Intranasal infusion of clotrimazole for the treatment of nasal aspergillosis in two cats

Eva Furrow Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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Reid P. Groman Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

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 DVM, DACVIM, DACVECC

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Abstract

Case Description—2 cats (13 and 11 years old) were evaluated to determine the cause of nasal discharge of varying duration (4 days and 5 months, respectively).

Clinical Findings—Computed tomography revealed marked turbinate destruction and soft tissue densities in the nasal passages. Histologic examination of nasal specimens revealed chronic active inflammation and branching fungal hyphae consistent with Aspergillus spp. Fungal culture of nasal specimens resulted in growth of Aspergillus spp. Testing yielded negative results for antibodies against Aspergillus spp.

Treatment and Outcome—Both cats were anesthetized and treated with a 1-hour intranasal infusion of clotrimazole. Recovery from the procedure was uncomplicated, and both cats had complete resolution of clinical signs.

Clinical Relevance—Little information is available on the treatment of nasal aspergillosis in cats, and the prognosis for affected animals is considered poor. The procedure for local intranasal infusion of clotrimazole in 2 cats was described here. Results and follow-up monitoring for both cats suggested that this may be a safe, effective, and durable treatment for cats with nasal aspergillosis.

Abstract

Case Description—2 cats (13 and 11 years old) were evaluated to determine the cause of nasal discharge of varying duration (4 days and 5 months, respectively).

Clinical Findings—Computed tomography revealed marked turbinate destruction and soft tissue densities in the nasal passages. Histologic examination of nasal specimens revealed chronic active inflammation and branching fungal hyphae consistent with Aspergillus spp. Fungal culture of nasal specimens resulted in growth of Aspergillus spp. Testing yielded negative results for antibodies against Aspergillus spp.

Treatment and Outcome—Both cats were anesthetized and treated with a 1-hour intranasal infusion of clotrimazole. Recovery from the procedure was uncomplicated, and both cats had complete resolution of clinical signs.

Clinical Relevance—Little information is available on the treatment of nasal aspergillosis in cats, and the prognosis for affected animals is considered poor. The procedure for local intranasal infusion of clotrimazole in 2 cats was described here. Results and follow-up monitoring for both cats suggested that this may be a safe, effective, and durable treatment for cats with nasal aspergillosis.

A 13-year-old spayed female Siamese cat was evaluated for bilateral nasal discharge and dyspnea of 4 days' duration. The clinical signs had progressed despite treatment with amoxicillin-clavulanate (16 mg/kg [7.3 mg/lb], PO, q 12 h). The cat had a history of diabetes mellitus, chronic renal disease (International Renal Interest Society stage 1, substages nonproteinuria and high-risk hypertension with no complications),1 and inflammatory bowel disease. Chronic diseases of the cat were being managed by administration of glargine insulin (0.5 U/kg [0.23 U/lb], SC, q 12 h), amlodipine (0.625 mg, PO, q 24 h), famotidine (1 mg/kg [0.45 mg/lb], PO, q 24 h), and immunosuppressive doses of prednisone (2.5 mg/kg [1.14 mg/lb], PO, q 24 h; changed from administration of budesonide 2 months prior to evaluation for nasal disease).

Physical examination revealed bilateral mucopurulent nasal discharge, stertor, and bradycardia (heart rate, 120 beats/min). The cat had inspiratory dyspnea when breathing nasally; the respiratory effort improved during open-mouth breathing. Results of examination of the oral cavity were unremarkable. The cat was underweight, with a body condition score of 2 (scale of 1 to 9). Thoracic radiography revealed hyperinflation of the lungs and aerophagia consistent with the history of increased respiratory effort. No evidence of pulmonary parenchymal disease was evident.

Electrocardiography revealed a sinus bradycardia with periods of sinus arrest and escape beats. Echocardiography did not reveal evidence of underlying myocardial disease; the bradycardia was attributed to increased vagal tone associated with pronounced respiratory effort.

A CBC revealed mild normocytic normochromic anemia (Hct, 29%; reference range, 31.7% to 48%). Abnormalities on serum biochemical analysis included mild increases in the glucose concentration and activity of aspartate aminotransferase. Isosthenuria, glucosuria, proteinuria, and hematuria were detected during urinalysis of a sample obtained via cystocentesis. Microbial culture of a urine sample did not yield bacteria. The cat had negative results when tested by use of an ELISAa for FeLV antigen and antibodies against FIV.

The following day, the cat was anesthetized for CT and retrograde rhinoscopy with collection of biopsy specimens. Marked bilateral destruction of the turbinates and thickening of the nasal mucosa were detected via CT (Figure 1). Nonenhancing soft tissue densities were evident in both nasal passages and within the sphenoid sinus. The cribriform plate appeared to be intact. Rhinoscopy revealed a large number of white-gray plaques in the caudal portion of the nasal passages. Multiple retrograde and antegrade biopsy specimens of nasal mucosa were collected and submitted for histologic examination and fungal culture. The nasal cavity was flushed with sterile saline (0.9% NaCl) solution. Serum was submitted for testing by use of ELISAs to detect Cryptococcus antigenb and antibodies against Aspergillus spp.b

Figure 1—
Figure 1—

Transverse plane, precontrast, CT image of a 13-year-old Siamese cat with bilateral nasal discharge and dyspnea of 4 days' duration. Turbinate destruction is evident bilaterally. Notice the soft tissue densities throughout the right nasal cavity and in the ventral portion of the left nasal cavity.

Citation: Journal of the American Veterinary Medical Association 235, 10; 10.2460/javma.235.10.1188

Histologic examination revealed fungal rhinitis with extensive necrosis, fibrin deposition, and degenerate granulocytes admixed with large mats of fungal hyphae and spores in 3 of 5 biopsy specimens. Morphology of the hyphae was most consistent with Aspergillus spp. Examination of the other 2 biopsy specimens revealed mild chronic active rhinitis. Fungal culture yielded growth of Aspergillus niger. Serologic testing rendered negative results for antibodies against Aspergillus spp and Cryptococcus antigen.

Four days after initial examination, the cat was anesthetized for intranasal infusion of clotrimazole. The procedures used were similar to those that have been described in dogs2–4 and a cat.5 The cat was positioned in right lateral recumbency. A 3.5-F red rubber catheter was inserted through the left nasal opening, and the tip was grasped in the caudal portion of the oropharynx with hemostats, pulled out through the cat's mouth, and sutured to the end of an 8-F Foley catheter whose tip had been cut off proximal to the cuff. The cuff of the Foley catheter was partially inflated, and traction was placed on the end of the catheter that exited the left naris until the cuff traveled back into the mouth and lodged in the rhinopharynx. The cuff was inflated further (until resistance was felt) to seal the caudal opening of the nasal cavity. A second 8-F Foley catheter with the tip cut off was inserted a short distance into the left nasal opening; the cuff of this Foley catheter was inflated to seal the rostral opening of the nasal cavity. A third 8-F Foley catheter was inserted and inflated in the right nasal opening. Because of extensive bony destruction, the Foley catheter on the right side could not be positioned tightly; even when fully inflated, traction on the catheter resulted in it being pulled out of the nasal opening. Therefore, this Foley catheter was replaced by an 8-F red rubber catheter that was fixed to the external naris with a purse-string suture to prevent leakage of the clotrimazole. The caudal portion of the pharynx was packed with gauze to protect the larynx and esophagus. Next, 8 to 10 mL of clotrimazolec (10 mg/mL suspension in polyethylene glycol 400) was instilled through each of the rostral catheters until substantial resistance was felt. The catheters were clamped with plastic tube-occluding forceps. The cat was placed in each of 4 positions (ventral, right lateral, dorsal, and left lateral recumbencies, respectively; 15 min/position). The total infusion time was 1 hour. At the conclusion of the infusion, the purse-string suture was removed, cuffs of the Foley catheters were deflated, and the catheters and gauze were removed. An esophagostomy tubed was inserted because the cat had been anorectic during the 4 days preceding the infusion. During recovery from anesthesia, the cat's head was positioned at a downward angle to allow rostral drainage of excess antifungal solution from the nares.

The cat recovered well from the procedures, and the nasal discharge and respiratory distress resolved during the subsequent 3 days. The cat was discharged to the owner, who was instructed to administer metronidazole (10 mg/kg [4.5 mg/lb], PO, q 24 h), prednisone (2.5 mg/kg, PO, q 24 h), and famotidine (1 mg/kg, PO, q 24 h) for management of the cat's inflammatory bowel disease and glargine insulin (0.25 U/kg [0.11 U/lb], SC, q 12 h) for management of diabetes mellitus. Hypertension was not detected at any time during hospitalization, despite discontinuation of amlodipine. Therefore, it was recommended that the owner not administer this medication.

The esophagostomy tube was removed 5 weeks later. At that time, the cat's appetite had returned, and it was eating appropriate amounts of food. At 2 years after treatment, the cat was doing well with no evidence of rhinitis.

An 11-year-old spayed female domestic short-hair cat was evaluated because of a 5-month history of sneezing, nasal congestion, and discharge from the right naris. Prior to examination, the cat had been receiving antimicrobials (amoxicillin-clavulanate, sulfadimethoxine-ormetoprim, and sulfamethoxazole-trimethoprim; dosages unknown), but no improvement was evident. Results of a CBC and serum biochemical analysis were within reference limits. Evaluation of skull radiographs taken by the referring veterinarian revealed an increased opacity in the right nasal passage and right frontal sinus; results for thoracic radiographs were unremarkable. The referring veterinarian had performed nasal flushes and normograde biopsy to obtain specimens of nasal mucosa from the cat; histologic examination revealed severe rhinitis and fungal hyphae consistent with Aspergillus spp. Bacterial culture of the nasal mucosa yielded growths of Pasteurella spp and α-hemolytic Streptococcus spp. The cat had access to the indoors and outdoors and had been vaccinated annually against FeLV.

Mucopurulent discharge from the right naris was the only abnormality detected during physical examination. The cat was anesthetized for CT and rhinoscopy with collection of biopsy specimens. The CT revealed bilateral destruction of turbinates and mild bony lysis. Soft tissue densities were evident throughout the right nasal cavity and frontal sinus. The cribriform plate appeared to be intact. Rhinoscopy did not reveal any gross abnormalities. Retrograde and antegrade biopsies of the nasal passages were performed, followed by flushing of the nasal passages with sterile saline solution. Histologic examination of the nasal biopsy specimens identified chronic active rhinitis. Serologic testing with an ELISAd to detect antibodies against Aspergillus spp yielded negative results. The cat was discharged to the owner, who was instructed to administer clindamycin to empirically treat and prevent secondary bacterial infection.

Five months later, the cat was returned to our facility because of persistent discharge from the right naris. A second CT examination was performed. The CT findings were unchanged, compared with the findings for the first CT examination. A flush of the nasal passages was performed. Thick brown material was removed during the flushing and submitted for cytologic examination. The cytologic examination revealed abundant necrotic cellular debris and branching fungal hyphae. Fungal culture resulted in growth of unspecified Aspergillus spp. The cat's clinical signs improved after the nasal flush, and the owner declined further treatment at that time.

Three months later, the cat was admitted because of recurrence of nasal discharge. No abnormalities were evident in results of a CBC and serum biochemical analysis. Thoracic radiography was repeated, but no abnormalities were detected. A third CT examination was performed to assess progression of disease and integrity of the cribriform plate. The cribriform plate was intact. The degree of turbinate destruction was unchanged, and there was less soft tissue density in the right frontal sinus, compared with results of previous CT examinations. At this time, the owner elected to proceed with antifungal treatment. Intranasal infusion of clotrimazole was performed as described previously. The cat had an uncomplicated recovery after the procedures, and it did not require a feeding tube. Four years after the clotrimazole infusion, the cat was doing well and had no clinical signs of nasal disease.

Discussion

Aspergillus spp are saprophytic fungi that are ubiquitous in the environment and have been isolated from the coat of healthy cats and dogs.6–8 Aspergillus spp are considered opportunistic pathogens that induce systemic disease in immunocompromised humans and other animals.9–15 In cats with systemic aspergillosis, 70% have underlying diseases, such as feline panleukopenia, FeLV, feline infectious peritonitis, and endoparasites.11,12 In dogs, systemic aspergillosis is most often reported in German Shepherd Dogs that have been suggested to have a hereditary immune defect.13–15 The most commonly infiltrated organs in cats and dogs with systemic aspergillosis include the lungs, kidneys, intestines, liver, spleen, lymph nodes, and CNS.11,13 In contrast to systemic infection, nasal infection is considered a local disease that can develop in immunocompetent animals.2,16,17

Nasal aspergillosis is a rare disease in cats.18–20 Other than the 2 cats reported here, there are only 13 previously described cases of aspergillosis or penicilliosis in cats affecting the nasal cavity, sinuses, or orbits.5,21–27 Those 13 cats ranged from 1 to 12 years of age. The cats reported here were 13 and 11 years old. Seven of the 13 previously reported cats were Persians or Himalayans, which suggests a possible breed predisposition. The cats reported here were a Siamese and a domestic shorthair cat.

As stated previously, incompetence of the immune system is not believed to be required for nasal infection with aspergillosis. Only 1 of the 13 previously reported cats with sinonasal or orbital aspergillosis had a confirmed immunosuppressive condition (ie, FeLV).23 In the cats reported here, one had diabetes mellitus and was receiving corticosteroids, either of which could have contributed to an immunosuppressive state; the other cat appeared healthy.

In the 2 cats described here, signs of nasal disease were evident with no ocular abnormalities. In the 13 previously reported cats, 6 exclusively had nasal signs,5,23,25 3 exclusively had orbital signs,22,26,27 and 4 had both nasal and orbital signs5,21,24,25; signs of orbital involvement included exophthalmos, epiphora, resistance to retropulsion, anterior uveitis, and prolapse of the nictitating membrane.5,21,22,24–27

It can be difficult to diagnose nasal aspergillosis because no single test result is deemed definitive. In dogs, 2 or more criteria must be fulfilled to reach a diagnosis. These criteria include characteristic imaging findings, direct observation of fungal plaques, identification of organisms via cytologic or histologic examinations, positive results for fungal culture, and positive results for serologic tests.2,3,28–30

Turbinate destruction, thickened nasal mucosa, hyperostosis, and soft tissue densities or masses are the most common lesions detected during imaging in dogs with nasal aspergillosis.29–32 These findings have high sensitivity but low specificity because they can also be found in dogs and cats with neoplastic and even inflammatory rhinitis.33–35 Nasal imaging via CT of the cats described here revealed marked turbinate destruction and soft tissue densities in both cats and thickened nasal mucosa in 1 cat. One of the cats had visible fungal plaques detected during rhinoscopy. This appears to be a common finding in cats with nasal aspergillosis because 11 of the previously reported 13 cats had grossly visible white, gray, or yellow plaques or granulomas detected during rhinoscopy, surgery, or necropsy.5,21–27

The sensitivity of histologic examination of nasal specimens for the diagnosis of aspergillosis is variable. In 1 study36 of dogs with nasal aspergillosis, fungal hyphae were detected in only 17 of 41 (41%) dogs from which nasal biopsy specimens were obtained. In another study37 in dogs, investigators reported a higher detection rate, with fungal elements visible in 17 of 21 (81%) dogs. In the cats reported here, identification of fungal elements via histologic examination was inconsistent. In the first cat, examination revealed that 3 of 5 biopsy specimens had fungal rhinitis, whereas the other 2 were interpreted as chronic active rhinitis. In the second cat, histologic and cytologic findings from samples obtained on 2 separate dates were consistent with fungal rhinitis, whereas examination of biopsy specimens collected between those 2 dates failed to reveal fungal elements. In the previous reports of cats with nasal aspergillosis, detection of fungal rhinitis via histologic examination was similarly complicated. Of 6 cats that had specimens obtained via rhinoscopy, 3 were identified with fungal rhinitis, whereas the other 3 were interpreted to have lymphocytic-plasmacytic or mixed-cell rhinitis. In these latter cats, additional biopsy specimens obtained from the frontal sinus (via trephination or rhinoscopy) revealed Aspergillus infection.5,25 The low sensitivity of histologic examination may be attributable to the distribution of the fungi; Aspergillus spp are found primarily on the mucosal surface without invasion into deeper tissues.38 Cytologic examination may yield more favorable results; one study28 in dogs with nasal aspergillosis revealed that cytologic review of samples obtained via brushing of lesions or squash preparation of biopsy specimens had an excellent sensitivity of 93% to 100%.

Fungal culture is another diagnostic test that has high specificity but poor sensitivity in dogs with nasal aspergillosis.36,37,39 The most common species cultured in dogs is Aspergillus fumigatus.2,3,37 Both of the cats reported here had fungal cultures that yielded Aspergillus spp (one yielded growth of A niger, and the other yielded growth of an unspecified Aspergillus spp). Of the previously reported cats, fungal cultures were performed for 8, 5 of which yielded Aspergillus organisms (1 A niger, 1 A fumigatus, 1 Aspergillus udagawae, and 2 unspecified Aspergillus spp).5,21–27

Serologic testing for Aspergillus spp may also have a high rate of false-negative results. In dogs, sensitivity and specificity of serologic testing are reported to be 67% to 76.5% and 98% to 100%, respectively, for agar-gel double immunodiffusion and 88.2% and 96.8%, respectively, for ELISA.37,40 Seven of the previously reported cats were serologically tested for Aspergillus spp, but only 4 had positive results.5,23,25,27 Both of the cats reported here had negative results for serologic tests to detect Aspergillus spp. We can infer on the basis of this information that the sensitivity for serologic testing in cats is low. However, the specificity for serologic testing to detect Aspergillus spp has not been established in cats.

Information regarding effective treatment of cats with nasal aspergillosis is extremely limited. There is no standard of care, and prognosis is considered poor.5,18,21–25 Of the 13 previously reported cats, 6 had resolution of clinical signs at follow-up examinations. However, no 2 cats had resolution of clinical signs after receiving the same treatment. The successful treatments included nasal lavage, rhinotomy with application of iodoform paste, oral administration of itraconazole, oral administration of fluconazole, oral administration of posaconazole, and intranasal infusion of clotrimazole.5,21,23,24 The majority (8/13) of the cats were initially treated with itraconazole; 3 cats developed adverse effects (hepatotoxicosis), another 3 cats failed to respond or relapsed, 1 cat was lost to follow-up monitoring, and only 1 cat had long-term resolution of clinical signs.5,24–27 Solely on the basis of these reports, it is difficult to make a recommendation for the treatment of cats with nasal aspergillosis.

In contrast to treatments in cats, treatments for dogs with nasal aspergillosis have been clearly described. The treatment of choice is intranasal infusion of clotrimazole or enilconazole. The antifungal agent is infused via nonsurgically placed catheters. The procedure is performed in anesthetized dogs, with a treatment time of 1 hour. Prognosis is good, with resolution of clinical signs in 47% to 65% of dogs after 1 treatment and 80% to 90% of dogs after additional treatments.4,41,42 Rhinoscopic debridement is recommended prior to infusion of an antifungal agent.41,42 In 1 study,43 investigators found that a similarly high success rate can be achieved with deposition of clotrimazole cream into the frontal sinus via trephination. This procedure allows a shorter anesthetic period with a potentially prolonged period of antifungal contact. Lower success rates (60% to 70%) are seen with orally administered systemic treatments such as itraconazole or fluconazole.2,3

The 2 cats in this report, combined with 1 cat from a previous report,5 offer evidence that nasal aspergillosis can resolve in cats after intranasal infusion of clotrimazole via a technique similar to that described for dogs. The 3 cats each received a 1-hour nasal infusion of clotrimazole administered via nonsurgically inserted catheters. All of the cats had resolution of clinical signs after a single treatment. No adverse effects were reported as a result of this treatment.

It is important to mention that 2 additional cats in the previous reports24,26 were treated with an infusion of clotrimazole. One had no response to this treatment. The other cat responded but was euthanatized several months later because of development of new clinical signs (dysphagia and anorexia); it was not determined whether the signs were attributable to recurrence of fungal disease. Both of those cats were unusual in that they had substantial fungal disease of the orbit, and the clotrimazole was administered via trephination of the frontal sinus. In contrast, the 3 cats that responded successfully to clotrimazole had only sinonasal disease and received the drug via intranasal infusion.

Clotrimazole infusion is not without disadvantages. It requires that an animal be anesthetized for a minimum of 1 hour. The clotrimazole solution contains isopropanol and propylene glycol, which are irritants that can cause pharyngeal edema and inflammation. Enilconazole infusion should be investigated as an alternative to clotrimazole for the treatment of cats with nasal aspergillosis. Topically administered enilconazole (1% or 2%) is less systemically toxic and locally irritating than clotrimazole and may have sporocidal activity in the vapor phase at distances of up to 1 cm.41,42,44

Topical infusion of clotrimazole is generally contraindicated in animals in which the cribriform plate is damaged.2,3 And, as mentioned previously, clotrimazole infusion may not be successful in animals with aspergillosis that involves the orbit.24,26 Finally, it has been suggested that debridement of fungal plaques is critical prior to treatment of nasal aspergillosis in dogs. Debridement may be difficult in cats because of the small size of their nasal passages. None of the 3 cats that have been treated successfully with clotrimazole underwent debridement prior to intranasal treatment, and it is unknown whether debridement would improve the efficacy of treatment in this species.

Although information for dogs has been incorporated into the discussion, the authors recognize that there are anatomic and physiologic differences between these species; thus, the canine data cannot be directly applied to cats. The current recommendation for the treatment of nasal aspergillosis in dogs via intranasal infusion of clotrimazole or enilconazole was reached after years of extensive research.2–4,41,42,45,46 In the present report, the procedure for safe intranasal administration of clotrimazole in 2 cats is described. Results suggest that intranasal infusion of clotrimazole is an effective treatment without concurrent or subsequent oral administration of antifungal agents, but the conclusion is greatly limited by the small number of cases. Future prospective studies are needed to determine whether intranasal administration of clotrimazole should be recommended as the standard of care in cats with nasal aspergillosis.

ABBREVIATION

CT

Computed tomography

a.

SNAP FIV/FeLV Combo Test, Idexx Laboratories Inc, Westbrook, Me.

b.

Antech Diagnostics Inc, Pottstown, Pa.

c.

Clotrimazole topical solution, USP 1%, Taro Pharmaceutical Inc, Bramalea, ON, Canada.

d.

Surgivet 14-F silicone catheter, Smiths Medical PM Inc, Waukesha, Wis.

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