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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
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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
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
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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
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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
Medical Therapiesfor AdultChronic Sinusitis Review ClinicalReview & Education
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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.
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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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