JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
November 2018
D-V15

Signalment (JPC #2550468):  Heifer

HISTORY:  This animal had bilateral corneal edema, mucopurulent nasal discharge, enlarged peripheral lymph nodes and respiratory distress.

HISTOPATHOLOGIC DESCRIPTION:  Colon:  Multifocally, within the submucosa, small and medium caliber blood vessels are surrounded by thick cuffs of mononuclear inflammatory cells, which transmurally infiltrate and expand the tunica adventitia, and extend to a lesser degree into the tunica media, and tunica intima.  The infiltrate is composed primarily of large lymphocytes with a high nuclear to cytoplasmic ratio and large open nuclei with prominent nucleoli (lymphoblasts), small lymphocytes, fewer macrophages, and rare neutrophils admixed with moderate amounts of necrotic cellular debris and brightly eosinophilic hyalinized material (fibrinonecrotizing vasculitis). Multifocally tunica media myocytes have vacuolated sarcoplasm (degeneration) or are shrunken with bright eosinophilic cytoplasm and a pyknotic nucleus (necrosis).  The endothelium of these vessels is segmentally hypertrophic.  The lamina propria is infiltrated by moderate numbers of lymphocytes, lymphoblasts, plasma cells, macrophages, and fewer neutrophils, which widely separate crypts.  There is multifocal mucosal erosion. Multifocally, colonic crypts contain neutrophils and cellular debris (crypt abscesses).  The lamina propria is mildly expanded by lymphocytes and plasma cells. The submucosa and tunica muscularis are moderately expanded by increased clear space and ectatic lymphatics (edema).

MORPHOLOGIC DIAGNOSIS:  Colon:  Vasculitis, fibrinonecrotizing, lymphocytic and lymphoblastic, multifocal, moderate, with moderate chronic-active colitis, breed unspecified, bovine.

CAUSE:  Alcelaphine herpesvirus 1 (wildebeest associated) or ovine herpesvirus 2 (sheep associated)

CONDITION:  Malignant catarrhal fever (MCF); malignant head catarrh; and snotsiekte

GENERAL DISCUSSION:

• Gammaherpesvirus in the genus Macavirus, family Herpesviridae
• Causes lymphoproliferation, vasculitis, and erosive to ulcerative mucosal lesions
• Affects numerous species of cervids, bovids, and occasionally pigs; it has adapted to domestic rabbits, hamsters, rats and guinea pigs
• Bali cattle or banteng, water buffalo, bison, and deer (except fallow deer) are highly susceptible
• Usually sporadic; occasional outbreaks with mortality approaching 100%
• There are ten forms in the MCFV group and each subtype in the group has a reservoir host (subclinical with virus shedding) and another host species capable of developing clinical disease when infected (but don’t shed virus, i.e. end stage host)
  • Six forms cause it naturally (Alcelaphine herpesvirus-1, Ovine herpesvirus-2, Caprine herpesvirus-2, Caprine herpesvirus-3 or MCFV-WTD, Alcelaphine herpesvirus-2, Ibex MCF virus),
  • One only causes MCF experimentally in rabbits (HipHV-1), and
  • The other three have yet to be associated with disease (Gemsbok, Muskox, and Aoudad-MCFV); must possess a 15-A antigen epitope to be in the MCFV group
• Most natural outbreaks are associated with AlHV-1 and OvHV-2

PATHOGENESIS:

• Wildebeest are infected for life and transmit AlHV-1 to their calves without showing clinical signs; the calves are infected within the first 2-3 months and shed cell-free virus in nasal and ocular secretions and feces
• In East Africa, wildebeest calves are considered the main source of infection to cattle
• Virus is transmitted mainly through nasal and ocular secretions and in utero infections have also been reported; aerosol transmission is also suspected.
• Mucosa of upper respiratory tract and/or tonsil is most likely route where it is phagocytized by macrophages and spreads to BALT
• Infects lymphocytes, macrophages, and monocytes, spreads systemically in CD8+ T lymphocytes to blood vessels which produce pro-inflammatory cytokines and express viral glycoproteins which leads to lymphoproliferative necrotizing vasculitis
• Two peaks of OvHV-2 gene expression: a preclinical peak in respiratory tract and second in multiple organs leading to clinical disease
• Incubation period: Usually 2-10 weeks
• In sheep, OvHV-2 replicates in type II pneumocytes; most sheep are PCR positive (endemic in domestic sheep)
• The mechanism of vasculitis is proposed to be immune-mediated, but demonstration of immunoglobulin and complement has been inconsistent; may be related to cell mediated type IV hypersensitivity
• Cattle appear to shed only cell-associated virus; transmission among cattle is rare

TYPICAL CLINICAL FINDINGS:

• Fever, nasal/ocular discharge, edema of eyelids and palpebral conjunctivae, corneal opacity, diarrhea, lymphadenopathy, dermatitis, oral erosions and CNS signs (hyperesthesia, head pressing, trembling, nystagmus, incoordination and behavioral changes)

Four clinical forms:

1. Peracute: 1-3 day course with fever and possible hemorrhagic diarrhea
2. Intestinal: 4-9 day course with fever, lymphadenopathy, diarrhea
3. Head and eye: Typical form, longer duration than above with depression, high fever, profuse mucopurulent nasal discharge, dyspnea, ocular discharge, blepharospasm
4. Mild: In experimental cases that recover

TYPICAL GROSS FINDINGS:

• Lymph nodes: Enlarged, edematous (common in all species, except bison)
• Mucosal surfaces: Hyperemia and edema, erosions and ulcerations
• Increased size of visceral organs due to lymphoproliferative vasculitis
• Eye: Oculonasal discharge, conjunctivitis, corneal opacity (starting at the limbus  and progressing centripetally)  and occasionally corneal ulceration
• Kidney: 2-4 mm, raised white foci in cortex infarcts
• Bladder: Hemorrhagic cystitis
• Liver: Slightly enlarged and mottled
• Spleen: Enlarged with prominent lymphoid follicles
• Skin (base of horns and hooves, loins and perineum): Hyperemia to exanthema with crust formation and shedding of hoof wall
• CNS: Meninges wet, possibly with petechial hemorrhages

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Three basic lesions: Widespread arteritis-phlebitis of medium caliber blood vessels, lymphoid proliferation and production of large lymphocytes, and mucosal ulceration in digestive, urinary, and respiratory tracts
• Hallmark lesion in cattle is severe lymphocytic arteritis-periarteritis with necrosis of tunica media (medial myocyte necrosis); accumulation of lymphocytes in adventitia and intima and less in the tunica media; endothelial hypertrophy and fibrinoid change may be present
• Perivascular and intramural infiltrates of large lymphocytes with large open nuclei and prominent nucleoli; fibrinoid necrotizing vasculitis of any organ; best sites:  brain and leptomeninges, carotid rete, kidney, liver, adrenal capsule and medulla, salivary gland, and any section of skin or alimentary tract with gross lesions
• Lymphocytic infiltrate in kidneys, liver (periportal), GI mucosa, dermis, meninges, heart, etc.
• Lymph node:  Lymphoid hyperplasia (active proliferation of large lymphocytes, especially in T cell- dependent areas of interfollicular and paracortical zones); arteritis, pericapsular edema and lymphoid infiltration
• Eye:  Lymphocytic uveitis; exudate from ciliary processes into the filtration angle resulting in opacity; anterior or posterior synechiae
• Spleen: Variation between lymphoid cell hyperplasia in the periarteriolar     sheaths to atrophy and depletion of lymphocytes
• CNS: Necrotizing arteritis, plasma exudation into the meninges or Virchow-Robin space, and the predominantly adventitial lymphocytic response are unique  to MCF in cattle brain
• Skin and squamous mucosa of alimentary tract: Lichenoid infiltrate of altered and proliferating lymphoid population; necrosis and ulceration

ULTRASTRUCTURE:

• Both naked and enveloped particles in infected cells
• Enveloped virions are 140-220 nm in diameter, with an 85-100 nm central capsid
• Large lymphocytes have eccentric, round to irregular nuclei, and euchromatic chromatin

DIAGNOSIS:

• Recently developed in-situ hybridization technique allows for localization of OvHV-2 nucleic acids in lymphocytes of experimentally and naturally infected animals

DIFFERENTIAL DIAGNOSIS:

• Combination of arteritis, lymphoid hyperplasia and lymphocytic infiltrates is very characteristic of MCF

Gross differential diagnoses for oral or gastrointestinal ulcerative diseases:

• Rinderpest (morbillivirus, Paramyxoviridae): Necrotic stomatitis and enteritis, necrosis of lymphocytes in Peyer’s patches, spleen, and lymph nodes
• Bovine viral diarrhea virus (pestivirus, Flaviviridae): Shallow erosions with little inflammation on muzzle, mouth, pharynx, larynx, and posterior nares; linear erosions in esophagus, eroded Peyer’s patches, epithelial destruction of small intestinal crypts, less frequently vasculitis and fibrinoid necrosis; associated with atrophy of lymphoid tissue whereas MCF associated with lymphoid proliferation; MCF affects tissues not generally involved in BVD
• Infectious bovine rhinotracheitis (bovine herpesvirus 1, alphaherpesvirus): Lesions restricted to upper respiratory tract in adults (rhinotracheitis, bronchopneumonia); alimentary tract necrosis in calves
• Vesicular stomatitis (vesiculovirus, Rhabdoviridae): Papules in the mouth which progress to vesicles and erosions; epithelial intercellular edema and keratinocyte necrosis
• Foot and mouth disease (aphthovirus, Picornaviridae): Indistinguishable from vesicular stomatitis
• Bluetongue (orbivirus, Reoviridae): Hyperemia of mucous membranes and thin skin, lip and conjunctival edema, oral ulcerations, laminitis, and necrosis of lingual, pharyngeal, and esophageal muscle
• Epizootic hemorrhagic disease (orbivirus, Reoviridae) in deer: Similar to bluetongue

Differential diagnoses for lymphoproliferation:

• Lymphoma (bovine leukosis virus): Enlarged lymph nodes in retrobulbar area; enteric form characterized by diffuse thickening of the abomasal submucosa with eventual ulceration and hemorrhagic anemia
• Jembrana disease (lentivirus, Retroviridae): Bali cattle; lacks mural vasculitis; causes pneumonia and mesangial glomerulonephritis; may produce granular intracytoplasmic inclusions

COMPARATIVE PATHOLOGY:

• Cervids commonly have prominent gastrointestinal lesions and is characteristically acute
• Pigs present with head and eye form
• Rabbits can be infected by transfer of lymphocytes or T lymphoblast cell lines derived from MCF-affected cattle and deer; they are the most commonly used model to study the pathogenesis of MCF
• Other gammaherpesviruses include:

1. Epstein-Barr virus (human herpesvirus 4):  Infectious mononucleosisin humans; associated with Burkitt’s lymphoma, nasopharyngeal carcinoma and Hodgkin’s disease
2. Herpesvirus saimiri (saimiriine herpesvirus 2): Carried by squirrel monkeys; causes lymphoma in owl monkeys and marmosets
3. Herpesvirus ateles (ateline herpesvirus 2): Carried by spider monkeys; causes lymphoma in owl monkeys and marmosets
4. Herpesvirus sylvilagus (leporid herpesvirus 1): Lymphoma and infectious mononucleosis-like syndrome in cotton-tail rabbits
5. Marmoset lymphosarcoma virus: Spontaneous fatal lymphoproliferative disease in captive marmosets; novel lymphocryptovirus

• In some sheep who were previously diagnosed with polyarteritis nodosa or idiopathic systemic necrotizing vasculitis using the recently developed ISH technique OvHV-2 has been identified as the cause

REFERENCES:

1. Bildfell RJ, Li H, Alcantar BE, Cunha CW, et al. Alcelaphine gammaherpesvirus 1-induced malignant catarrhal fever in a Watusi (Bos taurus africanus) steer in a North American game park. J Vet Diagn Invest. 2017; 29(4):579-582.
2. Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadephia, PA: Elsevier; 2016:459-460.
3. Headley SA, Pimentel LA, Oliveira VHS, Toma HS, et al. Transplacental transmission of ovine herpesvirus 2 in cattle with sheep-associated malignant catarrhal fever. J Comp Path. 2015; 153(4):206-211.
4. Keel KK, Patterson JG, Noon TH, Bradley G A, Collins JK. Caprine herpesvirus-2 in association with naturally occurring malignant catarrhal fever in captive Sika deer (Cervus Nippon). J Vet Diagn Invest. 2003:(15):179-183.
5. Li H, Dyer N, Keller J, Crawford TB. Newly recognized herpesvirus causing malignant catarrhal fever in white-tail deer (Odocoileus virginianus). J Clin Micro. 2000;38:1313-1318.
6. O’Toole D, Li H. The pathology of malignant catarrhal fever, with an emphasis on ovine herpesvirus 2. Vet Pathol. 2014;51:437-452.
7. Otter A, Pow I, Reid HW. Outbreak of malignant catarrhal fever in Welsh black cattle in Carmarthenshire. Vet Rec. 2006:(151):321-323.
8. Pesavento PA, Cunha CW, Li H, Jackson K, O’ Toole D. In situ hybridization for localization of ovine herpesvirus 2, the agent of sheep-associated malignant catarrhal fever, in formalin fixed tissues. Vet Pathol. 2018; [Epub ahead of print].
9. Pesavento PA, Dange RB, Ferreras MC, Dasjerdi A, et al. Systemic necrotizing vasculitis in sheep is associated with ovine herpesvirus 2. Vet Pathol. 2018; [Epub ahead of print].
10. Phillips IL, Cunha CW, Galbraith D, Highland MA, et al. High copy number of ovine gammaherpesvirus 2 DNA associated with malignant catarrhal fever-like syndrome in a lamb. J Vet Diagn Invest. 2018; 30(4):623-627.
11. Radostits OM, Gray CC, Hinchcliff KW, Constable PD. Veterinary Medicine: A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats, 10th ed. Philadelphia, PA: Saunder; 2007:1245-1248.
12. Robinson WF, Robinson NA. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadephia, PA: Elsevier; 2016:70.
13. SAC C VS disease surveillance report: Skin lesions in a heifer with malignant catarrhal fever. Vet Rec. 2015; 177(2):40-43.
14. Seeley KE, Junge RE, Jennings RN, Cunha CW, Li H. Moose (Alces alces) mortality associated with caprine herpesvirus 2 (CPHV-2) in a zoological collection. J Zoo Wildl Med. 2018; 49(3):774-778.
15. Slater OM, Peters-Kennedy J, Lejeune M, Gummer D, et al. Sheep-associated malignant catarrhal fever-like skin disease in a free-ranging bighorn sheep (Ovis Canadensis), Alberta, Canada. J Wildl Dis. 2017; 53(1):153-158.
16. Smith BP. Malignant catarrhal fever (bovine malignant catarrh, malignant head catarrh). In: Smith BP, ed. Large Animal Internal Medicine. 4th ed. St. Louis, MO: Mosby Elsevier; 2009:798-800.
17. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadephia, PA: Elsevier; 2016:131-136.
18. Vikoren T, Klevar S, Li H, Hauge AG. A geographic cluster of malignant catarrhal fever in moose (Alces alces) in Norway. J Wildl Dis. 2015; 51(2):471-474.
19. Zachary JF, McGavin MD. Pathologic Basis of Veterinary Disease, 5th ed. St. Louis, Missouri, Mosby Elsevier; 2007:219, 385, 846-847.

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