JPC SYSTEMIC PATHOLOGY

HEMOLYMPHATIC SYSTEM

April 2024

H-V04

 

Signalment (JPC #2257451): Male rhesus monkey

 

HISTORY: A male rhesus monkey was found dead

 

HISTOPATHOLOGIC DESCRIPTION: Spleen: Diffusely, periarteriolar lymphoid sheaths are pale and surrounded by a rim of hemorrhage, fibrin, and edema. Within white pulp there is fibrin and edema admixed with cellular and karyorrhectic debris (necrosis), apoptotic lymphocytes (lymphocytolysis), tingible body macrophages that often contain intracytoplasmic phagocytosed cellular and karyorrhectic necrotic debris, and few scattered neutrophils. The rim of hemorrhage surrounding periarteriolar lymphoid sheaths is admixed with small amounts of necrotic debris that separates the follicle from the follicular mantle. Diffusely, the red pulp is expanded by abundant fibrin, mild edema, karyorrhectic debris, and few scattered macrophages and neutrophils. Multifocally and transmurally, the tunica muscularis, tunica media, and tunica intima of vessels are disrupted and replaced by abundant fibrin, cellular and karyorrhectic debris, and few neutrophils (vasculitis) with frequent endothelial cell hypertrophy, vacuolation, or detachment (reactivity, degeneration, and necrosis). 

 

MORPHOLOGIC DIAGNOSIS: Spleen, periarteriolar lymphoid sheaths and follicular mantle zone: Lymphoid necrosis, diffuse, moderate, with lymphocytolysis, vasculitis, perifollicular hemorrhage, and extensive fibrin deposition, rhesus macaque (Macaca mulatta), nonhuman primate.

 

ETIOLOGIC DIAGNOSIS: Arteriviral splenitis

 

CAUSE: Simian hemorrhagic fever virus (SHFV)

 

CONDITION: Simian hemorrhagic fever (SHF)

 

GENERAL DISCUSSION:  

• Viral family Arteriviridae, genus simartevirus; an enveloped, single-stranded RNA virus
• Simian hemorrhagic fever virus (SHFV), an arterivirus, is highly contagious and mortality approaches 100% in macaques
• SHFV can naturally infect several species of African nonhuman primates (NHP), including patas monkeys, African green monkeys, vervets, and baboons, which may be persistent carriers without clinical signs and with seronegativity (50% of wild patas had antibodies to SHFV in one study); epizootics occur when macaques are exposed to species that are subclinical carriers

 

 

PATHOGENESIS:

• Initial exposure of the macaque colony is through parenteral inoculation (tattoo machines, reuse of tuberculin needles, biting insects) of infected blood or tissue from carrier animals, then subsequent transmission is through direct contact, aerosol, and fomites, with rapid spread
• Macrophages are the principal target cell (similar to other arteriviruses); macaque macrophages have a unique propensity to support viral growth
• Shock is the underlying cause of death

 

TYPICAL CLINICAL FINDINGS:

• Macaques: Bleeding diathesis (epistaxis, hematuria, melena, ecchymoses, petechiae, subcuticular and retrobulbar hemorrhage) with rapid onset and rapid progression to death (between 5 and 25 days post infection), with fever, depression, dehydration, anorexia, facial edema, photophobia, and cyanosis in terminal stages; may present with sudden death; fetal loss is common
• African monkeys: Typically asymptomatic, but specific pathogenic strains may cause fever, facial edema, dehydration, diarrhea, ataxia, anorexia
• Laboratory findings:
  • Consumption coagulopathy: Increased aPTT, PT, and fibrin degradation products (FDPs); thrombocytopenia
  • Anemia: Decreased hematocrit (HCT), hemoglobin (HGB)
  • Elevated liver enzymes: LDH, GGT, AST, AST is higher than ALT
  • Elevated BUN and creatinine if there is kidney involvement
  • Proteinuria and hematuria

 

TYPICAL GROSS FINDINGS:

• Striking locally extensive congestion, hemorrhage, and necrosis of the proximal duodenum, with sharp demarcation at the pylorus as well as random congestion and hemorrhage throughout the GI tract, liver, renal capsule, retrobulbar tissue, subcutis, myocardium, and lung
• Splenomegaly +/- infarction, with gross absence of white pulp 
• Fibrinous exudates in the lungs and heart, generalized edema

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Macaques: 
  • Spleen: Extensive lymphoid necrosis, with prominent perifollicular hemorrhage and fibrin that often separates the follicle from the follicular mantle; sinuses may be distended by fibrin and plasma; fibrin thrombi
  • Lymphoid tissue: Lymphoid necrosis of germinal centers; thymic cortical necrosis with medullary sparing is unique to SHFV
  • Systemic lesions are consistent with disseminated intravascular coagulation (DIC) including fibrin thrombi in glomeruli, hepatic sinusoids, lung
  • Vasculitis 
  • +/- Lymphohistiocytic meningoencephalitis
  • Absence of hepatic and/or adrenal necrosis (as opposed to Ebola, Marburg, or Kyasanur Forest disease viruses)
• Patas monkeys: Lysis of peritoneal macrophages

 

ADDITIONAL DIAGNOSTICS

• Serological testing: ELISA, IFA
• Virus isolation

 

DIFFERENTIAL DIAGNOSIS:

Splenic perifollicular hemorrhage:

• Filovirus (H-V12): Ebola and Marburg viruses; lesions are essentially the same as SHFV, with the distinguishing features of hepatocellular necrosis and necrosis within the adrenal cortex, and large amphophilic intracytoplasmic inclusion bodies; occasionally there may be interstitial pneumonia
• Flavivirus: Yellow Fever and Kyasanur Forest viruses 
  • Yellow Fever virus (D-V23): Lesions are multifocal hepatocellular necrosis with councilman bodies and fatty degeneration of remaining hepatocytes;  DIC and depletion of vitamin K-dependent clotting factors leads to bleeding diathesis; lymphoid depletion may be prominent
  • Kyasanur Forest virus: Lesions are multifocal hepatocellular necrosis accompanied by hemorrhages within the adrenal gland, brain, kidney, and lung; prominent leukopenia, anemia, and thrombocytopenia
• Bacillus anthracis (anthrax; H-B01): Abundant large bacilli are present

 

Epistaxis:

• Moraxella macacae /Moraxella catarrhalis (formerly known as Branhamella catarrhalis)
• Ebola (especially Ebola Reston)

 

COMPARATIVE PATHOLOGY:

Arteriviruses:

• Equine Viral Arteritis (Equine Arteritis Virus, horse): Viral lysis of endothelial cells, myocytes, and pericytes of small muscular arterioles and venules of multiple organ systems, especially the lungs, resulting in systemic disease with arteritis, abortion, fetal death, and pneumonia in foals; transmission is predominantly through urine, following release of virus from lysed renal tubular epithelium 
• Porcine respiratory and reproductive syndrome (PRRS virus, pig, see P-V25): Systemic disease with reproductive failure in sows, causing abortion, stillbirths, mummified fetuses, birth of weak pigs with increased preweaning mortality, and pneumonia in young pigs
• Lactate dehydrogenase-elevating virus of mice (mouse): Chronic, asymptomatic infection causing elevated levels of certain plasma enzymes (especially LDH); virus tropism for specific macrophages (F4/80+, expressed only on mature macrophages) à depleted subpopulation of macrophages and altered macrophage function à impaired clearance of plasma enzymes (especially LDH) à 5 to 10x elevation of LDH; infection may confound experiments by transiently altering immune response to a variety of antigens

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:25-26.
2. Brady AG, Carville AAL. Digestive System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds.  Nonhuman Primates in Biomedical Research: Diseases. Vol. 2.  2nd ed.  Waltham, MA: Academic Press; 2012:605.
3. Mätz-Rensing K, Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London: Academic Press; 2018:356.
4. Simmons J, Gibson S.  Bacterial and Mycotic Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds.  Nonhuman Primates in Biomedical Research: Diseases. Vol. 2.  2nd ed.   Waltham, MA: Academic Press; 2012:130.
5. Stanton JB, Zachary JF. Mechanisms of Microbial Infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022:258.
6. Wachtman L, Mansfield K.  Viral Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds.  Nonhuman Primates in Biomedical Research: Diseases. Vol. 2.  2nd ed.   Waltham, MA: Academic Press; 2012:38-41, 47-49, 51-52.

 

 

Click the slide to view.

---