JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
November 2021
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 hepatocyte with pyknotic nuclei (apoptotic hepatocytes/bodies, acidophil bodies) 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 degeneration).  Remaining centrilobular and periportal hepatocytes have slightly basophilic, discretely microvacuolated cytoplasm, vesiculate nuclei, and a prominent central nucleolus.  Within periportal regions and scattered randomly throughout the hepatic parenchyma are few lymphocytes, plasma cells, macrophages, and fewer neutrophils.

 

MORPHOLOGIC DIAGNOSIS:  Liver:  Hepatocellular necrosis/apoptosis, 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 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
  • Apoptotic bodies: apoptotic hepatocytes (Councilman bodies); 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 (lipidosis, lipid-type degeneration)
  • 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

 

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 ) are highly susceptible to YFV infection, more than capuchin monkeys, and marmosets are less affected (Santos, Vet Pathol. 2020)
• Titi Monkeys (Callicebus ) 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

 

Other flaviviruses that affect humans

• Murray Valley encephalitis virus
• St Louis encephalitis virus
• Dengue virus

 

REFERENCES:

1. Balasuriya UBR, Reisen W, Towner J. Flaviviridae. In: MacLachlan NJ, Dubovi EJ, eds. Fenner’s Veterinary Virology. 5th ed. San Diego, CA: Elsevier; 2017:531-537.
2. Bearcraft WGC. The histopathology of the liver of yellow fever infected rhesus monkeys. J Pathol Bact. 1957:74;295-303.
3. Fernandes NCCA, Cunha MS, Guerra JM, et. al. Yellow Fever as Cause of Death of Titi Monkeys (Callicebus). Vet Pathol. 2021;58(4):730-735.
4. 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.
5. Paules CL, Fauci AS. Yellow fever – once again on the radar screen in the Americas. N Engl J Med. 2017; 376(15):1397-1399.
6. 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.
7. 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.
8. Tesh RB, Guzman H, Travassos da Rosa APA. Experimental yellow fever virus infection in the Golden hamster (Mesocricetus auratus): Virologic, biologic, and immunologic studies. J Inf Dis. 2001:183;1431-1436.
9. Tomori O. Yellow fever: the recurring plague. Critical Reviews in Clinical Laboratory Sciences.  2004:41;391- 428.
10. 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. 2. 2^nd ed. San Diego, CA: Elsevier; 2012:50-51.
11. Xiao S, Zhang H, Guzman H, Tesh RB. Experimental yellow fever virus infection in the Golden hamster (Mesocricetus auratus) II. Pathology. J Inf Dis. 2001:183;1437-1444.

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