JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
May 2022
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 90% 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, multifocal to coalescing, acute, severe, with hepatocellular necrosis and degeneration and basophilic intranuclear inclusion bodies.

2. Heart: Hemorrhage, diffuse, acute, severe, with multifocal cardiomyocyte degeneration and necrosis and rare endothelial basophilic intranuclear inclusion bodies.

 

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
• 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); susceptibility to disease is poorly understood
• Disease in Asian elephants typically occurs in animals 1-8 years of age; primarily EEHV1a
• 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 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 is endotheliotropic, so viral infection results in endothelial damage and vascular compromise with subsequent hemorrhage, edema, and coagulopathy
• Mechanism of endothelial cell damage is not yet determined, but direct viral injury is most likely
• Capillary endothelium appears to be primary site of damage; however, EEHV3 has been reported to cause damage in larger vessels

 

TYPICAL CLINICAL FINDINGS:

• Cyanosis/hemorrhage of the tongue
• Edema of the trunk, head, neck, limbs, and dependent abdomen
• Coagulopathy

 

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 heterophils and macrophages/lymphocytes
• Endothelial cell hypertrophy and/or necrosis
• Endothelial cell basophilic to amphophilic intranuclear inclusions with margination of nuclear chromatin
• Different strains have different tissue predilections, but EEHV1 (the most common pathogenic strain) primarily results in lesions in the heart, tongue, and liver

 

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

 

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, and immune response is usually effective so immunodeficient or immunosuppressed animals are more likely to develop disease
• Pigs: Suid herpesvirus-2 (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

 

REFERENCES:

1. Bauer KL, Latimer E, Finnegan M. Long-term, intermittent, low-level elephant endotheliotropic herpesvirus 1A viremia in a captive Asian elephant calf. J Vet Diagn Invest. 2018;30(6):917-919.
2. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 537.
3. Garner MM, et al. Clinico-pathologic features of fatal disease attributed to new variants of endotheliotropic herpesviruses in two Asian elephants (Elephas maximus). Vet Pathol. 2009;46(1):97-104.
4. Kochakul V, et al. Development of in situ hybridization for detection of elephant endotheliotropic herpesvirus in Asian elephants. J Vet Diagn Invest. 2018;30(4):628-632.
5. Landolfi JA, Terrell SP. Proboscidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018:420-423.
6. Long SY, Latimer EM, Hayward GS. Review of elephant endotheliotropic herpesviruses and acute hemorrhagic disease. ILAR J. 2016;56(3):283-296.
7. Ortega J, et. al. Acute death associated with freundii infection in an African elephant (Loxodanta africana). J Vet Diagn Invest. 2015;27(5):632-636.
8. Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016: 433.
9. Wachtman L, Mansfield K. Viral disease of non-human primates. In: Abee CR, Mansfield K, Tardif S., Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. San Diego, CA: Elsevier, Inc.; 2012:19-20.
10. Zachariah A, et al. Fatal herpesvirus hemorrhagic disease in wild and orphan Asian elephants in southern India. J Wildl Dis. 2013;49(2)381-393.

Click the slide to view.

---