Introduction

Feline upper respiratory tract aspergillosis (URTA) is a commonly reported form of aspergillosis, an infection affecting the nasal and paranasal sinuses, with two types: sinonasal aspergillosis (SNA) and sino-orbital aspergillosis (SOA). SNA infections remain confined to the sinonasal cavity and have a favorable prognosis with treatment, whereas SOA extends into the orbit and paranasal structures and carries a poor prognosis. In cats, SOA is the most common form of URTA, occurring in up to 65% of cases, whereas in dogs, SNA accounts for more than 99% of URTA cases.^1–5 A diverse range of Aspergillus spp has been identified in cases of feline URTA, unlike in dogs in which Aspergillus fumigatus is the single most common agent of SNA.⁶

Aspergillus udagawae causes invasive infections in humans and cats. In humans, illness duration is up to seven times longer than A fumigatus infections.⁷A udagawae is resistant to standard therapy, and the minimum inhibitory concentrations (MICs) of various antifungal drugs against A udagawae isolates were higher than those for A fumigatus.⁷ Although SOA secondary to A udagawae in cats has been reported,^2,8–10 treatment and follow-up were only described in three reports.^2,9,10

This case report details the presentation, diagnostic process, and successful treatment of a 10 yr old spayed female ragdoll cat diagnosed with SOA secondary to A udagawae. Despite initial failure of standard antifungal therapies, the cat responded well to a prolonged course of oral posaconazole. This report highlights the potential efficacy of posaconazole as a treatment option for SOA caused by A udagawae and provides valuable insight into the management of this challenging condition.

Case Report

A 10 yr old spayed female ragdoll cat presented with a previous diagnosis of feline viral rhinotracheitis 2 mo ago. The cat had been treated with antibiotics since then; however, it did not improve the clinical signs, and the cat was referred to our clinic. The cat had lived in Düsseldorf, Germany for 3 yr with outdoor access, was indoor-only in New York City in the United States for 2 yr, and most recently lived in Japan with some outdoor access to the terrace only. No previous history of respiratory or ocular disease or trauma was reported before this clinical sign started 2 mo ago.

On day 1, the cat presented with nasal congestion, intermittent bilateral mucopurulent nasal discharge, stertor, lethargy, and decreased appetite. Physical examination and vital parameters were normal. The cat lost 20% of its weight in 2 mo, weighing 4.0 kg compared to 4.6 kg 2 mo ago, with a body condition score of 4/9. The complete blood count^a, plasma biochemistry^b (including albumin, creatinine, blood urea nitrogen, alanine aminotransferase [ALT], alkaline phosphatase, and electrolytes [sodium, potassium, chloride]) showed mild elevation of sodium (158 mmol/L, reference interval 147–156 mmol/L). Coagulation parameters^c (prothrombin time, activated partial thromboplastin time, and fibrinogen concentration) showed elevation of fibrinogen concentration (302 mg/dL, reference interval 67–203 mg/dL). Feline leukemia virus antigen and feline immunodeficiency virus antibody tests^d were negative.

Computed tomography (CT) and antegrade rhinoscopy were performed on day 9. On the CT images (Figure 1A), soft-tissue attenuating material filled the nasal cavities bilaterally with mild destruction of nasal turbinates and occupied the frontal and sphenoidal sinuses bilaterally but was more severe in the left with mild rightward displacement of the nasal septum without cribriform plate lysis. These findings suggested rhinosinusitis, with neoplasia less likely. Rhinoscopy showed mucosal irregularity (Figure 1C), enabling nasal brushing and biopsy. Both Feline Upper Respiratory RealPCR Panel^e and nasal brushing cultures were negative. The biopsy revealed neutrophilic-eosinophilic rhinopharyngitis with necrosis and fibrin deposition (Figure 2A), and fungal hyphae by periodic acid-Schiff (Figure 2B) and Grocott’s stainings (Figure 2C). Given the morphology of the fungal hyphae and the clinical presentation in the feline patient, an Aspergillus spp. infection was suspected. To substantiate this presumptive diagnosis, polymerase chain reaction (PCR) analysis was performed. PCR amplified from formalin-fixed paraffin-embedded biopsy samples. Genomic DNA was extracted using a QIAamp DNA formalin-fixed paraffin-embedded Tissue Kit^f. The internal transcribed spacer 2 (ITS2) region of the ribosomal RNA gene cluster and part of the calmodulin (CaM) gene were amplified using primer pairs ITS3 and ITS4¹¹ and cmd5 and cmd6,¹² respectively. Their sequences were confirmed by direct sequencing and recorded in the DNA Data Bank of Japan (accession numbers LC726271, LC726272). A Basic Local Alignment Search Tool search in DNA Data Bank of Japan showed 100% and 99.4% similarity for ITS2 and CaM sequences to the A udagawae reference strain (accession BBXM02000016, LT796068). These results confirmed the diagnosis of sinonasal aspergillosis (SNA) secondary to A udagawae.

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Following the diagnosis of SNA on day 18, oral itraconazole^g treatment (13.5 mg/kg q 24 hr) was started. Despite itraconazole treatment, clinical signs worsen, and on day 29, left exophthalmos, nictitating membrane protrusion, and lacrimation was observed (Figure 1D). Concurrently, a decrease in body weight to 3.6 kg was recorded. In response to the progression of clinical signs, a therapeutic adjustment was made on Day 29, transitioning to oral posaconazole^h (7 mg/kg q 24 hr). The absence of clinical improvement led to an escalation in posaconazole dosage to 7 mg/kg q 12 hr on day 39. By day 44, marginal improvement in clinical signs was observed, including reduced lacrimation, nasal congestion, and nictitating membrane protrusion. However, the degree of left exophthalmos remained notably unchanged. Consequently, a follow-up nonsedated head CT scan was performed on day 44 to assess disease progression. This second CT study revealed reduction of soft-tissue material in the nasal passages but extension into the left retrobulbar space through the medial wall of the left orbit, resulting in dorsolateral exophthalmos of the left eye. These findings corroborated the diagnosis of SOA (Figure 1B).

On the day of the second CT scan (day 44), elevated liver enzymes (ALT 296 U/L) were detected, prompting a temporary reduction in posaconazole dosage to 4.5 mg/kg q 12 hr. Additionally, liver supplements (e.g., silymarinⁱ) were added to the treatment. Normalization of liver enzyme levels (ALT) was achieved by day 46, allowing for the restoration of the posaconazole dosage (7 mg/kg q 12 hr). Nasal and eye clinical signs were gradually improved, and on day 177, posaconazole treatment was finished due to complete resolution of clinical signs, approximately 4.5 mo after the initial posaconazole therapy. At the 918 day follow-up, no recurrence of clinical signs had been reported.

Concomitant treatments during this period included, for hyporexia, mirtazapine^j (0.5 mg/kg q 24 hr) administered from day 41 to day 44, mosapride citrate hydrate^k (0.65 mg/kg q 12 hr) from day 50 and Mirtazapine ointment^l from day 57, continued until an increase in body weight and activity level was noted on day 76. In addition, hypokalemia (2.7 mEq/L) detected on day 50 was treated with subcutaneous administration of potassium chloride solution (0.18% w/v) and oral potassium gluconate^m (0.32 mEq/kg q 12 hr), which was continued until potassium levels normalized on day 57.

Discussion

Feline URTA comprises SNA and SOA. SOA is more prevalent in cats compared to dogs, where SNA is predominant. Various Aspergillus spp are implicated in feline URTA. A fumigatus and A niger are the most common species in cats with SNA,^1,3,13 whereas Aspergillus felis and A udagawae are the two most common species in cats with SOA.^2,8,9,14 These species belong to the section Fumigati, which also includes other morphologically similar species such as Aspergillus lentulus and Neosartorya pseudofischeri. Phenotypic methods for identification of these species are unreliable, but molecular methods such as gene sequence analysis of ITS, beta-tubulin, and/or CaM can distinguish them. In the current report, A udagawae was identified as the causative fungus in a cat with URTA using PCR of the ITS2 and CaM when fungal culture from a nasal brushing sample was unsuccessful.

A udagawae causes invasive infections in humans and cats, exhibits higher resistance to standard therapies, and has higher MICs for antifungal drugs compared to A fumigatus. Detailed treatment and follow-up for SOA secondary to A udagawae in cats have been described in only three reports. One cat was treated with itraconazole, amphotericin B (AMB), and micafungin but died after the treatment failed.⁹ The other two cats were successfully treated with high-dose itraconazole (12.5 mg/kg per os q 12 hr)² and with combination treatment of terbinafine, caspofungin, and posaconazole.¹⁰

Cats with SOA caused by A udagawae show low susceptibility to AMB and ketoconazole.^2,9 MICs of other antifungal drugs should be examined because AMB is commonly used to treat aspergillosis in cats and dogs, including feline orbital aspergillosis.¹⁵ In this case, drug susceptibility testing could not be performed because of negative cultures. Because of the reported poor response to regular dose itraconazole or clotrimazole treatment in cats with aspergillosis involving the orbit,¹⁵ in the present case, treatment with posaconazole was initiated. Alternative antifungals may be used to treat systemic aspergillosis, include terbinafine and caspofungin.^1,10,16 Studies have shown that combining these with posaconazole often improves the condition in cats.^1,10 MICs of posaconazole and effective levels of three echinocandins have been found to be low in patients with SOA.¹² According to case reports,^1,2,5,15 initial oral posaconazole monotherapy is suggested until susceptibility testing results are available.¹⁷ One SOA case responded well to posaconazole monotherapy.¹⁵ Previously, caspofungin and terbinafine were commonly combined with posaconazole^1,10 and were therefore selected for this study. For nonresponders, additional drugs, including terbinafine or caspofungin, are recommended.¹⁷

Posaconazole is a fungicidal triazole structurally similar to itraconazole that was developed to be a more efficacious treatment of invasive aspergillosis in humans and to improve on the absorption, tolerability, and drug interaction profile of itraconazole. Posaconazole is well tolerated with rare liver enzyme elevations following oral administration.^1,4,15,17,18 In our case, liver enzyme elevation was observed but resolved after a temporary reduction in posaconazole dose and concomitant administration of liver supplements. After increasing the posaconazole dose while continuing the liver supplements, no further liver enzyme elevation was observed. Given the inability to completely exclude the possibility of concurrent conditions that may contribute to elevated liver enzymes, such as pancreatitis or hepatopathy, the exact cause of the liver enzyme elevation in our case remains undetermined. As a result, it cannot be definitively determined whether the resolution of the liver enzyme elevation was directly attributable to the adjusted posaconazole dose, the supportive role of the liver supplements, or the presence of concurrent disease. A daily dose of 7.5 mg/kg is required to achieve a target plasma concentration of 0.5–0.7 μg/mL.¹⁸ However, absorption and accumulation may vary, especially in sick individuals, requiring monitoring of plasma concentrations.¹⁹ Our case did not respond to a dose of 7.0 mg/kg q 24 hr but improved when the dose was increased to q 12 hr. A decrease to 4.5 mg/kg q 12 hr caused a relapse, but a return to the higher dose resolved it, suggesting that the previously recommended dosage may be inadequate in this case. Unfortunately, we couldn’t measure posaconazole blood concentrations.

The successful treatment of feline SOA and SNA with posaconazole monotherapy has been reported, but in all of those cases, the causative agent was A fumigatus^15,20 and not A udagawae. The doses of posaconazole used for these cats with A fumigatus infection were between 2.5 mg/kg q 12 hr and 5 mg/kg q 24 hr. In cats, there are neither reports of monotherapy of posaconazole treatment for infections with A udagawae nor reports of treatment with this dose of posaconazole (7 mg/kg q 12 hr) for long-term regardless of Aspergillus spp. In our case, the cat maintained a good body condition during the 4 mo of treatment with the same dose of posaconazole and has remained clinically stable for 18 mo following the discontinuation of therapy without disease recurrence. This is the first report documenting the successful treatment of feline SOA secondary to A udagawae using oral posaconazole.

There were several limitations to the current study. First, culturing of the isolate was unsuccessful in this case, which requires case-specific susceptibility determination because of potential isolate variability. Second, posaconazole was effective, but further evaluation with a larger sample size is needed to assess its efficacy for the treatment of SOA in cats. Third, we used divided enteric-coated tablets rather than liquid posaconazole, which is not available in Japan, which may alter absorption rates compared with previous studies.¹⁸ Finally, we didn’t measure blood concentrations of posaconazole; continuous monitoring would have been important.

Conclusion

A udagawae is the second most common cause of SOA in cats but is challenging to treat because of its low susceptibility to antifungal drugs, including the topical administration of clotrimazole. This case report describes the successful treatment of SOA caused by A udagawae in a cat using oral posaconazole monotherapy, specifically at a dose of 7 mg/kg q 12 hr.