Aspergillosis

Edited October 28, 2015

 

The aspergillosis guidelines were first published in J Feline Med Surg 2013; 15: 605-610; the present update has been authorized by Katrin Hartmann.

 

 

Synopsis

 

Aspergillosis is a sporadic mycosis that occurs worldwide in mammals and birds and leads to a usually chronic, only rarely acute disease that mainly affects the nasal cavity and sinuses. Aspergillus spp. infections are commonly associated with predisposing local or systemic factors.3 Local disease can spread and involve the central nervous system or the lungs. Some Aspergillus spp. can also disseminate, causing systemic infections. In contrast to dogs, in which (nasal) aspergillosis is relatively common, aspergillosis is rare in cats, but considered an emerging infection in e.g. Australia.1 There are two clinical forms of aspergillosis in cats, the sinonasal (characterized by signs of chronic nasal infection) and the newly emerging more invasive sinoorbital form (characterized by signs of orbital and surrounding tissue invasion). Sinoorbital involvement has been described now in approximately half of the reported cases.2,3 Treatment should consist of local and systemic antifungal therapy.

 

 

Agent Properties

 

Aspergillosis is caused by fungal organisms of the genus Aspergillus. Aspergillus spp. are ubiquitous saprophytes. The organism is occasionally also isolated from healthy animals.

 

There is some confusion in the nomenclature of these fungi. Species identification only by phenotypic features probably leads to overidentification of A. fumigatus. Some species initially identified as A. fumigatus by conventional methods now have been classified as Neosartorya spp., Aspergillus lentulus, and Aspergillus udagawae using molecular techniques. Differences in virulence and invasion ability between species exist, and severe cases commonly seem to be associated with Neosartorya spp. infections.2 Species included in the A. fumigatus complex are responsible for the majority of infections in cats, but Aspergillus flavus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus have also been detected. Recently, Aspergillus udagawae, a rare opportunistic pathogen was identified in a cat causing fatal orbital aspergillosis.4 

 

 

Epidemiology

 

Aspergillus spp. are found worldwide in soil and decaying vegetation. All mammals, including humans, are susceptible to aspergillosis. Immunosuppressed persons (e.g. by a human immunodeficiency virus infection) are particularly prone to acquiring the disease. Cats and other animals are infected through contamination from the environment. Direct transmission does not occur – thus aspergillosis is not a zoonosis.

 

Aspergillosis occurs worldwide. Most of the cases have been reported from Australia, but feline aspergillosis has been described in North America, the United Kingdom, Switzerland, Germany, Japan, and Italy.2,5,6,10 No age or sex predisposition has been detected. A predisposition was found in brachycephalic breeds, especially Persian and Himalayan cats.2,5,7,8 Reduced drainage of upper respiratory secretions1 has been suggested as a predisposing factor. Additional suggested factors include innate defects of mucosal immunity, previous viral upper respiratory tract infections, and antibiotic treatment.5 A relationship between sinoorbital aspergillosis and lymphoplasmacytic rhinitis in a cat treated with oral prednisone has been suggested,6 indicating that immunosuppression may play a role. No association of aspergillosis and feline retrovirus infections has been reported.12 

 

 

Pathogenesis

 

Infection usually occurs from Aspergillus spp. accumulated in pet food and litter. The spores are inhaled and deposited in the sinosal cavity, the primary site of infection. The fungus must adhere to the respiratory epithelium, penetrate it, destroy surrounding cells, and resist phagocytosis. Aspergillus spp. conidia bind to various cell surface proteins using specific adhesion molecules, such as hydrophobins. A. fumigatus also produces an immunosuppressive toxin (gliotoxin) that inhibits macrophage phagocytosis. Other metabolites impair mucociliary action and prolong the organisms’ epithelial resistance, while enzymes (e.g., proteases) help to invade tissues.

Fig. 1. Exophthalmos of the left eye in a cat with a left retrobulbar fungal granuloma (sino-orbital aspergillosis). There is prolapse of the third eyelid. A partial lateral tarsorrhaphy was performed to prevent exposure keratitis (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

Fig. 1. Exophthalmos of the left eye in a cat with a left retrobulbar fungal granuloma (sino-orbital aspergillosis). There is prolapse of the third eyelid. A partial lateral tarsorrhaphy was performed to prevent exposure keratitis (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

 

Clinical signs

 

Aspergillosis occurs in two main forms in cats, sinonasal aspergillosis (SNA) and sinoorbital aspergillosis (SOA). SNA is characterized by more local signs of chronic nasal infection, such as sneezing, uni- or bilateral serous to mucopurulent nasal discharge, and sometimes epistaxis. Sterterous breathing, granuloma formation, soft tissue masses protruding from the narines, and bone lysis are less frequent abnormalities.5,8

 

Fig. 2. Right exophthalmos, third eyelid prolapse and oedema and swelling of the right side of the face in a cat with a right retrobulbar and paranasal fungal granuloma (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

Fig. 2. Right exophthalmos, third eyelid prolapse and oedema and swelling of the right side of the face in a cat with a right retrobulbar and paranasal fungal granuloma (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

 

SOA is the more invasive form. The clinical manifestation depends on the invading fungal species, and SOA probably represents an extension of SNA to orbital and subcutaneous tissues, caused by invasive Aspergillus spp., like Neosartorya spp. Most cats with SOA indeed have a history of nasal discharge, and nasal lesions have been identified at necropsy as well as lysis of the orbital lamina using imaging techniques.2,6,7 SOA is characterized by signs of orbital and surrounding tissue invasion, including unilateral exophtalmus, third eyelid prolapse (Fig. 1) , conjunctival hyperaemia, and keratitis (Fig. 2.) In some cases, a mass in the pterygopalatine fossa (Fig. 3) or an ulceration of the hard palate, or even extension and destruction of the nasal cavity (sometimes with swelling and skin ulcers) can be seen. The CNS can be involved leading to neurological signs, peripheral vestibular signs, and blindness, and regional lymphadenopathy and fever can occur.

 

Fig. 3. Ventral expansion of retrobulbar fungal granulomas causes a mass effect in the pteryoplatine fossa as seen in this cat with a right retrobulbar fungal granuloma (arrow) (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

Fig. 3. Ventral expansion of retrobulbar fungal granulomas causes a mass effect in the pteryoplatine fossa as seen in this cat with a right retrobulbar fungal granuloma (arrow) (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

 

Atypical cases of aspergillosis have been reported, including pneumonia (Fig.4) and pyothorax in a diabetic cat,9 a cat with generalized systemic infection,10 and a cat with ulcerative keratitis.11

 

Fig. 4. Thoracic radiographs (latero-lateral view) of a cat with pulmonary aspergillosis, diagnosed at necropsy (courtesy of Katrin Hartmann, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany).

Fig. 4. Thoracic radiographs (latero-lateral view) of a cat with pulmonary aspergillosis, diagnosed at necropsy (courtesy of Katrin Hartmann, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany).

 

Laboratory abnormalities in cats with aspergillosis are not specific and the result of chronic inflammation. Hyperglobulinemia is the most frequently reported abnormality.2,7,13,14 

 

 

Immunity

 

Immunity against Aspergillus spp. infection is poorly understood. Many cats develop antbidies, but some cats produce only low or undetectable antibody levels (mostly in cases of Aspergillus fumigatus infection).8 Additionally, cats can produce antibodies without clinical disease which is likely the result of non-invasive mucous membrane colonization that occurs in many healthy cats.

 

Fig. 5a. Haematoxylin and Eosin stained section of a retrobulbar fungal granuloma consisting of a large central granuloma surrounded by smaller satellite granulomas. Centrally each granuloma contains necrotic cellular debris within which branching, septate fungal hyphae are confined as seen on the Grocott stained section

Fig. 5a. Haematoxylin and Eosin stained section of a retrobulbar fungal granuloma consisting of a large central granuloma surrounded by smaller satellite granulomas. Centrally each granuloma contains necrotic cellular debris within which branching, septate fungal hyphae are confined as seen on the Grocott stained section

Fig. 5b. There are surrounding zones of neutrophils and eosinophils, macrophages, fibroblasts and a peripheral cuff of lymphocytes and plasma cells (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

Fig. 5b. There are surrounding zones of neutrophils and eosinophils, macrophages, fibroblasts and a peripheral cuff of lymphocytes and plasma cells (courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia).

 

Diagnosis

 

Diagnosis is based in the demonstration of fungal hyphae by cytology or histology (Fig. 5) and definitive confirmation by fungal culture (Fig. 6). Advanced imaging techniques (CT or MRI) are helpful to assess disease extension and to find the best location for obtaining diagnostic samples during rhinoscopy (Fig. 7).8 CT and MRI are also important tools to rule out neoplasia. However, in a study including ten cats (five with aspergillosis), CT findings did neither allow to discriminate between different fungal infections nor to distinquish aspergillosis from neoplasia.15

 

 

 

 

 

 

 

 

Fig. 6a. Growth of Aspergillus fumigatus on malt extract agar (MEA). Colonies are typically olive green and velvety due to rapid sporulation. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

Fig. 6a. Growth of Aspergillus fumigatus on malt extract agar (MEA). Colonies are typically olive green and velvety due to rapid sporulation. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

Fig. 6b. Some species of Aspergillus in the fumigatus complex that cause sino-orbital aspergillosis are slow to sporulate and the colonies appear whitish until sporulation occurs. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

Fig. 6b. Some species of Aspergillus in the fumigatus complex that cause sino-orbital aspergillosis are slow to sporulate and the colonies appear whitish until sporulation occurs. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

 

 

 

 

 

 

 

 

 

Fig. 7. Rhinoscopy picture of a cat with sinonasal aspergillosis. Courtesy of Bianka Schulz, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany.

Fig. 7. Rhinoscopy picture of a cat with sinonasal aspergillosis. Courtesy of Bianka Schulz, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany.

 

Fig. 8. Rhinoscopy procedure in a cat with chronic nasal discharge to obtain samples for histology and culture of Aspergillus spp. Courtesy of Bianka Schulz, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany.

Fig. 8. Rhinoscopy procedure in a cat with chronic nasal discharge to obtain samples for histology and culture of Aspergillus spp. Courtesy of Bianka Schulz, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany.

 

Direct detection of the organism

 

A definitive diagnosis is usually obtained by histology and detection of the organism in biopsy specimens obtained by rhinoscopy (Fig. 8) or nasal cavity lavage techniques. As Aspergillus spp. are also found on mucosal surfaces of healthy animals, an infection can only be diagnosed if the sample is taken from a deep layer of tissue, and it is important to take samples directly from affected areas. Within tissues, Aspergillus spp. grows with branched, septate hyphae (2 – 5 µm diameter).

 

Cytology of fine needle aspiration of orbital or palate lesions can sometimes demonstrate fungal hyphae, but a negative result does not rule out aspergillosis.

 

If cultured on special growth media (e.g., Sabouraud agar), Aspergillus spp. form mycelia with clearly visible conidia on conidiophores within five to seven days (Fig. 9). A single positive culture from swabs or secretions without histological evidence is not diagnostic, as the organism is ubiquitous.

 

Fig. 9. Aspergillus fumigatus conidial heads from a squash preparation of fungal plaques (inset) in a Scottish shorthair cat with sinonasal aspergillosis. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

Fig. 9. Aspergillus fumigatus conidial heads from a squash preparation of fungal plaques (inset) in a Scottish shorthair cat with sinonasal aspergillosis. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

 

PCR has recently been offered for the detection of Aspergillus spp., but its relevance in veterinary medicine is not yet clear.16

 

A new noninvasive test is the measurement of serum galactomannan, a polysaccharide fungal cell-wall component by one-stage, immunoenzymatic sandwich ELISA. Overall, the test is moderately specific, but has a poor sensitivity, and thus, is not very helpful to rule-out the disease.19

 

 

Detection of antibodies

 

Aspergillus spp. antibody testing for cats is available on the basis of agar gel immunodiffusion (AGID), latex agglutination (LA), counter-immunoelectrophoresis (CIE), or ELISA. Due to high numbers of false positive results (up to 15%), positive test results should always be evaluated in combination with clinical signs and histology results. Negative results should also be interpreted with caution, as some individuals only produce low amounts of antibodies (mostly when infected with Aspergillus fumigatus) that might be missed. Antibody testing was not useful in two of four cats with fungal rhinitis.8 Nevertheless, antibody titres can give useful hints in some potentially affected cats when interpreted carefully and can be very helpful in the decision to perform more invasive diagnostics.2 

 

 

Treatment

 

No prospective controlled studies exist on the treatment of aspergillosis in cats, and information available is only based on retrospective case reports. In general, response to therapy and prognosis in SNA is good when intensive and sufficiently long treatment is instituted. Response to treatment is less successful in invasive SOA, and prognosis is worse.1 In systemic aspergillosis, prognosis is generally poor.

 

In SNA, treatment of choice is a combination of systemic antifungal tretment (amphotericin B, itraconazole, posaconazole, voraconazole, or terbinafine) in combination with local therapy, using clotrimazole or enilconazole intranasal infusions under general anesthesia. Systemic antifungal treatment should be administered over several months, and owners should be informed early about the long treatment required. Based on case series, best choices for systemic treatment are itraconazole (5 mg/kg q 12 h PO) alone or in combination with amphotericin B, or the new azoles posaconazole (2.5 – 4.5 mg/kg q 12 h PO) and voriconazole (5 – 12 mg/kg q 24 h PO). Voriconazole looks like a promising drug, but can result in adverse neurological effects, including ataxia, paraplegia, and cranial nerve deficits.18

 

Fig. 10. Local infusion of clotrimazole under general anesthesia in a cat with sinonasal aspergillosis. Courtesy of Bianka Schulz, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany.

Fig. 10. Local infusion of clotrimazole under general anesthesia in a cat with sinonasal aspergillosis. Courtesy of Bianka Schulz, Medizinische Kleintierklinik, Ludwig-Maximilians-Universität München, Germany.

 

Therefore, voriconazole should only be used in selected cases until more studies on safety in cats have been performed. The local treatment is usually performed with local infusion of clotrimazole (Fig. 10). This local treatment requires access to affected tissues. It is less effective when the infection occurs deep in the tissue. Surgical debridement of gross fungal lesions (Fig. 11) before local treatment is recommended to increase the chance of complete remission.1,3 A single intranasal infusion of clotrimazole led to long-term resolution of clinical signs in two studies, involving three cats5 and two cats.17 Multiple local treatments probably are better to reduce relapses. Systemic treatment solely without local infusions is not as successful. Four cats with fungal rhinitis were treated with itraconazole orally; when therapy was discontinued, clinical signs recurred.8

 

Fig. 11. Retrobulbar granuloma after radical orbital debridement surgery. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

Fig. 11. Retrobulbar granuloma after radical orbital debridement surgery. Courtesy of Vanessa Barrs, University Veterinary Teaching Hospital, Sydney, Australia.

 

In SOA, treatment is more difficult. In severe SOA, surgery is necessary for either lateral orbitotomy or eye enucleation.14 In a series of three cases with SOA, two cats were treated with voriconazole and surgery with successful results.14 Other drugs have been used in cats with SOA, including echinocandins in two cats, caspofungin as single treatment with good results in one cat,2 and micafungin in one cat showing no success.4 In one case, posaconazole cured a cat with SOA which had not responded to itraconazole plus amphotericin B;13 in another case, long clinical remission was achieved with posaconazole after not improving with itraconazole plus terbinafine treatment.3

 

If only the eyes are involved, local treatment can be successful. An 8-year-old cat that suffered from ulcerative keratitis with stromal loss, stromal infiltrate, corneal oedema, perilimbal vascularization, and miosis was treated with 1% voriconazole solution, and the keratomycosis resolved successfully.11

 

Although associated with a poor prognosis, one cat with pulmonary aspergillosis was successfully managed with a combination of surgery (lung lobectomy and chest drainage) and systemic itraconazole therapy for one month.9  Table 1 lists the treatment options for this infection.

 

DrugDoseComments
ClotrimazoleSingle or multiple intranasal local instillation
Itraconazole5 mg/kg p12h POSuggested drug of choice after local treatment (should be given for at least 2-3 months, or 1 month beyond clinical cure)
Fluconazole1.25-2.5 mg/kg q12h POShould be considered in cases of CNS infection (should be given for at least 2-3 months, or 1 month beyond clinical cure)
PO = oral; CNS = central nervous system
Table 1. Systemic treatment for aspergillosis (most commonly used drugs)

 

 

Prevention

 

Due to the ubiquitous occurrence and the high resistance of the pathogen, prophylaxis is hardly possible. Although an association of aspergillosis with immunosuppression is not clearly establsihed, prophylactic measures in immunocompromized animals consists of reducing exposure. Therefore, immunosuppressed animals should be kept indoors.

 

 

References

 

1 Barrs VR, Beatty JA, Lingard AE, Malik R, Krockenberger MB, Martin P, et al. Feline sino-orbital aspergillosis: an emerging clinical syndrome. Aust Vet J 2007; 85: N23.

 

2 Barrs VR, Halliday C, Martin P, Wilson B, Krockenberger M, Gunew M, et al. Sinonasal and sino-orbital aspergillosis in 23 cats: aetiology, clinicopathological features and treatment outcomes. Vet J 2012; 191: 58-64.

 

3 Giordano C, Gianella P, Bo S, Vercelli A, Giudice C, Della Santa D, et al. Invasive mould infections of the naso-orbital region of cats: a case involving Aspergillus fumigatus and an aetiological review. J Feline Med Surg 2010; 12: 714-723.

 

4 Kano R, Itamoto K, Okuda M, Inokuma H, Hasegawa A, Balajee SA. Isolation of Aspergillus udagawae from a fatal case of feline orbital aspergillosis. Mycoses 2008; 51: 360-361.

 

5 Tomsa K, Glaus TM, Zimmer C, Greene CE. Fungal rhinitis and sinusitis in three cats. J Am Vet Med Assoc 2003; 222: 1380-1384, 1365.

 

6 Barachetti L, Mortellaro CM, Di Giancamillo M, Giudice C, Martino P, Travetti O, et al. Bilateral orbital and nasal aspergillosis in a cat. Vet Ophthalmol 2009; 12: 176-182.

 

7 Hamilton HL, Whitley RD, McLaughlin SA. Exophthalmos secondary to aspergillosis in a cat. J Am Anim Hosp Assoc 2000; 36: 343-347.

 

8 Whitney BL, Broussard J, Stefanacci JD. Four cats with fungal rhinitis. J Feline Med Surg 2005; 7: 53-58.

 

9 Hazell KL, Swift IM, Sullivan N. Successful treatment of pulmonary aspergillosis in a cat. Aust Vet J 2011; 89: 101-104.

 

10 Schulz B, Unterer S, Hartmann A, Werckenthin C, Brühschwein A, Hartmann K. Diagnostik und Therapie der nasalen Aspergillose bei der Katze – Fallbeschreibung und Literaturübersicht. Tierärztl Prax 2007; 35: 281-286.

 

11 Labelle AL, Hamor RE, Barger AM, Maddox CW, Breaux CB. Aspergillus flavus keratomycosis in a cat treated with topical 1% voriconazole solution. Vet Ophthalmol 2009; 12: 48-52.

 

12 Goodall SA, J.G. L, Warnock DW. The diagnosis and treatment of a case of nasal aspergillosis in a cat. J Small Anim Pract 1984; 25: 627-633.

 

13 McLellan GJ, Aquino SM, Mason DR, Kinyon JM, Myers RK. Use of posaconazole in the management of invasive orbital aspergillosis in a cat. J Am Anim Hosp Assoc 2006; 42: 302-307.

 

14 Smith LN, Hoffman SB. A case series of unilateral orbital aspergillosis in three cats and treatment with voriconazole. Vet Ophthalmol 2010; 13: 190-203.

 

15 Karnik K, Reichle JK, Fischetti AJ, Goggin JM. Computed tomographic findings of fungal rhinitis and sinusitis in cats. Vet Radiol Ultrasound 2009; 50: 65-68.

 

16 Lau A, Chen S, Sorrell T, Carter D, Malik R, Martin P, et al. Development and clinical application of a panfungal PCR assay to detect and identify fungal DNA in tissue specimens. J Clin Microbiol 2007; 45: 380-385.

 

17 Furrow E, Groman RP. Intranasal infusion of clotrimazole for the treatment of nasal aspergillosis in two cats. J Am Vet Med Assoc 2009; 235: 1188-1193.

 

18 Quimby JM, Hoffman SB, Duke J, Lappin MR. Adverse neurologic events associated with voriconazole use in 3 cats. J Vet Intern Med 2010; 24: 647-649.

 

19  Whitney J, Beatty JA, Martin P, Dhand NK, Briscoe K, Barrs VR. Evaluation of serum galactomannan detection for diagnosis of feline upper respiratory tract aspergillosis. Vet Microbiol 2012 Sep 12. pii: S0378-1135(12)00500-7. doi: 10.1016/j.vetmic.2012.09.002. [Epub ahead of print]

 

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