Control of Bovine Viral Diarrhea Virus in Ruminants

Bovine viral diarrhea virus (BVDV) is a diverse group of viruses responsible for causing disease in ruminants worldwide. Since the first description of BVDV as a cause of disease, it has undergone surges and lulls in importance. Epizootics of disease caused by BVDV are described. Although naming of the virus and illness implies gastrointestinal disease in cattle, BVDV is a pathogen that affects multiple organ systems in many animal species. Infection, disease, or both have been described in cattle, sheep, goats, pigs, bison, alpacas, llamas, and white-tailed deer, among others. In 2007, the Office of International Epizootics added bovine viral diarrhea to its list of reportable diseases, but the listing is as a reportable disease of cattle rather than as a reportable disease of multiple species. Although initial descriptions of disease caused by BVDV were of digestive disease, respiratory disease and reproductive losses because of BVDV are the most important economically. BVDV uses multiple strategies to ensure survival and successful propagation in mammalian hosts, and this includes suppression of the host's immune system, transmission by various direct and indirect routes, and, perhaps most importantly, induction of persistently infected (PI) hosts that shed and transmit BVDV much more efficiently than non-PI animals. Successful control and eventual eradication of BVDV requires a multidimensional approach, involving vaccination, biosecurity, and identification of BVDV reservoirs. The following consensus statement reflects current knowledge and opinion regarding the virus, prevalence and host range, clinical manifestations, and most importantly, the control and potential for ultimate eradication of this important viral pathogen of ruminants. BVDV is an enveloped, single-stranded RNA virus, and is the prototypic member of the genus Pestivirus within the family Flaviviridae. Currently recognized species within the Pestivirus genus include BVDV1, BVDV2, border disease virus, and classical swine fever virus (hog cholera virus).1 Strains of BVDV can exist as different biotypes, which are either cytopathic (CP) or noncytopathic (NCP). The classification of biotype is independent of genotype, as there exist CP and NCP BVDV1 strains and CP and NCP BVDV2 strains. Only NCP strains of BVDV induce persistent infection.2 CP BVDV strains are relatively rare, with NCP isolates accounting for approximately 90% of BVDV isolates at a diagnostic laboratory.3 The NCP biotype is the source for CP strains, which arise by mutations and recombinations in the NCP strain. A 3rd biotype of BVDV, the lymphocytopathic biotype, consists of a subpopulation of NCP strains that are capable of causing CP effect in lymphocytes cultured in vitro. NCP strains that are lymphocytopathic have been associated with severe clinical disease.4 As BVDV is an RNA virus, genetic mutations occur readily, leading to substantial genetic, antigenic, and pathogenic variation. Because of frequent mutation in viral RNA replication, BVDV exists as a quasi-species, which are different but closely related mutant viral genomes subjected to continuous competition and selection, thus resulting in genetic and antigenic variation. Nucleotide sequence differences are the most reliable criteria for differentiation of BVDV species. The differences between BVDV species are not restricted to any 1 genomic region and are found throughout the genome5; however, some BVDV genomic regions are more amenable to comparison or have greater biological importance between BVDV1 and BVDV2. The 5′ untranslated region (5′-UTR) is the most commonly used region for detection and characterization of BVDV because of highly conserved areas that are favorable to PCR amplification, but the first nonstructural protein region is unique to pestiviruses, and comparison of this region among BVDV strains is being used for characterization of putative pestivirus species.6 Subgenotypes of BVDV are described within BVDV1 and BVDV2 species, 12 among BVDV1 viruses (BVDV1a through BVDV1l)7 and 2 among BVDV2 viruses (BVDV2a and BVDV2b).8 Phylogenetic survey of the 5′-UTR genomic sequences of BVDV1 and BVDV2 strains reveals a similar level of sequence variation within each species,9 and this finding suggests that these 2 species have been evolving for a similar time span. Within the U.S. cattle population, there are 3 major subtypes, BVDV1a, BVDV1b, and BVDV2a, with the BVDV1b subtype predominating from diagnostic laboratory submissions and PI prevalence studies, accounting for 78% of persistent infections in cattle in one North American study.10 Cattle are the natural host for BVDV, and BVDV is distributed in cattle populations throughout the world as indicated by serologic surveys. The prevalence of seropositive cattle varies among countries, and is influenced by vaccine use and management practices. Surveys in North America have indicated individual-animal seropositive rates between 40 and 90%.11,12 Herd-level prevalence, ie, the percentage of herds with unvaccinated cattle that are seropositive to BVDV, varies from 28 to 53% depending on geographic region.13–15 In contrast, the prevalence of PI cattle is much lower and is generally believed to be <1% of all cattle.16 PI cattle can cluster within groups of cattle, elevating the prevalence within populations. There are no random surveys that estimate the prevalence of PI cattle in North America. Despite reduced survivability, the prevalence of PI calves arriving at feedlots in the United States is between 0.1 and 0.4%,17–19 which is similar to the 0.17% reported for U.S. beef cow-calf operations.16 BVDV does not possess strict host specificity. Classically, pestivirus isolates have been assigned according to the species from which they were isolated, with most BVDV, classical swine fever virus, and border disease virus isolates being recovered from cattle, pigs, and sheep, respectively. Evidence of BVDV infection as demonstrated by the identification of serum antibodies exists in over 50 species within 7 of the 10 families of the mammalian order Artiodactyla.20–22 Species that are susceptible to BVDV infection include cattle, pigs, sheep, goats, bison, captive and wild cervids, and Old World and New World camelids, with recent accounts of BVDV infections in alpacas and wild cervids in North America receiving much attention. Clustering of pestivirus strains among 3 host groups (domestic ruminants, camelids, deer) has been proposed; however, the implications for transmission between these clusters are unknown.23 Identification of heterologous PI hosts might have important implications for the epidemiology of BVDV, most importantly as these nonbovid PI animals can serve as reservoirs for BVDV. BVDV infections have been identified in Old and New World camelids. In New World camelids, seroprevalence rates <20% have been reported in both North and South America.24–26 In North America, highest antibody titers to BVDV were detected on farms on which PI crias were present.26 The herd-level prevalence is 25% where crias were tested in 63 alpaca herds in the United States.27 Historically, seroepidemiologic and experimental infection studies suggested that New World camelids could be infected with BVDV but have few or no clinical signs of disease.25 Reports of BVDV isolation and identification of PI alpacas have concerned the alpaca industry, and the virus is now considered an emerging pathogen of New World camelids.28 The first description of a PI alpaca was made in Canada where a BVDV1b strain was isolated from a PI cria after natural exposure of its dam to a chronically ill cria.29 Several cases of PI alpacas have since been reported in North America and Great Britain.28,30–32 PI alpacas can survive for several months, but low birth weights, failure to thrive, and chronic respiratory and gastrointestinal infections occur in PI alpacas. Diagnosis of BVDV infection in PI alpacas has been made through traditional virological techniques, by RT-PCR, and through immunohistochemistry (IHC); however, these tests have not been formally validated for camelids. Similar to PI cattle, BVDV antigen is identified in many tissues of PI alpacas.28–30 All isolates examined in North America and the United Kingdom belonged to BVDV 1b genogroup when subgenotyping was performed.28–30 All 46 BVDV isolates from alpacas in North America were NCP BVDV1b strains31; furthermore, the nucleotide identity in 45 of 46 isolates was ≥99% using the highly conserved 5′-UTR genomic region. This finding suggests an association of the BVDV1b genotype with infections in North American alpacas.31 Possible explanations for this predominance of BVDV1b strains in alpacas include introduction and intraspecific spread and maintenance of BVDV1b into North American alpaca populations or that unique BVDV1b subgenotypes are able to establish transplacental infections in alpacas.31 When simultaneous intranasal inoculation of alpacas with 3 different BVDV strains of cattle BVDV 1b of alpaca or BVDV2 of cattle was PI crias were with BVDV1b strains of cattle or alpaca but not for a unique of BVDV1b in alpacas. species of BVDV were isolated from alpacas and llamas, from North America and Great and were when alpacas were with BVDV1b or BVDV2 of BVDV and are important for BVDV control in alpacas, as of alpacas, with between farms for is associated with reproductive disease and birth of PI are to BVDV, and the virus has been isolated from animals. The is of for a of diseases, classical swine fever virus, but is the of in the epidemiology of BVDV. can infected with BVDV, but of the virus, and of might the of BVDV reservoirs. Similar to cattle, PI are a in the of and PI animals have been identified in and captive species. PI animals were detected among in and white-tailed in the United prevalence rates of persistent infections in U.S. populations are in in and in the source for BVDV infection in these populations is with cattle, or the of an is but for both and both explanations are not Although 1 not a between cattle and BVDV seroprevalence rates in seroprevalence rates in white-tailed are on where cattle were the management of cattle could have an important on transmission of BVDV, as there is with cattle with beef cattle in of BVDV is indicated by seroprevalence rates of that no to cattle, and of a in In a group of captive white-tailed deer, BVDV was by exposure of does to a PI resulting in birth of PI transmission of BVDV by transplacental infection in birth of PI animals in a of in a the potential for maintenance of BVDV in are the most ruminants in North America. between white-tailed and cattle can occur in a North American and this species has potential to be a for BVDV. of white-tailed with BVDV occur by experimental and natural Similar to cattle, the most of BVDV infections in white-tailed are and or in infected and PI white-tailed deer, and in transmission to white-tailed In to transmission of BVDV among white-tailed deer, or infection of cattle as a of exposure to white-tailed has not been but because of its The of in species might to within the genus from a is different from of species, on comparison of genomic sequences and nucleotide in the A pestivirus isolated from an is highly from Although BVDV is not considered a its highly to in to and isolation from 2 a disease and of 2 some regarding A of clinical from to disease occur in association with BVDV The clinical and the of BVDV infection on with host being and these include immune the species of and of the and the of infections with clinical and these include and antigenic but it is important to that BVDV1 and BVDV2 strains can be in the of clinical The and have been used to BVDV infection in cattle, with the to to BVDV. The source of most infections is cattle PI with BVDV, infected cattle can be a source of virus to susceptible The most of transmission to be The of BVDV infections in and cattle are however, BVDV infections not as cattle an infection could and in the infected animal is can occur in the BVDV infections in signs that include and with laboratory by and BVDV infections described in Canada and the United States in severe clinical disease and than of BVDV isolates from infected cattle from these indicated the BVDV2 genotype, and this a in BVDV clinical disease in cattle infected with BVDV is the which is by The first descriptions of both calves and cattle infected with BVDV, with severe in of the are related to and include and from or BVDV infections have been with NCP BVDV2 has been described with experimental BVDV thus and to the in infected BVDV infection of is important in the of BVDV is and infected cattle are as a of in immune and of immune The of is an to disease and the bovine respiratory disease is an where BVDV an important in of both the and immune are by BVDV. in most infected cattle, but the of can be influenced by BVDV strain. in and in to be in calves infected with BVDV1 strains than with some BVDV2 however, this can be because of the of BVDV strains for In highly strains of BVDV induce greater in the than strains. and and are the major of by the immune system, of immune by BVDV, and of immune into of viral are all responsible for in the and tissues and the might be strain in immune has been described BVDV and include and and The importance of BVDV on the reproductive has not the to the on infected with BVDV are capable of virus in The virus can survive and of for Although infected shed lower of BVDV in than PI infection of can from with from infected BVDV infections generally in a with of the virus by the host immune however, infection of has been described both natural and experimental infection with BVDV was first identified in the of a at an This shed BVDV in throughout the of a and the of of serum antibodies that the viral strain that was persistently shed in the infections with BVDV have been after infection of with BVDV. RNA has been detected in for after BVDV and virus from has been detected to after BVDV from a immune because of a is believed to be the for the exists regarding with a infection can and to animals. of cattle with BVDV can in transplacental transmission and infection of the The caused by BVDV in susceptible herds is associated with the of which are 3 of the at the time of organ in the and biotype, and of the persistent of reproductive infections include or as and infections as calves or calves of Although and are most the first and and can be caused by are by BVDV infection between and of and include and The of BVDV to cause has been of cattle This could be in to infection and as a of BVDV and the of viral antigen in occur in cattle infected with and rates are lower the animals are at the time of Cattle with NCP BVDV at the time of a as with for the control studies have this that BVDV is in and infection is considered by many the most important of BVDV infection as this is the by which the virus and in the cattle in diagnostic have on identification of PI cattle, and a of BVDV control is the identification and of this major of the PI calves are the of in BVDV infection the of from 45 to which is the by the of the and the of variation is regarding the at which bovine and it is important to that is not an for immune variation is and infection with either biotype is capable of causing NCP strains are associated with persistent infection.2 all and subgenotypes to be capable of causing BVDV infection to arise from and is to the NCP strain of BVDV, and PI animals can to heterologous strains of this PI animals can be seropositive to BVDV, and seropositive be to persistent is found in many tissues in PI animals and shed from multiple and and thus PI animals transmission is as all PI birth to PI PI calves are and after birth or as they but some PI calves are and are to from PI animals can have an immune more susceptible to and this could to of the clinical the importance of is the that they shed of virus thus as the major source of virus spread both within and between disease is the most of clinical disease because of the and of disease when PI cattle with a CP Because PI cattle <1% of the cattle population, disease is by a low but The of the CP BVDV can be as virus CP BVDV, or as the of mutations of the NCP BVDV PI resulting in CP of that from the strain of BVDV to disease in a of This when 1 PI a mutation of the NCP BVDV resulting in a CP BVDV, which is spread to PI clinical of disease exist and can be into disease, chronic disease, chronic disease with and The clinical of disease are to the antigenic between the PI NCP strain and the CP diagnostic tests are for BVDV and the of on the clinical the of and The of diagnostic tests are used to PI animals. of BVDV infection laboratory and an is losses are by of management and control of BVDV in using validated is the for of BVDV but because of the greater and time to a for this antigen detection or detection has virus isolation for of BVDV The virus can be cultured and isolated from a of and various from are the for tissues are from A virus isolation has been and as a virus isolation for the detection of PI This is not for is it to use this for calves of as antibodies with the detection as and antigen are used for BVDV detection because they and detection when with virus from antigen tests are highly between The and tests on have used and for the detection of PI are to and can be on PI animals that by virus virus and on serum because of of the tests by The and tests are for the detection of PI animals. Although these tests not infected a might be for infected is using antibodies that an which is not by and the uses a antibody the antigenic that a strain of BVDV has been detected in the United States that is not detected by and for of BVDV infection have use as a diagnostic of with and viral RNA techniques, has made for detection of viral genomic The is and can from to lower of virus than virus thus more than virus The of has it to be for of or this an to BVDV infection in of and by is and are not validated and in BVDV control might be that detection of viral RNA does not to detection of can be used to BVDV infection but there is in antibodies in to a natural after vaccination, or as a of of antibodies from dam to can be used to vaccine and vaccine and by of animals to BVDV exposure has in the The serum virus is the most commonly used serologic to BVDV antibody This can be used for the detection of antibodies BVDV1 or BVDV2 strains depending the viral strain used in the there are no strains for the which of from different pathogen reservoirs and transmission from infected to susceptible animals are the major for disease PI cattle are the major of BVDV, infected animals to a serve as a or of is to BVDV and of that exposure of cattle to BVDV are important for successful When a BVDV and control 3 be identification and of PI through vaccination, and to BVDV exposure of susceptible of these has been to BVDV control and greater can be when used in BVDV control Several have successful eradication and this has and in the United States to control The major source for BVDV transmission is cattle PI with BVDV. of PI animals occur into This can be more in beef cow-calf that a In this all and calves be tested for PI of the Because PI PI a of a a PI for the of calves to be tested for PI PI calves from infection of that could the cattle are at the time of in herds with a they be and calves be tested to the In herds a calves be tested and as as to transmission to the calves for PI is by or on The use of for calves is in that is can be from calves that have and a PI Because the infected animal might be or cattle be after using virus isolation or on all of a is and strategies can be more strategies include of BVDV of use of strategies by and BVDV on or and and are considered the level of and are the but this level of in a PI As an of the in clinical as a to BVDV was isolated from cattle in 53% of herds where there was no of the and BVDV PI animals were not identified in of herds where BVDV was the BVDV in or or in the for for BVDV PI animals. Because of using have been to herds for PI of and have been in by is and for populations of cattle for PI animals. to this in multiple the of the to in or of within the can be by virus or or vaccine are for BVDV, and the of these BVDV in with bovine respiratory and reproductive In the most BVDV BVDV1 strains, but because of antigenic and both BVDV1 and BVDV2 strains are now There are and to use of BVDV viral and of BVDV is that are for the initial and a major with using is the of among by to the are an important to BVDV and has been to transmission and clinical disease rather than infections with BVDV, as has been demonstrated in experimental and studies using either or BVDV from clinical disease is important for and and cattle that at a with antibody titers to BVDV to have bovine respiratory disease cattle by and BVDV and respiratory and the of bovine respiratory disease in BVDV and of virus throughout the infection of the reproductive and The for vaccine has from clinical disease to infections after BVDV being influenced by use of or the of and the of between vaccine and strains. is when animals are with strains from the Although is not the level of is to that when is not as by rates of PI animals in unvaccinated the of PI strict is to of the All cattle be isolated and tested for PI into the of for 3 into the transmission of BVDV from infected animals. in PI cattle or cattle with BVDV of the cattle be isolated and tested to ensure that they are of BVDV. be used from that have been tested for BVDV herds and of for PI is of cattle to ruminants at be and animals be for 3 into the for BVDV control disease control of include of with and of and the Since the of BVDV, control have been and at the control to be multidimensional and on 1 as BVDV control requires a that with first the virus, its associated clinical and it might the with this are able to and more it related to BVDV control that can be different for and a control can be from BVDV from a with an to the virus from a BVDV these 2 different diagnostic vaccination, and be using the BVDV current management and the of introduction of the virus on animal and the BVDV is a of serologic or to the of the virus can the control to be to criteria as of or of BVDV animals can be used to the the control has on the of the control of control requires that and the to through a are by a of and a of associated with that The of is the of the can be through There is a that BVDV be to the and there is the of disease it is There are associated with strategies to the or are and is control strategies can be be to BVDV is in to this in and importantly, PI animals to be identified and BVDV is detected in the to the of infection or virus on the be BVDV is not in the to the of BVDV be in have BVDV control or eradication with several of BVDV in cattle The has that BVDV can be and however, an eradication for 1 of the world might not to geographic or eradication be with on virus and management into the A for of a is level of and of cattle of animal of animal and potential for with reservoirs are that can and of a BVDV control among BVDV strains and vaccine in the region could of All to be considered time and are BVDV eradication in or regions of In North America, and have on BVDV for control and eventual eradication of the virus in North have BVDV control and at it is to have been made regarding of BVDV, its associated diseases, and the for BVDV infections a source for losses in the cattle worldwide. and antigenic of BVDV strains, potential for hosts, and in vaccine and diagnostic are and areas of as control and eradication are important to virus are and with control and eradication thus are through have to and strategies at the detection and of PI and this has to the of control of PI animals is the for BVDV control and but and and are important for ultimate are in a unique to the of and BVDV. knowledge and with the to the cattle these