Acute & Chronic Sinusitis לימודי המשך Ephraim Eviatar Assaf Harofeh Medical Center

Acute & Chronic Acute & Chronic SinusitisSinusitis

לימודי המשךלימודי המשך

Ephraim Eviatar

Assaf Harofeh Medical Center

סינוסיטיס היא האבחנה החמישית אשר סינוסיטיס היא האבחנה החמישית אשר אנטיביוטיקה מומלצת עבורה. אנטיביוטיקה מומלצת עבורה.

מכלל הילדים מכלל הילדים 9%9% סינוסיטיס מהווה סינוסיטיס מהווה במבוגרים. במבוגרים.21%21%שקיבלו אנטיביוטיקה ו-שקיבלו אנטיביוטיקה ו-

RhinosinusitisRhinosinusitis

Acute rhinosinusitisAcute rhinosinusitis

Subacute rhinosinusitisSubacute rhinosinusitis

Chronic rhinosinusitisChronic rhinosinusitis

Recurrent ARSRecurrent ARS

Acute rhinosinusitis superimposed on CRS Acute rhinosinusitis superimposed on CRS

Acute rhinosinusitisAcute rhinosinusitis

Acute sinusitis Acute sinusitis 7-21 days7-21 days (7 days viral (7 days viral illness)illness)Spontaneous resolution of ARS -40%Spontaneous resolution of ARS -40%The most common pathogens: strep The most common pathogens: strep pneumonia-30%, pneumonia-30%, non typeabale hemophilus infl.-20%, non typeabale hemophilus infl.-20%, moraxella catarrhalis.(20% in children)moraxella catarrhalis.(20% in children)Staph aureus- 30%Staph aureus- 30%Anaerobes- rareAnaerobes- rare

Recurrent ARSRecurrent ARS

EpisodesEpisodes of bacterial infection of the of bacterial infection of the paranasal sinuses, each lasting less than paranasal sinuses, each lasting less than 30 days and 30 days and separated by intervalsseparated by intervals of at of at least least 1010 daysdays during which the patient is during which the patient is asymptomatic.asymptomatic.

Subacute sinusitisSubacute sinusitis

Subacute Subacute RS:3W-3monthsRS:3W-3months

The same pathogens as in ARS The same pathogens as in ARS

Chronic rhinosinusitisChronic rhinosinusitis

Beyond 3 monthsBeyond 3 months

Bacteria are as in ARS, butBacteria are as in ARS, but

More non-typeable H InfluezaeMore non-typeable H Influezae

More staph aureus, anaerobic bacteria, More staph aureus, anaerobic bacteria, gram- Negative, pseudomonase gram- Negative, pseudomonase aeruginosaaeruginosa

Polymicrobials with resistant organismPolymicrobials with resistant organism

Culture recommendedCulture recommended

Acute bacterial sinusitis Acute bacterial sinusitis superimposed on chronic sinusitissuperimposed on chronic sinusitis

Patients with residual respiratory Patients with residual respiratory symptoms develop new respiratory symptoms develop new respiratory symptoms. When treated with symptoms. When treated with antimicrobials, these new symptoms antimicrobials, these new symptoms resolve, but the underlying residual resolve, but the underlying residual symptoms do not.symptoms do not.

Major & Minor signs and symptoms Major & Minor signs and symptoms in diagnosis of Chronic RSin diagnosis of Chronic RS

Majors:Majors:Facial pain/pressureFacial pain/pressureNasal congestion/fullnessNasal congestion/fullnessN. obstruction/blockageN. obstruction/blockageN. discharge/purulenceN. discharge/purulenceHyposmia/ anosmiaHyposmia/ anosmiaPurulent rhinitisPurulent rhinitisFever (acute sinusitis only)Fever (acute sinusitis only)

MinorsMinors::HeadacheHeadacheFeverFeverHalitosisHalitosisFatigueFatigueDental painDental painCoughCoughEar pain/ Ear pain/

pressure/fullnpressure/fulln

Clinical Diagnosis of rhinosinusitisClinical Diagnosis of rhinosinusitis

2 or more major2 or more major factors factors

1 major & 2 minor1 major & 2 minor factors factors

Or Or Purulence Purulence on examinationon examination

Duration of symptoms Duration of symptoms > 10 days> 10 days or or worsen after worsen after 5-7 days5-7 days

Kinney WC : otolaryngol Head Neck Surg 2002

Predisposing factorsPredisposing factors

URIURI

AllergyAllergy

TraumaTrauma

Dental infectionDental infection

Environmental Pollutants Environmental Pollutants

GERD GERD

Cystic FibrosisCystic Fibrosis

Facial painFacial pain on percussion or palpation, on percussion or palpation, sedimentation ratesedimentation rate and and white blood countwhite blood count have little diagnostic valuehave little diagnostic value. .

Purulent secretions by history Purulent secretions in the nasal cavity on examination

Lack of response to decongestants and antihistamines Unilateral maxillary pain

Double-sickening": an upper respiratory infection that initially improves then worsens

The The gold standardgold standard for the diagnosis of for the diagnosis of acute bacterial sinusitis is the acute bacterial sinusitis is the recovery of recovery of bacteriabacteria in high density (>10 in high density (>10 colony-colony-forming units/mL) from the cavity of a forming units/mL) from the cavity of a paranasal paranasal sinussinus

4

Rhinosinusitis definitions for patient careRhinosinusitis definitions for patient care

Type of rhinosinusitis

Acute rhinosousitis CRS without polyposis

Pattern of symptoms * Symptoms minimum 10d-28d

*severe disease

*worsening disease

Symptoms >12w

Symptoms for diagnosis *Ant./post purulent discharge

*nasal obstruction

*facial pain-pressure

The following symtoms

*ant/post mucupurulent

*nasal obstruction

*facial pain- Objective documentation Nasal exam:purule

Radiographic evidence

Nasal exam to exclude polyps

CT sinus not essential

Rhinosinusitis definitions for patient careRhinosinusitis definitions for patient care

Type of rhinosinusitis

AFRSCRS with polyposis

Symptoms for diagnosis

Objective documentation

>2 of the symptoms :

*ant/pos mucupurulent d

*nasal obstruction

*decrease sense of smell

>1 of the symptoms:

*ant/pos rhinitis

*nasal obstruction

*facial pain/pressure

Nasal exam.to confirm bilat polyps.

CT is not essential

Nasal exam. Allergic mucin, inflammation &

polyps

*fungal specific IgE

No invasion

CT is not essential

Fungal culture , total IgE

Dose the patient have 2 or more Dose the patient have 2 or more major factorsmajor factors?... ?...

Yes:Yes:

AmoxicillinAmoxicillin

Or BactrimOr Bactrim

No:No:

Treat symptomaticallyTreat symptomatically

Saline irrigationSaline irrigation

Oral decongestant Oral decongestant

Antihistamine (allergy)Antihistamine (allergy)

Reevaluate in 10 daysReevaluate in 10 days

Kinney WC : otolaryngol Head Neck Surg 2002

typetypeorganismorganismdrugsdrugscommentscomments

acuteacuteStrep pneumoniaeStrep pneumoniae

h. Influenzaeh. Influenzae

m. catarrhalism. catarrhalis

Amoxicillin 10 Amoxicillin 10 daysdays

22ndnd generation generation cephalosporin,cephalosporin,

Macrolide, Macrolide, for for

penicillin allergypenicillin allergy

subacutesubacuteIncreased resistant of Increased resistant of bacteriabacteria

22ndnd line drugs line drugs

chronicchronicPolimicrobial, Polimicrobial, psudomonase a, psudomonase a, anaerobes, moreanaerobes, more

resistantresistant

Augmentin, Augmentin, 22ndnd cephalo. cephalo. macrolide, macrolide, clinda,3-4w clinda,3-4w

Culture Culture whenever whenever possiblepossible

Recurrent Recurrent chronicchronic

ResistantResistant , , polimicrobialpolimicrobial

consider 3-4w consider 3-4w profilaxis profilaxis

CultureCulture guidedguided

Suppurative Suppurative complicationscomplications

G(-). Staph G(-). Staph aureusaureus

CefuroximeCefuroxime,,aminoglicozidaminoglicozidee

Surgery if no Surgery if no responceresponce

Severe sinusitis with suspected Severe sinusitis with suspected orbital or orbital or intracranial complicationsintracranial complications –cefuroxime or –cefuroxime or ceftriaxoneceftriaxone

The best in The best in crscrs treat according to treat according to cultureculture

For crs treat 3 weeks, while improvement For crs treat 3 weeks, while improvement within 3-5 dayswithin 3-5 days

3-6 weeks prophylaxis once daily therapy 3-6 weeks prophylaxis once daily therapy for patients with rapid recurrence?? for patients with rapid recurrence??

Antimicrobial treatment guidelinesAntimicrobial treatment guidelines

1. mild symptoms, 1. mild symptoms, not receivednot received antibiotics antibiotics within 4-6w.within 4-6w.

2. mild disease, who 2. mild disease, who received received antibiotics antibiotics within 4-6w, within 4-6w,

or with moderate disease regardless of or with moderate disease regardless of recent antibiotic exposure,recent antibiotic exposure,

מטרת הטיפול האנטיביוטי:מטרת הטיפול האנטיביוטי:

לחסל את החיידקים באתר של הזיהום כדי שלהשיב לחסל את החיידקים באתר של הזיהום כדי שלהשיב את הסינוסים לבריאותםאת הסינוסים לבריאותם

לקצר את תקופת המחלה ולשוב לשגרת חיים לקצר את תקופת המחלה ולשוב לשגרת חיים נורמאליתנורמאלית

למנוע סיבוכים קשים, כמו מנינגיטיס.למנוע סיבוכים קשים, כמו מנינגיטיס.

למנוע התפתחות מחלה כרונית למנוע התפתחות מחלה כרונית

According to the guidelines

טיפול במבוגריםטיפול במבוגרים

מגיעה מגיעה האנטיביוטיקה שיעילותה הקלינית המנובאתהאנטיביוטיקה שיעילותה הקלינית המנובאת כמו כמו fluoroquinolonesfluoroquinolones הינם: הינם: 90-92%90-92%ל ל

levofloxacinlevofloxacin -ו- ו moxifloxacinmoxifloxacin.. ceftriaxoneceftriaxone , ,augmentinaugmentin

cefiximecefixime high dose high dose: : 83-88%83-88%יעילות של יעילות של amoxicillin, cefpodoxime proxile, cefuroxime amoxicillin, cefpodoxime proxile, cefuroxime

axetil, cefdinir TMP/SMXaxetil, cefdinir TMP/SMX , , docxycyline, clindamycindocxycyline, clindamycin::77-81%77-81%יעילות של יעילות של

azitromycin, clarithromycin, erythromycinazitromycin, clarithromycin, erythromycin cefaclor,loracarbefcefaclor,loracarbef: : 65-66%65-66% יעילות של יעילות של


טיפול בילדיםטיפול בילדים

91-92% 91-92% : ceftriaxone, augmentin: ceftriaxone, augmentin

82-87%82-87%: amoxicillin, cefpodoxime proxetil, : amoxicillin, cefpodoxime proxetil, cefixime, cefuroxime axetil,cefdinir,TMP/SMXcefixime, cefuroxime axetil,cefdinir,TMP/SMX

78-80%78-80%: : clindamycin, cefprozil, azithromycin, clindamycin, cefprozil, azithromycin, clarithromycin, erythromycinclarithromycin, erythromycin

67-68% 67-68% : cefaclor: cefaclor


ההמלצות לטיפול התחלתי במבוגרים ההמלצות לטיפול התחלתי במבוגרים עם מחלה קלהעם מחלה קלה

Augmentin, amoxicillin, cefpodoxime proxetil, Augmentin, amoxicillin, cefpodoxime proxetil, cefuroxime axetil, or cefdinircefuroxime axetil, or cefdinir

For b-lactam allergies patients: TMP/SMX, For b-lactam allergies patients: TMP/SMX, doxycilline, azithromycin, doxycilline, azithromycin, clarithromycin,erythromycinclarithromycin,erythromycin

Failure after 72h: reevaluation or switch to Failure after 72h: reevaluation or switch to alternate antimicrobial therapyalternate antimicrobial therapy


המלצות לטיפול התחלתי במבוגרים המלצות לטיפול התחלתי במבוגרים עם מחלה קלה שטופלו קודםעם מחלה קלה שטופלו קודם

Respiratory flouroquinolones, augmentin Respiratory flouroquinolones, augmentin (4g/day),ceftriaxone (1-2 g/day 5 days), (4g/day),ceftriaxone (1-2 g/day 5 days), combination of g+ and g-combination of g+ and g-

Failure after 72h: switch to alternate Failure after 72h: switch to alternate antimicrobial therapy, or reevaluation antimicrobial therapy, or reevaluation

CT scan, endoscopy, sinus aspiration and CT scan, endoscopy, sinus aspiration and culture culture


המלצות לטיפול התחלתי בילדים עם המלצות לטיפול התחלתי בילדים עם מחלה קלהמחלה קלה

Augmentin (90mg/k/day), amocixillin (90 Augmentin (90mg/k/day), amocixillin (90 mg/k/day), cefpodoxime proxetil, mg/k/day), cefpodoxime proxetil, cefuroxime axetil, or cefdinircefuroxime axetil, or cefdinirType I hypersensitivity to b-lactams Type I hypersensitivity to b-lactams patients: TMP/SMX, azithromycin, patients: TMP/SMX, azithromycin, clarithromycin or erythromycin.clarithromycin or erythromycin.Make differentiate an immediate Make differentiate an immediate hypersensitivity from other side effectshypersensitivity from other side effectsFailure after 72 h Failure after 72 h


המלצות לטיפול בילדים עם מחלה המלצות לטיפול בילדים עם מחלה קלה (טופלו לאחרונה) או מחלה קלה (טופלו לאחרונה) או מחלה

בינוניתבינוניתAugmentin(90mg/k/day), cefpodoxime Augmentin(90mg/k/day), cefpodoxime proxetil, cefuroxime axetil or cefdinir.proxetil, cefuroxime axetil or cefdinir.Beta lactams allergic patients: TMP/SMX, Beta lactams allergic patients: TMP/SMX, azithromycin, clarithromycin, erythromycinazithromycin, clarithromycin, erythromycinClindamycin for s pneumoniae Clindamycin for s pneumoniae Ceftriaxone (5 days, parenteral), or Ceftriaxone (5 days, parenteral), or combination therapy for G+ and G- combination therapy for G+ and G- Clindamycin or amocixillin and cefiximeClindamycin or amocixillin and cefiximeClindamycin or amoxicillin and rifampinClindamycin or amoxicillin and rifampin


New insights into the role of New insights into the role of bacteria in CRSbacteria in CRS

Bacterial Bacterial superantigenssuperantigens--exotoxinsexotoxins that are that are able to activate T lymphocytes able to activate T lymphocytes

Pathogenesis of nasal polyposis- Pathogenesis of nasal polyposis- superantigens from S aureussuperantigens from S aureus

Biofilms-Biofilms-a artificial or damaged a artificial or damaged biologic biologic surfacesurface that formed communicating that formed communicating organization of microorganisms organization of microorganisms surrounded by a glycocalyssurrounded by a glycocalys

Biofilms is relatively impervious to Biofilms is relatively impervious to antibiotics and is never eradicatedantibiotics and is never eradicated

Mechanical debridement- the only way to Mechanical debridement- the only way to resolve biofilms resolve biofilms

Osteitis: the role of the boneOsteitis: the role of the bone

Osteomyelitis can be seen at a distance Osteomyelitis can be seen at a distance from the primary infectionfrom the primary infection

Inflammatory bone changes were noted on Inflammatory bone changes were noted on contralateral side in 52% of the animalscontralateral side in 52% of the animals

The changes in the involved bone can The changes in the involved bone can explain why CRS is relatively resistant to explain why CRS is relatively resistant to medical therapy. medical therapy.

Khalid et al. laryngoscope 2002

Failed CRSFailed CRS

To sinus surgery or systemic steroid/antibioticsTo sinus surgery or systemic steroid/antibiotics

Macrolid therapyMacrolid therapy (long term, low dose) (long term, low dose) effectiveeffective

Cervin A et al: Otolaryngol Head Neck Surg 2002

CRS CRS

78 had criteria to CRS 78 had criteria to CRS

37- CT findings: positive37- CT findings: positive

41- CT findings: negative41- CT findings: negative

35: endoscopy negative & CT negative 35: endoscopy negative & CT negative

20: endoscopy negative & CT positive20: endoscopy negative & CT positive

55: endoscopy negative 55: endoscopy negative

17 endoscopy: positive

6 endoscopy : positive

Stankiewicz & Chow: Otolaryngol Head Neck Surg 2002

Radiology & clinical examRadiology & clinical exam

Correlated with a Sensitivity of 75%Correlated with a Sensitivity of 75%

And specificity of 84% And specificity of 84%

Endoscopy correlated poorly with sinus Endoscopy correlated poorly with sinus disease and not predictive disease and not predictive


Endoscopy/ct findings/clinicalEndoscopy/ct findings/clinical

Easy to diagnose CRS by endoscopy Easy to diagnose CRS by endoscopy alone when alone when nasal polyps, purulence, or nasal polyps, purulence, or fungusfungus is observed, is observed,

when absent, establishing the diagnosis when absent, establishing the diagnosis may be more difficultmay be more difficult

45%45% of patients with clinical CRS of patients with clinical CRS were were both both endoscopically and radiographically endoscopically and radiographically negative.negative.

Stankiewicz and Chow. Otolaryngol head neck surg 2002Stankiewicz and Chow. Otolaryngol head neck surg 2002

Endoscopy/ct findings/clinicalEndoscopy/ct findings/clinical

Negative endoscopyNegative endoscopy alone is insufficient to alone is insufficient to rule out sinusitis.rule out sinusitis.

26% of patients who were negative on 26% of patients who were negative on endoscopy had positive CT – this would endoscopy had positive CT – this would suggest that if endoscopy is negative suggest that if endoscopy is negative most of the time the ct will be also most of the time the ct will be also negative, even with a positive history.negative, even with a positive history.


בילדיםבילדים

) יופיע ) יופיע URIURI הסיכון שזיהום חיידקי (בעקבות הסיכון שזיהום חיידקי (בעקבות ימים ימים 1010גדול יותר אם המחלה נמשכת מעל גדול יותר אם המחלה נמשכת מעל

אבחנה תעשה בילדים ומבוגרים עם אבחנה תעשה בילדים ומבוגרים עם שלא השתפרו שלא השתפרו VIRAL URIVIRAL URIסימפטומים של סימפטומים של

ימים. ימים. 5-75-7 ימים או הוחמרו אחרי ימים או הוחמרו אחרי 1010אחרי אחרי The The diagnosisdiagnosis of acute bacterial sinusitis is of acute bacterial sinusitis is based on based on clinical criteriaclinical criteria in children who in children who present with present with upper respiratory symptomsupper respiratory symptoms that are either that are either persistent or severepersistent or severe

Guidelines of American Academy of Pediatrics


Persistent symptomsPersistent symptoms are those that last are those that last longer than longer than 10 to 1410 to 14, but less than , but less than 3030, , daysdays. Such symptoms include . Such symptoms include nasalnasal or or postnasal dischargepostnasal discharge (of any quality), (of any quality), daytime daytime coughcough (which may be worse at (which may be worse at night), or both.night), or both.



Severe symptomsSevere symptoms include a temperature include a temperature of at least 102°F of at least 102°F (39oC(39oC) and ) and purulent purulent nasal dischargenasal discharge present concurrently for at present concurrently for at least least 3 to 43 to 4 consecutive consecutive days days in a child in a child who seems ill. The child who seems who seems ill. The child who seems toxictoxic should be should be hospitalizedhospitalized and is not and is not considered in this algorithm.considered in this algorithm.


childrenchildren

יש קושי לפעמים להבדיל בילדים בין מחלה וירלית של

דרכי נשימה עליונים ואדנואידיטיס מסינוסיטיס

חריפה

רק נזלת מוגלתית וסמיכה מקורה בסינוסים עצמם, והאף משמש כצינור, בעוד שנזלת מוקואדית,

וירלית מערבת את האף בילבד.

יש דמיון רב בין דלקת אוזן חריפה לסינוסיטיס חריפה בילדים מבחינת פטוגנסיס ומיקרוביולוגיה

בגלל הקשר לנאסופארינקס

ARS in childrenARS in children

DiagnosisDiagnosis in children based on in children based on clinical clinical criteriacriteria

RadiologyRadiology is only for is only for complicationscomplications, , persistent persistent oror recurrent recurrent sinusitis sinusitis

For prevention there is For prevention there is no prophylacticno prophylactic antimicrobial treatment, ancillary antimicrobial treatment, ancillary therapies, complementary/alternative therapies, complementary/alternative medicinemedicine


Surgical managementSurgical management of crs in of crs in childrenchildren

5-8 events of colds/year5-8 events of colds/year

5%-13% will complicate by acute RS5%-13% will complicate by acute RS

Most of children with RS respond to Most of children with RS respond to medical treatmentmedical treatment

Today surgery consist of sinus lavage, Today surgery consist of sinus lavage, ESS, adenoidectomyESS, adenoidectomy

Goal of surgeryGoal of surgery

Surgery is for Surgery is for control of symptomscontrol of symptoms, , better better quality of lifequality of life and and to prevent complicationsto prevent complicationsIndications to surgery are not uniform Indications to surgery are not uniform between OL and Pbetween OL and P““cure”-the goalcure”-the goal for surgery, but is not the for surgery, but is not the likely end pointlikely end pointReversible mucosal disease may be Reversible mucosal disease may be possible in the long run, but is unlikely to possible in the long run, but is unlikely to be realized in the short term be realized in the short term

Maximal medical managementMaximal medical management

RefluxReflux

MacrolidsMacrolids

AntileukotriensAntileukotriens

Irrigations-nasal spraysIrrigations-nasal sprays

Alternative medical approachesAlternative medical approaches

Surgical management childrenSurgical management children

BiomaterialsBiomaterials

Subperiosteal abscessSubperiosteal abscess

The surgical site in childrenThe surgical site in children

There is strong evidence to support the There is strong evidence to support the fact that thefact that the OMC OMC area is the area is the primary siteprimary site of involvement of inflammatory sinuses of involvement of inflammatory sinuses disease. disease.

Surgical management in childrenSurgical management in children

Role of adenoidectomyRole of adenoidectomy::1. reservoir for pathogenic bacteria1. reservoir for pathogenic bacteria2. interfere with nasal mucociliary 2. interfere with nasal mucociliary clearanceclearance3.better drainage3.better drainageOverall successOverall success of adenoidectomy- of adenoidectomy-5050%%Studies show reduction in the number of Studies show reduction in the number of bacterial pathogens in the nasopharynx bacterial pathogens in the nasopharynx after adenoidectomyafter adenoidectomy

Fear of surgeryFear of surgery??

Surgery may cause Surgery may cause growth retardation of growth retardation of the midfacethe midface

Bothwell et al. showed no difference in Bothwell et al. showed no difference in facial growth of children with CRS who facial growth of children with CRS who operated compare with children who operated compare with children who refused surgery.refused surgery.

SurgerySurgery

Children who fail medical therapy benefit Children who fail medical therapy benefit from surgeryfrom surgery

AdenoidectomyAdenoidectomy recommended recommended initially initially for for children 6 years of age (no asthma, low children 6 years of age (no asthma, low CT score)CT score)

ESS and adenoidectomyESS and adenoidectomy for children older for children older than 6 (asthma and high CT score)than 6 (asthma and high CT score)

Ramadan. Laryngoscope.2004Ramadan. Laryngoscope.2004

Results of surgery childrenResults of surgery children

Older childrenOlder children do better than youngest do better than youngest

Old children (>6 y/o)- Old children (>6 y/o)- successes ratesuccesses rate is is 89%89% , but younger children (>6 y/o)- , but younger children (>6 y/o)- successes rate is only 73%successes rate is only 73%

>3 y/o>3 y/o who were operated have who were operated have 75%75% chance chance to be reoperateto be reoperate

Antibiotic therapyAntibiotic therapy

Amoxicillin -1Amoxicillin -1stst choice choice In children give high dose In children give high dose 60mg/kg/day 60mg/kg/day To consider 2To consider 2ndnd generation cephalosporin, or generation cephalosporin, or erythromycin with sulfonamide ,or high dose erythromycin with sulfonamide ,or high dose penicillin in areas with a high incidence of penicillin in areas with a high incidence of bacterial antibiotic resistance.bacterial antibiotic resistance.Based on studies showing a 20% incidence of Based on studies showing a 20% incidence of viable bacteria through maxillary sinus tap after viable bacteria through maxillary sinus tap after 7 days of antibiotic therapy, most authors 7 days of antibiotic therapy, most authors recommend recommend 10 days of therapy10 days of therapy in the manage in the manage of acute sinusitisof acute sinusitis

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Acute & Chronic Sinusitis לימודי המשך Ephraim Eviatar Assaf Harofeh Medical Center