Signalment:  

Three-year-old, intact female cat (Felis cats). This was a feral cat submitted from a spay-neuter project in southern CA. The history was -�-�unknown death. The submitter wished to rule out viral disease and poisons.

Gross Description:  

The carcass was in good post mortem condition but poor body condition, with minimal fat stores, prominent ribs and decreased muscle mass. The most significant lesions were in the lungs. All lung lobes did not collapse and were expanded by multiple coalescing, slightly firm, tan nodules. Tracheobronchial lymph nodes were 4 times normal size. An impression smear of the nodules showed numerous macrophages filled with 2-4 μm yeasts.

All other organs including liver and spleen were considered to be grossly within normal limits.

Histopathologic Description:

The architecture of over 80% of the lung in all evaluated sections was distorted by dense sheets of abundant inflammatory infiltrate composed of many epithelioid macrophages that expand the interstitium and fill the alveoli and bronchioles. Mixed with the macrophages were fewer lymphocytes, fibrin and edema residue. Macrophages were commonly distended by 8 to 20 intracytoplasmic yeast bodies that were round, 3 to 4 μm diameter and had a basophilic center surrounded by a 2 μm halo. Multifocally large areas of the lung were replaced by eosinophilic cellular debris, karyorrhectic debris and degenerate cells (necrosis). Small scattered areas were interrupted by hemorrhage.

The tracheobronchial lymph nodes (not submitted) were expanded by sheets of epithelioid macrophages, many of which contained similar yeast bodies. Organisms were further demonstrated by Gomori methenamine silver and periodic acid-Schiff on lung and lymph node. Fewer, scattered macrophages with intracellular yeasts were identified in the liver and spleen with special stains.

Morphologic Diagnosis:  

Bronchopneumonia, histiocytic, focally extensive to coalescing, severe with multifocal necrosis and intralesional, intracytoplasmic yeasts.

Lab Results:  

After DNA extraction from the paraffin block, the D1D2 region of the 28S ribosomal RNA gene was amplified by PCR using universal fungal primers. When this PCR amplicon was directly sequenced, the sequence most closely matched that of Ajellomyces capsulatus (Histoplasma capsulatum) (>99 % sequence identity with GenBank acc # AB176473 and others ) when compared with sequences in GenBank.

Condition:  

Histoplasma capsulatum

Contributor Comment:  

Histoplasmosis is a non-contagious infectious disease of man and animals caused by the dimorphic fungus Histoplasma capsulatum var. capsulatum.(3) It is a soil-born infection often associated with exposure to soil contaminated either with bird or bat feces. Although affecting both man and animals, it is not considered a zoonotic disease.(7) It is distributed world-wide but is considered endemic in the Ohio, Mississippi and St. Lawrence River Valley. However, any area with the right conditions can produce cases, such as the reported outbreak in dogs and cats in the Rio Grande Valley of Texas.(2) In that report, exposure was attributed to urbanization of rural land once occupied by chicken farms, and to a local bat cave. Local irrigation made conditions ripe for fungal growth, even in the arid southwest. In endemic areas many people and animals are exposed but few develop clinical disease.(5) Risk factors include extremes in age and immunosuppression. The travel history was not available for the cat in this report, so it was not determined if the cat traveled from an endemic area or if exposure was local. The FeLV/FIV status of this cat was unknown, but as a feral animal it presumably was at high risk for exposure to immunosuppressive viruses and potentially high doses of infectious agent.

Inoculation is by inhalation of spores from contaminated soil. The spores are then taken up by pulmonary macrophages and spread to local lymph nodes and, often, throughout the body. Respiratory disease is most common, but the frequency of gastrointestinal lesions in animals suggests that oral inoculation is also possible.(7) Localized infections in the skin and eye are also reported(1); disseminated disease is invariably fatal. Clinical signs include fever, malaise and respiratory distress; hepatic and splenic enlargement are present if the disease is disseminated. Debilitated patients are often anemic and maybe be terminally leukopenic.(7) Gross lesions are dependent upon the extent of dissemination in the body. The lesions illustrated in the lungs and lymph nodes of this cat are a classic presentation of the respiratory lesions of histoplasmosis in cats.(1,2) Histologically, the organisms are easily distinguished from other dimorphic fungi (Cryptococcus neoformans, Blastomyces dermatitidis and Coccidioides immitis) by their size and obligate intracellular location.

The pathogenesis of the disease is best characterized in people.(3) Once phagocytized by pulmonary macrophages, the conidia convert to the yeast form and disseminate within the reticuloendothelial system. Dendritic cells present antigen to T lymphocytes and within 2-3 weeks, cell mediated immune responses stimulate cytokine dependent killing of yeast by effector macrophages. In the absence of effective cell-mediated immunity (as in HIV-AIDS patients), fungus disseminates and leads to terminal illness. In the immunocompetent human host infections are most often inapparent, with occasional acute or chronic localized manifestations.(5) Localized chronic pulmonary infections are often mistaken clinically for neoplasia. The pathogenetic factors that determine inapparent and clinical disease in animals is less well characterized, but presumably involves similar cell mediated immune mechanisms.(7)

Diagnosis can be made by fine needle aspirates or impression smears, confirmed by histopathology and may be verified by culture or PCR. Fungal culture, however, is a risk to laboratory personnel, as the chlamydospores of the mycelial phase are highly infective.(7)

JPC Diagnosis:  

Lung: Pneumonia, interstitial, granulomatous, multifocal to coalescing, severe with numerous intrahistiocytic yeasts.

Conference Comment:  

The contributor provides an excellent review of the dimorphic fungus, Histoplasma capsulatum. The two forms of dimorphic fungi include the mold form which occurs in the environment and the yeast form which forms in animal tissues.(4) Several species of dimorphic fungi are opportunistic pathogens in domestic animals, the most common of which are Histoplasma capsulatum var. capsulatum, Blastomyces dermatitidis and Coccidioides immitis. Other dimorphic fungi, Sporothrix schenckii, Histoplasma capsulatum var. duboisii and Histoplasma farciminosum cause disease less frequently. Another fungal pathogen, Cryptococcus neoformans, can also be considered dimorphic, although it rarely appears in its filamentous form, and more often is found in its yeast form. Candida albicans can also exist as yeast or hyphae and pseudohyphae; however, its mold form occurs in animal tissues and its yeast form occurs in the environment.(4) The included table summarizes differential diagnoses for fungal yeast infections:(4,6)

	Blastomyces dermatitidis	Coccidioides immitis	Histoplasma capsulatum	Histoplasma farciminosum	Sporothrix schenckii	Cryptococcus neoformans
Disease	Blastomycosis	Coccidioidomycosis	Histoplasmosis	Epizootic lymphangitis	Sporotrichosis	Cryptococcosis
Species most affected	Dogs, humans	Dogs, horses, cats, humans	Dogs, cats, humans	Horses	Horses, cats, dogs, humans	Cats, horses, humans
Organs affected	Lungs, skin, metastasis to other tissues	Lungs, metastasis to bones, skin, and other tissues	Lungs, metastasis to other organs	Skin, lymphatic vessels, lymph nodes	Skin, lymphatic vessels	Nasal cavity, lungs, brain, eye, skin
Tissue morphology	Large (8 to 10 μm), broad-based unipolar budding yeast cells	Large (10 to 80 μm) spherules with numerous 2 to 5 μm endospores	Small (1 to 5 μm) narrow base budding yeast cells *var. duboisii are larger (5 to 20 μm)	Small (1 to 5 μm) narrow base budding yeast cells	Small (2 to 5 μm) narrow base budding yeast cells	Small (4 to 8 μm) narrow base budding, thick-walled yeast surrounded by a large 5 to 10 μm gelatinous capsule

References:

1. Brilhante RSN, Coehlo CGV, Sidrim JJC, et al. Feline histoplasmosis in Brazil: Clinical and laboratory aspects and a comparative approach of published reports. Mycopathologica. 2012;173:193-197.
2. Kabali S, Koschmann JR, Robertstad GW, et al. Endemic canine and feline histoplasmosis in El Paso, Texas. J Med and Vet Mycol. 1986;24:41-50.
3. Knox KS, Hage CA. Histoplasmosis. Proc Am Thoracic Soc. 2010;7:169-172.
4. Quinn PJ, et al. Actinobacteria. In: Veterinary Microbology and Microbial Disease. 2nd ed. Ames, Iowa: Wiley Blackwell; 2011, Kindle edition, location 17002 of 35051.
5. McKinsey DS, McKinsey JP. Pulmonary histoplasmosis. Sem in Resp and Critical Care Med. 2011;32:735-744.
6. University of Adelaide Mycology Online. Dimorphic Systemic Mycoses, http://www.mycology.adelaide.edu.au/Mycoses/Dimorphic_systemic /. Accessed online on 28 March 2013. 
7. Valli VEO. The hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5th ed. Vol. 3. Edinburgh, Scotland: Elsevier; 2007:299-301.

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4-1. Lung

4-2. Lung

4-3. Lung

4-4. Lung

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