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Fungal Diseases of the Nasal Cavity of the Dog and Cat
UPDATE ON RESPIRATORY DISEASES
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FUNGAL DISEASES OF THE NASAL CAVITY OF THE DOG AND CAT Alice M. Wolf, DVM
Fungal infections are a common cause of nasal disease in the dog and cat. Common clinical signs include obstructed or noisy breathing (stertor, stridor), sneezing,· and unilateral or bilateral nasal discharge that may contain fresh blood. Destruction and distortion of the nasal cavity occurs with chronic fungal infections and pain secondary to periosteal involvement is present in some affected patients. Exophthalmos or pain on opening the mouth suggests extension of the infection behind the orbit. Gagging may be evident in patients with excessive postnasal drainage. Central nervous system signs are rare but can occur if the infection breaches the cribriform plate. , A thorough diagnostic evaluation should be performed in all patients with signs of nasal disease. Routine hematologic studies and biochemistry profiles are usually normal in patients with fungal rhinitis. Radiographs should be taken with the patient under a surgical plane of anesthesia in order to obtain accurate positioning. Nonscreen film or high-detail screens and film are required to adequately assess the nasal cavity structures. The radiographic study should include an openmouth, angled-beam, ventrodorsal view or a dorsoventral- intraoral view, and a rostrocaudal (skyline) view of the frontal sinuses. The lateral view of the nasal cavity usually is not helpful in the evaluation of patients with nasal mycoses. If available, computer-assisted tomography (CT scanning) or magnetic resonance imaging (MRI) provides exquisitely detailed definition of intranasal structures and lesions. From the Department of Small Animal Medicine and Surgery, Texas Veterinary Medical Center, Texas A&M University College of Veterinary Medicine, College Station, Texas
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Microbiologic cultures from the nasal cavity should be interpreted cautiously, because some potentially pathogenic fungi can be isolated from normal animals and animals with other diseases and because secondary bacterial infections may mask the presence of or accompany fungal disease. Cytologic examination of traumatic nasal cavity aspirates or flushes and histologic examination of pinch or punch biopsy specimens are more likely to provide an accurate diagnosis of mycotic disease. Serologic tests can be used to confirm the presence of and monitor the response to treatment of some mycotic diseases. Surgical exploration may be required to obtain tissue for diagnosis in some patients with mycotic disease. However, because this procedure is very traumatic and is rarely needed for appropriate therapy of nasal mycoses, all less invasive methods of diagnosis should be exhausted before surgical invasion of the nasal cavity is performed. ASPERGILLOSIS AND PENICILLOSIS Pathogenesis
Aspergillus and Penicillium spp are saprophytic hypha! fungi that are ubiquitous in the environment. Aspergillus fumigatus is the species most commonly isolated from nasal infections in dogs and cats; however, A. niger, A. nidulans, and A. flavus also have been recovered from this location. 35 Penicillium spp are rarely reported as causing invasive nasal disease.35 Because both agents appear to cause an identical clinical syndrome, aspergillosis and penicilliosis are discussed as a single disorder. Fungal colonization of the nasal passages occurs following inhalation of spores from the environment. Aspergillosis in humans usually occurs in immunosuppressed individuals. Investigation into the immune status of dogs affected with nasal aspergillosis has only rarely demonstrated evidence of any underlying immunosuppression. 35 One of three cats with nasal aspergillosis had concurrent feline leukemia virus infection. 10 Signalment
The age range of dogs affected with nasal aspergillosis is 6 months to 15 years; however, most infections occur in young to middle-aged dogs (1- 7 years). 35 Dogs with a dolichocephalic (long-nosed) conformation are predisposed to nasal aspergillosis; brachycephalic breeds are rarely affected. 26• 35 Golden Retrievers are overrepresented in one study/5 German Shepherds are overrepresented in one study/4 and underrepresented in another. 35 Male dogs appear to be at greater risk than females. There are few reports of cats with nasal aspergillosis; therefore, little is known about risk factors in this species.
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Clinical Signs
Sneezing and mucopurulent, sanguinopurulent, or hemorrhagic nasal discharge are the most common clinical signs of nasal aspergillosis.10· 24· 32· 35 The nasal discharge may initially be unilateral but usually becomes bilateral over time. 35 Some affected dogs develop ulceration of the external nares secondary to the chronic nasal drainage.34· 35 Some exhibit nasal pain by rubbing or pawing the faceY Pain also may be evident during palpation over the nasal cavity during physical examination.34 · Diagnosis
Hematology and Biochemistry
Routine hematology and serum biochemistry profiles usually are normal in dogs with nasal aspergillosis. Peripheral eosinophilia and lymphopenia has been observed in a few patients. 11 Radiographic Evaluation
The Aspergillus organisms or toxins destroy the nasal turbinates, resulting in increased radiolucency in the rostral portion of the nasal cavity. 32· 36 Punctate lysis of the frontal bones or vomer is present in some patients.36 The fungal growth and mucus accumulation in the caudal portion of the nasal cavity produces a mixed pattern of osteolysis and increased radiodensity in this area (Fig. 1). Increased density in the frontal sinuses may be due to fungal involvement or mucus accumulation. 32 Evidence of increased frontal bone thickness or lysis suggests the former36 (Fig. 2). Rhinoscopy
Rhinoscopic examination can be performed with an otoscope, arthroscope, or fiberoptic endoscope. Excess mucus obscuring examination of the nasal cavity can be removed by gentle flushing with warmed normal saline solution. The nasal mucosa will appear hyperemic and edematous; yellow-green to grey-black Aspergillus colonies may be present as plaque-like lesions on the mucosal surface. 20· 24· 35 Occasionally, a large fungal mass may completely occlude the nasal cavityY Material can be collected for cytologic and histologic examination by aspiration, flushing, or pinch biopsy. Cytologic specimens can be stained with routine Wright's hematologic stains or prepared as wet mounts with 10 to 20% KOH or new methylene blue. Branching, septate Aspergillus hyphae usually can be seen in histologic specimens stained with hematoxylin and eosin (Fig. 3); however, special fungal stains (periodic acid Schiff, Gomori's methenamine silver) may improve detection if few organisms are present.
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Figure 1. Ventrodorsal, open-mouth, angled-beam radiograph of a 6-year-old mixed-breed dog with nasal aspergillosis. Osteolysis is present in the rostral portion of the right nasal cavity. Turbinate lysis and increased density due to a fungal granuloma is apparent in the caudal portion of the right nasal cavity.
Figure 2. Rostrocaudal (skyline) view of the frontal sinuses in the same dog as Figure 1. Increased fluid density associated with punctate lysis and thinning of the frontal bone suggests active fungal involvement in the right sinus.
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Figure 3. Septate Aspergillus hyphae in a biopsy specimen from a dog with nasal aspergillosis. Original magnification, x 40. (Courtesy of Dr. Michael D. Willard, Texas A&M University, College Station, TX.)
Fungal Culture
Aspergillus spp grow well on routine fungal culture media incubated at room temperature. Isolation of Aspergillus in fungal cultures taken from the nasal cavity should be interpreted cautiously, .however, because the organism is a common contaminant in this location. 14 Conversely, failure to culture the organism does not rule out a diagnosis of aspergillosis. Fungal Serology
Agar gel double diffusion (AGDD), counterimmunoelectrophoresis (CIE), and enzyme-linked immunosorbent assay (ELISA) techniques to detect serum antibodies against Aspergillus can be used as an aid in the diagnosis of aspergillosis. 10• 26• 32• 35 Although positive serology results support active Aspergillus infection, false positivity rates for the first two techniques range from 5 to 15% and have not been critically evaluated for the third. 35 Cross-reactivity with Penicillium spp has been reported with all three test procedures. Serology results also may be falsely negative, particularly early in the course of disease. 26 Therefore, the results of serology studies for Aspergillus should always be correlated with clinical findings and the results of other diagnostic procedures.
Treatment Surgical excision alone is rarely successful, because removal of all affected tissues is not possible. If the diagnosis of aspergillosis is made
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at the time of surgical exploration, indwelling catheters should be placed in both frontal sinuses and nasal cavities to provide access for followup topical therapy. Postsurgical flushing of the nasal cavity with thiabendazole or povidone-iodine solution has been useful in reducing postoperative recurrence rates; however, enilconazole and clotrimazole are the preferred agents for topical therapy. Systemic treatment with thiabendazole (10 ·mg/kg PO q12h) or ketoconazole (5-10 mg/kg PO q12h) for 6 to 8 weeks has resulted in clinical cure rates of approximately 50%. 13• 32 Itraconazole (10 mg/kg PO q24h) has been used in human beings and dogs with aspergillosis with good results. 3 · 4 · 7• 37 At the time of writing, this drug is still under investigational new drug status but may be commercially available in the near future. Topical treatment with enilconazole appears to be very effective in curing nasal aspergillosis. 33• 35 Indwelling catheters are surgically placed bilaterally in the caudal aspect of the frontal sinuses and in the nasal cavity. Curretage of the nasal cavity at the time of tube placement is not necessary for effective treatment and is not recommended. Enilconazole (10 mg/kg) is diluted with an equal volume of water immediately prior to use. The dose is divided equally and instilled into each side of the nasal cavity, twice daily for 7 to 10 days. The dog's head should be held down during instillation of the drug to improve delivery of medication into the nasal cavity. Enilconazole apparently has an aversive taste, and many dogs will salivate profusely following treatment and exhibit avoidance behavior to subsequent drug administration. Both sides of the nasal cavity must be treated, because most dogs have bilateral involvement even if obvious clinical and radiographic signs of bilateral disease are not present. Clinical cure rates following enilconazole treatment are approximately 90%. 33· 35 A similar protocol has been developed using clotrimazole in polyethylene glycol instilled intranasally twice daily as described previously or used as a single intranasal treatment with prolonged contact time. (Davidson A, Pappagiannis 0, personal communication) Analysis of clinical cure rates following clotrimazole treatment is currently in progress.
CRYPTOCOCCOSIS Pathogenesis
Cryptococcus neoformans is a saprophytic yeast with a worldwide distribution. Nasal infection is believed to occur by inhalation of small yeast organisms from the environment. However, recent studies using intravenous or intraperitoneal inoculation of rhinotropic strain of Cryptococcus suggest that some strains of the organism may preferentially localize in the nasal cavity regardless of their portal of entry. 6 Cryptococcosis is the most common systemic mycotic infection of cats but is rare in dogs. 27• 29
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Signalment
The age range of cats affected with cryptococcosis is 1 to 13 years; the average age is 5.2 years. There is no apparent breed or sex predilection. Clinical Signs
Clinical signs are most commonly associated with the nasal cavity and sinuses. Infection induces the formation of granulomatous mass lesions in the nasal cavity and results in nasal discharge that ranges in character from mucopurulent to hemorrhagic.19 Local extension of the infection produces facial granulomas or regionallymphadenopathy19• 29 (Fig. 4). Distant skin lesions and peripheral lymphadenopathy occur in approximately 30% of feline patients. 29 The central nervous system (CNS) may be invaded by extension of nasal infection through the cribriform plate or by hematogenous spread. Clinical signs of CNS involvement are variable and include depression, amaurotic blindness, ataxia, circling, paresis, paralysis, and seizures. 16• 18 Ocular lesions are common and include optic neuritis, granulomatous chorioretinitis, retinal detachment, and anterior uveitis. 16• 18 Cryptococcus occasionally affects the lung, bone, and kidney. Fever usually is absent but malaise, anorexia, and weight loss may occur in patients with disseminated disease.
Figure 4. Facial granulomas and nasal distortion in a 3-year-old mixed-breed cat with cryptococcosis. This cat is also exhibiting anisocoria secondary to central nervous system and ocular involvement.
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Diagnosis
Clinical Pathology
Hematologic parameters usually are normal, but leukocytosis and a degenerative left shift have been reported. Biochemistry profiles usually are normal; hyperproteinemia is an occasional finding. Examination of the cerebrospinal fluid of patients with CNS involvement usually demonstrates increased cellularity, neutrophilia, elevated protein concentration, and numerous cryptococcal organisms. 18 Feline leukemia virus (FeLV) antigen and Feline immunodeficiency virus (FIV) antibody tests are usually negative in cats with cryptococcosis restricted to the nasal passage. Disseminated cryptococcosis is more common in FlY-infected cats. 15 Radiography
Radiographs of the nasal cavity early in the course of disease often reveal only increased soft-tissue density in one or both sides of the nasal cavity. As the fungal granulomas expand, the nasal turbinates and overlying nasal bones may be destroyed, causing nasal cavity distortion (Fig. 5). Thoracic radiographs rarely reveal significant pathology. Cytology and Biopsy
The diagnosis of cryptococcosis is confirmed by identifying the Cryptococcus organisms in Wright's stained aspirates or impression
Figure 5. Ventrodorsal, openmouth, angled-beam radiograph of a 7-year-old cat with nasal cryptococcosis. Increased density is present on the left side of the nasal cavity, and the nasal septum is deviated slightly to the right side.
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smears made from affected tissues or body fluids. Cryptococcus organisms have a 1 to 7 fLm center surrounded by a nonstaining 1 to 30 fLm capsule. The organism usually is found extracellularly, because the mucinous capsule apparently shields the organism from the host immune system. However, some strains of Cryptococcus may be more susceptible to host detection and cellular phagocytosis. These cryptococcal strains incite a granulomatous inflammatory reaction in which small yeast organisms are found within macrophages (Fig. 6). Cryptococcus usually is readily identified in hematoxylin and eosin-$tained tissue biopsy specimens collected from affected tissues. Fungal stains, particularly Mayer's mucicarmine stain, may be required to demonstrate the organism in some specimens. Serology
The latex cryptococcal antigen test (LCAT) is a sensitive and accurate method to detect cryptococcal capsular polysaccharide antigen in serum and cerebrospinal fluid. 21• 22· 27 In a recent study21 this test had a sensitivity of 95% and specificity of 100%. Cryptococcal antigen titers increase with the severity of the disease and can be used to monitor the response to therapy. 22· 27 Treatment
Ketoconazole at a dose of 10 mg/kg by mouth every 12 to 24 hours appears to be highly efficacious in the treatment of nasal cryptococ-
Figure 6. Intracellular and extracellular Cryptococcus neoformans organisms are present in this aspiration cytology specimen from a cat with nasal cryptococcosus.
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cosis. 19• 22• 23• 27• 29 Itraconazole (10 mg/kg PO q24h) and fluconazole (2.55.0 mg/kg PO q12-24h) also have promise on the basis of clinical and experimental stuqies in cats, humans, and laboratory animals, 3• 22• 30• 37 Both of these drugs have the advantage of having few~r side effects in cats (e.g., anorexia, hepatotoxicity) than ketoconazole. Fluconazole has the additional property of excellent penetration into the central nervous system and is preferred for patients with CNS involvement. 30 Treatment usually is continued for at least 8 weeks or at least 1 month after clinical signs have resolved. The LCAT can be monitored and should be decreasing if treatment is progressing satisfactorily.ZZ The prognosis for nasal cryptococcosis is guarded to fair depending on the stage of the disease and the degree of involvement. When CNS involvement is present, the prognosis is grave. RHINOSPORIDIOSIS Pathogenesis
Rhinosporidiosis is a rare disease of the canine nasal cavity. The causative agent, Rhinosporidium seeberi, is a soil-borne fungus of uncertain classification. 8 Damage to the nasal mucosa may be a predisposing factor in establishing infection following inhalation of fungal spores from dust or stagnant water. The organism is most frequently found in warm, humid regions of the world; however, sporadic cases have been reported from many locales. Signalment
Rhinosporidiosis occurs most commonly in large-breed dogs; males are more frequently affected than females. The majority of affected dogs are less than 6 years of age. No cases have been reported in cats. Clinical Findings
Common clinical signs include sneezing, snoring, and unilateral nasal discharge.L 2• 8• 25 The appearance of the discharge may be mucopurulent, serosanguineous, or hemorrhagic. 8 Rhinosporidia! polyps often develop in the anterior portion of the nasal cavity and may protrude from the external naris.1' 2 Rhinosporidiosis does not disseminate to other organs or tissues, and there are no systemic signs of illness. Diagnosis
Clinical Pathology
Routine hematologic and biochemical parameters usually are normal. Peripheral eosinophilia was present in a dog in one report. 8
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Radiography
Radiography is not usually performed, because the nasal mass is often readily visible. Radiographic findings in a few reported cases were nonspecific and included increased density in the nasal cavity and variable degrees of turbinate disruption. 8 • 9 Cytology and Biopsy
Cytologic examination of the nasal exudate or aspirates from the nasal cavity often reveals mucus, a mixed population of inflammatory cells, and 6 to 10 f.1m spherular fungal spores. L 8 Histopathologic examination of biopsy specimens demonstrates fibrovascular connective tissue, focally extensive mixed inflammatory infiltrate, and developing fungal sporangia. 2• 8 Fungal Culture
Rhinosporidia seeberi will not grow on routine cell-free bacterial or fungal culture media. The .organism has been successfully cultivated on monolayers of rectal tumor cells. 8 Treatment
Complete surgical excision is the treatment of choice for rhinosporidiosis and may be curative. L 2· 8 Medical approaches to treatment have been less successful. Diaminodiphenylsulfone (Dapsone) has been used successfully in the treatment of rhinosporidial polyps in humans. This drug was used at a dose of 1 mg/kg orally every 12 hours to successfully arrest the growth of rhinosporidial polyps in one dog. 1 Side effects o. dapsone may be life-threatening and include hemolytic anemia, methemoglobinemia, thrombocytopenia, and agranulocytosis. 1 Azole antifungal drugs may be effective against R. seeberi, but their use has not been reported to date. MISCELLANEOUS UNUSUAL NASAL MYCOSES AND RELATED INFECTIONS Phaeohyphomycosis
Several species of dematiaceous fungi, including Exophiala spinifera and Alternaria alternata, have been reported to cause nasal granulomas in cats.5 · 17 Local trauma or systemic immunosuppression is believed to predispose to infection with these organisms. 5 Complete surgical excision may be curative. Chemotherapy with flucytosine or azole antifungals has been successful alone and as an adjunct to surgery in several reported cases. 5• 17• 31
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Trichosporonosis
Trichosporon spp are saprophytic, filamentous yeasts. Infection with these fungi usually occurs in immunocompromised individuals. A single case of nasal trichosporonosis has been reported in a cat. 12 Recommended treatment for trichosporonosis includes surgical removal of affected tissue followed by topical or systemic azole antifungal therapy. 12
Blastomycosis and Histoplasmosis
Nasal infection with Blastomyces dermatidis and Histoplasma capsulatum has been reported in a few dogs and cats (Fig. 7). Infections with these systemic mycoses are unusual in this location, and a thorough search should be made for other sites of disseminated disease. The diagnosis usually is confirmed by finding the causative organisms in cytologic or histologic specimens. Surgery is usually unsuccessful in these patients because of the invasive and usually widespread nature of the disease. Treatment with amphotericin B and/or azole antifungal agents may be curative.
Figure 7. Nasal cavity swelling and distortion in an 11-month-old Burmese cat with Histoplasma capsulatum infection in the nasal cavity.
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Protothecosis
Prototheca wickerhamii is a colorless alga that is found as a saprophyte in moist environments. Nasal protothecosis has been reported in one cat. 28 Prototheca infections are very resistant to treatment. Complete surgical excision is recommended and may be curative. Medical therapy with amphotericin B and azole antifungals has been successful in a few cases. 28 References 1. Allison N, Willard MD, Bentinck-Smith J, eta!: Nasal rhinosporidiosis in two dogs. JAm Vet Med Assoc 188:869, 1986 2. Castellano MC, Idiart JR, Martin AA: Rhinosporidiosis in a dog. Vet Med 79:45, 1984 3. Denning DW, Tucker RM, Hanson LH, et a!: Itraconazole in opportunistic mycoses: Cryptococcosis and aspergillosis. JAm Acad Dermatol 23:602, 1990 4. Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: Review of 2,121 published cases. Rev Infect Dis 12:1147, 1990 5. Dhein CR, Leathers CW, Padhye AA, eta!: Phaeohyphomycosis caused by Alternaria alternata in a cat. J Am Vet Me~ Assoc 193:1101, 1988 6. Dixon DM, Polak A: In vivo and in vitro studies with an atypical rhinotropic isolate of Cryptococcus neoformans. Mycopathologica 96:33, 1986 7. Dupont B: ltraconazole therapy in aspergillosis: Study in 49 patients. J Am Acad Dermatol 23:607, 1990 8. Easley JR, Meuten DJ, Levy MG, et al: Nasal rhinosporidiosis in the dog. Vet Pathol 23:50, 1986 9. Fox SM: Surgical extirpation for rhinosporidiosis in a dog. Compend Contin Educ Pract Vet 8:152, 1986 10. Goodall SA, Lane JG, Warnock DW: The diagnosis and treatment of nasal aspergillosis in a cat. J Small Anim Pract 25:627, 1984 11. Goring RL, Stiff ME, Gross TL, et al: A contrast rhinographic diagnosis of nasal and sinusoidal aspergillosis in the dog: A case report. J Am Anim Hosp Assoc 19:920, 1983 12. Greene CE, Miller DM, Blue JL: Trichosporon infection in a cat. JAm Vet Med Assoc 187:946, 1985 13. Harvey CE: Nasal aspergillosis and penicilliosis in dogs: Results of treatment with thiabendazole. J Am Anim Hosp Assoc 184:48, 1984 14. Harvey CE: Therapeutic strategies involving antimicrobial treatment of the upper respiratory tract in small animals. J Am Vet Med Assoc 185:1159, 1984 15. Hutson CA, Medleau L, Wolf AM: Prevalence and clinical aspects of feline immunodeficiency virus in cryptococcosis-infected felines in the United States (abstr) In Proceedings of the First International Conference of Feline Immunodeficiency Virus Researchers, Davis, CA, 1991 16. Jergens AE, Wheeler CA, Collier LL: Cryptococcosis involving the eye and central nervous system of a dog. JAm Vet Med Assoc 189:302, 1986 17. Kettlewell P, McGinnis MR, Wilkinson GT: Phaeohyphomycosis caused by Exophiala spinifera in two cats. J Med Vet Mycol 27:257, 1989 18. Kock ND, Lane EP, Rowbotham F, et a!: Concurrent systemic cryptococcosis and haemangiosarcoma in a dog. J Comp Pathol 104:117, 1991 19. Legendre AM, Gompf R, Bone D: Treatment of feline cryptococcosis with ketoconazole. J Am Vet Med Assoc 181:1541, 1982 20. Medleau L, Marks MA, Brown J, et a]: Clinical evaluation of a cryptococcal antigen latex agglutination test for diagnosis of cryptococcosis in cats. J Am Vet Med Assoc 196:1470, 1990 21. McCarthy TC, McDermaid SL: Rhinoscopy. Vet Clin North Am Small Anim Pract 20:1265, 1990
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22. Medleau L, Greene CE, Rakich PM: Evaluation of ketoconazole and itraconazole for treatment of disseminated cryptococcosis in cats. Am J Vet Res 51:1454, 1990 23. Mikicuik MG, Fales WH, Schmidt DA: Successful treatment of feline cryptococcosis with ketoconazole and flucytosine. JAm Anim Hosp Assoc 26:199, 1990 · 24. Mortellaro CM, Della Franca P, Caretta G: Aspergillus fumigatus, the causative agent of infection of the frontal sinuses and nasal chambers of the dog. Mycoses 32:327, 1989 25. Mosier DA, Creed JE: Rhinosporidiosis in a dog. JAm Vet Med Assoc 185:1009, 1984 26. Norris AM, Laing EJ: Diseases of the nose and sinuses. Vet Clin North Am Small Anim Pract 15:865, 1985 27. Noxon JO, Monroe WE, Chinn DR: Ketoconazole therapy in canine and feline cryptococcosis. JAm Anim Hosp Assoc 22:179, 1986 28. Pedersen NC: Protothecosis. In Feline Infectious Diseases. Santa Barbara, CA, American Veterinary Publications, 1988, p 189 29. Pentlarge VW, Martin RA: Treatment of cryptococcosis in three cats using ketoconazole. JAm Vet Med Assoc 188:536, 1986 30. Perfect JR, Savani DV, Durack DT: Comparison of itraconazole and fluconazole in
31. 32.
33. 34. 35. 36. 37.
treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother 29:579, 1986 Sharkey PK, Graybill JR, Rinaldi MG, et a!: Itraconazole treatment of phaeohyphomycosis. JAm Acad Dermatol 23:577, 1990 Sharp N, Burrell MH, Sullivan M: Canine nasal aspergillosis: Serology and treatment with ketoconazole. J Small Anim Pract 25:149, 1984 Sharp NJH, Sullivan M: Treatment of canine nasal aspergillosis with systemic ketoconazole and enilconazole. Vet Rec 118:560, 1986 Sharp NJH, Sullivan M: Use of ketoconazole in the treatment of canine nasal aspergillosis. J Am Vet Med Assoc 194:782, 1989 Sharp NJH, Harvey CE, Sullivan M: Canine nasal aspergillosis and penicilliosis. Compend Contin Educ Pract Vet 13:41, 1991 Sullivan M, Lee R, Jakovljevic S, et a!: The radiological features of aspergillosis of the nasal cavity and frontal sinuses in the dog. J Small Anim Pract 27:167, 1986 Viviani MA, Tortorano AM, Langer M, et al: Experience with itraconazole in cryptococcosis and aspergillosis. J Infect 18:151, 1989
Address reprint requests to Alice M. Wolf, DVM Department of Small Animal Medicine and Surgery Texas Veterinary Medical Center Texas A&M University College of Veterinary Medicine College Station, TX 77843- 4474
0195-5616/92 $0.00 + .20
FUNGAL DISEASES OF THE NASAL CAVITY OF THE DOG AND CAT Alice M. Wolf, DVM
Fungal infections are a common cause of nasal disease in the dog and cat. Common clinical signs include obstructed or noisy breathing (stertor, stridor), sneezing,· and unilateral or bilateral nasal discharge that may contain fresh blood. Destruction and distortion of the nasal cavity occurs with chronic fungal infections and pain secondary to periosteal involvement is present in some affected patients. Exophthalmos or pain on opening the mouth suggests extension of the infection behind the orbit. Gagging may be evident in patients with excessive postnasal drainage. Central nervous system signs are rare but can occur if the infection breaches the cribriform plate. , A thorough diagnostic evaluation should be performed in all patients with signs of nasal disease. Routine hematologic studies and biochemistry profiles are usually normal in patients with fungal rhinitis. Radiographs should be taken with the patient under a surgical plane of anesthesia in order to obtain accurate positioning. Nonscreen film or high-detail screens and film are required to adequately assess the nasal cavity structures. The radiographic study should include an openmouth, angled-beam, ventrodorsal view or a dorsoventral- intraoral view, and a rostrocaudal (skyline) view of the frontal sinuses. The lateral view of the nasal cavity usually is not helpful in the evaluation of patients with nasal mycoses. If available, computer-assisted tomography (CT scanning) or magnetic resonance imaging (MRI) provides exquisitely detailed definition of intranasal structures and lesions. From the Department of Small Animal Medicine and Surgery, Texas Veterinary Medical Center, Texas A&M University College of Veterinary Medicine, College Station, Texas
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Microbiologic cultures from the nasal cavity should be interpreted cautiously, because some potentially pathogenic fungi can be isolated from normal animals and animals with other diseases and because secondary bacterial infections may mask the presence of or accompany fungal disease. Cytologic examination of traumatic nasal cavity aspirates or flushes and histologic examination of pinch or punch biopsy specimens are more likely to provide an accurate diagnosis of mycotic disease. Serologic tests can be used to confirm the presence of and monitor the response to treatment of some mycotic diseases. Surgical exploration may be required to obtain tissue for diagnosis in some patients with mycotic disease. However, because this procedure is very traumatic and is rarely needed for appropriate therapy of nasal mycoses, all less invasive methods of diagnosis should be exhausted before surgical invasion of the nasal cavity is performed. ASPERGILLOSIS AND PENICILLOSIS Pathogenesis
Aspergillus and Penicillium spp are saprophytic hypha! fungi that are ubiquitous in the environment. Aspergillus fumigatus is the species most commonly isolated from nasal infections in dogs and cats; however, A. niger, A. nidulans, and A. flavus also have been recovered from this location. 35 Penicillium spp are rarely reported as causing invasive nasal disease.35 Because both agents appear to cause an identical clinical syndrome, aspergillosis and penicilliosis are discussed as a single disorder. Fungal colonization of the nasal passages occurs following inhalation of spores from the environment. Aspergillosis in humans usually occurs in immunosuppressed individuals. Investigation into the immune status of dogs affected with nasal aspergillosis has only rarely demonstrated evidence of any underlying immunosuppression. 35 One of three cats with nasal aspergillosis had concurrent feline leukemia virus infection. 10 Signalment
The age range of dogs affected with nasal aspergillosis is 6 months to 15 years; however, most infections occur in young to middle-aged dogs (1- 7 years). 35 Dogs with a dolichocephalic (long-nosed) conformation are predisposed to nasal aspergillosis; brachycephalic breeds are rarely affected. 26• 35 Golden Retrievers are overrepresented in one study/5 German Shepherds are overrepresented in one study/4 and underrepresented in another. 35 Male dogs appear to be at greater risk than females. There are few reports of cats with nasal aspergillosis; therefore, little is known about risk factors in this species.
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Clinical Signs
Sneezing and mucopurulent, sanguinopurulent, or hemorrhagic nasal discharge are the most common clinical signs of nasal aspergillosis.10· 24· 32· 35 The nasal discharge may initially be unilateral but usually becomes bilateral over time. 35 Some affected dogs develop ulceration of the external nares secondary to the chronic nasal drainage.34· 35 Some exhibit nasal pain by rubbing or pawing the faceY Pain also may be evident during palpation over the nasal cavity during physical examination.34 · Diagnosis
Hematology and Biochemistry
Routine hematology and serum biochemistry profiles usually are normal in dogs with nasal aspergillosis. Peripheral eosinophilia and lymphopenia has been observed in a few patients. 11 Radiographic Evaluation
The Aspergillus organisms or toxins destroy the nasal turbinates, resulting in increased radiolucency in the rostral portion of the nasal cavity. 32· 36 Punctate lysis of the frontal bones or vomer is present in some patients.36 The fungal growth and mucus accumulation in the caudal portion of the nasal cavity produces a mixed pattern of osteolysis and increased radiodensity in this area (Fig. 1). Increased density in the frontal sinuses may be due to fungal involvement or mucus accumulation. 32 Evidence of increased frontal bone thickness or lysis suggests the former36 (Fig. 2). Rhinoscopy
Rhinoscopic examination can be performed with an otoscope, arthroscope, or fiberoptic endoscope. Excess mucus obscuring examination of the nasal cavity can be removed by gentle flushing with warmed normal saline solution. The nasal mucosa will appear hyperemic and edematous; yellow-green to grey-black Aspergillus colonies may be present as plaque-like lesions on the mucosal surface. 20· 24· 35 Occasionally, a large fungal mass may completely occlude the nasal cavityY Material can be collected for cytologic and histologic examination by aspiration, flushing, or pinch biopsy. Cytologic specimens can be stained with routine Wright's hematologic stains or prepared as wet mounts with 10 to 20% KOH or new methylene blue. Branching, septate Aspergillus hyphae usually can be seen in histologic specimens stained with hematoxylin and eosin (Fig. 3); however, special fungal stains (periodic acid Schiff, Gomori's methenamine silver) may improve detection if few organisms are present.
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Figure 1. Ventrodorsal, open-mouth, angled-beam radiograph of a 6-year-old mixed-breed dog with nasal aspergillosis. Osteolysis is present in the rostral portion of the right nasal cavity. Turbinate lysis and increased density due to a fungal granuloma is apparent in the caudal portion of the right nasal cavity.
Figure 2. Rostrocaudal (skyline) view of the frontal sinuses in the same dog as Figure 1. Increased fluid density associated with punctate lysis and thinning of the frontal bone suggests active fungal involvement in the right sinus.
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Figure 3. Septate Aspergillus hyphae in a biopsy specimen from a dog with nasal aspergillosis. Original magnification, x 40. (Courtesy of Dr. Michael D. Willard, Texas A&M University, College Station, TX.)
Fungal Culture
Aspergillus spp grow well on routine fungal culture media incubated at room temperature. Isolation of Aspergillus in fungal cultures taken from the nasal cavity should be interpreted cautiously, .however, because the organism is a common contaminant in this location. 14 Conversely, failure to culture the organism does not rule out a diagnosis of aspergillosis. Fungal Serology
Agar gel double diffusion (AGDD), counterimmunoelectrophoresis (CIE), and enzyme-linked immunosorbent assay (ELISA) techniques to detect serum antibodies against Aspergillus can be used as an aid in the diagnosis of aspergillosis. 10• 26• 32• 35 Although positive serology results support active Aspergillus infection, false positivity rates for the first two techniques range from 5 to 15% and have not been critically evaluated for the third. 35 Cross-reactivity with Penicillium spp has been reported with all three test procedures. Serology results also may be falsely negative, particularly early in the course of disease. 26 Therefore, the results of serology studies for Aspergillus should always be correlated with clinical findings and the results of other diagnostic procedures.
Treatment Surgical excision alone is rarely successful, because removal of all affected tissues is not possible. If the diagnosis of aspergillosis is made
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at the time of surgical exploration, indwelling catheters should be placed in both frontal sinuses and nasal cavities to provide access for followup topical therapy. Postsurgical flushing of the nasal cavity with thiabendazole or povidone-iodine solution has been useful in reducing postoperative recurrence rates; however, enilconazole and clotrimazole are the preferred agents for topical therapy. Systemic treatment with thiabendazole (10 ·mg/kg PO q12h) or ketoconazole (5-10 mg/kg PO q12h) for 6 to 8 weeks has resulted in clinical cure rates of approximately 50%. 13• 32 Itraconazole (10 mg/kg PO q24h) has been used in human beings and dogs with aspergillosis with good results. 3 · 4 · 7• 37 At the time of writing, this drug is still under investigational new drug status but may be commercially available in the near future. Topical treatment with enilconazole appears to be very effective in curing nasal aspergillosis. 33• 35 Indwelling catheters are surgically placed bilaterally in the caudal aspect of the frontal sinuses and in the nasal cavity. Curretage of the nasal cavity at the time of tube placement is not necessary for effective treatment and is not recommended. Enilconazole (10 mg/kg) is diluted with an equal volume of water immediately prior to use. The dose is divided equally and instilled into each side of the nasal cavity, twice daily for 7 to 10 days. The dog's head should be held down during instillation of the drug to improve delivery of medication into the nasal cavity. Enilconazole apparently has an aversive taste, and many dogs will salivate profusely following treatment and exhibit avoidance behavior to subsequent drug administration. Both sides of the nasal cavity must be treated, because most dogs have bilateral involvement even if obvious clinical and radiographic signs of bilateral disease are not present. Clinical cure rates following enilconazole treatment are approximately 90%. 33· 35 A similar protocol has been developed using clotrimazole in polyethylene glycol instilled intranasally twice daily as described previously or used as a single intranasal treatment with prolonged contact time. (Davidson A, Pappagiannis 0, personal communication) Analysis of clinical cure rates following clotrimazole treatment is currently in progress.
CRYPTOCOCCOSIS Pathogenesis
Cryptococcus neoformans is a saprophytic yeast with a worldwide distribution. Nasal infection is believed to occur by inhalation of small yeast organisms from the environment. However, recent studies using intravenous or intraperitoneal inoculation of rhinotropic strain of Cryptococcus suggest that some strains of the organism may preferentially localize in the nasal cavity regardless of their portal of entry. 6 Cryptococcosis is the most common systemic mycotic infection of cats but is rare in dogs. 27• 29
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Signalment
The age range of cats affected with cryptococcosis is 1 to 13 years; the average age is 5.2 years. There is no apparent breed or sex predilection. Clinical Signs
Clinical signs are most commonly associated with the nasal cavity and sinuses. Infection induces the formation of granulomatous mass lesions in the nasal cavity and results in nasal discharge that ranges in character from mucopurulent to hemorrhagic.19 Local extension of the infection produces facial granulomas or regionallymphadenopathy19• 29 (Fig. 4). Distant skin lesions and peripheral lymphadenopathy occur in approximately 30% of feline patients. 29 The central nervous system (CNS) may be invaded by extension of nasal infection through the cribriform plate or by hematogenous spread. Clinical signs of CNS involvement are variable and include depression, amaurotic blindness, ataxia, circling, paresis, paralysis, and seizures. 16• 18 Ocular lesions are common and include optic neuritis, granulomatous chorioretinitis, retinal detachment, and anterior uveitis. 16• 18 Cryptococcus occasionally affects the lung, bone, and kidney. Fever usually is absent but malaise, anorexia, and weight loss may occur in patients with disseminated disease.
Figure 4. Facial granulomas and nasal distortion in a 3-year-old mixed-breed cat with cryptococcosis. This cat is also exhibiting anisocoria secondary to central nervous system and ocular involvement.
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Diagnosis
Clinical Pathology
Hematologic parameters usually are normal, but leukocytosis and a degenerative left shift have been reported. Biochemistry profiles usually are normal; hyperproteinemia is an occasional finding. Examination of the cerebrospinal fluid of patients with CNS involvement usually demonstrates increased cellularity, neutrophilia, elevated protein concentration, and numerous cryptococcal organisms. 18 Feline leukemia virus (FeLV) antigen and Feline immunodeficiency virus (FIV) antibody tests are usually negative in cats with cryptococcosis restricted to the nasal passage. Disseminated cryptococcosis is more common in FlY-infected cats. 15 Radiography
Radiographs of the nasal cavity early in the course of disease often reveal only increased soft-tissue density in one or both sides of the nasal cavity. As the fungal granulomas expand, the nasal turbinates and overlying nasal bones may be destroyed, causing nasal cavity distortion (Fig. 5). Thoracic radiographs rarely reveal significant pathology. Cytology and Biopsy
The diagnosis of cryptococcosis is confirmed by identifying the Cryptococcus organisms in Wright's stained aspirates or impression
Figure 5. Ventrodorsal, openmouth, angled-beam radiograph of a 7-year-old cat with nasal cryptococcosis. Increased density is present on the left side of the nasal cavity, and the nasal septum is deviated slightly to the right side.
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smears made from affected tissues or body fluids. Cryptococcus organisms have a 1 to 7 fLm center surrounded by a nonstaining 1 to 30 fLm capsule. The organism usually is found extracellularly, because the mucinous capsule apparently shields the organism from the host immune system. However, some strains of Cryptococcus may be more susceptible to host detection and cellular phagocytosis. These cryptococcal strains incite a granulomatous inflammatory reaction in which small yeast organisms are found within macrophages (Fig. 6). Cryptococcus usually is readily identified in hematoxylin and eosin-$tained tissue biopsy specimens collected from affected tissues. Fungal stains, particularly Mayer's mucicarmine stain, may be required to demonstrate the organism in some specimens. Serology
The latex cryptococcal antigen test (LCAT) is a sensitive and accurate method to detect cryptococcal capsular polysaccharide antigen in serum and cerebrospinal fluid. 21• 22· 27 In a recent study21 this test had a sensitivity of 95% and specificity of 100%. Cryptococcal antigen titers increase with the severity of the disease and can be used to monitor the response to therapy. 22· 27 Treatment
Ketoconazole at a dose of 10 mg/kg by mouth every 12 to 24 hours appears to be highly efficacious in the treatment of nasal cryptococ-
Figure 6. Intracellular and extracellular Cryptococcus neoformans organisms are present in this aspiration cytology specimen from a cat with nasal cryptococcosus.
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cosis. 19• 22• 23• 27• 29 Itraconazole (10 mg/kg PO q24h) and fluconazole (2.55.0 mg/kg PO q12-24h) also have promise on the basis of clinical and experimental stuqies in cats, humans, and laboratory animals, 3• 22• 30• 37 Both of these drugs have the advantage of having few~r side effects in cats (e.g., anorexia, hepatotoxicity) than ketoconazole. Fluconazole has the additional property of excellent penetration into the central nervous system and is preferred for patients with CNS involvement. 30 Treatment usually is continued for at least 8 weeks or at least 1 month after clinical signs have resolved. The LCAT can be monitored and should be decreasing if treatment is progressing satisfactorily.ZZ The prognosis for nasal cryptococcosis is guarded to fair depending on the stage of the disease and the degree of involvement. When CNS involvement is present, the prognosis is grave. RHINOSPORIDIOSIS Pathogenesis
Rhinosporidiosis is a rare disease of the canine nasal cavity. The causative agent, Rhinosporidium seeberi, is a soil-borne fungus of uncertain classification. 8 Damage to the nasal mucosa may be a predisposing factor in establishing infection following inhalation of fungal spores from dust or stagnant water. The organism is most frequently found in warm, humid regions of the world; however, sporadic cases have been reported from many locales. Signalment
Rhinosporidiosis occurs most commonly in large-breed dogs; males are more frequently affected than females. The majority of affected dogs are less than 6 years of age. No cases have been reported in cats. Clinical Findings
Common clinical signs include sneezing, snoring, and unilateral nasal discharge.L 2• 8• 25 The appearance of the discharge may be mucopurulent, serosanguineous, or hemorrhagic. 8 Rhinosporidia! polyps often develop in the anterior portion of the nasal cavity and may protrude from the external naris.1' 2 Rhinosporidiosis does not disseminate to other organs or tissues, and there are no systemic signs of illness. Diagnosis
Clinical Pathology
Routine hematologic and biochemical parameters usually are normal. Peripheral eosinophilia was present in a dog in one report. 8
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Radiography
Radiography is not usually performed, because the nasal mass is often readily visible. Radiographic findings in a few reported cases were nonspecific and included increased density in the nasal cavity and variable degrees of turbinate disruption. 8 • 9 Cytology and Biopsy
Cytologic examination of the nasal exudate or aspirates from the nasal cavity often reveals mucus, a mixed population of inflammatory cells, and 6 to 10 f.1m spherular fungal spores. L 8 Histopathologic examination of biopsy specimens demonstrates fibrovascular connective tissue, focally extensive mixed inflammatory infiltrate, and developing fungal sporangia. 2• 8 Fungal Culture
Rhinosporidia seeberi will not grow on routine cell-free bacterial or fungal culture media. The .organism has been successfully cultivated on monolayers of rectal tumor cells. 8 Treatment
Complete surgical excision is the treatment of choice for rhinosporidiosis and may be curative. L 2· 8 Medical approaches to treatment have been less successful. Diaminodiphenylsulfone (Dapsone) has been used successfully in the treatment of rhinosporidial polyps in humans. This drug was used at a dose of 1 mg/kg orally every 12 hours to successfully arrest the growth of rhinosporidial polyps in one dog. 1 Side effects o. dapsone may be life-threatening and include hemolytic anemia, methemoglobinemia, thrombocytopenia, and agranulocytosis. 1 Azole antifungal drugs may be effective against R. seeberi, but their use has not been reported to date. MISCELLANEOUS UNUSUAL NASAL MYCOSES AND RELATED INFECTIONS Phaeohyphomycosis
Several species of dematiaceous fungi, including Exophiala spinifera and Alternaria alternata, have been reported to cause nasal granulomas in cats.5 · 17 Local trauma or systemic immunosuppression is believed to predispose to infection with these organisms. 5 Complete surgical excision may be curative. Chemotherapy with flucytosine or azole antifungals has been successful alone and as an adjunct to surgery in several reported cases. 5• 17• 31
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Trichosporonosis
Trichosporon spp are saprophytic, filamentous yeasts. Infection with these fungi usually occurs in immunocompromised individuals. A single case of nasal trichosporonosis has been reported in a cat. 12 Recommended treatment for trichosporonosis includes surgical removal of affected tissue followed by topical or systemic azole antifungal therapy. 12
Blastomycosis and Histoplasmosis
Nasal infection with Blastomyces dermatidis and Histoplasma capsulatum has been reported in a few dogs and cats (Fig. 7). Infections with these systemic mycoses are unusual in this location, and a thorough search should be made for other sites of disseminated disease. The diagnosis usually is confirmed by finding the causative organisms in cytologic or histologic specimens. Surgery is usually unsuccessful in these patients because of the invasive and usually widespread nature of the disease. Treatment with amphotericin B and/or azole antifungal agents may be curative.
Figure 7. Nasal cavity swelling and distortion in an 11-month-old Burmese cat with Histoplasma capsulatum infection in the nasal cavity.
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Protothecosis
Prototheca wickerhamii is a colorless alga that is found as a saprophyte in moist environments. Nasal protothecosis has been reported in one cat. 28 Prototheca infections are very resistant to treatment. Complete surgical excision is recommended and may be curative. Medical therapy with amphotericin B and azole antifungals has been successful in a few cases. 28 References 1. Allison N, Willard MD, Bentinck-Smith J, eta!: Nasal rhinosporidiosis in two dogs. JAm Vet Med Assoc 188:869, 1986 2. Castellano MC, Idiart JR, Martin AA: Rhinosporidiosis in a dog. Vet Med 79:45, 1984 3. Denning DW, Tucker RM, Hanson LH, et a!: Itraconazole in opportunistic mycoses: Cryptococcosis and aspergillosis. JAm Acad Dermatol 23:602, 1990 4. Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: Review of 2,121 published cases. Rev Infect Dis 12:1147, 1990 5. Dhein CR, Leathers CW, Padhye AA, eta!: Phaeohyphomycosis caused by Alternaria alternata in a cat. J Am Vet Me~ Assoc 193:1101, 1988 6. Dixon DM, Polak A: In vivo and in vitro studies with an atypical rhinotropic isolate of Cryptococcus neoformans. Mycopathologica 96:33, 1986 7. Dupont B: ltraconazole therapy in aspergillosis: Study in 49 patients. J Am Acad Dermatol 23:607, 1990 8. Easley JR, Meuten DJ, Levy MG, et al: Nasal rhinosporidiosis in the dog. Vet Pathol 23:50, 1986 9. Fox SM: Surgical extirpation for rhinosporidiosis in a dog. Compend Contin Educ Pract Vet 8:152, 1986 10. Goodall SA, Lane JG, Warnock DW: The diagnosis and treatment of nasal aspergillosis in a cat. J Small Anim Pract 25:627, 1984 11. Goring RL, Stiff ME, Gross TL, et al: A contrast rhinographic diagnosis of nasal and sinusoidal aspergillosis in the dog: A case report. J Am Anim Hosp Assoc 19:920, 1983 12. Greene CE, Miller DM, Blue JL: Trichosporon infection in a cat. JAm Vet Med Assoc 187:946, 1985 13. Harvey CE: Nasal aspergillosis and penicilliosis in dogs: Results of treatment with thiabendazole. J Am Anim Hosp Assoc 184:48, 1984 14. Harvey CE: Therapeutic strategies involving antimicrobial treatment of the upper respiratory tract in small animals. J Am Vet Med Assoc 185:1159, 1984 15. Hutson CA, Medleau L, Wolf AM: Prevalence and clinical aspects of feline immunodeficiency virus in cryptococcosis-infected felines in the United States (abstr) In Proceedings of the First International Conference of Feline Immunodeficiency Virus Researchers, Davis, CA, 1991 16. Jergens AE, Wheeler CA, Collier LL: Cryptococcosis involving the eye and central nervous system of a dog. JAm Vet Med Assoc 189:302, 1986 17. Kettlewell P, McGinnis MR, Wilkinson GT: Phaeohyphomycosis caused by Exophiala spinifera in two cats. J Med Vet Mycol 27:257, 1989 18. Kock ND, Lane EP, Rowbotham F, et a!: Concurrent systemic cryptococcosis and haemangiosarcoma in a dog. J Comp Pathol 104:117, 1991 19. Legendre AM, Gompf R, Bone D: Treatment of feline cryptococcosis with ketoconazole. J Am Vet Med Assoc 181:1541, 1982 20. Medleau L, Marks MA, Brown J, et a]: Clinical evaluation of a cryptococcal antigen latex agglutination test for diagnosis of cryptococcosis in cats. J Am Vet Med Assoc 196:1470, 1990 21. McCarthy TC, McDermaid SL: Rhinoscopy. Vet Clin North Am Small Anim Pract 20:1265, 1990
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22. Medleau L, Greene CE, Rakich PM: Evaluation of ketoconazole and itraconazole for treatment of disseminated cryptococcosis in cats. Am J Vet Res 51:1454, 1990 23. Mikicuik MG, Fales WH, Schmidt DA: Successful treatment of feline cryptococcosis with ketoconazole and flucytosine. JAm Anim Hosp Assoc 26:199, 1990 · 24. Mortellaro CM, Della Franca P, Caretta G: Aspergillus fumigatus, the causative agent of infection of the frontal sinuses and nasal chambers of the dog. Mycoses 32:327, 1989 25. Mosier DA, Creed JE: Rhinosporidiosis in a dog. JAm Vet Med Assoc 185:1009, 1984 26. Norris AM, Laing EJ: Diseases of the nose and sinuses. Vet Clin North Am Small Anim Pract 15:865, 1985 27. Noxon JO, Monroe WE, Chinn DR: Ketoconazole therapy in canine and feline cryptococcosis. JAm Anim Hosp Assoc 22:179, 1986 28. Pedersen NC: Protothecosis. In Feline Infectious Diseases. Santa Barbara, CA, American Veterinary Publications, 1988, p 189 29. Pentlarge VW, Martin RA: Treatment of cryptococcosis in three cats using ketoconazole. JAm Vet Med Assoc 188:536, 1986 30. Perfect JR, Savani DV, Durack DT: Comparison of itraconazole and fluconazole in
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treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother 29:579, 1986 Sharkey PK, Graybill JR, Rinaldi MG, et a!: Itraconazole treatment of phaeohyphomycosis. JAm Acad Dermatol 23:577, 1990 Sharp N, Burrell MH, Sullivan M: Canine nasal aspergillosis: Serology and treatment with ketoconazole. J Small Anim Pract 25:149, 1984 Sharp NJH, Sullivan M: Treatment of canine nasal aspergillosis with systemic ketoconazole and enilconazole. Vet Rec 118:560, 1986 Sharp NJH, Sullivan M: Use of ketoconazole in the treatment of canine nasal aspergillosis. J Am Vet Med Assoc 194:782, 1989 Sharp NJH, Harvey CE, Sullivan M: Canine nasal aspergillosis and penicilliosis. Compend Contin Educ Pract Vet 13:41, 1991 Sullivan M, Lee R, Jakovljevic S, et a!: The radiological features of aspergillosis of the nasal cavity and frontal sinuses in the dog. J Small Anim Pract 27:167, 1986 Viviani MA, Tortorano AM, Langer M, et al: Experience with itraconazole in cryptococcosis and aspergillosis. J Infect 18:151, 1989
Address reprint requests to Alice M. Wolf, DVM Department of Small Animal Medicine and Surgery Texas Veterinary Medical Center Texas A&M University College of Veterinary Medicine College Station, TX 77843- 4474