The Laryngoscope

VC
2013 The American Laryngological,
Rhinological and Otological Society, Inc.
Contemporary Review
Use of Topical Nasal Therapies in the Management of Chronic
Rhinosinusitis
Calvin C. Wei, MD; Nithin D. Adappa, MD; Noam A. Cohen, MD, PhD
Objectives/Hypothesis: To determine whether the use of topical nasal therapies with saline alone and in combination
with antibiotics, antifungals, or corticosteroids is effective in the treatment of patients with chronic rhinosinusitis (CRS).
Data Sources: A systematic literature search was performed utilizing the MEDLINE database (1966 to May 2012),
EMBASE database (1980 to May 2012), and the Cochrane Central Register of Controlled Trials.
Review Methods: Electronic databases were searched by three otolaryngologists. Studies on five major categories of
topical nasal therapies searched included saline (hypotonic, isotonic and hypertonic); topical antibiotics, topical steroids, and
topical antifungals were obtained. Randomized controlled trials and meta-analyses of randomized controlled trials were
included.
Results: Sixteen randomized controlled trials were identified examining topical saline (hypertonic or isotonic) in CRS
patients. Two randomized controlled trials were found studying the effect of topical antibiotics in patients with CRS. Four
randomized controlled trials were identified studying topical antifungal treatment for CRS. Twenty-five randomized controlled
trials were found studying topical steroids in CRS patients.
Conclusion: A high aggregate quality of evidence supports the effectiveness of saline irrigations in treating CRS. There
is insufficient evidence to support a clear benefit of topical antibiotics in patients with chronic rhinosinusitis. Topical antifun-
gal therapies have not been shown to be significantly different in efficacy than saline controls on CRS outcomes. Topical ste-
roids are beneficial in the treatment of CRS with nasal polyps, but have not been shown to be effective in CRS without nasal
polyps.
Key Words: Chronic rhinosinusitis; antifungals; antibiotics; antimicrobials; nasal irrigations; topical therapy.
Laryngoscope, 123:23472359, 2013
INTRODUCTION
Chronic rhinosinusitis (CRS) is characterized by
chronic inflammation of the mucosa of the nasal cavity
and paranasal sinuses. According to the most recent prac-
tice guidelines, chronic rhinosinusitis is defined as 12
weeks or longer of two or more of the following subjective
signs and symptoms: mucopurulent drainage; nasal
obstruction; facial pain, pressure or fullness; or decreased
sense of smell in addition to inflammation documented by
one or more of the following objective findingspurulent
mucus or edema in the middle meatus or ethmoid region;
polyps in the nasal cavity or middle meatus; and/or radio-
graphic imaging showing inflammation of the paranasal
sinuses.
1
However, the exact pathophysiology of chronic
rhinosinusitis remains an enigma.
Currently, there is a paradigm shift within the rhi-
nologic community from utilizing surgical intervention
solely as means for establishing a patent drainage path-
way to improving access to the paranasal sinuses for
topical therapy to the mucosa to prevent infection,
inflammation, and to facilitate sinonasal mucociliary
clearance. That said, evidence for the use of topical nasal
therapies both with and without pharmacologic adjuncts
is often contradictory. The purpose of this article is to
identify the current literature and give recommenda-
tions regarding the use of these topical nasal therapies.
MATERIALS AND METHODS
A systematic literature search was performed utilizing the
MEDLINE database (1966 to May 2012), EMBASE database
(1980 to May 2012), and the Cochrane Central Register of Con-
trolled Trials. This search was performed by three individuals
(C.C.W, N.D.A, N.A.C.). Initially, a screening literature search iden-
tified studies on four major categories of topical nasal therapies
including saline (hypotonic, isotonic, and hypertonic), topical
antibiotics, topical steroids, and topical antifungals. Methods of
From the Department of OtolaryngologyHead and Neck Surgery
(C.C.W.), St. LukesRoosevelt Hospital, New York, New York; the Depart-
ment of OtorhinolaryngologyHead and Neck Surgery (N.D.A., N.A.C.),
University of Pennsylvania School of Medicine, Hospital of the Univer-
sity of Pennsylvania; and the Philadelphia Veterans Affairs Medical Cen-
ter (N.A.C.), Philadelphia, Pennsylvania, U.S.A
Editors Note: This Manuscript was accepted for publication January
31, 2013.
Noam A. Cohen is a consultant for Medtronic and G. Pohl Bos-
kamp. The authors have no other funding, financial relationships, or
conflicts of interest to disclose.
Send correspondence to Noam A. Cohen, Department of Otorhino-
laryngologyHead and Neck Surgery, University of Pennsylvania School
of Medicine, Hospital of the University of Pennsylvania Ravdin 5th
Floor, 3400 Spruce Street, Philadelphia, PA 19104. E-mail:
Noam.Cohen@uphs.upenn.edu
DOI: 10.1002/lary.24066
Laryngoscope 123: October 2013 Wei et al.: Use of Topical Nasal Therapies in the Management of Chronic Rhinosinusitis
2347
application used for topical therapies included nasal irrigation,
nasal spray, nasal drops, nebulization, and direct insufflation of
medication in powder form. All abstracts were reviewed and
randomized controlled trials and meta-analyses of randomized
controlled trials were included. Inclusion criteria included
patients with CRS based on published diagnostic criteria.
For topical antibiotics, medical subject headings and main
key words used in the database searches were topical, nasal,
antibiotics, and rhinosinusitis. For topical steroids, medical
subject headings and main key words used in the database
searches were topical, nasal, steroids, corticosteroids, and
rhinosinusitis. For topical saline irrigations, medical subject
headings and main key words used in the database searches were
topical, nasal, irrigations, saline, and rhinosinusitis. For
topical antifungals, medical subject headings and main key words
used in the database searches were topical, nasal,
antifungal, amphotericin, and rhinosinusitis. The results
were refined to identify randomized controlled trials and existing
meta-analyses on topical therapies.
The quality of evidence in each article was assessed using
the categories of evidence defined by the Oxford Center for Evi-
dence-Based Medicine Levels of Evidence (May 2001). After
quality evaluation for each study, a summary was produced
that includes the aggregate grade of evidence and recommenda-
tions based on the American Academy of Pediatrics (AAP)
guidelines.
RESULTS
Nasal Saline Irrigations
Many theories for the potential physiologic benefits
of saline irrigations have been proposed, including
improvement in mucous clearance, enhanced ciliary beat
activity, disruption and removal of antigens, biofilms
and inflammatory mediators, and direct protection of the
sinonasal mucosa. The use of nasal saline irrigations
has been recommended by otolaryngologists both as ad-
junctive therapy for chronic sinonasal symptoms and in
the postoperative period to moisten and cleanse sino-
nasal clots and crust, as well as to promote mucosal
healing.
Sixteen randomized controlled trials were identified
examining topical saline (hypertonic or isotonic) in CRS
patients
218
; of these, six examined the use of topical sa-
line irrigations in postoperative patients
1318
(Tables I
and II). A Cochrane review published in 2009 analyzed
the use of nasal saline irrigations and sprays for the
treatment of symptoms of CRS and concluded that the
beneficial effects of topical saline outweigh minor side
effects.
19
Eight trials from 1998 to 2005 satisfied their
inclusion criteria.
29
They included randomized con-
trolled trials in which saline was compared either to no
treatment, a placebo, or as an adjunct to other treat-
ments in the treatment of persistent sinonasal disease.
Methods of application utilized in these studies
included both nasal saline irrigations and sprays. The
trials included patients with rhinitis with seasonal exac-
erbations, perennial rhinitis and recurrent acute rhinosi-
nusitis. These studies made a diversity of comparisons.
Three of these trials (Garavello, Garavello, Rabago) com-
pared the use of hypertonic saline to no irrigation.
4,5,7
After pooling the symptom scores of these three studies,
use of topical saline produced statistically significant
improvement in both symptom scores (P <0.00001) and
disease-specific quality of life scores (P <0.00001) over
the nontreatment group. The study populations in these
studies were heterogeneous: patients in the Garavello
studies were children with symptoms of allergic rhinitis
or rhinoconjunctivitis, while those in the Rabago study
were adults with symptoms of chronic rhinosinusitis or
recurrent acute rhinosinusitis. In addition, both the vol-
ume and method of saline administration differed among
the studies. Heatley et al. compared the effect of nasal
saline delivered by bulb syringe or an irrigation pot ver-
sus a reflexology control that served as a placebo.
6
The
use of nasal saline delivered by either method did not
produce a statistically significant improvement in dis-
ease-specific quality of life scores compared to the reflex-
ology control group.
Another study sought to compare the addition of sa-
line spray to the use of a standard therapy (antihist-
amine) for chronic rhinitis versus the standard therapy
alone (Rogkakou).
8
The addition of saline spray to the
antihistamine produced a statistically significant
improvement in disease-specific quality of life scores
(P50.001). Cordray et al., in a three-arm study with 21
patients, compared the effectiveness of hypertonic saline
spray, isotonic saline spray, and triamcinolone spray in
patients with persistent nasal symptoms of rhinitis.
3
No
improvement in disease-specific quality of life scores was
produced by isotonic or hypertonic saline over the intra-
nasal steroid. Two studies (Bachmann, Shoseyov) com-
pared hypertonic to isotonic saline. Symptom and
radiology scores from hypertonic compared to isotonic sa-
line groups were pooled. This pooled data found that
there was no statistically significant difference in symp-
tom and radiology scores between the two groups.
2,9
Two recent randomized controlled trials investi-
gated methods of saline administration and compared
the efficacy of hypertonic versus isotonic concentrations
of saline (Pynnonen, Hauptman).
10,11
Pynnonen et al.
compared the use of large volume isotonic saline irriga-
tion to nasal saline sprays. Saline irrigations delivered
with large volume and low positive pressure demon-
strated statistically significantly improvements in qual-
ity of life scores (SNOT-20) compared to those patients
receiving nasal saline sprays.
10
Hauptman et al. com-
pared the effect of hypertonic versus isotonic nasal
sprays and found that, while both solutions improved
mucociliary clearance as measured by saccharine clear-
ance times, buffered normal saline significantly
improved nasal airway patency, while hypertonic saline
did not. Additionally, they found that hypertonic saline
caused increased nasal burning and irritation compared
with isotonic saline (P <0.0001).
11
The lack of improve-
ment in nasal patency with hypertonic saline may sug-
gest that hypertonic saline-induced neural responses
lead to localized vascular change causing swelling and
obstruction.
12
Six randomized controlled trials were identified
studying the effect of nasal saline irrigation in postopera-
tive CRS patients (Table II).
1318
Rudmik et al. in an evi-
dence-based review for postoperative care following
endoscopic sinus surgery (ESS) evaluated these six
Laryngoscope 123: October 2013 Wei et al.: Use of Topical Nasal Therapies in the Management of Chronic Rhinosinusitis
2348
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Laryngoscope 123: October 2013 Wei et al.: Use of Topical Nasal Therapies in the Management of Chronic Rhinosinusitis
2349
studies and found that three of the four studies demon-
strated improved symptom scores with saline irrigations
after ESS.
20
The highest quality study by Liang et al.
compared saline irrigations combined with postoperative
debridement versus debridement alone and demonstrated
that postoperative debridement with saline irrigations
significantly improved patient symptoms and endoscopic
appearance in the mild CRS cohort, although there was
no improvement in these parameters in the moderate-
severe CRS cohort.
15
Rudmik et al. concluded that postop-
erative nasal saline irrigations are well tolerated and
improve early postoperative symptoms and endoscopic
appearance based on level 1b and 2b evidence.
20
Recommendation:. A relatively high level of
evidence supports that saline is beneficial in the treat-
ment for the symptoms of chronic rhinosinusitis, both as
a sole modality of treatment and as a treatment adjunct
following ESS.
Aggregate Quality of Evidence: A.
Topical Antibiotics
Despite uncertainty surrounding the pathogenesis of
CRS, the effectiveness of oral antibiotics in the treatment
of CRS suggests that topical antibiotics may also be effec-
tive. However, the use of topical antibiotics is complicated
by controversies in the choice of antibacterial agent, dos-
age, delivery method, and whether its efficacy is improved
in a postoperative cavity. A recent in vitro study found
that the increased concentrations of antibiotics attained
in topical irrigations are effective at eradicating Staphylo-
coccus aureus and Pseudomonas aeruginosa isolates in
biofilms.
21
A subsequent prospective open-label pilot trial
studied the efficacy and tolerability of topical mupirocin
(0.05%) with lactated ringers salt lavage in patients with
surgically recalcitrant CRS and endoscopically guided cul-
tures that were positive for Staphylococcus aureus. They
found that after 3 weeks of treatment 15 of 16 patients
had improved endoscopic findings, and 12 of 16 had nega-
tive swab results after treatment.
22
Despite these early favorable results and multiple
low level studies supporting the effectiveness of topical
antibiotics delivered by nasal irrigation and nebuliza-
tion,
2331
our literature search identified only two
randomized control trials studying the effectiveness of
topical antibiotic therapies in patients with CRS (Table
III).
32,33
Both of these studies (Sykes, Desrosiers) utilized
empiric therapy, one using nasal spray
32
and the other
nebulization
33
as the method of application. Both studies
concluded that the addition of an antibiotic (neomycin,
32
tobramycin
33
) to a topical solution did not provide any
statistically significant improvement in symptom, quality
of life, and endoscopy scores compared to the nontreat-
ment groups (propellant alone
32
and normal saline with-
out tobramycin
33
). The Desrosiers trial studied patients
with recalcitrant symptoms of CRS following endoscopic
sinus surgery.
33
The lack of culture-directed antibiotic
therapy is a significant limitation of both studies.
The use of topical antibiotics in CRS appears safe,
with no trial reporting serious adverse effects compared
to placebo.
23
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Laryngoscope 123: October 2013 Wei et al.: Use of Topical Nasal Therapies in the Management of Chronic Rhinosinusitis
2350
Recommendation:. There is insufficient evidence
to support a clear benefit of topical antibiotics in
patients with CRS. Larger and better-designed random-
ized, double-blind, placebo-controlled trials using cul-
ture-directed topical antibiotic therapy are necessary.
Aggregate Quality of Evidence: C.
Topical Antifungals
A total of four randomized, double-blind, placebo-
controlled trials were identified where the primary objec-
tive was to evaluate the effect of topical amphotericin B
on CRS clinical outcomes (Table IV).
3437
Although an
initial prospective open-label trial using 20 mL of intra-
nasal amphotericin B (100 lg/mL) in 2002 showed a rel-
ative reduction in mucosal thickening on CT and
improvement in endoscopy score in patients with CRS
treated with amphotericin B intranasal irrigations (Poni-
kau 2002),
38
and a subsequent randomized, placebo-con-
trolled, double-blind trial in 2005 demonstrated similar
improvements (Ponikau 2005),
34
three larger, double-
blind, randomized controlled trials have concluded that
topical amphotericin B is ineffective for the treatment of
chronic rhinosinusitis.
3537
Weschta et al. studied 78 patients with chronic rhi-
nosinusitis, 60 of which completed the study protocol.
Thirty-two were allocated into the control group receiv-
ing nasal saline spray, and 28 were allocated to receiving
topical amphotericin B spray. The primary outcome vari-
able was the response rate, defined as the number of
patients with a 50% reduction of their pretreatment
computed tomography (CT) score. The CT score was cal-
culated by the sum of the scores assigned to each maxil-
lary, anterior and posterior ethmoid, sphenoid, and
frontal sinus (0 5not opacified, 1 5less than 1/3 opaci-
fied, 2 5between 1/3 and 2/3 opacified, 3 5more than 2/
3 opacified but still air containing, 45complete opacifi-
cation). Additional outcome variables included a symp-
tom score, a quality of life score, and an endoscopy
score. The primary outcome measure, the CT score
TABLE II.
Summary of Randomized Controlled Trials of Postoperative Topical Nasal Saline.
Study Study Design
Number of
Patients Study Groups Primary Endpoints
Level of
Evidence Conclusions
Pigret 1996 RCT, single-blind 20 Sea salt irrigations
(mechanical la-
vage); sea salt,
mucolytic and
antiseptic irriga-
tions (chemical
lavage)
Weight of ethmoid
crust, symptom
score
1b No significant difference
was found between
weight of ethmoid crust
and symptom scores.
Pinto 2006 RCT 60 NS spray; HS
spray; no spray
Symptom scores 1b Symptom scores showed
higher nasal discharge
scores in HS group;
there was not significant
improvement in symp-
tom scores from no
treatment.
Fooanant 2008 RCT 128 NS irrigation; dex-
panthenol spray
Symptom scores,
mucociliary
clearance
1b No statistically significant
difference in symptom
scores and mucociliary
clearance between NS
and dexpanthenol
spray.
Freeman 2008 RCT, single-blind,
intrapatient
23 NS irrigation; no
irrigation
Endoscopic
appearance
1b NS irrigation significantly
improved presence of
nasal discharge and
nonsignificantly reduced
edema compared to
nontreatment side.
Liang 2008 RCT 77 NS irrigation and
debridement; de-
bridement alone
Symptom scores,
endoscopic
appearance
1b NS irrigation produced
significant reductions in
endoscopy and symp-
tom scores in patients
with mild CRS (CT score
<12); no significant
reduction noted with
severe CRS (CT score
>12)
Staffieri 2008 RCT 80 NS irrigation; SFT
irrigation
Postoperative mu-
cosal histology
1b SFT treatment produced
significant reduction of
eosinophil count
(P50.04) while NS did
not
CRS5chronic rhinosinusitis; CT5computed tomography; HS5hypertonic saline; NS5normal saline; SFT 5sulfurous-arsenical-ferruginous thermal
water nasal irrigation.
Laryngoscope 123: October 2013 Wei et al.: Use of Topical Nasal Therapies in the Management of Chronic Rhinosinusitis
2351
difference before and after 8 weeks of treatment, was
similar between the two groups. The median symptom
score in the amphotericin B group was worse than in
the control group. The difference in quality of life scores
and endoscopy score did not differ significantly between
the treatment arms.
35
Ebbens et al. performed the largest trial in the lit-
erature, studying amphotericin irrigations in patients
with chronic rhinosinusitis. In a double-blind, placebo-
controlled, multicenter trial, 116 patients with chronic
rhinosinusitis who had already undergone endoscopic
sinus surgery to facilitate adequate access to the nasal
mucosa were randomized into two groups; 59 patients
received topical amphotericin B, while 57 received a pla-
cebo irrigation using an Emcur nasal douching device.
Follow-up visits were performed at 2, 6, and 13 weeks
after randomization. Primary outcome measures
included the change from baseline in patient symptoms
utilizing the total visual analog scale (VAS) score, in
addition to endoscopic grading of mucosal disease. The
amount of mucosal disease was graded based on the
presence or absence of nasal secretions (0 5absent,
1 5clear to opaque, 2 5purulent), amount of crusting
(0 5absent, 1 5mild, 2 5severe), and presence or ab-
sence of nasal polyps (0 5absent, 2 5present). Total
scores were obtained by adding all independent values
for both nasal cavities. Secondary outcome measures
included change in baseline in disease-specific patient
symptoms using the Rhinosinusitis Outcome Measure-31
(RSOM-31) questionnaire, quality of life using the Short
Form-36 (SF-36) questionnaire, change in nasal patency
using peak nasal inspiratory flow (PNIF), and change in
polyp scores. No significant differences were noted for
mean VAS scores, nasal endoscopy scores, RSOM-31 and
SF-36 data, PNIF values, and polyp scores at 13 week
follow-up. Adverse effects included acute exacerbation of
sinusitis, headache, facial pain, and epistaxis. The pro-
portion of patients experiencing an adverse effect was
similar between the two groups.
36
Gerlinger et al. conducted a prospective randomized,
placebo-controlled trial involving 33 patients randomized
into a treatment group with a nasal spray containing 5
mg/mL of amphotericin B compared to a placebo nasal
spray for 1 year of treatment. The amphotericin B treat-
ment group produced no significant improvement in
Lund-Mackay CT scores or sinonasal symptom scores
(SNAQ-11) compared to the placebo group.
37
Recommendation: Topical antifungal therapies have
not been shown to be significantly different in efficacy
than saline controls on CRS outcomes.
Aggregate Quality of Evidence: A
Topical Corticosteroids
Topical corticosteroid treatment has been shown as
an effective adjuvant treatment for acute bacterial rhi-
nosinusitis and as a method for reducing inflammation
in patients with allergic rhinitis and nasal polyps.
39,40
A
2009 Cochrane review concluded that limited current
evidence supports the use of intranasal corticosteroids
as a monotherapy or adjuvant therapy to antibiotics for
acute rhinosinusitis.
41
Because significant differences
exist between chronic rhinosinusitis with and without
nasal polyps in terms of the specific inflammatory cellu-
lar infiltrate, cytokine and mediator profiles, immune
responses to Staphylococcus aureus enterotoxins, and
differences in bony remodeling, the effectiveness of
intranasal steroids have been examined independently
between the two groups.
39
Two meta-analyses of randomized controlled studies
have recently been published, one evaluating intranasal
steroids in chronic rhinosinusitis with nasal polyps, and
TABLE III.
Summary of Randomized Controlled Trials of Topical Antibiotics.
Study Study Design Number of Patients Study Groups
Method of
Application Primary Endpoints
Level of
Evidence Conclusions
Sykes
1986
Randomized,
double-blind,
placebo-
controlled
50 Dexa-metha-
sone, trama-
zoline, neo-
mycin; dexa-
methasone,
tramazoline;
placebo (pro-
pellant alone)
3 2 weeks
Nasal spray Symptom
scores,
mucociliary
clearance,
nasal airway
resistance
1b Neomycin treat-
ment produced
no significant
improvement in
symptom scores,
mucociliary clear-
ance and nasal
airway resistance
compared to
spray without an-
tibiotic and
placebo.
Desrosiers
2001
Randomized,
double-blind,
placebo-
controlled
20 (patients with
recalcitrant
symptoms
postoperatively)
Tobramycin-NS
solution (20
mg/mL) 4 mL
tid, NS
solution
Nebulization
with RinoFlow
Nasal and
Sinus Wash
System
QOL
questionnaire
(Juniper
RQLQ),
endoscopic
score
1b Tobramycin treat-
ment produced
no significant
improvement in
QOL question-
naire or endos-
copy score
reductions com-
pared to placebo
group.
NS5nasal saline; QOL 5quality of life questionnaire; RQLQ5Rhino-conjunctivitis Quality of Life Questionnaire.
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the other without.
42,43
It is hoped that the use of topical
corticosteroid therapy may reduce the need for treat-
ment with systemic steroids which may cause serious
side effects, including weight gain and loss of bone
density.
Joe et al. performed a meta-analysis of 13 studies
from 1990 to 2006 utilizing intranasal steroids in CRS
with nasal polyposis (Table V). The evidence demon-
strated that the use of intranasal steroids was effective
in decreasing the size of nasal polyps.
42
Of the 13 stud-
ies found,
4456
seven studies were excluded due to insuf-
ficient statistical analysis.
44,49,50,52,53,55,56
The patients
from the remaining six trials, which were randomized,
double-blinded, and placebo-controlled studies (Stjarne,
Butkus Small, Filiaci, Jankowski, Tos, Lildholdt) were
pooled.
4548,51,54
Nasal sprays, nasal drops, and direct
insufflation of medication in powder form were utilized
as methods of application. The primary outcome mea-
sure used for the meta-analysis was the difference in the
mean changes of polyp size between the treatment and
control groups. The majority of the studies used a com-
mon polyp grading system on a 0 to 3 scale as judged by
the examining physician (0 5no polyps; 1 5polyps in the
middle meatus not extending below the inferior portion
of the middle turbinate; 2 5polyps extending beyond the
inferior edge of the middle turbinate; 3 5large polyps
below the inferior edge of the inferior turbinate). Two of
the six studies treated patients with topical mometasone
furoate
45,46
and the remaining used topical
budesonide.
47,48,51,54
The optimistic and conservative difference in mean
changes in polyp size between the treatment and placebo
groups were calculated. Both conservative and optimistic
estimates of the difference in the changes of polyp size
score between the treatment and control groups were
positive; the participants assigned to the treatment
group had greater mean reductions in the polyp size
score compared with the control group at the end of the
study phase.
Kalish et al. performed a meta-analysis of 9
randomized controlled trials from 1986 to 2004 studying
the use of topical steroids in CRS without polyps (Dijk-
stra, Parikh, Mastalerz, Lund, Lavigne, Qvarnberg,
Giger, Sykes, Cuenant)
5765
(Table VI). Of these nine
studies, eight trials compared a topically administered
corticosteroid with a placebo
57,58,6065
; the remaining
study compared beclomethasone daily to twice-daily dos-
ing and did not have a placebo control.
59
Nasal irriga-
tion, nasal spray, and nebulization were utilized as
methods of application. It is important to note that only
one of these studies, the trial by Dijkstra in 2004, stud-
ied patients who had previously undergone endoscopic
TABLE IV.
Summary of Randomized Controlled Trials of Topical Antifungals.
Study Study Design
Number of
Patients Study Groups
Primary Outcome
Measure
Level of
Evidence Conclusions
Weschta 2004 Randomized,
double-blind
78 AMB (3 mg/mL) 1.2
mg qid, NS qid
3 8 weeks
Response rate
(defined as 50%
reduction of CT
score), symptom
score
1b AMB produced no
significant
improvement in
response rate;
symptom scores
were significantly
worse in the
AMB group com-
pared to the NS
group (P <0.005).
Ponikau 2005 Randomized,
double-blind,
placebo-
controlled
24 AMB (250 lg/mL)
40 mL qD, pla-
cebo 3 6 months
Reduction in muco-
sal thickening on
CT using digital
analysis, nasal
endoscopy
scores
1b AMB produced a
significant rela-
tive reduction of
mucosal thicken-
ing of digitized
CT images and
nasal endoscopy.
Ebbens 2006 Randomized,
double-blind,
placebo-
controlled,
multicenter
116 AMB (100 lg/mL)
50 mL bid, pla-
cebo 3 3 months
Reduction in total
visual analogue
scale scores,
nasal endoscopy
scores
1b AMB produced no
significant differ-
ence in mean
VAS or nasal en-
doscopy scores
compared to
placebo.
Gerlinger 2009 Randomized,
double-blind,
placebo-
controlled
33 AMB (5 mg/mL) 2
mg bid, placebo
3 1 year
Modified Lund-
Mackay CT
score, sinonasal
symptom score
(SNAQ-11)
1b AMB produced no
significant
improvement in
Lund-Mackay CT
score or sino-
nasal symptom
scores compared
to placebo
group.
AMB5amphotericin B; CT5computed tomography; NS5nasal saline; VAS5visual analog score.
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TABLE V.
Summary of Randomized Controlled Trials of Topical Steroids in CRS Patients with Polyps.
Study Study Design
Number of
Patients Study Groups
Primary Outcome
Measures
Level of
Evidence Conclusions
Ruhno 1990 Randomized, dou-
ble-blind, pla-
cebo-controlled
36 BANS 400 lg bid;
placebo
Symptom scores,
obstruction
caused by
polyps
1b BANS produced statis-
tically significant
reductions in symp-
tom scores and
polyp scores com-
pared to placebo.
Johansen 1993 Randomized, dou-
ble-blind, pla-
cebo-controlled,
multicenter
91 BANS 200 lg bid
(aerosol or aqua);
placebo 3 3
months
Polyp score, PIF,
symptom scores
1b BANS produced a
statistically signifi-
cant decrease in
mean total polyp
size, PIF index, and
symptom scores
compared to
placebo.
Lildholdt 1995 Randomized, dou-
ble-blind, pla-
cebo-controlled
126 Budesonide pow-
der (Rhinocort
Turbuhaler) 200
lg bid; 400 lg
bid; placebo 3 1
month
Reduction in polyp
size, symptom
scores
1b Budesonide powder
groups produced
statistically signifi-
cant improvement in
symptom score and
polyp size compared
to placebo.
Holmberg1997 Randomized, dou-
ble-blind, pla-
cebo-controlled
55 FPANS 200 lg bid,
BecDANS 200 lg
bid, placebo 3
26 weeks
Assessment of
symptoms and
polyp score
1b FPANS and BecDANS
produced significant
improvement in
polyp grade and
symptom scores
compared to
placebo.
Lund 1998 Randomized, dou-
ble-blind, pla-
cebo-controlled
34 FPANS 200 lg bid,
BecDANS 200 lg
bid, placebo 3
12 weeks
Need for polypec-
tomy at end of
treatment, polyp
score, acoustic
rhinometry, PNIF
1b No significant differ-
ence seen between
treatment groups in
number of patients
requiring polypec-
tomy; polyp score
significantly
decreased in
FPANS-treated
group; nasal cavity
volume significantly
increased in both
steroid groups.
Tos 1998 Randomized, dou-
ble-blind, pla-
cebo-controlled
138 BANS Aqua 128 lg
bid, BANS Tur-
buhaler 140 lg
bid, placebo 3 6
weeks
Assessment of
polyp size
1b Budesonide produced
significant reduc-
tions in polyp size
compared to pla-
cebo; no significant
difference between
aqua and Turbuhaler.
Penttila 2000 Randomized, dou-
ble-blind, pla-
cebo-controlled,
multicenter
142 FPND 400 lg qD,
bid, placebo 3
12 weeks
Change in polyp
size, degree of
nasal blockage,
overall rhinitis
symptoms, PNIF
1b FPND 400 lg bid pro-
duced statistically
significant reduction
in polyp size com-
pared to placebo;
significant improve-
ment in clinical
assessment of nasal
blockage, overall rhi-
nitis, PNIF with both
doses.
Keith 2000 Randomized, dou-
ble-blind, pla-
cebo-controlled,
multicenter
104 FPND 400 lg qD,
placebo 3 12
weeks
Assessment of
polyp size at end
of treatment
period
1b FPND 400 lg qD pro-
duced reduction in
polyp grade in sig-
nificantly higher pro-
portion of patients
than placebo.
Filiaci 2000 Randomized, dou-
ble-blind, pla-
cebo-controlled,
multicenter
157 BANS 140 lg qD or
bid, 280 lg qD,
placebo
Mean change in
bilateral polyp
score
1b BANS 280 lg qD (280
lg qD and 140 bid)
significantly reduced
polyp size compared
with placebo; BANS
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2354
sinus surgery.
58
The topical steroids used in these stud-
ies included fluticasone, budesonide, beclomethasone,
dexamethasone, and tixocortol.
The quality of these nine studies were assessed by
allocation concealment, blinding, study dropout rate,
and intention-to-treat analysis. Data was pooled when
possible, and data pooled in regards to the outcome of
the number of patients not responding to treatment
found a trend toward benefit favoring topical steroids (6
trials: RR 0.7, 95% CI 0.491.01, P50.06).
57,58,6265
The
significance of this data is weakened by the fact that cri-
teria for this overall response was variably defined
across studies and included an average decrease of
>50% from initial visual analogue symptom score
63
; re-
solution of recurrent complaints of CRS in addition to re-
solution of CRS signs on nasal endoscopy and CT after
TABLE V.
(Continued)
Study Study Design
Number of
Patients Study Groups
Primary Outcome
Measures
Level of
Evidence Conclusions
140 lg qD had no
significant effect; all
three doses signifi-
cantly reduced
symptoms scores
without significant
differences between
doses.
Jankowski 2001 Randomized, dou-
ble-blind, pla-
cebo-controlled
183 BANS 128 lg a.m.
and placebo
p.m.; 128 lg bid;
256 lg a.m. and
placebo p.m.;
placebo
Mean change from
baseline in polyp
score and com-
bined and indi-
vidual symptom
scores
1b All doses of BANS sig-
nificantly reduced
polyp size (P <0.01)
and improved com-
bined and individual
symptom scores
and sense of taste;
higher dose BANS
(256 lg daily) did
not show significant
additional efficacy.
Butkus Small 2005 Randomized, dou-
ble-blind, pla-
cebo-controlled,
multicenter
354 MFNS 200 lg daily;
MF 200 lg bid;
placebo
Change in bilateral
polyp grade
score; change
from baseline in
subject-assessed
nasal congestion
1b MF 200 lg given once
or twice daily pro-
duced greater
reductions in polyp
grade and improving
congestion/obstruc-
tion and return of
sense of smell than
placebo.
Stjarne 2006a Randomized, dou-
ble-blind, pla-
cebo-controlled,
multicenter
310 MFNS 200 lg a.m.
and placebo
p.m.; MF 200 lg
a.m. and p.m.;
placebo a.m. and
p.m.
Change in polyp
grade score from
baseline
1b MF 200 lg given once
or twice daily pro-
duced greater
reductions in bilat-
eral polyp grade at
the end point than
placebo, statistical
significance was
reached with twice-
daily dosing
(P50.04); over 1
month, MF once and
twice daily produced
statistically signifi-
cant improvement
from baseline in
congestion and/or
obstruction score vs.
placebo.
Stjarne 2006b Randomized, dou-
ble-blind, pla-
cebo-controlled
298 MFNS 200 qD,
placebo
Improvement in
nasal congestion
score from base-
line; polyp score
as secondary
outcome
1b Statistically significant
greater proportion of
MF 200 qD group
had improvement in
nasal congestion
score than placebo
group (74.3% vs.
46.8%; P <0.001).
Polyp size score
also significantly
reduced.
BANS5budesonide aqueous nasal spray; BecDANS5beclomethasone dipropionate aqueous nasal spray; CRS5chronic rhinosinusitis; FPANS5fluti-
casone propionate aqueous nasal spray; FPND5fluticasone propionate nasal drops; MFNS5mometasone furoate nasal spray; PIF 5peak inspiratory flow;
PNIF 5peak nasal inspiratory flow.
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2355
endoscopic sinus surgery;
58
substantial, or total control
of symptoms
5764
; patients not requiring surgical inter-
vention (Caldwell-Luc) within 1 year following a 90 day
trial period
62
; and right maxillary ostial patency.
65
This
weakness is demonstrated in that when the Cuenant
et al. trial was excluded due to its use of ostial patency
TABLE VI.
Summary of Randomized Controlled Trials of Topical Steroids in CRS Patients without Polyps.
Study Study Design
Number of
Patients Study Groups Primary Endpoints
Level of
Evidence Conclusions
Cuenant 1986 Randomized,
double-blind
60 Tixocortol pivalate
50 mg and neo-
mycin irrigation,
neomycin irriga-
tion alone 3 11
days
Nasal resistance by
manometry
1b Tixocortol produced stat-
istically significant
improvement in nasal
resistance compared to
neomycin irrigation
alone.
Sykes 1986 Randomized,
double-blind,
placebo-
controlled
50 Dexa-methasone,
tramazoline, neo-
mycin spray;
dexa-methasone,
tramazoline
spray; propellant
alone 3 2 weeks
Symptom scores,
mucociliary clear-
ance, nasal air-
way resistance
1b Dexamethasone-tramazo-
line group with or with-
out neomycin produced
statistically significant
improvement in symp-
tom scores, mucociliary
clearance and nasal air-
way resistance com-
pared to placebo; there
was no significant differ-
ence between the ste-
roid group with and
without neomycin.
Qvarnberg 1992 Randomized,
double-blind,
placebo-
controlled
40 Budesonide aerosol
400 lg qD,
placebo
Mucosal thickening
score on CT
1b No statistically significant
reduction in mucosal
thickening between the
two groups.
Mastalerz 1997 Randomized,
double-blind,
placebo-
controlled
15 FPANS 400 lg qD,
placebo 3 4
weeks
Symptom score,
PNIF
1b FP produced statistically
significant improvement
in symptom scores and
PNIF measurements
compared to placebo in
patients with chronic
eosinophilic rhinosinusi-
tis with aspirin-induced
asthma.
Parikh 2001 Randomized,
double-blind,
placebo-
controlled
22 FPANS 200 lg bid,
placebo
Symptom score
(visual analogue
scale), endos-
copy score
1b No statistically significant
reduction in symptom
score and endoscopy
score between the two
groups.
Lavigne 2002 Randomized,
double-blind,
placebo-
controlled
26 Budesonide 256 lg
qD, placebo via
maxillary antrum
sinusotomy tube
3 3 weeks
Symptom score
(visual analogue
scale), posttreat-
ment eosinophil
count
1b Budesonide produced
statistically significant
improvement in symp-
tom scores and reduc-
tion in eosinophil count
compared to placebo
group.
Giger 2003 Randomized,
double-blind
112 BDP 400 lg qD,
BDP 400 lg bid
Nasal and ocular
symptom scores,
NAR
1b Twice daily dosing pro-
vided no significant
improvement in symp-
tom scores and NAR, or
difference in adverse
events.
Lund 2004 Randomized,
double-blind,
placebo-
controlled,
multicenter
167 BANS 128 lg bid,
placebo 3 20
weeks
Combined symp-
tom scores, PNIF
1b BANS produced statisti-
cally significant reduc-
tion in morning
combined symptom
scores (P50.005); PNIF
increased significantly
during BANS treatment.
Dijkstra 2004 Randomized,
double-blind,
placebo-
controlled
162 FPANS 400 lg bid,
FPANS 800 lg
bid, placebo bid
3 1 year
Symptom score
(visual analogue
scale), recurrence
rate of nasal pol-
yps or CRS
1b Both doses of FPANS pro-
duced no significant
improvement in symp-
tom scores or reduction
in recurrence rate com-
pared to placebo group.
CRS5chronic rhinosinusitis; BANS5budesonide aqueous nasal spray; BDP5beclomethasone dipropionate aqueous nasal spray; FPANS5fluticasone
propionate aqueous nasal spray; NAR5nasal airway resistance measured on anterior rhinomanometry; PNIF 5peak nasal inspiratory flow.
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2356
as the criteria for overall response, no statistically sig-
nificant benefit was found (5 trials: RR 0.75, 95% CI
0.501.10, P50.14).
57,58,6264
Data involving the mean
percentage change in total symptom score was also
pooled from three of the eight studies.
57,60,63
These
results showed a standardized mean difference again
favoring the effectiveness of topical steroids (RR 0.63,
95% CI 0.161.09, P50.009). None of these trials
reported any significant adverse effects, including
increased frequency of infections.
43
Although pooled data
did find that topical steroids produced overall sympto-
matic benefit compared to control in six of eight trials,
the accuracy of the trend toward favoring topical ste-
roids when comparing topical steroids to control in terms
of number of patients not responding to treatment is
limited by the significant variability in definition of
treatment response.
Of these nine studies, the highest quality study was
performed by Lund et al.
57
It was the only study that
demonstrated allocation concealment, blinding, and
intention-to-treat analysis. This trial was a randomized,
double-blind, placebo-controlled, multicenter study that
compared the efficacy of budesonide aqueous nasal spray
(BANS) to placebo aqueous sprays in CRS patients.
Patients were followed for 20 weeks and maintained di-
ary records of CRS symptoms in the morning and eve-
ning. The primary outcome measure was the combined
symptom score, which was calculated as the sum of the
scores for four groups of symptoms: facial pain, pressure
or headache; facial congestion, nasal obstruction or
blockage; nasal discharge; and impairment in sense of
smell. In addition, patients provided an overall evalua-
tion of treatment efficacy at 4 week intervals on a 5
point scale (0 5no control over symptoms; 1 5minor con-
trol; 2 5moderate control; 3 5substantial control;
4 5total control). Of a total of 244 patients enrolled in
the study, 167 patients were eligible for randomization,
and 134 patients completed treatment.
The adjusted mean change in combined morning
symptom scores from baseline to week was significantly
greater in patients receiving BANS than in the placebo
group (21.85 vs. 21.02, P50.005). BANS treatment
compared with placebo was associated with a significant
decrease in scores for all symptoms except facial pain
and sense of smell in the evening. A total of 43.1% of
patients receiving BANS reported substantial or total
symptom control compared to 25.9% of placebo-treated
patients (P50.015). Subgroup analysis between allergic
and nonallergic patients revealed that, while BANS sig-
nificantly reduced both morning and evening combined-
symptom scores in allergic patients, reductions in com-
bined symptom scores in nonallergic patients was not
significant. Limitations of the study included inability to
demonstrate improvement in disease-specific quality of
TABLE VII.
Summary of Randomized Controlled Trials of Postoperative Topical Steroids.
Study Study Design
Number of
Patients Study Groups Primary Endpoints
Level of
Evidence Conclusions
Dijkstra 2004 Randomized, dou-
ble-blind, pla-
cebo-controlled
162 FPANS 400 lg bid,
FPANS 800 lg
bid, placebo bid
3 1 year
Symptom score
(visual analogue
scale), recurrence
rate of nasal pol-
yps or CRS
1b Both doses of
FPANS produced
no significant
improvement in
symptom scores
or reduction in
recurrence rate
compared to pla-
cebo group.
Rowe-Jones 2005 Randomized, dou-
ble-blind, pla-
cebo-controlled
109 FPANS 200 mcg
bid, placebo 3 5
years
Symptom score
(VAS), endoscopy
score
1b FPANS produced a
statistically signif-
icant reduction in
symptom score
and endoscopic
polyp score at 5
years.
Jorissen 2009 Randomized, dou-
ble-blind, pla-
cebo-controlled
99 MFNS 200 lg bid,
placebo 3 6
months, placebo
Total endoscopy
score
1b MFNS produced
greater, although
not statistically
significant,
reductions in
total endoscopy
scores compared
to placebo.
Stjarne 2009 Randomized, dou-
ble-blind, pla-
cebo-controlled,
multicenter
104 MFNS 200 lg daily,
placebo
Time to relapse,
defined as
increase of 1
point or more on
endoscopic
polyp scale
1b Postoperative use
of MFNS pro-
vided a statisti-
cally significant
increase in time
to relapse of
nasal polyps
compared to
placebo.
CRS5chronic rhinosinusitis; FPANS5fluticasone propionate aqueous nasal spray; MFNS5mometasone furoate nasal spray; VAS5visual analog
score.
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2357
life scores (Chronic Sinusitis Survey, SF-36) and the rel-
atively high number of participants not completing the
trial (20%). Nevertheless, this trial supports the efficacy
of topical budesonide as significantly reducing symptom
scores.
57
The use of nasal irrigation with high dose budeso-
nide respules (0.5 mg/2 mL) diluted into 240 cc of saline
irrigations has become increasingly popular in the treat-
ment of CRS. Budesonide irrigations have been shown to
decrease the size of nasal polyps
66
and have been shown
not to cause adrenal suppression.
6769
However, irriga-
tion with high dose budesonide has not yet been rigor-
ously evaluated in CRS.
A recent literature review performed by Rudmik
et al. identified four randomized, double-blind, placebo-
controlled trials evaluating the role of standard topical
nasal steroid sprays in post-ESS patients
58,7072
(Table
VII; please note that the Dijkstra 2004 study is repeated
in this table.). Three of the four trials found significant
clinical improvement in post-ESS patients in terms of
decreased recurrence rates and a prolonged time to
recurrence of nasal polyps.
7072
The fourth study by
Dijkstra et al. compared fluticasone nasal spray to pla-
cebo in post-ESS patients and did not show a clinical
improvement 1 year after ESS.
58
This study, however,
did not use a validated rhinosinusitis health-related
quality of life instrument, and had a low number of
patients with nasal polyps in their study cohort (68/162).
The use of topical steroids in CRS both with and
without nasal polyps appears safe, with no trial report-
ing serious adverse effects compared to placebo, includ-
ing the increased incidence of infections.
43
In addition,
multiple studies have been performed assessing the sys-
temic absorption of topical steroids, and it has not been
found to affect the hypothalamic-pituitary-adrenal
axis.
73
Recommendation:. There is insufficient evidence
to support a clear benefit of topical steroids in patients
with CRS without polyps, although symptomatic benefit
is shown. A relatively high level of evidence supports
the use of topical steroids as being effective in decreas-
ing the size of nasal polyps. Currently, there is a lack of
data to make a recommendation on high dose budeso-
nide irrigations.
Aggregate Quality of Evidence: A.
CONCLUSION
The role of topical therapies in CRS as a means of
avoiding the side effects of systemic steroids and antibi-
otics will likely grow in the future. A low level of evi-
dence supports the use of culture-directed antibiotics in
patients with chronic rhinosinusitis. A high level of evi-
dence supports the use of nasal saline irrigations. A
high level of evidence demonstrates that topical antifun-
gals are not significantly different in efficacy than saline
controls on CRS outcomes. Although there is insufficient
evidence to support the use of topical corticosteroids in
patients with chronic rhinosinusitis without nasal pol-
yps, a relatively high level of evidence supports the use
of topical steroids as being effective in decreasing the
size of nasal polyps. Additional trials are clearly war-
ranted, particularly larger and better-designed random-
ized, double-blinded, placebo-controlled trials to clarify
the use of topical antibiotics and topical corticosteroids,
particularly budesonide as a nasal irrigation, in patients
with CRS.
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