Etiology Aujeszky’s disease virus (suid herpesvirus 1) (SHV-1)
Epidemiology In pigs worldwide and major economic importance in swine-raising areas. High prevalence of infection; lower incidence of disease. Infected pig source of infection; latent infection is characteristic; spread occurs within herds, between herds, and due to infected carriers; long-distance aerosol transmission occurs from area to area; immunity follows infection or vaccination
Signs Fever, incoordination, recumbency, convulsion and death in piglets. Coughing, nasal discharge, sneezing, and dyspnea in older growing pigs. In cattle and sheep, intense pruritus at site of bite, excitement, circling, convulsions, fever, recumbency, paralysis, and death in 48 hours or less
Clinical pathology Serology for virus neutralizing antibodies. Detection of virus in tissues
Diagnostic confirmation Detection of virus in tissues; serology; inclusion bodies in nervous tissue and respiratory tract
Pseudorabies is associated with porcine herpesvirus-1, Aujeszky’s disease virus, or pseudorabies virus, a member of the family of Herpesviridae, subfamily Alphaherpesvirinae. The biological functions of the virus in the pathogenicity, immunogenicity, and transmission of vaccine strains of the virus in pigs have been described and reviewed.1
Pseudorabies primarily affects pigs and occurs incidentally in other species. Pseudorabies had a wide geographical distribution including the United States, Britain, Europe, North Africa, Asia, South America, New Zealand, and Ireland. Recently, many countries have achieved freedom from the disease and those that have not have started some form of control and eradication scheme.
Epidemiologic modeling of the herd-to-herd transmission of pseudorabies over a 20-year period in the United States concluded that, if there is no eradication program in place, the projected prevalence would be 43% in high-risk States, 22% in moderate-risk States, and 5% in low-risk States by 2012.2 The current program of eradication projected 23% prevalence rate in high-risk States, 10% in moderate-risk States, and 1% in low-risk States. With an increase in expenditure for eradication programs of 25%, the respective prevalence rates by 2012 would be 14%, 3% and <0.3%. In Belgium the overall herd prevalence was deemed to be 35%.3 Many countries including Australia, Canada, and Norway are free of the infection.
Pseudorabies is primarily a disease of pigs, and naturally occurring cases in cattle and horses are rare and usually fatal. Cases in cattle occur only sporadically but a number of animals may be affected when cattle and pigs are commingled. An outbreak of clinical disease occurred in sheep in Northern Ireland after the sheep had been shorn and housed adjacent to pigs excreting the virus4; cats on the same farm were also affected. The disease has occurred in goats that have been housed with swine, and the virus has been isolated from horses with neurological disease.5 Pseudorabies infection has been recorded in feral swine in Florida, and may undermine eradication efforts in domestic swine.6
Typically, the disease spreads rapidly in infected herds over a period of 1–2 weeks and the acute stage of the outbreak lasts 1–2 months. In sucking pigs, the morbidity and mortality rates approach 100%, but in mature swine there may be no clinical signs, and affected animals usually recover. The highest morbidity occurs initially in unweaned piglets, but as the outbreak continues and piglets become passively immunized through the sow’s colostrum, the major incidence may occur in weanlings.
In recent years there has also been an increase in the morbidity and case fatality rates in older pigs associated with the intensification of pig rearing and the dominance of more virulent strains.
The seroprevalence of infection varies widely between herds, and between breeding and finishing pigs within herds.7 The most important animal risk factors of virus persistence are herd size and the population density of the sows in the herd.8 Endemic infection is more likely in herds of breeding sows with more than 66 sows. In Belgium, when testing 720 herds, 40% of the herds with young sows were highly positive.3 Herds over 70 sows were also more likely to be infected.3 In breeding herds, spread of infection is positively associated with increasing size of the herd, having the gilts in the same barn as the sows (gestation barn), and serological evidence of infection in the finishing pigs.9 The seroprevalence of infection is low in quarantined breeding herds, which makes them prime candidates for elimination of the disease by test and removal.10
In the early period of a compulsory vaccination program with gI-deleted vaccines, in an area endemically infected with the disease, the seroprevalence of infected breeding females is higher in farrow–finish than farrow–feeder herds.11 Mandatory vaccination is beneficial in both herds but the pattern is linear in farrow– feeder herds and curvilinear in farrow– finish herds, being more rapid in the early period of the program. In the farrow– finish herds, the odds of infected breeding females were associated positively with seropositivity in the finishing pigs of the herd and with the density of the pigs in the county in which the herd is located.11 In Belgium the presence of finishing pigs in the same herd increased the chances of being infected.3 The spread and transmission of the virus between herds can be reduced by a reduction in the contact rate between the herds and their size and by a reduction of the transmission within the herd.12
The factors associated with circulation of the virus within herds include:
• Confinement of finishing pigs
• Concurrent infection with Actinobacillus pleuropneumoniae
• The length of time since the herd has been under quarantine
In general, pseudorabies does not increase the susceptibility of animals to infection with other pathogens.7 In an experimental situation it has been shown that the virus is transmitted between vaccinated conventional pigs but not amongst vaccinated SPF pigs.13
The primary risk factors associated with seroprevalence of the virus in 500 swine herds in Illinois included total confinement and density of infected herds in the geographical area.14 For counties with a high regional density of pseudorabies infection, the prevalence of infection within a county increased with increasing average herd size and increasing geographical density of swine herds in the county.15 In Minnesota, there was a high geographical density of pseudorabies infected herds within 5 km.16 Similarly it was calculated than in Belgium if there were over 455 pigs/km2 then there was a 10-fold increase in the risk of PRV.3 Total confinement is associated with higher seroprevalence, presumably because of increased density of population and increased risk of transmission. In Pennsylvania, decreased density of pseudorabies-quarantined herds was associated with reduced risk of a herd becoming quarantined, whereas increased density of non-quarantined, uninfected herds was associated with a decreased probability of a herd becoming quarantined.17 A farrow–finish herd was associated with increased probability of becoming quarantined, compared with being a feeder pig herd. Seroprevalence is higher in vaccinated herds, increases over the course of the eradication program, and decreases with an increased time between quarantine and the development of a herd plan.
In The Netherlands, the risk factors contributing to seroprevalence of infection in breeding herds included:
• Production type (producers of finishing pigs had a higher prevalence than producers of breeding stock)
• Vaccination of sows during nursing (in comparison to vaccinating all sows simultaneously at 5-month intervals, or vaccination during the second half of gestation)
• Pig density in the municipality where the herd was located (seroprevalence increased with higher pig density)
• Herd size of fewer than 100 sows
• Average within-herd parity (seroprevalence increased with higher within-herd parity)
• Replacement pigs raised on the premises
• Vaccine strain administered to the sows.18
The survival capabilities of the virus under various environmental conditions influences the methods of transmission and control procedures.19 The virus may survive for 2–7 weeks in an infected environment, dependent on temperature fluctuations and pH level, and for up to 5 weeks in meat. The stability of the virus suspended in aerosol under different conditions of temperature and relative humidity has been examined.20 The infectivity of the virus in an aerosol decreases by 50% in 1 hour. Environments at 4°C supported the survival of the virus in aerosol better than at 22°C. The virus is lipophilic and sensitive to several commonly used disinfectants. Sodium hypochlorite (5.25%) is the most desirable and practical disinfectant. Suspensions of the virus in saline G solution and on the solid fomites, whole corn, and steel remained infectious for at least 7 days. Loam soil, straw, and concrete supported survival of the virus at 25°C for up to 1 week.19 During shipment of pigs, bedding material and surfaces in contact with pigs may become contaminated. Rinsing a needle between sampling may reduce the probability of mechanically transmitting the disease.21
Field strains of the virus differ in virulence. Numerous genomically different strains of the virus exist, and restriction endonuclease (RE) analysis can distinguish between virus isolates, which is useful for identifying new isolates of the virus as they appear in pig populations.22 A retrospective analysis of virus isolates from England and Wales over a 22-year period revealed considerable homogeneity of certain RE sites (BamHI), both in number and size. The appearance of an isolate with a new DNA fragment in 1981 coincided with a marked increase in the number of outbreaks of disease.22 A PCR assay was able to discriminate between the established strains and the new type. By relating this type to pig movement records it was possible to trace the spread of the new type virus which was isolated in 65% of the new outbreaks of pseudorabies in England and Wales in 1982.22 In Denmark, restriction fragment analyses of older clinical isolates, and of isolates from all the virologically confirmed outbreaks since 1985, indicated the introduction of foreign strains. Strain variation in virulence has been observed in field isolates and produced by laboratory attenuation. The viral proteins that determine virulence of the virus have been described.1 Some field strains of the virus from Poland and Hungary have been identified by restriction fragment pattern analysis as derivatives of conventionally attenuated vaccine strains.23 This is considered a rare event but must be considered in relation to trade in semen from vaccinated boars or trade in live animals between disease-free areas and areas where vaccination with live attenuated strains is practiced.
Pigs, and possibly rodents, appear to be the primary host for the virus. The virus is present in the nasal discharge and in the mouth of affected pigs on the first day of illness and for up to 17 days after infection.
Transmission within herds occurs by direct oral–nasal contact between infected and susceptible pigs, and aerosols from projection of discharges during sneezing, but may also occur via contaminated drinking water and feed. Transmission within herds is independent of the size of the population.24
The spread of virus from infected animals to contact-exposed animals can be predicted using a reproduction ratio. The ratio of secondary cases to originally infected animals is called the basic reproduction ratio denoted as R0. In the model, R0 has a threshold property. When R0 >1, the infection can spread; when R0 <1, the infection will not spread and will disappear, and the animal population is effectively protected.25 Experimentally, the quantification of vaccine-induced reduction in virus transmission indicates that vaccinating twice with a marker vaccine significantly reduced virus transmission. In unvaccinated groups, the R0 was 10.0; in the vaccinated group the R0 was 0.5.26 Thus, it is possible to measure transmission experimentally.
The transmission of virus decreases rapidly following the start of a vaccination program27 but extensive spread can still occur even among finishing pigs vaccinated twice.28 Vaccinated pigs may shed more virulent virus than mildly virulent virus but there are no significant differences in magnitude of transmission.29 Mixing of chronically infected pigs with seronegative pigs may not result in seroconversion in the seronegative pigs until a clinical outbreak of disease occurs.30
Transmission between herds is due to introduction of infected animals, and the virus may still be introduced into vaccinated breeding herds.31 Other methods of transmission of the virus into uninfected herds have been suggested, including farm laborers, vehicles, feedstuffs, rodents, and wild or domestic animals.
Transmission within an area is a major problem and not well-understood. Spread is occurring across the United States despite an intensive eradication program.16 Some evidence indicates that area spread may be associated with which swine market is used and the frequency of delivery of pigs to market per year.32 In France it has been suggested that the presence of an infected herd within 1 km is an important factor in the spread of PRV.33 The concurrent occurrence of an outbreak of disease on many farms in the same area in Denmark suggested long-distance airborne transmission of the virus.32
Infection is spread by airborne transmission.34 Exposing pigs to aerosols of the virus results in respiratory and other clinical signs similar to field cases.35 Sneezing probably generates the airborne virus. In a series of outbreaks in Britain between 1981–1982, seven of 11 were found to be likely to have been transmitted by aerosol on meteorological grounds.36 Airborne spread occurred between herds 2–9 km apart. An epidemic in Denmark in 1987–1988, associated with foreign strains of the virus, suggests that airborne transmission occurred across the German–Danish border34 especially as a southerly wind was blowing during the period of transmission. An epidemic occurred in 10 herds located within close proximity of each other in Indiana, and the clinical and meteorological data supported aerosol transmission of the virus.37 An epidemic during the winter of 1987/88 was associated with an unusual predominance of southerly winds, supporting the hypothesis of airborne transmission of the disease.32
Computer modeling based on the mean dose of virus received by an animal at a farm downwind can be used to predict the airborne spread of the virus.38 To test the hypothesis that the virus can be spread by aerosol, the application of a Gaussian diffusion model has been applied to an epidemic of pseudorabies in 10 herds located in Indiana.39 The epidemic spread through 10 farms across an area of 150 km. The county was free of infected herds for 2 years prior to the epidemic, which was well-documented. The transport of the virus was assumed to occur during the prepatent period from 3 to 7 days prior to the onset of clinical signs. Estimates of the virus dose received at a given barn indicate that transport of the virus was more efficient during the night than during the day. The low temperatures during the night resulted in decreased ventilation of the barn and greater cycling of air contaminated with the virus over the pigs.
The infection is transmitted in feral swine through the venereal route.40 Following commingling of uninfected gilts with virus infected boars, the virus could be recovered from the reproductive tracts of the gilts and could not be recovered from the upper respiratory tract.
Virus is excreted in the milk of infected sows and in utero infection occurs. The virus is inactivated in meat after 35 days of storage at −18°C (0.5°F). Meat from infected pigs may cause infection when fed to dogs. Venereal transmission of latent infection in sows and boars has been suspected, but there is no direct evidence. The effects of pseudorabies infection in adult boars are related to the effects of the clinical disease rather than any direct effect on semen quality. The virus cannot usually be isolated from the urine or semen from infected boars, and therefore the preputial secretions and the ejaculate are unlikely vehicles for shedding of the virus.
Pigs that recover from infection are latent carriers of the virus for life. Reactivation, followed by shedding and spreading the virus, may occur following stress such as transport or farrowing, or by the administration of corticosteroids.41,42 Serological testing of latent carriers detects the antibody response to the whole virus or to a pseudorabies virus glycoprotein.43 During natural infection, the virus replicates at the site of infection, usually in the oronasal areas. The virus gains entry into the nerve endings and ascends by retrograde axonal transport, to the cell body in the trigeminal ganglion. Viral components can be found in both the trigeminal ganglion and the tonsils.41 The tonsil is a primary site of virus replication and serves as an area for monitoring virus shedding during acute infection and reactivation. The virus can be isolated from tissue fragments of pigs clinically recovered from disease for up to 13 months and followed by a challenge with the live virus, which may be shed by sows for up to 19 months after initial infection. Virus gene products can be found in the trigeminal ganglia and tonsils for many weeks following acute infection.44 Latent infection can also occur in vaccinated pigs.
The rarity of spread to other species is due to the scanty nasal discharge and the improbability of the discharge coming into contact with abraded skin or nasal mucosa of animals other than pigs. The disease has occurred in sheep and cattle following the use of a multiple-dose syringe previously used in infected swine. The disease may spread from normal or clinically affected pigs to animals of other species, but does not usually spread between animals of the other species. For example, sheep and calves can be infected experimentally, but there is no evidence that they excrete the virus. The disease may occur in pigs, sheep, and cattle on the same farm. Brown rats may be a minor source of infection but are unlikely to be an important reservoir; they are capable of spreading the disease to dogs. The wild Norway rat is thought to have only a minor role in the transmission of the disease to farm animals. The virus causes fatal disease in dogs, which are usually infected from close association with infected pigs. The raccoon can be infected experimentally, but is not considered to be a long-term subclinical carrier of the virus. The possible role of wild animals in transmission of pseudorabies in swine has been examined with inconclusive results. It has been seen in Kodiak, Polar and Himalayan bears fed on a diet of raw pig’s heads.45 five viral isolates were recovered from latently infected wild boar originating from two regions of East Germany46 but in the Netherlands the wild boar were said to be rarely affected.47 The PRV infections in the wild boar in Germany are said to exist in the country as an endemic infection and persist completely separately to the domestic population and also do not appear to affect it.48 The sacral ganglia and trigeminal ganglia of wild pigs were said to be a source of infection.49 The latency was shown in 9/16 sacral ganglia, 7/16 trigeminal ganglia and 5/13 tonsils49 from feral swine in the USA, but even so most of the transmission in feral swine is expected to be venereal. There seems to be little evidence of a high infection rate in the wild boar of the Netherlands but they are in contact with the wild boar of Germany.50 It seems quite common in Spanish wild boar with 36% of a study of 78 being serologically positive. The wild boar strain is adapted to the wild boar pig.51 A group 1 virus was isolated from a wild boar in 1993 and it was suggested that the virus persisted for several years in the wild boar population in Italy52 and that the species should be considered a reservoir.52 In Croatia approximately 55% of tested wild boars were found to be seropositive.53 The experimental infection of wild boars and domestic pigs with different strains has been carried out51 and the clinical signs depended on the strain but the wild boar could infect the domestic strains and vice versa. The low virulence strains were highly adapted to the wild boar.
When infected with a virulent strain of the virus, pigs develop an immune response that can completely, or almost completely, prevent the virus from replicating after the pig becomes reinfected.1 Following natural infection, sows acquire immunity, which is transferred to their piglets in the colostrum and persists in the piglets until 5–7 weeks of age. Following intranasal challenge, piglets with colostral immunity from naturally infected sows are protected from clinical disease, but not against subclinical infection.
Vaccination of pigs with attenuated pseudorabies virus prevents clinical disease and death that may otherwise follow exposure to the virulent virus. Vaccination does not, however, prevent either acute or latent infection with virulent virus. As a consequence, vaccinated pigs, as well as non-vaccinated pigs that survive infection with the virulent virus, can become virus carriers and a source of the virus following reactivation of a latent infection. This is of vital importance in eradication programs wherein it is necessary to identify infected pigs regardless of their vaccination status. Maternal immunity interferes with inactivated virus vaccination much more than with live virus vaccination.54
Vaccination of pregnant sows induces a maternal immunity, which protects piglets from experimental disease. However, latent infection of young pigs with highly virulent virus can develop in the absence of clinical signs. The virus can reach the uterine and fetal tissues, via infected mononuclear cells, the presence of circulating antibodies induced on vaccination.55 Vaccination of piglets before challenge exposure has little or no effect on the rate of establishment of virus latency, but vaccination does reduce shedding after subsequent experimental reactivation of the virus with dexamethasone. Attenuated thyrosine kinase-negative vaccine strains of the virus can also establish a reactivatable, latent infection.56
In growing and finishing pigs in quarantined herds, the serological status is unpredictable because the infection may continue to spread, may cease temporarily, or may cease altogether. Evaluation of the serological status of the boars in a breeding herd does not accurately reflect the serostatus of the herd.
It has been suggested that the T cells are more important than the B cells in the clearance of PRV from the host57 and it has been shown that strong T-cell mediated responses after challenge produce the best protection.58
The economic losses associated with pseudorabies in swine are due to clinical disease, and the costs of serological analysis and vaccination programs.32 Because of the variability of expression of the infection in different herds, a description of a single farm’s experience with pseudorabies is difficult to put into a larger perspective regarding the impact of disease at a state or national level.59 Economic loss estimates must include the measurement of losses during and immediately after clinical outbreaks of disease, and the indirect losses incurred until after eradication of the disease. Losses have been estimated at US $25–50/sow per year; these include only losses during the period of the outbreak and the direct losses attributable to death and abortions. When expanding the observations of economic losses to 3 months after the termination of the outbreak, estimated losses may be as high as US $ 145/sow per year.32 Economic analyses of the losses in a commercial farrow– finish herd of 240 breeding age sows in the United States revealed that the major part of the loss was caused by death of suckling pigs at 76% of total loss, nursery pig mortality accounted for 12.6% of total net loss, sow culling and deaths accounted for 9.4% of net loss, and market pig deaths accounted for 1.2% of net losses.32
The costs of eradicating pseudorabies vary depending on the methods employed.Depopulation–repopulation is the most expensive method because it requires culling of animals, clean-up costs, and downtime which represents the largest proportion of expense. In addition, the probability of reinfection following repopulation is a risk.Test and removal is the most inexpensive, and segregation of offspring is intermediate in costs. The cost of eradicating the virus from a swine herd can be in excess of US $ 220/inventoried sow; some estimates are much higher.60 In large breeding herds or finishing herds with the continual influx of susceptible pigs, the disease may become endemic. Pseudorabies may also be a significant cause of reproductive inefficiency in pig herds, and infection within the herd may be initially manifest by abortions in the sow herd, followed later by the more typical occurrence of neurological disease in suckling and growing pigs. The economic losses due to the disease can be very high because of mortality in young pigs, decreased reproductive performance, and the necessity to depopulate to eradicate the disease from a herd. An economic assessment of an epidemic of pseudorabies in a 150-sow farrow–finish operation on selected production and economic variables has been made. The mean litter size remained the same throughout the period of observation, but there was a two-fold increase in suckling pig mortality and 3.5-fold increase in stillbirths during the months of the epidemic compared with the period before the epidemic. Following the epidemic, suckling pig mortality was 14% greater and stillbirth rate was 71% greater than during the months preceding the outbreak. The major economic losses (88% of the total loss) were related to breeding herd removal/depopulation and production downtime.
The portal of entry is through abraded skin or via the intact nasal mucosa. The virus is pantropic and affects tissues derived from all embryonic layers. Receptor and receptor-binding virion proteins which can mediate the virus entry into the cell and cell to cell spread have been described.61 The various glycoproteins of the virus are required for various stages of virion morphogenesis. For example deletion of glycoproteins gE, gI, and gM inhibits the virion maturation.62 Pseudorabies glycoprotein gK is a virion structural component involved in virus release from the cell but not viral entry and its presence is important to prevent immediate reinfection.63 Viremia occurs with localization of the virus in many viscera, but with multiplication occurring primarily in the upper respiratory tract. Spread to the brain occurs by way of the olfactory, glossopharyngeal, or trigeminal nerves i.e. via the autonomic nerves.64 Cells with the common leukocyte antigen CD45+ populate the CNS infected areas from the local capillaries and the number of cells is increased in proportion to the number of infected neurons.65 Virus disappears from the brain by the 8th day, coinciding with the appearance of neutralizing antibody in the blood. When the virus gains entry through a skin abrasion, it quickly invades the local peripheral nerves, passing along them centripetally and causing damage to nerve cells. It is this form of progression that causes local pruritus in the early stages of the disease, and encephalomyelitis at a later stage when the virus has invaded the central nervous system. In pigs, pruritus does not develop after IM injection, but a local paralysis indicative of damage to low motor neurons occurs prior to invasion of the central nervous system in some pigs. In cattle, pruritus of the head and neck is usually associated with respiratory tract infection, while perianal pruritus is usually due to vaginal infection.
Inoculation of the virus into the nasal cavities or brain results in signs of encephalitis rather than local pruritus. With oral inoculation there is an initial stage of viral proliferation in the tonsillar mucosa, followed by systemic invasion, localization, and invasion of the central nervous system along peripheral and autonomic nerve trunks and fibers. Lesions of Auerbach’s myenteric plexus and the skin may also occur.66 The peripheral blood mononuclear cells, tonsil, lymph nodes and bone marrow are a poor source of virus after experimental infection.67 The trigeminal ganglia and olfactory bulb are good sources of virus.67 The virus may be present in the trigeminal ganglion of a naturally infected sow without any history of clinical disease. Experimental inoculation of the virus into young pigs can result in a mild pneumonia which may progress to a severe suppurative bronchopneumonia.68
The virus can invade the uterus and infect pre-implantation embryos, which can lead to degeneration of the embryo and reproductive failure.69 Virulent pseudorabies virus can cause lesions in the uterine endothelium and ovarian corpora lutea of pigs in early pregnancy, and gene-deleted mutant virus vaccine given IV during estrus can cause ovarian lesions, which may affect fertility.69 Through the use of embryo transfer procedures, infected embryos may disseminate the virus from donors to recipients.
The incubation period in natural outbreaks is about one day.
The major signs are referable to infection of the respiratory, nervous and reproductive systems. There is considerable variation in the clinical manifestation, depending on the virulence and tropism of the infecting strain. Nervous system disease is the major manifestation, but with some strains, respiratory disease may be the initial and prime presenting feature. There is also strain variation in the pattern of age susceptibility.
Young pigs a few days to a month old are most susceptible. Very young sucklings develop an indistinct syndrome, but prominent nervous signs occur in older piglets. A febrile reaction, with temperatures up to 41.5°C (107°F), occurs prior to the onset of nervous signs. Incoordination of the hindlimbs causing sideways progression is followed by recumbency, fine and coarse muscle tremors, and paddling movements. Lateral deviation of the head, frothing at the mouth, nystagmus, slight ocular discharge, and convulsive episodes appear in a few animals. A snoring respiration with marked abdominal movement occurs in many, and vomiting and diarrhea in some affected pigs. Deaths occur about 12 hours after the first signs appear. In California, a consistent sign has been blindness due to extensive retinal degeneration.
In growing and adult pigs, the disease is much less severe but there is considerable variation depending upon the virulence of the infecting strain. In growing pigs, mortality falls with increasing age and is generally less than 5% in pigs at 4–6 months of age. With some strains, fever is a prominent sign, while depression, vomiting, and sometimes marked respiratory signs, including sneezing, nasal discharge, coughing, and severe dyspnea are common. Trembling, incoordination, and paralysis and convulsions follow, and precede death. With others, the disease may be manifest at this age by mild signs of posterior incoordination and leg weakness. Concurrent infection has been described with both PCV2 and ADV.70 In adults, fever may not be present and the infection may cause only a mild syndrome of anorexia, dullness, agalactia, and constipation. However, virulent strains may produce acute disease in adults, characterized by fever, sneezing, nasal pruritus, vomition, incoordination and convulsions, and death. Infection in early pregnancy may result in embryonic death, or abortion, and early return to heat. An abundant vaginal discharge may occur. Infection in late pregnancy may result in abortion, or in the subsequent birth of mummified fetuses, which may involve all or only part of the litter. Abortion may result from the effects of fever or from viral infection of the fetus.
There may be sudden death without obvious signs of illness. More commonly, there is intense, local pruritus with violent licking, chewing, and rubbing of the part. Itching may be localized to any part of the body surface, but is most common about the head, the flanks, or the feet, the sites most likely to be contaminated by virus. There is intense excitement during this stage, and convulsions and constant bellowing may occur. Maniacal behavior, circling, spasm of the diaphragm, and opisthotonos are often evident. A stage of paralysis follows in which salivation, respiratory distress, and ataxia occur. The temperature is usually increased, sometimes to as high as 41–41°C (106–107°F). final paralysis is followed by death in 6–48 hours after the first appearance of illness. A case of non-fatal pseudorabies in a cow is recorded. There is also a report of pseudorabies occurring in feedlot cattle in which there were nervous signs, bloat, and acute death, but no pruritus. In young calves, it is characterized clinically by encephalitis, no pruritus, erosion in the oral cavity and esophagus, and a high case fatality rate. An outbreak in sheep was associated with skin abrasions acquired at shearing. Affected ewes were dull, inappetent, and had a fever of 41.1°C. About 23 of 29 affected sheep developed the ‘mad itch’, with nibbling of their fleece and frenzied attempts to bite one area of the skin and rub it against the wall and bars of their pen. Terminally, recumbency, tremors, and opisthotonos were common, and death occurred within 12–24 hours after onset.4 five farm cats also became ill and died; the virus was isolated from the brain of one cat. In goats, rapid deaths, unrest, lying down and rising frequently, crying plaintively, profuse sweating, and spasms and paralysis terminally are characteristic. There may be no pruritus.
The clinical findings in dogs and cats are similar to those in cattle, with death occurring in about 24 hours.9 In France, cases in dogs have been linked to strains of virus from wild boars.71
The commonly used serological tests for pseudorabies-specific antibodies are the serum-neutralization (SN) and ELISA.
The SN test using the Shope strain has been the ‘gold standard’ against which other serological tests are compared and has been most widely used because of its sensitivity and specificity. Specific virus-neutralizing antibodies are detectable in the serum of recovered pigs, and this test is in routine use for herd diagnosis and survey purposes. Antibody is detectable on the 7th day after infection, reaches a peak about the 35th day, and persists for many months. Paired serum samples taken as early as possible, and about 3 weeks later, show a marked antibody rise. However, the SN test lacks the sensitivity necessary for detection of pigs with low levels of humoral titers of specific SN antibodies which can be enhanced by using the Bartha gIII strain.72
Some herds may have no serological evidence of previous infection or current spread of the virus, but have single reactors in the herd which may be infected with the virus.73 Such singleton reactors may be found in herds being monitored serologically for presence of infection. These singleton reactors may be infected with strains of the virus that are relatively avirulent.
The ELISA is more sensitive than the SN test, especially early in the immune response to pseudorabies antigens. However, because of its high sensitivity, screening ELISAs yield some false-positives which must be confirmed by another test, such as another ELISA, SN test or latex agglutination test.74 False-positives are unlikely to be due to infection with other herpesviruses. ELISA has also been used as a meat juice test75,76 with high sensitivity (93%) and specificity (98%). The indirect ELISA is a more rapid and convenient procedure, offering many advantages over the SN test for routine serodiagnostic work. An indirect ELISA, using whole blood collected onto paper discs, is a rapid and convenient test and eliminates the costs of using vacutainer tubes and separating the blood. An indirect ELISA based on recombinant and affinity-purified glycoprotein E of PRV to differentiate vaccinated from naturally infected animals has been developed.77 An indirect ELISA has been developed in the Czech Republic78 that can be used because of its high sensitivity and specificity for blood serum or frozen pork samples. It has allowed the demonstration of ADV in meat juice with only marginal titers in the blood. Commercial ELISA kits are available and some are more specific than others.74 A highly sensitive and specific competitive ELISA based on baculovirus expressed pseudorabies virus glycoprotein gE and gI complex has been described.79 This allows detection as early as 2 weeks post-infection and can handle large numbers of tests without the need to handle live virus.
In countries where vaccination is regularly used for control of the disease, an assay to serologically distinguish infected from vaccinated pigs is critical. While a vaccination program will reduce the circulation of virus in the field, it will not eliminate the virus from the pig population. To eradicate the virus, the ability to differentiate infected from vaccinated pigs is crucial. Several commercial ELISA kits can differentiate between vaccinated and naturally infected pigs.80 Differentiation is possible when vaccine virus strains have either a natural, or a genetically engineered, deletion that encodes for either glycoprotein-I (gI), gIII, or gX genes. Commercial ELISA kits that specifically detect antibody responses to gI of the virus offer considerable advantages as diagnostic tests for the virus, with a sensitivity of 99.2% and specificity of 100%.80 The gI ELISA is able to distinguish infected pigs from those vaccinated with gI-negative vaccines81,82 The field strains of the virus produce antibodies to gI when inoculated into pigs. Unvaccinated pigs, or pigs vaccinated with gI-negative vaccines, that become subclinically infected with field strains of the virus may be detected with the gI–ELISA for a long time after infection. Thus, pigs that are seropositive in the gI–ELISA have either been infected with the pseudorabies virus or have been vaccinated with gI-positive vaccines; gI-seronegative pigs can be considered to be uninfected. Eradication of the virus from swine herds is possible by gI–ELISA testing, and culling gI-seropositive pigs in herds using gI-negative vaccines.
Detection of pigs in the latent phase of infection can be done serologically.43 Pigs of any age that survive the acute infection phase become latent carriers for life, and serologic testing consistently detects animals in the latent phase of infection if the test detects the antibody response to the whole virus or to a reliable pseudorabies-virus glycoprotein.43 Of several serological tests examined, the glycoprotein-I and glycoprotein-III marker systems, which performed with similar sensitivity as the screening tests, were superior to the glycoprotein-X marker system in detecting antibodies in infected pigs.
In infected pigs the virus is usually present in nasal secretions for up to 10 days. A common method for the diagnosis of pseudorabies in sows is to take swabs from the nasal mucosa and vagina. Polyester and wire swabs shipped in 199 tissue culture medium supplemented with 2% fetal bovine serum (FBS) buffered with 0.1% sodium bicarbonate and HEPES will yield optimum recovery of the virus. Wooden applicator sticks with cottonwool have antiviral activity and recovery of the virus may not be possible after 2 days, which is of practical importance if the samples are shipped by mail. The virus can be demonstrated in nasal cells by immunofluorescence and immunoperoxidase techniques.83 The virus can be detected by direct filter hybridization of nasal and tonsillar specimens from live pigs.44 The virus survives on tonsil swabs taken with Dacron-tipped applicators for up to 72 hours in cell culture medium under transport.84
New PCR techniques have been used67 and have been used to differentiate between true and false serological positives when single reactor pigs have been found.85
There are no gross lesions typical and constant for the disease, and diagnosis must rely on laboratory examination. When pruritus has occurred there is considerable damage to local areas of skin, and extensive subcutaneous edema. The lungs show congestion, edema, and some hemorrhages. Hemorrhages may be present under the endocardium and excess fluid is often present in the pericardial sac. In pigs, there are additional lesions of visceral involvement. Slight splenomegaly, meningitis, and excess pericardial fluid are observed, and there may be small necrotic foci in the spleen and liver. Foci of hepatic necrosis may also be seen in aborted fetuses. Histologically, in all species, there is severe and extensive neuronal damage in the spinal cord, paravertebral ganglia, and brain. Perivascular cuffing and focal necrosis are present in the gray matter, particularly in the cerebellar cortex. Intranuclear inclusion bodies occur infrequently in the degenerating neurons and astroglial cells, particularly in cerebral cortex in the pig. These inclusions are of considerable importance in differential diagnosis. Necrotizing lesions with inclusion-body formation in the upper respiratory tract and lungs is strongly suggestive of porcine pseudorabies. Ultrastructural observations have been made which included syncytia, cellular debris and macrophages and lymphocytes with vacuoles in their cytoplasm.86 Virus may be detected by direct fluorescent antibody examination or by growth in tissue culture. The tissues of the head and neck regions of non-immune pigs yield virus most consistently and in the highest concentration after challenge. The immunoperoxidase test can be used to study the distribution of the virus in different tissues. Latent virus can be detected using a DNA hybridization dot blot assay. Where possible, whole carcasses and fetuses should be submitted for laboratory examination. The location of the optimal neural samples, including the paravertebral ganglia, has been described for sheep.87 The placental lesions in pregnant sows that have aborted from natural infection with pseudorabies consist of necrotizing placentitis and the presence of intranuclear inclusions. In an experimental infection of loops of intestine it was shown88 that there was necrosis of the follicles in the Peyer’s patches and degeneration of the epithelial cells in the crypts and villi and degeneration of the cells in the myenteric plexuses. Intranuclear inclusion bodies were found 2–4 days after inoculation. The primary target of the wild ADV was the macrophages of the sub-epithelial area of the dome of the Peyer’s patch.
• Histology – one half of midsagittally-sectioned brain, spinal cord with paravertebral ganglia, Gasserian ganglion, placenta, liver, lung, spleen, tonsil, retropharyngeal lymph node (LM). Immunohistochemistry has been used to confirm rare cases in countries where the disease is rare89 and other corroborating evidence is lacking.90 Can also collect muscle samples for meat juice ELISAs91
• Virology – brain, spinal cord, liver, spleen, tonsil, retropharyngeal lymph node (FAT, ISO). CSF is not good for virus isolation.67
The different clinical forms of pseudorabies in pigs and ruminants resemble several diseases.
Teschen disease occurs in similar forms in certain areas; the diagnosis is dependent on serology and pathology.
Rabies is rare in pigs and is usually accompanied by pruritus at the site of the bite.
Streptococcal meningitis is restricted to sucking pigs of 2–6 weeks of age, the lesions are usually obvious at necropsy, and the causative organism is readily cultured from the meninges. The response to treatment with penicillin is good and is of value as a diagnostic test.
Encephalopathy associated with hog cholera, African swine fever, salmonellosis, Glasser’s disease, Escherichia coli septicemia and erysipelas are considerations, and are usually obvious at necropsy.
Bowel edema causes typical edema of the head and eyelids, undo typical circumstances in weaner pigs and rapid death.
Salt poisoning causes typical intermittent nervous signs, with a typical history of water deprivation.
Respiratory form of pseudorabies should be considered in any outbreak of respiratory disease that is poorly responsive to usually effective therapeutic measures.
Reproductive inefficiency associated with enterovirus (SMEDI) and parvovirus infections closely resembles that associated with pseudorabies, and requires laboratory differentiation by virus isolation and serological testing.
In cattle the local pruritus is distinctive, but the disease may be confused with the nervous form of acetonemia in which paresthesia may lead to excitement. The rapid recovery that ordinarily occurs in this form of acetonemia is an important diagnostic point. The furious form of rabies and acute lead poisoning cause signs of mania, but pruritus does not occur.
The control of pseudorabies is difficult and currently unreliable because normal healthy pigs may be infected and shed the virus for up to several months.
An important principle in control and eradication of the disease is the reproduction ratio, R0, which is defined as the average number of new infections caused by one typical infectious animal. When R0 >1, the infection can spread; when R0 <1, the infection will disappear. In eradication programs it is essential that R be less than 1 and the infection will die out in the herd.
The methods of control or eradication include depopulation and repopulation, test and removal, segregation of progeny, and vaccination. The selection of a strategy for the control or elimination of the disease depends on the following:
1. Source of the herd infection
2. Method of transmission of the virus
3. Survival of the virus in the environment
4. Sensitivity and specificity of the diagnostic test
5. Risk factors in the herd,92 which include:
The eradication of the disease from small herds was described in Hungary.93 In this country the shared use of boars, the pig density and the infection in the surrounding area were the most significant influences on the spread and control of the disease.
Breeding stock producers favor eradication, farrow–finish producers that do not sell breeding stock or feeder pigs are generally more concerned with the reduction of losses from clinical pseudorabies infection than with eradication. In the USA offsite all in/all out finishing was more frequent amongst the successful farms than the unsuccessful.94 The unsuccessful also had other infected herds within 3.2 km (2 miles) and often no cleaning or disinfection.94
Depopulation–repopulation is the most expensive, segregation of progeny method is next, and the test and removal the most inexpensive per sow.60 A computerized decision-tree analysis and simulation modeling can evaluate the economics of control and eradication strategies. The optimal alternative is to test and remove seropositive animals if the initial prevalence is ∼57%; otherwise vaccination of sows only is preferred. Vaccination may be recommended at lower prevalence rates as a conservative approach. Eradication by test and removal combined with the use of gene-deleted vaccines is advantageous at any prevalence rate of infection.95 Depopulation and repopulation is not the best option under any circumstances. Once formulated, a decision-tree analysis can be adapted to the prevailing economic or epidemiological conditions.
An epidemiological model projected future herd–herd disease transmission under alternative eradication or control programs over 20 years, from 1993 to 2012.60 With current eradication program funding in the United States, the prevalence of infection would be 23% in high-risk states, 10% in moderate-risk states, and 1% in low-risk states. Increased funding for the eradication program would substantially reduce the prevalence of infection. Profitability for the average size farrow–finish herd was estimated to be US $ 6 per cwt of swine produced for virus-infected herds than for uninfected herds. Estimates of the value of economic welfare indicated that consumers would be the major beneficiaries of eradication because of reduced prices and increased consumption of pork.
In Sweden, it was estimated that an eradication program is economically viable.96 The maximum benefits are derived where the Swedish agricultural sector is deregulated and consumers obtain about 50% of the benefits excluding program costs. In the current case where Sweden is a member of the European Union, the benefits are reduced mainly due to lower prices of inputs and pork.
An economic analysis of alternative control programs found that, for regions of high pig density, the most economical strategy is to lower herd prevalence by intensive vaccination before completing eradication by test-and-removal of remaining positive animals.97
Eradication and control programs used in France have been reviewed.97 The eradication of PRV in a 170 sow herd was described98 in which the affected animals were killed and the rest were then vaccinated and the total cost to the farm was about $50 000.
In large herds, the virus must be eliminated from the growing–finishing pigs and the breeding herd. Large herds that are virus-positive are infected in both groups; smaller herds are frequently infected in only the breeding herd.99 An initial step in eradication is to determine the prevalence of infection. Representative samples of finishing pigs older than 4 months, and of breeding sows, gilts, and boars are tested. On the basis of the test results and the risk factors in the herd, a cost-effective plan can be devised for the individual herd.
When the prevalence of infection in the herd is over 50%, eradication can be achieved by depopulation and repopulation with virus-free breeding stock. However, depopulation is the most expensive method and is not compatible with the retention of valuable pedigree stock. The entire herd is depopulated over a period of months as the animals reach market weight. After removal of the animals the entire premises are cleaned and disinfected. Repopulation should be delayed at least 30 days after the final disinfection, and swine should originate from a pseudorabies-free qualified herd and be isolated on the premises and retested 30 days after introduction. All herd additions should be isolated and tested 3 0 days after introduction.
The test and removal program is recommended when the prevalence of infection in the herd is below 50%. This method requires testing of the entire breeding herd and immediate removal of all seropositive animals; 30 days after removal of seropositive animals, the herd is retested, and if necessary at 30-day intervals, until the entire herd tests are negative. Following a second negative test, the testing regimen may be changed to test only 25% of the herd every 4 months. Seropositive animals are identified and culled. The test and removal method is superior to the vaccination system as a method of control. Valuable genetic material from breeding stock that are seropositive may be salvaged using embryo transfer techniques. Embryos may be transferred safely to susceptible recipient gilts from sows that have recovered from infection, but not from sows that are in the active stages of infection. The virus does not penetrate the outer covering of the embryo, but it can become attached to it so that it may physically transfer to the uterus of the recipient. This transfer of infection may occur if the donor sow is in the active phase of infection.
The objective of this strategy is to raise a pseudorabies-negative breeding herd to replace the infected herd. Once the herd is diagnosed as pseudorabies-infected, a regular schedule of vaccination is instituted. Gilts are vaccinated at first breeding, and both sows and gilts are vaccinated 2–4 weeks before farrowing to provide a high level of colostral immunity to their piglets. Offspring are removed at weaning and raised apart from the infected herd. At 4 months of age, and then again before breeding, the segregated replacements are tested for antibody. Since colostral immunity is no longer detectable by 4 months of age, any animals over 4 months of age that are seropositive are considered pseudorabies infected. As the gilts reach reproductive maturity, the old sow herd is replaced. Segregation between the infected sow herd and the clean gilt herd is maintained until all positive sows have been removed and the facilities disinfected. Groups of seronegative pigs are identified and combined into larger groups to establish a new herd. The original herd is gradually depopulated, and the premises cleaned and disinfected. The new herd is then monitored on a regular basis.
Pseudorabies was first diagnosed in the North Island of New Zealand in 1976, an eradication program started in 1989 and the virus was cleared from the North island in 1997.100
A pseudorabies control program was introduced in England in 1983 when the infection was spreading rapidly. New legislation imposed restrictions on the movement of pigs where clinical signs of the disease were present in the herd. The first part of the eradication scheme involved testing all of those herds previously known to have pseudorabies. Within several months after the beginning of the eradication campaign, 417 herds had been slaughtered, involving 342 275 pigs, of which 72.5% were salvaged. Only 121 herds had been known to be previously infected, while the remaining 296 herds had been identified through tracebacks and reports of new cases. By 1985 it was concluded that the disease was well-controlled in England with only 10–14 infected herds remaining. Farmers were compensated for all animals slaughtered and also for consequential loss associated with the loss of stock. The cost of the eradication program was financed by a levy on all pigs normally marketed for slaughter in England. In 1995, England was free of Aujeszky’s disease. Following the successful use of the gene deletion vaccination and eradication program the Netherlands is now free101 and also Germany.102 There were originally 70% seropositive sows in 1993, 1% in 1998 and now none (as above). In Sweden the herds were declared free from 12–53 months after the start of the programme.103 Now In Northern Ireland, pseudorabies is more widespread than it ever was in Britain before the eradication program. Because the infection rate is over 50%, an eradication program based on slaughter of infected herds would destroy the swine industry. Thus the control program in Northern Ireland is based on the use of vaccination, the culling of seropositive animals, and the gradual introduction of seronegative animals.
In the United States, the national pseudorabies eradication program was implemented in 1989 as a joint State– Federal–Industry-sponsored program.104 Pilot projects were conducted in Iowa, Illinois, Pennsylvania, Wisconsin, and North Carolina from 1984 to 1987. In the pilot projects, 97.5% of 116 herds that were initially pseudorabies-positive were successfully cleared of infection. This indicated that eradication of pseudorabies virus from herds of swine can be efficiently achieved, and is most effective applied on an area basis. The introduction of the gene-deleted pseudorabies vaccines in the program was the technical breakthrough needed to be able to offer the national eradication program, since it was now possible to distinguish between naturally infected and vaccinated animals.104 The program consisted of:
Stage III, mandatory herd clean-up
In Ohio, the eradication has made progress and eradication is expected in 1996 at a minimum cost to the public and the process in Illinois has also been described.105 In practice what it meant was that all were at stage I by 1991, stage II was in states with over 1% affected and stage III in the states with less than 1% affected, there were still 10 states in stage IV on 1/1/2000 but on the 1/1/2000 33 states were free and all were cleared by 2002. When an outbreak of the disease occurs in a susceptible herd the mortality may be very high, and the first consideration is to prevent spread to uninfected sows and litters and pregnant sows from infected pigs. They should be attended by separate personnel, or adequate barriers to mechanical transmission of infection should be arranged. On affected premises, cattle should be separated from pigs, and dogs and cats should be kept from the area. The affected herd should be quarantined, and all pigs sold off the farm should be for slaughter only.
Vaccination is used to reduce clinical disease when outbreaks occur or when the disease is endemic in the herd. An effective immunity develops after natural infection or vaccination, and piglets from immune sows are protected from clinical disease during the nursing period by colostral immunity. However, the presence of circulating antibody does not prevent infection, the development of latency and subsequent activation and excretion of the virus. However, vaccination reduces viral shedding after natural infection. On farms in which the disease is endemic or outbreaks have occurred, vaccination of the sows, and management procedures to reduce the spread of infection, have markedly reduced preweaning mortality and reproductive failures. field studies in large numbers of herds where the sows were vaccinated three times annually show that the reproduction ratio was below 0.66, which is significantly below 1,106 and massive spread of the virus does not occur.
It is often virtually impossible to prevent the spread of infection in a susceptible herd and vaccination of all pigs at risk, especially pregnant sows, is recommended. The vaccine reduces losses in infected herds, limits the spread of infection, and decreases the incidence in endemic areas. With a properly controlled and monitored vaccination and culling program in a breeding herd it is possible to control clinical disease and reduce the infection pressure. All breeding stock present during an outbreak are subsequently vaccinated regularly until they are all culled, which removes the major sources of virulent virus. Following this phase, newly introduced gilts and boars are tested, and monitored regularly. This is considered to be less costly than the test and slaughter policy.
However, in vaccinated herds, the virus continues to circulate and an accurate epidemiological analysis is not possible because titers caused by vaccination cannot be distinguished from those caused by natural infections.
Control of the diseases in many countries has always been based on compulsory intensive vaccination of the entire population.102,107
Conventional modified live virus and inactivated virus vaccines have been available. Both vaccines will reduce the incidence rate and severity of clinical disease in an infected herd. They also reduce the field virus shedding and latency in the trigeminal ganglion after exposure to field virus.108 The vaccine efficiency is however markedly influenced by the modified live virus vaccine strain and the route of administration. The vaccine genotype plays a very important role in the effectiveness of the vaccine program. Recently needle-free transdermal vaccination using a modified live PRV vaccine has been described thereby preventing the loss of any needles in the carcase.109 Cell mediated immunity in the form of cytotoxic T-cells may play an important part in the effectiveness of the vaccine.110 The deficiencies of inactivated vaccines in producing virus specific interferon gamma (IFN) can be enhanced by the use of simultaneous administration of IL-12 which appears to upregulate Th1/Th2 expression.111
Vaccination of pregnant sows induces SN antibodies, which are transferred to the newborn piglets and provide protection against infection. Vaccination during pregnancy produces more protection against PRV for piglets than sow vaccination before mating.112 A better protection was observed in sows vaccinated with an attenuated virus than in sows vaccinated with inactivated virus.113 Piglets rely on colostral and milk antibodies for protection, and the vaccination of piglets born from vaccinated sows does not produce a significant serological response until the piglets are about 12 weeks of age. Earlier vaccination of piglets from infected or vaccinated sows is ineffective because high levels of maternal antibodies interfere with a serological response stimulated by the vaccine.114 Maternal immunity interferes with the development of active immunity from vaccination until at least 15 weeks of age, even when the colostral titers are low. Thus, in a situation in which the majority of sows have been infected or vaccinated, vaccination of weaned pigs may not yield desirable results. Both inactivated virus and attenuated live virus vaccines provide similar results when piglets born from vaccinated sows are vaccinated before colostral immunity has waned.
The optimal vaccination strategy for growing and finishing pigs in an eradication program is controversial. In eight persistently infected herds vaccinations, both I/N and I/M115 were made at 4 and 10 weeks of age.116 Only one vaccination is given to finishing pigs in endemic areas in Europe. However, this does not reduce the prevalence of infection in finishing pigs in herds with a high prevalence. Double vaccination of finishing pigs will reduce the spread of the virus, but extensive spread can still occur.28 The presence of maternal antibodies may interfere with the induction of antibodies, and double vaccination 4 weeks later may boost immunity. Mean daily weight gain was also improved by a second vaccination with a direct economic benefit.
A major development in vaccination against pseudorabies has been the introduction of genetically engineered live vaccine strains used to make marker or subunit vaccines. Vaccination with modified live gene-deleted vaccines is now an integral part of pseudorabies eradication programs worldwide.117 The most common gene deletions are for glycoproteins E (gE) or gI and G (gG) or gX, and gIII.118 A gD/gE negative vaccine was described.119 In Europe, use of gE-vaccines has become the standard. In the United States, a gG–gE– pseudorabies vaccine has been introduced.63 These vaccines in conjunction with a companion diagnostic test, can distinguish between naturally infected and vaccinated animals. Colostrum can also be used to monitor antibodies against gI protein of the virus.120
A study comparing I/N and I/M vaccination showed that pigs given both vaccines (I/N and I/M) had a significantly better clinical and virological protection after challenge than the single I/N vaccination.121 The recombinant vaccines are able to circumvent the inhibition of active immunity that occurs when maternally derived antibody is still present.117,122 Animals vaccinated with a deleted vaccine are not able to mount an immune response against the protein whose gene has been deleted in the vaccine virus genome. In contrast, wildtype virus-infected animals produce antibodies against all the viral glycoproteins. Differentiating ELISAs, specific for the deleted marker protein, then allow discrimination between infected animals, which can be culled from the herd, and vaccinated animals. These vaccines reduce the severity of clinical disease and viral shedding. However, the presence of colostral antibodies in growing pigs may interfere with an immune response, which may result in increased virus excretion on challenge exposure. Repeated vaccination is needed to provide some protective immunity against challenge exposure to virulent virus.
These mutants have also been rendered thymidine kinase-deficient (TK–) mutants, and are avirulent and immunogenic. Pigs inoculated with these mutants are resistant to experimental challenge with the virulent virus, and the virulent virus cannot be recovered from the ganglia, which suggests that vaccination reduced colonization of the ganglia. The ideal vaccine strain should prevent clinical disease and mortality, should not be transmitted to non-immunized animals, should prevent colonization of the ganglia by a potential superinfecting virulent virus and thereby reduce the natural reservoir of the virus. The TK– mutant virus possesses these desirable characteristics. The high efficacy of recently constructed gI-negative deletion mutant vaccines of pseudorabies virus provide a sound basis for implementing the ‘gI’ approach to the future control of the disease.
Piglets born from sows vaccinated with deleted (gIII-, TK) strains at 3 days and 9 and 11 weeks of age developed detectable antibodies that lasted up to 100 days of age when vaccinated.123 Maternal antibodies in piglets from sows vaccinated with gIII-deleted vaccine decay to undetectable levels at 7 weeks of age. Vaccination of these piglets at 3 days of age with the same vaccine results in a priming effect, which protects the piglets against virulent virus challenge at 7 weeks of age.124,125 Thus, effective protection could be provided by active immunization from birth through weaning, in the nursery and into the growing and finishing stages of production.
Although genetically engineered live virus vaccines have been shown to be efficacious and safe, there is a possibility of spread between vaccinated and unvaccinated animals, of persistence in the field and of recombination between different vaccine strains, which can lead to enhanced virulence. New viral mutants lacking glycoproteins gD, gE, gG, and gI may form the basis for the development of new vaccines that do not recombine.126 A gB deletion vaccine has been described for I/N use and has been shown to produce both local and serum antibodies.127 Recently, a DNA vaccine was shown to give as good a response as gD plasmid vaccine but the DNA vaccine had to be given intradermally.128 It can overcome maternally derived antibody129 and the vaccine described in this case still gave protection against infectious PRV challenge at the end of the finishing period.
Even more radical is a vaccine with a granulocyte-macrophage colony stimulating factor (GM-CSF) which has also been given in a DNWA formulation.130
Experimentally, immunized pigs can be latently infected with the wild-type virus without being detected by the gE-specific ELISA routinely used to discriminate between infected and vaccinated pigs.124 Thus, gE seronegative pigs may still be infected and be a source of infection.
Remarkable progress has been made with the use of gI-deleted vaccines. Intensive regional vaccination of finishing pigs with a gI-deleted vaccine along with companion diagnostic tests, reduced the seroprevalence in infected finishing herds from 81% to 19% in 2 years.131 Vaccination increases the virus dose needed for establishment of infection, and decreases the level and duration of virus excretion after infection. In the control group, with routine disease control, no significant change in seroprevalence occurred. The consistent application of intensive vaccination of all breeding herds in a region, including those herds participating in a production chain, can also decrease the prevalence of infection in heavily infected areas.132 The intensive regional vaccination did not completely eliminate virus infections within these herds; the source of infection was not determined.31 It is suggested that the virus either circulated at a low level within herds, or its introduction or reactivation did not lead to an extensive spread of the virus. A voluntary vaccination program on individual farms was unsuccessful in reducing the prevalence of virus-infected breeding pigs. The importation of breeding stock from outside the area is associated with a higher prevalence of virus-infected pigs because of lack of vaccination. The introduction of infections can be reduced by purchasing virus-free animals and by increasing farm biosecurity procedures.
Vaccination of breeding herds three times annually to insure a high level of immunization can lead to elimination of the disease when the reproduction ratio is less than 1.133
The method used for vaccination may influence the effect of the vaccine.134 Using glycoprotein vaccines, IM vaccination in the neck, and six-point ID vaccination in the back provided the best protection; six-point ID injections resulted in a better vaccination than two-point injections. Body weight changes and viral excretion after challenge were compared with virus-neutralizing titers, antigen-specific IgG and IgA responses in serum, and virus-specific lymphoproliferative responses in peripheral blood during the immunization period.
An intensive eradication program in farrow–finish herds using a gI-deleted vaccine in breeding and growing– finishing pigs, and decreases of movement and mixing of growing–finishing pigs was successful in 3 years.135 The initial goal was to decrease viral spread in the growing–finishing pigs, which enabled production of seronegative replacement gilts. Increases in the number of sows culled, combined with an increase in the number of seronegative replacement gilts, resulted in a decrease in seroprevalence of sows. Bimonthly serological monitoring indicated minimal spread of the virus in the growing–finishing pigs after 1 year. Beginning at 18 months after initiation of the program, test and removal of seropositive sows commenced in all herds. All herds were released from quarantine within 3 years, indicating that eradication can be achieved by vaccination and management changes designed to minimize the spread of virus combined with test-and-removal procedures.
An attenuated gI-deleted–TK-deleted vaccine was used to eradicate the virus from a large farrow–finish herd in Sweden.136 At the start of the program, 86% of the breeding animals were seropositive. The breeding stock was vaccinated every 4 months and monitored serologically. Seropositive sows and boars were culled at an economic rate. The herd was declared gI-negative 39 months after the start of the program. Monitoring the herd for another 4 years, until all vaccinated animals had been culled, revealed the herd free of the virus.
In New Zealand, progress towards eradication using a subunit vaccine is reported.137 Those farms that combined vaccination with good management techniques, intensive testing and culling eradicated the wild virus infection within 2 years; those that made little or no progress has less than satisfactory standards of hygiene and did not practise an intensive testing and culling program.
Vaccination of both breeding stock and growing pigs is recommended. A combined vaccination–eradication program for the disease would generally comprise four phases:
1. A systematic and intensive vaccination campaign
2. Screening of pigs for gI-antibodies
Piglets at 3 days of age can be vaccinated with one of these genetically engineered vaccines and be protected from experimental challenge at 5 weeks of age.
A recent study has shown that infection with PRRSv does not inhibit the development of a vaccine-induced protection against PRV.138
Vaccination of cattle with an inactivated vaccine is recommended where they are in close contact with swine and where a low level of exposure is likely.
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Etiology Porcine enteroviruses capable of causing encephalomyelitis. Teschen virus, Talfan virus, and others
Epidemiology Certain European countries, Scandinavia, and North America. Morbidity 50%; case fatality 70–90%. Teschen in Europe. Talfan in UK. Viral encephalomyelitis in North America.
Signs Acute: Teschen. Fever, stiffness, unable to stand, tremors, convulsions, and death in few days
Subacute: Talfan. Milder than acute form. Most common in pigs under 2 weeks of age. Morbidity and case fatality rate 100%. Outbreaks. Hyperesthesia, tremors, knuckling of fetlocks, dog-sitting, convulsions, blindness, and death in a few days. Milder in older growing pigs and adults
Clinical pathology Virus-neutralization tests
Lesions Non-suppurative encephalomyelitis
Diagnostic confirmation Demonstrate lesion and identify virus
A number of closely related, but antigenically different, enteroviruses, capable of growth in tissue culture, are causes of encephalomyelitis in pigs.1 Porcine enteroviruses comprising at least 13 serotypes are grouped into three groups.2,3 They can cause neurological disturbances, infertility and dermal lesions in pigs. Teschen virus, initially isolated in Czechoslovakia, is the most virulent and there have been a number of independent isolates, such as the Konratice and Reporyje strains.4 Talfan virus, isolated from England, and other unnamed isolates appear less virulent. Teschen and Talfan virus occur in subgroup 1, which is now called porcine enterovirus group 1 (PEV-1) but isolates from encephalomyelitis are also associated with other subgroups. In 2001 it was proposed that the teschoviruses be regrouped into three5 with group 1 being the teschoviruses, group 2 the old PEV8 (V13 virus) and group 3 the old PEV9. In the system proposed6 these are PEV-A and PEV-B. It is now proposed that the PEV-1 Talfan group be regarded as a new genus for the family Picornaviridae.7 A recent study of group 2 suggests that it may have unique features and may be better called a new picornavirus genus.8 Within subgroups, strains may be further differentiated using a complement fixation test and monospecific sera. There is variation in virulence between strains, and with many strains, clinical encephalitis following infection appears to be the exception rather than the rule.
Prior to the early 1940s, the incidence of porcine viral encephalomyelitis was restricted to certain districts in Czechoslovakia. Since then, reports of the disease have come from many countries and there is serological evidence that the disease occurs throughout the world. The most severe form of the disease – Teschen disease – appears to be limited to Europe and Madagascar, but the milder forms – Talfan disease, poliomyelitis suum, and viral encephalomyelitis – occur extensively in Europe,9 Scandinavia, and North America and recently in Japan.10 A recent outbreak in Indiana has been described8 and it was ascribed to porcine enterovirus serogroup 5 or 6 with the only characteristic feature being the histological lesions of polioencephalomyelitis. Losses due to the disease result primarily from deaths.
Serological surveys in areas where the disease occurs indicate that a high proportion of the pig population is infected without any clinical evidence of the disease. In the majority of field occurrences, porcine encephalomyelitis is a sporadic disease affecting either one or a few litters, or a small number of weaned pigs.
The morbidity rate is usually about 50% and the case fatality rate 70–90% in Teschen disease as it is described in eastern Europe. The disease in Denmark and the United Kingdom is much milder, and the morbidity rate about 6%.
Infection is transmitted by ingestion and the aerosol routes. The virus replicates primarily in the intestinal tract but also in the respiratory tract. When infection first gains access to a herd the spread is rapid and all ages of pigs may excrete virus in feces.
Depending upon the virulence of the infecting strain, clinical disease primarily affects young pigs but may occur in older pigs at the same stage. As infection becomes endemic and herd immunity develops, excretion of the virus is largely restricted to weaned and early grower pigs. Adults generally have high levels of serum antibody, and suckling piglets are generally protected from infection by colostral and milk antibody. Sporadic disease in suckling pigs may occur in these circumstances in the litters of non-immune or low antibody sows, and may also occur in weaned pigs as they become susceptible to infection. In the recent outbreak in the USA the major factor was the rapid decline of the maternal antibody in the piglets (<21 days). Seroconversion then coincided with the increased mortality in the herd.
The causative viruses will infect only pigs and are not related to any of the viruses that cause encephalomyelitis in other species. They are resistant to environmental conditions, including drying, and are present principally in the central nervous system and intestine of affected pigs.
The virus multiplies in the intestinal and respiratory tracts and may invade to produce viremia. Invasion of the CNS may follow, depending upon the virulence of the strains and the age of the pig at the time of infection.1 There is some strain difference in the areas of the CNS primarily affected, which accounts for variations in the clinical syndrome, and it is possible for histopathological evidence of encephalitis to be present in pigs that have shown no clinical signs of the disease. This may also occur with adenovirus infection.
An incubation period of 10–12 days is followed by several days of fever (40–41°C, 104–106°F). Signs of encephalitis follow, although these are more extensive and acute after intracerebral inoculation. They include stiffness of the extremities, and inability to stand, with falling to one side followed by tremor, nystagmus, and violent clonic convulsions. Anorexia is usually complete, and vomiting has been observed. There may be partial or complete loss of voice due to laryngeal paralysis. Facial paralysis may also occur. Stiffness and opisthotonos are often persistent between convulsions, which are easily stimulated by noise and often accompanied by loud squealing. The convulsive period lasts for 24–36 hours. A sharp temperature fall may be followed by coma and death on the 3rd–4th day, but in cases of longer duration the convulsive stage may be followed by flaccid paralysis affecting particularly the hind limbs. In milder cases, early stiffness and weakness are followed by flaccid paralysis without the irritation phenomena of convulsions and tremor. In a recent case in the UK the pigs were off-color, showed anterior limb paralysis and were reluctant to rise and were therefore euthanased. Pigs were bright and keen to eat and drink.
This is called Talfan disease in the United Kingdom, viral encephalomyelitis in North America and Australia, and poliomyelitis suum in Denmark. The subacute disease is milder than the acute form, and the morbidity and mortality rates are lower. The disease is most common and severe in pigs less than 2 weeks of age. Older sucking pigs are affected also, but less severely and many recover completely. Sows suckling affected litters may be mildly and transiently ill. The morbidity rate in very young litters is often 100% and nearly all the affected piglets die. In litters over 3 weeks old there may be only a small proportion of the pigs affected. The disease often strikes suddenly – all litters in a piggery being affected within a few days – but disappears quickly, subsequent litters being unaffected. Clinically, the syndrome includes anorexia, rapid loss of condition, constipation, frequent vomiting of minor degree, and a normal or slightly elevated temperature. In some outbreaks, diarrhea may precede the onset of nervous signs. Nervous signs appear several days after the illness commences. Piglets up to 2 weeks of age show hyperesthesia, muscle tremor, knuckling of the fetlocks, ataxia, walking backwards, a dog-sitting posture and terminally lateral recumbency, with paddling convulsions, nystagmus, blindness, and dyspnea. The Dresden type of Teschovirus caused an ataxia and recumbency in a large group of pigs about 5 days after removal of the sows and housing in the production unit.11 Older pigs (4–6 weeks of age) show transient anorexia and posterior paresis, manifested by a swaying drunken gait, and usually recover completely and quickly. In the Japanese outbreak the pigs had at 40 days of age a flaccid paralysis of the hind limbs and became recumbent although they could move using their forelegs.10 After the initial group of affected piglets the disease disappeared.
Individual instances or small outbreaks of ‘leg weakness’ with posterior paresis and paralysis in gilts and sows may also occur with this disease.
Virus-neutralization and complement fixation are useful serological tests. Antibodies are detectable in the early stages and persist for a considerable time after recovery.
Virus is present in the blood of affected pigs in the early stages of the disease, and in the feces in very small amounts in the incubation period before signs of illness appear, but brain tissue is usually used as a source of virus in transmission experiments. A nested –PCR has recently been described in which all 13 serotypes and field isolates were detected2 using three sets of primer pairs. It is more rapid and less time-consuming as a test than tissue culture and serotyping.
There are no gross lesions. Microscopically, there is a diffuse non-suppurative encephalomyelitis and ganglioneuritis with involvement of gray matter predominating. This takes the form of perivascular cuffing with mononuclear cells,10 focal gliosis, neuronal necrosis and neuronophagia. The brain stem and spinal cord show the most extensive lesions, often with the most severe lesions in the cord. These take the form of degenerated or necrotic nerve cells in the ventral horns, glial nodules, occasional hemorrhage, and a diffuse infiltration of mononuclear cells. In the white matter the changes were not so severe.10 Infiltration of mononuclear cells was also seen in the dorsal root ganglia (together with degenerated ganglion cells and neuronophagia) spinal nerves and sciatic nerves. Swollen myelin sheaths and axonal spheroids were seen in the peripheral nerves. Meningitis, particularly over the cerebellum, is an early manifestation of the disease. No inclusion bodies are visible in neurons, in contrast to many cases of pseudorabies. Virus can be isolated from the brain and spinal cord early in the disease course, or from the blood during the incubation period. Recovery of the virus from the gastrointestinal tract does not confirm the diagnosis, as asymptomatic enteric infection is common. Isolation attempts may prove unrewarding, necessitating the correlation of clinical, serological and necropsy findings in order to confirm the diagnosis.2 Recently, an experimental infection with PEV3 produced tremors and paralysis 3–7 days post-infection with all the animals having pericarditis and myocarditis.12
• Histology – one-half of mid-sagittally-sectioned brain, spinal cord including spinal ganglia, gasserian ganglion (LM)
• Virology – one-half of mid-sagittally-sectioned brain, spinal cord (ISO, FAT). In the recent German cases11 the virus was isolated from all the tissues examined but not from the blood. A technique using monoclonal antibodies has been described that can be used either as an immunofluorescent agent or for immuno-electron microscopy.13 New techniques using the reverse transcription polymerase chain reaction (RT-PCR) have recently been described that allow the distinction of both Porcine Teschoviruses (group I) and viruses of PEV1 and 2.14 In the recent Japanese description cytopathogenic agents were recovered from the tonsil, brainstem and cerebellar homogenates The PCR products from these were then sequenced and the isolate confirmed as PTV. Isolation of virus is not easy and needs to be from the brain and spinal cord. There are no firm indications of when to take material and a good consistent site in the brain for isolation as yet.15
The diagnosis of diseases causing signs of acute cerebral disease in pigs is difficult because of the difficulty in neurological examination of pigs, and the diagnosis usually depends on extensive diagnostic laboratory work.
Pseudorabies and hemagglutinating encephalomyelitis virus disease are similar clinical syndromes. In general, viral diseases, bacterial diseases, and intoxications must be considered as possible groups of causes; careful selection of material for laboratory examination is essential. The differentiation of the possible causes of diseases resembling viral encephalomyelitis is described under pseudorabies.
The sporadic occurrence of the disease in a herd is usually an indication that infection is endemic. When outbreaks occur the possibility that introduction of a new strain has occurred should be considered. However, by the time clinical disease is evident it is likely that infection will be widespread and isolation of affected animals may be of little value. A closed herd policy will markedly reduce the risk of introduction of new strains into a herd, but there is evidence that they can gain access by indirect means. The sporadic nature of the occurrence of most incidents of porcine encephalomyelitis does not warrant a specific control program.
Teschen disease is a different problem. Vaccines prepared by formalin inactivation of infective spinal cord and adsorption onto aluminium hydroxide have been used extensively in Europe. Two or three injections are given at 10- to 14-day intervals and immunity persists for about 6 months. A modified live virus vaccine is also available.
In the event of its appearance in a previously free country, eradication of the disease by slaughter and quarantine should be attempted if practicable. Austria reported eradication of the disease which had been present in that country for many years. A slaughter policy was supplemented by ring vaccination around infected premises.
1 Long JF. Pathogenesis of porcine polio encephalomyelitis. Olsen RG, et al, editors. Comparative pathobiology of viral diseases, Vol. 1. Boca Raton: CRC Press. 1985:179.
2 Zell R, et al. J Virol Meth. 2000;88:205.
3 Zell R, et al. J Virol. 2001;75:1620.
4 Edington N, et al. J Comp Path. 1972;82:393.
5 Kaku Y, et al. J Gen Virol. 2001;82:417.
6 Faquet CM, Pringle CR. Arch Virol. 1999;144:393.
7 Kaku Y, et al. Arch Virol. 1999;144:1845.
8 KrumBholz A, et al. J Virol. 2002;76:5813.
9 Done SH, et al. Pig J. 2005;55:106.
10 Yamada M, et al. Vet Rec. 2004;155:304.
11 Roost H, et al. Tierarztl Umsch. 2002;57:653.
12 Shin T, et al. J Vet Med Sci. 2001;63:1017.
13 Dauber M. Vet Microbiol. 1999;67:1.
Sporadic bovine encephalomyelitis (SBE) is associated with a chlamydia, and characterized by inflammation of vascular endothelium and mesenchymal tissue. There is secondary involvement of the nervous system, with nervous signs, in some cases.
The disease is associated with Chlamydophila (Chlamydia) pecorum.1,2 It resists freezing but is highly susceptible to sodium hydroxide, cresol, and quaternary ammonium compounds in standard concentrations. The chlamydia can be passaged in guinea-pigs and hamsters, and adapted to grow in the yolk sac of developing chick embryos.
The disease has been reported only from the United States, Japan, and Israel but a provisional diagnosis has been made in Australia, where it is thought that the disease may have been present for some time, and in Canada, South Africa and Hungary. In the United States, it occurred most commonly in the midwestern and western States but there have been no reports of its occurrence for the last 30 years.
Sporadic cases or outbreaks occur in individual herds. Although the disease has not reached serious economic proportions in the endemic, there is some serological evidence that widespread subclinical infections occur.1
Only cattle and buffalo are affected, and calves less than 6 months of age are most susceptible. Other domestic and experimental species appear to be resistant. There is no seasonal incidence, cases appearing at any time of the year. A strong and apparently persistent immunity develops after an attack of the disease.
The occurrence is sporadic, but outbreaks have occurred resulting in severe loss due to both deaths of animals and loss of condition. Morbidity rates average 12.5% (5–50%), being highest in calves (25%) and lowest in animals over a year old (5%). Mortality rates average about 31% and are higher in adults than in calves. In affected herds a stage of herd immunity is reached when only introduced animals and newborn calves are susceptible.
The method of spread is not known. Spread from farm to farm does not occur readily. On some farms only sporadic cases may occur, but on others one or two cases occur every year. In still other herds the disease occurs in outbreak form, with a number of animals becoming affected within a period of about 4 weeks. The epidemiology of SBE resembles in many ways that of bovine malignant catarrh (BMC). The organism can be isolated from many organs, including liver, spleen and central nervous system, and from the blood, feces, urine, nasal discharges, and milk in the early stages of the disease. There is some evidence that the organism is eliminated in the feces for several weeks after infection.
The causative agent is not specifically neurotropic and attacks principally the mesenchymal tissues and the endothelial lining of the vascular system, with particular involvement of the serous membranes. Encephalomyelitis occurs secondarily to the vascular damage.
Affected calves are depressed and inactive, but the appetite may be unaffected for several days. Nasal discharge and salivation with drooling are frequently observed. A fever is common (40.5–41.5°C, 105–107°F), and remains high for the course of the disease. Dyspnea, coughing, a mild catarrhal nasal discharge, and diarrhea may occur. During the ensuing 2 weeks, difficulty in walking and lack of desire to stand may appear. Stiffness with knuckling at the fetlocks is evident at first, followed by staggering, circling, and falling. Opisthotonos may occur but there is no excitement or head-pressing. The course of the disease varies between 3 days and 3 weeks. Animals that recover show marked loss of condition and are slow to regain the lost weight.
In experimental cases, leukopenia occurs in the acute clinical stage. There is a relative lymphocytosis and depression of polymorphonuclear cells.
A fibrinous peritonitis, pleurisy and pericarditis, accompanied by congestion and petechiation are characteristic. In the early stages, thin serous fluid is present in the cavities, but in the later stages this has progressed to a thin fibrinous net covering the affected organs, or even to flattened plaques or irregularly shaped masses of fibrin lying free in the cavity. Histologically, there is fibrinous serositis involving the serosa of the peritoneal, pleural, and pericardial cavities. A diffuse encephalomyelitis involving particularly the medulla and cerebellum, and a meningitis in the same area are also present. Minute elementary bodies are present in infected tissues and in very small numbers in exudate. The necropsy findings are diagnostic for SBE and confirmation can be obtained by the complement fixation test or serum neutralization tests.
Clinically, the disease resembles other encephalitides of cattle. The epidemiology and pathogenesis resembles bovine malignant catarrh (BMC), but the mortality rate is much lower, there are no ocular or mucosal lesions, and the serositis of SBE does not occur in bovine malignant catarrh. A viral encephalomyelitis of calves (Kunjin virus) has been identified, but has not been associated with clinical signs of disease of the nervous system. An encephalomyocarditis virus, a primary infection of rodents that also occurs in primates and causes myocarditis in pigs, has been transmitted experimentally to calves but without causing significant signs of disease.
Listeriosis is usually sporadic and is accompanied by more localizing signs, especially facial paralysis and circling.
Rabies may present a very similar clinical picture, but the initial febrile reaction and the characteristic necropsy findings as well as the epizootiological history of SBE should enable a diagnosis to be made.
Lead poisoning can be differentiated by the absence of fever, the more severe signs of motor irritation, and the shorter course of the disease. Because of the respiratory tract involvement, SBE may be easily confused with pneumonic pasteurellosis, especially if outbreaks occur, but in the latter disease nervous signs are unusual and the response to treatment is good.
Louping-ill virus belongs to the genus Flavivirus, which is divided into eight groups, one of which is the tick-borne encephalitis group. Louping-ill is antigenically related to the tick-borne encephalitis viruses most of which cause disease in man but not in sheep. Louping-ill virus occurs in Great Britain and Norway, but similar disease occurs elsewhere and there is antigenic diversity between isolates from different geographic areas. Viruses that are closely related to louping-ill virus, and that cause very similar disease but in different regions of the world, include Russian spring-summer encephalitis virus, Turkish sheep encephalitis virus, Spanish sheep encephalitis virus and Greek goat encephalomyelitis.1-3 In sheep, concurrent infection with the agent of tick-borne fever Ehrlichia (Cytoecetes) phagocytophila enhances the pathogenicity of the virus.4
Louping-ill was originally considered to be restricted to the border counties of Scotland and England but is now recognized as also occurring in upland grazing areas of Scotland, in Ireland, south west England, and in Norway; related viruses and disease occur in Spain, Bulgaria, and Turkey.2,3,5 The distribution of the disease is regulated by the occurrence of the vector tick Ixodes ricinus, which requires suitable hosts and a ground layer microclimate of high humidity throughout the year. In these areas, louping-ill can be a common infection and may be a significant cause of loss.
Louping-ill virus can infect and produce disease in a wide variety of vertebrates including man, but predominantly sheep are affected because of their susceptibility and the fact that they are the main domestic animal species that graze the tick-infested areas.
While sheep (and red grouse) are the only animals that commonly develop clinical disease, Ixodes ricinus feeds on a number of different hosts and the adult tick requires a large mammalian host. As a consequence, seropositivity and occasional clinical disease occur in all other domestic species, especially goat kids, but also cattle, horses,6 pigs,7 and humans.8
Traditionally, pigs have not been free-ranged on upland tick-infested areas,7 but they are susceptible to experimental infection by all routes.
Red deer (Cervus elaphus) and roe deer (Capreolus capreolus) are hosts for the tick in Scotland,9 and the elk (Alces a. alces) may be in Sweden. Infection in these species is usually sub-clinical; however, when these animals are subjected to the stress of captivity, clinical illness is more likely to occur. This may be important to commercial deer farmers.10
The reservoir for the disease and the major vector is the three host tick I. ricinus, which requires a single blood meal at each stage of development. The tick feeds for approximately 3 weeks every year and completes its life cycle in 3 years. The larval and nymphal stages will feed on any vertebrate but the adult female will engorge and mate only on larger mammals.3,9 The tick becomes infected by feeding on a viremic host and the virus translocates to the salivary gland of the subsequent stage to provide a source of infection at feeding in the following year. Transtadial transmission of the virus occurs, but transovarial transmission does not, and thus only the nymph and adult ticks are capable of transmitting the disease. The activity of the tick is seasonal. The tick is active at temperatures between 7 and 18°C, and most ticks feed in the spring with peak activity dependent upon the latitude and elevation of the pasture but generally occurring in April and May. In some areas there is a second period of activity of a separate population of I. ricinus in the autumn during August and September. While infected ticks can transmit the infection to a large number of vertebrate hosts, only sheep, red grouse (Lagopus scoticus), and possibly horses attain a viremia sufficient to infect other ticks and act as maintenance hosts.3,4,9 Grouse amplify the virus, deer amplify the vector and hares (Lepus timidus) amplify both. Infection in red grouse is accompanied by a high mortality, and the louping-ill virus is essentially maintained in an area by a sheep–tick cycle and hare tick cycle.9
Although the major method of spread is by the bites of infected ticks, spread by droplet infection is of importance in man, and the infection can be transmitted in animals by hypodermic needle contamination and other methods. The virus is not very resistant to environmental influences and is readily destroyed by disinfectants. Pigs fed the carcasses of sheep that had died of louping-ill become infected with the louping-ill virus. The virus is excreted in the milk of experimentally infected female goats, and infects sucking kids to produce an acute disease.11 Virus is also excreted in the milk of ewes during the acute stages of infection but, paradoxically, does not result in the transmission of the infection to lambs. Grouse can be infected by eating infected ticks and this is considered a major mechanism of infection for grouse.11
The epidemiology of disease is dictated by the biology of the tick, and disease is seasonal with occurrence during spring when the ticks are active. The prevalence of infection, as measured by seropositivity, is high in areas where the disease is enzootic. In these areas, the annual incidence of disease varies but there are cases every year and they occur predominantly in yearlings and in lambs. In enzootic areas, the majority of the adult sheep have been infected and are immune. Colostral immunity from these ewes will protect their lambs for approximately 3 months and these lambs are resistant to infection during the spring rise of the ticks. Ewe lambs that are retained in the flock are susceptible to infection at the second exposure the following spring.
The proportion of infected animals that develop clinical disease in any year is estimated to vary from 5 to 60% and is influenced by the intensity of the tick vector, the immune status of the flock, the age at infection, nutritional status, and factors such as cold stress, herding and transport, and the occurrence of intercurrent disease.3,4,9 Naive animals introduced to an enzootic area are at high risk for infection and clinical disease.
Intercurrent infection with Ehlichia (Cytoecetes) phagocytophilia and Toxoplasma gondii have been shown to increase the severity of experimental tick-borne fever in young lambs, but the relevance of this association to naturally occurring disease is uncertain. It would appear that concurrent infection with louping-ill and tick-borne fever is unlikely to occur in the field in young lambs because colostral immunity will protect against infection with the louping-ill virus, whereas colostral immunity is not protective against tick-borne fever. Similarly, the superinfection of Rhizomucor pusillus on this concurrent infection has been observed in experimental conditions, but is not a commonly recorded observation in natural disease.
Louping-ill is a zoonosis.8 The major risk for veterinarians is with the postmortem examination and handling of tissues from infected animals. Laboratory workers are also at risk. Shepherds and abattoir persons who handle infected sheep are also at risk. The occurrence of virus in the milk of goats and sheep is a risk for human disease where raw milk is consumed.
After tick-borne infection, the virus proliferates in the regional lymph node to produce a viremia which peaks at 2–4 days and declines with the development of circulating antibody prior to the development of clinical disease. Invasion of the central nervous system occurs in the early viremic stage in most if not all infected animals, but in most the resultant lesions are small and isolated and there is no clinical neurological disease.12 The occurrence of clinical disease is associated with the replication of the virus in the brain, severe inflammation throughout the central nervous system, and necrosis of brainstem and ventral horn neurons. The reason for more severe disease in some animals appears to be related to the rapidity and extent of the immune response. Animals that survive exposure to louping-ill virus have an earlier immune response to the infection and have high concentrations of antibody in the cerebrospinal fluid.
In experimental studies, there is a more severe and prolonged viremia and a higher mortality from louping-ill when there is concurrent infection with tick-borne fever. Sheep with tick-borne fever have severe neutropenia, lymphocytopenia, defective cellular and humoral immunological responses,13 and the high mortality associated with concurrent infection with this agent is believed due to enhanced viral replication of the louping-ill virus.3
The dual infection in experimental sheep also facilitates fungal invasion and a systemic mycotic infection with Rhizomucor pusillus.4
In most sheep, infection is inapparent. There is an incubation period of 2–4 days followed by a sudden onset of high fever (up to 41.5°C, 107°F) for 2–3 days followed by a return to normal. In animals that develop neurological disease there is a second febrile phase during which nervous signs appear. Affected animals stand apart, often with the head held high and with twitching of the lips and nostrils. There is marked tremor of muscle groups and rigidity of the musculature, particularly in the neck and limbs. This is manifested by jerky, stiff movements and a bounding gait, which gives rise to the name ‘louping-ill’. Incoordination is most marked in the hindlimbs. The sheep walks into objects and may stand with the head pressed against them. Hypersensitivity to noise and touch may be apparent. Some animals will recover over the following days, although there may be residual torticollis and posterior paresis. In others, the increased muscle tone is succeeded by recumbency, convulsions and paralysis, and death occurs as early as 1–2 days later. Young lambs may die suddenly with no specific nervous signs.
The clinical picture in cattle is very similar to that observed in sheep, with hyperesthesia, blinking of the eyelids and rolling of the eyes, although convulsions are more likely to occur in cattle, and in the occasional animals that recover from the encephalitis there is usually persistence of signs of impairment of the central nervous system.
Horses also show a similar clinical picture to sheep, with some showing a rapidly progressing nervous disease with a course of approximately 2 days and others a transient disorder of locomotion with recovery in 10–12 days.
The infection is usually subclinical in adult goats but the virus is excreted in the milk and kids may develop severe acute infections. In humans an influenza-like disease followed by meningoencephalitis occurs after an incubation period of 6–18 days. While recovery is common, the disease can be fatal and residual nervous deficiencies can occur.8
The initial viremia that occurs with infection declines with the emergence of serum antibody and virus is no longer present in the blood at the onset of clinical signs. Hemagglutination inhibition, complement-fixing and neutralizing antibodies can be detected in the serum of recovered animals. Hemagglutination inhibition and complement-fixing antibodies are relatively transient, but neutralizing antibodies persist. Hemagglutination inhibition IgM antibody develops early in the disease and can be used as an aid to diagnosis in animals with clinical disease.3 Analysis of CSF is usually not considered because of the zoonotic risk.
No gross changes are observed. Histologically, there are perivascular accumulations of cells in the meninges, brain and spinal cord, with neuronal damage most evident in cerebellar Purkinje cells and, to a lesser extent, in the cerebral cortex. Louping-ill virus can be demonstrated in formalin-fixed tissues by the avidin–biotin–complex immunoperoxidase technique.14
The disease is restricted to areas where the vector tick occurs and this allows or denies a possible diagnosis.
• In lambs, the disease has clinical similarities with delayed swayback, spinal abscess, and some cases of tick pyemia. Spinal abscess occurs shortly following a management procedure such as docking or castration or with tick pyemia; it has a longer clinical course, is commonly present at C7–T2, and can be established by radiographic examination. Tick pyemia can also occur in flocks that have louping-ill and the determination of the contribution of each disease to flock mortality relies on clinical, epidemiological, and postmortem examination
• In yearlings, the disease has similarities to spinal ataxia due to trauma, to gid (Coenuris cerebralis), and to the early stages of polioencephalomalacia
• In adults, the disease in sheep bears resemblance to some stages of scrapi, tetanus, hypocalcemia, hypomagnesemia, pregnancy toxemia, and ovine kangaroo gaite.
An antiserum has been used and affords protection if given within 48 hours of exposure, but is of no value once the febrile reaction has begun. It is not available commercially. Animals with clinical disease should be sedated if necessary during the acute course of the disease, and should be kept in a secluded and dark area with general supportive care.
The prevention of louping-ill requires either the prevention of exposure of sheep to tick-infested pastures or the immunization of animals prior to exposure. Immunization has been the traditional approach.
Historically, a formalinized tissue vaccine derived from brain, spinal cord, and spleen was used, and provided excellent immunity in enzootic areas. The vaccine was not without risk for persons manufacturing it and at one stage led to an outbreak of scrapie where the vaccine was prepared from sheep incubating the disease. Currently, vaccination is with a formalin-killed tissue culture derived vaccine where the virus has been concentrated ten-fold by methanol precipitation or ultrafiltration.15 The vaccine is administered in an oil adjuvant. A single dose of this vaccine will give protection for at least 1 year and possibly up to 3 years, and has been shown to give excellent results in field trials. The vaccine is used in the autumn, or in the early spring 1 month before the anticipated tick rise, in all ewe lambs that will be held for flock replacements. Vaccination of pregnant ewes twice in late pregnancy is recommended to insure adequate passive immunity to the lambs via the colostrums.15 A recombinant vaccine has also been shown to offer protection against infection.16
The limited geographical occurrence of this disease and commercial economics has, and may, restrict the availability of vaccines. Consequently tick control, or the elimination of infection from pastures, may be the required approach in the future. The intensity of tick infestation of pastures can be reduced by influencing the microclimate that they require for survival. In some areas this can be achieved by ditching and drainage of the pastures. The control of the causative tick using acaricides is detailed in the section on ticks and provides some protection against disease.
Epidemiological, modeling, and experimental studies indicate that sheep and red grouse and hares are the only maintenance hosts for the virus9,11 and this, coupled with the fact that there is no transovarial transmission of the virus in the tick, offers a potential method for eradication of the infection from an area. This approach, the elimination of grouse and hares, would be radical and would require an economic assessment of its benefit–cost in relation to alternate methods of control.
Brodie TA, Holmes PH, Urquhart GM. Some aspects of tick-borne diseases of British sheep. Vet Rec. 1986;118:415-418.
Reid HW. Ticks and tick-borne diseases. Goat Vet Soc J. 1986;7:21-25.
Reid HW. Controlling tick-borne diseases of sheep in Britain. In Practice. 1987;9:185-191.
Hudson PJ, et al. Persistence and transmission of tick-borne viruses: Ixodes ricinus and louping-ill in red grouse populations. Parasitology. 1995;111:S49-S58.
Reid HW. Louping ill. Monath T, editor. The arboviruses: epidemiology and ecology, Vol III. Boca Raton, Florida: CRC Press. 1988:117-135.
Reid HW. Louping ill. In Practice. 1991;13:157-160.
Gritsun TS, Lashkevich VA, Gould EA. Tick-borne encephalitis Antiviral Res. 2003;57:129-146.
1 Hubalek Z, et al. Acta Virol. 1995;39:251.
2 Martin MS, et al. Res Vet Sci. 1995;58:11.
3 Reid HW. In Practice. 1993;13:157.
4 Reid HW, et al. Res Vet Sci. 1986;41:56.
5 Gonzales L, et al. Vet Rec. 1987;121:12.
6 Reid HW, et al. Vet Rec. 1981;108:497.
7 Ross HM, et al. Vet Rec. 1994;134:99.
8 Davidson MM, et al. J Infect. 1991;23:241.
9 Gilbert L, et al. J Anim Ecol. 2001;70:1953.
10 Reid HW, et al. Vet Rec. 1987;102:463.
11 Gilbert L, et al. Proc Royal Soc Lond B. 2004;271(Suppl 4):S202.
12 Sheahan BJ, et al. J Comp Pathol. 2002;126:137.
13 Larson HJS, et al. Res Vet Sci. 1994;56:216.
14 Krueger N, Reid HW. Vet Rec. 1994;135:224.
Epidemiology Persistent infection with perinatal and horizontal spread. Management of herd influences extent of seropositivity
Clinical findings This disease of goats is characterized by arthritis, especially of the carpal joints (big knee), in mature goats, and acute leukoencephalomyelitis in young goats. Indurative mastitis, and less commonly chronic pneumonia and chronic encephalomyelitis, occur in older goats
Clinical pathology Increased mononuclear cell count in CSF. Lower or inverted CD4:CD8 ratio in peripheral blood
Lesions Chronic polysynovitis, degenerative joint disease in adults. Non-suppurative demyelinating encephalomyelitis. Interstitial pneumonia
Diagnostic confirmation Microscopic lesions and agar gel immunodiffusion test (AGID)
Control Segregation of the newborn from seropositive animals, and feeding of virus-free colostrum and milk. Prevention of horizontal transmission. Regular testing with segregation or culling
Caprine arthritis encephalitis (CAE) viruses are non-oncogenic retroviruses belonging to the subfamily Lentvirinae. The causal viruses are not identical but are of a single virus type, and genetically distinct isolates may have different virulence. Antigenic drift is common and may facilitate the persistence of the virus in the host and the development of disease. There is a high degree of relatedness with the lentivirus associated with maedi-visna and ovine progressive pneumonia in sheep; the ovine and caprine lentiviruses share nucleotide homology and serological properties,1 and there is a similarity in the disease pathogenesis.
There is serological evidence of infection in most areas of the world, including Europe, the United Kingdom, North America, Africa, Arabia, Australia, New Zealand, and South America.2 While there is sampling bias, one global study indicates that there are marked differences in prevalence between countries and that the prevalence is noticeably less in developing countries that have not had importations of dairy-type goats from North America or Europe. Other countries, such as New Zealand, have a low prevalence with a distribution related to exotic importations.3
There may also be variation in seroprevalence within countries. In the United States, the prevalence of infection in goats in the western and middle parts of the country is approximately 50% of all goats tested, which is about twice that in the eastern and Rocky Mountain areas.3,4 Herd seroprevalence is greater than 60% in all regions. The seroprevalence within herds shows clustering, with most herds falling into either high or low seroprevalence groups. There are area differences in age prevalence of seropositivity, with some surveys showing no difference and others showing an increasing prevalence with increasing age.3,5,6
Clinical disease is much less common than infection and the annual incidence of disease in heavily infected flocks is usually low and approximates 10%.
All breeds are susceptible to infection but several studies have recorded apparent differences in breed susceptibility, which may reflect differences in management practices such as feeding practices of colostrum and milk, or genetic differences in susceptibility.2,4,6,7 There is a higher prevalence of seropositive goats in family-owned farms as compared to institutional herds, which might reflect a greater movement of goats among the former.3
There is no age difference in susceptibility to experimental infection. Some herds show similar seroprevalance across age groups, while others show an increasing seroprevalence with increasing age. These differences probably reflect differences in management between herds and differences in the relative importance of the mechanisms of transmission between herds. Increasing prevalence with age reflects management systems that increase the risk of acquiring infection from horizontal transmission. Leukoencephalomyelitis occurs predominantly in young kids and arthritis in older goats.
Greater than 75% of kids born to infected dams may acquire infection, and infection can potentially be transmitted to them by several routes. Infection can also occur in older goats by different routes.
Observation of the natural disease and experimental studies indicate that the primary mode of transmission is through the colostrum and milk. The presence of antibody in colostrum does not prevent infection. The virus can be isolated both from the cells in the milk and from cell-free milk from infected dams; kids born of non-infected dams but fed colostrum and/or milk from infected dams become infected.7 A single feeding of infected milk can be sufficient to infect a kid.8 Conversely, the risk of infection is much lower in kids that are removed from the doe immediately after birth and reared on pasteurized milk, and some can be reared free from infection.9
It is probable that intrauterine infection can occur, but this appears to be of infrequent occurrence and not of significance to the control of the disease.4,7 The disease can be transmitted by contact both during and following the perinatal period, and perinatal transmission is important in the epidemiology of the disease. Perinatal transmission could result from contact with vaginal secretions, blood, saliva or respiratory secretions but the relative importance of these is not known.
Horizontal transmission occurs at all ages and older goats can be infected by oral challenge with virus.10 Contact transmission will result in the spread of the disease when an infected animal is introduced into an infection-free herd and has been one cause of spread in countries where the infection has been introduced with imported animals.
Prolonged co-mingling of uninfected with infected animals is likely to promote horizontal transmission.
Milk contains free virus and virus-infected cells and shared milking facilities increase the risk of cross-infection. Possibly this results from the transfer of infected cells in milk during the milking process. Iatrogenic and venereal transmission are possible but appear of limited significance.7
Arthritis and mastitis have been reproduced by oral, intravenous and intra-articular challenge with virus; however, pneumonia is not a feature of the experimental disease. Leukoencephalomyelitis in young lambs can be reproduced by intracerebral challenge but this form of the disease has not been reproduced by more natural challenge routes. Strains of the virus can be neuroadapted by passage and show increased neurovirulence but not neuroinvasiveness, suggesting that these are separate characteristics.10,11
The relatedness of the caprine and the ovine lentiviruses is evident with experimental infections. Experimentally, infection with the caprine virus has been transferred to lambs by feeding them infected colostrum or by injection. Experimental infection of lambs is followed by viremia and seroconversion, but some strains of the virus produce no clinical or histopathological evidence of disease. Kids have been similarly infected with the maedi virus. The arthritic form of the disease has been produced experimentally in Cesarean-derived kids injected with virus isolated from the joints of infected goats. Despite these experimental cross-species transmissions, there is no evidence for cross-species transmission in the field.7
There is a high prevalence of infection in many countries, and several of these have opted for national or breed-associated control programs. There is a higher cull rate in infected herds, as high as 5–10% of goats are culled each year for arthritis, and affected animals cannot be entered for show. Seropositive herds have a higher incidence of disease.12
There are conflicting reports on the effect of infection on productivity in goat herds,12-15 but seropositive goats are reported to have significantly lower milk production, a reduced length of lactation, lower 300-day yields of milk, and impaired reproductive performance.13,14
Animals infected at birth remain persistently infected for life, although only a proportion develop clinical disease. The virus persistently infects a proportion of cells of the monocyte–macrophage type, and the expression and shedding of virus occurs as infected monocytes mature to macrophages.16,17 Disease is the result of inflammation resulting from the reaction of the host immune system to expressed virus. The development of neutralizing antibody does not arrest viral replication because of the continual expression of antigenic variants of the virus with differing type-specific neutralization epitopes.18,19 However, the immune complexes are believed to be the basis for the chronic inflammatory changes in tissues.20 Goats that are vaccinated with the virus develop more severe clinical disease following challenge than non-vaccinated controls. The lesions are lymphoproliferative in nature and the virus causes a multisystem disease syndrome, which primarily involves synovial-lined connective tissue causing chronic arthritis, the udder causing swelling and hardening of the glands, with or without mastitis, and the lungs causing a chronic interstitial pneumonia.
A retrovirus infection, detected by electron microscopy and the presence of reverse transcriptase activity is suspected as the cause of an immunodeficiency syndrome in llamas characterized by failure to thrive, anemia, leukopenia, and recurrent infection.21
Arthritis occurs predominantly in adult goats and is a chronic hyperplastic synovitis, which is usually noticeable only in the carpal joints, giving rise to the lay term of big knee. Tarsal joints may also be clinically affected. The onset may be insidious or sudden, and unilateral or bilateral. If the goat is lame in the leg, lameness is not severe. Affected goats may live a normal life span but some lose weight gradually, develop poor hair coats, and eventually remain recumbent most of the time with the consequent development of decubitus ulcers. Dilatation of the atlantal and supraspinous bursae occurs in some cases. The course of the disease is long, lasting several months. The arthritis may be accompanied by enlargement and hardening of the udder and by interstitial pneumonia, although this may be clinically inapparent. There can be herd and area differences in the clinical expression of the disease, and in some outbreaks in Australia pneumonia has been a prominent feature.
Radiographically, there are soft tissue swellings in the early stages, and calcification of periarticular tissues and osteophyte production in the later stages. Quantitative joint scintigraphy provides an accurate non-invasive method for assessing the severity of the arthritis in a live animal.22
Leukoencephalitis occurs primarily in kids from 1 to 5 months of age. The syndrome is characterized by unilateral or bilateral posterior paresis and ataxia. In the early stages, the gait is short and choppy, followed by weakness and eventually recumbency. In animals that are still able to stand, there may be a marked lack of proprioception in one hindlimb. Brain involvement is manifested by head tilt, torticollis and circling. Affected kids are bright and alert, and drink normally. Kids with unilateral posterior paresis usually progress to bilateral posterior paresis in 5–10 days. The paresis usually extends to involve the forelimbs so that tetraparesis follows. Most kids are euthanized. The interstitial pneumonia that commonly accompanies the nervous form of the disease is usually not sufficiently severe to be obvious clinically.
The synovial fluid from affected joints is usually brown to red-tinged, and the cell count is increased up to 20000 μL with 90% mononuclear cells. The cerebrospinal fluid may contain an increased mononuclear cell count. There is a reduction in monocytes in peripheral blood, a decrease in the number of CD4+ lymphocytes, and a lower or inverted CD4:CD8 ratio.23
For the live animal there are a number of test systems available whose sensitivity and specificity varies.24 Agar gel immunodiffusion test (AGID) is widely used for detection of infection. Seropositive animals are considered to be infected with the virus, maternal antibody is lost by approximately 3 months of age, a seropositive test in a goat older than 6 months of age is considered evidence of infection and most, but not all, animals have a persistent antibody response and remain seropositive for life.
A negative test does not rule out the possibility of infection. There may be a considerable delay between infection and the production of test reactive antibody. It is possible that in some infected goats there is insufficient virus expression to lead to an antibody response.10,25
A competitive-inhibition ELISA that detects antibody to the surface envelop of the virus has very high sensitivity and specificity and may aid considerably in the determination of the infection status for animal movement.29 Tests with possibly greater sensitivity and/or specificity are described,24 but are not generally available.
Identification of the presence of CAE is usually provided by isolation of the virus from tissue explants into tissue culture.1 PCR techniques can be used to detect the presence of antigen.26,30
At necropsy of a case of the arthritic form there is emaciation and chronic polysynovitis. Typically, degenerative joint disease affects most of the joints of animals submitted for necropsy. Periarticular tissues are thickened and firm and there is hyperplasia of the synovium. The local lymph nodes are grossly enlarged and a diffuse interstitial pneumonia is usually present. Mammary glands are frequently involved although gross changes are restricted to induration and increased texture. Microscopically, lymphoplasmacytic infiltrates of the interstitial tissues of mammary gland, lung and synovium are characteristic. In the neural form the diagnostic lesions are in the nervous system and involve the white matter, especially of the cervical spinal cord and sometimes the cerebellum and the brain stem. The lesion is a bilateral, non-suppurative demyelinating encephalomyelitis. The infiltrating mononuclear leukocytes tend to be more numerous in the periventricular and subpial areas. There is usually also a mild, diffuse, interstitial pneumonia in this form of the disease. In some cases, a severe lymphoplasmacytic interstitial pneumonia with extensive hyperplasia of type II pneumocytes can occur in the absence of neurologic disease.
Culture of the virus is difficult but can be attempted. A variety of nucleic acid recognition tests, including in situ hybridization and PCR have been developed.30 An immunohistochemical technique for detection of the virus has also been reported.27 For most cases, confirmation of the diagnosis is based on the characteristic microscopic lesions, preferably supported by antemortem serologic results.
• Histology – formalin-fixed lung, bronchial lymph node, mammary gland, synovial membranes, one-half of midsagittally-sectioned brain, spinal cord (LM, IHC)
• Serology – heart blood (ELISA, AGID)
• Virology – lung, synovial membrane, mammary gland, hindbrain (PCR, VI).
A measure of control can be achieved by testing the herd every 6 months, and segregating or culling of seropositive animals. More complete control is dependent on preventing/minimizing perinatal transmission of infection to the kid, particularly colostrum and milk transmission, coupled with identifying infected animals and maintaining them physically separated from the non-infected animals or culling them from the herd.
Early recommendations for control concentrated on control of milk transmission but it is now recognized that this must be coupled with segregation. Newborn kids should be removed from the dam immediately at birth. There should be no contact with the dam, and fetal fluids and debris should be rinsed off the coat. Heat-treated goat colostrum or cow colostrum should be fed, followed by pasteurized milk or a commercial milk replacer. The kid should be segregated from the doe and other infected animals. There is a significant difference in subsequent seroconversions in herds that feed pasteurized colostrum and milk between those that segregate the kids at birth and for rearing and those that do not.7
Animals over 3 months of age should be tested by AGID every 6 months, and seropositive animals should be segregated or culled from the herd. The interval between infection and seroconversion varies between goats, and the optimal interval for testing has not been determined. More frequent testing may be required for large herds with high seroprevalence.7 Segregation of seropositive and seronegative goats is essential, as horizontal spread in adult goats is important in maintaining and increasing infection rates in some herds and even a brief contact time can allow transmission.28 Seropositive goats should be milked after seronegative goats where culling is not practised. The use of common equipment should be avoided.
Several countries have programs for herd accreditation of freedom from infection. The stringency of these schemes varies and they may be governmental or breed society accreditation programs. In general, they require that all adults in the herd test negative on two herd tests at a 6-month interval. There are also restrictions on the movement and purchase of animals, and periodic serological surveillance.
Robinson WF, Ellis TM. Caprine arthritis-encephalitis virus infection; from recognition to eradication. Aust Vet J. 1986;63:237-241.
Cheever WP, McGuire TC. The lentiviruses: maedi/visna caprine arthritis encephalitis and infectious Equine anemia. Adv Virus Res. 1988;34:189-215.
Dawson M. The caprine arthritis encephalitis syndrome. Vet Ann. 1989;29:98-102.
Bulgin MS. Ovine progressive pneumonia caprine arthritis encephalitis and related lentivirus diseases of sheep and goats. Vet Clin North Am Food Anim Pract. 1990;63:691-704.
McGuire TC, O’Rourke K, Knowles DF, Cheever WP. Caprine arthritis encephalitis lentivirus. Transmission and disease. Curr Top Microbiol Immunol. 1990;160:61-75.
Knowles DP. Laboratory diagnostic tests for retrovirus infections of small ruminants. Vet Clin North Am Food Anim Pract. 1997;131:1-11.
Rowe JD, East NE. Risk factors for transmission and methods for control of caprine arthritis-encephalitis virus infection. Vet Clin North Am Food Anim Pract. 1997;131:35-53.
1 Clements JE, Zinc MC. Clin Microbiol Rev. 1996;9:100.
2 Adams DS, et al. Vet Rec. 1984;115:493.
3 Cutlip RC, et al. J Am Vet Med Assoc. 1992;200:802.
4 Rowe JD, et al. Am J Vet Res. 1991;52:510.
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11 Craig LE, et al. J Neurovirol. 1997;3:417.
12 Nord K, Adnoy T. J Dairy Sci. 1997;80:2391.
13 Smith MC, Cutlip R. J Am Vet Med Assoc. 1988;193:63.
14 Greenwood PL. Prev Vet Med. 1995;22:71.
15 Kreig A, Peterhan E. Schweiz Arch Tierheilkd. 1990;132:345.
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17 Zink MC, et al. Am J Pathol. 1990;136:843.
18 Cheever WP, et al. J Infect Dis. 1991;164:679.
19 Knowles D, et al. J Virol. 1990;64:2396.
20 Wilkerson MJ, et al. Am J Pathol. 1995;146:1433.
21 Underwood WJ, et al. J Am Vet Med Assoc. 1992;200:358.
22 Papageorges M, et al. Vet Radiol. 1991;32:82.
23 Jolly PE, et al. Vet Immunol Immunopathol. 1997;56:97.
24 Knowles DP. Vet Clin North Am Food Anim Pract. 1997;131:1.
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