JPC SYSTEMIC PATHOLOGY

HISTOPATHOLOGIC DESCRIPTION:

Lung: Approximately 30% of the lung contains multifocal nodules of consolidation up to 3mm in diameter centered on bronchioles (pocks). In these nodules, type I pneumocytes are replaced by markedly hyperplastic type II pneumocytes and alveolar lumina are often filled with eosinophilic fluid, hemorrhage, necrotic neutrophils, necrotic debris, lymphocytes, plasma cells, and moderate numbers of macrophages that have vesiculate nuclei and abundant amphophilic, foamy cytoplasm that contains one to multiple, round, 28µm, pale eosinophilic, intracytoplasmic viral inclusion bodies (sheeppox cells). Bronchioles within consolidated nodules are lined by hyperplastic epithelium that is piled up to ten cell layers thick, rarely contains 2-4 µm eosinophilic intracytoplasmic viral inclusion bodies, and is transmigrated by occasional neutrophils. Predominantly in areas of consolidation, there is moderate expansion of the arterial and arteriolar tunica intima and tunica adventitia by edema, fibrin, lymphocytes, and few necrotic neutrophils (vasculitis). Endothelial cells lining these vessels are multifocally hyperplastic (reactive). The remaining alveolar septae are mildly expanded up to 4x normal by lymphocytes, macrophages, and neutrophils.

GENERAL:

• Capripoxvirus (subfamily Chordopoxvirinae; family Poxviridae) – enveloped, dsDNA virus with complex ovoid or brick-shaped virions
• Sheeppox is the most serious of the pox diseases in domestic animals and causes systemic illness
• Acute to chronic, contagious, systemic disease characterized by generalized pox lesions throughout the skin (especially sparsely wooled areas) and mucous membranes with persistent fever, lymphadenitis, and often pneumonia
• Endemic in North Africa, Asia, and the Middle East; exotic to the Americas, Australia and New Zealand; OIE list A reportable disease with expanding range and occasional epidemics
• Occurs in all ages, but most severe in young lambs; high mortality (80-100%; 50% in adults)
• Fine-wooled sheep (Merinos) are especially sensitive; breeds native to endemic areas are more resistant to infection (i.e., Algerian sheep)
• Extensive losses result from high mortality in lambs, abortions and mastitis in ewes, and skin defects (loss of milk, meat, and/or fiber yield); also costs of quarantine and disease prevention efforts
• The virus is resistant to desiccation and may remain viable in wool for up to 2 months or in dried crusts for up to 6 months

PATHOGENESIS:

• Introduction of virus is predominately via the respiratory tract, but also through skin abrasions → local viral replication in epidermis, dermis, or oronasal pharynx (epitheliotropic) → trafficked to regional lymph nodes via macrophages → replicates in cytoplasm of epithelial cells, mucosal lymphocytes, macrophages, and dendritic cells → exits via efferent lymphatics into blood → cell-associated viremia occurs, causing extensive vasculitis in arterioles and postcapillary venules (immune-mediated complex deposition), thrombosis, and ischemic necrosis with marked neutrophilic inflammation; virus has not been identified in endothelial cells
• Stomoxys calcitrans (stable fly) is an efficient mechanical vector of capripoxvirus, though the role of mechanical vectors in spread of the disease is probably limited

TYPICAL CLINICAL FINDINGS:

• Fever, seromucinous oculonasal discharge, increased respiratory rate, eyelid edema, drooling, and hyperesthesia
• Highly susceptible animals often develop hemorrhagic papules early in disease course; later develop ulcers in the GI and respiratory tracts
• Vesicular stage: Generalized, prominent, umbilicated, multilocular vesicles and cutaneous nodules (0.5-1.5cm in diameter)
• Pustular phase: Coalescing vesicles covered by a thin crust
• In animals that recover, the lesions ultimately heal, leaving permanent, depressed, stellate scars on the skin

TYPICAL GROSS FINDINGS:

• Most cutaneous lesions (vesicles, nodules, papules, ulcerations, and crusts) are confined to sparsely wooled skin and mucous membranes (eyelids, cheeks, nostril, udder, etc.) and characterized by a prominent vesicular stage followed by a pustular stage with thin crusts and gelatinous dermal edema
• One-third of the animals develop respiratory lesions: disseminated, random, miliary to nodular, white foci of consolidation due to hematogenous infection; may be a concurrent tracheitis (hyperplastic nodules)
• Renal lesions consist of multifocal, circular, fleshy nodules throughout cortex

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Cutaneous lesions:
  • Epidermis and follicular epithelium display marked vacuolar degeneration of stratum spinosum, microvesiculation, eosinophilic intracytoplasmic viral inclusion bodies (ICIB), epidermal hyperplasia, hemorrhage, and pustule formation
  • Extensive dermal edema during papular stage with accumulation of many mononuclear cells around blood vessels and between collagen bundles
    • these cells have vacuolated cytoplasm with eosinophilic ICIB and vacuolated nuclei with marginated chromatin; known as “sheeppox cells” or cellules claveleuses
    • “Sheeppox cells” are virus-infected monocytes, macrophages, and fibroblasts, but not endothelial or epithelial cells
    • Some sheeppox cells are CD14 and CD172a positive (antigens expressed on monocytes and macrophages); others are negative (likely fibroblasts) (MacNeill, 2025)
  • Severe necrotizing vasculitis develops in arterioles and post-capillary venules, resulting in dermal and epidermal ischemic necrosis
• Respiratory lesions:
  • Lung: proliferation of virus-containing bronchiolar epithelium and type II pneumocytes (proliferative alveolitis and bronchiolitis) with areas of focal caseous necrosis with infiltration of sheeppox cells, neutrophils, and lymphocytes, and formation of gland-like structures; alveolar septal and bronchiolar epithelial cells may contain ICIB
  • Trachea: May cause hyperplastic nodules in the trachea
  • proliferative lesion attributed to expression of surfactant proteins, thyroid transcription factor 1 (TTF1), and proliferating cell nuclear antigen in the cytoplasm of type II pneumocytes (JVDI, 2026)
    • infiltration of CD3+ T cells also plays role in proliferative character
• Additional lesions:
  • Accumulation of sheeppox cells may occur in heart, kidney, adrenal glands, thyroid gland, and pancreas; may see necrosis and lymphoid depletion in lymphoid organs

ULTRASTRUCTURAL FINDINGS:

• Intracytoplasmic oval (“brick-shaped”) virions measuring 220-300x140-170nm in epithelial cells and macrophages
• Infected cell nuclei often have marginated chromatin and a central, less electron dense area with fine filaments arranged singly or in bundles

ADDITIONAL DIAGNOSTIC TESTS:

• Virus isolation from enlarged lymph nodes; Virus neutralization; Indirect fluorescent antibody (IFA)
• PCR

DIFFERENTIAL DIAGNOSIS:

Respiratory Lesions:

• Ovine Pulmonary Adenocarcinoma (P-V16, Betaretrovirus): Multifocal well-differentiated pulmonary carcinoma
• Ovine Progressive Pneumonia (P-V17, Lentivirus; Retroviridae): Mononuclear interstitial pneumonia, BALT hyperplasia, smooth muscle hyperplasia, minimal type II pneumocyte hyperplasia; no intraalveolar inflammation; no viral inclusions
• Parainfluenza type 3 (Paramyxovirus): Bronchointerstitial pneumonia with eosinophilic ICIB and occasional syncytial cells

Cutaneous Lesions:

• Foot and Mouth Disease (D-V17, Aphthovirus; Picornavirus): Vesicles on feet and mucosa of dental pad
• Contagious ecthyma (I-V11, Orf virus, Parapoxvirus): Lesions on muzzle, eyelids, and teats; most severe in lambs and kids; zoonotic
• Bluetongue (D-V16, M-V01, N-V02; Orbivirus; Reoviridae): Nonpurulent conjunctivitis; congested and edematous muzzle; coronitis; deformed aborted fetuses
• Peste des Petits Ruminants (P-V04, Morbillivirus; Paramyxoviridae): White, raised, necrotic oral lesions; pneumonia and diarrhea

COMPARATIVE PATHOLOGY:

Selected other poxviruses:

• Capripoxvirus:
  • Goats: Goatpox - clinically similar disease, but is usually milder and with low mortality rate
  • Cattle and water buffalo: lumpy skin disease (reportable) - Capripoxvirus lumpyskinpox - ulcers in mouth, nares; well-circumscribed lesions of skin, lungs, and alimentary tract; nodules undergo central necrosis and sequestration known as a “sit-fast”; Jersey and Guernsey most susceptible; transmitted by blood-feeding arthropods; systemic infection that causes vasculitis; must be differentiated from pseudo-lumpy skin disease (bovine alphaherpesvirus-2)
  • Capripoxviruses approx. 96% genetically similar and provide some cross-protection from one another (MacNeill, 2025; Bhat, 2025)
• Orthopoxvirus: Camelpox, Cowpox, Ectromelia (mousepox), Monkeypox, Vaccinia (buffalopox, rabbitpox), Uasin Gishu disease virus, Elephant pox
• Parapoxvirus: Bovine papular stomatitis, Contagious ecthyma, Parapox of red deer, Squirrel pox, Pseudocowpox, Sealpox, Camel and chamois contagious ecthyma
• Avipox: Fowlpox, Pigeonpox
• Leporipox: Myxomatosis, Rabbit (Shope) fibroma, squirrel fibroma virus
• Suipox: Swinepox
• Molluscipox: Molluscum contagiosum
• Yatapox: Tanapox, Yaba monkey tumor
• Cetacean poxvirus: forms a unique tattoo pattern on skin; has characteristics of both parapox and orthopoxviruses via TEM and SEM
• Crocodile poxvirus

REFERENCES:

1. Agnew, D. Camelidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:192-195.
2. Bhat BA, Alqahtani FM, Alhomrani M, et al. Recent advances in techniques used in the diagnosis of lumpy skin disease: a review. J Vet Diagn Invest. 2025;37(6):845-853.
3. Buckles EL. Phoenicopteriformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:688-689.
4. Cassidy JP. Interstitial lung disease in small ruminants. J Vet Diagn Invest. 2026;38(4):626-637.
5. Caswell JL, Williams KJ. Respiratory System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 2. 7th ed. Elsevier; 2026:553.
6. Cheville NF. Cytopathology of viral diseases. In: Ultrastructural Pathology. 2nd ed. Wiley-Blackwell;2009:324.
7. Conley KJ, Shilton CM. Crocodilia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:852.
8. Crespo R, Franca MS, Fenton H, Shivaprasad HL. Galliformes and Columbiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier;2018:748-749.
9. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:487,489.
10. Delaney MA, Treuting PM, Rothenburger JL, Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:506.
11. Farina LL, Lankton JS. Cetacea. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:552-553.
12. Farina LL, Lankton JS. Chiroptera. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:619.
13. Higgins D, Rose K, Spratt D. Monotremes and Marsupials. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:465-466.
14. Landolfi JA, Terrell SP. Proboscidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:423-424.
15. Leger JS, Raverty S, Mena A. Cetacea. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:552.
16. Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Academic Press; 2018:383.
17. MacLachlan NJ, Dubovi EJ, eds. Fenner’s Veterinary Virology. 5th ed. Elsevier Academic Press; 2017:164-167.
18. MacNeill AL, Micheloud JF, Parvin R, et al. Poxvirus pathology and pathogenesis in agriculturally important species. Vet Pathol. 2025;62(6):849-866.
19. Mauldin EA, Welle MM. Integumentary System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 7th ed. Elsevier; 2026:626,632-634.
20. Rensing KM, Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:352-353.
21. Stanton JB, Zachary JF. Mechanisms of Microbial Infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier;2022:183,275-277.
22. Stidworthy MF, Denk D. Sphenisciformes, Gaviiformes, Podicipediformes, Procellariiformes, and Pelecaniformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:659-660.
23. Trupkiewicz J, Garner MM, Juan-Salles C. Passeriformes, Caprimulgiformes, Coraciiformes, Piciformes, Bucerotiformes, and Apodiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Elsevier; 2018:799-801.
24. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. Elsevier; 2022:1162,1224-1225.