Advances in Medical and Surgical Therapy
Woodworth BA, Poetker DM, Reh DD (eds): Rhinosinusitis with Nasal Polyposis.
Adv Otorhinolaryngol. Basel, Karger, 2016, vol 79, pp 138147 (DOI: 10.1159/000445151)
Oral Therapeutics for Rhinosinusitis with
Nasal Polyposis
AndrewJ.Thomas JeremiahA.Alt
Division of Head and Neck Surgery, Rhinology-Sinus and Skull Base Surgery Program, Department of Surgery,
University of Utah, Salt Lake City, Utah, USA
Abstract
Oral therapeutics for chronic rhinosinusitis with nasal
polyps (CRSwNP) include oral corticosteroids (OCS), anti-
biotics, antifungals and anti-leukotrienes. Of these treat-
ments, the strongest evidence exists to support the use
of a short course of OCS for treatment of CRSwNP, and
OCS are the most consistently recommended oral thera-
py in practice guidelines. Antibiotics have demonstrated
some utility, which appears more likely related to an anti-
inflammatory rather than antimicrobial effect. The non-
macrolide antibiotics lack sufficient evidence to support
their use, though among this class doxycycline has some
limited evidence of benefit in CRSwNP. Greater evidence
exists for the use of macrolide antibiotics which have
shown reduction of subjective and objective measures of
CRSwNP severity. A short course of a macrolide should be
considered as an option. Oral antifungals are not recom-
mended in the treatment of CRSwNP given disappoint-
ing results and known potential adverse effects, except
in allergic fungal rhinosinusitis where they may play a
role. Leukotriene antagonists have demonstrated some
promise in the treatment of CRSwNP, though studies are
limited, but should be considered a potentially useful
oral therapeutic. The current level of evidence for these
oral therapeutic options for CRSwNP is reviewed in this
chapter. 2016 S. Karger AG, Basel
Introduction
Chronic rhinosinusitis (CRS) is a condition of in-
flammation of the nose and paranasal sinuses
with signs and symptoms lasting greater than 12
weeks [1]. When CRS is associated with mucosal
polyps, it is specifically classified as CRS with na-
sal polyps (CRSwNP) [2]. Nasal polyps are hyper-
plastic growths of the nasal mucosa, which con-
tain primarily type 2 T-helper cell (Th2) inflam-
matory cells and mediators such as eosinophils
and immunoglobulin E (IgE) [3, 4]. Based on this
inflammatory profile of polyps, it has historically
been suggested that CRSwNP may represent a
form of atopic disease. However, no clear link has
been established between the presence of nasal
polyps and atopic disease; the prevalence of
CRSwNP has been shown to be similar between
both atopic and non-atopic patients [5], and only
0.5% of atopic patients are reported to have nasal
polyps [6]. Though many theories exist, the
pathophysiology of CRSwNP remains unclear
and likely multifactorial [7, 8].
Treatment guidelines for CRSwNP from the
American Academy of Otolaryngology, Head and
Neck Surgery (AAO-HNS) recommend topical
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nasal steroid sprays for long-term treatment of
polyps in CRS, with a short course of oral cortico-
steroids (OCS) if there is no response in 3 months
[1]. These guidelines also recommend against
chronic antibiotics for CRSwNP but suggest that
oral antibiotics of the macrolide class may be use-
ful, particularly because of their anti-inflammato-
ry effects. The European position paper on rhino-
sinusitis and nasal polyps 2012 (EPOS 2012) sim-
ilarly supports the use of a short course of OCS,
suggests potential utility of short duration macro-
lide therapy and is unable to conclude about long-
term treatment with antibiotics in CRSwNP due
to limited data [9]. A 2011 Cochrane review on
the use of oral steroids also supports their use for
patients with nasal polyposis [10]. This chapter
focuses on the current level of evidence for oral
therapeutics for the treatment of CRSwNP.
Oral Corticosteroids
Studies evaluating a short course of OCS for
CRSwNP have generally demonstrated improve-
ments in both subjective and objective measures
of disease severity, and their use is supported by
major practice guidelines and systematic reviews
[1, 911]. OCSs are the only medical therapy that
has demonstrated significant improvement in
both subjective and objective olfaction scores
[12]. Here, we will primarily focus our discussion
on the 5 randomized controlled trials (RCTs)
evaluating different regimens of OCS for
CRSwNP, that have been performed within the
last 10 years and provide level 1b evidence to sup-
port their use [1318].
Kroflic et al. [15] performed a RCT of 40 pa-
tients with nasal polyposis in 2006, comparing
the efficacy of topical furosemide and oral
methylprednisolone therapy. Either nebulized
furosemide (6.6 mmol/l solution) or oral methyl-
prednisolone (1 mg/kg/day) was given for 7 days
prior to sinus surgery, and both groups demon-
strated significant improvement in subjective na-
Oral Therapeutics
Woodworth BA, Poetker DM, Reh DD (eds): Rhinosinusitis with Nasal Polyposis.
Adv Otorhinolaryngol. Basel, Karger, 2016, vol 79, pp 138147 (DOI: 10.1159/000445151)
sal obstruction, olfaction and nasal secretions, as
well as polyposis severity by nasal endoscopy. In
a double-blind, randomized, placebo-controlled
trial (DBRCT) by Hissaria et al. [13], 41 patients
with CRSwNP randomized to either oral pred-
nisolone (50 mg/day) or placebo for 14 days.
Symptoms reported on the 31-item Rhinosinus-
itis Outcome Measure as well as objective im-
provement in polyposis severity (nasal endosco-
py and MRI) improved significantly more in the
prednisolone group. Overall, this steroid regi-
men was well tolerated with no serious adverse
reactions. Longer term outcomes after 2 weeks
were not evaluated.
In a prospective casecontrol study by Alobid
et al. [19], patients with CRSwNP were assigned
to a short course of oral prednisone (n= 60) or no
treatment (n= 18). After evaluation at 2 weeks,
the prednisone group then received long-term in-
tranasal budesonide and was re-evaluated at 12,
24 and 48 weeks. All patients demonstrated re-
duced quality of life (QOL) scores on the Medical
Outcome Study Short Form-36 (SF-36) at initial
evaluation. At 2 weeks, the prednisone group
demonstrated significant improvement in QOL,
scores of nasal symptoms (obstruction and sense
of smell) and polyp size score (endoscopy), which
was maintained at the 48-week evaluation. This
study suggests that long-term treatment with in-
tranasal steroids may maintain the benefits of a
short course of oral steroids.
A DBRCT by Kirtsreesakul et al. [14] random-
ized patients with CRSwNP (n= 109) 3:2 to pred-
nisolone (50 mg) or placebo daily for 14 days.
The prednisolone group demonstrated a signifi-
cantly greater peak expiratory flow index, reduc-
tion in nasal polyp size (endoscopy) and im-
provement in nasal symptoms. However, more
severe disease was associated with significantly
less improvement in both subjective and objec-
tive measures. In another 2011 DBRCT, Van Zele
et al. [17] compared the efficacy of oral methyl-
prednisolone to doxycycline in the treatment of
CRSwNP. A total of 47 patients were randomized
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to 20 days of either methylprednisolone taper or
doxycycline or placebo. Methylprednisolone re-
sulted in a significant reduction in symptoms of
nasal congestion, post-nasal drip (PND) and loss
of smell. The OCS group demonstrated signifi-
cant objective reduction in polyp size (endosco-
py) and improved peak nasal inspiratory flow
(PNIF), as well as decreased blood eosinophil
count, IgE level, eosinophilic cationic protein
(ECP; eosinophil degranulation marker) and sol-
uble interleukin (IL)-5R. Despite initial benefit,
both symptoms and polyp size returned rapidly
after discontinuing OCS. Polyp size was no dif-
ferent from baseline or placebo treatment pa-
tients after 12 weeks.
Vaidyanathan et al. [16] further explored the
role of combined oral and topical treatment in a
2011 RCT, which randomized 60 patients with
CRSwNP to either oral prednisolone (25 mg) or
placebo daily for 2 weeks. All patients then re-
ceived long-term topical fluticasone. Similar to
other studies [13], the 2-week course of OCS re-
sulted in significantly reduced hyposmia, reduced
nasal symptom score and improved scores on the
mini Rhinoconjunctivitis Quality of Life Ques-
tionnaire. There was also significant reduction in
polyp size (endoscopy), improved PNIF and re-
duction in serum markers of inflammation and
eosinophil activation compared to placebo treat-
ment. The reduction in polyp size and hyposmia
after prednisolone treatment remained signifi-
cant up to 10 weeks. Prednisolone caused tran-
siently suppressed adrenal function and increased
bone turnover at 2 weeks, but this returned to
normal at 10 weeks. This study demonstrated an
initial 2-week course of OCS followed by topical
steroids is more effective than topical steroids
alone, but the added effect is lost by 28 weeks.
Given the short-term efficacy and minimal ad-
verse effects of a single course of oral steroids, ap-
propriate frequency of repeated OCS courses is
an important question to consider. Leung et al.
[20] determined the threshold at which the risks
of continued medical therapy exceed the risks of
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Woodworth BA, Poetker DM, Reh DD (eds): Rhinosinusitis with Nasal Polyposis.
Adv Otorhinolaryngol. Basel, Karger, 2016, vol 79, pp 138147 (DOI: 10.1159/000445151)
performing surgery, focusing on the economic
impact. The simulated patient in this model was a
CRSwNP patient who experiences the benefits of
a short course of OCS without prior adverse
events. The risk analysis was performed using di-
rect costs (surgery, medical admissions and med-
ications) and indirect costs (morbidity, mortality
and decreased QOL). The threshold number of
courses of OCS at which the risks exceeded those
of endoscopic sinus surgery (ESS) was 0.21/year
(once every 5 years). This threshold was lower for
CRSwNP patients with asthma and Samters tri-
ad, at 0.53/year (every 2 years) and 1.81/year (ev-
ery 6 months), respectively. The society analysis,
focusing on the most economical use of resourc-
es, demonstrated a higher threshold for surgery:
once every 2 years (CRSwNP), 1 year (CRSwNP/
asthma) or 5 months (Samters). For simplicity,
responsible resource utilization and bias against
surgery, the authors recommend considering en-
doscopic sinus surgery (ESS) for patients requir-
ing OCS more frequently than once every 2 years
for CRSwNP patients, yearly for CRSwNP/asth-
ma or twice per year for patients with Samters
triad.
The 2013 evidence-based review with recom-
mendations (EBRR) on OCS in CRS by Poetker
et al. [11] makes a strong recommendation for
the use of OCS in the short-term management of
CRSwNP. Similarly, the EPOS 2012 European
recommendations for treatment of CRSwNP
conclude that systemic corticosteroids offer clear
though short-lived benefits in the treatment of
CRSwNP [9]. The long-term efficacy of an oral
steroid taper followed by maintenance with top-
ical nasal steroids appears to be approximately
812 weeks [11]. Overall, there is good evidence
for the use of oral steroids for short-term man-
agement of CRSwNP and the decision of when to
progress to ESS after repeated OCS treatments
should be individualized, considering patient
factors such as presence of asthma and Samters
triad.
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Antibiotics
Despite limited evidence, antibiotics are com-
monly prescribed for the treatment of CRSwNP.
While CRSwNP has historically been considered
a Th2-driven atopic disease process, more recent
research has demonstrated that the distinction
between the etiologies of these CRS entities is not
clearly defined [21, 22]. Some studies have sug-
gested a microbial role in the pathogenesis of
CRSwNP and possible utility of antimicrobials as
therapeutics. Theories include the superantigen
hypothesis, in which colonizing Staphylococcus
aureus secrete super-antigens that then lead to in-
creased IgE and polypoid change [23]. Increased
mucosal permeability has been demonstrated in
CRS as well as a robust immune response in nasal
polyps containing B lymphocytes and immuno-
globulins [24, 25]. Bacteria may increase mucosal
permeability and susceptibility to environmental
triggers of inflammation or cause a greater local
immune response due to an already compro-
mised mucosal barrier. This could induce immu-
noglobulin class-switch and production, activa-
tion of eosinophils and formation of polyps [25].
However, there is no clear microbial etiology for
CRSwNP and non-macrolide antibiotics have
lacked utility.
Non-Macrolide Antibiotics
Van Zele et al. [17] randomized patients with
CRSwNP to placebo (n= 19) or doxycycline (n=
14) (200 mg on day 1, then 100 mg daily) for 20
days. Doxycycline resulted in polyp size reduc-
tion that persisted up to 12 weeks after dosing, as
well as a significant reduction in PND after
2 weeks. However, there was no significant im-
provement in PNIF or in symptom scores of nasal
congestion, rhinorrhea or loss of smell. The
mechanism for this benefit (antimicrobial versus
anti-inflammatory) is unclear. Based on the re-
sults of this study, 3 other RCTs (level 1b evi-
Oral Therapeutics
Woodworth BA, Poetker DM, Reh DD (eds): Rhinosinusitis with Nasal Polyposis.
Adv Otorhinolaryngol. Basel, Karger, 2016, vol 79, pp 138147 (DOI: 10.1159/000445151)
dence), and 2 observational cohort studies (level
4 evidence), the EBRR by Soler et al. [26] recom-
mends considering short-term non-macrolide
antibiotics as an option in the treatment of CRS,
but with caution that the limited reported bene-
fits may be outweighed by the typical side effects
of antibiotics, cost and societal considerations
such as the development of antibiotic resistance.
For CRSwNP specifically, the evidence for use
non-macrolide is even weaker (single level 1b
study) and the risks and costs may outweigh any
potential benefit. There is currently no evidence
for treatment of CRSwNP using non-macrolide
antibiotics 3 weeks.
Macrolide Antibiotics
Macrolides have anti-inflammatory properties
and are effective in treating conditions associated
with chronic airway inflammation, such as dif-
fuse panbronchiolitis and cystic fibrosis [27, 28].
Clarithromycin has been shown to decrease the
production of pro-inflammatory cytokines (IL-5
and IL-8) in nasal mucosa of patients with CRS
[29], and to decrease nuclear factor-kappa B ac-
tivity [30]. Erythromycin and roxithromycin
have also been demonstrated to increase neutro-
phil apoptosis [28].
A DBRCT by Wallwork et al. [27] in 2006 in-
vestigated macrolides as treatment for CRS, but
did not separate CRSwNP from CRSsNP. This
study found significant improvements in SNOT-
20 scores, nasal endoscopy, saccharine transit
time, as well as reduced IL-8 levels in lavage fluid,
suggesting the utility of this treatment (150 mg
roxithromycin daily for 3 months). A DBRCT by
Haxel et al. [31] randomized patients to 3 months
of low-dose erythromycin treatment (250 mg dai-
ly; n= 29) or to placebo (n= 29) starting 2 weeks
after ESS for CRS. All patients received topical na-
sal fluticasone daily. There was no significant dif-
ference in ECP in nasal secretions, subjective se-
verity of nasal disease, olfaction, saccharin transit
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time or in SNOT-20 scores. Significant improve-
ment in endoscopy scores at the end of the medi-
cation trial was seen for the erythromycin group,
but this was nonsignificant at follow-up 12 weeks
later.
A 2014 RCT by Varvyanskaya and Lopatin
[32] randomized 66 patients with CRSwNP to no
oral medication (controls) or to clarithromycin
250 mg daily for either 12 or 24 weeks. All patients
also received topical mometasone furoate. SNOT-
20 scores, nasal resistance and nasal endoscopy
scores of polyposis were all significantly im-
proved in the macrolide-treated groups com-
pared to controls. LundMackay scores of disease
severity on CT improved from pre-op to post-op
in all groups, but at 24 weeks there was a signifi-
cantly greater improvement in the 24-week mac-
rolide group compared to controls. Both macro-
lide treatment groups had significantly reduced
ECP levels at 24 weeks after ESS, whereas levels of
ECP in control patients increased up to approxi-
mately 3 times baseline at 24 weeks; macrolides
may control eosinophilic inflammation and per-
haps thereby decrease polyp recurrence.
The above RCTs focused on macrolide treat-
ment following ESS, rather than as primary med-
ical therapy, and only one study specifically fo-
cused on CRSwNP patients [32]. The efficacy of
macrolide treatment has been demonstrated to be
significantly less for patients with polyps, and is
improved significantly after polypectomy for pa-
tients with multiple polyps [33]. Pre-operative
macrolides may also delay polyp recurrence after
surgery, as patients treated with clarithromycin
500 mg twice daily for 8 weeks prior to ESS dem-
onstrate significantly less endoscopic evidence of
disease recurrence 12 months post-operatively,
compared to patients undergoing ESS with no
pre-treatment [34]. In prospective cohort studies,
patients with CRSwNP treated with clarithromy-
cin for 8 weeks have demonstrated significantly
decreased symptoms of nasal obstruction, smell
dysfunction, PND and rhinorrhea, as well as re-
duced polyp size (CT and endoscopy) and de-
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Woodworth BA, Poetker DM, Reh DD (eds): Rhinosinusitis with Nasal Polyposis.
Adv Otorhinolaryngol. Basel, Karger, 2016, vol 79, pp 138147 (DOI: 10.1159/000445151)
creased levels of IL-8 in nasal fluid [35, 36]. Co-
hort studies using roxithromycin and erythromy-
cin have also demonstrated subjective and
objective benefit, supporting the class effect of the
macrolides [37, 38].
Based on the available evidence from a single
RCT focused on macrolide treatment in patients
with CRSwNP [32] and observational cohort
studies, macrolides appear to significantly reduce
symptoms as well as objective polyp disease. A
majority of the evidence is specifically applicable
to the post-ESS setting, rather than as primary
medical management. Patients with low IgE lev-
els may obtain more benefit from macrolide ther-
apy than atopic patients [27], and patients with
multiple polyps may experience more benefit af-
ter undergoing polypectomy [33]. Benefits must
be weighed against potential harms. Though
there were no significant adverse events reported
in the studies evaluated here for CRSwNP, mac-
rolides have been associated with potential risk of
arrhythmia, liver function abnormalities, ototox-
icity and the potential for development of antibi-
otic resistance [26, 39]. Particular caution is rec-
ommended in patients at risk of cardiac arrhyth-
mia [39]. Adverse effects reported in studies of
CRS patients were mild to moderate GI distur-
bance and rash [26, 40]. The more extensive pul-
monary literature on the long-term use of macro-
lides has described increased risk of bacterial re-
sistance and some increased risk of hearing
impairment (RR 1.168; 95% CI 1.0301.325) [41].
Antifungals
Past attempts to broadly define the underlying
pathophysiology of CRS focused on the role of
fungus. The fungal hypothesis suggested that eo-
sinophilic inflammation of the sinonasal mucosa
resulting from environmental fungi, particularly
Alternaria fungi, was responsible for the develop-
ment of CRS [4244]. Despite some early enthu-
siasm for the potential utility of antifungals for
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CRS [44], subsequent studies have cast doubt on
the utility of antifungal therapy [45, 46]. Fungi
have been demonstrated not-only in mucosa of
patients with CRS, but in nearly all healthy con-
trol patients as well, and treatment of CRS with
antifungals has had disappointing results [46, 47].
The use of oral antifungals for CRS is discour-
aged consistently throughout recent systematic
reviews and guidelines, including the most recent
AAO-HNS clinical practice guidelines for adult
sinusitis, a 2013 EBRR by Soler et al. [26], and the
2012 EPOS guidelines [1, 9]. Harm and cost ap-
pears to outweigh potential benefits. There has
been some lower level evidence for benefit of oral
antifungals (primarily itraconazole and ketocon-
azole) in the treatment of CRS (primarily AFRS)
reported in mostly retrospective case series and
using non-validated outcome measures [48].
Thanasumpun and Batra [48] performed a sys-
tematic review of 27 of these level 4 (n= 15) and
5 (n = 12) evidence studies, in addition to one
single RCT by Kennedy et al. [49] (level 1 evi-
dence), and found significant symptom improve-
ment with oral antifungal therapy and some ob-
jective improvement in select studies, with ele-
vated liver enzymes (1720%) being the most
common adverse event reported. Higher level
evidence was specifically evaluated in a Cochrane
review on the efficacy of oral and topical antifun-
gal agents for the treatment of CRS performed by
Sacks et al. [50] in 2011, which identified 6 ran-
domized placebo-controlled trials addressing
this question. This meta-analysis identified no
significant benefit to antifungal therapy in CRS
and a significantly increased incidence of adverse
events in the antifungal groups. Only the DBRCT
by Kennedy et al. [49] specifically investigated
systemic oral antifungal treatment (not topical),
and this trial did not distinguish CRSwNP from
CRSsNP.
Oral antifungal treatments are discouraged
for CRSwNP given the limited data available,
negative results described in the meta-analysis
and trials above, as well as known potential ad-
Oral Therapeutics
Woodworth BA, Poetker DM, Reh DD (eds): Rhinosinusitis with Nasal Polyposis.
Adv Otorhinolaryngol. Basel, Karger, 2016, vol 79, pp 138147 (DOI: 10.1159/000445151)
verse effects [4951]. There is, however, likely an
exception in the case of allergic fungal sinusitis
(AFS). Patients with AFS treated with a month of
preoperative itraconazole prior to surgery have
significantly improved symptoms (SNOT-20),
objective disease severity (CT and endoscopy
scores), and fungal load (cultures) compared to
patients treated with surgery alone [52]. The po-
tential harms of oral antifungal therapy should be
considered carefully, particularly hepatic toxicity
with elevated liver function tests reported in 4%
of patients, unpleasant side effects including nau-
sea and fatigue, as well as the potential for drug
interactions with itraconazole [9]. These recom-
mendations do not apply to invasive fungal si-
nusitis which is a distinct and dangerous disease
process treated with surgical debridement and
antifungal therapy.
Leukotriene Antagonists
Leukotrienes (LTs) are inflammatory mediators
formed in the breakdown of arachidonic acid by
5-lipoxygenase (5-LO), and are synthesized in a
number of inflammatory cell types including eo-
sinophils and mast cells [53]. Leukotriene C4 syn-
thase (LTC4S) activity is specifically required for
the production of the cysteinyl leukotrienes
(CysLTs) [9]. The CysLTs increase mucous pro-
duction, cause mucosal edema, release of mast
cell cytokines, and promote chemotaxis of neu-
trophils and eosinophils [5456]. The CysLTs
have been implicated in the pathogenesis of
CRSwNP [9]. Increased arachidonic acid metab-
olism [57, 58] and levels of both CysLTs and
CysLT receptors have been demonstrated in the
nasal mucosa of patients with CRSwNP [55, 59
61]. Levels of 5-LO, LCT4S, and the CysLTs have
been shown to be significantly increased in nasal
tissue of patients with CRSwNP relative to
CRSsNP and controls [62]. Inhibition of LT activ-
ity, either by antagonism of the LT receptor with
montelukast, zafirlukast or pranlukast (competi-
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tive antagonists of the CysLT1 receptor; LTA), or
inhibition of CysLT synthesis with zileuton (se-
lective 5-LO enzyme inhibitor) has therefore been
considered as a potential treatment for CRSwNP.
LT antagonists (LTAs) have been used as ad-
junctive treatments for CRSwNP [55], though
their use is not supported by recent practice
guidelines. There is no recommendation regard-
ing LTAs in the 2015 AAO-HNS practice guide-
lines for CRSwNP, and the EPOS 2012 guidelines
specifically recommend against the use of LTAs
(Grade of recommendation A) [1, 9]. However, 2
recent literature reviews suggest a benefit of LTAs
for both symptoms and objective measures of
CRSwNP severity [55, 56]. Wentzel et al. [56]
identified 2 placebo-controlled RCTs, 3 non-pla-
cebo controlled RCTs and 7 case series that evalu-
ated LTA treatment either alone or as adjunct
therapy for CRSwNP. Smith and Sautter [55] re-
viewed 4 of the same trials, as well as an in-vitro
study which activated mast cells with CysLT then
blocked this activation with a combination of
montelukast (LTA) and zileuton (5-LO inhibitor)
[56]. Overall, LTAs were found to significantly
decrease symptom severity as well as polyposis
and inflammatory mediators compared to place-
bo. Addition of an LTA to topical and oral steroid
therapy also demonstrated significant improve-
ment in individual symptoms compared to topi-
cal/oral steroid alone, but this benefit was lost
soon after discontinuing the LTA [63].
The 2 placebo controlled trials were performed
by Schper et al. in 2011 and Pauli et al. in 2007.
Schper et al. treated CRSwNP patients (n= 24)
with 10 mg montelukast daily for 6 weeks and
evaluated the same patients with placebo in a
crossover design, half randomized to placebo be-
fore treatment and half after. This study found a
significant improvement with montelukast, from
baseline and compared to placebo, for nasal
symptoms, objective findings on rhinoscopy, na-
sal airway flow and olfaction. Montelukast was
also associated with significant decreases in in-
flammatory mediators on nasal lavage and for
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Woodworth BA, Poetker DM, Reh DD (eds): Rhinosinusitis with Nasal Polyposis.
Adv Otorhinolaryngol. Basel, Karger, 2016, vol 79, pp 138147 (DOI: 10.1159/000445151)
both peripheral and nasal eosinophils. No ad-
verse effects were noted during the trial [64]. Pau-
li et al. randomized CRSwNP patients to either
10mg montelukast daily (n= 20) or placebo (n=
10) for 4 weeks and found a significant improve-
ment in nasal symptoms, practical problems,
headaches and non-nasal symptoms with monte-
lukast compared to placebo, though no signifi-
cant change in nasal ECP or polyp size were iden-
tified [65].
An RCT by Vuralkan et al. [66] in 2011 ran-
domized 50 patients with nasal polyposis to post-
FESS treatment with either 10 mg montelukast
daily (n = 25) or 400 mcg mometasone furoate
nasal spray twice daily (n= 25) for 6 months. Both
treatment groups demonstrated significant post-
operative improvement in SNOT-22 scores and
the LundMackay CT score at 6 months, but
there was no significant difference between the
groups. However, the incidence of polyp recur-
rence reported in the LTA treatment group (48%)
was significantly greater compared to the nasal
steroid group (20%). A similar study by Mostafa
et al. [67] in 2005 did not identify any difference
in recurrence rate between patients with nasal
polyps treated post-ESS with either 10 mg monte-
lukast daily (n= 25) or 400 mcg beclomethasone
nasal spray daily (n = 20) at 1 year follow-up,
though similar and significant improvement in
symptom scores were seen throughout the study
period in both groups.
Almost all studies have evaluated CysLT re-
ceptor antagonists, particularly montelukast, and
there is limited data available on the utility of
5-LO inhibitors (zileuton). Two studies used
zileuton or zafirlukast as treatment for CRSwNP
and found improvements in symptoms and de-
crease in polyposis reported similar to studies us-
ing montelukast [68, 69]. A DBRCT crossover
study by Dahlen et al. [70] in 1998 also demon-
strated reduction of nasal symptoms such as ol-
factory dysfunction and rhinorrhea, and increase
in PNIF, when zileuton was added to existing
medical therapy of inhaled and/or oral steroid in
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treatment of patients with aspirin-intolerant
asthma. The limited research using zileuton in
CRSwNP precludes recommendations for its use
at this time, though the theoretical utility is an in-
teresting point raised by Smith and Sautter [55].
They suggest that given an observed increase in
CysLT2 receptor in the nasal mucosa of patients
with CRSwNP, but a lack of antagonist action of
montelukast, pranlukast, and zafirlukast at this
receptor (all act on CysLT1), inhibition of CysLT
synthesis by 5-LO inhibition (zileuton) may be a
better strategy. Cell culture experiments suggest
the possibility for some combined benefit of
CsyLTA and 5-LO inhibitors [55].
Though data on the use of LTAs for CRSwNP
is limited, there is evidence from 2 RCTs that
demonstrate a significant improvement with
montelukast relative to placebo in subjective
symptoms, objective findings of disease severity,
as well as immunologic evidence of disease. Com-
bination therapy with an LTA and oral or topical
steroid demonstrates unclear benefit over single
modality treatment. Though no major adverse ef-
fects were reported in the literature reviewed
here, LTAs have been associated with skin rash,
behavior change, tremor or potentially a para-
doxical worsening of sinus symptoms and asthma
[9, 65]. Specifically, montelukast has shown min-
imal adverse effects, while zileuton is associated
with liver function test abnormalities and poten-
tial for hepatotoxicity and zafirlukast is known to
decrease warfarin clearance [66, 67]. The benefit
of LTA therapy appears to be lost soon after dis-
continuation [56], but long term treatment ap-
pears relatively safe. Overall, LTAs have demon-
strated some utility in the treatment of CRSwNP,
and additional research is indicated to further de-
fine the role of these drugs as well as 5-LO inhib-
itors as therapeutics for CRSwNP.
Conclusions
While the mainstay of treatment for CRSwNP re-
mains topical nasal steroids, oral therapeutics can
be considered as a useful adjunct for patients with
an inadequate response to topical therapy. The
strongest evidence from multiple RCTs supports
the use of a short course of OCS for short-term
improvement in both subjective and objective
measures of disease severity. There is also evi-
dence suggesting the utility of macrolide antibiot-
ics, which have anti-inflammatory effects, for re-
ducing symptoms and polyp burden. This is re-
flected in the major practice guidelines for the
treatment of CRSwNP, which endorse the use of
OCS and suggest potential utility of macrolide
class antibiotics. Although the evidence is less ro-
bust, LTAs have also demonstrated promise and
have a favorable safety profile (particularly mon-
telukast) for potential longer term treatment.
Non-macrolide antibiotics and oral antifungals
lack evidence of benefit for treatment of CRSwNP.
The exception being in AFS where oral antifun-
gals likely have a positive effect by reducing fun-
gal load and the resulting allergic response in the
sinuses.

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