JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
August 2021
D-B14

SIGNALMENT (JPC #1953401):  Beaver (Castor canadensis)

 

HISTORY:  Multiple beavers died in one stream without showing prior clinical signs.

 

HISTOPATHOLOGIC DESCRIPTION:  Liver: Multifocally and randomly replacing 40% of the hepatic parenchyma are numerous variably sized (up to 1mm in diameter) areas of lytic necrosis characterized by abundant eosinophilic cellular and karyorrhectic debris admixed with moderate numbers of degenerate neutrophils and fibrin.  Heptocytes at the margins of the areas of lytic necrosis are often dissociated from hepatic cords and have hypereosinophilic cytoplasm and pyknotic nuclei (single cell death).  Hepatocytes often contain granular, yellow-brown, or green-brown cytoplasmic pigment (hemosiderin, lipofuscin, or bile).  Within and directly adjacent to areas of lytic necrosis, all vascular tunics of multiple central veins and portal blood vessels are effaced and replaced by necrotic debris, fibrin, hemorrhage, degenerate neutrophils, and necrotic cellular debris (necrotizing vasculitis). Occasionally, fibrin thrombi variably occlude vessels.  Multifocally, portal areas are minimally expanded by low to moderate numbers of lymphocytes, plasma cells, neutrophils, and macrophages.

 

MORPHOLOGIC DIAGNOSIS:  Liver:  Hepatitis, necrotizing, acute, multifocal and random, moderate, with necrotizing vasculitis and fibrin thrombi, beaver (Castor canadensis), rodent.

 

ETIOLOGIC DIAGNOSIS:  Hepatic francisellosis

 

CAUSE:  Francisella tularensis

 

SYNONYMS:  Tularemia, Rabbit Fever, Deerfly Fever, O’Hara’s Disease (Japan)

 

GENERAL DISCUSSION:

• Small, pleomorphic, gram-negative, non-spore forming, aerobe, facultative intracellular coccobacillus
• Highly infectious zoonotic disease; endemic worldwide; most prevalent in the western US
• Disease manifests most severely in rodents, lagomorphs and humans; reported in over 125 species of mammals, birds, reptiles, and amphibians
• The organism is abundant in nature as an infection of many species of rodents
• Transmitted by ticks (Dermacentor variabilis, Amblyomma americanum, and andersoni), which pass the infection trans-stadially and transovarially and act as reservoirs, and by other arthropods (mosquitoes, deerfly)
• Reported that tularemia is a relevant cause of death in free ranging wild brown hares, with the most likely ports of entry for the bacteria being the respiratory and digestive tract (lesions resembling those in humans)
• Since tularemia is not always easily detectable on gross inspection, there is a risk for people handling hares and dogs fed uncooked material from infected hares
• Four subspecies (biovars):
  • F. tularensis ssp. tularensis: Jellison type A; most virulent, especially for laboratory rabbits; North America; wildlife reservoir; tick-rabbit infection cycle
  • F. tularensis ssp. holarctica, formerly ssp. palaearctica: Jellison type B; less virulent; Europe, Asia and North America (N. hemisphere); aquatic species (beavers, muskrats)
  • F. tularensis ssp. mediaasiatica: Central Asia
  • F. tularensis ssp. novicida, formerly Francisella novicida: North America

PATHOGENESIS:

• Organism enters host via percutaneous inoculation by arthropods, penetration of skin or mucous membranes, ingestion (including predation and carcass contamination of water), and inhalation
• Organisms are phagocytized by macrophages à multiply à disseminate via lymphatics à invade and damage vascular endothelium à vasculitis/thrombosis
• Occasional caseating granuloma formation in older lesions or chronic infections (mistaken for tuberculosis)
• Disease susceptibility varies among species:
  • Rodents and lagomorphs: Most susceptible; septicemia; Sprague-Dawley rats are more resistant to disease than Fischer 344 rats  
  • Other herbivores and birds: Susceptible; low mortality (fatalities most common in sheep with heavy tick infestation and foals)
  • Carnivores: Least susceptible; rarely clinical disease but it may be under-diagnosed
• Cell immunity is important in defense against this intracellular organism

 

TYPICAL CLINICAL FINDINGS:

• Lagomorphs and rodents: Usually found dead or moribund; weakness, pyrexia, lymphadenopathy

 

TYPICAL GROSS FINDINGS:

• Numerous pinpoint to small (2 mm to 1 cm) white foci in the enlarged liver, spleen, lymph nodes, and kidneys, less commonly in the heart, lung, and bone marrow, with occasional caseous granuloma formation
• Hemorrhagic enteritis with ulcerations of the Peyer’s patches
• Purulent lymphadenitis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Liver, lymph node, spleen, kidneys: Multifocal to coalescing areas of lytic necrosis that progress to purulent to pyogranulomatous to caseous inflammation surrounded by a few lymphocytes, degenerate neutrophils, and macrophages
• Vasculitis and thrombosis
• +/- Lymphoid cortical necrosis (spleen, thymus, LN, GALT)
• Bacteria within lesions and intracellular bacteria in histiocytes (difficult to see on H&E)

 

ADDITIONAL DIAGNOSTIC TESTS:

• Culture – gold standard
• Serology – microagglutination test or competitive ELISA
• Fluorescent antibody
• Immunohistochemistry
• PCR – 16S rRNA

 

DIFFERENTIAL DIAGNOSIS:

For hepatic necrosis/necrotizing hepatitis in rodents and lagomorphs:

• Tyzzer’s disease (Clostridium piliforme, D-B06): Stacked sheaves of intracellular gram-negative to gram-variable bacilli; multifocal necrosis in the liver, spleen, and intestine; intracellular bacilli stain positive with Warthin-Starry 4.0 and similar silver stains
• Salmonella spp. (D-B01): Gram-negative bacilli; “paratyphoid nodules” (multifocal to coalescing areas of necrosis progressing to microgranulomas)
• Listeria monocytogenes (N-B04): Gram-positive facultative intracellular coccobacillus; multifocal necrosis in the liver +/- other organs with septicemia; differentiate with a Gram stain
• Toxoplasma gondii (P-P01, N-P02, F-P01, R-P01): Multifocal coagulative necrosis in the liver and other organs; intralesional tachyzoites
• Yersinia pseudotuberculosis and enterocolitica (D-B11): Multifocal hepatic necrosis with large, lobulated colonies of gram-negative coccobacilli
• Mouse Hepatitis Virus (Coronavirus, D-V04): Multifocal hepatic necrosis with syncytia
• Idiopathic hepatic necrosis of guinea pigs: Multifocal to coalescing hepatic coagulative necrosis
• Corynebacterium kutscheri (P-B05): Solitary or multiple hepatic abscesses and/or necrosis

 

COMPARATIVE PATHOLOGY:

• Zoonotic; humans frequently infected by ticks or contact with infected animals, especially rabbits, rodents and sheep; people have also been infected by cat bites and scratches
• Hares: Urinary tract and mammary glands are important routes of shedding (Hestvik, et. al, 2017)
• Six syndromes in humans and NHP: Ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, and typhoidal
• Sheep: Late term abortions; listlessness and death in lambs; anemia (due to heavy tick infestation) and secondary pneumonia are common; sheep also exhibit high fever, stiffness of gait, depression, diarrhea, and hyperpnea
• Foals: Systemic and febrile illness with hepatosplenomegaly and enlarged kidneys
• Non-human primates: Pyrexia, tachycardia, increased systolic and mean arterial blood pressure; oropharyngeal lesions including granulomatous pharyngitis and tonsillitis; and ulcerative glossitis; recent outbreaks associated with contact with rabbits or rodents that recently experienced a large die-off
• Dogs: Dogs are highly resistant to the disease; most dogs develop short periods of listlessness and low-grade fever; lymphadenomegaly, uveitis, and conjunctivitis are rather rare
• Cats: Tularemia in cats is a severe systemic disease with various manifestations depending on the dissemination or localization; grossly there are miliary white foci 2 mm or more in diameter in the liver, spleen, and lymph nodes; mild illness with lymphadenopathy and pyrexia to severe overwhelming infection and death
• Hamsters: Tularemia is rare in laboratory hamsters, reported a breeding colony resulting in 100% mortality; hamsters were hunched, had ruffled fur, and died within 48 hours; gross lesions included mottled and hemorrhagic lungs, pale and swollen livers, and splenomegaly

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4^th Ames, IA: John Wiley and Sons, Inc; 2016: 185-186, 278.
2. Brown DL, Van Wettere AJV, Cullen JM. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:442, 444.
3. Delaney MA, Treuting PM and Rothenburger JL. Lagomorpha and Rodentia. In: Terio K, McAloose D, Leger J, ed. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 492, 509.
4. Hestvik G, Uhlhorn H, Södersten F,et al. Tularaemia in European Brown Hares (Lepus europaeus) and Mountain Hares (Lepus timidus) Characterized by Histopathology and Immunohistochemistry: Organ Lesions and Suggestions of Routes of Infection and Shedding. J Comp Pathol. 2017;157(2-3):103-114.
5. Lowenstine LJ, McManamon R and Terio KA. Apes. In: Terio K, McAloose D, Leger J, ed. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 396.
6. Matz-Rensing K and Lowenstine LJ. New World and Old World Monkeys. In: Terio K, McAloose D, Leger J, ed. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 358.
7. McAloose D and Stalis IH. Prosimians. In: Terio K, McAloose D, Leger J, ed. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 335.
8. Origgi FC, Pilo P. Francisella Tularensis Clades B.FTN002-00 and B.13 Are Associated With Distinct Pathology in the European Brown Hare (Lepus europaeus). Vet Pathol. 2016;53(6):1220-1232.
9. 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; 2012:127-128.
10. Valli VEO, Kiupel M, Bienzle D. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: 184-186.      

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