nasal polyposis an inflammatory condition.6

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CURRENTOPINION Nasal polyposis: an inflammatory conditionlammatory treatment

arveya,c,d

lyps (CRSwNP) has focussed on inflammatoryistopathological features of the disease, rather thannderstanding of the disease and approach tofo

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conclusion founded on the inflammatory basis of CRSwNP/ECRS.

SummaThere ishistopathpathogeanti-infla

Keyworchronic

INTRODUCTION

The diagnosis chronnasal polyps (CRSwNPtype rather than a coimmunological homobacteria, fungi, allergesively reported in thefactors may representative factors. Conteminflammatory processlocal immune functioinvolving the inabilitepithelial barrier and regulate an appropriate, coor-dinated inflammatory response to[2,3]. Key to understanding this phacknowpatientbacterithe firimmun

Vincents Hospital, Sydney, Australia, Department of Otolaryngology,Head & Neck Surgery, Changi General Hospital, Singapore, cAustralian

919; e-mail: [email protected]

1068-95

REVIEWst group has a heightened proinflammatorye response. Recent evidence suggests a

Curr Opin Otolaryngol Head Neck Surg 2013, 21:2330

DOI:10.1097/MOO.0b013e32835bc3f9

08 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-otolaryngology.comrs are exposed to the same allergens, fungi anda (including Staphylococcus aureus), yet only

hurst,93609ight Lippincott WilliamNP and normal Correspondence to Richard Harvey, MD, 354 Victoria Street, Darling-NSW 2010, Australia. Tel: +61 2 93604811; fax: +61 2ledgement that both CRSwMedicine, University of New South Wales, Sydney, Australiaforeign antigensilosophy is the

School of Advanced Medicine, Macquarie University and dFaculty ofrymounting evidence for CRSwNP as a predominantly inflammatory disease. Even simpleological classification on the basis of degrees of tissue eosinophilia reflects the underlyingnic mechanisms with diagnostic and prognostic implications. Optimal treatment involves topicalmmatory therapy delivered locally via a wide, postsurgical corridor.

dsrhinosinusitis, corticosteroid, endoscopic sinus surgery, eosinophilic, irrigations

ic rhinosinusitis (CRS) with) represents a clinical pheno-ndition with histological orgeneity. Although the role ofns and superantigens is exten-literature [1], these associatedexacerbative rather than caus-porary concepts focus on

es secondary to dysregulatedn, with a fundamental defecty to maintain integrity of the

crucial role for the epithelial-derived cytokines thatmediate the cells of the immune system.

The goal of this article is to review importantand recent findings relating to the pathogenesis ofCRSwNP. The rationale for a disease classificationbased on histopathological characteristics is dis-cussed. Current concepts in therapeutic approachtowards managing the condition are summarized.

aDepartment of Otolaryngology, Head & Neck, Skull Base Surgery, Stbor noneosinophilic is practical and correlates with disease severity and prognosis. The practice and utilityof endoscopic sinus surgery to create a single neosinus for topical corticosteroid delivery is a logicalrequiring effective anti-inf

David China,b and Richard J. H

Purpose of reviewRecent literature in chronic rhinosinusitis with nasal pomechanisms underlying the disease. Endotyping the hsimple clinical phenotypes, reflects a change in our umanagement. This is paralleled by renewed evidenceanti-inflammatory therapy.

Recent findingsRecent research into patterns of dysfunction in innateepithelium in mediating the inflammatory response. Emucosa in CRSwNP and their interaction via innate lyenvironment interface and T-helper 2 dominated inflaimmunological profiling of CRSwNP is not routinely as & Wilkins. Unauthorizer the need for wide postsurgical access and topical

unity suggests a crucial role of respiratoryted interleukins, IL-25 and IL-33, from sinushoid cells may represent the link between the host-ation that characterizes CRSwNP. While thoroughlable, classification of CRS as eosinophilic (ECRS)d reproduction of this article is prohibited.

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CHROPOLYDISEA

The evaetiolocharactmationdecreascytokinleukincationiECP/M

WiinflammCRSwNvarietytern ofland Chof CRSwTh1/Thinflammother slationsnated ethan nomost retype innophil

A mpreviouthe infhistoloit wasneutroptant hissuggestneutrop

characterized by high levels of IL-5 without eitherIL-17 or interferon was associated with increasedtendency for eosinophilic inflammation [5]. In

Nalropese

on7 RotestomestrnhennsNrentiodaaucghinfexeltoopexeesencceificlae

KEY POINTS

CRSwNP is a predominantly inflammatory diseaseassoepith

Endoclassnonenon-Eassopoor

Durinpolypa wipolypinflam

Nose and paranasal sinuses

24NIC RHINOSINUSITIS WITH NASALPS AS AN INFLAMMATORYSE

idence for a predominant inflammatorygy for CRSwNP is abundant. CRSwNP iserized by excessive T-helper 2 (Th2) inflam-, prominent eosinophilic infiltration [4] anded regulatory T-cell (Treg) function. Thee profile is characterized by increased inter-(IL)-5 and elevated ratio of eosinophilicc protein (ECP) to myeloperoxidase (MPO),PO more than 1 [5].th the advance in our understanding of theatory processes, it is clear that although

P is a clinical diagnosis, it encompasses aof conditions with heterogeneity in the pat-inflammation. Although research in main-inese populations has identified a subgroupNP patients inwhom there is a predominant17, intermediate-eosinophilic pattern ofation [6], this is neither represented in

outh-east Asian countries nor in Asian popu-

AsianCRSwcriticneutChinbothmati(IL-1phensuggpredin thmenpatte

TrespoextriCRSwtherespofuncarilystillprodthouTh2latedepithsiveeosinanddegrtoryenhainduSpecpopuof th

ciated with dysregulated interaction between sinuselium and the innate lymphoid system.

typing CRS patients, using histopathologicalification into simple eosinophilic versusosinophilic chronic rhinosinusitis (ECRS versusCRS), reflects an underlying inflammatory processciated with increased disease severity ander prognosis.

g surgery, although the removal of establisheds occurs, the goal in CRSwNP/ECRS is to createde, postsurgical corridor rather than simpleectomy for effective delivery of topical anti-matory therapy.t Lippincott Williams & Wilkins. Unauthorized

in western countries. A Th2 and IL-5 domi-osinophilic process remains more commonneosinophilic inflammation [7,8

&

], with thecent study reporting an eosinophilic pheno-76%, including 36% who had a mixed eosi-icneutrophilic pattern [8

&

].ixed inflammatory pattern in CRS has beensly reported. Initially, investigation intolammatory cytokine profile, with respect togical characteristics, seemed to suggest thatthe balance of proeosinophilic versus pro-hilic cytokines that determined the resul-tologic phenotype. However, recent researchs that CRS is neither an eosinophilic norhilic disorder. The cytokine profile

cytokinincreasnasal pfrom hIL-25 aof IL-1crucialinflammphilic C

TSLdrivingdendritdendritthoughproduc

www.co-otolaryngology.comreproduction of this article is prohibited.

patients with intermediate-eosinophilicP, the regulation of IL-17 activity may be afactor in determining the relative degree ofhilic or eosinophilic inflammation [6]. Ine CRSwNP, enhanced IL-17 was found inosinophilic and noneosinophilic inflam-, but high expression of IL-17 receptor DD) was associated with the noneosinophilicype [7]. Most importantly, these findingsthat a disordered inflammatory response,inantly involving eosinophils, is occurringe patients and represents an acknowledge-that this is not the classic inflammatorythat occurs in primary infective conditions.upstream mechanisms that incite the Th2

se may hold the key to understanding howic factors influence the pathogenesis ofP (Fig. 1). There is growing evidence thatspiratory epithelium mediates the Th2se [912]. Whether this is a result of a dys-nal epithelium (i.e. permanently or tempor-maged) or as the result of local sinus factors istopic of debate. IL-25 and IL-33 are bothed in sinonasal epithelial cells and aret to play an important role in promotinglammation in CRSwNP. Baseline and stimu-pression of IL-33 have been demonstrated inial cells from CRSwNP that was not respon-treatment [13]. Both are overexpressed inhilic compared with noneosinophilic CRSpression was significantly associated withof tissue eosinophilia and overall inflamma-verity [14

&&

]. IL-25 has been shown toe thymic stromal lymphoprotein (TSLP)-d Th2 cell expansion and function [15].ally, both act on a non-B-non-T (NBNT)tion of innate lymphoid cells, independentadaptive immune response, to produce Th2es, for example IL-5 and IL-13 [16,17]. Aned concentration of NBNT cells was found inolyp tissue compared with nasal mucosaealthy individuals and their activation bynd IL-33 resulted in increased production3 [18

&

]. Thus, IL-25 and IL-33 may be thelink between epithelial cells and the Th2atory response that characterizes eosino-RSwNP.P has been implicated as a key mediator ininflammation at the epithelial cell

ic cell interface [19]. TSLP is produced byic cells, mast cells and basophils and ist to equip dendritic cells with the ability toe a variety of inflammatory cells, including

Volume 21 Number 1 February 2013

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Th2 lincreasallergiconly depatientallergicsinus mwas us

Environmental

Co

Microbes Allergens

FIGURE

Even thomicrobiachronic

Nasal polyposis Chin and Harvey

1068-950Host-environmentinterface

damagee.g. pollution

Epithelial dysfunction1. Mucociliary function2. Epithelial damage3. Loss of epithelial integrity4. Genetic predisposition5. Acquired epigenetic defects

Biofilmight Lippincott Williams & Wilkins. Unauthorize

ymphocytes and eosinophils. There ised expression of TSLP in nasal polyps versusrhinitis [8

&

]. However, this difference wastected when the polyp tissue from CRSwNPs was compared with the mucosal tissue ofrhinitis patients. In fact, when nonpolypucosal tissue from these CRSwNP patients

ed for comparison with the allergic rhinitis

patientficant dmay beanotheCRS (w[20]. Inin TSLversus

Innateimmuneresponse

Adaptiveimmuneresponse

Phenotype

TH2 type, Eosinophilic inflammation Eosinophil / mast cell degranulation IgE production Mucus production Edema / Polyp formation

Chemoattractantse.g. Eotaxiin

Innate lymphoid cells(Nuocytes*, NHCs, IHCs, MPP Type2)

Tissue eosinophiliamast cells

T-helper 2cell

Eosinophils

Mast cell

IL25 IL33

IL13IL4IL5IL9

1. The current understanding of epithelial mediation of the Th2ugh there may be sinus lumen antigens (fungus, staph, biofilms etl flora are often present in normal patients and this highlights therhinosinusitis with nasal polyps.

8 2013 Wolters Kluwer Health | Lippincott Williams & Wilkinslonization

Locale.g. Staph Ag

Inhaled

Sinus epitheliumd reproduction of this article is prohibited.

s instead of the actual polyp tissue, no signi-ifference was observed. This suggests TSLPoverexpressed in nasal polyp tissue only. Inr study, the TSLP receptor was increased inith and without nasal polyps) versus controlsa more recent study, there was no differenceP mRNA expression between eosinophilicnoneosinophilic inflammation in CRS

Antigen presenting cells(th2 inducing subpopulations)Loss of regulatory cell function

Nave T cells

MHC class II interactions(Staph superantigen effects)

s

Lymphocytes

TSLP, CCL2/20, GMCSF

immune response and a local tissue eosinophilia.c) that might be implicated in the process, thesedisordered inflammatory response in patients with

www.co-otolaryngology.com 25

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[14&&

]. Although the precise role of TSLP in CRSrequires further clarification, it appears to facilitate,rather than drive, Th2 inflammation [21]. There areexamp[22,23]recalcit

Eviis conslationforkheaof TregCRSwNated wicriticaltissue rgrowthpromotductionwithoucantlyof tissreducedfibroblapolyps,esses rnasal pless he[28

&

].

INTERACTION OF THE UPPER AND LOWERAIRW

With inand imCRSwNHistolotract d[29]; hoclinicality and

Theand lowunifiedHistoriSamterintolerexacerbever, thtopic,limitedup to 6ically olocal ILtissue[5,32].process

patients explain the close clinical associations thatare seen. The degree of sputum eosinophilia canpredict the upper airway severity [33] and con-

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AY

creasing severity, the inflammatory diseasemune dysregulation which characterizeP are also manifested in the lower airways.gical characteristics of the lower respiratoryo not permit the development of polyposiswever, the results of inflammation presently loosely as asthma, with bronchial reactiv-mucus hypersecretion.evidence for an association between upperer airways inflammation, aptly named the, united or common airway, is abundant.cally, the most obvious phenotype was thes triad of nasal polyposis, asthma and aspirinance. This was more recently named aspirin-ated respiratory disease (AERD) [30]. How-e association between CRSwNP and nona-late-onset (or adult onset) asthma is notto patients with AERD. Epidemiologically,0% of patients with CRSwNP also had clin-vert asthma [31]. As in CRSwNP, increased-5, Th2-dominated immune response andeosinophilia are associated with asthmaSuch links in the common immunologicunderlying airway inflammation in these

HISCHRPOL

A hreprenostcondphiliphenpatheosinhighwou

Ttionradio[35]parealthoasthinflafor Etissueverlatio

www.co-otolaryngology.comles of TSLP-dominated asthma subtypesand it is likely that such a subgroup withrant features does exist in the upper airway.dence for decreased Treg activity in CRSwNPistent with the concept of immune dysregu-as a main pathogenic process. Diminishedd box P3 gene (FoxP3) expression, a markeractivity [24], has been demonstrated in

P versus allergic rhinitis [25] and is associ-th increased Th2 cell activity [6,26]. Anothereffect of decreased Treg activity is alteredemodelling via a decrease in transcriptionfactor b (TGF-b). TGF-b attracts, induces andes fibroblasts activity and enhances pro-of extracellular matrix. In contrast to CRS

t nasal polyps (CRSsNP), TGF-b is signifi-reduced in CRSwNP [27]. The accumulationue albumin and edema stemming from

production of extracellular matrix andst activity permits development of nasala defining feature of CRSwNP. These proc-

epresent the downstream endpoint in theolyp formation and, not surprisingly, entailterogeneity in terms of cellular markers

versethe lbronportwithasth

Iandprov[36]of shatedare sclinian alikeleveninfladistr

F[40requ[44]unifibeneaddireproduction of this article is prohibited.

LOGICAL SUBCLASSIFICATION OFNIC RHINOSINUSITIS WITH NASALPS

ological approach to classifying CRSwNPnts the first logical step for improved prog-tion and evidence-based management of theon. In the white population, tissue eosino-is strongly associated with the nasal polypype [45

&&

]. However, with structured histo-gy of sinus tissue using defined criteria forhilic CRS or greater than 10 eosinophils perower field, an additional 20% of CRSsNPbe classified as ECRS [46

&

] (Fig. 2 a and b).diagnosis of ECRS has prognostic implica-CRS is associated with greater clinical andgical severity [35,46

&

], higher risk of asthmad higher risk of polyp recurrence when com-to non-ECRS [47]. Serum eosinophilia,h associated with ECRS and predictive of[35], is less representative of the localizedatory processes [48], and was less sensitive

RS [46&

]. Nasal cytology as an estimate ofosinophilia has been proposed [49]; how-he diagnostic accuracy and clinical corre-require further definition.

Volume 21 Number 1 February 2013, the degree of nasal eosinophilia can predicter airway reactivity and asthma severity byodilator response [34,35]. The lower pro-of ECRS patients in the Chinese patients

RSwNP might also explain the lower risk ofin this ethnic population [6].as been more than 10 years since Braunsthalleagues published on segmental lower airwayation generating upper airway eosinophiliad the same process in reverse [37]. A processed inflammation that is systemically medi-generally accepted, although the mediatorsdebated [38,39]. However, this describes theassociations rather than causative factors ofay working as an integrated unit. It is highlyhat the same environmental and epigeneticthat have resulted in epithelial-driven Th2atory events are likely to be patchy andted across the entire airway.ally, improvement in asthma symptoms] and/or reduction in asthma medicationment after endoscopic sinus surgery (ESS)d further evidence to the hypothesis of theairway and suggest that these patients dofrom management of sinonasal disease inn to that for the lower airways.

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Validation of the concept of ECRS versusnon-ECnonwhportionAlthouing Th2processStaphyStaphymate indrivingavailabimplyrelevanhistoloformatstandaring is eFig. 3)ogists f

THE ENASA

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1068-950RS requires further research, especially inite populations, in which a significant pro-of CRSwNP may have lower eosinophilia.

gh a thorough inflammatory profile includ-cytokines (IL-4, IL-5, IL-13) along with Treges (TGF-B, IL-10, IL-17) and even evidence oflococcal colonization (Immunoglobulin E,lococcal exotoxins) may represent the ulti-describing our current understanding of theforces behind CRSwNP, this is simply notle to routine clinical practice. This does notapathy to the histological process andt data can be rendered available if tissuegy is described in a structured synopticrather than qualitative descriptions. Fordization, structured histopathology report-ncouraged (an example of which is shown inand developed in conjunction with pathol-or integration into routine practice.

be liE

paraprodandspraymenditiois totopicobsttiondisea[50,5atedbutioirrigcorristerothat2. (a and b) Histological appearance of eosinophilic asitis (CRS). (a) Eosinophilic CRS with more than 10 eosinophilight Lippincott Williams & Wilkins. Unauthorize

NDPOINT FOR INTERVENTIONS INL POLYPS

propriate management for nasal polyps mustn controlling the common inflammatoryrather than on treatment of polyps per se.further emphasized with a shift towards thet of treating ECRS as an inflammatory dis-similar to asthma or dermatitis. At present,steroids are the foundation of anti-inflam-therapy. However, the riskbenefit ratio of

ged systemic steroids for nasal polyps is unac-y high. Local (or topical) delivery provides ane method of disease control with minimalcomplications. With regards to CRSwNP, itot be an overstatement to say that if oral

reductisinus suprocedas ostiaand canto the mdeflecticommo

Theinto eitnasal irvolumesprays)nasal irhyperseadditio

8 2013 Wolters Kluwer Health | Lippincott Williams & Wilkinssteroids had no side-effects then there wouldrole for surgery.ctive local delivery of pharmaceuticals to thesal sinus is a demanding equation. It is at of both the surgical state of the sinusese method of topical delivery. Simple nasalnd polypectomy do not achieve an advance-f the patients situation to control the con-The goal of sinus surgery in CRSwNP or ECRSreate permanent wide access for long-termtherapy rather than for relieving sinustion or promoting sinus drainage and aera-g. 4 a and b). Neither CRSwNP nor ECRS ares that are due to ostiomeatal occlusion]. The variation in the size of surgically cre-cess greatly affects topical delivery and distri-[52,53]. Complete distribution of sinus

on is optimized by a wide post-ESS surgicalr [54]. In a meta-analysis comparing topicals versus placebo, one of the key findings wase subgroup with sinus surgery had greater

noneosinophilic tissue from patients with chronicer high power field. (b) Noneosinophilic CRS.d reproduction of this article is prohibited.

on in nasal polyposis than those withoutrgery [55

&&

]. Conversely, minimally invasiveures have a limited impact on topical accessl size greater than 45mm is required [56]even reduce distribution of nasal irrigationaxillary sinus, presumably due to uncinate

on or secondary ostium formation which isn in these procedures [57].options in topical delivery can be classifiedher high volume high-pressure systems (e.g.rigation with netipot, squeeze bottles) or lowlow-pressure systems (e.g. nasal drops and

. In the presence of a wide surgical corridor,rigation facilitates mechanical lavage of thecretory mucus that occurs in CRSwNP inn to drug delivery [53]. High volume,

www.co-otolaryngology.com 27

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positivremovaruptionnasal irthan nremainto 100%

FIGURE s w

FIGURE

(a) Preoppostoper


283. Structured histopathology reporting for chronic rhinosinusitit Lippincott Williams & Wilkins. Unauthorized

e pressure delivery systems can enhancel of mucus, inflammatory products and dis-of bacterial biofilms [58]. When mixed intorigation, topical steroids may even be saferasal drops as only 5% of the total doses in fluid residuals [53] compared with upfor nasal drops which may be swallowed

and absvolumetreatmeCommsqueezeapproxwherea

(a) (b)

4. (a and b) Creation of a wide surgical corridor after sinus surgerative endoscopic picture showing the dysfunctional sinuses of aative endoscopy of the same patient showing a single neosinus ca

www.co-otolaryngology.comith or without nasal polyps.reproduction of this article is prohibited.

orbed via the gastrointestinal tract [59]. Highsteroid irrigations are not a high dosent and such a description is a misnomer.on regimes of 1mg budesonide in 240mlbottle represents a 4.2mg/ml dose and only

imately 1020ml (80mg) is delivered,s a four-spray dose (apart from being

ery for eosinophilic chronic rhinosinusitis.patient with nasal polyposis. (b) Three yearsvity with good access for topical therapy.

Volume 21 Number 1 February 2013

Copyr ize

ineffectively delivered to the target organ)represents a 256mg dose. Wide sinus surgery andthen post-ESS steroid irrigation has been shown tobe effectherapyoral prresistancandidresponeosinop[8

&

]. Thhistopasimplequestiotion (h(low vowith aand su

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REFERENCES AND RECOMMENDEDREADINGPapers of particular interest, published within the annual period of review, havebeen highlighted as:

speoutnalLite

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seas:12chetibomor6.ang

chesmunngtien11;en We re9:1

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1068-950ight Lippincott Williams & Wilkins. Unauthor

wledgements

h to acknowledge and thank Dr Peter Earls,ent of Anatomical Pathology, St Vincentsl, for his ongoing support, collaboration andion of the histopathology figures as well as Msan for her assistance in the illustrations for.

cts of interest

s no financial disclosures or conflicts of interest.has previously received grant support from, served on an advisory board for Schering-and Glaxo-Smith-Kline, is a consultant withic and Olympus and is on the speakers bureauck Sharp & Dohme and Arthrocare.

ce20

18.&

MtypNa

This arleading19. Ito

huAl

20. BochPh

21. LiureRe

22. Hapras

23. ShthIm

8 2013 Wolters Kluwer Health | Lippincott Williams & Wilkinstive for disease control with failure of localin 6% of CRSwNP [60

&

]. Poor response toednisone preoperatively may predict steroidce and these patients may not be goodates for topical steroid therapy. A greaterse to oral prednisone was demonstrated inhilic versus noneosinophilic nasal polyposisis finding further supports the usefulness ofthologic (ECRS) as a valid refinement ofphenotype-based diagnoses (CRSwNP). Then of the relative effectiveness of nasal irriga-igh volume, high pressure) versus nasal spraylume, low pressure) needs to be addresseddouble-blinded randomized controlled trialch a study is currently in progress.

LUSION

gh multiple aetiologies for nasal polyps haveudied, it is evident that dysregulated inflam-at the epithelium has a central role in thement of CRSwNP. It is not a systemic con-but is characterized by sporadic involvementirway for most affected patients. A histologi-sification of ECRS and its severity is recom-d as it is associated with increased diseaseand the need for long-term local anti-atory control. Topical steroids, when effec-elivered, are associated not only with symp-ntrol but objective endoscopic resolutionucosal control. Like asthma, ECRS shouldsidered a condition to be controlled ratherred with the use of long-term anti-inflam-treatment and a maintenance regime

d. At present, optimal treatment involvestopical steroid, via nasal irrigation, in theof a wide, postsurgical corridor.

& of&& ofAdditioWorld

1. Foan

2. Kerh55

3. Tian

4. Vadi61

5. Baanco96

6. ZhorIm

7. Jiapa20

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16. Kod reproduction of this article is prohibited.www.co-otolaryngology.com 29stromal lymphopoietin in patients with sol 2012; 129:104111; e101-109.cial intereststanding interestreferences related to this topic can also be found in the Currentrature section in this issue (p. 88).

ns WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitissal polyps 2012. Rhinol Suppl 2012; 3:1298.C, Conley DB, Walsh W, et al. Perspectives on the etiology of chronic

inusitis: an immune barrier hypothesis. Am J Rhinol 2008; 22:549

rley D, Schlosser RJ, Harvey RJ. Chronic rhinosinusitis: an educationeatment model. Otolaryngol Head Neck Surg 2010; 143:S3S8.ele T, Claeys S, Gevaert P, et al. Differentiation of chronic sinuses by measurement of inflammatory mediators. Allergy 2006;801289.rt C, Zhang N, Holtappels G, et al. Presence of IL-5 protein and IgEdies to staphylococcal enterotoxins in nasal polyps is associated withbid asthma. J Allergy Clin Immunol 2010; 126:962968; 968 e961-

N, Van Zele T, Perez-Novo C, et al. Different types of T-effector cellstrate mucosal inflammation in chronic sinus disease. J Allergy Clinol 2008; 122:961968.XD, Li GY, Li L, et al. The characterization of IL-17A expression ints with chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy25:e171e175., Liu W, Zhang L, et al. Increased neutrophilia in nasal polyps reduces

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vels of IL-25 and IL-33 in ECRS versus non-ECRS provides validationept of tissue eosinophilia as a diagnostic criteria in CRS. Additionally, it

er evidence for altered interaction between sinus epithelium and thehoid system as a key process in ECRS.YH, Angkasekwinai P, Lu N, et al. IL-25 augments type 2 immuneses by enhancing the expansion and functions of TSLP-DC-activatedemory cells. J Exp Med 2007; 204:18371847.u S, Moro K. Type 2 innate immune responses and the natural helpermunology 2011; 132:475481.

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This is an important and comprehensive review of the evidence for inflammatorypathogenetic mechanisms in CRS. It provides detailed description of the inflam-matory profile and a balanced perspective of the role of micro-organisms in thepersistence of disease.29. Pezato R, Voegels RL. Why do we not find polyps in the lungs? Bronchial

mucosa as a model in the treatment of polyposis. Med Hypotheses 2012;78:468470.

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By demonstrating distinct histological characteristics for eosinophilic versusnoneosinophilic CRSwNP, the concept of histopathological classification ofdisease is validated with implications on the prognosis and treatment options.46.&

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Approximately 20% of nonpolypoid CRS demonstrate significant tissue eosino-philia with increased disease severity. The possibility of poorer treatment outcomeswith ECRS suggests that structured histopathologic profiling of all forms of CRSshould be advocated.47. Soler ZM, Sauer D, Mace J, Smith TL. Impact of mucosal eosinophilia and

nasal polyposis on quality-of-life outcomes after sinus surgery. OtolaryngolHead Neck Surg 2010; 142:6471.

48. Hu Y, Cao PP, Liang GT, et al. Diagnostic significance of blood eosinophilcount in eosinophilic chronic rhinosinusitis with nasal polyps in Chineseadults. Laryngoscope 2012; 122:498503.

49. Armengot M, Garin L, de Lamo M, et al. Cytological and tissue eosinophiliacorrelations in nasal polyposis. Am J Rhinol Allergy 2010; 24:413415.

50. Leung RM, Kern RC, Conley DB, et al. Osteomeatal complex obstruction isnot associated with adjacent sinus disease in chronic rhinosinusitis withpolyps. Am J Rhinol Allergy 2011; 25:401403.

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ttern of ECRS is shown to be independent of ostiomeatal complextion. Therefore, the concept of limited endoscopic sinus surgery in ECRSuppidvoter p6.rvesalrvergerckidvolypsda

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a is related to sputum eosinophilia. J Allergy Clin Immunol 2002;21626.m MM, Araruna A, Caetano LB, et al. Nasal eosinophilia: an indicator ofphilic inflammation in asthma. Clin Exp Allergy 2010; 40:867874.a Y, Ishitoya J, Komatsu M, et al. New clinical diagnostic criteria forphilic chronic rhinosinusitis. Auris Nasus Larynx 2011; 38:583588.

stahl GJ, Kleinjan A, Overbeek SE, et al. Segmental bronchial provoca-duces nasal inflammation in allergic rhinitis patients. Am J Respir Crit

ed 2000; 161:20512057.stahl GJ, Overbeek SE, Kleinjan A, et al. Nasal allergen provocations adhesion molecule expression and tissue eosinophilia in upper andairways. J Allergy Clin Immunol 2001; 107:469476.son PA, Vaidyanathan S, Clearie K, et al. Airway dysfunction in nasal

sis: a spectrum of asthmatic disease? Clin Exp Allergy 2011;791385.stahl GJ. Chronic rhinosinusitis, nasal polyposis and asthma: the uniteds concept reconsidered? Clin Exp Allergy 2011; 41:13411343.PS, Kern RC, Tripathi A, et al. Outcome analysis of endoscopic sinusy in patients with nasal polyps and asthma. Laryngoscope 2003;7031706.s E, Papadakis CE, Chimona TS, et al. The effect of functional

copic sinus surgery on patients with asthma and CRS with nasal. Rhinology 2010; 48:331338.ge A, Olsson P, Kolbeck KG, et al. One year after endoscopic sinusy in polyposis: asthma, olfaction, and quality-of-life outcomes. Otolar-Head Neck Surg 2012; 146:834841.S, Scadding GK, Lund VJ, Saleh H. Treatment of chronic rhinosinusitiseffects on asthma. Eur Respir J 2006; 28:6874.

Cohen-Kerem R, Barzilai G, et al. Functional endoscopic sinus surgerytreatment of massive polyposis in asthmatic patients. J Laryngol Otol116:185189.

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orted.ngs K, Chaowanapanja P, Aeumjaturapat S, et al. Does nasal irrigationaranasal sinuses in chronic rhinosinusitis? Am J Rhinol 2008; 22:483

y RJ, Debnath N, Srubiski A, et al. Fluid residuals and drug exposure inirrigation. Otolaryngol Head Neck Surg 2009; 141:757761.y RJ, Goddard JC, Wise SK, Schlosser RJ. Effects of endoscopic sinusy and delivery device on cadaver sinus irrigation. Otolaryngol HeadSurg 2008; 139:137142.ngs K KL, Sivasubramaniam R, Cope D, et al. Topical steroid for nasal. Cochrane Database Syst Rev 2012; (in press).

ta from meta-analyses demonstrate improved outcomes with topicaloids for the management of CRSwNP, especially if this occurs in thecopic sinus surgery.r A, Weitzel EK, Buele A, et al. Pre and postoperative sinus penetration

al irrigation. Laryngoscope 2008; 118:20782081.er PS, Abadie WM, Weitzel EK, et al. Unexpected consequences ofasal balloon dilation of the maxillary ostium. Int Forum Allergy Rhinol1:466470.

y RJ, Schlosser RJ. Local drug delivery. Otolaryngol Clin North Am42:829845; ix..n R, Mackay I, Wilson R, Cole P. Double blind, placebo controlledf betamethasone nasal drops for nasal polyposis. Br Med J 1985;88.ngs K, Pratt E, Chin D, et al. Corticosteroid nasal irrigations after

copic sinus surgery in the management of chronic rhinosinusitis. IntAllergy Rhinol 2012; 2:415421.emonstrates better outcomes for ECRS versus non-ECRS with topical

oids after endoscopic sinus surgery. It affirms the utility of a wide,al corridor for topical therapy and validates the predominant inflamma-of ECRS.

Volume 21 Number 1 February 2013159:588595.inke A, Grootendorst DC, Schmidt JT, et al. Chronic sinusitis in severe

The paobstruc

nasal polyposis an inflammatory condition.6

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