Signalment:  

16-year-old male intact mandrill (Mandrillus sphinx) non-human primate.The animal lived in a zoological garden as the alpha male of a mandrill group. At the age of ten years, the animal developed multifocal ulcerative and nodular, pruritic lesions of the facial skin, at the nasal mucocutaneous junctions as well as on the oral and nasal mucosa. The course of disease was undulating with periods of improvement alternating with phases of deterioration with expansion of the cutaneous and mucosal wounds associated with inappetence, apathy, and stridors. Skin biopsies taken one years after the onset of clinical signs revealed a granulomatous inflammation with evidence of fungal structures. Although the etiological agent could not be classified, an aspergillosis, a mucormycosis, and a trichophytosis were ruled out on the basis of the histomorphology of the fungal elements. During the course of disease, different sole and combined antimycotic therapeutic approaches were applied. However, permanent recovery could not be achieved. Due to worsening of the skin lesions, the development of new ulcers in the left gluteal region, and increasing psychosocial stress within the group, the mandrill was finally euthanized for animal welfare reasons. The mandrill was serologically positive for simian immunodeficiency virus (SIV) and negative for simian t-cell leukemia virus (STLV) and herpes B.

Gross Description:  

At necropsy, the mandrill was in good nutritional condition. The skin on the bridge of the nose revealed a severe multifocal to confluent ulcerative dermatitis with marked, partly nodular thickening of the subcutis and superficial crust formation. The ulcerative lesions extended to the corners of the mouth and also involved the anterior nasal and oral mucosa. A focally extensive ulcerative and proliferative skin lesion (ca. 8 x 5 cm) was also present between the anus and the left ischial tuberosity. The mandibular and left inguinal lymph nodes were moderately enlarged.

Histopathologic Description:

At microscopic examination, the dermis and subcutis of the nasal skin respectively the propria of the oral mucosa contained multifocal to coalescing nodular inflammatory foci beneath an extensively ulcerated squamous epithelium. The nodules were composed of abundant macrophages, eosinophils, multinucleated giant cells, viable and degenerate neutrophils, and fewer lymphocytes and plasma cells and were separated by strands of mature collagenous connective tissue. In addition, a few fibroblasts aligned along the periphery of the inflammatory cell infiltrates. Multinucleated giant cells were primarily Langhans type, with occasional foreign-body type, and contained up to 20 nuclei. There were multifocal slight hemorrhages. Multifocally within giant cells but also located in the extracellular space, there were faintly stained fungal organisms represented by round, thick-walled, yeast-like bodies as well as short hyphae. The fungal elements were strongly positive with Grocott stain and with PAS reaction. They were only weakly stained by Congo red. Hyphae were characterized by rare, irregular branching, infrequent septation, thin, non-pigmented walls, and occasional bulbous dilations. The yeast-like bodies measured between 5 and 10 μm, were sometimes surrounded by a clear halo and sporadically seemed to form pseudohyphae. There was no evidence of angioinvasion.

Morphologic Diagnosis:  

Mucocutaneous junction: dermatitis/panniculitis and stomatitis, granulomatous and eosinophilic, chronic, multifocal to coalescing, marked, with multifocal ulceration, hemorrhages, and numerous intralesional fungal organisms (short hyphae and yeast-like bodies), mandrill, nonhuman primate.

Lab Results:  

Immunohistochemistry using a polyclonal anti-Candida albicans-antibody revealed a positive reaction of the fungal organisms. Fungal culture of the skin revealed fast-growing, light green yeast colonies on a chromogene medium. Microscopically, the colony material consisted of gram positive, narrow-budding, round yeasts with a size of 2-5 μm. On the species level, the isolated yeast was identified as Candida albicans using MALDI-TOF MS.(1) The etiology was confirmed by a PCR with Candida albicans-specific primers targeting the gene for the integrin like protein alpha INT1,(6) which was positive on the fungal culture material.

Condition:  

Candida

Contributor Comment:  

Candidiasis is caused by yeasts of the genus Candida, usually C. albicans, and is the most frequently occurring mycotic disease in nonhuman primates.(5) Candida spp. are ubiquitous dimorphic fungi that normally inhabit the alimentary and genital mucosa as well as the skin of mammalian animals and humans.(5,11) They represent opportunistic pathogens as disease generally only develops when the host resistance is lowered due to pre-existing disease (metabolic disorders, hematologic malignancies etc.), retrovirus infection, immunosuppressive drugs, or penetrating trauma or burns. Further risk factors include stress, cachexia, nutritional deficiencies, and immunologic defects.(5,9) Candida infections most often cause localized or systemic suppurative to necrotizing, ulcerative mucosal lesions with pseudomembrane formation, but they are also rarely associated with chronic deep cutaneous granulomatous lesions with evidence of giant cells.(5,6,12) In humans, chronic mucocutaneous candidiasis (CMC) is defined as the inability to clear fungal infections leading to persistent and recurring infections of skin and mucous membranes with yeasts, mostly Candida albicans. Although CMCs can arise from a variety of clinical conditions (HIV infection, steroid therapy etc.), they also may present as primary, hereditary immunodeficiencies due to impaired cell-mediated immunity against Candida species, mainly reflecting defects in the T_h17 response.(10) Obvious predisposing immunosuppressive factors to facilitate tissue invasion of the opportunistic fungi could not be identified in the present case. As mandrills are natural and asymptomatic carriers of SIV, the SIV infection of the animal did probably not represent an immunocompromising factor.(8,15) However, it cannot be excluded that a possible immunosuppressive factor could have been social stress due to the mandrills role as the alpha male of the group at a rather young age. The presence of a primary immunodeficiency with general increased susceptibility for mucocutaneous candidiasis is also not unlikely and might also explain the poor success of the antimycotic therapy.

Other common etiologies for fungal infections of the skin in nonhuman primates include dermatophytes (Microsporum canis, Trichophyton mentagrophytes), Histoplasma capsulatum var. duboisii, Sporothrix schenckii, and Coccidioides immitis. While dermatophytes usually cause a mild superficial inflammatory response with hyperkeratosis and alopecia, infections with Histoplasma capsulatum var. duboisii, Sporothrix schenckii, and Coccidioides immitis may lead to ulcerative and granulomatous dermatitis.(3,5,15) Further descriptions of cutaneous mycoses in nonhuman primates include cutaneous zygomycosis characterized by necrotizing dermatitis and panniculitis in two adult female rhesus monkeys following extensive fight wound trauma and a focal fungal granuloma in the skin of the nose caused by Madurella mycetomatis in a female adult mandrill.(2,13)

JPC Diagnosis:  

Mucous membrane: Stomatitis, granulomatous, multifocal to coalescing, severe, with ulceration and numerous intracellular yeasts, pseudohyphae, and hyphae.

Conference Comment:  

Candida persists in the oropharyngeal cavity in the yeast form by ligand-receptor interactions. Yeast ligands include mannose, C3d receptors, and mannoproteins; and host receptors include fibrinogen, fibronectin, thrombin, collagen, laminin, and vitronectin-binding proteins. Candida yeast mainly bind mannose receptors, while Candida hyphae primarily bind complement receptor 3 (CR3) and the Fc-gamma receptor. Binding induces the yeast form to switch to the invasive filamentous form, which proliferates at normal body temperatures(14). Candida spp. produce a large number of functionally distinct adhesins that are important determinants of virulence; they also produce enzymes, including aspartyl proteinases, which degrade extracellular matrix proteins; catalases, which resist oxidative killing by phagocytic cells; and adenosine which blocks neutrophil oxygen radical production and degranulation(4,15).

Candidiasis is mainly a disease of keratinized epithelium in young animals, especially pigs, calves, and foals and typically presents as a superficial infection that produces relatively mild lesions in skin and mucous membranes that grossly appear as white pseudomembranes which, when removed, reveal ulcerated or erythematous tissue underneath. In birds it is a common infection in the mouth, esophagus, crop, and proventriculus. In piglets, lesions present in the oral cavity (thrush), esophagus, and gastric squamous mucosa. In calves, lesions are present in the ventral sac of the rumen, omasum, or reticulum following prolonged antibiotic therapy, and in foals, gastroesophageal candidiasis involves the squamous epithelium and is associated with ulceration adjacent to the margo plicatus(4).

In adult ruminants, Candida is one of several angioinvasive fungi that can produce mycotic abomasitis or rumentits and subsequent fungal hepatitis. The feeding of a high carbohydrate diet increases volatile fatty acids, leads to the disruption of normal rumen flora and proliferation of Streptococcus bovis, with subsequent lactic acid production. Ruminal acidosis results in mucosal ulceration allowing fungal hyphae to penetrate the mucosa, invade the vasculature, cause thrombosis, infarction, and acute necrosis. Subsequent hematogenous or direct spread leads to dissemination via portal vasculature to the liver(14). 

References:

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2. Baskin GB, Chandler FW, Watson EA: Cutaneous zygomycosis in rhesus monkeys (Macaca mulatta). Vet Pathol 21:125-128, 1984.
3. Bernstein JA and Didier PJ: Nonhuman primate dermatology: a literature review. Vet Dermatol 20:145-156, 2009. 
4. Brown CC, Baker DC, Barker IK. Alimentary system. In: Maxie MG, ed.  Jubb, Kennedy and Palmers Pathology of Domestic Animals. 4th ed. Philadelphia, PA: Elsevier ; 2007: 230.
5. Gibson SV: Bacterial and mycotic diseases, pp. 60-110. In Bennett BT, Abee CR, Henrickson R, eds. Nonhuman primates in biomedical research: diseases. San Diego: Academic Press, 1998.
6. Kirkpatrick CH: Chronic mucocutaneous candidiasis. J Am Acad Dermatol 31:S14-S17, 1994.
7. Lim YH and Lee DH: Rapid PCR method for detecting Candida albicans using primers derived from the integrin-like protein gene ɑINT1 of Candida albicans. Journal of Microbiology, 38, 105-108, 2000.
8. Liovat AS, Jacquelin B, Ploquin MJ, Barr+�-�-Sinoussi F, M+�-+ller-Trutwin MC: African non human primates infected by SIV Why dont they get sick? Lessons from studies on the early phase of non-pathogenic SIV infection. Curr HIV Res 7:39-50, 2009.
9. Migaki G, Schmidt RE, Toft JD, Kaufmann AF: Mycotic infections of the alimentary tract of nonhuman primates: a review. Vet Pathol 19:93-103, 1982.
10. Netea MG and Mar³di L: Innate immune mechanisms for recognition and uptake of Candida species. Trends Immunol 31:346-353, 2010.
11. Samaranayake YH, Samaranayake LP: Experimental oral candidiasis in animal models. Clin Microbiol Rev 14:398-429, 2001.
12. Slater DN, Harrington CI, Wylde P, Worth R: Systemic candidiasis: Diagnosis from cutaneous manifestations. JRSM 75:875-878, 1982.
13. Voracek T, Vielgrader H, Vogel B, Konar M: A case of fungal granuloma in a female mandrill (Mandrillus sphinx). Proc Eur Assoc Zoo Wildl Vet 4th scientific meeting, Heidelberg, pp. 501-502, 2002. Wachtman LM and Mansfield KG: Opportunistic infections in immunologically compromised nonhuman primates. ILAR J 49:191-208, 2008.
14. Zachary JF. Mechanisms of microbial infections. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO:Mosby; 2011:234-7.
15. Z+�-�ller M, et al. Mucocutaneous Candidiasis in a Mandrill (Mandrillus sphinx). J Comp Pathol. 2012 Jan 31. [Epub ahead of print]

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