JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

November 2022

I-V16

 

Signalment (JPC# 2593663): An adult male cynomolgus monkey (Macaca fascicularis)

 

HISTORY: This monkey developed generalized, acute, multifocal to coalescing, erythematous and vesicular skin lesions and died.

 

MICROSCOPIC DESCRIPTION: Mucocutaneous junction, lip: Affecting approximately 30% of the hyperplastic oral mucosal epithelium and 10% of the epidermis are multifocal to coalescing intact and ruptured vesicles within the stratum spinosum. Vesicles contain enlarged, pale, degenerate and necrotic sloughed individualized and small clusters of epithelial cells that often form syncytial cells with up to 10 nuclei that contain multifocal eosinophilic intranuclear viral inclusion bodies that measure up to 15µm and are surrounded by a clear halo with peripheralized chromatin. Vesicles also contain low numbers of neutrophils, pale flocculent eosinophilic material, and occasional scant hemorrhage.  Keratinocytes overlying intact vesicles are often shrunken and hypereosinophilic with pyknotic nuclei (necrotic). Keratinocytes within the epithelium surrounding vesicles are often discohesive, exhibit variable intracellular edema (hydropic degeneration), and often form similar syncytial cells with previously described intranuclear viral inclusions. Sebaceous gland epithelium also contains intranuclear viral inclusion bodies. There is hyperplasia of the mucosal epithelium and (to a lesser degree) the epidermis characterized by acanthosis and prominent rete ridges; there is also multifocal spongiosis. Multifocally within both the superficial subepithelial connective tissue and dermis are areas of hemorrhage admixed with few neutrophils and few moderately ectatic lymphatics (edema). Multifocally separating, surrounding, and occasionally replacing labial salivary glands are moderate numbers of plasma cells, fewer Mott cells, occasional lymphocytes, macrophages, and rare neutrophils.

 

MORPHOLOGIC DIAGNOSIS:  Mucocutaneous junction: Cheilitis, vesicular, multifocal, moderate, with viral syncytia and intraepithelial (epidermal, mucosal, and sebocytic) eosinophilic intranuclear viral inclusion bodies, cynomolgus monkey (Macaca fascicularis), primate.  

 

ETIOLOGIC DIAGNOSIS:  Herpesviral cheilitis

 

CAUSE:  Simian varicella virus (Cercopithecine herpesvirus 9)

 

ETIOLOGY SYNONYMS:  Delta herpes, Liverpool vervet virus, patas herpesvirus, medical lake macaque virus

 

CONDITION:  Simian varicella

 

GENERAL:  

• SVV affects the cutaneous, digestive, respiratory, and lymphoid organs 
• Cercopithecine herpesvirus 9 (Simian varicella virus, SVV) is an alphaherpesvirus in the genus Varicellovirus sharing similar antigenic properties with human herpesvirus 3 (varicella-zoster virus (VZV), chickenpox/shingles)
• Natural host of SVV is not identified
• SVV belongs to a group of related viruses that include Liverpool vervet virus, Medical Lake macaque virus, and Delta herpesvirus (named for facility and location of first identification)
• Acute, fatal, highly contagious, systemic disease of Old World monkeys including African green monkeys (Ceropithecus aethiops), pig-tailed macaques (Macaca nemestrina), Japanese macaques (Macaca fuscata), cynomolgus monkey (Macaca fascicularis), and patas monkeys (Erythrocebus patas)
• Human varicella virus or human varicella vaccine may provide cross protection

 

PATHOGENESIS:  

• Asian macaque species experience less severe disease and neutralizing antibodies have been detected in asymptomatic stump-tailed macaque; macaques transmit virus to more susceptible species (African cercopithecines)
• Immunosuppresion, stress (shipping, transport) → recrudescence in clinically affected animals
• Simian varicella pathogenesis closely parallels fatal human varicella zoster virus; rapid spread via respiratory route with possible transmission through direct contact with skin lesions  
• High morbidity and variable mortality with early outbreak 
• Transient viremia by day 3; virus transported in B and T cells
• Vesicular dermatitis by day 10 which is often hemorrhagic; lesions progress from papule to vesicle to crust
• By 8 days the virus has disseminated to the liver, lungs, spleen, adrenal glands, kidneys, lymph nodes, and trigeminal ganglion, and causes necrotizing lesions in the liver, lungs, and throughout the gastrointestinal tract
• Dissemination is more likely in immunosuppressed animals and can cause widespread necrosis in various organs
• Latency established within neural ganglia; competing hypotheses suggest hematogenous versus transaxonal transport to ganglia
• SVV infection is lifelong and reactivation may occur

 

CLINICAL SIGNS:

• Disseminated hemorrhagic vesicular exanthema characterized by diffuse inguinal rash that spreads centripetally and progresses to vesiculoulcerative dermatitis of trunk, face, and extremities; cutaneous lesions progress from papule to vesicle to crust; multiple stages present simultaneously 
• Vesicular eruption extends to trunk, face, extremities +/- mucocutaneous junctions and oral mucosa, but spares the palms and soles
• Lesions are pruritic with evidence of self-excoriation; secondary bacterial infections may occur
• Fever, anorexia, lymphadenopathy, hepatitis, and respiratory signs may occur with organ involvement
• Animals may experience spontaneous resolution, subclinical disease, or a high fatality rate

 

TYPICAL GROSS FINDINGS:  

• Lungs-  edema, hemorrhage, necrosis, and emphysema
• Gastrointestinal tract - diffuse ulcerative, hemorrhagic and necrotic disease
• Skin, oral mucosa, esophagus - generalized hemorrhagic epidermal rash with vesicle formation 
• Liver, spleen, lymph nodes, endocrine organs, and bone marrow - necrosis

 

TYPICAL MICROSCOPIC FINDINGS:  

• Cutaneous lesions - multiple vesicles within epidermis that contain variably sized acantholytic epithelial cells, debris, erythrocytes, and rare syncytial cells; hyperplasia of basal cell layer; eosinophilic Cowdry-type A intranuclear inclusions in acantholytic cells and cells adjacent to vesicle; necrotizing vasculitis in dermis with inclusions in endothelial cells
• Liver – multifocal to coalescing hepatocellular necrosis; Cowdry-type A inclusions in hepatocytes bordering foci of necrosis
• Lung and GI tract – similar necrotizing lesions

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Serology 
• Electron microscopy
• Viral culture

 

DIFFERENTIAL DIAGNOSIS:  

• Macacine herpesvirus 1 (B virus)- commonly causes latent infection in young macaques via trigeminal and lumbosacral ganglia;  vesicles and ulcers may occur on dorsal surface of tongue, on the lip, and less extensively the skin; normally does not include extensive cutaneous involvement 
• Morbillivirus infection (measles) – rash is not vesicular
• Other alpha herpesviruses that are associated with herpetic skin lesions; commonly at mucocutaneous junctions
  1. Herpesvirus 1 (herpes simplex virus)
  2. Saimiriine herpesvirus 1 (marmoset and tamarin herpesvirus)
  3. Cercopithecine herpesvirus 2 (simian agent 8)
• Monkey pox – syncytial cells, large eosinophilic intracytoplasmic inclusion bodies, generalized cutaneous rash and pocks

 

COMPARATIVE PATHOLOGY:

• Human varicella has been reported in a captive gorilla
• VZV-like herpesvirus isolated from chimpanzee, gorilla, and orangutan; mild self-limiting vesicular dermatitis

 

REFERENCES:  

1. Kramer JA, Bielitzki J. Integumentary System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases Vol 2.  San Diego, CA: Elsevier Inc.; 2012:569-570.
2. Matz-Rensing K, Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:350. 
3. Wachtman L, Mansfield K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases Vol 2.  San Diego, CA: Elsevier Inc.; 2012:17-18, 569-570.

 

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