JPC SYSTEMIC PATHOLOGY
SIGNALMENT (AFIP Accession #1953401): Beaver (Castor canadensis)
HISTORY: Multiple beavers died in one stream without showing prior clinical signs.
HISTOPATHOLOGIC DESCRIPTION: Liver: Multifocally and randomly replacing approximately 40% of the hepatic parenchyma, there 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 often are dissociated from hepatic cord and have hypereosinophilic cytoplasm and pyknotic nuclei (necrosis). Hepatocytes often contain granular, yellow-brown or green-brown cytoplasmic pigment (hemosiderin, lipofuscin or bile). Within multiple central veins and portal vessels, when areas of lytic necrosis are directly adjacent to vessels, vessel walls, including all vascular tunics, are effaced and replaced by necrotic debris, fibrin, hemorrhage and degenerate neutrophils (vasculitis and vascular necrosis). Occasionally, fibrin thrombi 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)
- Highly infectious zoonotic disease; endemic worldwide; most prevalent in the western US
- Most severe disease manifestations 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)
- Small, pleomorphic, gram-negative, non-spore forming, facultative aerobe, intracellular coccobacillus
- 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).
- Infection may be common in animals; disease is not
- 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):
- tularensis ssp. tularensis: Jellison type A; most virulent, especially for laboratory rabbits; North America; wildlife reservoir; tick-rabbit infection cycle
- tularensis ssp. holarctica, formerly ssp. palaearctica: Jellison type B; less virulent; Europe, Asia and North America; waterborne disease of rodents
- tularensis ssp. mediaasiatica: Central Asia
- tularensis ssp. novicida, formerly Francisella novicida: North America
- Organism enters host via percutaneous inoculation by arthropods, penetration of skin or mucous membranes, ingestion (including predation and carcass contamination of water), and inhalation; one report implies zoonotic transmission through bird inflicted wounds
- Organisms are phagocytized by macrophages à multiply à disseminate via lymphatics à invade and damage vascular endothelium à vasculitis/thrombosis
- Necrotic foci in liver, spleen, lymph nodes, lung, and bone marrow from thrombotic development
- 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. The pathogenesis of pneumonic tularemia in the female F344 rat model appears to replicate the disease in humans.
- 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
- Virulence factor: Francisella DnaK inhibits tissue nonspecific alkaline phosphatase
- Little is known about other virulence factors of this bacteria; tularensis is not consistently documented to produce toxins
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 and lung with occasional caseous granuloma formation
- Hemorrhagic enteritis with ulcerations of the Peyer’s patches has been reported
- Purulent lymphadenitis
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Liver, lymph node, spleen, kidneys: Multifocal to coalescing areas of lytic necrosis that progresses to purulent to pyogranulomatous to caseous inflammation surrounded by a few lymphocytes, degenerate neutrophils and macrophages
- Vasculitis and thrombosis
- +/- Lymphoid cortical necrosis
- Bacteria within lesions and intracellular bacteria in histiocytes
ADDITIONAL DIAGNOSTIC TESTS:
- Culture – gold standard
- Serology – microagglutination test or competitive ELISA
- Fluorescent antibody
- PCR – 16S rRNA
For hepatic necrosis/necrotizing hepatitis in rodents and lagomorphs:
- Tyzzer’s disease (Clostridium piliforme): Intracellular gram-negative to gram-variable bacillus; multifocal necrosis in the liver, spleen and intestine; intracellular bacilli stain positive with Warthin-Starry 4.0 and similar silver stains
- Salmonella spp.: Gram-negative bacilli; “paratyphoid nodules” (multifocal to coalescing areas of necrosis progressing to microgranulomas)
- Listeria monocytogenes: Gram-positive coccobacillus; multifocal necrosis in the liver +/- other organs with septicemia; differentiate with a Gram stain
- Toxoplasma gondii: Multifocal coagulative necrosis in the liver and other organs; intralesional tachyzoites
- Yersinia pseudotuberculosis and enterocolitica: Multifocal hepatic necrosis with large, lobulated colonies of gram-negative coccobacilli
- Mouse Hepatitis Virus (Coronavirus): Multifocal hepatic necrosis with syncytia
- Idiopathic hepatic necrosis of guinea pigs: Multifocal to coalescing hepatic coagulative necrosis
- Corynebacterium kutscheri: Solitary or multiple hepatic abscesses and/or necrosis
- 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
- 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. Vesiculopapular rash. 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 in cats it is recognized by the presence of 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, yet has been reported in a hamster 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
- Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: John Wiley and Sons, Inc; 2016: 185-186, 278.
- Brown VR, Adney DR, Bielefeldt-Ohmann H, et al. Pathogenesis and immune responses of Francisella tularensis strains in wild-caught cottontail rabbits (Sylvilagus spp.). J Wildl Dis. 2015;51(3):564-575.
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