The dog had been presented to the referring veterinarian five months earlier for evaluation of intermittent inappetence, polyuria, and polydipsia. The dog had a history of skin allergies, which had been treated with prednisone (0.5 mg/kg) intermittently and hyposensitization.
The results of a complete blood count and serum chemistry profile had been normal except for eosinophilia (2,048 cells/μl, reference range = 100 to 1,250 cells/μl). Urinalysis of a free-catch sample revealed isosthenuria with mild hematuria, pyuria, and bacteriuria. Cephalexin (22 mg/kg orally t.i.d. for 14 days) had been prescribed for a presumed bacterial urinary tract infection. No clinical improvement had been noted.
The dog had been brought back to the referring veterinarian three months later with the same presenting complaint. A complete blood count and serum chemistry profile performed at that time revealed persistent eosinophilia (2,125 cells/μl), hyperproteinemia (8.6 g/dl, reference range = 5.1 to 7.8 g/dl), hyperglobulinemia (5.4 g/dl, reference range = 2 to 4 g/dl), hypercalcemia (11.5 mg/dl, reference range = 8.5 to 11.3 mg/dl), and azotemia (blood urea nitrogen [BUN] 57 mg/dl, reference range = 7 to 27 mg/dl; creatinine 4.2 mg/dl, reference range = 0.4 to 1.8 mg/dl). The urinalysis results had been similar to those of the previous examination. The results of an aerobic bacterial urine culture, a serum total thyroxine measurement, and an abdominal radiographic examination had been normal. Phenylpropanolamine was prescribed at that time.
Physical examination and diagnostic tests
At presentation to Tufts University two months later, the dog weighed 93 lb (42.2 kg). It had lost 4.5 lb (2 kg) since the initial examination by the referring veterinarian. The dog's temperature, pulse, and respiration were normal, and the physical and ophthalmic examination results were unremarkable except for abdominal discomfort during palpation.
A serum chemistry profile revealed azotemia (BUN 47 mg/dl, reference range = 8 to 29 mg/dl; creatinine 5.6 mg/dl, reference range = 0.6 to 2 mg/dl), hypercalcemia (12.7 mg/dl, reference range = 9.4 to 11.6 mg/dl), and hyperkalemia (5.7 mEq/L, reference range = 3.8 to 5.4 mEq/L); the results were suggestive of renal disease. A complete blood count was not done at this time. Pending further diagnostic evaluation, the dog was treated with intravenous lactated Ringer's solution (170 ml/h) and ampicillin (22 mg/kg intravenously t.i.d.) for possible leptospirosis.
An ACTH stimulation test was performed to rule out hypoadrenocorticism as a cause of the polyuria, polydipsia, and eosinophilia. The results were normal (baseline cortisol = 3.1 μg/dl, reference range = 2 to 6 μg/dl; cortisol concentration an hour after cosyntropin administration = 13.8 μg/dl, reference range = 6 to 18 μg/dl). The dog was seronegative for antibodies to Leptospira species (serovars pomona, hardjo, icterohaemorrhagiae, grippotyphosa, canicola, and bratislava). Serologic testing for tick-borne diseases was not indicated based on the absence of such clinical signs as fever, lethargy, lameness, or lymphadenopathy.
Urinalysis of a sample collected by cystocentesis revealed isosthenuria (urine specific gravity 1.012), hematuria (20 to 30 red blood cells/hpf, 10 to 20 white blood cells/hpf), and many fungal hyphae. Aerobic bacterial and fungal urine cultures yielded no growth.
Differential diagnoses and further tests
The history, physical examination results, and laboratory findings were consistent with chronic renal disease. The ultrasonographic findings suggested chronic nephritis (interstitial, glomerular, or tubular nephritis) or pyelonephritis. However, the amorphous echogenic material seen in the collecting system was considered unusual in the absence of macroscopic hematuria. Our differential diagnoses for this finding were a blood clot, cellular debris, or, less likely, neoplastic or proliferative changes associated with the lining of the collecting system. In the absence of macroscopic hematuria, a blood clot was also considered less likely. And because there was no shadowing, the echogenic material was not considered to be a calculus. The echogenic material appeared amorphous and moved slightly during the examination, so cellular debris was considered most likely.
To establish a definitive diagnosis, the dog was anesthetized two days later, and an ultrasound-guided renal biopsy and pyelocentesis (for bacterial and fungal cultures) were performed. Pyelectasis and proximal hydroureter were present bilaterally and appeared to have mildly progressed since the previous ultrasonographic examination. Microscopic examination of the urine sample obtained by pyelocentesis revealed moderate neutrophilic inflammation and mats of branching, septate fungal hyphae. The morphologic features of the fungus were initially considered to be most consistent with Aspergillus species. A blood sample was obtained to test for Aspergillus species antibodies.
Diagnosis and outcome
We presumptively diagnosed renal aspergillosis. Because of the uncertain prognosis and the need for long-term therapy, the owners elected euthanasia. A postmortem examination was not performed.
The results of the aerobic and anaerobic bacterial cultures of the urine sample collected by pyelocentesis were negative. The Aspergillus species antibody titer (agar gel immunodiffusion test) results were also negative.
Paecilomyces species are found in soil and decaying vegetation worldwide. The genus Paecilomyces has mycelia that have broad, branching, septate hyphae with characteristic phialides swollen at the base. Colony size, color, and rate of growth vary among species.2 Members of this genus are often encountered in clinical microbiology laboratories as contaminants. Nevertheless, many cases have been reported in which the role of this fungus as a pathogen has been clearly demonstrated. These infections are referred to as paecilomycosis (a subtype of the hyalohyphomycosis group).
Disseminated paecilomycosis has been reported in dogs, a cat, rats, reptiles, a rhesus monkey, horses, and people.2-18 Additionally, Paecilomyces species are among the many emerging causative agents of opportunistic mycoses in immunocompromised people (most commonly associated with cutaneous infections, catheter-related fungemia, sinusitis). Most published case reports of paecilomycosis among otherwise healthy, nonimmunocompromised people have been infections involving the cornea, prosthetic lens implants, lacrimal sacs, maxillary sinuses, prosthetic mitral and aortic valves, the skin, and the peritoneum.2,17,18
In the veterinary literature, paecilomycosis most commonly affects dogs, with the disease typically manifesting as a systemically disseminated form or as diskospondylitis.3-11,16 In some animals, localized cutaneous disease is the only clinical sign of occult disseminated disease.3,12 The German shepherd is the breed most commonly affected with paecilomycosis or other systemic mycosis.15,19 Adult female dogs make up more than 90% of the reported cases of paecilomycosis in dogs.16 The areas most commonly involved in disseminated paecilomycosis are intervertebral disks, the liver, the spleen, visceral or peripheral lymph nodes (e.g. pancreatic, iliac, inguinal, renal, hepatic, mesenteric, sublumbar, cranial mediastinal, hilar, peritracheal, prescapular, and popliteal), and the kidneys.11
Paecilomyces species infection has been reported in two cats. One cat presented with local skin lesions that progressed into disseminated paecilomycosis after two months. This cat was treated with ketoconazole for three months without success.12 The second cat was 5 years old and had localized recurrent cutaneous infections of the left metacarpal region and upper lip. The cat was successfully treated with multiple excisions of the affected cutaneous tissues, débridement of surrounding tissues, and postoperative treatment with itraconazole.13
The location of the primary lesion in systemic paecilomycosis is not usually determined in animals. The authors of previously reported cases suspected cutaneous or mucosal wounds.3,5-7,9-12 The fungus can spread to different locations and progress slowly. Our patient had a history of skin allergies. It had been treated with prednisone and desensitization injections. It is possible that the prednisone and desensitization predisposed the dog to Paecilomyces species colonization. However, the route of entry of the fungus in our patient is unknown.
Paecilomycosis typically has a chronic course with clinical manifestations dependent on the affected organs. The most commonly reported clinical signs are fever, ataxia, paresis or paralysis, weight loss, and lameness3-16 ; however, vestibular signs, bilateral deafness, generalized seizures, chorioretinitis, and anemia have also been reported. All dogs reported to have paecilomycosis showed rapidly progressing clinical signs and were eventually euthanized.3-16
Systemic paecilomycosis affecting the kidneys has been previously reported in dogs. Renal lesions similar to the ones seen in our patient were observed in many of the reported cases of paecilomycoses,4,8-11,16 but the clinical signs associated with renal dysfunction were not present in any of the affected dogs. In our patient, renal involvement was manifested both clinically and histologically. Biopsy samples showed severe membranoproliferative glomerulonephritis and multifocal, pyogranulomatous nephritis. The most commonly encountered hematologic abnormalities in dogs with paecilomycosis are hyperglobulinemia,6,7,11,16 eosinophilia,5-7 and hypoalbuminemia.6-8 This dog exhibited hyperglobulinemia and eosinophilia.
In the published veterinary cases of paecilomycosis, most animals did not have obvious immunosuppressive conditions (e.g. terminal illness, immunosuppressive drugs) or an alteration of the normal microbial balance by prolonged antibiotic use. German shepherds have a relative deficiency of immunoglobulin A (IgA) compared with other purebred and mixed-breed dogs,20 supporting the possibility that local immunity might be defective in German shepherds and may play a role in the development of fungal infections. IgA is a component of mucosal surface immunity, which includes the skin and the respiratory, digestive, and reproductive tracts. The total serum IgA concentration was not measured in this dog.
Paecilomyces species infection is often difficult to diagnose because its presentation and the histologic appearance of the fungus are similar to the better-known Aspergillus species. In the localized form, paecilomycosis may be especially difficult to diagnose, but it is important to distinguish an active fungal infection from another disease with fungal contamination. The precise identification of a fungus can be made only by isolation in a pure culture. In this case, a microscopic examination of the urine collected in the renal pelvis demonstrated numerous fungal elements, while the biopsy sample obtained with ultrasound guidance demonstrated few fungal elements. Many of the histologic features were compatible with some of the more invasive and commonly encountered fungi such as Aspergillus species. However, after Paecilomyces species was cultured from the urine sample collected by pyelocentesis and the histologic samples were re-reviewed, some morphologic features were noted to be indicative of Paecilomyces species rather than Aspergillus species. Thus, fungal organisms may be difficult to identify based on histologic appearance, particularly with a limited sample size and the presence of few organisms, such as occurred with these core biopsy samples.
If systemic mycosis is suspected, especially in a mature German shepherd, obtain a urine sample in a sterile manner to look for fungal hyphae, which can often be identified in urine,15,19 and to perform a fungal culture. In addition, perform a cytologic examination and fungal culture of the lesion itself.15,19
In most veterinary reports, paecilomycosis is definitively diagnosed on postmortem examination.3-7,9-12 In this dog, we based our diagnosis of renal Paecilomyces species infection on findings from samples taken antemortem. Most of the findings in our patient suggested chronic pyelonephritis or glomerular, tubular, or interstitial nephritis21 ; however, the presence of echogenic material within the proximal collecting system (pelvis, proximal ureter) was unusual. Ultrasound-guided pyelocentesis is a safe procedure with which to collect urine samples for culture.22,23
Treating this rare disease is challenging. Several antifungal medications have been used, including itraconazole, ketoconazole, and amphotericin B. In vitro susceptibility testing in one study suggested that amphotericin B and itraconazole are optimal choices for treating paecilomycosis in veterinary patients.11 However, susceptibility-testing results often do not correlate with clinical outcome.2,11,18 For this reason, it is difficult to make specific recommendations regarding treatment. Nevertheless, sensitivity testing of each clinical isolate of Paecilomyces species is justified because it indicates a definite trend in susceptibility of the organism to antifungal agents.16
Fluconazole is a synthetic fungistatic triazole compound that penetrates the blood-brain, blood-prostate, and blood-ocular barriers well, and high drug concentrations are found in cerebrospinal fluid, urine, and ocular fluids. In addition, it is often used to treat systemic mycoses in cats when itraconazole is contraindicated or has been ineffective.24
Itraconazole, another synthetic fungistatic triazole compound that is widely distributed throughout the body, reaches high concentrations in the skin, sebum, and female reproductive tract and minimal concentrations in cerebrospinal fluid, urine, aqueous humor, and saliva. Paradoxically, fungal infections involving the central nervous system, prostate, or eyes often respond well to itraconazole. Adverse effects of itraconazole are dose-dependent and include gastrointestinal toxicity and hepatotoxicity.24
Ketoconazole, a less expensive imidazole antifungal agent, reaches high concentrations in the liver, adrenal glands, and pituitary gland and moderate concentrations in the kidneys, lungs, and bladder. Adverse effects include gastrointestinal signs, hepatotoxicity (cats are more prone), and thrombocytopenia.25
Amphotericin B, a macrolide antifungal agent, penetrates well into most tissues with the exception of the pancreas, muscle, bone, and aqueous humor. It must be administered intravenously and can be nephrotoxic.25
When dealing with invasive fungal diseases, it is important to administer antifungal therapy based on clinical signs until microbiologic identification is available. Antifungal therapy is typically required for several months.
In this dog, fluconazole would have been our treatment of choice because a high urine concentration is achieved. Amphotericin B would have been contraindicated because of its nephrotoxicity potential.
Paecilomyces species infection is an uncommon but devastating disease. To date, all cases with disseminated paecilomycosis have not responded favorably to treatment, although two dogs did achieve temporary remission. One dog was in remission for 12 weeks while being treated with amphotericin B and ketoconazole.8 A second dog temporarily responded to ketoconazole until it was euthanized nine months after initial diagnosis.16
Although our patient's lesions were not pathognomonic for fungal disease, it is recommended to further investigate urine fungal hyphae, particularly in German shepherds, because it may lead to an antemortem diagnosis of disseminated fungal disease. Early culture and sensitivity testing may offer assistance in determining effective antifungal therapy. An effective systematic approach and early diagnosis are paramount to potentially successfully treating paecilomycosis.
We gratefully acknowledge John Keating, DVM, DACVP, for his assistance in providing the photomicrographs, helpful corrections, and suggestions. We also wish to thank Joyce Knoll, DVM, DACVP, for her assistance with the cytologic diagnosis.
Kristina Feigin, DVM
Dominique Penninck, DVM, DVSc, DACVR, DECVDI
Mary Anna Labato, DVM, DACVIM
Mark Acierno, DVM, DACVIM*
Department of Clinical Sciences
Cummings School of Veterinary Medicine
North Grafton, MA 01536
Department of Veterinary Clinical Sciences
School of Veterinary Medicine
Louisiana State University
Baton Rouge, LA 70803
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