Bovine Leukosis: Introduction - The Merck Veterinary Manual

Bovine Leukosis: Introduction
(Bovine lymphosarcoma, Leukemia, Malignant lymphoma)

Etiology, Transmission, and Epidemiology

Pathogenesis

Clinical Findings

Lesions

Diagnosis

Treatment and Control

Prevention

Enzootic bovine leukosis is a viral disease of adult cattle characterized by neoplasia of lymphocytes and lymph nodes. The prevalence of infection in a herd may be high, but only a few animals develop fatal lymphosarcoma. Infection is spread by contact with contaminated blood from an infected animal. Sporadic bovine leukosis consists of juvenile, thymic, and cutaneous lymphosarcomas. These may resemble enzootic bovine leukosis, but affected animals are seronegative for bovine leukemia virus (BLV).

Outbreaks of lymphosarcoma in sheep have been observed with clinical, epidemiologic, hematologic, and necropsy findings similar to those of enzootic bovine leukosis. Infection of other species with BLV has not been demonstrated. Epidemic occurrences of lymphosarcoma have been observed in pigs. Cases in horses are sporadic.

Etiology, Transmission, and Epidemiology:

Enzootic bovine leukosis is caused by BLV, an exogenous C-type oncovirus in the family Retroviridae. Infection occurs by iatrogenic transfer of infected lymphocytes and is followed by a permanent antibody response and, less frequently, development of persistent lymphocytosis or lymphosarcoma. This form is rarely seen in animals <2 yr of age and is most common in the 4- to 8-yr age group. Sporadic bovine leukosis occurs in 3 forms: 1) juvenile in calves <6 mo old, characterized by multiple lymph node enlargement; 2) thymic in cattle <2 yr old, characterized by a swelling in the neck causing bloat and edema; and 3) cutaneous in cattle 1-3 yr old, characterized by the development of nodes and plaques in the skin. There is no evidence that these forms of sporadic bovine leukosis are caused by an infectious agent.

Prevalence rates within cattle herds in the USA range from 0-100%. The disease does not spread rapidly, but in infected herds the number of seropositive animals may be 80%. Dairy cattle are more commonly infected than beef cattle and have a higher incidence of lymphosarcoma. In severely affected dairy herds, the annual mortality rate may be as high as 5%. All breeds of cattle are susceptible to BLV infection. Infection occurs rarely in animals <2 yr of age and increases in incidence with increasing age. Lymphosarcoma is one of the 3 main causes of condemnation at slaughter.

Horizontal transmission is the usual method of spread. Close physical contact and exchange of contaminated biologic materials are required. The virus is present mostly in lymphocytes and can be found in the blood, milk, and tumors. Susceptible cattle usually become infected by exposure to infected lymphocytes. Natural transmission occurs mostly in cattle >1.5 yr old, usually during the summer months between in-contact animals and possibly by insect or bat transmission of infected lymphocytes in whole blood. An increased risk of infection in dairy cattle during the periparturient period suggests that vaginal secretions, exudates and placentas from cows, and contaminated calving instruments may serve as sources of infected blood cells.

Transmission can occur via contaminated surgical instruments, eg, dehorning gouges, ear tattooing pliers, and hypodermic needles. Transmission can also occur during blood transfusions, tuberculin testing, and administration of vaccines containing blood. Transmission via infective milk is possible by the passage of infected lymphocytes through intestinal mucosal epithelium during the first few hours of life. However, infection via this route is rare, possibly because of the presence of maternal antibodies in the milk. Congenital infection is seen in 4-8% of calves born from BLV-positive cows, presumably as a result of transplacental exposure to the virus during gestation.

Infection is not synonymous with clinical disease. Lymphosarcoma, the terminal stage of BLV infection involving the clonal transformation of infected B cells, occurs in <5% of BLV-infected cattle.

Outbreaks of leukosis typically follow the introduction of BLV-infected animals in farms or areas previously free of the virus. The level of calf management in dairy herds is also a major risk factor. Any environmental factor or management practice that allows newborn calves access to infective blood, such as prolonged close contact of cow and calf immediately after parturition, use of colostrum or milk from seropositive cows, use of contaminated equipment or needles, and large fly populations in calf barns, will increase infection rates in calves.

Pathogenesis:

Exposure of cattle to BLV leads to 4 possible outcomes: 1) failure of the animal to become infected, probably due to genetic resistance, 2) establishment of a permanent infection and the development of detectable antibody levels (latent carriers), 3) establishment of a permanent infection and a persistent benign lymphocytosis, or 4) development of malignant lymphosarcoma, with or without persistent lymphocytosis. Whether the animal becomes infected or develops any of the other forms of the disease depends on its genetic constitution and immune status and on the infective dose of virus.

Clinical Findings:

Bovine leukosis

Enzootic bovine leukosis is characterized by multiple cases of adult, multicentric lymphosarcoma within a herd, with tumors developing rapidly in many sites and thus variable clinical signs. The usual incubation period is 4-5 yr. Persistent lymphocytosis without clinical signs occurs earlier, but rarely before 2 yr of age. Many cows remain in the preclinical stage for years, often for their complete productive lifetime, without any apparent reduction in performance.

In 5-10% of clinical cases the course is peracute; often affected animals die suddenly without prior evidence of illness. Involvement of the adrenal glands, rupture of an abomasal ulcer, or an affected spleen followed by acute internal hemorrhage are known causes. In most clinical cases, the course is subacute (up to 7 days) to chronic (several months) and initiated by an unexplainable loss of body condition, anorexia, pallor, and muscular weakness. Production may drop abruptly in dairy cows. The heart rate is not increased unless the myocardium is involved, and the temperature is normal unless tumor growth is rapid and extensive, when it rises to 103-104°F (39.5-40°C). Once signs of clinical illness and tumor development are detectable, the course is rapid and death occurs in 2-3 wk.

Bovine leukosis, skin lesions

The superficial lymph nodes enlarge in 75-90% of cases, and this is often an early clinical finding. It is usually accompanied by small (1 cm diameter) subcutaneous lesions, often on the flanks and perineum. However, peripheral lesions may be completely absent in many cases with advanced visceral involvement. Enlargement of visceral lymph nodes is common, but this is usually subclinical unless they compress other organs such as intestine or nerves. They may be palpable on rectal examination, and special attention should be give to the deep inguinal and iliac nodes. In advanced cases, extensive spread to the peritoneum and pelvic viscera occurs, and the tumor masses are easily palpable. The enlargement may be confined to the pelvic nodes or to one or more subcutaneous nodes. Involvement of the nodes of the head is sometimes observed, often with exophthalmos. The affected nodes are smooth and resilient; in dairy cows, they are easily seen and may be marked by local edema. Occasionally, the entire body surface is covered with subcutaneous masses 5-11 cm in diameter.

In addition to the lymph nodes, tissues most commonly affected include the abomasum, heart, spleen, kidneys, uterus, spinal meninges, and retrobulbar lymphatic tissue. Heart sounds are commonly muffled, and other cardiac abnormalities may be obvious. Neural lymphomatosis may lead to the gradual onset of posterior paralysis over several weeks.

The calf, thymic, and cutaneous forms are designated sporadic bovine leukosis. Clinical signs of calf lymphosarcoma include gradual weight loss, sudden generalized lymph node enlargement, depression, and weakness. Fever, tachycardia, and posterior paresis are less frequent signs. Death occurs in 2-8 wk. Signs of pressure on internal organs, including bloat and congestive heart failure, may occur.

Bone and bone marrow necrosis, with associated unthriftiness and inactivity, posterior ataxia, superficial lymph node enlargement, lameness, and respiratory distress have been recorded.

Thymic lymphosarcoma is a common finding in animals 1-2 yr of age and is characterized by massive thymic enlargement in the brisket area and lesions in bone marrow and regional lymph nodes. Jugular vein engorgement and marked brisket edema extending to the submandibular region are common. Moderate bloat due to inability to eructate because of esophageal compression may occur. The thymic mass is usually not palpable. This form is more common in beef than in dairy cattle. An atypical lymphosarcoma in a mature cow negative for BLV and similar to the thymic form has been reported.

The cutaneous form is most common in cattle 1-3 yr of age. It is rare and manifest by cutaneous plaques (1-5 cm diameter) appearing on the neck, back, croup, and thighs. Spontaneous regression may occur. Relapse may occur in 1-2 yr with reappearance of cutaneous lesions and involvement of internal organs as in the enzootic form of the disease.

Lesions:

Bovine leukosis, abomasal ulcer

Bovine leukosis, cardiac lesions

Firm, white tumors may be found in any organ, although 2 patterns of distribution are apparent. In newborn and young animals, the common sites are the kidneys, thymus, liver, spleen, and peripheral and internal lymph nodes. In adults, the heart, abomasum, and spinal cord are often involved. In the heart, the tumor masses invade particularly the right atrium, although they may be found throughout the myocardium and extend to the pericardium. The abomasal wall may show gross, uneven thickening with tumor material in the submucosa, particularly in the pyloric region. Similar lesions are common in the intestinal wall. Deep ulcerations in the affected area are not uncommon. Involvement of the nervous system usually includes thickening of the peripheral nerves coming from the last lumbar or first sacral cord segment, or more rarely, in a cranial cervical site. This may be associated with one or more circumscribed thickenings in the spinal meninges. Affected lymph nodes may be enlarged and composed of both normal and neoplastic tissue.

Lymphosarcoma may appear as discrete nodular masses or a diffuse tissue infiltrate. The latter pattern results in an enlarged, pale organ and can be easily misinterpreted as a degenerative change rather than neoplasia. Histologically, the tumor masses are composed of densely packed, monomorphic lymphocytic cells.

Diagnosis:

Because of the wide range of clinical findings, a definitive diagnosis is often difficult. Enlargement of peripheral lymph nodes without fever or lymphangitis is unusual in other diseases, except for tuberculosis, which can be differentiated by the tuberculin test. Diagnosis of the viral infection is made by serology or virology, persistent lymphocytosis is identified by hematology, and neoplastic tumors are identified by histologic examination of biopsies.

Agar gel immunodiffusion (AGID) is a good screening test for identifying infected animals or herds. It has an estimated specificity of 99.8% and sensitivity of 98.5%. This test is recognized by most governments as the official standard for testing imported animals. Radioimmunoassay is useful for the detection of BLV antibodies in cattle exposed ≤2 wk, in milk samples, and in serum samples from periparturient dams. Serum ELISA is more sensitive than other serologic tests and may also be used on milk. The ELISA may be used for pooled serum samples and allows detection of antibodies in herds with a prevalence of <1%. The bulk tank milk ELISA is useful for identification of herds that are negative for BLV infection. Herds identified as positive by the ELISA require further testing at the individual or herd level to definitively establish their BLV status.

In a control and eradication program, early detection of infected calves is difficult because colostral antibodies to BLV cannot be differentiated from antibodies resulting from natural infection. Calves that have ingested colostrum from seropositive cows usually have maternal antibodies; PCR is necessary to distinguish between infected and virus-free calves in such cases.

PCR is a sensitive and specific assay for direct diagnosis of BLV infection in peripheral blood lymphocytes. The test can identify proviral DNA of BLV in the lymphocytes of neonates born to infected cows, differentiate uninfected newborn calves with colostral antibodies from BLV-infected calves, and detect the presence of the virus in the presence of antibodies.

Enzootic bovine leukosis cannot be distinguished from sporadic bovine leukosis on histopathologic examination. ELISA is recommended to differentiate between enzootic and sporadic bovine leukosis because it is rapid, reliable, and sensitive. In cases in which no blood or other fluids are obtained, PCR is the most useful method for direct detection of BLV.

Treatment and Control:

There is no treatment, but the disease can be eradicated from a herd or country or controlled at a low level. Significant costs are associated with control and eradication programs. Denmark established a national program for control of the disease in 1959, Sweden introduced a control program in 1990 with the aim of complete eradication of BLV from the Swedish cattle population, and Britain introduced a national testing program in 1992. Voluntary eradication programs using the AGID test have been effective in other member countries of the European Community in the last 20 yr in reducing the prevalence of infection and disease. These programs have been successful in part because of the low prevalence of infection, and because the economic losses from culling seropositive cows has not been large.

In Canada and the USA, it is economically cost prohibitive to cull and slaughter all seropositive cattle because of the high prevalence of infection. Thus, all control and eradication programs in these countries are herd-based and strictly voluntary. The efficiency of such programs depends on the accuracy of the test used to identify the infected animals and repetition of the test at an appropriate interval. The recommended procedure is: 1) identify infected animals using the AGID test, 2) cull and slaughter seropositive animals immediately, 3) retest the herd 30-60 days later, and 4) use PCR to test young calves and as a complementary test for clarifying doubtful test results in herds with a low prevalence of infection. Testing is repeated until the herd tests negative. Testing is then repeated every 6 mo and the herd declared free when there have been no positive reactors for 2 yr. Future introductions into the herd are managed most safely by artificial insemination, fertilized ovum transfer, or importation of animals that have been tested and are seronegative on 2 tests, done 30 and 60 days prior to arrival.

In herds with a high prevalence of infection, in which the test and slaughter method of eradication is not economically viable, various methods of testing and segregation may be used to control infection. Seropositive cows cannot be exported to many countries.

Prevention:

Several management techniques can be used to prevent infection in calves. Feeding newborn calves colostrum and milk from seronegative cows has been widely accepted as effective in preventing infection. The use of colostrum and milk from seronegative cows permits early serologic detection of infected calves. However, feeding colostrum from seropositive cows can provide significant protection from infection during the first 3 mo of life. The replacement of whole milk feeding with high-quality milk replacer may also be considered. Bloody milk should not be fed to calves.

Transmission to newborn calves can also be reduced by avoiding exposure to maternal blood at the time of parturition, housing calves in individual hutches with individual feeders and waterers, and implementing management techniques that avoid iatrogenic transmission. When handling a group of calves, the youngest ones should be handled first and the older and sick calves last. Equipment that could act as fomites in transferring blood should be disinfected with chlorhexidine between calves.

Dehorning calves by electrocautery before 2 mo of age can reduce the prevalence of infection compared with gouge dehorning, which allows the transfer of infected blood between calves. Handling facilities that become contaminated with blood should be cleaned between calves. Single disposable needles should be used for vaccination, treatments, and blood collection. Transmission can be reduced by segregation of seropositive and seronegative cows. Use of individual sleeves for rectal palpation may also be considered.

Infection in a herd can be prevented by ensuring that all imports into the herd have tested seronegative at least 30 days prior to arrival. Control of biting insect vectors is desirable. Blood transfusions and vaccines containing blood, such as those used for babesiosis and anaplasmosis are particularly potent means of spreading the disease, and donors must be carefully screened. Embryo transfer from valuable, pedigreed seropositive cows may aid in reducing prenatal infection. Insemination is not a method of transmission.