U-V04 (NP)

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 rarely a 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 µm in diameter, amphophilic to basophilic intranuclear inclusion body surrounded by a clear halo. 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)

GENERAL DISCUSSION:

Cytomegalovirus is in the family Betaherpesviridae

Highly host-specific viruses of humans, non-human primates, pigs, horses, mice, guinea pigs and other animals
In non-human 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; infection is lifelong
Transplacental infection may result in congenital cytomegalic inclusion disease and CNS damage due to intrauterine encephalitis

PATHOGENESIS:

In SIV infected macaques, opportunistic infections typically develop when absolute CD4 T-cell count drops below 300-400 cells/mm^3.
Primary infection > viremia > latent infection in multiple tissues with periodic viral shedding > reactivation, immunosuppression, and pregnancy > disseminated disease to brain, LN, liver, spleen, kidney, small intestine, nervous system, arteries
Transmission: Urine, saliva, semen, blood, and milk
Viral glomerulitis is usually mild and results from viral replication in glomerular capillary endothelium
Latent infections tend to persist in glandular tissue, lymphoreticular cells, and kidneys rather than neurons (in contrast to alphaherpesviruses)

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, etc.
In non-human primates, the lung is the most commonly affected organ, with related clinical signs

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, raised hyperemic papules
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 µm) with characteristic large, dense, intranuclear inclusions surrounded by a halo (owl’s eye cells) that can be in any organ; in kidney, INIBs usually within glomerular capillary endothelium
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

ULTRASTRUCTURAL FINDINGS:

Inclusions are typical of herpesvirus

Virion measures 120-200 nm in diameter; icosahedral capsid measures 100-110 nm

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

DIFFERENTIAL DIAGNOSIS:

For intranuclear inclusions with a degree of cytomegaly:

Adenovirus

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 with 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

COMPARATIVE PATHOLOGY:

Cytomegaloviruses are species specific

Swine – Suid herpesvirus 2 (Betaherpesvirus):
- Cause of inclusion body rhinitis; large inclusions in the mucus gland of the turbinate mucosa, 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, small litters, mummified fetuses, or stillborn/weak piglets in pregnant sows; severe debilitating disease or death in piglets
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

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 cytomegalic inclusion disease (CID)

References:

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