Bovine Viral Diarrhea and Mucosal Disease Complex

Bovine viral diarrhea (BVD) is most common in young cattle (6-24 mo old) and generally is accompanied by typical mucosal lesions; it must be distinguished from other viral diseases that produce diarrhea and mucosal lesions. These include malignant catarrhal fever ( Malignant Catarrhal Fever: Introduction), which usually is a sporadic disease in more mature cattle, and rinderpest ( Rinderpest: Introduction), which can be seen in outbreak form but is exotic in most countries.

Bovine viral diarrhea virus (BVDV), the causal agent of BVD and mucosal disease 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. Isolates of BVDV are separated into noncytopathic and cytopathic biotypes based on cytopathic effects observed in infected cell cultures. Noncytopathic BVDV are the predominant viral biotype in nature. Cytopathic BVDV are relatively rare and arise in cattle that are persistently infected with noncytopathic BVDV. The switch in viral biotype is triggered by mutations that often involve recombination of noncytopathic viral RNA with itself, with heterologous viral RNA, or with host cell RNA. Based on viral RNA sequence, there are at least 2 viral genotypes of BVDV that can be further divided into subgenotypes. The viral genotypes are termed BVDV type 1 and BVDV type 2, and both cytopathic and noncytopathic BVDV are represented in each viral genotype. Although the viral genotypes are antigenically related, serologic assays can separate BVDV type 1 from BVDV type 2.

Etiology and Epidemiology:

Serologic surveys indicate that BVDV is distributed worldwide. The prevalence of antiviral antibody in cattle varies among countries and may vary between geographic regions within a country. Prevalence of antiviral antibody may be >90% if vaccination is practiced commonly in a geographic region. Although cattle of all ages are susceptible, most cases of overt clinical disease are seen in cattle that are between 6 mo and 2 yr of age.

Cattle that are 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 mo 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 results in abortion, congenital malformations, or birth of normal calves that have antibody against BVDV. The prevalence of persistent infection varies among countries and between regions within a country. In some areas, the prevalence of persistent infection in calves may be as high as 1-2% of cattle <1 yr of age. 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. Biting insects, fomites, semen, biologic products, and possibly wild ruminants also can spread BVDV.

Clinical Findings and Lesions:

Disease induced by BVDV varies in severity, duration, and organ systems involved. Acute disease results from infection of susceptible cattle with either noncytopathic or cytopathic BVDV. Acute BVD, also termed transient BVD, often is an inapparent to mild disease of high morbidity and low 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 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 induce clinically severe 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 moderate mortality 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 or genotype.

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 mo 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 lifespan, and death before 2 yr of age is common. Persistently infected cows 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 the viral neutralization test to identify animals that lack antiviral antibody may not detect some persistently infected cattle.

Mucosal disease is a highly fatal form of BVD that may be acute or chronic and is seen infrequently in persistently infected cattle. Mucosal disease is induced when persistently infected cattle become superinfected with cytopathic BVDV. The origin of the cytopathic BVDV 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. 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. Acute mucosal disease is characterized by 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 mucosal disease may last several weeks to months and are less severe than those of acute mucosal disease. 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.

Diagnosis:

BVD is diagnosed tentatively from disease history, 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 mucosal disease or clinically severe acute BVD because either disease may appear similar to rinderpest ( Rinderpest: Introduction) or malignant catarrhal fever ( Malignant Catarrhal Fever: Introduction).

Laboratory tests for BVDV include virus isolation and assays that detect antibody in serum or detect viral RNA or viral antigen in clinical specimens and tissues. Because antibody against BVDV is prevalent in most cattle populations, a single serologic test is seldom sufficient for diagnosis. A >4-fold increase in antibody titer in paired serum samples obtained 2 more 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 wk apart. 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 from blood or serum, 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 usually is done by PCR or PCR followed by nucleic acid sequencing. Monoclonal antibody binding assays and nucleic acid hybridization assays also differentiate viral genotypes.

Treatment and Control:

Treatment of BVD is 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 wk 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 1 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 is done by virus isolation from serum or buffy coat cells, antigen-capture ELISA from serum or buffy coat, or antigen detection in 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 sold for slaughter as soon as possible.

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 may be 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 mo after birth. Vaccination of neonatal cattle that have acquired colostral antibody may not stimulate a protective immune response, and revaccination at 5-9 mo of age may be necessary.