Received: 28 August 2019 | Accepted: 30 September 2019

DOI: 10.1111/coa.13455

EDITORIAL COMMENT

Understanding and clinical relevance of chronic rhinosinusitis

endotypes

Qasim Husain1 | Ahmad R. Sedaghat2

1
Department of Otolaryngology – Head &
Neck Surgery, Massachusetts Eye and Ear Abstract
Infirmary, Harvard Medical School, Boston, Background: Chronic rhinosinusitis (CRS) is the downstream manifestation of het‐
MA, USA
2 erogeneous pathophysiologic mechanisms leading to chronic sinonasal inflammation.
Department of Otolaryngology – Head
& Neck Surgery, University of Cincinnati Traditional grouping of patients by symptoms or clinical findings/phenotypes is being
College of Medicine, Cincinnati, OH, USA
replaced by classification of CRS patients based on the underlying pathophysiologic
Correspondence mechanisms: endotypes.
Ahmad R. Sedaghat, Department of
Objective of Review: To provide an up‐to‐date review on the current knowledge
Otolaryngology – Head and Neck Surgery,
University of Cincinnati College of Medicine, of CRS endotypes with a focus on how the pathophysiologic mechanisms defined
Medical Sciences Building Room 6410,
by each endotype may be targeted therapeutically. Special emphasis is placed on
231 Albert Sabin Way, Cincinnati, OH
45267‐0528, USA. the clinical relevance of the material and how it may inform the current practice of
Email: ahmad.sedaghat@uc.edu
otolaryngologists.
Type of Review: A systematic review of contemporary literature review focusing on the
latest studies examining the role of endotypes in the management and treatment of CRS.
Search Strategy: A MEDLINE and PubMed Central search were undertaken to per‐
form this review using the keywords “Endotype” and “Sinusitis.”
Evaluation Method: Articles containing the keywords, as well as the references of
those articles, were then examined for relevance.
Results: The endotypes for CRS are often defined based on the balance of T‐helper
cell patterns of inflammation and can be grouped into Th2 and non‐Th2 inflamma‐
tion. These groups have shown a variable response to medical and surgical therapy,
demonstrating that existing mainstream treatments can be tailored to patients with
specific endotypes. The inflammatory mediators of Th2 inflammation, IL‐4, IL‐5 and
IL‐13 as well as IgE, are targeted by available biologic drugs that can be used for treat‐
ment of refractory disease.
Conclusions: Increased understanding of CRS endotypes has led to the identification
of biomarkers that define these endotypes and act as targets for potential thera‐
peutics. Increasing knowledge about characteristics associated with these endotypes
and their responses to treatments, including both established mainstream CRS treat‐
ments and novel biologic medications, has allowed incorporation of CRS endotypes
into the current clinical decision‐making. Treatment of CRS patients based on consid‐
eration of their endotypes is therefore not only presently possible but may improve
clinical outcomes of those patients as well.

Clinical Otolaryngology. 2019;00:1–11. wileyonlinelibrary.com/journal/coa

© 2019 John Wiley & Sons Ltd | 1
2 | HUSAIN and SEDAGHAT

KEYWORDS

biologics, chronic rhinosinusitis, endotypes, outcomes, pathophysiology, polyps, Th1,

Th2

1 | BAC KG RO U N D
Keypoints
Chronic rhinosinusitis (CRS) is the culmination of a multitude of path‐
• Endotypes of CRS are representative of distinct patho‐
ogenic mechanisms that converge on a final clinical manifestation of
physiologic mechanisms for the disease and can be
chronic sinonasal inflammation. CRS may be prevalent in up to ap‐
identified using biomarkers and the detection of hyperac‐
proximately ten per cent of the population and it is associated with a
tivation of specific inflammatory pathways.
significant quality of life detriment for affected patients and billions
• Endotypes of CRS are most often defined based on the
of dollars in healthcare costs.1-3 CRS negatively impacts quality of
balance of T‐helper cell patterns of inflammation and are
life through chronic symptomatology, acute exacerbations of symp‐
commonly broken into Th2 and non‐Th2 endotypes.
toms, as well as exacerbation of comorbid pulmonary disease.4-7
• Although formally defined by the relative levels of inflam‐
Billions of dollars in cost are associated with direct expenses related
matory mediators in the sinonasal mucosa, usually in the
to medications and physician visits as well as indirect expenses re‐
setting of research protocols, readily available clinical
lated to missed work or lost productivity.8
characteristics can be used to predict patients’ endo‐
Historically, patients have been classified phenotypically; cate‐
types. The Th2 endotype is associated with atopy, comor‐
gories developed based on a constellation of symptoms or clinical
bid asthma, nasal polyps, as well as elevated level of IgE
features. However, these clinical phenotypes simplify the complex
and eosinophils in the peripheral blood and/or sinonasal
interplay between the cellular and molecular pathophysiology
mucosa.
involved in CRS. With recent advances in our understanding of
• The biologic therapies have been mostly developed
CRS pathophysiology, the emphasis is moving away from classi‐
against Th2 inflammation—with targets including IL‐4,
fying patients based on clinical findings reflective of sinonasal
IL‐5, IL‐13 and their associated biomarkers, as well as IgE.
inflammation—that is radiologic and nasal endoscopic findings—
• Patients with the non‐Th2 endotypes often have im‐
and towards classifying patients based on the underlying inflam‐
proved outcomes with long‐term macrolide antibiotics
matory mechanisms driving the disease. Classifications of CRS as
and limited surgical therapy, whereas patients with the
subtypes, defined based on common underlying pathophysiologic
Th2 endotype have improved outcomes with corticoster‐
mechanisms, are collectively referred to as endotypes. Although
oids and comprehensive surgical therapy.
phenotypes of CRS may be more clinically apparent, clinical phe‐
notype or appearance of a disease does not necessarily translate
to prognosis or treatment response. In contrast, distinct mecha‐
nisms of disease—which are reflected by disease endotypes—are reviewing knowledge of CRS endotypes, but also discussing the
much more likely to be predictive of long‐term disease prognosis clinical relevance with respect to treatment, we believe that this
and response to treatments. review will be informative for both researchers and practicing
Endotypes of CRS represent distinct pathophysiologic mech‐ otolaryngologists.
anisms of disease and can be identified using biomarkers and the
detection of hyperactivation of specific inflammatory pathways
in the sinonasal mucosa, nasal mucus or peripheral blood of CRS 2 | M E TH O DS
patients. By studying and focusing on endotype‐specific inflam‐
matory mediators, we can better understand persistent symptoms The objective of this article is to provide a systematic review on CRS
as well as physiologic abnormalities. This review highlights cur‐ endotypes with a focus on clinical applicability. With that goal in
rent knowledge of CRS endotypes with a special focus not only mind, the MEDLINE and PubMed Central databases were queried
on the various mechanisms of disease that have been identified using PubMed for studies and review articles that addressed the ob‐
as distinct CRS endotypes, but also how these mechanisms may jective of this review. Searches were performed between July and
be targeted therapeutically. Much of the research that has been October 2019 using primary search terms including “rhinosinusitis”
performed on CRS has paralleled that which has been previously and “endotype” and included only publications in the last 10 years.
described for elucidation of asthma endotypes.9 In fact, many of The references of identified articles were also searched for pertinent
the biological targets and current therapeutics under study for articles. Given the objective of this review, the focus of the search
various CRS endotypes have been described for effective endo‐ was primary literature that provided insight into how CRS endotypes
type‐driven treatment of asthma, suggesting the high likelihood could be identified and used to inform clinical decision‐making for
of similar efficacy for treatment of CRS. By focusing on not only presently practicing otolaryngologists.
HUSAIN and SEDAGHAT | 3

F I G U R E 1 Publication selection
process based on Preferred Reporting
Items for Systematic Reviews and Meta‐
Analyses

3 | R E S U LT S classify phenotypes of CRS patients. Patients can be classified based

on the severity of their symptoms (mild, moderate, severe)11 or the
Our search identified 34 studies. Following a manual bibliography preponderance of nasal and extra‐nasal symptoms.11-14 Patients may
search, an additional 16 articles were identified with the goal of also be classified by the frequency with which they experience acute
identifying primary literature. Studies were excluded if they were exacerbations of CRS or acute super‐infections.15 Most commonly,
review articles (n = 20), off scope (n = 5), included phenotype clus‐ CRS patients have been catalogued based on the presence of comor‐
tering without biomarkers (n = 4), were non‐English (n = 1) and had bid signs or conditions such as nasal polyps, asthma or atopy.16 While
unobtainable full text (n = 1) (Figure 1). Included articles (n = 19) categorising CRS by phenotypes seems logical, these groupings have
described the measurement of biomarkers as surrogates for endo‐ not been shown to accurately predict treatment outcomes.
types and how they relate to CRS (Table 1). Primary literature was Clinical consensus statements by both the American and
sourced and integrated with the available literature in this review. European Rhinologic Societies recommend the use of intranasal
corticosteroids and saline irrigations for appropriate medical man‐
agement of CRS as only these treatments are supported by level
4 | D I S CU S S I O N
1 evidence for all CRS patients.3,17 Despite these evidence‐based
recommendations for appropriate medical management of CRS,
4.1 | Phenotypes and endotypes of CRS
medical treatment failures occur in up to 50% of CRS patients and
clinical phenotypes have been not been helpful in predicting which
4.1.1 | CRS phenotypes
patients will respond to medical management.18-20 Within each clin‐
An important distinction to be made is the difference between CRS ical phenotype of CRS, there are patients who respond well and
phenotypes and endotypes. The term phenotype was originally those who respond poorly to therapy. For example, montelukast
derived from the study of human genetics and development, as a has been reported to have little effect in patients with chronic rhi‐
reflection of specific observable traits without implication for the nosinusitis with nasal polyposis (CRSwNP), but may have a poten‐
underlying mechanism. Phenotype is used in contrast to the term tially greater effect in the subset of CRSwNP patients with allergic
genotype, which refers to traits in the context of underlying genet‐ fungal rhinosinusitis (AFRS).7,21 Given the inconsistent treatment
ics/heredity (specifically reflecting the underlying mechanism of the responses amongst patients of the same CRS phenotype, there is
trait). In the context of human disease, phenotypes similarly reflect a clear need for better ways to predict responders from non‐re‐
observable disease characteristics without a consideration of the sponders—a necessity in moving towards personalised medicine/
underlying mechanism of the disease. treatment for CRS. Since it is accepted that CRS is mediated by a
Chronic rhinosinusitis is a heterogeneous collection of dis‐ complex interplay between environmental factors (eg extrinsic
eases whose end result is sinonasal inflammation causing nasal ob‐ pathogens, the sinonasal microbiome, allergens) and host suscep‐
struction, discharge, loss of smell or facial pain lasting longer than tibility (anatomical obstruction, immune system, impaired mu‐
3,10
12 weeks. Classically, CRS patients have been classified based cociliary clearance), it is increasingly believed that knowledge of
on their phenotypes—clinical characteristics that were observed to patient‐specific pathophysiologic mechanisms may be more predic‐
easily divide patients into subsets. There are a variety of ways to tive of treatment response.
4 | HUSAIN and SEDAGHAT

TA B L E 1 Studies meeting criteria for systematic review

Lead author Year Patients Biomarkers

38
Cao et al 2009 45 CRSwNP FOXP3, IFN‐γ, IL‐5, IL‐10, IL‐17A, IL‐22, IL‐23, RORC,TBET, TGF‐β1, Valpha24
36 CRSsNP
17 Control
Divekar et al31 2017 13 CRSwNP EGF, Eotaxin, G‐CSF, IFN‐γ, IL‐2, IL‐3, IL‐5, IL‐7, IL‐8, IL‐9, IL‐13, IL‐17A, MIP,
13 CRSsNP MCP, MDC, PDGF, TNF, VEGF
6 Control
Gevaert et al58 2006 24 CRSwNP ECP, Eotaxin, IL‐5, SOL IL‐5Rα
Ho et al27 2014 13 E‐ CRS IgE, ILC2
13 NE‐ CRS
9 Control
Ikeda et al33 2013 130 CRsNP Eotaxin, IL‐17A, MUC5AC, SOD
Kim et al69 2017 69 CRSwNP IFN‐γ, IL‐1β, IL‐5, IL‐17A, IL‐22, IL‐33, TNF‐ α
61 CRSsNP
19 Control
Kim et al29 2018 140 CRS COL1A1, CCL‐11, CCL‐24, CXCL‐1, CXCL‐2, FOXP3, GATA3, IFN‐γ, IL‐5, IL‐10,
20 Control IL‐13, IL‐17A, IL‐22, IL‐23, Periostin, ST2, T‐bet, TSLP, RORC
Kim et al28 2019 11 NE‐ CRSwNP CCL‐11, CCL‐24, CXCL‐1, CXCL‐2, CXCL‐8, ICAM‐1, IFN‐γ, IL‐1α, IL‐1β, IL‐2,
16 E‐ CRSwNP IL‐2Rα, IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, IL‐17A, IL‐23, MCP‐4, RANTES, TNFα,
20 CRSsNP VCAM‐1
9 Control
Lam et al41 2012 12 CRSwNP CRP, ESR, Eotaxin‐3, IgE, IL‐25. IL‐ 33, TSLP
18 CRSsNP
7 Control
Li et al37 2010 12 CRSwNP Collagen, FOXP3, MMP ‐2, MMP ‐7, MMP – 9, TGF‐β1, TIMP‐ 1, TIMP‐ 2,
12 CRSsNP TIMP‐ 3, TIMP‐ 4
12 Controls
Maxfield et al56 2018 71 CRS Periostin
62 Control
Mortuaire et 2018 57 CRSwNP ECP, EDN, IL‐5, IL‐9
al35
Stevens et al25 2015 15 CRSwNP BCA‐1, ECP, Eotaxin‐1, Eotaxin‐2, Eotaxin‐3, GM‐CSF, IFN‐γ, IFN‐α2, IL‐4,IL‐5,
9 CRSsNP IL‐6, IL‐10, IL‐13, IL‐33, MCP‐ 1, MCP‐4, RANTES, TARC, SCF, SDF
17 Control
Tan et al36 2016 RNA CLC, ECP, IFN‐γ, IL‐5, IL‐13, IL‐17A
69 CRSwNP
105 CRSsNP
54 Control
Protein Extracts
45 CRSwNP
83 CRSsNP
34 Control
Tomassen et 2016 443 CRSwNP Albumin, ECP, IgE, IFN‐γ, IL‐1β, IL‐5, IL‐6, IL‐8, IL‐17, IL‐22, MPO, SE‐ IgE, TNF‐
al30 239 CRSsNP α, TGF‐β1
187 Control
Van Zele et al24 2006 10 CRSwNP Eotaxin, IFN‐γ, IL‐1β, IL‐2Rα, IL‐5, IL‐8, MPO, TGF‐β1, TNF‐ α
13 CFNP
8 CRSsNP
9 Control
Van Zele et al32 2014 21 CRSwNP no recurrence ECP, IFN‐γ, IgE, IL‐1β, IL‐5, IL‐6, IL‐17, SE‐IgE, TGF‐β1
15 CRSwNP with recurrence
Wang et al57 2015 37 CRSwNP Fibronectin, IFN‐γ, IL‐4, IL‐5, IL‐13, IL‐17, Periostin, Tenascin C, TGF‐β1
14 CRSsNP
15 Control

(Continues)
HUSAIN and SEDAGHAT | 5

TA B L E 1 (Continued)

Lead author Year Patients Biomarkers

39
Wang et al 2016 271 CRSwNP ECP, IgE, IL‐8, MPO, SE‐ IgE
138 CRSsNP
164 Control

Abbreviations: Patient Groups: CFNP, cystic fibrosis nasal polyposis; CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without polyps;
CRSwNP, chronic rhinosinusitis with polyps; E‐CRSwNP, eosinophilic chronic rhinosinusitis; NE‐CRS, non‐eosinophilic chronic rhinosinusitis.
Biomarkers: CLC, Charcot‐Leyden crystal galectin; COL1A1, type I collagen; CRP, C‐reactive protein; ECP, eosinophilic cationic protein; EDN, eo‐
sinophil‐derived neurotoxin; EGF, epidermal growth factor; ESR, erythrocyte sedimentation rate; FGF, fibroblast growth factor; G‐CSF, granulocyte
colony stimulating factor; GM‐CSF, granulocyte monocyte colony stimulating factor; ICAM, intercellular adhesion molecule; IFN, interferon; IL,
Interleukin; ILC, innate lymphoid cells; MCP, monocyte chemotactic protein; MDC, macrophage‐derived chemokine; MIP, macrophage inflammatory
protein; MMP, matrix metalloproteinases; MPO, myeloperoxidase; MUC5AC, mucin 5AC; PDGF, platelet‐derived growth factor; RORC, RAR‐related
orphan receptor C; SCF, stem cell factor; SDF, stromal cell‐derived factor; SE‐IgE, staphylococcus aureus enterotoxin‐specific IgE; SOD, superoxide
dismutase; SOL, secreted IL‐5Rα; TARC, thymus and activation regulated chemokine; TIMP, tissue inhibitors of metalloproteinases; TNF, tumour
necrosis factor; TSLP, thymic stromal lymphopoietin; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.

are defined by putative inflammatory mediators of disease, classifi‐

4.1.2 | CRS endotypes
cation of patients based on endotypes may translate into the individ‐
In contrast to phenotypes, which were developed without a consid‐ ualisation of therapy that is targeted to the inflammatory mediators
eration for the underlying mechanisms, endotype refers to disease that characterise each patient's disease endotype.
traits (usually related to clinical outcomes, disease course and treat‐ In less prevalent cases, endotypes of CRS may be related to well‐
ment response) that may be explained by specific underlying mecha‐ defined mechanisms of disease that can be delineated using clinical
nisms. In comparison with genotype which refers to specific genetic knowledge. For example, AFRS may represent a distinct endotype of
reasons for a trait, endotypes more broadly reference cellular and CRS that is defined as rhinosinusitis produced through a chronic aller‐
molecular mechanisms of disease. Characterising endotypes of CRS gic reaction to ambient fungal elements that may reach or colonise the
is particularly attractive since it is increasingly recognized that CRS, paranasal sinus cavities.23 CRS in the setting of eosinophilic granulo‐
while defined based on consensus clinical criteria, is in reality a highly matosis with polyangiitis (EGPA) may also be considered a distinct CRS
heterogeneous disease from the standpoint of pathophysiology. endotype defined by sinus disease caused by the underlying vasculitis.
The heterogeneity of CRS may be attributable to the identi‐ Patients with cystic fibrosis also fall into this category; this genetic con‐
fied variation in activation of distinct inflammatory pathways that dition affects the respiratory epithelium in the sinonasal tract causing
is observed from patient to patient. Research seeking to translate dysfunction in mucociliary clearance. These patients have CRSwNP
the variability in inflammatory mechanisms of CRS to the variabil‐ that is predominantly neutrophil driven.24 Aspirin exacerbated respi‐
ity in clinical outcomes of CRS has been motivated by research on ratory disease (AERD), while often conceptually lumped into CRSwNP,
endotypes (and their subsequent clinical relevance in management has been shown to have differing pathophysiology with hyperactiva‐
and treatment) of asthma, another inflammatory airway disorder. By tion of the 5‐lipoxygenase pathway leading to decreased anti‐inflam‐
classifying asthmatics based on putative underlying pathophysio‐ matory prostaglandins and the activation of platelets.25 These changes
logic mechanisms, reflected by biomarkers of activated inflammatory at the cellular level manifest as increased sinonasal symptoms, mucosal
pathways, treatment of asthma using both conventional medications inflammation and polyps that are often refractory to both medical and
as well as novel biological therapies (including monoclonal antibod‐ surgical treatment.26 However, the ability to categorise CRS patients
ies) has been significantly optimised. Specifically, this enhanced un‐ into such neatly defined endotypes where the exact underlying mech‐
derstanding of asthma has helped determine which patients would anism is identifiable is uncommon. In any case, targeting the underlying
benefit most from which treatments. 22 mechanisms of the CRS disease process is logically expected to provide
Although the underlying governing principle of an endotype is that more effective treatments and superior outcomes.
it represents a distinct pathophysiologic mechanism, from a practical As noted above, endotypes of inflammatory disease are most
standpoint endotypes are often defined based on the presence of often defined by the relative abundance of soluble (eg cytokines) and
biomarkers that are inferred to be reflective of the pathophysiology. cellular mediators of inflammation. There is a plethora of cytokines
For an inflammatory disease such as CRS, biomarkers that are used and cellular mediators of inflammation that may eventually be used
to define endotypes understandably often consist of cytokines and to very specifically define distinct endotypes. 27 At present, how‐
inflammatory cell types that are detected in the affected tissue or ever, endotypes of inflammatory airway disease—in particular for
systemically in the peripheral blood. Moreover, because these endo‐ CRS—are most often defined based on the balance of T‐helper cell
type‐defining soluble and cellular mediators of inflammation are also patterns of inflammation (eg type‐1 [Th1], type‐2 [Th2] and type‐17
believed to be important components of the inflammatory mecha‐ [Th17] as the most commonly described). As a critical component
nisms of the disease, characterisation of endotypes provides insights of adaptive immunity and the central regulators of the immune re‐
into therapeutic targets as well. In other words, because endotypes sponse, T‐helper cells can determine the character of an immune
6 | HUSAIN and SEDAGHAT

response through the cytokines they produce and the subsequent literature review of medical treatments for CRS with special em‐
downstream differentiation or recruitment of other inflammatory phasis on endotype‐targeted treatments has suggested differential
cells (which in total define the T‐helper pattern of inflammation). approaches to medical management of CRS based on endotype.16
Recent comprehensive studies of CRS endotypes have examined While saline and topical intranasal corticosteroid sprays may be
the association between CRS disease characteristics and cytokines first line in both CRSwNP and CRSsNP, off‐label use of topical in‐
isolated from the sinonasal mucosa of patients with CRS.28-33 Using a tranasal corticosteroid irrigations—which have also been shown
clustering analysis to group patients based on the levels of individual to be effective treatments—may be more appropriate in Th2‐high
cytokine levels found in the sinonasal mucosa, they were able to show CRS and particularly inflamed CRSwNP.43 Oral corticosteroids tar‐
four distinct inflammatory signatures that correlated with CRS disease get the eosinophilic, Th2 response better than non‐Th2 responses
characteristics; these inflammatory signatures were related to eosino‐ and, not surprisingly, therefore have generally been shown to be
philic Th2‐driven inflammation, Th1 inflammation, neutrophilic or gen‐ most effective in CRSwNP (which is usually dominated by an eo‐
erally proinflammatory cytokines, and Th17/Th22 inflammation. The sinophilic and Th2 inflammatory profile) by reducing objective dis‐
variability in the levels of activation of these inflammatory pathways ease burden/polyp size and improving symptoms. 3 However, oral
was associated with the presence of clinical characteristics such as nasal corticosteroids are expected to be effective even in the subset
polyposis or comorbid asthma.30 Clustering of CRS patients based on of CRSsNP patients who have Th2 inflammation and eosinophilia
the inflammatory signatures observed in the nasal mucus, which cor‐ and this may explain why although oral corticosteroids have not
relates with clinical disease characteristics, has also been reported.34,35 been shown to definitively be effective for CRSsNP, there exist re‐
Interestingly, studies have shown diversity in association be‐ ports in the literature for efficacy for these medications for some
tween inflammatory signatures and CRS disease characteristics CRSsNP patients.44 In addition to antimicrobial properties, some
based on geography and racial backgrounds.36-38 For example, in antibiotics have also been found to inhibit different inflammatory
Europe, North America and Oceania CRSwNP is associated with a pathways as well. For example, doxycycline negatively effects Th2
predominantly Th2 inflammatory signature in the sinonasal mucosa inflammation, while low‐dose macrolides have been more success‐
in contrast to a mixed Th1/Th2/Th17 cytokine profile with gener‐ ful in patients with non‐eosinophilic, neutrophilic inflammation or
ally lower levels Th2 inflammation in Asian CRSwNP patients.39 This low IgE CRS.45-47 In contrast, topical antibiotics, surfactants and
divergence in inflammatory profiles in CRSwNP is also supported homeopathic treatments such as Manuka honey have not been
by the finding that sinonasal tissue eosinophilia is present more shown to exert a specific effect on a particular endotype and use
prominently in European or North American CRSwNP patients of these medications continues to be empiric.16
compared to CRSwNP patients from the China, Japan or Korea.40
These findings show not only geographic and/or genetic variation in
4.2.2 | Surgical management of CRS
CRS mechanism but also highlight that very different inflammatory
mechanisms can lead to the same clinical phenotype (eg CRSwNP). The nature of surgical intervention with functional endoscopic
More recent work has also started to connect inflammatory sinus surgery can also be modulated based on disease pathway.
profiles with treatment outcomes.41 Liao et al42 were able to dif‐ Surgical treatment of CRSsNP has generally been described as a
ferentiate patients into various clusters (ie CRS subtypes as puta‐ limited mucosal sparing approach to facilitate mucociliary clear‐
tive endotypes) taking into account both inflammatory markers and ance through the natural ostium. In contrast, a more aggressive
treatment responses after endoscopic sinus surgery. Cluster 1 (pre‐ approach to CRSwNP is based on an assumption of underlying
dominantly Th2, eosinophilic CRSwNP) had the most severe clinical (Th2‐driven) pathophysiology and predicated on the belief that if
manifestations and poor treatment outcomes. Patients in cluster 2 diseased mucosa is not removed, there will be increased possibility
(highly atopic CRS with mild inflammation [lower levels of inflam‐ of failure from continued Th2 inflammation.48,49 More extensive
matory cytokines in the sinonasal mucosa]) and cluster 4 (young, endoscopic sinus surgery in a “reboot” approach has been shown
predominantly male subjects with mild inflammation) were not as to be effective in patients with CRSwNP with a Th2‐high inflam‐
difficult to treat. Cluster 3 (CRS with neutrophilic inflammation) and matory profile, leading to  decreased recurrence rates without in‐
cluster 6 (CRSwNP with long disease duration) had increased neu‐ creased complications.49,50
trophils and were difficult to treat. Cluster 5 (CRS with high levels of
IL‐10) and cluster 7 (mild CRS symptom burden with low inflamma‐
4.3 | Biological therapeutics
tory load) both had favourable outcomes.
A biologic therapeutic is a treatment that uses substances made
from living organisms to treat disease. Biologics used to treat in‐
4.2 | Treatment approaches based on endotype
flammation of the upper and lower airways are composed of mon‐
oclonal antibodies that are targeted to (and neutralise) specific
4.2.1 | Conventional medical management of CRS
inflammatory mediators or their cognate receptors. The desire to
Knowledge of specific endotypes can influence treatment even in treat those with recalcitrant CRS despite appropriate medical and
the initial medical therapy stage for patients with CRS. A recent surgical therapy has led to the expansion of biologic therapeutics
HUSAIN and SEDAGHAT | 7

targeting the mediators of sinonasal inflammation at a molecular

Abbreviations: ACQ, Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; LM, Lund‐Mackay; mAB, monoclonal antibody against the specified target; NP, nasal polyp; QOL, qual‐
eosinophils
and cellular level. Because biomarkers of CRS endotypes are as‐

↓ Tissue
sumed to be inflammatory mediators that are major drivers of dis‐
ease, the goal of biologic therapy is to target these mediators in an

√
endotype‐specific manner.
↓ Serum IgE

4.4 | Th2 endotypes as the target of

biological therapeutics

√
Th2 inflammation is associated with eosinophilia and atopy, and it is
eosinophils

the inflammatory pathway that is most commonly and prevalently

↓ Blood

activated in CRSwNP as well as asthma. Several biological agents

have been developed to target various mediators of the Th2 inflam‐
√

matory pathway, and they have been well studied for disease control
in asthma. Due to the success of these therapies in asthma, they
ACQ, AQLQ
↑ Asthma

have been identified as potential therapeutic candidates for use in

CRSwNP.
√

Th2 inflammation is regulated by a subset of CD4 + T cells,

known as Th2 cells, which produce the characteristic cytokines
↑ FEV1

IL‐4, IL‐5 and IL‐13. These cytokines act on and activate other cell
types such as the sinonasal epithelium, innate immune cells, B cells
√

to produce IgE and eosinophils. IL‐4 and IL‐13 have important func‐
SNOT‐22

tions in controlling mucous production in epithelial cells as well as

↑ QOL

the IgE response from B cells and plasma cells. IL‐5 is involved in
the activation and survival of eosinophils. 51 As a result, the first
√

biologic therapeutic options for Th2‐mediated disease have been

ity of life; SNOT‐22, Sinonasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification Test.
↑ Smell

developed for the blockade of IL‐4, IL‐5 and IL‐13 as well as IgE
UPSIT
Results of investigations on therapeutic targets for biologic medications in CRSwNP

(Table 2).
√

√
↓ Nasal symptoms

4.4.1 | Targeting the IgE pathway

Omalizumab is a monoclonal antibody that selectively binds and
inhibits circulating IgE. In a randomized control trial (RCT) per‐
formed by Gevaert et al,52 participants received 4‐8 injections over
√

16 weeks and were found to have significant reductions in polyp

size and Lund‐MacKay scores, with improved smell, quality of life
↓LM

and lung function. In another study using omalizumab performed by

√

Pinto et al,53 patients received monthly infusions over the course

↓NP

of 6 months and had improved Lund‐MacKay scores and SNOT‐20

√

scores, but no changes with regard to cellular inflammation, nasal

airflow and olfaction. This study, however, may have been under‐
mAB IL‐4Rα

powered due to issues with recruitment and also did not differenti‐
mAB IL‐5

mAB IL‐5

mAB IgE

ate between CRSsNP and CRSwNP. Taken on the whole, results from
MOA

these studies have suggested that biologics targeting the IgE path‐
way may be most effective in patients with CRSwNP and high levels
IL‐4/IL‐13

of Th2 inflammation and atopy (ie high levels of IgE). 52 In research

Target

performed on asthmatics, the use of periostin as a biomarker was

IL‐5

IL‐5

IgE

useful in predicting the efficacy of anti‐IgE antibodies, as high levels

of periostin corresponded with a greater response to treatment.54,55
Gevaert et al

Gevaert et al

Gevaert et al
Mepolizumab

Elevated periostin levels have also been used as a distinguishing

Bachert et al
Omalizumab
Reslizumab

Dupilumab
Pinto et al
TA B L E 2

characteristic between CRSsNP (low periostin) and CRSwNP (high

Drug

periostin), but further studies investigating its use as a specific CRS

endotype marker are ongoing.56,57
8 | HUSAIN and SEDAGHAT

F I G U R E 2 Schematic for present‐

day treatment of chronic rhinosinusitis
using the concept of endotypes as the
foundation for clinical decision‐making

production and tissue remodelling.62 Dupilumab is one agent that si‐

4.4.2 | Targeting the IL‐5 pathway
multaneously inhibits both IL‐4 and IL‐13 signalling by blocking the
IL‐5 is a Th2 cytokine essential for the maturation of eosinophils and alpha chain of the IL‐4 receptors (IL‐4Rα), which is a component of
has been well described to be elevated in the setting of CRSwNP (in both IL‐4 receptor and the IL‐13 receptor. Dupilumab has shown
particular in Europe and North America). Reslizumab, an anti‐IL‐5 promising results in patients with CRSwNP. When compared to
antibody, was studied in an RCT where participants received a sin‐ intranasal corticosteroids alone, dupilumab (dosed weekly) used in
gle dose of 1mg/kg and had decreased polyp size, improved symp‐ addition to intranasal corticosteroids led to a significant reduction in
toms and decreased blood eosinophilia at 4 weeks.58 In an RCT with nasal polyp burden, Lund‐Mackay scores and SNOT‐22 scores with
CRSwNP patients, mepolizumab, another monoclonal antibody improvements in sense of smell and asthma function at 16 weeks.63
that binds IL‐5, led to reduced nasal polyp size, improved symp‐ Biological agents specifically targeting just IL‐13 have not
toms, olfaction, quality of life and decreased blood eosinophilia been well studied in CRS. When studied in asthmatics, however,
after 8 weeks when dosed in two treatments of 750 mg monthly. 59 anti‐IL‐13 agents have shown the most promise and efficacy in
Another therapeutic, benralizumab, is an anti‐IL‐5R antibody, which Th2‐high endotypes that are characterised by high periostin lev‐
can modulate the recruitment of eosinophils that occurs through els. 54 It remains to be seen if periostin levels can be used in CRS to
IL‐5 signalling. In addition, benralizumab was also known to in‐ predict efficacy of biologics targeting IL‐13 or other inflammatory
duce apoptosis of eosinophils and basophils by causing antibody‐ mediators.
dependent cell‐mediated cytotoxicity.60 In a study of asthmatics,
benralizumab treatment resulted in improved asthma control and
4.5 | Non‐Th2 inflammation
reduced exacerbations. A study of benralizumab in treatment of pa‐
tients with CRSwNP, however, has not yet concluded.61 In Europe and North America, many studies have shown that the Th2
inflammatory response is predominantly seen in CRSwNP whereas
non‐Th2 mediated processes are found more prominently in CRSsNP.
4.4.3 | Targeting the IL‐4/IL‐13 pathway
However, recent findings have demonstrated that there is in fact a
The IL‐4/IL‐13 signalling pathway regulates multiple effector arms of mix of inflammatory processes regardless of polyp status.30,36,39,46,64
the Th2 inflammatory response by driving B cell class‐switching for Non‐Th2 inflammation may be present and have a dominant role in
IgE synthesis as well as mast cell, eosinophil, and basophil recruit‐ the pathophysiology of both CRSwNP and CRSsNP. There are three
ment. IL‐4 and IL‐13 also play a role in airway remodelling by inducing endotypes most frequently related to non‐Th2 inflammation. The
mucous hypersecretion from goblet cell hyperplasia and matrix depo‐ first is neutrophilic inflammation that is reflected and/or modulated
sition. In the study of asthmatics, the IL‐4/IL‐13 signalling pathway has by IL‐8, IL‐6 and myeloperoxidase (MPO). A Th17/Th22 predominant
been the target of several biologic therapies including tralokinumab endotype has also been described, most commonly in Asian CRS pa‐
(anti‐IL‐13), lebrikizumab (anti‐IL‐13), anrukinzumab (anti‐IL‐13), pas‐ tients, and is mediated primarily by IL‐17 and IL‐22, which augment
colizumab (anti‐IL‐4) and altrakincept (soluble IL‐4R that binds free host defence by recruiting neutrophils and macrophages. Lastly, a
IL‐4) with varying therapeutic response. The simultaneous target‐ Th1 predominant endotype, mediated by interferon gamma (IFN‐γ)
ing of both IL‐4 and IL‐13 provides a more complete blockage of the and IL‐12, has classically been associated with CRSsNP but can be
Th2 inflammatory response by affecting Th2 cell differentiation, IgE found in all clinically defined subtypes of CRS.36
HUSAIN and SEDAGHAT | 9

Biologics have not been well studied for non‐Th2 inflammation in neutrophilic inflammation.68 In patients with CRSwNP, adjunctive
CRS. Currently, there are two anti‐IL‐17 antibodies that are approved oral corticosteroids and/or doxycycline may be considered for
for the management of advanced psoriasis: brodalumab and secuki‐ their effects on Th2 and eosinophilic inflammation, which domi‐
numab.62,65,66 There is growing evidence for the involvement of IL‐17 nate in CRSwNP (in particular in European and North American
in non‐eosinophilic variants of asthma, and for involvement of both patients). For those patients failing appropriate medical manage‐
IL‐17 and IL‐22 in CRS, suggesting another possible application of ment, endoscopic sinus surgery may be considered. In addition to
this target for biologic therapy.30,62,67 the therapeutic role of endoscopic sinus surgery, it also provides
an opportunity to ascertain objective information about a patient's
CRS endotype based on surgical pathology, which can easily be ex‐
4.6 | Translation into clinical practice
amined for neutrophilic‐ and/or eosinophilic‐dominant patterns of
Guidelines for the treatment of CRS have been developed by inflammation. This surgical pathology information, in conjunction
the leading otolaryngic and rhinologic societies from around the with blood markers, can be subsequently used to drive postop‐
world. 2,3,10 None have yet to incorporate endotypes as means to erative medical management in a more evidence‐based usage of
differentiate treatment approaches. Bachert et al49 have developed endotype‐specific treatments that either leverage the anti‐inflam‐
integrated care pathways (ICPs) which function as a structured care matory properties of antibiotics or utilise biologic treatments.
plan to help translate guidelines and new knowledge of CRS endo‐ Ideally, detailed information about endotypes could be ascer‐
types into clinical practice. These ICPs function by using endotypes tained at the beginning of the CRS management algorithm. This is the
to help classify patients and help guide treatments aimed at specific future of CRS management, which may include evaluation of a broad
pathophysiologic signalling pathways after careful patient selection. panel of biomarkers through conveniently obtained biological speci‐
The basis of the ICP classifies patients into those whose disease has mens, for example nasal mucus, mucosal biopsy or blood. Evaluation
non‐Th2 dominant inflammation, moderate Th2 inflammation and of endotype‐specific and biologic medication‐targeted inflamma‐
severe Th2 inflammation. These endotype‐based categories of CRS tory mediators, such as IL‐4, IL‐5, IL‐13 and even IFN‐γ or IL‐17—all
patients are approached with a treatment ladder consisting first of of which are being studied in active research investigations—will one
standard medical management, followed by endoscopic sinus sur‐ day be ascertainable at the time of CRS diagnosis and be included in
gery, and finally biologic treatments. the clinical decision‐making process from the beginning.
Formulating a pathway to treat CRS with consideration of en‐
dotypes is an important step forward in the management of this
disease process. While endotypes of CRS have been the focus of re‐ 5 | CO N C LU S I O N S
search, the consideration of endotypes in routine CRS management
is increasingly possible for every practicing otolaryngologist. At Advances in scientific understanding of pathophysiologic mechanism
present, management of CRS—including evaluation and treatment— of CRS have led to the development of the concept of endotypes.
is driven by clinical characteristics and outcomes. However, infor‐ These endotypes are characterised by inflammatory biomarkers
mation about CRS endotypes can be not only hypothesised from which are inferred to be the primary drivers of disease and there‐
clinical characteristics but also conveniently obtained from surgical fore serve as targets for potential therapeutics. The consideration
pathology when patients undergo endoscopic sinus surgery and can of endotypes in the management of asthma has proven to improve
therefore be incorporated into the clinical decision‐making process outcomes and has shown great promise to improve outcomes of CRS
for patients who have had endoscopic sinus surgery (Figure 2). treatment as well. Information about CRS endotypes may already be
Following diagnosis, intervention should always begin with incorporated into management of patients to deliver patient‐specific
medical therapy using topical intranasal corticosteroids and saline treatment of CRS. Further investigation is required to fully delineate
irrigations as these treatments are uniformly supported by level 1 the different CRS endotypes that exist, the biomarkers that define
evidence for the treatment of CRS. 2,3 It is possible that measure‐ them, and the treatment protocols that will optimise outcomes for
ment of blood markers, such as eosinophil count or IgE level, may each endotype. In particular, the integration of clinical outcomes into
also provide insight into a patient's CRS endotype. For CRSwNP, in the characterisation of endotypes will lend clinical significance to—
particular those with objective/laboratory findings suggestive of and establish justification for—the determination of CRS endotypes
Th2‐driven disease, irrigations may also be considered as the main in routine clinical practice.
method for intranasal delivery of corticosteroids. Adjunctive med‐
ications such as systemic corticosteroids and systemic antibiotics
C O N FL I C T O F I N T E R E S T
may be considered especially for the latter when there is obvious
bacterial super‐infection. Although there is conflicting evidence for None to declare.
the uniform treatment of all CRSsNP patients with macrolide anti‐
biotics, knowledge of CRS endotypes may be used to empirically
ORCID
consider macrolide antibiotics for CRSsNP based on the common
association of this clinical CRS phenotype with non‐eosinophilic, Ahmad R. Sedaghat https://orcid.org/0000-0001-6331-2325
10 | HUSAIN and SEDAGHAT

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