Philippe Gevaert, MD, PhD Michael A. Kaliner, MD Paul Van Cauwenberge, MD, PhD Reviewers: Kamal Hanna, Richard F. Lockey, Todor Popov Chronic Rhinosinusitis

Philippe Gevaert , MD, PhDMichael A. Kaliner, MD

Paul Van Cauwenberge, MD, PhDReviewers: Kamal Hanna, Richard F. Lockey, Todor Popov

Chronic Rhinosinusitis and Nasal Polyposis

Updated: June 2011

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Module 10:Chronic Rhinosinusitis

and Nasal Polyposis

Lecture objectives

At the end of this presentation, participants willbe able to:

Discuss the underlying pathology of acute andchronic rhinosinusitis and nasal polyposis

Describe the management of acute and chronicrhinosinusitis and nasal polyposis

Rhinosinusitis

Facts: 14.7% incidence in US population: 31,000,000 cases

per year Incidence increased by 18% over the past 11 years

26 million office visits for sinusitis in 1997 >21 million antibiotic prescriptions in 1997

Third most common diagnosis for antibiotics >70 restricted activity days in 1992 250,000 surgeries per year

Survey IMS Health 2001 USA, 1997 Germany, 7/2000-6/2001

Acute sinusitis Diagnosis: 6.3 millionPrescriptions: 8.5 million

Chronic sinusitis Diagnosis: 2.6 millionPrescriptions: 3.4 million

Nasal polyposis: Diagnosis: 221 000

Prevalence of sinusitis: 14.7%

Prescriptions of antibiotics for sinusitis

985 5.8 million 1992 13 million

Work loss (days)1986 50 million1992 73 million

1. Maxillary sinus2. Ethmoidal bulla3. Ethmoidal cells4. Frontal sinus5. Uncinate process6. Middle turbinate7. Inferior turbinate8. Nasal septum9. Ostiomeatal

complex

Infections induce changes in sinus mucosa

B

MT

MS

I T

The ostiomeatal complex

Key

B: bulla ethmoidalisIT: inferior turbinateMT: middle turbinateMS: maxillary sinus

Ventilationand

Drainage

Inflammationand

Remodeling

Anatomy & physiology

Coronal Axial

Ethmoid sinus

Frontal sinuses

RADIOGRAPHIC ANATOMY OF THE PARANASAL SINUSES

Maxillary sinus

Sphenoid sinus Anterior ethmoid

Posterior ethmoid

Sphenoid sinus

Anterior Posterior

Anatomy and physiologyMUCOSAL IMMUNITY

Anatomical and mechanical factors: Epithelial barrier

Mucus/mucociliary clearance

Mucosal immune system:

Innate immunity: Antimicrobial peptides: Defensins

Receptors: Toll-like receptors

Cells: Macrophages, neutrophils, dendritic cells, NK cells, mast cells

Adaptive immunity: Antigen-presenting cells

T-lymphocytes

B-lymphocytes => IgA

Rapid, non-

specific

Specific, memory

Aetiology of rhinosinusitis Allergy

Seasonal Perennial

Infection Acute Chronic: specific e.g.

Bacterial, fungal or nonspecific

Possible host defense deficency

Structural Ostiomeatal complex:

Deviated nasal septum Hypertrophic turbinates

Others Dental, periapical

abcess Underlying diseases,

cystic fibrosis Occupational irritants

and allergens Drug induced, rhinitis

medicmentosa Irritants induced

rhinitis Atrophic rhinitis

After International Consensus Report on the diagnosis and management of rhinitis. Allergy Suppl 19,49,1994

Anatomy and physiology

COMMON COLD

BACTERIAL SUPERINFECTIONStrep pneu./Haemo inf./Morax

catar.

Increasing symptoms after 5 DAYS

No resolution after 10 DAYS

ACUTE rhinosinusitis

MULTIFACTORIAL ETIOLOGY

CHRONIC rhinosinusitis EAACI Position Paper on Rhinosinusitis and Nasal Polyps, Allergy 2005: 60: 583-601

Underlying conditions Sinusitis and Immunodeficiencies

Sinusitis and cystic fibrosis

Humoral immunodeficencies frequently associated with sinusitis

Congenital immunodeficencies

Selective IgA deficency, Common variable IgG immunodeficency, Agammaglobulinemia, specific antibody deficency, (rarely IgG Subclass deficency)

Acquired immunodeficencies

Immunosupressive agents, HIV

Classification: chronic rhinosinusitis

with and without nasal polyps2 OR MORE MAJOR SYMPTOMS nasal blockage anosmia/hyposmia purulent nasal discharge/post-nasal drip facial pain/pressure

AND EITHER endoscopic findings of polyps mucopurulent discharge edema or obstructionOR CT scan abnormality: mucosal changes within ostiomeatal

complex or sinus cavity

EAACI Position Paper on Rhinosinusitis and Nasal Polyps, Allergy 2005: 60: 583-601

Classification: chronic rhinosinusitis

with and without nasal polyps

DURATION

ACUTE/intermittent < 12 weekscomplete resolution of symptoms

CHRONIC / persistent > 12 weeksincomplete resolution of symptoms


Symptoms associated with rhinosinusitis

Major symptoms: Minor symptoms:

Facial pain/pressure HeadacheFacial congestion/fullness FeverNasal obstruction/blockage HalitosisNasal discharge/purulence/postnasal drip FatigueHyposmia/Anosmia Dental painFever Cough

Ear pain/fullness

MicrobiologyNormal sinuses: Free of growthAcute rhinosinusitis:ViralBacterial (Strept. Pneumoniae,H. Influenzae, M.

Catharralis)Chronic rhinosinusitis:Anaerobes: Propionibacterium, Bacteriodes, PeptococcusAerobes: Staphylococcus, Corynebacterium, PseudomonasFungi (Aspergillus fumigatus, Curvularia, Dreschelaria)Dental sinusitis: Microaerophilic strept. species

Nasalpolyps

Imaging of sinsusesMRI: only recommended in tumor diagnosisCT sinuses: current standard imaging- Acute rhinosinusitis: only for possible complications

- Chronic sinusitis: only after 4+ weeks of treatment!

Septal deviation

Dental sinusitis

Chronic Sinusitis

Nasal polyps

The signs and symptoms of acute sinusitis

(>10 days and < 12 weeks): Prerequisite symptoms

Persistent upper respiratory infection (>10 days)

Persistent muco-purulent nasal or posterior pharyngeal discharge

Cough

Supporting symptoms Congestion Facial pain/pressure Post-nasal drip Fever Headache Anosmia, hyposmia Facial tenderness Periorbital edema Ear pain, pressure Halitosis Upper dental pain Fatigue Sore throat

Diagnosis of acute bacterial sinusitis (ABS)

or

Have not improved after 10 days

Have worsened after 5 to 7 days

A diagnosis of ABS is suggested when Symptoms of a viral URI

International Rhinosinusitis Advisory Board. ENT J 1997;76(suppl):1; Lanza and Kennedy. Otolaryngol Head Neck Surg 1997;117:S1.

Association between viral and bacterial sinusitis infections

Viral infections Self-limiting 2 to 3 acute viral respiratory infections per year (6-8

in children) >80% symptoms resolve in 7-8 days Often inciting event for development of sinusitis and

other respiratory tract infections 0.5%–2% of cases complicated by acute bacterial

infection (>20 million cases)

Brook. Primary Care 1998;25:633; Gwaltney. Clin Infect Dis 1996;23:1209; Gwaltney et al. N Engl J Med 1994;330:25.

Acute bacterial rhinosinusitis (ABRS)

Sinus and Allergy Health Partnership, 2000

Copyright permission for reproduction pending

Therapy

Decongestives/pain Saline washes Antibiotics (oral, IV) Corticosteroids (local, oral) Surgery: Adenoidectomy (child) Endoscopic sinus surgery (adult) chronic

acute

Strength of evidence for treatment of

acute rhinosinusitisTherapy Level Recommendation Relevance

antibiotic Ia (49 studies) A yes: after 5-10days,or in severe cases

topical corticosteroid 1b (1 study) A yes

addition of topical steroid toantibiotic

Ib (5 studies) A yes

oral steroid no evidence(1 study)

D no

addition of oral antihistaminein allergic patients

Ib (1 study) B no

nasal douche no evidence(3 studies)

D no

decongestion no evidence(3 studies)

D Yes as symptomaticrelief

mucolytics no evidence (3 studies)

D no


An update on acute rhinosinusitis management:

antibiotics in adultsCochrane Review Antibiotics for acute maxillary sinusitis

7330 subjects in 32 studies (10 double blind) antibiotic vs. control (n=5) newer, non-penicillin antibiotic vs. penicillin class

(n=10) amoxicillin-clavulanate vs. other extended spectrum

antibiotics (n=10)

Confirmed radiographically or by aspiration, current evidence is limited but supports penicillin or amoxicillin for 7 to 14 days. Clinicians should weight the moderate benefits of antibiotic treatment against the potential for adverse effects

Williams Jr JW, The Cochrane Library 2003

Evidence for treatment of rhinosinusitis with topical

corticosteroids plus antibiotics - 1Study Drug Antibiotic Number Effect X-ray

Meltzer, 2000

(340)

Momet.furuate

amox/clav 407 Significant effect incongestion, facialpain, headache andrhinorrhea. No significant effect inpostnasal drip

No statistical

difference inCT outcome

Nayak, 2002(341)

Momet.furuate

amox/clav 967 Total symptomScore (TSS) wasimproved(nasal congestion,facial pain, rhinorrheaand postnasal drip)

No statistical

difference inCT outcome


corticosteroids plus antibiotics - 2

Study Drug Antibiotic Number Effect X-ray

Dolor, 2001(342)

FP cefurox 95 Significant effect.

Effect measuredAs clinicalsuccess depending onPatient’sself-judgment of symptomatic improvement

Not done


corticosteroids plus antibiotics - 3Study Drug Antibiotic Number Effect X-ray

Barlan, 1997 (343)

Bud amox/clav 89 children

Improvement incough and nasalsecretion seen atthe end of thesecond week of treatment in theBUD group

Not done

Meltzer, 1993 (344)

Flunisol. amox/clav 180 Significantsympt: overall score for global assessment of efficacy wasgreater in thegroup with flunisolide

No effecton x‑ray

J Allergy Clin Immunol. 2005 Dec;116(6):1289-95.


Community-acquired acute sinusitis

Inflammatory component:Topical corticosteroidsSymptomatic treatment

Infectious bacterial component:

Antibiotic treatment

If unsuccessful, prolonged,

or primary signs

Primary signs of bacterial infection:Localized severe headachePus in the middle meatusComplications (orbital, skin, etc.)

Surgical intervention

If unsuccessful on

several trials,or complications

Considerations in antibiotic selection

Cost/ Formulary Status

Considerationsin Antibiotic

Selection

Activity Against Likely PathogenPharmacokinetics (PK)/ Pharmacodynamics (PD)

Medication Allergy

Adverse Effects

Ease of Dosing

Adapted from Kennedy et al. Ann Otol Rhinol Laryngol Suppl 1995;167:22; Sinus & Allergy Health Partnership. Otolaryngol Head Neck Surg. 2000;123:S1.

Resistance Patterns

Conditions for effective antibiotic treatment

Appropriate spectrum Appropriate penetrance and local activity Minor side-effects Good tolerance Liklihood of no resistence Affordable Available

Antibiotic therapy for sinusitis 2007

AmoxicillinAmoxicillin/clavulanate

CephalosporinCefuroximeCefopodoximeCefiximeCefprozilCefdinir

Erythromycin/sulfisoxazoleClarithromycinAzithromycin

MiscellaneousKetolidesQuinalonesMetronidazole Trimethoprin/sulfamethoxazoleClindamycin

Penicillin Macrolide

Recommended antibiotic choices - 2007

First choice: Amoxicillin/clavulante or cephalosporin Good second choice: Clarithromycin

Back-ups: QuinalonesUse metronidazole plus one of the above or clindamycin when gram negative is suspectedTopical mupiricin very useful in select cases

An update on acute rhinosinusitis management: Antibiotics in acute

rhinosinusitis? Don’t treat viral common cold with antibiotics Use symptomatic treatment in mild acute rhinosinusitis

saline decongestant NSAID

Use topical steroids in acute and chronic sinusitis (evidence)

Reserve antibiotics for severe acute presumably bacterial

rhinosinusitis Prescribe antibiotics based on local resistance patterns

Sinusitis - conclusions

Sinusitis is common and over-looked Causes are complex Treatment requires appreciation of causes and careful

follow-up Medical management is effective in most cases Functional endoscopic surgery is helpful in resistant

sinusitis after adequate medical management

Definitions and classificationCLINICAL DEFINITION OF RHINOSINUSITIS/NASAL

POLYPS

2 OR MORE MAJOR SYMPTOMS nasal blockage smell dysfunction nasal discharge/post-nasal drip facial pain/pressureAND EITHER endoscopic findings of polyps mucopurulent discharge edema or obstructionOR CT scan abnormality: mucosal changes within ostiomeatal

complex or sinus cavity


The signs and symptomsof chronic sinusitis (symptoms persisting >12 weeks):

Prerequisite symptoms Purulent nasal and

posterior pharyngeal discharge

Plus: Facial pain/pressure Persistent nasal

obstruction Cough/post-nasal

drip/throat clearing

Supporting symptoms Hyposmia, anosmia Sore throat Malaise Fever Headache, facial

pressure, dental pain Halitosis Sleep disturbance Fatigue

Diagnosis of chronic rhinosinusitis

Symptoms suggestive of chronic rhinosinusitis

Initial evaluation: Medical history: major, minor symptoms General examination Evaluation of underlying disease and co-morbidities Anterior rhinoscopy, Nasal endoscopy CT scan (not in an acute episode)

Special indications (differential diagnosis and underlying

disease) Allergy tests Microbiology (eventually sinus puncture) Challenge test for aspirin sensitivity Nasal cytology

(eosinophils, neutrophils) MRI (if tumor or fungus suspected) Ciliary function studies Biopsy

Biopsy Blood examinations

(Wegener’s, immunodeficencies)

Sweat chloride test Electron microscopy of cilia Genetic analyses Consultations of other specialities

(ophthalmologist, neurologist etc.)

Differential diagnosis of chronic rhinosinusitis - 1

Infectious rhinitis: viral upper respiratory tract infection

Allergic rhinitis: seasonal, perennial, occupational Nonallergic rhinitis: “Vasomotor rhinitis”, NARES,

aspirin- exacerbated respiratory disease Rhinitis medicamentosa Rhinitis secondary to pregnancy, hypothyroidism Anatomical abnormalities: severe septal deviation, foreign body Nasal polyps Inverted papilloma, benign and malignant tumors

Claus Bachert, Allergy: principles and practice.

Differential diagnosis of chronic rhinosinusitis - 2

Cerebrospinal fluid leak, meningoencephaloceles Mucoceles Wegener‘s granulomatosis Cocaine abuse Atrophic rhinitis Specific or tropic infections Fungal sinus disease Ophthalmologic or neurologic diseases

Claus Bachert, Allergy: principles and practice.

Chronic rhinosinusitis: why?

Chronic inflamed (eosinophilic) mucosa Possible superimposed infections

Bacteria Fungi

Superantigens Biofilms Osteitis

Chronic rhinosinusitiswith and without nasal polyps

Chronic Rhinosinusitis Nasal Polyps

Nasal Polyps

The spectrum of sinus disease

Rhinosinusitis - Eosinophils +

Chronic rhinosinusitiswith and without nasal polyps

Chronic Sinusitis

Nasal Polyposis

Facial pain/pressure Yes Sometimes

Facial congestion/fullness Yes Yes

Nasal obstruction/blockage Yes Yes

Nasal discharge/purulence/postnasal drip Yes Yes

Anosmia Sometimes Yes

Blood eosinophils Sometimes Often

Asthma Yes Often

Aspirin exacerbated respiratory disease Rarely 10% of cases

Chronic sinusitis - without nasal polyps

Prevalence of 14.7% in the normal population

Th1 type Inflammation with increased IFN increased TGF and remodeling

Pathogenic role of infections is unclear

Nasal polyposisPrevalence approx. 2- 4%

Asthma in approx. 40-65%

Aspirin sensitivity in 10-15%

Mixed cellular infiltrate withprominent eosinophilia in 90%

Inflammation with local IgE production increased IL-5, eotaxin, cys-LTs and ECP

Superantigens or superallergens

Bacterial Superantigens Staph aureus enterotoxins: SEA, SEB, SEC, SED,

SEE, TSST-1 Strep. pyogenes, Mycoplasma arthritidis, Yersinia pseudotuberculosis ……

Highly potent immune stimulators Interact with T-cell R

and MHC class II 20% of all T-cells are activated by SEA

SAg

T-Cell

V V

MHC II

TCR

APC

S. aureus colonization and IgE antibodies to

S. aureus enterotoxin mix in mucosal tissue

T. Van Zele, P. Gevaert et al. JACI 2004


Nasal polyposis: aetiology and pathogenesis

Chemokines

TB

Cytokines Hyper IgE

Eosinophils ( apoptosis)

SuperantigensIL-5

ECP

Albumin

Eotaxin

Polyclonal IgE

Epithelial damage (barrier dysfunction)

chronic microbial trigger

S. Aureus enterotoxins: disease modifiers

Recommended approach to the treatment of chronic rhinosinusitis

2007 Hydration (6 - 8 glasses of water per day) Antibiotics X 14-21+ days (until asymptomatic +7 days)

Choices: cephalosporin, amoxicillin/clavulanate, clarithromycin, quinalone

Long-acting nasal decongestant, BID X 7 days (oxymetazoline)

Nasal saline applied with nasal irrigation device, BID Topical nasal CCS:

2 sprays BID, until symptoms resolved Reduce to lowest effective dose, to maintain remission Aim towards the eye and away from the nasal septum

Next recommended approaches

Switch antibiotics CT scan; limited cut, coronal plane

Treat bacterial rhinitis rarely MRI – fungal or possible tumors

Add metronidazole or clindamycin (especially with foul smell)

Consider fungal Rx (itraconazole, amphotericin) Oral CCS (Daily followed by QOD) Topical antibiotics (tobramycin, mupirocin nasal

ointment)

Evidence-based treatment of CRSTherapy Level Grade of

Recommend.Relevance

oral antibiotic therapyshort term < 2 weeks

III (4) C no

oral antibiotic therapylong term ~ 12 weeks

III (6) C yes

topical steroidswithout significant systemic absorption

II (2) B yes

oral steroid no dataavailable

- no

nasal douche III C yes, forsymptomrelief

decongestion topical/oral no data in single-use

- no

Evidence-based treatment of CRS

Therapy Level Grade ofRecommend.

Relevance

mucolyticssystemic antimycotics

IV (1)VI

DD

nono

topical antimycotics III D no

oral antihistaminein allergic patients

Ib (1) B no

allergic therapyin allergic patients

Studies includepatients withNP

D yes

allergen avoidancein allergic patients

Studies includepatients withNP

D yes

proton pump inhibitors III (3) D no

Evidence-based long-term antibiotics in CRS

Study Drug Number Time/Dose Effect onsymptoms

Evidence

Hashiba et al,

1996(379)

clarithromycin 45 400mg/dfor 8 to 12weeks

clinical improvement in71%

III

Nishi et al,1995 (381)

clarithromycin 32 400mg/d pre- and post-Therapyassesment ofnasal clearance

III

Gahdhi et al,1993 (382)

Prophylaticantibiosis details notmentioned

26 Notmentioned

19/26 decrease Of acuteexacerbation by50%7/26 decrease ofacute exacerbation byless than 50%

III

Evidence-based long-term antibiotics in CRS

Study Drug Number Time/Dose Effect onsymptoms

Evidence

Ichimura et

al, 1996(18)

roxithromycin

Roxithromycin

and azelastine

20

20

150mg/dfor at least8 weeks

1mg /d

clinical improvement and polyp-shrinkage in52%

Clinicalimprovementand polypshrinkage in68%

III

Strength of evidence for treatment of CRS/NP

Intervention Chronic rhinosinusitis Nasal polyps

Corticosteroids Topical A A Systemic / C

Antibiotics Oral short term < 2w C DOral long term >12w C C

Antimycotics Topical / Systemic D DAntihistamines D BAnti-leukotrienes / C Nasal saline douche C D Decongestants D DAllergen avoidance D D

Treatment options for polyposis

Treat underlying sinusitis High dose nasal CCS Oral CCS Chronic/prophylactic antibiotics, systemic and/or

topical Anti-fungal, systemic and/or topical Anti-IL5

Nasal corticosteroid spray in nasal polyposis

Lund V, et al. Arch Otolaryngol Head Neck Surg 1994; 124: 513-8


Nasal corticosteroid drops in nasal polyps

Aukema, Mulder, Fokkens; JACI 2005


Budesonide use, 2007

Dilute budesonide solution (Pulmicort Respules), 500-1000 ug in 2-4 Oz saline and irrigate the sinuses BID

Have head positioned to the side so that gravity helps get washings into the sinuses; turn head as if to put the ear on knee

Has resolved polyp resistant to nasal fluticasone sprays

Topical anti-fungal treatment in nasal polyposis

A Richetti et al. 2002 J Laryngology & Otology


Topical anti-fungal treatment in nasal polyposis

Open study: - with 4 w Amphotericin B + nasal GCS

- in 74 patients with NP 48% improvement of NP (>> small polyps)

13 13

27

48

5

13

Before treatment

After treatment

0% cured

42% cured

62% cured

Stage I Stage II Stage III

n

50

40

30

20

10

Nasal lavages with Amphotericin B is in 2 DBPC studies:

- Ebbens F & Fokkens W J Allergy Clin Immunol. 2006 Nov;118(5):1149-56.

- Weschta M & Riechelmann H. , Arch Otolaryngol Head Neck Surg. 2006 Jul;132(7):743-7

Oral antifungal terbinafine is ineffective:

- Kennedy DW, Laryngoscope. 2005 Oct;115(10):1793-9

Long term antibiotic treatment in nasal polyposis

DBPC study in 90 patients: 3m low-dose erythromycin, nasal douche, nasal GCS vs. sinus surgery 50% Improvement of symptoms no difference vs sinus surgery

Mupiricin use Use mupiricin with

Recurrent crusting, particularly anterior Congestion, headache, green secretions & normal CT

– contact points, spurs Polyps

Mupiricin (Bactroban 2%) anteriorly with finger or Q tip, blot nose

Dissolved in saline, irrigate nose and sinuses with sinus rinse, along with budesonide

Polyp treatments - 2007 Anticipate 25+% improve with sinus Rx + nasal CCS Another 25-50% improve with sinus Rx + high dose nasal

CCS (FP drops or MDI, or nasal lavages with budesonide) The remainder improve with oral CCS + FP or nasal

lavages with budesonide solution Overall medical treatment can get close to 100%

success Mupiricin appears to help prevent regrowth, especially

with crusting Surgery, properly done, is successful short-term but

polyps can and do recur and repeated surgery gets progressively more difficult and dangerous!

Polyps – recommended treatment - 2007

Treat underlying sinusitis High dose nasal CCS

Fluticasone (FP), either nasal drops (EU) or MDI (USA) through nasal adapter (such as a baby bottle nipple)

Prednisone 20-30 mg Daily x 3-4 weeks, then QOD, then taper to 0

Budesonide solution (Pulmicort Respules) dissolved in sinus lavage Wash with the head positioned with ear turned to the knee

Mupiricin ointment topically or dissolved in sinus lavavge Consider careful surgery if polyps are persistent, resistant or

recur Consider oral or topical anti-fungal treatment

Conclusions - 1

Lack of controlled studies in Chronic Rhinosinusitis/Nasal Polyps!!

Current standard treatment for CRS: Nasal douche with saline Topical corticosteroidsBUT in NP: reversible effect, no resolution of NP Surgery: endoscopic sinus surgeryBUT in NP: high recurrence rate!!

Conclusions - 2Treat associated diseases: Allergic rhinitis

Combinations? Nasal douche Topical steroids (drops) Antibiotic ointment (mupiricin) Long term antibiotics (macrolides or doxycycline)

Anti IgE

Anti-IgE?

Antibiotics? Anti-fungal?

IL-5

ECP

Eotaxin

IgEAnti

IL-5

Anti-IL-5?

Corticosteroids? Anti-LTs?

Anti-CCR3?

Tacrolimus?

Future therapies in nasal polyposis

Summary - chronic rhinosinusitis

CRS is common; nasal polyposis occurs in about 25% CRS

Nasal polyposis is a complex disease to treat and few etiologic answers are known

Polyposis is nearly always associated with CRS and makes treating underlying sinusitis more difficult

Treat for sinusitis plus high dose nasal corticosteroids, particularly in solution. Consider topical antibiotics

Surgery may be beneficial, especially when combined with good medical care

Nasal polyps recur – this is a chronic, relapsing disease

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WAO Secretariat555 East Wells Street, Suite 1100

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Tel: +1 414 276 1791Fax: +1 414 276 3349

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Documents

Philippe Gevaert, MD, PhD Michael A. Kaliner, MD Paul Van Cauwenberge, MD, PhD Reviewers: Kamal Hanna, Richard F. Lockey, Todor Popov Chronic Rhinosinusitis