Bovine viral diarrhea and mucosal disease are caused by infection with the bovine viral diarrhea virus, which can affect cattle and other ruminants. Infection leads to immunosuppression, and the virus can affect various organ systems in addition to the GI tract. Mucosal disease is typically a fatal clinical presentation that only affects persistently infected cattle. Depending on the strain virulence and immune status of the animal, clinical signs can range from inapparent infection to fever, depression, decreased milk production, abortion, diarrhea, and death. Diagnosis is based on clinical signs, PCR assay, virus isolation, and serological testing. Treatment consists of supportive care. Improved biosecurity, identification and elimination of persistently infected animals, and vaccination are techniques used for control and prevention.
Bovine viral diarrhea (BVD) is caused by bovine viral diarrhea virus (BVDV). It affects cattle and some other ruminant species. The name "bovine viral diarrhea" is misleading in that the disease does not specifically affect the GI tract. Instead, its hallmark sign is immune suppression. Disease associated with BVDV infection is most common in young cattle (6–24 months old). The clinical presentation can range from inapparent or subclinical infection to acute and severe enteric disease.
Mucosal disease (MD) is an uncommon and highly fatal form of BVD that occurs only in individuals that were first infected as fetuses between the 40th and 120th days of gestation, resulting in lifelong infection. These animals are considered persistently infected (PI). MD is induced when PI cattle become superinfected later in life with cytopathic BVDV.
The origin of the cytopathic BVDV that causes superinfection can be internal or external. Internal superinfection results from a mutation of the resident persistent, noncytopathic BVDV. In those cases, the cytopathic virus is antigenically similar to the resident noncytopathic virus and does not induce an immune response. External origins for cytopathic BVDV include other cattle and modified live virus vaccines.
Cattle that develop MD because of exposure to a cytopathic BVDV of external origin often produce antiviral antibodies. The prevalence of persistent infection is usually low, and many PI cattle do not develop MD, regardless of exposure. MD is a highly fatal disease complex characterized by profuse enteritis in association with the typical mucosal lesions.
BVD must be distinguished from other viral diseases that produce diarrhea and mucosal lesions. These include malignant catarrhal fever, which usually is a sporadic disease in more mature cattle; bluetongue; epizootic hemorrhagic disease; and rinderpest, which is currently considered to have been eradicated worldwide.
BVDV, the causative agent of BVD and MD complex, is classified in the genus Pestivirus in the family Flaviviridae. Cattle are the primary host for BVDV; however, several reports suggest most even-toed ungulates are also susceptible (1). Typically, isolates of BVDV are separated into noncytopathic and cytopathic biotypes according to their ability to cause overt cytopathic change and cell death in cell cultures.
Noncytopathic BVDV is the predominant viral biotype in nature. Cytopathic BVDV is relatively rare and of little epidemiological relevance. The cytopathic biotype arises in cattle that are persistently infected with the noncytopathic biotype of the same or a genetically similar BVDV strain. The switch in biotype is the result of mutations that often involve recombination of noncytopathic viral RNA with itself, heterologous viral RNA, or host cell RNA.
Comparisons of nucleotide sequence in the viral RNA indicate there are at least two viral genotypes (distinct genetic groups) of BVDV that can be further divided into subgenotypes or genogroups. The viral genotypes are termed BVDV type 1 and BVDV type 2, and both cytopathic and noncytopathic BVD viruses are represented in each viral genotype.
A new group of atypical pestiviruses, apparently forming a separate species, of which cattle are the most likely host species, was recognized in 2004 (2). Viruses of this third Pestivirus genotype are designated as "HoBi"-like pestiviruses. The subgenotypes are clusters of viruses within a viral genotype whose viral RNA has highly similar nucleotide sequence. (Subgenotypes are designated by lowercase letters; thus, subgenotypes of BVDV genotype 1 are represented as 1a, 1b, 1c, etc). Currently, at least 12 subgenotypes for BVDV-1 (BVDV-1a through BVDV-1l) and two subgenotypes for BVDV-2 (BVDV-2a and BVDV-2b) are recognized.
BVDV type 1 and BVDV type 2 appear to be distributed worldwide; however, the prevalence of each type varies considerably among regions. The distribution of viral subgenotypes is more restricted; many are found in only certain regions of the world and, in some cases, in only certain regions of a country.
All BVD viruses, regardless of genotype or subgenotype, are antigenically related. However, serological assays that use serum obtained from convalescent cattle can distinguish type 1 from type 2. The extent of antigenic variation among BVD viruses of different genotypes and subgenotypes remains unknown; however, there is concern that the antigenic differences among BVD viruses might be sufficient to affect protection conferred by vaccination.
Etiology and Epidemiology of Bovine Viral Diarrhea
Serological surveys conducted throughout the world suggest that bovine viral diarrhea virus is endemic in the cattle population of most cattle-producing countries. In some countries, bovine viral diarrhea is considered the single most important viral infection of cattle.
The prevalence of antiviral antibodies in cattle varies greatly among countries and geographical regions because of differing cattle-housing practices, population densities, vaccination practices, and implementation of control or eradication programs. The prevalence of antiviral antibodies can be > 90% if vaccination is commonly practiced in a geographical region. Since the 1990s in Europe, several countries have achieved or will be achieving eradication of BVD after vigorous disease control (3).
Cattle of all ages are susceptible to BVD; however, most cases of overt disease occur in cattle between 6 months and 2 years old.
Cattle persistently infected with noncytopathic BVDV serve as a natural reservoir for the virus. Persistent infection develops when noncytopathic BVDV is transmitted transplacentally during the first 4 months of fetal development. The calf is born infected with the virus, remains infected for life, and is usually immunotolerant to the resident noncytopathic virus. Transplacental infection that occurs later in gestation can result in abortion, congenital malformations, or birth of apparently healthy calves that have antibodies against BVDV.
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The prevalence of persistent infection varies among countries and between regions within a country. The estimated mean animal prevalence of persistent infection with BVDV is approximately 1–2%; however, it can approach 4% on dairy farms with endemic BVDV infection. On a given farm, PI cattle are often found in cohorts of animals that are approximately the same age.
PI cattle can shed large amounts of BVDV in their secretions and excretions and readily transmit virus to susceptible herdmates. Clinical signs and reproductive failure often occur after healthy cattle come into contact with a PI animal. PI cattle are important in the transmission of BVDV; however, the virus can also be transmitted via biting insects, fomites, semen, biological products, and other animals, including swine, sheep, goats, camelids, and possibly wild ruminants.
Clinical Findings and Lesions of Bovine Viral Diarrhea
Disease induced by bovine viral diarrhea virus varies in severity, duration, and the organ systems involved. Infection of immunocompetent susceptible animals with either noncytopathic or cytopathic BVDV is termed acute or transient bovine viral diarrhea. Inapparent or subclinical infection without any clinical signs that is followed by seroconversion is the most common form of infection in the field.
Acute BVD can range from mild disease of high morbidity and low mortality to severe enteric disease with considerable mortality. Biphasic fever (approximately 40°C [104°F]), depression, decreased milk production, transient decrease in appetite, rapid respiration, nasal secretion, lacrimation, and diarrhea are typical signs of acute BVD.
Clinical signs of BVD usually occur 6–12 days after infection. Transient leukopenia can occur with onset of signs of disease. Recovery is rapid and coincides with the production of viral-neutralizing antibodies. Gross lesions are rare in cases of mild disease. Lymphoid tissue is a primary target for replication of BVDV, which might lead to immunosuppression and enhanced severity of intercurrent infections.
Some BVDV type 2 isolates have been associated with severe disease that manifests as high fever (approximately 41–42°C [105.8-107.6°F]), oral ulcerations, eruptive lesions of the coronary band and interdigital cleft, diarrhea, dehydration, leukopenia, and thrombocytopenia. In thrombocytopenic cattle, petechial hemorrhages can occur in the ocular conjunctiva, sclera, and nictitating membrane and on mucosal surfaces of the mouth and vulva. Prolonged bleeding from injection sites also occurs.
Swollen lymph nodes, erosions and ulcerations of the GI tract, petechial and ecchymotic hemorrhages on the serosal surfaces of viscera, and extensive lymphoid depletion are associated with severe forms of acute BVD. The duration of overt disease can be 3–7 days. High morbidity with a mortality of ≥ 25% is common. The severity of acute BVD is related to the virulence of the viral strain infecting the animal and does not depend on the viral biotype.
In pregnant cattle, BVDV can cross the placental barrier and infect the fetus. The consequences of fetal infection are usually evident several weeks to months after infection of the dam and depend on what stage of development the fetus is in when infected and on the strain of BVDV.
Infection of the dam near the time of fertilization might result in decreased conception rates.
Infection during the first 4 months of fetal development can lead to embryonic resorption, abortion, growth delay, or persistent infection.
Congenital malformations of the eye and CNS result from fetal infections that occur between months 4 and 6 of development.
Fetal mummification, premature birth, stillbirth, and birth of weak calves also occur after fetal infection.
Persistent infection is an important sequela of fetal infection with noncytopathic BVDV. PI calves can appear healthy and normal in size, or they might show stunted growth and be prone to respiratory or enteric ailments. They often have a short lifespan, and death before 2 years old is common. PI cows always give birth to PI calves; however, most calves sired by a PI bull will not be infected with the virus in utero.
Lesions attributable to BVDV often are not evident in PI cattle at necropsy. Antibodies against BVD are seldom detected in PI cattle in the absence of vaccination or superinfection with an antigenically heterologous BVDV. PI cattle exposed to BVDV that is antigenically different from their resident noncytopathic virus can produce antiviral antibodies. Therefore, screening for persistent infection using serological tests to identify animals that lack antiviral antibodies might not detect some PI cattle.
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Clinical signs of acute mucosal disease include fever, leukopenia, dysenteric diarrhea, decreased appetite, dehydration, erosive lesions of the nares and mouth, and death within a few days after onset. At necropsy, erosions and ulcerations might be found throughout the GI tract. The mucosa over Peyer’s patches might be hemorrhagic and necrotic. Extensive necrosis of lymphoid tissues, especially gut-associated lymphoid tissue, is present on microscopic examination.
Clinical signs of chronic mucosal disease can last several weeks to months and are less severe than those of acute MD. Intermittent diarrhea and gradual wasting are common. Coronitis and eruptive lesions on the skin of the interdigital cleft cause lameness in some cattle. Lesions found at necropsy are less pronounced than, but similar to, those evident in acute MD. Often, the only gross lesions are focal ulcerations in the mucosa of the cecum, proximal colon, or rectum, and the mucosa over Peyer’s patches of the small intestine might appear sunken.
Diagnosis of Bovine Viral Diarrhea
Clinical examination
Virus isolation, serological testing, or PCR assay
Ear notch testing: immunohistochemistry
Bovine viral diarrhea is diagnosed tentatively from disease history of the herd, clinical signs, and gross and microscopic lesions. Diagnostic laboratory support is required when clinical signs and gross lesions are minimal. Laboratory support is also required in some outbreaks of mucosal disease or of clinically severe acute BVD, because either disease can appear similar to bluetongue, epizootic hemorrhagic disease, malignant catarrhal fever, or rinderpest.
Laboratory tests for bovine viral diarrhea virus include isolation of virus or viral antigen in clinical specimens and tissues as well as detection of anti-BVDV antibodies in serum or milk. Because antibodies against BVDV can be highly prevalent in regions with high infection prevalence and/or common use of BVD vaccines, a single serological test is seldom sufficient for diagnosis of acute infection.
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A > 4-fold increase in antibody titer in paired serum samples obtained ≥ 2 weeks apart is necessary to verify acute BVD infection. Isolation of BVDV from blood, nasal swab specimens, or tissues confirms active infection. Identification of persistent infection requires detection of virus in clinical specimens obtained at least 3 weeks apart. Colostral antibodies can impair the sensitivity of virus isolation in blood during the first month of life.
A cost-effective sensitive approach that bypasses the problem of maternal antibodies impairing virus isolation from blood in young calves consists of obtaining an ear notch from newborn calves. Ear notches are formalin fixed and sent to a diagnostic laboratory to be assayed for the presence of BVDV in the tissue specimen by immunohistochemistry.
In contrast to BVDV isolation in blood, identification of PI animals by ear notching does not require repeated sampling. Transiently infected animals can be differentiated from PI animals by the much larger amount of virus present in tissue obtained from PI calves. At necropsy, tissues of choice for viral isolation include the spleen, lymph nodes, and ulcerated segments of the GI tract.
Alternatives to viral isolation include the following:
antigen-capture ELISA to detect virus in blood, serum, or tissue biopsies
immunohistochemistry to detect viral protein in frozen or fixed tissues
PCR assay to detect viral RNA in clinical specimens
PCR assay or in situ hybridization to detect viral RNA in fresh or fixed tissues
Viral genotypes and subgenotypes can be differentiated by PCR assay alone or by PCR assay followed by analysis of nucleotide sequence, restriction fragment analysis, or palindromic nucleotide substitution analysis. Monoclonal antibody–binding assays and viral neutralization assays also differentiate viral genotypes.
Treatment and Control of Bovine Viral Diarrhea
Supportive care
Testing: eliminate PI cattle; screen replacement animals, embryos, and semen
Vaccination
Treatment of bovine viral diarrhea remains limited primarily to supportive therapy. Control is on the basis of sound management practices that include the use of biosecurity measures, elimination of persistently infected cattle, and vaccination. Replacement cattle should be tested for persistent infection before entry into the herd. Quarantine or physical separation of replacement cattle from the resident herd for 2–4 weeks should be considered, and replacement cattle should be vaccinated for BVD before being commingled with the resident herd.
Embryo donors and recipients should also be tested for persistent BVD infection. If vaccination of embryo donors or recipients is warranted, it should be done at least one estrous cycle before embryo transfer is performed. Because bovine viral diarrhea virus is shed into semen, breeding bulls should be tested for persistent infection before use. Artificial insemination should be done only with semen obtained from bulls free of persistent infection.
The following techniques can be used to screen cattle herds for persistent infection:
PCR assay using blood or milk
virus isolation methods using serum or buffy coat cells
antigen-capture ELISA using serum, buffy coat, milk, or skin biopsies
antigen detection using immunochemical methods on tissue or skin biopsies
Several strategies, based on herd size, type of herd being screened, financial limitations of the herd owner, and testing ability of the diagnostic laboratory being used, are available to screen herds for persistent infection. When identified, PI cattle should be removed from the herd as soon as possible, and direct or indirect contact with pregnant cattle should be prevented.
Inactivated and modified live virus BVD vaccines are available. They contain a variety of strains of BVDV representing both viral biotypes and viral genotypes 1 and 2. Antigenic diversity among BVD viruses can affect the efficacy of a given vaccine if the vaccine virus or viruses differ substantially from the challenge virus.
Proper and safe immunization of cattle with either inactivated or modified live virus BVD vaccines requires adherence to the manufacturer’s instructions. Because BVDV is fetotropic and immunosuppressive, use of modified live virus vaccines is not recommended in pregnant cattle that are due to be vaccinated for the first time against BVD.
Inactivated BVD vaccines can be used in pregnant cattle for basic immunization. Protection conferred by inactivated vaccines might be of short duration, and frequent vaccination might be necessary to prevent disease or reproductive failure. Colostral antibodies confer partial to complete protection against disease in most calves for 3–6 months after birth.
Vaccination of neonatal cattle that have acquired colostral antibodies might not stimulate a protective immune response, and revaccination at 5–9 months old might be necessary. A booster dose of vaccine is often administered before first breeding, and additional booster doses can be administered in subsequent years before breeding.
Key Points
Signs of bovine viral diarrhea can range from inapparent infection to severe enteritis, abortion, and death.
Mucosal disease is a form of infection that occurs in persistently infected cattle and is typically fatal.
Diagnosis can be confirmed by virus isolation, PCR assay, or serological testing.
Control and prevention can be accomplished through improved biosecurity and vaccination.
Identification and elimination of persistently infected animals is a key element of any control and eradication program.
For More Information
Evans CA, Pinio B, Larska M, et al. Global knowledge gaps in the prevention and control of bovine viral diarrhoea (BVD) virus. Transbound Emerg Dis. 2018;66(2):640-652.
Evans CA, Reichel MP. Non-bovine species and the risk to effective control of bovine viral diarrhoea (BVD) in cattle. Pathogens. 2021;10(10):1263.
Moennig V, Houe H, Lindberg A.BVD control in Europe: current status and perspectives. Anim Health Res Rev. 2005;6(1):63-74.
References
Evans, CA, Reichel, MP. Non-bovine species and the risk to effective control of bovine viral diarrhoea (BVD) in cattle. Pathogens. 2021;10(10), 1263. doi:10.3390/pathogens10101263
Decaro N, Lucente MS, Mari V, et al. Atypical pestivirus and severe respiratory disease in calves, Europe. Emerg Infect Dis. 2011;(17)8, 1549-1552. doi:10.3201/eid1708.101447
Moennig V, Yarnall MJ. The long journey to BVD eradication. Pathogens. 2021;10(10), 1292. doi:10.3390/pathogens10101292
