JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
March 2025
C-V05
Signalment (JPC #4048428): 2 year, 8 month, male Asian elephant (Elephas maximus)
HISTORY: Presented with partial anorexia, decreased alertness, mild lameness of left forelimb, and focal, 2 cm diameter ulcer on the hard palate. Treatment initiated with daily flunixin. No significant improvement or deterioration. Found dead approximately 72 hours later.
HISTOPATHOLOGIC DESCRIPTION: Liver: Affecting 60% of this section are multifocal to coalescing areas of hemorrhage, fibrin, and edema, primarily within the centribulobular regions. In these areas of hemorrhage, sinusoidal architecture is disrupted and hepatocytes are surrounded, separated, and individualized by the hemorrhage. Hepatocytes are frequently either: shrunken, with a hypereosinophilic cytoplasm and karyolysis (necrosis), or swollen with a vacuolated nucleus (degeneration). Admixed are variable numbers of heterophils, lymphocytes, and rare histiocytes. Multifocally, sinusoidal endothelial cells have enlarged nuclei (10-15 µm) that contain a single, basophilic, intranuclear 3-5 µm inclusion body surrounded by a clear halo and peripheralized chromatin.
Heart: Affecting 70% of the myocardium are multifocal to coalescing areas of hemorrhage, fibrin, and edema that surround, separate, and individualize cardiac myocytes. These myocytes occasionally demonstrate one of two changes: shrunken with hypereosinophilic sarcoplasm and a pyknotic nucleus (necrosis), or swollen, vacuolated sarcoplasm with a vesiculate nucleus (degeneration). Rarely in these areas of hemorrhage or immediately adjacent there are endothelial cells with enlarged nuclei (10-15 µm) that contain a single, basophilic, intranuclear 3-5 µm inclusion body that peripheralizes the chromatin. Occasionally inflammatory infiltrates composed of lymphocytes, histiocytes, and fewer plasma cells and heterophils, are present within areas of hemorrhage.
MORPHOLOGIC DIAGNOSIS: 1. Liver: Hemorrhage, centrilobular, acute, multifocal to coalescing, severe, with hepatocellular necrosis and degeneration and basophilic intranuclear viral inclusions.
2. Heart: Hemorrhage, acute, diffuse, severe, with multifocal cardiomyocyte degeneration and necrosis and rare endothelial basophilic intranuclear viral inclusions.
ETIOLOGY: Elephant endotheliotropic herpesvirus-1
ETIOLOGIC DIAGNOSIS: Herpesviral hepatic and myocardial hemorrhage
GENERAL DISCUSSION:
- Elephant endotheliotropic herpesvirus (EEHV) is a double-stranded, DNA, betaherpesvirus in the genus Proboscivirus; causative agent of EEHV hemorrhagic disease (EEHV-HD)
- Multiple strains exist, and different strains are associated with African vs. Asian elephants
- Asian – EEHV1a, EEHV1b, EEHV4, and EEHV5
- African – EEHV2, EEHV3, EEHV6, and EEHV7
- Infection is nearly ubiquitous in all adult elephants (both African and Asian); affects both wild and zoo animals; susceptibility to disease is poorly understood
- Infection in susceptible individuals manifests as acute, multisystemic hemorrhagic syndrome that is often fatal.
- Disease in Asian elephants typically occurs in animals 1-8 years of age; primarily EEHV1a; significant cause of mortality in young; can be shed in trunk secretions of clinically healthy individuals
- Disease in African elephants typically associated with EEHV2
- Rarely, cross-species infection has occurred so co-housing of African and Asian elephants is a risk factor
- In healthy adult African elephants additional syndromes associated with EEHV2, EEHV3, EEHV6, and/or EEHV7 infection include:
- Non-lethal, subclinical cutaneous nodular papillomas; frequently inverted, with intranuclear viral inclusions
- Nodular lymphoid hyperplasia in lung and distal urogenital mucosa without intranuclear viral inclusions
PATHOGENESIS:
- Pathogenesis is poorly understood, particularly factors related to disease-susceptibility; EEHV-HD develops when primary infection of the calf is not controlled by normal innate cellular and humoral immune response.
- EEHV is endotheliotropic, so viral infection results in endothelial damage and vascular compromise with subsequent hemorrhage, edema, and coagulopathy (hypocoagulability and/or DIC)
- Mechanism of endothelial cell damage is not yet determined, but direct viral injury is most likely with increase vascular permeability
- Capillary endothelium appears to be primary site of damage; however, EEHV3 has been reported to cause damage in larger vessels
- Cardiac vasculature is severely affected in most cases
- Death is hypothesized to be due to cardiac and circulatory collapse
TYPICAL CLINICAL FINDINGS:
- Cyanosis/hemorrhage of the tongue
- Edema of the trunk, head, neck, limbs, and dependent abdomen
- Petechia or ecchymosis
TYPICAL GROSS FINDINGS:
- Multifocal petechial to ecchymotic hemorrhages of the tongue, heart, lung, and serosal surfaces of visceral organs
- Lingual cyanosis
- Pericardial effusion
- Widespread edema
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Microhemorrhages with interstitial edema
- Low levels of inflammation, primarily neutrophils and macrophages/lymphocytes
- Endothelial cell hypertrophy and/or necrosis
- Endothelial cell basophilic to amphophilic intranuclear inclusions with variable margination of nuclear chromatin
- Vascular mural edema and fibrinoid degeneration; microthrombosis
- Different strains have different tissue predilections, but EEHV1 (the most common pathogenic strain) primarily results in lesions in the heart, tongue, and liver
- Ultrastructurally, endothelial cell intranuclear inclusions contain 70-90 nm hexagonal herpesviral particles.
ADDITIONAL DIAGNOSTIC TESTS:
- PCR
- ISH
DIFFERENTIAL DIAGNOSIS:
- Encephalomyocarditis virus (ECMV, C-V02) is the primary differential – ECMV results in more pronounced myocardial degeneration and necrosis with less hemorrhage and no viral inclusions
- In the absence of intranuclear inclusions, differentials include bacterial sepsis, other systemic infections, or coagulopathies (e.g., toxins, autoimmune mediated, and parasitic)
COMPARATIVE PATHOLOGY:
Other Betaherpesviruses of veterinary importance:
- Primarily of the genus Cytomegalovirus; tend to have a limited host-range, have a more chronic course of disease, slowly cytolytic, induces cytomegaly, latent infection persists in lymphoreticular and kidney cells, spreads through body secretions, and immune response is usually effective so immunodeficient or immunosuppressed animals are more likely to develop disease; recrudescence occurs due to stressors such as infections and immunosuppressive drugs.
- Pigs: Suid herpesvirus-2 , inclusion body rhinitis, (P-V13) causes mild to severe nonsuppurative necrotizing rhinitis in neonates; large basophilic intranuclear inclusions in epithelium; if pregnant sows are infected may cause small litters, fetal mummification, or stillborn piglets
- NHPs: Immune response is generally effective, so infection of immunocompetent animals does not result in disease; symptoms depend on specific anatomic sites affected; necrotizing vasculitis is seen frequently (betaherpesviral nephritis U-V04, betaherpesviral pneumonia P-V12)
- Cercopithicine herpesvirus-5 – African green monkey CMV
- Macacine herpesvirus-3 – Rhesus monkey CMV
- Panine herpesvirus-2 – Chimpanzee CMV
- Aotine herpesvirus-1/3 – Aotus CMV
- Guinea pigs: Caviid herpesvirus 2 (guinea pig cytomegalovirus, D-V12) causes lymphoplasmacytic sialoadenitis with eosinophilic intranuclear viral inclusions. Also may affect kidney and liver
- Mice:
- Mouse cytomegalovirus (MCMV) causes cytomegalic inclusion disease with a tropism for salivary glands; oronasal or direct contact transmission and is excreted in the saliva, tears, urine, and semen
- Mouse thymic virus (MTV) causes the formation of intranuclear inclusion bodies and necrosis of thymocytes and affects infant mice; salivary tissue also affected
- Rat: Rat cytomegalovirus (RCMV) is common in wild rats; infects the salivary and lacrimal glands causing cytomegaly with both intracytoplasmic and intranuclear inclusion bodies
- Hamsters: Cricetid Herpesvirus (CrHV-1) affects Chinese hamsters; infects the salivary gland
- Little brown bat: Cytomegalovirus has been detected in acinar cells of the submandibular salivary gland of two captive Myotis lucifugus
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