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Compendium December 2012 (Vol. 34, No. 12)

Clinical Snapshot: Multicentric Disease in a Young German Shepherd

by Dionne Ferguson, DVM, DACVIM

    Case Presentation

    A 2-year-old, spayed German shepherd was evaluated for incontinence, polyuria, polydipsia, lameness, decreased appetite, weight loss, and cloudiness in the eyes. Eleven weeks before presentation, the owner noticed that the dog was urinating more frequently and exhibiting nocturia. A urinalysis conducted at this first visit to the referring veterinarian revealed a low urine specific gravity (1.015), and the dog was treated with a course of antibiotics for suspected urinary tract infection. Five weeks later, the dog presented to the referring veterinarian again, this time for lameness that was minimally responsive to NSAIDs and cage rest. Additionally, a week before, the owner had noticed a cloudy appearance to the right eye, and the referring veterinarian had prescribed an antibiotic ointment. The owner stated that the dog continued to decline after this visit and had decreased appetite and loss of body condition.

    Upon presentation to the referral practice, the dog was bright, alert, and responsive and all vital signs were within normal limits. The body condition score was 3/9, with generalized muscle wasting that was most prominent in the proximal left forelimb. Limited examination of the right eye revealed mucopurulent discharge, conjunctival hyperemia, diffuse corneal edema, hyphema, and hypopion. No menace response was present in this eye, and pupillary light reflexes could not be evaluated due to severe changes (FIGURE 1). The left eye was within normal limits. There was intermittent non-weight-bearing lameness in the left forelimb, with pain and crepitus elicited upon flexion of the shoulder joint. The patient became fractious during examination, making pain otherwise difficult to localize. Thoracic radiography revealed lucency in the glenoid cavity of the left shoulder; otherwise, the radiographic findings were unremarkable. Radiography of the left shoulder (FIGURE 2) found an aggressive bone lesion of the left distal scapula with lysis and periosteal reaction at the caudal aspect of the neck of the scapula.

    Eye photograph

    Figure 1. Ophthalmic examination of right eye showing flocculent material in the anterior chamber, corneal edema, corneal vascularization, and episcleral injection.

    Courtesy of R. Carter

    A complete blood count, chemistry panel, and urinalysis revealed a mild leukocytosis (17.1 × 103/µL; reference range: 8 × 103/µL to 14.5 × 103/µL) due to a mild mature neutrophilia (13.3 × 103/µL; reference range: 3 × 103/µL to 11.5 × 103/µL) and a mildly increased blood urea nitrogen level (24 mg/dL; reference range: 8 to 22 mg/dL) with isosthenuria (1.012). Urine was submitted for bacterial culture and susceptibility testing. Abdominal ultrasonography revealed hypoechoic splenic nodules most consistent with nodular hyperplasia, but the diagnostic differentials included metastases, lymphoma, and granuloma. Spinal radiography revealed no evidence of diskospondylitis or other bony lesions.  

    Radiograph

    Figure 2. Radiographs of the left shoulder found an aggressive bone lesion of the left distal scapula with lysis and periosteal reaction at the caudal aspect of the neck of the scapula. The humerus was unaffected. The lesion was most consistent with neoplasia or osteomyelitis.

    With the patient under general anesthesia, ultrasound-guided arthrocentesis and bone aspiration were conducted to collect samples from the shoulder joint and lytic lesion. Synovial fluid cytology revealed mild neutrophilic inflammation; no organisms were detected. Joint fluid was submitted for bacterial and fungal culture. The bone aspiration samples were nondiagnostic, with only mild neutrophilic inflammation evident. Samples of aqueous and vitreous humor were collected for cytologic evaluation as well as bacterial and fungal culture. Cytologic evaluation of these samples revealed pyogranulomatous inflammation, with no infectious organisms noted. Culture results from the joint fluid, ocular fluid, and urine were pending, as were results of a quantitative urine antigen enzyme immunoassay for Blastomyces and Histoplasma spp. The next diagnostic steps offered to the owner were biopsy of the lytic lesion in the scapula and enucleation and histopathology of the right eye, which were declined. Four days after discharge, the dog presented for abnormal behavior and vomiting. Upon reexamination, it was noted that a right head tilt and severe horizontal nystagmus were now present with ambulatory ataxia. Due to worsening of the dog’s condition, the owner elected to euthanize.

    1. What are some diagnostic differentials for this patient at presentation and based on further diagnostic findings?

    2. What would be your top differential and why?

    3. How do you diagnose this disease, and what are the treatment recommendations and prognosis?

    Answers and Explanations

    1. The uveitis and multifocal signs raise suspicion of a systemic infectious disease, especially fungal disease. Immune-mediated disease (e.g., systemic lupus, immune-mediated polyarthropathy, glomerulonephritis) could also cause multifocal disease and the clinical signs seen in this case. Lymphoma with ocular involvement and other neoplasms with paraneoplastic syndromes were also considered. Osteochondritis dissecans was initially considered for the lameness. However, radiography findings suggested neoplastic or infectious disease. Congenital kidney diseases, such as renal dysplasia, were considered for the low urine specific gravity, although these were thought to be unlikely as the dog was older than 1 year when polyuria was first noted.

    2. Disseminated aspergillosis was suspected in this dog due to clinical findings of multifocal signs, renal involvement, the lytic bone lesion, uveitis, and signalment and the lack of findings consistent with other differentials. Aspergillus spp are saprophytic molds found ubiquitously in the environment. Disseminated aspergillosis is thought to occur after inhalation of spores and hematogenous spread.1–9 However, these cases often present with no history of nasal or pulmonary involvement.1 The disease typically involves multiple organ systems, with most patients being terminally ill at diagnosis.1,4 In one study, nine of 12 dogs presented with end-stage renal failure.4 Osteomyelitis and mycotic granulomas of the myocardium, spleen, kidneys, liver, thymus, lymph nodes, eyes, intervertebral disks, pancreas, prostate, brain, uterus, and thyroid gland have been reported.1–8,10 Clinical signs are nonspecific and related to organ involvement, with lameness, paraparesis, draining tracts, anorexia, weight loss, pyrexia, lethargy, muscle wasting, and fever being the most common signs.1–8,10,11 Renal insufficiency or failure is also a common component of disease in these patients.4–8,10,12,13 In some cases, ocular signs may precede the onset of generalized disease.1,4,8 Neurologic signs are usually due to diskospondylitis, although brain involvement does occur in humans.3,12 Brain lesions have been reported in a few veterinary patients with neurologic signs similar to those in this dog.3,5,8,11

    Disseminated aspergillosis was first described in a young German shepherd dog,2 and the breed continues to be overrepresented in the literature.1–12,14–17 In people, disseminated aspergillosis occurs secondary to immune disorders or other diseases that result in immune suppression.2–4 Genetic predisposition and dysfunctional mucosal immunity are suspected, and defective and/or decreased IgA has been identified in some German shepherds.1,4,14–23 A few cases have been reported in dogs with concurrent Candida infections, again suggestive of immunocompromise.24,25

    3. Suspicion of disseminated aspergillosis may be supported by observation of fungal hyphae in the urine sediment or in serum, synovial fluid, lymph node aspiration, bone biopsy, or intervertebral disk aspiration samples.1,4 Urine sediment reportedly has good diagnostic yield,4–7,10–12 but the diagnosis should always be confirmed by fungal culture as serology is not reliable.1 Aspergillus terreus is the most common species identified in these cases.1–7,12 However, other species, such as Aspergillus deflectus,10 Aspergillus flavipes, and, rarely, Aspergillus fumigatus,24 have been reported.1

    The prognosis for recovery is poor despite aggressive antifungal therapy and supportive care.1 Intravenous antifungals are advised initially (ABELCET, Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD), and long-term oral azole therapy can be attempted if the patient shows a favorable response to therapy.1 One case series reported success in four dogs, with elimination of infection in one dog.6 Surgical excision of fungal granulomas may be helpful, if feasible,1 but as stated, most dogs present with terminal illness.

    ***

    The dog’s remains were submitted for necropsy. Gross findings included marked muscle wasting that was most notable in the left forelimb, multifocal white areas in the diaphragm and myocardium (FIGURE 3), pinpoint white spots in the spleen, and irregular, mottled kidneys (FIGURE 4A, FIGURE 4B, and FIGURE 4C). The left kidney was more severely affected and had a white area at the apex of the papillary region and amorphous light red material in the renal pelvis. Other findings included enlarged tracheobronchial and mesenteric lymph nodes, flocculent material in the left shoulder joint with irregular articular surfaces, a markedly cloudy anterior chamber of the right eye, and pale, multifocal nodules in the bone marrow. Urine antigen test results were negative for Histoplasma and Blastomyces spp.

    Myocardium

    Figure 3. Granulomas (arrows) identified in the myocardium at necropsy.

    Courtesy of K. Holder

    Kidney surface

    Figure 4A. This image of the outer surface of the left kidney shows white, pitted areas (arrows) that histology revealed to be granulomas. Multifocal granulomas were identified in both kidneys during gross examination at necropsy.

    Courtesy of K. Holder

    Cut kidney

    Figure 4B. The cut surface of left kidney shows that the white pits in Figure 4A correlate with lesions deeper in the cortex (arrows).

    Courtesy of K. Holder

    Cut kidney

    Figure 4C. Close-up view of lesions (arrows) in Figure 4B.

    Courtesy of K. Holder

    Histopathology found Gömöri methenamine silver–positive fungal granulomas in the spleen, myocardium, liver, kidneys, pancreas, bone marrow, and lymph nodes. The kidneys also had large areas of hemorrhage, tubular degeneration, necrosis, and fibrosis affecting 70% to 80% of the organs. The light red material from the left renal pelvis was determined to be a mat of fungal hyphae, necrotic material, and inflammatory cells (FIGURE 5). Strangely, in this case, prior urinalysis was not diagnostic, despite discovery of this fungal mat. The right eye had severe inflammation and edema with moderate numbers of fungal hyphae in the posterior chamber and vitreous. Hyphae were found in amorphous protein material adhered to the lens. The retina was separated from the retinal pigmented epithelium by inflammatory cells, hemorrhage, fibrin, and edema. Eosinophilic and histiocytic inflammation was present in the pulmonary parenchyma, and increased numbers of eosinophils were found in the lamina propria of the gastrointestinal tract. No gross or microscopic lesions were identified in the brain. Aspergillus was cultured from the shoulder joint fluid (premortem sample) and a tracheobronchial lymph node (postmortem sample). Bacterial cultures from all samples were negative. The Aspergillus sp was identified as Aspergillus terreus, 99% identity by β-tubulin gene.

    Fungal stain

    Figure 5. Sample taken from the fungal mat in the left renal pelvis (hematoxylin-eosin stain on right, Gömöri methenamine silver stain on left highlighting Aspergillus hyphae).

    References

    1. Davidson AP. Aspergillosis. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed. Philadelphia, PA: WB Saunders; 2010:996-1002.

    2. Wood GL, Hirsh DC, Selcer RR, et al. Disseminated aspergillosis in a dog. J Am Vet Med Assoc 1978;172(6):704-707.

    3. Mullaney TP, Levin S, Indrieri RJ, et al. Disseminated aspergillosis in a dog. J Am Vet Med Assoc 1983;182(5):516-518.

    4. Day MJ, Penhale WJ, Eger CE, et al. Disseminated aspergillosis in dogs. Aust Vet J 1986;63:55-59.

    5. Neer TM. Disseminated aspergillosis. Compend Contin Educ Pract Vet 1988;10(4):465-471.

    6. Kelly SE, Shaw SE, Clark WT. Long-term survival of four dogs with disseminated Aspergillus terreus infection treated with itraconazole. Aust Vet J 1995;72:311-313.

    7. Berry WL, Leisewitz AL. Multifocal Aspergillus terreus discospondylitis in two German shepherd dogs. J South Afr Vet Assoc 1996;67(4):222-228.

    8. Bruchim Y, Elad D, Klainbart S. Disseminated aspergillosis in two dogs in Israel. Mycoses 2006;49:130-133.

    9. Tapia ALH, Mejía ECS, Lezama JR, et al. Systemic presentation of Aspergillus spp with neurological involvement in a German shepherd: clinical case report. Vet Mex 2010;41(1):13-24.

    10. Robinson WF, Connole MD, King TJ, et al. Systemic mycosis due to Aspergillus deflectus in a dog. Aust Vet J 2000;78:600-602.

    11. Elad D, Lahav D, Blum S. Transuterine transmission of Aspergillus terreus in a case of disseminated aspergillosis. Med Mycol 2008;46:175-178.

    12. Dallman MJ, Dew TL, Tobias L, et al. Disseminated aspergillosis in a dog with diskospondylitis and neurologic deficits. J Am Vet Med Assoc 1992;200(4):511-513.

    13. Wilson SM, Odeon A. Disseminated Aspergillus terreus infection in a dog. J Am Anim Hosp Assoc 1992;28:447-450.

    14. Pérez J, Mozos E, de Lara FC, et al. Disseminated aspergillosis in a dog: an immunohistochemical study. J Comp Pathol 1996;115:191-196.

    15. Day MJ, Eger CE, Shaw SE, et al. Immunologic study of systemic aspergillosis in German shepherd dogs. Vet Immunol Immunopathol 1985;9:335-347.

    16. Day MJ, Penhale WJ. An immunohistochemical study of canine disseminated aspergillosis. Aust Vet J 1991;68:383-386.

    17. Day MJ, Penhale WJ. Humoral immunity in disseminated Aspergillus terreus infection in the dog. Vet Microbiol 1988;16:283-294.

    18. Whitbread TJ, Batt RM, Garthwaite G. Relative deficiency of serum IgA in the German shepherd dog: a breed abnormality. Res Vet Sci 1984;37:350-352.

    19. Day MJ, Penhale WJ. Serum immunoglobulin A concentrations in normal and diseased dogs. Res Vet Sci 1988;45:360-363.

    20. Batt RM, Barnes A, Rutgers HC, Carter SD. Relative IgA deficiency and small intestinal bacterial overgrowth in German shepherd dogs. Res Vet Sci 1991;50:106-111.

    21. Day MJ. Low IgA concentration in the tears of German shepherd dogs. Aust Vet J 1996;74(6):433-434.

    22. German AJ, Hall EJ, Day MJ. Relative deficiency in IgA production by duodenal explants from German shepherd dogs with small intestinal disease. Vet Immunol Immunopathol 2000;76:25-43.

    23. Littler RM, Batt RM, Lloyd DH. Total and relative deficiency of gut mucosal IgA in German shepherd dogs demonstrated by faecal analysis. Vet Rec 2006;158:334-341.

    24. Clercx C, McEntree K, Snaps F, et al. Bronchopulmonary and disseminated granulomatous disease associated with Aspergillus fumigatus and Candida species infection in a golden retriever. J Am Anim Hosp Assoc 1996;32:139-145.

    25. Berkowitz A, Perl S, Elad D, et al. Disseminated aspergillosis in association with Candida glabrata infection in a vizsla dog in Israel. Isr J Vet Med 2010;65(2):68-71.

    References »

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