Small Ruminant Lentivirus Infections

Mary O. Smith • Lisle W. George •

John R. Middleton

Maedi-visna virus and caprine arthritis-encephalitis (CAE) virus are retroviruses in the subfamily Lentivirinae that con­stitute a single virus group, termed the small ruminant Ientiviruses, which can cross between small ruminant species.^1-3 These agents are enveloped RNA viruses.⁴

■ Definition and Etiology

Maedi-Visna Virus Infection (Ovine Progressive Pneumonia Virus Infection; Zwoegerziekte)

Maedi-visna virus causes a chronic disease of sheep.^1-4 Visna virus, which affects the brain, is closely related to the many lentiviruses that cause immunodeficiency and neurologic disease in other species; these viruses include equine arteritis virus, CAE virus, and simian, feline, and human immunodeficiency viruses.⁵ The respiratory aspects of the viral infection (maedi virus) are discussed in Chapter 31.

■ Epidemiology Maedi-visna virus is spread through ingestion of infected milk by neonates, through in utero transmission, and horizontally within a herd.

■ Pathogenesis After exposure to the virus, sheep develop an asymptomatic infection for as long as 6 weeks. Replication of the virus occurs in circulating cells during this stage of the infection.⁶ Once the disease has been recognized, affected sheep should be slaughtered. Control measures are discussed in Chapter 31.

The lesions of maedi-visna virus infection are partly induced by the host's inflammatory response. Experimental immunosup­pression of infected sheep ameliorates the severity of the clinical signs and reduces the CNS lesions without altering the amount of viral shedding.^7,8 The maedi-visna virus is in itself immu­nosuppressive, and infections may lead to a variety of secondary bacterial infections.⁹ Chronic viremia is typical.

■ Clinical Signs Neurologic disease caused by maedi-visna virus is relatively rare. Adult sheep and lambs as young as 4 months of age can be affected.¹⁰ Nervous system signs may be characteristic of a diffuse encephalitis and include ataxia, twitching of the facial muscles, conscious proprioceptive deficits, circling, and blindness; gait along a straight path is normal, but the animal staggers or stumbles when turned or when forced to perform a complex maneuver. Coma, convulsions, and hyperexcitability may occur in the terminal stages. Other sheep have gradually progressive limb weakness and ataxia, often worse in the rear limbs; neurologic dysfunction localized to the spinal cord may be the sole clinical manifestation of maedi-visna virus infection.¹¹ Some sheep merely show emaciation without neurologic signs. Others may show nonsuppurative, progressive arthritis of one or more joints or symmetric enlargement of the mammary gland. The time between the onset of clinical signs and death is highly variable but can be as long as 2 years. The presence of antibody in the serum is considered evidence of active infection.¹²,¹³

■ Clinical Pathology The CSF of affected animals is characterized by pleocytosis, with the cell counts ranging from 1012/dL to 1478/dL in animals infected for 1 month and 4 years, respectively.¹⁴ The protein concentrations of CSF can range from 50 to 100 mg/dL for 30 days after infection. Antiviral antibody and virus can be detected in CSF specimens.

■ Pathology Gross lesions of visna infection are rare when inflammation and malacia are extensive. In such cases, areas of yellowish tan discoloration are present in white matter.¹⁵ The microscopic lesions of visna are predominantly those of a diffuse, nonsuppurative, perivascular inflammation throughout the neuraxis; white matter is affected more severely than gray matter. Lesions include demyelination, gliosis, lymphocytic choriomeningitis, and focal necrotic areas that are infiltrated by macrophages.^16,17

■ Diagnosis The diagnosis of visna infection starts with recognition of the clinical neurologic disease in groups of animals in which the pulmonary, joint, or mammary form of the disease is also present.

■ Treatment and Control No effective treatment for maedi-visna virus infection is available. Prevention is based on herd hygiene and culling of affected animals, as described in Chapter 31.

■ Definition and Etiology

Caprine Arthritis-Encephalitis Virus Infection (Infectious Leukoencephalomyelitis)

CAE is caused by a small ruminant lentivirus that is closely related to the virus that causes maedi-visna virus infection in sheep.¹

■ Epidemiology The disease is distributed worldwide but tends to be more common in regions with intensive goat-rearing operations.

■ Pathogenesis When inoculated into goats, the virus causes a chronic infection characterized by demyelinating encephalomyelitis, arthritis, and interstitial pneumonia. The pathologic changes resemble those of an autoimmune process and are probably caused by interactions among the host's immunologic responses, denatured myelin, and the virus.²

■ Clinical Signs The systemic manifestations of the disease are thoroughly discussed in Chapter 38. The leukoencepha- lomyelitis form of CAE occurs predominantly in goats younger than 1 year of age; occasional cases occur in older goats.³ The clinical signs of leukoencephalomyelitis are highly variable but typically involve the spinal cord. Signs include progressive ataxia, paraparesis, paraplegia, tetraparesis, tetraplegia, hemi­paresis, and hemiplegia. Goats with lesions in the cervical spinal cord (L1 to L4 levels) are recumbent and unable to raise their heads from the ground. They may show resistance to passive neck flexion. Spinal reflexes range from hypertonia and hyperreflexia to hypotonia and hyporeflexia. Intracranial signs may also develop; these include head tilt, nystagmus, tremors, torticollis, salivation, depression, coma, and opisthotonos.^4-10 Vision and pupillary light reflexes may be diminished.

Other signs that may be associated with CAE infection include fever (although the occurrence of this, too, is highly variable), enlarged joints, mammary gland enlargement (usually symmetric), vague and shifting leg lameness, weight loss, and tachypnea without significant auscultatory abnormalities.

The major differential diagnostic considerations for the neurologic form of CAE include head or spinal trauma, listeriosis, cerebrospinal nematodiasis (verminous meningoencephalomy- elitis caused by Parelapbostrongylus tenuis, the meningeal worm of the white-tailed deer), and multisystemic infections with Mycoplasma spp. The CAE virus causes neurologic lesions in numerous regions of the CNS, whereas the lesions of listeriosis are generally restricted to the brainstem. Mycoplasmal infections typically affect kids 1 to 6 months of age, and affected animals are systemically ill and often display septic polyarthritis and polyserositis. Mycoplasma infections of goats are described further in Chapter 38. Verminous meningoencephalomyelitis and CAE virus can be presumptively distinguished by serologic or PCR testing for CAE virus and CSF analysis, season, and geographic distribution of the white-tailed deer host for meningeal worm. However, the neurologic forms of these diseases cannot be definitively diagnosed by these means.

■ Clinical Pathology The results of hematologic and blood chemistry analyses are generally normal; however, in one study of affected goats, total plasma protein levels were increased and hypergammaglobulinemia was common.⁴ The changes in the CSF are characteristic of a chronic granulomatous inflam­mation. Specific changes include an increased protein concentra­tion and pleocytosis.¹¹ Cell counts in the CSF of affected goats range from 5/dL to 1800/dL, and the protein concentration ranges from 0 to 700 mg/dL.³

■ Pathology Gross pathologic changes in the CNS of naturally infected goats include cloudiness of the meninges and tan discoloration of the white matter.³ Microscopic changes include disseminated perivascular accumulations of mononuclear cells, demyelination originating in the subependymal region, astrocytosis, and mononuclear leptomeningitis.^2,4,8,12,13 Spinal cord lesions are most frequently observed in the thoracolumbar segments.³

■ Diagnosis Previously, an AGID test was used for the diagnosis of CAE, but this has been superseded by ELISA and PCR tests.^12,14 The virus may also be cultured from infected tissue.¹⁵

■ Treatment and Control No treatment is available for goats with leukoencephalomyelitis.

Border Disease (Hairy Shaker Lambs; Hypomyelogenesis Congenita)

■ Definition and Etiology Border disease is a congenital infection of sheep and goats caused by a noncytopathic togavirus (genus Pestivirus).¹ The border disease agent is antigenically similar to the viruses that cause bovine viral diarrhea (BVD) and hog cholera (classical swine fever). Once introduced into a flock, the border disease virus causes abortion, infertility, and deformities in lambs. In a naive ewe, viral infection during pregnancy results in a variety of complications, including early embryonic death, abortion, and stillbirth, and lambs that survive are small and malformed. It is important to note that lambs infected in utero become immunotolerant and remain viremic for life, similar to calves persistently infected with BVD virus.² Adult sheep that become infected with the border disease virus develop an inapparent, short-lived viremia and become immune to reinfection.

■ Epidemiology Border disease is transmitted both verti­cally and horizontally.^3,4 As with BVD in cattle, the major reservoir in infected herds is the congenitally infected, sero­negative animal that shows no symptoms.^2,5 Such animals may shed the virus through the placenta, infected offspring, saliva, respiratory secretions, urine, or feces.^3,6 In one seroepidemio- logic study of infected ewes in the western United States, lambs were more often seropositive than were ewes.² A large percentage of the seropositive lambs were born to seronegative ewes, which indicated the presence of a large amount of virus cycling from carriers that have no symptoms. Strain-related differences in viral pathogenicity appear to exist.⁷

■ Pathogenesis Hypomyelination is probably caused by a combination of virus-induced degeneration of the oligoden­droglial cells (dysmyelinogenesis), persistent viral infection, and diminished secretion of the thyroid hormones.⁸ The diminished production of thyroid hormones is thought to be related to direct inhibition of the thyroid gland, because the pituitary activity of affected lambs appears to be normal.

■ Clinical Signs The severity of clinical signs in affected lambs varies. Changes are most marked in newborn lambs infected in early gestation (before 50 days). The CNS, skin, and skeleton are the most seriously affected. The hairs of congenitally affected lambs are coarse, straight, and elongated and stand out from the body like a halo.¹² The coat is abnor­mally pigmented and may have a dark-gray appearance or hyperpigmented spots that are especially prominent over the top of the neck.¹³ Animals that survive shed the abnormal hairs at 9 to 12 weeks of age and replace them with normal hair fibers. Affected lambs also have a short, thickened body, shortened legs, smaller orbital size, and doming of the frontal bone.^14,15

Arthrogryposis occasionally occurs. Some infected lambs show neurologic symptoms such as ataxia and uncontrollable tremors; the latter sign, combined with the characteristic hair coat, accounts for the common term “hairy shakers.” The tremors are coarse, involve the trunk and head, and disappear when the animal is asleep.^16,17 Affected lambs are often alert and appetent but initially need assistance to stand and nurse. Some animals walk normally but hop on the rear limbs when forced to run. The CNS signs usually disappear by 20 weeks of age, but the animals appear stunted. Affected animals have far lesser viability than do uninfected herdmates and may die unexpectedly. Aside from neonatal death losses, economic burdens imposed by the viral infection include low birth weights, diminished weaning weights, lowered carcass quality, and infertility.^15,18

Abortions occurred 9 to 106 days after inoculation in 30% of experimentally infected sheep.^6,13,14 In field outbreaks, the average gestational age of the aborted fetus is 63 days. Tera­togenic effects are most often observed when lambs are infected at 50 to 90 days of gestation.¹⁹ Fetal mummification occasionally occurs.

The border disease virus is also pathogenic in goats.²⁰ As in sheep, inoculation of pregnant does results in fetal mum­mification and abortion. The spinal cords of infected kids are hypomyelinated, but the haircoat is normal.

The border disease virus has low pathogenicity in cattle. Abortions can be induced in cows inoculated with the virus at approximately 50 days of gestation, and affected calves have cerebral cavitations.²¹ When cattle comingle with infected sheep, cattle can be naturally infected.²²

■ Pathology The macroscopic changes associated with border disease virus infection are hydranencephaly, poren­cephaly, microcephaly, cerebellar hypoplasia, abnormal curvature of the ribs, brachygnathia, doming of the frontal bones of the skull, narrowing of the distance between the orbits, a decrease in orbital size, shortening of the crown-to-rump and diaphyseal lengths, retention of secondary hair fibers, and abnormal skin pigmentation.

Microscopic changes in lambs with congenital infection include hypomyelinogenesis and hypercellularity of the white matter with abnormal-appearing glial cells.^16,17,19 The CNS shows dysmyelinogenesis, secondary demyelination, and periarteritis. Viral antigen can be demonstrated in CNS arterioles.²³

■ Diagnosis Identification of the viral antigens in tissues with fluorescent antibody tests is the most accurate method of diagnosing border disease. Tissues that most consistently contain viral antigens are those of the abomasum, pancreas, kidneys, thyroid, and testicles.^24,25 Serodiagnostic methods such as serum neutralization, AGID, and complement fixation tests have been developed.²⁶ In most cases, the BVD virus has been used as the indicator antigen. Serodiagnosis of infected lambs is difficult because the lambs tend to be immunotolerant and therefore do not develop strong serologic responses. The presence of viral antibodies in the CSF suggests border disease virus infection.

The differential diagnosis for border disease virus infections in sheep and goats includes other causes of infectious abortion, copper deficiency (swayback), and other viral diseases that may result in hydranencephaly, such as those caused by the Cache Valley, bluetongue, and Schmallenberg viruses.

■ Treatment and Control There are no specific treat­ments. Control measures are centered on disease monitoring and biosecurity. In herd situations, virus isolation from whole blood or examination of skin biopsy samples by fluorescent antibody tests can help identify carriers.²⁴ Serologic testing is not a reliable indicator of infection because congenitally, persistently infected animals may be immunotolerant of the virus. Noninfected pregnant sheep should be separated from other members of the flock for the first 60 days of gestation to ensure that in utero infections do not occur.

Encephalitic Bovine Herpesvirus Infection

■ Definition and Etiology Two herpesviruses, bovine herpesvirus type 1 (BoHV-1) and type 5 (BoHV-5), have in rare cases been associated with encephalitis in cattle.^1-4 BoHV-1 infection typically results in infectious bovine rhinotracheitis (IBR), an acute upper respiratory tract disease characterized by fibrinonecrotic white plaques of the nasal, pharyngeal, and tracheal mucosa and by abortions (see Chapter 31). Other clinical conditions associated with bovine herpesvirus infections include epizootic conjunctivitis (Chapter 39) and infectious balanoposthitis or vulvovaginitis (Chapter 43).

■ Epidemiology Bovine herpesviruses cause disease in cattle worldwide. Epidemiologic factors that appear to favor dissemination of herpesviruses among cattle include a high stocking rate, repeated introduction of animals from diverse backgrounds, and mass weaning of calves at a time when the passively acquired anti-IBR antibodies are waning.² BoHV-1 may survive in the environment for up to a month; cooler ambient temperatures and higher humidity promote virus survival.⁵ Calves younger than 6 weeks are most susceptible, but infection and resultant neurologic disease also have been described in adult cattle.^1,3,4,6-9 Animals that survive the disease become persistently infected; virus survives in the nasal and tracheal mucosa and the trigeminal ganglion.⁹ Reactivation and virus shedding may occur during periods of stress.^4,5,9 Although clinical disease caused by reactivation of latent virus is usually mild and may go unnoticed, shedding of virus during such episodes can cause infection of in-contact animals. The viruses replicate in the nasal and pharyngeal mucosa. Brain involvement results from centripetal spread along the sensory neurons of the trigeminal and olfactory nerves.⁹

■ Pathogenesis Encephalitic IBR infections cause a nonsuppurative meningoencephalitis that is widely distributed in the gray matter of the brain, primarily in the cerebrum and thalamus. The virus can usually be isolated from affected calves.¹⁰ Signs of respiratory disease may precede or occur coincidentally with neurologic disease.¹⁰

■ Clinical Signs The clinical signs of encephalitis include depression, mild nasal and ocular discharge, conscious pro­prioceptive deficits, head pressing, aimless circling, bellowing, salivation, bruxism, paralysis of the tongue, head tilt, nystagmus, convulsions, blindness, coma, and death.^2,3 Seizure activity is characterized by a tonic-clonic convulsion with violent spasms or tremors of the head, with all four legs flexed and the head in opisthotonos. Rectal temperatures of 41° C and 42° C (108° F) have been reported.⁶ Encephalitic herpesvirus infection is frequently fatal, although asymptomatic cases have been induced experimentally.¹⁰ In experimental infection, signs develop 1 to 2 weeks after infection.

■ Clinical Pathology and Pathology Mononuclear pleocytosis is found on analysis of CSF.¹⁰ Extensive lymphocytic meningoencephalitis is evident on histologic examination. Intranuclear inclusion bodies are rarely observed in bovine herpesvirus encephalitis. Encephalitis may be evident on histopathologic examination of fetuses from cows that abort as a result of BoHV-1.¹¹

■ Diagnosis Accompanying respiratory disease raises the index of suspicion for herpesvirus encephalitis in animals with neurologic clinical signs. A rising serum titer of neutralizing antibody in surviving animals can be used to confirm infection, although this does not distinguish between BoHV-1 and BoHV-5. Specific diagnosis is usually made at necropsy through a number of modalities, including virus isolation, immunohis­tochemistry, and PCR.^12-14 Many of these tests do not distinguish between BoHV-1 and BoHV-5; more specific PCR tests can differentiate between these two virus types.¹⁵

Differential diagnoses for encephalitic herpesvirus infections in cattle include almost all encephalitic, encephalopathic, and neurotoxic diseases of cattle, including rabies, polioencepha- lomalacia, salt poisoning, and lead toxicity.

■ Treatment and Control No specific therapy exists for the encephalitic form of BoHV-1 infection. Treatment is palliative and supportive and should include oral or intravenous fluid support, NSAIDs, antibiotics in animals with secondary bacterial pneumonia, and nursing care. Benzodiazepines or phenobarbital may be used for seizure control when necessary (Table 35.4). Animals with severe clinical signs may be eutha­nized for humane reasons.

Vaccines that protect against BoHV-1 have traditionally been considered potentially useful in the prevention of BoHV-5 infection because of the close antigenic relationship between the two viruses.^7,16 However, more recent trials have shown that certain BoHV-1 vaccines may not confer protection on cattle challenged with BoHV-5.^17,18

In some European countries, eradication programs that employ testing and culling of infected animals have been successful in eliminating BoHV-1. Bovine herpesviruses can be spread through fomites and by aerosol transmission for up to 4 miles (6.4 km).⁵ Strict biosecurity procedures are therefore essential for developing and maintaining virus-free herds.

■ TABLE 35.4

Recommended Drug Dosages for Treatment of Cerebrocortical Disease

Many of the drugs and dosages listed below are not approved by the U.S. Food and Drug Administration (FDA) for use in food-producing animals for the treatment of Cerebrocortical disease (lettered superscripts are explained in the table footnotes). Off-label use of drugs in food-producing animals should follow specific guidelines in the jurisdiction where the drugs are being administered.

Additional notes on use of these drugs in food-producing animal in the Umited States:

^aDiazepam, phenobarbital, methylprednisolone, mannitol, phenylbutazone, dimethyl sulfoxide (DMSO), and aspirin are not FDA-approved for use in food-producing animals in the United States.

^bPentobarbital is approved at dosages of 0.44-1.1 mg/kg as a general anesthetic and 0.11-0.275 mg/kg as a sedative-relaxant in beef and dairy cattle.

^cDexamethasone is approved as an antiinflammatory for use in calves and in beef and dairy cattle administered IV or IM at a dose of 5-20 mg per animal or as an oral bolus or powder at 5-10 mg/animal on day 1 and 5 mg/day thereafter as required.

^dFurosemide is approved at a dosage of 500 mg/animal once daily or 250 mg/animal IV or IM twice daily for no more than 48 hours after parturition for treatment of parturient mammary edema in beef and dairy cattle.

^eFlunixin meglumine is approved at 1.1-2.2 mg/kg IV as a single dose or divided evenly into two doses administered 12 hours apart for up to 3 days for the control of inflammation associated with endotoxemia. It is also approved as a transdermal pour-on material for use in beef and dairy cattle for the control of pyrexia associated with bovine respiratory disease complex or pain associated with foot rot.

^fMonitor for signs of gastric or abomasal bleeding (fecal occult blood).

^gAn initial oral loading dose of 10 to 20 mg/kg, followed by 2.5 to 5 mg/kg PO daily or 10 mg/kg PO every 48 hours thereafter, has been recommended for cattle. Because of the prolonged plasma half-life in ruminants, serial administration of the drug should be accompanied by careful monitoring of renal function and gastrointestinal bleeding. Use of phenylbutazone in dairy cattle over 20 months of age is prohibited in the United States by the FDA. Other use in food­producing animals in the U.S. would be off-label, in which case the guidelines set forth in the Animal Medicinal Drug Use Clarification Act should be followed.

IM, Intramuscular; IV, intravenous; PO, oral; SC, subcutaneous.