Sinusistis JAMA 2015

7/23/2019 Sinusistis JAMA 2015

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Copyright 2015 American Medical Association. All rig hts reserved.

Medical Therapies for Adult Chronic Sinusitis

A Systematic Review

Luke Rudmik, MD, MSc; Zachary M. Soler, MD, MSc

IMPORTANCE Chronic sinusitisis a common inflammatory condition defined by persistent

symptomatic inflammation of the sinonasal cavities lasting longer than3 months. It accounts

for1% to 2% of total physicianencounters andis associated with large healthcare

expenditures. Appropriate use of medical therapies for chronic sinusitisis necessary to

optimize patient quality of life (QOL) and daily functioningand minimize therisk of acute

inflammatory exacerbations.

OBJECTIVE To summarize the highest-quality evidence on medical therapies for adult chronic

sinusitis and provide an evidence-based approach to assist in optimizing patient care.

EVIDENCE REVIEW A systematic review searched Ovid MEDLINE (1947-January 30,2015),

EMBASE, and Cochrane Databases. The search was limited to randomized clinical trials

(RCTs), systematic reviews, and meta-analyses. Evidence was categorized into maintenanceandintermittent or rescue therapies andreported based on the presence or absence of nasal

polyps.

FINDINGS Twenty-nine studies met inclusioncriteria:12 meta-analyses (>60 RCTs), 13

systematic reviews, and 4 RCTs that were not included in anyof themeta-analyses. Saline

irrigation improved symptom scores compared with no treatment (standardized mean

difference [SMD], 1.42 [95% CI, 1.01 to 1.84]; a positive SMD indicates improvement). Topical

corticosteroid therapy improved overall symptom scores (SMD, 0.46 [95% CI, 0.65 to

0.27]; a negative SMD indicates improvement), improved polyp scores (SMD, 0.73 [95%

CI,1.0 to 0.46];a negative SMDindicates improvement), andreduced polyp recurrence

after surgery (relative risk, 0.59 [95% CI, 0.45 to 0.79]). Systemic corticosteroids and oral

doxycycline (both for3 weeks)reduced polyp size compared with placebo for 3 monthsafter

treatment (P< .001). Leukotriene antagonists improved nasal symptoms compared withplacebo in patients with nasalpolyps (P< .01). Macrolide antibiotic for 3 months was

associated with improved QOL at a singletime point (24 weeks after therapy) compared with

placebo forpatientswithout polyps(SMD, 0.43 [95% CI,0.82 to 0.05]).

CONCLUSIONS AND RELEVANCE Evidence supports dailyhigh-volume saline irrigation with

topical corticosteroidtherapy as a first-line therapy for chronic sinusitis. A short course of

systemic corticosteroids (1-3 weeks), short course of doxycycline (3 weeks), or a leukotriene

antagonist may be considered in patients with nasal polyps. A prolongedcourse (3 months)

of macrolide antibiotic may be considered for patients without polyps.

JAMA. 2015;314(9):926-939. doi:10.1001/jama.2015.7544

Author AudioInterview at

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JAMAPatientPage page964

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Author Affiliations: Department of

Surgery, Division of Otolaryngology

Headand NeckSurgery, Universityof

Calgary, Calgary, Alberta (Rudmik);

Department of Otolaryngology

Headand NeckSurgery, Division of

Rhinologyand SinusSurgery, Medical

Universityof SouthCarolina,

Charleston (Soler).Corresponding Author: Luke

Rudmik, MD,MSc, Departmentof

Surgery, Division of Otolaryngology

Headand NeckSurgery, Richmond

RoadDiagnostic and Treatment

Centre, Universityof Calgary,

1820RichmondRd SW,

Calgary, AB,Canada, T2T5C7

([email protected]).

Section Editors: Edward Livingston,

MD,Deputy Editor,and MaryMcGrae

McDermott, MD,Senior Editor.

Clinical Review& Education

Review

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Chronic sinusitis, or chronic rhinosinusitis, is an inflamma-

toryconditiondefinedbysymptomaticinflammationofthe

paranasal sinuses lasting longer than 3 months (Box 1).1-3

Commonpresenting symptomsincludenasalobstruction,facialpres-

sure or fullness, nasaldischarge(anterioror posterior),and olfactory

loss(Table 1).4-7Furthermore, chronic sinusitis is associated with re-

ductions in patientquality of

life (QOL),

8

sleep quality,

9

and daily productivity.10 It is

a common yet underrecog-

nized chronic inflammatory

disease affecting approximately 3% to 7% of the population11,12 and

accounting for 1% to 2% of total physician visits.13,14 Health care ex-

pendituresrelated tochronicsinusitisexceed$9 billion peryearwith

societal costs exceeding $13billion per year.15

Although previously thought to be entirely infectious in etiol-

ogy, chronicsinusitis is nowrecognized as an inflammatory disease

of theupperairways analogousto asthmain thelower airways.16,17

The etiology is multifactorial16,18 and includes bacterial superanti-

gens, epithelial cell defects, bacterial biofilms, T helper 1 and 2 in-

flammation,tissue remodeling19 (increased fibrosisof sinonasal mu-

cosa),andgeneticvariationsinhumanleukocyteantigenhaplotypes

and bitter-taste receptors. For example, healthy sinonasal-ciliated

epithelialcells express bitter-tastereceptors, whichare stimulated

by bacterial products and activate an innate host immune re-

sponsetoremoveandkillbacteriabylocallyreleasingnitricoxide.20,21

Geneticvariationsinbitter-tastereceptorshavebeenassociatedwith

refractorychronicsinusitis and mayrepresenta novel future thera-

peutic target.22,23

Similar to asthma, current research focuses on categorizing

chronic sinusitis into chronicsinusitis endotypes,24which are dis-

ease classifications definedby distinctclinical features,pathophysi-

ologic molecular mechanisms, andtreatment responses.25,26 How-

ever, validated chronic sinusitis endotypes havenot been defined.

Therefore, chronicsinusitisis currentlyclassifiedbasedon thepres-ence or absence of nasal polyps.

Medicaltreatmentsfor chronicsinusitisreduce mucosalinflam-

mation, remove mucus, and modulate environmental triggers

(Figure 1).30 This systematic review identifies the most effective

treatments for the medical management of adult chronic sinusitis

and presents the evidence supportingeach therapeutic option.

Methods

OvidMEDLINE(1947-January30, 2015),EMBASE,the CochraneCen-

tralregisterof Controlled Trials, and the CochraneDatabase of Sys-

tematic Reviews were searched using the terms: chronic, *sinusitis(using * as an unlimitedtruncationstrategy to capture all variations

of sinusitis). The results were combined withthe following chronic

sinusitismedical therapyterms:saline,antibiotic, antimicrobial, cor-

ticosteroid,steroid, antifungal,leukotriene receptor antagonist, an-

tihistamine, immunotherapy, omalizumab, anti-IL5, macrolide. The

following search limits werethen applied: randomized clinicaltrials

(RCTs) of humans 18 years or older, systematic reviews, andmeta-

analyses. Inclusion criteria required that all patients in each study

were considered to have chronic sinusitis, although diagnostic cri-

teria wereallowed tovaryacrossindividual studies. Studieswere ex-

cluded if they focused on perioperative medications, acute sinus-

itis,allergic fungalsinusitis,cystic fibrosis,primary ciliarydyskinesia,

aspirin-exacerbated respiratory disease, sarcoidosis, immunodefi-

ciency, or granulomatosis withpolyangiitis. Unstructured narrative

reviews wereexcluded.Referencesfrom allidentifiedstudieswere

reviewed for additional relevant articles.

Bothauthors independentlyreviewedincludedstudiesand as-

signed a level of evidence

31

for each study. When applicable, thequantitative effect size and confidence interval from meta-

analyses and RCTs were reported. The standardized mean differ-

ence (SMD)wasused toreporteffectsizefroma meta-analysis when

studies reported outcomes using different instruments. When im-

provement wasassociated withhigher scoreson theoutcome mea-

sure, then the SMD would be greater than 0. If improvement was

associated with lower scores on the outcome measure (ie, polyp

scores), then theSMD would be less than 0.An aggregategrade of

evidence(A-C)and recommendation(I-III)for eachtreatmentstrat-

egywasassignedusingtheAmericanHeartAssociationgradingscale

(Box2).32Differences in evidencegradingwere resolvedby discus-

sion.Theriskofbiasforeachmeta-analysiswasquantifiedusingthe

Cochrane Handbook for Systematic Reviews of Interventions.33

Results

Three hundred twenty-eight studies were screened for eligibility.

Twenty-nine studies met inclusion criteria, including 12 meta-

analyses (evaluating>60 RCTs), 13 systematic reviews, and 4 indi-

vidualRCTs that werenotincludedin anyof themeta-analyses(eFig-

ure in the Supplement).The evidence for each treatment strategy

is organized into either maintenance or intermittent or rescue

therapies, with the understanding that these designations are not

necessarily mutually exclusive in clinical practice.

Maintenance Medical Therapies for Chronic SinusitisTopical Corticosteroids

Corticosteroids reduce sinonasal mucosal inflammation, decrease

vascular permeability, and reduce glycoprotein release from sub-

mucosal glands(ie, thin mucus)(eTable 1 in theSupplement). Ben-

efits associated with this therapy have the strongest level of evi-

dence with 6 meta-analyses quantifying the evidence from more

than 40 RCTs (Table 2).34-39 Three meta-analyses (>3624

patients)34,37,38 evaluated patients with nasal polyps and demon-

strated an association with improvements in overall symptoms

scores, polypsize, and recurrence rateafter sinussurgery. RCTs in-

cludedin thelargestmeta-analysisby Kalishet al38wereofhighqual-

ity withonly 6 of40 trialshaving a highriskof bias(eTable2 inthe

Supplement).Thedegreeofreductioninpolypsizeisassociateddi-rectly with thedegree of improvement in QOL.45

Twometa-analyses (>657 patients)35,36evaluatedpatientswith-

outnasalpolypsanddeterminedthattopicalcorticosteroidswereas-

sociated withimproved overall symptom scoresand greaterpropor-

tionof symptomresponders.Qualityassessment demonstrateda low

riskofbiasforblinding;however,therewasahighriskofbiasforgroup

allocation(ie,topicalcorticosteroidvsplacebo),whichindicatesaneed

forhigher-quality trialsin patients without polyps.

In summary, an A-Igrade andrecommendation supports using

topical corticosteroid therapy for chronic sinusitis with and with-

IL-5 interleukin 5

QOL quality oflife

RCT randomized clinicaltrial

Medical Therapiesfor AdultChronic Sinusitis Review ClinicalReview & Education

jama.com (Reprinted) JAMA September 1,2015 Volume 314, Number9 927




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out nasal polyposis. Although early evidence suggests that high-

volume corticosteroidirrigations (ie,techniques thatinvolve deliv-

ering >100 mL of solutioninto the nasal cavity46) (eg, budesonide

irrigations47) aremore effectivethanlow-volume corticosteroidspray

techniques (ie, meter-dosed spray, atomized, or nebulized

solutions),46clinicaltrials arerequired before a recommendationon

optimaldelivery methodcan be provided. Doses,durations, andpo-

tential adverse effects of available medical therapies are reported

in Table 3.

Saline Irrigations

Sinonasalsaline irrigationsassistin removingmucus andpossibleen-

vironmentaltriggers andassist in restoring normalmucociliaryclear-

ance. Outcomes from 2 systematic reviews41,42 and 1 meta-

analysis (399 patients)40 support an association between the use

of sinonasal saline irrigations and improved symptom scores

(Table 2). However, when saline irrigation was the only treatment,it was associated with less improvement when directly compared

with topical corticosteroid therapy.

In summary, an A-Igrade and recommendationsupportsusing

sinonasal saline irrigation asan adjunctive therapyto intranasalcor-

ticosteroidsforpatients withandwithoutnasal polyps.Isotonic and

hypertonic saline irrigations provide similar symptom improve-

ment. High-volume (>100 mL) saline irrigation is superior to low-

volume nasal saline spray techniques.46,48

Leukotriene Pathway Antagonists

Leukotriene pathwayantagonists blockleukotrienesD4, C4,andE4frombindingthe cysteinylleukotrienereceptorslocated in respira-

tory mucosa or block the production of leukotrienes from arachi-donicacid byinhibiting5-lipoxygenase.These effectscan reduceeo-

sinophil recruitment, vasodilation, and mucus secretion. Five

RCTs49-53 evaluated an oral leukotriene antagonist, montelukast

(10 mg once daily), in patients with nasal polyposis (Table 2).49-53

Only 2 RCTs met the high-quality requirements for quantitative

meta-analysis43 (174 patients). Overall, montelukast may improve

symptoms compared with placebo; however, there was no differ-

encebetween oralmontelukastand topical corticosteroidtherapy.

Noadditionalimprovementwas seenwhenmontelukast wasadded

to existingtopical corticosteroid therapy.

In summary, an A-II grade andrecommendationsupportsusing

a leukotrieneantagonist (montelukast) in patients withnasal polyps.

No evidence grade is assigned foruse of leukotriene antagonists in

patients without nasal polyps.

Antihistamines and Allergy Immunotherapy

Antihistamines and allergy immunotherapy reduce an allergen in-

duced IgE-mediated hostresponse, which decreases vascular per-

meability, vasodilation, and nasal secretions. An estimated20% to

60%of chronicsinusitispatientshaveallergicrhinitis,withthe high-

estprevalence in those withnasalpolyposis.54,55 Despite thisasso-

ciation, it remains unclear whether allergy plays a causal role in

chronic sinusitis and whether treating allergic rhinitis improves

chronic sinusitis-specificoutcomes.56One systematic reviewiden-

tified 6 case series evaluating the association of allergy immuno-

therapy on sinusitis-specific outcomes and reported improved

allergy-specific symptomsbut noconsistentimprovementin sinus-specific symptoms (Table 2).44

In summary, a C-IIgrade andrecommendation is designated to

allergy immunotherapy for the specific management of chronic si-

nusitis. No grade ofevidenceis provided forthe useof oral antihis-

tamines during specific management of chronic sinusitis.Evidence

supports antihistamines and allergy immunotherapyfor managing

concurrent allergic rhinitis.57

Intermittent or Rescue Medical Therapies

for Chronic Sinusitis

Systemic Corticosteroids

Patientscommonlypresentwith severe nasal polyposisor acute in-

flammatory exacerbations requiring intermittent or rescue sys-temiccorticosteroid to treatacute mucosal inflammation.30 Three

systematic reviews evaluated oral corticosteroids for nasal polyp-

osis (Table 4).58-60 Oral corticosteroids were associated with im-

provedsymptoms,QOL,andreducedpolypsizecomparedwithpla-

ceboinall5RCTs.However,theRCTswereoflowtomoderatequality,

short duration (2-3 weeks), and limited follow-up (2 weeks-6

months). Improvementswere notsustainedfor morethan 3 months

in the absence of maintenance topical corticosteroid therapy.45,73

No RCTs evaluatedoralcorticosteroidsfor chronic sinusitiswith-

outnasal polyps. Thehighestlevel of evidencefor patientswithout

Box1. Consensus-BasedDiagnostic Criteriafor Chronic Sinusitis

2 ofthe Following 4 SymptomsLastingfor >3Months (PODS)a

Pressure/pain (facial)

Obstruction (nasal)

Discharge(nasal)anterior or posterior

Smell reduced

Symptom Criteria Supportedby Demonstratingat Least 1 of the

Following 3 ObjectiveSigns of Inflammation

Nasalpolyps on anteriorrhinoscopy or nasal endoscopy

Edema or purulencewithin middlemeatus

CT scanof the paranasal sinuses demonstratinginflammation

CT indicatescomputed tomography.

a Oneof the2 symptomsmust be either obstruction or discharge.

Source: US,European, andCanadianguidelineson chronicsinusitis1-3

Table 1. Presenting Symptomsof Chronic Sinusitis

Presenting SymptomFrequency of PresentingSymptom, %

Sinonasal-specific

Nasal obstruction/congestion 81-95

Nasal discharge 81-93

Facial pressure/fullness 70-85

Reduced sense of smell 66-84

Other

Fatigue 83-92

Headache 73-83

Difficulty sleeping 62-74

Toothache 30-67

Ear pain/fullness 39-56

Datasources:Bhattacharyya,4,5Soleret al,6 and Dietz deLoos etal.7

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Figure 1. ProposedMechanismsof Action for Chronic SinusitisMedicalTherapies

Respiratorypathogens

Respiratorypathogen

Cell membrane

phospholipid

Leukotrienes

Neutrophil

Neutrophil

Neutrophil

Neutrophil

Monocyte Neutrophil

Eosinophil

Antigen-

presenting

cell

Antigen-

presenting

cell

TH2 cell

B cell

Mast cell

IgE

Apoptoticneutrophil

Histamine

Leukotrienes

Other cytokines

Arachidonic acid

Increase ciliary

clearance

Epithelial cell

Environmental

allergens

Phospholipase A2

5-LO

Corticosteroids

Corticosteroids

Macrolides

5-LO inhibitors

Mepolizumab

Inhibit arachidonic

acid synthesis

Inhibit NF-B

pathway

Activation of

NF-B pathway

Block leukotriene

synthesis

B-cell

activation

TH2-cell

activation

Eosinophil

migration and

activation

Neutrophil

activation

Neutrophil migration

Release of proteases

and superoxides

Binds free IL-5

Synthesis and

release of IgE

Histamine release

and mast cell

migration

NF-B

NF-B

Macrolides

IL-4

IL-13

IL-5

Omalizumab

Binds free IgE

Leukotriene

synthesis

Antihistamine

Blocks histamine

release frommast cells

Release of

inflammatory

mediators

Release of

inflammatory

mediators

IL-8

Leukotriene B4

Macrolides

Inhibit neutrophil

migration

Promote neutrophil

apoptosis

Eosinophil

Eosinophil

Cysteinyl leukotriene

receptors 1 and 2

TGF-Macrolides

Block binding to

TGF- receptor

Fibroblast activation and

submucosal collagen

deposition with fibrosis

Doxycycline

Blocks IL-6,

IL-8, TNF-

Clears respiratory

pathogens and allergens

Increases ciliary clearance

Saline irrigation

Leukotriene receptor

antagonists

Nonmacrolide antibiotics

Treat bacterial infection

Block cysteinyl

leukotriene receptor

binding

IL-2

IL-6

IL-8

GM-CSF TNF-

R E S P I R A T O R Y

E P I T H E L I A L C E L L

S U B E P I T H E L I A L

M A S T C E L L

Recruitment of

inflammatory

cells

N A S A L M U C O S A

GM-CSF indicates granulocyte-macrophage colony-stimulating factor; IL, interleukin; LO, lipoxygenase;NF-B, nuclear factor enhancerof B cells;

TGF, transforminggrowth factor; TH2, T helper2; TNF, tumornecrosisfactor.






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polyps comesfrom prospective caseseries without control groupsand heterogeneous concurrent medical therapy protocols. These

studies report that oral corticosteroids are associated with im-

proved olfactory and symptom scores.74-77

Insummary,anA-Igradeandrecommendationsupportstheuse

ofintermittentshort-course(1-3weeks) oralcorticosteroids forsymp-

tomatic nasal polyposis. A C-II grade and recommendation sup-

portsthe useof oral corticosteroidsfor chronicsinusitis withoutna-

sal polyps. Because of the adverse effects associated with oral

corticosteroids,78 patients and physicians should participate in an

open discussion about the risks, benefits, and alternative treat-

mentsto facilitate a shared decision-making process.

Short-term Oral Antibiotics (Nonmacrolide)Short-term courses of antibiotics are intended to eradicate active

infection through several potential mechanisms such as inhibiting

bacterial cellwall formation,inhibitingbacterialfolate synthesis,and

promoting bacterial DNA fragmentation (eTable 1 in the Supple-

ment). One systematic review evaluated short-term oral antibiot-

ics for chronic sinusitis61 (Table 4). Three RCTs compared 2 differ-

ent antibiotics (cefotiam vs cefixime79; amoxicillin/clavulanate vs

ciprofloxacin80;andcefaclorvsamoxicillin81)for3weeksorlesswith-

out a placebo group and showed no difference between antibiot-

ics. Heterogeneity between studies precluded quantitative meta-

analysis.One RCTevaluated 200mg of doxycycline once, followed

by 100 mg daily for 20 days (n = 14) compared with methylpred-

nisolone (n = 14) and placebo (n = 19) for nasal polyposis.73 Doxy-

cycline was associated with an improved polyp score 12 weeks af-

ter discontinuing treatment compared with placebo (P= .015).

Methylprednisolone was associated with a larger improvement in

polyp score at 2 weeks compared with doxycycline and placebo;

however, there was no difference in polyp score between methyl-prednisoloneanddoxycycline12weeksafterdiscontinuingthetreat-

ment. This suggests that doxycycline does not provide as large of

an early improvement but provides a similar longer-term improve-

ment in polyp reduction. The only symptom that improved in the

doxycycline group was postnasal drainage at 2 weeks.

In summary, a B-Igradeand recommendationsupportsa short-

courseof doxycycline(200 mgoncethen 100mg dailyfor20 days)

for nasal polyposis. An A-II recommendation supports the use of

short-course oral antibiotics (


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Table 3. Medical Therapies for Chronic Sinusitisand Potential AdverseEffects

Name Dose Frequency Potential Adverse Effects

Saline Irrigations

Various over-the-counteroptions

Varying volumes(range: 100-240 mLsplit between 2 nasalcavities)

Once t o 3 t imes a d ay Nasal b urning, e ar p lugging, n ausea, b acterialcontaminationfrom irrigation bottle

Topical CorticosteroidNasal Spray

Mometasonefuroate 50g perspray 1 spray eachnostril twice dai ly Local irritat ion,epistaxis,unwantedsystemicabsorption

Beclomethasonedipropionate monohydrate

42gper spray 1 spray eachnostril twice daily

Fluticasone propionate 50gper spray 2 sprayseachnostril oncedaily

Fluticasonefuroate 50g perspray 2 sprayseachnostriloncedaily

Budesonide 32gpers pray 1 to 4sprayseachnostriloncedaily

Ciclesonide 50g p er s pray 2 s prays e ach n ostril o nce d aily

Flunisolide Not listed 2 sprays each nostril twice daily

Triamcinoloneacetonide 55gper spray 2 sprayseachnostril oncedaily

Prednisolonenasaldrops 1%solution 2 to 4 dropspernostrilonceortwicedaily

Budesonide respules 0.5mg(2mLof0.25mg/mL) or1 mg(2mL of0.5mg/mL)

Mix budesonide respule intohigh-volume salineirrigation andrinse bothnasal cavitiesonce ortwicedaily

SystemicCorticosteroids

Prednisone 5-60 mg Once daily Early systemic: mood disturbances, sleep disturbances,nausea, hyperglycemia, hypertension,electrolyteabnormalities; long-term: cataracts,glaucoma, increasedriskof infection, osteoporosis, thinskin and easybruising,acne, weight gain, avascular necrosisof the hip or shoulder

Prednisolone 5-60 mg Once daily

Methylprednisolone 7.5-60 mg Once daily

Dexamethasone 0.5-4.5 mg Twice daily

Nonmacrolide Antibiotic

Amoxicillin/clavulanate 875 m g Twice d aily f or1 0-14 d Allergy/hypersensitivity ( 5%-10% patients),gastrointestinaldisturbance, nausea, rash, andurticaria

Cefuroxime 250 mg Twice daily for 10-14 d

Cefaclor 250-500 mg 3 daily for 10-14 d

Cefprozil 250 mg-500 mg Twice daily for 10-14 d

Cefpodoxime 200 mg Twice daily for 10-14 d

Trimethoprim-sulfamethoxazole

160 mg/800 mg Twice dai lyfor10-14 d Al lergy/hypersensit iv ity(3%patients),genitourinarydisturbances, hemopoieticdisorders, and porphyria

Levofloxacin 500 mg Once daily for 1 0-14 d Nausea/vomiting, gastrointestinal disturbance, risk oftendinitis andrupture (especially Achillestendon),myastheniagravis exacerbation,and prolongedQT intervalMoxifloxacin 400 mg Once daily for 10 d

Macrolide

Clarithromycin 500 m g Short-course: t wice d aily f or 1 4 d; l ong-termcourse: once dailyfor 12 weeks

Gastrointestinal upset anddiarrhea(10%-15%), prolongedQT interval, rhabdomyolysis (co-administration withstatins), increased bleeding risk (co-administration withwarfarin), and increasedsedation (co-administration withbenzodiazepines)

Azithromycin 500 mg Once daily for 3 d

Erythromycin 250-800 mg 4 a day for 10 d

Roxithromycin 150 m g Short-course: o nce d aily f or 1 0 d; l ong-termcourse: once dailyfor 12 weeks

Leukotriene Pathway Antagonists

Montelukast 10 mg Once daily Hypersensitivity reaction, gastrointestinal disturbances,headaches, sleep disturbance,increased bleeding risk, riskof Churg-Strauss syndrome, andzileuton: elevatedLTA(5%); hepatotoxicity withjaundice (1%)

Zafirlukast 20 mg Twice daily

Zileuton 600 mg 4 a day

H1 Antihistamine

Diphenhydramine 25-50 mg 4 a day as needed Drowsiness (first generation), fatigue, dry mouth,

headache,and gastrointestinal disturbancesCetirizine 5-10 mg Once daily

Loratadine 10 mg Once daily

Fexofenadine 180 mg Once daily

Desloratadine 5 mg Once daily

Anti-IgE

Omalizumab 150-300 mg Subcutaneous injectionevery4 weeks Anaphylaxis, increasedstrokerisk, increasedheartdiseaserisk, and riskof Churg-Strauss syndrome

Mepolizumabandreslizumab

Noapproveddose Noapprovedfrequency Nasopharyngit is, pharyngolaryngealpain,fatigue,andnausea

Abbreviations: IL, interleukin; LTA, leukotriene receptorantagonist.






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Table4.

Highest-LevelEvidenceforIntermittentorRescueTherapiesforChronicSinusitis(continued)

Source

StudyDesign

(LOEa)

No.

ofStudies

(LOEa)

SampleSize

Population

Treated

StudyGroups

PrimaryEn

dPoint

Conclusions

TopicalAntibiotics

Limetal,68

2008

Systematicrevie

w

(2a)

5(2b),2(3b),

and7(4)

NA

Nopolyps

Neomycin,

tobramycin,

ceftazidime,

N-chlorotaurine,

dibekacin,

fosfomycin,

mupirocin,andamphotericinB

QOL,endoscopyscore,

andbacterialculturerates

Nebulizedandspray-deliveredtop

icalantibioticsfailedto

improveoutcomesinlevel2bstud

ies;lower-qualitystudies

demonstrateapotentialbenefitoftopicalantibiotictherapyfor

chronicsinusitiswithoutpolyps

Rudmiketal,41

2013

Systematicrevie

w

(2a)

2(1b),1(2b),

1(2c),2(3a),

and4(4)

NA

Nopolyps

Neomycin,

tobramycin-saline,

bacitracin,gentamycin,and

mupirocin

QOLanden

doscopyscore

Evidencedoesnotsupporttherou

tineuseoftopicalantibiotic

therapychronicsinusitis;singlelevel1bstudydemonstrated

thathigh-volumemupirocinirriga

tionsweresuperiorto

placebowhensinuscultureswere

positivefor

Staphylococcusaureus

Soleretal,61

2013

Systematicrevie

w

(2a)

2(1b),1(2b),

2(2c),and

4(4)

NA

Nopolyps

Fosfomycin,

N-chlorotaurine,

bacitracin,

tobramycin,

mupirocin,andneomycin

Symptom,QOL,

andendosc

opy

Evidencedoesnotsupporttherou

tineuseoftopicalantibiotic

therapyforchronicsinusitis

Weietal,69

2013

Systematicrevie

w

(2a)

2(2b)

NA

Nopolyps

Tobramycinandneomycin

Symptom,QOL,

andendosc

opy

Thereisinsufficientevidencetosu

pporttheuseoftopical

antibiotictherapyforpatientswithoutpolyps

TopicalAntifungals

Isaacsetal,70

2011

Meta-analysis(1

a)

3(1b)and

3(2b)

284patients

Topical

amphotericinB

vsplacebo

Nopolyps

Symptom,endoscopy,

andradiolo

gic

TopicalamphotericinBwasnodifferentthanplaceboinall3

outcomes(allP

>.1

1)

Sacksetal,71

2011

Meta-analysis(1

a)

5(1b)

327patients

Topical

amphotericinB

vsplacebo

Nopolyps

Symptom,QOL,

andadverseeffects

Topicalamphotericinfailedtoimp

roveQOL(SMD,

0.1

8

[95%CI,0.0

5to0.4

2])andendoscopyscores(SMD,

0.0

0

[95%CI,0.2

6to0.2

6]);placebo

improvedsymptomscores

comparedwithtopicalamphoteric

inB(SMD,

0.3

5[95%CI,

0.0

7to0.6

3])

Wangetal,72

2014

Meta-analysis(1

a)

5(1b)

300patients

Topical

amphotericinB

vsplacebo

Nopolyps

QOLanden

doscopy

TopicalamphotericinBwasnodifferentthanplacebofor

nopolyps

Abbreviations:CT,computedtomograph

y;IL,

interleukin;INS,

intranasalsteroid;LOE,

levelofevidence;NA,not

applicable;QOL,qualityoflife;RCT,rand

omizedclinicaltrial;SMD,standardizedmeandifferen

ce.

a

Levelofevidencescalewasf

rom

theOxfordCentreforEvidence-basedMedicine.

3

1






10/14


serumIgE/mL;maxdoseof375mg)toplacebo(Table4).Bothstud-

ieslackedstatisticalpowerandcontainedmoderateestimatesofbias

making it challenging to draw definitive conclusions from the re-

ported associations between improved radiologic (ie, computer-

ized tomography scan) and polyp scores at 16 weeks of omali-zumab compared with placebo.

In summary, an A-II grade and recommendation is designated

to anti-IgE therapy for chronic sinusitis with nasal polyposis and

asthma.Noevidencegradeandrecommendationisassignedforanti-

IgE therapy for patients without nasal polyps.

AntiInterleukin 5 Therapy

Anti-interleukin 5 (IL-5) therapy involves delivering a humanized

IgG monoclonal antibody that binds free IL-5 and impairs

eosinophilic-mediated inflammation.89 Two RCTs evaluated anti-

IL-5 therapy (reslizumab and mepolizumab) for nasal polyposis

(Table 4).66,67 Both studies were small (n30), lacked long-term

follow-up, and contained moderate to high estimates of bias.Reslizumab (1 or 3 mg/kg) did not improve symptom scores com-

pared with placebo but slightly reduced blood eosinophil levels.

Mepolizumab (2 injections of 750 mg received 28 days apart) was

associated with improved polyp scores in approximately 50% of

patients compared with placebo but the study did not evaluate

patient-reported outcomes.

In summary, an A-II grade and recommendation is designated

foranti-IL-5monoclonalantibodytherapy inpatients withnasal pol-

yposis.Nogradeofevidenceorrecommendationisassignedforanti-

IL-5 therapy for patients without nasal polyps.

Topical Antibacterials

Four systematic reviews41,61,68,69 evaluated topical antibiotics for

chronic sinusitis without nasal polyps (Table 4). All RCTs contained

small sample sizes, evaluateddifferent topicalantibiotics,and used

differentapplication techniques. Three RCTs demonstrated no dif-ference inclinical outcomescompared withplacebo.One RCTdem-

onstratedimprovedshort-termsymptomimprovementusingahigh-

volume (240 mL divided between 2 nasal cavities) mupirocin

irrigationcomparedwithplaceboin a specificcohortof patientswith

a sinus culture positive forStaphylococcus aureus.90 There was no

difference in sinus-specific QOL with mupirocin irrigation com-

pared with placebo.

Insummary,theroutineuseoftopicalantibioticsduringtheman-

agement of chronic sinusitis without nasal polyps is not recom-

mendedandhasanA-IIIgradedesignation.High-volumetopicalmu-

pirocin irrigations may be appropriate therapy in select cases of

recalcitrantdiseasewithasinusculturepositiveforS aureus.Nograde

of evidence or recommendationis designated for theuse of topicalantibiotics for nasal polyposis.

Topical Antifungals

Fungi colonize the nasal mucosa in 96% of both chronic sinusitis

patients and healthy controls.91,92 This created a hypothesis that

an abnormal immunological response to fungi may cause chronic

sinusitis and eradication of fungi may resolve sinus disease.93,94

Topical amphotericin B binds ergosterol (a component of the fun-

gal cell membrane) and creates a transmembrane ion channel

leading to fungal death.

Table 5. Comparison of GuidelineRecommendationsfor Medical Therapies in theManagementof Chronic Sinusitis

Recommendation Levela

Grade of Evidence andRecommendation: Current Review EPOS Guidelines 20122

Canadian SinusitisGuidelines 20111 BSACI Guidelines 200895

Nasal Polyps No Polyps Nasal Polyps No Polyps Nasal Polyps No Polyps Nasal Polyps No Polyps

Maintenance Therapies

Topical corticosteroid A-I A-I ++ ++ ++ ++ ++ ++

Saline irrigations A-I A-I + ++ + + ++ ++

LTA A-II None None + None + NE

Systemic antihistamineb None None None None + + ++ ++

Allergy immunotherapy C-II C-II None None NE NE + +

Intermittent or Rescue Therapies

Systemic corticosteroid A-I C-II ++ + ++ + ++ +

Short-term antibiotic B-Ic A-II + + + + + +

Long-term macrolide B-III A-II + + + ++

Anti-IgE monoclonal antibody A-II None None NE NE NE NE

Anti-IL-5 monoclonal antibody A-II None None NE NE NE NE

Topical antibiotic None A-III None NE NE

Topical antifungal None A-III None NE NE

Abbreviations: BSACI, British Society forAllergy and Clinical Immunology;

EPOS,EuropeanPosition Paper on Sinusitis; LTA, leukotriene antagonist; NE,

not evaluated.

a Recommendationlevel symbols indicate the following:+ +, strong

recommendationfor use; +, weakrecommendation foruse; , strong

recommendationagainstuse; , weakrecommendationagainstuse; none,

represents thetopic wasevaluated butlackof evidenceresultedin no

recommendationprovided.

bAntihistaminesare not indicated as sinusitis-specifictreatment but should be

considered in patients withconcurrent allergic rhinitis.

c Short-term antibioticuse in patients withnasal polyps limited to doxycycline

200 mgoncethen100 mgdaily for20 days.73






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Three meta-analyses(327 patients)70-72 demonstrated no ben-

efitoftopicalamphotericinBcomparedwithplaceboforpatientswith-

out nasal polyps. Therefore, use of topical antifungals forchronic si-

nusitiswithoutnasalpolypsisnot recommendedandhasan A-IIIgrade

designation. No grade of evidence canbe made fornasal polyposis.

Discussion

Basedonavailableevidence,medicaltherapyfor chronicsinusitisshould

beginwithdailyapplicationofatopicalintranasalcorticosteroidincon-

junctionwith high-volumesalineirrigation. Subsequenttherapiesare

basedon thepatientspolypstatusandseverityof symptomsor QOL

impairment. Although there havebeen several published guidelines

evaluatingadultchronicsinusitis,1-3,95only3includespecifictreatment

recommendations.1,2,95Table5summarizestheoverallgradesofevi-

dencefromthisreviewandhow they comparewithpublished guide-

lines from Europe, Canada, andthe UnitedKingdom.

First, there were differences regarding use of leukotriene an-

tagonists for treating nasal polyposis. The outcomes from 2 RCTs

evaluating leukotriene antagonists demonstrated mixed results;

therefore, available evidence is consistent withan A-IIgrade of evi-

dence and recommendation. This differs from the A grade of evi-

denceand recommendationagainst the use of leukotriene antago-

nists (ie, equivalent to anA-IIIgrade) totreatnasal polyposismade

in the European guidelines.

Second,thereweredifferencespertainingtotheuseoflong-term

macrolidetherapy in patients with nasal polyps.The only RCTevalu-

atinglong-termmacrolide therapy,which included patients with na-

sal polyposis, demonstrated no difference compared with placebo.

Figure 2. Evidence-Based Approach to Medical Therapyfor Chronic Sinusitis

Chronic sinusitis

(see Box 1)

Reassess in 1 to 3 months

Topical intranasal corticosteroids (daily)

and saline irrigations (daily)

Short-course antibiotic

Culture-directed or broad

spectrum when indicated

Active mucopurulence present?

Yes

No

Resolved or mild symptomsb

Continue treatment

Persistent symptomsa

or acute exacerbation

Persistent symptomsa

Does patient have concurrent

allergic rhinitis?

Consider endoscopic sinus surgery

Continue treatment

Consider

Systemic antihistamine

Leukotriene pathway antagonist

Allergy immunotherapy

Resolved or mild symptomsb

Nasal polyps present?Yes No

No

No

Short course of systemic corticosteroidcfor

14-21 days

Prednisone 30-50 mg daily (taper when indicated)

Prednisolone 20-60 mg daily (taper when indicated)

Consider

Short course of doxycycline 200 mg once followed

by 100 mg daily for 21 days

Culture-directed antibiotic (in the presence

of mucopurulent discharge on examination)

Long-term antibiotic (macrolide)d

Clarithromycin 250-500 mg daily for 3 months

Roxithromycin 150 mg daily for 3 months

Consider

Short course of systemic corticosteroidc

Culture-directed short-course antibiotic (only in the

presence of mucopurulent discharge on examination)

Yes

Yes

a Persistent symptoms impliesthat

thepatient is stillexperiencing

chronic sinusitisspecific symptoms

thatare negativelyeffectingquality

oflife anddailyproductivity or

functioning.

bMild symptoms implies thatthe

patient is stillexperiencingchronic

sinusitisspecificsymptomsbut

theyare notnegatively effecting

quality of life anddailyproductivity

or functioning.

c Patient and physician should

participatein an opendiscussion

about theknown benefits andthe

potentialadverse effects of

systemiccorticosteroids to helpinform patient decision making.

dRiskof cardiac arrhythmiaand

cardiovascular death; riskof

rhabdomyolysisin patients

currentlytaking an oral

3-hydroxy-3-methylglutaryl-

coenzymeA (HMG-CoA)reductase

inhibitor.






12/14


Thus, this review placed a B-III grade of evidence andrecommenda-

tionagainstthe useof long-termmacrolidefor nasal polyposis.This is

incontrast toa C gradeof evidenceand recommendationforitsuse in

patients with nasal polypsby theEuropeanand British guidelines.

This review has limitations. First, the quality of included stud-

ies used to generate evidence-based conclusions was limited. Sev-

eralmedicaltherapies lacked level 1 evidenceand severalRCTscon-

tained moderate to high risk of bias (eTable 2 in the Supplement).Second, some studies used different diagnostic criteria for chronic

sinusitis and included mixed cohorts of sinusitis patients (eg, with

and without nasal polyps), limiting the ability to makespecific con-

clusions.Third,some of themeta-analysesincludedthe sameRCTs

(ie, a RCTmay be included in more than 1 meta-analysis).

Evidence-Based Medical Therapy Approach: Chronic

Sinusitis With Nasal Polyposis

An evidence-basedbut nonvalidatedapproachfor themedicalman-

agementof patients with nasalpolyposisis provided in Figure2.The

goal isto reducethesizeor eliminatenasalpolypsbecausetheycan

obstruct thenasal cavity andimpair thesenseof smell,restrictthe

ability tobreathe throughthe nose, andobstructphysiologic drain-

ageof thesinuses.45,96 Patientswith symptomatic nasal polyps af-

ter initial medical therapy (ie, topical corticosteroid withsaline irri-

gations) maywarrant a short-courseof oralcorticosteroids. Because

the expected benefit of systemic corticosteroids is relatively brief

(


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Sinusistis JAMA 2015