Signalment:  

11-year-old spayed female Pembroke Welsh Corgi dog (Canis lupus familiars).One year duration of immune-mediated hemolytic anemia (IMHA) with recent resolution of pneumonia. The dog presented to Colorado State University Veterinary Teaching Hospital for acute onset of panting and reluctance to move.


Gross Description:  

The abdomen is pendulous with approximately 20 milliliters of brown, thick fluid which is confined to the left cranial dorsal quadrant. This fluid corresponds to a full thickness, elliptical perforation of the gastric fundus measuring 1 -+ cm in length with regional serosal fibrinous adhesions to the omentum. There are multifocal hemorrhages within the greater leaf of the omentum and greater curvature of the stomach. The liver is mild to moderately enlarged diffusely with rounded edges and contains multiple tan, soft, round nodules that exude thick viscous material and measuring 1mm-2cm in diameter. Within the left frontal lobe there is a moderately well demarcated, soft, gelatinous, gray to tan foci measuring no more than 2cm in diameter. There are multifocal renal, capsular pits which correspond with collapse and loss of cortical parenchyma.


Histopathologic Description:

Brain: Focally expanding approximately 25% of the section there is rarefaction and effacement of the neuropil by marked numbers of inflammatory cells, karyorrhectic debris and abundant numbers of brown pigmented fungal hyphae. Hyphae have parallel walls and are occasionally septate and branching. Inflammatory infiltrates consist primarily of epithelioid macrophages, occasionally multinucleated cells and intact and degenerative neutrophils. Hyphae are typically extracellular but a few are intimately associated with multinucleated cells. Vessels within this region are lined by prominent, hypertrophied endothelium, surrounded and disrupted by macrophages, lymphocytes, plasma cells and lesser neutrophils. Multifocally there are patches of perivascular fibrin exudate. At the periphery of this region there are scattered neurons with pale nuclei and dispersion of Nissl substance (chromatolysis). The leptomeninges contain moderate perivascular lymphocytes and plasma cells.


Morphologic Diagnosis:  

Brain: Pyogranulomatous encephalitis, focally extensive, marked with intralesional dematiaceous fungal hyphae and vasculitis.


Lab Results:  



Complete blood count:
ParameterResultReference range
Nucleated cells2.9 x 103/μl4.5-15.0 x103/μl
Segmented neutrophils1.9x103/μl2.6-11.0x103/μl
Lymphocytes0.2x103/μl1.0-4.8x103/μl
Eosinophils0.1x103/μl0.1-1.2x103/μl
nRBCs0.1 x103/μl0.0x103/μl
RBC4.1x103/μl5.5-8.5x103/μl
HGB9.7 g/dl13.0-20.0 g/dl
PCV30.0% 40.0-55.0%
MCV75.0 fl 62.0-73.0 fl
MCHC 32.0 g/dl 33.0-36.0 g/dl
Reticulocytes 85,050/μl 0.0-60,000/μl

Serum Chemistry:
ParameterResultReference range
Total protein 7.3 gm/dl 5.3-7.2 gm/dl
Globulin 3.9 gm/dl 2.0-3.8 gm/dl
ALP 437 IU/l 20-142 IU/l
ALT 179 IU/l 10-110 IU/l
GGT 68 IU/l 0-9 IU/l
Glucose 534 mg/dl 75.0-130.0 mg/dl
Anion gap 26 13-22

Blood gas (venous):
ParameterResultReference range
pH 7.119 7.3-7.5
pCO2 40.3 mmHG 24.0-39.0 mmHG
pO2 166.0 mmHG 67.0-92.0 mmHG
HCO3 12.5 mm/L 15.0-24.0 mm/L
Anion gap 24 mEq/l 13.0-22.0 mEq/l


Condition:  

Phaeohyphomycosis


Contributor Comment:  

Phaeohyphomycosis in domestic animals is an uncommon, opportunistic infection caused by a variety of fungal species.(4) Characteristic of phaeohyphomycotic fungi is the presence of variable melanin pigment in the cell wall giving it a distinct brown color.(4) Production of melanin pigment is thought to contribute to the organisms virulence.(4,9) DHN-melanin (1, 8-dihydroxynaphthalene) and DOPA-melanin (L-3, 4- dihydroxyphenylalanine) are two specific melanin pigments thought to play a role in the pathogenicity of dematiaceous fungi.(9) The role of such pigment has been implicated in contributing to organisms resistance to ultraviolet radiation, extreme temperature variation, oxidation, enzymatic degradation, as well as structural functions and guarding against desiccation.(2,9,14)

The various fungal species are not morphologically distinct on routine H&E histologic examination.(4) Culture, fungal morphology or molecular techniques are generally required for speciation.(6) Organisms in general have a dark brown to light yellow pigment, although degree of pigmentation can vary, and have 2-6 μm in width septate hyphae that can be branched or unbranched.(4,7) If melanin pigment is not identifiable, Fontana-Masson histochemical stain may assist in identification of subtle pigment.(4,7)

Phaeohyphomycotic fungi are composed of more than 100 different dematiaceous species presenting clinically as cutaneous, central nervous system and disseminated infections.(6,14,16) Reported most frequently in cats, phaeohyphomycosis has been occasionally documented in horses, dogs, cattle and goats.(5,7,12,15) Typically feline infections are limited to subcutaneous tissues although disseminated and cerebral forms do occur and are most often associated with immunologic compromise.(14,16) Cutaneous forms are thought to occur due to introduction of the organism via a penetrating wound.(14,16) Specifically, Cladophialophora bantiana, (also known as Cladosporium bantianum, Cladosporium trichoides, and Xylohypha bantiana) has a tropism for nervous tissue and has been reported as a cause for cerebral phaeohyphomycosis in both dogs and cats.(11,12)

Immunosuppression likely contributed to the pathogenesis of cerebral phaeohyphomycosis in this dog with a history of cyclosporine and prednisone administration for treatment of IMHA. Route of infection was unclear at the time of necropsy although ultimately hematogenous dissemination was suspected due to the presence of fungal organisms within the liver.

Cutaneous infection may have been the route of entry although lesions were absent at necropsy examination. Ingestion of the fungus and entry via the compromised stomach was considered but unlikely due the absence of histologic identification of the organism within sections of the stomach at the location and distant to the perforation.


JPC Diagnosis:  

Cerebrum: Encephalitis, necrotizing and granulomatous, multifocal to coalescing, severe, with vasculitis, mild lymphohistiocytic meningitis and rare dematiaceous fungal hyphae.


Conference Comment:  

Several species of dematiaceous fungi demonstrate a predilection for the central nervous system and phaeohyphomycosis (cerebral and/or disseminated) has been reported in an alpaca, a snow leopard, reptiles, including a tortoise and an iguana and leafy and weedy sea dragons,(1,3,8,13) in addition to the domestic species previously listed.

As noted in the summary, immunosuppression secondary to repeated administration of cyclosporine and prednisone for treatment of immune mediated hemolytic anemia likely predisposed this dog to fungal infection. With that in mind, conference participants briefly discussed the clinical pathologic findings in this case, which were consistent with the history of treatment for IMHA and the diagnosis of disseminated phaeohyphomycosis. Macrocytic, hypochromic, regenerative anemia is an expected finding in dogs with IMHA.(10) Corticosteroid treatment typically induces lymphopenia, and while neutrophilia is a common finding in cases of hemolysis and corticosteroid administration, the neutropenia observed in this case probably occurred due to the disseminated fungal infection.(10) Globulin concentration also increases in infection and inflammation.(10) Anemia induced hypoxic injury to centrilobular hepatocytes may result in elevation of ALT, while increased ALP and GGT may occur following corticosteroidinduced hepatocellular glycogen accumulation.(10) Corticosteroids also induce hyperglycemia.(10)


References:

1. Bonar CJ, Garner MM, Weber ES 3rd, et al. Pathologic findings in weedy (Phyllopteryx taeniolatus) and leafy (Phycodurus eques) seadragons. Vet Pathol. 2013;50(3):368-376.

2. Fothergill AW. Identification of dematiaceous fungi and their role in human disease. Clinical Infectious Diseases. 1996;22(8uppl 2): 8179-8184.

3. Frank C, Vemulapalli R, Lin T. Cerebral phaeohyphomycosis due to Cladophialophora bantiana in a Huacaya alpaca (Vicugna pacos). J Comp Pathol. 2011;145(4):410-413.

4. Ginn PE, Mansell JEKL, Rakich PM. Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5th ed. Vol. 1. Philadelphia, PA: Elsevier Inc; 2007:702-703.

5. Giri DK, Sims WP, Sura R, Cooper JJ, Gavrilov BK, et al. Cerebral and renal phaeohyphomycosis in a dog infected with Bipolaris species. Vet Pathol. 2011;48:754-757.

6. Grooters AM, Foil CS. Miscellaneous Fungal Infections. In: Greene CE ed. Infectious Disease of the Dog and Cat. 3rd ed. Elsevier Inc; 2006:647-649.

7. Herra-�ez P, Rees C, Dunstan R. Invasive phaeohyphomycosis caused by Curvularia species in a dog. Vet Pathol. 2001;38:456459.

8. Janovsky M, Grone A, Ciardo D, Vollm J, Burnens A, Fatzer R, et al. Phaeohyphomycosis in a snow leopard (Uncia uncia) due to Cladophialophora bantiana. J Comp Pathol. 2006;134(2-3):245-248.

9. Langfelder K, Streibel M, Jahn B, Haase G, Brakhage AA. Biosynthesis of fungal melanins and their importance for human pathogenic fungi. Fungal Genetics and Biology. 2003;38:143158.

10. Latimer KS, ed. Duncan and Prasses Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Ames, IA: John Wiley and Sons; 2011:65,178-179,386-388.

11. Lavely J, Lipsitz D. Fungal infections of the central nervous system in the dog and cat. Clin Tech Small Anim Pract. 2005;20:212-219.

12. Migaki G, Casey HW, Bayles WB. Cerebral phaeohyphomycosis in a dog. J Am Vet Med Assoc. 1987;191: 997-998.

13. Olias P, Hammer M, Klopfleisch R. Cerebral phaeohyphomycosis in a green iguana (Iguana iguana). J Comp Pathol. 2010;143(1):61-64.

14. Revankar SG, Patterson JE, Sutton DA, Pullen R, Rinaldi MG. Disseminated Phaeohyphomycosis: Review of an emerging mycosis. Clinical Infectious Diseases. 2006;34:467476.

15. Singh K, Flood J, Welsh RD, Wickoff III JH, Snider TA, Sutton DA. Fatal systemic phaeohyphomycosis caused by Ochroconis gallopavum in a dog (Canis familaris). Vet Pathol. 2006;43:988992.

16. Swift, IM, Griffin A, Shipstone MA. Successful treatment of disseminated cutaneous phaeohyphomycosis in a dog. Australian Veterinary Journal. 2006;84:431-435.


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4-1. Cerebrum


4-2. Cerebrum


4-3. Cerebrum


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