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REVIEW

Sinonasal aspergillosis in dogs: a review

M. J. Sharman and C. S. Mansfield
Faculty of Veterinary Science, University of Melbourne, 250 Princes Highway, Werribee, Victoria 3030, Australia

Sinonasal aspergillosis is an uncommon, yet debilitating and often frustrating condition to treat in
dogs despite years of research evaluating pathogenesis, diagnosis and treatment. The disease is most
commonly caused by non-invasive fungal infection, thought to be secondary to altered innate and/
or adaptive immune responses. Attempts to confirm this have however failed. A variety of conflicting
opinions regarding the diagnosis and treatment of sinonasal aspergillosis exist. Often the use of a particular treatment protocol is based upon personal or regional preference. Evaluation of the veterinary
literature demonstrates that the evidence base in support of individual treatment recommendations is
weak. A number of recent publications have helped to expand the current knowledge base and therefore our understanding of important practicalities for both diagnostic options and treatment protocols.
The following review examines the current evidence for the pathogenesis of sinonasal aspergillosis in dogs, as well as the various diagnostic options. The available evidence for frequently utilised
therapeutic options and their likely outcomes is also explored.
Journal of Small Animal Practice (2012) 53, 434444
DOI: 10.1111/j.1748-5827.2012.01245.x
Accepted: 14 May 2012; Published online: 12 July 2012

INFECTION AND IMMUNITY

Fungal infections of the nasal cavity are relatively uncommon in
dogs (Sharp and others 1991b, Tasker and others 1999, Peeters
and Clercx 2007, Meler and others 2008). A variety of infections
are reported in the veterinary literature with Aspergillus spp., particularly Aspergillus fumigatus, most common (Peeters and Clercx
2007). These ubiquitous soil saphrophytes play important roles
in environmental recycling, sporulating abundantly to produce
vast quantities of conidia which are distributed via air currents
(Latge 1999). Conidia are small enough (2 to 3 m) to reach pulmonary alveoli and exposure occurs with inhalation, but disease
does not develop in every individual (Latge 1999).
The capacity of fungal elements to result in infection may
depend upon both host immunocompetence and virulence factors associated with the fungal organism. Trapping and removal
of inhaled fungal elements by the respiratory tract mucociliary
defences usually prevent further access. Where this fails, additional innate immune system mechanisms are employed, including
the alternative complement system, phagocytic cells (neutrophils,
macrophages and dendritic cells), natural killer and T-cells
which work to destroy pathogens intracellularly or by secretion
of compounds extracellularly (Romani 2004, Shoham and Levitz
2005). Reduced mucociliary clearance, decreased phagocytic cell
numbers or impairment in their capacity to destroy organisms
can cause infection.
434

Stimulation of phagocytic cell surface receptors, particularly

toll-like receptor (TLR)-4, by Aspergillus spp. conidia results in
macrophage production of pro-inflammatory cytokines such as
tumour necrosis factor (TNF)-, interleukin (IL)-1 and IL-1.
Hyphae result in IL-10 production via TLR-2-mediated pathways (Shoham and Levitz 2005). These factors initiate pathways
that may counteract host protective mechanisms. Importantly,
by processing and presenting antigen and aiding inflammatory
mediator production, the innate immune system instructs the
adaptive immune system which provides long-term protection
(Romani 2004, Shoham and Levitz 2005). Dendritic cells play
an important linking role by capturing and processing fungal
antigen, by expressing lymphocyte co-stimulatory molecules and
by migrating to lymphoid organs to secrete cytokines and initiate
adaptive immune responses.
The array of cytokines released determines protection or susceptibility to infection by resulting in differentiation of CD4+
T-lymphocytes to either a T-helper (Th)-1 or Th-2 cell response
(Shoham and Levitz 2005). Interferon (IFN)-, IL-6, TNF-
and IL-12 result in a Th-1 response, while a Th-2 response is seen
when IL-4 and IL-10 predominate (Shoham and Levitz 2005).
Immunological studies demonstrate that Th-1 biased responses
convey protection with only mild or asymptomatic infection
occurring, whilst Th-2 biased responses result in severe or allergic
disease. Normally these responses are balanced to aid elimination
of infectious agents, whilst limiting autoimmune injury (Romani
2004, Shoham and Levitz 2005).

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ORGANISM VIRULENCE FACTORS

Fungal metabolites and secretory products produced by individual Aspergillus spp. may convey survival advantages by suppressing localised host immune factors or allowing immune
system evasion. Aspergillus fumigatus possesses various fungal
toxins and metabolites that may reduce mucociliary function.
Gliotoxin has been implicated, although fumagillin and helvolic
acid, amongst others, have similar effects (Tomee and Kauffman
2000). Reduced mucociliary clearance provides an opportunity
for fungal elements to reach epithelial surfaces, resulting in further damage and potentially invasion. Invasion may be enhanced
by improved adherence of fungal elements to host tissues via
extracellular matrix and serum proteins including laminin, fibronectin, collagen, fibrinogen and complement component C3
(Tomee and Kauffman 2000).
In addition, fungal metabolites impair phagocytic functions that would normally destroy conidial and hyphal forms
(Tomee and Kauffman 2000). Gliotoxin reduces adherence
and phagocytosis of fungal elements, while aflatoxins affect
phagocytosis, intracellular killing and spontaneous superoxide
production. Complement binding and activation of bound
opsonins, which normally enhance phagocytosis, are affected
too, reducing susceptibility to destruction (Tomee and Kauffman 2000).
Localised inhibition of host cell growth and subsequently
enhanced fungal growth may also be facilitated by toxins. Again
gliotoxin is largely implicated, reducing T-cell proliferation and
activation of cytolytic T-lymphocytes, blood monocytes, fibroblasts and other cells (Tomee and Kauffman 2000). Toxins such
as ribotoxins inhibit protein synthesis and are highly toxic to
eukaryotic cells (Tomee and Kauffman 2000).

MYCOTIC RHINOSINUSITIS IN HUMANS

PARALLELS WITH CANINE DISEASE
In humans, fungal infections are grouped into those affecting
immunocompromised or immunocompetent patients (Hamilos
and Lund 2004). Immunocompetent patients are typically diagnosed with non-invasive infection such as allergic rhinosinusitis/
bronchopulmonary disease or chronic erosive rhinosinusitis (Uri
and others 2003, Barnes and Marr 2006). Granuloma formation has been reported in chronically obstructed paranasal sinuses
(Latge 1999, Barnes and Marr 2006, Day 2009). Invasive fungal
sinusitis, pulmonary infection and disseminated systemic fungal
disease are more likely in immunocompromised patients (Latge
1999, Barnes and Marr 2006, Day 2009).

CANINE MYCOTIC RHINOSINUSITIS

In previous studies of dogs with chronic nasal disease, mycotic
rhinosinusitis occurred with a frequency of 7 to 34% (Sharp and
others 1991b). Aspergillus fumigatus is most frequently isolated,
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although various other species including A. Niger, A. nidulans

and A. flavus have been reported. Penicillium spp. and other fungal species are rare causes (Sharman and others 2010).
Marked nasal turbinate destruction is invariably identified,
with extension of disease into periorbital soft tissue and destruction of the cribriform plate in severe cases. Destruction is attributed to host inflammatory responses and dermonecrolytic fungal
toxins, rather than direct action of the fungal organisms involved
as histopathologic studies suggest that infection is non-invasive
in dogs (Peeters and others 2005). This differs from sinonasal
aspergillosis (SNA) in cats where progression to periorbital disease is frequently reported and is more challenging to treat (Barrs
and others 2012).
The pathogenesis of non-invasive fungal infections in dogs
is poorly understood. Defects of innate and adaptive immune
mechanisms are not typically observed in SNA (Romani 2004,
Shoham and Levitz 2005, Peeters and others 2006). Concurrent
disease or systemic immunodeficiency is not typically recognised;
however, facial trauma, nasal foreign bodies and dental disease
are occasionally implicated (Sharp and others 1991b, Peeters and
Clercx 2007, Day 2009).
Limited evaluation of adaptive immunity has occurred
in dogs (Peeters and others 2006, 2007). Cytokine profiling
identifies significant up-regulation of mRNA for cytokines
predominantly associated with a Th-1 response compared
with normal controls or dogs with lymphoplasmacytic rhinitis (Peeters and others 2006, 2007, Vanherberghen and others
2012). Up-regulation of IL-8, IL-18 and TNF- in SNA may
promote phagocytic killing and recruitment of immune cells
(Peeters and others 2006). Local immune responses may therefore be adequate to prevent invasion and dissemination, but
insufficient to prevent inflammation. Up-regulation of IL-10
and TGF- may relate to failure to clear infection, despite significant inflammation (Peeters and others 2007). Additional
evaluation is required, before adjunctive immunotherapeutics
can be recommended.

SIGNALMENT AND CLINICAL COURSE

Mesocephalic and dolicocephalic dogs are most commonly diagnosed with SNA. Specific breed predispositions are not observed
and brachycephalic breeds can be affected (Sharp and others
1991b, Zonderland and others 2002). Affected dogs are generally
young to middle-aged with very young or very old dogs occasionally reported. A male predisposition is not consistently supported
(Sharp and others 1991b, Zonderland and others 2002, Johnson
and others 2006).
Nasal signs may be present for weeks to months or even years
with chronic mucopurulent to purulent nasal discharge, nasal
pain and nasal planum ulceration/depigmentation most commonly reported (Fig 1). Sneezing, epistaxis, decreased appetite
and signs of depression may be observed. Epistaxis may be so
severe that life-threatening anaemia develops requiring blood
transfusion. Additionally in severe disease facial deformity,
epiphora and seizures may be identified.

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M. J. Sharman & C. S. Mansfield

FIG 1. Mucopurulent nasal discharge and nasal depigmentation in a

dog receiving treatment for sinonasal aspergillosis with enilconazole
via indwelling catheters in the frontal sinuses and nasal cavity. Image
courtesy of Associate Professor Peter Irwin, Murdoch University, Western
Australia

DIAGNOSTICS
Although clinical findings and course of disease may increase
suspicion for SNA, a combination of diagnostics encompassing
diagnostic imaging [computed tomography (CT) or radiography], rhinoscopy/sinuscopy, histopathology, cytology, fungal
culture and serology are recommended for definitive diagnosis.
Other common causes of chronic nasal disease including neoplasia, nasal foreign bodies, rhinitis secondary to dental disease and
idiopathic lymphoplasmacytic rhinitis should also be considered
and excluded.

FIG 2. Open mouth, ventrodorsal projection of the left and right nasal
cavities showing a patchy increase in opacity within the mid to caudal
left and right nasal cavities. An increased lucency is also present within
the mid right nasal cavity indicating turbinate lysis

DIAGNOSTIC IMAGING
Radiographic features of SNA are well described and detectable
in most cases (Sullivan and others 1986). Accurate head positioning is imperative for diagnosis. Radiographs should include
dorsoventral and lateral views of the skull, intraoral views of the
nasal cavities and maxilla as well as a rostrocaudal view of the
frontal sinuses. Intra-oral, dorsoventral and rostrocaudal views of
the frontal sinuses allow for evaluation of nasal cavity symmetry
and frontal sinus involvement (Figs 2 and 3) (Sullivan and others
1986).
Turbinate destruction within the nasal cavity is evident as
wide-spread punctuate lucencies or a generally increased radiolucency. Mixed-density patterns or an overall increase in opacity may be seen with accumulation of fungal plaques, debris or
discharge. Rostrocaudal views of the sinuses are essential to avoid
misdiagnosis. Soft tissue density, hyperostosis and punctuate
lucencies may be seen within the frontal bones on these views
(Sullivan and others 1986).
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FIG 3. Rostrocaudal projection of the frontal sinuses showing an

increased opacity within the left frontal sinus

CT improves sensitivity (88 to 92%) compared with radiographs (72 to 84%) (Saunders and van Bree 2003). Cavitary
destruction of the turbinates (Fig 4), mucosal thickening and
thickened and reactive maxillary, vomer and frontal bones may be
evident using CT, particularly with subtle or unilateral changes
(Fig 5) (Saunders and others 2002, Saunders and van Bree 2003).
CT is more sensitive for cribriform plate involvement (Saunders
and others 2002, Saunders and van Bree 2003).
Magnetic resonance imaging (MRI) in canine SNA is considered more sensitive than CT for soft tissue change, whilst the
opposite is true for evaluation of hyperostosis and lysis within
the bones surrounding the nasal cavity. Despite this there is no

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FIG 4. Destruction of the nasal turbinates identified on computed tomography (CT) of the nasal cavity. Image courtesy of Murdoch University
Veterinary Hospital, Western Australia

FIG 6. Severe nasal turbinate destruction and fungal plaques within the
nasal cavity of a dog affected by sinonasal aspergillosis. Image courtesy
of Associate Professor Vanessa Barrs, University of Sydney Veterinary
Teaching Hospital, New South Wales, Australia

demonstrable difference between CT and MRI for diagnosing

nasal cavity mycoses (Saunders and others 2004).

RHINOSCOPY AND SINUSCOPY

Direct visualisation with rhinoscopy may demonstrate turbinate
destruction, mucoid nasal discharge and fungal plaques (Fig 6).
It is important to remember that at least one study showed that 8
of 46 dogs (17%) had disease confined to the frontal sinuses that
was only identified with sinuscopy (Johnson and others 2006).
Sinus trephination may therefore be advantageous where nasal
cavity disease is minimal to confirm fungal disease and additionally provides access for debridement of fungal plaques before
treatment. In some cases significant nasal turbinate destruction
allows direct sinus access by endoscopy via the nasal cavity without trephination.

CYTOLOGY AND HISTOPATHOLOGY OF NASAL

SPECIMENS

FIG 5. Marked hyperostosis of the frontal bone associated with severe

involvement of the right frontal sinus, as identified using computed
tomography (CT). Image courtesy of Murdoch University Veterinary
Hospital, Western Australia
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Cytology of nasal discharge is considered to have poor diagnostic

accuracy in mycotic nasal disease. Fungal organisms found on
nasal cytology could reflect normal nasal cavity colonisation or be
present secondary to any chronic nasal cavity disease that reduces
mucociliary clearance. Comparison of direct smears of nasal discharge, blind endonasal swabs, mucosal brushings of suspected
lesions under endoscopic guidance and squash preparations

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M. J. Sharman & C. S. Mansfield

FIG 7. Histologic section of a nasal cavity biopsy showing an Aspergillus

spp. conidial head and many small conidia. Many septate hyphae are also
seen (arrow). H&E, scale bar = 1008 m. Image courtesy of Murdoch
University Veterinary Hospital, Western Australia

from nasal biopsies collected under endoscopic guidance show

the greatest accuracy for samples collected under direct visual
guidance. Fungal elements were detected in 14 of 15 (933%)
of cases using mucosal brushings and 15 of 15 (100%) using
squash preparations of nasal biopsies. Detection rates were poorest with samples prepared from nasal discharge which identified
fungal elements in two cases only (133%) (De Lorenzi and others 2006).
Histopathological examination is generally accepted as being
more accurate (Fig 7), although in one histological study of 15
dogs with SNA, fungal elements were demonstrated in only 6
cases (40%). Interestingly, hyphae were not identified within or
below the mucosal surface in any samples suggesting that infection is non-invasive (Peeters and others 2005). More recently,
fungal hyphae were detected in 18 of 22 (82%) nasal biopsy
samples collected under direct endoscopic guidance (Pomrantz
and Johnson 2010). Sampling areas adjacent to plaques rather
than plaques themselves, or erroneous identification of mucus or
secondary mucosal irregularities could contribute to lower-thanexpected detection rates.
Other histopathological findings include mucosal ulceration
and inflammation with the inflammatory infiltrate usually comprising a mix of neutrophils and mononuclear cells, although
predominantly lymphoplasmacytic infiltrates may be seen
(Peeters and others 2005, 2008). Histopathological findings are
consistent with human chronic, erosive, non-invasive mycotic
rhinosinusitis (Peeters and others 2005, Day 2009).

FUNGAL CULTURE
Definitive diagnosis by fungal culture of biopsy samples has previously been considered to lack sensitivity and specificity because
of potential for false-positive results in dogs with other primary
nasal cavity disease (Harvey and others 1981, Sharp and others 1991b). Endoscopic guidance for sample collection improved
438

sensitivity (75 to 96%) in recent studies (Billen and others 2009a,

Pomrantz and Johnson 2010).
Laboratory methodology is very likely to contribute to disparate results between studies, although direct comparisons are
often difficult as culture media and incubation temperatures vary
and these can influence fungal growth. Recently, fungal culture
yields from dogs with mycotic rhinosinusitis were found to be
influenced by sample type (perendoscopic mucosal biopsies were
superior to blinded swabs), and were greatly enhanced at 37C
compared with incubation at room temperature (Billen and
others 2009a). Time until positive culture was also reduced to
a mean of 4017 days at 37C compared to 923 days at room
temperature (Billen and others 2009a). Blind endonasal swabs
lacked sensitivity regardless of incubation temperature with only
1 of 16 (625%) and 3 of 16 (1875%) positive cultures obtained
at room temperature and 37C, respectively (Billen and others 2009a). Of interest is that no samples from normal dogs or
those with non-fungal nasal disease produced fungal growth in
two recent studies (Pomrantz and others 2007, Billen and others
2009a). This suggests that the predictive value of positive cultures is high and likely more specific to fungal infection than
previously thought.

DNA QUANTIFICATION
There is limited benefit in quantification of fungal DNA in
nasal tissue. Using an A. fumigatus specific assay, results overlap between affected dogs, controls and those with lymphocytic
plasmacytic rhinitis (LPR) or nasal neoplasia (Peeters and others
2008). Detection of fungal DNA in control samples likely represents filtration or nasal cavity colonisation.
Detection of fungal DNA in whole blood is also of little benefit. This is due to poor sensitivity (21%), as there is little communication with the vascular system, and poor specificity (45%)
from a high frequency of false-positive results (Peeters and others
2008).

SEROLOGY
Agar gel immunodiffusion (AGID), enzyme-linked immunosorbent assay (ELISA) and counter immunoelectrophoresis have
all been used to assess SNA in dogs, although the latter is not
widely available (Pomrantz and others 2007, Billen and others
2009b). Serology is widely regarded as unreliable because of variable sensitivities and specificities (Garcia and others 2001, Dial
2007, Pomrantz and others 2007, Billen and others 2009b).
Two studies of AGID showed potential benefit (sensitivity of 67
to 765%, specificity of 98 to 100%), although SNA can obviously not be excluded with negative results (Pomrantz and others 2007, Billen and others 2009b). No significant difference
is found between sensitivity (882%) or specificity (968%) for
AGID versus ELISA (Billen and others 2009b). ELISA is potentially superior although quantification of the immune response
has no proven benefit for canine disease and serial monitoring

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throughout therapy using AGID also does not appear a useful

indicator of disease status (Pomrantz and Johnson 2010).
Antibody detection is not reliable for diagnosis in people with
invasive aspergillosis (Young and Bennett 1971, Garcia and others 2001). Diagnosis relies instead upon detection of fungal antigens and measurement of galactomannan (GM), an Aspergillus
spp. cell wall component (Aquino and others 2007, Woods and
others 2007). Limited evaluation of GM in canine (and feline)
SNA fails to consistently detect elevated levels, making it less
useful for this presentation (Garcia and others 2001, Billen and
others 2009b). False-positive results are frequently documented
in young people, and those receiving certain antibiotic therapies,
reducing specificity. This phenomenon has also been reported in
cats (Whitney and others 2011).

TREATMENT
Despite similarities between human chronic, erosive rhinosinusitis and canine SNA, treatment differs significantly. In human
patients endoscopic surgery to removal fungal plaques is curative
without topical therapy or ongoing medical management with
antifungal agents (Uri and others 2003). By contrast, treatment
of dogs remains challenging despite available therapeutic options.
In some cases a degree of uncertainty may remain despite a comprehensive diagnostic approach and in these circumstances the
decision to treat may be based upon the degree of suspicion.
The most widely used antifungal agents in canine SNA treatment are the azole group comprising the benzimidazoles (thiabendazole), imidazoles (ketoconazole, clotrimazole, enilconazole,
miconazole) and triazoles (fluconazole, itraconazole, posaconazole, voriconazole). These agents impede ergosterol biosynthesis, an integral component of fungal membranes, via the p450
enzyme system by blocking 14-sterol demethylase resulting
in lanosterol accumulation within fungal membranes (Hector
2005). Topical azoles such as clotrimazole and miconazole also
have a direct lytic effect (Hector 2005). Although selective for
fungi, individual azoles vary in their interactions with mammalian cytochrome p450 which can cause hepatotoxicity and a range
of drug interactions of varying importance. Cutaneous vasculitis
secondary to itraconazole administration has also been reported
(Legendre and others 1996). Degree of protein binding, oral bioavailability and solubility also vary between azoles and frequently
dictate the way they are used. Azoles such as clotrimazole and
enilconazole have poor oral bioavailability and are administered
topically (Hector 2005).
Topical application of clotrimazole formulated with a propyleneglycol base is associated with severe, life-threatening side-effects
in dogs including nasopharyngeal swelling severe enough to
necessitate temporary tracheostomy placement (Caulkett and
others 1997, Peeters and Clercx 2007). These effects are not
observed when a polyethylene glycol base is used (Mathews and
Sharp 2006, Peeters and Clercx 2007). A small case series has
documented nasal neoplasia following topical treatment with
clotrimazole in a polyethylene glycol base, although a direct causal relationship has not been confirmed (Greci and others 2009).
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Other classes of antifungal agents include allylamines, which

inhibit ergosterol synthesis at an earlier step in the pathway than
azoles, and echinocandins, which interfere with -1,3-glucan
synthesis, both important components of fungal cell walls in
some species. These antifungals have not been extensively evaluated in dogs, but may in the future prove useful adjunctive therapies (Hector 2005).

ORAL THERAPY
Poor clinical responses are reported when oral azole antifungal
agents alone are prescribed. Cure rates of only approximately
50% were achieved in older studies (Harvey 1984, Sharp and
Sullivan 1986, 1989). Newer triazoles (fluconazole, itraconazole)
improve success (70%) (Sharp and others 1991a). Positive clinical responses with fluconazole are interesting given its efficacy
against Aspergillus spp. and other filamentous fungi is questionable and ineffective in vitro (Hector 2005). Improved effect is
seen in vitro against Aspergillus spp. when fluconazole is combined with the allylamine terbinafine; however, this has not
been evaluated in canine SNA (Mosquera and others 2002).
Voriconazole and posaconazole are currently prohibitively expensive and unproven in canine SNA.
Limited response to oral antifungal agents is not surprising
given histopathological studies show no fungal invasion. Duration of therapy required for cure is often markedly prolonged,
increasing costs.

TOPICAL THERAPY
Topical antifungal administration remains the most widely used
method of treatment in dogs. Various different techniques have
been assessed including surgically implanted administration catheters in the frontal sinuses, endoscopic placement of temporary
frontal sinus catheters, a non-invasive nasal technique, and trephination of the frontal sinuses with instillation of depot therapy.
Topical therapeutic techniques allow direct penetration and therefore direct action on fungal plaques; however, frequently even with
these methods multiple treatments are required. When assessing
published reports using an evidence-based medicine approach,
the majority of studies regarding the treatment of SNA are caseseries describing a single treatment type (n=3) or case-series where
two treatment types are compared (n=7). The level of evidence,
using the scheme devised by Tivers and others (2012) (Table 1),
for each of the major studies reporting outcome in canine SNA is
included in Table 2. Care should particularly be taken comparing
reported outcomes for the described techniques in the available
studies as the method used to determine therapeutic success often
varies from clinical reassessment alone to a comprehensive diagnostic reassessment including advanced imaging and rhinoscopy.
Indwelling catheters and enilconazole
Original topical therapeutic techniques involved instillation of
enilconazole (10 mg/kg) twice daily for 7 to 14 days, via catheters

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M. J. Sharman & C. S. Mansfield

Table 1. Levels of evidence

Grade
1a
1b
2a
2b
3a
3b
4a

4b
4c
4d
4e
5

Description
Systematic review of randomised controlled trials (RCTs)
Individual RCT (with narrow confidence interval)
Systematic review of cohort studies*
Individual cohort study (including low-quality RCT)
Systematic review of case-control studies
Individual case-control study
Lower-quality prospective cohort/case-control study concerns regarding definition of comparison groups and/or
objective (preferably blinded) nature of assessment and/
or consideration of confounding factors and/or adequacy of
follow-up
Retrospective cohort/case-control study
Case series describing outcome for one treatment method
with no control group
Case series describing novel aspect of management and
providing some information regarding outcome
Lower-quality case series concerns regarding study design
and/or ability to interpret information
Expert opinion without explicit critical appraisal, or based on
physiology, bench research or first principles

Scheme devised by Tivers and others (2012)

*A cohort study is a study that follows a group of patients over a period of
time and investigates the effect of a treatment or risk factor

A case-control study is one that examines the effect of a risk factor on

the outcome for a group of patients with a disease compared to that of a
matched control group without the disease

surgically implanted into the nasal cavity (Fig 1). For the five
dogs treated initially, therapy was 100% successful with resolution of nasal signs in all cases (Table 2) (Sharp and Sullivan 1986).
Subsequent cures were reported in 20 of 24 (83%) of cases, 50%
based on reassessment with radiography, rhinoscopy and mycological examination and 33% with clinical scoring alone (Sharp
and others 1993).
Although successful, prolonged hospitalisation and morbidity led to declining popularity. Complications including catheter
dislodgement, inappetence, pytalism and aspiration pneumonia
were reported and dogs also become intolerant of daily administrations requiring sedation for each treatment. Disease extension into periorbital regions appears to limit efficacy (Sharp and
others 1993). This may be due to inadequate penetration of
antifungal agents to this region; however, as disease is considered non-invasive this may be more likely to reflect inadequate
attenuation of the inflammatory response.
Temporary trephination and non-invasive infusion
Alternative techniques aimed to avoid prolonged hospitalisation and potential complications. Frontal sinus trephination
for temporary catheterisation (Fig 8) was the first of these to be
described (Davidson and others 1992). This was well tolerated

Table 2. First and overall treatment success rates in previously published studies of mycotic rhinosinusitis
Treatment type
Indwelling catheters enilconazole
Sharp and Sullivan (1986)
Enilconazole (10 mg/kg) + ketoconazole (10 mg/kg)
Sharp and others (1993)
Enilconazole (10 mg/kg) + ketoconazole (10 mg/kg)
Enilconazole (10 mg/kg) only
Temporary trephination 1% clotrimazole
Mathews and others (1998)
Friend and others (2002)
Sharman and others (2010)
Non-invasive catheter soaks 1% clotrimazole
Mathews and others (1998)
Sharman and others (2010)
Non-invasive catheter soaks 1% enilconazole
Zonderland and others (2002)
Saunders and others (2003)
Schuller and Clercx (2007)
Endoscopically inserted catheters 2% enilconazole
Zonderland and others (2002)
Schuller and Clercx (2007)
Topical and depot clotrimazole therapy
Sissener and others (2006)
Sharman and others (2010)
Depot bifonazole therapy Billen and others (2009a,b)
Including topical enilconazole soak
Depot therapy alone

Number of dogs

First treatment success

(%)

Overall treatment success

(%)

100

Level of
evidence*

NA

4d

100
NA

4e

7
24

857
50 (83)

37
23
24

62
769
541

837
869
NA

4b
4e
4b

23
45

695
40

913
NA

4b
4b

19
36
15

473
555
466

895
944
933

4a
4d
4d

7
12

857
583

100
833

4a
4d

14
10

86
70

86
NA

4d
4b

12
5

583
60

100
60

4a

As outlined by Tivers and others (2012)

Includes five dogs from Sharp and Sullivan (1986)
Twelve dogs (50%) were considered cured based upon re-examination which included radiologic examination and rhinoscopy. A further eight dogs (33%) were
possibly cured based upon the absence of clinical signs (n=7) or the absence of disease at post-mortem examination following death from unrelated disease
(n=1). Two dogs failed treatment and did not receive further therapy.

A total of 23 dogs were included in the study. For Group A dogs (n=13) 10 had a successful first treatment (769%) and 12 dogs were successful following
multiple treatments. As Group B dogs routinely received a second treatment regardless of whether disease was determined to be present upon reassessment,
first treatment outcome in this group could not be assessed. Twenty dogs (869%) were reported as having successful outcomes when all treatments were
considered

All 12 of the dogs in the topical enilconazole + depot bifonazole group were cured after a second treatment. Three of the five dogs that required additional
therapy following the first treatment also received enilconazole plus bifonazole for the second treatment. Two of the five dogs received topical bifonazole depot
therapy alone
*

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FIG 8. A dog undergoing treatment via temporary trephination of the

frontal sinuses

with an excellent outcome in 21 dogs (Davidson and others

1992). Further evaluation gave first and overall treatment success
of 62% and 837%, respectively (Mathews and others 1998). No
significant difference was found when a routine second treatment
was administered compared with dogs receiving only one (Friend
and others 2002).
Non-invasive protocols eliminate trephination altogether. The
simplest technique involves blind placement of catheters into the
nasal cavity and rotation of the head through 360 to improve
distribution to the sinuses. The procedure is of at least 1 hour
duration, but may be longer where significant debridement of
disease is required. Minor side-effects seen with trephination
(emphysema, incision site infections) are avoided. Enilconazole
and clotrimazole have both been evaluated at varying concentrations with outcomes varying from 466 to 695% for first treatment outcome and 895 to 944% for overall success (Table 2),
albeit in small numbers of dogs for some studies (Bray and others 1998, Mathews and others 1998, Friend and others 2002,
Zonderland and others 2002, Saunders and others 2003, Schuller and Clercx 2007). A non-invasive protocol using enilconazole
as a 10% solution was unsuccessful in four dogs (Bray and others
1998).
Although experimental models demonstrate improved distribution to the sinuses using a non-invasive technique, limited
evaluation of distribution in clinical disease is reported (Richardson and Mathews 1995, Mathews and others 1996, Sharman
and others 2012). In one study, six dogs were treated using a
non-invasive technique (with 1% clotrimazole, mixed with ioxaglate to a 20% solution) and assessed with CT at completion of
a 1 hour infusion (Mathews and others 1996). Good distribution throughout the nasal cavity and frontal sinuses was achieved,
although the volume of antifungal agent within the sinuses varied
(Mathews and others 1996). Frontal sinus disease was present
in only a small number of the included cases, however in one
was considered to have diminished the volume of infusate entering this region (Mathews and others 1996). Although this study
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demonstrated distribution to the frontal sinuses, subsequent

studies reported high rates of single treatment failures. A requirement for further therapy was theorised to result from inadequate
or impaired sinus distribution in dogs with significant sinus disease. Modification of the technique involved placement of additional catheters within the frontal sinuses, via flexible endoscopy,
to improve distribution. Improved distribution has not been
confirmed with further imaging studies. First treatment outcome
does appear improved; however, this has only been in small numbers of dogs (Zonderland and others 2002, Schuller and Clercx
2007).
Despite increased invasiveness, techniques utilising trephination offer an opportunity to debride disease within the frontal
sinuses and ensure patency of the nasal ostium, both likely key
factors improving distribution and influencing outcome. No
studies evaluate and compare distribution using a trephination
technique with that achieved using a non-invasive soak in clinical
cases. A recent study of dogs with SNA performed by the authors
demonstrated that distribution to the frontal sinuses and nasal
cavity via temporary trephination was achievable; however, retention of clotrimazole and enilconazole was poor, as assessed by CT
5 minutes after initial infusion was completed. This likely reflects
continued loss of agent to the nasal cavity and leakage from the
nares or nasopharynx (Sharman and others 2012). Distribution
and retention were independent of severity assessed by CT, clinical or rhinoscopic scoring.
It would seem that whilst trephination improves access for
debridement, and ensures delivery of antifungal agent to the
sinuses, a demonstrated poor retention confirms the necessity
for continuous infusion using this technique. Additionally the
study by Sharman and others (2012) demonstrated retention of
saline used to flush the nasal cavity which may have impaired
filling and distribution of antifungal agent. Ensuring frontonasal
ostia patency and the contribution of flushing to debridement
likely outweigh any negative impact, but sufficient time for saline
drainage, or suctioning of residual saline before infusion may be
beneficial.
Short infusion and depot therapy
Both non-invasive and temporary trephination techniques
require long durations of anaesthesia.
Combined trephination, short clotrimazole (1%) soak and
application of clotrimazole (1%) cream to the frontal sinuses (10
to 20 g per sinus) were therefore developed to reduce procedural
time (Sissener and others 2006). Application of more viscous
cream was postulated to improve antifungal agent retention, thus
improving contact time and treatment success. Clotrimazole
cream also moved slowly from the sinuses to the nasal cavity, theoretically allowing improved contact for this region also. Procedure duration and hospitalisation were greatly reduced and good
success achieved with 12 of 14 (86%) clinical cures (Sissener
and others 2006). In a recent retrospective series, depot therapy
was successful in 7 of 10 (70%) of dogs on first treatment alone,
although this was not statistically significant compared to other
treatment types (Sharman and others 2010). Depot therapy with
bifonazole cream via per-endoscopic frontal sinus catheters has

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M. J. Sharman & C. S. Mansfield

also been described and in combination with debridement and

enilconazole infusion resulted in 7 of 12 (583%) clinical cures
(Billen and others 2010).
Experimentally, retention of commercially available cream
in vitro using glass funnels is poor compared to compounded
1% clotrimazole gels made from hydroxypropyl cellulose, poloxamer and carboxymethyl cellulose in various concentrations.
Until recently, distribution of only the compounded gels had
been evaluated in vivo, although not in clinical cases (Mathews
and others 2009). A recent study has since demonstrated good
distribution of a commercial 1% clotrimazole cream (Canestan
cream; Bayer) within the sinuses, with retention of at least 96
hours duration (Hayes and Demetriou 2012). This was again
within normal cadavers and therefore may not adequately reflect
retention in disease as already discussed (Hayes and Demetriou
2012).
Improved retention and therefore contact may improve outcome; however, ideal contact times for successful therapy with
any of the topical agents are not established.
Other topical therapies
Other topical protocols are described. Povidone-iodine (10%)
painted onto turbinates or povidine-iodine impregnated
cadexomer dressings (Iodoflex; Smith and Nephew) following rhinotomy and debridement both proved successful in
small numbers of dogs (Pavletic and Clark 1991, Moore 2003).
Combination treatment with surgical rhinotomy, enilconazole
soak and adjunctive oral itraconazole has also been evaluated
(Claeys and others 2006). Dogs initially treated had recurrence
of disease associated with the bone flap and cerclage wires, but
therapy in additional cases was successful where bone flaps were
discarded (Claeys and others 2006).
While these protocols result in good success in small numbers
the ability to extensively debride disease is very likely to have
improved success rates, rather than the type or way in which the
topical agent was applied. These methods are invasive and therefore less attractive as first-line therapies.

REASONS FOR TREATMENT FAILURE

Treatment failure is often attributed to disease severity, and criteria designed to assess severity, including clinical, rhinoscopic
and radiographic scoring systems, have been evaluated. Initial
evaluation of CT scoring to predict outcome, using a 1-hour
clotrimazole (1%) infusion, found reasonable sensitivity (71 to
78%) and specificity (79 to 93%) (Mathews and others 1998,
Saunders and others 2003). However, results were contradicted
in a subsequent study. This second study, using a 1-hour enilconazole (1%) infusion, found that although a high sensitivity was
achievable (100%), the specificity was low (30%). CT therefore
appears unhelpful in predicting therapeutic success although it
is possible that variation in the application of the same scoring
system between different investigators, or the use of a different
antifungal agent, may have contributed (Saunders and others
2003).
442

In a recent prospective study by the authors, focal disease on

occasion had a poorer outcome in comparison with those dogs
whose disease resulted in severe turbinate destruction, despite
the latter having a higher severity score with currently reported
schemes (unpublished data). This could reflect more difficult
access with focal disease and therefore insufficient debridement.
Certainly outcome appears improved with significant exposure
of the nasal cavity using invasive treatments (Pavletic and Clark
1991, Moore 2003, Claeys and others 2006). Equally, severe
turbinate destruction improves access and potentially drug distribution in the nasal cavity. However, in a recent prospective
study, whilst debridement was considered complete on visual
assessment via rhinoscopy, CT demonstrated significant residual
disease indicating that the former is not always a reliable means
of assessment (Sharman and others 2010).
Factors potentially influencing outcome in a multi-centre
retrospective study found only younger age to be significantly
associated with success (Sharman and others 2010). Subjectively
severity was not associated with outcome, although dogs with
unilateral disease were 27 times more likely to have a successful first treatment compared with bilateral disease. Application
of previous severity scoring systems was unable to be performed
because of the studys retrospective nature (Sharman and others
2012).
Antifungal resistance is likely insignificant. Although susceptibility testing is not routinely performed in veterinary medicine,
high concentrations of antifungal agents are achieved locally with
topical treatment protocols, making it unlikely to be important
for canine SNA.
Inadequate distribution and retention are far more likely reasons for failure. Theoretically, improved retention of antifungal
agents should improve treatment outcome by increasing contact
time and penetration of fungal plaques. However, ideal retention times have not been developed. Whether retention of agents
within the frontal sinus and nasal cavity for days or weeks is better than hours is unknown. Variations in frontal sinus and nasal
cavity anatomy within and between breeds may also influence
distribution and retention and therefore outcome (Burrow and
others 2012).
An inability to predict first-treatment success rate despite
comparable treatment protocols is frustrating, but likely multifactorial. Severity of disease, minor modification of technique,
particular antifungal agent chosen, experience of the treating
clinician and the ability and extent to which debridement is performed are all potential factors.

SUMMARY AND CONCLUSIONS

SNA is an uncommon, debilitating and challenging condition in
dogs. Infection resembles non-invasive, chronic rhinosinusitis in
humans, with only small numbers of dogs exposed to inhaled fungal elements developing infection. Most likely this is explained by
altered innate and adaptive immune responses, although mechanisms for failure of these responses are unproven. Evaluation of
innate mechanisms suggests a response that is sufficient to limit

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Canine sinonasal aspergillosis

infection, but inadequate to eliminate the organism (Peeters and

others 2006). Diagnosis itself can be challenging, relying upon a
combination of clinical findings and diagnostics.
Topical antifungal administration is preferred; however, the
evidence base is currently insufficient to support a recommendation for one individual treatment protocol over another. Multiple treatments are required in approximately 50% of patients,
regardless of the protocol chosen (Pomrantz and Johnson 2010,
Sharman and others 2010). Treatments allowing extensive
debridement and/or direct administration of antifungal agents to
the frontal sinuses may be more likely to be successful (Pavletic
and Clark 1991, Mathews and others 1998, Friend and others
2002, Zonderland and others 2002, Moore 2003, Claeys and others 2006, Sissener and others 2006, Schuller and Clercx 2007).
Predicting first-treatment outcome based on clinical findings or
advanced imaging findings remains challenging (Mathews and
others 1998, Saunders and others 2003). Scoring systems may
guide therapy, but an assumption that severity alone is responsible
for outcome appears misguided. Severity of destruction may not
correlate with the amount of fungal infection, and scoring systems
fail to assess subtle change that may significantly impact outcome.
Almost certainly distribution and adequate retention of antifungal agents in regions of residual disease are important. Additional factors such as treatment protocol, antifungal agent used
and experience of the treating clinician are also likely to impact
outcome.
Conflict of interest
None of the authors of this article has a financial or personal
relationship with other people or organisations that could inappropriately influence or bias the content of the paper.
References
AQUINO, V., GOLDANI, L. & PASQUALOTTO, A. (2007) Update on the contribution of
galactomannan for the diagnosis of invasive aspergillosis. Mycopathologia
163, 191-202
BARNES, P. & MARR, K. (2006) Aspergillosis: spectrum of disease, diagnosis and
treatment. Infectious Disease Clinics of North America 20, 545-561
BARRS, V. R., HALLIDAY, C., MARTIN, P., WILSON, B., KROCKENBERGER, M., GUNEW, M.,
BENNETT, S., KOEHLMEYER, E., THOMPSON, A., FLIEGNER, R., HOCKING, A., SLEIMAN, S.,
OBRIEN, C. & BEATTY, J. A. (2012) Sinonasal and sino-orbital aspergillosis in
23 cats: aetiology, clinicopathological features and treatment outcomes. The
Veterinary Journal 191, 58-64
BILLEN, F., CLERCX, C., LE GARERRES, A., MASSART, L., MIGNON, B. & PEETERS, D. (2009a)
Effect of sampling method and incubation temperature on fungal culture in
canine sinonasal aspergillosis. Journal of Small Animal Practice 50, 67-72
BILLEN, F., PEETERS, D., PETERS, I., HELPS, C., HUYNEN, P., DE MOL, P., MASSART, L., DAY,
M. & CLERCX, C. (2009b) Comparison of the value of measurement of serum
galactomannan and Aspergillus-specific antibodies in the diagnosis of canine
sino-nasal aspergillosis. Veterinary Microbiology 133, 358-365
BILLEN, F., GUIEU, L., BERNAERTS, F., MERCIER, E., LAVOUE, R., TUAL, C., PEETERS, D. &
CLERCX, C. (2010) Efficacy of intrasinusal administration of bifonazole cream
alone or in combination with enilconazole irrigation in canine sino-nasal
aspergillosis: 17 cases. Canadian Veterinary Journal 51, 164-168
BRAY, J. P., WHITE, R. A. & LASCELLES, B. D. (1998) Treatment of canine nasal
aspergillosis with a new non-invasive technique. Failure with enilconazole.
Journal of Small Animal Practice 39, 223-226
BURROW, R., MCCARROLL, D., BAKER, M., DARBY, P., MCCONNELL, F. & CRIPPS, P. (2012)
Frontal sinus depth at four landmarks in breeds of dog typically affected by
sinonasal aspergillosis. Veterinary Record 170, 20p
CAULKETT, N., LEW, L. & FRIES, C. (1997) Upper-airway obstruction and prolonged
recovery from anesthesia following intranasal clotrimazole administration.
Journal of the American Animal Hospital Association 33, 264
CLAEYS, S., LEFEBVRE, J., SCHULLER, S., HAMAIDE, A. & CLERCX, C. (2006) Surgical
treatment of canine nasal aspergillosis by rhinotomy combined with enilconazole infusion and oral itraconazole. Journal of Small Animal Practice 47,
320

Journal of Small Animal Practice

Vol 53

August 2012

DAVIDSON, A., KOMTEBEDDE, J., PAPPAGIANIS, D. & HECTOR, R. (1992) Treatment of nasal
aspergillosis with topical clotrimazole. In: ACVIM Forum 10th Proceedings,
San Diego, California
DAY, M. (2009) Canine sino-nasal aspergillosis: parallels with human disease.
Medical Mycology 47(Suppl 1), S315-S323
DE LORENZI, D., BONFANTI, U., MASSERDOTTI, C., CALDIN, M. & FURLANELLO, T. (2006)
Diagnosis of canine nasal aspergillosis by cytological examination: a comparison of four different collection techniques. Journal of Small Animal Practice
47, 316-319
DIAL, S. (2007) Fungal diagnostics: current techniques and future trends.
Veterinary Clinics Small Animal Practice 37, 373-392
FRIEND, E., WILLIAMS, J. & WHITE, R. (2002) Invasive treatment of canine nasal
aspergillosis with topical clotrimazole. Veterinary Record 151, 298-299
GARCIA, M., CABALLERO, J., CRUZADO, M., ANDRINO, M., GONZALEZ-CABO, J. & BLANCO,
J. (2001) The value of determination of anti-Aspergillus IgG in the serodiagnosis of canine aspergillosis: comparison with galactomannan detection.
Journal of Veterinary Medicine 48, 743-750
GRECI, V., STEFANELLO, D., DI GIANCAMILLO, M. & MORTELLARO, C. M. (2009) Sinonasal
tumor in 3 dogs after successful topical treatment for frontal sinus aspergillosis. Canadian Veterinary Journal 50, 1191-1194
HAMILOS, D. & LUND, V. (2004) Etiology of chronic rhinosinusitis: the role of fungus. The Annals of Otology, Rhinology and Laryngology 113, 27
HARVEY, C. (1984) Nasal aspergillosis and penicillosis in dogs: results of
treatment with thiabendazole. Journal of the American Veterinary Medical
Association 184, 48
HARVEY, C., OBRIEN, J., FELSBURG, P., IZENBERG, H. & GOLDSCHMIDT, M. (1981)
Nasal penicillosis in six dogs. Journal of the American Veterinary Medical
Association 178, 1084-1087
HAYES, G. M. & DEMETRIOU, J. L. (2012) Distribution and persistence of topical
clotrimazole after sinus infusion in normal canine cadavers. Journal of Small
Animal Practice 53, 95-100
HECTOR, R. (2005) An overview of antifungal drugs and their use for treatment of
deep and superficial mycoses in animals. Clinical Techniques in Small Animal
Practice 20, 240-249
JOHNSON, L., DRAZENOVICH, T., HERRERA, M. & WISNER, E. (2006) Results of rhinoscopy alone or in conjunction with sinuscopy in dogs with aspergillosis: 46
cases (20012004). Journal of the American Veterinary Medical Association
228, 738-742
LATGE, J. (1999) Aspergillus fumigatus and aspergillosis. Clinical Microbiology
Reviews 12, 310-350
LEGENDRE, M. A., ROHRBACH, B. W., TOAL, R. L., RINALDI, M. G., GRACE, L. L. & JONES, J.
B. (1996) Treatment of blastomycosis with itraconazole in 112 dogs. Journal
of Veterinary Internal Medicine 10, 365-371
MATHEWS, K. & SHARP, N. (2006) Aspergillosis and penicilliosis. In: Infectious
Diseases of the Dog and Cat. Ed C. Greene. Saunders Elsevier, St. Louis, MO,
USA. pp 613-627
MATHEWS, K., KOBLIK, P., RICHARDSON, E. & PAPPAGIANIS, D. (1996) Computed tomographic assessment of non-invasive intranasal infusions in dogs with fungal
rhinitis. Veterinary Surgery 25, 309-319
MATHEWS, K., DAVIDSON, A., KOBLIK, P., RICHARDSON, E., KOMTEBEDDE, J., PAPPAGIANIS,
D., HECTOR, R. & KASS, P. (1998) Comparison of topical administration of
clotrimazole through surgically placed versus nonsurgically placed catheters
for treatment of nasal aspergillosis in dogs: 60 cases (19901996). Journal
of the American Veterinary Medical Association 213, 501-506
MATHEWS, K., LINDER, K., DAVIDSON, G., GOLDMAN, R. & PAPICH, M. (2009) Assessment
of clotrimazole gels for in vitro stability and in vivo retention in the frontal
sinus of dogs. American Journal of Veterinary Research 70, 640-647
MELER, E., DUNN, M. & LECUYER, M. (2008) A retrospective study of canine persistent nasal disease: 80 cases (19982003). Canadian Veterinary Journal
49, 71-76
MOORE, A. (2003) Use of topical povidone-iodine dressings in the management of
mycotic rhinitis in three dogs. Journal of Small Animal Practice 44, 326-329
MOSQUERA, J., SHARP, A., MOORE, C., WARN, P. & DENNING, D. (2002) In vitro interaction of terbinafine with itraconazole, fluconazole, amphotericin B and 5-flucytosine against Aspergillus spp. Journal of Antimicrobial Chemotherapy 50,
189-194
PAVLETIC, M. & CLARK, G. (1991) Open nasal cavity and frontal sinus treatment of
chronic nasal aspergillosis. Veterinary Surgery 20, 43
PEETERS, D. & CLERCX, C. (2007) Update on canine sinonasal aspergillosis.
Veterinary Clinics Small Animal Practice 37, 901-916
PEETERS, D., DAY, M. & CLERCX, C. (2005) An immunohistochemical study of
canine nasal aspergillosis. Journal of Comparative Pathology 132, 283-288
PEETERS, D., PETERS, I., CLERCX, C. & DAY, M. (2006) Quantification of mRNA encoding cytokines and chemokines in nasal biopsies from dogs with sino-nasal
aspergillosis. Veterinary Microbiology 114, 318-326
PEETERS, D., PETERS, I., HELPS, C., GABRIEL, A., DAY, M. & CLERCX, C. (2007) Distinct
tissue cytokine and chemokine mRNA expression in canine sino-nasal aspergillosis and idiopathic lymphoplasmacytic rhinitis. Veterinary Immunology
and Immunopathology 117, 95-105
PEETERS, D., PETERS, I., HELPS, C., DEHARD, S., DAY, M. & CLERCX, C. (2008) Whole
blood and tissue fungal DNA quantification in the diagnosis of canine sinonasal aspergillosis. Veterinary Microbiology 128, 194-203
POMRANTZ, J. & JOHNSON, L. (2010) Repeated rhinoscopic and serologic assessment of the effectiveness of intranasally administered clotrimazole for the

2012 British Small Animal Veterinary Association

443

M. J. Sharman & C. S. Mansfield

treatment of nasal aspergillosis in dogs. Journal of the American Veterinary

Medical Association 236, 757-762
POMRANTZ, J., JOHNSON, L., NELSON, R. & WISNER, E. (2007) Comparison of serologic evaluation via agar gel immunodiffusion and fungal culture of tissue for
diagnosis of nasal aspergillosis in dogs. Journal of the American Veterinary
Medical Association 230, 1319-1323
RICHARDSON, E. & MATHEWS, K. (1995) Distribution of topical agents in the frontal
sinuses and nasal cavity of dogs: comparison between current protocols for
treatment of nasal aspergillosis and a new noninvasive technique. Veterinary
Surgery 24, 476-483
ROMANI, L. (2004) Immunity to fungal infections. Nature Reviews Immunology
4, 11-24
SAUNDERS, J. & VAN BREE, H. (2003) Comparison of radiography and computed
tomography for the diagnosis of canine nasal aspergillosis. Veterinary
Radiology and Ultrasound 44, 414-419
SAUNDERS, J., ZONDERLAND, J., CLERCX, C., GIELEN, I., SNAPS, F., SULLIVAN, M., VAN BREE,
H. & DONDERLINGER, R. (2002) Computed tomographic findings in 35 dogs with
nasal aspergillosis. Veterinary Radiology and Ultrasound 43, 5-9
SAUNDERS, J., DUCHATEAU, L., STORK, C. & VAN BREE, H. (2003) Use of computed
tomography to predict the outcome of a non-invasive intranasal infusion in
dogs with nasal aspergillosis. Canadian Veterinary Journal 44, 305
SAUNDERS, J., CLERCX, C., SNAPS, F., SULLIVAN, M., DUCHATEAU, L., VAN BREE, H. &
DONDERLINGER, R. (2004) Radiographic, magnetic resonance imaging, computed tomographic, and rhinoscopic features of nasal aspergillosis in dogs.
Journal of the American Veterinary Medical Association 225, 1703-1712
SCHULLER, S. & CLERCX, C. (2007) Long-term outcomes in dogs with sinonasal
aspergillosis treated with intranasal infusions of enilconazole. Journal of the
American Animal Hospital Association 43, 33-38
SHARMAN, M., PAUL, A., DAVIES, D., MACKAY, B., SWINNEY, G., BARRS, V., ARTEAGA, A.,
ROBERTSON, I. & MANSFIELD, C. (2010) Multi-centre assessment of mycotic rhinosinusitis in dogs: a retrospective study of initial treatment success (1998
to 2008). Journal of Small Animal Practice 51, 423-427
SHARMAN, M., LENARD, Z., HOSGOOD, G. & MANSFIELD, C. (2012) Clotrimazole and
Enilconazole distribution within the frontal sinuses and nasal cavity of nine
dogs with sinonasal aspergillosis. Journal of Small Animal Practice 53, 161-167
SHARP, N. & SULLIVAN, M. (1986) Treatment of canine nasal aspergillosis with
systemic ketoconazole and topical enilconazole. Veterinary Record 118, 560
SHARP, N. & SULLIVAN, M. (1989) Use of ketoconazole in the treatment of canine
nasal aspergillosis. Journal of the American Veterinary Medical Association
194, 782
SHARP, N., HARVEY, C. & OBRIEN, J. (1991a) Treatment of canine nasal aspergillosis/penicilliosis with fluconazole. Journal of Small Animal Practice 32,
513-516

444

SHARP, N., HARVEY, C. & SULLIVAN, M. (1991b) Canine nasal aspergillosis and penicilliosis. Compendium on Continuing Education for the Practicing Veterinarian
13, 41-47
SHARP, N., SULLIVAN, M., HARVEY, C. & WEBB, T. (1993) Treatment of canine nasal
aspergillosis with enilconazole. Journal of Veterinary Internal Medicine 7,
40-43
SHOHAM, S. & LEVITZ, S. (2005) The immune response to fungal infections. British
Journal of Haematology 129, 569-582
SISSENER, T., BACON, N., FRIEND, E., ANDERSON, D. & WHITE, R. (2006) Combined
clotrimazole irrigation and depot therapy for canine nasal aspergillosis.
Journal of Small Animal Practice 47, 312-315
SULLIVAN, M., LEE, R., JAKOVLJEVIC, S. & SHARP, N. (1986) The radiological features
of aspergillosis of the nasal cavity and frontal sinuses in the dog. Journal of
Small Animal Practice 27, 167-180
TASKER, S., KNOTENBELT, C., MUNRO, E., STONEHEWER, J., SIMPSON, J. & MACKIN, A.
(1999) Aetiology and diagnosis of persistent nasal disease in the dog: a retrospective studv of 42 cases. Journal of Small Animal Practice 40, 473-478
TIVERS, M. S., UPJOHN, M. M., HOUSE, A. K., BROCKMAN, D. J. & LIPSCOMB, V. J. (2012)
Treatment of extrahepatic congenital portosystemic shunts in dogs - what is
the evidence base? Journal of Small Animal Practice 53, 3-11
TOMEE, J. F. C. & KAUFFMAN, H. F. (2000) Putative virulence factors of Aspergillus
fumigatus. Clinical and Experimental Allergy 30, 476-484
URI, N., COHEN-KEREM, R., ELMALAH, I., DOWECK, I. & GREENBERK, E. (2003) Classification
of fungal sinusitis in immunocompetent patients. Otolaryngology-Head and
Neck Surgery 129, 372-378
VANHERBERGHEN, M., BUREAU, F., PETERS, I. R., DAY, M. J., CLERCX, C. & PEETERS, D.
(2012) Analysis of gene expression in canine sino-nasal aspergillosis and
idiopathic lymphoplasmacytic rhinitis: a transcriptomic analysis. Veterinary
Microbiology. doi:10.1016/ j.vetmic.2011.12.009
WHITNEY, J. L., MARTIN, P., BEATTY, J. A. & BARRS, V. R. (2011) Serum Galactomannan
Detection - Evaluation of a new diagnostic test for upper respiratory tract
aspergillosis in cats. Australian College of Veterinary Scientists - Science
Week. Gold Coast, Australia. p 9
WOODS, G., MICELI, M., GRAZZIUTTI, M., ZHAO, W., BARLOGIE, B. & ANAISSE, E. (2007)
Serum Aspergillus galactomannan antigen values strongly correlate with
outcome of invasive aspergillosis: a study of 56 patients with haematologic
cancer. Cancer 110, 830-834
YOUNG, R. & BENNETT, J. (1971) Invasive aspergillosis. Absence of detectable
antibody response. American Review of Respiratory Disease 104, 710-716
ZONDERLAND, J., STRK, C., SAUNDERS, J., HAMAIDE, A., BALLIGAND, M. & CLERCX, C.
(2002) Intranasal infusion of enilconazole for treatment of sinonasal aspergillosis in dogs. Journal of the American Veterinary Medical Association 221,
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