JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

November 2024

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 arteries and to a lesser extent veins are surrounded by thick cuffs of mononuclear inflammatory cells that multifocally and variably transmurally infiltrate the vessel walls, expanding the tunica adventitia and 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 as well as 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 either are swollen with vacuolated sarcoplasm (degeneration) or are shrunken with bright eosinophilic cytoplasm and a pyknotic nucleus (single cell death). The endothelium of these vessels is segmentally hypertrophic, with lymphocytes directly subjacent to endothelium. The lamina propria is infiltrated by moderate numbers of large and small lymphocytes, plasma cells, macrophages, and fewer neutrophils; this infiltrate widely separates crypts. Multifocally, colonic crypts are mildly dilated and lumina contain neutrophils and cellular debris (crypt abscesses). There is multifocal mucosal erosion and the mucosal epithelium is replaced by extracellular, amorphous, eosinophilic material admixed with necrotic neutrophils, scant hemorrhage, fibrin, edema, and cellular and karyorrhectic debris (lytic necrosis). The submucosa and tunica muscularis are moderately expanded by increased clear space (edema) and ectatic lymphatics.

 

MORPHOLOGIC DIAGNOSIS: Colon: Vasculitis, fibrinonecrotizing and lymphoproliferative, 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; see also S-V01 and U-V02
• 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 are unable to shed virus, i.e. end stage host)
  • Six forms cause disease 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) 
  • 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
• Primarily targets tissues of vasculature, lymphoid organs and epithelium (esp respiratory and GI)
• 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
• Recent study implicates macrophages as being critical to the development and progression of MCF (Saura-Martinez, Vet Pathol, 2021)
• 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); latent virus in T-lymphocytes
• 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 
• Development of antibodies does not prevent a fatal outcome
• Characterized by marked T lymphocyte hyperplasia 

 

TYPICAL CLINICAL FINDINGS:

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 (i.e. catarrh), 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

• Lesions are most severe in the rostral third of the nasal cavity 
• Lower GI may not have lesions (oral lesions present in most cases though)
• Lesions tend to start at the mucocutaneous junctions leading eventually to large areas of oral mucosa being effected (tongue, dental pad, buccal papillae, gingiva, palate and cheeks)
• Esophageal 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

• Will have a dark red brush border around the iris within the cornea Widespread arteritis-phlebitis of medium caliber vessels

• Kidney: 2-4 mm, raised, white foci in cortex, infarcts; pelvic and ureteral mucosa have petechia and ecchymotic hemorrhage
• 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 (sloughing) 
• CNS: Meninges wet (edema due to vasculitis), 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, marked corneal edema
• 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; however, lesions vary and may not have necrotizing arteritis; molecular detection of OvHV-2 is warranted in cattle with nonsuppurative encephalitis even without necrotizing arteritis (Hierweger, Vet Pathol, 2021)
• 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
• IHC can be used to reliably detect viral antigens in a variety of infected tissues (Headley, J Comp Pathol, 2020)

 

DIFFERENTIAL DIAGNOSIS:

 

Gross differential diagnoses for oral or gastrointestinal ulcerative diseases:

• Rinderpest (morbillivirus, Paramyxoviridae) (D-V28): Necrotic stomatitis and enteritis, necrosis of lymphocytes in Peyer’s patches, spleen, and lymph nodes
• Bovine viral diarrhea virus (pestivirus, Flaviviridae) (D-V09): 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) (R-V02): Lesions restricted to upper respiratory tract in adults (rhinotracheitis, bronchopneumonia); alimentary tract necrosis in calves
• Vesicular stomatitis (vesiculovirus, Rhabdoviridae) (D-V11): Papules in the mouth which progress to vesicles and erosions; epithelial intercellular edema and keratinocyte necrosis
• Foot and mouth disease (aphthovirus, Picornaviridae) (D-V17): Indistinguishable from vesicular stomatitis
• Bluetongue (orbivirus, Reoviridae) (D-V16): 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) (C-V03) 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:

MCF in other species:

• 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
• Goats have been shown to initially manifest a skin disease and as an erythema multiforme (Makoni, J Vet Diagn Invest. 2024)

 

Other notable gammaherpesviruses:

1. Epstein-Barr virus (human herpesvirus 4): Infectious mononucleosis in humans; associated with Burkitt’s lymphoma, nasopharyngeal carcinoma and Hodgkin’s disease
2. Herpesvirus saimiri (saimiriine herpesvirus 2) (H-V02): 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

 

REFERENCES:

1. Callan RJ. Malignant catarrhal fever (bovine malignant catarrh, malignant head catarrh). In: Smith BP, Van Metre DC, Pusterla N, eds. Large Animal Internal Medicine. 6th ed. St. Louis, MO: Elsevier; 2020:830-833. 
2. Carvallo FR, Uzal FA, Moore JD, et al. Ibex-associated malignant cararrhal fever in duikers (Cephalophus spp.). Vet Pathol. 2020;57(4):577-581.
3. 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. Comeau D, Spinato MT, Ojkic D, Foster RA, Caswell JL. Bovine astrovirus and its role in lymphocytic encephalitis in cattle in Ontario, Canada, 1988-2019. J Vet Diagn Invest. 2024;36(3):447-456.
4. Constable PD, Hinchcliff KW, Done SH, Grunberg W, eds. Veterinary Medicine: A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats, 11th ed. St. Louis, MO: Elsevier; 2017:2076-2080.
5. Gal A, Castillo-Alcala F. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:687.
6. Headley SA, Oliveira TES, Li H, 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.
7. Hierweger MM, Boujon CL, Kauer RV, Meylan M, Seuberlich T, Oevermann A. Cerebral Ovine herpesvirus 2 infection of cattle is associated with a variable neuropathological phenotype. Vet Pathol. 2021;58(2):384-395.
8. Howerth EW, Nemeth NM, Ryser-Degiorgis MP. Cervidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA:Elsevier. 2018:156-157.
9. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA:Elsevier. 2018:124-126.
10. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 1427.
11. Makoni GM, Gerspach C, Fischer N, et al. Malignant catarrhal fever in a goat: manifestation of virus-induced erythema multiforme. J Vet Diagn Invest. 2024;36(2):243-247.
12. Miller AD, Porter, BF. Nervous System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:968-969.
13. Milliron SM, Stranahan LW, Rivera-Velez AG, Nagy DW, Pesavento PA, Rech RR. Systemic proliferative arteriopathy and hypophysitis in a cow with chronic ovine herpesvirus 2-induced malignant catarrhal fever. J Vet Diagn Invest. 2022;34(5):905-908.
14. Robinson WF, Robinson NA. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier; 2016:70.
15. Saura-Martinez H, Al-Saadi M, Stewart JP, Kipar A. Sheep-associated malignant cararrhal fever: Role of latent virus and macrophages in vasculitis. Vet Pathol. 2021;58(2):332-345.
16. Spagnoli ST, Gelberg HB. Alimentary System and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:471. 
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. Philadelphia, PA: Elsevier; 2016:131-136.
18.  Westermann T, Demeter EA, Diel DG, et al. Granulomatous mural folliculitis in 16 domestic goats: Infection with malignant catarrhal fever viruses and colocalization with ovine herpesvirus-2 using in situ hybridization. Vet Pathol. 2023;60(6):876-887.
19. Wilcock BP, Njaa BL. Special Senses. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:453.

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