Malignant Catarrhal Fever (MCF)

Malignant catarrhal fever (MCF) is a frequently fatal disease syndrome primarily of certain ruminant species, caused by one of several herpesviruses to which they are poorly adapted. The disease is characterized by inflammation, ulceration, and exudation of the oral and upper respiratory mucous membranes, and sometimes eye lesions and nervous system disturbances. The causative viruses exist in nature as subclinical infections in other species that serve as carriers, to which they are well-adapted. Two major epidemiologic forms of MCF are recognized, defined by the reservoir ruminant species from which the causative virus arises. One, known as the African form, is referred to as wildebeest-associated MCF (WA-MCF). The other is referred to as sheep-associated MCF (SA-MCF).

MCF has been recognized as a distinct disease for over 200 years. It was first described in the late 1700’s, and subsequent mentions of the disease in the literature are scattered throughout the 1800’s. The association between wildebeest and MCF in domestic cattle was recognized early on by Maasai pastoralists and by South African farmers, who referred to the disease as snotziekte (snotting sickness) ( 45,65 ). Experimental studies on MCF began to appear in the first third of the 20th century ( 16,17,22,43 ). These and other early studies described the basic nature of the disease and began the process of defining the factors governing transmission of the MCF viruses between the carrier hosts and the clinically-susceptible species, a process which continues to this day. A large contribution to the understanding of MCF was made by researchers in Africa such Plowright et al., who isolated the wildebeest (subfamily Alcelaphinae) strain of MCF virus in vitro and Plowright and Mushi, who conducted numerous experiments to examine the basic epizootiology and pathogenesis of the disease and to define the characteristics of the virus (for reviews, see 52,64,69 ). Knowledge of the sheep-associated agent historically has been constrained by the fact that it has never been successfully isolated, and studies on its biology have necessarily used less direct approaches than were possible with the wildebeest (Alcelaphine) strains, which can be propagated in vitro. Development of molecular tools to efficiently detect antibody and viral DNA have just in the last decade begun to enable definitive studies on SA-MCF and to facilitate recognition of more subtle disease expressions than classical MCF, such as mild and chronic disease ( 10,16,24,56,57 ), and recognition of new MCF viruses that originated from neither sheep nor wildebeest ( 33,35 ).

The economic impact of MCF varies widely. The losses have never been systematically determined, partly because there is no organized, enforced reporting system for the disease and partly because MCF is seriously under-reported. In cattle, in particular the European breeds, it is generally a sporadic, low-morbidity disease, with isolated cases occurring at unpredictable intervals. MCF outbreaks occasionally reach severe proportions however, resulting in death of many animals over a period of a few weeks or months ( 13,20,23,42,58,63 ). In Africa, it is responsible for very significant losses to domestic cattle herds each year, estimated in 1970 to be about 7% annually ( 71 ).

MCF is often devastating to operations involving more highly susceptible species, such as bison, banteng, and many species of deer. The impact is often seen on deer farms, exotic game farms, research herds and zoological collections. Over 40% of the annual death losses in New Zealand farmed deer are caused by MCF ( 8 ). The disease has destroyed entire collections of rare deer species (11). The true incidence is probably even higher than commonly believed, due to the prevalent under-diagnosis of MCF ( 56,79 ).

MCF is recently emerging as a serious problem for bison breeding and feeding operations in the U.S.( 55,78 ). Bison producers have been put out of business by MCF after their neighbors moved a sheep flock onto near-by premises. A 2003 outbreak in a bison feedlot in Idaho has resulted in over 800 head lost, with losses in the vicinity of a million dollars (Crawford, et al., U.S. Animal Health Association Proceedings, in preparation).

MCF is present anywhere either of the two principal carrier hosts, the domestic sheep or wildebeest, are present. Since wildebeest are present in Africa and elsewhere only in zoos, game farms or zoological gardens, the determining factor for most of the world’s MCF is the presence or absence of domestic sheep, which are universally infected with one of the causative viruses. Sheep exist in virtually all countries, thus the distribution of MCF is worldwide. Reports exist which document its presence in North and South America, Africa, virtually all countries of Europe, Indochina, Japan, Australia, New Zealand, Indonesia, Israel, Russia, the Philippines, and many other countries. It safely can be assumed that the distribution of the disease is virtually universal.

The natural hosts for the MCF viruses are found within the Artiodactyl Families Bovidae, Cervidae, and Giraffidae. Two types of hosts exist: well-adapted asymptomatic carriers, and poorly-adapted hosts, in which both clinical disease and latent, subclinical infections occur. The well-adapted carrier hosts shed virus into the environment and are capable of transmitting it to clinically-susceptible hosts when contact is sufficiently close, or when indirect means of transfer of virus, such as suitable fomites, are present. Poorly-adapted hosts are generally considered not to shed infectious virus, and therefore to be dead-end hosts. The Families Cervidae and Giraffidae have to date been found to contain only clinically-susceptible species. The Family Bovidae contains both carrier and clinically-susceptible species. Some subfamilies of the Bovidae, such as the Bovinae tend to contain clinically-susceptible species, whereas members of other Subfamilies, such as Caprinae, Alcelaphinae, and Hippotraginae, are generally well-adapted carriers. Exceptions exist, however, and a full picture of the various viruses involved in the MCF syndrome and the relative susceptibility of the various mammalian taxons to those viruses cannot be constructed until more data is available.

Two principal viruses are responsible for most MCF seen in domestic animals. One exists as a ubiquitous infection in various species of wildebeest (subfamily Alcelaphinae), and is known as Alcelaphine herpesvirus-1 (AlHV-1). It is present on the African continent and in zoos and game farms anywhere in the world that these species are kept. The other major MCF virus exists as a ubiquitous infection in domestic sheep (Ovis aries), and is referred to as the sheep-associated MCF virus, or Ovine herpesvirus-2 (OvHV-2). Because of the cosmopolitan distribution of sheep, OvHV-2 is responsible for most cases of MCF world-wide. MCF of OvHV-2 origin and of AlHV-1 origin cannot be distinguished from one another clinically or histopathologically. Domestic goats harbor their own closely-related strain of MCF virus. It has been termed caprine herpesvirus-2 (CpHV-2) ( 18,35 ). Disease caused by this virus has to date been described only in deer ( 14,31,38 ). Thus its pathogenicity is not yet well defined.

It is becoming increasingly clear that many other ruminant species harbor their own strains of well-adapted rhadinoviruses that are very closely related to the ovine and wildebeest viruses. Some of the viruses appear to cause spontaneous disease in other species ( 35 ), and others do not ( 11,51 ). Moreover, MCF-group viruses have been found in deer dead from MCF, the origin for which has not yet been identified ( 32,33 ). The known number of ruminant species harboring members of this group will undoubtedly expand as research progresses. Rather than simply "MCF virus", these agents are probably more appropriately termed "MCF-group viruses", since the MCF syndrome can be caused by any one of several members of this closely-related group.

Perhaps surprisingly, MCF occasionally is found in domestic pigs, producing acute, lethal disease with typical lesions, due to OvHV-2 ( 1,2,41 ). Little is known about the epidemiology or pathogenesis in this species.

The domestic rabbit (Oryctolagus cuniculus) is readily infected experimentally with both wildebeest and ovine MCF viruses, and develops significant lymphoproliferative disease that may have promise as a comparative disease model. For references, see Plowright ( 64,69 ). Other laboratory animals that have been successfully infected include the rat and hamster ( 74 ).

MCF is predominantly a disease of domestic cattle (Bos taurus and B. indicus), water buffalo (Bubalus bubalis), Bali cattle (banteng) (Bos javanicus), American bison (Bison bison) and deer (cervid species). However, extensive lists of clinically-susceptible species of ruminants, primarily belonging to the subfamilies Bovinae, Cervinae, and Odocoileinae, have been compiled from cases occurring in zoos and on game farms ( 27,67 ) Both of the two major strains of MCF virus, the ovine and wildebeest strains, are capable of causing indistinguishable disease in any of these species. The general factors affecting animal-to-animal transmission such as viral stability, environmental factors, and spatial considerations are what would be expected for a herpesvirus: efficient transmission via infected secretions is favored by close contact and a cool, moist environment. The virus is relatively unstable in the environment, losing over 99.9% of its titer within 3 hours under hot, dry weather conditions ( 76 ). The epidemiology of the two major strains of MCF viruses, the alcelaphine and the ovine viruses, within their natural, well-adapted hosts differs significantly from one another, and thus will be discussed separately.

The epidemiology of clinical MCF, that is, patterns of virus transmission from well-adapted host to non-adapted or ‘susceptible’ host, is better defined for the alcelaphine strain of virus than for the other strains. In contrast to the ovine strain, the alcelaphine strain can be propagated in vitro, more readily induces experimental disease, and can be reisolated and titrated from tissues and secretions of clinically-susceptible hosts. Thus it has been more thoroughly characterized. Both strains are shed into the environment via oral, nasal, and perhaps ocular secretions from their respective well-adapted reservoir hosts in a manner similar to rhadinovirus infections of primates and humans. Clinically-susceptible species acquire the virus through inhalation, ingestion of virus-laden secretions, or through ingestion of contaminated foodstuffs or water.

AlHV-1. The wildebeest-associated MCF (WA-MCF) virus (WA-MCFV) is harbored in all species of wildebeest as a life-long, asymptomatic infection. Viral shedding by adults is at relatively low levels, except during periods of stress or parturition, at which time infectious virus titers in oropharyngeal and ocular secretions rise significantly ( 68 ). Although MCF is occasionally transmitted from adult wildebeest, most clinical disease originates from young wildebeest calves, up to the age of about 4 months. The epidemiology within the wildebeest species involves both horizontal and vertical transmission. Occasional wildebeest calves are born infected through the transplacental route. Most calves, however, are infected horizontally from previously infected cohorts, which develop viremia and shed virus through ocular and nasal secretions ( 54,69 ). Infectivity titers in wildebeest calf secretions exceed 10³ TCID₅₀ /ml during peak shedding periods, most of which is cell-free ( 50 ). Neutralizing antibody develops by about 3 months of age, after which viral shedding declines dramatically ( 54 ).

Whereas WA-MCF occurs most frequently in Africa during the wildebeest calving season, in zoological parks, sporadic cases occur throughout the year. Most shedding from adult wildebeest is in the form of highly cell-associated virus, but cell-free virus shedding can be induced by stress ( 68 ) or steroid administration ( 77 ). WA-MCFV is not transmitted by natural means from one clinically-susceptible host to another; affected animals are dead-end hosts. As opposed to the ovine strain (see below), WA-MCFV readily can be transmitted experimentally among clinically-susceptible species by injection of blood or tissue, but little or no cell-free virus is shed into secretions ( 53 ), thus these animals generally pose no hazard for their herd-mates. However, the virus occasionally passes via intrauterine transmission from latently-infected domestic cows to their calves ( 4,72 ).

OvHV-2. Experimental transmission of the sheep-associated MCF virus (SA-MCFV) from a clinically-affected cow to another cow is much more difficult than with the wildebeest strain of virus. On the few reported occasions where it has been successfully accomplished, it has required the transfer of large volumes of very fresh blood or tissue suspension ( 62,81 ), suggesting that infectivity titers in diseased animals are lower with the ovine strain of virus than with the wildebeest strain. Both careful field observations of many natural outbreaks and substantial experimental data indicate that horizontal transmission from clinically-ill cattle does not occur ( 20,42 ). There are suggestions that transmission of the ovine strain between members of clinically-susceptible species may rarely happen in some highly clinically-susceptible species of deer, such as Pere David’s ( 28 ).

The epidemiology of the ovine MCF virus within sheep is currently controversial. Baxter and coworkers ( 7 ) reported that all the lambs in their study were infected by 2 months of age, similar to wildebeest calves. Data from the author’s lab however, indicates that transmission of the sheep virus differs from the wildebeest strain in some significant aspects. Whereas intense viral shedding from the wildebeest occurs predominantly during the first 90 days of life, lambs did not begin to shed significantly until after 5 months of age ( 37 ). Although occasional intra-uterine infections occur in sheep, the majority of lambs are not infected until after 2 to 2 months of age under natural flock conditions. If removed from contact with infected sheep prior to that age, lambs remain uninfected and can be raised free of the virus ( 18 ). This method is being used by sheep producers and zoos in the U.S. and in Europe ( 49 ) to produce virus-free sheep. This supports the concept of delayed, rather than congenital or perinatal infection of lambs with their MCF virus.

Transmission of clinical SA-MCF occurs both from adolescent lambs and from adults. Virus is shed from the nose in uncommon, discrete, short bursts between 6 and 9 months of age. Afterward, the frequency of shedding episodes declines. Adults do occasionally experience shedding episodes, but at significantly lower rate than adolescents. No correlation between parturition and shedding levels has been found, suggesting that the likelihood of transmission from a given adult sheep is relatively stable year-round. Neither is significant virus present in amniotic fluid or placental tissues.

In contrast to WA-MCF, bovine SA-MCF occurs year-round ( 3,20 ), with only a moderately higher incidence during the lambing season ( 25,49 ). The small increase at this time could reflect factors other than shedding levels, such as climatologic conditions and seasonal variations in stocking densities that could influence exposure intensity. In American bison (Bison bison), MCF is a late-fall and winter disease. It is likely that the distinct seasonality associated with the wildebeest strains has historically exerted an unwarranted influence on judgments about the seasonality of sheep-associated MCF.

The source of virus for transmission is nasal and perhaps ocular secretions in both sheep and wildebeest ( 50,69 , 34 ). Field observations indicate that the virus is transmitted most efficiently by intimate contact, but that remote transmission, presumably by shared water sources, mechanical vectors and other ill-defined routes is not infrequent. Transmission over considerable distances—up to a couple miles, has been observed.

A significant feature of the epidemiology of MCF is the often perplexing phenomenon of clinical cases occurring in the absence of any carriers such as sheep or wildebeest. Much discussion and confusion has swirled around this issue, stimulating the postulation of a variety of alternate transmission modes ranging from insect vectors to horizontal transmission between susceptibles ( 5,19,28,60,78 ). For an excellent review of early contributions to this subject, see reference ( 64 ). Significant prevalence rates of antibody against this group of viruses has been repeatedly shown in many clinically-susceptible ruminant species, using a variety of lab tests (for reviews, see ( 3,44,73,75 )). The respectable seropositivity rates indicate that a large pool of latent infection by these herpesviruses exists among populations of clinically-susceptible species. That recrudescence of latent MCFV infections is a common phenomenon, as in many other herpesviruses, has been shown and discussed by a number of studies ( 61,73 ). However, only lately has its level of significance begun to be appreciated. Recrudescence will probably eventually be shown to explain much of the enigmatic epidemiology so commonly observed with MCF.

The MCF viruses belong to the Rhadinovirus genus of the Gammaherpesvirinae subfamily of the Family Herpesviridae.  The rhadinoviruses are lymphotropic herpesviruses that share a common genome structure and are consistently associated with lymphoproliferation.  They persist in nature as inapparent, subclinical infections in their well-adapted hosts, usually causing disease only when they infect other, poorly-adapted hosts.  It is becoming increasingly evident that the lymphocytes of most, if not all, species of ruminants are inhabited by their respective resident rhadinoviruses ( 35,44,73 ). The rhadinoviruses of primates and humans have received considerable attention because of their potential role in neoplasia and other chronic diseases, but their role in diseases of ruminants is just beginning to be examined.

As with most herpesviruses, these agents are fragile and quickly inactivated in harsh environments.  Experimental transmission between members of clinically-susceptible species, where feasible at all, requires viable cells from blood or tissue, which are killed by freezing.  This suggests that the agent exists in a highly cell-associated, perhaps latent, form in the lymphocytes  of the clinically-susceptible hosts, in a manner reminiscent of primate ( 9 ) and human ( 48 ) rhadinoviruses.

The transmission of one of the virulent strains of MCF viruses from their carrier hosts to clinically-susceptible ruminants can initiate the syndrome of classic malignant catarrhal fever, which is an acute polysystemic disease characterized by lymphoproliferation and inflammation oriented toward mucosal surfaces and blood vessels.  Reported incubation periods vary widely, and are of limited usefulness in MCF, as there are numerous complicating factors that affect disease expression.  Recrudescence of existing infections for example, can occur at any time, giving the impression of extremely prolonged incubation periods.  Estimates from studies of experimental exposures have ranged from 9 to over 60 days  ( 28,66,70,82 ).  Reported incubation periods of several months or more probably represent recrudescences of previously established infections.

Classical MCF cases are often, but not always, fatal.  The case-fatality rate varies with the species of animal and perhaps with the particular virus involved.  Highly susceptible species such as bison, banteng, and some cervid species generally experience shorter, more acute courses than do somewhat less susceptible species such as domestic cattle.  It is a common field observation that those animals that die the fastest are often the ones in the best flesh ( 20 ). Many deer die within 48 hours of the first signs of MCF, but this time frame is highly variable.  Some cases linger for weeks before dying, and a few recover.  Bison generally expire within 2 to 5

days of initial signs, but occasional animals will linger as poor-doers, sometimes with vision impairment, for weeks.  A higher percentage of affected cattle than deer or bison will survive longer than a week or so.  It has been suggested that strains of varying virulence exist, some more prone to produce mild disease and recovery than other strains ( 16 ).  Mild cases which recover have been observed more frequently in cattle than in other species ( 24 ).  Studies indicate that as many as one-third of cattle with clinical MCF exhibit chronicity, surviving for several weeks to months ( 10,56 ) and developing characteristic chronic MCF lesions ( 57 ).  A few eventually recover completely, but most either eventually recrudesce suddenly and die or linger indefinitely as poor-doers.

The disease generally presents suddenly, with little preliminary indications of illness.  Although there are some rather constant signs, there is also considerable variability in presentation.  Typical signs in cattle include sudden fever, drop in milk production, inappetance, serous discharge from the eyes and nose with matting of facial hair. Temperature may spike to 106 oF  for a day or two before declining to 103 to 104 oF.  Within a day or two of initial signs, corneal edema appears, typically starting around the limbus and spreading centrally.  Episcleral injection, lid swelling and sensitivity to light are common.  Deep corneal inflammation  frequently progresses to blindness within 4 to 5 days.  Prolonged inflammation of the cornea can terminate in perforation and herniation of the iris.  Nasal exudate becomes mucoid in character within a few days, with mucopurulent discharges from the nose, stertorous breathing, and often dyspnea.  Muzzle epithelium is initially inflamed and later necrotic, resulting in encrustation, cracking and often dislodging of affected epithelial patches to reveal the underlying inflamed subepithelium. At this stage, animals are usually severely depressed, and may separate from herd mates and stand immobile with head hanging.  CNS involvement is common, however, and can lead to hyperexcitability, aggressiveness, twitching, incoordination, nystagmus, and muscular tremors. 

Skin lesions are common in cattle and deer with the ovine strain of MCFV, and with the recently-described caprine strain, but less so with the wildebeest strains ( 69 ).  Areas of erythema and exudation may be found in any area of the body, including the bulbs of the heels and between the digits.  Affected skin often becomes thickened and corrugated in appearance. Either generalized or patchy hair loss is prominent, tending to predominate over the cervical region, along the spino-dorsal axis, or on the medial aspects of the hind limbs. Small elevated circumscribed areas may be present on the udder or vulva.  The skin of the teats and udder may become inflamed, then dry, thickened and may crack, leading to fissure formation and scabbing. 

The widespread inflammatory process does not spare the joints.  Signs of arthritis may be seen, such as joint puffiness, shifting of the weight, and reluctance to move.  Generalized lymph node swelling is the rule in cattle, and can often be seen in the prescapular or inguinal nodes. This feature is either not as prominent or not as easily detected in bison.  Diarrhea is uncommon in cattle, but more frequent in bison and deer, in which it is often bloody.  Urine may be bloody, as hemorrhagic cystitis is common. 

MCF clinical presentations were divided into 4 “forms” by Gotze ( 21 ): 1) peracute, 2) head and eye, 3) alimentary, and 4) mild.  Addition of a fifth category of “chronic” was proposed by Berkman ( 10 ).  There is, however, little underlying data on pathogenesis differences that support this categorization.  Although there is some diagnostic usefulness to the scheme, it should be borne in mind that rather than being distinct and clearly delineated, there is much overlap between the ‘forms’. The author agrees with the opinion of Heuschele ( 27 ) that the classification is therefore of limited value.

Gross lesions are quite variable, depending on the species affected, and both severity and duration of clinical illness. The nasal and oral mucus membranes are inflamed, with either focal or diffuse necrosis, erosion and ulceration.   Erosions may be found anywhere along the alimentary tract, from the muzzle to the colon.  Punctate or larger ulcers are common on the gums, palate, tips of the oral papillae, esophagus, abomasum, rumen, and both small and large intestine.  Erosions in the esophagus and intestine may be linearly oriented.   Ulcerated areas, often covered by fibrin, are frequent in the mucosa of the nose and turbinates, as well as in the GI tract.  Significant gross lesions are not common in the lungs per se, other than occasional non-specific interstitial emphysema.  Ocular panophthalmitis underlies the conjunctivitis and corneal edema.  Lymph nodes may be grossly swollen, particularly in cattle. Fibrin may be found in inflamed joints of lame animals. Bladder lesions are common, consisting of focal areas of hemorrhage and swelling.  More chronic presentations of MCF can result in prominent renal arteries that are accentuated by scarring, comprised of intimal, medial and perivascular fibroproliferation.  This lesion is most common in cattle, but is also seen in deer, water buffalo and occasionally in other species.   Other organs such as heart, brain and liver generally do not exhibit significant gross abnormalities. 

Microscopically, infiltrations of proliferating lymphocytes and other mononuclear cells are found in most organs, with particular orientation to vascular structures and beneath inflamed mucous membranes. The classic histologic lesion is inflammation and fibrinoid necrosis of the media of small muscular arteries, but these lesions may be difficult to locate, particularly in more rapidly fatal cases.  No inclusion bodies are seen in the disease.  Likewise, all reported attempts to demonstrate viral antigens in tissues have been unsuccessful.  Diagnosticians should be aware that significant differences exist between clinically-susceptible species in the organ-specific character and severity of MCF lesions ( 55,78 ).  Since detailed species-specific descriptions are beyond the scope of this review, diagnosticians should consult pathology references for specifics ( 10,12,26,28,39,40,45,57,69,80,84-86 ).

Signs and Lesions.  Strong suspicion of MCF should be raised by animals of a clinically-susceptible species which present with  characteristic signs at a low morbidity rate.  A history of contact with sheep, goats or wildebeest is also indicative, although this contact is often non-apparent or absent in many cases that are a result of recrudescence.  Swollen nodes, corneal edema, erosive and inflammatory changes in the GI tract, and skin and bladder lesions are all compatible with the diagnosis.  Pathologists consider the vascular lesions, if present, highly indicative of MCF.  Animals suspected of MCF should be necropsied promptly upon expiration or euthanasia, as autolysis is often significant in large animals.  Tissues (lymph node, spleen, lung, kidney, brain, gut, thyroid, adrenal, affected skin, etc.) should be submitted for histological examination fixed in formalin as usual.  Fresh tissues should be promptly refrigerated and submitted unfrozen to provide a source of DNA for demonstration of viral DNA by PCR (6 ,30,35 ): the definitive lab test for acute MCF.  The tissues may also be needed to rule out other differentials such as mucosal disease and IBR by virus isolation or other means.    

PCR.  EDTA-anticoagulated blood should be submitted from live animals for PCR on peripheral blood leukocyte DNA.  Any animals that are ill from MCF will have sufficient levels of viral DNA in their leukocytes and tissues to detect readily by PCR.  If fresh blood or tissue is not available, PCR ( 15,83 ) and in situ hybridization ( 46 ) effectively can be run on DNA extracted from fixed, embedded tissues, assuming fixation time did not exceed 3-4 weeks.  For longer-term storage, tissues can be preserved for PCR in 70% to 80% ethanol ( 15 ).  Careful PCR primer selection by the lab is important, as PCR tests are generally specific for a given strain of virus.  For example, primers currently in widespread use for the sheep agent (OvHV-2) ( 6 ) will not detect DNA of the wildebeest agent (AlHV-1), nor of the recently-described goat virus (CpHV-2).  Until broader-spectrum primers for specific detection of the entire MCF-group of viruses are developed, the clinician should inform the laboratory as to which MCF agent is suspected in order to guide the lab in selection of appropriate primers. 

Serology.  A broad array of serological assays has been used to detect antibody against MCF viral antigens.  These are generally run only in a few laboratories in each country.  Personnel of most diagnostic labs will forward samples to appropriate labs that are capable of MCF testing.  Serologic tests that have been used include viral neutralization, complement fixation, indirect immunofluorescence or immunohistochemistry, direct-binding ELISA, and competitive-inhibition ELISA (CI-ELISA).  Viral neutralization tests utilize the Alcelaphine virus for a neutralization target, and are reliably specific for the MCF group of viruses.  Neutralizing antibody against the sheep agent cross-reacts with the Alcelaphine virus, albeit weakly, so that it has been used to detect antibody against OvHV-2 as well as AlHV-1.  Polyclonal assays other than viral neutralization can suffer from non-specificity arising from well-documented sharing of  antigens between different herpesviruses ( 27,44 ) and thus require very careful interpretation on the part of the operator.   The viral neutralization test, though a highly specific assay for anti-MCF antibody, is labor-intensive and expensive, and works better for antibody against the Alcelaphine group than the ovine or caprine viruses.  The CI-ELISA, a monoclonal-based assay that is specific for the antibody against the MCF group of viruses is specific, rapid and economical.  Reagents for this assay ( 36 ) are commercially available, and the number of labs offering the test are increasing. 

Serological results must be interpreted with certain features of MCF in mind.  Animals that die quickly may not develop detectable levels of antibody prior to death.  Also, the significant percentages of cattle, bison and other clinically-susceptible species that are latently infected provides a sizeable pool of clinically-normal seropositive animals.  Thus the presence of antibody alone is not etiologically diagnostic.  This requires demonstration of significant levels of viral DNA in the blood or tissues by PCR.  The main usefulness of serology is surveying for subclinically-infected individuals in a herd. 

No practical, consistently-effective treatments are available.  Many therapeutic attempts have been described, including the use of corticosteroids, antibiotics, antivirals, vitamins, and other supportive treatments.  Occasional reports exist of recovery of cattle following treatment, typically with corticosteroids ( 47,59 ), but the role of the treatment remains to be proven, since significant numbers of cattle also recover without treatment ( 24,29,56 ). 

Preventing contact between carriers and clinically-susceptible species remains the primary control method.  Scrupulous care should be taken to avoid allowing sheep, wildebeest, and goats to come into contact with deer, bison, Bali cattle, water buffalo, and to a lesser extent, European breeds of cattle. Operations that depend upon mixing species, such as petting zoos, may wish to consider producing their own virus-free sheep or goats ( 18 ).  Reduction of stress also is beneficial in reducing the number of cases, particularly with the more susceptible species.  No vaccine is available.