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24 Leukotriene Modiers forRecalcitrant Chronic Rhinosinusitis
Signicant reduction in symptom
scores in both groups.
Greater improvement in itching,
postnasal discharge, and headache
in montelukast group.
Greater improvement in smell
disturbances and obstruction in
steroid group
Signicant improvement in
symptom score and polyp
eosinophilia in the perineal allergies
group
Signicant improvement in
symptom scores.
Signicant decrease in polyposis
symptom scores (headache, facial
pain, and sneezing) with
montelukast. No signicant effect
on nasal blockage, hyposmia, or
nasal discharge b/w groups.
Effects were not maintained
VAS symptom
score
ICSD symptom
score, polyp
eosinophilia
Symptom score,
polyposis stage
ICSD Signicantly greater reduction in
295
(continued)
4weeks after stopping montelukast
Signicant decrease in CT score and
nasal polyp score at 6 and
12months
Nasal polyp
score, peripheral
blood
eosinophilia, CT
score
daily×1year vs.
Beclomethasone dipropionate
spray (200 ⎧g) BID×1year
Montelukast Montelukast (10mg)
CRSwNP
postoperatively
RCT:
Prospective,
double blind
n=40
Mostafa
(2005)
[19]
daily×3months as add-on
therapy to INC
Montelukast Montelukast (10mg)
CRSwNP
(excluded
seasonal
Prospective
case series
n=24
Kieff
(2005)
[23]
daily×4weeks vs.
Placebo×4weeks
allergies)
CRSwNP Montelukast Montelukast (10mg)
DBPCT
Pauli
CRSwNP Montelukast Two-week oral steroid taper plus
n=30
RCT
(2007)
[28]
Stewart
montelukast (10mg)
daily+INC×8weeks vs.
Two-week oral steroid taper plus
INC×8weeks
Montelukast Montelukast (10mg) daily and
CRSwNP and
n=35
(2008)
[21]
Prospective
Nonaka
intranasal uticasone propionate
(200 ⎧g) daily×1year
asthma
case series
n=20
(2010)
[22]
296
Conclusion
Signicant reduction in SNOT
Outcome
measures
SNOT, polyp
scores in both groups but no
signicant difference b/w the
groups. Signicant reduction in CT
score in both groups. Signicantly
more recurrences with montelukast
Signicant improvement in nasal
symptom score with montelukast.
No signicant changes in symptoms
with placebo. Signicant
improvement in edema, nasal
grades, CT
score,
eosinophils in
peripheral blood
and polyp tissue
Nasal symptom
scores,
rhinomanometry,
olfactometry,
nasal lavage
airow, inammatory mediators,
and eosinophils in nasal secretion
with montelukast
sense of smell, sneezing, headache,
and overall score with montelukast.
No statistical difference in
discharge, facial pain, or nasal
blockage between groups
procedure
ICSD Signicant improvement in the
A. Ganju et al.
Type Disease Drug Intervention
Study
Table 24.1 (continued)
daily×6months vs. Intranasal
mometasone furoate (400 ⎧g)
BID×6months
Montelukast Montelukast (10mg)
CRSwNP
postoperatively
RCT
n=50
Vuralkan
(2011)
[18]
daily×6weeks vs.
Placebo×4weeks
Montelukast Montelukast (10mg)
CRSwNP
postoperatively
and asthma
SBPCT
Crossover
n=24
Schaper
(2011)
[25]
taper×2weeks+INC×8weeks
vs. PO steroid
taper×2weeks+INC and
montelukast (10mg)
daily×8weeks
CRSwNP Montelukast PO steroid
RCT:
Prospective
n=40
Suri
(2015)
[20]
24 Leukotriene Modiers forRecalcitrant Chronic Rhinosinusitis
All patients: SNOT-20 and
Lund-Kennedy endoscopy scores
with montelukast were signicantly
lower than the scores without
montelukast therapy
Hx of AERD: No signicant
improvement
Hx of asthma: Signicant
Comparison of
SNOT-20 and
endoscopic
scores at the
single time point
improvement in both categories
immediately
prior to a lapse
in therapy with
scores at the
visit when the
patient rst
Signicantly reduced T5SS, NPS,
and LMK score in both groups
reported
noncompliance
Total ve-
symptom score
without signicant differences
between the groups
[T5SS], nasal
polyp score
[NPS],
Lund-Mackay
[LMK] score,
Montelukast and aspirin
olfactometry
SNOT,
297
desensitization had signicantly less
polyp recurrences compared to INS
after >12months.
Montelukast showed signicant
improvement in nasal symptoms
endoscopic exam
in montelukast therapy for
1month or longer
Montelukast Review of patients with a lapse
CRSwNP
postoperatively
Retrospective
review
n=52
Yelverton
(2016)
[27]
intranasal mometasone furoate
(200⎧g) BID×1year vs.
Intranasal mometasone furoate
(200⎧g) BID×1year
Montelukast Montelukast (10mg) daily and
CRSwNP
postoperative
RCT:
Prospective,
randomized
n=72
Van
Gerven
(2018)
[17]
aspirin desensitization
Montelukast Montelukast daily or INS or
AERD
postoperative
Retrospective
study
San Nicolo
(2020)
n=61
[26]
DBPCT double-blind placebo-controlled trial; AERD aspirin-exacerbated respiratory disease; QID four times per day; INC intranasal corticosteroids; PO oral;
VAS visual analog scale; BID two times per day; CRSwNP chronic rhinosinusitis with nasal polyposis; NIPF nasal inspiratory peak ow; ICSD International
Classication of Sinus Disease; RCT randomized controlled trial; SBPCT single-blind placebo-controlled trial; SNOT Sino-Nasal Outcome Test
298
A. Ganju et al.
Montelukast is a well-known therapeutic in asthma management. Three studies
investigated nasal symptoms and polyposis in a cohort with both CRSwNP and
asthma. One study reviewed a cohort with just aspirin-exacerbated respiratory disease (AERD) [22, 24–26]. Ragab etal. found signicant symptomatic nasal relief in
aspirin-tolerant asthma (ATA) but not in AERD, while none of the patients had
improvement on objective outcome measures [24]. When accounting for AERD,
Yelverton et al. also did not nd signicant nasal changes with montelukast,
although San Nicolo etal. demonstrated symptomatic improvement and less polyp
recurrence in a small cohort [26, 27]. Nonak etal. found general improvement in CT
and nasal polyp scores with montelukast added to INC, and Schaper etal. found
improvement in edema, inammatory mediators, and symptoms with montelukast
alone [22, 25]. In studies that were not fully composed of asthma patients but
accounted for the demographic within both treatment arms, there was no signicant
difference in nasal symptoms or polyp score in those with or without asthma [14].
There are only a few randomized controlled trials studying montelukast for the
treatment of nasal polyposis. Two placebo-controlled studies showed signicant
improvement in symptom score with montelukast alone compared to placebo [25,
28]. Two studies showed similar improvement in symptoms with intranasal cortico-
steroids when compared to montelukast [18, 19]. A meta-analysis of three RTCs
evaluating the addition of montelukast to standard INC therapy found no signicant
additive benet [16, 17, 20, 21].
Only three studies examined the alternative leukotriene receptor antagonist zafirlukast or the lipoxygenase inhibitor zileuton in relation to nasal symptoms in
CRSwNP and AERD.Dahlen etal. conducted a double-blind, placebo-controlled
crossover trial with zileuton in AERD and showed a signicant improvement in the
sense of smell and rhinorrhea [29]. Ulualp etal. retrospectively examined 15 AERD
patients who received zarlukast or zileuton post-polypectomy, revealing symptomatic and endoscopic improvement [30]. Lastly, Parnes etal. conducted a prospective
trial of zarlukast or zileuton in CRSwNP with similar results as above [31].
Overall, high-quality evidence involving leukotriene modiers in CRSwNP is
lacking. Leukotriene antagonists could potentially benet patients who have failed
or are intolerant to INC as studies have shown superiority to placebo and effects
similar to INC [14]. Current evidence suggests that montelukast does not have additive benet to standard of care with INC.
Additionally, although montelukast is a well-known therapeutic in AERD, there
is insufcient evidence to support its use for improving nasal symptoms and polyps;
further investigations are necessary. It appears to be more advantageous for the
treatment of asthma in AERD.The European EPOS2020 steering group published
recommendations based on previous randomized controlled trials, stating that they
did not advise the addition of montelukast to INC in CRSwNP but may consider its
use in situations where INC have failed or are not tolerated. Further studies are
needed to determine the exact benet in this setting [16].
Side effects should be considered when determining the therapeutic benet of
leukotriene antagonists. In 2020, the FDA released a drug safety communication
requiring a boxed warning on montelukast to describe the risk of neuropsychiatric
24 Leukotriene Modiers forRecalcitrant Chronic Rhinosinusitis
299
events. Therefore, leukotriene antagonists are only recommended to patients who
have suboptimal response or intolerance to alternative therapeutics in asthma and
allergic rhinitis [6]. This recommendation should furthermore be applied to its use
in CRSwNP.Zileuton requires monitoring of liver function tests due to the risk of
hepatotoxicity and monitoring of certain drug plasma concentrations [32].
Conclusions
Leukotriene receptor antagonists may have a role in the management of refractory
chronic rhinosinusitis, but current evidence regarding their efcacy is lacking, with
the current body of literature demonstrating conicting data or showing minimal to
no benet from the addition of this class of medications.
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301
Biological Treatment forChronic
Rhinosinusitis withNasal Polyposis
JosephK.Han andDafnaGershnabelMilk
Key Points
• Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a challenging, difcult-
to- treat disease with a signicant impact on the patient’s quality of life (QOL)
and well-being.
• New insights on chronic rhinosinusitis (CRS) pathophysiology have revealed
that it is a heterogeneous condition with several phenotypes and pathophysiological mechanisms. These insights have led to a shift towards endotype-driven
management of CRS.
• The common endotype of CRSwNP among Caucasian patients is type 2
inammation.
• In CRSwNP, the term “biological medications” refers to monoclonal antibodies
targeting specic type 2 inammatory mediators.
• The implementation of biological medications to the treatment scheme of
CRSwNP is considered a “game changer” in the management of severe type 2
CRS, with signicant improvement in patients’ subjective and objective factors.
25
J. K. Han (*)
Division of Rhinology & Endoscopic Sinus and Skull Base Surgery,
East Virginia Medical School, Norfolk, VA, USA
e-mail: hanjk@evms.edu
D. G. Milk
Department of Otolaryngology Head and Neck Surgery, Eastern Virginia Medical School,
Norfolk, VA, USA
Department of Otolaryngology Head and Neck Surgery, Meir Medical Center,
Kfar Saba, Israel
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
J. T. Lee et al. (eds.), Advances in Surgical and Medical Interventions for
Recalcitrant Chronic Rhinosinusitis,
https://doi.org/10.1007/978-3-031-89191-5_25
303
304
J. K. Han and D. G. Milk
Background
In the Western world, most patients with CRSwNP show a type 2 inammatory
signature [1]. Type 2 inammation is characterized by the activation of both innate
and adaptive inammatory cells: group 2 innate lymphoid cells (ILC2s), mast cells,
and T helper 2 lymphocytes. This leads to the release of type 2 cytokines (IL-5,
IL-13, and IL-4), eosinophil activation, and IgE formation [2] (Fig.25.1).
Type 2 CRS is associated with severe sinus disease that is recalcitrant to standardof- care medical treatment and with prompt polyp recurrence following ESS, leading
to multiple operations. It is also associated with comorbidities that share similar
inammatory pathways, such as asthma and aspirin-exacerbated respiratory disease
(AERD) [3].
In the last decade, monoclonal antibodies targeting specic type 2 inammatory
mediators were developed to treat type 2 diseases such as asthma and atopic dermatitis. Their success in controlling these diseases has led to further research and
Fig. 25.1 Type 2 inammatory pathway inside the sinonasal cavity and biological mechanism of
action (with permission from Claus Bachert). DC Dendritic cell, ECP eosinophil cationic protein,
EDN eosinophil-derived neurotoxin, Eos eosinophils, EPO eosinophil peroxidase, IL-4Ra IL-4
receptor a, TSLP thymic stromal lymphopoietin
25 Biological Treatment forChronic Rhinosinusitis withNasal Polyposis
305
adaptation of the medications to treat CRSwNP.Three monoclonal antibodies are
currently approved by the Food and Drug Administration (FDA) and the European
Medicines Agency (EMA) for patients with uncontrolled severe CRSwNP, and
more monoclonal antibodies are expected to be approved in the future.
Patient Selection
The currently accepted treatment algorithm, supported by several published guidelines, suggests that biologics are indicated for patients with uncontrolled type 2
CRS, despite appropriate medical treatment and surgical failure [3–5]. The term
“appropriate medical treatment” requires further clarication. A recently published
international survey among otolaryngologists found that most participants (73%)
would prescribe biologics in case of failure of topical steroidtherapy postoperatively [6]. Fokkens etal. recommend considering biologics in adult patients with
CRSwNP who have a history of previous ESS or in patients who are unt to undergo
surgical intervention, as well as three of the ve described characteristics: (1) presence of type 2 eosinophilic inammation, (2) regular need for systemic corticosteroids or contraindication to systemic steroids, (3) signicant impact of CRSwNP on
quality of life, (4) loss of sense of smell, and/or (5) comorbid asthma [5]. These
criteria are listed in Fig.25.2.
*Adult paent with CRS with bilateral nasal polyps
and
*History of previous ESS/ paent is not fit for surgery
and
*Three of the following characteriscs:
1. Presence of type 2 inflammaon: ssue eosinophils ≥10/HPF
or blood eosinophils ≥150 cells/μL or total IgE ≥100 IU/mL
2. Regular need for systemic corcosteroids (≥2 courses per
year OR >3 months low dose steroids) or contraindicaon to systemic
steroids
3. Significant impact on QOL (SNOT-22 score ≥40)
4. Loss of smell (anosmic on smell test)
5. Comorbid asthma (asthma needing regular inhaled
corcosteroids)
Fig. 25.2 Eligibility criteria for biological therapy [5]