month-old cattle<ref name="fofive">Brownlie, J (1990) '''Pathogenesis of mucosal disease and molecular aspects of bovine virus diarrhoea virus''' ''Veterinary Microbiology'', 23, 371-382.</ref>. Disease follows a course of several days to weeks and intially presents as pyrexia, depression and weakness. Anorexia leads to emaciation, and animals suffer watery, foul-smelling and sometimes bloody diarrhoea. Dehydration ensues. As suggested by the name, lesions are localised to mucosal surfaces. These include the oral mucosa, tongue, external nares, nasal cavities and conjunctiva<ref name="thone"/>, where large lesions  cause excessive salivation, lacrimation, and oculo-nasal discharge. The coronet and interdigital surface are also affected, causing the animal to become disinclined to walk and eventually recumbent.

Mucosal disease arises from superinfection of persistently infected animals with a cytopathic virus antigenically similar to the original, non-cytopathic strain persisting in the animal. In one animal, a cytopathic virus is produced by mutation of the persistent non-cytopathic virus. The new cytopathic isolate can then be transmitted to other animals where it will cause mucosal disease if they are persistently infected with the same non-cytopathic strain. Immune tolerance induced by the persistent virus prevents the immune system recognising the superinfecting cytopathic strain: the two biotypes are said to be "homologous" to the immunotolerance.⁴⁵. "Heterologous" superinfection with a non-related cytopathic biotype does not result in mucosal disease because a normal immune response is mounted.

Mucosal disease arises from superinfection of persistently infected animals with a cytopathic virus antigenically similar to the original, non-cytopathic strain persisting in the animal. In one animal, a cytopathic virus is produced by mutation of the persistent non-cytopathic virus. The new cytopathic isolate can then be transmitted to other animals where it will cause mucosal disease if they are persistently infected with the same non-cytopathic strain. Immune tolerance induced by the persistent virus prevents the immune system recognising the superinfecting cytopathic strain: the two biotypes are said to be "homologous" to the immunotolerance.<ref name="fosix">Brownlie, J (1990) '''Pathogenesis of mucosal disease and molecular aspects of bovine virus diarrhoea virus''' ''Veterinary Microbiology'', 23, 371-382.</ref>. "Heterologous" superinfection with a non-related cytopathic biotype does not result in mucosal disease because a normal immune response is mounted.

===Laboratory Tests===

===Laboratory Tests===

There are several techniques available for the laboratory diagnosis of BVD. These can detect antibody to BVDV or parts of the virus itself.

There are several techniques available for the laboratory diagnosis of BVD. These can detect antibody to BVDV or parts of the virus itself.

Tests that detect anti-BVDV antibody include the serum neutralisation test, and an ELISA³⁴. The serum neutralisation test depends on the ability of antibodies in the serum to neutralise BVD virus and thereby prevent infection of cell culture. The test takes four to seven days and requires cell culture facilities and an experienced observer. The ELISA can detect either BVDV antibody or BVDV antigen. The BVDV ELISA test can be completed within hours and is simple to perform. Because antibody against BVDV is prevalent in most cattle populations, a single serologic test is not usually sufficient for diagnosis of a recent infection. Therefore, an increase in antibody titre between paired serum samples must be more than four-fold to confirm recent infection³⁹.

Tests that detect anti-BVDV antibody include the serum neutralisation test, and an ELISA<ref name="thone"/>. The serum neutralisation test depends on the ability of antibodies in the serum to neutralise BVD virus and thereby prevent infection of cell culture. The test takes four to seven days and requires cell culture facilities and an experienced observer. The ELISA can detect either BVDV antibody or BVDV antigen. The BVDV ELISA test can be completed within hours and is simple to perform. Because antibody against BVDV is prevalent in most cattle populations, a single serologic test is not usually sufficient for diagnosis of a recent infection. Therefore, an increase in antibody titre between paired serum samples must be more than four-fold to confirm recent infection<ref name="forty"/>.

Viral antigen or RNA can be detected using clinical specimens or tissue samples. Bovine viral diarrhoea virus can be isolated from blood, nasal swabs or tissues to confirm active infection, and demonstration of virus in samples obtained at least three weeks apart is suggestive of persistent infection. The best tissues for virus isolation are skin, spleen, lymph node and segments of the gastrointestinal tract showing ulcerative lesions. An antigen-capture [[ELISA]] is also available to detect the presence of BVDV antigen in blood or serum. The ELISA for BVDV antigen will detect viral infection and is widely used to diagnose persistently infected calves. Two samples taken 3-4 weeks apart will confirm a persistent infection. Immunohistochemistry will demonstrate the presence of antigen in fixed or frozen sections. Viral RNA may also be detected, using PCR for clinical specimens or ''in situ'' hybridisation on fresh or fixed tissues³⁹.  

Viral antigen or RNA can be detected using clinical specimens or tissue samples. Bovine viral diarrhoea virus can be isolated from blood, nasal swabs or tissues to confirm active infection, and demonstration of virus in samples obtained at least three weeks apart is suggestive of persistent infection. The best tissues for virus isolation are skin, spleen, lymph node and segments of the gastrointestinal tract showing ulcerative lesions. An antigen-capture [[ELISA]] is also available to detect the presence of BVDV antigen in blood or serum. The ELISA for BVDV antigen will detect viral infection and is widely used to diagnose persistently infected calves. Two samples taken 3-4 weeks apart will confirm a persistent infection. Immunohistochemistry will demonstrate the presence of antigen in fixed or frozen sections. Viral RNA may also be detected, using PCR for clinical specimens or ''in situ'' hybridisation on fresh or fixed tissues<ref name="forty"/>.  

Genotype is generally determined by PCR with subsequent nucleic acid sequencing.

Genotype is generally determined by PCR with subsequent nucleic acid sequencing.

[[Image:Comparison normal and necrotic Peyer's Patch.jpg|center|thumb|150px|Above is a normal Peyer's Patch and below is a necrotic Patch from a cow with mucosal disease (Courtesy Prof Joe Brownlie)]]

[[Image:Comparison normal and necrotic Peyer's Patch.jpg|center|thumb|150px|Above is a normal Peyer's Patch and below is a necrotic Patch from a cow with mucosal disease (Courtesy Prof Joe Brownlie)]]

In cases of mild, acute BVD, lesions are rarely seen. When disease is more severe, the lymph nodes may appear swollen, there may be erosions and ulcerations of the gastrointestinal tract tract and serosal surfaces of the viscera may show petechial and ecchymotic hemorrhages³⁹.

In cases of mild, acute BVD, lesions are rarely seen. When disease is more severe, the lymph nodes may appear swollen, there may be erosions and ulcerations of the gastrointestinal tract tract and serosal surfaces of the viscera may show petechial and ecchymotic hemorrhages<ref name="forty"/>.

The pathology associated with mucosal disease is much more striking³⁴. Oral, lingual and buccal erosions are observed, and buccal lesions often coalesce to form larger areas of necrosis and sloughed epithelium. Oesophageal lesions present similarly. The gastrointestinal tract often shows characteristic pathology, but post-mortem examination must be performed soon after death so that these are not masked by autolytic changes. In the rumen, ulceration is less common but, with congestion and oedema, may be seen along the pillars, and papillae can be reduced in size. Several discoid erosions of around 5mm in diameter appear in the abomasum, with hyperaemia of the surrounding mucosa and petechiation of the submucosa, particularly at the pylorus. Abomasal erosions occasionally enlarge and ulcerate. Oval erosions can be seen along the antimesenteric surface of the small intestine, overlying the lymphatic tissue of the Peyer's patches and measuring 2-5 centimetres in length. The erosions become larger and more numerous towards the terminal ileum, and the exposed surfaces varies in appearance. In more chronic lesions, food is seen to adhere to the underlying submucosa, and in acute disease the exposed surface is acutely congested and often haemorrhages into the gut lumen. In the large intestine, the mucosal folds may be thickened, giving the organ a striped appearance inwardly. Petechiation and erosions are occasionally seen along the folds, and the large intestinal contents are watery, dark and foul-smelling.

The pathology associated with mucosal disease is much more striking<ref name="thone"/>. Oral, lingual and buccal erosions are observed, and buccal lesions often coalesce to form larger areas of necrosis and sloughed epithelium. Oesophageal lesions present similarly. The gastrointestinal tract often shows characteristic pathology, but post-mortem examination must be performed soon after death so that these are not masked by autolytic changes. In the rumen, ulceration is less common but, with congestion and oedema, may be seen along the pillars, and papillae can be reduced in size. Several discoid erosions of around 5mm in diameter appear in the abomasum, with hyperaemia of the surrounding mucosa and petechiation of the submucosa, particularly at the pylorus. Abomasal erosions occasionally enlarge and ulcerate. Oval erosions can be seen along the antimesenteric surface of the small intestine, overlying the lymphatic tissue of the Peyer's patches and measuring 2-5 centimetres in length. The erosions become larger and more numerous towards the terminal ileum, and the exposed surfaces varies in appearance. In more chronic lesions, food is seen to adhere to the underlying submucosa, and in acute disease the exposed surface is acutely congested and often haemorrhages into the gut lumen. In the large intestine, the mucosal folds may be thickened, giving the organ a striped appearance inwardly. Petechiation and erosions are occasionally seen along the folds, and the large intestinal contents are watery, dark and foul-smelling.

[[Image:Mucosal disease Ulcerated nose.jpg|right|thumb|150px|Ulcerated nose and mouth of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]  

[[Image:Mucosal disease Ulcerated nose.jpg|right|thumb|150px|Ulcerated nose and mouth of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]  

[[Image:Mucosal disease Ulcerated tongue.jpg|center|thumb|150px|Ulcerated tongue of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]  

[[Image:Mucosal disease Ulcerated tongue.jpg|center|thumb|150px|Ulcerated tongue of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]  

Acute BVDV infection is usually mild and does not require treatment, and treatment of more severe cases is symptomatic and supportive. There is no known treatment for mucosal disease and cases are euthanased on welfare grounds; recovery is most unlikely.

Acute BVDV infection is usually mild and does not require treatment, and treatment of more severe cases is symptomatic and supportive. There is no known treatment for mucosal disease and cases are euthanased on welfare grounds; recovery is most unlikely.

Control of BVD is practiced to a greater extent than treatment. The aim is eradication on individual farms but some countries, for example in Scandinavia, have achieved national eradication. There are several elements to control, including effective biosecurity, strategic testing, elimination of persistently infected animals, and vaccination strategies³⁹.

Control of BVD is practiced to a greater extent than treatment. The aim is eradication on individual farms but some countries, for example in Scandinavia, have achieved national eradication. There are several elements to control, including effective biosecurity, strategic testing, elimination of persistently infected animals, and vaccination strategies<ref name="forty"/>.

Biosecurity measures can include the usual hygiene precautions taken on farms, by visitors and during veterinary attention, as well as scrutiny of bought-in livestock and biologicals. Replacement cattle should be tested for persistent infection and quarantined on-farm in case of acute infections before entering the herd. If the resident herd is BVD-vaccinated, new animals should be brought up to date before joining the cohort. Embryo donors should be tested for persistent infection before transfer occurs, and purchase of in-calf heifers should be avoided as their offspring may be persistently infected. BVDV is shed in semen, so breeding bulls and semen for artificial insemination should be tested before coming into contact with cows.

Biosecurity measures can include the usual hygiene precautions taken on farms, by visitors and during veterinary attention, as well as scrutiny of bought-in livestock and biologicals. Replacement cattle should be tested for persistent infection and quarantined on-farm in case of acute infections before entering the herd. If the resident herd is BVD-vaccinated, new animals should be brought up to date before joining the cohort. Embryo donors should be tested for persistent infection before transfer occurs, and purchase of in-calf heifers should be avoided as their offspring may be persistently infected. BVDV is shed in semen, so breeding bulls and semen for artificial insemination should be tested before coming into contact with cows.

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