ISRAEL JOURNAL OF
VETERINARY MEDICINE
Vol. 60 (1) 2005
SHEEP-ASSOCIATED MALIGNANT CATARRHAL FEVER IN CAT
RECENT
CLINICAL
AND EPIDEMIOLOGICAL
ASPECTS
Brenner,
J.
and
David,
Kimron Veterinary Institute, 50250, Bet Dagan
Summary
Malignant catarrhal fever (MCF) in cattle is associated with their close proximity to sheep. In Africa there is a similar diseas
there is direct or indirect contact between cattle and wildebeest. Therefore, these two diseases are known as MCF, but the for
sheep-associated MCF type (SA-MCF) while the latter is defined as wildebeest associated (WA-MCF). The disease, that is c
herpes virus -1 (AlHV-1), is restricted to those areas of Africa where wildebeest are found, while the ovine herpes virus-2 fo
occurs worldwide wherever sheep are reared and is called SA-MCF.
Only the causative agent of WA-MCF virus has been isolated so far, and there is no reliable diagnostic tool available for the
MCF. Although we are more familiar (clinically speaking), with SA-MCF, the lack of appropriate diagnostic tools has cause
diagnosing suspected MCF cases and has deprived us of important epidemiological data.
Since the recent introduction of the polymerase chain reaction (PCR) for the detection of ovine herpes-2 virus (OvHV-2), we
of the clinical and epidemiological features of SA-MCF.
Introduction
Malignant catarrhal fever (MCF) is a sporadic but almost invariably fatal viral disease
affecting many species of Artiodactyla and is characterized by a generalized
lymphadenopathy and mucopurulent nasal and ocular discharges. This disease has
worldwide distribution. MCF is also defined by the appearance of characteristic lymphoid cell
aggregates in non-lymphoid organs, vasculitis and lymphoid hyperplasia in lymphoid organs,
and can be caused by several viruses of the gammaherpesvirus family (1). Several clinical
forms of presentation have been described including syndromes involving particularly the
head and eye, the respiratory form associated with the gastro-intestinal tract (GIT) form, the
central nervous system (CNS) and a rare cutaneous form (1-5).
The clinical signs include very high fever (410-420C), lachrymation, nasal exudates that as
the disease progresses become mucopurulent, and bilateral corneal opacity. In addition
respiratory distress and sometimes bloody diarrhea may precede death by 24 hours.
Lymphadenopathy, especially noted in the palpable superficial lymph nodes, is a sign of the
ongoing generalized pathological process involving many internal organs. On clinical
inspection, erosions in the oral cavity, mainly on the tongue, gums and the hard palate are
noted (2,5).
Hyperesthesia, convulsions, torticollis, nystagmus, and tremor indicate CNS involvement.
The most characteristic lesion involves the bladder where petechial hemorrhages are noted.
This lesion is considered a pathognomonic sequel of gammaherpesvirus infections (Figure 1).
Thus, this organ should be examined when MCF is suspected. This lesion is particularly
important in the diagnosis of suspected MCF in wild ruminants where the causative agent
might be unidentifiable and the serology is negative (1,6,7). Erosions and hemorrhages are
present in the GIT where catarrhal or muco-purulent changes might also be encountered. Mild
petechial to extensive hemorrhages can be found in the lymph nodes.
As mentioned, vasculitis and lymphoid hyperplasia in lymphoid organs especially in the
brain, liver and possibly in other parenchymal organs and in the tegument are histological
findings (3,4,8,9,11).
A competitive-inhibition (CI)-ELISA has been developed for detecting antibodies to OvHV-2
using a MAb to the Minnesota viral isolate, which is indistinguishable from the AlHV-1, the
causative agent of WA-MCF. The test is employed to detect serum antibody in wild and
domestic ruminants and appears to have some merits. However, there is a poor correlation
between antibodies detected in serum of lambs and OvHV-2 infection as indicated by the
presence of viral DNA detected by PCR since only some of the sheep were found to be seropositive (7,10).
Although AlHV-1 is so far the only isolate of the gammaherpesviruses that form the MCF
viruses cluster, PCR technology now enables the identification of other members of this
complex (5,6,8,12,18).
Figure 1 - The bladder of an animal with MCF.
Petechial hemorrhages are visible on the mucosa.
Figure 2 - SA-MCF in a dairy cow that becam
OvHV-2 for a period of more than 2 years givin
Note the corneal opacity.
Sheep-associated malignant catarrhal fever (SA-MCF)
SA-MCF is almost always a fatal communicable disease of cattle, caused by the ovine
herpes virus-2 (OvHV-2), belonging to the gammaherpesvirus group (1,2). The most
prominent clinical signs of SA-MCF are pyrexia (410-420C), abundant and repugnant nasal
and/or ocular secretions, bilateral blindness, hyperpnoea (Figures 2 and 3) and death. The
general picture of SA-MCF does not differ from that of WS-MCF described elsewhere (1).
SA-MCF is expected to be occur in every region and country where cattle, sheep, and
probably goats graze together, probably because all the sheep flocks (and probably the goats
GA-MCF (18)) are infected with gammaherpersviruses, especially OvHV-2 (1,2).
The incubation period in cattle can last up to 9 months (3). The detection by PCR of OvHV2 DNA in peripheral blood lymphocytes from a persistently infected (PI) animal that survived
MCF for 14 months is indicative of the establishment of a chronic carrier state of SA-MCF
(13,14,17).
The primary lesions in cattle with acute SA-MCF are lymphoid proliferation and infiltration,
necrotizing vasculitis, perivascular lymphoid accumulation and necrosis of the mucous
epithelium (8,11). The predominant infiltrating cell type in the lesions is CD8+ T-lymphocytes
and large numbers of these cells are infected with OvHV-2. The lesions also contain
macrophages, but not CD4+ or B-lymphocytes (11). The extended and variable incubation
periods and the long prepatent viremia are evidence that the changes in MCF represent
primarily a cell-mediated immunopathological event (9). The lesions observed during the rare
chronic cutaneous form might be considered as a possible sequeal of an immunopathogenic
reaction that characterizes SA-MCF infection (4,9,11). The recently described cutaneous form
adds an additional dimension to this multi-faceted clinical manifestation and may mislead the
veterinarian to suspect a cutaneous hypersensitivity reaction of unknown etiology (Figure 4)
(4).
Figure 3 - SA-MCF in a dairy cow that became a carrier of the OvHV-2 Figure 4 - Various aspects of the cutaneous form of
for
over
6
months
giving
birth
to
a
mummy. hypersensitivity or streptotrichosis.
Note
the
ocular,
mouth
and
nasal
discharge.
SA-MCF in Israel
The first identification in Israel of OvHV-2, the causative agent of the SA-MCF, was
reported in 2001, in describing an epidemic causing the death of 34 out of 100 feedlot calves
while the remaining animals were slaughtered. The clinical presentations were the head and
eye form, the CNS form and the respiratory/intestinal form. OvHV-2 involvement was
confirmed by the hemi-nested PCR method, which was adopted in our laboratory. This
method became the principal diagnostic tool for confirmation of SA-MCF in Israel (4,5,15).
Before 2001, MCF reporting was based in Israel, as in most countries, upon clinical,
pathological, histo-pathological diagnosis and completed with epidemiological data (the
presence of sheep flocks). This is generally regarded as reliable concerning MCF disease.
The disease has been reported from Israel since the establishment of Veterinary Services
during the 1920s, and is a notifiable disease since 1945.
Sporadic cases were reported almost every year over this period. For instance, during the
period 1973-1982, a total of 36 cases were reported. Nevertheless between 1991 and 2001,
no SA-MCF cases were reported, and since the 2001 epidemic, 30 clinical cases of SA-MCF
have been diagnosed by demonstrating OvHV-2 in the blood, tissues or secretions of sick
animals. Of particular interest is the first published description of the cutaneous form (4). In
total, 6 “atypical” SA-MCF cases have been confirmed so far, including 4 cutaneous cases
and 2 with lameness. The latter is of great interest because no other clinical signs were noted
other than the inter-digital lesions.
The possibility of introducing SA-MCF or the WA-MCF to other ruminants kept in captivity
or semi-captivity was demonstrated in a Barbary sheep with some clinical signs of MCF and
the demonstration of OvHV-2 in its blood and internal organs. On the fifth day of illness, the
animal presented with swollen eyelids, lachrymation, and mucopurulent nasal discharge,
muscular trembling and bilateral corneal opacity. The most prominent postmortem finding
presented as well as the typical lesions suggestive as MCF included bladder hemorrhages
(15).
This animal grazed alongside sheep in a pet zoo, and OvHV-2 was demonstrated in both
animals while the PCR product displayed the same sequences of the analyzed fragment (15).
Suspected cases of MCF were seen in an Israeli antelope (Gazella gazella) with typical
sings of the disease, but we failed to demonstrate gammaherpesvirus involvement. The most
prominent lesions were bilateral corneal opacity, petechial hemorrhages in the bladder and
vasculitis affecting the internal organs and brain (personal communication, B.J).
On one occasion while performing the hn-PCR in one herd of dairy goats (Table 1), a
different gammaherpes virus was detected in 2 out of 25 goats, when using the “consensusprimer”. This consensus-primer can detect goat herpesvirus-2 (CpHV-2) and other
herpesviruses, which belong to the MCF complex (10). No sequencing has yet been
performed of the replicon of the “new” unidentified virus.
A group of 3 pregnant lactating PI cows, or carriers, has been observed extensively until
calving. One of them, with a low economic value to the breeder (due to the drop in milk yield),
was culled before calving, a second delivered a mummified fetus and the third gave birth to a
normal calf. This cow was inseminated on two consecutive years despite being a SA-MCFV
carrier, and gave birth to two healthy offspring, one at each calving. These PI cases exceeded
the longest PI period for a cow (14 months) previously reported (13).
No OvHV-2 DNA was recovered from the live newborn’s peripheral blood (only the second
calf was examined) or from the placenta or the vaginal fluids. Attempts to detect OvHV-2 DNA
in the mummified calf, the fetal and placental membranes were also negative. OvHV-2 DNA
was identified in the two dams throughout pregnancy and OvHV-2 antigens were present in
their milk and the first colostrum. The newborn was fed 3 meals with the contaminated milk
immediately after birth. These findings agree with other reports that vertical transmission of
SA-MCF is quite possible (1,2,3,17).
A high prevalence of up to 70-95% of OvHV-2 carriers in 5 sheep flock was found by hnPCR (Table 1), as has been published elsewhere (1,2,3). In almost all the SA-MCF cases,
either direct contact (sharing the same premises) or indirect contact (sharing the same feed or
equipment) was demonstrated. These contacts were confirmed by sequencing the OvHV-2
recovered from both species.
So far five distinct viral strains have been demonstrated in Israel. The possibility that SAMCF diagnosis was probably underestimated in Israel and elsewhere could be gleaned from
the Israeli Veterinary Services (IVS) epidemiological bulletins reporting communicable
diseases. The last SA-MCF reported case by the IVS before the 2001 episode (5) was in
1991 and it seems unlikely that Israel was free of SA-MCF during the interim period (19912001). Moreover, 17 cases of MCF were diagnosed in the first 6 months following the 2001
outbreak. Most of these cows were sent to the KVI for diagnosis because they had central
nervous system manifestations, for differential diagnosis of rabies and listeriosis.
As mentioned previously, four of these cases were the cutaneous form, and another two
demonstrated interdigital inflammation before SA-MCF was diagnosed. This last lesion merits
more attention, especially in a herd with a history of SA-MCF.
We propose that MCFV be considered a possible causal agent for many clinical
manifestations because it causes a complex systemic disease. For example, the generalized
lymphadenopathy demonstrates that it is a systemic disease.
The PCR assay for detection of OvHV-2 has becomes internationally recognized although
OvHV-2 has never been isolated (12). Li et al, (10) has reported that presence of OvHV-2
RNA in the milk of all the OvHV-2 positive sheep that were tested. We have adopted this milk
test as a diagnostic tool for SA-MCF virus in dairy herds, and have identified carriers of ovine
herpes-2 (OvHV-2), the causative agent of SA-MCF, in bulk milk using hn-PCR. The
applicability of the bulk tank test has to be approved.
A simple sensitive CI–ELISA test for detection of MCF antibody (16) might facilitate largescale surveys and replace some of the tests mentioned above.
LINKS TO OTHER ARTICLES IN THIS ISSUE
References
1. 1. Malignant catarrhal fever: In: O.I.E. Manual of Diagnostic Tests and Vaccines for Terrestrial
Animal, pps. 570-579, Fifth Edition, 2004, France
2. Radostits, O.M., Gay, C.C., Blood, D.C. & Hinchcliff, K.W. (eds), (2000). Malignant
catarrhal fever. In: Veterinary Medicine, pp 1081-1085. W.B. Saunders Company Ltd.,
London.
3. Selman, I.E. The epidemiology of malignant catarrhal fever. The Vet. Ann. 27: 98-102,
(1987).
4. David, D., Dagoni, I., Garazi, S. Perl, S. and Brenner, J. Cutaneous malignant catarrhal
fever in cattle. Vet. Rec. (in press), 2005.
5. Brenner, J., Perl, S., Lahav, D., Garazi, S., Oved, Z., Shlosberg, A. and David, D. An
unusual outbreak of malignant catarrhal fever in a beef herd in Israel. J. Vet. Med B, 46: 304307, 2002.
6. Oliver, R. E., Beatson, N. S., Cathcart, A. and Poole, W, S. Experimental transmission of
malignant catarrhal fever of red deer (Cervus claphus). New Zealand Vet. J. 31: 437-444,
1983.
7. Li, H., Shen, D. T., Knowles, D. P., Gorham, J. and Crawford, T. Competitive inhibition
enzyme-linked immunosorbent assay for antibody in sheep and other ruminants to a
conserved epitope of malignant catarrhal fever virus. Clin. Microbiol. 32: 1674-1679, 1994.
8. Pierson, R. E., Hamdy, F. M. Dardiri, A. H., Ferris, D. H. and Scholoer, G. M. Comparison
of African and American forms of malignant catarrhal fever: transmission and clinical signs.
Am. J. Vet. Res. 40: 1091-1095, 1979.
9. Rossiter, P.B. Immunology and immunopathology of malignant catarrhal fever. Progress in
Veter. Microbiology and Immunology 1: 121-144, 1985.
10. Li, H., Shen, D. T., O’Toole, D., Knowles, D. P., Gorham, J. R. & Crawford, T.B.
Investigation of sheep-associated malignant catarrhal fever virus infection in ruminants by
PCR and competitive inhibition enzyme-linked immunosorbent assay. J. Clin. Microbiol. 33:
2048-2053, 1995.
11. Simon, S., Li, H., O’Toole, D., Crawford, T.B. and Oaks, J.L. The vascular lesions of a
cow and bison with sheep-associated malignant catarrhal fever contain ovine herpes 2infected CD8+ T lymphocytes. J. Gen. Virol. 84: 2009-2013, 2003.
12. Baxter, S.I.F., Pow, I., Bridgen, A. & Reid, H.W. PCR detection of the sheep-associated
agent of malignant catarrhal fever. Arch. Virol. 132:145-159, 1993.
13. Milne, E.M. & Reid, H.W. Recovery of a cow from malignant catarrhal fever. Vet. Rec.
126: 640-641, 1990.
14. O’Toole, D., Li, H., Miller, D., Williams, W.R. & Crawford, T.B. Chronic and recovered
cases of sheep-associated malignant catarrhal fever in cattle. Vet. Rec. 140: 519-524, 1997.
15. Yerucham, I., Brenner, J., David, D., Perl, S. Malignant catarrhal fever in Barbary Sheep Ammortragus lervia. Vet. Rec. 155: 463-465, 2004.
16. Li, H., McGuire, T. C., Muller-Doblies, U. U. and Crawford, T. B. A simpler, more sensitive
competitive inhibition ELISA for detection of antibody to malignant catarrhal fever viruses. J.
Vet. Diag. Invest. 13: 361-364, 2001.
17. Müller-Doblies, U.U., Egli, J., Braun, U. and Ackerman. (2001). Epidemiology of malignant
catarrhal fever in Switzerland. Schweizer Ach. Tier. 143: 173-183 (in German).
18. Keel, M.K., Patterson, J.G., Noon, T.H., Bradley, G.A. and Collins, J.K. Caprine
herpesvirus-2 in association with naturally occurring malignant catarrhal fever in captive Silka
deer (Cervus Nippon). J. Vet. Diagn. Invest. 15: 179-183, 2003.