Accepted Manuscript

Nasal polyposis pathophysiology: Endotype and phenotype open

issues

Giuseppe Brescia, Claudia Zanotti, Daniela Parrino, Umberto

Barion, Gino Marioni

PII: S0196-0709(18)30178-9
DOI: doi:10.1016/j.amjoto.2018.03.020
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 ACCEPTED MANUSCRIPT
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Nasal polyposis pathophysiology:

Endotype and phenotype open issues.

Giuseppe Brescia, MDa*;

Claudia Zanotti, MDa; Daniela Parrino, MDa; Umberto Barion, MDa;

Gino Marioni, MDa.

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a
Department of Neurosciences DNS, Otolaryngology Section, Padova University,

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Padova, Italy.

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Running title: Endotyping CRSwNP

Word count: 3051

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Number of figures:0

Number of tables:0
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A preliminary version of this review was presented at the 63rd Meeting of “Alta
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Italia” Group of Otolaryngology, Padova (Italy), December 2, 2017.

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Corresponding author
*
Giuseppe Brescia, MD; Department of Neurosciences DNS, Otolaryngology
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Section, Padova University, Via Giustiniani 2, 35128 Padova, Italy, fax

+39 049 8213113, e-mail giuseppe.brescia@aopd.veneto.it

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ABSTRACT

Purpose: Endotyping chronic rhinosinusitis with nasal polyps

(CRSwNP) poses a challenge for rhinologists nowadays. Phenotyping

CRSwNP proved inappropriate as an approach to their classification

because of their common clinical features. Endotyping, being

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based on the pathogenic mechanism, provides a precise picture more

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appropriate for use in clinical practice. Patients’ treatment and

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follow-up can thus be tailored to cope with the degree of

aggressiveness of a specific CRSwNP endotype.

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The aim of this study was to analyze the available

information about the main currently accepted endotypes of CRSwNP;

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furthermore, we reported and commented evidence regarding some

clinical conditions associated with nasal polyposis which could be

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related with new endotypes.

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Materials and Methods: Pubmed and Scopus electronic database were

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searched. The main available studies about CRSwNP endotyping

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published predominantly in the last 5 years were critically

analyzed.
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Results: The pathophysiological features of some asthma-related

CRSwNP (allergic fungal rhinosinusitis, aspirin-exacerbated

respiratory disease) are quite well understood, including them

among known endotypes of CRSwNP. On the other hand, because of

their known pathophysiological mechanisms, some well-known

diseases associated with aggressive forms of CRSwNP, such as

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eosinophilic granulomatosis with polyangiitis, primary ciliary

dyskinesia and cystic fibrosis, should be investigated as

potentially related with CRSwNP endotypes.

Conclusions: CRSwNP comprises several inflammatory endotypes

defined by different pathogenic mechanisms. These endotypes

correlate with the disease’s clinical manifestations and behavior.

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A thorough understanding of CRSwNP endotypes will enable targeted

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medical therapies and tailored follow-up protocols.

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Key words: Chronic rhinosinusitis; nasal polyps; endotypes;
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aspirin-exacerbated respiratory disease; allergic fungal

rhinosinusitis; eosinophilic granulomatosis with polyangiitis.

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1. Introduction

Chronic rhinosinusitis (CRS) is commonly divided into two

phenotype-based groups on the presence (CRSwNP) or absence of

nasal polyps (CRSsNP), which are clinically diagnosed by nasal

endoscopy and/or computed tomography (CT) of the paranasal

sinuses. It is clear that this classification is over simple,

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since the same patients may or may not have nasal polyps at

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different times in their clinical history, even after appropriate

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medical or surgical treatment.

A different, more comprehensive approach is therefore needed

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to classify CRS more accurately. There is evidence to suggest that

some forms of nasal polyposis, associated with certain conditions

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(e.g. allergy, asthma, aspirin sensitivity), have particular

characteristics: local aggressiveness, a weak response to drugs,

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and high recurrence rates after surgical treatment. Such forms are
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quite homogeneous from the clinical viewpoint, and have been

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called "phenotypes", but this classification also reveals some

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weaknesses in clinical practice [1, 2]. In 2008, Anderson [3]

observed that intrinsic bronchial asthma (which could be

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considered as an "unicum" in terms of its clinical profile)

differed between young adult and elderly patients in terms of

severity and response to therapy. Surmising that the two forms of

asthma had a different pathogenesis, Anderson introduced the

concept of "endotype". Endotyping is based on the fact that some

diseases have the same pathogenic mechanism even though their

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etiology and final clinical features may differ.

The endotyping approach prompted the idea that some forms of

disease sharing the same mechanism of action could be treated with

targeted therapies to interrupt their progression. Investigations

revealed that some elements were capable of triggering a common

inflammatory mechanism [4, 5]. For example, bacteria, fungi,

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viruses, biofilms, and proteins are all able to activate T-helper

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(TH) cells, which shift from a quiescent native state (TH naive),

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through an intermediate T-helper Ø (THØ) stage, to reach a final T-

helper specialization stage as type 1, 2 and 17 (TH1, TH2, TH17).

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These activated lymphocytes produce a spectrum of substances

called interleukins (ILs). They can regulate the activity of other

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blood cells in the immune system, especially eosinophils and

basophils, giving rise to an inflammatory microenvironment. The

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cells attracted to a site of inflammation are capable of producing

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other cytokines that can enrich the microenvironment and

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facilitate the inflammatory process. Among these cytokines, at the

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endothelial level there are chemokines (eotaxins 1, 2 and 3) that

are able to activate and recruit eosinophils, basophils, and TH

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lymphocytes at the inflammatory site. Adhesins (intercellular

adhesion molecule-1, and vascular cell adhesion molecule-1) make

cells adhere to vessels and tissues, and cause cellular

transmigration through the endothelium. Then there are the metal

proteinases 2 and 9 which locally degrade the extracellular matrix

by allowing inflammatory cells to pass through and spread into the

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nasal polyp tissue. The final stage leads to the synthesis of DNA

transcription factors, such as G-A-T-A binding core sequence

transcription factors, or signal transducers and transcription

activators. These proteins produced by inflammatory cells migrate

into the cell nucleus, binding to specific DNA sites, and blocking

or triggering the action of RNA polymerase and RNA synthesis,

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which results in an altered cell turnover. For example, action on

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eosinophils has the effect of inhibiting apoptosis, leading to an

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exponential increase in eosinophils in nasal polyps.

It is now believed that T helper cells are compartmentalized:

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interleukins 4, 5 and 13 are produced, and eosinophils are

recruited in the TH2 environment, while interleukins 17 and 22 are

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mainly produced, and neutrophils are recruited in the TH1 and TH17

environments. It has also been suggested, however, that multiple

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cell lines can coexist at the same site of inflammation.

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We are still unable to classify all CRS endotypes. Some

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endotypes have been understood and associated with a clearly-

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defined form of CRS thanks to a close correspondence between

endotype and phenotype. Different forms of CRS sometimes seem to

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share the same pathogenesis (i.e. there may be several phenotypes

with the same endotype). Finally, as Anderson [3] suggested for

asthma, if the same form of CRS shows different clinical

characteristics (e.g. a phenotype with different degrees of

aggressiveness), this may be due to various pathogenic mechanisms

(different endotypes with the same phenotype). These complexities

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can only be clarified by means of a significant improvement in our

understanding of the pathogenic mechanisms involved.

The need for identifying individual phenotypes and endotypes

extends to the approaches that currently considered the mainstay

of treatment of CRS [6]. In particular, the endotypes

classificative approach has to focus on defining CRS pathogenic

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mechanisms rather than describing the inflammatory pattern of CRS

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even in an advanced biological way. The aim of this study was to

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analyze the available information about the main currently

accepted endotypes of CRSwNP [6, 7]; furthermore, we reported and

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commented evidence regarding some clinical conditions associated

with nasal polyposis which could be related with new endotypes.

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2. CRSwNP endotypes
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In 2013, a preliminary attempt to classify CRSwNP endotypes was

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performed by Akdis et al [1]. Different CRSwNP endotypes can be

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characterized by differences in responsiveness to different

treatments, including topical intranasal corticosteroids and

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biological agents, such as anti–IL5 and anti-IgE antibody, and can

be based on different biomarkers that are linked to underlying

mechanisms. In 2016, Dennis et al. [2] proposed four distinct, but

partially overlapping, classification modalities for identifying

endotypes within the CRSwNP phenotype: 1) type 2 cytokine based

approach, 2) eosinophil-mediated approach, 3) immunoglobulin IgE-

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based approach, and 4) cysteinyl leukotriene (CysLT)-based

approach. In the same year, however, a multicentric investigation

by Tomassen et al. [8] proposed a classification for clusters

based on tissue analysis of IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-

1β, IL-6, IL-8, cationic eosinophilic protein, myeloperoxidase,

TGF-β1, IgE, Staphylococcus aureus IgE specific for enterotoxin

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and albumin in CRS patients. The clustering of 173 CRS cases had

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resulted in 10 groups, of which 4 clusters with low or

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undetectable IL-5, eosinophilic cationic protein, IgE and albumin

concentrations and 6 clusters with high concentrations of such

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markers. The aim was to identify inflammatory endotypes of CRS

through biomarkers’ clusters analysis. Nevertheless the current

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difficulties in classifying CRSwNP into endotypes (one phenotype

could include several molecular mechanisms and one endotype could

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include several phenotypes), very recently, Kim et al. [5]

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concluded that endotypes depended on the epithelial barrier

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function, epithelial cytokines, and T cell subsets.

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2.1 CRSwNP and inflammatory cells

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As mentioned previously, the first step in the inflammatory

process in patients with CRSwNP involves nasal mucosa colonization

by immune system cells. The subsequent recruitment of other immune

system cells and the formation of the inflammatory

microenvironment give rise to a chronic disorder. Some cells

involved in this process are neutrophils and eosinophils [4, 5]

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through a process that involves basophils, type 2 innate lymphoid

cells, and type 2 helper lymphocytes as promoters [9, 10].

CRSwNP shows a great cytological variety. A first difference has

to do with geographical/racial distributions. In Western

countries, cases of eosinophilic CRSwNP are prevalent, sustained

by TH2 inflammation, whereas in Asia, eosinophilic and non-

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eosinophilic CRSwNP histotypes are equally represented [4]. In

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Western countries, tissue eosinophilia staging in cases of CRSwNP

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has now become sufficiently standardized: after staining with

hematoxylin & eosin, three microscopic high-power fields (HPF)

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(400x magnification) are examined. The number of eosinophils is

counted for each field, and the average for the three fields is
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calculated. Values ≥10 eosinophils/HPF characterize eosinophilic

CRSwNP, and values <10/HPF non-eosinophilic CRSwNP. In the Asian

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rhinological literature, the cut-off is less clearly defined, and

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can vary from 5 to more than 100 eosinophils/HPF. This variability

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may depend also on the greater heterogeneity of the T-helper cell

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lines; TH1, TH2 and TH17 environments coexist in the same patient,

and thus give rise to different cell lines [4].

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The eosinophilic histotype has been extensively studied and

found associated with the prognosis for CRSwNP [11-15]. Generally

speaking, eosinophilic CRSwNP are associated with higher

recurrence rates and shorter disease-free intervals after

treatment than non-eosinophilic or neutrophilic forms. Another

histotype, the basophilic one, has recently become the object of

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preliminary investigations [16] showing that basophils have a

common pathway with eosinophils, and are represented at the

inflammatory site, correlating strongly with eosinophilia and

prognosis.

Brescia et al. [17] recently focused on the role of

eosinophilia and basophilia in CRSwNP patients’ blood. Tissue and

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blood eosinophilia were closely related in eosinophilic CRSwNP

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(including cases associated with asthma and allergy), and in

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aspirin-exacerbated respiratory disease. Blood basophilia also

correlated closely with blood eosinophilia in this form of CRSwNP.

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A role for blood sampling of these cells to predict the course of

CRSwNP was consequently hypothesized. Basophil and eosinophil

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levels in the blood were also found to vary significantly between

different endotypes and phenotypes. Some authors [16, 18-20] have

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suggested considering blood and/or tissue basophil and eosinophil

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levels for the purpose of CRSwNP endotyping.

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2.2 Aspirin-exacerbated respiratory disease (AERD)

AERD has a known pathogenesis and is associated with severe asthma

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and recurrent nasal polyposis; it can be counted among CRSwNP

endotypes [5, 7].

AERD usually occurs in the third and fourth decades of life,

most frequently in males (M/F 2.3/1). It is characterized by a

reaction to aspirin or other non-steroidal anti-inflammatory drugs

(NSAIDs) that inhibit cyclooxygenase-1 (COX-1). The clinical

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features of AERD include asthma, eosinophilic nasal polyps, and

blood eosinophilia (often without atopia, but with intolerance to

alcoholic beverages) [2, 21].

Eosinophilic type CRSwNP accounts for 8.7% to 9.7% of all

CRSwNP patients [2, 21-23]. Asthma develops after the onset of

CRSwNP in 14.89% of all patients with severe asthma [22]. Not all

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AERD patients develop asthma, however (though they may suffer from

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abdominal and dermatological disorders as well as CRSwNP), which

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is why the term AERD is preferable to "aspirin-intolerant asthma".

From a pathophysiological standpoint, AERD has been

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associated with enzymatic defects in eicosanoid metabolism,

including a functional reduction of COX-1 enzymes with a decrease

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in prostaglandin levels, and an increase in 5-lipoxygenase

activity and cysteinyl-leukotriene (CysLT) levels, especially

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leukotriene C4 [2]. High CysLT levels are related to the downstream

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activation of effector cells, such as eosinophils, basophils and

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mast cells, which stimulate the inflammatory response within the

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sinonasal and respiratory mucosa. Other cytokines comprising the

inflammatory milieu of AERD include IL‐4, IL‐33, and interferon‐γ,

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which goes to show the mechanistic overlap between AERD and CRSwNP

in aspirin‐tolerant patients [2, 24].

AERD treatment begins with the avoidance of aspirin and

NSAIDs. Steroid treatments are administered systemically and

topically (inhalations). Anti-leukotriene therapy is indicated and

has recently been implemented using monoclonal antibodies capable

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of blocking IL-4, IL-5 and IL-13 [21]. Endoscopic sinus surgery

(ESS) for AERD offers symptomatic benefits and enables a more

limited use of systemic steroid therapy. ESS plus steroids

significantly improves patients’ asthma symptoms by reducing their

systemic inflammatory state [18]. If medical and surgical

treatments for AERD yield poor results, then aspirin

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desensitization should be considered [21].

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2.3 Allergic fungal rhinosinusitis (AFRS)

Considering the classification of Dennis et al. [2], and in

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particular their IgE-based approach for endotyping CRSwNP

hypothesis, local IgE may be a stronger pathophysiological driver

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than systemic IgE; AFRS should also be counted among emerging

endotypes [5].
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AFRS accounts for 5-10% of all cases of CRSwNP in

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immunocompetent patients. It is caused mainly by Aspergillus,

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Bipolaris, Curvularia and Alternaria species colonizing the

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paranasal sinuses, and impairing mucociliary clearance [25]. In

1994, Bent and Kuhn [26] diagnosed AFRS in patients with type I
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hypersensitivity, nasal polyps, and eosinophilic mucin found at

the time of surgery and on CT scan. Asthma, positive fungal

staining or Charcot-Leyden crystals in surgical specimens, and

serum eosinophilia could also be found. These criteria are still

valid today, but it is important to emphasize that the presence of

fungi in the nasal sinus and serum IgE cannot always be confirmed.
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IgE are only found locally in some cases. Asthma reportedly

develops in 50% of AFRS patients, and becomes severe in 5-10% of

asthmatics. The Alternaria species has been associated with life-

threatening acute asthma attacks and asthma-related deaths [25].

In 2004, Collins et al. [27] concluded that AFRS was the

result of a local, not systemic, hypersensitivity reaction type I.

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Their conclusion was based on having found specific IgE in the

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mucin of AFRS patients. Their investigation underscored the role

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of an IgE-mediated hypersensitivity reaction, explaining why not

all AFRS patients had signs of systemic allergy. High levels of

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local and systemic IgE have been found in all forms of CRSwNP,

with the exception of AERD, and local IgE can be even more
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powerful as a driver of disease pathophysiology than systemic IgE

[2]. The most accredited hypothesis is that local sinonasal IgE

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production contributes to the development of nasal polyps,

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particularly in association with asthma [2]. Given the high

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mucosal IgE concentrations in nasal polyposis, using high-affinity

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IgE-blocking monoclonal antibodies may be appropriate as a

targeted treatment [2].

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More recently, other authors [25, 28] have suggested that

different immunological reactions against fungal antigens might

coexist, including: (i) type I hypersensitivity to fungal IgE;

(ii) type III hypersensitivity, with IgG forming a complex with

fungal antigens; and (iii) type IV hypersensitivity, with T-cell–

mediated eosinophilic inflammation. All of these inflammatory

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reactions interfere with mucus drainage from the nasal sinus,

subsequently causing fungal growth and the maintenance of

inflammation.

AFRS is usually treated surgically to remove the polyps and

eosinophilic mucin, clear the affected sinuses, and create an

access route for topical intranasal medication. If the sinuses are

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not cleared completely, the inflammatory process usually

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continues, and resistance to anti-inflammatory drugs develops.

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Patients should undergo nasal irrigations and take intranasal

steroids to reduce the inflammation and enable sinus drainage

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[25]. Immunotherapy can cure the allergic diseases, relieve

symptoms, and reduce the need for medication. Fungal extracts are
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not standardized, however, and immunotherapy is not recommended

for patients with asthma because it quite frequently prompts

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adverse reactions [25]. Oral steroids are still recommended for

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AFRS [29].
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3. Potential new CRSwNP endotypes

Some diseases have very clear phenotypes associated with nasal

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polyps and are caused by well-known pathophysiological mechanisms.

Eosinophilic granulomatosis with polyangiitis (EGPA) -

formerly known as Churg-Strauss syndrome, primary ciliary

dyskinesia (PCD) [30] - also known as Kartagener syndrome, and

cystic fibrosis (CF) are considered phenotypes associated with CRS

that have a distinctive clinical profile and behavior.

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EGPA is a systemic vasculitis characterized by extravascular

granulomas, blood eosinophilia and eosinophilic tissue

infiltration. Clinically, it begins with allergic rhinitis, nasal

polyps, and asthma. With time, EGPA features blood and tissue

eosinophilia, chronic eosinophilic pneumonia, and/or eosinophilic

gastroenteritis. In advanced stages, a potentially life-

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threatening vasculitis involving several organs may be diagnosed.

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The diagnosis of EGPA is based on the presence of 4 or more

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American College of Rheumatology criteria: asthma, >10%

eosinophilia in blood, rhinosinusitis, pulmonary infiltrates

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(sometimes transient), histological evidence of vasculitis with

extravascular eosinophils, and mono- or poly-neuropathy [31]. The

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presence of CRS in more than 80% of patients with early EGPA

enables rhinologists to diagnose the disease at an early stage,

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and prompt appropriate therapy can prevent it from progressing

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further [32]. The known TH2 pathogenic mechanism seems to be

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involved, which triggers and maintains eosinophilic inflammation.

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In the setting of EGPA, eosinophilic polyposis is extremely

aggressive and resistant to common steroid treatments. Recurrences

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are frequent after endoscopic surgery, and immunosuppressants

should be added to steroids in some cases.

In 2015, Stevens et al. [33] said that almost all patients

with CF or PCD develop CRS, and it often proves more recalcitrant

to therapy in these patients than in cases of idiopathic CRS.

Patients with CF or PCD are predisposed to CRS because of a

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defective mucociliary clearance (MCC), which allows bacterial

colonization of the sinus. That is why CRSwNP in CF and PCD is

usually characterized by a neutrophilic histotype. The upper

airways play an important part in removing particulates and

pathogens from inspired air by means of MCC, a specialized

function unique to the airway epithelium. In CF, defects in the

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transmembrane conductance regulator anion channel result in an

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impaired salt and water secretion, and possibly also an enhanced

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absorption, causing mucus dehydration and impairing MCC [33]. CF

patients frequently develop severe recurrent sinonasal infections

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that may also seed or exacerbate lung infections. There are also

higher than normal levels of the epithelial anion transporter,

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pendrin, in nasal polyps than in uncinate tissue isolated from

healthy controls. An upregulated pendrin expression in the airway

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has been linked to IL-4, IL-13, and IL-17A [34, 35]. Defects
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involving the epithelial cell cilia can also affect MCC and
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contribute to chronic sinonasal inflammation. In PCD, for example,

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an abnormal ciliary function and/or structure result in an

impaired MCC and a higher incidence of upper respiratory

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infections. More commonly, though, ciliary dysfunctions are

acquired through exposure to environmental or microbial toxins,

and/or as a secondary consequence of disease via exposure to

inflammatory stimuli. In both CF and PCD, the pathogenic picture

seems to involve the known TH1 mechanism that triggers and

maintains neutrophilic inflammation [35].

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4. Conclusion

Current CRS phenotyping is of limited value because common

clinical manifestations seem to overlap in different forms of CRS.

This heterogeneity of behavior also collides with a homogeneous

approach to therapy, based mainly on the use of steroids and

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endoscopic sinus surgery, with variable results in terms of

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recurrence rates. Hence the need to endotype CRS in order to

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classify the variants of this disease no longer from the clinical

standpoint, but according to the pathogenic mechanisms behind it.

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For some CRSwNP, the pathogenic mechanism seems to be fairly

clear, and they take on the role of endotypes [5, 7]. Because of
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their quite well-known pathophysiological mechanism, several

phenotypes, associated with some of the more aggressive forms of

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CRSwNP, such as EGPA, CF and PCD, may however be considered as

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promising potential CRSwNP endotypes to investigate.

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Another challenge for modern rhinologists lies in correlating

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histotypes (eosinophils, basophils, neutrophils) with cytokines in

the local inflammatory microenvironment, and tissue DNA

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modifications. A growing interest in inflammatory blood cells

(eosinophils, basophils) has recently emerged: these cells seem to

correlate with histotypes, comorbidities (asthma, allergy),

endotyping, and CRS recurrence rates. It remains to be seen

whether this systemic phenomenon is a consequence of the local

inflammatory state, or whether local inflammation is an expression

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of a systemic disease. The main goal of this field of

investigation is to identify specific, not generic mechanisms

behind nasal polyposis in order to tailor endotype-based therapies

and thereby achieve significantly lower disease recurrence rates.

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Funding

This study was partly supported by grant No. DOR 1658072/16

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(G. Marioni) from the University of Padova, Italy.
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Declarations of Interest

None
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Informed consent
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Not applicable.
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Aknowledgements

The authors thank Frances Coburn for correcting the English

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version of this paper.

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