History

A 5-year-old 21-kg (46.2-lb) castrated male Shetland Sheepdog was evaluated because of penile necrosis and stranguria. Four weeks earlier, the dog was presented to the primary veterinarian for evaluation of blue discoloration of the distal portion of the penis, diarrhea, and general malaise. At that time, the dog was febrile (rectal temperature, 40°C [104°F]) with fecal staining around its anus. Radiography revealed no abnormality of the os penis. A urethral catheter was placed without difficulty, and the urinary bladder was emptied. The dog was treated with deracoxib for pain relief, metronidazole as an antidiarrheal agent, and cephalexin for a suspected bacterial infection. Two days later, the dog was presented because of preputial swelling and stranguria, in addition to unilateral epistaxis. A presumptive diagnosis of immunemediated thrombocytopenia was made on the basis of moderate to marked thrombocytopenia (46 × 10³ platelets/mm³; reference interval, 200 × 10³ to 500 × 10³ platelets/mm³), and treatment with prednisone was initiated. The urinary bladder was emptied via urethral catheterization. Over the subsequent days, the dog's penis became progressively darker in color and the stranguria persisted, prompting referral to a veterinary teaching hospital.

Clinical and Clinicopathologic Findings

At the referral examination, signs of pain were elicited on abdominal palpation. The distal portion (approx 3 to 4 cm in length) of the penis and a smaller area (approx 2 cm in length) of the distal aspect of the prepuce appeared devitalized. Serum biochemical analysis revealed azotemia (urea concentration, 21.8 mmol/L [reference interval, 2.8 to 8.9 mmol/L]; creatinine concentration, 334 μmol/L [reference interval, 54 to 122 μmol/L]), hyperphosphatemia (2.71 mmol/L; reference interval, 0.84 to 1.83 mmol/L), hypoalbuminemia (24 g/L; reference interval, 30 to 36 g/L), and hyperglobulinemia (40 g/L; reference interval, 25 to 38 g/L). Analysis of a urine sample obtained via catheterization revealed a urine pH of 5, specific gravity of 1.026, 1 to 3 neutrophils/hpf (400X), and 0 to 2 RBCs/hpf.

Ultrasonography revealed a large amount of echogenic free fluid in the dog's abdomen. The urinary bladder was mildly distended with echogenic fluid, and a discontinuous segment of the caudal ventral aspect of the bladder wall was identified. Within this region of the wall, hyperechoic, distally attenuating foci were present and interpreted as free air. These findings were suggestive of a perforation of the urinary bladder. Ultrasound-guided abdominocentesis yielded cloudy serosanguineous fluid that had the following characteristics: 48.9 × 10⁹ nucleated cells/L, 0.03 × 10¹² RBCs/L, and protein concentration < 25 g/L. The creatinine, urea, and potassium concentrations of the abdominal fluid were 1,139 μmol/L, 39.7 mmol/L, and 11.2 mmol/L, respectively. Cytologic analysis of the abdominal fluid revealed a predominance of degenerated neutrophils along with a few macrophages and mesothelial cells, a low to moderate number of intracellular coccoid to diplococcoid bacteria, and a low number of small (approx 2- to 3-μm-wide × 3- to 4-μm-long), ovoid yeast-like organisms that were surrounded by a thin-walled, nonstaining capsule (Figure 1). These organisms were free within the fluid, within neutrophils, and rarely within macrophages. Contrast cystography with iohexol^a was subsequently performed, and leakage of the contrast agent into the peritoneum was not evident.

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Photomicrograph of a cytocentrifuge preparation of a sample of abdominal fluid from a Shetland Sheepdog with a history of penile necrosis and stranguria. There are degenerated neutrophils along with intracellular coccoid to diplococcoid bacteria (arrowhead) and small (approx 2- to 3-μm-wide × 3- to 4-μm-long), ovoid organisms that are surrounded by a thin-walled, nonstaining capsule (arrow). Wright-Giemsa stain; bar = 10 μm.

Citation: Journal of the American Veterinary Medical Association 257, 2; 10.2460/javma.257.2.161

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Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→

Additional Clinicopathologic Findings

Hematologic evaluation at the time of referral revealed normocytic, normochromic, nonregenerative anemia (Hct, 0.31 L/L; reference interval, 0.40 to 0.56 L/L); the platelet count was within the reference interval. There was leukocytosis (WBC count, 28.2 × 10⁹ cells/L; reference interval 5.4 × 10⁹ to 14.3 × 10⁹ cells/L) characterized by neutrophilia (25.9 × 10⁹ neutrophils/L; reference interval, 2.8 × 10⁹ to 10.1 × 10⁹ neutrophils/L) that was accompanied by lymphopenia (0.6 × 10⁹ lymphocytes/L; reference interval, 0.9 × 10⁹ to 4.6 × 10⁹ lymphocytes/L).

Case Management

The dog underwent an exploratory laparotomy, which revealed a defect in the urinary bladder wall. The bladder wall defect was repaired, and the necrotic portion of the penis was resected along with the remaining excess preputial skin, which included the devitalized preputial tissue. Specimens of the bladder wall and the resected portion of the penis were submitted for histologic evaluation. Samples of the abdominal fluid and urine were also submitted for aerobic bacterial and fungal cultures. The abdomen was lavaged thoroughly with sterile saline (0.9% sodium chloride) irrigation solution, and a closed suction drain was placed.

Histopathologic Findings

The tissue specimens from the penis and urinary bladder were examined histologically. At the proximal margin of the resected penile tissue, there was viable tissue that transitioned distally to complete coagulative necrosis. Relatively large areas of hemorrhage, fibrin exudation, and aggregates of mostly degenerated inflammatory cells (apparently neutrophils) were scattered throughout many areas. At the junction between the viable and necrotic tissue, a few medium-sized arteries contained fibrin thrombi that had appeared to be in the early stage of organization as evidenced by the presence of fibroblasts. Sections of the urinary bladder specimen had evidence of widespread ulceration with a layer of fibrin admixed with neutrophils overlying the surface (Figure 2). Multifocally within the ulcer bed, bacteria and small to moderate numbers of yeast, occasionally in aggregates, were present. These fungal organisms were round to slightly oval (approx 2 to 3 μm in length) and had occasional budding. The underlying submucosa revealed patchy to widespread hemorrhage and, in several areas, fibroplasia. In sections from a presumed area of bladder wall perforation, hemorrhage and fibroplasia extended through the muscle layers.

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Photomicrograph of a section of the urinary bladder with a layer of fibrin admixed with neutrophils overlying a widely ulcerated mucosa (asterisks). H&E stain; bar = 200 μm. Inset—Many neutrophils contain yeast (arrows) that are round to slightly oval (approx 2 to 3 μm in length). H&E stain; bar = 20 μm.

Citation: Journal of the American Veterinary Medical Association 257, 2; 10.2460/javma.257.2.161

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Microbiological Findings

Culture of an abdominal fluid sample on blood agar yielded 1+ growth of Candida glabrata and scant growth of Staphylococcus sp. Culture of a urine sample also revealed scant growth of C glabrata and heavy growth of Staphyloccocus epidermidis.

Morphologic Diagnosis and Case Summary

Morphologic diagnosis: penile vascular thrombosis with infarction (dry gangrene) of undetermined etiopathogenesis; severe, chronic-active, locally extensive, ulcerative, and fibrinosuppurative cystitis with bladder wall perforation, fibroplasia, and intralesional bacteria and yeast (S epidermidis and C glabrata); uroabdomen; and bacterial and fungal peritonitis (Staphylococcus sp and C glabrata).

Case summary: bacterial and fungal peritonitis and cystitis in a dog.

Comments

Candida spp, which are ubiquitous and dimorphic fungi, are commensals of the mammalian oral cavity and upper respiratory, gastrointestinal, and urogenital tract mucosae.^1,2 As opportunistic agents, members of the genus Candida can invade host tissues and cause clinical disease when host defenses are compromised or when there are influences that favor proliferation of the organisms, such as previous antimicrobial treatment or gastrointestinal tract surgery.^1,3–8 Tissue invasion and overgrowth of Candida spp can result in various forms of disease ranging from urinary tract infections to severe, life-threatening bloodstream infections with disseminated disease and potential multi-organ involvement.^1,7 Although Candida albicans is most often implicated in dogs, cats, and humans with candidiasis, the number of infections with non-C albicans Candida (NCAC) spp, such as C glabrata, among humans has increased in recent years.^9,10 The increased incidence of NCAC spp infection in humans has been postulated to be a result of a combination of higher numbers of immunocompromised patients; increased and widespread use of immunosuppressive, antimicrobial, and antimycotic agents; increased resistance of fungi to antifungal agents; and improvements in diagnostic techniques to better differentiate Candida spp.⁹ Although uncommon, reports of infections involving NCAC spp in companion animals have also increased during the last decade.^4–6 In particular, urinary tract infections involving C glabrata have been identified in dogs⁵ and cats,^4,5 and peritonitis associated with C glabrata infection in 2 dogs has been reported.⁶

Invasive candidiasis can be diagnosed on the basis of results of culture of various types of samples, including blood, urine, or other tissues.¹ With regard to blood samples collected for culture to identify Candida spp, arterial blood samples are preferred over venous samples because the organisms often are effectively filtered by various tissues.¹ A PCR assay has also been used to detect and identify Candida spp in veterinary patients.^1,11 However, isolation of Candida spp from cutaneous or mucosal surfaces does not confirm the presence of an invasive infection¹; to prove invasive infection is present, morphological evidence of tissue invasion and host reaction must be sought.^1,12 In the dog of the present report, cytologic identification of yeast organisms within inflammatory cells in the abdominal fluid sample evaluated suggested proliferation of the organism within the peritoneum (ie, a true infection), thereby prompting rapid submission of specimens for fungal culture and initiation of antifungal treatment. Furthermore, histologic identification of organisms in sections of inflamed bladder wall confirmed the diagnosis of invasive candidiasis.

The initiating cause of the penile vascular thrombosis in the dog of the present report was not known. However, considering the damage to the penile tissues and difficulties with urination that developed as a result of the penile vascular thrombosis, it was not surprising that the lower urinary tract became compromised, predisposing the dog to cystitis caused by both bacterial and fungal agents. Additionally, the administration of prednisone to the dog may have further compromised its immune system,¹³ allowing for proliferation of commensal bacteria and yeast. The dog had a concurrent staphylococcal infection, which is not an uncommon finding because other aerobic or anaerobic organisms may be isolated along with Candida spp from septic peritoneal fluid.⁷ For the dog of the present report, dissemination of bacteria and yeast into the abdomen was suspected to have occurred as a result of ulcerative cystitis and subsequent perforation of the urinary bladder wall. The azotemia (primarily postrenal) was likely attributable to uroabdomen, which was diagnosed because the creatinine and potassium concentrations in the abdominal fluid sample were 2 times their respective concentrations in serum.¹⁴ The mildly low urine specific gravity may have been normal for this dog or related to recent steroid administration.¹⁵ Although underlying renal disease could not be definitively ruled out, the azotemia ultimately resolved, making renal disease less likely. The dog's neutrophilia was attributed to inflammation and stress, the latter of which was further supported by lymphopenia.¹⁶ The hyperglobulinemia, hypoal-buminemia, and nonregenerative anemia were also all attributed to inflammation.^17,18

For the dog of the present report, resolution of the fungal peritonitis and cystitis was attained with fluconazole treatment, and doxycycline was administered for treatment of the concurrent staphylococcal infection based on results of antimicrobial susceptibility testing. Although fluconazole was effective in this case, it is important to note that resistance of Candida spp to antifungal agents has been documented.^19,20 In particular, C glabrata has intrinsic and acquired resistance to azoles, such as fluconazole.^20,21 For animals with candidiasis, definitive species identification and antifungal susceptibility testing of the infective microorganism may therefore be important for therapeutic reasons.^19,20

Despite several published reports of Candida peritonitis in dogs, there remains a paucity of information about this condition in the veterinary medical literature. The case described in the present report should help increase awareness of NCAC spp-associated cystitis and peritonitis in companion animals, in light of the more common fungal peritonitis attributable to C albicans infection.^6,7,22,23 To the authors’ knowledge, this is only the third report of C glabrata peritonitis in a dog, and the first report of C glabrata peritonitis secondary to a bladder wall defect and uroabdomen. The previous 2 reported cases of C glabrata peritonitis in dogs involved leakage of bile or gastrointestinal contents into the abdominal cavity.⁶ The case described in the present report has highlighted the importance of considering candidiasis as a differential diagnosis for septic peritonitis secondary to uroabdomen because signs of fungal peritonitis may mimic those of bacterial peritonitis. It also has highlighted the importance of cytologic and histologic evaluation and culture of appropriate specimens to help determine the clinical relevance of the organisms identified. Finally, this case has underscored the importance of determining the species of Candida in infected patients for both epidemiological and therapeutic reasons.