Difference between revisions of "Bovine Viral Diarrhoea Virus"

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Also known as: '''''Bovine Viral Diarrhoea — Bovine Virus Diarrhoea (Virus) — [[Bovine Viral Diarrhoea Virus#Mucosal Disease|Mucosal Disease]]
  
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==Description==
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==Introduction==
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[[Image:BVD-MD.gif|right|thumb|200px|Small erosions of MDV/BVDV - vesicles are microscopic (Courtesy of Alun Williams, RVC)]]
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Bovine viral diarrhoea is a viral disease that affects cattle worldwide. Caused by a pestivirus, it gives rise to significant economic losses in both dairy and beef cattle through its effects on production and reproduction. Bovine viral diarrhoea virus can lead to a variety of clinical outcomes that ranging from subclinical infections to the more severe presentations including abortion, infertility, and the fatal mucosal disease. The condition is highly immuno-suppressive and secondary respiratory and enteric complications often occur.
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[[Image:Bvd2.gif|right|thumb|200px|Coalescing lesions of BVDV (Courtesy of Alun Williams, RVC)]]
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[[Image:Comparison normal and necrotic Peyer's Patch.jpg|right|thumb|200px|Above is a normal Peyer's Patch and below is a necrotic Patch from a cow with mucosal disease (Courtesy Prof Joe Brownlie)]]
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[[Image:Mucosal disease Ulcerated nose.jpg|right|thumb|200px|Ulcerated nose and mouth of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]
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[[Image:Mucosal disease Ulcerated tongue.jpg|right|thumb|200px|Ulcerated tongue of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]
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Bovine viral diarrhoea is a viral disease that affects cattle worldwide. Caused by a [[:Category:Pestiviruses|Pestivirus]], it gives rise to significant economic losses in both dairy and beef cattle through its effects on production and reproduction. Bovine viral diarrhoea virus can lead to a variety of clinical outcomes that range from subclinical infections to the more severe presentations including abortion, infertility, and the fatal mucosal disease. The condition is highly immuno-suppressive and secondary respiratory and enteric complications often occur.
  
 
==Bovine Viral Diarrhoea Virus==
 
==Bovine Viral Diarrhoea Virus==
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===Classification===
 
===Classification===
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The  viral aetiology of BVD was first established over 60 years ago, but it was not until the 1960s that the agent was assigned to the newly penned "Pestivirus" genus. At this stage Pestiviruses were considered to be non-arthropod-borne [[:Category:Togaviridae|Togaviruses]]; later, sequencing of genomic RNA showed that they are taxonomically better suited to the [[:Category:Flaviviridae|Flaviviridae]] family<ref name="one">Collett, M S et al (1988) '''Proteins encoded by bovine viral diarrhoea virus: The genomic organisation of a pestivirus.''' ''Virology'', 165(1), 200-208.</ref><ref name="two">Meyers, G et al (1989) '''Molecular Cloning and nucleotide sequence of the genome of hog cholera virus.''' ''Virology'', 171(2), 555-567.</ref>. Many members of the Flaviviridae family are indeed arthropod-borne, such as the Flaviviruses [[West Nile Virus]] and Yellow Fever Virus. However, Pestiviruses are not transmitted by insects, and the genus includes pathogens of cattle (BVDV), sheep ([[Border Disease Virus]]) and pigs ([[Classical Swine Fever]] Virus).
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The  viral aetiology of BVD was first established over 60 years ago, but it was not until the 1960s that the agent was assigned to the newly penned "Pestivirus" genus. At this stage Pestiviruses were considered to be non-arthropod-borne togaviruses; later, sequencing of genomic RNA showed that they are taxonomically better suited to the Flaviviridae family<sup>1, 2</sup>. Many members of the Flaviviridae family are indeed arthropod-borne, such as the Flaviviruses West Nile Virus and yellow fever virus. However, Pestiviruses are not transmitted by insects, and the genus includes pathogens of cattle (BVDV), sheep (Border Disease virus) and pigs ([[Classical Swine Fever]] Virus).
 
  
 
===Virus Structure===
 
===Virus Structure===
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Donis, 1995 Dubovi, 1990
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The BVDV genome comprises a single strand of positive sense RNA which is around 12.3 kilobases in length<ref name="three">Donis, R O(1995) '''Molecular biology of bovine viral diarrhea virus and its interactions with the host.''' ''The Veterinary Clinics of North America: Food Animal Practice'' 11(3), 393-424.</ref>. The genome is read in one 3898-codon open reading frame that contains no non-coding sequences. BVDV polyprotein is translated directly from the ORF and is cleaved by viral and cellular proteinases to form mature viral proteins<ref name="three"/><ref name="four">Dubovi, E J (1990) '''Molecular biology of bovine virus diarrhoea virus.''' ''Revue Scientifique et Technique'', 9(1), 105-114.</ref>. At either end of the ORF, 5’ and 3’ untranslated regions exist. These regions are long, allowing them to accomomdate functions conferred in eukaryotic DNA by the 5’ cap and the 3' poly-A tail, such as controlling the initiation of translation, facilitating the entry of replicases, and contributing to RNA stability<ref name="four"/>. BVDV's RNA genome encodes both structural and non-structural proteins. These include Npro, whose protease action generates the N-terminus of the protein C. C is the capsid protein that packages genomic RNA and assists in the formation of the eventual enveloped virion. Erns, E1 and E2 are all glycoproteins, with Erns possessing RNase activity involved in viral replication and pathogenesis<ref name="five">Van Gennip, H G P et al (2005) '''Dimerisation of glycoprotein Erns of classical swine fever virus is not essential for viral replication and infection.''' ''Archives of Virology'', 150(1), 2271-2286.</ref>. E1 is membrane-anchored and initiates the translocation of the antigenic protein E2 to the envelope<ref name="three"/>. P7 has an uncertain function<ref name="six">Tautz, N et al (1999) '''Establishment and Characterization of Cytopathogenic and Noncytopathogenic Pestivirus Replicons.''' ''Journal of Virology'', 73(11), 9422–9432.</ref>. NS2-3 is the first non-structural protein to be translated. Sequence similarities are shown by NS2-3 to a region that in other Flaviviridae is split into two distinct polypeptides, NS2 and NS3. In BVDV, NS2 and NS3 can be expressed as separate polypeptides: NS3 is found exclusively in cytopathic isolates from 6 hours post-infection, making it a marker of this biotype<ref name="three"/>. NS2 is also expressed as a discrete polypeptide in some cytopathic isolates. NS2-3, along with the other non-structural proteins, plays an important role in genome replication. A serine protease domain within NS2-3 functions to release NS4A, NS4B, NS5A and NS5B<ref name="seven">Harada, T et al (2000) '''E2-p7 Region of the Bovine Viral Diarrhea Virus Polyprotein: Processing and Functional Studies.''' ''Journal of Virology'', 74(20), 9498–9506.</ref>. NS4A is a cofactor for the serine protease<ref name="seven"/>, and NS5B possesses an RNA-dependent RNA polymerase activity<ref name="eight">Zhong, W et al (1998) '''Identification and Characterization of an RNA-Dependent RNA Polymerase Activity within the Nonstructural Protein 5B Region of Bovine Viral Diarrhea Virus.''' ''Journal of Virology'', 72(11), 9365–9369.</ref>. Knowledge of the role of NS4B is limited.
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The BVDV genome comprises a single strand of positive sense RNA which is around 12.3 kilobases in length<sup>3</sup>. The genome is read in one 3898-codon open reading frame that contains no non-coding sequences. BVDV polyprotein is translated directly from the ORF and is cleaved by viral and cellular proteinases to form mature viral proteins<sup>3, 4</sup>. At either end of the ORF, 5’ and 3’ untranslated regions exist. These regions are long, allowing them to accomodate fuctions conferred in eukaryotic DNA by the 5’ cap and the 3' poly-A tail, such as controlling the initiation of translation, facilitating the entry of replicases, and contributing to RNA stability.  
 
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The first structural protein coded is Npro, which has a protease action that generates the N-terminus of the next protein, C. C packages genomic RNA and provides interactions necessary for formation of the enveloped virion. Erns, E1 and E2 are all glycoproteins. Erns has an RNase activity that is probably involved in viral replication and pathogenesis (van Gennip, 2005). E1 is membrane-anchored and initiates the translocation of E2 to the virion envelope where it is highly antigenic, causing the production of neutralising antibodies following infection or vaccination (Donis, 1995).  
 
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The next protein is P7. Although P7 function is uncertain, studies have suggested that the C-terminal part acts as a signal sequence required for correct processing and membrane translocation of NS2 (Tautz et. al, 1999).
 
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NS2-3 is the first non-structural protein translated. Sequence similarities are shown by NS2-3 to a region that in other flaviviruses is split into two distinct polypeptides, NS2 and NS3 (Donis, 1995). NS2-3’s N-terminus is homologous to NS2, and its C-terminus to NS3. After the first 6 hours of infection, NS3 is found exclusively in cytopathic biotypes expressed as a separate polypeptide, making it a marker of cytopathic BVDV (Donis, 1995). NS2 is also expressed as a discrete polypeptide in some, but not all, cytopathic isolates.
 
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The non-structural proteins play important roles in genome replication. The action of a serine protease domain within NS2-3 releases NS4A, NS4B, NS5A and NS5B (Harada et. al, 2000). NS4A goes on to act as a cofactor for the serine protease (Harada et. al, 2000), but knowledge of the role of NS4B is limited. NS5B possesses an RNA-dependent RNA polymerase activity (Zhong et. al, 1998). In the related Hepatitis C virus NS5B is an essential part of the replication complex (Brass et. al, 2006), and the function may be similar in BVDV.  
 
  
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The structural proteins and the genomic material created by the actions of the non-stuctural proteins come together to form the 40-60nm BVDV virion. A central core of RNA packaged in the capsid protein (C), which is surrounded by a lipid membrane. The glycoproteins E1 and E2 are anchored within the membrane, and Erns is loosely associated. Since naked BVDV RNA is infectious (Dubovi, 1990; Donis, 1995), it is clear that virions do not contain RNA replication proteins. Instead, virion proteins and lipids “capture” the viral genome from the host cell cytoplasm and deliver it to that of uninfected cells. Enzymes for the production of new RNA from the genomic RNA template are provided by the infected host cell.
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Newly formed genomic material is packaged by structural proteins to create the BVDV virion which is 40-60nm in diameter. The capsid is surrounded by a membranous envelope, in which the glycoproteins ''E1'' and ''E2'' are anchored. Naked BVDV RNA is infectious<ref name="three"/><ref name="four"/>, and so it can be deduced that the virions do not contain enzymes necessary for RNA replication: these are provided by the host cell.
  
 
===Virus Genotypes===
 
===Virus Genotypes===
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There are two recognised genotypes of BVDV; type 1 and type 2. These differ antigenically (Paton et al., 1995), although classification based on sequence variation is more precise. Analysis of the 5’UTR has divided BVDV1 into 11 subtypes and BVDV2 into 3 subtypes (Vilcek et al., 2001). Despite large intra-genotype antigenic differences, type 1 vaccines give some degree of cross-protection against disease caused by type 2 viruses (Carman et al., 1998; Cortese et al., 1998; van Oirschot et al., 1999).
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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>.
  
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A split in virulence between genotypes is evident. BVDV1 species, including classical strains and common vaccine strains, tend to cause milder disease (Deregt, 2004) and are found worldwide. Alternatively, BVDV2 isolates typically cause more severe disease, characterised by fever, diarrhoea, thrombocytopaenia, haemorrhage, respiratory signs, and high abortion and mortality rates (Corapi et al., 1989; Carman et al, 1998). These viruses were first reported in Canada and the USA, although their distribution is widening. The first British case of type 2 BVDV was identified in 2002 (Drew et al., 2002).
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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.  
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However, genotype is not always an accurate indicator of virulence. Some type 2 strains cause only subclinical or mild disease (Ahn et. al, 2005), and the spectrum of type 1 disease is also broad.
 
  
 
===Virus Biotypes===
 
===Virus Biotypes===
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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>.
  
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Within both BVDV genotypes, isolates can be classified as one of two biotypes. Noncytopathic (ncp) viruses produce no visible cytopathic effect in cell cultures, and infected cells appear normal (Figure 1.2a). Conversely, cytopathic (cp) viruses cause cell vacuolation and death (Figure 1.2b) within 24-48 hours post-infection. Cytopathogenicity gives no indication of disease-causing potential.Noncytopathic BVDV is responsible for the majority of acute and persistent BVDV infections worldwide. Cytopathic biotypes are usually found in cases of the fatal BVD-associated condition, mucosal disease, and are always isolated alongside noncytopathic strains.
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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>.
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Cytopathic viruses have been shown to originate from noncytopathic strains by several mechanisms of mutation. These include insertions of cellular origin, such as ubiquitin sequences, and viral gene rearrangements, duplications and deletions (Deregt and Loewen, 1995). Accumulation of point mutations in the NS2 region and various RNA recombination events are also important (Tautz et al., 1994).
 
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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 noncytopathic virus (Donis and Dubovi 1987; Pocock et al., 1987; Magar et al. 1998). This marker of cytopathic viruses is a smaller version of the larger structural protein, NS2-3, expressed in noncytopathic isolates. The mutational generation of cytopathic strains gives a cleavage site in NS2-3, resulting in the independent expression of NS3 as well as the larger protein in these strains (Meyers and Thiel, 1996).
 
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Figure 2 summarises the classification of BVDV down to the biotype level. For each biotype, there are many virus strains all with varying virulence and distribution.
 
  
 
==Transmission and Epidemiology==
 
==Transmission and Epidemiology==
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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>.
  
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According to antibody-detection based studies, 70 to100% of herds are currently or have recently been infected with BVDV, reflecting the endemic nature of the virus (reviewed by Houe, 1999).  
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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.
  
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BVDV can be transmitted from infected to susceptible cattle in several ways. Direct contact with a PI animal is the most efficient method, although interaction with those acutely infected can also give infection. BVDV is also excreted in the semen of both PI and acutely infected bulls, often causing seroconversion of female cattle after insemination (Kirkland et. al, 1991). Bulls and semen should therefore be tested before use for artificial insemination.
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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.
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Virus may also be spread indirectly. Use of live or infected vaccines and reuse of needles, nose tongs (Gunn, 1993) or rectal gloves (Lang-Ree et al., 1994) may cause transmission. Blood feeding flies may also spread BVDV (Tarry et. al, 1991).
 
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BVDV is diagnosed by the detection of virus or antibody in blood and milk samples. Antibody detection shows exposure of the herd to disease, whereas tests for antigen identify PI animals which may be antibody negative (Brownlie et. al, 2000).  
 
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===Epidemiology===
 
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*A major concern is that it can be confused with [[Foot and Mouth Disease (FMDV)|FMD]] (especially as it often occurs with clinical signs of salivation and depression)
 
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*Virus is widespread: 60-70% exposure by 4 years of age
 
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**Often may sweep through a whole colony of young stock causing profuse diarrhoea (perhaps febrile) for a few days and then recover
 
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**Due to primary exposure to cytopathic strain of virus
 
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*PI cows:  
 
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**100% vertical transmission to offspring
 
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**Are infected with BVDV-1nc and NEVER BVDV-1c
 
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**Are often antibody-negative (though they can show low levels of Ab to ''heterologous'' virus)
 
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**Show a wide range of clinical signs:
 
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***Severe congenital damage (ataxia)
 
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***Poor body condition
 
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***Increased susceptibility to enteric and respiratory disease
 
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**Act as the herd '''reservoir''' of BVDV
 
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**Can ONLY be identified by blood testing
 
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*Transfer via '''semen''', '''direct contact''' with acutely infected animals, or vertical from dam to offspring
 
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*Transfer can be iatrogenic: repeated use of needles and gloves, etc.
 
  
 
==Pathogenesis==
 
==Pathogenesis==
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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.
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Initially, BVDV replicates in the nasal mucosa and tonsil to high titres. After spreading to regional lymph nodes, the virus disseminates throughout the body reaching highest concentrations in the tonsil, thymus and ileum. Leucocytes are also infected (Bruschke et al., 1998). BVDV can infect cells of the bone marrow (Spagnuolo et al., 1997), and intestinal mucosa. Lymphoid tissue of the Peyer’s patches and thymus is often depleted.
 
  
 
==Diagnosis==
 
==Diagnosis==
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Clinical appearance of BVD infection is highly variable, often underlying many calf infections due to its immunosuppressive effect permitting secondary respiratory and enteric infection. Furthermore, the persistently infected calves can appear either unthrifty or perfectly normal. Therefore laboratory testing for the virus is essential.
  
 
===Clinical Signs===
 
===Clinical Signs===
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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.
  
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BVDV infection can result in a range of clinical diseases, from subclinical infections to the highly fatal mucosal disease. While inter-genotype virulence differences are partially responsible for the variations in clinical manifestation, host factors are also important. Immuno-competence or immunotolerance, pregnancy status, gestational age of foetus, passively versus active immunity and levels of environmental stress may all contribute to the severity of disease.
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====Acute Infections: Non-Pregnant Cattle====
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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"/>.
  
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1.2.1 Infection of the Immunocompetent, Non-Pregnant, Seronegative Animal
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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]].
  
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BVDV is generally considered a mild disease in immunocompetent cattle; it has been estimated that 70% to 90% of BVDV infections occur without clinical signs (Ames, 1986). If closely observed, sub-clinically infected cattle may show a small increase in body temperature, mild leucopaenia, and agalactia (Perdrizet et. al, 1987; Moerman et. al, 1994).
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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>.
  
−
Clinical disease is known as BVD. This tends to affect animals 6-12 months of age with high morbidity, although fatality is uncommon (Baker, 1995). An incubation period of 5-7 days is followed by pyrexia and leucopaenia. Viraemia is apparent from 4-5 days post-infection, and may continue until day 15 (Duffell and Harkness, 1985). BVD no longer seems to present as herd outbreaks of diarrhoea (Brownlie, 1985). Although diarrhoea does sometimes occur, clinical findings more commonly include depression, anorexia, occulo-nasal discharge, decreased milk production and, occasionally, oral lesions (Baker, 1995). A rapid respiratory rate resembling pneumonia may also be observed (Perdrizet et. al, 1987).
+
====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<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'''.
  
−
Acutely infected non-pregnant animals shed low concentrations of virus compared to persistently infected cattle (Duffell and Harkness, 1985). Animals produce antibodies to BVDV 2 to 4 weeks after infection (Baker, 1995), which persist for life.
+
'''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 are 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.
  
−
“Severe BVD” also exists, seen in the UK in 1992-1993 (Hibberd and Turkington, 1993), and in herd outbreaks between 1993 and 1995 in Ontario (Carman et. al, 1998). Infected animals showed acute onset of diarrhoea, fever and decreased milk production, sometimes proving fatal. Non-cytopathic, type 2 viruses were implicated in these cases, raising the issue of the degree of cross protection afforded by type 1 vaccines. However, severe disease was only seen in cattle where vaccine manufacturers’ instructions had not been followed, implying protection is usually given.
+
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'''.
  
−
BVDV2 infection may also result in haemorrhagic syndrome (HS), reported in both North America (Perdrizet et. al, 1987; Rebhun et.al, 1989) and Europe. This is characterised by significant thrombocytopaenia, giving rise to bloody diarrhoea, petechial haemorrhages of mucous membranes and epistaxis (Rebhun et. al, 1989). Fever and leucopaenia are also seen.  
+
====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 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>
  
−
1.2.2 Infection of the Immunocompetent, Pregnant, Seronegative Animal
+
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"/>.
  
−
Immunocompetent, pregnant cattle show the same responses to BVDV infection as non-pregnant animals. However, BVDV has a high potential to cross the placenta and infect the developing foetus, meaning additional outcomes of infection may occur in the calf. The main factor influencing the virus’s effects on the foetus is the gestational age at the time of transplacental infection.
+
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"/>.
  
−
Infection at the time of insemination may result in reduced conception rates, and that shortly after increases loss of embryos (Carlsson et. al, 1989; McGowan et. al, 1993). Foetal infection in the first trimester (50-100 days) can cause death, although expulsion of the foetus may not occur until several months later.
+
====Mucosal Disease====
 +
[[Image:Mucosal disease cartoon.jpg|right|thumb|200px|Cartoon depicting the development of mucosal disease (Courtesy Prof Joe Brownlie, RVC)]]
  
−
   
+
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.
−
Figure 1.4: (from Brownlie et al., 2000) A calf stillborn due to transplacental BVDV infection.
 
  
−
Transplacental infection between days 100 and 150 may result in congenital defects. At this stage the immune system is in the final phase of development, and mounts an inappropriate inflammatory response to BVDV to cause these effects (Duffell and Harkness, 1985). Growth defects in organs such as the thymus, and central nervous system pathologies such as cerebellar hypoplasia, often arise (Brownlie, 1985). Calves with cerebellar hypoplasia are ataxic, reluctant to stand and may suffer tremors (Baker, 1995). Infection at this point may also cause visual problems, including blindness and cataracts. Virus may localise to the vascular endothelium, causing vasculitis and associated inflammation, oedema, hypoxia and cellular degeneration (Brownlie, 2000). Weak, stunted calves may also be produced.
+
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.
  
−
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.
+
===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.
  
−
1.2.3 Persistent Infection- Immunotolerant Animals.
+
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"/>.
  
−
Infection of the foetus with non-cytopathic virus before 120 days gestation may result in the birth of immunotolerant and persistently infected (PI) calves. The immune system, although competent, recognises the antigen as “self” rather than “foreign” and no response is mounted. The calf therefore develops a tolerant state to the virus which persists into neonatal life. Although no antibodies are produced against the original, transplacental-infecting strain, heterologous BVDV strains can elicit a response in PI cattle. Therefore, these may prove seropositive if tested (Bolin, 1985).
+
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"/>.  
  
−
While they may appear clinically healthy, PI animals continuously shed large amounts of virus throughout their lives, providing a major source of infectious virus for naïve cattle. (Houe, 1999). PI dams produce PI calves, resulting in PI family lines which maintain the virus in a herd (Baker, 1995). 1-2% of the cattle population are PI (Houe, 1999), rising to 13% in foetal calves.  
+
Genotype is generally determined by PCR with subsequent nucleic acid sequencing.
  
−
PI cattle are predisposed to other diseases, and have a reduced survival rate (Houe, 1993) with 50% dying within their first year (Duffell and Harkness, 1985). This increased susceptibility may be due to BVDV-associated immunosupression, considered in section 1.2.5. Animals may be undersized and slow-growing, and persistent infection is the prerequisite for mucosal disease.
+
===Pathology===
  
−
1.2.4 Mucosal Disease
+
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"/>.
  
−
Mucosal disease (MD) primarily affects 6-18 month-old cattle and is invariably fatal (Brownlie et. al, 2000). Baker (1995) summarises the characterising symptoms, which last several days to weeks. These include pyrexia, depression and weakness. Anorexia gives emaciation and dehydration. Foul-smelling, sometimes bloody, watery diarrhoea develops 2-3 days after the onset of disease. Animals are often euthanised for humane reasons.  
+
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.
  
−
As suggested by the name, lesions develop on mucosal surfaces including the oral mucosa, tongue, external nares and the buccal and nasal cavities (Brownlie, 1985). Coalition of lesions gives larger areas of necrosis (Baker 1995), leading to excessive salivation, lacrimation, and ocular discharge. The coronet and interdigital surface are also affected, causing the animal to become disinclined to walk and eventually recumbent (Brownlie, 1985). Lesions of the abomasum and small intestine are seen on post-mortem examination, and congestion of the large intestine mucosa results in a stripy, thickened appearance (Brownlie, 1985). Figure 1.5 shows examples of tongue and small intestine lesions.
+
==Treatment and Control==
 +
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.
  
−
MD occurs when animals persistently infected with noncytopathic BVDV are superinfected with an antigenically similar cytopathic strain. Cytopathic virus arises from the persistent noncytopathic virus by mutation (see 1.1.4), and may then be transmitted to cause MD in animals PI with the same noncytopathic strain. Immunotolerance induced by the noncytopathic strain prevents superinfecting virus being recognised by the immune system; the biotypes are “homologous” to the immunotolerance (Brownlie, 1990). “Heterologous” superinfection with a non-related cytopathic biotype causes an antibody response and mucosal disease does not usually occur.
+
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.
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Figure 1.5: (From Brownlie, 1985) a) Tongue of a calf suffering mucosal disease. Complete loss of the epithelium has occurred at the apex. b) Lesion of the small intestine due to MD. These may appear chronic, and have food adhering to the surface.
 
  
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1.2.5 Immunosupression in Mixed Infections
+
A protocol for screening cattle herds for persistent infection should be implemented. Testing can be achieved by virus isolation or antigen-capture ELISA from serum or buffy coat cells, or by antigen detection in skin biopsies. The selected programme should be designed around the type and size of herd, financial limitations and the techniques available at the chosen diagnostic laboratory. Once identified, persistently infected animals should be culled as soon as possible.
  
−
BVDV-induced leucopaenia reduces the defences available against invading pathogens, enhancing the pathogenicity of co-infecting organisms. BVDV can therefore be considered an immunosuppressive agent.  
+
Both modified live (not in the UK) and chemically-inactivated BVDV vaccines are available for use. Although cross-protection between strains and genotypes is generally good, antigenic diversity among challenge viruses may affect the efficacy of a given vaccine. Because BVDV is tropic for the foetus, modified live vaccines should not be used in pregnant animals. The virus is also immunosuppressive and so modified-live vaccination of animals showing signs of disease is not recommended. Maternally-derived antibody wanes at 3-6 months of age, and so to ensure that vaccination induces a protective immune response animals should be vaccinated (or re-vaccinated) by this age.
  
−
BVDV-associated immunosupression has a particularly important role in bovine respiratory disease, with an association between BVDV antibody titre and respiratory disease treatment being demonstrated (Martin and Bohac, 1986). BVDV is the virus most frequently isolated from pneumonic lungs, often found in association with Pasteurella haemolytica (described by Baker, 1995). This pathogen combination causes severe fibrino-purulent bronchopneumonia, with the area of pneumonic lesions increasing by 35-60% compared to that caused by Pasteurella infection alone (Brownlie, 1985). Synergism is also displayed with parainfluenza, bovine rhino-tracheitis and respiratory syncitial viruses.
+
==Links==
  
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===Laboratory Tests===
+
*[http://www.rvc.ac.uk/bvd/Index.cfm Royal Veterinary College BVD page]
 +
*[http://www.scotland.gov.uk/Publications/2010/06/29143957/1 Bovine Viral Diarrhoea (BVD): An Eradication Scheme for Scotland - Consultation Paper]
  
−
*Traditional test: virus isolation followed by serology on infected cells
 
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*'''ELISA''' for virus '''antigen''' in animals with persistent viremia (will show up 3-8 days post-infection)
 
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*PI calves often appear virus negative as a result of receiving neutralizing Ab in colostrum: can be countered by RT-PCR
 
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*'''Paired serum samples''' from cows with acute BVDV
 
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*'''Herd sampling''' by ELISA for antibody on bulk milk
 
  
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===Pathology===
+
{{Learning
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[[Image:BVD-MD.gif|right|thumb|125px|<small><center>Small erosions of MDV/BVDV - vesicles are microscopic (Courtesy of Alun Williams (RVC))</center></small>]]
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|videos = [[Video: Bovine Viral Diarrhoea Virus (BVDV) - part 1|Bovine Viral Diarrhoea Virus (BVDV) - part 1]]<br>[[Video: Bovine Viral Diarrhoea Virus (BVDV) - part 2|Bovine Viral Diarrhoea Virus (BVDV) - part 2]]<br>[[Video: Bovine Viral Diarrhoea Virus (BVDV) - part 3|Bovine Viral Diarrhoea Virus (BVDV) - part 3]]
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[[Image:Bvd2.gif|right|thumb|125px|<small><center>Coalescing lesions of BVDV (Courtesy of Alun Williams (RVC))</center></small>]]
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|literature search = [http://www.cabdirect.org/search.html?rowId=1&options1=AND&q1=title:(%22bovine%22)+AND+title:(vir*)+AND+title:(diar*)&occuring1=title&rowId=2&options2=OR&q2=BVD&occuring2=title&rowId=3&options3=OR&q3=%22Mucosal+disease%22&occuring3=title&rowId=4&options4=OR&q4=BVDV&occuring4=title&publishedstart=2000&publishedend=yyyy&calendarInput=yyyy-mm-dd&la=any&it=any&show=all&x=62&y=8 Bovine Viral Diarrhoea Virus publications]
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*'''Mucosal Disease''': erosive condition produces small multiple, cleanly punched out lesion in mouth
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|full text = [http://www.cabi.org/cabdirect/FullTextPDF/2007/20073161537.pdf '''Bovine viral diarrhoea: an emerging disease of ruminants in India.''' Richa Sood; Intas Pharmaceuticals Ltd, Ahmedabad, India, Intas Polivet, 2007, 8, 1, pp 145-152, 37 ref.]
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*[[Neutrophils|Neutrophils]] invade the ulcer and if bacterial colonisation occurs, further excavation follows. Either:
+
}}
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::#This lesion develops a granular base and becomes diphtheritic.  
 
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::#If bacterial colonisation does not take place, healing occurs within fourteen days.
 
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*Seen in most parts of mouth (or maybe on muzzle) e.g. dental pad, [[Cheeks - Anatomy & Physiology|cheeks]], sides of [[Oral Cavity - Tongue - Anatomy & Physiology|tongue]]
 
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*Lesions extend throughout gut with particularly big ulcers in small intestine over [[Peyer's Patches - Anatomy & Physiology|Peyers patches]]. Necrosis occurs in lymph nodes and [[Spleen - Anatomy & Physiology|spleen]]
 
  
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*No vesicular stage, prickle cells die off from surface resulting in layer of necrotic debris over epithelial layer
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==References==
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*Infection penetrates inward through stratum germinativum.
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<references />
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*Epithelium does not recover as animal does not recover
 
  
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==Treatment and Control==
 
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Once a herd’s status has been established, BVDV control measures can be implemented. Previously, PI animals have been used as natural “vaccinators” to increase herd immunity, although naïve animals must endure acute infection before this is achieved. Eradication by identification and culling of PI animals is possible, having been successfully accomplished in Scandinavia. However, this gives many seronegative, susceptible animals- an imperfect solution for those units not completely biosecure or highly committed to the scheme. Killed and live vaccines afford a good level of protection providing they are used correctly and boosted regularly. A combination of eradication and vaccination gives the best level of control (Brownlie et. al, 2000), and the development of “marker” vaccines that allow natural- and vaccine-induced immunity to be distinguished will help this cause in future.
 
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*No known treatment to reverse persistent infection or to cure mucosal disease
 
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*BUT, without exposure to BVDV, the whole herd is at risk as there is no developed immunity
 
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*'''Vaccination of dams''' before pregnancy will prevent PI calves being born
 
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**'''Beta-propiolactone inactivated''' vaccine
 
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**Combine with screening for antigen and removal of PI animals
 
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==Links==
 
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==References==
 
  
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#Collett, M S et al (1988) Proteins encoded by bovine viral diarrhoea virus: The genomic organisation of a pestivirus. ''Virology'', '''165(1)''', 200-208.
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{{Joe Brownlie
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#Meyers, G et al (1989) Molecular Cloning and nucleotide sequence of the genome of hog cholera virus. ''Virology'', '''171(2)''', 555-567.
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|date = July 8, 2011}}
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#Donis, R O(1995) Molecular biology of bovine viral diarrhea virus and its interactions with the host. ''The Veterinary Clinics of North America: Food Animal Practice'' '''11(3)''', 393-424.
 
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#Dubovi, E J (1990) Molecular biology of bovine virus diarrhoea virus. ''Revue Scientifique et Technique'', '''9(1)''', 105-114.
 
  
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[[Category:Pestiviruses]][[Category:Cattle]]
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[[Category:Pestiviruses]][[Category:Cattle Viruses]][[Category:Alimentary Diseases - Cattle]][[Category:Reproductive Diseases - Cattle]]
 
[[Category:Oral_Cavity_-_Erosive_&_Ulcerative_Pathology]]
 
[[Category:Oral_Cavity_-_Erosive_&_Ulcerative_Pathology]]
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[[Category:Enteritis,_Ulcerative]][[Category:Enteritis,_Viral]][[Category:To_Do_-_Lizzie]]
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[[Category:Enteritis,_Ulcerative]][[Category:Enteritis,_Viral]] [[Category:Joe Brownlie reviewed]]

Latest revision as of 07:17, 5 June 2015


Also known as: Bovine Viral Diarrhoea — Bovine Virus Diarrhoea (Virus) — Mucosal Disease

Introduction

Small erosions of MDV/BVDV - vesicles are microscopic (Courtesy of Alun Williams, RVC)
Coalescing lesions of BVDV (Courtesy of Alun Williams, RVC)
Above is a normal Peyer's Patch and below is a necrotic Patch from a cow with mucosal disease (Courtesy Prof Joe Brownlie)
Ulcerated nose and mouth of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)
Ulcerated tongue of a cow with mucosal disease (Courtesy Prof Joe Brownlie, RVC)

Bovine viral diarrhoea is a viral disease that affects cattle worldwide. Caused by a Pestivirus, it gives rise to significant economic losses in both dairy and beef cattle through its effects on production and reproduction. Bovine viral diarrhoea virus can lead to a variety of clinical outcomes that range from subclinical infections to the more severe presentations including abortion, infertility, and the fatal mucosal disease. The condition is highly immuno-suppressive and secondary respiratory and enteric complications often occur.

Bovine Viral Diarrhoea Virus

Classification

The viral aetiology of BVD was first established over 60 years ago, but it was not until the 1960s that the agent was assigned to the newly penned "Pestivirus" genus. At this stage Pestiviruses were considered to be non-arthropod-borne Togaviruses; later, sequencing of genomic RNA showed that they are taxonomically better suited to the Flaviviridae family[1][2]. Many members of the Flaviviridae family are indeed arthropod-borne, such as the Flaviviruses West Nile Virus and Yellow Fever Virus. However, Pestiviruses are not transmitted by insects, and the genus includes pathogens of cattle (BVDV), sheep (Border Disease Virus) and pigs (Classical Swine Fever Virus).

Virus Structure

The BVDV genome comprises a single strand of positive sense RNA which is around 12.3 kilobases in length[3]. The genome is read in one 3898-codon open reading frame that contains no non-coding sequences. BVDV polyprotein is translated directly from the ORF and is cleaved by viral and cellular proteinases to form mature viral proteins[3][4]. At either end of the ORF, 5’ and 3’ untranslated regions exist. These regions are long, allowing them to accomomdate functions conferred in eukaryotic DNA by the 5’ cap and the 3' poly-A tail, such as controlling the initiation of translation, facilitating the entry of replicases, and contributing to RNA stability[4]. BVDV's RNA genome encodes both structural and non-structural proteins. These include Npro, whose protease action generates the N-terminus of the protein C. C is the capsid protein that packages genomic RNA and assists in the formation of the eventual enveloped virion. Erns, E1 and E2 are all glycoproteins, with Erns possessing RNase activity involved in viral replication and pathogenesis[5]. E1 is membrane-anchored and initiates the translocation of the antigenic protein E2 to the envelope[3]. P7 has an uncertain function[6]. NS2-3 is the first non-structural protein to be translated. Sequence similarities are shown by NS2-3 to a region that in other Flaviviridae is split into two distinct polypeptides, NS2 and NS3. In BVDV, NS2 and NS3 can be expressed as separate polypeptides: NS3 is found exclusively in cytopathic isolates from 6 hours post-infection, making it a marker of this biotype[3]. NS2 is also expressed as a discrete polypeptide in some cytopathic isolates. NS2-3, along with the other non-structural proteins, plays an important role in genome replication. A serine protease domain within NS2-3 functions to release NS4A, NS4B, NS5A and NS5B[7]. NS4A is a cofactor for the serine protease[7], and NS5B possesses an RNA-dependent RNA polymerase activity[8]. Knowledge of the role of NS4B is limited.

Newly formed genomic material is packaged by structural proteins to create the BVDV virion which is 40-60nm in diameter. The capsid is surrounded by a membranous envelope, in which the glycoproteins E1 and E2 are anchored. Naked BVDV RNA is infectious[3][4], and so it can be deduced that the virions do not contain enzymes necessary for RNA replication: these are provided by the host cell.

Virus Genotypes

There are two antigenically distinct[9] 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[10]. Despite the large antigenic differences between the genotypes, some cross-protection against type 2 viruses is afforded by type 1 vaccines[11][12][13].

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 disease[16], 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

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[17].

Cytopathic viruses originate from non-cytopathic strains by mutation, including viral gene rearrangements, duplications and deletions[18], and insertions of cellular origin, such as ubiquitin sequences. Point mutations in the NS2 region and various RNA recombination events are also important[19]. 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[20][21][22]. This marker molecule arises from when NS2-3, expressed in non-cytopathic isolates, is cleaved at a site created by the mutations above[23].

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 virus[24].

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 semen[25]. The testes is an immunoprivileged site, and the virus can persist in this location despite otherwise systemic clearance[26]. Indirect spread is possible: BVDV has been shown to spread through the re-use of needles, nose tongs[27] and rectal gloves[28], and blood feeding flies also give transmission.

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 monocytes[29]. 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[30] 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

Clinical appearance of BVD infection is highly variable, often underlying many calf infections due to its immunosuppressive effect permitting secondary respiratory and enteric infection. Furthermore, the persistently infected calves can appear either unthrifty or perfectly normal. Therefore laboratory testing for the virus is essential.

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 disease[31]. 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

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[32]. If these subclinically affected cattle are observed closely, body temperature may marginally rise and mild leukopenia and agalactia may be seen [33][34]. 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[35]. Although some cattle suffer diarrhoea in BVDV infection, the disease no longer seems to present as herd outbreaks of diarrhoea[31]. Clinical signs more commonly include depression, anorexia, occulo-nasal discharge, decreased milk production and oral lesions[36], with a rapid respiratory rate resembling pneumonia sometimes apparent[33]. Acutely infected, non-pregnant animals shed low concentrations of virus compared to persistently infected cattle[35], and antibodies are produced 2-4 weeks post-infection which persist for many years[36].

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[37]. BVDV is the virus most frequently isolated from pneumonic lungs and is often found in association with Pasteurella haemolytica[36], causing severe fibrino-purulent bronchopneumonia and increasing the total lesion area by 35-60% compared to pasteurellosis alone[31]. Synergism is also displayed with parainfluenza, bovine rhinotracheitis and 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][38]. 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[39] 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[40].

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[41][42]. 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 stage[35]. Examples of common congenital abnormalities include defects of the thymus, ocular changes and cerebellar hypoplasia[31]. Calves with cerebellar hypoplasia are ataxic, reluctant to stand and may suffer tremors[36], 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.

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 life[17]. 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.[43]

Persistently infected animals continuously shed large amounts of virus throughout their lives, providing a major source of infection for naive cattle[24]. Persistently infected dams produce persistently infected calves, resulting in family lines capable of maintaining the virus in a herd[36]. It is estimated that 1-2% of the cattle population and up to 13% of foetal calves are persistently infected[31].

50% of persistently infected cattle die within the first year of life[35]. Animals may be undersized and slow-growing, and are predisposed to other diseases.[44] Persistent infection with BVDV is the prerequisite for developing mucosal disease[17].

Mucosal Disease

Cartoon depicting the development of mucosal disease (Courtesy Prof Joe Brownlie, RVC)

Mucosal disease is an invariably fatal condition of 6-18 month-old cattle[45]. 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[31], 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.[46]. "Heterologous" superinfection with a non-related cytopathic biotype does not result in mucosal disease because a normal immune response is mounted.

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.

Tests that detect anti-BVDV antibody include the serum neutralisation test, and an ELISA[31]. 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[40].

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[40].

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

Pathology

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[40].

The pathology associated with mucosal disease is much more striking[31]. 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.

Treatment and Control

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 strategies[40].

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.

A protocol for screening cattle herds for persistent infection should be implemented. Testing can be achieved by virus isolation or antigen-capture ELISA from serum or buffy coat cells, or by antigen detection in skin biopsies. The selected programme should be designed around the type and size of herd, financial limitations and the techniques available at the chosen diagnostic laboratory. Once identified, persistently infected animals should be culled as soon as possible.

Both modified live (not in the UK) and chemically-inactivated BVDV vaccines are available for use. Although cross-protection between strains and genotypes is generally good, antigenic diversity among challenge viruses may affect the efficacy of a given vaccine. Because BVDV is tropic for the foetus, modified live vaccines should not be used in pregnant animals. The virus is also immunosuppressive and so modified-live vaccination of animals showing signs of disease is not recommended. Maternally-derived antibody wanes at 3-6 months of age, and so to ensure that vaccination induces a protective immune response animals should be vaccinated (or re-vaccinated) by this age.

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References

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  40. ↑ 40.0 40.1 40.2 40.3 40.4 Merck & Co (2008) The Merck Veterinary Manual (Eighth Edition), Merial.
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ Houe, H (1993) Survivorship of animals persistently infected with bovine virus diarrhoea virus (BVDV) Preventative Veterinary Medicine, 115, 275-283.
  45. ↑ Brownlie, J (1990) Pathogenesis of mucosal disease and molecular aspects of bovine virus diarrhoea virus Veterinary Microbiology, 23, 371-382.
  46. ↑ Brownlie, J (1990) Pathogenesis of mucosal disease and molecular aspects of bovine virus diarrhoea virus Veterinary Microbiology, 23, 371-382.


This article has been expert reviewed by Prof Joe Brownlie DSc BVSc PhD FRCVS FRCPath DipECVP

Date reviewed: July 8, 2011



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