JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

November 2022

I-V06

 

SIGNALMENT: Mouse

 

HISTORY:  This mouse died after a short period of malaise.  Many cutaneous lesions were present.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin: The epidermis is diffusely ulcerated and replaced by an eosinophilic necrotic coagulum composed of numerous necrotic neutrophils, karyorrhectic debris, and colonies of bacterial cocci and fewer colonies of mixed bacteria. This serocellular crust extends into the underlying dermis, replacing normal dermal and adnexal architecture. Multifocally follicular epithelial cells exhibit ballooning degeneration and both follicular epithelial cells and sebocytes occasionally contain one to multiple, round to oval, eosinophilic, intracytoplasmic viral inclusion bodies up to 15 um in diameter (Marchal bodies). There is marked perifollicular, follicular, and dermal inflammation characterized by numerous neutrophils, lymphocytes, and plasma cells with fewer macrophages and mast cells. This inflammation extends into the underlying panniculus carnosus and often separates and surrounds myofibers, adipocytes, and nerve bundles. There is multifocal, marked edema and fibrosis within the dermis and panniculus carnosus as well as diffuse congestion and scattered hemorrhage. Affected myofibers are multifocally swollen, with pale, vacuolated sarcoplasm (degeneration) or are shrunken with hypereosinophilic sarcoplasm and pyknotic nuclei (necrosis).

 

MORPHOLOGIC DIAGNOSIS:  Haired skin:  Dermatitis, necrotizing, diffuse, subacute, severe, with follicular epithelial ballooning degeneration, neutrophilic and lymphoplasmacytic folliculitis and panniculitis, and follicular epithelial and sebocytic eosinophilic intracytoplasmic viral inclusion bodies, strain unspecified mouse, rodent. 

   

ETIOLOGIC DIAGNOSIS:  Orthopoxviral dermatitis

 

CAUSE:  Ectromelia virus (murine orthopoxvirus)    

 

CONDITION:  Mousepox

 

CONDITION SYNONYM:  Ectromelia 

 

GENERAL DISCUSSION:  

• Ectromelia virus is an intracytoplasmic, large, double-stranded DNA, cytocidal virus that causes mousepox; ectromelia virus is in the family Poxviridae and the genus Orthopoxvirus, to which vaccinia, variola, monkeypox, cowpox and others belong
• Cutaneous trauma is the main route of entry and requires direct contact of infected scabs or excretions containing virus particles
• Virus can be isolated from feces, urine, saliva, conjuntival discharge, and skin lesions  
• Mousepox is of a restricted species range, causes severe disease and has a high mortality rate; economic importance in laboratory animal colonies, but not recognized in wild mouse populations
• Enzootic in Europe and Asia; outbreaks in United States research laboratories due to importation of infected mice or mouse products from Europe
• Two recognized forms of the disease:  
  1. Rapidly fatal with few if any cutaneous lesions  
  2. Chronic form with ulceration of skin, particularly feet, tail and snout often resulting in loss of limbs and tail
• Poxviruses are generally highly resistant and may survive in scabs for years
• Resistance to the disease is inherited in a dominant fashion and exhibits neither sex nor color linkage 
  1. Resistant strains: C57BL/6 (B6), AKR; allow inefficient virus replication and excretion
  2. Susceptible strains: C3H, A, SWR, CBA, DBA and BALB/c- die acutely; do not usually survive long enough to develop skin lesions
  3. Mice with intermediate susceptibility are necessary for disease outbreaks; they develop disseminated infections (including cutaneous lesions) and shed virus
  4. Immunocompetent mice recover completely from infection and do not generally serve as carriers; immunodeficient mice cannot clear the virus

 

PATHOGENESIS:  

• Invasion via primary skin lesion > virus extends to lymphatics, regional lymph nodes, then the blood > localizes and replicates in the liver and spleen > dissemination to viscera including the lungs, pancreas, lymph nodes, small intestines, kidney and skin
• Rapid multiplication of the virus in the liver and/or spleen results in death before subsequent cutaneous lesions are apparent  
• The secondary cutaneous infection causes localized lesions in the epidermis characterized by a generalized papular rash that progresses to ulcerations and gangrene of the extremities
• Viral replication occurs in the cytoplasm of infected cells; some mature viral particles move to the Golgi complex, acquire an envelope, and are released from the cell by exocytosis; the majority of virus particles are not enveloped and are released when the cells are ruptured

 

TYPICAL CLINICAL FINDINGS:  

• There is marked variation in signs and severity between different strains of mice and virus; mice can be asymptomatic or die acutely due to liver failure
• Chronic infection results in cutaneous ulceration (snout, feet, and tail) with variable mortality rates
•  Mice are often hunched, depressed, and may have swollen faces; infection during pregnancy may cause fetal death 

 

TYPICAL GROSS FINDINGS:

• Spleen:  The most commonly affected site; focal coagulative necrosis; recovered animals have a unique feature of splenic fibrosis
• Skin:  Crusts on face, snout, ears, tail, extremities, and other sites; necrosis (dry gangrene) and loss of extremities and tail; multiple hairless scars on skin in recovered animals
• Liver:  Swollen, friable with multifocal to coalescing foci of necrosis
• Small intestine:  Hemorrhage
• Lymph nodes, Peyer’s patches, and spleen: Enlargement with patchy necrosis
• Eye:  Conjunctivitis (virus particles shed in ocular discharge), blepharitis

 

TYPICAL MICROSCOPIC FINDINGS:  

• The combination of splenic and hepatic necrosis along with cutaneous lesions with intracytoplasmic viral inclusion bodies is pathognomonic
• Intracytoplasmic viral inclusion bodies (1-6um diameter):  

• Eosiniphilic A-type (Marchal bodies):  Appear late in the disease and are common in epidermis, lymphoid tissue, pancreas and intestine, but not liver  
• Basophilic B-type (Guarnieri bodies):  Present in all poxvirus-infected cells early in the disease and are at sites of viral replication including keratinocytes (indistinct) and in hepatocytes at the periphery of necrotic foci

• Epidermis:  Early- focal epidermal hyperplasia, hypertrophy, and spongiosis with ballooning degeneration and viral inclusion bodies;  later- necrosis and ulceration 
• Liver:  Multifocal random coagulative necrosis with minimal inflammation, intracytoplasmic eosinophilic viral inclusion bodies, vacuolar degeneration at margins
• Spleen:  Focal necrosis involving both lymphoid follicles and red pulp
• Intestine:  Mucosal erosions, focal necrosis, particularly of Peyer’s patches, in visceral organs
• Bone marrow:  Degeneration

 

ULTRASTRUCTURE:  

• Virions are large (100 x 300 nm), brick or dumbbell-shaped with two "lateral bodies" enclosed within an outer membrane
• Surface is covered with tubular projections (parapox virions are the only poxviruses to have the characteristic spool of thread appearance on EM)
• Occasionally poxviruses have envelopes;  presence or absence of an envelope does not affect virulence

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Skin biopsy; Immunohistochemistry
• Electron microscopy
• Polymerase chain reaction
• Inclusion body staining can be enhanced by doubling hematoxylin-staining time

 

DIFFERENTIAL DIAGNOSIS:  

Cutaneous lesions: 

• Trauma (e.g. bite wounds)
• Ectoparasitism:  Myobia sp., Mycoptes sp.
• Bacterial:  Streptobacillus moniliformis; Staphylococcus aureus
• Environmental (low humidity):  Ringtail, annular constrictions on tail and feet resulting in edema and dry gangrene   

Hepatic necrosis:

• Mouse hepatitis virus (Coronavirus, D-V04):  Syncytial cells, splenomegaly; no necrosis
• Clostridium piliforme (D-B06):  Tyzzer’s disease, hepatitis, enteritis, myocarditis
• Salmonella Typhimurium (D-B01) Necrotizing or granulomatous
• Corynebacterium kutscheri:  Focal caseous necrosis with "Chinese characters"

 

COMPARATIVE PATHOLOGY:

Genus Orthopox:

• Variola (smallpox):  Humans
• Vaccinia virus: Used to immunize humans against smallpox; lesions similar to smallpox; infectious for rabbits, mice, cattle, sheep, swine, monkeys and humans
• Monkey pox:

• Old World monkeys, New World monkeys and great apes are susceptible
• Zoonotic; historically rare in humans in Africa, but pandemic in 2022; systemic disease 

• Cowpox:

• Wide host range:  Humans (hands), cats, large cats and elephants (severe fatal pneumonia); rodents are the natural host/reservoir (bank voles, wood mice)
• Uncommon self-limiting disease in cattle; lesions found only on teats and udder
• Recent report of atypical cowpox virus infection in five cats; skin lesions of edema, hyperemia and plaque-like alterations on hindlimbs (Jungwirth, J Comp Pathol 2018)

Genus Parapox:

• Contagious ecthyma (Orf virus) (I-V11, D-V22)
• Bovine papular stomatitis (D-V21)
• Pseudocowpox

 

REFERENCES:  

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents & Rabbits, 4th ed. Ames, IA: Blackwell Publishing; 2016: 21-23. 
2. Jungwirth N, Puff C, Koster K, et al. Atypical cowpox virus infection in a series of cats. J Comp Pathol. 2018;158:71-76. 
3. MacLachlan NJ, Dubovi EJ. Fenner’s Veterinary Virology, 5th ed. London, UK: Elsevier; 2017:157-162; 170.
4. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol 1. 6th ed. Philidelphia, PA: Elsevier Saunders; 2015: 616.

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