The I'etetqnmyJournal1997, 153, 253-268

Review Herpesviral Abortion in Domestic Animals

K. C. SMITH

Centrefi~r Preventive Medicine, Animal Health Trust, P.O. Box 5, Newmarket, &tffolh CB8 7DW, UK

SUMMARY

Abortion or neonatal disease may follow infection with several c~, [3 and y-herpesviruses. The c~-herpesvirus, equid herpesvirus-1 (EHV-1), causes single or epizootic abortions or neonatal deaths in equids, and the closely related virus EHV-4 causes sporadic equine abortions. In cattle, the ~-herpesviruses, bovine herpesvirus-1 (infectious bovine rhinotracheitis virus) and bovine herpesvirus-5 (bovine encephalitis virus), and a y-herpesvirus, bovine herpesvirus-4, have all been implicated as causes of abortion. In pigs, suid herpesvirus-1 (SHV-I: pseudorabies virus), an 0~-herpesvirus, and SHV-2 (porcine cytonaegalovirus), a ~-herpesvirus, each cause abortion or neonatal piglet losses. Caprine herpesvirus-1, canine herpesvirus and feline herpesvirus-1, all ~-laerpesviruses, cause abortions or neonatal deaths in goats, dogs and cats, respectively. This review discusses the pathogenesis, pathology and laboratory diagnosis of these herpesviral abortions and neonatal diseases, with an emphasis on experimental studies of each disease. Alternative reviews covering other aspects of each infection, such as the genetic and antigenic structure of the viruses, host immune responses and approaches to vaccination and disease control are indicated at appropriate points in the text.
KE:YWORDS:Virus; herpesvirus; abortion; neonatal; pathogenesis.

H E R P E S V I R A L A B O R T I O N IN H O R S E S

E q u i d herpesvirus 1

Equid herpesvirns-1 (EHV-I: formerly EHV-1 subtype 1, or equine abortion virus) and EHV-4 (formerly EHV-1 subtype 2, or equine rhinopnenmonitis x4rus) are serologically cross-reactive, but show limited DNA homology on restriction endonuclease (RE) digests (Sabine et al., 1981; Studdert et al., 1981; Turtinen et al., 1981). EHV-1 causes acute respiratory disease in foals and yearlings, and is the most important viral cause of equine abortion (for reviews see Allen & Bryans, 1986; Crabb & Studdert, 1995). Some EHV-1 isolates also cause a neurological syndrome in horses (Jackson & Kendrick, 1971; Jackson et al., 1977; Edington et al., 1986), which may precede or accompany abortion epizootics. This syndrome differs from other neurotropic 0t-herpesvirus infections as viral antigen has not been demonstrated in neurones, but in endothelial cells of the
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brain and spinal cord, resulting in vascnlitis and local thrombo-ischaemic necrosis. Primary EHV-1 replication occurs in the upper respiratory tract and local lymph nodes (Patel et al., 1982; Kydd et al., 1994a,b) and may be succeeded by a cellassociated viraemia involving a latent or non-productive infection of T lymphocytes, monocytes or macrophages (Patel et al., 1982; Dutta & Myrup, 1983; Scott et al., 1983; Edington et al., 1986; Edington, 1992; Gibson et al., 1992; Slater et al., 1994a). Latent virus has been detected in lymphoreticular tissues and trigeminal ganglia (Welch et al., 1992; Edington et al., 1994; Slater et al., 1994b). EHV-1 research has been hampered by inconsistent experimental reproduction of abortion in equids (Gleeson & Coggins, 1980), and most equine studies have employed highly virulent EHV-1 isolates also able to cause neurological disease (Mumford et al., 1994). Respiratory disease, viraemia and abortion can be induced by intranasal challenge of young Balb/c mice (Awan et aL,
1997 Bailli~re Tindall

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1990, 1991), but basic differences in the anatomy of murine and equine placentae limit extrapolation of findings on the abortigenic disease in this model. Early experimental studies in ponies (Prickett, 1970; Jackson el aL, 1977) d e m o n s t r a t e d vasculitis or perivascular cuffing of deep endometrial blood vessels in mares exalnined prior to and after abortion, and it was suggested that abortion occurred due to o e d e m a between trophol)last and endometrial epithelia (BD,ans & Prickett, 1970), possibly as a result of an imnaulae reaction between the infected toetus and sensitized maternal lymplaocytes. An ilnportant breaktlarougla came in 19t)l (Edington et aL, 1991) in an experimental study which d e m o n s t r a t e d that transplacental spread of EH-V-1 was preceded bv viral replication in endothelial cells of the uterus in a paralysed pregnant pony mare infected by the intranasal route. There was an associated lymphocytic vasculitis, local thrombosis and infarction of the microcotyledons of the pregnant uterus. EI-D/-1 antigen was also d e m o n s t r a t e d in endothelial cells of the allantochorion and umbilical vein. This work was corroborated by Smith et al. (1992, 1993) who infected a series of ponies intranasally with a different EHV-I paresis isolate and detected viral antigen expression in endothelial cells of deep endometrill arterioles fi'om 6 days post infection (PI). A novel finding fi'om these studies was that EHV-I antigen expression was widespread in endometrial blood vessels over days 9-13 PI, and the associated severe vasculitis and multifocal thronaboischaemic microcotTledonm T necrosis could result in precipitate abortion of a virologically negative foetus before detectable transplacental infection had occurred (Smith el ak, 1992). Comparable abortions had occurred early in previous EHV-1 challenges and field outbreaks (Gleeson & Coggins, 1983; Carrigan el aL, 1991) but had been assumed to be due to maternal stress or pyrexia (Daels el aL, 1989; Swerczek, 1990), and the incidence and epidemiological significance of such abortions in natural EHV-1 epizootics is not known. Focal thrombosis and cotyledonary infarction have been d e m o n s t r a t e d in mares experimentally infected with EHV-1 and e x a m i n e d over days 14-91 PI, either when carrTing an infected foetus or immediately after abortion of an infected foetus, with a more limited EHV-1 replication in endometrial blood vessels (Smith et aL, 1993). In contrast, endometrial thrombi w e r e rare in

infected mares carrying normal foetuses. These data formed the basis of tile hypothesis that the degree of viral vasculitis and tln'ombosis ill tile pregnant uterus following an EFIV-I infection could d e t e r m i n e the o u t c o m e of the pregnancy (Smith, 1994), possihly as a resuh of local prostaglandin release in addition to direct leakage of free virus or infected cells into the placental circulation at sites of infarction. Endotheliotropism has not been d e m o n s t r a t e d in all abortigenic EH\/-I isolates (Patel el al., 1982), and experimental studies suggest that dilI'erent EH\:-I isolates vm-v in abortigenic potential (Mumtbrd et aL, 1994). The possibiliD' of an ahernative meclaanism of foetal infection not reliant on vascular compromise cannot therefore be ignored. The role of latently infected, or 'inamunologically privileged', leucocytes in the transfer of EHV-1 across the placenta (BD'ans, 1969, 1980) is uncertain, as is the relative importance of prolonged low-level viraemia versus lymphoid or ganglionic latency as sites of viral persistence prior to abortions occurring after prolonged incubation periods in mares with high levels of neutralizing antil)ody. Answers to these important questions require sensitive molecular assays such as the in situ polymerase chain reaction (PCR) to visualize cells h a r b o u r i n g latent viral DNA in the blood, e n d o m e t r i u m , local lympla nodes and senso D, ganglia. Up to 95% of EHV-1 abortions occur in the last third of pregnancy, and have rarely been observed u n d e r natural conditions before 4 m o n t h s (Doll, 1952; Allen & BD,ans, 1986). This increased susceptibility of the late pregnant mare to abortigenic infection is likely to relate tO anatomical and e n d o c r i n e changes in the placental barrie," which facilitate cotTledonm T infarction as pregnancy proceeds, although EHV-1 infection of uterine blood vessels does occur at low level in mares challenged intranasally with virus as early as three m o n t h s of gestation (Smith, 1994; Smith et al., 1996). A potential association between EHV-1 infection, early embD,onic death and resorption has not been investigated. T h e incubation period for EHV-1 abortion varies fi'om 9-121 days (Mumford el aL, 1987), and premonitor T signs of respirator 3, disease in the aborting mare are tmusual. Following abortion, virus is cleared rapidly from the genital tract, and future breeding capacitT is not impaired unless some uterine damage has occurred due to dystocia. The post-aborting mare is not i m m u n e to sub-

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sequent infection, but abortions in successive pregnancies are rare (Doll et al., 1955; Osthmd, 1993). Since the aborted foetus and placenta are a major source of infection for in-contact mares, management practices to nlinimize foetal losses during an abortion epizootic rely on rapid diagnosis and isolation of the aborting mare (Horserace Betting LeW Board, 1994). EHV-1 infected foetuses aborted in late pregnancy are often fresh and enclosed in the placenta, with death due to suffocation following rapid placental separation. Gross examination D,pically reveals some combination of icterus, meconiuna staining of the integument, transudation into the body cavities, splenomegaly, perirenal oedema, puhnonary oedema or haemorrhage and pale miliary loci on the capsule and cut surfaces of the liver. Histological examination shows necrosis in the liver, adrenal gland, thymus, spleen, lung and small intestine (Dimock, 1940; Westerfield & Dimock, 1946; Hong el al., 1993). If infection occurs close to term, the infected foal may be born weak, and usually dies within 7 days dne to interstitial pneumonia and viral damage to the liver, lymphoreticular system and adrenal glands, often complicated by seconda D, bacterial infection (Bryans el aL, 1977; Hartlev & Dixon, 1979). In the rare early gestational EHV-I abortion (Doll el aL, 1955; Prickett, 1970), the foetus is grossly autolysed, indicating prior death in utero, with a diffuse scattering of viral inclusion bodies in the major viscera. Diagnosis of EHV-I abortion or neonatal disease is achieved by recognition of pathognomonic lesions accompanied by virus isolation (\q) or application of the polymerase chain reaction (PCR) using a pooled sample of foetal hmg, liver, thymus and spleen (.Jones el aL, 1948; Randall el aL, 1953; Ballagi-Pord~ny et aL, 1990; Lawrence el al., 1994; O'Keefe et al., 1994). Imnmnofluorescent (IF) (Smith et al., 1972; Gunn, 1991) or immunoperoxidase (IP) staining of tissue sections (Gimeno el al., 1987;Jonsson el aL, 1989; Whitwell el al., 1992; Schultheiss el al., 1993) are also required in some cases. Immunoperoxidase techniques are of value in examination of autolysed tissues (Whitwell et aL, 1992), and may occasionally serve to demonstrate viral antigen in blood vessels of the allantochorion if the aborted foetus is not available. Neither maternal nor foetal serology are reliable diagnostic aids for EHV-1 abortion (Whitwell et al., 1995a). In addition to mares, colts, stallions and geld-

ings are also susceptible to EHV-1 paresis (Saxegaard, 1966; Crowhurst et aL, 1981; Meyer et al., 1987; Carman et al., 1993), and may develop scrotal oedema and loss of libido in field cases (Greenwood & Simson, 1980; Carman et al., 1993; McCartan et al., 1995). Recent experimental studies on pony colts and stallions have shown that virus localizes in blood vessels of the testes and epididymides in association with vasculitis and thrombosis on days 8 and 9 after intranasal challenge, and that infectious virus may subsequently be shed venereally (Tearle et al., 1996). The epidemiological implications of these findings for abortions occurring on studs remain to be assessed.
E q u i d herpesvirus-2 There is no evidence that equid herpesvirus-2 (EHV-2), a y-herpesvirus, has abortigenic potential (for re~ew see Agius & Studdert, 1994). Experimental infection of a mid-gestational equine foetus i~l utero resulted in normal term delivery, although the foal did show mild rhinitis and conjunctivitis, with nasal shedding of EHV-2 for 65 days (Gleeson & Studdert, 1977). E q u i d helpesvirus-3 Equid herpesvirus-3 (EHV-3) causes the self-limiting venereal infection equine coital exanthema (for review see Blanchard el al., 1992). Vesicular and ulcerative lesions occur on the external genitalia of mares and stallions, and generally resolve in 10-14 days, often leaving areas of depigmented epithelium. Repeated infections can occur in successive covering seasons, although it is not clear whether these represent periodic reactivations fi'om latency (Burrows & Goodridge, 1984). Im,oh,ement of the teats of a nursing mare resulted in minor lesions on the lips and nostrils of the suckling foal (Crandell & Davis, 1985). There is a single experimental report of inoculation of EHV-3 into the amniotic sac of a mid-gesrational mare, resuhing in abortion after 11 days (Gleeson et al., 1976), but there is no evidence that the virus is abortigenic in natural infections. E q u i d herpesvinls 4 Equid herpesvirus-4 (EHV-4) is a major cause of acute respiratory disease (for review see Crabb & Studdert, 1995), but is only occasionally recovered from aborted equine foetuses (Shimuzu et al., 1959; Studdert & Blackney, 1979; Allen et al., 1983). The infection accounted for less than 1% of equine herpes~dral abortions occurring in Ken-

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tucky broodmares between 1983 and 1992 (Ostlund, 1993), but represented up to 16% of such virus abortions diagnosed in England between 1987 and 1993 (Whitwell et al., 1995b). EHV-4 ~4raemias have been observed but are rare (Matsumura et aL, 1992). Specific pathological findings in EHV-4 versus EHV-I abortion have been summarized (Whitwell et aL, 1995b). Lesions common to abortions caused by both EHV-I and EHV-4 included infection of foetal endothelium. The recent finding of a field EHV-4 isolate capable of replicating in vascular endothelial cells of a conventionally reared 6-week-old Welsh pony foal (Bhmden et al., 1995) suggests that EI-~*-4 abortions may have a uterovascular basis similar to that described for EHV-I.

H E R P E S V I R A L A B O R T I O N IN CATTLE B o v i n e he~pesvirus-1

Bovine laerpesvirus-1 (BHV-1) causes repeated outbreaks of respiratm T disease (infectious bovine rhinotracheitis: IBR) and abortion in cattle, and is also the cause of the venereal infections, infectious pustular vulvovaginitis and infectious balanoposthitis (for reviews see Gibbs & Rweyemamn, 1977; Wentick et aL, 1993). Concurrent outbreaks of respiratm T and genital disease are rare (McKercher & Wada, 1964), suggesting that virus usually remains localized at the site of primary infection, with latency in regional sensm y ganglia (Homan & Easterday, 1983; Ackermann & Wyler, 1984). The virus is commonly isolated fi'om bull semen (for rexqew see Afshar & Eaglesome, 1990), and natural or artificial insemination with such semen can cause endometritis, poor conception rates and shortened oestrous periods (Parsonson & Snowdon, 1975). The risk of disease transmission by emblTo transfer is low (tbr review see Philpott, 1993). It is difficult to differentiate respiratmy and genital isolates by RE subtyping (Kennedy & Miller, 1993), and both can cause foetal death and abortion, with some strain variation in abortigenic potential (Miller el al., 1991). Some highly virulent IBR isolates can also cause endometritis, oophoritis, mastitis, dermatitis and fatal diarrhoea in young calves. BHV-I is occasionally recovered from abortions in pigs and sheep. BHV-1 abortion is a sequel to respiratory infection and viraemia rather than an extension fi'om the vagina. Viral replication has been demonstrated in monocytes (Nyaga & McKercher, 1980),

although the number of circulating infected cells is considered to be low and the form of the viraemia remains controversial (Yates, 1982). The incubation period between intranasal, intravenous or imramnscular challenge with BHV-1 and abortion is 15-64 days, regardless of the stage of gestation (Gibbs & Rweyemamu, 1977). Virus can be isolated fi'oln tbe placenta as early as day 8 PI in experimental infections and slow cell-to-cell spread of virus within placentomes may account for the variable delay between maternal and foetal infection (Kendrick, 197"8). The route of BHV-1 fl-om the placentome to the foetus is unknown, but as viral lesions occur consistently in the liver, baematogenons spread via the umbilical vein is likely. Foetal death occurs within 24 48 h of the onset ot" ioetal infection, but expulsion is delayed for up to 7 days, and virus titres may decline in the foetus over this period, despite remaining stable or increasing in the placenta (Kendrick & Straub, 1967). Positive virus isolations fi'om the placenta may occur in the absence of placental lesions (Kendrick el al., 1971), and Molello el al. (1966) have suggested that late placental degeneration of BHV-I abortion is seconda D, to the effects of virus activi D, on the foetus. Their study of experimentall}, infected pregnant heifers demonstrated extensive placental oedema and detachment, with abundant debris at the uteroplacental interface. Histological examination of the placenta revealed marked stromal and perivascular oedema, necrosis and sloughing of endothelial cells, and extensive coagulative necrosis of villous and nonvillous chorioallantois. Lesions were hard to find in the infected foetus owing to death in ulero and autolysis, and viral lesions were not recognized'in the maternal uterus. It was concluded that tbe foetal infection had resulted in severe visceral damage, gradual cessation of placental circulation and generalized placental degeneration leading to detachment and abortion. Experimental infection of heifers has also indicated a role for BHV-1 in earl}, embD,onic death, with viral antigen in necrotic follicles, corpora lutea and e m b u o n i c remnants (Miller & Van der Maaten, 1986). Maternal uterine lesions were confined to infection of occasional epithelial cells in the horn containing embD, onic debris, with a mononuclear cell infiltration of the underlying stroma. When expel'imentally infected heifers were reactivated by dexamethasone, infectious virus was most commonly recovered from the maternal adrenal

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glands, which contained necrotic BHV-1 lesions, but specific pathological changes were not recognized in reproductive tissues despite virus isolation fi'om the ovaries of one out of six animals tested (Miller and Van der Maaten, 1987). A 10 year survey of 8995 bovine abortions in the United States of America revealed BHV-1 in 5.41% of cases (Kirkbride, 1992). Major outbreaks of abortion have occurred in American beef herds, with over 60% of cows aborting, although the prevalence of abortion in a region generally declines with a reduction in the naive cattle population owing to natural exposure or vaccination (Kirkbride, 1990a). In a smaller British study of causes of abortion in dairy cattle, BHV-1 was diagnosed in 19 out of 149 cases (12.75%) (Murray, 1990). Naturally occurring BHV-1 abortions are usually observed at 4--8 months of gestation, ahhough intrafoetal or parenteral inoculations of susceptible heifers prior to 3 months reproduces fk)etal disease experimentally (Chow et aL, 1964). There are no premonitory signs, and there may be so little maternal readiness for birth that traction is required to remove the foetus. Placental retention and co~,ledonary degeneration are common, and the aborted foetal carcase is in an advanced stage of autolysis (Gibbs & Rweyemamu, 1977). Gross BHV-I foetal lesions are usually obscured by antolysis, but there may be white to tan 1-3 mm diameter foci on the liver and lung, serosanguinous perirenal oedema and massive renal cortical necrosis and haemorrhage (Owen et al., 1964; Kendrick, 1973; Kirkbride, 1990a). Histologically, there are foci of necrosis with minimal cellular infiltrate in the liver, adrenal, kidney, intestine, lymph node, lung and spleen. Inchlsion bodies may be recognized in cells of the adrenal cortex adjacent to necrotic loci. A necrotizing placental vasculitis is connnon (Kennedy & Richards, 1964). Diagnosis of BHV-1 abortion is based on immunostaining of foetal tissues (Reed et al., 1971; Edwards et al., 1988), or in situ hybridization for viral DNA (Ayers et al., 1989). The IP technique using BHV-1 monoclonal antibodies is more sensitive than VI (Smith et al., 1989), which is hindered by autolysis and may only be successful in approximately one-third of cases with histological lesions (Kirkbride, 1990a). Maternal antibody titres are usually low at abortion, but examination of paired sera by ELISA from at least 10 in-contact animals may provide indirect evidence of a herd problem. Although the bovine foetus is immunocolnpetent for responding to BHV-1 from 5

months, there is little e~fdence of foetal antibody production, owing to rapid foetal death following virus infection (Kendrick & Osburn, 1973). Neonatal calves may experience a fatal congenital or early post-natal infection with BHV-1 (Reed et al., 1973; Miller et al., 1978; Higgins & Edwards, 1986). Colostrum-deprived calves are especially at risk, and show clinical signs of pyrexia, excessive salivation, nasal discharge and diarrhoea. Post mortem examination reveals multifocal mucosal necrosis in the nasal cavity, oropharynx, oesophagus, forestomachs, abomasum, small and large intestines, and miliary foci of necrosis may also be recognized in the liver, spleen, thymus, Peyers patches and adrenal glands. Inclusion bodies are consistently present at the periphery of necrotic lesions outside the alimentary tract, but may only be demonstrable in the epithelial surfaces of early cases. Confirmation of the diagnosis may be achieved by VI, IF or electron microscopy of affected tissues.
B o v i n e he~pesvirus-4

The boxfine herpesvirus4 (BHV-4) group comprises several antigenically related y-herpesviruses (for reviews see Thiry et al., 1989; Gol~ & Ludwig, 1991). The majority of BHV-4 isolates are only mildly pathogenic or avirulent for cattle, and their role as primary abortigenic pathogens is debatable. Relatively higher prevalences of BHV-4 antibodies have been recorded in aborting compared with clinically normal animals (Naeem et aL, 1989; Fitton et aL, 1990), and recovery of B H V 4 from 47 out of 8995 aborted bovine foetuses is recorded (Kirkbride, 1992), but these data must be balanced against the fact that viruses of the B H V 4 group are frequently isolated from a varie D, of organs in clinically normal cattle (Thiry et al., 1989). Co-infections with other agents such as bovine diarrhoea virus may occur in aborted calves (Reed et al., 1979). BHV-4 has also been associated with metritis, particularly in the post-parturient period, when the ~firus may be excreted for long periods in uterine exudate (Parks & Kendrick, 1973; Wellemans et al., 1984; Castrucci et al., 1986; Abraham & Zissman, 1989). BHV-4 viraemia involves circulating mononucleat" cells, which may facilitate transplacentai infection (Osorio & Reed, 1983). There is a single report of lesions in an aborted calf (Schiefer, 1974): microscopy revealed alveolar thickening in the lungs, with cytomegalovirus-like inclusions demonstrated by electron microscopy in pneumo-

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cytes, bile ducts, myocardium, spleen and renal tubules, but no attempt was made to confirm the diagnosis by virus isolation. Kendrick et al. (1976) inoculated an isolate recovered fi'om a case of metritis into foetuses in ulero at various stages of gestation, and this resulted in the death of two foetuses at 3--4 months of gestation with lesions of lymphoid hyperplasia in the lungs and lymph nodes. The pathogenic potential of different BHV-4 isolates has also been studied in rabbits (Naeem et al., 1990): all strains showed a predilection for the reproductive tract, but the fl'equency of abortion and severity of disease varied. Viral DNA could be detected by DNA hybridization and PCR in the rabbit ovary, uterus, placentome and foetus (Naeem el al., 1991a, b). Caution should however be exercised in extrapolating data fi'om these rabbit studies unless parallel experiments have been done in cattle.
B o v i n e he~pesvirus-5 Bovine herpesxdrus-5 (B\q-I-5) is antigenically cross-reactive with BHV-1, but is genetically distinct (tor review see Brake & Studdert, 1985; Studdert, 1989). The virus causes sporadic cases of infectious encephalitis in calves and yearling cattle, and has occasionally been isolated fi'om aborted boxqne foetuses.

H E R P E S V I R A L A B O R T I O N IN PIGS

S u i d herpesvirus-1 Suid herpesvirus-1 (pseudorabies virus: PRV) causes reduced fertility, abortion, stillbirth, foetal resorption and mummification in pigs (for reviews see Basker~flle et al., 1973; Christianson, 1992; Mengeling et aL, 1993). Mortality in nursing and young weaner pigs is high, while the disease in older pigs is generally mild (McNutt, 1943). The virus is unusual among the ~-herpesviruses in having a wide host range, with high mortality rates in species other than pigs. Molecular and imlnunological factors contributing to virulence have been reviewed (Mettenleiter, 1991; Chinsakchai & Molitor, 1994). In pigs, latency is established in both lymphoid and neural tissues (Sabo & Raicani, 1976; Sabo, 1985; Rziha et aL, 1986). PRV ~4raemia involves latent infections of the lymphocyte and neutrophil fractions of peripheral blood (Wittmann et aL, 1980), which facilitate haematogenous and lymphatic dissemination of virus to secondary sites such as the pregnant uterus.

Viraemia is not considered to be important in PRV neurological disease, with signs being ascribable to ascending spread of virus along peripheral nerves. Spread of PRV between pigs is usually by the respiratory route, although other species may be infected either intranasally or by local inoculation. Different isolates of PRV may differ in vil-ulence (Baskerville el al., 1973; Iglesias & Harkness, 1988). The latter authors used two clones from a PRV isolate to infect 12 sows at 85 days of gestation, and noted that whereas one clone (Ls-1) produced severe and acute illness, the other (Ls2) caused only mild transient or subclinical infection. Some sows infected with Ls-1 produced munanfified virus-negative piglets, but transplacental infection only occurred in one sow infected with Ls-2. Perinatal infection occurred in piglets fi-om both groups. This study confirms that while abortion may occur due to viral infection of toetuses and placentae, reproductive failure can he due to the non-specific effects of severe maternal pyrexia. The latter presentation involves abortion or term deliver)' of mummified foetuses which do not yield infectious virus or contain viral lesions, and maternal anorexia or neurological dysflmction may precede or accompany abortion. This p h e n o m e n o n has also been reproduced experimentally in gilts by Kluge and Mare (1973), who did not demonstrate viral lesions in aborted foetuses, placentae or maternal uteri, but estimated that the time of intrauterine foetal death of mumnaified toetuses had coincided roughly with the peak of pyrexia in the dam. Uterine patholo~, associated with establishment of a toetal infection has not been detailed, and it was suggested by Hsu el aL (1980) that foetal death was generally due to severe placental pathology. Nau~3,nck and Pensaert (1992) used surgical inoculation of the uterine artelT with either PRV-infected mononuclear cells or cell-fi'ee virus to demonstrate that only cell-associated PRV was abortigenic by this route in vaccinated sows. These data suggest a critical role for cell-to-cell spread of virus within the porcine endometrium in allowing transplacental infection of piglets despite high levels of neutralizing antibody. The authors further suggested that the likelihood of transplacental PRV spread would be related to the number of circulating virus-infected cells. A correlation was noted between the experinaental incubation period for abortion, the pathological and virological findings in the aborted foetuses and

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the duration of virus excretion in vaginal discharges. Abortions occurring 3 clays PI were associated with grossly normal loetuses presenting small early visceral lesions on inamunofluorescence, and virus was excreted in vaginal discharges for 4-5 da},s after abortion. By contrast, abortions occurring 10-12 days PI showed variable foetal mummification, large foci of necrosis affecting the liver and skin positive by immunofluorescence, and absent or short-lived (24-48 hours) vaginal excretion of virus. The effects of PRV infection on unborn pigs vary with the stage of gestation. Sows infected in the first third of gestation may resorb or abort the embD'os, and return earl}* to oestrus. D,qaen infection occurs in mid-gestation, most of the litter may die in ulero, and such sows commonly deliver a mixture of live normal piglets and mumnaified foetuses at term (Morrison &Joy, 1985). If infection occurs during the last month, then both weak live piglets and dead foetuses showing variable degrees of autolysis will be delivered. Characteristic gross and microscopic PRV lesions are produced when foetuses and placentae are infected in late gestation. Pale miliary foci may be recognized grossly on dissection of the liver and spleen. Microscopic lesions of coagulative necrosis are present in liver, spleen, adrenal gland and hmgs, with viral inclusion bodies occasionally evident in surrounding hepatocytes and interstitial cells (Wohlgenmth et aL, 1978). Examination of the loetal brain may reveal non-suppurative meningo-encephalitis. The tissues of munanaified fbetuses seldom have histological lesions. A proportion of placentae show multifocal coagulative necrosis of the chorionic villi, with viral inclusion bodies in the trophoblast and occasionally in naesenchvnaal cells (Hsu el aL, 1980); in less severe cases, extensive searching is required to find trophoblast inclusions. In piglets with disseminated neonatal disease, viral replication has been demonstrated in epithelial surfaces, endothelial cells and local parenchyma, with an organ distribution similar to EHV-1 in aborted foetuses (Corner, 1965). Laboratory diagnosis of PRV abortion may be assisted by IF, IP and VI (Allan el aL, 1985; Kirkbride, 1990b). Virus isolation in cell culture or in rabbits is more sensitive than IF, and both tests are more likely to yield positive results where infection has occurred late in gestation without subsequent mummification. The preferred tissues for examination are foetal lung, liver, and spleen for

IF, with the addition of kidney and brain in a tissue pool for VI. The mummified tissues o f piglets which have died prior to 12 weeks of gestation and been carried to term are seldom diagnostic, but collection of paired sera from at least 10 in-contact pigs should demonstrate seroconversion in a proportion of animals in which PRV is circulating.
S u i d he~pesvirus-2

Suid herpesvirus-2 ( S H V - 2 : porcine cytomegalovirus) is a [3-herpesvirus (for review see Ohlinger, 1989). Infection of pregnant sows results in small litters and a combination of mummified, premature and weak undel-weight or stillborn term fbetuses. Subsequent conception rates and litter sizes may be reduced. Neonatal infection canses valTing degrees of necrotizing non-suppurative rhinitis with cytomegalic inclusions in nasal glands (inclusion body rhinitis) (Done, 1955). Pigs up to 12 weeks old may be affected in naive herds, but high mortality occurs only in animals younger than 4 weeks (Corner et al., 1964). Severe systemic disease in mature pigs is unusual. Transplacental SHV-2 infection has been reproduced experimentally by intranasal challenge of pregnant sows between 31 and 85 days of gestation and post mortem examination of piglets removed by Caesarean section at term (Edington el aL, 1977). Foetal death occurred 4-6 weeks PI regardless of the stage of gestation, and decomposing or mummified foetuses were retained in ulero. Autolysis often hampered VI and histopatholo~;, but cytomegaly and intranuclear inclusion bodies were noted in the liver and lung of better preserved piglets. SHV-2 was never isolated from placental tissues, and no histological lesions were seen in the placentae of virologically positive foetuses which had recently died. In natural outbreaks of disease, transplacental infection close to farrowing results in congenitally infected foetuses which usually die within the frst week of life. Post mortem examination reveals pulmonary oedema, congestion or consolidation; hydrothorax; and haemorrhages on the heart, lungs, intestines and kidneys. .Cytomegalic inclusions may be recognized in capillary endothelium, macrophages and renal tubules. Some piglets may show a non-suppurative meningoencaphalitis. Studies in young piglets have demonstrated a striking age-related variation in the outcome of SHV-2 infection. Experimental infection of 1-day-

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old gnotobiotic piglets resulted in severe disseminated infection, with viral replication in endothelial cells and macrophages leading to haemorrhage and oedema in the hmg, kidney, adrenal and lymph nodes. Less severe and non-fatal cases in piglets infected at 16 days of age showed a more epitheliotropic pattern of viral replication, with infection of nasal glands, renal tubules, salivary glands, seminiferous and epithelium, gastrointestinal mucosa and hepatocytes. A number of cases showed infection of both reticulo-endothelial and epithelial cells (Edington et al., 1976).

lung or caprine choroid plexus cultures, or by immunostaining or electron microscopy of tissue sections.

H E R P E S V I R A L A B O R T I O N IN D O G S

C a n i n e he~pesvirus

HERPESVIRAL A B O R T I O N IN G O A T S

Caprine heTpesvirus

Caprine herpesvirus-1 (CHV-1) causes abortion and neonatal mortality, vulvovaginitis and balanoposthitis in goats (Hornet, 1987; Merrall, 1987; Thompson, 1987; Tarigan et al., 1990; for review see Koptopoulos, 1992). Abortion can be induced experimentally by the intravenous or intranasal infection of pregnant goats with CHV-1 at 3-4 months of gestation (Berrios et al., 1975; Waldvogel et al., 1981). The latter authors were able to recover infectious virus from the placentae of two goats and from the lung of one foetus following experimental CHV-1 abortion, but nonetheless suggested that the abortions had occurred primarily due to maternal disease and pyrexia. Severe disease may occur in neonatal kids, which show clinical signs of pyrexia, conjunctivitis, oculonasal discharge, dyspnoea, abdominal pain and weakness leading to death within 1-4 days (Be,'rios et aL, 1975; Brake & Studdert, 1985). Post mortem examination reveals erosive, ulcerative and necrotic mucosal lesions throughout the gastrointestinal tract, but especially the large intestine. Local epithelial cells are swollen and vacuolated on microscopy, and may contain intranuclear inclusion bodies. In the caecum and colon, extensive mucosal ulceration may progress to transmural necrosis and oedema, with accompanying submucosal inflammation. Viral replication outside the alimentary tract is very restricted following intranasal administration, but specific lesions can also occur in the brain, adrenal glands, urinary bladder, heart, liver, kidneys, spleen, hmgs, lymph nodes and skeletal muscles of kids infected with CHV-1 by the intravenous route (Waldvogel et al., 1981; Papanastasopoulou, 1991). Diagnosis may be confirmed by VI on bovine turbinate, foetal

Canine herpesvirus (CHV) is associated with abortion, stillbirth, infertility and neonatal disease in bitches (for review see Anvik, 1991). Self-linfiting lesions occur on the penis and prepuce of male dogs and vagina of bitches, and generally involve hyperaemia and lymphoid nodules rather than vesiculation or ulceration (Poste & King, 1971; Hill & M a r c 1973; Ladds, 1993). Infection may also cause mild upper respiratory tract disease in puppies over 5 weeks of age and in aduh dogs (Appel et al., 1969; Huxsoll & Hemelt, 1970). Canine herpesvirus viraemia is difficult to detect in bitches, and is entirely leucocyte-associated (Carmichael, 1970). Foetal infection has been produced by intravenous inoculation of bitches with CHV at 47-53 days of gestation, resulting in term delivery of stillborn or congenitally infected puppies (Hashimoto et al., 1982), although the more usual clinical presentation is of neonatal or early post-natal infections acquired either on passage through the birth canal at whelping or from oronasal secretions from the bitch or infected littermates (Carmichael el at, 1965; Stewart el at, 1965; Carmichael, 1970). Microscopic examination of tissues from stillborn or premature puppies following suspect intra-uterine infection reveals foci of necrosis with intranuclear inclusion bodies in the liver, spleen, kidney and heart. Foetal endothelium is commonly involved, and virus can be recovered from many foetuses (Hashimoto et al., 1979). Where placentae are available for examination, multifbcal necrosis may be recognized in the labyrinth, with viral antigen and inclusion bodies in trophoblast epithelium and endothelial cells, and mural degeneration and vasculitis may affect allantoic blood vessels (Hashimoto et al., 1979, 1982). Recent work (Okuda et al., 1993a, b) has demonstrated that natural CHV infection in bitches is succeeded by latency, and that recrudescence and repeated nasal and vaginal shedding may be achieved by prednisoione administration. Infection of puppies up to 3 weeks of age is facilitated by the sub-adult body temperature and incompletely developed thermoregulatory

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261

capacity of the canine neonate, and viral replication and mortality can be reduced by artificial elevation of the body temperature (Carmichael, 1970). Signs of neonatal disease generally appear from 5-14 days of age, and are characterized by anorexia, abdominal pain, diarrhoea, dyspnoea and crying. Some puppies may show opisthotonus and paddling of the limbs (Cornwell & Wright, 1969). Post mortem examination of affected pups characteristically reveals ecchymotic renal haemorrhages, accompanied by splenomegaly and serosanguinous effusions into the body cavities, with muhifocal necrosis and haemorrhage in the kidneys, liver, spleen, hmgs and adrenal glands (Cornwell el al., 1966; Yanagisawa et al., 1987; Kojima et aL, 1990). Inclusion bodies are rare, but may be recognized in renal endothelium or in the adrenal cortex, and viral antigen is also present in reticulo-endothelial cells of lymph nodes and spleen. Infection of the brain resuhs in non-suppurative meningo-encephalitis (Percy et aL, 1968), with spread to the central nervous system being primarily haematogenous, ahhough viral antigen has been demonstrated by IF in nerve trunks and trigeminal ganglia. The virus may be isolated fi'om infected visceral tissues on canine cell monolayers. Mortaliu, approaches 100% in infected litters, and residual granulomatous encephalitis, interstitial pneumonitis, segmental renal necrosis and renal, cerebellar and retinal dysplasia may be present in stuMving puppies (Percy et al., 1971; Albert el al., 1976).

has resulted in abortion, stillbirth or generalized neonatal infection, but abortion is difficult to reproduce by intranasal inoculation (Johnson, 1964; Hoover & Griesemer, 1971a), and Gaskell and Dawson (1994) have suggested that abortions occuring after FHV-1 infection are usually due to severe maternal rhinopneumonitis rather than foetal infection. Isolation of virus from the tissues of foetuses aborting during naturally occurring feline viral rhinotracheitis has not been reported, although virus has been recovered from the uterus, placenta, amniotic fluid and vagina of intravenously infected queens with aborted or stillborn foetuses, and necrotic lesions with viral antigen expression occurred in the uterus, placenta, vagina and foetal liver of these experimental cases (Hoover & Griesemer, 1971a). Congenital infection of kittens has also been induced as a resuh of intravaginal instillation of virus (Bittle & Peckham, 1971). In this study, kittens died due to generalized herpesvirus infection in the first 3 weeks of life, and post mortem examination revealed fibrinosuppurative rhinotracheitis, bronchopneumonia and muhifocal hepatic necrosis, with viral inclusion bodies in respiratory epithelium and hepatocytes. In young kittens, an unusual predilection of this herpesvirus for growing bone at a variety of sites including the nasal turbinates has been recognized, with necrosis and viral inclusion bodies at sites of osteogenesis (Hoover & Griesemer, 1971b).

HERPESVIRAL ABORTION IN CATS Feline herpesvirus-1

CONCLUSIONS

Feline viral rhinotracheitis is caused by feline herpesvirus 1 (FHV-1). The respiratory disease is a problem in unvaccinated kittens and cats, particularly in catteries (for reviews see Crandell, 1972; Gaskell, 1988; Dawson & Gaskell, 1993). Most cats recover in 7-14 days, but mortality can be high in kittens and debilitated animals, particularly if immunosuppressed by concurrent infection with feline immtmodeficiency virus or feline leukaemia virus. Since respiratory infection is not usually succeeded by viraemia, subsequent abortion is rare (Kennedy & Miller, 1993). A carrier state is common in cats, and it is likely that latency is established in trigeminal ganglia (Gaskell & Povey, 1979; Gaskell et al., 1985). Intravenous inoculation of specific pathogen-free queens in late gestation

Most pathogenesis research on the abortigenic herpesviruses has concentrated on horses, cattle and pigs, and has been based upon intensive investigations of the aborted foetus and placenta. Studies of the experimentally infected pregnant uterus and factors affecting transplacental infection and foetal expulsion are less frequent. It will be apparent fi'om this review that the ability of a number of herpesviruses to initiate a leucocyteassociated viraemia is critical to the pathogenesis of abortion, and that abortigenic disease rarely resuhs from spread of infection from the l o w e r genital tract. Research into factors affecting the establishment and maintenance of viraemia in each infection is therefore crucial to an understanding of herpesviral abortion. As a general rule, those herpesviruses which rarely cause virae-

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mia, such as FHV-1 in cats a n d EHV-4 in equids, have a low a b o r t i g e n i c potential. Viral infection o f vascular e n d o t h e l i u m in the uterus, placenta a n d foetus is also a COmlnon a n d pathogenically i m p o r t a n t feature o f a b o r t i g e n i c herpesvirus infections, p r e s e n t i n g a rneans for virus to cross the placental barrier, a n d resulting in a characteristic s p e c t r u m o f foetal a n d placental lesions d u e to vascular d a m a g e , such as vasculitis, o e d e m a , perivascular necrosis, h a e m o r r h a g e a n d effusion into b o d v cavities. Variation in the clinical p r e s e n t a t i o n o f herpesviral a b o r t i o n , such as the t e n d e n c y for foetal autolysis or m u m mification in cattle a n d pigs r a t h e r than precipitate expulsion in equids may relate to the increased i m p o r t a n c e o f the c o r p u s luteunt over the f o e t o p l a c e n t a l unit in m a i n t a i n i n g p r e g n a n c y in the f o r m e r g r o u p , a n d n e e d not reflect fundantental differences in the m e c h a n i s m o f transplacental infection. T h e s p e c t r u m o f h e r p e t i c lesions in the a b o r t e d foetus or early n e o n a t e is r e m a r k ably consistent between species, with the liver, kidney, spleen a n d adrenal glands b e i n g c o m m o n target sites. Post-natal infections d u e to inhalation or ingestion o f infectious virus, such as BI-B/-1 in calves, SI-W-2 in o l d e r piglets a n d c a p r i n e herpesvirus in g o a t kids, typically assume a m o r e epitheliotropic pattern. H e r p e s - r e l a t e d a b o r t i o n s in which the foetus a n d p l a c e n t a do not b e c o m e infected, either d u e to severe m a t e r n a l disease or to d i s p r o p o r t i o n a t e u t e r i n e d a m a g e , have b e e n r e c o g n i z e d in the case o f El-IV-l, PRV a n d FHV-I infections, a n d may p r e s e n t a p r o b l e m in laborato D, diagnosis. In the case o f those infections, such as El-IV-l, for which vaccines fully protective against a b o r t i o n are not currently available, the continual i m p r o v e m e n t o f l a b o r a t o r y t e c h n i q u e s for rapid diagnosis is central to effective disease control in o r d e r that infected anintals may be p r o m p t l y isolated fi'om susceptible in-contacts.

ACKNOWLEDGEMENTS T h e a u t h o r is grateful to D r ] . A. M u m f b r d and Dr A. S. B l u n d e n for constructive criticisms o f this manuscript. Mrs Sandra T a t u m was m o s t helpful in u n d e r t a k i n g literature searches.

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