JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

November 2024

D-V22

 

SIGNALMENT (JPC #1956094): 5-month-old lamb

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Tongue: Multifocally and segmentally, the glossal epithelium is hyperplastic, expanded up to 500µm, and contains numerous variably sized inflammatory cell aggregates and larger pustules up to 600µm diameter. Predominantly within the stratum spinosum and extending through the ulcerated epidermis are many ruptured neutrophils, fewer macrophages, lymphocytes, and plasma cells admixed with hemorrhage, fibrin, and edema. Multifocally, pustules are ruptured and the associated superficial epithelium is eroded and covered in a disorganized coagulum of karyorrhectic and eosinophilic cellular debris (necrosis) and ruptured neutrophils. Adjacent keratinocytes in the stratum spinosum are swollen with abundant, pale eosinophilic to clear, vacuolated cytoplasm (hydropic/ballooning degeneration) and multifocally contain 5-10 µm diameter, round, eosinophilic, intracytoplasmic viral inclusion bodies. Multifocally, individual keratinocytes are shrunken with brightly eosinophilic cytoplasm and karyorrhexis, karyolysis, or nuclear pyknosis (single cell necrosis). Extending through the lamina propria and into the deeper skeletal muscle layers multifocally are moderate numbers of neutrophils, lymphocytes, and macrophages admixed with hemorrhage, fibrin, edema that expands the perimysium and separates and surrounds individual myofibers. There is a moderate increase in subepithelial, small caliber vessels which are frequently lined by markedly hypertrophied, reactive endothelium. Multifocally, individual skeletal myocytes are swollen with vacuolated sarcoplasm and loss of cross striations (degeneration) or are shrunken with brightly eosinophilic sarcoplasm, disorganization of myofibrils, and absent or pyknotic nuclei (single cell necrosis). Multifocally expanding skeletal myofibers are thin-walled, intra-sarcoplasmic, 80µm diameter, protozoal cysts that contain numerous crescentic, 2x8µm, basophilic bradyzoites (sarcocysts). On the epithelial surface and within the stratum corneum, there are multiple colonies of 1 x 3 µm filamentous bacilli.

 

MORPHOLOGIC DIAGNOSIS: 1. Tongue: Glossitis, proliferative and necrotizing, multifocal, moderate, with hydropic degeneration, intraepithelial pustules, and epithelial eosinophilic intracytoplasmic viral inclusion bodies, breed not specified, ovine.

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

ETIOLOGY: Ovine parapoxvirus (family Poxviridae, genus Parapoxvirus)

 

ETIOLOGIC DIAGNOSIS: Ovine parapoxviral glossitis and glossal sarcocystosis

 

CONDITION: Contagious ecthyma (CE)

 

SYNONYMS: Orf (human condition), contagious pustular dermatitis (stomatitis), sore mouth, scabby mouth

 

GENERAL DISCUSSION: 

• Orf virus is a linear dsDNA virus; Family: Poxviridae, Genus: Parapoxvirus; virions are ovoid and have a regular surface, whereas other poxviruses are large and pleomorphic or brick-shaped 
• Ovine parapoxvirus is closely related to the parapoxviruses causing pseudocowpox and bovine papular stomatitis
• Worldwide distribution with a broad host range to include sheep, goats, humans
• Predominantly a disease of lambs and kids that produces proliferative cutaneous, mucocutaneous, and oral lesions resulting in high morbidity, low mortality

• Mortality occurs with secondary bacterial infections (Fusobacterium necrophorum, Dermatophilus congolensis), lesion invasion by screwworm fly larvae, extension of the virus into the lung, or when oral lesions are severe enough to prevent nursing

• Resolution of uncomplicated disease takes approximately 2-4 weeks
• Very hardy virus; persists for extended periods of time on wool and indefinitely in crust material and in the environment
• “Orf” - Old English for “rough”

PATHOGENESIS: 

• Viral transmission via fomites from ruptured vesicles, scabs, and direct contact from infected animals
• Viral entry via small skin abrasions > infects Langerhans cells and capillary endothelium > virus uses F1L envelope protein to bind to heparin sulfate receptors on host cells > subsequent viral replication in epithelial cells > papule formation due to epithelial acantholysis and cytolysis > progresses to a vesicle and/or pustule that forms a thick brown/black scab over the original lesion > reparative and regenerative response contributes to epithelial hyperplasia
• Virulence factors: 

• Vascular endothelial growth factor (VEGF) is an important virulence factor
  • Increase vascular permeability, capillary growth, and epidermal hyperplasia increase viral replication and crust formation
  • ORF can cause atypical papilloma-like and angiomatous lesions in the skin and mucosa; viral VEGF (vVEGF), its receptor (VEGFR2) and IL-6 signaling by CD163+ macrophages and upregulation of host EGFR likely plays a role (Pintus et al, Vet Pathol, 2024).
• CD95-induced apoptosis of antigen presenting cells
• Bcl-2 inhibition of apoptosis in virally infected cells

• Dry and prickly pasture or forage can abrade the oral mucosa allowing viral entry
• Ulcerated lesions allow entry of secondary pathogens
• Zoonotic through entry of infected exudates through skin abrasions

 

TYPICAL GROSS FINDINGS: 

• Elevated brown-black to gray crusts are the most significant gross and clinical feature
• Typical pox lesions of proliferative and ulcerative dermatitis; however these tend to be more proliferative 
• Vesicles are brief and transient; pustules are flat rather than umbilicated
• Lesions start at lip commissures with spread to the muzzle and nostrils
• Lesions may develop on gingiva, dental pad, palate, tongue, udder, teats, coronary bands, interdigital cleft, heel bulb, anus, esophagus, and rumen
• Buccal lesions are raised, red or gray foci with surrounding zone of hyperemia
• Lesions may be spread to ewe's udder through nursing of lamb

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Vacuolation and swelling of keratinocytes in the outer stratum spinosum, hydropic (ballooning) degeneration, marked epidermal proliferation with elongated rete ridges, intraepidermal microabscesses, and accumulation of an overlying scaly crust 
• By 72 hours, eosinophilic intracytoplasmic inclusion bodies appear; inclusion bodies persist as long as hydropic cells are present, which is typically 3-4 days

ULTRASTRUCTURAL FINDINGS:

• Oval virions measuring 220-300 x 140-170 nm in cytoplasm of keratinocytes
• Infected cell nuclei often have marginated chromatin and a central, less electron dense area with fine filaments arranged individually or in bundles

ADDITIONAL DIAGNOSTIC TESTS: 

DIFFERENTIAL DIAGNOSIS:

• Grossly for oral lesions: 

• Sheep pox (Poxviridae, capripoxvirus, P-V24): High mortality, reportable disease; elevated papules in sparsely woolen areas; systemic disease (esp. pneumonia); inclusions common; less proliferative than parapoxvirus; may need molecular testing to distinguish from orf virus

• Ulcerative dermatosis (unclassified poxvirus): Ulcerated papules on the lips, face, legs, feet, and genitalia; no epithelial hyperplasia 
• Foot and mouth disease (Picornaviridae, aphthovirus, D-V17): Lesions of contagious ecthyma may be confined to the oral cavity, resembling FMD 

• Grossly for skin lesions:

• Ulcerative dermatosis (unclassified poxvirus): spread is by direct contact especially during breeding 
• Balanoposthitis - vulvitis is commonly seen in the fall breeding season
• Mycotic dermatitis - usually occurs in woolen skin; scabs are smaller, thinner, lighter, and usually yellow; the crusts are not firmly attached
• Blue tongue (Orbivirus, D-V16) - affects adults more than lambs and causes a severe systemic illness with high mortality and low morbidity
• Sheep pox (Poxviridae, capripoxvirus, P-V24) - similar skin lesions with systemic lesions and a high mortality rate; may need molecular testing to distinguish from orf virus

COMPARATIVE PATHOLOGY:  

• Contagious ecthyma in other species: reported in sheep, goats, cattle, camels, thinhorn (Dall’s) sheep, mountain goats, bighorn sheep, Sichuan takin, captive and wild muskoxen, Himalayan tahr, serow, gazelle, reindeer, musk ox, chamois, dogs, and cats
• Other parapoxviruses:

• Bovine papular stomatitis (Poxviridae, parapoxvirus, D-V21): Papules in oral cavity of young cattle that must be differentiated from other more serious causes of ulcerative oral lesions
• Pseudocowpox virus: occasionally transferred to udder via suckling calves with lesions identical to "milker's nodule" in humans
• Ausdyk virus: affects camels in Africa and Asia
• Sealpox virus: affects seals and humans, worldwide distribution
• Parapoxvirus of red deer: affects red deer in New Zealand

 

REFERENCES: 

1. Agnew D. Camelidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:185-206. 
2. Hampton AL, Dyson MC, Bergin IL. Pathology in practice. 3-week-old female Suffolk lamb with a large perianal mass. J Am Vet Med Assoc. 2012;240(11):1293-1295.
3. Jones MEB, Gasper DJ, Mitchell (nee Lane) E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 125-126.
4. MacLachlan NJ, Dubovi EJ. Fenner’s Veterinary Virology. 5th ed. London, UK: Academic Press; 2017: 158-160,171-172.
5. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:615-619.
6. Pintus D, Cancedda MG, Puggioni G, et al. ORF virus causes tumor-promoting inflammation in sheep and goats. Vet Pathol. 2024;61(5):803-814. 
7. 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; 2022:465.
8. Stanton JB, Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:247-248.
9. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, eds. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 140.
10. Welle MM, Linder KE. The Integument. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1225-1226.

 

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