JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2051827): 2-month-old mangabey monkey
HISTORY: This monkey died two weeks after sustaining a skull fracture.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Segmentally affecting approximately 20% of the glomerular tufts, the mesangium is moderately thickened and expanded by hypereosinophilic fibrillary matrix that obscures capillary lumina (segmental glomerulosclerosis). Within sclerotic glomeruli, there are few large cells with indistinct cell borders and a nucleus two to three times larger than adjacent cells. These nuclei have marginated chromatin and a central, round to oval, up to 12 um in diameter, amphophilic to basophilic intranuclear inclusion body surrounded by a clear halo (Cowdry-type A or "owl's eye" inclusion). Rare scattered tubules contain sloughed, shrunken, hypereosinophilic epithelial cells with pyknotic nuclei (necrosis). There are rare previously described intranuclear inclusions present within tubular epithelial cells. There is a focus of lymphocytes with fewer plasma cells in the pericalyceal connective tissue. There are scattered subcapsular immature glomeruli (consistent with immaturity).
MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulosclerosis, subacute, segmental, multifocal, mild with cytomegaly, karyomegaly, and intranuclear viral inclusion bodies, mangabey monkey, non-human primate.
ETIOLOGIC DIAGNOSIS: Betaherpesviral nephritis
CAUSE: Cytomegalovirus (CMV)
- Cytomegalovirus, subfamily Betaherpesviridae
- Highly host-specific viruses of humans, nonhuman primates, pigs, horses, mice, guinea pigs and other animals
- In nonhuman primates cytomegaloviruses are recognized in the rhesus, owl and African green monkeys, mangabeys and chimpanzees
- Primary infections are low-grade chronic infections that seldom result in clinically apparent disease, except in fetuses and immunodeficient individuals especially rhesus monkeys infected with simian immunodeficiency virus (SIV)
- Transmission of infection is usually through contact with infected cells in saliva, urogenital excretions, or free virus in aerosols
- Transplacental infection may result in congenital cytomegalic inclusion disease and CNS damage due to intrauterine encephalitis
- Primary infection > viremia > latent infection in multiple tissues with periodic viral shedding > reactivation, immunosuppression, and pregnancy > disseminated disease
- Transmission: Urine, saliva, semen, blood, and milk
- Latent infections tend to persist in glandular tissue, lymphoreticular cells, and kidneys rather than neurons
TYPICAL CLINICAL FINDINGS:
- Infection is usually asymptomatic
- Disseminated disease in neonates, fetuses, and immunosuppressed animals will produce signs related to the anatomic site(s) involved, i.e. meningitis, interstitial pneumonia, arteritis, enterocolitis, orchitis, hepatic and splenic necrosis
- In nonhuman primates, the lung is the most commonly affected organ, with related clinical signs
- Recent reported peripheral neuropathy in the facial nerve associated with systemic CMV infection in a group of SIV-positive rhesus macaques; the pathogenesis of the nerve damage is likely due to the bystander effect secondary to CMV-induced inflammation rather than direct viral infection of Schwann cells
TYPICAL GROSS FINDINGS:
- Lung: randomly scattered, bright red foci; or diffusely dark red, heavy, and wet
- Eye: retinal hemorrhage and necrosis
- Meninges: multifocal meningeal thickening, opacity, and edema
- Intestine: multifocal thickening of mucosa with occasional ulceration
- Skin and heart: multifocal hemorrhages
- Testicles: enlarged with wet, tan cut surface
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- The hallmark of disease is cytomegaly (up to 40 um) with characteristic large, dense, intranuclear inclusions surrounded by a halo (owl’s eye cells) that can be in any organ
- Less commonly there are granular, eosinophilic, intracytoplasmic inclusions
- Lesions reported in multiple organs: meninges, brain, spinal cord, spinal and peripheral nerves, arteries, lymph nodes, lung, liver, spleen, skin, heart, kidney, salivary gland, intestine, stomach, and testicle
- Lung is the most frequently affected organ with interstitial pneumonia that is multifocal or diffuse; there are frequently concurrent pathogens(SIV, Pneumocystis carinii)
- Other organs: necrotizing lesions with neutrophilic infiltrates
- CMV replication in endothelial cells may result in vasculitis
- Inclusions are typical of herpesvirus
- Virion measures 120-200 nm in diameter; icosahedral capsid measures 100-110 nm in diameter
- Although the capsid is icosahedral; appears round in images
- Enveloped and non-enveloped forms may be seen in infected cells
ADDITIONAL DIAGNOSTIC TESTS:
- Immunohistochemistry demonstrates early-stage productive infection before histologic lesions are apparent
For intranuclear inclusions with a degree of cytomegaly:
- Often asymptomatic in healthy adults; affects neonates and immunosuppressed animals
- Very large intranuclear inclusions are deeply basophilic, "smudgy", and are not surrounded by a clear halo
- B Virus or Cercopithecine Herpesvirus 1 (Alphaherpesvirus)
- Mild clinical presentation - oral and/or mucocutaneous vesicles or ulcers in macaques
- Zoonotic; may result in fatal encephalitis in humans
- Simian Virus 40 (Polyomavirus)
- Type II pneumocytes with prominent basophilic, "glassy" (clear) intranuclear inclusion bodies; bronchial and bronchiolar epithelium unaffected
Cytomegaloviruses are species specific
- Swine - Porcine Herpesvirus 2 (Betaherpesvirus):
- Large inclusions in the mucus gland of the turbinate mucosa (Inclusion Body Rhinitis), as well as in the lacrimal and salivary gland, and renal tubular epithelium
- Non-fatal form: non-suppurative, necrotizing rhinitis in piglets up to 10 weeks old usually confined to nasal mucosa
- Fatal form: disseminated, congenital infection; can result in abortion
- Guinea pig - Caviid Herpesvirus I (Betaherpesvirus)
- Widespread; up to 70-80% of guinea pigs infected; not clinically significant
- Tissues affected include the salivary gland and lung
- Model for Human CMV due to similarities in virus and placenta
- Mouse Cytomegalovirus - Muromegalovirus (Betaherpesvirus)
- Common in wild mice; uncommon in laboratory animals
- Major tissue affected is salivary gland
- Both intranuclear and intracytoplasmic inclusions in salivary glands
- Rat Cytomegalovirus
- Common in wild rats; uncommon in laboratory animals
- Major tissues affected are salivary and lacrimal glands
- Both intranuclear and intracytoplasmic inclusions in salivary glands
- Horse - Equine Herpesvirus 2 (Gammaherpesvirus)
- Recovered from nasal swabs of 70% of horses; causes clinically inapparent infection
- Cattle - Bovine Cytomegalovirus
- Isolated from both healthy and diseased cattle; role in disease unknown
- Hamster – Cricetid Herpesvirus-1
- Subclinically infected Chinese hamsters
- Both intranuclear and intracytoplasmic inclusions with cytomegaly in acinar epithelium of the submaxillary glands in salivary glands
- African Hedgehog – Betaherpesvirus
- Cytomegalic cells with intranuclear inclusion bodies in the salivary gland termed Cytomegaic inclusion disease (CID)
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