Nasal Polyps:

P a t h o g e n e s i s an d
Tre a t m e n t I m p l i c a t i o n s
Michael A. DeMarcantonio, MD, Joseph K. Han, MD*

KEYWORDS
! Sinusitis ! Asthma ! Unified airway
! Allergy ! Rhinosinusitis ! Polyp

Key Points: NASAL POLYPS: PATHOGENESIS AND TREATMENT IMPLICATIONS

! Nasal polyp (NP) is the end product of chronic rhinosinusitis (CRS).

! NPs are created through multiple inflammatory or infectious pathways.
! All types of CRS have the potential to develop NPs, given enough time and insult.
! Medical treatment depends on the pathogenesis of NPs.
! Surgical removal of inflammatory cell and mediators followed by medical treatment is likely
to have the best success in patients with severe nasal polyposis.
! Evaluation of allergy, whether it is negative or positive, is important in the management of
patients with nasal polyposis.

NPs represent a common clinical end point for a myriad of inflammatory disease
processes involving the paranasal sinuses. NP is common, with 1% to 4% of the
general population having evidence of an NP on autopsy.1 However, not everyone
with NP develops clinical symptoms because only a portion of population becomes
symptomatic, with a yearly incidence of 0.627 per 1000 people.1 Men seem to
outnumber women (2:1), with the overall incidence increasing in both sexes with
age. Even though these numbers of individuals with NP are small compared with
that of other more common chronic illnesses, such as hypertension, the overall effect
of NP should not be underestimated. In fact, NPs have been shown to have a signifi-
cant detrimental effect on the quality of life, which is similar in severity to chronic
obstructive pulmonary disease.2

The authors have nothing to declare.

Department of Otolaryngology–Head and Neck Surgery, Eastern Virginia Medical School, 600
Gresham Drive, Suite 1100, Norfolk, VA 23507, USA
* Corresponding author.
E-mail address: hanjk@evms.edu

Otolaryngol Clin N Am 44 (2011) 685–695

doi:10.1016/j.otc.2011.03.005 oto.theclinics.com
0030-6665/11/$ – see front matter ! 2011 Elsevier Inc. All rights reserved.
686 DeMarcantonio & Han

CLINICAL PRESENTATION AND DIAGNOSIS

When discussing trends in clinical presentation, the diversity of patients with NPs must
always be respected, and broad generalizations should be avoided. Nevertheless,
trends in clinical complaints have been shown when comparing patients with CRS
with polyps with those without evidence of polyps. Patients with NPs are more likely
to complain of a constellation of symptoms, including diminished olfaction, headache,
and postnasal drip.3 In addition, symptoms are more likely to be described as bilateral
in 80% to 90% of patients.4 Although a thorough clinical history taking is invaluable,
the gold standard for diagnosis of NPs remains endoscopy.5 In an effort to quantify
endoscopic findings, multiple staging systems have been proposed. The utility of
these systems lie primarily in their ability to allow for preinterventional and postinter-
ventional comparison. Lund and Mackay6 used a 3-tier system with scoring as follows:
0, no polyps; 1, confined to middle meatus; and 2, beyond middle meatus. Lildholdt
and colleagues7 used a slightly varied system to assess the effect of multiple treat-
ment methods. The 4-point system developed used the upper and lower edges of
the inferior turbinate as a landmark to describe polyp extension. The highest score
available extended to the inferior edge of the inferior turbinate, essentially contacting
the floor and filling the nasal cavity. To assess these systems and several new
methods, Johansson and colleagues5 evaluated interobserver and intraobserver vari-
ability in a well-designed clinical study. The Lildholdt system was found to provide
good repeatability and less interexaminer variability in comparison with the Lund-
Mackay scoring system. Of note, researchers have shown poor reliability or correlation
between patients’ recorded visual analog scores for nasal obstruction and the objec-
tive polyp burden regardless of the scoring system. Although objective measures are
needed for treatment studies, this lack of correlation with symptoms highlights the
weakness of using staging systems in clinical practice.

IMAGING FOR NASAL POLYPS

It is undeniable that computed tomographic (CT) imaging has become an essential

tool for the diagnosis and surgical management of sinusitis. Classically, CT scans of
sinuses in patients with NP are described as possessing polypoid masses associated
with partial or complete opacification of paranasal sinuses with infundibulum
widening.8 With respect to its use as a diagnostic tool, CT imaging’s major weakness
lies in its inability to differentiate polyps from mucous and other soft tissue masses.
However, many patients with CRS eventually require operative intervention, and there-
fore, a major benefit of CT imaging remains in its ability to provide a road map for
surgical planning. For patients with nasal polyposis, this information can be invaluable
because the deforming nature of the disease can lead to intraoperative disorientation,
making knowledge of anatomic variations crucial.

CHRONIC RHINOSINUSITIS AND NASAL POLYP

The largest proportion of patients with NP has a diagnosis of CRS. CRS affects about
30 million Americans, imparting an annual medical cost of $2.4 billion. Societal effects
are further compounded by sick days, lost work hours, and other indirect costs.9 To
standardize a formerly amorphous clinical diagnosis, CRS criteria have been set forth.
A diagnosis of CRS requires a symptom duration longer than 12 weeks with 2 of the
following symptoms: facial pain/pressure, hyposmia/anosmia, nasal obstruction, or
anterior/posterior nasal drip.10 Even though all types of CRS have the potential to
develop NPs, given enough time and insult, the presence of NPs has been used as
 Nasal Polyps: Pathogenesis and Treatment 687

a way to subdivide CRS into 2 groups: CRS with NPs (CRSwNP) and CRS without NPs
(CRSsNP). CRSwNP represents 20% to 33% of overall CRS cases,11 although this
can vary depending on the geographic location. Although only a portion of patients
with CRS have nasal polyposis, these patients likely represent a disproportionate
number of recalcitrant patients.
A diverse collection of chronic sinusitis can present with NPs, which include allergic
fungal sinusitis, aspirin-exacerbated respiratory disease (AERD), and cystic fibrosis
(CF). Despite having similar macroscopic findings, each of these disorders represents
a complex pathology and varying treatment strategy. This article outlines the current
understanding of pathogenesis in nasal polyposis and discusses the implications on
therapy.

PATHOGENESIS

In attempting to understand pathogenesis in nasal polyposis, it must be remembered

that this subject represents a topic in flux. To date, there exists no delineated pathway
that can clearly explain the journey from insult to tissue change. The current under-
standing is instead limited to comprehending and elucidating differing inflammatory
promoters and pathways. Much as in the mastery of any sport, it is essential to under-
stand the roles of the key players before tackling overall strategy. It is hoped that by
understanding the various inflammatory pathways and their effects eventually,
detailed classification will allow for prediction of clinical course and tailoring of
intervention.

Cytokines
The division of CRSwNP and CRSsNP has long centered on the separation of the
inflammatory pathways that drive them. Classically, CRSsNP is a helper T cell (TH)
subtype 1–dominant and neutrophil-dominant process, whereas CRSwNP represents
an eosinophilic TH2 process.12 This paradigm has been supported by the finding that
60% to 90% of the cell population in NPs is composed of eosinophils.13,14 It is
presumed that through degranulation and release of cytotoxic compounds, such as
eosinophilic cationic protein (ECP), these invading cells propagate inflammation and
cell damage.15 High levels of the TH2 cytokines interleukin (IL)-5 and IL-4 have long
been confirmed in NP tissues.4 Research in reactive airway diseases has also demon-
strated a clear link between these cytokines and both tissue and blood eosinophilia.16
IL-4 in particular seems to promote not only eosinophil migration and activation but also
T-cell differentiation from TH0 to TH2. The resultant cyclical TH2 upregulation further
spurs on eosinophilic inflammation.17 IL-5 arguably plays the most important role in
eosinophilic-driven processes. Like IL-4, this cytokine has a dual action and influence,
prompting propagation and activation while simultaneously preventing apoptosis.18
CRSsNP can be characterized by the presence of the TH1 cytokine interferon g
(INF-g). INF-g plays an essential role in both innate immunity and acute inflam-
mation.19 In contrast to IL-4 and IL-5, INF-g has been shown to prevent airway eosin-
ophilia and allergic response.17 As would be expected, the INF-g level is found to be
decreased in NPs.3 The role of another TH1 cytokine, IL-8, is not completely discerned.
IL-8 represents a neutrophil chemoattractant that is frequently associated with acute
sinus infections. In patients with CRSwNP, Chen and colleagues20 demonstrated that
IL-8 was diffusely upregulated throughout mucosa but without specific association
with polyp tissue.
The real goal of delineating the cytokine profile is to allow for the differentiation of
CRS subtypes. Van Zele and colleagues,3 in an attempt to realize this goal, evaluated
688 DeMarcantonio & Han

inflammatory cells and mediators in those with CRSsNP, CRSwNP, and CF and in
controls. This group confirmed statistically significant IL-5 and eosinophil levels in
individuals with CRSwNP compared with abundant INF-g in those with CRSsNP.
In contrast, individuals with CF nasal polyps (CF-NP) displayed neutrophil-dominant
markers with increases in IL-8 and myeloperoxidase (MPO) levels. The inflammatory
process responsible for CF-NP formation is not driven by the TH2 process or eosino-
phils as most typical CRSwNP but rather by the TH1 process. In addition, using
receiver operating characteristic analysis, the best cytokine profiles to differentiate
each group were identified. Of note, a sensitivity and specificity rate of 75% was
observed using IL-5, ECP, and IgE levels to differentiate CRSwNP from CRSsNP.
INF-g was found to offer a similar rate of successful differentiation. IL-8 and MPO
were found to provide a sensitivity and specificity of 75% for differentiation between
other forms of CRS. Such research offers a window into the future of CRS manage-
ment in which inflammatory cells and mediators may be used in combination with
history taking and examination to classify patients with CRS.

T-cell Regulation and Transforming Growth Factor b1

Once the primary cytokines involved in NPs have been described, it becomes
essential to examine the intracellular processes upstream that lead to T-cell differ-
entiation and propagation. An interesting avenue of research in this field examines
the interplay of forkhead box P3 (FoxP3) and T regulatory (Treg) cells. Treg cells,
also described as suppressor T cells, function to maintain self-tolerance and
immune hemostasis.21 The lack of adequate function can result in rampant and
uncontrolled immune activation seen in fatal autoimmune disease. The FoxP3
gene exerts control over immune hemostasis by regulating Treg production.21 The
characterization of this pathway has provided insight into a wide array of allergic
and inflammatory pathways. In the realm of CRS, Van Bruaene and colleagues22
have demonstrated diminished FoxP3 expression and Treg production in those
with CRSwNP compared with both those with CRSsNP and controls. It can be sug-
gested that such an environment of diminished immune control may act as the
priming pump for excessive inflammation. Levels of transforming growth factor b1
(TGF-b1) were also proportionally decreased in NPs for the CRSwNP group. This
association offers a possible link between the upregulation of inflammation and
TGF-b1–associated tissue damage. TGF-b1 is a cytokine produced by lymphocytes,
macrophages, eosinophils, and fibroblasts and is associated with local deposition
of extracellular matrix and eventual cellular damage.19,23 TGF-b1 seems to exert
an influence on fibroblasts, resulting in the production of fibrous stroma and hyper-
trophic scar tissue.24,25 This propensity for thick fibrous tissue formation offers
an additional point of differentiation between CRSwNP and CRSsNP. A cellular
disparity could explain the obvious differences in the gross pathology between
the edematous polypoid mucosa of CRSwNP and the thickened scarred sinuses
of CRSsNP.
The function of TGF-b1, however, does not seem to be 1-dimensional. In in vitro
studies of fibroblast activity, TGF-b1 has been shown to be increased 3-fold in
patients with NPs when exposed to IL-4.25 In a follow-up study, Little and colleagues26
examined the influence of increased TGF-b1 levels on NP-derived fibroblasts.
Although proliferation and fibrotic potential were clearly increased, TGF-b1 was also
associated with decreased levels of eotaxin and other eosinophilic inflammation
promoters. The investigators propose these findings to help define a dual role for
TGF-b1 as both an antiinflammatory agent and a promoter of fibrosis. Such a system
could explain the transition from acute/chronic inflammation to fibrotic changes.26
 Nasal Polyps: Pathogenesis and Treatment 689

EOSINOPHILIC AND NONEOSINOPHILIC NASAL POLYPOSIS

It has been well accepted that not all patients with CRS that form NPs demonstrate
TH2 eosinophilic-dominant pathology.27,28 New emphasis on noneosinophilic nasal
polyposis has emerged primarily from Asian research groups. It is notable that 80%
of Western patients with CRSwNP demonstrate tissue eosinophilia compared with
less than 35% of Korean patients.29 To examine the possible differences in Western
and Eastern nasal polyposis, Zhang and colleagues30 compared Chinese patients
with CRSwNP with their Belgian counterparts. These groups were found to have
similar symptoms, CT findings, and endoscopic examination results compared with
controls. In addition, both groups expressed upregulation of IL-2 levels and downre-
gulation of FoxP3 Treg cells and TGF-b1 levels, confirming previous findings.22,30
Differences were, however, noted with regard to inflammatory cells and T-cell domi-
nance. The Belgian contingent confirmed previous findings of TH2-dominant eosino-
philic inflammation. In comparison, the Chinese group displayed a neutrophilic
pattern with TH1/TH17 T-cell upregulation.
The role of TH17 in immunology has only recently been elucidated. Over the past
5 years, the basic CD4 differentiation pathway into TH1 and TH2 cells has been chal-
lenged by the discovery of TH17 as an alternative end point. The discovery of TH17 and
its associated cytokines IL-23 and IL-17 was prompted by the inability of TH1/TH2
subtypes to explain murine autoimmune models.31 Instead of IL-4 (TH2) or IL-12
(TH1), induction of TH17 differentiation is promoted by IL-1 and IL-6.31 Such a profile
was confirmed by Zhang and colleagues30 when patients with noneosinophilia dis-
played an upregulation in IL-1, IL-6, IL-17, and TH17 levels. This production eventually
results in the production of proinflammatory mediators, fibroblasts, and tissue
change.20

STAPHYLOCOCCUS AUREUS ENTEROTOXIN

S aureus enterotoxin (SAE) has been suggested as a possible instigating and/or

modifying factor in nasal polyposis. As in other superantigen reactions, SAE acts to
nonspecifically activate T cells by binding the major histocompatibility II complex.32
The unregulated upregulation results in an increase of TH2-biased proinflammatory
cytokine levels.33 This outcome is enhanced by S aureus colonization, with 60% of
patients with CRSwNP demonstrating colonization compared with 33% in controls.34
The effect of this colonization as shown by SAE IgE is not universal among patients
with CRSwNP. Instead, asthmatic patients are more likely to have colonization of S
aureus and detectable IgE levels, therefore resulting in elevated IL-5, eotaxin, and
ECP levels.4,34 Despite their different clinical and inflammatory phenotypes, Chinese
patients with asthma were also more likely to have detectable SAE levels.35 Although
these results are interesting, further work is needed to correlate SAE effects with clin-
ical symptoms and course. Further research should focus on defining the effect that
SAE plays, particularly in asthmatic eosinophilic CRSwNP.

ASPIRIN-EXACERBATED RESPIRATORY DISEASE

A small portion of patients with NPs and CRS are classified as having AERD, also
known as Samter triad or aspirin triad. These patients present with the classic Samter
triad with aspirin sensitivity, polyposis, and asthma. An additional near-universal
feature of these patients is hyperplastic eosinophilic sinusitis.36 The increased tissue
eosinophilia, infiltrating mast cells producing histamine, and increased levels of cys-
teinyl leukotrienes secondary to overexpression of leukotriene C4 synthase contribute
690 DeMarcantonio & Han

to systemic inflammation of this disease.37 Also for AERD, symptoms are worsened by
the introduction of cyclooxygenase (COX) 2 inhibitors with a metabolic shift of arach-
idonic acid toward lipoxygenase pathways with resultant increased leukotriene
products.36 Nasal mucosa of these patients has also been found to have diminished
COX-1 and COX-2 productions. Therefore, even before insult, these patients produce
less of the protective prostaglandin E2 (PGE2).38 Validation of this baseline deficiency
has been addressed by Sestini and colleagues.39 These researchers were able to
prevent aspirin-induced bronchospasm by using inhaled PGE2. Their findings were
confirmed objectively by forced expiratory volume in the first second of expiration
(FEV1) and urinary leukotriene E4 level measures. Also, when compared with other
patients with severe nasal polyposis and asthma, the incidence of allergy in these
patients with AERD are likely to be lower. Therefore, the examination of allergy is espe-
cially important in the evaluation and diagnosis of patients with severe nasal polyposis
and adult-onset asthma.

CYSTIC FIBROSIS

CF is a rare autosomal recessive genetic disorder affecting approximately 1 in every

2500 people. All patients with CF develop chronic sinusitis, but of these patients, 7%
to 48% demonstrate NPs (CF-NP).40 CF-NP stands out from other NP groups by way
of its obvious phenotype and diagnosis. Defects of ciliary clearance in these patients
create an environment in which bacterial colonization, particularly with Pseudomonas
aeruginosa, is a virtual constant.41 The resultant neutrophilic response to these patho-
gens may explain the dominance of IL-8 and MPO in the inflammatory cascade.3 The
role of bacterial pathogens is further supported by the role of toll-like receptors
(TLRs) and lack of clear benefit of corticosteroids in CF-NP.40,42
IL-8 and MPO levels have been previously shown to be increased in patients with CF-
NP compared with both those with CRS and bronchitis.3,43 Claeys and colleagues42
evaluated the differentiation of CF-NP from non–CF-NP by comparison of inflammatory
cytokines, innate antimicrobial peptides, and innate pattern recognition receptors
(PRRs). IL-8 and MPO were confirmed to dominate CF-NP compared with ECP,
eotaxin, and IgE in non–CF-NP. The innate antimicrobial peptide human defensin b2
(HBD2) and PRR TLR-2 levels were found to be significantly higher in CF-NP as well.
These findings suggest an inflammatory pathway instigated by bacterial exposure. In
such a system, TLRs recognize pathogen-associated molecular patterns with resultant
production of antimicrobial peptides and stimulation of an inflammatory cascade.44,45 A
system of excessive inflammatory response is supported by the findings that children
with CF display disproportionate neutrophil and IL-8 responses to bacteria compared
with controls.46 More research is required to assess the feasibility that in CF, bacterial
colonization may upregulate TLR-2, HBD2, and subsequently IL-8 levels, leading to
inflammation and polyp formation.

TREATMENT
Medical Therapy
Corticosteroids
For decades, corticosteroids have been the mainstay of therapy for nasal polyposis.
The mechanism of action involves the downregulating of inflammatory protein-
encoding genes by the activation of intracellular glucocorticoid receptors.47,48 Nasal
topical steroids have been shown to both decrease polyp size and improve nasal
symptoms.47 The use of these steroids postoperatively has also proved to reduce
recurrence and the need for systemic therapy.49 The undeniable benefits of nasal
 Nasal Polyps: Pathogenesis and Treatment 691

steroids have made them the first line of therapy in nasal polyposis. The benefit of oral
steroids, however, remains less definitive with little randomized data available and the
risk of systemic effect from oral steroids. Nevertheless, their use remains near univer-
sal as a means to abate NP symptoms. Regardless of documented effect, the use of
oral steroids will continue to be limited by their extensive and well-documented long-
term side effects.
Antileukotrienes
Cysteinyl leukotriene receptor (LTR) antagonists, such as montelukast, function by
blocking LTR sites. Multiple studies have shown clinical improvement in those with
CRSwNP, demonstrating reduction in polyps, decreased steroid use, and improved
overall symptoms.50–52 However, there remains a dearth of well-designed randomized
studies at this time. In patients with excessively high leukotriene levels, such as those
with AERD, simply blocking LTRs may be insufficient to meaningfully affect symptoms.
To increase effectiveness, the leukotriene pathway must be interrupted during
production. The 5-lipoxygenase inhibitor zileuton functions in this manner and has
been advocated in the treatment of AERD. As with LTR antagonists, further research
is needed to quantify the effects and use of this medication.
Immunomodulators
The development of immunomodulators represents a crucial step in the individualized
treatment of nasal polyposis. No other treatment modality offers such an obvious link
to inflammatory pathogenic cytokines. The role of IL-5 in inflammation has made it
a natural target for suppression. Use in CRS has been spurred on by success in
patients with eosinophilic asthma, otherwise known as patients with unified airway
disease.53 In these patients, treatment with anti–IL-5 results in improved serum eosin-
ophil levels, asthma control, and FEV1 levels.54 Gevaert and colleagues55 sought to
apply this therapy to patients with CRS and follow up the effect by measuring serum
and nasal ECP levels. Although no statistically significant differences were noted, it
was shown that responders were more likely to have higher pretreatment IL-5 levels.
The treatment of all patients with anti–IL-5 would be misguided because only those
with TH2-dominant eosinophilic disease are likely to benefit. Although the cost of
immunomodulators likely limits their overall use, their effect on the landscape of
CRS therapy may be the greatest as a model of individualized/tailored therapy.
The future for the medical management of CRS is defined by research that accounts
for and adjusts therapy with respect to pathogenesis. In a recent example of such
a model, Huvenne and colleagues56 compared in a randomized fashion doxycycline
and steroid therapy in patients with NP. The results of this study are perhaps less
important than the fact that the effect of each therapy was measured with respect
to inflammatory cytokines. Such a strategy in combination with further classification
of CRS subtypes makes targeted therapy a reality.
Surgical Therapy
CRSwNP
Endoscopic sinus surgery (ESS) has long been implemented with success in the treat-
ment of CRS. Overall success rates have been reported at 85%, with failure rates
ranging from 2% to 24%.57 However, success has been difficult to achieve in the
setting of nasal polyposis because surgical management does not rid the individual
of the inflammatory sinonasal mucosa. In 65 patients with NP, Dufour and colleagues57
examined symptom improvement with respect to nasal obstruction and anosmia. Less
than 50% of patients demonstrated major improvement of nasal obstruction, with even
less reporting improvement in olfaction. This failure of subjective improvement can
692 DeMarcantonio & Han

frustrate both the patient and surgeon. Although the polyp burden can be reduced by
surgical resection of the inflammatory mediators and cells, the correlation with symp-
toms may be lacking. In certain patient subsets, the benefit of surgery may be more or
less profound. In particular, patients with asthma or unified airway have experienced
significant subjective improvements after ESS,58,59 which is not surprising because
of the direct decrease of inflammatory load of these patients. Improvements of objec-
tive measures, however, have been inconsistent.58,59 In contrast, patients with AERD
seem to be particularly difficult to treat with surgery. In a study of olfaction status after
ESS, AERD was found to be an independent risk factor for poor recovery.60 It is impor-
tant to remember that surgical management or resection of NPs does not prevent the
recurrence of NPs, especially in individuals with inherent inflammatory mucosa.
However, surgical management can be used to decrease the amount of inflammation
so that the medical treatment becomes more effective and thus prevents the recur-
rence of NPs.
Cystic Fibrosis
In the setting of CF, ESS has been shown to be safe with a major complication rate
within the range of normal.61 Given the precarious pulmonary status of patients with
CF, it is important also to note that these patients experienced no increased anes-
thesia risk.61 Although ESS can safely be performed in patients with CF, the presence
of NPs should not alone be considered a reason for surgery62 because the recurrence
of the sinus disease is likely to return despite surgical management. It is important to
remember that less than 10% of patients with CF report sinonasal symptoms.63 Given
that surgical intervention has had mixed results demonstrating improvement in pulmo-
nary function, especially in the long term, symptom status should be used to deter-
mine need for functional endoscopic sinus surgery.64 In general, patients with CF
are considered good surgical candidates when imaging confirms that disease burden
and symptoms are persistent.40 In this setting, surgical intervention can improve upper
respiratory status, whereas the lower respiratory status remains in question.

SUMMARY POINTS: NASAL POLYPS

1. CRS is the most common cause for NPs, but not all NPs are created equally.
2. Patients with asthma and CRS represent clinical examples of the unified airway. As
such, these patients benefit from treatment aimed at control of TH2-driven eosino-
philic inflammation.
3. NPs are not a uniquely TH2-driven process. Recent research has demonstrated
a clear pathogenic role for TH1- and TH17-driven processes.
4. Future research in understanding the development of NPs will dictate the proper
medical management of NPs.

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