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Auris Nasus Larynx 37 (2010) 244–249

New treatment for invasive fungal sinusitis: Three cases of chronic

invasive fungal sinusitis treated with surgery and voriconazole

Kazuhiro Nakaya *, Takeshi Oshima, Takayuki Kudo, Iori Aoyagi, Yukio Katori,Jun Ota, Hiroshi Hidaka, Kiyoshi Oda, Toshimitsu Kobayashi

Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine,

1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8574, Japan

Received 7 March 2009; accepted 19 May 2009

Available online 23 June 2009

Abstract

Invasive fungal sinusitis is a relatively rare disease and can be divided into acute fulminant, chronic, and granulomatous invasive fungal

sinusitis. The conventional treatment is radical surgery combined with systemic amphotericin B administration, but the poor prognosis and

unestablished treatment options require a better therapeutic strategy. We report three cases of chronic invasive fungal sinusitis successfully

treated with a combination of surgery and voriconazole, a new antifungal agent, with good responses in all patients. Voriconazole

administration could form the basis for a new standard treatment for invasive fungal sinusitis.

# 2009 Elsevier Ireland Ltd. All rights reserved.

Keywords: Chronic invasive fungal sinusitis; Voriconazole; Amphotericin B

1. Introduction

Fungal sinusitis often occurs as the non-invasive type and

only simple removal of the fungus is required for full recovery.

In contrast, invasive fungal sinusitis is rare and requires

systemic administration of antifungal agent plus extended

surgical removal. Invasive fungal sinusitis is defined as fungal

sinusitis with mucosal infiltration of mycotic organisms [1]

and can be classified into three categories, granulomatous,

acute fulminant, and chronic invasive, depending on the

histological features [2]. Both non-invasive and invasive

fungal sinusitis are usually the result of Aspergillus species

infection [3]. Acute fulminant invasive fungal sinusitis usually

occurs in an immunocompromised host, but any person can

suffer chronic invasive fungal sinusitis [4,5]. Thegoldstandard

for treatment has been wide surgical debridement, intravenous

administration of antifungal agents such as amphotericin B,

and correction of the underlying immunocompromised state

[4]. However, the prognosis remains poor, partly because the

* Corresponding author. Tel.: +81 22 717 7304.

E-mail address: kazuhiroe@gmail.com (K. Nakaya).

0385-8146/$ – see front matter # 2009 Elsevier Ireland Ltd. All rights reserved

doi:10.1016/j.anl.2009.05.006

strong side effects of amphotericin B, which are sometimes

critical and can hinder long time administration.

New antifungal agents have recently been developed with

weaker side effects and higher efficacy [6]. A large

randomized open multicenter trial comparing amphotericin

B and voriconazole for the treatment of invasive aspergil-

losis showed significant better outcome and fewer adverse

events with voriconazole group [7]. However, no standard

treatment option with the new antifungal agents has yet been

established for chronic invasive fungal sinusitis.

We describe three cases of chronic invasive fungal sinusitis

who were treated with the combination of surgery and

extended administration of voriconazole, resulting in good

clinical outcome in all three patients. Voriconazole may be the

first choice antifungal agent to treat chronic invasive fungal

sinusitis and might improve the conventional prognosis.

2. Case reports

2.1. Case 1

An 82-year-old man with a history of myocardial

infarction treated with percutaneous transluminal coronary

.

K. Nakaya et al. / Auris Nasus Larynx 37 (2010) 244–249 245

Fig. 1. Case 1. (a and b) Preoperative CT scans showing opacity of the right maxillary sinus with bone absorption, and the lesion protruding into the orbit. (c and d)

Magnetic resonance (MR) images showing mucosal hypertrophy of the right maxillary sinus with orbital involvement.

angioplasty, chronic obstructive pulmonary disease, and

hepatitis C virus infection was referred to our hospital in

March 2008 for right maxillary lesion confirmed with

computed tomography (CT), manifesting as right cheek

pain.

On admission, coronal CT demonstrated extensive

disease in the right maxillary sinus. The bone of the orbital

floor was absorbed and the lesion had intruded into the orbit.

Axial CT demonstrated widening of the natural ostium of the

right maxillary sinus (Fig. 1a and b). Coronal T1-weighted

magnetic resonance (MR) imaging with gadolinium showed

hypertrophic maxillary mucosa and orbital infiltration. Axial

T1-weighted MR imaging with gadolinium showed an

expansive lesion in the maxillary sinus (Fig. 1c and d).

Malignant disease was suspected, so biopsy was performed

through the canine fossa approach. Histological examination

confirmed tissue invasion by narrow septate hyphae, with

branching at 458 consistent with Aspergillus species, and

infiltration of chronic inflammatory cells, but no eosinophils

or granuloma were observed (Fig. 2a). Systemic micafungin

(MCFG) infusion (50 mg/day) was started 11 days after the

biopsy. The Caldwell-Luc procedure was performed with

removal of the maxillary mucosa. The mucosa was thick and

hyperemic, as typically observed with acute maxillary

sinusitis. No sign of necrosis was observed. The natural

ostium of the maxillary sinus was widened. The lesion in the

orbit was preserved. The pain in the right cheek persisted so

the antifungal agent was changed to voriconazole (loading

dose 600 mg/day on the first day and 400 mg/day thereafter).

Cheek pain remitted in a few weeks. Two months after the

start of voriconazole administration, the dose was reduced to

300 mg/day because of mild liver and kidney dysfunction.

Liver and kidney function recovered without additional

therapy.

Follow-up MR imaging performed in June, July, and

November 2008 showed that lesion in the orbit had been

significantly diminished (Fig. 2b–d). Voriconazole admin-

istration has been continued for 8 months without

recurrence.

2.2. Case 2

A 73-year-old man with a history of benign prostatic

hypertrophy was referred to our hospital in May 2008 with a

left sphenoid lesion confirmed with CT.

On admission, CT showed opacity of the left sphenoid

sinus with bone thickening (Fig. 3a and b). Axial T1-

weighted MR imaging demonstrated opacification of the left

sphenoid sinus with heterogeneous intensity. There was no

expansion to the surrounding tissue (Fig. 3c). Axial T2-

weighted MR imaging demonstrated opacification of the left

sphenoid sinus with signal void (Fig. 3d). The lesion limited

to within the sphenoid sinus indicated the differential

diagnosis of chronic sinusitis and fungal sinusitis. The signal

void in the sphenoid was compatible with one of the

characteristics of fungus ball. Functional endoscopic sinus

K. Nakaya et al. / Auris Nasus Larynx 37 (2010) 244–249246

Fig. 2. Case 1. (a) Photomicrograph of the biopsy specimen showing Aspergillus species invading the tissue, but no granuloma (hematoxylin and eosin

staining). Follow-up T1-weighted MR images with gadolinium: (b) at 1 month after the operation with administration of MCFG (50 mg/day); (c) after 1 month

of voriconazole administration showing the lesion in the orbit has diminished; (d) after 5 months of voriconazole administration showing the lesion has

significantly decreased. Arrow indicates the residual lesion.

surgery was performed with septoplasty. The sphenoid sinus

was filled with pus and blackish material. The mucosa of the

sphenoid was slightly edematous. Simple removal of the

fungus ball was performed without radical extraction of the

sphenoid mucosa. Histological examination of the sphenoid

mucosa confirmed mucosal Aspergillus invasion. Systemic

voriconazole administration (loading dose 600 mg/day on

the first day and 400 mg/day thereafter) was started 23 days

after the operation.

Follow-up CT in August 2008 showed no residual lesion

with partial thickening of the mucosa (Fig. 3e). CT in

November 2008 showed opacification of the left sphenoid

sinus (Fig. 3f). Re-operation with sphenoidotomy was

performed. The sphenoid sinus was filled with serous fluid

and the mucosa of the natural ostium was slightly

edematous. However, a biopsy specimen showed no

evidence of Aspergillus invasion. The sphenoid sinus is

observable with fiber scope and examined regularly. The

patient has since been taking voriconazole for 8 months

without recurrence.

2.3. Case 3

A 78-year-old woman with a history of hypertension,

arrhythmia, and neurogenic bladder was referred to our

hospital in June 2008 for left maxillary sinus lesion

confirmed with CT.

Coronal CT with contrast medium demonstrated a

hypodense mass and small calcification in the left maxillary

sinus. The maxillary sinus was partially aerated. The roof

and the medial wall of the maxillary sinus were absorbed.

The enhanced lesion had invaded the ethmoid sinus and orbit

(Fig. 4a). Axial CT demonstrated the absorbed medial

maxillary wall (Fig. 4b). MR imaging was not possible

because the patient had an artificial pacemaker. Calcification

in the maxillary sinus indicated fungal ball. Surgery was

performed trans-nasally and trans-antrally. Fungal ball and

yellow mucus filled the maxillary sinus. The mucosa of the

roof of the maxillary sinus was hypertrophic. Histological

examination of the fungus ball and edematous mucosa of the

roof of the maxillary sinus revealed Aspergillus in the

K. Nakaya et al. / Auris Nasus Larynx 37 (2010) 244–249 247

Fig. 3. Case 2. (a and b) Preoperative coronal and axial CT scans demonstrating opacification of the left sphenoid sinus with bone thickening. (c) Axial T1-

weighted MR image demonstrating opacification of the left sphenoid sinus. (d) Axial T2-weighted MR image demonstrating opacification of the left sphenoid

sinus with signal void. Follow-up CT scans: (e) after 1 month and (f) 4 months of voriconazole administration.

mucosa. Systemic voriconazole administration (loading

dose 600 mg/day on the first day and 400 mg/day thereafter)

was started 8 days after the operation.

Follow-up CT in September 2008 and February 2009

showed the maxillary and ethmoid sinuses remained clear

and the lesion in the orbit had diminished. Coronal CT

showed the maxillary sinus and the ethmoid sinus were

clear after 2 months of voriconazole administration. The

large opening of the antrostomy was maintained. The

intraorbital lesion had diminished significantly (Fig. 4c).

Coronal CT after 7 months of voriconazole administration

showed the intraorbital lesion had disappeared completely

(Fig. 4d). Voriconazole administration was discontinued

in February 2009 after a total of 7 months of voriconazole

administration.

3. Discussion

Recently, new systemically administered antifungal

agents have been approved for clinical use. Voriconazole

is a second generation triazole with a broad spectrum of

antifungal activity against Candida, Aspergillus, Crypto-

coccus, and other species, with superior effectiveness for

invasive aspergillosis compared to amphotericin B [7].

Voriconazole is a suitable alternative to amphotericin B

K. Nakaya et al. / Auris Nasus Larynx 37 (2010) 244–249248

Fig. 4. Case 3. (a) Preoperative coronal CT scan with contrast medium demonstrating a hypodense mass and small calcification in the left maxillary sinus. The

roof and the medial wall of the maxillary sinus are absorbed. (b) Axial CT scan with contrast medium demonstrating the absorbed medial maxillary wall.

Follow-up coronal CT scans with contrast medium: (c) after 2 months and (d) 7 months of voriconazole administration.

preparations for empirical antifungal therapy in patients

with neutropenia and persistent fever [8]. Therefore,

voriconazole has been recommended in international

guidelines as the primary therapy for acute invasive

aspergillosis [9]. However, invasive fungal sinusitis is rare

compared to pulmonary invasive aspergillosis, so any

evidence-based treatment is difficult to recommend. Only

a few case reports have described the clinical course of

invasive fungal sinusitis treated with new antifungal agents

[10–12]. A 12-year-old girl with diabetes mellitus who had

invasive fungal ethmoiditis with Rhizopus species extending

to the orbit and frontal lobe successfully treated with the new

triazole posaconazole for 15 months [12]. Four cases of

invasive sphenoidal aspergillosis were treated with sphe-

noidotomy and 3-month administration of voriconazole

(400 mg/day) [11]. Two of these patients received admin-

istration of amphotericin B which was soon discontinued

because of renal side effects before treatment with

voriconazole. One patient received combination therapy

with caspofungin and voriconazole for the first 3 days [11].

An 89-year-old woman with invasive ethmoidal aspergil-

losis extending to the nasopharynx, infratemporal fossa,

orbit, and cavernous sinus was treated with the combination

of caspofungin (loading dose 70 mg/day and 50 mg/day

thereafter) and voriconazole (loading dose 12 mg/kg per day

and 8 mg/kg per day thereafter) for several months [10].

The present three cases of chronic fungal sinusitis were

successfully treated with surgery and voriconazole admin-

istration. All patients were immunocompetent and had

chronic invasive aspergillosis. Case 1 underwent subtotal

removal of the maxillary mucosa because the diagnosis had

been established before the operation. The lesion in the orbit

was left untouched to avoid complications to his normal sight.

Systemic micafungin infusion for 1 month did not provide

therapeutic response. On the other hand, voriconazole

improved cheek pain within a few weeks. The difference

of efficacy may indicate the superiority of voriconazole over

micafungin. Cases 2 and 3 underwent surgery under diagnoses

of non-invasive fungal sinusitis, and the diagnosis of invasive

fungal sinusitis was only confirmed later with the analysis of

the biopsy specimen. Therefore, complete removal of the

affected tissue was not achieved in any case. Neuroimaging

and endoscopic examination indicated that the unresected

lesions in all three patients continued to diminish during

voriconazole administration.

The optimal duration of antifungal drug administration for

chronic invasive fungal sinusitis is controversial, and reports

vary widely depending on the severity of the disease and

institution from 3 months to more than 15 months [10–12].

Case 3 received administration of voriconazole for 7 months,

and Cases 1 and 2 have continued to receive voriconazole for 8

months and ongoing. The biopsy specimen taken at the second

K. Nakaya et al. / Auris Nasus Larynx 37 (2010) 244–249 249

surgery in Case 2 was free of fungal hyphae. The

discontinuation of voriconazole is an open question. We

have continued administration considering the risk of

recurrence and the safety of voriconazole to the patient.

Case 1 experienced mild liver dysfunction 7 weeks after

the initiation of voriconazole. After consultation with a

gastroenterologist, the dose of voriconazole was reduced to

300 mg/day. Drug-induced liver dysfunction was suspected.

One week after the reduction of voriconazole dose, the liver

dysfunction was relieved. The same laboratory study

showed the serum potassium level increased to 6.1 mmol/

L. A nephrologist was consulted. Potassium-restricted diet

improved the ion balance of the blood serum. No side effect

was encountered thereafter. Cases 2 and 3 have been taking

voriconazole without any side effects. We recommend that

liver function should be checked regularly when adminis-

tering voriconazole. Neuroimaging studies such as CT and

MR imaging with contrast medium are reliable methods to

monitor the clinical course.

4. Conclusion

Voriconazole is a new antifungal agent effective against

invasive aspergillosis. Three cases of chronic invasive fungal

sinusitis were treated successfully with subtotal surgical

removal and extended voriconazole administration. All

patients had good clinical outcome. Voriconazole use for

invasive fungal sinusitis may create the opportunity to

change the conventional treatment approaches based on

amphotericin B.

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