JPC SYSTEMIC PATHOLOGY

INTEGUMENT SYSTEM

November 2016

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 degenerate neutrophils, karyorrhectic debris and multifocal colonies of mixed bacteria.  This serocellular crust extends into the underlying dermis and disrupts 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, which extend into the underlying panniculus and often separate and surround myofibers, adipocytes and nerve bundles.  There is multifocal, marked edema within the dermis and panniculus, with diffuse congestion and scattered hemorrhage.  Myofibers multifocally undergo degeneration and necrosis.

MORPHOLOGIC DIAGNOSIS:  Haired skin:  Dermatitis, necrotizing, subacute, diffuse, 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
• Abraded skin is the main route of entry and transmission is 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; economical importance in laboratory animal colonies, but it is 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: Rapidly fatal form with few if any cutaneous lesions and the 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 many years
• Resistance to the disease is inherited in a dominant fashion and exhibits neither sex nor color linkage
  • Resistant strains: C57BL/6 (B6), AKR; limited infection, recover quickly
  • Susceptible strains: C3H, A, SWR, CBA, DBA and BALB/c- die acutely; do not usually survive long enough to develop skin lesions
  • Mice with intermediate susceptibility are necessary for disease outbreaks; they develop disseminated infections (including cutaneous lesions) and shed virus
• Susceptibility depends on age, sex, strain, immune status, virus strain
• 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 or 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; lymph nodes and Peyer’s patches may also be affected.
• 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 and Peyer’s patch: Enlargement and focal necrosis
• Urinary bladder, kidney and thymus: Focal necrosis
• Vagina and jejunum: Punctate erosions with hemorrhage
• 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
• ntracytoplasmic viral inclusion bodies:
  • 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 in visceral organs
• Bone marrow: Degeneration
• Conjunctiva: Mucosa is an excellent site to recover intracytoplasmic inclusion bodies

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, 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):  Syncytial cells, splenomegaly; no necrosis
• Clostridium piliformis: Tyzzer’s disease, hepatitis, enteritis, myocarditis
• Salmonella enteritidis typhimurium: 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; lesion similar to those of 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; rare in humans in Africa; systemic disease
• Cowpox:
  • Wide host range: Humans (hands), cats, large cats and elephants (severe fatal pneumonia); rodents are the natural host/reservoir (bank voles and wood mice)
  • Uncommon self-limiting disease in cattle; lesions found only on teats and udder
  • Recent report of ulcerative dermatitis secondary to concurrent cowpox-canine distemper virus infection in a cat
  • There is a similar recent report of a fatal outbreak of concurrent orthopoxvirus and canine distemper virus in a group of Asian marmots

Genus Parapox:

• Contagious ecthyma (Orf virus)- recent report of co-infection by vaccinia virus and an Orf virus-like parapoxvirus in an outbreak of vesicular disease in dairy cows (Brazil)
• Bovine papular stomatitis
• Pseudocowpox

 REFERENCES: 

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents & Rabbits, 4th ed. Ames, IA: Blackwell Publishing; 2016: 21-23.
2. Chapman JL, Nichols DK, Martinez MJ, Raymond JW. Animal models of Orthopoxvirus Vet Pathol. 2010;47(5):852-870.
3. De Sant’Ana FJ, Leal FA, Rabelo RE, et al. Coinfection by vaccinia virus and an Orf virus-like parapoxvirus in an outbreak of vesicular disease in dairy cows in midwestern Brazil. J Vet Diagn Invest. 2013;25(2):267-272.
4. MacLachlan NJ, Dubovi EJ. Fenner’s Veterinary Virology, 4th ed. London, UK: Elsevier; 2011: 151-165.
5. Origgi FC, Sattler U, Pilo P, Waldvogel AS. Fatal combined infection with canine distemper virus and orthopoxvirus in a group of Asian marmots (Marmota caudata). Vet Pathol. 2013;50(5):914-920.
6. Miller WH, Griffin CE, Campbell KL. Viral, rickettsial, and protozoal skin diseases. In: Miller WH, Griffin CE, Campbell KL eds. Small Animal Dermatology, 7th ed. Philadelphia, PA: WB Saunders Company; 2013: 344-345.
7. Wiener DJ, Welle MM, Origgi FC. Cutaneous lesions associated with dual infection caused by canine distemper virus and orthopoxvirus in a domestic cat. Vet Dermatol. 2013;24(5):543-e130.
8. 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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