JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2317372): Female rhesus monkey
HISTORY: This animal was experimentally infected six days before death.
HISTOPATHOLOGIC DESCRIPTION: Liver: There is marked, diffuse midzonal necrosis of hepatocytes characterized by disorganized hepatic chords composed of shrunken, hypereosinophilic cells with pyknotic nuclei or abundant, eosinophilic, granular to globular cellular and karyorrhectic debris. There are scattered intracytoplasmic, intensely eosinophilic (acidophilic), irregularly round, 5-25 um diameter inclusions (Councilman bodies or cytosegrosomes). Hepatocytes adjacent to areas of necrosis are swollen with pale vacuolated cytoplasm (degeneration). Remaining centrilobular and periportal hepatocytes have slightly basophilic vacuolated cytoplasm, vesiculate nuclei, and a prominent central nucleolus. Scattered throughout the hepatic parenchyma are few neutrophils, lymphocytes, plasma cells and macrophages. There are few periportal and centrilobular aggregates of lymphocytes, macrophages and fewer neutrophils.
MORPHOLOGIC DIAGNOSIS: Liver: Hepatocellular necrosis and degeneration, midzonal, diffuse, severe, with acidophilic Councilman bodies, rhesus monkey (Macaca mulatta), non-human primate.
ETIOLOGIC DIAGNOSIS: Flaviviral hepatocellular necrosis
CAUSE: Yellow fever virus (flavivirus)
CONDITION: Yellow Fever
- Yellow fever is a zoonotic disease of humans and nonhuman primates, characterized by widespread midzonal necrosis resulting in icterus
- The causative agent is an RNA flavivirus, which is transmitted via mosquitoes (Aedes spp., Haemagogus spp., Sabethes spp.) in tropical areas of Africa, Central and South America
- Severity of disease varies, with subclinical infections in Old World monkeys and clinical disease with high mortality in New World monkeys (howl monkeys, spider monkeys, and squirrel monkeys)
- Causes hemorrhagic fever syndrome in nonhuman primates and humans in tropical areas
- Asian primates are highly susceptible to infection and are considered to be a good model for the human disease
- Two distinct cycles of transmission
- Urban: Cycles between humans and Aedes aegypti mosquitoes
- Sylvatic: Cycles between forest primates and canopy mosquitoes (Aedes in Africa and Haemagogus spp. in Americas); incidental human infection (urban cycle)
- Wild hosts that support the sylvatic cycle: baboons, mangabeys, chimpanzees, red colobus monkeys, African green monkeys, and Patas monkeys
- Initial virus replication at bite site or in draining lymph nodes > macrophages take up virus > viremia > replication throughout RE system > spread to parenchymal tissues
- Cytotoxic viral replication in hepatocytes is the primary cause of clinical disease
- Hemorrhage occurs because of DIC secondary to hepatic injury
- There is evidence of viscerotropism and neurotropism in some strains; viscerotropic effects cause most of the clinical signs
TYPICAL CLINICAL FINDINGS
- Early signs include fever, nausea, vomiting
- In severe cases, jaundice and bleeding diathesis with hepato-renal involvement are common
TYPICAL GROSS FINDINGS
- Icterus; soft, friable, greasy, yellow liver
- Visceral organs are hemorrhagic, necrotic, and bile stained
TYPICAL LIGHT MICROSCOPIC FINDINGS
- Liver : widespread midzonal hepatocellular necrosis
- Councilman bodies (also known as cytosegrosomes or acidophilic bodies; 5-25 um eosinophilic round to oval intracytoplasmic inclusions; not viral particles but apoptotic or necrotic hepatocytes); suggests viral hepatitis but not specific for yellow fever
- Rarely, nuclei may contain inclusion bodies (Torres bodies) composed of histones, lipoproteins, and amino acids, not viral particles; most numerous acutely; more common in monkeys than humans
- Fatty degeneration of remaining hepatocytes
- Kupffer cells may be enlarged and vacuolated (usually occurs prior to hepatocyte necrosis)
- Few or no inflammatory cells present
- Kidney : acute tubular necrosis and fatty change secondary to hypoxia
- Necrosis of lymphoid follicle germinal centers in the spleen, lymph node, tonsils, and Peyer's patches
Hemorrhagic fever viruses:
- Simian hemorrhagic fever virus (arterivirus)(H-V04): Causes a highly infectious, fatal disease in macaques with widespread hemorrhages, lymphoid depletion and necrosis, and thymic cortical necrosis
- Kyasanur forest disease virus (flavivirus): Lesions in langurs and bonnet macaques include multifocal hepatocellular necrosis and hemorrhage in adrenal glands, brain, kidney, and lung
- Filovirus (H-V12): Two distinct viruses, Ebola and Marburg; an epidemic of Marburg virus caused hemorrhagic fever in laboratory workers preparing cell lines from African green monkey tissue; Ebola causes sporadic hemorrhagic disease in Zaire and Sudan; lesions are essentially the same as simian hemorrhagic fever with the addition of multifocal hepatic and adrenal gland necrosis and large amphophilic intracytoplasmic viral inclusion bodies; there may be mild interstitial pneumonia
- Animal model: Golden hamster - clinical and pathologic changes very similar to those described in experimentally infected macaques and in fatal human cases of yellow fever
- Other flaviviruses of veterinary significance:
- Japanese encephalitis virus: Encephalitis in various mammals
- Wesselsbron virus: Abortion in sheep
- Louping ill: Tick-borne encephalitis in sheep
- West Nile virus: Extensive mortality in birds and fatal encephalitis in humans and horses
- Usutu virus: Closely related to West Nile virus; has recently emerged in wild and zoo birds in Central Europe
- Other flaviviruses that affect humans
- Murray Valley encephalitis virus
- St Louis encephalitis virus
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