JPC SYSTEMIC PATHOLOGY
SPECIAL SENSES 
April 2021
S-V01 (NP)

Signalment (JPC #2238009):  Ten-year-old, female, Holstein, ox.

HISTORY:  This cow was killed following a two-day history of anorexia, fever, nasal discharge, and seizures.

HISTOPATHOLOGIC FINDINGS:  Eye:  Multifocally disrupting the tunica media of small and medium-sized vessels and expanding and infiltrating the tunica adventitia (vasculitis), infiltrating the perivascular and adjacent connective tissues of the cornea, conjunctiva, uveal tract, retina, sclera, and periocular skeletal muscle are moderate numbers of large lymphocytes with vesiculate nuclei (lymphoblastic cells).  Multifocally within affected areas, there is hemorrhage, fibrin, minimal lytic necrosis, and few neutrophils.  The cornea, and to a lesser extent the choroid, is expanded up to 2 to 3 times normal by increased clear space and ectatic lymphatics (edema).  Multifocally and predominantly affecting the periphery of the cornea, corneal epithelium piles up to 8 layers thick and forms rete ridges (hyperplasia), with intracellular edema (hydropic degeneration), intercellular edema (spongiosis), and occasional keratinocytes with hypereosinophilic cytoplasm and a pyknotic or karyolitic nucleus (necrosis) or swollen and pale with vesiculate nuclei (degeneration).  There is multifocal transmigration of the epithelium by neutrophils, and numerous small capillaries extending from the limbus into the corneal stroma (vascularization).  Multifocally, the corneal endothelium is vacuolated and/or hypertrophied. The anterior and posterior chambers contain a minimal amount of fibrin admixed with low numbers of lymphocytes and macrophages often containing phagocytized debris.  Multifocally, the conjunctival subepithelial connective tissue is infiltrated by many lymphocytes with fewer plasma cells and macrophages.

MORPHOLOGIC DIAGNOSIS:  Eye:  Vasculitis, perivasculitis, and panophthalmitis, lymphoproliferative, multifocal, moderate, with corneal hyperplasia, vascularization, and edema, and conjunctivitis, Holstein, bovine.

ETIOLOGY:  Alcelaphine herpesvirus-1 (AlHV-1) or ovine herpesvirus-2 (OHV-2)

ETIOLOGICAL DIAGNOSIS:  Gammaherpesviral panophthalmitis

CONDITION:  Malignant catarrhal fever (MCF)

SYNONYM:  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 MCF virus (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 MCF naturally (alcelaphine herpesvirus-1, ovine herpesvirus-2, caprine herpesvirus-2, caprine herpesvirus-3 or MCFV-WTD, alcelaphine herpesvirus-2, ibex MCF virus),
  • One only form causes MCF experimentally in rabbits (HipHV-1)
  • The other three form 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 AHV-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 OHV-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, OHV-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
• A recent study identified primarily macrophages and T cells within vasculitis lesions; within the rete mirabile, the inflammatory infiltrate was most intense and/or restricted to the tunica adventitia of the arteries (suggesting a “outside-in” pathway of recruitment); viral infection was detected in infiltrating leukocytes, as well as vascular endothelial cells, smooth muscle cells of the tunica media, and fibroblasts in the tunica adventitia (Saura-Martinez, Vet Pathol. 2021)
• 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:

• Eye: Oculonasal discharge, conjunctivitis, corneal opacity (starting at the limbus  and progressing centripetally) and occasionally corneal ulceration
• 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
• 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:

• Ocular lesions: Corneal edema, with ring of peripheral corneal stromal vascularization, and mitotic figures; arteritis often more prominent in iris
• In general, 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
• 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
• 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
  • Though necrotizing arteritis is often considered a pathognomonic feature of bovine MCF infection, a recent study determined necrotizing arteritis is not consistently found in the neuropathologic phenotype of bovine MCF (Hierweger, Vet Pathol. 2021)
• Skin and squamous mucosa of alimentary tract: Lichenoid infiltrate of altered and proliferating lymphoid population; necrosis and ulceration

ADDITIONAL DIAGNOSTICS:

• Recently developed in-situ hybridization technique allows for localization of OvHV-2 nucleic acids in lymphocytes of experimentally and naturally infected animals (Pesavento, Vet Pathol. 2019)
• Immunohistochemistry: Positive immunoreactivity to monoclonal antibody 15A (Mab-15A) recently demonstrated in the cytoplasm of epithelial cells and leukocytes in OHV-2 infected cattle (Headley, J Comp Path. 2020)
• Complement fixation
• ELISA
• PCR

DIFFERENTIAL DIAGNOSIS:

Causes of corneal edema 

• Trauma: Usually unilateral and evidence of abrasions or lacerations
• Infectious bovine keratoconjunctivitis (pinkeye): Caused by Moraxella bovis or M. bovoculi; central or paracentral corneal edema initially, then conjunctivitis and ulcerative keratitis
• Infectious bovine rhinotracheitis (BHV-1, alphaherpesvirus): Peripheral corneal edema, corneal vascularization, and conjunctivitis
• Congenital corneal opacity: An autosomal recessive inherited disorder of Holstein-Friesian cattle in England and Germany with bilateral diffuse corneal edema       

Diseases causing vasculitis in cattle and wild ruminants

• Viral: Bovine virus diarrhea (BVD) virus (pestivirus), bluetongue (orbivirus), adenoviral hemorrhagic disease
• Bacterial: Salmonellosis, Histophilus somni
• Mycotic: Phycomycosis, aspergillosis
• Parasitic: Elaeophora schneideri
• Immune-mediated: Polyarteritis nodosa, drug-induced hypersensitivity

Lymphoproliferative diseases

• 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

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

COMPARATIVE PATHOLOGY:

• Rabbits: Common model to study pathogenesis of both causative agents of MCF; rapidly fatal lymphoproliferative disorder
• Hamsters, rats, and guinea pigs develop MCF-like lesions when exposed to AHV-1
• Pigs can develop clinical disease due to OHV-2
• In some sheep previously diagnosed with polyarteritis nodosa or idiopathic systemic necrotizing vasculitis, OvHV-2 has been identified as the cause using the recently developed ISH technique (Pesavento, Vet Pathol. 2019)

Selected other gammaherpesviruses:

Non-human primates

• Saimiriine herpesvirus 2 (Herpesvirus saimiri): Subclinical latent infections in squirrel monkeys; rapid, fatal lymphoproliferative disease in marmosets, tamarins, and owl monkeys
• Herpesvirus atelesI (ateline herpesvirus-2): Spider monkey is the natural host; produces lymphoma and leukemia similar to Herpesvirus saimiri in tamarins, owl monkeys, and certain rabbit strains
• Cercopithecine herpesvirus 17 (rhesus rhadinovirus): Can produce a marked B-cell lymphocytosis and hypergammaglobulinemia when co-infected with SIV; also associated with retroperitoneal fibromatosis
• Retroperitoneal fibromatosis herpesvirus: Causes disease in association with simian retrovirus-2
• Callitrichine herpesvirus-3 (marmoset lymphocryptovirus): Rapidly fatal lymphoma (typically B-cell) or chronic mononucleosis in marmosets
• Cercopithecine herpesvirus-15 (rhesus lymphocryptovirus): Rhesus EBV-like virus; in rhesus monkeys it produces an SIV-associated lymphoma (B-cell origin) with concurrent infection with rhesus lymphocryptovirus in 94% of affected monkeys
• Marmoset lymphosarcoma virus: Spontaneous fatal lymphoproliferative disease in captive marmosets; novel lymphocryptovirus

Ruminants

• Bovine herpesvirus-4: Mammary pustular dermatitis

Equids

• Equid herpesvirus-2 (EHV-2): Low pathogenicity; upper and lower respiratory disease and keratoconjunctivitis in foals
• Equid herpesvirus-5: Associated with equine multinodular pulmonary fibrosis

Rabbits

• Herpesvirus sylvilagus (leporid herpesvirus-1): Lymphoma and infectious mononucleosis-like syndrome in cotton-tail rabbits

REFERENCES:

1. Alcaraz A, Warren A, Jackson C, et al. Naturally occurring sheep-associated malignant catarrhal fever in North American pigs.  J Vet Diagn Invest.  2009; 21:250-253.

2. English R, Gilger BC. Ocular Immunology. In: Gelatt KN, Gilger BC, Kern TJ, eds. Veterinary Opthalmology. Vol1, 5th Ed. Ames, IA: Wiley-Blackwell; 2013:312-313.
3. Headley SA, et al. Immunohistochemical detection of intralesional antigens of ovine gammaherpesvirus-2 in cattle with sheep-associated malignant catarrhal fever. J Comp Pathol. 2020; 174:86-98.
4. Headley SA, Pimentel LA, Oliveira VHS. Transplacental transmission of ovine herpesvirus 2 in cattle with sheep-associated malignant catarrhal fever. J Comp Pathol. 2015; 153(4):206-211.
5. Hierweger MM, Boujon CL, Kauer RV, Meylan M, Seuberlick T, Oevermann A. Cerebral ovine herpesvirus-2 infection of cattle is associated with a variable neuropathological phenotype. Vet Pathol. 2021; 58(2):384-395.
6. Knowles DP. Herpesvirales. In: MacLachlan NJ, Dubovi EJ, eds. Fenner’s Veterinary Virology. 4th ed. San Diego, CA: Elsevier/Academic Press.
7. O’Toole D, Li H. The pathology of malignant catarrhal fever, with an emphasis on ovine herpesvirus 2. Vet Pathol. 2014; 51(2):437-52.
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; 56(1):78-86.
9. Pesavento PA, Dange RB, Ferreras MC, Dasjerdi A, et al. Systemic necrotizing vasculitis in sheep is associated with ovine herpesvirus 2. Vet Pathol. 2019; 56(1):87-92.
10. Suara-Martinez H, Al-Saadi M, Stewart JP, Kipar A. Sheep-associated malignant catarrhal fever: role of latent virus and macrophages in vasculitis. Vet Pathol. 2021; 58(2): 332-345.
11. 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. St. Louis, MO: Elsevier Limited; 2016:131-133.
12. Wilcock BP, Njaa BL.: Special Senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol. 1. 6th ed. St. Louis, MO: Elsevier Limited; 2016:453.
13. Zemljic T, Pot SA, Haessig M, Spiess BM. Clinical ocular findings in cows with malignant catarrhal fever: ocular disease progression and outcome in 25 cases (2007-2010). Vet Ophthalmol. 2012;15:46-52.

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