JEN, KACKER, HUANG, ANAND

692 ENT-Ear, Nose & Throat Journal

October 2004
Fluconazole nasal spray in the
treatment of allergic fungal sinusitis:
A pilot study
ORIGINAL ARTICLE
From the Department of Otolaryngology, Head and Neck Surgery, New
York Presbyterian Hospital of Columbia and Cornell University,
New York.
Dr. Anand is a consultant for SinuCare, Inc., one of the pharmacies used
to formulate the nasal spray used in this study, but has no nancial
interest in the company.
Reprint requests: Dr. Vijay Anand, MD, 205 E. 64th St., New York,
NY 10021. Phone: (212) 832-3222; fax: (212) 832-3287; e-mail:
Vijayanandmd@aol.com
Originally presented at the Combined Otolaryngology Spring Meet-
ing of the American Rhinological Society, May 11, 2002, Boca
Raton, Fla.
Albert Jen, MD; Ashutosh Kacker, MD; Clark Huang, MD; Vijay Anand, MD
Abstract
The authors describe a prospective pilot study designed to
investigate the use of topical nasal antifungal spray in ad-
dition to systemic steroids and itraconazole in the treatment
of allergic fungal sinusitis. Sixteen patients with a history of
allergic fungal sinusitis were given uconazole nasal spray
and followed for 3 months. Stabilization or improvement
of disease without signicant side effects was observed in
12 of the 16 patients who were treated with this protocol.
These results indicate that topical uconazole application
may help patients with allergic fungal sinusitis; however,
a larger multicenter study with longer patient follow-up
is required to validate these initial ndings.
Introduction
Allergic fungal sinusitis (AFS) is a form of chronic sinusitis
characterized by nasal obstruction, sinus pain, rhinorrhea,
and frequent orbital symptoms. Computed tomography
(CT) frequently shows unilateral involvement with areas of
hyperdensity in the affected sinuses. Histologically, fungal
hyphae are not seen in all patients, and there is usually
evidence of bony erosion of the sinus walls. Extensive
eosinophilic inltrate may be seen with major basic pro-
tein (MBP) in the mucosal site of disease. Conventional
treatment consists of sinus surgery with extirpation of the
allergic mucus, followed by postoperative ventilation of
the sinuses and the use of systemic steroids. Frequent sa-
line nasal irrigation has been used to clear the nasal and
sinus cavity. Despite all of these interventions, AFS has a
high rate of recurrence.
Fungal sinusitis presents in ve major forms, each of
which requires a different approach to treatment and has
a different prognosis based on the extent of disease. Acute
fulminant invasive fungal sinusitis is commonly seen in
an immunocompromised host. This disease is clinically
aggressive, destroying tissue and bone. Histopathologi-
cally, the fungus is angioinvasive and causes widespread
necrosis. Treatment is aggressive surgical debridement
and the use of antifungal drugs. If the underlying im-
munocompromised state is not corrected, the prognosis
is signicantly worse.
1-3
Chronic invasive fungal sinusitis occurs mainly in dia-
betic patients, causing a chronic low-grade inammatory
reaction, as well as tissue necrosis. Aggressive surgical
debridement and antifungal drugs are again the treatments
of choice. However, this disease commonly recurs and has
a poor prognosis.
1-3

Granulomatous invasive fungal sinusitis occurs in an im-
munocompetent host and is usually unilateral. The organism
is invasive but limited to the supercial mucosa and well
contained within surrounding granulomas. Surgery fol-
lowed by antifungal drugs is usually the treatment of choice,
and the prognosis is satisfactory in most patients.
1-3

Fungal ball or sinus mycetoma occurs in a unilateral
sinus in an immunocompetent host. Histologically, there
is no evidence of tissue invasion or granulomatous inam-
mation. Surgical removal is the treatment of choice, and
patients usually have an uneventful recovery.
1-3
AFS was rst described by Millar et al in 1981, when
they reported 5 patients with signicant Type I hyper-
sensitivity to Aspergillus and sinus pathology similar to
pulmonary ndings in patients with allergic bronchopul-
monary aspergillosis (ABPA).
4
These patients present
with asthma, increased total serum immunoglobulin E
(IgE), pulmonary eosinophilia, specic allergic immune
response, and thick, tenacious mucus that causes bronchial
obstruction and bronchiectasis. In 1983, Katzenstein et al
reviewed 113 consecutive histopathologic specimens from
chronic sinusitis surgeries and identied 7 cases of allergic
aspergillus sinusitis.
5
They described this as allergic mucin,
JEN, KACKER, HUANG, ANAND
694 ENT-Ear, Nose & Throat Journal

October 2004
which consisted of degenerating eosinophils, desquamated
respiratory epithelial cells, and Charcot-Leyden crystals.
Fungal stains revealed fungal hyphae but no evidence of
tissue invasion. Subsequent case reports described identi-
cal ndings with other fungi, and the disease was termed
allergic fungal sinusitis.
3
The ve major criteria for AFS are evidence of IgE-
mediated hypersensitivity, nasal polyposis, characteristic
CT ndings, eosinophilic mucus, and positive fungal smear
or culture. The minor criteria include asthma, unilateral
predominance, radiographic bone erosion, fungal culture,
Charcot-Leyden crystals, and serum eosinophilia.
1,2,6
Treat-
ment consists of surgery followed by postoperative oral
corticosteroids.
7
Conventional treatment consists of eth-
moidectomy and middle meatal antrostomy with removal of
the allergic mucus followed by postoperative oral cortico-
steroids. Systemic antifungals have not proved consistently
benecial because the fungi are noninvasive.
8,9

The goal of this study was to evaluate the role of a topi-
cal antifungal spray in the treatment of AFS.
Material and methods
This prospective study was based at a tertiary teaching
hospital. Using an open enrollment, patients with a history
of AFS were selected because of progression of symptoms
during treatment. Participants were advised of the non-
FDA-approved use of an FDA-approved drug and given
the option to withdraw from the study.
Sixteen patients with a history of AFS were given u-
conazole nasal spray and followed for 3 months (table).
Of the 16 patients who participated in the study, 8 were
men and 8 were women. Their ages ranged from 39 to 74
years. Previous treatment included systemic itraconazole
alone in 5 patients and systemic itraconazole and oral
prednisone in 8 patients. Three patients did not have any
previous treatment.
The uconazole used in the study was formulated by
SinuCare, Inc. (Altamonte Springs, Fla.). It consisted of
100 mg of uconazole in 500 ml of normal saline solu-
tion administered as 5 sprays (0.5 cc/spray) in each nostril
twice daily.
Patients were followed monthly with nasal endoscopy,
and their response to treatment was assessed through
the serial nasal endoscopic examinations comparing the
presence of polyps and mucosal edema. The patients
symptoms and their perception of response to treatment
also were recorded.

Results
Twelve of the 16 patients (75%) had stable disease or
a decrease in mucosal edema during treatment with the
antifungal nasal spray; 4 patients (25%) had progression
of the edema during treatment with the nasal spray.
Three patients (19%) had polyps prior to starting treat-
ment; their polyps did not regress with treatment. Thirteen
patients showed no evidence of polyps prior to starting
treatment. Ten patients continued to be free of polyps
during treatment; however, 3 patients developed polyps
during treatment.
Subjectively, 12 patients (75%) perceived no worsening
or improvement in their symptoms with treatment. The
other 4 patients felt their symptoms were worse during
treatment.
Three patients were treated with the nasal spray only.
Two showed improvement or were stable; one did not
respond to treatment.
Table. Proles of patients with allergic fungal sinusitis who were treated with uconazole nasal spray

Mucosal Edema Patient
Patient Age Gender Before After perception

1 43 M Mild Moderate Improved
2 54 F Moderate Mild Stable
3 41 M Severe Mild Stable
4 61 F Mild Mild Stable
5 40 M Moderate Mild Stable
6 39 F Mild Moderate Stable
7 40 M Mild Mild Worse
8 67 M Mild Mild Improved
9 74 M Moderate Moderate Improved
10 41 F Moderate Moderate Stable
11 45 M Moderate Moderate Worse
12 57 F Mild Mild Stable
13 54 F Mild Moderate Worse
14 53 F Mild Severe Worse
15 44 M Moderate Mild Stable
16 56 F Moderate Mild Improved
Volume 83, Number 10 695
FLUCONAZOLE NASAL SPRAY IN THE TREATMENT OF ALLERGIC FUNGAL SINUSITIS: A PILOT STUDY
Discussion
The initial treatment of AFS is surgical debulking of the
affected sinuses and removal of allergic mucin and reactive
hypertrophied or hyperplastic mucosa. Both the fungus
and the diseased mucosa are removed, and the obstructed
sinuses are reventilated.
7,10
Waxman et al suggested the
use of systemic corticosteroids postoperatively, based on
the treatment modalities used in ABPA.
11
They looked at
26 patients, 10 of whom received postoperative steroids,
and noticed that the patients given steroids had less disease
on follow-up endoscopic examination. Kuhn and Javer
followed 11 patients with AFS who were given systemic
steroids postoperatively and noticed a signicant decrease
in mucosal disease.
9
Incomplete surgical removal of the
pathologic tissue usually renders the patient susceptible
to relapse of the disease.
3,7,12

Antifungal drugs given systemically have not proved
effective for treatment of AFS, primarily because the drugs
are not secreted into the nasal secretion. The fungus is not
invasive; and because the drugs are not secreted into the
mucus, fungicidal levels are not achieved in the mucous
lining of the nasal cavity and the paranasal sinuses.
3,8,9
In
this study, topical antifungals were studied as the only in-
tervention or in combination with systemic antifungals and
systemic steroids. In AFS, tissue damage is not caused by
invasive fungus but rather by the immunologic hyperreac-
tion associated with the presence of a fungal antigen in an
atopic individual.
2,3,9,12-14
Application of topical antifungals
should achieve fungicidal concentrations in the nasal and
paranasal sinus mucosa, eradicating the fungus and thus
reducing fungal antigen load.
Most of the patients in this study had stable symptoms
with application of the topical antifungal spray. We in-
terpreted this as success of the antifungal spray, because
the majority of patients in this treatment regimen had no
progression of the disease. However, relapses in AFS have
been shown to occur as much as 2 years after treatment.
This study followed 16 patients for only 3 months.
The next step would be to add a placebo group, utilize
a standard quality-of-life questionnaire, and follow the
patients longer.
Conclusion
AFS is a difcult disease to treat, because patients often
experience multiple relapses. The mainstay of treatment
is surgical debridement followed by systemic steroids.
Systemic antifungals have not proved effective; however,
based on the preliminary ndings in this study, there may
be a role for topical antifungals. Further investigation is
warranted.
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