An unusual outbreak of malignant catarrhal fever in a beef herd in Israel

Malignant catarrhal fever (MCF. corrizza contagiosa) is an invariably fatal communicable disease in cattle, whose causative agent is the ovine herpes virus-2, or the alcelaphine herpes virus-1. In one feed-lot family farm, 34 calves out of 100 became ill at the rate of one to four calves per week, and all of them subsequently died over a period of 4 months. Most of the initial cases were manifested clinically as the head and eye form, but most of the entire clinical spectrum of forms (the respiratory, intestinal and nervous forms) characteristic for MCF were observed as this epidemic progressed. Very few calves died without showing any specific signs of MCF. Pathological examinations revealed characteristic obliterative arteriovasculitis in the brain of calves with nervous signs, typical of MCF. Polymerase chain reaction (PCR) testing revealed 100% homology between the 238 bp hemi-nested PCR fragment and the ovine herpes virus-2 sequences. Based on the clinical signs, epidemiological data, pathological, and histopathological findings, and the PCR results, it was concluded that MCF occurred on the farm. The fact that sheep and goats were housed in close proximity on the same farm reinforced this diagnosis.     

Outbreak of malignant catarrhal fever in Welsh Black cattle in Carmarthenshire

An outbreak of malignant catarrhal fever (MCF) resulted in the deaths of 12 cattle in a herd of 77 animals during seven weeks in 1999; in addition, one cow developed a milder disease which was confirmed as MCF by PCR for ovine herpesvirus 2 DNA and an immunofluorescent antibody test for antibodies to the virus, but recovered. Further PCR and serological testing revealed the infection in three other animals, none of which developed clinical disease. Hypocuprosis and the possibility of a genetic predisposition were identified as factors which may have contributed to the outbreak.     

Studies concerning etiology of sheep-associated malignant catarrhal fever in Europe.

The etiological agent of sheep-associated malignant catarrhal fever (MCF) in Europe has not been isolated directly from sheep. The occurrence of antibodies against the African bovine herpesvirus (BHV-3, WC 11) in cattle and sheep was examined using recently modified indirect immunofluorescence test (IIFT) and neutralization test (NT) methods. Studies revealed that sheep and cattle sera in Europe were free from neutralizing antibodies of BHV-3. The IIFT could not establish the presence of antibodies to African BHV-3 in cattle but revealed that about 22.4% of sheep sera reacted to it. Apart from the well known ovine herpesvirus (BHV-5), occurrence of another herpesvirus in Europe had been expected. This virus is not identical with the WC 11 strain, but it is in antigenic relationship to it. We had for the first time substantial serological evidence to the effect that sheep-associated MCF in Europe is a herpesvirus related to the African strain.     

Sheep-associated malignant catarrhal fever in a petting zoo.

In a privately owned petting zoo in Arizona, 17 deer from five different species, white-tailed deer (Odocoileus virginianus), Reeve's muntjac (Muntiacus reevesi), mule deer (Odocoileus hemionus), reindeer (Rangifer tarandus), and axis deer (Axis axis), died of suspected malignant catarrhal fever (MCF) over a period from late 1992 to early 1995. A PCR assay specific for ovine herpesvirus 2, the putative causative agent of sheep-associated MCF, and a competitive-inhibition enzyme-linked immunosorbent assay based on a monoclonal antibody specific to an epitope conserved among all known MCF viral isolates were used to investigate the outbreak. Ovine herpesvirus 2 DNA sequences were detected by PCR from fresh-frozen and/or formalin-fixed, paraffin-embedded tissue samples in seven deer out of eight available animals previously suspected as cases by histopathology. A high seroprevalence to the virus was found among mouflon (Ovis musimon, 80%) and pygmy goats (Capra hircus, 61%), both of which were present on the farm during the outbreak. Sixteen percent of fallow deer (Dama dama) were also seropositive to the virus. After removal of the mouflon and positive pygmy goats, no further MCF cases occurred on the farm, confirming the importance of careful management to avoid mixing clinically susceptible species with carrier species. Until better control measures are available, adherence to this practice is necessary if MCF is to be prevented in intense exposure environments such as zoos and densely populated animal parks.     

Malignant catarrhal fever: a review

Malignant catarrhal fever (MCF) is a fatal lymphoproliferative disease of cattle and other ungulates caused by the ruminant γ-herpesviruses alcelaphine herpesvirus 1 (AlHV-1) and ovine herpesvirus 2 (OvHV-2). These viruses cause inapparent infection in their reservoir hosts (wildebeest for AlHV-1 and sheep for OvHV-2), but fatal lymphoproliferative disease when they infect MCF-susceptible hosts, including cattle, deer, bison, water buffalo and pigs. MCF is an important disease wherever reservoir and MCF-susceptible species mix and currently is a particular problem in Bali cattle in Indonesia, bison in the USA and in pastoralist cattle herds in Eastern and Southern Africa.MCF is characterised by the accumulation of lymphocytes (predominantly CD8⁺ T lymphocytes) in a variety of organs, often associated with tissue necrosis. Only a small proportion of these lymphocytes appear to contain virus, although recent results with virus gene-specific probes indicate that more infected cells may be present than previously thought. The tissue damage in MCF is hypothesised to be caused by the indiscriminate activity of MHC-unrestricted cytotoxic T/natural killer cells. The pathogenesis of MCF and the virus life cycle are poorly understood and, currently, there is no effective disease control.Recent sequencing of the OvHV-2 genome and construction of an AlHV-1 bacterial artificial chromosome (BAC) are facilitating studies to understand the pathogenesis of this extraordinary disease. Furthermore, new and improved methods of disease diagnosis have been developed and promising vaccine strategies are being tested. The next few years are likely to be exciting and productive for MCF research.     

Experimental induction of malignant catarrhal fever in pigs with ovine herpesvirus 2 by intranasal nebulization

Malignant catarrhal fever (MCF), a frequently fatal herpesviral disease primarily of ruminant species, has been sporadically reported in pigs. All cases of naturally occurring porcine MCF reported to date have been linked to ovine herpesvirus 2 (OvHV-2), a gammaherpesvirus in the genus Macavirus carried by sheep. Experimental induction of MCF by aerosolization of the virus in nasal secretions collected from infected sheep has been successful in bison, cattle and rabbits. The goals of this study were to determine the susceptibility of pigs to MCF following experimental intranasal inoculation of OvHV-2, and to characterize the disease. Twelve pigs in four groups were nebulized with 10(5), 10(6), 10(7), or 10(8) DNA copies of OvHV-2 from sheep nasal secretions. Three control pigs were nebulized with nasal secretions from uninfected sheep. Three additional pigs were inoculated intravenously with 10(7) DNA copies of OvHV-2 to evaluate this route of infection with cell-free virus. Seven of twelve intranasally challenged pigs became infected with OvHV-2. Five of these seven, all in higher dose groups, developed MCF. Lesions resembled those reported in natural cases of porcine MCF. The most striking and consistent histological lesions were in trachea, lung, kidney and brain. These comprised mucopurulent tracheitis, interstitial pneumonia, necrotizing arteritis-periarteritis, and nonpurulent meningoencephalitis. No infection was established in the intravenously challenged or control groups. The study showed that MCF can be experimentally induced in pigs by aerosol challenge using sheep nasal secretions containing OvHV-2. Domestic pigs are a natural clinically susceptible host for sheep-associated MCF. They represent a useful, cost-effective model for MCF research.     

Probable malignant catarrhal fever presented as transient generalised crusting dermatitis in a cow

CASE HISTORY: A 2-year-old crossbred cow developed crusting ulcerative lesions that covered approximately 40% of the body. They were first observed 2 weeks after the cow calved, and were most severe over the caudal aspect of the proximal hindlegs and perineum. CLINICAL FINDINGS AND DIAGNOSIS: Generalised variably confluent 1-2-cm diameter foci of ulceration and crusting were visible. No ocular or oral lesions were visible, and the cow did not have diarrhoea. Skin biopsies revealed lesions consistent with those previously described for malignant catarrhal fever (MCF). Additionally, prominent multinucleate cells were visible. The DNA for ovine herpesvirus type 2 (OHV-2) was amplified from the skin biopsies, using PCR. The cow spontaneously made a complete clinical recovery. CLINICAL RELEVANCE: Malignant catarrhal fever should be considered in cases of ulcerative skin disease in cattle. The disease is difficult to diagnose, and a combination of skin histology as well as PCR is required. Although probably rare, it appears complete recovery from MCF is possible when the disease is confined to the skin.     

Transmission of caprine herpesvirus 2 in domestic goats

Caprine herpesvirus 2 (CpHV-2) is a recently recognized gammaherpesvirus that is endemic in domestic goats and has been observed to cause clinical malignant catarrhal fever (MCF) in certain species of deer. In this study, transmission of CpHV-2 in goats was examined. A total of 30 kids born to a CpHV-2 positive goat herd were selected and divided into two groups: group 1 (n=16) remained in the positive herd; group 2 (n=14) was separated from the herd at 1 week of age after obtaining colostrum. Peripheral blood samples from each kid were examined regularly by competitive ELISA for MCF viral antibody and by PCR for CpHV-2 DNA. Fifteen out of 16 goats (94%) that remained with the positive herd seroconverted and became PCR-positive for CpHV-2 by 10 months of age. In contrast, all kids (100%) that were separated from the positive herd at 1 week of age remained negative until termination of the experiment at 1 year of age. Additional transmission experiments revealed that all CpHV-2-free adult goats were susceptible to CpHV-2 or ovine herpesvirus 2 (OvHV-2) infection. The data indicate that the transmission pattern of CpHV-2 in goats is similar to the pattern of OvHV-2 in sheep and that CpHV-2-free goats can be established by early separation of kids from positive herds, which has significant implications for MCF control programs.     

Virus in sheep's skin

In a double sense, the ovine gamma herpesvirus type 2 (OvHV-2) is a virus in sheep's skin. Not only is it present world wide in all sheep breeds but also it causes malignant catarrhal fever (MCF) in cattle pigs, elk, and bison. OvHV-2 cannot be propagated in cell culture. Therefore, new results from OvHV-2 research are based on molecular techniques and may be summarized as follows. OvHV-2 is transmitted by respiratory routes as well as by sexual intercourse. Lambs are infected within the first few months of life. Leucocytes, primarily latently infected lymphocytes, are responsible for disseminating the virus over the entire organism. On rare occasions, virus particles could be visualized by electron microscopy in explanted lymphocyte cultures. Structural antigens were detected by immunohistology in M-cells of diseased rabbits. Immunologically and cell biologically active genes have been detected on the viral genome.The products arising from those are thought to fine balance, the number of latently infected cells in sheep and to keep them alive without causing harm. Thus, it seems that this balance has been found through co-evolution, favoring both virus and natural host. In contrast, other host species that were exclude from the process of co-evolution, are bound to fall from MCF.     

Development of a management program for a mixed species wildlife park following an occurrence of malignant catarrhal fever

During late 2001 and early 2002, a mixed species wildlife park in North Carolina experienced an acute outbreak of morbidity and mortality in Pere David's deer (Elaphurus davidianus), axis deer (Axis axis), blackbuck antelope (Antelope cervicapra), white-tailed deer (Odocoileus virginianus), and Rocky Mountain elk (Cervus elaphus). Clinical signs varied from fulminant disease, progressing from depression to bloody scours to death in fewer than 4 days in Pere David's deer, to a more protracted form of disease, ranging from 2 wk to 3 mo, in axis deer. In moribund axis deer, high levels of anti-malignant catarrhal fever (MCF) virus antibody by competitive-inhibition enzyme-linked immunosorbent assay were detected. Ovine herpesvirus 2 (OvHV-2) DNA was detected in peripheral blood leukocytes of the affected axis deer. No other MCF viruses were detected. Retrospective examination of frozen tissue samples from the affected Pere David's deer and blackbuck antelope also confirmed the presence of OvHV-2 DNA. Initial control efforts were directed at preventing further deaths of clinically susceptible animals by removing MCF virus reservoir species, particularly ovine species. The most prevalent ovine species in the wildlife park was mouflon sheep (Ovis musimon). All sheep were removed from the park by June 2002, and the last MCF death occurred in October 2002. Since mouflon sheep had been a prominent attraction in the wildlife park, the owner wanted a means to reintroduce this species to the park. Derivation of OvHV-2-uninfected mouflon lambs was undertaken using the previously described program for production of OvHV-2-free sheep (Ovis ovis). The rederived MCF virus-negative mouflon sheep were introduced into the park in approximately January 2004. As of December 2007, no further cases of MCF have occurred since the removal of OvHV-2-positive mouflon sheep and reintroduction of the virus-free lambs. This paper describes the successful management and control of MCF in a densely populated mixed species animal park.     

Evaluation of ovine herpesvirus type 2 infections, as detected by competitive inhibition ELISA and polymerase chain reaction assay, in dairy cattle without clinical signs of malignant catarrhal fever

OBJECTIVE: To monitor ovine herpesvirus type 2 (OvHV-2) infection status and the association between OvHV-2 infection and development of clinical signs of malignant catarrhal fever (MCF) in cattle. DESIGN: Longitudinal study. ANIMALS: 30 mature adult cows and 18 cattle submitted for necropsy. PROCEDURE: Blood and milk samples were collected at monthly intervals from 30 adult cows for 20 consecutive months. Nasal and ocular swab specimens were also collected during months 9 through 20. Polymerase chain reaction (PCR) assay for detection of OvHV-2 was performed on blood, milk, nasal swab, and ocular swab specimens. Competitive inhibition ELISA (CI-ELISA) for detection of antibodies against MCF viruses was performed on serum samples obtained prior to study initiation and monthly during the last 12 months. Tissues obtained from herdmates without clinical signs of MCF that were submitted for necropsy were analyzed for OvHV-2 DNA via PCR assay for possible sites of latency. RESULTS: Initially, 8 of 30 cows had positive CI-ELISA results. Seroconversion was detected in 4 cows. Ovine herpesvirus type 2 DNA was intermittently detected in blood, milk, nasal secretions, or ocular secretions from 17 of 30 cows. Twenty-one cows had positive CI-ELISA or PCR assay results. No cattle in the study developed clinical signs of MCF. Results of PCR assays performed on tissue samples from 2 of 18 animals submitted for necropsy were positive for OvHV-2. CONCLUSIONS AND CLINICAL RELEVANCE; OvHV-2 infection can occur in cattle without concurrent development of clinical MCF. Ovine herpesvirus type 2 DNA was detected intermittently, suggesting fluctuating viral DNA loads or reinfection in subclinical cattle. A definitive site of latency was not identified from tissues obtained during necropsy.     

A devastating outbreak of malignant catarrhal fever in a bison feedlot.

In early 2003, an outbreak of malignant catarrhal fever (MCF) occurred in a bison feedlot in southern Idaho. The outbreak resulted in a 51.2% (n = 825) mortality rate among bison, which had been exposed to sheep for 19 days. Diagnosis was made by detection of ovine herpesvirus 2 (sheep-associated MCF virus) DNA in tissues or peripheral blood by polymerase chain reaction (PCR), and by histological examination of tissue lesions. Peak losses occurred between 41 and 55 days postmean exposure time (PME), and reached a maximum of 41 head per day. No known cases of MCF were observed among the 177 head of bison that arrived in the lot 3 1/2 weeks after the departure of the sheep. Of the several thousand head of beef cattle in the lot during the outbreak, only a single case of MCF was identified. This outbreak illustrates the devastating impact the MCF virus can have on bison under certain exposure conditions, the high threat posed by adolescent lambs to susceptible species, the significantly greater susceptibility of bison than beef cattle to MCF, and the lack of horizontal transmission from clinically affected bison to herdmates.     

Detection and molecular characterization of naturally transmitted sheep associated malignant catarrhal fever in cattle in India

Malignant catarrhal fever (MCF) is a fatal herpesvirus infection of domestic and wild ruminants, with a short and dramatic clinical course characterized primarily by high fever, severe depression, swollen lymph nodes, salivation, diarrhea, dermatitis, neurological disorders, and ocular lesions often leading to blindness. In the present study, fatal clinical cases of sheep associated malignant catarrhal fever (SA-MCF) were identified in cattle in the state of Karnataka. These cases were initially presented with symptoms of diarrhea, respiratory distress, conjunctivitis, and nasal discharges. Laboratory diagnosis confirmed the detection of ovine herpesvirus-2 (OvHV-2) genome in the peripheral blood samples of two ailing animals. The blood samples collected subsequently from sheep of the neighboring areas also showed presence of OvHV-2 genome indicating a nidus of infection in the region. The positive test results were further confirmed by nucleotide sequencing of the OIE approved portion of tegument gene as well as complete ORF8 region of the OvHV-2 genome. Phylogenetic analysis based on the sequence of the latter region indicated close genetic relationship with other OvHV-2 reported elsewhere in the world.     

Experimental aerosol infection of cattle (Bos taurus) with ovine herpesvirus 2 using nasal secretions from infected sheep

Infection of clinically susceptible ruminants, including domesticated cattle and American bison, with ovine herpesvirus 2 (OvHV-2) can result in the fatal lymphoproliferative and vasculitis syndrome known as malignant catarrhal fever (MCF). A reliable experimental infection model is needed to study the pathogenesis of MCF and to develop effective vaccination strategies to control the disease. An experimental aerosol infection model using sheep, the natural carriers of OvHV-2, has been developed (Taus et al., 2005). Using the protocol and OvHV-2 inoculum established in the previous study, eight calves were nebulized with four different doses of OvHV-2 in nasal secretions from infected sheep. Two control calves were nebulized with nasal secretions from uninfected sheep. Infection status of all calves was monitored using competitive inhibition ELISA, PCR and clinical parameters. Six of eight nebulized calves became infected with OvHV-2. One calf receiving the highest dose of virus developed typical clinical, gross and histological changes of MCF. This study showed that nasal secretions collected from sheep experiencing OvHV-2 shedding episodes were infectious for cattle and capable of inducing MCF. The data also indicate that cattle are relatively resistant to disease following infection. The use of more susceptible species as experimental animal models, such as bison and selected cervid species should be examined.     

Malignant catarrhal fever in cattle experimentally inoculated with a herpesvirus isolated from a case of malignant catarrhal fever in Minnesota USA

A malignant catarrhal fever (MCF)-like syndrome was experimentally induced in three steers, which were under immunization trials with a herpesvirus previously isolated from a case of MCF in a cow in Minnesota USA. The clinical signs observed in the three steers, and the pathological and histological lesions observed in two of these steers which succumbed to the disease syndrome were indistinguishable from those described for MCF. Although seroconversion was readily demonstrated in the three animals, virus was not re-isolated from the blood leucocytes, secretions and tissues obtained from the two animals which succumbed to the syndrome during the course of the disease and after death. However, a herpesvirus which showed cell rounding cytopathic effects (cpe) in bovine thyroid cells (Bth), was re-isolated from the one steer which survived the disease.     

A simpler, more sensitive competitive inhibition enzyme-linked immunosorbent assay for detection of antibody to malignant catarrhal fever viruses.

An earlier competitive inhibition enzyme-linked immunosorbent assay (CI-ELISA) was developed for detection of specific antibody against malignant catarrhal fever (MCF) viruses (MCFV) in ruminants. In this study, the indirect CI-ELISA was improved by conjugating the monoclonal antibody 15-A directly with horseradish peroxidase and by developing a method of producing precoated, dried antigen plates. This new test is referred to as a direct CI-ELISA. The reformatted test yielded a significantly improved sensitivity, and the time required was reduced to about one-sixth of the previous time. Of 37 MCF cases in cattle that were confirmed by histopathology and polymerase chain reaction (PCR) assay, 37 (100%) were positive by the new test, whereas the indirect CI-ELISA detected only 23 (62%). The direct CI-ELISA detected antibody to MCFV in 100% of 48 sheep that had been defined as infected with ovine herpesvirus 2 (OvHV-2) by PCR, whereas the indirect CI-ELISA detected only 41 (85%). Comparison of antibody titers measured by the 2 assays for sera collected from OvHV-2-infected sheep and from cattle, bison, and deer with clinical sheep-associated MCF revealed that the direct CI-ELISA offered a 4-fold increase in analytical sensitivity over the indirect format. The number of seropositive animals detected by the direct CI-ELISA among apparently normal cattle and bison was 2-3 times greater than the number detected by the indirect CI-ELISA, indicating that a significant percentage of normal cattle and bison are subclincally infected with MCFV.     

Malignant catarrhal fever in Switzerland: 2. Evaluation of the diagnosis]

Malignant catarrhal fever (MCF) is a mostly fatal lymphoproliferative disease of cattle. In 1995 a PCR based method was introduced for the detection of the ovine herpesvirus 2 (OvHV-2), which is regarded as the causative agent of the sheep-associated form of the disease. This PCR can be regarded as a gold standard for the in vivo diagnosis of sheep-associated MCF in cattle (Müller-Doblies et al., 1998). This semi-nested PCR was now used as a reference test for the reassessment of diagnostic criteria in the clinical and post mortem diagnosis that could previously not be quantitated. Based on 83 suspected cases with a complete clinical record the clinical signs were weighted and grouped according to their sensitivity and specificity into lead signs indicative of MCF and frequently accompanying signs supportive for the diagnosis of MCF and general clinical signs that were less reliable for the diagnosis. Differential diagnoses are discussed, which are of particular significance due to their status as OIE list A diseases e.g. foot-and-mouth disease or rinderpest. 38 PCR confirmed cattle with MCF served for the quantitative analysis of organ lesions. For the post mortem diagnosis an essential set of organ samples is defined to permit a reliable histological diagnosis, as the gross pathology often did not give any indication for the diagnosis. These criteria should help to improve the diagnostic efficiency and to select the appropriate laboratory diagnostic procedures for MCF-suspected cattle.     

Pathogenesis of gammaherpesvirus infections

Gammaherpesviruses are members of an emerging subfamily among the Herpesviridae. Two genera are discriminated: (i) lymphocryptovirus, including its type species Epstein-Barr virus (EBV), and (ii) rhadinovirus, including viruses of interest for medicine, veterinary medicine, and biomedical research, i.e. alcelaphine herpesvirus 1, bovine herpesvirus 4, equine herpesvirus 2, human herpesvirus 8, mouse herpesvirus 68, and ovine herpesvirus 2 (OvHV-2). The perception that these viruses have a narrow host range is misleading, since they cover a surprisingly wide host range, both on the cellular and the organism's level. For example, the natural range of OvHV-2 infection extends over a common animal order. While the host range determinants of EBV are well known, the corresponding features of the rhadinoviruses need still to be defined. Similarly, the gene expression patterns of the veterinary rhadinoviruses during latency require further characterization. In vivo, the gammaherpesviruses have evolved to actively protect their latently infected cells from being destroyed by immune functions of their native host. In return, those reservoir hosts have evolved to being infected and transmit the virus without overt disease symptoms. However, a balanced immune response needs to be in control over the number of infected cells. Virus excretion is usually at low level and may occur either constantly or intermittently. Animal species that are targeted by the virus but did not participate in the process of co-evolution as well as hosts with immune deficiencies are known to loose control over the amount of latently infected cells, which results in the development of lethal diseases, such as malignant catarrhal fever or Kaposi's sarcoma.