Invasive Fungal Infections
World Small Animal Veterinary Association World Congress Proceedings, 2013
Vanessa Barrs, BVSc(hons), MVetClinStud, FANZCVSc (Feline Medicine)
Small Animal Medicine, Faculty of Veterinary Science, The University of Sydney, NSW, Australia

Introduction and Aetiology

The most common invasive fungal infections reported in cats worldwide are cryptococcosis, aspergillosis, sporotrichosis and phaeohyphomycoses. Others encountered in more geographically restricted regions include blastomycosis, histoplasmosis and coccidiomycosis. Cryptococcosis (Cryptococcus neoformans-Cryptococcus gattii species complex) and sporotrichosis (Sporothrix schenckii) are caused by dimorphic fungi that grow in the environment as molds and in the higher temperatures of infected hosts as yeasts. C. neoformans has 4 major molecular types (VNI-VNIV) as does C. gattii (VGI-VGIV). Aspergillosis is most commonly caused by fungi from the Aspergillus fumigatus complex, including A. fumigatus and A. felis sp. nov.1 Phaeohyphomycoses are caused by species of molds (e.g., Alternaria spp.) that form pigmented (dematiaceous) hyphal elements in tissue and culture.

Environmental niche

Cryptococcus neoformans and C. gattii are found in plant matter, air and water. C. neoformans is also found in pigeon droppings. Aspergillus spp. and S. schenckii grow on decaying organic matter in soil, while the dematiaceous fungi are soil and wood saprophytes. Most can also be found indoors, thus indoor-only access does not preclude infection.

Route of Infection and Pathogenesis

 In cryptococcosis and aspergillosis fungal spores are inhaled and preferentially colonise the mucosa of the upper respiratory tract (URT). The systemic form of aspergillosis is rare in cats. In aspergillosis invasion of the orbital bone to involve the retrobulbar space and other paranasal tissues is common (sino-orbital aspergillosis; SOA). Neurological signs/blindness occurs in both mycoses when there is extension through the cribriform plate/sphenoid sinus or along the optic nerve or haematogenous dissemination.

 In phaeohyphomycoses and sporotrichosis, infection results from direct inoculation of the fungus into skin via contact with plants or soil and less frequently from inhalation.

 Haematogenous dissemination can occur with cryptococcosis, phaeohyphomycoses and sporotrichosis but has not been documented in URT aspergillosis.

Zoonotic Potential

Except for S. schenckii, these fungi are shared environmental pathogens and unlikely to be transmitted directly from cats to humans. Since cats with sporotrichosis have abundant organisms they can directly infect humans without a skin-penetrating injury through contact with lesions or through cat scratches.

Signalment and Predisposing Factors

Cats with fungal URT infections are generally young to middle-aged. Brachycephalics, especially Persians and Himalayans, are at increased risk for aspergillosis. Males are at increased risk for sporotrichosis. FIV and FeLV infection do not appear to be particular risk factors for any of these mycoses.

Clinical Signs

Rhinitis and Nasopharyngeal Disease

Sneezing, stertor, nasal discharge - usually mucopurulent. Intermittent epistaxis, facial swelling or discharging sinus fistula are less common.

Cutaneous Lesions

 Cryptococcosis - masses protruding from the nares, masse/nodules/ulcers on the nasal planum/nasal bridge. Haematogenous dissemination results in widespread multiple cutaneous nodules that ulcerate.

 Phaeohyphomycosis/sporotrichosis - single or multiple lesions, especially on extremities (nose, pinnae, digits, hind limbs. Concurrent nasal signs may or may not be present.2

Sino-orbital Disease

Fungal orbital granulomas (SOA) occur in 63% of all cats with URT aspergillosis and occasionally in cats with cryptococcosis or phaeohyphomycosis. Orbital granulomas cause exophthalmos, exposure keratitis and an oral cavity mass/ulcer ventral to the orbit. Paranasal soft-tissue involvement is common.

Neurological and Ocular Signs

CNS involvement is most common with cryptococcosis. Signs include ataxia, behavioral change, vestibular signs, seizures, mydriasis and blindness. CNS involvement occurs in 15% of cases of SOA and is rare in the other mycoses.

Diagnosis

1. Fundic Examination and Neurological Examination

2. Serology

Cryptococcal antigen latex agglutination serology (CALAS): high sensitivity (96–98%) and specificity (97–100%).3

Serum galactomannan antigen detection - galactomannan is a fungal cell wall polysaccharide of Aspergillus spp. Poor sensitivity (23%) and moderate specificity (78%) for diagnosis of URT aspergillosis. Not recommended.

Anti-Aspergillus spp. antibodies - detected in the serum of 5 of 10 cats with URT aspergillosis in published case reports, but sensitivity/specificity not determined.

3. Nasal Swab Fungal Culture

Should not be used as a stand-alone diagnostic test since the nasal cavity can be transiently colonized with fungi. Indicated in all cats with positive CALAS for species identification and antifungal susceptibility testing.

4. Diagnostic Imaging - Skull and Thorax

CT is superior to plain radiography. Findings cannot be differentiated from neoplasia: lysis of turbinates/ethmoturbinates, paranasal bone lysis, and soft tissue opacification of the nasal cavity/sphenoid/frontal sinuses. Disease is often bilateral. In SOA there is a ventromedial orbital mass with heterogeneous post-contrast enhancement. Thoracic radiography or CT is useful to screen for LRT involvement, which is uncommon.

5. Rhinoscopy, Nasopharyngoscopy & Biopsy

Fungal plaques are seen in the nasal cavity of some cats with SNA but not typically with SOA. Sinus trephination using a Jacob chuck and intramedullary pin (3.2–4 mm) enables endoscopic examination of the frontal sinuses and sampling for culture & histology where indicated. Not suitable for some brachycephalic cats (shallow sinuses in close proximity to the cranial vault).

Biopsy mass lesions/nasal mucosa for histology & culture. Most fungi are readily cultured on standard commercial laboratory fungal media (e.g., Sabouraud's-dextrose agar).

6. Advanced Diagnostics - Panfungal ITS PCR & sequencing

A panfungal PCR that amplifies the internal transcribed spacer regions (ITS1 & ITS2) of the ribosomal DNA gene cluster. These regions are highly variable and allow identification of a diverse range of fungal genera from clinical specimens, including both filamentous fungi and yeasts.1

Treatment & Prognosis

Drug dosages are listed in Table 1.

Cryptococcosis

Fluconazole is the recommended first-line therapy. Itraconazole is effective but has more adverse effects and longer courses of therapy may be required. Antifungal susceptibility testing is strongly recommended.

In severe/CNS disease add in amphotericin B (AMB) and/or flucytosine.

AMB deoxycholate can be given as a subcutaneous infusion on an outpatient basis.

Liposomal-AMB is less nephrotoxic, however azotaemia is still common and monitoring of serum creatinine should be performed during therapy.

Treatment should be continued until the CALAS is zero with follow-up antigen testing one month after therapy has been stopped and at subsequent recheck examinations.

Good prognosis where no CNS involvement but long treatment courses of many months may be required and recrudescent infection occurs in 15–20% cases.4

Aspergillosis and Phaeohyphomycoses

Fluconazole should not be used because of intrinsic resistance. Posaconazole or itraconazole are recommended for first-line therapy. Voriconazole is not recommended due to adverse neurological events.5

SNA: Add in topical treatment with intranasal clotrimazole or enilconazole. Debride sinonasal fungal plaques endoscopically. Good prognosis for resolution.

SOA: Addition of AMB and terbinafine may improve outcomes. The prognosis for SOA is poor (< 20% cure rate).

Sporotrichosis

 Itraconazole is indicated for first-line therapy. Severe cases add in AMB.

 Good prognosis for resolution (median 28 weeks treatment)6

Table 1. Useful drugs for treating invasive fungal infections in cats

Drug & formulation

Dosage, Route of Administration

Adverse effects

Fluconazole
50 mg capsules
10 or 40 mg/ml oral suspension

2.5–10 mg/kg q 12 h PO or 50 mg/cat q 12–24h

Gastrointestinal - inappetence
Hepatotoxicty (rare)

Itraconazole
100 mg capsules
10 mg/ml oral suspension
(Sporanox; Janssen)

5 mg/kg q 12 h PO or 10 mg/kg q 24 h PO
Administer with food

Gastrointestinal - anorexia, vomiting
Hepatotoxicity - elevated liver enzymes, jaundice. Monitor ALP/ALT monthly. If hepatotoxicity occurs, reduce dose to 5 mg/kg q 24 h or 10 mg/kg q 48 h.

Posaconazole
40 mg/ml liquid (Noxafil, Schering- Plough)

5–7.5 mg/kg divided twice daily PO
Administer with food

Hepatotoxicity. Unlikely to occur at 5 mg/kg q 24 h
NB - pharmacology of this drug has not been determined in cats.

Ketoconazole
200 mg capsule

5–10 mg/kg q 8–12 h PO after meals

Gastrointestinal - anorexia, vomiting
Hepatotoxicity

Voriconazole
50 mg tablets
40 mg/ml powder for oral suspension
(Vfend, Pfizer)

5 mg/kg q 24 h PO

Gastrointestinal - anorexia
Neurological problems - blindness, ataxia, stupor
Should only be used as a last resort when other therapies have failed.

Terbinafine
250 mg tablets
(Lamisil, Novartis)

30 mg/kg q 24 h PO

Gastrointestinal - anorexia, vomiting, diarrhea

Flucytosine
250 mg capsules
75 mg/ml oral suspension

50 mg/kg q 8 h PO or 75 mg/kg q 12 h PO

Gastrointestinal - anorexia, vomiting, diarrhoea
Caution - cytotoxic drug. Wear gloves when handling.

Amphotericin B deoxycholate
50 mg vial
(Fungizone, Bristol-Myers)

0.5 mg/kg of 5 mg/ml stock solution in 350 ml/cat of 0.45% NaCl + 2.5% dextrose SC 2–3 x weekly to a cumulative dose of 10–15 mg/kg.

Nephrotoxicity- pretreatment of stock solution by heating to 60°C for 5 minutes reduces nephrotoxicity. Monitor urea/creatinine every 2 weeks. Discontinue for 2 to 3 weeks if azotaemic.

Liposomal Amphotericin B (AmBisome, Gilead)

1–1.5 mg/kg IV q 48 h to a cumulative dose of 12 to 15 mg/kg.
Given as a 1–2 mg/ml solution in 5% dextrose by IV infusion over 1–2 h

Nephrotoxicity - Azotemia can occur. Monitor urea/creatinine every 2–3 days during administration

References

1.  Barrs VR, et al. Vet J. 2012;191:58.

2.  Dye C, et al. J Feline Med Surg. 2009;11:332–336.

3.  Trivedi SR, et al. J Feline Med Surg. 2011;13:163.

4.  O'Brien CR, et al. Aust Vet J. 2006;84:384.

5.  Quimby JM, et al. J Vet Intern Med. 2010;24:647.

6.  Pereira SA, et al. Vet Rec. 2010 ;166:29.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Vanessa Barrs, BVSc(hons), MVetClinStud, FANZCVSc (Feline Medicine)
Faculty of Veterinary Science
The University of Sydney
Sydney, NSW, Australia


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