Introduction

Blastomycosis is a systemic infection caused by the dimorphic, soil-borne fungus Blastomyces dermatitidis. Within the United States, it is endemic east of the Missouri River, including the river valleys (Ohio and Mississippi), Great Lakes region, and East Coast (from Georgia to Vermont).^1,2 Infection occurs when spores produced by the Blastomyces organism are inhaled into the lungs. The infection can remain confined to the lung or disseminate to other organs such as bone, eyes, skin, lymph nodes, and brain.^3–8

Compared to dogs, blastomycosis is rare in cats. Retrospective studies conducted over the prior 40 yr have identified 1144 canine and 73 feline blastomycosis cases.^3–10 Because the respiratory tract is the primary site of infection, clinical signs consistent with disease of this system are present in at least 50% each of canine and feline cases.^3–7 However, the clinical signs are almost exclusively localized to the intrathoracic or lower respiratory tract, namely, tachypnea, dyspnea, or cough.^3–7 Far less commonly, blastomycosis can affect the upper respiratory tract of dogs (pharynx, larynx, and nasal cavity) and cats (larynx and nasal cavity).^7,8,11–14 To date, the authors are aware of only two reported cases of confirmed feline nasal blastomycosis, neither of which had the treatment and outcome described.⁸ We report a case of nasal blastomycosis in the cat successfully treated with itraconazole therapy.

Case Report

A 4.9 kg 5 yr old castrated male domestic longhair presented for a 3 wk history of left-sided facial swelling and epistaxis. The cat was otherwise healthy, with no prior illness reported, and lived exclusively as a barn cat in rural West Virginia. Despite left maxillary carnassial tooth extraction and treatment with clindamycin prior to referral, clinical signs persisted. On physical examination, soft-tissue swelling originated at the left nasal bridge, extended along the left side of the face dorsal and ventral to the zygomatic arch, and terminated in the left submandibular region. The ipsilateral submandibular salivary gland was enlarged. Stertorous breathing was also present.

A mild normocytic, normochromic nonregenerative anemia (hematocrit 27.1%, reference range 30.3–52.3% and reticulocyte count 4900 cells/μL, >50,000 cells/μL is regenerative) and mild hyperglobulinemia (5.6 g/dL, reference range 2.8–5.1 g/dL) were the only abnormalities on complete blood count and serum biochemistry, respectively. Thoracic radiographs evaluated by a board-certified radiologist demonstrated only tracheobronchial lymphadenomegaly (Figure 1). Head computed tomography performed under general anesthesia and evaluated by a board-certified radiologist revealed an ill-defined 1 × 1.5 cm space-occupying lesion within the left nasal cavity, approximately 1 cm caudal to the left external nares, and multifocal regions of osteolysis along the left sinonasal margin of the left nasal cavity (Figure 2). Moreover, left-sided soft-tissue swelling of the nasal bridge, face, and submandibular region was present. Blind biopsies of the nasal cavity lesion using soft-tissue alligator forceps and aspirates of the nasal bridge and submandibular swelling were obtained. The former were fixed in 10% neutral buffered formalin, processed, sectioned at 7 µm, and stained with hematoxylin and eosin or Grocott’s methenamine silver.

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Pyogranulomatous inflammation containing yeasts of two different morphologies was present on histologic examination of the nasal cavity lesion by a board-certified anatomic pathologist (TC) (Figure 3A). The smaller yeast form, 10–15 µm in diameter, had a thick, double-contoured cell wall and demonstrated broad-based budding, distinctive of B dermatitidis (Figure 3B). The larger yeast form, 30–40 µm in diameter, had a thick, refractile undulating cell wall too, but it appeared reminiscent of Coccidioides immitis (Figure 3C). Examination of cytology samples from the nasal bridge and submandibular swelling by a board-certified clinical pathologist revealed only the smaller yeast form admixed with a pyogranulomatous inflammatory infiltrate. A Blastomyces urine antigen test^a and Coccidioides serology^b were submitted for clarification as to whether this was a single or mixed organism infection, with the former positive (10.80 ng/mL) and the latter negative for both immunoglobulin G and immunoglobulin M. The combination of histopathology, Blastomyces antigen, and Coccidioides serology confirmed pyogranulomatous rhinitis secondary to blastomycosis. Itraconazole^c 10 mg/kg per os q 24 hr was prescribed.

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Upon re-evaluation 3 wk after diagnosis, all clinical signs had resolved aside from mild soft-tissue swelling in the left submandibular region. Blastomyces urine antigen tests performed at 2, 4, and 6 mo after diagnosis were positive at 8.11 ng/mL, 1.72 ng/mL, and below the limit of quantification, respectively. Two subsequent urine antigen tests at 7 and 8 mo after diagnosis were negative, at which time the itraconazole was discontinued. All clinical signs were fully resolved subsequent to the initial 3 wk recheck. The cat, now completely indoors, remains free of clinical signs. Periodic monitoring of the cat with a Blastomyces urine antigen test performed every 3 mo was recommended to monitor for disease relapse; however, the cat did not return for follow-up.

Discussion

Feline blastomycosis is rare, constituting only 7% of deep mycotic infections in cats.⁵ Systemic illness due to disseminated disease of multiple organs, particularly the lungs, skin, eyes, and central nervous system, is the most common clinical manifestation.^5–8 Because >60% of cats with disseminated disease have lung involvement, cough, tachypnea, and dyspnea are frequent clinical signs.^5–7 On the contrary, isolated upper respiratory tract signs of blastomycosis are extremely rare in the cat. Brieder et al reported a cat with a laryngeal mass due to blastomycosis but no associated clinical signs, whereas Gilor et al reported a single case of feline blastomycosis with sneezing.^6,7 In this latter case, no definitive diagnosis of nasal cavity involvement nor clarity on concurrent lower respiratory tract signs was present.⁶ Merely two cases of confirmed feline nasal blastomycosis are published in the literature, but the associated clinical signs, treatment, and outcome for the cats are not described.⁸ The successful treatment of a cat with nasal blastomycosis is described here.

A diagnosis of blastomycosis is most often successful using cytological examination of tissue lesions because the organism displays distinctive morphologic features. Characteristically, B dermatitidis yeast are 10–15 µm in diameter, have a thick, double-contoured cell wall, and exhibit broad-based budding.¹ Although rare in humans, Blastomyces yeast can attain a “giant” form with a diameter of 30–40 µm.¹⁵ When not actively budding, this solitary “giant” yeast form can resemble a C immitis spherule. Histopathology of the nasal cavity lesion in this cat revealed yeast organisms with morphologies similar to both B dermatitidis and C immitis. Appropriate antigen and serologic testing for each of these fungal diseases was consistent with a Blastomyces infection only. Given the cat had no travel history to a region in which Coccidioides is endemic, the larger yeast organisms likely represent “giant” B dermatitidis as opposed to C immitis. However, confirmatory testing (polymerase chain reaction and/or culture) of the “giant” yeast organisms was not performed, hence failing to eliminate the possibility of a mixed infection with B dermatitidis and C immitis. From a clinical perspective, differentiating between coccidioidomycosis and blastomycosis is important, because the commonly accepted drug treatment, treatment duration, and treatment monitoring are unique to each disease.^1,16 Consistent with treatment recommendations for blastomycosis, itraconazole therapy was prescribed, and the owner prepared for a 4–6-mo treatment duration with periodic rechecks of clinical signs and/or imaging abnormalities.¹

A Blastomyces quantitative urine antigen enzyme immunoassay (EIA) is available to aid in the diagnosis of blastomycosis. This test detects Blastomyces surface antigens with high sensitivity in confirmed Blastomyces infected humans and dogs; however, cross-reactivity with other common fungal surface antigens such as on histoplasmosis lowers test specificity.^17–19 Unfortunately, there are no recognized studies evaluating the diagnostic sensitivity and specificity of the Blastomyces antigen EIA in cats; nevertheless, this test can be positive in cats with a confirmed Blastomyces infection.⁸ The magnitude of the antigen concentration increase, however, was not reported.⁸ Although the Blastomyces antigen EIA was positive in this particular case, the extent of elevation relative to other published feline Blastomyces infections is unknown.

In dogs with blastomycosis, the Blastomyces antigen EIA likewise exhibited a high sensitivity for detecting active disease during treatment, with urine antigen concentrations significantly lower following 2–4 mo of treatment and at clinical remission.¹⁹ Based on these findings, the authors recommended a Blastomyces antigen EIA be performed at the time of disease diagnosis and when treatment discontinuation is being considered.¹⁹ Additionally, it is recommended that the antigen test be performed during treatment if clinical response is poor, because a failure of the antigen level to decline would be expected if the animal is not responding to the prescribed treatment.¹⁹ Although no such studies have been conducted in cats, the urine antigen test served as an effective monitoring tool in this case. Antigen levels decreased during treatment, the most sizeable reduction occurring between the 2 and 4 mo rechecks and were negative at treatment discontinuation. The resolution of clinical signs also correlated well with a decreasing antigen level. In cases of nasal blastomycosis, wherein repeat computed tomographic imaging of the nasal cavity would have been expensive for guiding treatment discontinuation decisions, physical examination in conjunction with serial urine antigen levels may serve as an adequate alternative; however, a prospective study with a larger number of cats would be needed to substantiate this assertion.

Bony lesions are reported in approximately 15% of canine blastomycosis cases.³ In cats, the prevalence of bony lesions is unknown but likely less than in dogs given that no cases with bone involvement are reported in the 4 feline retrospective studies published.^5–8 Appendicular skeletal lesions in dogs tend to affect the end of long bones, with 78% occurring distal to the stifle and 100% distal to the elbow in one study.²⁰ Moreover, 76% of fungal lesions appear osteolytic on survey radiographs.²⁰ Blastomycosis affecting the axial skeleton in dogs also occurs, with lesions appearing osteolytic on advanced imaging.^11,12 To the authors’ knowledge, the imaging appearance of bony lesions with feline blastomycosis is not described; however, the osteolytic appearance of the flat bones of the skull in this case is similar to that reported in dogs.^11,12,20

Retrospective studies evaluating cats with chronic nasal discharge having a confirmed etiologic diagnosis found 45 cases of neoplasia compared to only 3 cases of fungal rhinitis (all Cryptococcus neoformans).^21,22 Additionally, cats with hemorrhagic nasal discharge were twice as likely to have neoplasia compared to rhinitis of any other cause.²² Given these findings, along with the significant treatment expense associated with radiation therapy and the shorter median survival time (67 days) when facial deformity is present, palliative care or humane euthanasia in such cases would not be unsurprising.²³ Consequently, this case illustrates the importance of considering rhinitis secondary to regionally endemic fungal organisms in a cat with invasive nasal cavity signs such as epistaxis or facial deformity, because the treatment outcome might be more favorable. However, a prospective study of cats treated for nasal blastomycosis is needed to substantiate or refute this possibility.

Radiographic signs of lower respiratory tract disease are common in feline blastomycosis, with 100% of cases in one study having at least one abnormality.⁶ Such abnormalities include a diffuse nodular interstitial pulmonary infiltrate, focal alveolar pulmonary infiltrate, diffuse bronchial lung pattern, and tracheobronchial lymphadenomegaly.⁶ Interestingly, despite pronounced pathology, 25% of cases lacked lower respiratory tract clinical signs.⁶ No clinical signs of lower respiratory tract disease were present in this case despite having a radiographic abnormality described with feline blastomycosis. The discrepancy between imaging abnormalities and clinical signs illustrates the insensitivity of radiographic imaging as an accurate indicator of the extent of lower respiratory tract involvement with this specific infection. From an imaging perspective, a thoracic computed tomography scan would have been ideal to better ascertain the extent of lower respiratory tract involvement; however, without consistent clinical signs, it would have been of academic interest.

The primary route of blastomycosis infection is through the inhalation of spores into the lungs, followed by hematogenous or lymphatic dissemination to other tissues.¹ In this particular case, the chronology of events by which the nasal cavity became infected is uncertain. Given the presence of tracheobronchial lymphadenomegaly, dissemination of a primary pulmonary infection to the nasal cavity is conceivable, yet no cytological or histopathological sample of the enlarged lymph nodes was obtained to verify infection with B dermatitidis. However, the identification of Blastomyces organisms in an endotracheal wash or bronchoalveolar lavage fluid sample could have provided evidence for lower respiratory tract and lymph node involvement. Consequently, it is plausible that infection of the nasal cavity was the result of direct spore inhalation or inoculation into the nose as previously suggested in canine nasal blastomycoses cases.^11,12 Knowing the route of infection for the nasal cavity in this cat did not change the treatment plan; however, it did raise interesting inquiries regarding other routes of Blastomyces infection.

The itraconazole dose used to treat this cat was higher than is required for oral suspensions of the drug as demonstrated by a recent study in which a 4 mg/kg dose once daily was sufficient to achieve human target serum itraconazole concentrations in cats.²⁴ Because of the higher dose used in this cat without monitoring of serum drug levels, the development of adverse effects (anorexia, vomiting, and hepatotoxicity) was more likely.²⁵ Accordingly, the cat was vigilantly monitored for these adverse effects with a serum chemistry at each recheck visit (2, 4, 6, 7, and 8 mo).

Conclusion

A cat with clinical signs of invasive nasal cavity disease and/or a space-occupying nasal mass on head computed tomography imaging should prompt consideration of fungal rhinitis (including blastomycosis) if within an endemic area. Prompt treatment with appropriate azole antifungals can lead to a full recovery. In addition to clinical signs, Blastomyces urine antigen testing can serve as a monitoring tool of treatment response and assist with treatment discontinuation decision-making, although more data are needed to confirm this hypothesis. Finally, awareness of the “giant” yeast form of Blastomyces is important so that cytological misdiagnosis as Coccidioides does not occur.