JPC SYSTEMIC PATHOLOGY

CARDIOVASCULAR SYSTEM

April 2022

C-F01 (NP)

 

SIGNALMENT (JPC #1376220):  Military working dog, age and gender unspecified

 

HISTORY:  This dog had a thickened pericardium with numerous adhesions.

 

HISTOPATHOLOGIC DESCRIPTION: Pericardium (per contributor): The pericardium is diffusely thickened up to 4mm by fibrosis and fibroplasia, and 70% is expanded and replaced by multifocal to coalescent granulomas up to 500 µm in diameter that are frequently centered on fungal spherules that are 20-60 µm in diameter with a 4-5 µm thick, double-contoured, hyaline wall. Spherules contain granular to flocculent, basophilic material and occasionally few 5-8 µm diameter, round endospores. Admixed with these spherules is abundant basophilic necrotic cellular debris and degenerate neutrophils further surrounded by epithelioid macrophages, fewer lymphocytes and plasma cells, occasional multinucleated giant cells, abundant eosinophilic fibrillar material (fibrin), reactive fibroblasts, and layer of dense fibrous connective tissue (fibrosis).  Granulomas are separated and surrounded by abundant fibrous connective tissue and varying numbers of lymphocytes, plasma cells, degenerate neutrophils, and macrophages mixed with small amounts of hemorrhage, fibrin, and edema. Multifocally, the parietal pericardium is expanded and lined by a dense, brightly eosinophilic, fibrin mat that entraps moderate numbers of inflammatory cells, hemorrhage, necrotic debris, and fungal spherules.

 

MORPHOLOGIC DIAGNOSIS:  Pericardium (per contributor): Pericarditis, granulomatous, diffuse, severe, with fibrinous pleuritis, and numerous fungal spherules, etiology consistent with Coccidioides sp., breed unspecified, canine.

 

ETIOLOGIC DIAGNOSIS: Pericardial coccidioidomycosis

 

CAUSE:  Coccidioides immitis or C. posadasii

 

SYNONYMS:  Coccidioidal pericarditis, Valley fever, San Joaquin Valley fever

 

GENERAL DISCUSSION:

• Primarily respiratory disease; disseminates hematogenously from the lung (P-F03) to the heart and pericardium, CNS, eyes, skin, bone, liver, spleen, kidney, and/or testes; disseminated form most common in dogs with occasional infections in domestic and wild animals
• Coccidiomycosis is caused by C. immitis and C. posadasii; both are a geophilic dimorphic fungus
• Not contagious; acquired primarily by inhalation of infectious barrel-shaped arthroconidia (spores) from the environment 
• Endemic in the Western Hemisphere (southwestern U.S., focal areas of Mexico, and Central and South America)
  • C. immitis is endemic to Mexico and the San Joaquin Valley of California
  • C. posadasii is endemic to the rest of California, Arizona, Texas, Mexico, and South America 

 

PATHOGENESIS:

• Fungi survives in hot dry conditions and saphrophytic hyphae grow in the soil after intense rainfall; releases arthroconidia via wind-blown dust after the soil desiccates 
• Inhalation of arthroconidia (from environment) or local inoculation (less common) > at body temperature, arthroconidia transition into spherules > migrate to subpleural areas > subpleural inflammation
  • Arthroconidia develop into immature spherules; maturing spherules enlarge and form numerous, uninucleate, intraspherular endospores via endosporulation
  • Mature spherules rupture and release endospores that form new spherules in tissue, or mycelia if released to the environment
• Systemic lesions (including pericardial infections) spread hematogenously from the lung, resulting in granulomas 
• Rarely, transplacental (vertical) transmission can occur to fetuses as a result of placentitis or from neonatal aspiration of infected amniotic fluid or vaginal secretions during delivery; typically abortion occurs in these cases, however a recent paper described a three-month-old cria born in Missouri who was suspected to have been transplacentally infected (Havis, J Comp Pathol. 2021)

 

TYPICAL CLINICAL FINDINGS:

 

TYPICAL GROSS FINDINGS:

  

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Granulomas and pyogranulomas with fibrosis often surrounding spherule; in chronic cases organisms not always visualized
• Spherule (size and presence of mature spherules with endospores is characteristic):
  • 20-200 um diameter; sizes varies during development:
    • Immature spherules, 10 - 20 µm in diameter 
    • Mature spherules enlarge up to 200 µm in diameter, contain myriad 2-5 um endospores
    • Organisms have a double contour wall and undergo endosporulation
    • Endospores, 2 - 5 µm in diameter

4-5um thick, double contoured, refractile, hyaline wall

 

ULTRASTRUCTURAL FINDINGS:

• Cell wall and highly folded plasma membrane; occasional club-like projections radiate from the surface
• Cysts contain endospores with cleavage furrows and distinct nuclei

 

ADDITIONAL DIAGNOSTIC TESTS:

• Histochemical stains:
  • PAS:  Spherules PAS (+), cell wall is PAS (-) 
  • GMS (+): Endospores, +/- wall 
• PCR
• Cytology: pyogranulomatous inflammation with few to no organisms; when present, spherules are blue, double-walled, round structures up to 200um with finely granular protoplasm; spherules may be folded or crumpled; may see endospores scattered in the background or phagocytized by neutrophils or macrophages 

 

DIFFERENTIAL DIAGNOSES: 

• Organisms that produce spherule-like structures: 
  • Rhinosporidium seeberi (P-F01):  Sporangia up to 350 um diameter, 3-5 um thick wall and 6-10 um diameter endospores; main differential
  • Chrysosporium parva and C. crescens: Respiratory fungal infection of wild rodents, insectivores, herbivores, and carnivores; thick walled uninucleate adiaspores and fibrotic granulomas; no endospores; spherules 200-400 um diameter
  • Blastomyces dermatitidis (P-F05, I-F06, S-F02): Similar in size to C. immitis immature spherules, but have budding 
  • Prototheca sp. (D-F03, S-M03, U-M05)
  • Chlorella sp. 
• Dimorphic fungal infections:
  • Blastomyces dermatitidis (P-F05, I-F06, S-F02)
  • Cryptococcus neoformans (P-F04, I-F08, N-F02, S-F01)
  • Histoplasma capsulatum (P-F02, D-F01, N-F01)
• Organisms that reproduce by endosporulation:
  • Coccidioides immitis/posadasii
  • Rhinosporidium seeberi (P-F01, main differential for coccidioidomycosis)
  • Prototheca sp. (D-F03, S-M03, U-M05)
  • Chlorella sp.
  • Batrachochytrium dendrobatidis (I-F10)

 

COMPARATIVE PATHOLOGY:

• Cats: Lesions usually limited to skin, lungs, and associated lymph nodes; cutaneous nodular lesions are the most common presentation in cats
• Non-human primates (New World, Old World monkeys, and Great Apes): All NHPs are susceptible; increased occurrences when housed outdoors; tissues affected in decreasing order: lungs, vertebral column, abdominal organs
  • Baboons: may exhibit either bone or thoracic lesions but not intrathoracic and extrathoracic lesions
  • Hypertrophic osteopathy has been reported in chimpanzees
• Swine, sheep, goats: Granulomatous lesions primarily in the bronchial and mediastinal lymph nodes, and occasionally incidental pulmonary lesions
• Cattle: Spherules are often enmeshed in eosinophilic material similar to the Splendore-Hoeppli phenomenon; this may reflect a higher level of resistance 
• Horse: Granulomas form most often in lungs, liver, kidney, and spleen; recurring nasal granulomas, abortions, and lameness resulting from osteomyelitis; multiple case reports of coccidioidomycosis in wild young male Przewalski's horses
• Llamas: Most significant fungal disease in camelids; particularly susceptible to disseminated coccidioidomycosis; clinical signs related to the location of the lesion
• Marine mammals (sea lions, sea otters, and dolphins): Coccidioides infection is a common cause of systemic mycosis along central California coast

 

REFERENCES:

1. Agnew D. Camelidae. In:  Terio KA, McAloose D, St. Leger J.  Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:119.
2. Burkhard MJ. Respiratory Tract. In: Raskin RE and Meyer DJ.  Canine and Feline Cytology, A Color Atlas and Interpretation Guide. 3^rd Ed. St Louis, MI: Elsevier; 2016:170-171.
3. Caswell JL, Williams KJ. The respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol 2, 6th ed. St. Louis, MO: Elsevier; 2016:583-584.
4. Colegrove KM, Burek-Huntington KA, Roe W, et al. Pinnipediea. In: Terio KA, McAloose D, St. Leger J.  Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:582-583.
5. Duncan M. Perissodactyls. In:  Terio KA, McAloose D, St. Leger J.  Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:449.
6. Havis BM, Walker KE, Adkins PRF, et al. Systemic coccidioidomycosis in a llama cria native to Missouri. J Vet Diagn Invest. 2021;33(3):587-590. 
7. Fernandez JA, Hidalgo MN, Hodzic E, Diab SS, Uzal FA. Pathology of coccidioidomycosis in llamas and alpacas. J Vet Diagn Invest. 2018 Jul;30(4):560-564.
8. Koistinen K, Mullaney L, Bell T, et. al. Coccidioidomycosis in nonhuman primates: pathologic and clinical findings. Vet Pathol. 2018 ;55(6):905-915
9. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, and Ailuridae. In:  Terio KA, McAloose D, St. Leger J.  Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:245.
10. Lopez A and Martinson SA. Respiratory system, thoracic cavities, mediastinum and pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022:631-632, 636.  
11. Lowenstine LJ, McManamon R, Terio KA. Apes. In:   Terio KA, McAloose D, St. Leger J.   Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:397.
12. Martinez MAJ, Gasper DJ, Mucino MCC, et al. Suidae and Tayassuidae. In:  Terio KA, McAloose D, St. Leger J.  Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:220.
13. McAloose D and Stalis IH. Prosimians. In:  Terio KA, McAloose D, St. Leger J.  Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:335-336.
14. Simmons J and Gibson S. Bacterial and mycotic diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, et al, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. San Diego, CA: Academic Press; 2012:151-152. 
15. Stanton JB and Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022: 280.
16. St Leger J, Raverty S, Mena A. Cetacea, Ursidae, and Ailuridae. In:  Terio KA, McAloose D, St. Leger J.  Pathology of Wildlife and Zoo Animals.  London, England: Elsevier; 2018:562.
17. Vane LV, Yang PJ, Cowell RL. Selected Infectious Agents. In: Valenciano AC and Cowell RL.  Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5^th Ed. St Louis, MI: Elsevier; 2020:50, 55.

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