Bovine viral diarrhea (BVD) is a pestivirus infection affecting cattle and some other ruminant species. The name bovine viral diarrhea is misleading in that the disease does not specifically affect the digestive tract but rather has immune suppression as a hallmark sign. Clinical disease associated with BVD virus 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 but highly fatal form of BVD occurring in persistently infected (PI) cattle and can have an acute or chronic presentation. MD is induced when PI cattle become superinfected with cytopathic BVDV. The origin of the cytopathic BVDV causing superinfection is usually internal, resulting from a mutation of the resident persistent, noncytopathic BVDV. In those cases, the cytopathic virus is antigenically similar to the resident noncytopathic virus and thus does not induce an immune response. External origins for cytopathic BVDV include other cattle and modified-live virus vaccines. Cattle that develop mucosal disease due to exposure to a cytopathic virus of external origin often produce antiviral antibody. Prevalence of persistent infection usually is low, and many persistently infected cattle do not develop mucosal disease, regardless of exposure. MD is a highly fatal disease complex characterized by profuse enteritis in association with 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, and rinderpest, which is currently considered to be eradicated worldwide.
Bovine viral diarrhea virus (BVDV), the causal agent of BVD and MD complex, is classified in the genus Pestivirus in the family Flaviviridae. Although cattle are the primary host for BVDV, several reports suggest most even-toed ungulates are also susceptible. Classically, isolates of BVDV are separated into noncytopathic and cytopathic biotypes based on their ability or lack of ability to cause overt cytopathic change and cell death in cell cultures. Noncytopathic BVDV is the predominant viral biotype in nature, whereas cytopathic BVDV is relatively rare and of little epidemiologic relevance. The cytopathic biotype arises in cattle that are persistently infected with 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, with heterologous viral RNA, or with host cell RNA.
Based on comparisons of nucleotide sequence in the viral RNA, 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 BVDV are represented in each viral genotype. In recent years, a new group of atypical pestiviruses, apparently forming a separate species, of which cattle are the most likely host species, have been recognized. Virus of this third Pestivirus genotype are designated as "HoBi"-like pestiviruses. The subgenotypes are clusters of viruses within a viral genotype that are highly similar in nucleotide sequence of the viral RNA. (Subgenotypes are designated by lower case letters; thus, subgenotypes of BVDV genotype 1 are represented as 1a, 1b, 1c, etc). Currently, at least 12 subgenotypes for BVDV-1 (BVDV-1a to BVDV-1l) and two subgenotypes for BVDV-2 (BVDV-2a and BVDV-2b) are recognized.
BVDV type 1 and type 2 appear to be distributed worldwide; however, the prevalence of each type of virus varies considerably among regions. The distribution of viral subgenotypes is more restricted, with many viral subgenotypes being found only in certain regions of the world and, in some cases, only certain regions of a country. All BVDV, regardless of genotype or subgenotype, are antigenically related. However, serologic assays that use serum obtained from convalescent cattle can distinguish BVDV type 1 from type 2. The extent of antigenic variation among BVDV of different genotypes and subgenotypes remains unknown, but there is concern that the antigenic differences among BVDV may be sufficient to affect protection conferred by vaccination.
Serologic 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, BVD is considered the single most important viral infection of cattle. The prevalence of antiviral antibody in cattle varies greatly among countries and geographic regions because of differing cattle housing practices, population densities, vaccination practices, and implementation of different control or eradication programs. Prevalence of antiviral antibody may be >90% if vaccination is commonly practiced in a geographic region. Although cattle of all ages are susceptible, most cases of overt clinical disease are seen in cattle between 6 months and 2 years old.
Cattle persistently infected with noncytopathic BVDV serve as a natural reservoir for virus. Persistent infection develops when noncytopathic BVDV is transmitted transplacentally during the first 4 months of fetal development. The calf is born infected with virus, remains infected for life, and usually is 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 antibody against BVDV.
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 ~1%–2% but may approach 4% on dairy farms with endemic BVDV infection. On a given farm, persistently infected cattle are often found in cohorts of animals that are approximately the same age.
Persistently infected cattle can shed large amounts of BVDV in their secretions and excretions and readily transmit virus to susceptible herdmates. Clinical disease and reproductive failure often are seen after healthy cattle come in contact with a persistently infected animal. Although persistently infected cattle are important in transmission of BVDV, the virus also may be spread by biting insects, fomites, semen, biologic products, and other animals, including swine, sheep, goats, camelids, and possibly wild ruminants.
Disease induced by bovine viral diarrhea virus varies in severity, duration, and organ systems involved. Infection of immunocompetent susceptible animals with either noncytopathic or cytopathic BVDV is termed acute or transient BVD. Inapparent or subclinical infection without any clinical signs that is followed by seroconversion is the most common form of infection in the field. Acute clinical disease may range from mild disease of high morbidity and low mortality to severe enteric disease with considerable mortality. Biphasic fever (~104°F [40°C]), depression, decreased milk production, transient inappetence, rapid respiration, excessive nasal secretion, excessive lacrimation, and diarrhea are typical signs of acute clinical BVD.
Clinical signs of disease usually are seen 6–12 days after infection and last 1–3 days. Transient leukopenia may be seen with onset of signs of disease. Recovery is rapid and coincides with production of viral neutralizing antibody. Gross lesions seldom are seen in cases of mild disease. Lymphoid tissue is a primary target for replication of BVDV, which may lead to immunosuppression and enhanced severity of intercurrent infections.
Some isolates of BVDV (BVD type 2) have been associated with severe clinical disease that manifests as high fever (~107°F [41°–42°C]), oral ulcerations, eruptive lesions of the coronary band and interdigital cleft, diarrhea, dehydration, leukopenia, and thrombocytopenia. In thrombocytopenic cattle, petechial hemorrhages may be seen in the conjunctiva, sclera, nictitating membrane of the eyes, 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 the viscera, and extensive lymphoid depletion are associated with severe forms of acute BVD. The duration of overt disease may be 3–7 days. High morbidity with a mortality of ≥25% is common. Severity of acute BVD is related to the virulence of the viral strain infecting the animal and does not depend on viral biotype.
In pregnant cattle, BVDV may cross the placental barrier and infect the fetus. The consequences of fetal infection usually are seen several weeks to months after infection of the dam and depend on the stage of fetal development and on the strain of BVDV. Infection of the dam near the time of fertilization may result in reduced conception rates. Infection during the first 4 months of fetal development may lead to embryonic resorption, abortion, growth retardation, or persistent infection. Congenital malformations of the eye and CNS result from fetal infections that occur between months 4–6 of development. Fetal mummification, premature birth, stillbirth, and birth of weak calves also are seen after fetal infection.
Persistent infection is an important sequela of fetal infection with noncytopathic BVDV. Persistently infected calves may appear healthy and normal in size, or they may show stunted growth and be prone to respiratory or enteric ailments. They often have a short life span, and death before 2 years of age is common. Persistently infected cows always give birth to persistently infected calves, but most calves sired by a persistently infected bull will not be infected with virus in utero. Lesions attributable to BVDV often are not seen in persistently infected cattle at necropsy. Antibody against BVD seldom is detected in persistently infected cattle in the absence of vaccination or superinfection with an antigenically heterologous BVDV. Persistently infected cattle exposed to BVDV that is antigenically different from their resident noncytopathic virus can produce antiviral antibody. Therefore, screening for persistent infection using serologic tests to identify animals that lack antiviral antibody may not detect some persistently infected cattle.
Clinical signs of acute MD include fever, leukopenia, dysenteric diarrhea, inappetence, dehydration, erosive lesions of the nares and mouth, and death within a few days of onset. At necropsy, erosions and ulcerations may be found throughout the GI tract. The mucosa over Peyer’s patches may be hemorrhagic and necrotic. Extensive necrosis of lymphoid tissues, especially gut-associated lymphoid tissue, is seen on microscopic examination.
Clinical signs of chronic MD may 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 seen in acute mucosal disease. Often, the only gross lesions seen are focal ulcerations in the mucosa of the cecum, proximal colon, or rectum, and the mucosa over Peyer’s patches of the small intestine may appear sunken.
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 also is required in some outbreaks of MD or clinically severe acute BVD, because either disease may appear similar to rinderpest or malignant catarrhal fever.
Laboratory tests for BVDV include isolation of virus or viral antigen in clinical specimens and tissues, and assays that detect anti-BVDV antibody in serum or milk. Because antibody against BVDV can be highly prevalent in regions with high infection prevalence and/or common use of BVD vaccines, a single serologic test is seldom sufficient for diagnosis of recent infection. A >4-fold increase in antibody titer in paired serum samples obtained ≥2 weeks apart is necessary to verify recent 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 antibody can impair the sensitivity of virus isolation in blood during the first month of life.
A cost-effective sensitive approach to bypass the issue of maternal antibody impairing the virus isolation from blood in young calves consists of obtaining an ear notch when newborn calves are to be tested for possible PI status. Obtained ear notches are formalin fixed and sent to a diagnostic lab to be assayed for presence of BVDV in the tissue specimen by immunohistochemistry. In contrast to virus isolation in blood, identification of PI animals by ear notching does not require repeated sampling. Transiently infected animals can be differentiated from PI animals based on the much larger amount of virus present in tissue obtained from PI calves. At necropsy, tissues of choice for viral isolation include spleen, lymph node, and ulcerated segments of the GI tract.
Alternatives to viral isolation include antigen-capture ELISA to detect virus in blood, serum, or tissue biopsies; immunohistochemistry to detect viral protein in frozen or fixed tissues; PCR to detect viral RNA in clinical specimens; and PCR or in situ hybridization to detect viral RNA in fresh or fixed tissues. Differentiation of viral genotypes and subgenotypes may be accomplished by PCR assays alone, or by PCR assays 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 of bovine viral diarrhea remains limited primarily to supportive therapy. Control is based on sound management practices that include 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 vaccination of replacement cattle for BVD should be done before commingling with the resident herd. Embryo donors and recipients also should be tested for persistent 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 BVDV 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.
Screening cattle herds for persistent infection can be done by PCR assays using blood or milk; by classical virus isolation methods using serum or buffy coat cells; by antigen-capture ELISA using serum, buffy coat, milk, or skin biopsies; or by 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, persistently infected 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 vaccines are available. They contain a variety of strains of BVDV representing both viral biotypes and viral genotypes 1 and 2. Antigenic diversity among BVDV may affect the efficacy of a given vaccine if the vaccine virus or viruses differ significantly from the challenge virus. Proper and safe immunization of cattle with either inactivated or modified-live virus vaccines requires adherence to the manufacturer’s instructions. Because BVDV is fetotropic and immunosuppressive, use of modified-live virus vaccines is not recommended in cattle that are pregnant or showing signs of disease.
Inactivated viral vaccines may be used in pregnant cattle. Protection conferred by inactivated vaccines may be of short duration, and frequent vaccination may be necessary to prevent disease or reproductive failure. Colostral antibody confers partial to complete protection against disease in most calves for 3–6 months after birth. Vaccination of neonatal cattle that have acquired colostral antibody may not stimulate a protective immune response, and revaccination at 5–9 months of age may be necessary. A booster dose of vaccine is often administered before first breeding, and additional booster doses of vaccine may be administered in subsequent years before breeding.
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, serology, or PCR.
Control and prevention can be accomplished through improved biosecurity and vaccination.