JPC SYSTEMIC PATHOLOGY

CARDIOVASCULAR SYSTEM

February 2025

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 abundant fibrosis and 70% is expanded and replaced by multifocal to coalescing 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, chronic, diffuse, severe, with fibrinous pleuritis, and numerous fungal spherules, 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; draining skin lesions are often associated with underlying bone lesions
• Disease can be found in cats and dogs visiting endemic areas within 3 years.
  1. Boxers and Doberman pinchers predisposed to disseminated disease
• 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 
• Although most animals in endemic areas probably become infected during their life, relatively few develop disease
• 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 
• Dust storms in endemic areas may be cause of epizootics; windblown spores can be carried miles away from original source
• Zoonotic; exposure risk for laboratories performing necropsies due to aerosolization of the arthroconidia; direct transmission from animals is rarely reported

 

PATHOGENESIS:

• Fungi survives in hot dry conditions and saphrophytic hyphae (mycelial) grow in the soil after intense rainfall; releases arthroconidia (asexual spores) via wind-blown dust after the soil desiccates 
• Inhalation of arthroconidia (from environment, most common) or local inoculation (less common) > at body temperature, arthroconidia transition into the yeast form, spherules, resistant to phagocytosis > deposit in the lung > endosporulation leads to spores that get phagocytosed and become second generation spherules within the phagocyte cytoplasm-> colonization of lung airways > infected macrophages spread via leukocyte trafficking in lymphatic vessels and circulatory system to lymphoid tissues > lymph nodes> systemically 
  • Arthroconidia (3-6 µm) 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
  • Inhaled arthroconidia and endospores released by mature spherules incite suppurative inflammation and transitions into pyogranulomas/granulomas 
• Systemic lesions (including pericardial infections) spread hematogenously from the lung, resulting in granulomas
• In the heart, granulomatous lesions present in the pericardium or myocardium and can cause right sided heart failure
• 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)
• Virulence factors
  1. Spherule outer wall glycoprotein
  2. Depletion of spherule outer wall glycoprotein for endospores
  3. Production of host tissue arginase I and coccidiodal urease
  4. Exposed laminin and collagen may serve as fungal ligands 

TYPICAL CLINICAL FINDINGS:

 

TYPICAL GROSS FINDINGS:

• Discrete to confluent gray-white variably sized nodules, +/- caseous, liquefied center
• Tracheobronchial lymph nodes frequently enlarged 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Granulomas and pyogranulomas with multinucleated giant cells and fibrosis often surrounding spherule; in chronic cases organisms not always visualized
• Spherule (size and presence of mature spherules with endospores is characteristic):
  • 20-200 µm diameter; sizes varies during development:
  • 4-5µm thick, double contoured, refractile, hyaline wall
  • Immature spherules, 10 - 20 µm in diameter 
  • Mature spherules enlarge up to 200 µm in diameter, contain myriad non-budding 2-5 µm endospores
  • Organisms have a double contour wall and undergo endosporulation
  • Endospores, 2 - 5 µm in diameter
  • Mycelial is septate with racquet hyphae and barrel-shaped arthrospores 

 

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 
  • Methenamine silver: Endospore (+), cell wall (+)
• PCR, ISH, culture
• Cytology: Better seen on wet mount preparations; pyogranulomatous inflammation with few to no organisms; when present, spherules are blue, double-walled, round structures up to 200µm with finely granular blue protoplasm; spherules may be folded or crumpled; may see endospores that are round to ovoid, 2-5 µm in diameter, with clear to light blue cytoplasm, dark blue to purple eccentric nuclei, and thin clear cell wall scattered in the background or phagocytized by neutrophils or macrophages 
• Serum antibodies detected in acute stages of the disease; high titers suggest active disease
• Radiographs can reveal severe pulmonary disease with multiple cavitary lesions or lysis of vertebral bone

 

DIFFERENTIAL DIAGNOSES: 

• Organisms that produce spherule-like structures: 
  • Rhinosporidium seeberi (P-F01): Sporangia up to 350 µm diameter, 3-5 µm thick wall and 6-10 µm 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 µm 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)
  • Mucor amphibiorum
• Organisms that reproduce by endosporulation:
  • Coccidioides immitis/posadasii
  • Rhinosporidium seeberi (P-F01, main differential for coccidioidomycosis)
  • Prototheca sp. (D-F03, S-M03, U-M05)
  • Scenedesmus sp.
  • 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 and bone lesions are rare
• Non-human primates (New World, Old World monkeys, and Great Apes): All NHPs are susceptible to systemic infections; increased occurrences when housed outdoors; affected tissues include: Lungs, bone (most commonly the vertebrae), brain, eye, abdominal organs
  • Hypertrophic osteopathy has been reported in chimpanzees
• Prosimian: Pulmonary and disseminated disease reported in captive ring-tail lemur
• Swine, sheep, goats: Granulomatous lesions primarily in the bronchial and mediastinal lymph nodes, and occasionally incidental pulmonary lesions; in Texan Peccaries neurological-like disorder has been seen
• 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; leading cause of death in captive young male Przewalki horses housed in Southern California, frequently horses had hind quarter skeletal muscle lesions consistent with bite wound infection or systemic disease
• New world camelids (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; associated with disturbance of dry soil; California sea lions have highest prevalence; lung miliary nodules with central caseous necrosis; can be difficult to distinguish grossly from urogenital carcinoma masses; organisms have been found histologically in the brain within areas of necrotizing encephalitis
• San Joaquin kit fox case with serological evidence of Coccidiodes spp infections
• Snakes: C. immitis associated pneumonia with mixed inflammation surrounding spherules reported in Sonoran gopher snake
• Bats: C. posadasii lung infection has been reported in free ranging Carollia perspicillata in Brazil
• Mustelids: Single case report; low pathogenicity.
• Black rhinoceros: Incidental lesion found in the lung, lymph node, and synovium with chronic progressive lameness
• Rodents: High concentration found in rodent burrows in endemic areas

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