Intranasal Steroids and the Myth of Mucosal Atrophy: a Systematic Review of Original Histological Assessments

Intranasal steroids and the myth of mucosal atrophy: A systematic review of original histological assessments

Misha M. Verkerk, M.B.B.S.,1 Daman Bhatia, M.B.B.S.,2 Janet Rimmer, F.R.A.C.P.,3 Peter Earls, F.R.C.P.A.,4 Raymond Sacks, M.D.,5 and Richard J. Harvey, M.D.6

ABSTRACT Background: Intranasal corticosteroids (INCSs) are well established in the treatment of allergic rhinitis, chronic rhinosinusitis, and nasal polyposis. Although reversible atrophy of keratinized skin is seen with corticosteroids, the respiratory mucosa is histologically very different and but concerns remain among patients and some health-care professionals over local side effects on nasal respiratory mucosa. A systematic review and meta-analysis were performed of the available evidence for nasal mucosal atrophy as an adverse effect of INCSs in patients with sinonasal disease. Methods: A systematic search of Embase (1974-) and Medline (1946-) databases to September 27, 2013 was performed. Inclusion criteria selected any study where the histopathology of nasal mucosa was assessed in patients with sinonasal disease using intranasally administered corticosteroids with or without a control group. Results: Twenty-three hundred sixty-four publications were retrieved with a subsequent full text review of 149 publications for 34 articles that met the selection criteria. These articles included 11 randomized controlled trials, 5 cohorts, and 20 case series. Duration of treatment varied from 5 days to 5.5 years. “Mucosal atrophy” as an outcome was reported in 17 studies. The definition of “mucosal atrophy” was highly variable with a definition given in only 10 studies. One hundred thirty-six patients were represented in controlled studies of atrophy with only one study reporting the event in both groups with an odds ratio of “mucosal atrophy” at 0.51 (95% CI, 0.09–3.11; p ϭ 0.47). Conclusion: The concept of nasal mucosal atrophy is poorly defined and there is no histological evidence for deleterious effects from INCS use on human nasal mucosa. (Am J Rhinol Allergy 29, 3–18, 2015; doi: 10.2500/ajra.2015.29.4111)

ntranasal corticosteroids (INCSs) are recommended in the manage- roid allergy, poor applicator technique, preexisting conditions, or I ment of rhinitis and chronic rhinosinusitis (CRS), which represent natural progression of the underlying disease process.12–20 Common a significant burden of disease and a substantial proportion of pri- local adverse effects reported in the literature include epistaxis, throat mary-care consultations.1–3 Since their introduction in the 1970s, con- irritation, nasal dryness, and burning and stinging sensations.8,21 Such cerns over systemic and local adverse effects of INCSs have been side effects occur in 5–10% of patients using INCSs in RCTs of acute fuelled partly by adverse effects of oral, inhaled, and potent topical rhinosinusitis,22 allergic rhinitis (AR),23 and CRS.24 With the exception corticosteroids.4–6 Recent reviews of randomized controlled trials of epistaxis, the incidence of such side effects is similar to placebo and (RCTs) have shown that INCSs, when used appropriately at the they are mild in severity, usually resolving without discontinuation of recommended dosage, are not associated with adverse effects on the treatment.25–29 Epistaxis leads patients to believe that mucosal dam- hypothalamic–pituitary axis, bone mineral density, childhood growth age is occurring. rate, glaucoma, cataract, and skin atrophy.7,8 Recent reviews addressing a limited range of evidence found no Although INCSs have little systemic impact, a clinically relevant mucosal atrophy after prolonged courses of INCSs for sinonasal concern to patients and some health-care professionals is that using disease.8,21 Recent patient surveys reveal concerns about this partic- INCSs may cause local damage to the nose.9–11 Such fears may be ular side effect.9,10,30 This study was designed to provide a systematic confounded by wider use of these medications and case reports of and critical appraisal of the available evidence on INCS and mucosal nasal atrophy or septal perforation in patients using older formula- atrophy. tions of INCSs, although it remains unclear whether such reports represent clinically relevant adverse effects, examples of corticoste- METHODS

From the 1Department of Otolaryngology, Head and Neck Surgery, and Freeman Eligibility Criteria 2 Hospital, Newcastle University, Newcastle-upon-Tyne, United Kingdom, Department Case series, case–control studies, cohorts, and RCTs were included. of Otolaryngology, Hornsby Ku-ring-gai Hospital, Sydney, New South Wales, Aus- Only articles published in English were eligible; reviews, guidelines, tralia, Departments of 3Thoracic Medicine and 4Pathology, St. Vincent’s Hospital, Sydney, New South Wales, Australia, 5Department of Otolaryngology, Head and Neck letters, case reports, editorials, and in vitro and animal studies were Surgery, Concord General Hospital, University of Sydney, and Macquarie University, excluded. Only studies involving histological measurement of nasal DO6 NOT COPY Sydney, New South Wales, Australia, and Department of Otolaryngology, Head and mucosa in patients with sinonasal disease (excluding malignancy) Neck Surgery, St. Vincent’s Hospital, University of New South Wales, and Macquarie treated with INCSs were included. All reasonable definitions of al- University, Sydney, New South Wales, Australia lergic rhinitis and nonallergic rhinitis (NAR), CRS, and nasal polyp- Presented at the Ear, Nose, and Throat Annual Conference London, United Kingdom, osis were included, as were all known formulations and delivery September 13, 2013, and the Annual Scientific Meeting of the Australian Society of methods of INCSs (see electronic search strategy in the Appendix). Otolaryngology, Head and Neck Surgery, Brisbane, Australia, March 30, 2014 Studies with participants of all ages, with any comorbidity and with RJ Harvey, has served on an advisory board for Schering-Plough and GlaxoSmithKline, any duration of treatment and any length of follow-up, were in- as a previous consultant with Medtronic and Olympus, and speakers bureau for Merck Sharp Dolme and Arthrocare and has received grant support from NeilMed. The cluded. Studies that involved the explicit concomitant use of inhaled remaining authors have no conflicts of interest to declare pertaining to this article or systemic corticosteroids or without histological analysis reported Address correspondence to Misha M. Verkerk, M.B.B.S., Department of Otolaryngol- were excluded. ogy, Head and Neck Surgery, Freeman Hospital, Freeman Road, Newcastle-upon-Tyne, NE7 7DN United Kingdom Information Sources E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A. The Embase database was searched from 1974 to September 27, 2013, and the Medline database was searched from 1946 to September

American Journal of Rhinology & Allergy 3 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 1. Study protocol. Based on the PRISMA statement. Source: Reference 74.

27, 2013, using Ovid SP. Bibliographies of studies selected for full-text INCS; tissue biopsy source; sampling method; method of sample analysis were also searched for studies missed by the search strategy. analysis; stated outcome measures; and key results. Outcome mea- An electronic search strategy (see Appendix) was designed to include sures considered relevant to mucosal atrophy were defined as all studies concerning the use of INCSs in patients with sinonasal disease where nasal mucosa was assessed. • Loss of epithelial integrity. • Epithelial thinning. • Epithelial ulceration. Study Selection • Basement membrane thinning. Study selection was performed by unblinded by two authors (M.M.V. • Loss of basement membrane integrity. and D.B.) according to predefined selection criteria, and results were • Squamous metaplasia. reconciled to compile a single group of studies for analysis. The publi- • Loss of cilia. cations retrieved in the initial search were reviewed by title and grouped • Change in subepithelial glands. into thoseDO studies containing any reference toNOT sinonasal disease, INCSs, COPY • Subepithelial fibrosis. or nasal mucosal atrophy. Remaining studies were subject to abstract • Loss of goblet cells. review. Studies concerning INCS and sinonasal disease with defined • Increased apoptosis/cell turnover. sinonasal groups or those where biopsy specimens of the upper airway • Epithelial edema. were taken were subject to full text analysis. Risk of bias. Data Collection Risk of bias in RCTs was assessed at a study level using the Data were extracted from the final group of included studies using Cochrane Risk of Bias Assessment Tool.31 For cohort studies, risk of a standardized data sheet. This was performed independently in bias was assessed in accordance with the Newcastle–Ottawa Scale.32 duplicate (by authors M.M.V. and D.B.) and all authors reconciled the results. For each study, the following variables were recorded: study type; number of patients; atrophy definitions; exclusion of patients Statistical Analysis with systemic disease, prior surgery, or exposure to systemic cortico- Raw data were extracted from graphs and tables. Odds ratios (ORs) steroids; type, delivery method, dose, frequency, and duration of were calculated for dichotomous variables in a fixed-effects model.

4 January–February 2015, Vol. 29, No. 1 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm ϭ TEM Biopsy Anals Turbinate LM Turbinate LM not otherwise specified; NR ϭ 150 Turbinate LM Ͻ d d 168 Turbinate LM 365 Turbinate LM, IHC 365 Turbinate LM Յ (day) 730 2007 Յ Ն Ͻ Duration 0 g 1095 g 365 Turbinate LM

␮ ␮ g 300 Mucosa NOS LM

g, B. 400 g; B. 200 ␮

␮ ␮ Dose gggg 6 365g Turbinate Turbinate 365 LM, LM, IHC TEM g A: 42 84; B: 252 Turbinateg Turbinate Turbinate LM LM, IHC LM, SEM, 35 28 Turbinateg LM g Turbinate LM g 21 84 Turbinate Turbinate 365 LM g LM Mucosa NOSg (3), 400 LM, IHC gg9 60 Turbinate TEM 90 Turbinate LM nonallergic rhinitis; NOS

␮ ␮ ␮ ␮ ␮ ␮ ␮ ␮ ␮ ␮ ␮ ␮ ␮ ␮ g, 2. 10 mg g g (9) Total Daily ϭ ␮ ␮ ␮ 2–8 mg 365 Turbinate LM, IHC A. 220 300 NRA. 110 A. 90–150; B. Method insufflation spray aerosol aerosol spray Spray 200 Spray 200 not applicable; NAR ϭ ) Delivery n placebo (8), transmission electron microscopy. ϩ ϭ light microscopy; NA Placebo (6) drops (30) ϭ NA Spray 100 Cetirizine (23) A. Spray; B. A. Placebo (6); B. NA A. Aerosol; B. A. Placebo (3); B. NA A. Aerosol; B. NA A. Spray; B. NANA Aerosol 400 Aerosol 400 ) Comparison ( ϩ n immunohistochemistry; LM loratadine (12); mometasone furoate (12) (21); B. beclomethasone dipropionate (26) dipropionate (5); B. beclomethasone dipropionate (9) dipropionate (7); B. Beclomethasone dipropionate (6) B. Mometasone furoate (42) dipropionate (20) dipropionate (7) ϭ A. Beclomethasone scanning electron microscopy; TEM DO NOT COPYϭ B. 9 mixed rhinitis A. 11 Mixed rhinitis; A. 10 AR; B. 6 AR A. Beclomethasone benzalkonium chloride; IHC ϭ randomized controlled trial; SEM case series B. case series ϭ RCT*RCT#RCT# 21 AR 51 ARRCT* 70 ARRCT*A. RCT*; 29 B. AR 22 Budesonide AR (10) Fluticasone propionate (26) A. Triamcinolone Terfenadine acetonide Cohort# (25)Cohort* 90 Fluticasone Placebo NAR propionate (11)A. (17) cohort#; Fluticasone Spray propionate Placebo (8) (12) 15 AR BKC Case 200 series Flunisolide Spray (30) 79 AR SprayCase series Flunisolide (7)Case series 29 256 AR 24 AR 200 Silver nitrate (30); saline Case series A. FluticasoneCase furoate series (37); 52 AR Placebo 48 (8) MixedCase rhinitis series Mometasone furoate 24 Mometasone Mixed furoate Case Fluocortin rhinitis series butyl 50 MixedCase Budesonide rhinitis NA series (24) Mometasone furoate Spray (52) 20 ARCase Budesonide series (50) NA NA 12 NARCase series 400 Case NA series 15 ARCase series 10 AR NA 7 Beclomethasone AR Spray Budesonide (12) Spray Powder Budesonide (15) 200 Flunisolide (10) Aerosol Beclomethasone NA 200 Aerosol 200 or 400 NA NA 200 or 400 Aerosol Aerosol 200 Spray 200–400 200 40 41 30 37 81 53 36 44 77 43 72 52 82 51 79 76 75 42 et al. 78 Study characteristics—Rhinitis et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. 80 34 et al. et al. et al. allergic rhinitis; BKC et al. et al. et al. et al. Study Design Participants Intervention ( et al. ϭ et al. et al. not reported; RCT Knight Pipkorn Table 1 *Double blinding. #No blinding. AR Baroody Klossek Braat Erhan Spector Poynter Can Minshall Orgel Pipkorn Chatterjee Uller Holm Ozgur Balle Fokkens Lindqvist Elwany Sahay

American Journal of Rhinology & Allergy 5 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm TEM SEM, Cyt LM IHC LM, IHC LM, IHC, nasal polyposis; ϭ Biopsy Analysis specimen turbinate (control) turbinate (control) specimen not applicable; NP ϭ 1080 Polyp biopsy365 LM, SEM Polyp biopsy LM, Ͻ Ͻ d d (day) 180 Polypectomy 90 Polyp biopsy LM Յ Յ Duration, Ն Ն gg 28g 120 Polypectomy/ 365 Polyp biopsy Turbinate LM g LM 56g 270 Polypectomy/ g 270

␮ ␮ ␮ ␮ ␮ ␮ light microscopy; NA Dose Daily transmission electron microscopy. 2 mg 5 Sinus LM ϭ ϭ tube Merocel sponges NR 7 Sinus LM immunohistochemistry; LM ϭ ) Delivery Method Total n scanning electron microscopy; TEM ϭ cytology; IHC ϭ Gentamicin (16) Placebo (15) Powder insufflator 400 NANANANA Maxillary antrostomy Powder insufflatorNA 400 Spray Aerosol Aerosol 400 mg 400 d 400 Placebo (8) SprayPlacebo (11)No treatment (13) 400 Spray NR NR NR d 14 Polypectomy ) Comparison ( n dipropionate (22) (30) (10), Mygind NOS (50) dipropionate (33) dipropionate (33) propionate (8) propionate (11) propionate(16) randomized controlled trial; SEM Beclomethasone ϭ chronic rhinosinusitis with nasal polyps; Cyt

DO NOT COPYϭ not reported; RCT ϭ ethmoidectomy 30 CRSsNP10 NP50 Dexamethasone NP33 NP Budesonide 33 NP Corticosteroid Beclomethasone Beclomethasone series series series series series RCT* 48 MixedRCT* CRS 16 CRScNPRCT* Budesonide (16) 16 NPRCT* Manuka honey (16), 37 Fluticasone Post- RCT* 22 NPCohort# Budesonide 29 (8) NPCase Placebo (8)Case Fluticasone Case Fluticasone SprayCase Case 400 85 39 38 87 et 83 47 et 46 84 48 et al. et al. Study characteristics—CRS et al. et al. not otherwise specified; NR chronic rhinosinusitis; CRScNP et al. et al. et al. et al. et al. Study Design Participants Intervention ( ϭ ϭ 45 86 al. al. Mygind Chang Sorensen Molet Mastruzzo Holopainen Lacroix Drvis Table 2 Klemi Saunders *Double blinding. #No blinding. CRS Alatas NOS

6 January–February 2015, Vol. 29, No. 1 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm For continuous data, mean differences were calculated from baseline and final means and SD of change using an inverse variance, fixed- effect model with 95% CIs (Review Manager [RevMan] Version 5.2., Copenhagen, The Nordic Cochrane Center, The Cochrane Collabora- tion, 2012). Where SDs of change were not available, this was imputed from baseline and final means as described in the Cochrane Hand- book.33 Forest plots were visually inspected to investigate statistical Biopsy Analysis heterogeneity. Heterogeneity between studies was assessed clinically for each study and investigated using the I2 statistic, which provides an estimate of the percentage of variation observed in results that is

1825 Mucosa NOS LM Ն

1080 Septum LM unlikely to be due to chance. A value of 50% was taken to indicate Ͻ

Ͻ heterogeneity. d d (day) Յ Duration Յ RESULTS A total of 2774 articles were retrieved. One publication was added from bibliographic searching of an included article.34 After removal of g/d 365 duplicates, 2364 publications remained. A systematic review of titles, ␮ abstracts, and full-text publications was performed, as described in Dose Fig. 1. Two publications reported the same data from the same Total Daily not reported. patients and therefore were treated as one study.35,36 A total of 34

ϭ publications remained for data extraction (see Fig. 1). Some publications reported more than 1 study, so a total of 36 clinical studies (from 34 publications) were analyzed.

Method The characteristics of the included studies are shown in Tables 1–3. Demographic details and efforts to control confounding were incom-

) Delivery pletely reported. Eleven RCTs, 5 prospective cohort studies, and 20 n case series were included. The final group of studies included 23 studies on patients with rhinitis, 11 studies on patients with CRS, and 2 studies that assessed a mixed cohort of patients with rhinitis and

not otherwise specified; NR nasal polyposis.

ϭ In the 16 controlled trials, 251 patients received INCSs and 266 NA Spray 0–400 No treatment (10) NR NR 60 patients received placebo or non-INCS medications. In the case series, 564 patients received INCSs.

Study Objectives ) Comparison ( n The aims of included studies were variable, ranging from the assessment of long-term safety and efficacy to specific aims to exam- not applicable; NOS ine the effects of INCSs on histological appearances of nasal mucosa. ϭ Seventeen included studies explicitly mentioned nasal mucosal atrophy in the body of the article.

Definitions of Atrophy (23) dipropionate or budesonide or both (11)

Beclomethasone dipropionate The histological features that were taken to characterize mucosal atrophy varied among the studies that included a definition of this pathology (Table 4). A total of 7/17 studies that mentioned mucosal light microscopy; NA atrophy did not provide a definition. The remaining definitions var- ϭ ied from the presence of squamous metaplasia alone36–39 to com- nasal pound definitions encompassing thinning of the epithelial and colla- ϩ gen layers, increase in tissue edema, and increased regularity of collagen fibrils.40,41

DO NOTInterventions COPY Several INCSs were subject to investigation, with some studies

polyposis investigating more than one agent (Tables 1–3). Duration of treatment

chronic rhinosinusitis; LM also varied considerably from 5 days to 5.5 years (Tables 1–3). ϭ Methods of Sampling and Analysis Biopsy specimens of nasal mucosa were taken in a clinic setting in 26 studies, and surgical specimens were used in 9 studies. In 20 Cohort# 21 Mixed nasalCase polyposis/AR series Beclomethasone 23 dipropionate Mixed rhinitis studies, tissue from turbinate biopsy was used for analysis, with the remaining studies analyzing tissue from sinus, septum, unspecified Study characteristics—Mixed rhinitis/CRS nasal mucosa, nasal polyp biopsy, and polypectomy specimens. Thirty- 50 49 allergic rhinitis; CRS five studies used light microscopy for sample analysis, with 9 studies ϭ Study Design Participants Intervention ( et al. et al. using immunohistochemistry, 4 studies using transmission electron Bende Table 3. #No blinding. AR Holopainen microscopy, and 3 studies using scanning electron microscopy.

American Journal of Rhinology & Allergy 7 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm basal ϩ ϩ m, ratio of area to length)

␮ dissociated columnar cells; BM ϩ m, mean of 3 measurements on LM)

␮ m, mean of 5 measurements on LM) m, median of 5 measurements)

␮

2 ␮ m; edema (ordinal scale) basal cells ␮ m, median of 5 measurements)

ϩ ␮ Atrophy-related Outcome Measures intact columnar cells; intact epithelium inc. cilia) cells/0.1 millimeter BM ϩ ϩ cells (mitochondria, cilia, ER) basal cells; BM per hpf; thickness of basal membrane thickening of the basal lamina scale goblet cells; presence ofpropria focal morphology; metaplasia; morphology BM of structure; vessels lamina and glands. (nominal scale) edema, fibrosis. TEM: Non-quantified examination of epithelial ultrastructure Number or damage to cilliated cells on LM or EM. Thickness of BM ( Appearance of mucosal epithelium Thickness of epithelium ( Collagen layer thickness ( Percent ratio of goblet cells to epithelial cells Thickness of BM, nominalNumber scale of glands per hpf Epithelial thickness (ratio ofEpithelial epithelial phenotype cross-sectional (% area of to epithelium BM composed length) of: BM only; BM Number of goblet cellsThickness (nominal of scale) basal membrane (nominal scale) Four-point ordinal scale: squamous epithelium; number of goblet cells; Goblet cells in nasal brushings, percent of epithelial cell count, ordinal Epithelium layer thickness ( Appearance of epithelial layer Degree of tissue edema Thickness of the epitheliumRatio (mean, of mm) epithelial crossPercentage sectional of area ciliated to intact BMQualitative epithelium. length comments on: epithelial type and integrity; abundance of Mucosal epithelium cell type, BM thickness, edema,Eosinophil inflammation count, ordinal scale SEM: Subjectively assessed ratioLM: of epithelial ciliated/nonciliated cells/ cells per hpf Total apoptotic cells/mm Semiquantitative measurement of epithelial metaplasia (details not published) Qualitative changes in EM appearances compared to baseline Ordinal scale: BM thickness, number of submucous glands, degree of Ki-67 Presence of edema (4-pointRegularity ordinal of scale, collagen EM) fibrils (3-point ordinal scale, EM) Nasal mucosal epithelium thickness ( Squamous metaplasia nominal scale (absent/focal/diffuse) Type of epithelium, nominal scale Atrophy Definition thickness; (iii) increase inregularity edema; of (iv) collagen increase fibrils in in ratio of epithelialBM; cross-sectional (iii) area squamous to metaplasia. length of DO NOT COPY AR Squamous metaplasia Mixed rhinitisMixed rhinitisNAR Squamous metaplasia and BM thinning “Atrophy,” not otherwise defined NA Nominal scales (3-point): epithelial metaplasia; number of goblet cells Epithelial metaplasia (nominal scale) AR Epithelial thinning ARARAR NA AR Epithelial or BM thinning Any of (i) epithelial thinning; (ii) reduction collagen layer “Atrophy,” not otherwise defined Four-point ordinal scale (details not published): ARNARAR Any of: (i) reduction in epithelial thickness; (ii)Mixed reduction rhinitis NA NA Squamous metaplasia AR NA ARNA ARMixed rhinitisAR “Atrophy,” not otherwise defined NA “Atrophy,” not otherwise defined Presence/absence of BM thickening or squamous metaplasia Type of surface epithelium, nominal scale 1986 1998 2001 2001. 2012 1988 1983 1983 80 1983 2011 40 36 1996 1980 41 30 1998 1991 37 81 1995 44 2010 1982 43 2006 72 52 82 51 79 76 Atrophy-related definitions and outcomes et al. 75 42 et al. et al. 78 et al. et al. Study Population et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. Orgel Fokkens Holm Ozgur Pipkorn Lindqvist Elwany Balle Minshall Erhan Braat Sahay Knight Pipkorn Table 4 Baroody Klossek* Can Uller

8 January–February 2015, Vol. 29, No. 1 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm chronic ϭ chronic rhinosinusitis without ϭ allergic rhinitis; CRS ϭ Atrophy-related Outcome Measures endoplasmic reticulum; AR III collagen deposition (staining intensity, extent of collagen damaged epithelium on 4-point ordinal scale ϩ ) ϭ Ϯ scanning electron microscopy; CRSsNP cells per hpf in epithelium and stroma e-%of ϭ ϩ not quantified ?binary outcome Љ hyperplasia, epithelial desquamation, andhyalinization BM and rupture), glandular edema, hyperplasia. fibroblastic density, stromal deposition, BM thickness) Atrophy, Quality of epithelium Thickness of basal membrane Edema of lamina propria Presence of mucous glands Presence of fibrosis Presence/absence ciliated cells Percent of Ki67 Љ Category of epithelium on SEM, nominal scale Presence/absence edema, Goblet cells per mmSurface epithelium epithelium type on LM,Surface ordinal epithelium scale type (0–100, on squamous SEM, to pseudostratified) ordinal scale (0–100) Presence/absence: Squamous metaplasia, epithelial damage (defined as surface epithelial Qualitative description of epithelium BM thickness, nominal scale Presence/absence of edema Collagenous fibres (normal/abundant) Four-point ordinal scale: Number of inflammatory cells Edema Fibrosis Seromucous glands Goblet cell density Mean cell count perNominal hpf score (type for V type collagen) I Fibrosis (7-point ordinal scale) Squamous metaplasia ( BM appearance, nominal scale Degree of edema, ordinal scale Epithelial damag Integrity of epithelium (details not given) Percent of apoptotic/mitotic cells per hpf in epithelium and stroma Qualitative: Appearances of epithelium, BM, edema, eosinophilia, collagen Semiquantitative appearances of polyp tissue on LM (details not reported) Tissue edema, 3-point ordinal scale electron microscopy; ER ϭ nonallergic rhinitis; SEM ϭ basement membrane; EM ϭ not applicable; NAR ϭ light microscopy; BM “Atrophy,” not otherwise defined Epithelial metaplasia, nominal scale Squamous metaplasia or BM thinning Thickness of basal membrane (7-point ordinal scale) ϭ high powered field. ϭ

DO NOT COPYnasal ϩ polyposis AR chronic rhinosinusitis with nasal polyps; NA Mixed CRS NA NP, ACP NA Postethmoidectomy “Atrophy,” not otherwise defined Qualitative comments on: Mixed rhinitis ARCRSsNP NA NA CRScNP NA Nasal polyposisMixed nasal polyposis/ Squamous metaplasia AR NA Nasal polyposis NA Nasal polyposisNasal polyposis NA “Atrophy,” not otherwise definedNasal polyposis Squamous metaplasia Qualitative description of epithelial degeneration, metaplasia & mucosal atrophy Nasal polyposis NA AR NA ϭ antrochoanal polyp; hpf et ϭ 2003 1977 1999 1976 86 1978 1977 34 1980 2002 85 2011 39 2006 1992 1980 2003 2004 38 53 77 87 83 47 50 et al. 46 84 et al. 48 Continued et al. transmission electron micoroscopy; LM et al. 1982 Study Population Atrophy definition et al. et al. et al. et al. et al. 1982 49 et al. et al. et al. ϭ et al. et al. 45 al. et al. rhinosinusitis; CRScNP nasal polyps; ACP Holopainen, Grahne Drvis Mygind Alatas Klemi Molet Bende Table 4 Poynter TEM Spector Saunders Holopainen, Malmberg Sorensen Lacroix Chang Mastruzzo Chatterjee

American Journal of Rhinology & Allergy 9 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm SD: SD): SD: 41), Ϯ Ϯ Ϯ ϭ n loratadine 0.81, BM SEM: Ϯ ϩ , not defined: ϭ Љ 0.001 0.006 (0.018). p Ϫ ϭ 40, pre-INCS vs p ϭ 0.05; % ciliated cells: n Ͼ 0.46 thickening p Љ Ϯ SEM): INCS: 0.053 (0.003) Ϯ 10), data post-INCS only, ϭ Summary n 0.05, pre-INCS vs post-INCS; Ratio 1.00 2.1 (10.44); Mometasone 0.7 (10.63); 0.92 vs 0.17 0.05) 0.05) Epithelium thickness: No change Ϫ Ͼ ϭ Ϯ Ͼ Ͼ p p p p 0.008 (0.019); mometasone: 0.662 (4.5452); Mometasone 1.926 (16.1207). Ϫ Ϫ SD): 0.83 Ϯ 0.05) but not INCS alone. BM thickness: No change 0.77, Goblet cells: 11/39 increase, 18/39 no change, Ͻ SD): Fluticasone ϭ p Decreased with treatment with mometasone mean INCS: 0.046 (0.002), 0.045 (0.002) from baseline ( from baseline ( vs 0.052 (0.003), ( of cross-sectional area to length of BM, ratio 59% vs 71%, pre-INCSepithelium: vs 21.6% post-INCS, vs NS, 29.4%,Squamous Intact pre-INCS metaplasia: vs 11.8% post-INCS, vsINCS, NS. 7.8%, NS. pre-INCS No vs changenot post- in given), integrity No of changecells BM in (data post-INCS distribution not (data or given)features density No of of change vessels goblet in andgiven) morphological glands in lamina propria (data not Fluticasone: 9.183 (42.3472); Mometasone 2.878 (40.8399). fluticasone: % intact ciliated cells: Mean change from baseline Fluticasone % Goblet cells inϮ biopsies (mean change from baseline % epithelium BM only: Mean change from baseline post INCS): Columnar: 15Squamous vs 13 28; vs cuboidal 6, 12 BM vs quality 6; (no. of biopsies, pre-INCS vs post-INCS: Thinning:destruction: 15 4 vs vs 12; 6;17 Partial Complete vs destruction: 21; 3 notin vs in methods, 2; sample not Normal 2 in vs results 0, No of glands: mentioned increase vs no change4 vs vs decrease: 4 Epithelial vsvs9vs1 metaplasia: 2, BM thickness: 2 vs 7 vs 1, Goblet cell no.: 0 change in epithelial metaplasia,cells. BM No. thickness of or biopsies goblet ( increase, 22/40 no change, 8/40 decrease, thickness: 7/39 increase, 27/39p no change, 5/39 decrease, 10/39 decrease, Baseline vs 48 weeks INCS, BM 13/16 vs 7/9, baselinemucosal vs atrophy 48 (details weeks not INCS. given). No evidence of Edema Cell Turnover Increased Apoptosis/ Cells Goblet Loss of Fibrosis Subepithelial Glands Change in Subepithelial Cilia Loss of Atrophy Outcomes Squamous Metaplasia BM Loss Integrity Thinning

DOUlceration BM NOT COPY Thinning Epithelial Loss NR NR NR Absent NR Absent NR NR NR Absent NR NR No statistical analysis reported. No statistically significant NR NR NR Absent NR Absent NR NR NR Absent NR NR Data are no. of biopsies, Epithelial metaplasia: 10/40 NR NR NR Absent Absent Absent NR NR NR NR NR NR Epithelial metaplasia (No. of biopsies, NR NR NR Absent NR Present NR NR NR NR NR NR Data are no. of biopsies, Squamous metaplasia: 4/16 vs 5/9, Integrity Epithelial rhinitis rhinitis rhinitis rhinitis AR NR Absent NR Absent NR Absent NR NR NR NR NR NR Quantitative data not published. Squamous metaplasia: AR NR NR NR NR NR NR NR NR NR Present NR NR Goblet cell cytology ordinal score (pre-INCS vs post-INCS, AR Absent Absent NR NR Absent Absent NR Absent NR Absent NR NR Epithelial thickness (mm, mean Mixed Mixed AR Absent Absent NR NR NR NR Absent NR NR Absent NR NR Epithelial thickness: mm, mean change from baseline ( Mixed ARMixed NR NR NR NR NR NR Absent Present NR Present NR Absent No quantitative data. Atrophy outcomes—Noncontrolled studies only 79 et 78 et et et et 2011 1998 1988 2012 1983 80 1983 et et al. 72 40 37 30 43 44 et al. Study Population 2006 al. 1986 al. al. et al. 1991 al. al. (B) al. Can Table 5 Ozgur Minshall Pipkorn Lindqvist Orgel Knight Fokkens Elwany

10 January–February 2015, Vol. 29, No. 1 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm 0.01), only Ͻ p Љ normal Љ Summary chronic rhinosinusitis with nasal ϭ INCS: No pretreatment biopsy data, 0.05), Goblet cells decreased ( ϩ Ͻ p reported in edema, fibrosis,glands number or of goblet seromucous cell density). damage seen after INCSdifferences (ordinal in scale). collagen No staininggiven) macroscopic or distribution (data not graphical data, No consistentsquamous tendency metaplasia towards African (no INCS), Chinese(INCS). (no No INCS) significant vs BM Caucasian thickening (data not given) distribution of pseudostratified, ciliatedepithelium. and SEM: squamous No tendencysquamous towards epithelium respiratory observed or during INCS treatment change in subepithelial glandsedema (no decreased quantitative with data), INCSscore, (2.4 vs 1.6, mean of ordinal pre-INCS vs post-INCS, MetaplasiaINCS after 6 yr: 4/6 on post INCS, No changesremained seen thickened in pre the andstructures epithelium post of or INCS. lamina BM. Collagenous propria BM Squamous changes: 3/6 biopsies,Hyperplasia Oedema: of 4/6 subepithelial biopsies, glands:0/6 1/6, BM thinning: metaplasia (any degree, no.BM of thickening: biopsies): None 5/10 seen,number vs Glands: of 5/10, 3/10 glands, cases 0/10Oedema:5/10 increased decrease, vs 7/10 4/10 stayed pre-INCS3/10 same, vs vs post-INCS, 3/10 Fibrosis: pre-INCS vs post-INCS INCS treatment (graphical data only). no. of biopsies): 3/9Presence vs of 5/12, goblet pre-INCS cellsvs vs (any 10/12, post-INCS, degree, pre-INCS no. vsdegree, of post-INCS, no. biopsies): BM of 6/9 thickening biopsies)post-INCS (any 11/12 vs 12/12, pre-INCS vs Edema allergic rhinitis; CRScNP ϭ Cell Turnover Increased Apoptosis/ Cells Goblet Loss of Fibrosis Subepithelial scanning electron microscope; AR ϭ Glands Change in Subepithelial Cilia Loss of Atrophy Outcomes light microscope; SEM ϭ Squamous Metaplasia BM Loss Integrity not significant; LM Thinning ϭ standard deviation. ϭ DOUlceration BM NOT COPY not reported; NS Thinning Epithelial ϭ Loss Absent NR NR NR NR NR NR NR Absent NR NR NR Only graphical data. Improvement in markers of epithelial NR NR Absent Absent NR NR NR NR NR NR NR NR Data are % of biopsies. Ulceration: 20% vs 10% vs 10%, NR NR NR NR NR Absent NR NR NR NR NR NR No quantitative data given. LM: No change seen in NR NR NR Absent NR Absent Absent Absent NR Present NR Absent No change in BM thickness (no quantitative data), No NR NR NR NR NR Present NR NR NR NR NR NR Data are no. of biopsies, Metaplasia after 2 yr: 6/17 vs 9/17, Integrity Epithelial intranasal corticosteroid; SD polyposis polyposis polyposis polyposis rhinitis/ nasal polyposis ϭ Nasal Nasal Nasal Nasal Mixed CRSsNP NR NR NR NR NR NR NR Absent Absent Absent NR Absent No quantitative data published. No statistical difference AR NR NR NR Absent NR Absent NR Absent Absent NR NR Absent Data for 2 yr AR NR NR NR Absent NR NR NR NR NR NR NR Absent Data are no. of biopsies, Oedema: 5/6 vs 0/6, baseline vs AR NR NR NR Absent NR Absent NR Absent Absent NR NR Absent No statistical analysis. Data are no. of biopsies, Squamous AR NR NR NR NR NR Present NR NR NR NR NR NR Tendency towards increased metaplasia with duration of NAR NR NR Absent NR Absent NR NR NR Absent NR NR NR No statistical analysis. Squamous epithelium (any degree, Continued et 48 42 et basement membrane; NR et et et et 2002 1976 1978 1977 1977 1980 1983 86 49 et et al. et al. ϭ 87 39 38 53 34 82 81 Study Population al. 2003 al. al. 1982 et al. al. 2004 (B) Malmberg et al. al. al. 1982 al. Poynter Mastruzzo Lacroix Sorensen Mygind Holopainen, Drvis Chatterjee Sahay Table 5 BM polyps; INCS Balle Pipkorn

American Journal of Rhinology & Allergy 11 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm , Љ Љ 0.3 not Ϫ p normal m m change Љ

␮ ␮ 8.2 (6.7), ,1 Љ Љ Ϫ 0.05 vs non- BM, m): 28.55 (4.27)

␮ Ͻ ϩ thick m): 11.71 (0.87) vs Љ 0.05.

p ␮ Epithelial damage Љ SE): Cetirizine Ͼ abundant 21 Ϯ Љ p ϭ 25, Lucent spaces ordinal vs 2/3 ,1 n Љ ϭ Љ ) or % or Baseline, Post or SE): Cetirizine n n 0.06 (INCS vs placebo for type Ϯ 0.23, ϭ SE), change scale data (baseline vs normal ϭ p 0.47, Љ Ϯ p Change Scale Data thick BM ϭ Љ p 22, regularity of collagen fibrils score, 0.1 between groups. No change in ϭ vs 2/3 ϭ Љ n p 0.95 between groups. BM thickness ( 20 ϭ ϭ normal study end), epithelium thickness ( INCS), collagen thickness/BM ( treatment, Squamous changes: 1/3thinning: vs 3/3 2/3, BM expressing cells: V only) 12.46 (0.87), vs 20.91 (2.50), p edema: 3/3 vs 1/3,Љ Collagenous fibres: 3/3 epithelium: 8/8 vs 8/8,edema BM (mean intact, ordinal 2/7 score), vs 0.38 2/7, vs 0.94 1.75 (0.14) vs 1.85n (0.11), NS, given), epithelium, Saline: 89% (25/28),(7/29), Silver BM nitrate: thinned: 24% Saline:nitrate: 33% 10% (10/30), (3/30), Silver BMSilver eroded: nitrate Saline 20% 67% (6/30),63% (20/30), Severe (19/22), edema: Silver Saline: nitrate:no 16% statistically (4/25), significant Reported differenceoutcome, as between INCS any vs no INCS (-0.7), change from baseline, mean from baseline, mean squamous metaplasia, data notdestruction, given, data No not epithelial given score (edema), 1.09 (0.15) vs 1.14 (0.17), NS ( metaplasia:2/8 vs 0/8 pre-Atrophy: and No post-solvent biopsies only), vs 5/15, pre vs(data post, not No given), change Change13% in in (2/15) BM oedema decreased; thickness after 73%(2/15) treatment: (11/15) increased no change, 13% pre-INCS vs post INCS.BM Oedema: thickening: 0.8 0.9 vs vs 0.8, 0.7, NS, NS, NOS, 1.2 vs 1.1 NS Evidence of “Atropy” ( ) 3 No stats. Data as no. of biopsies pre vs post 3 month 8 Incomplete reporting, Number of type I, III or V 8 No. of biopsies (pre-INCS vs post-INCS): Squamous 8 Data are no. of biopsies, Epithelial (squamous) 6 See INCS column n 23 Mucosal thickness (total epithelium 32 see INCS column 11 see INCS column 15 Data are no. of biopsies, Squamous metaplasia: 3/15 14 See INCS column 12 All data are mean scores from 4-point ordinal scale, ( 25 (max) All data as mean ( 60 (max) Data as % biopsies post-treatment, Squamous Non INCS 0.1 21, B. ϭ ϭ ϭ p SEM): p n NOS, 1 26, 0.05. 20 Ϯ SE): Љ 0.05 26, ϭ ϭ vs 6/7 Ϯ Ͼ ϭ Љ n Ͻ m change n values. No. of p

␮ n p p 9.1 (6.8) 0.68, Ϫ 0.86 respectively vs BM, normal Љ ϭ ϭ ϩ 1.0(0.9) p p Ϫ 0.627), Ciliated cells: no ve/mmˆ2, mean 21, regularity of collagen 0.95 between groups. BM Epithelial damage ϩ ϭ 0.63, Љ ϭ ) or % or Baseline, Post, or ϭ p 0.001 respectively) n n ϭ p SE): A. TAA: , ϭ p Љ Ϯ p 0.46). Cilia appear similar in most 21, B: BDP 26, ϭ ϭ ϭ SE), baseline vs study end, epithelium 0.83, Change Scale Data m): 27.77 (4.97) vs 35.17 (5.14), n n p Ϯ

␮ ϭ 0.002, not given), p abundant m change from baseline, mean 0.05 vs non-INCS), collagen thickness/BM Љ ϭ p ␮ p Ͻ ,1 Љ 6.0 (7.6) p Ϫ 0.06 (INCS vs placebo for type V only), (Increased 0.02, 25 ( m): 11.45 (0.58) vs 11.97(0.84), ϭ ϭ ϭ

␮ normal fibrils score, 1.83 (0.16) vs 2.05 (0.14), NS, between groups. No changedata in not squamous given, metaplasia, Nogiven epithelial destruction, data, not BDP, thickness ( ( 0.37, n from baseline, mean between groups (5-point nominal scale) Lucent spaces ordinal score(0.18), (edema) NS 1.19 ( (0.15) vs 1.05 epithelium: 4/7 vs 3/7,(mean BM ordinal intact, score), 6/7 0.93 vs vs 6/7, 0.57 edema Љ baseline);, Number of typep I, III or V expressing cells: collagen I, III andp V in NPs vs control at baseline only; A.TAA 1.7(1.1), thickness BM ( placebo vs INCS, decreased with INCS, (graphical data) treatment, Squamous changes: 1/7post-INCS, vs BM 2/7, thinning: pre-INCS 0/7INCS, vs vs edema: 0/7; 6/7 pre-INCS vsChange vs 1/7, in post- pre-INCS collagenous vs fibres: post-INCS, 7/7 1/8 vs 0/8, pre-INCSbiopsies vs post-INCS, Atrophy: No type I, III orpost-INCS) V ( collagen-expressing cells (pre-INCS vs INCS 33% (9/27), BMeroded: thinned: INCS INCS 37% 20% (11/30),(7/23), (6/30), Severe Reported BM edema: as INCS nobetween 30% statistically any significant outcome, difference INCS vs no INCS 8/22, pre-INCS vs post-INCS,thickness No (data change not in given),treatment: BM Change 35% in (8/22) oedema patientsno after decreased, change, 64% 0% (14/22) increased. change at 12 wk.found (no at data), baseline Squamous and metaplasia 12 weeks (no data) specimens on TEM. No INCS-specific data from SEM INCS vs post INCS,thickening: edema: 0.6 0.8 vs vs 0.8, 0.7, NS, NS, BM between groups on LM ( significant change in ciliatedgroups cell on counts LM between ( vs 0.7, NS ) Evidence of “Atropy” ( n 8 Incomplete reporting, No data given, only 7 No. of biopsies (pre-INCS vs post-INCS), Squamous 7 No stats. Data as no. of biopsies pre and post 3 months 8 Edema: No significant change in ordinal score of edema 17 All data are mean scores from 4-point ordinal scale. pre- 10 Total apoptotic cells (TUNEL Population INCS (

DOn NOT COPY 2003 RCT 16 CRS 2011 RCT 48 Mixed CRS 16 No change in mucosal inflammation/tissue necrosis 1980 Cohort 15 AR 1977 Cohort 10 AR 1998 RCT 29 AR 1995 RCT 22 AR 2001 RCT 51 AR 26 (max) All data as Mean ( 1982 RCT 16 Nasal polyposis 8 Data are no. of biopsies, Epithelial (squamous) metaplasia: 2001 RCT 70 AR A. 21, B. 26 Mucosal thickness (total epithelium 2010 RCT 21 AR 1996 Cohort 90 NAR 30 (max) Data as % biopsies post-treatment, Squamous epithelium: 1980 RCT 37 CRS, Post ethmoidectomy 22 Data are no. of biopsies, Squamous metaplasia: 2/22 vs 1983 RCT 11 Mixed rhinitis 5 Obvious BM thickening in most baseline biopsies, no 45 et al. (A) (A) 41 53 36 77 Results—Controlled studies only 43 83 52 46 84 51 76 75 Author Yr Design et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. Chang Table 6 Molet Spector Holopainen, Grahne Baroody Poynter Klossek Holm Erhan Klemi Knight Uller Braat

12 January–February 2015, Vol. 29, No. 1 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Measurement of Atrophy Outcomes n ϩ ϭ ϭ 0.412 1.0

p There were no standardized methods for measuring mucosal atro- p ϭ ϭ

p phy across the studies. Epithelial or basement membrane thickness p was reported variably as one measurement, the mean or median of not otherwise 0.065 (non- SD), INCS vs No several measurements, the ratio of epithelial cross-sectional area to ϭ Ϯ ϭ 0.036 (allergic NPs), 0.038 (allergic) p basement membrane length, or qualitatively on an ordinal or nominal ϭ ϭ 0.036 (allergic NPs,

p scale (Table 4). p 0.065 (non-allergic); 100%, 0.061 (allergic), Ki-67 values compare INCS vs ϭ ) or % or Baseline, Post or p ϭ ϭ p n p p Rhinitis 0.055 (non-allergic); 100%, Change Scale Data ϭ The results are summarized in Tables 5 and 6. None of the 11 p 8);, 100%,

ϭ studies (RCTs, cohorts, or case series) that included atrophy as an n terminal deoxynucleotidyl transferase

nasal polyposis; NOS outcome reported atrophy in nasal mucosal biopsy specimens from 0.455 (allergic NPs), Edema: 71.4%, ϭ ϭ 5), Fibrosis: 42.9%, ϭ patients with rhinitis using INCSs. In controlled studies measuring no treatment, Epithelial damage: 14.3%, Squamous metaplasia: 42.9%, treatment INCS group allergic. cells: 57.1%, (non-allergic NPs);, 100% (non-allergic); 100%, p ϭ 0.061 (allergic), Glandular hyperplasia: .9%, 0.055 (non-allergic); 10%, treatment, BM thickness: 2.7(1.7),2.8(1.4), NS, NS, Fibrosis: Numbers ofEpithelial biopsies metaplasia: post 7/10, treatment, NS

Evidence of “Atropy” ( epithelial or basement membrane thinning, squamous metaplasia, loss of cilia, fibrosis, increased apoptosis, or mucosal edema, no studies reported significant changes in these outcomes among users

) of INCSs compared with patients receiving placebo or non-INCS n 11 see INCS column 10 All data as Mean of ordinal score ( ( medications (Table 6). Squamous metaplasia was seen in 2/9 case 13 (max) % of biopsies pre treatment, only, combined with pre- Non INCS series that reported this outcome in patients with rhinitis using

not significant; NP 42,43

, INCSs. One case series reported a qualitative finding of loss of Љ ϭ goblet cells and a change in subepithelial glands in patients with AR 0.98, 0.412 ϭ ϭ 0.61, 0.89, 44 ϭ p

ϭ using beclomethasone dipropionate aerosol, although these out- p ϭ ϭ p 0.061 p p p comes were not investigated in control subjects. ϭ allergic NPs triamcinolone acetonide; TUNEL p Љ SE): values compare SE), 12.7(1.7) vs Ϯ ϭ p 0.065 Ϯ

transmission electron microscopy. Chronic Rhinosinusitis 0.455 (allergic NPs), ϭ 0.036 ( 0.038 (allergic) SD), INCS vs No p ϭ ϭ ϭ 45,46 38,39 ϭ Ϯ

0.055 (non-allergic); Two controlled studies and two case series of CRS patients p p p

ϭ included atrophy as an outcome. No studies reported atrophy in nasal light microscopy; NS p ) or % or Baseline, Post, or ϭ n mucosal biopsy specimens from patients with CRS using INCSs (Ta- 0.036 (allergic NPs), Fibrosis: 0% values are INCS vs placebo, 10);, 0% SE): 4.34(0.6) vs 2.12(0.6), P ϭ ϭ ble 6). One cohort study found significant improvements in epithelial Ϯ p n cells: 0% 1.0 (non-allergic); 33.3%

Change Scale Data integrity and squamous metaplasia but increased glandular hyper- ϩ ϭ

p plasia in the INCS group relative to baseline biopsy specimens of 0.092 0.061 (allergic), Glandular hyperplasia: 100%

SE): 0.16(0.08) vs 0.38(0.08), INCS vs placebo, 47 38,40,48 ϭ control patients. Three case series measured loss of goblet cells, ϭ p Ϯ

p with Mygind et al. reporting a significant loss among users of beclo- chronic rhinosinusitis; TAA 0.065 (non-allergic); 66.7% 0.055 (non-allergic); 100% 0.06, Apoptotic index/Mitotic index ratio 6), Squamous metaplasia: 0% ϭ ϭ ϭ ϭ methasone dipropionate aerosol compared with baseline, although ϭ (non-allergic);, 0% p Edema: 80% (non-allergic NPs, (allergic), Ki-67 33.3% p n 8.5(1.7), INCS vs no treatment, Epithelial damage: 0% Ki-67 cell count (epithelium, median treatment, BM thickness: 3.0(1.6),NS, NS, Numbers Fibrosis: of 2.5(1.4), biopsiesmetaplasia: post 6/11, treatment, NS Epithelial p (epithelium,median Mitotic index (% mitoticmedian cells, epithelium, 0.018, Ki-67 cell count (stroma, median 0.72, Mitotic index (% mitotic cells, stroma), Apoptotic index (% apoptotic cell, epithelium), Apoptotic index (% apoptotic cells, stroma), this outcome was not investigated in control subjects. Two studies investigated a mixed population of rhinitis/CRS pa- basement membrane; LM tients (Tables 5 and 6). The finding of squamous metaplasia in a case ) Evidence of “Atropy” ( ϭ n 49 scanning electron microscopy; TEM series of patients using INCSs was not replicated in a controlled

ϭ study that reported no significant changes in basement membrane 16 (max) All data as % of biopsies post treatment, thickness, fibrosis, or squamous metaplasia between patients receiving INCSs and those on no treatment.50

basement membrane; CRS Meta-Analysis ϭ For those controlled studies declaring an outcome of “mucosal atrophy,” 136 patients on INCSs were compared with 99 of the control arm.36,41,43,45,46,50,51 The OR for the chance of developing mucosa atro- Population INCS (

intranasal corticosteroid; BM phy was 0.51 (95% CI, 0.09, 3.11) and was nonsignificant (Fig. 2).

ϭ Other subanalyses were performed for BM thinning for two studies polyps with OR of 0.90 (95% CI, 0.31, 2.68)52,53 and BM thickness for two

randomized controlled trial; SEM studies with OR of 0.23 (95% CI, Ϫ1.12, 1.58).36,41 When the two ϭ n studies reporting squamous metaplasia in AR patients were as- DO NOT52,53 COPY sessed, there was significant reduction in the OR for the development of squamous metaplasia in patients using INCSs with an OR of 0.37 (95% CI, 0.15, 0.91; Fig. 3). This finding was not seen in CRS 45,46 budesonide propionate aerosol; BM standard error; INCS patients (OR, 1.14 [95% CI, 0.29, 4.55]). ϭ ϭ 2006 Cohort 29 Nasal polyposis, antrochoanal 1992 Cohort 21 Mixed nasal polyposis, /AR 11 All data as Mean of ordinal score ( 1980 RCT 22 Nasal polyposis 11 Data not always given. Risk of Bias Comprehensive reporting of study methodology was inconsistent

nonallergic rhinitis; RCT among RCTs and cohort studies (Tables 7 and 8). Among RCTs,

ϭ sequence generation for randomization was invariably not reported. Nine studies (64%) blinded participants effectively. Only one study Continued 47 50 reported efforts to conceal allocation. Six RCTs (43%) addressed in- Author Yr Design 85 allergic rhinitis; BDP et al. et al. complete outcome data such as dropouts, and five RCTs (36%) were ϭ completely free of selective outcome reporting. Four RCTs (26%) Alatas Bende Table 6 AR Saunders dUTP nick end labeling; SE specified; NAR excluded patients that had undergone prior nasal surgery, and nine

American Journal of Rhinology & Allergy 13 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Figure 2. Forest plot of controlled studies measuring nasal mucosal atrophy as a defined outcome. An odds ratio (OR) less than one suggests a reduction in risk of mucosal atrophy and an OR that includes the value one implies similar risk between control and intranasal corticosteroids (INCSs).

Figure 3. Forest plot of controlled allergic rhinitis (AR) studies measuring squamous metaplasia. An odds ratio (OR) less than one suggests a reduction in risk of squamous metaplasia and an OR that includes the value one implies similar risk between control and intranasal corticosteroids (INCSs).

RCTs excluded patients taking systemic corticosteroids. Eleven RCTs layer, a basement membrane, and an underlying lamina propria (79%) reported blinded histological assessments. Nine RCTs declared consisting of a loose connective tissue,56 containing glands, blood the involvement of pharmaceutical companies as authors or sponsors, vessels, and extravascular cells without the high density of elastin, with the remaining studies not publishing a conflict of interest state- collagen, and lipid found in skin. Such marked differences in struc- ment. ture and function between skin and nasal mucosa may make direct In the non-RCT studies, eight studies (42%) excluded patients tak- comparisons of pharmacodynamics and pharmacokinetics inappro- ing systemic corticosteroids, and only one study (5%) reported exclu- priate.4,55,56,64 sion of patients with prior nasal surgery. Blinded histological assess- A number of CRS studies examined polyp biopsy specimens, in ment was performed in 13 studies (68%). Twelve studies (63%) contrast to rhinitis studies where turbinate mucosa was sampled. The reported adequate follow-up or accounted for incomplete outcome validity of extrapolating polyp biopsy studies to the population with- data. Ten studies (53%) declared involvement with a pharmaceutical out nasal polyps is questionable because such findings may not company, either as authors or sponsors, with eight studies not includ- represent histological changes in the remaining nasal mucosa, be- ing a conflict of interest statement. Only one study with a conflict of cause marked differences in structure are well known between these interest statement declared no financial interests among the authors.40 tissues.56,65 No publications regarding nasal septal perforation met our inclu- DISCUSSION sion criteria, despite the inclusion of this adverse effect in our search Systematic review of the literature indicated that mucosal atrophy strategy. A number of case reports regarding nasal septal perforations 12–15,66 is very uncommon in any group (control or intervention group). This in users of INCSs were noted, and septal perforation is cited as 18,20 finding held for studies involving patients with AR and NAR, and an adverse effect in two case series. These studies offer no histo- CRS with and without nasal polyps. Moreover, it was independent of logical assessment (thus excluded from this study) or control group the type, dose, or duration of INCS used. This lack of evidence for and did not remove additional confounding factors associated with nasal atrophy is consistent with other reviews that have reported septal perforation including decongestant use, chemical insult, sur- excellent safety and tolerability of INCSs.8,21,54 Corticosteroids had no gery or radiotherapy to the nose and sinuses, nose picking, and effect on the integrity of nasal epithelium or basement membrane and cocaine use.67 These findings were not replicated by studies that did not result in epithelial or basement membrane thinning, an in- examined histological changes to the nasal mucosa in patients using crease in fibrosis or mucosal edema. When a meta-analysis was INCSs and likely represent very rare adverse effects. Taken together, performed for the two studies that defined squamous metaplasia there is insufficient evidence that INCSs represent a significant direct among patients with AR, a protective effect was observed. cause of nasal septal perforation. The lack of evidence for atrophy of the respiratory nasal mucosa is The presence of tissue remodeling may affect the interpretation of not surprising.DO The role of skin as a physical NOT and immunologic barrier studies in this review,COPY especially in the absence of adequate controls. has necessitated a keratinized stratified squamous epithelium and an Tissue remodeling is a well-established concept in asthma and in- extracellular matrix rich in lipid, collagen, and elastin.55 Conversely, cludes structural changes associated with thickening of the basement with the exception of small areas of vestibular squamous epithelium membrane, breaks in epithelial integrity, squamous metaplasia, and and olfactory neuroepithelium in humans, nasal mucosa comprises increased goblet cells and submucous glands.68 Epithelial remodeling pseudostratified ciliated columnar epithelium with a superficial layer is seen in CRS, viz., basement membrane thickening, epithelial shed- of mucus and is specialized for the warming, cleaning, and humidi- ding, and squamous metaplasia,69–71 and is thought to be part of a fying of air.56,57 The mechanism of epidermal atrophy by topical natural nasal defense mechanism.7 The loss of goblet cells and a glucocorticoids relies on the suppression of the mitotic rate of kera- change in submucous glands after treatment with INCSs in two CRS tinocytes and fibroblasts,58–60 thinning the lipid-rich stratum corneum case series and one AR case series comparing baseline and posttreat- of the epidermis, and decreasing the elasticity and tensile strength of ment biopsy specimens38,44,72 in this review may represent a partial the dermis. Moreover, glucocorticoids reduce extracellular matrix slowing or reversal of the process of remodeling in the nasal airway, components, particularly type III collagen, lipid, and proteoglycans, rather than atrophy. Importantly, the protective effect of INCSs for further destroying the skin’s barrier function.61–63 The nasal mucosa the development on squamous metaplasia in AR may prevent dele- has only a surface ciliated epithelium without a lipid-rich keratinized terious remodeling events.73

14 January–February 2015, Vol. 29, No. 1 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Follow-Up Adequacy of of Bias 2 > Free of Other Sources wk Follow-Up Reporting Outcome Assessment of Free of Selective Outcome #*** #*** Prior Surgery cohorts Comparability of Addressed Steroids Systemic Outcome Data Baseline Present at Blinding Incomplete chronic rhinosinusitis with nasal polyp. Outcome Not ϭ Allocation Concealment Exposure Ascertainment of chronic rhinosinusitis; CRScNP Cohort ϭ Generation Selection of Nonexposed ##*## #*### Cohort

DO NOT of the Exposed COPY allergic rhinitis. Mixed CRS Unclear Yes Yes Yes Yes No Nasal polyposisPost-ethmoidectomy Unclear Unclear Unclear Unclear Yes Yes Unclear Unclear Yes No Unclear No ARARMixed rhinitisCRScNP Unclear Unclear Unclear Unclear No Unclear Yes Yes Unclear Yes Unclear Unclear Yes Yes No Unclear No Yes No Yes No No No No ARNasal polyposis Unclear Unclear Unclear Unclear Unclear Yes Yes No Unclear Unclear No No AR Unclear Unclear Yes Yes Yes No AR Unclear No No Yes Unclear No ϭ randomized controlled trial; CRS ϭ 45 et al. polyposis polyposis/ AR NARARARNasal *Mixed nasal # # * * # * * # * * * # * # # # # # * # * * * * * # 1999 2001 2001 1983 (A) 85 2011 41 1980 2003 1998 53 36 1995 2010 77 43 83 47 50 46 52 84 51 Study Population Adequate Sequence 76 75 et al. Cochrane Risk of Bias Assessment tool for RCTs Newcastle–Ottawa scale for assessment of risk of bias in cohort studies et al. et al. et al. nonallergic rhinitis; AR et al. et al. et al. et al. et al. et al. et al. et al. allergic rhinitis; RCT et al. et al. et al. ϭ Study Population Representativeness ϭ 1982 1996 1980 1977 (A) 2006 1992 Erhan Uller Molet Holopainen, Grahne Baroody Knight Chang Saunders Table 7 Braat Klemi AR Table 8 Spector Poynter Alatas *Study met criteria. #Study did not meetNAR criteria. Klossek Holm Bende

American Journal of Rhinology & Allergy 15 Delivered by Publishing Technology to: Richard Harvey IP: 120.19.114.213 On: Wed, 28 Jan 2015 03:15:01 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm The limitations of this review include the wide heterogeneity of Outcome: atrophy or (wast* or atrophy or atroph* or thinning* or included studies with respect to definitions of atrophy and, conse- thin*) or ((nasal or intranasal or nose or sinus or sinonasal or endo- quently, the selection and measurement of outcomes. Only 17 studies nasal or paranasal) and (biops* or histol* or histopath* or patholo* or specifically mentioned atrophy in the body of the article, despite microscop*)) or (nasal and (septum or septal) and perforat*) or ulcer including relevant histological outcomes. This represents the lack of a or ulcerat.* specific definition of mucosal atrophy. For example, it should be noted that the only controlled study to report a positive histological finding of mucosal atrophy50 used “squamous metaplasia” to define REFERENCES atrophy (Fig. 2). Methods to assess epithelial thickness may have a 1. Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosi- high risk of bias because of the difficulty standardizing between nusitis: Definitions, diagnosis, epidemiology, and pathophysiology. biopsy samples and angles of histological sections. Studies such as Otolaryngol Head Neck Surg 129(suppl):S1–S32, 2003. Minshall et al.,40 Baroody et al.,41 and Fokkens et al.30 that used an 2. Bhattacharyya N. Contemporary assessment of the disease burden of average of multiple measurements or quantification of length to sinusitis. Am J Rhinol Allergy 23:392–395, 2009. cross-sectional area, may provide more robust assessments. Only 3. Lee LN, and Bhattacharyya N. 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