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 pregnant alpacas with 3 different BVDV strains (BVDV1b of cattle origin, BVDV 1b of alpaca origin, or BVDV2 of cattle origin) was performed, PI crias were born with only BVDV1b strains of cattle or alpaca origin, but not BVDV2,33 providing further support for a unique role of BVDV1b in alpacas. Both species of BVDV were isolated from Chilean alpacas and llamas, contrasting findings from North America and Great Britain.34 Viremia, nasal shedding, and seroconversion were observed when alpacas were inoculated with BVDV1b or BVDV2 strains.35 Irrespective of BVDV genotypes, biosecurity and surveillance principles are important for BVDV control in alpacas, as movement of alpacas, including dams with crias, between farms for breeding purposes is associated with reproductive disease and birth of PI offspring.27,29,30 Some wildlife are serologically positive to BVDV, and the virus has been isolated from individual animals. The livestock-wildlife interface is of great concern for a number of infectious diseases, including classical swine fever virus, but less is known about the role of wildlife in the epidemiology of BVDV. Wildlife can become infected with BVDV, but other factors, including shedding of the virus, intrapopulation maintenance, and amount of interspecies contact might influence the establishment of BVDV wildlife reservoirs. Similar to cattle, PI wildlife are likely a central factor in the establishment of wildlife reservoirs, and PI animals have been identified in free-ranging and captive species. PI animals were detected among free-ranging eland (Taurotragus oryx) in Zimbabwe and white-tailed deer (Odocoileus virginianus) in the United States.36–38 Apparent prevalence rates of persistent infections in U.S. cervid populations are 0.2% in Alabama, 0.03% in Colorado, and 0.3% in Indiana.36–38 Whether the source for BVDV infection in these populations is contact with cattle, or the result of an endemic cycle is unknown, but evidence for both hypotheses exists, and both explanations are not mutually exclusive. Although 1 study did not identify a correlation between cattle stocking densities and BVDV seroprevalence rates in wildlife,39 seroprevalence rates in white-tailed deer are higher on ranches where cattle were present.40 Also, the management of cattle could have an important impact on interspecific transmission of BVDV, as there is likely less wildlife contact with housed dairy cattle compared with beef cattle in pastures.41 Endemic presence of BVDV is indicated by seroprevalence rates exceeding 60% of caribou (Rangifer tarandus) that had no contact to cattle, and 60% of a mule deer population in Wyoming.22,42 In a group of captive white-tailed deer, BVDV was maintained by exposure of pregnant does to a PI fawn, resulting in birth of PI offspring.43 Vertical transmission of BVDV by transplacental infection resulted in continued birth of PI animals in a maternal lineage of lesser Malayan mouse deer in a zoological collection, emphasizing the potential for maintenance of BVDV in wildlife.44 White-tailed deer are the most abundant free-ranging ruminants in North America. Contact between white-tailed deer and cattle can occur in a typical North American pastoral setting, and this species has potential to be a reservoir for BVDV. Infections of white-tailed deer with BVDV occur by experimental and natural exposure.45,46 Similar to cattle, the most dramatic effects of BVDV infections in white-tailed deer are fetal resorption, fetal mummification, stillbirth, and abortion.46,47 Nasal or rectal shedding occurs in acutely infected and PI white-tailed deer, and results in transmission to other white-tailed deer.43,48 In contrast to transmission of BVDV among white-tailed deer, spill-back infections, or infection of cattle as a result of exposure to white-tailed deer has not yet been demonstrated, but because of its importance, warrants further evaluation. The discovery of novel pestiviruses in wildlife species might lead to new classifications within the genus Pestivirus.49 An isolate from a giraffe is different from pestiviruses of domestic species, based on comparison of complete genomic sequences and palindromic nucleotide substitutions in the 5′-UTR.50 A pestivirus isolated from an immature blind pronghorn is highly divergent from other pestiviruses.51 Although BVDV is not considered a human pathogen, its highly mutable nature, ability to replicate in human cell lines,52 similarity to human hepatitis C virus,53 and isolation from 2 clinically healthy people,54,55 a Crohn's disease patient,56 and feces of children under 2 years old who had gastroenteritis54,55,57 create some concern regarding zoonotic potential. A wide range of clinical manifestations from subclinical to fatal disease occur in association with BVDV infection. The clinical presentation and the outcome of BVDV infection depend on numerous factors, with host influences being very important, and these include immune status, the species of host, pregnancy status and gestational age of the fetus, and the presence of concurrent infections with other pathogens. Viral factors influence clinical presentation and these include biotypic variation, genotypic variation, and antigenic diversity, but it is important to note that BVDV1 and BVDV2 strains can be involved in the entire spectrum of clinical disease. The terms "acute,""transient," and "primary" have been interchangeably used to describe BVDV infection in postnatal cattle, with the ability to respond immunologically to BVDV. The source of most acute infections is cattle PI with BVDV, although acutely infected cattle can be a source of virus to other susceptible cattle.58 The most effective route of transmission appears to be nose-to-nose contact. The majority of BVDV infections in immunocompetent and seronegative cattle are subclinical; however, truly benign BVDV infections probably do not exist, as cattle undergoing an "inapparent" infection could exhibit mild fever, leukopenia, anorexia, and decrease in milk production if observed closely. Moreover, if the infected animal is pregnant, deleterious effects can occur in the fetus. Acute BVDV infections result in signs that include diarrhea, depression, oculonasal discharge, anorexia, decreased milk production, oral ulcerations, and pyrexia, with laboratory findings including leukopenia characterized by lymphopenia and neutropenia. Peracute BVDV infections originally described in Canada and the United States result in severe clinical disease manifestations and higher than expected case fatality rates.59 Genomic analysis of BVDV isolates from infected cattle from these outbreaks indicated the BVDV2 genotype, and this ultimately raised a renewed interest in acute BVDV infections.9,59 Another clinical disease manifestation in cattle acutely infected with BVDV is the hemorrhagic syndrome, which is characterized by thrombocytopenia.60,61 The first descriptions of hemorrhagic syndrome included both calves and adult cattle naturally infected with BVDV, with severe depressions in platelet count.60 Clinical manifestations of the hemorrhagic syndrome are primarily related to thrombocytopenia and include bloody diarrhea, epistaxis, petechial hemorrhages, ecchymotic hemorrhages, and bleeding from injection sites or insect bites. Thrombocytopenic BVDV infections have been experimentally reproduced, almost exclusively with NCP BVDV2 strains.61,62 Platelet dysfunction has also been described with experimental BVDV infection,63 thus quantitative and qualitative platelet defects contribute to the hemorrhagic diathesis observed in infected cattle. BVDV infection of bone marrow megakaryocytes is important in the etiology of BVDV-induced thrombocytopenia.62,64 BVDV is lymphotrophic, and acutely infected cattle are immunosuppressed as a result of reduction in circulating immune cells and diminished function of immune cells. The consequence of immunosuppression is an increased susceptibility to other infectious disease agents, and the bovine respiratory disease complex is an example where BVDV plays an important role in polymicrobial disease. Cells of both the innate and adaptive immune responses are affected by BVDV. Leukopenia occurs in most acutely infected cattle, but the severity of leukopenia can be influenced by BVDV strain. Decreases in total leukocyte count and in leukocyte subpopulations appear to be less dramatic in calves experimentally infected with BVDV1 strains than with some BVDV2 strains; however, this can be simply because of the selection of BVDV strains chosen for study.62,65,66 In general, highly virulent strains of BVDV induce greater declines in the white blood cell count than less virulent strains. Lymphopenia (T-lymphocytes and B-lymphocytes) and neutropenia are the major hematologic abnormalities.66,67 Removal of BVDV-infected leukocytes by the immune system, destruction of immune cells by BVDV, and increased trafficking of immune cells into tissue sites of viral replication are all responsible for leukopenia. During acute infection, lymphoid depletion in the thymus, spleen, lymph nodes, and gut-associated lymphoid tissues (Peyer's patches), and the severity might also be strain dependent.62 Diminished function in immune system cells has also been described during acute BVDV infection, and affected cells include lymphocytes, neutrophils, and monocytes and macrophages.68–70 The importance of BVDV on the male reproductive tract has not received the attention equivalent to the effects on female reproduction. Bulls infected with BVDV are capable of shedding virus in semen.71–73 The virus can survive cryopreservation and processing of semen for artificial insemination.74 Although acutely infected bulls shed lower concentrations of BVDV in semen than PI bulls, infection of artificially inseminated heifers can result from insemination with semen collected from acutely infected bulls before seroconversion.72 Acute BVDV infections generally result in a transient viremia with subsequent clearance of the virus by the host immune system; however, prolonged infection of testicular tissue has been described under both natural and experimental conditions.71,73 Prolonged testicular infection with BVDV was first identified in the testes of a seropositive, nonviremic bull at an artificial insemination center.73 This bull continuously shed infectious BVDV in semen throughout his life despite the absence of a viremia and the presence of consistently high concentrations of circulating serum antibodies that neutralized the specific viral strain that was persistently shed in the semen.75 Localized, prolonged testicular infections with BVDV have also been experimentally reproduced after acute infection of peripubertal bulls with BVDV. Viral RNA has been detected in semen for 2.75 years after BVDV exposure, and infectious virus grown from testicular tissue has been detected up to 12.5 months after BVDV from a immune because of a is believed to be the for the prolonged testicular infection. exists regarding bulls with a prolonged testicular infection can become and infectious to other animals. of pregnant cattle with BVDV can result in transplacental transmission and infection of the fetus. The caused by BVDV in susceptible breeding herds is associated with the of infections, which are 3 gestational age of the at the time of organ system involved in the and biotype, and cell range of the persistent infection, other of reproductive tract infections include or fetal as mummification, and infections as calves or calves of Although and are most during the first and and can be caused by are by BVDV infection between and of and include and The ability of BVDV to cause has been of cattle before insemination This could be in to infection and dysfunction as a result of BVDV and the presence of viral antigen in tissue occur in cattle acutely infected with and pregnancy rates are lower if the animals are at the time of Cattle with NCP BVDV at the time of insemination had a as compared with for the control studies have this that BVDV is involved in and breeding 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 central of BVDV control is the identification and of this major reservoir of the PI calves are the result of in BVDV infection during the of fetal from 45 to which is the gestational by the of the and the of fetal variation is regarding the gestational age at which bovine become and it is important to note that is not an for immune system variation is important, and infection with either biotype is capable of causing fetal only NCP strains are associated with persistent infection.2 all and subgenotypes appear to be capable of causing BVDV infection appears to arise from specific and is specific to the NCP strain of BVDV, and postnatal PI animals can respond immunologically to heterologous strains of this PI animals can be seropositive to BVDV, and seropositive status be to persistent infection. is found in many tissues in PI animals and shed from multiple including nasal and and thus PI animals Vertical transmission is as all PI birth to PI PI calves are born and after birth or as they but some PI calves are born and are to from PI animals can have an immune more susceptible to and this could contribute 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 dramatic of clinical disease because of the severity and of disease occurs when PI cattle become with a CP Because PI cattle <1% of the cattle population, disease is characterized by a low case but high case fatality The of the CP BVDV can be as virus CP BVDV, or as the result of mutations of the NCP BVDV PI resulting in CP of that from the strain of BVDV to disease in a of This occurs 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 acute fatal 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 majority of diagnostic tests are used to identify PI animals. of BVDV infection laboratory and an positive is further losses are by of management and control of BVDV in cell using validated is the for of BVDV but because of the greater and time to a result for this antigen detection or detection has virus isolation for of BVDV infection. The virus can be cultured and isolated from a of including nasal and various cells from blood are the for lymphoid tissues are from A virus isolation has been and as a virus isolation primarily for the detection of PI This is not for acute infections, is it to use this for calves months of as antibodies with the detection as and antigen are used for BVDV detection because they and detection when compared with virus results from antigen tests are highly between The and tests on have become 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 do not acutely infected a positive results might be observed for acutely infected is using antibodies that an which is not by and the also uses a antibody the antigenic note 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 specific and can from to lower concentrations of virus than virus thus more than virus The high of has it to be for of or milk this an to BVDV infection in of and by is and if are not validated and in BVDV control might be also note that detection of viral RNA does not to detection of infectious can also be used to BVDV infection but there is in antibodies in to a natural infection, after vaccination, or as a result of of maternal antibodies from dam to can be used to vaccine and vaccine and by of animals to if BVDV exposure has in the The serum virus is the most commonly used

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