JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

November 2024

D-V16

 

Signalment (JPC #1523819): A sheep

 

HISTORY: None 

 

HISTOPATHOLOGIC DESCRIPTION: Tongue: There are multifocal mucosal erosions and ulcerations affecting 20% of the mucosal surfaces, both dorsal and ventral, with replacement by a thick serocellular crust composed of numerous viable and necrotic neutrophils, necrotic cellular debris, fibrin, hemorrhage, and edema. Adjacent epithelium is multifocally hyperplastic (acanthosis), there is prominent intercellular bridging (spongiosis), and epithelial cells contain variably sized, often large, intracytoplasmic, clear vacuoles (hydropic degeneration) that compress nuclei. Within the affected epithelium, there are variably sized clefts filled with viable and necrotic neutrophils, fibrin, and hemorrhage (hemorrhagic pustules). Within the submucosa, there is an inflammatory infiltrate surrounding vessels composed of moderate number of macrophages and neutrophils with fewer lymphocytes and plasma cells, fibrin, edema, and abundant hemorrhage that also separates collagen and skeletal muscle bundles. Multifocally, vessel within walls are expanded by edema and fibrin (fibrinoid vasculitis), and endothelial cells are often either hypertrophic with enlarged, vesiculate nuclei (reactive), shrunken with hypereosinophilic cytoplasm and pyknotic nuclei (necrosis), or lost. Multifocally, lingual salivary glands adjacent to areas of inflammation are shrunken and atrophic and/or acinar cells are hypertrophic and vacuolated (degeneration), there are ectatic ducts, and glands are infiltrated by low numbers of lymphocytes, plasma cells, and few histiocytes. Multifocally, striated muscle cells are distended by intrasarcoplasmic, oval to elongate, 200-400 µm, protozoal cysts filled with numerous tightly packed, deeply basophilic, crescent-shaped, 7-20µm, bradyzoites (sarcocysts).

 

MORPHOLOGIC DIAGNOSIS: 

1. Tongue: Glossitis, ulcerative, subacute, multifocal, moderate, with hemorrhagic pustules, fibrinoid vasculitis, and subepithelial hemorrhage and edema, breed unspecified, ovine.

2. Tongue, skeletal muscle: Intrasarcoplasmic protozoal cysts, multiple.

 

ETIOLOGY: Ovine orbivirus

 

ETIOLOGIC DIAGNOSIS: Orbiviral glossitis

 

CONDITION: Bluetongue

 

GENERAL DISCUSSION:

• Bluetongue virus (BTV) is a vector-borne viral disease of wild and domestic ruminants transmitted by Culicoides spp. (i.e., midges), gnats; virus multiplies within Culicoides 

• Seasonality of disease associated with vector availability 

• Reoviridae family, orbivirus genus, Bluetongue virus; non-enveloped, icosahedral, dsRNA virus with at least 26 serotypes

• Immunity to one serotype does not confer resistance to another

• Up to 80% morbidity and 30% mortality with the introduction of a novel strain
• Sheep, goats, cattle are of most concern among domestic species; sheep are most highly susceptible

 

PATHOGENESIS:

• Following insect bite (Culicoides species midges or gnats), virus replicates in regional lymph nodes and spleen and disseminates via efferent lymph and blood; virus replicates in lymph nodes and spleen, monocytes/ macrophages, and endothelial cells, with greater susceptibility reported in endothelial cells of lung microvascular system > viremia develops in 4-6 days > secondary infection, localization within the vascular endothelium (arterioles, capillaries, and venules) > endothelial degeneration and necrosis > microvascular thrombosis, increased permeability > hemorrhage, edema, ischemic necrosis of many tissues
• Attachment and penetration of BTV to targeted cells is by VP2 and VP5 (attachment/capsid structural proteins) which bind glycosaminoglycans in target cell membranes 
• Viremia persists for 2-4 weeks in sheep and for up to 10 weeks in cattle; persistent infection does not occur
• Vertical transmission may result in congenital anomalies in newborn lambs lesions vary with stage of gestation at infection:

• <50 days: Fetal absorption or abortion
• 50-55 days: Severe necrotizing encephalopathy and retinopathy resulting in congenital hydranencephaly and retinal dysplasia 
• 75 days: Multifocal encephalitis and white matter vacuolation causing porencephalic cysts at parturition
• 100 days: Mild focal meningoencephalitis

• BTV infection in cattle can cause abortion and congenital defects

 

TYPICAL CLINICAL FINDINGS:

Sheep:

• Highly variable causing inapparent infection or acute fulminant disease 
• Severity varies with species infected, virus strain, and environmental conditions
• Pyrexia 
• Ptyalism, serosanguineous to mucopurulent nasal discharge
• Swelling, edema, cyanosis, and hyperemia of the face, tongue, and buccal mucosa often followed by excoriation and ulceration
• Focal hemorrhage may be present on the lips and gums, and the tongue may become edematous and congested or cyanotic
• Muscle stiffness, coronitis, and laminitis
• Diarrhea, vomiting, and secondary aspiration pneumonia
• Partial or complete loss of fleece
• Abortion and congenital defects (hydranencephaly early in gestation)
• Stiffness, reluctance to move, and recumbency due to muscle lesions

 

Cattle & Goats:

• Clinical bluetongue in cattle is rarely apparent; in endemic areas it may never be evident
• Fever, loss of appetite, and leukopenia after an incubation period of 6-8 days
• Typically mild, often subtle disease; however, BTV serotype 8 epizootic in Europe (2006 major outbreak) have been associated with clinical disease similar to BTV in sheep
• Calves from BTV-infected cows have been born with various congenital defects (e.g. porencephaly, and hydranencephaly)

 

TYPICAL GROSS FINDINGS:

Sheep:

• Early lesions: Hyperemia affecting oral and nasal mucosa, fever
• Followed by: Edema, hyperemia, petechiae, focal ulcerations and excoriations of the skin, mucosa of oral and nasal cavity, forestomachs, and abomasum
• Acute cases: Subcutaneous and intermuscular edema (serous or suffused with blood)

• Bruise-like, gelatinous hemorrhages and contusions
• Focal or multifocal pallid areas of streaky myodegeneration may be present throughout the carcass

• Superficial lymph nodes: enlarged and edematous
• Tongue: Edema and cyanosis is characteristic of BTV
• Heart: Necrosis deep in left ventricle papillary muscles, subendocardial and subepicardial hemorrhage 
• Additional sites of hemorrhage:

• Pulmonary artery, base: Focal hemorrhage, petechial or up to 1 cm wide x 2-3 cm long, is classic (more pathognomonic in sheep)
• Base of the aorta 
• Pharyngeal and laryngeal area: Petechial or ecchymotic hemorrhage and edema

• Rumen pillars: Necrosis and hemorrhage of ruminal pillars is highly suggestive (sheep)
• Skeletal and cardiac muscle: hemorrhage, edema, and necrosis

• Chronic: Stellate healing ulcers or scars on the wall of the forestomachs
• Laminitis and coronitis
• Pulmonary edema

 

Cattle: 

• Ulceration and necrosis of muzzle, teats, and gingival, lingual, or buccal mucosa (most consistent on dental pad)

• Limb edema, muscle stiffness, laminitis characterized by hyperemia and edema of the sensitive laminae at the coronet and sloughing of hooves

• Rarely, severely affected cattle develop pulmonary edema
• May succumb to effusions in thorax, pericardium, lung, as well as myocardial hemorrhages and myocarditis
• Erosive to ulcerative lesions of the upper gastrointestinal mucosa
• Focal hemorrhage and necrosis of smooth, skeletal, and cardiac muscles

 

Nondomestic ungulates:

• White-tailed deer: Highly susceptible, develop DIC and hemorrhagic diathesis, abortion and mummification are reported 
• Bison, BTV serotype 8: Transient but severe corneal edema in adults
• Disease in wild ruminants in North America similar to disease in sheep and may include sloughing of hooves; necrosis of velvet antler 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Swollen and degenerate endothelium; vasculitis
• Fibrin and platelet thrombi in small vessels with edema and hemorrhage of surrounding tissues
• Vacuolation and necrosis of overlying mucosal epithelium
• Mild neutrophilic and mononuclear cell infiltrates

 

ADDITIONAL DIAGNOSTICS:

• Virus isolation
• Serology
• Detection of antigen: Immunohistochemistry, PCR

 

DIFFERENTIAL DIAGNOSIS: 

For erosive and ulcerative stomatitis/glossitis in sheep:

• Foot and mouth disease (aphthovirus, Picornaviridae, D-V17): Mild disease in sheep; vesicles in the mouth, muzzle, interdigital space, and teats
• Peste des petits ruminants (morbillivirus, Paramyxoviridae, P-V04): Diphtheritic plaques and ulcers, intranuclear and intracytoplasmic inclusions, and syncytia
• Contagious ecthyma (parapoxvirus, Poxviridae, I-V11): Vesicles, pustules, scabs on the skin of the lips, nostrils and eyes; often distinctly proliferative; may see eosinophilic ICIB
• Sheep pox (capripox virus): ICIB within epithelial cell, monocytes, and fibroblasts
• Photosensitization (see discussion in D-T06)

 

In cattle consider the following differential diagnoses:

• Foot and mouth disease (aphthovirus, Picornaviridae, D-V17): Vesicles in the mouth, muzzle, interdigital space, and teats
• Vesicular stomatitis (vesiculovirus, Rhabdoviridae, D-V11): Similar to foot and mouth disease
• Bovine viral diarrhea (pestivirus, Flaviviridae, D-V09)
• Rinderpest (morbillivirus, Paramyxoviridae, D-V28): Intranuclear and intracytoplasmic inclusions and syncytia; officially declared eradicated worldwide by OIE in 2011
• Malignant catarrhal fever (macavirus, Gammaherpesvirinae, Herpesviridae, D-V15): Lymphoproliferative and necrotizing vasculitis and perivasculitis admixed with characteristic lymphoblasts
• Photosensitization (see discussion in D-T06)

 

White-tailed deer, and mule deer:

• Epizootic hemorrhagic disease (EHDV, orbivirus, Reoviridae, C-V03): 

• Causes epizootic hemorrhagic disease of deer, cattle, and other ruminants; in North America, White-tailed deer are most susceptible
• There are 8+ strains including the Ibaraki strain that causes disease in cattle in Japan but does not affect sheep (produces disease similar to BTV as well as ephemeral fever virus [ephemerovirus, Rhabdovirus, P-V22])
• OIE-listed
• Both BTV and EHDV circulate endemically in north America, are clinically indistinguishable, and cross-react on some serologic tests

• Adenovirus hemorrhagic disease of deer (Odocoileus adenovirus 1, Atadenovirus, Adenoviridae) 

• Closely antigenically related to ovine adenovirus-7, goat adenovirus-1, and bovine adenovirus-7
• Affects White-tailed deer (fatal infections reported), mule deer (most susceptible, outbreak in 1990s in California and elsewhere in the US since), Columbian black-tailed deer (more frequently affected, especially fawns and juveniles, in a recent retrospective review of cervid accessions in California [Woods, J Vet Diagn Invest. 2018]), and moose (fatal infections reported) 
• Two manifestations: (1) systemic (pulmonary edema and/or gastrointestinal hemorrhage) and (2) localized (upper intestinal)
• Endotheliotropic, causing damage to endothelial cells (hyperplasia and necrosis with characteristic adenoviral intranuclear inclusions in endothelial cells) resulting in DIC; targets larger vessels (vs. microvasculature of BTV and EHDV)

 

COMPARATIVE PATHOLOGY:

BTV in other species:

• Highly susceptible: Sheep, white tailed deer, mule deer, bighorn sheep, pronghorn antelope, camelids; significant mortality

• Less susceptible: Cattle, goats, and elk; mild or in apparent infections

• South American camelids have been considered to be resistant: Individual cases described in alpacas and llamas; lesions included hydrothorax, hydropericardium, pulmonary edema, myocardial hemorrhage, and pericarditis; no alimentary tract lesions 
• Recent reports of outbreaks in Ilamas and alpacas; may cause disease in various wildlife species in North America including elk, bison, antelope, white tailed and mule deer
• BTV serotype 8: 

• Outbreak in Europe zoo animals included: American bison, European bison, yak, mouflon, alpine ibex, Siberian ibex, and muskoxen in Europe; outbreaks reported in pronghorn in North America 
• Large cats: Although there is evidence of subclinical/asymptomatic infection in free-ranging felids, disease has been reported in captive Eurasian lynx fed stillborn or aborted fetuses from farms with confirmed BTV infection; caused anemia, subcutaneous hematomas, petechial hemorrhages, pulmonary congestion, edema and death; histologic lesions included vasculitis, edema, and reactive endothelial cells

• A common underlying cause for congenital ocular abnormalities in cervids is undetermined: Two cases of congenital ocular abnormalities in free-ranging white-tailed deer were seropositive for BTV, but was not confirmed as the cause of the lesions (Clarke, Vet Pathol 2018)

 

Other selected Orbiviruses:

• Epizootic Hemorrhagic Disease Virus (EHDV, orbivirus, Reoviridae, C-V03): see discussion in Differential Diagnosis 
• African horse sickness virus (orbivirus, Reoviridae, P-V23)
• Equine encephalosis virus (orbivirus, Reoviridae): causes facial swelling, pelvic limb incoordination

 

REFERENCES:

1. Cantile C, Youssef S. Nervous System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St Louis, MO: Elsevier; 2016: 281.
2. Clarke LL, Niedringhaus KD, Carmichael KP, Keel MK, Fenton H. Congenital Ocular Abnormalities in Free-Ranging White-Tailed Deer. Vet Pathol. 2018;55(4):584-590.
3. Fox KA, Kopanke JH, Lee JS, Wolfe LL, Pabilonia KL, Mayo CE. Bovine viral diarrhea in captive Rocky Mountain bighorn sheep associated with administration of a contaminated modified-live bluetongue virus vaccine. J Vet Diagn Invest. 2019;31(1):107-112.
4. Howerth EW, Nemeth NM, Ryser-Degiorgis MP. Cervidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA Academic Press; 2018:157-160.
5. 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. Cambridge, MA Academic Press; 2018:128.
6. Lopez A, Martinson SA. Respiratory System, Thoracic Cavities, Mediastinum, and Pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:604.
7.   Schlafer DH, Foster RA. Female Genital System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016: 431.
8. Stanton JB, Zachary JF. Mechanisms of Microbial Infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:259-260.
9. Terio KA, McAloose D, Mitchell E. Felidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA Academic Press; 2018:274.
10. Uzal FA, Platter 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; 2016: 136-139, 145-146.
11. Woods LW, Schumaker BA, Pesavento PA, Crossley BM, Swift PK. Adenoviral hemorrhagic disease in California mule deer, 1990–2014. J Vet Diagn Invest. 2018;30(4):530-537.

 

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