Caprine Arthritis-Encephalitis Virus

Shelly Logan, DVM; Heather L. Tarpley, DVM, PhD; Kenneth S. Latimer, DVM, PhD

Class of 2004 (Logan) and Department of Pathology (Tarpley, Latimer), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Caprine arthritis-encephalitis virus (CAE) is a single-stranded, icosahedral, RNA virus of the family Retroviridae and the sub-family Lentivirinae. This virus is magnesium-dependent and has a RNA-dependent DNA polymerase (reverse transcriptase).^5,6,12 Infection with CAE results in a persistent, lifelong infection. This disease was first diagnosed in goats in 1974. Since that time, it has been diagnosed in North America, Europe, Kenya, Peru, Australia, and New Zealand.^5,12,16 The CAE virus has a predilection to infect mononuclear cells, specifically tissue macrophages of the lung, central nervous system, synovium, and mammary gland. CAE virus is one of only two lentiviruses that currently are known infect sheep and goats.^6,12,13 CAE viral infection results in arthritis in adult animals and encephalitis in kids between 2 and 6 months of age.¹³ Other clinical presentations can include a hard udder or mastitis, hypogalactia, chronic interstitial pneumonia, and progressive weight loss.¹⁶

Etiology

The prevalence of CAE, first known as viral leukoencephalomyelitis of goats, is highest where there is intensive dairy goat management in confinement. Countries with the highest prevalence of CAE infection include the United States, France, Norway, Switzerland, and Canada.¹⁶ Viral transmission usually occurs horizontally through the ingestion of viral-infected goat milk and/or goat colostrum.^1,13 Other potential sources of viral transmission include transmission in utero; contact with the vagina of an infected doe during parturition; via saliva or respiratory secretions; via contact with infected blood; viral contamination of milking equipment, needles, tattooing equipment; and breeding an infected animal with a non-infected animal.¹

Pathogenesis

CAE virus infects goats primarily by horizontal transmission via ingestion of infected colostrum or infected milk. The virus is absorbed across the small intestine and infects the mononuclear cells.^3,16 There is also transmission of CAE virus by direct contact between goats via shedding of the virus in the saliva, the urogenital secretions, and the feces. Contact with the blood of an infected animal can also transmit the disease.⁹ Some sources speculate in utero or vertical transmission; however, studies to date have not documented this form of viral transmission.^13,15 CAE virus remains latent until the monocytes mature into macrophages.^16,17 The macrophages then disseminate to other tissues such as mammary gland, choroid plexus, synovium, lung interstitium, and their associated draining lymph nodes.¹⁷ Clinical signs and lesions of CAE are associated with the viral replication in the infected macrophages. Active viral infection induces a strong, but non-protective, humoral and cell mediated immune response.^10,12,16 It is also important to note that the maternal antibodies passed in the colostrum are not protective for kids ingesting the colostrum.¹

Recent research has shown that lentiviruses can develop a tropism for and replicate within epithelial cells.^2,11,18 Caprine oviduct epithelial cells (COEC) are often utilized from untested slaughterhouse animals to aid in vitro fertilization techniques. These COEC cells are highly susceptible to CAE infection. Therefore, this discovery indicates that embryo transfer also may be a possible mode of transmission for CAE.⁷

Clinical Signs

Most goats infected with CAE virus are asymptomatic, but there are five major clinical presentations associated with viral infection including arthritis, encephalitis, interstitial pneumonia, mastitis, and progressive weight loss.^9,16 The arthritic form of CAE viral infection is the most common manifestation of the disease and is generally observed in sexually mature goats (6 months and older).^12,16 The arthritis tends to be chronic and progressive, though there have been reports of a sudden onset of lameness. Joints that are commonly affected (in descending prevalence) include: carpal joints, tarsal joints, stifle joints, fetlock joints, alantooccipital joint, and coxofemoral joints. All synovial membranes can be affected by CAE virus, and the number of joints affected in any one animal can vary. Early arthritic signs may be subtle or severe. Subtle signs include stiffness, shifting leg lameness, decreased ambulation, weight loss, reluctance to rise, and abnormal posture after rising. More severe arthritic signs can include acute swellings without pain upon palpation; joints that are drained of the fluid simply refill. Eventually these signs lead to a painful arthritis.^5,9,12,16

The encephalitic form of CAE viral infection most commonly affects kids between 2 and 6 months of age. The kids may show incoordination and inappropriate placement of limbs while standing and walking. A gradual paresis and paralysis, more commonly affecting the hindlimbs and often progressing to the forelimbs, can occur. Eventually, the animal is unable to rise to a standing position. If only the hindlimbs are affected, these kids have been seen to pull themselves around with their forelimbs. The kids can remain bright, alert, and responsive early in the disease process, but more commonly display additional neurologic deficits including depression, nystagmus, abnormal pupillary response, blindness, head tilt, head tremor, dysphagia, torticollis, circling, and facial nerve deficits. Affected kids are afebrile unless a secondary disease present.^5,9,12,16

CAE viral infection also can cause chronic interstitial pneumonia. Initially, a deep chronic cough can be observed. Later, chronic dyspnea, weight loss, tachypnea, and abnormal lung sounds can develop. It has also been noted that enlarged lymph nodes may contribute to some of the respiratory distress.^8,12

Mastitis, especially interstitial mastitis, is another form of CAE. Clinical signs include a firm, distended udder from which milk cannot be expressed. The mastitis usually is observed around parturition.^5,8

The final major form of CAE viral infection is chronic progressive weight loss. The progressive weight loss also can occur with any of the other forms of the disease.^9,16

Diagnosis

A combination of history, clinical signs, positive serology tests, postmortem lesions, histopathological lesions, and exclusion of all other possible diseases is necessary to diagnose CAE.^9,16

Synovial Fluid and Joint Examination

In CAE-associated arthritis, arthrocentesis may reveal synovial fluid that is serous and has a dark yellow to red-brown color. The fluid also contains an increased number of lymphocytes and macrophages (mononuclear cells). The nucleated cell counts in the synovial fluid are > 1,000 cells /µl, and the predominant cell type is the lymphocyte.^5,8 Radiographic changes ranges from soft tissue swelling to periarticular osteophyte production to calcification of periarticular structures.^5,8 During post-mortem examination of the joints, marked proliferation of the synovial lining (pannus), extensive osteophyte formation, free floating concretions (rice bodies or joint mice), degenerative joint disease with destruction of subchondral bone, ulceration and erosion of articular cartilages, and mineralization of surrounding tissues of the joint can be observed (Fig. 1).^5,8 Histopathology reveals subsynovial infiltration with mononuclear cells and the presence of lymphoid follicles (Fig. 2). Synovial villus hypertrophy and focal areas of necrosis in the synovial membrane and/or the connective tissue surrounding the joint are often observed.^5,10,16

Figure 1. Carpal joint of a goat with caprine arthritis-encephalitis. The synovial membrane is thickened and has a villous surface (Hematoxylin and eosin stain; Courtesy of Noah's Arkive, The University of Georgia).	Figure 2. Synovial membrane of a goat with caprine arthritis-encephalitis. The synovial membrane is thickened and has a villous surface (Courtesy of Noah's Arkive, The University of Georgia).

CSF and CNS Tissue Evaluation

With the encephalitic form of CAE viral infection, the CSF has an increased protein concentration with a mononuclear pleocytosis.^8,12 Post mortem examination may reveal asymmetrical, gray to pink foci of discoloration in the brain and/or spinal cord (Fig. 3). Histopathology reveals widespread perivascular infiltration by mononuclear cells. This infiltrate is composed of macrophages, lymphocytes, and plasma cells (Fig. 4). Coagulative necrosis and demyelination of the white matter also is observed; for this reason CAE previously was known as viral leukoencephalomyelitis.^5,8,12

Figure 3. Cross section of the brain from a goat with caprine arthritis-encephalitis. Coagulative necrosis is present (arrow) (Courtesy of Noah's Arkive, The University of Georgia).	Figure 4. Section of the brain from a goat with caprine arthritis-encephalitis. Perivascular infiltrates of mononuclear cells are present (Hematoxylin and eosin stain; Courtesy of Noah's Arkive, The University of Georgia).

Radiography

Radiographs of the lungs of animals with the respiratory form of CAE have interstitial consolidation. At necropsy, the cranioventral and/or caudal lung lobes are swollen in association with enlarged mediastinal lymph nodes (Fig. 5). Histopathology reveals nodular lymphoid aggregates, proliferation of smooth muscle, and massive infiltration of the alveolar walls by lymphoid cells.^5,8

Figure 5. Swollen cranioventral lung lobes in a goat with caprine arthritis-encephalitis. (Courtesy of Noah's Arkive, The University of Georgia).

Mammary Gland Evaluation

Because normal goat milk can contain large numbers of epithelial cells and macrophages, the interstitial mastitis caused by CAE viral infection is definitively diagnosed by histological examination. Histopathology reveals foci of inflammatory cells within the interstitium. Extensive nodular lymphoid proliferation can be observed around the alveolar ducts. With a chronic mastitis, chronic inflammatory cells and increased deposition of connective tissue replaces the parenchyma.⁸

Serologic Detection of Anti-CAE Antibodies

Serologic testing is a necessary and important component in diagnosising CAE. Most CAE-infected goats seroconvert within 3 to 12 weeks after viral exposure.¹³ Antibody detection tests are used because, with a lentivirus infection, the animal is infected for life. Therefore, the presence of antibodies indicates that the animal is infected with CAE virus.⁶ The gold standard in testing for CAE antibodies is the immunoprecipitation assay (IP), but it is too expensive to use as a common diagnostic tool.

The most widely used serologic test to detect anti-CAE antibody is the agar gel immunodiffusion test (AGID). Currently, there are two antigens that can be used in the AGID test, the CAE gp 135 surface glycoprotein and the less sensitive CAE p28 core protein. The specificity for the AGID test is 100% when compared to the gold standard IP test. The sensitivity for the CAE gp 135 surface glycoprotein detection is 91% compared to that of IP.⁶ Both of these AGID tests have an increased likelihood, when compared to the IP, to yield false negative test results.

Indirect enzyme linked immunosorbant assays (ELISA) are used to detect CAE antibodies in both the serum and milk. However, the milk ELISA would not provide timely information to prevent the transfer of CAE virus in the colostrum and/or milk. Therefore, the milk ELIAS is not widely used. These ELISAs use recombinant and native viral antigens in to detect CAE antibodies. They have a very high sensitivity (i.e., there are false-positive results associated with indirect ELISAs when compared to the IP test). To decrease the sensitivity and increase the specificity of the ELISA test, the samples often are diluted 1:100 before being run.¹³

There is a competitive ELISA (cELISA) that has just been developed to detect serum antibodies to CAE. The cELISA is more sensitive than the IP test in detecting CAE antibodies. This can increase false-positive test results. The cELISA can evaluate undiluted serum, thus detecting lower titers of anti-CAE antibody than the indirect ELISAs. This feature may possibly allow for the earlier detection of CAE positive animals. If the serum is diluted when using the cELISA, the sensitivity of the test decreases. This cELISA also may be able to detect antibodies in colostrum and milk samples.⁴

Other methods of detecting CAE virus include the polymerase chain reaction (PCR) and virus isolation (VI). PCR can be used to detect CAE virus in milk and serum; however, PCR testing is not yet commercially available for the routine diagnosis of CAE. VI has poor sensitivity and often takes 3 to 4 weeks to culture the virus.^6,12

Currently, there also is variability in CAE test results because of a lack of standardization in the testing among laboratories that perform AGID and ELISA tests.¹³

Treatment

The prognosis for the encephalitic form of CAE is poor, while the prognosis for the other four forms of disease is guarded. Currently, there is no specific treatment for CAE. Symptomatic therapy and supportive care have been used, but most affected animals are culled and/or euthanized because these animals are sources of infection and their clinical signs worsen over time.^9,12

Current symptomatic therapy for the arthritic form of CAE includes frequent proper foot trimming, providing soft bedding, good pasture management, and administration of nonsteroidal anti-inflammatory drugs. Physical therapy may be of benefit for recumbent kids with the encephalitic form of CAE. Antibiotic therapy may be used if secondary bacterial infection is present in animals with CAE-induced interstitial pneumonia and/or mastitis.^9,12

Prevention

Prevention of CAE viral infection is important in goat herd management because there is no treatment that eliminates CAE virus or vaccine to prevent this disease. Most sources recommend maintaining a closed herd status. Within the herd, all animals should be tested for CAE every 6 months beginning at 6 months of age. Seropositive individuals should be segregated and culled. If culling is not an option, a variety of measures can be taken to minimize CAE viral transmission on the farm. One measure is to remove kids from does immediately after birth to prevent any contact (including sniffing and licking) that may promote viral transmission. Also, seropositive and seronegative does should be housed in separate pastures. Kids born to seropositive does should be segregated from kids born to seronegative does until the CAE viral status of the kids can be determined.

Kids should only be fed heat-treated/pasteurized goat colostrum and heat-treated/pasteurized goat milk. To properly heat-treat colostrum, it should be heated at 56° C for one hour. The virus is inactivated while the immunoglobulins remain intact.¹² If pasteurized milk is not available, then cow colostrum and cow milk can been used as an alternative. Quality milk replacers for goats also are available for use.

Seronegative animals should be milked first and the milking parlor should be disinfected after every milking. Seropositive and seronegative animals should not be bred to each other. Iatrogenic transmission of CAE virus should be avoided by using different instruments (needles, tattooing equipment, dehorning equipment, etc.) for seropositive and seronegative animals. Also, any equipment should be cleaned and disinfected between each animal. In the pasture, seropositive and seronegative animals should be segregated by double fencing, maintaining at least 2 meters of distance between the fences. Finally, if an open herd is maintained, goats should only be purchased from CAE virus-free herds. New herd additions subsequently should be quarantined for at least 60 days and all animals should be CAE test-negative before adding them to the herd.^{1,5,6,8,9,12,13,14}

Australia and New Zealand have established voluntary official accreditation programs to establish CAE-free goat herds. Although the United States has no such program, goat herds exist that serologically test and cull any CAE-seropositive goats. Such herds claim to have established a CAE-free goat herd status.¹³

Bibliography

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9. Matthews JG. Diseases of the Goat, 2^nd ed. Blackwell Science, Chelmsford, UK, 1999, pp. 80-87.

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11. Mselli-Lakhal L, Guiguen F, Fornazero C, Favier C, Durand J, Grezel D, Moussa A, Mornex JF, Chebloune Y. Immortalized goat milk epithelial cell lines replicate CAEV at high level. Vet Res 2001;32:429-40.

12. Pugh DG. Sheep and Goat Medicine. W.B. Saunders Company, Philadelphia, 2002, pp. 126, 239-240, 296, 388.

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14. Rowe JD, East NE, Franti CE, Thurmond MC, Pedersen NC, Theilen GH. Risk factors associated with the incidence of seroconversion to caprine arthritis-encephalitis virus in goats on California dairies. Am J Vet Res 1992;53:2396-2403.

15. Rowe JD, East NE, Thurmond MC, Franti CE, Pedersen NC. Cohort study of natural transmission and two methods for control of caprine arthritis-encephalitis virus infection in goats on a California dairy. Am J Vet Res 1992;53:2386-2395.

16. Smith MC, Sherman DM. Goat Medicine. Lea & Febiger, Philadelphia, 1994, pp. 73-79, 135-138.

17. Zink MC, Narayan O, Kennedy PG, Clements JE. Pathogenesis of visna/maedi and caprine arthritis-encephalitis: new leads on the mechanism of restricted virus replication and persistent inflammation. Vet Immunol Immunopathol 1987;15:167-80.

18. Zink MC, Yager JA, Myers JD. Pathogenesis of caprine arthritis encephalitis virus. Cellular localization of viral transcripts in tissues of infected goats. Am J Pathol. 1990;136:843-54.

Photograph of Jerry, a Nubian goat owned by Dr. Melanie Johnson, is by Dr. Perry Bain.

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