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ASSALAMUALAIKUM.WR.WB.


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DISUSUN OLEH:GITHA AYU ASTARIKA

01.208.5662

JOURNAL READINGChronic rhinosinusitis and emerging treatment

options

Pembimbing: Kolonel. CKM. dr. Budi W, Sp.THT-KL

FAKULTAS KEDOKTERAN UNIVERSITAS ISLAM SULTAN AGUNG

SEMARANG

2013


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JOURNAL IDENTITY


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This review describes the epidemiology and various treatments

in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) andCRS without nasal polyps (CRSsNP). Evidence for short-term useof systemic corticosteroids has been shown to be favorable inCRSwNP, but still limited in CRSsNP. Topical corticosteroidsimprove symptom scores in both CRS subgroups. The role ofmicrobes in CRS is still controversial. Culture-directedantibiotics are recommended for CRSsNP with exacerbation.Long-term use of low dosage antibiotics is recommended forCRSsNP for their anti-inflammatory effects. Other emergingtreatment options are also discussed.

Keywords: rhinosinusitis, chronic, nasal polyps, therapy, sinus


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Rhinosinusitis is an inflammatory disease of the

nasal and paranasal sinus mucosa

It is defined as chronic when it lasts longer than 3months without complete symptom resolution.

Diagnostic criteria consist of the presence of symptoms including purulent nasaldischarge, nasal obstruction, facial pain/pressure/fullness, and/or decreasedsense of smell plus either endoscopic findings of inflammation, purulentdischarge or edema of the middle meatus or ethmoid region, polyps in the nasalcavity or the middle meatus, and/or radiographic imaging showing inflammationof the paranasal sinuses.

Chronic rhinosinusitis (CRS) is further divided into CRS with nasalpolyps (CRSwNP) and CRS without nasal polyps (CRSsNP).

As for the use in epidemiologic studies, CRS is defined as the presence oftwo or more symptoms, one of which should be either nasalblockage/obstruction/congestion or nasal discharge (anterior/posteriornasal drip) and/or facial pain/pressure and/or reduction or loss of smell for

more than 12 weeks with validation by telephone or interview.


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CONT...

The pathogenesis of CRS remainscontroversial..

Multifactorial factors altering thehost-environment interaction such

as bacteria, fungi, viruses, allergens,or environmental toxins may trigger

the inflammatory process


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CRS is a common health problem whichsignificantly affects quality of life

Patients have significantly higher bodily pain anddecreased social function compared to other chronic

diseases (congestive heart failure, angina, chronicobstructive pulmonary disease, and back pain) ( P , 0.05)

An epidemiology study in Europe was conducted by TheGlobal Allergy and Asthma Network of Excellence

(GA2LEN) by sending questionnaires on The European

Position Paper on Rhinosinusitis and Nasal Polyps (EPOS)criteria to a random sample of adults aged 15 75 years.


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The etiology and pathogenesis of chronicrhinosinusitis are not clearly understood.

Traditionally, it was believed that thechronic inflammatory process is the end

stage of untreated or partially treated acuterhinosinusitis or severe atopy from nasal

polyps.

This hypothesis leadsto the use of

antibiotics and anti-inflammatory drugs,eg, corticosteroids

for treating CRSpatients.

Alternative hypotheses includeexcessive host response to fungi,aspirin intolerance due to defects

in the eicosanoid pathway,staphylococcal superantigenresulting in exotoxin effects

including tissue damage,coordinated mechanical barrier

and the innate immune responseof the sinonasal mucosa, defects in

the immune barrier and biofilmsformation.

There is a growing body ofevidence supporting an emerginghypothesis that a dysfunctionalhost environment interaction

involving various exogenousagents results in the sinonasalinflammation.

In concert with the definition ofCRS as an inflammatory disorder,there has been movement away

from pathogen-drivenhypotheses.

This overall concept is inagreement with the current

understanding of the etiologyand pathogenesis of chronic

mucosal inflammatory disordersin general, which describes a

balance of interactions betweenthe host, commensal flora,potential pathogens, and

exogenous stresses.


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RhinosinusitisChronic

Loss of Cilia

Inadequatereply Drenase

Changes ofmucosa

Infection

Pollution,Chemicalsubstances

Residual SepsisInadequate treatment

Mechanicalobstruction

Allergy, immunodeficiencies

Figure. Cycle of recurringevents on chronic rinosinusitis

(Hilger, 1997)


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inflammation of the nose andthe paranasal sinusescharacterized by two or moresymptoms, one of which should

be either nasalblockage/obstruction/congestion or nasal discharge(anterior/posterior nasal drip) facial pain/pressure reductionor loss of smell for $12 weeks.

CRS with or withoutnasal polyps in adults is

defined as:

nasal polyps, and/or

mucopurulent dischargeprimarily from middle meatusand/or edema/mucosalobstruction primarily in middlemeatus.

and/or

computed tomography (CT)changes: mucosal changeswithin the ostiomeatal complexand/or sinuses.

This should be supportedby demonstrable diseasewith endoscopic signs of:


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The aims of treatment in CRS include elimination of theinfection, reduced sinonasal inflammation, and maintainedpatent sinonasal passage drainage.

In addition, CRS may be associated with precipitating factorsincluding allergies, cystic fibrosis, gastroesophageal reflux,sinonasal anatomic obstruction in the ostiomeatal unit, andimmunologic disorders. Therefore, the management of theserisk factors should also be optimized.

Treatment of CRS includes medical and surgical therapy. Medicaltherapy often requires combining multiple medicationsincluding antibiotics, nasal decongestants, topical nasal steroidsand/or oral steroids, and saline irrigation.

The rationale of this regimen is to control precipitating factors,treat the infection, reduce mucosal edema, and facilitatedrainage.

However, some patients do not respond with full medical

treatment alone; in these cases treatment with endoscopicsinus surgery should be considered as an alternative.


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The aim of corticosteroidtherapy in CRS is to reduceinflammation via directly

reducing eosinophil viabilityand activation.

In addition, an indirecteffect can be to reduce thesecretion of chemotacticcytokines from the nasal

mucosa and polypsepithelial cells


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Systemic corticosteroid

Oral steroids have been introduced as asystemic form to control inflammation.They are administrated as part of amultidrug regimen. To date, noevidence advocates for their use alone


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Management scheme for chronicrhinosinusitis without nasal polyps


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Management scheme for chronicrhinosinusitis with nasal polyps.


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There is limitedevidence to support the

use of oral steroids inCRSsNP.

Tosca et al investigatedthe efficacy of oralsteroids as part of a

multidrug regimen inchildren with CRS and

asthma.


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Cont....

They demonstratedbetter outcomes andcytokine profiles aftertreatment including

improved nasal

endoscopic condition in

allergic children (87.5%)and nonallergic children

(85.7%),

statistically significantreduction of

inflammatoryinfiltration in all

children ( P , 0.05)

significant decrease ofinterleukin (IL)-4 in

allergic children (P =0.0002) and nonallergic

children (P = 0.0007),

significant increase ofinterferon-gamma in

allergic children (P =0.03), and

nonsignificant increasein nonallergic children.


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CRSwNP

According to a recentCochrane review,when

data of 166 patientswere pooled from threerandomized controlled

trials, the effectsfavored systemiccorticosteroids.

Prednisoloneand

methylprednisolone are most

commonly used.

Due to the side-effects of

corticosteroids, wedo not recommendsystemic form usage

for long-termtreatment.


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Safety and tolerability

Adversesystemic effects

of treatmentwith systemic

steroids

`includeCushings

syndrome,

steroidinduced

diabetes,

gastriculcers,

gastrointestinalbleeding,

andavascular

necrosis ofthe femoral

head.

l d


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Topical corticosteroids

Topical corticosteroids are usedas part of a multidrug regimen.

There are numerous preparationsthat can be classified by systemicbioavailability as first generation

intranasal corticosteroids

beclomethasonedipropionate

triamcinoloneacetonide

flunisolide budesonidethe newer generation

includes

fluticasonepropionate

mometasone furoate ciclesonide

fluticasonefuroate


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The delivery method of topicalsteroids is an imperative factor.

Nose

nasal siteincludedrops,

sprays, andnebulizers.

Paranasalsinus

Paranasalsinus

deliveryrequiresdevices

cannulated

through thenose.

Volume

sprayvolume lessthan 1 mL,

or largevolume,which is

defined asany

significantvolume

more than60 mL (eg,

simpleirrigationsyringe,

irrigationdevices).

Pressure

low pressure(eg, spray,nebulizers,

instilledsolution

through atube, and

nonpressureirrigation)

highpressuremethods

(eg, positivpressure

irrigation).

C Lund et al37 reported that the use of budesonide 128 g twice a day


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CR

SsN

P

Numerous clinical controlledtrials have investigated the

efficacy of inhaled intranasalcorticosteroids.

p g ysignificantly improved symptom scores ( P , 0.05). Similarly, Qvarnberg etal38 reported the beneficial effects of budesonide 400 g daily. It reduced

nasal symptoms to a greater extent than placebo together with asignificantly greater reduction in facial pain. In addition, Lavigne et al39 found a decrease in CD-3 (P = 0.02) and eosinophils (P = 0.002), and a

decrease in the density of cells expressing IL-4 (P = 0.0001) and IL-5messenger RNA (P = 0.006) after treatment.

Hansen et al40 studied the efficacy of fluticasone 400 g twice a day via anOptiNose device (Optinose US Inc; Yardley, PA, USA). When compared with

placebo, it improved mucosal edema ( P = 0.015), increased peak nasalinspiratory airflow at 4 and 8 weeks (P = 0.006 and P = 0.03, respectively),improved magnetic resonance imaging (MRI) scores after 12 weeks (P =

0.039), and improved nasal rhinosinusitis outcome measure-31 (RSOM-31)subscale scores at 4 and 8 weeks (P , 0.009 and P , 0.016, respectively). Inaddition, it significantly improved symptoms including sense of smell and

nasal discomfort (P , 0.05). Conversely, Dijkstra et al41 compared the efficacyof two regimes of fluticasone nasal spray (400 g versus 800 g twice a day)and placebo. The results showed no significant difference in total symptomscore on the 0 100 scale. Similarly, Jorissen et al42 reported no significant

difference in endoscopic score when mometasone nasal spray was comparedwith placebo ( P = 0.905).

Regarding the method of delivery, a meta-analysis showed significantly greater effects insinus delivery methods (direct cannulation or

irrigation post-surgery) than nasal delivery

methods (drops, sprays, or nebulizer) ( P =0.04).36

Although, the significant benefitof using intranasal corticosteroids

is not shown by severalstudies,41,42 the evidence from ameta-analysis36 showed benefits

in symptom improvement.


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CRSwNP Thirty-eight randomized controlled trials were included

for a meta-analysis.

Nasal aerosols and turbuhalers were more effectivethan nasal sprays in symptom control but there was no

difference in polyp size reduction.

The steroid agents used werefluticasone propionate,

beclomethasone dipropionate,betamethasone sodium

phosphate, mometasone furoate,flunisolide, and budesonide.

When compared to placebo, the steroid

group could decrease symptom scoresby 0.46 (95% confidence interval [CI]0.27 0.65) and decrease polyp sizescore by 0.48 (95% CI 0.21 0.75).


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Adverse effects reported were mostly mild ormoderate, consisting of local effects at the site ofapplication.

Giger et al presented side effects including epistaxis,dry nose, nasal burning, nasal itching, sinusitis,pharyngitis, otitis, change of taste, eczema,nausea/diarrheas, nasal irritation, and common cold.

Using intranasal corticosteroid is generally safe. It does not provide increased incidence of infection or

candidiasis, or produce a change in morning serumcortisol level


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Antibiotics The role of microbes in CRS as causative agents or for

colonization is unclear. There is substantial evidence ofbacterial colonization in CRS, antibiotics still play amajor role for occurrences of acute exacerbation ofCRS.

Bacterial organisms of CRS differ from acute rhinosinusitis. The main organismsinclude Staphylococcus aureus, Enterobacteriaceae spp., and Pseudomonas spp., and less commonly Streptococcus pneumoniae, Haemophilus influenza, and beta hemolytic streptococci. In addition, anaerobes (eg, Peptostreptococcus, Prevotella, Porphyromonas,

Bacteroides, Fusobacterium species) are possible organisms in CRS.


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Systemic antibiotics

Systemic antibiotic treatment of CRSsNP can beadministrated as either short- or long-term treatment.

Short-term treatment is defined as the duration ofusage less than 4 weeks in order to eradicate theorganisms; conversely, long-term treatment is used foranti-inflammatory effects rather than anti-bacterialeffects. Although, infection is not well established to becausative, the expert committee recommended using

antibiotics as short-term treatment in CRSsNP withexacerbation with a positive culture.

CRS NP


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CRSsNP The appropriate antibiotic for short-term treatment is usually broad spectrum to control both

aerobic and anaerobic organisms. In addition, beta-lactamase-producing organisms andmethicillin-resistant S. aureus (MRSA) are possible pathogens, thus empiric antibiotics are

frequently prescribed for coverage of these organisms.

Extended spectrum antibiotics (eg, amoxicillin/clavulanic acid, fluoroquinolone) are commonlyused. Legent et al79 compared amoxicillin/clavulanic acid with ciprofloxacin. The results showed

no significant differences in clinical cure (51.2% versus 58.6%) and bacteriological eradicationrate (90.5% versus 88.9%) for amoxicillin/clavulanic acid and ciprofloxacin. This result wassimilar to the result of Namyslowski et al80 which showed no significant difference betweenamoxicillin/clavulanic acid and cefuroxime axetil in clinical response (95% versus 88%) andbacterial eradication (65% versus 68%). Ciprofloxacin and cefuroxime axetil may be a usefulalternative choice of therapeutic treatment.

Regarding long-term antibiotic treatment, the anti-inflammatory effects of macrolides havebeen investigated. Numerous studies have demonstrated the efficacy of macrolides in reducinginflammatory markers and an increasing ciliary beat frequency, indicating less stickysecretions.81 85 Furthermore, Wallwork et al86 showed a significant anti-inflammatory effectof roxithromycin on the sinonasal outcome test (SNOT)-20 score, nasal endoscopy, saccharintransit time, and IL-8 levels ( P , 0.05) in a randomized placebo-controlled trial for CRSsNP.Conversely, the result of Videler et al87 showed no significant anti-inflammatory effects onSNOT-22, patient response rating scale, visual analog score, and SF-36.


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CONT... These different outcomes between the two studies may be

explained by using different inclusion criteria. Wallwork etal86 included only patients with CRSsNP, whereas Videler etal87 included both CRSwNP and CRSsNP. Subgroup analysisin the study of Wallwork et al86 demonstrated that thesubpopulation of patients with normal immunoglobulin E(IgE) levels had a higher response rate to the macrolidetreatment than patients with elevated IgE. Therefore,serum IgE is a helpful indicator to identify responders tolong-term macrolide treatment.

The recent Cochrane review78 found that there was limitedgood quality evidence to compare using antibiotics versusplacebo in CRS; thus, future well-designed studies shouldbe conducted.


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CRSwNP

There were tworandomized placebocontrolled trials

For short-termantibiotics.

could significantly reducepolyp size and post-nasaldrip score, while otherantibiotics (quinolone,amoxicillin/clavulanate, orco-trimoxazole) had no

significant effect but had atrend towards benefit.

Doxycycline 100mg for 20 days

which showed adecrease in polypsize and patientsymptoms, but allwerenonrandomizedtrials.

macrolides


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Common adverse effects of antibiotics include gastrointestinal symptoms,skin rash, and reversible elevation of liver enzymes. Adverse events fromantibiotic use in CRS were observed in an amoxicillin/clavulanic acid group(4.4%) and cefuroxime group (4.3%). These events were minorcomplications; diarrhea was the most common event. However, oneserious urticaria occurred in the cefuroxime group.

Resistant bacterial strains from long-term antibiotic treatment are ofconcern due to using the low dose form which does not reach the minimalinhibitory concentration. A controlled trial found that three of 50 cultureshad positive macrolide resistant strains before treatment, and four ofcultures had resistant strains after treatment. Although, there seems to be

no significant difference of resistant strains between before and aftertreatment, increased macrolide-resistant bacterial strains have beenreported. Therefore, development of resistant bacterial strains should bemonitored by nasal swab culture every 3 months.


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Topical antibiotics CRSsNP

Topical antibiotics have been administrated to treat CRS with the aimof providing higher concentrations of drug and acting directly on the

site of infection; however, placebo controlled trials showed onlyminimal benefit.

Desrosiers et al reported significant improvements in quality of life,symptoms, and sinonasal endoscopic appearance in both the saline

and tobramycin group ( P , 0.05).

Similarly, Videler et al compared bacitracin/colimycin topical spraywith placebo and reported improvements in both groups without

significant differences in SF-36 or sinonasal endoscopic appearance.These studies showed no significant additive effects of topicalantibiotics; therefore, topical antibiotics should not be used as first-

line management but may be prescribed in patients refractory totraditional topical steroids and oral antibiotics.


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There was no evidence regarding the useof topical antibiotics in CRSwNP.


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The mostcommonadverseeffects

included

Intranasalstinging or

burningsensation

Moderatepain

Throatirritation

Cough

Dry skin

O h i i


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Other emerging optionsMany adjunctive agents have been utilized to control CRS including

Antimycotics,

Anti-ige,Anti-il5,Antihistamine,Aspirin desensitization,Bacterial lysates,Capsaicin,Complementary and alternative medicine,Decongestants,Furosemide,Immunosuppressants,Leukotriene antagonistsNasal irrigation,Mucolytic agents,

Phototherapy,Probiotics, andProton pump inhibitors (ppis).

There was limited evidence on the effect of these options. We will focus thistopic only on medications with positive effects.


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Anti-IgE

Several investigators found that CRSwNP patientshave higher IgE in polyps and serum than controls.

One randomized controlled trial used omalizumab for6 months compared with placebo in CRS patients.

They found improvement of sinus opacification in CT-scans and the SNOT-20, but there was not asignificant difference.


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Anti-IL-5

IL-5 is the key mediator in eosinophil activation.

Sejima et al found that patients with CRSwNP had higherlevels of IL-5 compared with patients with CRSsNP. There weresome small Phase II randomized controlled trials that found apositive effect of reslizumab and mepolizumab in decreasingpolyp size.

These drugs may have a possible role in treatment of CRSwNPin the future.


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Bacterial lysates

The mechanisms of bacterial lysates arehypothesized to enhance the process ofpostnatal maturation of T helper (Th)1function and dendritic cells.

The efficacy of bacterial lysates(Broncho-Vaxom, OM Pharma, Geneva,Switzerland) was investigated comparedwith placebo.

They found a significant improvement insymptoms including headache, purulentdischarge, cough, and expectoration inthe bacterial lysates group.


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Capsaicin

The calcitonin gene-related peptide (CGRP) is

a vasodilator agentpresent in sensory

nerves and may play amajor role in the

vascular component of

neurogenicinflammation.

Complementary and alternative


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Complementary and alternativemedicine

The complementary and alternativemedicines used to treat CRS includeherbal medicine, vitamins, homeopathy,acupuncture, massage, reflexology, yoga,and chiropractics.

Richstein and Mann compared the herbal preparation(European elder, common sorrel, cowslip, European vervainand gentian) with placebo, and found improvement of theoverall clinical status and possible improvement on theradiological findings in the herbal preparation group (12/16patients) and placebo group (6/15 patients).

Another study reported a significant effect on nasal mucosainflammation reduction and overall rating in the herbalpreparation group, but no significant difference in othersymptoms including nasal mucosa edema, nasal discharge,

and breathing difficulties.


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Furosemide

Furosemide couldinduce cell shrinkageby mediating the net

influx of osmoticallyactive ions and

hypothetically haveimmunomodulatory

and anti-inflammatory effects

in hyperactiveairway disease.


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Nasal irrigation

removal of mucus,

infectivepathogens

inflammatorymediators and

promotes ciliarybeat frequency.


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Cont....

Freeman et al studied the efficacy of saline irrigation post-endoscopic sinus surgery.

At 3 weeks postoperatively, the outcomes showed a significantimprovement of discharge in the saline douching group

compared with no treatment ( P = 0.046).

However, at 3 months postoperatively, there was only aminimal difference with crusting (P = 0.18) and edema (P =

0.32), and no difference with adhesions, discharge, and polyps.

Khianey et al also found a small clinical benefit of the nasalsaline irrigation with minimal side effects.


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Mucolyticagents

Some studies usedmucolytic agentsas an adjunctivedrug for treating

patients withtenacious mucus.

Majima et al assessed theefficacy ofScarboxymethylcysteine inCRS patients without nasalpolyps or with small nasal

polyps.

After 12 weeks oftreatment, the nasal

discharge and post-nasal discharge weresignificantly

improved in the S-carboxymethylcystein

e group ( P = 0.008and P = 0.002,

respectively).


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Esophagealreflux was

considered apotentialcause of CRS.

Using PPIs todecrease acid

reflux may reducesinonasal mucosal

damage.

An uncontrolledtrial evaluating

PPIs in CRSpatients reportedimprovement insinus symptoms

(nasal congestion,

nasal drainage,sinus pressure,facial headache,

malaise) and globalsatisfaction (25%

89% and 91%,respectively).


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Near-infrared laserillumination (NILI),

with or without

photo-activated (PA)agents, hasbactericidal andwound healing

promoting effectswhich may have a

potential role inmanaging CRS.


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Surgery CRSsNP

The aim of surgery includesclearing diseased mucosa,

eliminating infection, relievingdrainage obstruction, and

restoring ventilation.

Two randomized controlledtrials compared the efficacy

between surgery andmedication in CRS. Hartog et al

showed no significantdifference in overall cure ratesbetween the medication group

(sinus irrigation plusloracarbef) and surgical group

(sinus irrigation plus loracarbefplus endoscopic sinus surgery).

The Cochrane reviewsuggested that functional

endoscopic sinus surgery hasnot been demonstrated toconfer additional benefits tothose obtained by medicaltreatment. We recommendsurgical intervention only

when there is no response tomaximal medical treatment.


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Surgical intervention involvesclearance of polyps and abnormalmucosa and opening of the sinusopenings. There was limited evidencebased on nonrandomized controlledtrials which found that endoscopic

sinus surgery was safe and effective.


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Conclusion

Several therapieshave been proven

by studies with ahigh level ofevidence to

improve clinicalsymptoms and

objectiveoutcomes.

Some therapies still need

validation through well-conducted studies, inwhich randomized

controlled trials may be adifficult task due to

confounding factors andtrial participation.

Even though itremains achallenge to curethe root cause of

CRS, an algorithmof multidrugregimen and

endoscopic sinussurgery after fullyimplemented

medication canhelp to decrease

the diseaseburden andimprove the

quality of life ofthis group of

patients.


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