The Fight Against Some Formidable Fungal Foes

Nasal cavity disease is common in cats. Feline herpesvirus type 1 (FHV-1) is probably the principal culprit, topping the list of differentials. By contrast, nasal foreign bodies are comparatively rare in cats (because they are smarter than dogs [!] and have smaller nares), although sometimes grass blades or awns, for example, are deposited in the nasopharynx after vomition. Cancer occurs too, of course — lymphoma, primarily, followed by various carcinomas — and needs to be considered in cats with deforming or invasive nasal cavity disease, especially in older individuals.

Less common infectious agents of the feline nasal cavity and paranasal sinuses include organisms normally regarded as saprophytes, such as fungi and oomycetes. Best known are the primary pathogens Cryptococcus neoformans and Cryptococcus gattii, which generally gain entry via the upper respiratory tract and may cause invasive disease at this site, with local spread to contiguous structures such as the nasal planum, bridge of the nose and brain (via the cribriform plate). ¹ The nasal passages of cats can also become infected with filamentous fungi, such as Aspergillus species, and this issue of JFMS describes one such sad case in detail, complete with the first magnetic resonance imaging findings in a cat with mycotic retrobulbar disease. ²

Growing numbers of cases of sinonasal and orbital mycosis have been reported in cats. The disease is sporadic, without clear geographical clustering.

MULTIMEDIA.

The entire CT scan from which Fig 1b is derived can be viewed at doi:10.1016/j.jfms.2010.07.010

The authors of the case report, which appears on pages 714–723, also conduct a detailed review of the literature concerning feline sinonasal and orbital mycosis, a syndrome that was first described in two cats some 30 years ago, one in St Louis in the USA, ³ the other in south-east Queensland, Australia. ⁴ Signs started with sneezing and a watery ocular discharge, and progressed to involve prolapse of the third eyelid and proptosis of both globes. In both instances, clinical and necropsy examinations demonstrated that the infection started in the nasal cavity and extended into the orbit via bony invasion. Cases of invasive rhinosinusitis attributable to other fungi have subsequently been described, including dematiaceous (pigmented) fungi ⁵ and unusual organisms such as Pythium insidiosum ⁶ (an oomycete) and Metarhizium anisopliae ⁷ (a fungal pathogen of insects). The next significant papers concerning sino-orbital mycoses appeared in 1997 and 2000, ^8,9 presenting computed tomography (CT) findings (Fig 1), and emphasising the presence of lesions in the pterygopalatine fossa of the oral cavity, a further site where tissue invasion by fungi follows a well-defined anatomical pathway. ²

FIG 1.

Radiograph (a) and CT scan (b) from a cat, seen in 2006, with invasive sino-orbital disease attributable to a Neosartorya species. In (a), the red arrow highlights areas of predominantly lysis within the rostral nasal cavity. In (b), the red arrow highlights radiodense material in the orbit, which is pushing the eye forward. Note also the material in the nasopharynx (blue arrow), and the small lytic areas in the bone between the nasal cavity and the orbit

Over the past few years, there has been a plethora of reports of sinonasal and orbital mycosis. The number is such that some refer to this as an ‘emerging infectious disease’. Although we don't think that is quite the case, patients have certainly been reported in growing numbers from a progressively large geographical range including Italy, ^2,10 Japan, ¹¹ several states in the USA, ^12–15 the UK ¹⁶ and eastern Australia. ¹⁷ Importantly, the disease is sporadic, without clear geographical clustering.

The present focus is on trying to formulate effective treatment regimens to deal with these devastating infections, which will likely rely on a combination of precise surgery to debride the frontal sinuses and affected periorbital tissues (Fig 2), intralesional therapy (using amphotericin B ^18,19 or voriconazole ¹⁴ ) and systemic therapy using variable combinations of posaconazole, ¹³ caspofungin, amphotericin B ¹⁹ (including liposomal formulations) and terbinafine. The use of bone cement or other vehicles impregnated with high concentrations of an appropriate antifungal as an eluting depot in the frontal sinus is worth considering also. Although voriconazole is a highly effective agent for treating such infections in people, when used systemically in cats there seems to be a high risk of adverse events, especially neurological side effects. ^14,20

FIG 2.

Dissection of infected tissues within the orbit of a Russian Blue cat with invasive bilateral sino-orbital disease due to a Neosartorya species. This case was diagnosed by Anna Deykin in 1999 and referred for treatment

The widespread use of molecular techniques to augment classical mycology has recently contributed to our understanding of these infections. The Aspergillus section Fumigati contains 10 Aspergillus species and around 23 Neosartorya species, ²¹ many of which are known pathogens. The term Neosartorya refers to the teleomorph (sexual state), while Aspergillus refers to the anamorph (asexual state) of the corresponding species — and this nomenclature makes describing infections somewhat confusing. Nonetheless, sequencing techniques can discriminate fungal species within this section that may be indistinguishable using standard phenotypic methods, but that display marked differences in their clinical features and therapeutic requirements. The first breakthrough was when a panfungal PCR developed at Westmead Hospital in Sydney, Australia, demonstrated that a cat with sino-orbital mycosis had a Neosartorya pseudofischeri infection, ^17,22 a finding echoed in cases from Japan (Aspergillus udagawae/Neosartorya udagawae) ¹¹ and the UK (Neosartorya aureola). ¹⁶

In those cases in which the fungus has been identified solely on morphology, it is not always clear whether Aspergillus fumigatus or in fact a closely related species was responsible for the infection. However, the evidence suggests that when filamentous fungi are restricted to the nasal cavity, perhaps with limited extension to the nasopharynx or nasal bridge (Fig 3), A fumigatus is most likely to be involved. This would explain why such cases can respond to topical therapy using clotrimazole ‘soaks’, if these are given before the underlying bone is breached. ^12,23 By contrast, where there is documented extension to the orbit, eye, brain or oral cavity, one should be suspicious of another species (eg, N pseudofischeri, ¹⁷ N udagawae, ¹¹ N aureola, ¹⁶ Aspergillus lentulus ¹⁷ ). This is especially germane because these close relatives of A fumigatus can be very resistant to both amphotericin B and the older azole drugs. ^24,25 Thus, definitive identification of the infectious agent may have important implications for treatment choices and disease prognosis. A multi-institutional study in Australia is currently bringing together these various clinical and laboratory observations. ¹⁷

FIG 3.

Six-year-old Himalayan cat, seen in 2003, with invasive rhinosinusitis. Infection had spread to the nasal bridge; note the draining tract over the frontal sinus

Case studies, such as the one in this issue of JFMS, ² focus our attention on a number of pertinent issues (see box). Added to which, there is an urgent need to determine pharmacokinetic data in cats for new antifungal agents, such as posaconazole and caspofungin, and for older agents such as amphotericin B and its newer formulations. To make progress in answering these questions, veterinarians need the help of laboratory scientists and human infectious disease clinicians who are interested in veterinary mycology and based at reference laboratories in medical mycology with expertise in both classical mycology and molecular methods. Four outstanding examples are listed as useful contacts on page 671. Finally, veterinarians in the UK in need of assistance with acquiring antifungals should e-mail admin@aspergillus.org.uk (citing ‘Antifungals’ in the subject line).

Questions surrounding mycotic rhinosinusitis.

• How do Aspergillus/Neosartorya species colonise the feline nasal cavity?

  • — Is colonisation following deposition of spores the first step in the development of infection?

  • — Do nasal or nasopharyngeal foreign bodies of plant origin play a role?

  • — Are there any predisposing factors such as defective host anatomy (eg, brachycephalic conformation), damage caused by previous FHV-1 infection, or use of sequential antimicrobials that disturb the normal bacterial flora?

• What factors underlie the marked differences in pathogenicity of these organisms?

  • — Why does A fumigatus tend not to invade the orbit or oral cavity while the closely related Neosartorya species do? Is this related to preferential deposition of ascospores in certain parts of the nasal cavity?

  • — Why do Cryptococcus species tend to spread to the nasal bridge and cribriform plate in the cat, but rarely to the orbit or oral cavity (they do not show this bias in dogs), ²⁶ in contradistinction to Neosartorya species?

• Might galactomannan and β-glucan antigen tests assist the diagnosis of these infections and could sequential antigen titres aid in monitoring therapy?

Useful contacts.

• Dr Catriona Halliday Catriona.Halliday@swahs.health.nsw.gov.au Westmead Hospital, Sydney, Australia

• Dr Runi Kano rkano@cdc.gov or kano@brs.nihon-u.ac.jp Centre for Diseases Control, Georgia, USA

• Professor David Denning david.denning@manchester.ac.uk National Aspergillosis Centre, University Hospital of South Manchester, UK

• Professor Malcolm Richardson malcolm.richardson@manchester.ac.uk Regional Mycology Laboratory, University Hospital of South Manchester, UK