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\begin{document}

\title{Endotypes of Chronic Rhinosinusitis; relationships to disease
phenotypes, pathogenesis, clinical findings and treatment approaches.}



\author[1]{Atsushi Kato}%
\author[2]{Anju Peters}%
\author[2]{Whitney Stevens}%
\author[2]{Robert Schleimer}%
\author[2]{Bruce Tan}%
\author[2]{Robert Kern}%
\affil[1]{Northwestern University }%
\affil[2]{Northwestern University}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Chronic rhinosinusitis (CRS) is a common clinical syndrome that produces
significant morbidity and costs to our health system. The study of CRS
has progressed from an era focused on phenotype to include endotype
based information. Phenotypic classification has identified clinical
heterogeneity in CRS based on endoscopically observed features such as
presence of nasal polyps, presence of comorbid or systemic diseases and
timing of disease onset. More recently, laboratory-based findings have
established CRS endotype based upon specific mechanisms or molecular
biomarkers. Understanding the basis of widespread heterogeneity in the
manifestations of CRS is advanced by findings that the three main
endotypes, Type 1, 2 and 3, orchestrate the expression of three distinct
large sets of genes. The development and use of improved methods of
endotyping disease in the clinic is ushering in an expansion of the use
of biological therapies targeting Type 2 inflammation now and perhaps
other inflammatory endotypes in the near future. The purpose of this
review is to discuss the phenotypic and endotypic heterogeneity of CRS
from the perspective of advancing the understanding of the pathogenesis
and improvement of treatment approaches and outcomes.%
\end{abstract}%



\sloppy


\textbf{Endotypes of Chronic Rhinosinusitis; relationships to disease
phenotypes, pathogenesis, clinical findings and treatment approaches.}

\textbf{Short Title:} Relating endotypes, phenotypes and treatments in
CRS

Atsushi Kato*, PhD\textsuperscript{1}, Anju T. Peters*, MD,
MSCI\textsuperscript{1,2}, Whitney W. Stevens, MD,
PhD\textsuperscript{1,2}, Robert P. Schleimer***,
PhD\textsuperscript{1,2}, Bruce K. Tan**, MD, MS\textsuperscript{1,2},
Robert C. Kern**, MD\textsuperscript{2}

*,** These authors contributed equally

*** Correspondence

\textsuperscript{\textbf{1}} Division of Allergy and Immunology,
Department of Medicine and \textsuperscript{2}Department of
Otolaryngology -- Head and Neck Surgery, Northwestern University
Feinberg School of Medicine, Chicago, IL, USA

\textbf{Conflicts of Interest:} AK reports a consultant fee from
Astellas Pharma and a gift for his research from Lyra Therapeutics. AP
has served on advisory boards for Sanofi-Genzyme/Regeneron, Optinose,
AstraZeneca, Novartis, and GSK. WWS served on advisory boards for
GlaxoSmithKline, Genentech, and Bristol Myers Squibb and on a speaker's
bureau for GlaxoSmithKline. RPS reports consulting fees from Intersect
ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech,
Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma, Allakos and
Otsuka. RPS also receives royalties from Siglec-8 and Siglec-8 ligand
related patents licensed by Johns Hopkins to Allakos Inc. BKT served on
advisory boards for Sanofi-Genzyme/Regeneron. RCK is a consultant for
Lyra Therapeutics.

\textbf{Keywords:} Chronic Rhinosinusitis, Endotype, Inflammation, Nasal
polyps, Phenotype

\textbf{Word Count:} 5,067

Address correspondence to Robert Schleimer, PhD

The Roy and Elaine Patterson Professor

Chief, Allergy and Immunology

Northwestern University Feinberg School of Medicine

240 E. Huron St., Room M-318

Chicago, IL 60611 USA

312-503-0076

rpschleimer@northwestern.edu

\textbf{Abstract}

Chronic rhinosinusitis (CRS) is a common clinical syndrome that produces
significant morbidity and costs to our health system. The study of CRS
has progressed from an era focused on phenotype to include endotype
based information. Phenotypic classification has identified clinical
heterogeneity in CRS based on endoscopically observed features such as
presence of nasal polyps, presence of comorbid or systemic diseases and
timing of disease onset. More recently, laboratory-based findings have
established CRS endotype based upon specific mechanisms or molecular
biomarkers. Understanding the basis of widespread heterogeneity in the
manifestations of CRS is advanced by findings that the three main
endotypes, Type 1, 2 and 3, orchestrate the expression of three distinct
large sets of genes. The development and use of improved methods of
endotyping disease in the clinic is ushering in an expansion of the use
of biological therapies targeting Type 2 inflammation now and perhaps
other inflammatory endotypes in the near future. The purpose of this
review is to discuss the phenotypic and endotypic heterogeneity of CRS
from the perspective of advancing the understanding of the pathogenesis
and improvement of treatment approaches and outcomes.



\textbf{Introduction}

The study of disease has progressed from an era focused on phenotype,
where all information was collected by the physician in collaboration
with the patient, with or without the use of tools such as the
stethoscope, endoscope, X-ray and Ct scanner. We have witnessed the
incorporation of ever more sophisticated laboratory-based findings,
collected via microscopy and instruments developed for biochemistry,
molecular biology and immunochemistry. Information gleaned by these
modern techniques can provide information on the underlying cellular and
molecular mechanisms that define the endotype. The purpose of this
review is to discuss the phenotypic and endotypic heterogeneity of
chronic rhinosinusitis from the perspective of advancing the
understanding of the pathogenesis and improvement of treatment
approaches and outcomes.

\textbf{Definition of phenotype and endotype}

To understand clinically observed variability in presentation and
outcomes, many chronic diseases have been classified by genotype,
phenotype and/or endotype. \emph{Genotypic} classification subdivides
disease based upon genetic polymorphisms and has been of limited utility
in CRS \textsuperscript{1}, aside from identifying related monogenic
conditions like cystic fibrosis \textsuperscript{2} or ciliary
dysmotility \textsuperscript{3}. \emph{Phenotypic} classifications
utilize clinically observable characteristics and have helped advance
understanding of natural history and treatment outcomes. In CRS,
phenotypic classification has utilized endoscopically observed features,
presence of comorbid or systemic illness and timing of disease onset.
Classification of CRS by the presence (CRSwNP) or absence (CRSsNP) of
nasal polyps has been the most widely applied phenotyping of CRS. CRSwNP
is viewed as a diffuse inflammatory process, while CRSsNP is linked, at
least in part, to sinus outflow obstruction with secondary inflammation
and infection, suggesting presence of a mechanical
process\textsuperscript{4}. Subclassification by the presence or absence
of common comorbidities such as asthma \textsuperscript{5} or
allergies\textsuperscript{6,7} has been used. Other phenotypic
subclassification has embraced recognized presentations such as Aspirin
Triad (AERD, NERD), Allergic Fungal Rhinosinusitis (AFRS), Eosinophilic
Granulomatosis with Polyangiitis (EGPA) \textsuperscript{8},
Granulomatosis with Polyangiitis (GPA), sinonasal sarcoidosis and CRS
with immunodeficiency \textsuperscript{9}, although these phenotypes are
relatively rare and variably defined.

There has been a growing appreciation that establishment of endotype,
which initially involved classification by histologic features such as
presence of neutrophilia, eosinophilia, fibrosis, glandular hypertrophy
and epithelial dysmorphosis, can provide insight into treatment response
or pathobiology. Classification based on the presence of fungi or
bacteria, has stimulated debate but not led to emergence of widely used
clinical protocols \textsuperscript{10-14}. Recent efforts seek to
define CRS \emph{endotypes} based upon specific molecular biomarkers or
mechanisms. It is gratifying that endotypes have strong associations
with phenotypes and histologic findings. Endotypic disease
classification is challenging because considerable tissue is required,
pathologist interpretations are variable, endotype assays are not
readily accessible and results may be influenced by treatment or
unstable \textsuperscript{15}. Nonetheless, there is an inexorable shift
of interest towards the molecular pathways that underlie endotypes that
drive inflammation, remodeling and clinical
phenotype\textsuperscript{16}. In conjunction with new, specific and
powerful interventions targeting molecular pathways, study of endotype
holds great promise.

\textbf{Early studies of CRS heterogeneity and indicators of underlying
endotypes}

Studies based on histology quantitated the numbers of eosinophils, mast
cells and neutrophils \textsuperscript{17-22}. In the West, CRSwNP
patients had higher numbers of eosinophils and mast cells while CRSsNP
expressed \emph{relatively} higher levels of neutrophils. Heterogeneity
of histology made it clear that there were multiple overlapping
processes \textsuperscript{23,24}. Specifically, many CRSwNP cases were
associated with both eosinophilic and neutrophilic infiltrates, while CF
polyps demonstrated a predominance of neutrophils \textsuperscript{25}.
Furthermore, a subset of CRSsNP cases exhibited elevated eosinophil
counts \textsuperscript{26}. Changes in remodeling including polypoid
edema, glandular hypertrophy and fibrosis have been used to subdivide
CRS \textsuperscript{27-29}. The combination of tissue remodeling
changes together with effector cell infiltrates has recently been
proposed in a \emph{structured histopathologic} classification system of
CRS \textsuperscript{30,31}. Histological phenotyping to distinguish
endotypes is only as good as the specificity of inflammatory cell counts
or tissue structural changes evaluated. For example, while current
evidence indicates that polyposis reflects formation of a fibrin matrix,
this feature can result from at least 3 distinct inflammatory
pathways\textsuperscript{32-34}. Although tissue eosinophilia and
remodeling are probably of value, histopathologic features have not been
defined in guidelines and remain experimental.

Early molecular studies indicated that IL-5 and IgE are important
biomarkers in eosinophilic CRS while IL-8 is found in neutrophilic
CRS\textsuperscript{35-39}. Recognition of a T cell cytokine expression
pattern was first made by Bachert and colleagues \textsuperscript{40}.
Interestingly, Asian CRSsNP expressed high levels of type 1
cytokines\textsuperscript{41} similar to Caucasians, but Asian CRSwNP
frequently expressed type 3 and type 1 cytokines, as in contrast to the
type 2 skewing in Caucasian polyps (see below for discussions of the
three types) \textsuperscript{42}. A landmark first attempt to define
the CRS endotypes was an international study that utilized a cluster
analysis of the presence of pre-selected biomarkers to distinguish 10
endotypes\textsuperscript{43}. The strength of the study was the
differential association of these endotypes with the phenotypic presence
of asthma or nasal polyposis. The 10 endotypes were further subdivided
into 3 groups based on high IL-5, low IL-5 or absence of IL-5
\textsuperscript{44}. Although the study did not associate endotype with
outcome data, it was an important starting point, and this publication
accelerated the search for biomarkers that could, at least in theory,
define endotypes that would respond uniquely to endotype-specific
therapeutics. 25\%

\textbf{Toward developing a current view of CRS molecular endotypes}

\emph{Underlying immunological mechanisms}

Pathology of CRSwNP has been well studied and tissue remodeling,
epithelial dysfunction, activation of innate and adaptive inflammatory
responses and fibrin deposition seem to be common features in
CRSwNP\textsuperscript{45,46}. CRSwNP is frequently divided into two key
endotypes, eosinophilic CRSwNP (ECRSwNP) and non-eosinophilic CRSwNP
(NECRSwNP) based on the presence and absence of large numbers of
eosinophils in nasal polyp (NP) tissue. Analysis of gene expression in
CRS tissues ultimately shifted focus to molecules produced by T
lymphocytes of types 1, 2 and 3 (also known as 17) that produce primary
cytokines that drive the inflammatory patterns observed in tissues
(referred to here as T1, T2 and T3 and Tun, signifying
``untypeable'').\textbf{Figure 1} shows microarray data from Chicago
using samples from CRS patients illustrating the stark contrast between,
and the strong similarity among, patients in the distinct endotypes, and
\textbf{Figure 2} shows a summary/overview of the driving cytokine,
source cells and effector cells in the tissues. ECRSwNP is characterized
by presence of type 2 (T2) cytokines (IL-4, IL-5 and IL-13) and
accumulation of type 2 immune cells including mast cells, basophils, CD4
T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2), B cells,
M2 macrophages and dendritic cells in addition to eosinophils. For this
reason, ECRSwNP is also called T2 CRSwNP \textsuperscript{45-55}.
NECRSwNP can also be subdivided based on presence of inflammatory
cytokines, including the type 1 (T1) endotype based on IFN-\selectlanguage{greek}γ \selectlanguage{english}signaling
and type 3 (T3) endotype based on IL-17A signaling; infiltrated cell
types include neutrophils, lymphocytes and plasma cells
\textsuperscript{52,56-59}. NECRSwNP is highly heterogeneous and the
frequency of each endotype varies geographically
\textsuperscript{56-58}. Transcriptomic approaches help to identify
immunological mechanisms in NP \textsuperscript{60-63}. Of note, two
groups presented distinct gene expression profiles in NP between ECRSwNP
and NECRSwNP in Asia and results also showed several similarities
\textsuperscript{56,63}. Both studies showed that eosinophil- and
T2-associated genes including \emph{CLC} , \emph{CCL23} ,\emph{CCL26} ,
\emph{SIGLEC8} , \emph{PRSS33} and \emph{ALOX15} were upregulated in
ECRSwNP, confirming that ECRSwNP is associated with the T2 endotype
\textsuperscript{56,63}. In contrast, NECRSwNP showed up-regulation of
IFN-\selectlanguage{greek}γ-\selectlanguage{english}induced genes (\emph{CXCL9} , \emph{CXCL10} and\emph{CXCL11} ),
IL-17A-induced genes (serum amyloid A, CXCL6 and CHI3L1) and neutrophil
chemokines (IL-8, CXCL1 and CXCL6), suggesting that NECRSwNP in Asia may
display mainly a mixed T1 and T3 endotype with neutrophilia
\textsuperscript{56,63}. Indeed, Wang and colleagues reported that the
T1 and T3 mixed (IFN-\selectlanguage{greek}γ\selectlanguage{english}\textsuperscript{+}, IL-17A\textsuperscript{+})
endotype is the most common endotype in NECRSwNP in Beijing
\textsuperscript{56}. Although ECRSwNP and NECRSwNP showed distinct
immunological mechanisms, both result in NP formation, suggesting that
some phenotypic features, such as formation of polyps, are not reliable
indicators of the transcriptomic pattern or molecular endotype. A
summary of gene expression in the primary endotypes and mixed endotypes
is found in \textbf{Figure 3} .

Transcriptome analysis may have value in identifying genes that are
associated with NP formation by extracting shared dysregulated genes in
NPs from both ECRSwNP and NECRSwNP. Epithelial-to-mesenchymal transition
(EMT) associated genes including HIF1A are elevated in both ECRSwNP and
NECRSwNP, suggesting that EMT may be a key event in NP
formation\textsuperscript{46,56,64}. Although transcriptome analysis
identifies similarities between ECRSwNP and NECRSwNP, the upstream
pathway for the affected molecules may be different in each endotype.
For example, reduced fibrinolysis associated with down-regulation of
tissue plasminogen activator (tPA) is a common feature of NPs in T2wNP
(ECRSwNP) and T1wNP (NECRSwNP) \textsuperscript{32,34,46}.

In contrast to CRSwNP, studies in CRSsNP have been complicated by the
use of variable sinonasal biopsy sites which have inherent
tissue-specific molecular differences that obscure the underlying
heterogeneity of inflammation \textsuperscript{57,58,62,65}. By the
exclusive use of ethmoid sinus mucosa for microarray, we recently
identified gene expression profiles in three inflammatory endotypes;
T1sNP, T2sNP and T3sNP, and predicted molecular mechanisms and
biomarkers for each endotype \textsuperscript{55}. The gene signatures
suggested that T1sNP is associated with T cells (Th1 cells and
CD8\textsuperscript{+} cytotoxic T cells), NK cells and antigen
presenting cells (APC); T2sNP is associated with eosinophils, mast
cells, basophils, Th2 cells, ILC2 and APC that are also found in T2wNP;
and T3sNP is associated with neutrophils, Th17 cells, B cells and
APC\textbf{(see Figure 2)} \textsuperscript{55}. We further found that
T1 (CXCL9 and CXCL10), T2 (eosinophilic proteins and CCL26) and T3
(CSF3) endotypic biomarkers can distinguish tissue endotypes in nasal
lavage fluids from patients with CRSsNP \textsuperscript{55}.

\emph{Pathological mechanisms and their relationships to features and
endotypes}

As mentioned above, in Western countries, CRSwNP is primarily
characterized by type 2 eosinophilic inflammation and mixed inflammatory
histopathology, while both eosinophilic and non-eosinophilic patterns
are found in polyps from Asian patients \textsuperscript{56,66}.
Interestingly, there has been a shift in the endotype distribution over
time with an increase in the degree of eosinophilia observed in NPs from
Asian patients \textsuperscript{67,68}. Furthermore, recent research
suggests that neutrophilic inflammation may also play a role in the
pathogenesis of Western NP \textsuperscript{69}. Thus, it is clear that
inflammatory patterns in CRSwNP show geographic variability across
Europe, Asia, and Oceania \textsuperscript{56}. While the neutrophilic
inflammatory endotype has been demonstrated in parts of Asia and Europe,
evidence is accumulating that, at least in the Western countries,
CRSsNP, like CRSwNP, has a predominantly type 2 eosinophilic
pattern\textsuperscript{57,70}.

Both innate and adaptive immune responses are important in the
pathogenesis and endotypes of CRS. The NP tissue is characterized by
dysregulated epithelium, elevated Th2 cells, innate lymphoid type 2
(ILC2) cells, B cells, mast cells, eosinophils, and
basophils\textsuperscript{48-51,54,71,72}. The sinonasal epithelium is
the principal source of TSLP which is essential for type 2 inflammation
and activates ILC2 cells and effector Th2 cells \textsuperscript{45}.
Investigators around the world have demonstrated elevated thymic stromal
lymphopoietin (TSLP) in eosinophilic NP tissue \textsuperscript{73-76}.
As already mentioned, Th2 and ILC2 are important sources of type 2
cytokines, including IL-4, 5, and 13 \textsuperscript{77}. IL-5 promotes
eosinophilic inflammation, and IL-4 and IL-13 activate isotype
switching, mucus production, M2 macrophage differentiation, and
remodeling in CRSwNP \textsuperscript{45}. Type 2 inflammation is
believed to drive NP formation by promoting fibrin deposition and
retention of plasma proteins and edema \textsuperscript{33,78}. In
addition to expansion of Th2 and ILC2, B cells and plasmablasts are also
increased and produce IgE and other immunoglobulins in NP
tissue\textsuperscript{40,79}. While CRSwNP is mainly type 2 (T2) in the
West, some patients manifest type 1 (T1), type 3 (T3), or mixed
inflammatory patterns with a combination of T1, T2, and T3 inflammation.
T1 and T3 inflammation are associated with elevated IFN \selectlanguage{greek}γ \selectlanguage{english}and IL-17A,
respectively. A subset of patients with CRS lacks an elevation of any
T1, T2, or T3 markers and are classified as untypeable. This subgroup
may represent another endotype of CRS whose inflammatory pattern is yet
to be identified \textbf{(see Figure 2)} .

The three major inflammatory endotypes are also present in
CRSsNP\textsuperscript{55,57,58}. It was initially proposed that type 1
inflammation associated with elevated IFN-\selectlanguage{greek}γ \selectlanguage{english}was present in CRSsNP;
however, this has not been confirmed in other
studies\textsuperscript{40,57,80}. Tan et al. investigated markers of
inflammation in the ethmoid tissue from patients with CRS and controls
and did not find a difference in IFN-\selectlanguage{greek}γ \selectlanguage{english}among CRSsNP, CRSwNP, and
controls. Type 2 markers of inflammation, including ECP, IL-5, and
IL-13, were highest in NP and ethmoid tissue from patients with
CRSwNP\textsuperscript{57}. Interestingly, T2 markers of inflammation
were also significantly elevated in the ethmoid tissue from patients
with CRSsNP compared to the ethmoid tissue from controls. Furthermore,
IL-17A, the primary marker of T3 inflammation, was elevated in the
ethmoid tissue of a subset of patients with CRSsNP. More recently, Kato
and colleagues have demonstrated that gene expression in CRSsNP is
reminiscent of that in CRSwNP. As in CRSwNP, in CRSsNP, T1 is associated
with T cells (Th1 and CD8\textsuperscript{+}), NK cells, and
antigen-presenting cells (APC), whereas T2 is associated with
eosinophils, mast cells, Th2 cells, ILC2, and APCs and T3 CRSsNP is
associated with Th17 cells, B cells, neutrophils, and
APCs\textsuperscript{55}. Wang et al. have also demonstrated that type 1
inflammation is predominant in Chinese patients from Beijing with
CRSsNP, whereas patients from Chendgu, China, lack elevation of T1, T2,
or T3 markers \textsuperscript{56}. \textbf{Figure 2} shows a
hypothetical overview of the inflammatory patterns of cells and
responses as related to the three primary endotypes, independent of the
phenotype (i.e. the presence or absence of polyps). We have adopted a
shorthand that encompasses both endotype and the major phenotype. Type 2
CRSwNP is \emph{T2wNP} in this scheme, while mixed type 1 and 3 CRSsNP
would be \emph{T1,3sNP} , etc. \textbf{Figure 3} presents the pure and
mixed endotypes and summarizes associated biomarkers. Occasionally,
either CRSsNP or CRSwNP patients are identified that have all three
endotypes elevated (T1,2,3sNP and T1,2,3wNP). The Tomassen paper
identified 10 clusters/endotypes based on type 1 and 2 cytokines and
inflammatory markers \textsuperscript{43}. Clusters associated with low
or no IL-5 resembled predominantly the CRSsNP phenotype and had a low
likelihood of comorbid asthma. The highest IL-5 clusters were mostly
CRSwNP patients expressing IgE to \emph{Staphylococcus
aureus}enterotoxins. One of their clusters expressed IL-17 and had a
mixed CRSsNP/wNP phenotype.

\emph{Genomics, proteomics and metabolomics}

Modern techniques including genomics (transcriptomics), proteomics and
metabolomics provide comprehensive and un-biased approaches to study
biological systems, identify previously un-recognized mechanistic
pathways in health and disease, and establish endotypes within a
disease\textsuperscript{81-83}. Systems biology has provided a more
holistic understanding of diseases and endotypes
\textsuperscript{81-83}. Proteomic analysis of nasal mucus and mucosa in
CRS suggested a trend of increased presence of immunological, metabolic,
tissue remodeling and apoptotic pathways in CRS \textsuperscript{84,85}.
Metabolomics analysis of low molecular weight compounds (up to 1,500 Da)
has been performed in CRS \textsuperscript{83}. Fazlollahi et al. found
that fatty acids (palmitic, oleic, stearic, and lauric) were highly
elevated in CRSwNP compared to CRSsNP and control tissues
\textsuperscript{86}. Miyata found impaired synthesis of cyclooxygenase-
and lipoxygenase-derived mediators (including prostaglandin
D\textsubscript{2}{[}PGD\textsubscript{2}{]}, PGE\textsubscript{2},
thromboxane B\textsubscript{2}, 15-hydroxyeicosatetraenoic acid and
lipoxin A\textsubscript{4}) and selective upregulation of leukotriene D4
in nasal polyp-derived eosinophils compared to healthy peripheral blood
eosinophils \textsuperscript{87}. Future proteome and metabolome studies
will require larger sample size and higher reproducibility to identify
endotypes. In contrast, transcriptome analysis by microarray and
RNA-Sequencing has been successfully used to characterize not only
phenotype-specific (e.g. CRSsNP and CRSwNP) but also endotype-specific
(e.g. eosinophilic and non-eosinophilic) gene expression profiles in
CRS.

\textbf{AERD as an informative phenotypic variant}

As many as 15\% of patients with CRSwNP have comorbid asthma and an
intolerance to inhibitors of cyclooxygenase 1
(COX-1)\textsuperscript{88,89}. This clinical triad is commonly referred
to as Aspirin Exacerbated Respiratory Disease (AERD) in North America.
The acronym NERD (NSAID Exacerbated Respiratory Disease) is often used
in Europe but has not been adopted in North America as the word has
negative connotations. While there is overlap between the phenotypes
(and endotypes) of AERD and CRSwNP, important distinctions exist. AERD
is the most severe sub-phenotype of CRSwNP. AERD patients typically have
more severe sinonasal inflammation, their polyps grow quickly, and they
undergo more sinus surgeries due to the recalcitrant nature of their
disease \textsuperscript{89,90}. Intolerance to COX-1 inhibitors has
unique implications for clinical management of AERD. Aspirin
desensitization followed by daily high-dose aspirin therapy can provide
clinical benefit for patients with AERD but not for those with CRSwNP
that tolerate COX-1 inhibitors \textsuperscript{91,92}. AERD is
predominantly characterized by type 2 inflammation. Studies are
conflicting as to whether type 2 cytokine levels in AERD are similar or
increased compared to CRSwNP, but levels are significantly elevated
versus healthy controls \textsuperscript{77,93}. In support of this,
AERD patients clinically respond to type-2
biologics\textsuperscript{94,95} and, in some studies, even more so than
patients with CRSwNP \textsuperscript{96}. As with observations in
CRSwNP and CRSsNP, Type 1 and type 3 endotypes have recently been
described in AERD\textsuperscript{93,97}. A dysregulation of arachidonic
acid metabolism uniquely distinguishes pathogenesis of AERD from CRSwNP.
AERD patients have a characteristic over-production of cysteinyl
leukotrienes and PGD\textsubscript{2} but reduced levels of
PGE\textsubscript{2}\textsuperscript{98}. AERD patients also have marked
activation of the 15 Lipoxygenase pathway, now thought to be important
in CRS.\textsuperscript{99,100} AERD patients with higher levels of
urinary PGD\textsubscript{2} may fail to tolerate an aspirin
desensitization compared to patients with lower PGD\textsubscript{2}
levels, suggesting that sub-endotypes of AERD may also be present and
clinically relevant\textsuperscript{101}\textbf{.}

\textbf{Relating endotypes to phenotypes and clinical findings of
disease}

Several groups have examined the association between endotypes and
clinical phenotypes in CRS. In general, T2 inflammation is associated
with NP (in the West) and asthma \textsuperscript{43,102}. The type 2
eosinophilic inflammation is also associated with disease recurrence and
severity in CRSsNP and CRSwNP \textsuperscript{70,103,104}. A study of
the association between endotypes and phenotypes was conducted by
Stevens et al., who examined inflammatory endotypes using markers
including IFN-\selectlanguage{greek}γ \selectlanguage{english}(T1), eosinophilic cationic protein (T2), Charcot-Leyden
crystal galectin (T2), and IL-17A (T3) in the ethmoid and NP tissue and
related them to clinical parameters from medical and surgical
records\textsuperscript{58}. The T2 endotype was associated with the
presence of NP, asthma comorbidity, smell loss, and allergic mucin in
all CRS patients. The presence of pus was associated with the T3
endotype, and headache/migraine was negatively associated with the T1
endotype. When assessing patients with CRSsNP alone, smell loss and
headache/migraine were associated with a T2 endotype, and the presence
of pus was more common in T1 and T3 endotypes. Similarly, the T3
endotype was also associated with pus in patients with CRSwNP, and the
T2 endotype tended to be associated with smell loss in patients with
mixed endotypes. In contrast to the CRSsNP subgroup, headache/migraine
was lower in the presence of T2 endotype in patients with CRSwNP
\textsuperscript{58}.\textbf{Figure 4} summarizes the relationship
between phenotype and endotype based on these findings.

A study using cluster analysis showed that older adults with CRS were
more likely to have neutrophilic inflammation in the sinus tissue and
elevated proinflammatory cytokines, IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-9, TNF-\selectlanguage{greek}α, \selectlanguage{english}and IL-6 in the
mucus compared to younger individuals with CRS \textsuperscript{105}.
The neutrophilic inflammatory pattern observed in older individuals was
clinically associated with purulent drainage and a higher likelihood of
bacteria. Potentially, these patients with predominantly neutrophilic
inflammation are less likely to respond to corticosteroids or biologics
and may respond to macrolides. Finally, elevated local IgE in NP tissue
compared to control sinonasal tissue has been observed in patients with
CRSwNP. Bachert and others have reported elevated levels of specific IgE
(sIgE) against \emph{Staphylococcus aureus} enterotoxins (SAE) in the NP
tissue and systemic circulation \textsuperscript{106,107}. The presence
of sIgE to SAE has been associated with comorbid asthma and more severe
sinonasal disease \textsuperscript{108,109}.

\textbf{Associations between endotypes and responses to surgical and
medical treatments}

Few studies have been performed evaluating the efficacy of specific
treatments for CRS as a function of endotype. Outcome studies for CRS
have generally not evaluated endotype prior to intervention, relying on
phenotype to subdivide patients. Further, the definition of treatment
success and the time point of evaluation post intervention have also
been variable. Despite these limitations, some tentative statements can
be made based on the presumed endotype of the population treated.

\emph{Short-Term Broad-Spectrum Antibiotics}

Three and even six-week courses were recommended for CRSsNP prior to
surgery for many years, based primarily on uncontrolled cohort
studies\textsuperscript{110}. Currently, no recommendation is made for
or against the use of antibiotics for CRS, given the lack of
placebo-controlled studies and avoidance of antibiotic
overuse\textsuperscript{111-113}. CRSsNP was historically presumed to be
the result of infection or secondary to biofilms, anaerobes or
intracellular pathogens \textsuperscript{13}. Later work indicated
alteration of the sinonasal microbiome rather than emergence of a
specific pathogen\textsuperscript{14}. Based on current dogma, the
tissue endotype resulting from bacterial infection should presumably be
T3, providing a theoretical rationale for the use of antibiotics in this
setting\textbf{(see Figure 2)} \textsuperscript{40}. More recent studies
on CRSsNP in Chicago have indicated that slightly over 50\% of CRSsNP
patient tissues exhibit at least a partial T2
endotype\textsuperscript{57}. It is reasonable to expect that a properly
selected group of CRS patients with T3 endotype, including polyp
patients, would be more likely to respond to broad-spectrum antibiotics.
A small prospective trial using 4 weeks of Augmentin documented
objective and subjective improvement in the non-T2 CRS subset
only\textsuperscript{114}. It has also been proposed
that\emph{Staphylococcus aureus} amplifies or causes T2 inflammation in
a subset of CRS patients \textsuperscript{115-117}, but studies
documenting efficacy of anti-staphylococcal antibiotics in association
with a reduction in this bacterium in the tissue have not been performed
to date.

\emph{Macrolides}

Macrolides exhibit immunomodulatory as well as antibiotic properties and
some mixed evidence exists to support long-term use in selected CRS
patients \textsuperscript{112,113}. The presumed mechanism of action is
the suppression of pro-inflammatory cytokines
\textsuperscript{118-120}Two randomized, placebo-controlled trials have
been performed in CRS.\textsuperscript{121,122} \emph{Post-hoc} analysis
of treatment response indicated that patients with low serum IgE (and
presumably non T2) responded best and these responders exhibited
decreased IL-8 levels in the mucus post treatment \textsuperscript{121}.
Later cohort studies demonstrated a lack of efficacy for macrolides in
eosinophilic CRSwNP patients \textsuperscript{123,124}. It remains to be
established whether responders exhibit T1, T3, null or mixed endotypes.
Studies of whether macrolides might have an additive effect with other
medications (e.g. corticosteroids or a biologic) dedicated to
suppressing T2 inflammation are worth pursuing
\textsuperscript{125-127}.

\emph{Doxycycline}

Doxycycline is an antibiotic that can also suppress cytokines,
chemokines and remodeling factors \textsuperscript{128-131}. Two small
randomized controlled trials on Western CRSwNP patients (80-90\% T2)
indicated modest polyp shrinkage and symptom improvement with
doxycycline, possibly by preventing enhancement of T2 responses
by\emph{Staphylococcus aureus} \textsuperscript{71,132-134}. Based on
these data, a role for doxycycline in the management of T2 CRSwNP has
been proposed. Mechanistic studies on doxycycline are unclear, however,
and a later clinical study indicated that low T2 biomarkers in CRSwNP
patients were predictors of a clinical
response\textsuperscript{135-137}.

\emph{Corticosteroids}

For many years, corticosteroids have been considered a mainstay of
treatment for CRS. Corticosteroids have potent anti-inflammatory
properties and suppress T2 inflammation greater than T1 and T3, possibly
explaining their better efficacy in CRSwNP than
CRSsNP\textsuperscript{138-141}. In the case of T2 inflammation,
corticosteroids suppress ILC2 cells, Th2 cells, basophils and
eosinophils \textsuperscript{142-145}. Neutrophils are relatively
resistant to corticosteroid effects, however \textsuperscript{146,147}.
Reduced activity against T3 inflammation may explain the decreased
corticosteroid responsiveness observed in clinical trials of Asian
CRSwNP as well as CRSsNP in general versus Western
CRSwNP\textsuperscript{66,147-154}. Topical corticosteroid sprays have
limited access to inflamed sinus tissue but high-volume steroid
irrigations, improved delivery devices and steroid-impregnated implants
have improved efficacy \textsuperscript{155-160}. Epithelial barrier
remodeling defects and basal cell hyperplasia induced by T2 inflammation
are partially reversed by corticosteroids \textsuperscript{161,162}.
Barrier defects may reflect expansions of basal epithelial cells due to
epigenetically determined events in T2 CRS and may increase antigen
access, heightening inflammation \textsuperscript{46,112,163}.

\emph{CRTH2 and Leukotriene Antagonists}

A subset of AERD patients may express a discrete T2 subendotype with
increased production of prostaglandin D2 (PGD\textsubscript{2}) and
cysteinyl leukotrienes compared to aspirin-tolerant T2
CRSwNP\textsuperscript{101}. PGD\textsubscript{2} activates the
chemoattractant receptor-homologous molecule expressed on Th2 cells
(CRTH2), which is important for eosinophil, basophil and lymphocyte
recruitment and activation \textsuperscript{164}. It is thus possible
that CRTH2 and leukotriene antagonists could play a more significant
role in managing patients with AERD compared to CRSwNP.

\emph{Surgery}

Surgery is an option after failure of appropriate medical
therapy\textsuperscript{113,165}. Modern endoscopic sinus surgery (ESS)
relieves sinus outflow obstruction, debrides inflamed tissue and
provides improved access for topical agents \textsuperscript{166}.
Relief of obstruction is more relevant in mild to moderate
CRSsNP\textsuperscript{4} and balloon dilation may be sufficient in
selected cases \textsuperscript{167}. Mucus stasis from obstruction
promotes microbial overgrowth and infectious inflammation predominantly
in non-polypoid T1,3 inflammation. Relieving obstruction is of less
value in CRS cases with diffuse inflammation as in CRSwNP and severe
CRSsNP, in particular when associated with T2
inflammation\textsuperscript{168,169}. Although high-level data is
lacking, more extensive surgical procedures such as a `full house ESS'
are typically recommended for these cases \textsuperscript{170-172}.
Maximum surgical approaches are reserved for the most severe cases and
involve removal of the floor of the frontal sinus and in some cases
sinus mucosa\textsuperscript{173-176}. Surgical recurrence rates are
generally correlated with the intensity of T2 tissue
inflammation\textsuperscript{177-181}. Systemic markers of T2
inflammation such as blood eosinophilia are associated with surgical
failure even in the absence of a T2 signature in the tissue
\textsuperscript{182}. In non-eosinophilic CRS, limited available data
suggests that higher intensity of T1 and T3 inflammation also favors
surgical failure\textsuperscript{182,183}.

\emph{Monoclonal Biologics}

Biologic therapies targeting type 2 inflammation are increasingly used
in patients with severe CRSwNP, which is associated with asthma
comorbidity, worse disease severity, and recurrence after surgery
(\textbf{Table 1} ). Several monoclonal antibodies are either approved
or under development for CRS. All inhibit aspects of T2 inflammation and
have minimal side effects. Use of anti-T1 or T3 monoclonal antibodies
for these respectively minor CRS endotypes (in the West) has not been
attempted. Such treatment, if safe, might benefit patients with T1 or T3
endotypes, especially in Asia, where they are more prevalent.

\emph{Dupilumab} is a monoclonal antibody that blocks IL-4 and IL-13 by
binding to the \selectlanguage{greek}α \selectlanguage{english}component of their shared receptors and inhibits T2
inflammation. In two phase 3 studies of only CRSwNP patients, SINUS-24
and SINUS-52, dupilumab reduced nasal polyp size, improved symptoms
including nasal congestion and anosmia, and improved quality of life in
patients with severe CRSwNP \textsuperscript{94}. A pooled analysis of
these studies showed that dupilumab reduced aggregate systemic
corticosteroid use and nasal surgery by 76\% compared to the placebo arm
and substantially decreased type 2 inflammatory markers in serum and
nasal secretions of patients with CRSwNP \textsuperscript{184}. Based on
these studies, dupilumab was approved for the treatment of inadequately
controlled CRSwNP.

\emph{Omalizumab} is a humanized monoclonal that selectively binds to
the C\selectlanguage{greek}ε\selectlanguage{english}3 domain of IgE and prevents IgE from binding to the high-affinity
IgE receptor on mast cells and basophils \textsuperscript{185}. Elevated
local IgE is found in NP and is associated with local eosinophilic
inflammation, severe NP, and comorbid
asthma\textsuperscript{11,43,49,72,79,106} . The POLYP 1 and POLYP 2
phase 3 trials found that omalizumab reduced polyp size and improved
sinonasal symptoms and quality of life in patients with
CRSwNP\textsuperscript{95}.

\emph{Mepolizumab} is a monoclonal antibody that inhibits IL-5, the
cytokine that is key in promoting eosinophil recruitment, activation and
survival. Phase 3 trials have demonstrated subjective and objective
efficacy and FDA approval for CRSwNP is expected late in 2021.
(ClinicalTrials.gov. NCT0308579). \emph{Benralizumab} is a cytotoxic
monoclonal antibody targeting the IL-5 receptor that eliminates
eosinophils and has undergone Phase 3 trials for CRSwNP
(ClinicalTrials.gov. NCT03401229). The completed phase 3 trials
reportedly met their primary endpoints at the time of this review.

Overall, although the monoclonal antibodies above are effective drugs
that target key elements of T2 inflammation, their efficacy relative to
each-other is presently unclear. T2 sub-endotypes likely exist, based
upon anecdotal reports of variable response to these monoclonal
antibodies. Intuitively, patients with eosinophil-driven disease should
respond best to mepolizumab or benralizumab, while patients with disease
driven by mast cells and IgE should respond best to omalizumab and
perhaps dupilumab; no head-to-head trials have been performed, and no
strong recommendations can be made as to which biologic to use first in
a patient with T2 disease. Nonetheless, expert panels have made some
recommendations for clinicians \textsuperscript{186}. There is the
untested impression that dupilumab has the greatest objective efficacy
and highest response rate of the currently available T2 targeting
monoclonal antibodies.

The success of T2 biologics in CRSwNP established the importance of
endotype targeted therapy in difficult to treat NP. Use of these drugs
is only approved in T2 polyp patients with established endotype. The use
of mucus samples to determine endotype is under development. Currently,
the presence of asthma, AERD and serum eosinophilia
(\textgreater{}300\selectlanguage{greek}µ\selectlanguage{english}l) are indicators of T2 CRSwNP in surgery na\selectlanguage{ngerman}ïve
patients. In post-surgery patients, eosinophilic histology is
definitive. T2 biologics are indicated for CRSwNP with severe symptoms
despite INS and more than one oral prednisone burst per year. Questions
remain about whether these drugs should be used in patients that have
not undergone surgery as the surgical revision rate at 5 years is only
approximately 20\% \textsuperscript{187-189}. While these drugs are
effective, QOL does not return to normal, and polyposis does not
completely resolve\textsuperscript{94}. The most effective and practical
treatment regimen for high risk, multi-recurrent patients may be surgery
followed by a planned post-operative biologic agent to prevent
recurrence and further reduce symptom burden.

\textbf{Summary and conclusions}

Understanding the basis of widespread heterogeneity in the
manifestations of CRS is advanced by findings that the three main
endotypes, T1, T2 and T3, orchestrate the expression of three distinct
large sets of genes. It is clear that T2 inflammation can be found
around the world and in both CRSwNP and CRSsNP phenotypes. Although the
prevalence of T2 endotype in Asia was very low decades ago, it is
increasing with industrialization. Another emerging view is that
endotype, rather than the phenotype, can drive clinical features, such
as the presence of comorbid asthma (T2sNP and T2wNP) and pus (T3sNP and
T3wNP). Drugs blocking T2 inflammation can shrink nasal polyps in
western countries; as trials are initiated in T2sNP patients, we expect
that this very large group of patients will be found to benefit from
blockade of type 2 inflammation. Studies of the microbiome may discover
that the higher prevalence of T3 forms of CRS in China reflect distinct
microbiological exposures. The development and use of improved methods
of endotyping disease in the clinic will likely usher in expansion of
the use of biological therapies targeting T2 and introduction of
treatments targeting other endotypes.

\textbf{Acknowledgments}

This research was supported in part by NIH grants, R01 AI137174, K23
AI141694, U19 AI106683 and P01 AI145818 and by a grant from the Ernest
S. Bazley Foundation.

\textbf{References}

1. Hsu J, Avila PC, Kern RC, Hayes MG, Schleimer RP, Pinto JM. Genetics
of chronic rhinosinusitis: state of the field and directions
forward.\emph{J Allergy Clin Immunol.} 2013;131(4):977-993, 993
e971-975.

2. Stevens WW, Lee RJ, Schleimer RP, Cohen NA. Chronic rhinosinusitis
pathogenesis. \emph{J Allergy Clin Immunol.} 2015;136(6):1442-1453.

3. Gudis D, Zhao KQ, Cohen NA. Acquired cilia dysfunction in chronic
rhinosinusitis. \emph{Am J Rhinol Allergy.} 2012;26(1):1-6.

4. Stammberger H, Posawetz W. Functional endoscopic sinus surgery.
Concept, indications and results of the Messerklinger
technique.\emph{Eur Arch Otorhinolaryngol.} 1990;247(2):63-76.

5. Song WJ, Lee JH, Won HK, Bachert C. Chronic Rhinosinusitis with Nasal
Polyps in Older Adults: Clinical Presentation, Pathophysiology, and
Comorbidity. \emph{Curr Allergy Asthma Rep.} 2019;19(10):46.

6. Chang EH, Stern DA, Willis AL, Guerra S, Wright AL, Martinez FD.
Early life risk factors for chronic sinusitis: A longitudinal birth
cohort study. \emph{J Allergy Clin Immunol.} 2018;141(4):1291-1297
e1292.

7. DelGaudio JM, Loftus PA, Hamizan AW, Harvey RJ, Wise SK. Central
compartment atopic disease. \emph{Am J Rhinol
Allergy.}2017;31(4):228-234.

8. Bacciu A, Buzio C, Giordano D, et al. Nasal polyposis in
Churg-Strauss syndrome. \emph{Laryngoscope.} 2008;118(2):325-329.

9. Ocampo CJ, Peters AT. Antibody deficiency in chronic rhinosinusitis:
epidemiology and burden of illness. \emph{Am J Rhinol
Allergy.}2013;27(1):34-38.

10. Ponikau JU, Sherris DA, Kern EB, et al. The diagnosis and incidence
of allergic fungal sinusitis. \emph{Mayo Clin Proc.} 1999;74(9):877-884.

11. Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P.
Total and specific IgE in nasal polyps is related to local eosinophilic
inflammation. \emph{J Allergy Clin Immunol.} 2001;107(4):607-614.

12. Perloff JR, Palmer JN. Evidence of bacterial biofilms on frontal
recess stents in patients with chronic rhinosinusitis. \emph{Am J
Rhinol.} 2004;18(6):377-380.

13. Kern RC, Conley DB, Walsh W, et al. Perspectives on the etiology of
chronic rhinosinusitis: an immune barrier hypothesis. \emph{Am J
Rhinol.} 2008;22(6):549-559.

14. Abreu NA, Nagalingam NA, Song Y, et al. Sinus microbiome diversity
depletion and Corynebacterium tuberculostearicum enrichment mediates
rhinosinusitis. \emph{Sci Transl Med.} 2012;4(151):151ra124.

15. Tan BK, Lu G, Kwasny MJ, et al. Effect of symptom-based risk
stratification on the costs of managing patients with chronic
rhinosinusitis symptoms. \emph{Int Forum Allergy
Rhinol.}2013;3(11):933-940.

16. Akdis CA, Bachert C, Cingi C, et al. Endotypes and phenotypes of
chronic rhinosinusitis: a PRACTALL document of the European Academy of
Allergy and Clinical Immunology and the American Academy of Allergy,
Asthma \& Immunology. \emph{J Allergy Clin
Immunol.}2013;131(6):1479-1490.

17. Harlin SL, Ansel DG, Lane SR, Myers J, Kephart GM, Gleich GJ. A
clinical and pathologic study of chronic sinusitis: the role of the
eosinophil. \emph{J Allergy Clin Immunol.} 1988;81(5 Pt 1):867-875.

18. Stoop AE, van der Heijden HA, Biewenga J, van der Baan S.
Eosinophils in nasal polyps and nasal mucosa: an immunohistochemical
study. \emph{J Allergy Clin Immunol.} 1993;91(2):616-622.

19. Jankowski R, Bene MC, Moneret-Vautrin AD, et al. Immunohistological
characteristics of nasal polyps. A comparison with healthy mucosa and
chronic sinusitis. \emph{Rhinol Suppl.} 1989;8:51-58.

20. Mygind N. Nasal polyposis. \emph{J Allergy Clin Immunol.} 1990;86(6
Pt 1):827-829.

21. Fokkens WJ, Holm AF, Rijntjes E, Mulder PG, Vroom TM.
Characterization and quantification of cellular infiltrates in nasal
mucosa of patients with grass pollen allergy, non-allergic patients with
nasal polyps and controls. \emph{Int Arch Allergy Appl
Immunol.}1990;93(1):66-72.

22. Drake-Lee A, Price J. Mast cell ultrastructure in the inferior
turbinate and stroma of nasal polyps. \emph{J Laryngol
Otol.}1997;111(4):340-345.

23. Polzehl D, Moeller P, Riechelmann H, Perner S. Distinct features of
chronic rhinosinusitis with and without nasal polyps.
\emph{Allergy.}2006;61(11):1275-1279.

24. Huvenne W, van Bruaene N, Zhang N, et al. Chronic rhinosinusitis
with and without nasal polyps: what is the difference? \emph{Curr
Allergy Asthma Rep.} 2009;9(3):213-220.

25. Sobol SE, Christodoulopoulos P, Manoukian JJ, et al. Cytokine
profile of chronic sinusitis in patients with cystic fibrosis.\emph{Arch
Otolaryngol Head Neck Surg.} 2002;128(11):1295-1298.

26. Soler ZM, Sauer D, Mace J, Smith TL. Impact of mucosal eosinophilia
and nasal polyposis on quality-of-life outcomes after sinus
surgery.\emph{Otolaryngol Head Neck Surg.} 2010;142(1):64-71.

27. Stierna P, Carlsoo B. Histopathological observations in chronic
maxillary sinusitis. \emph{Acta Otolaryngol.} 1990;110(5-6):450-458.

28. Berger G, Kattan A, Bernheim J, Ophir D. Polypoid mucosa with
eosinophilia and glandular hyperplasia in chronic sinusitis: a
histopathological and immunohistochemical study.
\emph{Laryngoscope.}2002;112(4):738-745.

29. Malekzadeh S, McGuire JF. The new histologic classification of
chronic rhinosinusitis. \emph{Curr Allergy Asthma
Rep.}2003;3(3):221-226.

30. Kuhar HN, Tajudeen BA, Heilingoetter A, et al. Distinct
histopathologic features of radiation-induced chronic
sinusitis.\emph{Int Forum Allergy Rhinol.} 2017;7(10):990-998.

31. Brescia G, Alessandrini L, Marioni G. Structured histopathology for
endotyping and planning rational treatment in chronic
rhinosinusitis.\emph{Am J Otolaryngol.} 2021;42(1):102795.

32. Takabayashi T, Kato A, Peters AT, et al. Excessive fibrin deposition
in nasal polyps caused by fibrinolytic impairment through reduction of
tissue plasminogen activator expression. \emph{Am J Respir Crit Care
Med.} 2013;187(1):49-57.

33. Takabayashi T, Kato A, Peters AT, et al. Increased expression of
factor XIII-A in patients with chronic rhinosinusitis with nasal
polyps.\emph{J Allergy Clin Immunol.} 2013.

34. Chen CL, Yao Y, Pan L, et al. Common fibrin deposition and tissue
plasminogen activator downregulation in nasal polyps with distinct
inflammatory endotypes. \emph{J Allergy Clin
Immunol.}2020;146(3):677-681.

35. Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5 synthesis is
upregulated in human nasal polyp tissue. \emph{J Allergy Clin
Immunol.}1997;99(6 Pt 1):837-842.

36. Bachert C, Wagenmann M, Rudack C, et al. The role of cytokines in
infectious sinusitis and nasal polyposis.
\emph{Allergy.}1998;53(1):2-13.

37. Takeuchi K, Yuta A, Sakakura Y. Interleukin-8 gene expression in
chronic sinusitis. \emph{Am J Otolaryngol.} 1995;16(2):98-102.

38. Suzuki H, Takahashi Y, Wataya H, et al. Mechanism of neutrophil
recruitment induced by IL-8 in chronic sinusitis. \emph{J Allergy Clin
Immunol.} 1996;98(3):659-670.

39. Riechelmann H, Deutschle T, Rozsasi A, Keck T, Polzehl D, Burner H.
Nasal biomarker profiles in acute and chronic rhinosinusitis. \emph{Clin
Exp Allergy.} 2005;35(9):1186-1191.

40. Van Zele T, Claeys S, Gevaert P, et al. Differentiation of chronic
sinus diseases by measurement of inflammatory mediators.
\emph{Allergy.}2006;61(11):1280-1289.

41. Cao PP, Li HB, Wang BF, et al. Distinct immunopathologic
characteristics of various types of chronic rhinosinusitis in adult
Chinese. \emph{J Allergy Clin Immunol.} 2009;124(3):478-484, 484
e471-472.

42. Zhang N, Van Zele T, Perez-Novo C, et al. Different types of
T-effector cells orchestrate mucosal inflammation in chronic sinus
disease. \emph{J Allergy Clin Immunol.} 2008;122(5):961-968.

43. Tomassen P, Vandeplas G, Van Zele T, et al. Inflammatory endotypes
of chronic rhinosinusitis based on cluster analysis of
biomarkers.\emph{J Allergy Clin Immunol.} 2016;137(5):1449-1456 e1444.

44. Bachert C, Akdis CA. Phenotypes and Emerging Endotypes of Chronic
Rhinosinusitis. \emph{J Allergy Clin Immunol Pract.} 2016;4(4):621-628.

45. Kato A. Immunopathology of chronic rhinosinusitis. \emph{Allergol
Int.} 2015;64(2):121-130.

46. Schleimer RP. Immunopathogenesis of Chronic Rhinosinusitis and Nasal
Polyposis. \emph{Annu Rev Pathol.} 2017;12:331-357.

47. Peterson S, Poposki JA, Nagarkar DR, et al. Increased expression of
CC chemokine ligand 18 in patients with chronic rhinosinusitis with
nasal polyps. \emph{J Allergy Clin Immunol.} 2012;129(1):119-127
e111-119.

48. Takabayashi T, Kato A, Peters AT, et al. Glandular mast cells with
distinct phenotype are highly elevated in chronic rhinosinusitis with
nasal polyps. \emph{J Allergy Clin Immunol.} 2012;130(2):410-420 e415.

49. Hulse KE, Norton JE, Suh L, et al. Chronic rhinosinusitis with nasal
polyps is characterized by B-cell inflammation and EBV-induced protein 2
expression. \emph{J Allergy Clin Immunol.} 2013;131(4):1075-1083, 1083
e1071-1077.

50. Derycke L, Eyerich S, Van Crombruggen K, et al. Mixed T helper cell
signatures in chronic rhinosinusitis with and without polyps. \emph{PLoS
One.} 2014;9(6):e97581.

51. Mahdavinia M, Carter RG, Ocampo CJ, et al. Basophils are elevated in
nasal polyps of patients with chronic rhinosinusitis without aspirin
sensitivity. \emph{J Allergy Clin Immunol.} 2014;133(6):1759-1763.

52. Shi LL, Song J, Xiong P, et al. Disease-specific T-helper cell
polarizing function of lesional dendritic cells in different types of
chronic rhinosinusitis with nasal polyps. \emph{Am J Respir Crit Care
Med.} 2014;190(6):628-638.

53. Poposki JA, Peterson S, Welch K, et al. Elevated presence of myeloid
dendritic cells in nasal polyps of patients with chronic
rhinosinusitis.\emph{Clin Exp Allergy.} 2015;45(2):384-393.

54. Poposki JA, Klingler AI, Tan BK, et al. Group 2 innate lymphoid
cells are elevated and activated in chronic rhinosinusitis with nasal
polyps. \emph{Immun Inflamm Dis.} 2017;5(3):233-243.

55. Klingler AI, Stevens WW, Tan BK, et al. Mechanisms and biomarkers of
inflammatory endotypes in chronic rhinosinusitis without nasal
polyps.\emph{J Allergy Clin Immunol.} 2020.

56. Wang X, Zhang N, Bo M, et al. Diversity of TH cytokine profiles in
patients with chronic rhinosinusitis: A multicenter study in Europe,
Asia, and Oceania. \emph{J Allergy Clin Immunol.} 2016;138(5):1344-1353.

57. Tan BK, Klingler AI, Poposki JA, et al. Heterogeneous inflammatory
patterns in chronic rhinosinusitis without nasal polyps in Chicago,
Illinois. \emph{J Allergy Clin Immunol.} 2017;139(2):699-703 e697.

58. Stevens WW, Peters AT, Tan BK, et al. Associations Between
Inflammatory Endotypes and Clinical Presentations in Chronic
Rhinosinusitis. \emph{J Allergy Clin Immunol Pract.} 2019;7(8):2812-2820
e2813.

59. Baba S, Kondo K, Toma-Hirano M, et al. Local increase in IgE and
class switch recombination to IgE in nasal polyps in chronic
rhinosinusitis. \emph{Clin Exp Allergy.} 2014;44(5):701-712.

60. Plager DA, Kahl JC, Asmann YW, et al. Gene transcription changes in
asthmatic chronic rhinosinusitis with nasal polyps and comparison to
those in atopic dermatitis. \emph{PLoS One.} 2010;5(7):e11450.

61. Tyler MA, Russell CB, Smith DE, et al. Large-scale gene expression
profiling reveals distinct type 2 inflammatory patterns in chronic
rhinosinusitis subtypes. \emph{J Allergy Clin
Immunol.}2017;139(3):1061-1064 e1064.

62. Wang W, Gao Z, Wang H, et al. Transcriptome Analysis Reveals
Distinct Gene Expression Profiles in Eosinophilic and Noneosinophilic
Chronic Rhinosinusitis with Nasal Polyps. \emph{Sci Rep.} 2016;6:26604.

63. Okada N, Nakayama T, Asaka D, et al. Distinct gene expression
profiles and regulation networks of nasal polyps in eosinophilic and
non-eosinophilic chronic rhinosinusitis. \emph{Int Forum Allergy
Rhinol.} 2018;8(5):592-604.

64. Ryu G, Mo JH, Shin HW. Epithelial-to-mesenchymal transition in
neutrophilic chronic rhinosinusitis. \emph{Curr Opin Allergy Clin
Immunol.} 2021;21(1):30-37.

65. Seshadri S, Rosati M, Lin DC, et al. Regional differences in the
expression of innate host defense molecules in sinonasal mucosa. \emph{J
Allergy Clin Immunol.} 2013;132(5):1227-1230 e1225.

66. Wen W, Liu W, Zhang L, et al. Increased neutrophilia in nasal polyps
reduces the response to oral corticosteroid therapy. \emph{J Allergy
Clin Immunol.} 2012;129(6):1522-1528 e1525.

67. Katotomichelakis M, Tantilipikorn P, Holtappels G, et al.
Inflammatory patterns in upper airway disease in the same geographical
area may change over time. \emph{Am J Rhinol
Allergy.}2013;27(5):354-360.

68. Kim SJ, Lee KH, Kim SW, Cho JS, Park YK, Shin SY. Changes in
histological features of nasal polyps in a Korean population over a
17-year period. \emph{Otolaryngol Head Neck Surg.} 2013;149(3):431-437.

69. Delemarre T, Holtappels G, De Ruyck N, et al. A substantial
neutrophilic inflammation as regular part of severe type 2 chronic
rhinosinusitis with nasal polyps. \emph{J Allergy Clin Immunol.} 2020.

70. Delemarre T, Holtappels G, De Ruyck N, et al. Type 2 inflammation in
chronic rhinosinusitis without nasal polyps: Another relevant
endotype.\emph{J Allergy Clin Immunol.} 2020;146(2):337-343 e336.

71. Van Zele T, Gevaert P, Holtappels G, van Cauwenberge P, Bachert C.
Local immunoglobulin production in nasal polyposis is modulated by
superantigens. \emph{Clin Exp Allergy.} 2007;37(12):1840-1847.

72. Buchheit KM, Dwyer DF, Ordovas-Montanes J, et al. IL-5Ralpha marks
nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated
respiratory disease. \emph{J Allergy Clin
Immunol.}2020;145(6):1574-1584.

73. Nagarkar DR, Poposki JA, Tan BK, et al. Thymic stromal lymphopoietin
activity is increased in nasal polyps of patients with chronic
rhinosinusitis. \emph{J Allergy Clin Immunol.} 2013;132(3):593-600 e512.

74. Liu T, Li TL, Zhao F, et al. Role of thymic stromal lymphopoietin in
the pathogenesis of nasal polyposis. \emph{Am J Med
Sci.}2011;341(1):40-47.

75. Boita M, Garzaro M, Raimondo L, et al. Eosinophilic inflammation of
chronic rhinosinusitis with nasal polyps is related to OX40 ligand
expression. \emph{Innate Immun.} 2015;21(2):167-174.

76. Ogasawara N, Klingler AI, Tan BK, et al. Epithelial activators of
type 2 inflammation: Elevation of thymic stromal lymphopoietin, but not
IL-25 or IL-33, in chronic rhinosinusitis with nasal polyps in Chicago,
Illinois. \emph{Allergy.} 2018;73(11):2251-2254.

77. Stevens WW, Ocampo CJ, Berdnikovs S, et al. Cytokines in Chronic
Rhinosinusitis. Role in Eosinophilia and Aspirin-exacerbated Respiratory
Disease. \emph{Am J Respir Crit Care Med.} 2015;192(6):682-694.

78. Takabayashi T, Schleimer RP. Formation of nasal polyps: The roles of
innate type 2 inflammation and deposition of fibrin. \emph{J Allergy
Clin Immunol.} 2020;145(3):740-750.

79. Feldman S, Kasjanski R, Poposki J, et al. Chronic airway
inflammation provides a unique environment for B cell activation and
antibody production. \emph{Clin Exp Allergy.} 2017;47(4):457-466.

80. Van Bruaene N, Perez-Novo CA, Basinski TM, et al. T-cell regulation
in chronic paranasal sinus disease. \emph{J Allergy Clin
Immunol.}2008;121(6):1435-1441, 1441 e1431-1433.

81. Pinu FR, Beale DJ, Paten AM, et al. Systems Biology and Multi-Omics
Integration: Viewpoints from the Metabolomics Research
Community.\emph{Metabolites.} 2019;9(4).

82. Veenstra TD. Systems Biology: Current Progress and Future
Outlook.\emph{Proteomics.} 2020:e2000235.

83. Michalik M, Samet A, Dmowska-Koroblewska A, et al. An Overview of
the Application of Systems Biology in an Understanding of Chronic
Rhinosinusitis (CRS) Development. \emph{J Pers Med.} 2020;10(4).

84. Kao SS, Bassiouni A, Ramezanpour M, et al. Scoping review of chronic
rhinosinusitis proteomics. \emph{Rhinology.} 2020;58(5):418-429.

85. Kao SS, Bassiouni A, Ramezanpour M, et al. Proteomic analysis of
nasal mucus samples of healthy patients and patients with chronic
rhinosinusitis. \emph{J Allergy Clin Immunol.} 2021;147(1):168-178.

86. Fazlollahi F, Kongmanas K, Tanphaichitr N, et al. Lipidomic
profiling of sinus mucosa from patients with chronic
rhinosinusitis.\emph{Clin Transl Sci.} 2015;8(2):107-115.

87. Miyata J, Fukunaga K, Kawashima Y, et al. Dysregulated fatty acid
metabolism in nasal polyp-derived eosinophils from patients with chronic
rhinosinusitis. \emph{Allergy.} 2019;74(6):1113-1124.

88. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of
aspirin-exacerbated respiratory disease among asthmatic patients: A
meta-analysis of the literature. \emph{J Allergy Clin
Immunol.}2015;135(3):676-681 e671.

89. Stevens WW, Peters AT, Hirsch AG, et al. Clinical Characteristics of
Patients with Chronic Rhinosinusitis with Nasal Polyps, Asthma, and
Aspirin-Exacerbated Respiratory Disease. \emph{J Allergy Clin Immunol
Pract.} 2017;5(4):1061-1070 e1063.

90. White AA, Stevenson DD. Aspirin-Exacerbated Respiratory
Disease.\emph{N Engl J Med.} 2018;379(11):1060-1070.

91. Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of
NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position
paper.\emph{Allergy.} 2019;74(1):28-39.

92. Stevens WW, Jerschow E, Baptist AP, et al. The role of aspirin
desensitization followed by oral aspirin therapy in managing patients
with aspirin-exacerbated respiratory disease: A Work Group Report from
the Rhinitis, Rhinosinusitis and Ocular Allergy Committee of the
American Academy of Allergy, Asthma \& Immunology. \emph{J Allergy Clin
Immunol.} 2020.

93. Scott WC, Cahill KN, Milne GL, et al. Inflammatory heterogeneity in
aspirin-exacerbated respiratory disease. \emph{J Allergy Clin
Immunol.}2020.

94. Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of
dupilumab in patients with severe chronic rhinosinusitis with nasal
polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two
multicentre, randomised, double-blind, placebo-controlled,
parallel-group phase 3 trials. \emph{Lancet.} 2019;394(10209):1638-1650.

95. Gevaert P, Omachi TA, Corren J, et al. Efficacy and safety of
omalizumab in nasal polyposis: 2 randomized phase 3 trials. \emph{J
Allergy Clin Immunol.} 2020;146(3):595-605.

96. Laidlaw TM, Mullol J, Fan C, et al. Dupilumab improves nasal polyp
burden and asthma control in patients with CRSwNP and AERD. \emph{J
Allergy Clin Immunol Pract.} 2019;7(7):2462-2465 e2461.

97. Jakiela B, Soja J, Sladek K, et al. Heterogeneity of lower airway
inflammation in patients with NSAID-exacerbated respiratory
disease.\emph{J Allergy Clin Immunol.} 2020.

98. Laidlaw TM, Boyce JA. Aspirin-Exacerbated Respiratory Disease--New
Prime Suspects. \emph{N Engl J Med.} 2016;374(5):484-488.

99. Stevens WW, Staudacher AG, Hulse KE, et al. Activation of the
15-lipoxygenase pathway in aspirin-exacerbated respiratory
disease.\emph{J Allergy Clin Immunol.} 2021;147(2):600-612.

100. Kristjansson RP, Benonisdottir S, Davidsson OB, et al. A
loss-of-function variant in ALOX15 protects against nasal polyps and
chronic rhinosinusitis. \emph{Nat Genet.} 2019;51(2):267-276.

101. Cahill KN, Bensko JC, Boyce JA, Laidlaw TM. Prostaglandin D(2): a
dominant mediator of aspirin-exacerbated respiratory disease. \emph{J
Allergy Clin Immunol.} 2015;135(1):245-252.

102. Wang M, Bu X, Luan G, et al. Distinct type 2-high inflammation
associated molecular signatures of chronic rhinosinusitis with nasal
polyps with comorbid asthma. \emph{Clin Transl Allergy.} 2020;10:26.

103. Szucs E, Ravandi S, Goossens A, Beel M, Clement PA. Eosinophilia in
the ethmoid mucosa and its relationship to the severity of inflammation
in chronic rhinosinusitis. \emph{Am J Rhinol.} 2002;16(3):131-134.

104. Kountakis SE, Arango P, Bradley D, Wade ZK, Borish L. Molecular and
cellular staging for the severity of chronic
rhinosinusitis.\emph{Laryngoscope.} 2004;114(11):1895-1905.

105. Morse JC, Li P, Ely KA, et al. Chronic rhinosinusitis in elderly
patients is associated with an exaggerated neutrophilic proinflammatory
response to pathogenic bacteria. \emph{J Allergy Clin
Immunol.}2019;143(3):990-1002 e1006.

106. Van Zele T, Gevaert P, Watelet JB, et al. Staphylococcus aureus
colonization and IgE antibody formation to enterotoxins is increased in
nasal polyposis. \emph{J Allergy Clin Immunol.} 2004;114(4):981-983.

107. Tripathi A, Kern R, Conley DB, et al. Staphylococcal exotoxins and
nasal polyposis: analysis of systemic and local responses. \emph{Am J
Rhinol.} 2005;19(4):327-333.

108. Bachert C, Zhang N, Holtappels G, et al. Presence of IL-5 protein
and IgE antibodies to staphylococcal enterotoxins in nasal polyps is
associated with comorbid asthma. \emph{J Allergy Clin
Immunol.}2010;126(5):962-968, 968 e961-966.

109. Jonstam K, Westman M, Holtappels G, Holweg CTJ, Bachert C. Serum
periostin, IgE, and SE-IgE can be used as biomarkers to identify
moderate to severe chronic rhinosinusitis with nasal polyps. \emph{J
Allergy Clin Immunol.} 2017;140(6):1705-1708 e1703.

110. Soler ZM, Oyer SL, Kern RC, et al. Antimicrobials and chronic
rhinosinusitis with or without polyposis in adults: an evidenced-based
review with recommendations. \emph{Int Forum Allergy
Rhinol.}2013;3(1):31-47.

111. Smith SS, Evans CT, Tan BK, Chandra RK, Smith SB, Kern RC. National
burden of antibiotic use for adult rhinosinusitis. \emph{J Allergy Clin
Immunol.} 2013;132(5):1230-1232.

112. Fokkens WJ, Lund VJ, Hopkins C, et al. European Position Paper on
Rhinosinusitis and Nasal Polyps 2020. \emph{Rhinology.} 2020;58(Suppl
S29):1-464.

113. Orlandi RR, Kingdom TT, Smith TL, et al. International consensus
statement on allergy and rhinology: rhinosinusitis 2021. \emph{Int Forum
Allergy Rhinol.} 2021;11(3):213-739.

114. Gunel C, Bleier BS, Meteoglu I. Antibiotics in eosinophilic chronic
rhinosinusitis: Rethinking maximal antimicrobial medical
therapy.\emph{Laryngoscope.} 2017;127(4):794-796.

115. Bachert C, Gevaert P, Zhang N, van Zele T, Perez-Novo C. Role of
staphylococcal superantigens in airway disease. \emph{Chem Immunol
Allergy.} 2007;93:214-236.

116. Lan F, Zhang N, Holtappels G, et al. Staphylococcus aureus Induces
a Mucosal Type 2 Immune Response via Epithelial Cell-derived
Cytokines.\emph{Am J Respir Crit Care Med.} 2018;198(4):452-463.

117. Bachert C, Holtappels G, Merabishvili M, et al. Staphylococcus
aureus controls interleukin-5 release in upper airway
inflammation.\emph{J Proteomics.} 2018;180:53-60.

118. Suzuki H, Shimomura A, Ikeda K, Oshima T, Takasaka T. Effects of
long-term low-dose macrolide administration on neutrophil recruitment
and IL-8 in the nasal discharge of chronic sinusitis
patients.\emph{Tohoku J Exp Med.} 1997;182(2):115-124.

119. Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of
macrolide antibiotics. \emph{Eur J Pharmacol.} 2001;429(1-3):209-229.

120. Healy DP. Macrolide immunomodulation of chronic respiratory
diseases. \emph{Curr Infect Dis Rep.} 2007;9(1):7-13.

121. Wallwork B, Coman W, Mackay-Sim A, Greiff L, Cervin A. A
double-blind, randomized, placebo-controlled trial of macrolide in the
treatment of chronic rhinosinusitis.
\emph{Laryngoscope.}2006;116(2):189-193.

122. Videler WJ, Badia L, Harvey RJ, et al. Lack of efficacy of
long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized
controlled trial. \emph{Allergy.} 2011;66(11):1457-1468.

123. Haruna S, Shimada C, Ozawa M, Fukami S, Moriyama H. A study of poor
responders for long-term, low-dose macrolide administration for chronic
sinusitis. \emph{Rhinology.} 2009;47(1):66-71.

124. Bezerra TFP, Pezato R, de Barros PM, et al. Prospective evaluation
of clarithromycin in recurrent chronic rhinosinusitis with nasal
polyps.\emph{Braz J Otorhinolaryngol.} 2019.

125. Huang Z, Zhou B. Clarithromycin for the treatment of adult chronic
rhinosinusitis: a systematic review and meta-analysis. \emph{Int Forum
Allergy Rhinol.} 2019;9(5):545-555.

126. Oakley GM, Harvey RJ, Lund VJ. The Role of Macrolides in Chronic
Rhinosinusitis (CRSsNP and CRSwNP). \emph{Curr Allergy Asthma
Rep.}2017;17(5):30.

127. Seresirikachorn K, Suwanparin N, Srisunthornphanich C,
Chitsuthipakorn W, Kanjanawasee D, Snidvongs K. Factors of success of
low-dose macrolides in chronic sinusitis: Systematic review and
meta-analysis. \emph{Laryngoscope.} 2019;129(7):1510-1519.

128. Lees KA, Orlandi RR, Oakley G, Alt JA. The Role of Macrolides and
Doxycycline in Chronic Rhinosinusitis. \emph{Immunol Allergy Clin North
Am.} 2020;40(2):303-315.

129. Henehan M, Montuno M, De Benedetto A. Doxycycline as an
anti-inflammatory agent: updates in dermatology. \emph{J Eur Acad
Dermatol Venereol.} 2017;31(11):1800-1808.

130. Gueders MM, Bertholet P, Perin F, et al. A novel formulation of
inhaled doxycycline reduces allergen-induced inflammation,
hyperresponsiveness and remodeling by matrix metalloproteinases and
cytokines modulation in a mouse model of asthma. \emph{Biochem
Pharmacol.} 2008;75(2):514-526.

131. Kuzin, II, Snyder JE, Ugine GD, et al. Tetracyclines inhibit
activated B cell function. \emph{Int Immunol.} 2001;13(7):921-931.

132. Van Zele T, Gevaert P, Holtappels G, et al. Oral steroids and
doxycycline: two different approaches to treat nasal polyps. \emph{J
Allergy Clin Immunol.} 2010;125(5):1069-1076 e1064.

133. De Schryver E, Derycke L, Calus L, et al. The effect of systemic
treatments on periostin expression reflects their interference with the
eosinophilic inflammation in chronic rhinosinusitis with nasal
polyps.\emph{Rhinology.} 2017;55(2):152-160.

134. Grammer LC. Doxycycline or oral corticosteroids for nasal
polyps.\emph{J Allergy Clin Immunol Pract.} 2013;1(5):541-542.

135. Cardell LO, Stjarne P, Jonstam K, Bachert C. Endotypes of chronic
rhinosinusitis: Impact on management. \emph{J Allergy Clin
Immunol.}2020;145(3):752-756.

136. Pinto Bezerra Soter AC, Bezerra TF, Pezato R, et al. Prospective
open-label evaluation of long-term low-dose doxycycline for
difficult-to-treat chronic rhinosinusitis with nasal
polyps.\emph{Rhinology.} 2017;55(2):175-180.

137. Sommer JU, Schultz JD, Grossbaier J, Stern-Straeter J, Hormann K,
Sauter A. In vitro effects of doxycycline on inflammatory cytokines and
gelatinases in chronic rhinosinusitis. \emph{In
Vivo.}2012;26(3):369-374.

138. Banuelos J, Lu NZ. A gradient of glucocorticoid sensitivity among
helper T cell cytokines. \emph{Cytokine Growth Factor
Rev.}2016;31:27-35.

139. Raundhal M, Morse C, Khare A, et al. High IFN-gamma and low SLPI
mark severe asthma in mice and humans. \emph{J Clin
Invest.}2015;125(8):3037-3050.

140. Halwani R, Al-Muhsen S, Hamid Q. T helper 17 cells in airway
diseases: from laboratory bench to bedside.
\emph{Chest.}2013;143(2):494-501.

141. Strehl C, Ehlers L, Gaber T, Buttgereit F.
Glucocorticoids-All-Rounders Tackling the Versatile Players of the
Immune System. \emph{Front Immunol.} 2019;10:1744.

142. Belvisi MG. Regulation of inflammatory cell function by
corticosteroids. \emph{Proc Am Thorac Soc.} 2004;1(3):207-214.

143. Walford HH, Lund SJ, Baum RE, et al. Increased ILC2s in the
eosinophilic nasal polyp endotype are associated with corticosteroid
responsiveness. \emph{Clin Immunol.} 2014;155(1):126-135.

144. Doherty TA, Broide DH. Pathways to limit group 2 innate lymphoid
cell activation. \emph{J Allergy Clin Immunol.} 2017;139(5):1465-1467.

145. Ogasawara N, Poposki JA, Klingler AI, et al. IL-10, TGF-beta, and
glucocorticoid prevent the production of type 2 cytokines in human group
2 innate lymphoid cells. \emph{J Allergy Clin
Immunol.}2018;141(3):1147-1151 e1148.

146. Schleimer RP, Freeland HS, Peters SP, Brown KE, Derse CP. An
assessment of the effects of glucocorticoids on degranulation,
chemotaxis, binding to vascular endothelium and formation of leukotriene
B4 by purified human neutrophils. \emph{J Pharmacol Exp
Ther.}1989;250(2):598-605.

147. Ray A, Kolls JK. Neutrophilic Inflammation in Asthma and
Association with Disease Severity. \emph{Trends
Immunol.}2017;38(12):942-954.

148. Chong LY, Head K, Hopkins C, Philpott C, Burton MJ, Schilder AG.
Different types of intranasal steroids for chronic
rhinosinusitis.\emph{Cochrane Database Syst Rev.} 2016;4:CD011993.

149. Kalish L, Snidvongs K, Sivasubramaniam R, Cope D, Harvey RJ.
Topical steroids for nasal polyps. \emph{Cochrane Database Syst
Rev.}2012;12:CD006549.

150. Head K, Chong LY, Piromchai P, et al. Systemic and topical
antibiotics for chronic rhinosinusitis. \emph{Cochrane Database Syst
Rev.} 2016;4:CD011994.

151. Zhou B, He G, Liang J, et al. Mometasone furoate nasal spray in the
treatment of nasal polyposis in Chinese patients: a double-blind,
randomized, placebo-controlled trial. \emph{Int Forum Allergy
Rhinol.}2016;6(1):88-94.

152. Hissaria P, Smith W, Wormald PJ, et al. Short course of systemic
corticosteroids in sinonasal polyposis: a double-blind, randomized,
placebo-controlled trial with evaluation of outcome measures. \emph{J
Allergy Clin Immunol.} 2006;118(1):128-133.

153. Britt RD, Jr., Thompson MA, Sasse S, Pabelick CM, Gerber AN,
Prakash YS. Th1 cytokines TNF-alpha and IFN-gamma promote corticosteroid
resistance in developing human airway smooth muscle. \emph{Am J Physiol
Lung Cell Mol Physiol.} 2019;316(1):L71-L81.

154. Nabe T. Steroid-Resistant Asthma and Neutrophils. \emph{Biol Pharm
Bull.} 2020;43(1):31-35.

155. Harvey RJ, Snidvongs K, Kalish LH, Oakley GM, Sacks R.
Corticosteroid nasal irrigations are more effective than simple sprays
in a randomized double-blinded placebo-controlled trial for chronic
rhinosinusitis after sinus surgery. \emph{Int Forum Allergy
Rhinol.}2018;8(4):461-470.

156. Kern RC, Stolovitzky JP, Silvers SL, et al. A phase 3 trial of
mometasone furoate sinus implants for chronic sinusitis with recurrent
nasal polyps. \emph{Int Forum Allergy Rhinol.} 2018;8(4):471-481.

157. Djupesland PG, Skretting A, Winderen M, Holand T. Breath actuated
device improves delivery to target sites beyond the nasal
valve.\emph{Laryngoscope.} 2006;116(3):466-472.

158. Fokkens W, Reitsma S. New delivery forms of nasal
corticosteroids.\emph{J Allergy Clin Immunol.} 2019;143(1):87-88.

159. Tait S, Kallogjeri D, Suko J, Kukuljan S, Schneider J, Piccirillo
JF. Effect of Budesonide Added to Large-Volume, Low-pressure Saline
Sinus Irrigation for Chronic Rhinosinusitis: A Randomized Clinical
Trial. \emph{JAMA Otolaryngol Head Neck Surg.} 2018;144(7):605-612.

160. Leopold DA, Elkayam D, Messina JC, Kosik-Gonzalez C, Djupesland PG,
Mahmoud RA. NAVIGATE II: Randomized, double-blind trial of the
exhalation delivery system with fluticasone for nasal polyposis. \emph{J
Allergy Clin Immunol.} 2019;143(1):126-134 e125.

161. Sekiyama A, Gon Y, Terakado M, et al. Glucocorticoids enhance
airway epithelial barrier integrity. \emph{Int
Immunopharmacol.}2012;12(2):350-357.

162. Steelant B, Farre R, Wawrzyniak P, et al. Impaired barrier function
in patients with house dust mite-induced allergic rhinitis is
accompanied by decreased occludin and zonula occludens-1
expression.\emph{J Allergy Clin Immunol.} 2016;137(4):1043-1053 e1045.

163. Ordovas-Montanes J, Dwyer DF, Nyquist SK, et al. Allergic
inflammatory memory in human respiratory epithelial progenitor
cells.\emph{Nature.} 2018;560(7720):649-654.

164. Corren J. New Targeted Therapies for Uncontrolled Asthma. \emph{J
Allergy Clin Immunol Pract.} 2019;7(5):1394-1403.

165. Ghogomu N, Kern R. Chronic rhinosinusitis: the rationale for
current treatments. \emph{Expert Rev Clin Immunol.} 2017;13(3):259-270.

166. Chin D, Harvey RJ. Nasal polyposis: an inflammatory condition
requiring effective anti-inflammatory treatment. \emph{Curr Opin
Otolaryngol Head Neck Surg.} 2013;21(1):23-30.

167. Chandra RK, Kern RC, Cutler JL, Welch KC, Russell PT. REMODEL
larger cohort with long-term outcomes and meta-analysis of standalone
balloon dilation studies. \emph{Laryngoscope.} 2016;126(1):44-50.

168. Leung RM, Kern RC, Conley DB, Tan BK, Chandra RK. Osteomeatal
complex obstruction is not associated with adjacent sinus disease in
chronic rhinosinusitis with polyps. \emph{Am J Rhinol
Allergy.}2011;25(6):401-403.

169. Snidvongs K, Kalish L, Sacks R, Sivasubramaniam R, Cope D, Harvey
RJ. Sinus surgery and delivery method influence the effectiveness of
topical corticosteroids for chronic rhinosinusitis: systematic review
and meta-analysis. \emph{Am J Rhinol Allergy.} 2013;27(3):221-233.

170. DeConde AS, Smith TL. Outcomes After Frontal Sinus Surgery: An
Evidence-Based Review. \emph{Otolaryngol Clin North
Am.}2016;49(4):1019-1033.

171. Snidvongs K, Pratt E, Chin D, Sacks R, Earls P, Harvey RJ.
Corticosteroid nasal irrigations after endoscopic sinus surgery in the
management of chronic rhinosinusitis. \emph{Int Forum Allergy
Rhinol.}2012;2(5):415-421.

172. Bassiouni A, Ou J, Rajiv S, Cantero D, Vreugde S, Wormald PJ.
Subepithelial inflammatory load and basement membrane thickening in
refractory chronic rhinosinusitis with nasal polyposis: a
histopathological study. \emph{Int Forum Allergy
Rhinol.}2016;6(3):248-255.

173. Jankowski R, Bodino C. Evolution of symptoms associated to nasal
polyposis following oral steroid treatment and nasalization of the
ethmoid--radical ethmoidectomy is functional surgery for
NPS.\emph{Rhinology.} 2003;41(4):211-219.

174. Barham HP, Ramakrishnan VR, Knisely A, et al. Frontal sinus surgery
and sinus distribution of nasal irrigation. \emph{Int Forum Allergy
Rhinol.} 2016;6(3):238-242.

175. Alsharif S, Jonstam K, van Zele T, Gevaert P, Holtappels G, Bachert
C. Endoscopic Sinus Surgery for Type-2 CRS wNP: An Endotype-Based
Retrospective Study. \emph{Laryngoscope.} 2019;129(6):1286-1292.

176. Morrissey DK, Bassiouni A, Psaltis AJ, Naidoo Y, Wormald PJ.
Outcomes of modified endoscopic Lothrop in aspirin-exacerbated
respiratory disease with nasal polyposis. \emph{Int Forum Allergy
Rhinol.} 2016;6(8):820-825.

177. Van Zele T, Holtappels G, Gevaert P, Bachert C. Differences in
initial immunoprofiles between recurrent and nonrecurrent chronic
rhinosinusitis with nasal polyps. \emph{Am J Rhinol
Allergy.}2014;28(3):192-198.

178. Lou H, Fang J, Li P, et al. Frequency, suppressive capacity,
recruitment and induction mechanisms of regulatory T cells in sinonasal
squamous cell carcinoma and nasal inverted papilloma. \emph{PLoS
One.}2015;10(5):e0126463.

179. Tokunaga T, Sakashita M, Haruna T, et al. Novel scoring system and
algorithm for classifying chronic rhinosinusitis: the JESREC
Study.\emph{Allergy.} 2015;70(8):995-1003.

180. Khairuddin NK, Salina H, Gendeh BS, Wan Hamizan AK, Lund VJ.
Quality of life and recurrence of disease in patients with eosinophilic
and non-eosinophilic 1 chronic rhinosinusitis with nasal
polyposis.\emph{Med J Malaysia.} 2018;73(1):1-6.

181. Rosati D, Rosato C, Pagliuca G, et al. Predictive markers of
long-term recurrence in chronic rhinosinusitis with nasal
polyps.\emph{Am J Otolaryngol.} 2020;41(1):102286.

182. Pan L, Liao B, Guo CL, et al. Inflammatory features and predictors
for postsurgical outcomes in patients with nasal polyps stratified by
local and systemic eosinophilia. \emph{Int Forum Allergy Rhinol.} 2020.

183. Ryu G, Kim DK, Dhong HJ, et al. Immunological Characteristics in
Refractory Chronic Rhinosinusitis with Nasal Polyps Undergoing Revision
Surgeries. \emph{Allergy Asthma Immunol Res.} 2019;11(5):664-676.

184. Bachert C, Mannent L, Naclerio RM, et al. Effect of Subcutaneous
Dupilumab on Nasal Polyp Burden in Patients With Chronic Sinusitis and
Nasal Polyposis: A Randomized Clinical Trial.
\emph{JAMA.}2016;315(5):469-479.

185. Chang TW, Davis FM, Sun NC, Sun CR, MacGlashan DW, Jr., Hamilton
RG. Monoclonal antibodies specific for human IgE-producing B cells: a
potential therapeutic for IgE-mediated allergic
diseases.\emph{Biotechnology (N Y).} 1990;8(2):122-126.

186. Bachert C, Han JK, Wagenmann M, et al. EUFOREA expert board meeting
on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP)
and biologics: Definitions and management. \emph{J Allergy Clin
Immunol.} 2021;147(1):29-36.

187. Hopkins C, Slack R, Lund V, Brown P, Copley L, Browne J. Long-term
outcomes from the English national comparative audit of surgery for
nasal polyposis and chronic rhinosinusitis.
\emph{Laryngoscope.}2009;119(12):2459-2465.

188. Smith TL, Schlosser RJ, Mace JC, et al. Long-term outcomes of
endoscopic sinus surgery in the management of adult chronic
rhinosinusitis. \emph{Int Forum Allergy Rhinol.} 2019;9(8):831-841.

189. Smith KA, Orlandi RR, Oakley G, Meeks H, Curtin K, Alt JA.
Long-term revision rates for endoscopic sinus surgery. \emph{Int Forum
Allergy Rhinol.} 2019;9(4):402-408.

\textbf{Table 1}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Biologic}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Dupilumab (anti IL-4R[?])\textsuperscript{1}}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Dupilumab (anti IL-4R[?])\textsuperscript{1}}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Omalizumab (anti IgE)\textsuperscript{2}}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Omalizumab (anti IgE)\textsuperscript{2}}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Mepolizumab (anti IL-5)\textsuperscript{3}}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Benralizumab (anti IL-5R[?])*}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Study Name} \textbf{(Total numbers)} \textbf{Treatment
Duration}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{SINUS-24} \textbf{(N=276)} \textbf{24 weeks}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{SINUS-52} \textbf{(N=448)} \textbf{52 weeks}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{POLYP 1} \textbf{(N=138)} \textbf{24 weeks}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{POLYP 2} \textbf{(N=127)} \textbf{24 weeks}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{SYNAPSE} \textbf{(N=407)} \textbf{52 weeks}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{OSTRO} \textbf{(N=413)} \textbf{56 weeks}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Co-Primary Outcomes}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
LS mean difference in NPS vs placebo (scale 0-8) 95\% CI (P value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
LS mean difference in NPS vs placebo (scale 0-8) 95\% CI (P value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Treatment arm difference in NPS vs placebo (scale 0-8) 95\% Cl (P
value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Treatment arm difference in NPS vs placebo (scale 0-8) 95\% Cl (P
value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Difference in median change from baseline for NPS (scale 0-8) 95\% Cl (P
value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
NPS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-2.06 -2.43, -1.69 (P\textless{}0.0001)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-1.80 -2.10, -1.51 (P\textless{}0.0001)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-1.14 -1.59, -0.69 (P\textless{}0.0001)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.59 -1.05, -0.12 (P=0.0140)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.73 -1.11, -0.34 (P\textless{}0.001)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Met primary endpoint\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
LS mean difference in NCS vs placebo (scale 0-3) 95\% Cl (P value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
LS mean difference in NCS vs placebo (scale 0-3) 95\% Cl (P value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Treatment arm difference in NCS vs placebo (scale 0-3) 95\% Cl (P
value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Treatment arm difference in NCS vs placebo (scale 0-3) 95\% Cl (P
value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Difference in median change from baseline in nasal obstruction VAS score
95\% Cl (P value)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Nasal blockage score\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.89 -1.07, -0.71 (P\textless{}0.0001)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.87 -1.03, -0.71 (P\textless{}0.0001)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.55 -0.84, -0.25 (P=0.0004)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.50 -0.80, -0.19 (P=0.0017)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-3.14 -4.09, -2.18 (P\textless{}0.001)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Met primary endpoint\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Secondary Outcomes}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Significant improvement with dupilumab vs placebo (week 24)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Significant improvement with dupilumab vs placebo (week 24)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Significant improvement with omalizumab vs placebo (week 24)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Significant improvement with omalizumab vs placebo (week 24)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Significant improvement with mepolizumab vs placebo (week 52)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
NOT PUBLISHED\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Quality of life (SNOT-22) Total symptom score Sense of smell (UPSIT) and
loss of smell score Radiographic assessment (Lund-Mackay score)
Increased time to oral corticosteroids or surgery\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Quality of life (SNOT-22) Total symptom score Sense of smell (UPSIT) and
loss of smell score Radiographic assessment (Lund-Mackay score)
Increased time to oral corticosteroids or surgery\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
UPSIT and loss of smell score SNOT-22 score UPSIT score TNSS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
UPSIT and loss of smell score SNOT-22 score UPSIT score TNSS\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
SNOT-22 VAS score Loss of smell Reduced need for surgery Reduced need
for systemic corticosteroid use\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Adverse reactions} \textbf{with active drug}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Injection site reaction, transient eosinophilia, conjunctivitis (7
cases), EGPA (1 case), eosinophilia with arthralgia (1 case)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Injection site reaction, transient eosinophilia, conjunctivitis (7
cases), EGPA (1 case), eosinophilia with arthralgia (1 case)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Headache, injection site reaction, dizziness, upper abdominal pain\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Headache, injection site reaction, dizziness, upper abdominal pain\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Nasopharyngitis\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

1. Bachert C, et al. Lancet 2019;394:1638-1650

2. Gevaert P, et al. J Allergy Clin Immunol 2020;146:595--605

3. Eur Respir J 2020;56:Suppl. 64, 4616

*Press release September 2020

LS: least squares; NPS: nasal polyp score; NCS: nasal congestion score;
SNOT-22: Sino-nasal Outcome Test; UPSIT: University of Pennsylvania
Smell Identification Test; VAS: visual analog scale; TNSS: Total nasal
symptom score

EGPA: eosinophilic granulomatosis with polyangiitis

\textbf{Figure Legends}

\textbf{Figure 1} . Gene expression patterns in sinonasal tissue from
patients undergoing surgery in Chicago at Northwestern. Data are from
samples from patients with no sinonasal disease (Control, n=11), CRSsNP
(9 TunsNP, 5 T1sNP, 8 T2sNP and 5 T3sNP) and CRSwNP (8 ET and 9 NP). The
heatmap shows genes with more than 3-fold elevated levels in T1sNP,
T2sNP or T3sNP compared to controls. Inspection of the gene expression
patterns shows that CRSwNP samples from ethmoid and from nasal polyps
are closely aligned with the T2 patterns seen in ethmoid tissue from a
subset of patients with CRSsNP. The figure was adapted from published
studies by Klingler al \textsuperscript{55}. Tun -- untypeable, T1 --
Type 1 endotype, T2 -- Type 2 endotype and T3 -- Type 3/17 endotype (see
text). ET -- ethmoid tissue, NP -- nasal polyp tissue.

\textbf{Figure 2} . Overview of the primary cytokines driving T1, T2 and
T3 endotypes, the source cells producing the primary cytokines and the
effector cells that are recruited to the tissue and activated. Classical
endotype refers to earlier endotyping based on the presence or absence
of eosinophils. The natural pathogenic targets of each immunological
endotype are listed at the bottom of the figure.

\textbf{Figure 3} . Summary of the major biomarker genes whose
expression is elevated in the T1, T2 and T3 endotypes of CRS (whether
CRSsNP or CRSwNP). Also shown are the ``mixed'' endotypes, as indicated
by T1,3, T1,2 and T2,3. Not shown are T untypeable (Tun), which do not
express the biomarker genes or T1,2,3, a rare group of patients that
have elevated levels of all three sets of biomarker genes.

\textbf{Figure 4} . Overview of recent studies linking disease
phenotypic signs and symptoms with molecular endotype, showing the
changes in prevalence of each phenotype in the indicated endotypes. It
is anticipated that future studies will increasingly link phenotypic
signs and symptoms with underlying endotype to better define pathogenic
mechanisms and indicate appropriate treatment regimens.

\selectlanguage{english}
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\end{document}

