JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

November 2024

D-V23 (NP)

 

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 characterized by disorganized hepatic cords and shrunken, hypereosinophilic hepatocytes with a pyknotic nucleus (necrosis/apoptosis) and abundant, eosinophilic, granular to globular, cellular debris and scant basophilic karyorrhectic debris. Hepatocytes adjacent to areas of necrosis are swollen with pale, discretely microvacuolated cytoplasm (lipid-type vacuolar change or have lacy cytoplasm (glycogen vacuolar change). Vacuolated hepatocytes often have vesiculate nuclei and a prominent central nucleolus. Within periportal regions and scattered randomly throughout the hepatic parenchyma there are few lymphocytes, plasma cells, macrophages, and fewer neutrophils.

 

MORPHOLOGIC DIAGNOSIS: Liver: Hepatocellular necrosis, midzonal, diffuse, severe, with lipid-type hepatocellular degeneration, rhesus monkey (Macaca mulatta), non-human primate.

 

ETIOLOGIC DIAGNOSIS: Flaviviral hepatocellular necrosis

 

CAUSE: Yellow fever virus (flavivirus)

 

CONDITION: Yellow Fever

 

GENERAL DISCUSSION

• 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 (titi monkeys [Fernandes, Vet Pathol. 2021], howler monkeys, spider monkeys, and squirrel monkeys), less severe in capuchin monkeys, and even less severe in marmosets (Santos, Vet Pathol. 2020)
• 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

 

PATHOGENESIS

• Two distinct cycles of transmission

• Urban: Cycles between humans and Aedes aegypti mosquitoes; incidental human infection (urban cycle)
• Sylvatic: Cycles between forest primates and canopy mosquitoes (Aedes spp. in Africa and Haemagogus spp. in Americas) 

• 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 monocyte-macrophage system > spread to parenchymal tissues
• Cytotoxic viral replication in hepatocytes is the primary cause of clinical disease
• Hemorrhage secondary to hepatic injury: hepatic injury > consumption coagulopathy > DIC > hemorrhage
• 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 
  1. Apoptotic hepatocytes (Councilman bodies); suggests viral hepatitis but not specific for yellow fever 
  2. Rarely, nuclei may contain inclusion bodies (Torres bodies) composed of histones, lipoproteins, and amino acids, not viral particles; most numerous acutely
  3. Fatty degeneration of remaining hepatocytes (lipidosis, lipid-type degeneration)
  4. Kupffer cells may be enlarged and vacuolated (usually occurs prior to hepatocyte necrosis)
  5. 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

 

DIFFERENTIAL DIAGNOSIS

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 
• Filoviruses (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

 

COMPARATIVE PATHOLOGY

Yellow fever virus in other animals:

• 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
• Howler Monkeys (Aloutta sp.) are highly susceptible to YFV infection, more than capuchin monkeys, and marmosets are less affected (Santos, Vet Pathol. 2020)
• Titi Monkeys (Callicebus sp.) are susceptible to YFV infection; severe panlobular hepatic lesions and high viral loads comparable to humans; viral immunolabeling in centrilobular hepatocytes; may be reliable sentinels for surveillance of YFV

 

Other flaviviruses of veterinary significance:

• Japanese encephalitis virus: Encephalitis in various mammals
• Wesselsbron virus (D-V29): Abortion in sheep
• Louping ill: Tick-borne encephalitis in sheep
• West Nile virus (N-V19, C-V04): Extensive mortality in birds and fatal encephalitis in humans and horses
• Usutu virus: Closely related to West Nile virus; has recently (2016-2018 timeframe) emerged in wild and zoo birds in Central Europe

 

REFERENCES:

1.   Fernandes NCCA, Cunha MS, Guerra JM, et. al. Yellow Fever as Cause of Death of Titi Monkeys (Callicebus Spp.). Vet Pathol. 2021;58(4):730-735.
2. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, Ailuridae. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:251.
3. Rensing KM, Lowenstine LJ. New World and Old Word Monkeys. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:353.
4. Santos DOD, de Oliveira AR, de Lucena FP. Histopathologic Patterns and Susceptibility of Neotropical Primates Naturally Infected With Yellow Fever Virus. Vet Pathol. 2020;57(5):681-686.
5. Wachtman L, Mansfield K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol. 2. 2^nd ed. San Diego, CA: Elsevier; 2012:50-51. 

 

Click the slide to view.

---