Full text of "كتب في علم الميكروبيولوجي"

See other formats

DK3789 half-series-title. qxd 7/19/05 3:26Am Page 1

Sinusitis

From Microbiology
to Management

DK3789 half-series-title. qxd 7/19/05 3:26Am Page 2

INFECTIOUS DISEASE AND THERAPY

Series Editor

Burke A. Cunha

Winthrop-University Hospital

Mineola, and

State University of New York School of Medicine

Stony Brook, New York

1. Parasitic Infections in the Compromised Host,
edited by Peter D. Walzer and Robert M. Genta

2. Nucleic Acid and Monoclonal Antibody Probes:
Applications in Diagnostic Methodology, edited by
Bala Swaminathan and Gyan Prakash

3. Opportunistic Infections in Patients with the Acquired
Immunodeficiency Syndrome, edited by

Gifford Leoung and John Mills

4. Acyclovir Therapy for Herpesvirus Infections, edited by
David A. Baker

5. The New Generation of Quinolones, edited by
Clifford Siporin, Carl L Heifetz, and John M. Domagala

6. Methicillin-Resistant Staphylococcus aureus: Clinical
Management and Laboratory Aspects, edited by
Mary T. Cafferkey

7. Hepatitis B Vaccines in Clinical Practice, edited by
Ronald W. Ellis

8. The New Macrolides, Azalides, and Streptogramins:
Pharmacology and Clinical Applications, edited by
Harold C. Neu, Lowell S. Young, and Stephen H. Zinner

9. Antimicrobial Therapy in the Elderly Patient, edited by
Thomas T. Yoshikawa and Dean C. Norman

10. Viral Infections of the Gastrointestinal Tract:
Second Edition, Revised and Expanded, edited by
Albert Z. Kapikian

11. Development and Clinical Uses of Haemophilus b
Conjugate Vaccines, edited by Ronald W. Ellis
and Dan M. Granoff

12. Pseudomonas aeruginosa Infections and Treatment,
edited by Aldona L. Baltch and Raymond P. Smith

DK3789 half-series-title. qxd 7/19/05 3:26^?M Page 3

13. Herpesvirus Infections, edited by Ronald G laser
and James F Jones

14. Chronic Fatigue Syndrome, edited by
Stephen E. Straus

15. Immunotherapy of Infections, edited by K. Noel Masihi

16. Diagnosis and Management of Bone Infections,
edited by Luis E. Jauregui

17. Drug Transport in Antimicrobial and Anticancer
Chemotherapy, edited by Nafsika H. Georgopapadakou

18. New Macrolides, Azalides, and Streptogramins in
Clinical Practice, edited by Harold C. Neu,
Lowell S. Young, Stephen H. Zinner,

and Jacques F. Acar

19. Novel Therapeutic Strategies in the Treatment of
Sepsis, edited by David C. Morrison and John L. Ryan

20. Catheter-Related Infections, edited by Harald Seifert,
Bernd Jansen, and Barry M. Farr

21. Expanding Indications for the New Macrolides,
Azalides, and Streptogramins, edited by

Stephen H. Zinner, Lowell S. Young, Jacques F Acar,
and Harold C. Neu

22. Infectious Diseases in Critical Care Medicine,
edited by Burke A. Cunha

23. New Considerations for Macrolides, Azalides,
Streptogramins, and Ketolides, edited by
Stephen H. Zinner, Lowell S. Young, Jacques F Acar,
and Carmen Ortiz-Neu

24. Tickborne Infectious Diseases: Diagnosis
and Management, edited by Burke A. Cunha

25. Protease Inhibitors in AIDS Therapy, edited by
Richard C. Ogden and Charles W. Flexner

26. Laboratory Diagnosis of Bacterial Infections,
edited by Nevio Cimolai

27. Chemokine Receptors and AIDS, edited by
Thomas R. O'Brien

28. Antimicrobial Pharmacodynamics in Theory

and Clinical Practice, edited by Charles H. Nightingale,
Takeo Murakawa, and Paul G. Ambrose

29. Pediatric Anaerobic Infections: Diagnosis and
Management, Third Edition, Revised and Expanded,
Itzhak Brook

DK3789 half-series-title. qxd 7/19/05 3:26^?M Page 4

30. Viral Infections and Treatment, edited by

Helga Ruebsamen-Waigmann, Karl Deres, Guy Hewlett,
and Reinhold Welker

31. Community-Aquired Respiratory Infections, edited by
Charles H. Nightingale, Paul G. Ambrose,

and Thomas M. File

32. Catheter-Related Infections: Second Edition,
Harald Seifert, Bernd Jansen and Barry Farr

33. Antibiotic Optimization: Concepts and Strategies in
Clinical Practice (PBK), edited by Robert C. Owens, Jr.,
Charles H. Nightingale and Paul G. Ambrose

34. Fungal Infections in the Immunocompromised Patient,
edited by John R. Wingard and Elias J. Anaissie

35. Sinusitis: From Microbiology to Management,
edited by Itzhak Brook

36. Herpes Simplex Viruses, edited by Marie Studahl,
Paola Cinque and Tomas Bergstrom

37. Antiviral Agents, Vaccines, and Immunotherapies,
Stephen K. Tyring

DK3789 half-series-title. qxd 7/19/05 3:26Am Page 5

Sinusitis

From Microbiology
to Management

edited by

Itzhak Brook

Georgetown University School of Medicine
Washington, D.C., U.S. A.

Taylor & Francis

Taylor & Francis Group

New York London

DK3789_Discl.fm Page 1 Wednesday, August 3, 2005 8:27 AM

Published in 2006 by
Taylor & Francis Group
270 Madison Avenue
New York, NY 10016

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper

10 987654321

International Standard Book Number- 10: 0-8247-2948-X (Hardcover)
International Standard Book Number- 13: 978-0-8247-2948-6 (Hardcover)

This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts
have been made to publish reliable data and information, but the author and the publisher cannot assume
responsibility for the validity of all materials or for the consequences of their use.

No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,
mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and
recording, or in any information storage or retrieval system, without written permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright.com
(http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive,
Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration
for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate
system of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only
for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data

Catalog record is available from the Library of Congress

T&F

informa

Taylor & Francis Group
is the Academic Division of T&F Informa pic.

Visit the Taylor & Francis Web site at
http ://w w w. taylorandf rancis. com

This book is dedicated to my wife, Joyce, and my children,

Dafna, Tamar, Yoni, and Sara

Preface

Upper respiratory tract infections and, especially, sinusitis are frequently
encountered in the day-to-day practice of infectious disease specialists, aller-
gists, pediatricians, otolaryngologists, internists, and family practitioners.
The range of causative agents and available therapies and the constantly
changing spectrum of antibiotic resistance can make it difficult to select
the most appropriate course of treatment. Given the increasing global con-
cerns regarding the scale of worldwide bacterial resistance, which is largely
because of the misuse and overuse of antibiotics, information that can
enable physicians to optimize management of infections such as sinusitis will
be of great value.

This book provides state-of-the-art information on management of
sinusitis tailored to the clinicians and health care providers of varied special-
ties. It contains a liberal number of figures and tables that clarify the
underlying concepts and illustrate specific details. The authors selected to
contribute to the book are the world experts and leaders in the topic(s) they
address.

The book opens with a comprehensive overview of the epidemiology,
clinical presentation, and diagnostic techniques of sinusitis. It then delves
into the pathophysiology and the microbiology underlying the condition.
The next section of the book addresses the medical management of acute
and chronic sinusitis as well as the comorbid medical symptoms. We then
conclude with the surgical management of these conditions and their com-
plications. It is our hope that this book will be a useful tool and an impor-
tant resource for clinicians in the management of sinusitis.

Itzhak Brook, M.D., M.Sc.

Contents

Preface .... v
Contributors .... xv

SECTION I. EPIDEMIOLOGY, PRESENTATION
AND DIAGNOSIS

1. Sinusitis: Epidemiology 1

Thomas M. File Jr.
Introduction .... 1
Prevalence and Burden of Disease .... 2
Epidemiology and Risk Factors .... 5
Pathogens of Bacterial Sinusitis .... 10
Sinusitis and HIV .... 11
Nosocomial Sinusitis .... 12
References .... 13

2. Classification of Rhinosinusitis 75

Peter A. R. Clement

Introduction .... 15

Classifications of Sinusitis .... 17

The Classification of Fungal Sinusitis .... 28

The Classification of Pediatric Rhinosinusitis .... 32

References .... 34

VII

viii Contents

3. Rhinosinusitis: Clinical Presentation and Diagnosis 39

Michael S. Benninger and Joshua Gottschall

Introduction .... 39

Definitions .... 40

Pathophysiology .... 41

Rhinosinusitis or Upper Respiratory Tract Infection? .... 42

Diagnosis of Rhinosinusitis .... 43

Conclusion .... 52

References .... 52

4. Imaging Sinusitis 55

Nafi Ay gun, Ovsev Uzunes, and S. James Zinreich

Introduction .... 55

Available Imaging Modalities .... 55

Anatomy .... 60

Imaging Rhinosinusitis .... 71

Presurgical Imaging Evaluation .... 84

Postsurgical Imaging Evaluation .... 87

Surgical Complications .... 87

Computer-Aided Surgery .... 89

References .... 89

SECTION II. ANATOMY AND PATHOPHYSIOLOGY

5. Anatomy and Physiology of the Paranasal Sinuses 95

John H. Krouse and Robert J. Stachler

Introduction .... 95

Embryology of the Nose and Paranasal Sinuses .... 96

Anatomy of the Nose and Paranasal Sinuses .... 100

Physiology of the Nose and Paranasal Sinuses .... 106

Conclusion .... 108

References .... 108

6. Pathophysiology of Sinusitis 109

Alexis H. Jackman and David W. Kennedy

Introduction .... 109

Definitions of Rhinosinusitis .... 113

Acute Rhinosinusitis .... 113

Chronic Rhinosinusitis .... 116

Etiologies of Chronic Rhinosinusitis .... 117

Contents ix

Summary .... 128
References .... 129

SECTION III. MICROBIOLOGY

7. Infective Basis of Acute and Recurrent Acute Sinusitis . . . 755

Ellen R. Wald

Introduction .... 135

Obtaining Specimens .... 135

Microbiology of Acute Sinusitis in Children .... 137

Microbiology of Acute Community- Acquired Sinusitis in

Adults .... 138
Conclusion .... 141
References .... 142

8. Infectious Causes of Sinusitis 145

Itzhak Brook

Introduction .... 145

The Oral Cavity Normal Flora .... 145

Interfering Flora .... 151

Nasal Flora .... 152

Normal Sinus Flora .... 153

Microbiology of Sinusitis .... 154

The Role of Fungi in Sinusitis .... 167

Conclusion .... 169

References .... 169

SECTION IV. THERAPEUTIC OPTIONS

9. Antimicrobial Management of Sinusitis 779

Itzhak Brook
Introduction .... 179
Antimicrobial Resistance .... 179
Beta-Lactamase Production .... 180
Antimicrobial Agents .... 186
Principles of Therapy .... 193
Conclusions .... 198
References .... 198

x Contents

10. Medical Management of Acute Sinusitis 203

Dennis A. Conrad

Introduction .... 203

Rationale for the Recommended Management of Acute

Bacterial Sinusitis .... 204
Current Recommendations for the Management of Acute

Bacterial Sinusitis .... 211
References .... 216

11. Medical Management of Chronic Rhinosinusitis 279

Alexander G Chiu and Daniel G Becker
Definition of CRS .... 220
Inciting Factors in Sinusitis .... 220
Antimicrobial Therapy .... 220
Antimicrobial Agents .... 221
Anti-inflammatory Agents .... 222
Adjunctive Therapy .... 223
Maximal Medical Therapy for CRS .... 224
Infections Following Functional Endoscopic

Sinus Surgery .... 225
Nebulized Medications .... 226
Topical Antibiotic Irrigations .... 227
Intravenous Antibiotics .... 227
Aspirin Desensitization .... 229
Conclusion .... 229
References .... 229

12. Surgical Management 233

David Lewis and Nicolas Y. Busaba
Introduction .... 233
Diagnostic Work-Up .... 234
Indications for Paranasal Sinus Surgery .... 236
Contraindications for Paranasal Sinus Surgery .... 238
Endoscopic (Endonasal) Sinus Surgery .... 238
Complications of Endoscopic Sinus Surgery .... 245
Image Guidance Systems .... 247
Microdebriders and Sinus Surgery .... 248
Types of Paranasal Sinus Surgery .... 249
Antibiotic Coverage in Paranasal Sinus Surgery: Prophylactic
and Post Surgery .... 264

Contents xi

Lasers and Sinus Surgery .... 265
Conclusion .... 265
References .... 266

13. Complications of Acute and Chronic Sinusitis and Their

Management 269

Gary Schwartz and Steve White

Introduction .... 269

Pathophysiology .... 270

Local Complications .... 270

Orbital Infections .... 272

Intracranial Complications of Sinusitis .... 278

References .... 288

SECTION V. SINUSITIS AND SPECIFIC DISEASES

14. Sinusitis and Asthma 297

Frank S. Virant

Introduction .... 291

Historical Association of Sinusitis and Asthma .... 291

Chemical, Cytokine, and Cellular Mediators of Airway

Disease .... 292
Impact of Medical Sinus Therapy on Asthma .... 294
Impact of Surgical Sinus Therapy on Asthma .... 294
Sinusitis as a Trigger for Asthma — Mechanisms .... 295
Clinical Implications .... 297
Conclusions .... 300
References .... 300

15. Rhinosinusitis and Allergy 305

Desiderio Passali, Valerio Damiani, Giulio Cesare Passali,
Francesco Maria Passali, and Luisa Bellussi
Epidemiology .... 305
Pathophysiology .... 306
Diagnosis .... 308
Treatment .... 310
Prevention .... 313
References .... 314

xii Contents

16. Nosocomial Sinusitis 319

Viveka Westergren and Urban Forsum

Introduction .... 319

Etiology and Pathogenesis .... 320

Epidemiology .... 328

Diagnosis of an Infectious Sinusitis in the ICU .... 339

Microbiology and Choice of Antimicrobials .... 342

Treatment .... 345

Complications .... 346

Prevention .... 347

References .... 348

17. Cystic Fibrosis and Sinusitis 357

Noreen Roth Henig

Introduction .... 357

Pathophysiology of CF .... 357

Pathophysiology of CF-Related Sinusitis .... 358

Microbiology .... 359

Clinical Overview of CF Sinusitis .... 361

Diagnosis of Cystic Fibrosis .... 363

Treatment of CF-Related Sinusitis .... 363

Experimental Therapies .... 366

Special Considerations .... 367

Conclusion .... 367

References .... 368

18. Chronic Rhinosinusitis With and Without

Nasal Polyposis 371

Joel M. Bernstein

Introduction .... 371

Potential Etiologies for the Early Stages of CRS .... 373

Microbiology .... 374

Epidemiology of CRS with Massive Nasal

Polyposis .... 375
The Clinical Diagnosis of Nasal Polyposis .... 377
Medical and Surgical Therapy of Nasal Polyposis .... 380
Pathogenesis of CRS .... 381
Conclusions .... 397
References .... 398

Contents xiii

19. Sinusitis of Odontogenic Origin 403

Itzhak Brook and John Mumford

Introduction . . .

. 403

Pathophysiology

.... 403

Microbiology . .

. . 407

Symptoms . . . .

411

Diagnosis ....

412

Management . .

. . 412

Summary ....

415

References . . . .

416

20. Fungal Sinusitis 419

Carol A. Kauffman
Introduction .... 419
Epidemiology .... 420
Pathogenesis .... 422
Diagnosis .... 424
Treatment .... 428
Conclusions .... 432
References .... 433

21. Sinusitis in Immunocompromised, Diabetic, and Human
Immunodeficiency Virus-Infected Patients 437

Todd D. Gleeson and Catherine F. Decker

Introduction .... 437

Sinusitis in Neutropenic Patients .... 438

Sinusitis in Diabetic Patients .... 444

Sinusitis in HIV-infected Patients .... 446

Conclusion .... 449

References .... 450

Index .... 455

Contributors

Nafi Aygun The Russell H. Morgan Department of Radiology and
Radiological Sciences, The Johns Hopkins Medical Institution, Baltimore,
Maryland, U.S.A.

Daniel G. Becker Department of Otorhinolaryngology — Head and Neck
Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Luisa Bellussi Ear, Nose, and Throat Department — University of Siena
Medical School, Viale Bracci, Siena, Italy

Michael S. Benninger Department of Otolaryngology-Head and Neck
Surgery, Henry Ford Hospital, Detroit, Michigan, U.S.A.

Joel M. Bernstein Departments of Otolaryngology and Pediatrics, School
of Medicine and Biomedical Sciences, Department of Communicative
Disorders and Sciences, State University of New York at Buffalo, Buffalo,
New York, U.S.A.

Itzhak Brook Departments of Pediatrics and Medicine, Georgetown
University School of Medicine, Washington, D.C., U.S.A.

Nicolas Y. Busaba Department of Otolaryngology, Harvard Medical
School, VA Boston Healthcare System, Massachusetts Eye and Ear
Infirmary, Boston, Massachusetts, U.S.A.

Alexander G. Chiu Division of Rhinology, Department of
Otorhinolaryngology — Head and Neck Surgery, University of
Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

xvi Contributors

Peter A. R. Clement Department of Otorhinolaryngology and ENT
Department, University Hospital, Free University Brussels (VUB), Brussels,
Belgium

Dennis A. Conrad Division of Infectious Diseases, Department of
Pediatrics, University of Texas Health Science Center at San Antonio,
San Antonio, Texas, U.S.A.

Valerio Damiani Ear, Nose, and Throat Department — University of Siena
Medical School, Viale Bracci, Siena, Italy

Catherine F. Decker Division of Infectious Diseases, Department of
Internal Medicine, National Naval Medical Center, Bethesda, Maryland,
U.S.A.

Thomas M. File, Jr. Northeastern Ohio Universities College of Medicine,
Rootstown, and Infectious Disease Service, Summa Health Service, Akron,
Ohio, U.S.A.

Urban Forsum Division of Clinical Microbiology, Department of
Molecular and Clinical Medicine, Faculty of Health Sciences, Linkoping
University, Linkoping, Sweden

Todd D. Gleeson Division of Infectious Diseases, Department of Internal
Medicine, National Naval Medical Center, Bethesda, Maryland, U.S.A.

Joshua Gottschall Department of Otolaryngology-Head and Neck
Surgery, Henry Ford Hospital, Detroit, Michigan, U.S.A.

Noreen Roth Henig Adult Cystic Fibrosis Center, Advanced Lung Disease
Center, California Pacific Medical Center, San Francisco, California,
U.S.A.

Alexis H. Jackman Department of Otorhinolaryngology Head and
Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania,
U.S.A.

Carol A. Kauffman Division of Infectious Diseases, University of
Michigan Medical School, Veterans Affairs Ann Arbor Healthcare System,
Ann Arbor, Michigan, U.S.A.

David W. Kennedy Department of Otorhinolaryngology Head and Neck

Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Contributors xvii

John H. Krouse Department of Otolaryngology Head and Neck Surgery,
Wayne State University, Detroit, Michigan, U.S.A.

David Lewis Department of Otolaryngology, Harvard Medical School,
Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.

John Mumford Department of Periodontics, Naval Postgraduate Dental
School, Bethesda, Maryland, U.S.A.

Desiderio Passali Ear, Nose, and Throat Department — University of
Siena Medical School, Viale Bracci, Siena, Italy

Francesco Maria Passali Ear, Nose, and Throat Department — University
of Siena Medical School, Viale Bracci, Siena, Italy

Giulio Cesare Passali Ear, Nose, and Throat Department — University of
Siena Medical School, Viale Bracci, Siena, Italy

Gary Schwartz Vanderbilt University Medical Center, Nashville,

Tennessee, U.S.A.

Robert J. Stachler Department of Otolaryngology Head and Neck
Surgery, Wayne State University, Detroit, Michigan, U.S.A.

Ovsev Uzunes The Russell H. Morgan Department of Radiology and
Radiological Sciences, The Johns Hopkins Medical Institution, Baltimore,
Maryland, U.S.A.

Frank S. Virant University of Washington, Seattle, Washington, U.S.A.

Ellen R. Wald Department of Pediatrics and Otolaryngology, University
of Pittsburgh School of Medicine, Allergy, Immunology, and Infectious
Diseases, Pittsburgh, Pennsylvania, U.S.A.

Viveka Westergren Division of Clinical Microbiology, Department

of Molecular and Clinical Medicine, Faculty of Health Sciences, Linkoping

University, Linkoping, Sweden

Steve White Vanderbilt University Medical Center, Nashville,
Tennessee, U.S.A.

S. James Zinreich The Russell H. Morgan Department of Radiology
and Radiological Sciences, The Johns Hopkins Medical Institution,
Baltimore, Maryland, U.S.A.

SECTION I. EPIDEMIOLOGY, PRESENTATION AND
DIAGNOSIS

Sinusitis: Epidemiology

Thomas M. File Jr.

Northeastern Ohio Universities College of Medicine, Rootstown, and
Infectious Disease Service, Summa Health Service, Akron, Ohio, U.S.A.

INTRODUCTION

Respiratory tract infections are the most common type of infections man-
aged by health care providers, and they are of great consequence (1,2). In
a recent report from the Centers for Disease Control, respiratory tract in-
fections (upper respiratory tract infections, otitis, and lower respiratory
tract infections) accounted for 16% of all outpatient visits of patients to
physicians (3).

Of all the respiratory infections, sinusitis is one of the most common
illnesses that affect a high proportion of the population. According to the
National Ambulatory Medical Care Survey data, sinusitis is the fifth most
common diagnosis for which an antibiotic is prescribed (4). Sinusitis
accounted for 9% and 21% of all pediatric and adult antibiotic prescrip-
tions, respectively, written in 2002 (5). Since many cases of sinusitis are viral
in etiology, these data actually suggest that antibiotics are frequently mis-
used for the management of this illness. Such inappropriate use leads to
increased resistance among respiratory tract pathogens. The inappropriate
use of antibiotics is related in part to the fact that sinusitis has been a rela-
tively poorly defined clinical syndrome which is often a self-limited illness
associated with wide variations in presenting symptoms, and an incomplete
understanding of the pathogenesis and clinical course of the disease.
However, recent classification of the sinusitis syndrome as well as the

File

publication of evidence-based guidelines has provided a clear approach to
its management (6-8).

The appropriate classification of sinusitis as well as an awareness of
its epidemiology can facilitate better management of this infection. This
chapter reviews information concerning the epidemiology of acute sinusitis.

PREVALENCE AND BURDEN OF DISEASE

The true prevalence of rhinosinusitis is unclear since various types of sinu-
sitis are often lumped into this single designation. The true prevalence rate
likely varies considerably from the diagnostic rate because not all indivi-
duals seek care for rhinosinusitis, and because of the inconsistencies in defi-
nitions. Nonetheless, available statistics confirm a high overall prevalence
and disease burden.

Estimates of the prevalence of acute rhinosinusitis can be extrapolated
based on its association with the common cold. A reasonable estimate is that
each adult has two to three colds per year, and each child has three to eight
colds per year (9). Up to 80% of these upper respiratory illnesses may be
associated with rhinosinusitis, equating to over one billion cases of rhinosi-
nusitis annually in the United States (10). It has been suggested that bacter-
ial maxillary sinusitis complicates 0.5% to 2% of all upper respiratory tract
infections, which translates into approximately 20 million cases of bacterial
acute rhinosinusitis annually (11). This estimate may understate the inci-
dence of rhinosinusitis because the focus was on maxillary sinusitis. Accord-
ing to the 2001 National Health Interview Survey, 17.4% of the American
adult population interviewed had been told by a doctor or health care
professional that they had sinusitis in the past 12 months (Table 1) (12).

The prevalence of chronic rhinosinusitis may be better defined (13).
According to the National Ambulatory Medical Care Survey, chronic sinu-
sitis accounts for 12.3 million office visits to physicians, or 1.3% of total
office visits annually (14). Among Canadian adults, the reported prevalence
of chronic rhinosinusitis is 5% (15). Unfortunately, the term chronic sinusitis
is used to characterize a wide and possibly disparate group of inflammatory
disorders, and this makes any specific approach to therapy problematic.

The economic impact of rhinosinusitis is considerable. In 1996, the
direct cost due to sinusitis was $5.8 billion (16). A primary diagnosis of chro-
nic rhinosinusitis accounted for more than 50% of all expenses. To these
costs, indirect costs need to be considered as well, such as days for work lost.
Birnbaum et al. recently evaluated the economic burden of respiratory
infection, including sinusitis, in an employed population to ascertain the
impact of these infections from the perspective of the employer (17). The
investigators evaluated more than 63,000 patients with at least one diagnosis
for a respiratory infection in 1997 who were identified in the claims database

Sinusitis

■*-»

CD
CO

co
• »— i

■*-»

■ r—>

fl
o

•—
PQ

CO
CN

O
"xT

c--

t--

CN
CO

ON
CN

»-H

l-H

t--

^t-

i— i

-H

r--

CD
>

CD
bX)

CD
OO

co
G

J-

OX)

CD
co

•^H

cd
^>

•^H

13
co

• »H

o
Jh

HG
U

ts" *

co
Cd

O
-4-»

• »H

o
Jh

CD
•4-»

■ »H
-4-»

• »H

CO-

c--

o
o

ON
O

CO
CO

t--

r--

OO h ON CO CN 00

ri h in ^h r^ cn

h (N ^h CN -h ^H

oo in in r-
t-^ i> in ©

O no in oo
© »-h i> ^d

<sf CO 00 Tf Tf © ON

C7\ (N t-h © OS 00 ©

CN I t^ on »n
cn no vd oo

CS sJ

o in oo
vd m: od

r»-

OO
CN

OO
CO

CN
CN

^1-

r--

in
m

On
CN

-h CN

^Hoocoa>r~-^t vo i^ m
O oo co os co oo odod^

Os
CN

On
CN

Os
CN

in
in

CO
CN

OO
On

'sl-

in
in

OO
CN

CN Os l>

in »-h o

Os
O

^1-

•n

OO
O

CN
CN

r- cn cn oo r^ vo so r^ *-h tj -on so ^ on o

»-H ^H O ^H Tt in ^H O i-H o co' O CN CN i ^—3

-t— »

o
o

CD
■*-»

co G

c D

«D

CLh to

(D
CD

a; -

• »-H
•4-»

• »-H

•4-»

CD
^5
U

-G
o

-<— »

C/3

c^ G

CD
>
O

-a

CO CO CO rH
J-H ^H u g

cS S a3 «

CD CD CD M

*? *7 ^

CD
>

• l-H

■*->

< o

G G
cd cd

o
o

c^3

G
G

■£ «

I— «

CD
cG

• H

»H

CD
hG

Jh
O

G
cd

• >H

• H

cd
cd

CD
>

• H
-t— »

• H
H

Jh
O

o cd

•»H -4-»

G co

J-H -*-»

CO Jh

o
o

Jh
O
O
Ph

J " C^ pu

G
O

OX)

File

T3
ID

■4-»

cS
«D

OD
<

<H-H

a>
Cl-
od

o
£
<

CO
03
co
«j

CD
CO

S-H

-4-<

5-H

• >-H

O,
CO

13
c/3

S-(

CS
•(— »

^3
K

o
o

co
CD
■*-»
CS

-4— »

C/3

i=D

• »-H
-I— »

• >-H

S-H

<L3

mm S—

.2 6

• t-H

pd
U

03
CO

S-h

-4— »
c3

03
Jh

<U
-»— »

O
^L3

13
in

CO
• •— I

-4— '

d
o
u

in
• .-h

• «-H

»H

oj
>

co
<

03
co

O ^h r- on

to rn (N (N

do do

OO CN Tf oo

"st- io vd Tt

r- ^h On O

u^ I/-} Tj- in

dodo

vq cn t-^ i>

no no d cn

o Ti-
en en

° ° W w
OO iO iO CN

O OO On CN

CN OO i/-) Tt

<n rn rn i;

d d d d

I> OO NO NO

^h d d d

no no en cn

dodo
co r— no i— i

-4-»

S-H

-«-*

43
o

«D

-4— >

•—

• »-H

43 -rt

C« TO

«J J3

O &

g -

— — •

<u as

9*43

S d

^ a

>^ ^

0)
4=

'70

5 41

d
o

C/5

Q, M-H

H O

-*->

— >
O

C-)

— '

■4->

-4— t

— ->

•—

03
03

■4->

— •

-4-'
t4-

* —

• -H

CJ
Ih

d
o

CJ
•—

• »H

•^N

— >

!/0

cr
— >

■4->

S-H

IT,

o S

•a ^

^ 2

CJ
Ih
CJ

-^— *

4=
CJ

d .

O <N

4J
. Cm

Irt

C ?H

'd 4^

53 2

O fi

a °

in Oh

03 C3

■r,

d
d

<--

*—

cS ^O

Sinusitis 5

of a national Fortune 100 company. Outcome measures were compared to
those of a 10% random sample of beneficiaries in the overall employed popu-
lation. The authors calculated a total cost of care that included not only
direct health-care costs, but also disability costs and absenteeism costs. Acute
and chronic sinusitis represented the fifth and sixth most common respira-
tory tract infection with a total number of 9856 and 7368 patients, respec-
tively. This compared to 10,852 treated for acute bronchitis, 5296 treated
for chronic bronchitis, 4464 treated for pharyngitis, and 4036 treated for
pneumonia. The total aggregate employer cost for treating acute sinusi-
tis and chronic sinusitis was $35,126,784 and $32,824,440, respectively
(compared to $46,591,584 and $6,692,439 for pneumonia and pharyngitis)
(Table 2) (17).

In addition, sinusitis can adversely affect other aspects of quality of life.
Matsui et al. observed an decline of cognitive function in elderly people using
the Mini-Mental State Examination (18). Chronic sinusitis may affect cogni-
tive function either by decreasing the power of concentration or affecting
specific cognitive functions, which can significantly have an impact on qual-
ity of life considerations. Therefore, early medical intervention for chronic
sinusitis should take into account this potentially neglected effect on cogni-
tive function in the elderly.

EPIDEMIOLOGY AND RISK FACTORS

Individuals with allergies or asthma and those who smoke may be predisposed
to rhinosinusitis (15,19). For unclear reasons, rhinosinusitis affects more fe-
males than males (12,15,20). Women patients between the ages of 25 and
64 years were seen most often (12). When results were considered by single race
without regard to ethnicity, Asian adults were less likely to have been told in
the preceding 12 months that they had sinusitis compared with white, black,
and American Indian or native- Alaska adults (12). Adults in families that were
not poor were more likely to have been told that they had sinusitis than adults
in poor families. The percentage of adults with sinusitis was higher in the
southern area of the United States than any other region (12).

Sokol recently reported results from a large study of sinusitis evaluated
in the primary care setting, the Respiratory Surveillance Program (20). This
study was undertaken over a 10-month period during the 1999-2000 respira-
tory infection season. Patients were evaluated from 674 community-based
practices for data including patient demographics and associated risk factors
(Table 3). The diagnosis of rhinosinusitis was based solely on the clinical
judgment of the physician investigator. Over 16,000 patients were evaluated
and similar to data presented above, females predominated (almost a two
to one ratio of female to male). Underlying conditions identified in this study
included smoking, diabetes, and the presence of chronic lung disease (20).

File

-<— >

o
U

CD
>

'Eh

d
O

• >H

«h

o
«H

• iH

S-H

• I-H

c--

on
on

co
d

ctf

CD
>>

2 -
g o
6 °

O O

<D -i-»

■H co

a o

CD O

-*— '

;=) co

X> co

«J O

co O

CD
CD

co s-*

CD
»h

C
(D

• i-H
-I— '

g
O

• »H

Ca3

^t-

"xt-

[--

«N

r»

#-■

"^t

c--

t--

1-H

«N

^t-

•O

1-H

i-H

^f-

i-H

C--

1-H

r--

'sf

CN
CN

OO
ON
O

CO
CO

•—
O

-4-»

OO
OO
SO

1-H

cd
!h

• H

i-H '-'
in Sh
OO CD

OO
CN

co
CD

Vh CD

tr* co

B %

CD
■*-»

co O

CD
.CD

Cu cn

CO i-H

•4-»

c^3

^sO

"xl-

^1-

^sO

«n 'sl-

t--

m o

1 — 1

m -xt

OO CN

OO O

co >0 ^

s ^ J

d
o

-4-»

SO
in

OO
ON

in .ti

oo 2

2 §

1~H • —

OO
SO

1-H

ON SO

j-h

^t-

Tl- ^H

1-H

Tt i n

'si" O

1^ oo

^1-

so r-

i-H

ON O

OO O

OO CN

1-H

'si"

C--

d o

d °°

.d so

co en

• H

hG
O

-O)

CD hG

2 s

Sinusitis

oo
oo
oo

^O
CN

•o
r-

ON.
"xT

S-.

c/n

r.
• f-H

• i-H

-4— »
• >-H

-+-»

• r—>

S-H

H — '
• >-H

OX)

S-H

-d

-4— »
O

S-H

>
CD

S-H

c£

43 „

-t— ' oa

O o

c/a d

(D <U

g *

.22 -d

s ^

d G

43 O

O +3

i— <

«-

»— 1

^t-

l*o

1— 1

"xf

OO
CN

"*fr

l*o

c--

^t-

Os O

"vf CO

SO CN
O CN

CN «0
<=t OS
CN

^t OS
O Tj-

SO rf

co «*o
o »*o

CN C--

O OO
On I>

NO
"xt

<L>
•4-»

S o

-h rrt
OX) ro

G 73

i >» d
II Jh cd

"^ Oh 2
O O
2 <->

NO
CO

"xt"

• i-H

l/-> NO

CN ^t
«*o CO

CN CO

NO 'xf

cn r-

l> CO

CO »— i

O OO
OO OS

so i*o

oo t-»

CO "xt

o o

*— 1

^t-

1— 1

i-H

l-H

C/3

H— »

-4-»

cu <

CN T~*

• t-H ^— '

• »-h rrt

W) N

^h On

- 3 <»

TO ,1> CO

C/3

"h-h

• *-H I

O w

d U
a- & S

^ <D TO
C S-H c^

■4->

-a

o .

D-
cTO

C/3

S-H
■!->

CJ
CJ

X)
=5

O >>

qj rs

qj .ed

<H-H

S-H

c >

• — H
•-H

■4->

-i— '

c/n

Cfl

-i— '

«\

O
CJ

-*— »

• «-H

-(-» .TO

O '^

^ QJ

g> S3

.9 o

d qj

X
CJ

OX)

T3
0> on

S-H

«-

^CJ

.a 5

on on

o d

s-h d ^

BQJ
SjH

QJ Cd

on
d QJ

2h .3

ox) cj

OX) C

m-h"
CJ

. S
8 2

2 g

£ co

8 File

Table 3 Demographic Data for Sinusitis (From the Respiratory
Surveillance Program)

Demographic

Overall (n= 16,135)

Age (yr), mean (range)

44 (1-97)

Sex (460 none specified) % female/% male

62/35

Ethnicity (% total)

White

13,603 (86%)

African American

1018 (6.3%)

Hispanic

557 (3.5%)

Asian

227 (1.4%)

Other

76 (0.5%)

Unknown

654(4.1%)

Smoker (%)

3813 (24%)

Diabetes (%)

674 (4.2%)

COPD (%)

688 (4.3%)

460 no sex specified.

Abbreviation: COPD, chronic obstructive pulmonary disease.

Source: From Ref. 20.

Predisposing Conditions of Rhinosinusitis

In addition to smoking, there are many other conditions associated with
rhinosinusitis. These include allergic rhinitis, asthma, nasal polyps, aspirin
hypersensitivity, cystic fibrosis, and immune deficiency [particularly immu-
nodeficiency virus (HIV) infection] (Tables 4 and 5).

The occurrence of secondary bacterial sinusitis is highly associated
with prior viral respiratory illnesses (10,11). An important area of disease
leading to secondary bacterial sinusitis is obstruction at the ostiomeatal
complex. A variety of factors may lead to obstruction of the ostium. The
most common predisposing factor is viral infection, which causes edema
and inflammation of the nasal mucosa. In addition to viral rhinosinusitis-
related cases, acute bacterial sinusitis occurs related to allergy and nasal
obstruction due to polyps, foreign bodies, and tumors. Less common risk
factors associated with a predisposition for bacterial sinusitis are immune
deficiencies such as agammaglobulinemia and human HIV infection;
abnormalities of polymorphonuclear cell function; structural defects, such
as cleft palate; and disorders of mucociliary clearance, including cilial dys-
function and cystic fibrosis (21).

Rhinosinusitis and the Common Cold

The relationship between rhinosinusitis and the common cold has been well
established. In a sentinel prospective study of 1 10 adults, Gwaltney et al. eval-
uated the findings on CT examination of patients with rhinosinusitis (10).

Sinusitis

Table 4 Extrinsic and Intrinsic Potential Causes of Chronic Rhinosinusitis

Extrinsic causes of CRS can broadly be broken down into:

1. Infectious (viral, bacterial, fungal, parasitic)

2. Noninfectious/inflammation

a. Allergic-IgE-mediated

b. Non-IgE-mediated hypersensitivities

c. Pharmacologic

d. Irritants

3. Disruption of normal ventilation or mucociliary drainage

a. Surgery

b. Infection

c. Trauma

Intrinsic causes contributing to CRS:

1. Genetic

a. Mucociliary abnormality
i. Cystic fibrosis

ii. Primary ciliary dysmotility

b. Structural

c. Immunodeficiency

2. Acquired

a. Aspirin-hypersensitivity associated with asthma and nasal polyps

b. Autonomic dysregulation

c. Hormonal

i. Rhinitis of pregnancy
ii. Hypothyroidism

d. Structural

i. Neoplasms

ii. Osteoneogenesis and outflow obstruction
hi. Retention cysts and antral choanal polyps

e. Autoimmune or idiopathic
i. Granulomatous disorders

1. Sarcoid

2. Wegener's granulomatosis
ii. Vasculitis

1. Systemic lupus erythematosus

2. Churg-Straus syndrome
iii. Pemphigoid

f. Immunodeficiency

Source: From Ref. 13.

Among 31 patients who had CT scans performed within 24 to 48 hours of
assessment, 24 (77%) had occlusion of the ethmoid sinus, 27 (87%), had
abnormalities of one or both maxillary sinuses, 20 (65%) had abnormalities
of the ethmoid sinuses, 10 (32%) had abnormalities of the frontal sinuses,
and 12 (39%) had abnormalities of the sphenoid sinuses. Rhinovirus was

File

Table 5 Factors Associated with Chronic Rhinosinusitis

Systemic host factors

Local host

Environmental

Allergic
Immunodeficiency

Genetic/congenital

Mucociliary dysfunction

Endocrine

Neuromechanism

Anatomic
Neoplastic viral,

bacterial, fungal
Acquired-mucociliary

dysfunction
Medications
Trauma
Surgery

Microorganisms

Noxious chemicals,
pollutant, smoke

Source: From Ref. 13.

detected in the secretions of 7 of 17 (41%) of these patients. The patients
received no medical treatment for their infections; 14 patients with sinus
abnormality as seen on the initial CT scan had repeat scans, and one of these
reported resolution of symptoms. Of significance, 1 1 of these 14 (79%) showed
clearing or marked improvement in sinus abnormalities. It is evident from
this study that the common cold is associated with frequent involvement of
the paranasal sinuses.

Rhinosinusitis and Allergy

Several studies suggest an association between rhinosinusitis and allergic
sinusitis (22,23). Allergic rhinitis predisposes the patient to sinusitis since
it can be associated with inflammation and obstruction of the ostia. Thus,
allergic rhinitis and acute bacterial sinusitis can overlap.

Rhinosinusitis and Asthma

Sinusitis is often seen in patients with asthma and often exacerbates the
severity of the episode (24). Although the pathophysiology of the associa-
tion between asthma and sinusitis is not very clear, it may be related to
damage induced by the eosinophil, a prominent component of the inflam-
matory process that is characteristic of both diseases. A reflex phenomenon
linking inflammation in the sinuses to subsequent inflammation in the lower
airways has been proposed.

PATHOGENS OF BACTERIAL SINUSITIS

Epidemiology of Streptococcus pneumoniae and
Haemophilus influenzae

When sinus puncture aspirates are used to obtain secretions for culture from
patients with acute sinusitis, results consistently show that Streptococcus
pneumoniae and Haemophilus influenzae are the most important bacterial

Sinusitis 1 1

pathogens. Other organisms occasionally found include Moraxella catarrhalis,
other streptococcal species (e.g., Streptococcus pyogenes), Staphylococcus
aureus, and anaerobes (e.g., Prevotella spp., Pep to streptococcus spp., Fuso-
bacterium spp.).

Of all the above pathogens, S. pneumoniae is considered the most sig-
nificant from the standpoint of virulence and clinical impact. S. pneumoniae
can be transmitted directly or through fomites; transmission is facilitated by
crowding, such as in daycare centers or extended care facilities. Children
are often heavily colonized with S. pneumoniae, and adults not exposed to
children generally have a lower prevalence of S. pneumoniae infection. Risk
factors for S. pneumoniae infection in adults include active or passive smoke
exposure and presence of chronic diseases. S. pneumoniae infections occur
most commonly during the winter months, in part due to the secondary
relationship to viral infections.

H. influenzae is indigenous to humans and readily colonize the naso-
pharynx. Spread from one individual to another occurs by airborne droplets
or by direct contact with secretions. The majority of sinus infections are due
to nonencapsulated strains.

SINUSITIS AND HIV

In the pre-highly active anti-retroviral therapy (HAART) era, up to 70% of
patients with HIV experienced at least one bout of acute sinusitis during the
course of their disease, and 58% experienced recurrent infections (25). As
patients are now living longer with the availability of HAART, the preva-
lence of acute and chronic sinusitis in HIV-infected patents has increased.
In a study of 7513 HIV-infected patients enrolled from November 1990 to
November 1999, the incidence of one or more diagnoses of sinusitis was
14.5% (26). The mean CD4 count at the time of sinusitis was 391. Although
the authors felt the incidence of sinusitis in individuals infected with HIV is
frequent, there was no association between sinusitics and an increased
hazard of death after adjusting results for the level of immunodeficiency
age, gender, and race.

The organisms associated with acute sinusitis in HIV patients are simi-
lar to the pathogens in other patients, with S. pneumoniae and H. influenzae
being predominant. However, there is a higher occurrence of S. aureus and
Pseudomonas aeruginosa in the HIV-infected patient than in the non-
infected patient (Table 6) (27). The common occurrence of P. aeruginosa
in HIV-infected patients probably reflects an impaired mucociliary transport
often associated with HIV infection. In addition, more unusual organisms
are also commonly found, particularly if immunodeficiency progresses. As
the CD4 counts of patients dip below 200, these patients become susceptible
to more opportunistic infections. Opportunistic and atypical infections
include cytomegalovirus, Aspergillus spp., and Mycobacterium spp. (27).

12 File

Table 6 Sinus Pathogens in HIV

Streptococcus pneumoniae 19%

Streptococcus viridans 19°/

Pseudomonas aeruginosa 17°

Haemophilus influenzae 13°

Coagulase-negative Staphylococci 13%

Staphylococcus aureus 9°/

Candida albicans 4%

Klebsiella pneumoniae 2°

Listeria monocytogenes 2°,

Torulopsis glabrata 2°

In antral washings from 41 HIV patients with acute sinusi-
tis, four had multiple pathogens.
Source: From Ref. 27.

NOSOCOMIAL SINUSITIS

Sinusitis is a relatively common infection in patients treated in an intensive
care unit (ICU). An epidemiologic study in an ICU orally-intubated popula-
tion found the incidence of sinusitis, as diagnosed by cultures of maxillary
sinus secretion, was 10% (28). In another study of 300 patients, the incidence
of infectious sinusitis was estimated at 20% after eight days of mechanical
ventilation in patients that were orotracheally or nasotracheal^ intubated
(29). However, in a study designed to search for nosocomial sinusitis in
patients who were intubated in an ICU, Holzapfel et al. found 80 patients
among 199 study patients to have infectious nosocomial maxillary sinusitis
(30). In this study, all patients who were nasotracheally intubated were eval-
uated by a sinus CT scan if body temperature was > 38°C. When CT scan
showed an air-fluid level and/or an opacification within a maxillary sinus,
a transnasal puncture was performed. Critieria for nosocomial sinusitis were
sinus CT scan findings consistent with sinusitis, mechanical ventilation,
macroscopic purulent sinus aspiration, and quantitative culture of the aspi-
rated material with > 10 cfu/mL. Among the 80 patients, infection was due
to polymicrobial flora in 44 patients and 138 organisms were isolated. The
most common organisms were Eshcerichia coli (12), P. aeruginosa (12),
Proteus spp. (10), Hemophilus spp. (7), Klebsiella spp. (6), Enter obacter spp. (6),
S. aureus (10), Streptococcus spp. (30), anaerobes (15), and Candida albicans (10).
Multiple factors can promote nosocomial sinusitis in critically ill
patients. Placement of endotracheal or gastric tubes through the nose can
irritate the nasopharyngeal mucosa, causing edema in the region of the
ostial meatal complex. Nasal tubes can also directly obstruct sinus drainage
by acting as foreign bodies. Placing tubes via the mouth does not entirely
eliminate the risk of nosocomial sinusitis, but studies suggest the risk is

Sinusitis 13

lessened. In one study, the incidence of sinusitis was higher in patients
intubated nasotracheal^ as compared to those by the oropharyngeal route
(31). Additional factors which may play a role in ICU patients include the
supine position and limitation of head movements (which may prevent nat-
ural sinus drainage normally caused by gravity), positive-pressure ventila-
tion, impaired ability to cough or sneeze, and the absence of airflow
through the nares in ventilated patients.

REFERENCES

1. File TM Jr. The epidemiology of respiratory tract infections. Semin Respir
Infect 2000; 15(3): 184-1 94.

2. File TM Jr, Hadley JA. Rational use of antibiotics to treat respiratory tract
infections. Am J Manag Care 2002; 8:713-727.

3. Armstrong GL, Pinner RW. Outpatient visits for infectious diseases in the
United States, 1980 through 1996. Arch Intern Med 1999; 159:2531-2536.

4. McCaig LF, Hughs JM. Trends in antimicrobial drug prescribing among office-
based physicians in the United States. JAMA 1995; 273:214-219.

5. Scott Levin Prescription Audit from Verispan, L.L.C., January-December,
2002.

6. Lanza DC, Kennedy DW. Adult rhinusitis defined. Otolaryngol Head Neck
Surg 1997; 117(3 Pt 2):S1-S7.

7. Anon JB, Jacobs MR, Poole MD, Ambrose PG, Benninger MS, Hadley JA,
Craig WA, and The Sinus and Allergy Health Partnership. Antimicrobial treat-
ment guidelines for acute bacterial rhinosinusitis 2004. Otolaryngol Head Neck
Surg 2004; 130(suppl 1):1^5.

8. Brook I, Gooch WM III, Jenkins SG, Pichichero ME, et al. Medical manage-
ment of acute bacterial sinusitis. Recommendations of a Clinical Advisory
Committee on Pediatric and Adult Sinusitis. St Louis: Annals Publishing, 2000.

9. Dingle JH, Badger GF, Jordan WS Jr. Illness in the home: a study of 25,000
illnesses in a group of Cleveland families. Cleveland: The Press of Western
Reserve University, 1964.

10. Gwaltney JM Jr, Phillips CD, Miller RD, et al. Computed tomographic study
of the common cold. N Engl J Med 1994; 330:25-30.

1 1 . Gwaltney JM Jr, Wiesinger BA, Patrie JT. Acute community-acquired bacterial
sinusitis: the value of antimicrobial treatment and the natural history. Clin
Infect Dis 2004; 38:227-233.

12. Lucas JW, Schiller JS, Benson V. Summary health statistics for U.S. adults:
National Health Interview Survey, 2001. National Center for Health Statistics.
Vital Health Stat 2001; 10:218.

13. Benninger MS, et al. Adult chronic rhinosinusitis: definitions, diagnosis, epide-
miology, and pathophysiology. Otolaryngol Head Neck Surg 2003; 129S(suppl 3):
S1-S32.

14. Cherry DK, Burt CW, Woodwell DA. National Ambulatory Medical Care Sur-
vey: 2001 Summary. Advance Data form Vital and Health Statistics; no. 337.
Hyattsville, MD: National Center for Health Statistics, 2003.

14 File

15. Chen Y, Dales R, Lin M. The epidemiology of chronic rhinosinusitis in
Canadians. Laryngoscope 2003; 113:1199-1205.

16. Durr DG, Desrosiers MY, Dassa C. Impact of rhinosinusitis in health care
delivery: the Quebec experience. J Otolaryngol 2001; 30:93.

17. Birnbaum HG, Morley M, Greenberg MS, Colice GL. Economic burden of
respiratory infections in an employed population. Chest 2002; 122:603-611.

18. Matusi T, Arai H, Nakajo M, Mauyama M, Ebihara S, et al. Role of chronic
sinusitis in cognitive functioning in the elderly. J Am Geriatr Soc 2003; 51:
1818-1819.

19. Lieu JE, Feinstein AR. Confirmations and surprises in the association of
tobacco use with sinusitis. Arch Otolarynygol Head Neck Surg 2000; 126:
940-946.

20. Sokol W. Epidemiology of sinusitis in the primary care setting: results from
the 1999-2000 respiratory surveillance program. Am J Med 2001; 111(9A):
19S-24S.

21 . Casiano RR. Sinusitis: a complex and challenging disease. Mediguide Infect Dis
2001; 21(l):l-5.

22. Alho OP, Karttunen TJ, Karttunen R, Tuokko H, Koskela M, Suramo I,
Ukhari M. Subjects with allergic rhinitis show signs of more severely impaired
paranasal sinuus function during viral colds than non allergic subjects. Allergy
2003; 58:767-771.

23. Mucha SM, Baroody FM. Relationships between atopy and bacterial infec-
tions. Curr Allergy Asthma Rep 2003; 3:232-237.

24. Osur SL. Viral respiratory infections in association with asthma and sinusitis: a
review. Ann Allergy Asthma Immunol 2002; 89:553-560.

25. Godofsky EW, Zinreich J, Armstrong M, et al. Sinusitis in HIV-infected
patients: a clinical and radiographic review. Am J Med 1992; 93:163-170.

26. Belafsky PC, Amedee R, Moore B, Kissinger PJ. The association between sinu-
sitis and survival among individuals infected with the human immunodeficiency
virus. Am J Rhinol 2001 Sept-Oct; 15(5):343-345.

27. Milgrim LM, Rubin JS, Rosenstreich DL, et al. Sinusitis in human immunode-
ficiency virus infection: typical and atypical organisms. J Otolaryngol 1994;
23:450-453.

28. George DL, Falk PS, Nunally K. Nosocomial sinusitis in medical intensive
care unit patients: a prospective epidemiologic study. Infect Control Hosp
Epidemiol 1992; 21:497.

29. Holzapfel L, Chevret S, Madinier G, Onen F, Demingeon G, Coupry A,
Chaudet M. Incidence of long term oro- or nastotracheal intubation on Nosoco-
mial maxillary sinusitis and pneumonia: results of a randomized clinical trial. Crit
Care Med 1993; 21:1132-1138.

30. Holzapfel L, Chastang C, Deningeon G, Bohe J, Piralla N, Coupry A. Rando-
mized study assessing the systematic search for maxillary sinusitis in Nasotra-
cheally Mechanically Ventilated Patients. Am J Respir Crit Care Med 1999;
159:695-701.

31. Rouby JJ, Laurent P, Gosnach M, et al. Risk factors and clinical relevance of
nosocomial maxillary sinusitis in the critically ill. Am J Respir Crit Care Med
1996; 150:776-783.

Classification of Rhinosinusitis

Peter A. R. Clement

Department of Otorhinolaryngology and ENT Department, University Hospital,

Free University Brussels (VUB), Brussels, Belgium

INTRODUCTION

In 1972, Douek wrote that "classification has an important place in
medicine, as it forms the framework upon which diagnosis is made possible,
etiology recalled and separated, and treatment decided. It remains, however,
an intellectual system imposed onto a nature that has rarely rigid bound-
aries" (1). Now, more than 30 years later, this statement is still valid.

This chapter reviews the different classifications of rhinosinusitis, and
attempts to explain why in the course of time these classifications were chan-
ged. By acquiring new information about the natural history of rhinosinu-
sitis based on novel imaging techniques such as MRI, CT scanning, and
nasal endoscopy, new insights on the pathophysiology of the disease were
gained. Because of better culture techniques; and recent advances in histo-
cytochemistry of inflammation; it became obvious that the classification
of this disease needed to be adapted and redefined step-by-step.

Rhinosinusitis Versus Sinusitis

There exists a general agreement that rhinosinusitis can be defined as any
inflammation of the paranasal sinus mucosa (2). Johnson and Ferguson
stated that because the lining of the mucosa and the paranasal sinuses is
continuous, an inflammation of the nasal cavity is usually associated with
inflammation of the sinus lining (3). The faculty of the staging and therapy

16 Clement

group shared the same opinion and stated that the term rhinosinusitis is
perhaps more precise than the term sinusitis. The reasons are that sinusitis
does not typically develop without prior rhinitis, isolated sinus disease with-
out rhinitis is rare, the mucous membrane lining of the nose and the para-
nasal sinus is continuous, and two of the prominent features of sinusitis —
nasal obstruction and drainage — are associated with rhinitis symptoms
(4). The Task Force on Rhinosinusitis (TFR) preferred the term rhinosinu-
sitis as well (5). On occurrences in children, the members of the Consensus
Panel on Pediatric Rhinosinusitis preferred to speak of rhinosinusitis since
rhinitis and sinusitis are often a continuum of the disease (6).

Radiological Changes as Signs of Sinusitis

Havas et al. (7) found abnormal appearances of the paranasal sinuses on CT
scan in 42.5% of asymptomatic adults and Bolger et al. (8) found a similar
proportion of 41.7% in patients scanned for nonsinus reasons. As a possible
explanation, Bolger et al (8). suggested that these abnormalities could be
induced by normal variations of the sinus mucosa, asymptomatic chronic sinus
disease, and mild to moderately symptomatic undiagnosed chronic sinusitis. In
a CT scan study of children undergoing nonsinusitis evaluation, Diament et al.
(9) detected maxillary and ethmoidal thickening in ~50% of the patients. Simi-
lar figures were found by Gordts et al. (10,11) who demonstrated in an MRI
study of a non-ENT population of adults (without any complaints and a blank
surgical history) that there existed on 40% abnormalities of the mucosa, and in
45% of the cases in a non-ENT population of children.

All these imaging studies show us that imaging signs of sinusitis, in
particular pathological mucosal swelling, can occur in completely asympto-
matic adults and children. The meaning of these findings is unclear, and
therefore, many clinicians claim that one has to treat patients and not CT
or MRI scans. The problem, however, remains that subclinical, silent, or
asymptomatic sinusitis exists. Whether it needs to be diagnosed or treated
in order to prevent manifest sinusitis is another question that has not been
investigated yet.

The aim of this chapter is to discuss the classification of symptomatic
rhinosinusitis. Rhinosinusitis can be defined as any inflammation of the
nasal and paranasal sinus mucosa, resulting in signs and symptoms.

Parameters Used for Classification

According to Pinheiro et al. (12), classification of rhinosinusitis should be
done along five axes:

i. Clinical presentation (duration: acute, subacute, and chronic)
ii. Anatomical site of involvement (ethmoid, maxillary, frontal, and

sphenoid)
hi. Responsible microorganism (viral, bacterial, and fungal)

Classification of Rhinosinusitis 17

iv. Presence of extra sinus involvement (complicated and uncompli-
cated)

v. Modifying or aggravating factors (e.g., atopy, immunosuppres-
sion, ostiomeatal obstruction, etc.)

According to these authors, a complete classification of sinusitis
according to these five axes is essential to tailor the treatment for the parti-
cular situation. As an example of this axes system, a possibility would be
chronic (i), frontal (ii), bacterial (iii) sinusitis complicated by frontal bone
osteomyelitis (iv) and aggravated by immunosuppression due to diabetes
mellitus (v).

CLASSIFICATIONS OF SINUSITIS

Most classification systems of rhinosinusitis, however, are based on the
duration of symptoms and/or the specific sinus involved (13). In 1984, Kern
stated that a classification of sinusitis based on pathology is useful in patient
management (14). In addition to naming the involved sinuses, the classifica-
tion should contain some concepts as to the duration of the sinus infection.
Kern defined acute suppurative sinusitis, on an arbitrary basis, as any infec-
tious process in a paranasal sinus lasting from one day to three weeks, and
subacute sinusitis as a sinus infection that lingers from three weeks to three
months, during which period epithelial damage in the sinuses may still be
reversible (14). Irreversible changes usually occur after three months of sub-
acute sinusitis, leading into the next phase of chronic sinusitis that is any
infection lasting longer than three months and requiring surgery for sinus
ventilation and drainage. From this definition, it is obvious that at that time
sinusitis was considered to be a mainly infectious process, and that after
three months the mucosal changes were considered to be irreversible. This
concept that after three months irreversible mucosal changes had occurred
corresponds with the philosophy of the Caldwell-Luc operation that insis-
ted on meticulously removing the mucus lining of the maxillary sinus in toto
(15). On the contrary Wigand showed that restoration of ventilation and
drainage after removal of cysts and polyps initiates the recovery of diseased
mucosa (16,17). At this time, a very new and important concept was intro-
duced to preserve as much mucosa as possible because most of the mucosal
disease seemed to be reversible after adequate drainage and ventilation.

In the eighties, the basic pathological concept of sinusitis consisted of
bacterial infection due to sinus ostium obstruction, followed by hypoxia and
a series of events leading to the production of thick retained secretions creat-
ing a perfect situation for bacterial multiplication (14), i.e., the sinusitis cycle
(18). It was demonstrated, however, from standard x-ray examination of the
paranasal sinuses in 144 consecutive adult patients with perennial rhinitis,
that 20% showed major changes (total opacity of the maxillary sinus) and

Clement

another 20% showed minor changes (19). Based on a CT scan study in ato-
pic patients, Iwens et al. concluded that signs of sinusitis exist in about 60%
of the children and adults (20). Young children (three-nine years of age)
showed more severe sinusitis (50% to total opacity of the involved sinuses)
on the CT scans in 30% to 40% of the cases, while older children and adults
more often had signs of mild sinusitis (mucosal swelling of more than 4 mm
and an opacity of less than 50%).

In 1992 Shapiro et al. concluded that there existed a general agreement
that sinusitis can be defined as an inflammation (not infection) of the para-
nasal mucosa (2). The authors proposed the following definition of sinusitis
(Table 1) (2):

• Acute sinusitis can be defined by certain major and minor criteria
that exist for longer than the typical viral upper respiratory tract
infection (URTI), more than seven days. The presence of two or
more minor criteria for more than seven days is highly likely to sig-
nify acute sinus disease, which is usually bacterial. If the signs and
symptoms fulfill these criteria, the presence of one positive major
diagnostic test result is confirmatory, whereas the minor tests
may be considered supportive. Another symptom, acute onset of
fever with purulent rhinorrhea, is also considered highly likely to
indicate acute bacterial sinusitis.

Table 1 Clinical Diagnosis of Sinusitis

Signs and symptoms

Diagnostic tests

Major criteria

Purulent nasal discharge
opacification

Purulent pharyngeal drainage t
mucosa

Purulent postnasal drip

Cough
Minor criteria

Periorbital oedema

Headache

Facial pain

Tooth pain

Earache

Sore throat

Foul breath

Increased wheeze

Fever

Major criteria

Water's radiograph or fluid level:

thickening filling >50% of antrum
Coronal CT scan: thickening of or

opacification of sinus mucosa

Minor criteria

Nasal cytology study (smear) with

neutrophils and bacterimiae
Ultrasound studies

Probable sinusitis

Signs and symptoms: 2 major, 1

minor and >2 minor criteria
Diagnostic tests: 1 major =
confirmatory, 1 minor = supportive

Source: Adapted from Ref. 2.

Classification of Rhinosinusitis 19

• Chronic sinusitis was referred as a disease that lasted more than
three months that is manifested by the presence of long-term symp-
toms without an ongoing need for antibiotic therapy. Thus,
chronic sinusitis might occur on a non-infectious basis.

• Subacute sinusitis was used for the gray zone between disease last-
ing less than a month (acute) and lasting more than three months
(chronic).

Since these guidelines were published, it became more appropriate to
refer to inflammation rather than infection when the term sinusitisis was
used. Inflammation covers infectious as well as noninfectious mechanisms.

Using CT scans, Gwaltney et al. showed that during a common cold of
two- to four-day duration, more than 80% of the cases showed abnormal-
ities of the sinuses mucosa (21). These abnormalities of the infindibula
and sinuses cleared or markedly improved within two weeks.

In a prospective study using MRI, Leopold et al. studied the evolution
of acute maxillary sinusitis (manifested by facial pain, fever, and purulent
rhinorrhea) in 13 previously healthy subjects (22). The MRI analysis of
the volume percentage of air in the involved sinuses showed that only half
of the opacification had resolved by 10 days and the sinuses were only about
80% aerated by 56 days. This study showed that although antibiotic treat-
ment of acute maxillary sinusitis generally results in clinical resolution of
symptoms within one week, mucosal changes, however, could persist for
eight weeks or more.

All these new insights showed that the classification of rhinosinusi
tis had to be redefined and these led in 1993 to an international con-
ference on sinus disease, chaired by Kennedy (23) in Princeton, New
Jersey. The following definitions were proposed in the Princeton meeting
classification.

1. Acute sinusitis is defined as a symptomatic sinus infection in
which symptoms persist no longer than six to eight weeks or
there are fewer than four episodes per year of acute symptoms
of 10 days duration. Sinusitis is acute when episodes of infection
resolve with medical therapy leaving no significant mucosal
damage.

2. Chronic sinusitis is a persistent sinusitis that cannot be alleviated
by medical therapy alone, and involves radiographic evidence of
mucosal hyperplasia. In adults, it is defined as eight weeks of
persistent symptoms or signs, or four or more episodes per year
of recurrent acute sinusitis, each lasting at least 10 days, in associa-
tion with persistent changes on CT scan four weeks after medical
therapy without intervening acute infection (URTI).

20 Clement

3. Recurrent acute sinusitis is defined as repeated acute episodes that
resolve with medical therapy, leaving no significant mucosal
damage.

The faculty of the staging and therapy group published the symptoms
and signs needed for establishing the diagnosis of chronic sinusitis and
divided them in major and minor ones (Table 2) (4).

In 1997, the International Rhinosinusitis Advisory Board (IRAB)
published the clinical classification of rhinosinusitis in adults (24). They
defined acute rhinosinusitis as a sinusitis with an acute onset of symptoms
and a duration of symptoms less than 12 weeks and symptoms that resolve
completely. Recurrent acute rhinosinusitis was defined as being more than
one and less than four episodes of acute rhinosinusitis per year, a complete
recovery between the attacks, and a symptom-free period of more than or equal
to eight weeks between the acute attacks in absence of medical treatment.

The diagnosis of acute community-acquired bacterial rhinosinusitis
(ACABRS) is judged probable if two major criteria (symptoms), or one
major and two or more minor criteria, are present. The authors, however,
recognize that none of these criteria are sensitive and specific for the diagno-
sis of ACABRS, so that an additional standard was necessary to prove the
diagnostic accuracy.

Sinus puncture studies had shown that the symptoms that persist
longer than 10 days without improvement are suggestive of bacterial rather
than viral rhinosinusitis (25). Hence, if a patient with a cold or influenza
illness does not improve or is worse after 10 days, the authors recommended
treatment with antibiotics. Some symptoms such as fever, facial erythema,
and maxillary toothache have high specificity but low sensitivity, and when
present, the diagnosis of ACABRS is warranted.

They recognized that ACABRS needs to be differentiated from acute
nosocomial or hospital-acquired bacterial rhinosinusitis (AHABRS). Noso-
comial sinusitis is most often polymicrobial and is usually caused by those
organisms that are most prevalent in that particular institution (12). AHABRS
is often seen in critically ill or immunosuppressed patients.

Table 2 Chronic Sinusitis

Major Minor

Nasal congestion or obstruction Fever

Nasal discharge Halitosis

Headache

Facial pain or pressure

Olfactory disturbance

Source: Adapted from Ref. 4.

Classification of Rhinosinusitis 21

Chronic rhinosinusitis was defined as a sinusitis with a duration of
symptoms more than 12 weeks, which shows persistent inflammatory
changes on imaging and lasts for more than or equal to four weeks after
starting appropriate medical therapy (with no intervening acute episodes).
The authors also defined the acute exacerbation of chronic rhinosinusitis
as a worsening of existing symptoms or appearance of new symptoms and
a complete resolution of acute (but not chronic) symptoms between episodes.
The authors presented their definitions and classification of infectious
rhinosinusitis with a summary of current views on etiology and management.
They admitted that the definitions based on the severity and duration of
symptoms were imperfect, the duration of the acute episodes chosen in the
various definitions was arbitrary, and the clinical significance of abnormal
findings on imaging investigation was debatable. For the duration in the
definition of chronic sinusitis, they followed the FDA recommendation to
consider the condition if symptoms persist for more than 12 weeks (24).

From a clinical perception, the authors admitted that the definition of
chronic rhinosinusitis (CRS) is often subjective and is based on symptoms
that are vague, nonlocalized, and nonspecific. The relationship between
the findings on endoscopic examination, the radiographic appearance and
specific symptoms, and the severity is poorly defined.

The authors also realize that there appears to be an ill-defined group
between the acute and the chronic conditions, and they suggest that this pro-
blem can be overcome by the use of the term "subacute" which spans the
interval, but in other respects defies the definition, and it does not represent
a histopathologic entity.

The IRAB also proposed another classification based on microbiological
etiology, i.e., probable viral rhinosinusitis (nasal congestion, obstruction, nasal
discharge, facial pressures/pain without fever, toothache, facial tenderness,
erythema, and swelling), acute bacterial rhinosinusitis (same symptoms as viral
rhinosinusitis) but with fever-fever is an exclusion criteria for viral rhinosinusitis
or persisting without improvement for more than eight days), recurrent acute
rhinosinusitis (incidence of more than four episodes a year), chronic sinusitis
(with symptoms lasting longer than 12 weeks), and acute exacerbation of
chronic rhinosinusitis (acute worsening of chronic sinusitis symptoms) (24).
Although the IRAB recognizes the occurrence of sinusitis in allergic patients,
it still considers every sinusitis to be of infectious origin. Their definition requires
the inclusion of the parameter of duration in the classification based on the
microbiological etiology. What was not taken into consideration by IRAB is
the report by Gwaltney et al. that in maxillary sinus aspirates of patients with
acute community acquired sinusitis (AC AS: the most typical example of bacte-
rial sinusitis), viruses and fungi are found in addition to bacteria (Table 3) (26).

The same working definitions that took into account the duration of
the diseases were developed by TFR, sponsored by the American Academy
of Otolaryngology/Head and Neck Surgery (AAO-HNS) (5). This report

22 Clement

Table 3 Clinical Criteria for the Diagnosis of Acute Com-
munity-Acquired Bacterial Rhinosinusitis (ACABRS)
IRAB Guidelines

Major Minor

Purulent anterior and Cough

posterior discharge

Nasal congestion Headache

Facial pressure or pain Halitosis

Fever Earache

Diagnosis of ACABRS: two major criteria, or one major criterion
and two or more minor criteria. Source: Adapted from Ref. 24.

details the major and minor symptoms (Table 4) and defines sinusitis as the
condition manifested by an inflammatory response of the nasal cavity and
sinuses, and not an infection of these structures. It prefers the term rhino-
sinusitis to sinusitis as the mucous blanket of the sinuses is in continuity with
that of the nasal cavity. They recognized that the multifactorial nature and
multiple causes of rhinosinusitis make it difficult to define its cause in a
given patient. They therefore concluded that it is currently impractical to
define rhinosinusitis on the basis of its cause. An important differentiation
between acute and chronic was made on the basis of histopathology, where

Table 4 Factors Associated with the Diagnosis of Chronic Sinusitis
Major factors Minor factors

Facial pain, pressure (alone does not Headache

constitute a suggestive history for Fever (all nonacute)

rhinosinusitis in absence of another Halitosis

major symptom)
Facial congestion, fullness Fatigue

Nasal obstruction/blockage Dental pain

Nasal discharge/purulence/discolored Cough

nasal drainage Ear pain/pressure/

Hyposmia/anosmia fullness

Purulence in nasal cavity on examination
Fever (acute rhinosinusitis only) in acute sinusitis

alone does not constitute a strongly supportive

history for acute in the absence of another major

nasal symptom or sign

Source: Adapted from Ref. 5.

Classification of Rhinosinusitis 23

acute rhinosinusitis is predominantly viewed as an exudative process
associated with necrosis, hemorrhage, and/or ulceration, in which neutrophils
predominate, whereas CRS is predominantly a proliferative process asso-
ciated with fibrosis of the lamina propria, in which lymphocytes, plasma cells,
and eosinophils predominate along with perhaps changes in bone.

Another important statement by the TRF is that a pathological review
may also reveal a variety of findings that include, but are limited to, varying
degrees of eosinophils in tissues and secretions, as well as the polyp forma-
tion and the presence of granulomas, bacteria, or fungi. This statement is
important as it highlights the importance of inflammation (eosinophilic infil-
tration) rather than the infection, the presence of fungi, or the formation of
nasal polyps in CRS.

The TFR also recognizes the concept of subacute rhinosinusitis for sev-
eral reasons (5):

1. When polled, the physicians serving on the TFR indicated that
they would treat rhinosinusitis lasting less than two to three weeks
differently than they would treat a rhinosinusitis lasting 6 to 12
weeks.

2. Similar issues concerning otitis media had been heatedly debated
until the otitis media literature arbitrarily defined acute otitis
media as those lasting three weeks, subacute as lasting 3 to 12
weeks, and chronic otitis media as those lasting more than 12
weeks (27).

3. The FDA had no formal definition to describe the condition that
lasts 4 to 12 weeks (less than four weeks is acute, more than four
weeks is chronic).

The TFR defines five different classifications of adult rhinosinusitis (5):

1 . Acute rhinosinusitis is a sinusitis with a sudden onset and lasting up
to four weeks. The symptoms resolve completely, and once the dis-
ease has been treated, antibiotics are no longer required. A strong
history consistent with acute rhinosinusitis includes two or more
major factors (Table 4) or one major and two minor factors. How-
ever, the finding of nasal purulence is a strong indicator of an
accurate diagnosis. A suggestive history for which acute rhinosinu-
sitis should be included in the differential diagnosis includes one
major factor, or two or more minor factors. In absence of other
nasal factors, fever or pain alone does not constitute a strong his-
tory. Severe, prolonged, or worsening infections may be associated
with a nonviral element. Factors suggesting acute bacterial sinusitis
are the worsening of the symptoms after five days, the persistence
of symptoms for more than 10 days, or the presence of symptoms
out of proportion to those typically associated with viral URTI.

24 Clement

2. Subacute rhino sinusitis represents a continuum of the natural
progression of acute rhinosinusitis that has not resolved. This con-
dition is diagnosed after a four-week duration of acute rhinosinu-
sitis, and it lasts up to 12 weeks. Patients with subacute rhinosinusitis
may or may not have been treated for the acute phase, and the symp-
toms are less severe than those found in acute rhinosinusitis. Thus,
unlike in acute rhinosinusitis, fever would not be considered as a major
factor. The clinical factors required for the diagnosis of subacute adult
rhinosinusitis are the same as for those CRS. Subacute rhinosinusitis
usually resolves completely after an effective medical regimen.

3. Recurrent acute rhinosinusitis is defined by symptoms and physical
findings consistent with acute rhinosinusitis, with these symptoms
and findings worsening after five days or when persisting more
than 10 days. However, each episode lasts 7 to 10 days or more,
and may last up to four weeks. Furthermore, four or more than
four episodes occur in one year. Between episodes, symptoms
are absent without concurrent medical therapy. The diagnostic cri-
teria for recurrent acute rhinosinusitis are otherwise identical to
those of acute rhinosinusitis.

4. Chronic rhinosinusitis is rhinosinusitis lasting more than 12 weeks.
The diagnosis is confirmed by the major and minor clinical factor
complex (Table 4) with or without findings on the physical exam-
ination. A strong history consistent with chronic rhinosinusitis
includes the presence of two or more major factors, or one major
and two minor factors. A history suggesting that CRS should be
considered in the differential diagnosis includes two or more minor
factors or one major factor. Facial pain does not contribute a
strong history in the absence of other nasal factors.

5. Acute exacerbation of chronic rhinosinusitis represents sudden wor-
sening of the baseline CRS with either worsening or new symp-
toms. Typically the acute (non-chronic) symptoms resolve
completely between occurrences.

The advantage of the TFR classification (5) over the Princeton meet-
ing classification (23) is that no CT scan is needed, and the diagnosis is made
on clinical grounds only (i.e., major and minor factors and duration).
Williams et al. demonstrated that the overall clinical impression that takes
into account 16 historical items is more accurate than a single physical
examination in predicting the presence of rhinosinusitis (28). Another
advantage of the TFR guidelines is that they do not include nasal endoscopy
or radiological imaging, and so they are not only applicable to the specialist
but also to the primary care physician. Kenny et al. (29) and Duncavage
(30), in a prospective study at the Vanderbilt Asthma Sinus and Allergy
Program evaluating the AAO-HNS guidelines, found that the severity of

Classification of Rhinosinusitis 25

sinus pain/pressures and sinus headache did not correlate with CT scan
findings. On the other hand, the severity of five other symptoms (fatigue,
sleep disturbance, nasal discharge, nasal blockage, and decreased sense of
smell), either alone or in combination, correlated with the severity of the
CT scan findings of sinusitis.

In another study, Orlandi et al. presented their experience with the TFR
guidelines in diagnosing chronic rhinosinusitis and reevaluated these guide-
lines three years after publication (31). They found that these criteria provide
a relatively sensitive (88%) working definition of chronic sinusitis in a patient
population scheduled for surgery. Nasal obstruction/blockage and facial con-
gestion/fullness were the most common symptoms. Their "gold standard" for
the definition of chronic sinusitis is a patient who has symptoms for more
than 12 weeks, evidence of rhinosinusitis that was discovered on CT, and
an inflammation that was found on the analysis of pathology specimens.

Hwang et al. (32) found a poor agreement between the rhinosinusitis
TFR set forth positivity of symptoms — based on diagnostic guidelines for
CRS — and the CT scan positivity. The sensitivity of the TFR criteria for
detecting a positive scan was 89%, but the specificity was poor at only 2%.
Finally, Stankiewicz et al. compared 78 patients that met the TFR criteria
of subjective diagnosis with CT scan findings and endoscopy (Table 5) (33).
They found that in 78 patients with a positive subjective diagnosis based on
the TFR criteria, 53% had a negative CT scan and 45% had a negative endo-
scopy and a negative CT scan. When they looked at the number of patients
with negative endoscopy and negative CT scans, and negative endoscopy
and minimal disease on the CT scan, then endoscopy was correlated with
CT scanning in about 80% of the patients. However, the sensitivity and speci-
ficity of endoscopy versus CT scan were 74% and 84%, respectively. On a
cost-analysis basis, they conclude that endoscopy performed by a specialist
should be used to corroborate the diagnosis. According to these authors, an
evidence-based and reliable subjective symptom score correlating better with
endoscopy and CT scan is needed (33).

Table 5 Total Patients in the Study Fulfilling the TFR Criteria for the Subjective
Diagnosis of Chronic Rhinosinusitis n = 78 (100%)

CT scan positive for rhinosinusitis 47%

CT scan negative for rhinosinusitis 53%

Endoscopy positive, CT positive 22%

Endoscopy positive, CT negative 8%

Endoscopy negative, CT positive 26%

Endoscopy negative, CT negative 45%

Negative endoscopy correlated with CT 65%

Source: Adapted from Ref. 33.

26 Clement

Bhattacharyya (34) stated that the scientific basis for grouping major
and minor symptoms in the TFR guidelines was not clear. According to
the author, criteria justifying the classification of a symptom as "major"
could include a higher prevalence in patients with CRS, a higher severity
level, or an increased specificity of the symptom for the diagnosis of CRS.
In a prospective study of 120 patients with CRS, the major symptoms of
CRS were both more prevalent and manifest to a more severe degree than
in patients without CRS. Fatigue, considered by the guidelines to be a minor
symptom, was a more common and severe symptom manifestation of CRS
in the patient population. When looking at the anatomical symptom
domains [nasal (nasal obstruction, rhinorrhea, and sense of smell), facial
(facial pain/pressure, facial congestion/fullness, and headache), oropharyn-
geal (halitosis, dental pain, and cuff and ear symptoms), and systemic], they
found that the nasal and paranasal symptoms were the most likely manifes-
tations to be found in patients with CRS.

Finally, in 1998 (13), part of the Joint Task Force on Practice Para-
meters representing the American Academy of Allergy, Asthma and Immu-
nology, The American College of Allergy, Asthma and Immunology, and
the Joint Council of Allergy, Asthma and Immunology, defined sinusitis
as an inflammation of one or more of the paranasal sinuses, but they imme-
diately add that the most common cause of sinusitis is infection. In their
definition, the borderline between acute and chronic depends on the clini-
cian and extends from three weeks to eight weeks.

It is obvious from all these classifications and definitions that there still
exists a controversy between the duration of acute and chronic sinusitis and
the use of the term subacute sinusitis. If the term subacute sinusitis is not
used, the duration of chronic sinusitis in the adult population is defined
to be more than eight weeks (23); if the term subacute is used, the duration
is more than 12 weeks (TFR guidelines) (5). One of the reasons the TFR
guidelines reintroduced the concept of subacute sinusitis is that a duration
of 8 to 12 weeks for the term acute sinusitis was considered to be too
long, whereas a duration of no more than four weeks seemed to be more
appropriate.

The TFR of the AAO-HNS states that their definitions were based on
an amended list of the major and minor clinical symptoms and signs
believed to be most significant for the accurate clinical diagnosis of all forms
of adult rhinosinusitis (5). Anterior rhinoscopy performed in the decon-
gested nose revealed hyperemia, edema, crusting, polyps, and/or, most sig-
nificantly, purulence in the nasal cavity. This statement is of importance
because it included the presence of nasal polyps or nasal polyposis in the defi-
nition of CRS. Hadley et al., also a members of the TFR, stated when discuss-
ing clinical evolution of rhinosinusitis, that CRS may predispose patients to
nasal polyposis, which aggravates hyposmia and may lead to anosmia. This
statement supports the opinion of several authors (35) who view nasal

Classification of Rhinosinusitis 27

polyposis as a subgroup of CRS. However, the lack of a good definition of
nasal polyps or nasal polyposis makes utilization of this definition difficult.

According to Stedman's Medical Dictionary, a polyp is a general
descriptive term with reference to any mass of tissue that bulges or
projects outwards or upwards from the normal surface level, thereby micro-
scopically visible as a hemispheroidal, spheroidal, or irregular mound-like
structure, growing from a relatively broad base or a slender stalk (36).
Dorland defines a polyp as a morbid excrescence or protruding growth from
mucous membrane, classically applied to a growth on the mucous mem-
brane of the nose (37). This means that any spheroidal outgrowth of the
nasal mucosa in the nose or the paranasal sinuses is to be considered a nasal
polyp. Some authors, however, consider chronic sinusitis and nasal polypo-
sis as different diseases of the respiratory mucosa of the paranasal sinuses
(38). They define every polyp that can be seen by endoscopy as nasal
polyposis and any polyp in the sinuses as hyperplasia. Ponikau stated that,
in the Mayo Clinic, they consider nasal polyposis the end stage of the
chronic inflammation process of chronic rhinosinusitis rather than two
different diseases (39). According to these authors, CRS is an inflammatory
disease of the nasal and paranasal sinuses that is present for more than three
months, and is associated with inflammatory changes ranging from poly-
poid mucosa thickening to gross nasal polyps. Orlandi et al. were not able
to see a significant difference between the number of major and minor factors
of patients with or without nasal polyps (31). They only found that nasal dry-
ness/crusting (not a TFR factor) was more prevalent in patients with nasal
polyposis. Also, the Sinus and Allergy Health Partnership Taskforce (SAHP)
described that one of the signs of inflammation must be present and identified
in association with ongoing symptoms [TFR guidelines (Table 4) (5)], consis-
tent with CRS (40). The presence of discolored nasal drainage arising from
the nasal passages, nasal polyps, or polypoid swelling as identified on a phy-
sical examination with anterior rhinoscopy or nasal endoscopy. Finally, in a
position paper on rhinosinusitis and nasal polyps, the European Academy of
Allergy and Clinical Immunology (EAACI) stated that chronic sinusitis is
the primary disease and nasal polyposis is its subpopulation (41).

According to Hamilos, (42) inflammation plays a key role in CRS.
This author describes two types of inflammation that occur in sinusitis, con-
tributing variably to the clinical expression of disease; those are the infec-
tious inflammation that is most clearly associated with acute sinusitis,
resulting from either bacterial or viral infection, and the noninfectious
inflammation that is so named due to the predominance of the eosinophils
and the mixed mononuclear cells, and relative paucity of neutrophils com-
monly seen in CRS. Mucosal thickening, sinus opacification, and nasal
polyposis are seen at both ends of the spectrum (43). In some, cases intensive
treatment with antibiotics and a short course of prednisone caused near-
complete resolution of mucosal thickening and sustained improvement of

28 Clement

symptoms. Such cases represent the infectious end of the spectrum. In other
cases, similar treatment causes minimal regression in mucosal thickening or
nasal polyposis, and minimal improvement in symptoms. Such cases can be
considered as at the inflammatory end of the spectrum. Nasal polyps are
most characteristic of noninfectious sinusitis but cannot be strictly categor-
ized as infectious and noninfectious. Therefore, Hamilos (43) prefers the
descriptive term "chronic hyperplastic sinusitis with nasal polyposis" or
CHS/NP because it avoids implication of disease pathogenesis. CHS/NP
has the following features:

1 . Presence of chronic sinusitis

2. Extensive bilateral mucosal thickening

3. Nasal polyposis (usually bilateral)

4. Without obvious underlying disease, such as hypogammaglobuli-
nemia, cystic fibrosis, or immotile cilia syndrome

In Hamilo's experience (43), asthma and aspirin-sensitivity are asso-
ciated with CHS/NP in 62% and 49%, respectively, of their patients.
According to Hamilos (43), a distinguishing feature of mucosal pathology
of CHS/NP is tissue eosinophilia that is accompanied by an infiltrate of
mononuclear cells, T cells, and plasma cells, neutrophilia being uncommon,
occurring in only 25% of nasal polyps (44).

THE CLASSIFICATION OF FUNGAL SINUSITIS

Ponikau et al. (45,46) confirmed the presence of sinus eosinophilia in the
majority (96%) of their patients with CRS by means of histological analysis
of 101 consecutive patients. In the same study, they also found fungal organ-
isms, as examined on the basis of culture (96% of patients) and histology
(81%), in the sinus mucus of patients with CRS, suggesting that these organ-
isms might be involved in the disease process of CRS. However, to their sur-
prise, fungal organisms were also detected in the nasal mucosa of the
majority of healthy control subjects. They concluded that the combination
of eosinophilia and the presence of fungi explain the chronic inflammation
in 96% of the patients with CRS.

As further proof of their theory, Ponikau et al. (39,45) highlighted
their observation that in 51 randomly selected patients given the diagnosis
of CRS and treated with intranasal amphotericin B lavage, 75% experienced
a significant improvement of nasal symptoms, especially nasal discharge and
nasal obstruction and 36% had a polyp-free nasal endoscopy. In those where
a control CT scan was performed, they observed an improvement of the
sinus opacification. The authors admit that the potential weakness of their
pilot study is the fact that they did not include a placebo group. The state-
ment of the Ponikau group from the Mayo Clinic that the majority of the
CRS cases are caused by an abnormal eosinophilic response of the patient

Classification of Rhinosinusitis 29

to fungi initiated an intense controversy about the validity of the fungal
hypothesis (see the following sections).

In 1976, Saflrstein (47) described a 24-year-old woman with allergic
bronchopulmonary aspergillosis (ABPA) associated with nasal obstruction,
nasal polyps, and nasal cast formation. Millar et al. (48) and Katzenstein
et al. (49) mentioned the histological similarity between sinus mucoid mate-
rial and mucoid impaction of the bronchi in patients with ABPA, and they
named it "allergic aspergillus of the maxillary sinus" and "allergic aspergil-
lus sinusitis,'' respectively. The latter (49) described the typical mucin-
containing numerous eosinophils, sloughed respiratory cells, cellular debris,
Charcot-Leyden crystals, and scattered fungal hyphae resembling Aspergil-
lus species.

Waxman et al. (50) described the clinical features of a young adult
patient with allergic aspergillus sinusitis, showing a history of asthma and
recurrent polyposis, radiographic evidence of pansinusitis, and the typical
mucinous material as described by Katzenstein et al. (49). The majority of
their patients had positive skin tests for Aspergillus (60%), 85% had IgE
serum levels, and 85% had precipitins to Aspergillus. Robson et al. (51)
introduced the term "allergic fungal sinusitis" (AFS) after they described
a case of an expansive tumor of the paranasal sinus caused by the rare fun-
gal pathogen Bipolaris hawiiensis.

Corey et al. (52) stressed the importance of the host's immunological
status, local tissue condition, and histopathological examination to differ-
entiate among different forms of fungal disease. They differentiate between:

1 . Allergic fungal sinusitis as the sinus counterpart of ABPA; patients
showing chronic sinusitis can be atopic and show elevated IgE
levels and eospinophilic counts in the peripheral blood.

2. Fungal ball or aspergilloma due to massive fungal exposure or local
tissue anoxia. Patients are not immunocompromised.

3. Invasive or fulminent fungal sinusitis occurring in immunocompro-
mised patients.

Other authors (53) also define AFS (previously allergic aspergillus
sinusitis) as a chronic sinusitis with nasal polyposis in young immunocom-
petent patients, showing diffuse expansive sinus disease on CT scan, with the
typical allergic mucine described earlier. All their patients had positive IgE
RAST to fungal antigens.

Taking into account the immune status of the patient, Bent et al. (54)
categorize fungal sinusitis into five subgroups: the role of the fungi, the pre-
sence of tissue invasion, the cause, and the affected sinus. A similar classifi-
cation for fungal sinusitis was already published earlier by Ence et al. (55).

1. Invasive fungal sinusitis is an acute fungal sinusitis affecting one
sinus in an immunocompromised patient, showing tissue invasion.

30 Clement

2. Indolent fungal sinusitis is a subacute sinus infection with variable
tissue invasion of one or more sinuses in a nonatopic immunocom-
petent patient.

3. Mycetoma or fungal ball is a chronic saprophytic sinusitis of one
sinus without tissue invasion in a non-atopic immunocompetent
patient.

4. AFS is a chronic fungal sinusitis in an immunocompetent atopic
patient, where the fungus acts as an allergen involving multiple
sinuses with a unilateral predominance without tissue invasion.
The patient must demonstrate the characteristic allergic mucine
and have evidence of fungal etiology, either by direct observation
in the surgical specimen, or by recovery of the organism in cultures
of the sinus content.

5. AFS like syndrome: these patients have the same features as AFS
patients, however, without the presence of fungi. Cody et al. (56)
found that 40% of these patients with allergic mucin have AFS-like
syndrome. Ferguson (57) named this AFS-like syndrome "Eosino-
philic Mucin Rhinosinusitis" (EMR) stating that the driving force
is not a fungus but a systemic dysregulation associated with upper
and lower eosinophilia.

In 1995, deShazo et al. (58) described the criteria for the diagnosis of
AFS in his study as follows:

1 . Sinusitis of one or more paranasal sinuses on x-ray film

2. Identification of allergic mucin by rhinoscopy or at the time of the
sinus surgery or subsequently on histopathological evaluation of
material from the sinus

3. Documentation of fungal elements in nasal discharge or in mate-
rial obtained at the time of surgery by stain or culture

4. Absence of diabetes, previous or subsequent immunodeficiency
disease, and treatment with immunosuppressive drugs

5. Absence of invasive fungal disease at the time of diagnosis or sub-
sequently

From the criteria for the diagnosis of AFS listed by deShazo and
Swain (58), for these authors absence of atopy, asthma, nasal polyps, ele-
vated IgE levels, and serum fungal precipitins do not exclude the diagnosis
of AFS. Furthermore, bilateral involvement of the sinus on x-ray examina-
tion does not exclude the diagnosis either.

On the basis of immunopathological findings in ABPA and AFS,
Corey et al. (59) concluded that both represent Gell and Coombs type I
and type III response. In AFS, IgG antibodies, in addition to elevated IgE
antibodies, to the specific fungus in the serum can be demonstrated. There-
fore, they suggest the following immunological workup: total eosinophil

Classification of Rhinosinusitis 31

count, total serum IgE, fungal antigen-specific IgE in vitro testing and/or
skin test, fungal antigen-specific IgG (if available), and precipitating antibo-
dies (if available).

In 1998, Manning et al. (60) showed that AFS is an antigen, IgE-and
IgG-mediated, hypersensitivity response with a late-phase eosinophilic
inflammatory reaction. On the basis of immunohistocytochemistry studying
major basic protein (MBP) eosinophil-derived neurotoxin (EDN) and a neu-
trophils mediator (neutrophils elastase) in tissue samples of CRS, they also
showed that in all cases there was evidence that MBP and EDN mediator-
release predominated over neutrophils elastase, proving that AFS is a pre-
dominantly eosinophilic-driven disease.

In a controversial publication, Ponikau et al. (46) reevaluated the
recurrent criteria for diagnosing AFS in CRS. By using a novel method of
mucous collection and fungal-culturing technique, the authors demon-
strated allergic mucin in 96% of 101 consecutive surgical cases of CRS. In
the majority of their patients, they were not able to find an IgE-mediated
hypersensitivity to fungal antigens. Since the presence of eosinophils in
allergic mucin, and not a type I hypersensitivity, was likely the common
denominator in the pathophysiology of AFS, they proposed a change of
terminology from AFS to "eosinophilic fungal rhinosinusitis (EFR)." Similar
results were found by Braun et al. (61). Other authors had their doubts about
the validity of the Mayo Clinic hypothesis (46). Marple (62) questioned
whether fungi are indeed ubiquitous and are present within 100% of normal
noses, and wondered what separates those patients who develop AFS from
the normal population. He also questioned if the fungal screening methods
used in the study were so sensitive that normal fungal colonization was
mistaken for AFS, or if CRS merely represents an early form of clinically
recognized AFS.

Although it is generally accepted that eosinophils play an important
role in the development of both AFS and some forms of CRS, the factors
that ultimately trigger eosinophilic inflammation remain in question.
Riechelmann et al. (63) disagree with the EFR theory. They were able to
show the presence of fungi only in 50% of the patients with nasal polyposis
when using the most sensitive detection techniques. Ragab et al. (64), using
the same culture technique used by Ponikau et al. (46), were able to show
positive fungal cultures in 44% of the middle meatal lavage and in 36% of
the nasal cavity lavage of patients with CRS. It seems, therefore, that the
rate of positive lavages is dependent of the site of collection of the sample.

The question whether fungi are present in the upper airways inducing
an eventual eosinophilic response may not be relevant because the presence
of these fungi can be a mere epiphenomenon of an unknown cause that initi-
ally induced the CRS. The fungi may have not been adequately removed by
the mucociliary clearance and ultimately resulted in an eosinophilic
response.

32 Clement

Novey et al. (65) showed that a normal person inhales about 50 million
spores a day. With normal mucociliary clearance, these fungal spores are
removed adequately and do not have the time to germinate and release their
toxins. Once the fungi are not cleared because of an unknown cause, fungi
start to colonize the sinuses and may contribute to the maintenance or
amplification of the disease. The therapeutical results with antifungal agents
such as amphotericin B lavage (39,45) or nasal spray (66) do not strongly
support the role of fungi in CRS, as only in 35% to 43%, respectively, of
the nasal cavities become disease-free.

Bernstein et al. (67), who are recently studying the molecular biology
and immunology of nasal polyps, were unable to demonstrate that fungi
play a principal role in CRS. Their data (67) support the hypothesis that
Stapylococcus aureus releases a variety of enterotoxins (superantigens) in
the nasal mucus that induce an interaction of antigen-presenting cells and
lymphocytes, resulting in an up-regulation of inflammatory cells (lympho-
cytes and eosinophils) following an up-regulation of cytokines (TFN, IL-
1(3, IL-4, and IL-5). Bachert et al. (68) described IgE antibodies to S. aureus
enterotoxins in polyp tissue, linked to a polyclonal IgE production and
aggravation of eosinophilic inflammation. A similar mechanism was
described by Perez-Novo et al. (69) in aspirin-sensitive nasal polyposis
patients. If this hypothesis proves to be true, then the classification of fungal
sinusitis needs to be reconsidered and the definitions redefined. It also illus-
trates that the constancy of the classifications based on the hypothetical
causes is not very reliable.

Finally, Ferguson (57) described a visible growth of fungus (in AFS or
EFR the fungus is not visible to the naked eye) within the nasal cavity of an
asymptomatic individual and uses the term "saprophytic fungal infestation"
for this condition.

THE CLASSIFICATION OF PEDIATRIC RHINOSINUSITIS

During the last decade, three manuscripts have been published that classi-
fied pediatric rhinosinusitis (6,70,71). The Lusk et al. guidelines (70) were
an extension of the TFR guidelines of the AAO-HNS (5) using the same
classifications. The Clement report (6) consisted of an International Consen-
sus Meeting (ICM), primarily of otorhinolaryngologists, and the Wald et al.
(71) clinical practice guideline was a consensus of the Subcommittee on
Management of Sinusitis and Committee on Quality Improvement of the
American Academy of Pediatricians (SMS/CQI-AAP). The three classifica-
tions of pediatric rhinosinusitis are similar, and therefore, their definitions
and classification can be discussed together:

1. Acute rhinosinusitis in children is defined as an infection of the
sinuses mostly introduced by a viral infection, where complete

Classification of Rhinosinusitis 33

Table 6 Symptoms of Severe and Non-severe Pediatric Rhinosinusitis
Non-severe Severe

Rhinorrhea of any quality Purulent rhinorrhea (thick, opaque,

colored)

Nasal congestion Nasal congestion

Cough Peri-orbital edema

Headache, facial pain, and Facial pain and headache

irritability (variable)

Low grade or no fever High fever (>39°C)

Source: From Ref. (6).

resolution of symptoms (judged on a clinical basis only) without
intermittent URTI may take up to 12 weeks (ICM) (6). Acute
sinusitis can be further subdivided into severe and nonsevere
(Table 6).

The SMS/CQI-AAP guideline (71) introduces the concept of acute
bacterial rhinosinusitis (ABRS) complicating an acute viral rhinosi-
nusitis. ABRS is an infection of the paranasal sinuses, lasting less
than 30 days, in which symptoms resolve completely. According to
Mucha et al. (72) the diagnosis of ABRS should be considered
after a viral URI, when symptoms worsen after five days, are pre-
sent for longer than 10 days, or are out of proportion to those seen
with most viral infections.

To cover the duration gap between acute and chronic, the SMS/
CQI-AAP guideline (71) also introduced the concept of "subacute
bacterial sinusitis" in children as an infection of the paranasal
sinuses lasting between 30 and 90 days in which symptoms resolve
completely. The term subacute sinusitis was not recommended by
the ICM (6) in Brussels, as the difference between acute and sub-
acute is very arbitrary and it does not imply a different therapeutic
approach in children.

2. Recurrent acute rhinosinusitis in children are episodes of the bac-
terial infection of the paranasal sinuses separated by intervals dur-
ing which the patient is asymptomatic. According to the SMS/
CQI-AAP guideline (71), these episodes last less than 30 days
and are separated by intervals of at least 10 days.

3. Chronic rhinosinusitis in children is defined as a nonsevere sinus
infection with low-grade symptoms that presents longer than 12
weeks.

4. Finally, recurrent acute rhinosinusitis in children has to be differen-
tiated from chronic rhinosinusitis with frequent exacerbations
(ICM) (6) or acute bacterial sinusitis superimposed on chronic

34 Clement

sinusitis (SMS/CQI-AAP) (71). These are patients with residual
respiratory symptoms who develop new respiratory symptoms.
When treated with antimicrobials, these new symptoms resolve,
but the underlying residual symptoms do not.

The members of the ICM noted that medical treatment such as anti-
biotics and nasal steroids may modify symptoms and signs of acute and
CRS, and it is sometimes difficult to differentiate infectious rhinosinusitis
from allergic rhinosinusitis in a child on clinical grounds alone. According
to the SMS/CQI-AAP, a viral infection in children induces a diffuse muco-
sitis and predisposes to a bacterial infection of the sinuses in 80% of cases
whereas in 20% of the cases an allergic inflammation is responsible for the
bacterial superinfection.

In conclusion, an internationally well-accepted classification of rhino-
sinusitis in adults as well as in children that is based on duration of signs and
symptoms exists. However, there still exists much controversy concerning
the classification of fungal sinusitis. This classification is controversial
because it is based on the eventual cause of CRS, which is still not well
understood.

REFERENCES

1. Douek E. Acute sinusitis. In: Ballentyne J, Groves J, eds. Scott-Brown's Dis-
eases of the Ear, Nose and Throat, 3rd ed. The Nose. London: Butterworths,
1972:183-213.

2. Shapiro GG, Rachelefsky GS. Introduction and definition of sinusitis. J Allergy
Clin Immunol 1992; 90:417-418.

3. Johnson JT, Ferguson BJ. Infection. In: Cummings CW, Fredrickson JM, Har-
ker LA, Krause CJ, Richardson MA, Schuller DE, eds. Otolaryngology Head
and Neck Surgery. Vol. 2. 3rd ed. St Louis: Mosby, 1998:1107-1108.

4. Lund VJ, Kennedy DW, Draf W, Friedman WH, Gwaltney JM, Hoffman SR,
Huizing EA, Jones JK, Lusk RP, MacKay IS, Moriyana H, Nacleirio RM,
Stankiewicz J A, van Cauwenberge P, Vining EM. Quantification for staging
sinusitis. Ann Otol Rhinol Laryngol 1995; 104(suppl 167): 17-22.

5. Lanza D, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck
Surg 1997; 117:S1-S7.

6. Clement PAR, Bluestone CD, Gordts F, Lusk RP, Otten FWA, Goossens H,
Scadding GK, Takahashi H, van Buchem L, van Cauwenberge P, Wald ER.
Management of rhinosinusitis in children. Arch Otolaryngol Head Neck Surg
1998; 124:31-34.

7. Havas TE, Motbey J A, Gullane PJ. Prevalence of incidental abnormalities on
computed tomographic scans of the paranasal sinuses. Arch Otolaryngol Head
Neck Surg 1988; 114:856-859.

8. Bolger WE, Butzin CA, Parsons DS. Paranasal sinus bony anatomic variations
and mucosal abnormalities CT analysis for endoscopic sinus surgery. Laryngo-
scope 1991; 101:56-64.

Classification of Rhinosinusitis 35

9. Diament MJ, Senac MO, Gilsanz V, Baker S, Gillespie T, Larsson S. Prevalence
of incidental paranasal sinuses opacification in pediatric patients: a CT study.
J Comput Assist Tomogr 1987; 3:426-436.

10. Gordts F, Clement PAR, Buisseret Th. Prevalence of sinusitis signs in a non-
ENT population. ORL 1996; 58:315-319.

1 1 . Gordts F, Clement PAR, Destryker A, Desprechin B, Kaufman L. Prevalence
of sinusitis signs on MRI in a non-ENT pediatric population. Rhinology 1997;
35:154-157.

12. Pinheiro AD, Facer GW, Kern EB. Sinusitis: current concepts and manage-
ment. In: Bailey BJ, Calhoun KH, eds. Head and Neck Surgery-Otolaryngol-
ogy. Vol. 1. 2nd ed. Philadelphia, New York: Lippincott-Raven, 1998:441-445.

13. Spector SL, Bernstein IL, Li JT, Berger WE, Kaliner MA, Schuller DE,
Blessing-Moore J, Dykewicz MS, Fineman SF, Lee RE, Nicklas RA. Complete
guidelines and references. Parameters for the Management of Sinusitis.
Supplement to J Allergy Clin Immunol 1998; 102:S1 17-S124.

14. Kern EB. Sinusitis. J Allergy Clin Immunol 1984; 73:25-31.

15. McNab J. The Caldwell-Luc and allied operations. In: Dudley H, Carter D,
Nose and Throat Consultant editor Ballantyne JC, Harrison DFN, eds. Rob
and Smith's Operative Surgery. 4th ed. London: Butterworths, 1986:116-120.

16. Wigand ME. Transnasale, endoscopische Chirurgie der Nasennebenhohlen bei
Chronische Sinusitis. I. Ein bio-mechanisches Konzept der Schleimhautchirur-
gie. HNO 1981; 29:215-221.

17. Wigand ME. Transnasale, endoscopische Chirurgie der Nasennebenhohlen bei
Chronische Sinusitis. II. Die endonasale Kieferhohlen Operation. HNO 1981;
29:263-269.

18. Reilly JS. The sinusitis cycle. Otolaryngol Head Neck Surg 1990; 103:856-862.

19. Mygind M. Perennial rhinitis. In: Mygind M, ed. Nasal Allergy. Oxford: Black-
well Scientific Publications, 1987:224-232.

20. Iwens P, Clement PAR. Sinusitis in allergic patients. Rhinology 1994; 32:65-67.

21. Gwaltney JM, Philips CD, Miller RD, Riker DK. Computed tomographic
study of the common cold. N Eng J Med 1994; 330:25-30.

22. Leopold DA, Stafforrd CT, Sod EW, Szeverenyi NM, Allison JD, Phipps RJ,
Juhlin KD, Welch MB, Saunders C. Clinical course of acute maxillary sinusitis
documented by sequential MRI scanning. Am J Rhinol 1994; 8:19-28.

23. Kennedy DW. Sinus disease. Guide to first-line management. In: Kennedy DW,
ed., Health Communications. Intermedia Partners, 1994:1-44.

24. Lund VJ, Gwaltney J Jr, Baquero F, Echols R, Kennedy D, Klossek J-M,
MacKay I, Mann W, Ohnishi T, Stammberger H, Vinig E, Wald E, Burridge
SM. Infectious rhinosinusitis in adults: classification, etiology and management.
ENT J 1997;12(suppl 76):l-22.

25. Evans FO Jr, Sydnor JB, Moore WE, Moore GR, Manwaring JL, Brill AH,
Jackson RT, Hanna S, Skaar JS, Holdeman LV, Fitz-Hugh S, Sande MA,
Gwaltney JM Jr. Sinusitis of the maxillary antrum. N Engl J Med 1975;
293:735-739.

26. Gwaltney JM Jr, Scheld M, Sande MA, Sydnor A. The microbial etiology and
antimicrobial therapy of adults with acute community-acquired sinusitis: a

36 Clement

fifteen-year experience at the University of Virginia and review of other selected
studies. J Allergy Clin Immunol 1992:457^62.

27. Senturia BH, Bluestone CD, Lim DJ. Report of the Committee on definitions
and classifications of otitis media and otitis media with effusion. Am Otol
Rhinol Laryngol 1980; (suppl 68):89.

28. Williams JW Jr, Simel DL, Roberts L, Samsa GP. Clinical evaluation of sinu-
sitis. Making the diagnosis by history and physical examination. Ann Intern
Med 1992; 117:705-710.

29. Kenny TJ, Duncavage J, Bracikowski J, Yildirim A, Murray JJ, Tanner SB.
Prospective analysis of sinus symptoms and correlation with paranasal com-
puted tomographic scan. Otolaryngol Head Neck Surg 2001; 125:40-43.

30. Duncavage JA. Rhinosinusitis, Editorial Commentary. Curr Opin Otorlaryngol
Head Neck Surg 2001; 9:1-2.

31. Orlandi RR, Terrell JE. Analysis of the adult chronic rhinosinusitis working
definition. Am J Rhinol 2002; 16:7-10.

32. Hwang PH, Irwin SB, Griest SE, Caro JE, Nesbit G. Radiologic correlates of
symptom-based diagnostic criteria for chronic rhinosinusitis. Otolaryngol Head
Neck Surg 2003; 128:489-196.

33. Stankiewicz J A, Chow JM. Cost analysis in the diagnosis of chronic sinusitis.
Am J Rhinol 2003; 17:139-142.

34. Bhattacharyya N. The economic burden and symptoms manifestations of
chronic rhinosinusitis. Am J Rhinol 2003; 17:27-32.

35. Hadley JA, Schaefer SD. Clinical evaluation of rhinosinusitis: history and phy-
sical examination. Otolaryngol Head Neck Surg 1997; (suppl 117):S9-S11.

36. Stedman's Medical Dictionary. 26th ed. Baltimore: Williams and Wilkins,
1995:1405.

37. Dorland's Illustrated Medical Dictionary. 25th ed. Philadelphia: Saunders WB,
1965:1235.

38. Watelet J-P, Gevaert P, Bachert C, Holtappels G, van Cauwenberge P. Secre-
tion of TGF-B1, TGF-B2, EGF and PDGF into nasal fluid after sinus surgery.
Eur Arch Otorhinolaryngol 2002; 259:234-238.

39. Ponikau JU. Antifungal nasal washes for chronic rhinosinusitis: what's thera-
peutic — the wash or the antifungal? J Allergy Clin Immunol 2003; 111:
1137-1139.

40. Benninger MS, Ferguson BJ, Hadley JA, Hamilos DL, Jacobs M, Kennedy
DW, Lanza DC, Marple BF, Osguthorpe JS, Stankiewicz JA, Anon J, Denneny
J, Emanuel I, Levine H. Adult chronic sinusitis: definitions, diagnosis, epide-
miology and pathophysiology. Otolaryngol Head Neck Surg 2003; 129:S1-S32.

41. Fokkens W, Lund V, Bachert C, Clement P, Hellings P, Holmstrom M, Jones
N, Kalogjera L, Kennedy D, Kowalski M, Malburborg H, Mullel J, Passali D,
Stammberger H, Stierna P. EAACI Position paper on rhinosinusitis and nasal
polyps. Allergy 2005; 60:583-601.

42. Hamilos DL. Chronic sinusitis. J Allergy Clin Immunol 2000; 106:213-227.

43. Hamilos DL. Non infectious sinusitis. Allergy Clin Immunol Int 2001; 13:
27-32.

44. Hamilos DL, Leung DYM, Wood R, Meyers A, Stephens JK, Barkans J, Meng
Q, Cunningham L, Bean DK, Kay AB, Hamid Q. Chronic hyperplastic sinusi-

Classification of Rhinosinusitis 37

tis: association of tissue eosinophilia with mRNA expression of granulocyte-
macrophage colony-stimulating factor and interleukine-3. J Allergy Clin Immu-
nol 1993; 92:39-40.

45. Ponikau JU, Sherris DA, Kita H, Kern EB. Intranasal antifungal treatment in 51
patients with chronic rhinosinusitis. J Allergy Clin Immunol 2002; 1 10:862-866.

46. Ponikau JU, Sherris DA, Kern EB, Homburger HA, Frigas E, Gaffey TA,
Roberts GD. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin
Proc 1999; 74:877-884.

47. Safirstein BH. Allergic bronchopulmonary aspergillosus with obstruction of the
upper respiratory tract. Chest 1976; 70:788-790.

48. Miller JW, Johnston A, Lamb D. Allergic aspergillosus of the maxillary sinus.
Prod Scott Thor Soc 1981; 36:710.

49. Katzenstein AL, Sale Sr, Greenberger PA. Pathologic findings in allergic asper-

gillus sinusitis. A newly recognized form of sinusitis. Am J Surg Pathol 1983;
7:439^43.

50. Waxman JE, Spector JG, Sale SR, Katzenstein A-LA. Allergic aspergillus sinu-
sitis: concepts in diagnosis and treatment of a new clinical entity. Laryngoscope
1987; 97:261-266.

51. Robson JM, Hogan PG, Benn RA, Gatenby PA. Allergic fungal sinusitis pre-
senting as a paranasal sinus tumour. Aust NZJ Med 1989; 19:351-353.

52. Corey JP, Delsupehe KG, Ferguson BJ. Allergic fungal sinusitis: allergic, infec-
tious or both. Otolaryngol Head Neck Surg 1995; 113:110-119.

53. Manning SC, Mabry RL, Schaefer SD, Close LG. Evidence of IgE-mediated
hypersensitivity in allergic fungal sinusitis. Laryngoscope 1993; 103:717-721.

54. Bent JP, Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head
Neck Surg 1994; 111:580-588.

55. Ence BK, Gourley DS, Jorgensen NL, Shagets FW, Parsons DS. Allergic fun-
gal sinusitis. Am J Rhinol 1990:169-178.

56. Cody DT, Neel BN, Fereiro JA, Roberts GD. Allergic fungal sinusitis: The
Mayo Clinic experience. Laryngoscope 1994; 104:1074-1079.

57. Ferguson BJ. Eosinophilic mucin rhinosinusitis: a distinct clinicopathologic
entity. Laryngoscope 2000; 110:799-813.

58. deShazo RD, Swain RE. Diagnostic criteria for allergic fungal sinusitis. J
Allergy Clin Immunol 1995; 96:24-35.

59. Corey JP, Romberger CF, Shaw G. Fungal disease of the sinuses. Otolaryngol-
ogy 1990; 103:1012-1015.

60. Manning SC, Holman M. Further evidence for allergic pathophysiology in
allergic fungal sinusitis. Laryngoscope 1998; 108:1485-1496.

61. Braun H, Buzina W, Freudenschuss K, Beham A, Stammberger H. Eosinophi-
lic fungal rhinosinusitis: a common disorder in Europe? Laryngoscope 2003;
113:264^269.

62. Marple BF. Allergic fungal rhinosinusitis: current theories and management
strategies. Laryngoscope 2001:1006-1019.

63. Riechelmann H. Pilze aund Polypen — Fakten und mythen. Laryngol Rhinol
Otol 2003; 82:766-768.

64. Ragab A, Clement P, Vincken W, Simones F, Nolard N. Fungal cultures of dif-
ferent parts of upper and lower airways in chronic rhinosinusitis 2004. In press.

38 Clement

65. Novey HS. Epidemiology of allergic bronchopulmonary aspergillosis. Immunol
Allergol N Am 1998; 18:641-653.

66. Lacroix J-S. Effects of antifungal local treatment on nasal polyposis. In:
Mladina R, ed. Nasal Polyposis. Zagreb, Croatia: Croation Medical Associa-
tion, 2002:42^14.

67. Bernstein JM, Ballow M, Schlievert PM, Rich G, Allen C, Dryja D. A super-
antigen hypothesis for the pathogenesis of chronic hyperplastic sinusitis with
massive polyposis. Am J Rhinol 2003; 17:321-326.

68. Bachert C, van Zele T, Gevaert P, De Schrijver L, van Cauwenberge P. Super-
antigens and nasal polyposis. Curr Allergy Asthma Rep 2003; 3:523-531.

69. Perez-Novo CA, Kowalski ML, Kuna P, Ptasinska A, Johansson S, Bachert C.
Asperin sensitivity and IgE antibodies to Staphylococcus aureus enterotoxins in
nasal polyposis: studies on the relationship. Int Arch Allergy Immunol 2004;
133:257-260.

70. Lusk RP, Stankiewicz JS. Pediatric sinusitis. Otolaryngol Head Neck Surg
1997; 117:S53-S57.

71 . Wald ER, Bordley WC, Darrow DH, Grimm KT, Gwaltney JM Jr, Marcy SM,
Senac MO, Williams PV. Clinical practice guideline: management of sinusitis.
Am Ac of Pediatrics, Subcommittee on management of sinusitis. Pediatrics
2001; 108:798-808.

72. Mucha SM, Baroody FM. Sinusitis update 2003. Curr Opin Allergy Clin
Immunol 3:33-38.

Rhinosinusitis: Clinical Presentation and

Diagnosis

Michael S. Benninger and Joshua Gottschall

Department of Otolaryngology-Head and Neck Surgery, Henry Ford Hospital,

Detroit, Michigan, U.S.A.

INTRODUCTION

It is a widely held assertion that the diagnosis of bacterial rhinosinusitis is
made too often (1). This is due to the inherent difficulty in making an accu-
rate diagnosis. Many diagnostic challenges exist when evaluating patients
with presumed rhinosinusitis. Since the sinuses cannot be observed directly,
the diagnosis is dependent upon the history of present illness and is often
aided by nonspecific symptoms and physical examination. Primary care
physicians are at a particular disadvantage as they do not have ready access
to nasal endoscopy or antral puncture with fluid analysis, which at times are
helpful for establishing a diagnosis. Particularly challenging is differentiat-
ing between a self-limiting upper respiratory tract infection (URTI) or
"common cold" and allergy from an acute bacterial rhinosinusitis (ABRS).
The most common symptoms of rhinosinusitis include nasal congestion,
purulent rhinorrhea, facial pressure or pain, and anosmia or hyposmia.
These symptoms are not unique to rhinosinusitis and may be features of
other inflammatory processes of the sinonasal tract. Frequently, a recent
viral infection or underlying allergy precedes the development of ABRS,
and thus makes the diagnosis of rhinosinusitis all the more difficult.

The current health care environment also poses inherent challenges for
physicians. Reduced time per office visit, direct advertising by pharmaceutical

40 Benninger and Gottschall

corporations, and expectations of patients or caregivers may result in a
hasty diagnosis of rhinosinusitis and the inappropriate administration of
antibiotics. Clearly, prescribing antibiotics for viral or nonbacterial illness
is inappropriate. However, more serious consequences of this action include
the promotion of bacterial resistance, mild-to-serious drug reactions, and
increased health care costs. These inherent challenges, along with the diffi-
culty of establishing an accurate diagnosis of rhinosinusitis, have contribu-
ted to the estimated US $5.8 billion in overall health care expenditures
attributed to rhinosinusitis each year (2). Thus, the accurate diagnosis of
rhinosinusitis in both the adult and pediatric populations cannot be over-
emphasized.

DEFINITIONS

Sinusitis refers to an inflammatory process localized within one or more of
the paranasal sinuses, whereas rhinitis is an inflammatory process within
the nasal cavity. Since it is unusual for sinusitis to be present without a
concurrent rhinitis, rhinosinusitis may be a more appropriate descriptor
for this clinical disease process. Rhinosinusitis has recently been defined
as "a group of disorders characterized by inflammation of the mucosa of
the nose and paranasal sinuses" (3). This definition has two important fea-
tures: the understanding that rhinosinusitis is a group of disorders with a
number of different potential etiologies, and that the hallmark is inflamma-
tion, whether that inflammation is caused by an infection or some other
inflammatory process. In this chapter, ABRS will specifically refer to a bac-
terial infection of the sinonasal tract unless stated otherwise. Chronic rhino-
sinusitis (CRS) may be associated with a number of different disorders or
pathogenic mechanisms.

In order to facilitate the management of rhinosinusitis and to improve
communication amongst health care professionals, definitions of rhinosinu-
sitis for both the adult and pediatric age groups have been adopted. These
definitions have been temporally related from the onset of symptoms and
include ABRS, subacute bacterial rhinosinusitis, and CRS (Table 1). ABRS
is defined as a bacterial infection of the paranasal sinuses lasting less than

Table 1 Rhinosinusitis: Definitions

Duration of symptoms

Acute bacterial rhinosinusitis (ABRS) <30 days

Subacute bacterial rhinosinusitis >30 and <90 days

Chronic rhinosinusitis (CRS) >90 days

Source: Adapted from Ref. 12.

Rhinosinusitis 4 1

30 days. In general, the symptoms resolve completely. Symptoms persisting
longer than 10 days or worsening after five days more likely due to ABRS.
Subacute bacterial rhinosinusitis is a bacterial infection of the paranasal
sinuses lasting between 30 and 90 days with a similar presentation as seen
in acute rhinosinusitis. CRS has recently been redefined as "a group of dis-
orders characterized by inflammation of the mucosa of the nose and para-
nasal sinuses of at least 12 consecutive weeks' duration" (3). Patients
often have persistent residual respiratory symptoms such as rhinorrhea or
nasal obstruction. Two additional categories of rhinosinusitis further
describe patients based upon frequency of infection. Recurrent acute bacterial
rhinosinusitis is defined as multiple episodes of bacterial infection of the
paranasal sinuses, each lasting for at least 7 to 10 days but less than 30 days,
and separated by intervals of at least 10 days during which the patient is
asymptomatic. Patients with recurrent acute bacterial sinusitis typically
have four or more such infections per year. Acute exacerbation of chronic rhi-
nosinusitis occurs when individuals with CRS develop new acute respiratory
symptoms. When treated with antimicrobials, these new symptoms resolve,
but the underlying chronic symptoms do not. True recurrent acute bacterial
rhinosinusitis tends to be relatively infrequent. Patients that fit this profile
are more likely to have recurrent viral URTIs or acute exacerbations of
CRS rather than true recurrent acute rhinosinusitis.

To facilitate the diagnosis of rhinosinusitis, it may be useful to con-
sider whether the sinonasal infection is a result of primary or secondary
factors. Rarely is any one factor the sole cause of rhinosinusitis. More
commonly, multiple medical conditions or underlying disorders can be
found, which often complicates treatment. Rhinosinusitis due to primary
factors is typically found in otherwise healthy individuals. The pathology
is limited to the sinonasal tract. Medical treatment of the acute infection
or the surgical correction of mucous outflow obstruction generally results
in resolution of symptoms and overall improvement. Rhinosinusitis due
to secondary factors is less common. Rhinosinusitis in these individuals is
a consequence of an underlying systemic disease process or condition, pre-
disposing patients to the development of rhinosinusitis as well as other
infections. Examples of secondary factors include aspirin intolerance
(Sampter's triad), immunodeficiency, primary ciliary dyskinesia, and cystic
fibrosis. Treatment of the systemic disorder, in general, results in reduction
in severity or resolution of the rhinosinusitis. A list of causative factors
associated with the development of rhinosinusitis is seen in Table 2.

PATHOPHYSIOLOGY

The pathophysiology of rhinosinusitis is multifactorial. However, regardless
of etiology, the common basis for the development of sinus disease is often
associated with mucous stasis due to osteomeatal obstruction and/or

Benninger and Gottschall

Table 2 Factors Predisposing to Bacterial Rhinosinusitis

Primary (local) factors

Secondary (systemic) factors

Viral URI

Allergic/nonallergic rhinitis
Anatomic obstruction

Deviated septum

Concha bullosa

Paradoxic middle turbinate
Maxillary dental disease
Medication effects

Rhinitis medicamentosa

Cocaine
Air pollution/irritants
Gastroesphageal reflux disease
Nasal polyposis
Neoplasm

Diabetes mellitus
Inhalant/food allergies
Immune deficiency

HIV

Hypogammaglobulinemia

Iatrogenic
Asthma

ASA intolerance (sampter's)
Mucociliary disorders

Primary ciliary dyskinesia

Cystic fibrosis
Pregnancy
Hypothyroidism
Autoimmune

Sarcoidosis

Wegener's granulomatosis

mucociliary dysfunction. Persistent obstruction results in decreased oxygen
tension, reduced sinus pH, ciliary dysfunction, and negative pressure within
the sinus cavity. Sneezing or nose blowing may cause a transient opening of
the sinus drainage pathways. This, in addition to negative pressure within
the sinus cavity, may result in the inoculation of pathogenic bacteria from
the nasal cavity or nasopharynx into an otherwise sterile sinus cavity (4).
An optimal environment for overgrowth is thereby achieved, resulting in
rhinosinusitis. There has been a great interest in identifying pathways for
the development of CRS. The inflammatory roles of bacteria and fungi,
and the subsequent response by inflammatory cells and production of
mediators of inflammation, have generated new thinking regarding the
pathophysiology (3). A noninfectious inflammatory response as a result of
bacterial or fungal colonization resembling "allergic or asthmatic" inflam-
mation has been described. The resultant host inflammatory response with
production of inflammatory cytokines may be the underlying cause of
CRS. Of particular interest in this area are the roles of bacterial and
fungal allergy, eosinophilic inflammation, biofilms, and superantigens (3).

RHINOSINUSITIS OR UPPER RESPIRATORY TRACT
INFECTION?

Rhinosinusitis is most often a sequela of an acute URTI (5). Viruses respon-
sible for URTIs include rhinovirus, parainfluenza virus, influenza virus
type A and B, coronavirus, respiratory syncytial virus, and adenovirus.

Rhinosinusitis 43

Rhinovirus is implicated in approximately 50% of common colds (1). In
addition to osteomeatal obstruction due to inflammation and edema,
respiratory viruses may have a direct cytotoxic effect on the nasal cilia that
may result in impaired mucociliary clearance long after resolution of the
acute viral infection. Rhinovirus has also been shown to increase the
adherence of pathogenic bacteria, such as Streptococcus pneumoniae and
Hemophilus influenzae in the nasopharynx, increasing the likelihood of
bacterial colonization and infection (6).

In the United States, the incidence of acute respiratory illness due to
the common cold is two-three/year in the adult with 0.5% to 2% progres-
sing into an ABRS (7). Children on average have six to eight upper respira-
tory infections per year, with 5% to 10% progressing into ABRS (8). Due to
this reason, children may be particularly susceptible to rhinosinusitis.

The time from onset of symptoms was found to play an important role
in differentiating URTI from rhinosinusitis. Most viral URTI will begin to
improve within seven days and completely resolve by 10 days. Symptoms
worsening after seven days or persisting for 10 days or more are highly
suggestive of bacterial rhinosinusitis (1,9).

DIAGNOSIS OF RHINOSINUSITIS

Clinical investigations regarding the diagnosis of rhinosinusitis have been
difficult until recently, due to a lack of consensus for the definition of rhino-
sinusitis. In 1996, the Rhinosinusitis Task Force of the American Academy
of Otolaryngology-Head and Neck Surgery published general criteria for the
diagnosis of rhinosinusitis (10). Diagnosis is based upon the time from onset
of symptoms, as well as the number and type of symptoms present. Thus, the
diagnosis of rhinosinusitis is dependent upon establishing a time frame for
the disease and then applying clinical criteria to assure the diagnosis.

History

Individuals with rhinosinusitis may present with symptoms of nasal
congestion, nasal discharge, facial pressure or pain, hyposmia, or anosmia.
The pain of acute rhinosinusitis is typically a stabbing pain or ache, loca-
lized over the involved sinus. Thus, pain may provide a clue as to which
sinus is involved (Table 3). Maxillary sinus pain may elicit infraorbital
tenderness extending to the maxillary teeth and occasionally to the ear.
Ethmoid pain is typically reported between the eyes and over the nasal
dorsum. Frontal pain may present as headaches extending to the temple
or occiput. Isolated sphenoid sinus pain may present with headache, parti-
cularly at the vertex of the skull. Headaches and facial pain are rarely asso-
ciated with rhinosinusitis, unless a concomitant nasal symptom is present.

44 Benninger and Gottschall

Table 3 Pain and Associated Sinus Involvement
Sinus Associated pain

Maxillary Infraorbital, maxillary teeth, referred otalgia

Ethmoid Medial canthus, nasal dorsum

Frontal Supraorbital, bitemporal, occipital

Sphenoid Vertex of skull

Children with rhinosinusitis may have a different presentation
compared to their adult counterparts. Since young children are unable to
verbalize their complaints, they may present with irritability as their only
symptom. Sinus pain is not a prominent feature; however, children may
have nasal obstruction and purulent rhinorrhea. Cough is a feature that
may be seen in children with rhinosinusitis, which is typically not seen with
adults. It may occur during the day or night; however, the cough is particu-
larly worse at night. Rhinosinusitis is the second most common cause of
chronic cough in children (11). Other symptoms include foul breath, bron-
chial hyperresponsiveness, and periorbital edema. The periorbital edema is
usually non-tender and is usually seen on the dependent side and is worse
upon awakening.

The symptoms of nasal congestion/obstruction, facial pressure/pain,
nasal purulence or rhinorrhea, and anosmia/hyposmia are considered
major symptoms. The presence of two major symptoms is sufficient for
the diagnosis of rhinosinusitis (12). Cough is a minor symptom in adults,
but a major symptom when seen in children. Minor symptoms include head-
ache, irritability, fever, halitosis, fatigue, dental pain, and ear pain. The
presence of one major symptom and two minor symptoms is also sufficient
for the diagnosis of rhinosinusitis (Table 4) (12). Although symptoms and
time-based criteria may be appropriate in making the diagnosis in ABRS,
they have been insufficient in CRS (3). A diagnosis of CRS is best made
through a combination of symptoms and time-based criteria as in ABRS,
but supported by nasal endoscopy or radiologic testing.

A thorough history of present illness is required for all patients,
particularly to identify the secondary causes of rhinosinusitis. Features of
the history important when evaluating an individual for rhinosinusitis
include presenting symptoms, onset and duration of symptoms, and asso-
ciated comorbid disorders. A history of asthma, aspirin intolerance, nasal
polyposis, and rhinosinusitis is consistent with the ASA intolerance
syndrome (Sampter's triad). This entity is difficult to treat, with persistent
bronchial hyperreactivity, despite treatment of rhinosinusitis. Immune
deficiencies including HIV, common variable immune deficiency, and IgG
and IgA hypogammaglobulinemia are associated with recurrent rhinosinu-
sitis. Patients with a history of recurrent pneumonia, otitis media, sterility,

Rhinosinusitis 45

Table 4 Factors Associated with the Diagnosis of Chronic Sinusitis
Major factor Minor factors

Facial pain, pressure (alone does not constitute Headache

a suggestive history for rhinosinusitis in absence

of another major symptom)
Facial congestion, fullness Fever (all non-acute)

Nasal obstruction/blockage Halitosis

Nasal discharge/purulence/discolored nasal Fatigue

drainage
Hyposmia/anosmia Dental pain

Purulence in nasal cavity on examination Cough

Fever (acute rhinosinusitis only) in acute sinusitis Ear pain/pressure/fullness

alone does not constitute a strongly supportive

history for acute in the absence of another

major nasal symptom or sign

Source: Adapted From Ref. 12.

and rhinosinusitis should be evaluated for primary ciliary dyskinesia.
Patients with Kartagener's syndrome present with primary ciliary dyskine-
sia, rhinosinusitis, situs inversus, and bronchiectasis.

Perennial or seasonal allergies may present with symptoms such as
nasal congestion, cough, and behavioral changes, which are seen in both
allergic rhinitis and rhinosinusitis. It may be the underlying etiology in failed
antimicrobial therapy directed at presumed rhinosinusitis. Symptoms and
signs consistent with allergies include sneezing, clear nasal secretions, and
itchy mucous membranes of the upper aerodigestive tract. Allergies can play
a significant role in recurrent acute and chronic rhinosinusitis. All patients
should be evaluated for allergies when the history is elicited, with a focus
on both food and inhalant allergies, such as dust mite, mold, dander, and
pollen (13). There may be a history of rhinosinusitis coinciding with the
allergy season. The tendency to have allergy is genetically determined and
therefore is reflected in the family history. If one parent has a history of
allergy problems, any child in that family has a 20% to 40% chance of
having an allergic disease. If both parents have allergy problems, any child
has a 50% to 70% chance of having allergic manifestations at some time in
his/her life (14). In 13% of children with a negative allergy history, skin test-
ing is nevertheless positive. This has prompted some to advocate formal
allergy testing in all cases of CRS who failed medical treatment, and prior
to proceeding with surgery (15). Appropriate allergy skin testing or in vitro
tests (RAST, ELISA, and IgE) may be performed. In vitro tests for allergy
are useful in young children who may not tolerate skin testing.

Gastroesphageal reflux disease, or GERD, has been implicated as an
underlying etiology of CRS, especially in children. Double lumen pH probe

46 Benninger and Gottschall

analysis of children with CRS has demonstrated esophageal reflux in
63% of patients and nasopharyngeal reflux in 32% (16). Seventy-nine per-
cent of patients had improvement in CRS symptoms after medical treatment
of GERD. In a separate study, 89% of patients initially deemed as candi-
dates for sinus surgery avoided an operation after reflux treatment (17).

Patients with a history of maxillofacial trauma may present with
recurrent rhinosinusitis or CRS due to disruption or obstruction of the
osteomeatal drainage pathways. Complete resolution of recurrent symptoms
may require surgical correction of the anatomic obstruction. Occasionally
mucosa may be trapped within the fracture line, resulting in the develop-
ment of a mucocele or a mucopyocele and CRS.

Nasal neoplasm, both benign and malignant, may be a cause of unilat-
eral nasal symptoms and rhinosinusitis due to obstruction of the nasal cavity
and sinus drainage pathways. Unilateral nasal polyposis unresponsive
to corticosteroid therapy should raise the index of suspicion for a nasal
neoplasm. Care must be taken to rule out CNS tissue prior to biopsy.

Inflammatory nasal polyposis is seen in bilateral nasal cavities and
responds well to systemic and topical corticosteroid therapy. They may
result from chronic nasal inflammation, often associated with nasal allergies.
Inflammatory polyposis often has the classic "water bag" appearance. Any
child with nasal polyposis should be evaluated for cystic fibrosis.

Physical Examination

Intranasal examination may provide clues for the diagnosis of rhinosinusi-
tis. However, this is often nonspecific and thus greater emphasis is placed
upon the aforementioned symptoms-driven diagnostic criteria. Intranasal
examination is facilitated through the use of a nasal speculum, handheld
otoscope, or nasal endoscopes, including fiber-optic and rigid types
(Fig. 1). The examination of the mucosal linings of the symptomatic nose
may demonstrate generalized rhinitis with erythema and edema. The inferior
turbinates, often engorged, may limit visualization beyond the anterior
aspect of the inferior turbinate. Topical decongestion with alpha-adrenergic
agonist, such as oxymetazoline, permits an improved visualization of the
middle turbinate and middle meatus. Nasal purulence may be seen along
the floor of the nasal cavity. The color of the mucous is not a dependable
sign to differentiate a bacterial infection from a viral URTI. Distinguishing
between purulent-appearing nasal secretions from an infected sinus versus
colonized stagnant secretions from the nasal cavity or chronic adenoiditis
may also prove difficult. However, purulence found within the middle
meatus is highly suggestive of rhinosinusitis. Nasal polyposis may be seen,
and should be characterized based upon its growth beyond the anatomic
limits of the middle meatus. This may be useful to document response
to therapy. Occasionally, differentiating a nasal polyp from the middle

Rhinosinusitis

Figure 1 Tools for intranasal examination include nasal specula and mirror,
otoscope, fiber-optic endoscope, and rigid telescope.

turbinate may be a source of confusion. Palpation of the structure after
application of topical 2% pontocaine may reveal a firm, tender structure
more consistent with that of the middle turbinate.

Significant anatomic causes of obstructed sinonasal drainage should
be noted, including septal deviation or spurring, concha bullosa, and para-
doxical middle turbinate. Occasionally, adequate assessment of the lateral
nasal wall may be problematic. Percussion over the maxillary and frontal
sinus may elicit tenderness, which is, however, largely nonspecific. Oral
cavity examination may demonstrate an oro-antral fistula, poor dentition,
or dental abscess. Purulent drainage from the nasopharynx may be seen
in the posterior oropharynx.

In young children or adults with mental illness, a foreign body must
be considered, especially in cases of unilateral purulent rhinorrhea. The
drainage is usually foul-smelling. An otoscopic examination may demons-
trate otitis media. Due to its communication with the nasopharynx via the
eustachian tube, in children the middle ear may be considered a paranasal
sinus. Children with rhinosinusitis may have an associated otitis media. If
allergy is present, the patients may display allergic shiners and a supratip

48 Benninger and Gottschall

crease due to chronic wiping of the nose. Children may have the classic
"adenoid fades" secondary to chronic nasal obstruction due to an enlarged
adenoid.

Diagnostic Aids

A number of diagnostic aids may be helpful in confirming or making
the diagnosis of rhinosinusitis. An evidenced-based report by the Agency
for Health Care Policy and Research suggested that ancillary tests and
radiographs are not cost-effective in making the diagnosis, and are typically
unnecessary in uncomplicated ABRS. Rather, a clinical diagnosis is pre-
ferred. In CRS, however, it is recommended that unless the diagnosis is clear
from history and physical examination, confirmation should be obtained
either through nasal endoscopy, CT scanning, or plain sinus X-rays. The
various tools that have been used to aid in the diagnosis and assessing the
response to treatment will be discussed.

Transillumination

Transillumination of the frontal or maxillary sinus may suggest the presence
of fluid; however, it cannot differentiate between fluid opacification, tumor,
and agenesis of the sinus. Also, evaluation of ethmoid and sphenoid sinuses
is not feasible. The utility of transillumination in the diagnosis of rhino-
sinusitis is questionable and would not likely facilitate the diagnosis or
treatment. Transillumination may have some value in confirming the
diagnosis or assessing the response to treatment, if it were positive at the
onset of treatment and negative later. Since clinical response may be a better
measure, transillumination has little value (18).

Rigid or Flexible Endoscopy

Rigid or flexible endoscopy gives the diagnostician unparalleled access to
the nose for the evaluation of the lateral nasal wall, which may otherwise
not be possible on anterior rhinoscopy (Fig. 2). The anatomy of the middle
meatus can be carefully evaluated. The presence of accessory ostia may
be confused for the natural os. Small polyps or purulence within the middle
meatus may be seen. Evaluation of the sphenoethmoidal recess is possible
by directing a fiber-optic scope along the floor of the nose and then directing
the tip 90 degrees cephalad (toward the top of the head). In children,
evaluation of the nasopharynx may demonstrate chronic adenoiditis.

Cultures may be taken from the middle meatus during rigid nasal
endoscopy. Although culture of the sinus cavity itself is not obtained, a
strong correlation between endoscopic culture of the middle meatus and
antral puncture with culture has been reported. Endoscopically obtained
cultures demonstrate a sensitivity of 85.7%, and a specificity of 90.6% when

Rhinosinusitis

Figure 2 Intranasal examination using 0° rigid telescope with video documentation.

compared to sinus puncture (19-21). Culture of the nasal cavity in the
absence of frank purulence will likely yield nasal flora, and thus would
not be useful. Although culture-directed therapy is ideal, treatment of
uncomplicated cases of rhinosinusitis is presumptive, and is directed at
S. pneumoniae, H. influenzae, and Moraxella catarrhalis. However, cultures
should be considered in patients who have failed previous therapy, have
a history of immunodeficiency, or have poorly controlled diabetes mellitus.
Although the concordance between cultures obtained from antral puncture
and those endoscopically obtained from the middle meatus appear pro-
mising, not enough evidence currently exists to recommend this technique
over antral puncture.

Sinus Aspiration and Culture

Although sinus aspiration and culture are considered the gold standard for
the diagnosis of rhinosinusitis, they are rarely indicated in uncomplicated
cases. The cost, need for specialty referral, and discomfort experienced by
the patient need to be considered. Although generally safe, sinus puncture
has been associated with rare but serious complications, including tissue
emphysema, air embolism of venous channels, vasovagal reactions, and soft
tissue or bony infection (19). Although adult patients readily tolerate

50 Benninger and Gottschall

the procedure in an outpatient setting, children often require a general
anesthetic. As previously stated, initial treatment of ABRS is presumptive,
directed at the most commonly identified organisms (S. pneumoniae,
H. Influenzae, M. catarrhalis) (1). The majority of cases of rhinosinusitis
would likely resolve even without antibiotics. Positive cultures are recovered
in only 50% to 60% of patients diagnosed with rhinosinusitis (7,19,20).

The maxillary sinus is readily accessible through a canine fossa
approach or via the inferior meatus. In children, an inferior meatal
approach is preferred since it carries less risk to the dentition and orbit.
This is performed under general anesthesia and often in conjunction with
adenoidectomy.

A sublabial, canine fossa sinus puncture is well tolerated, and can be
performed in the office setting with minimal morbidity. Commercial kits
are readily available (Fig. 2). A specialist finds the procedure simple to per-
form and accurate results can be obtained as long as proper steps are taken
to prevent contamination (Table 5). The aspirated fluid should be noted
for its gross appearance. Aerobic and anaerobic cultures as well as gram
stain should be obtained. Fungal cultures can be obtained if the index of
suspicion is high.

Individuals with rhinosinusitis who have failed multiple courses of
antibiotics and those with immune suppression should be considered for
sinus aspiration and culture. Those individuals with infection extending
to the orbit or threatened intracranial extension should be scheduled for
emergency surgery. However, critically ill patients who are not operative
candidates may tolerate sinus aspiration quite well. This procedure may
prove to be therapeutic as well as diagnostic.

Quantitative cultures may assist in identification of the pathogenic
organism from nasal flora. The recovery of bacteria in a density of at least
10 4 colony-forming units (CFU)/mL is considered representative of a true
infection (8). Also, the finding of at least one organism per high power field
on gram stain is significant, and correlates with the recovery of bacteria in a
density of 10 5 CFU/mL (8).

Table 5 Procedure for Maxillary Sinus Puncture

Approach through the canine fossa or inferior meatus
Prepare site with topical antiseptic (Betadine)

Local (1% lidocaine/1: 100,000 epinephrine) infiltrated with 27-gauge needle
Trocar and catheter is inserted into maxillary sinus directed away from orbit
Withdraw trocar and aspirate

If no frank pus, inject 2 cc sterile saline into maxillary sinus and aspirate
Therapeutic irrigation of maxillary sinus with 60 cc sterile saline
Specimen sent for gram strain, aerobic, and anaerobic cultures

Rhinosinusitis 51

Limitations of sinus aspiration include the inability to sample the
sphenoid and ethmoid sinuses. Frontal sinus sampling would engender risk
to the brain and would be inadvisable. Contamination by oral or nasal flora
may result in misleading results; however, quantitative cultures may prove
more reliable.

Imaging

The role of imaging is discussed in detail in another chapter, and will only be
briefly described here. Plain sinus radiographs have long been used to aid in
the diagnosis of rhinosinusitis. Given the poor sensitivity and specificity and
the likelihood of abnormal findings even with a viral URTI, plain sinus
radiographs have little value in ABRS. They have not been shown to be
cost-effective (18). They may be helpful in confirming the diagnosis of
CRS in patients who have appropriate signs and symptoms for a sufficient
duration of time, but cannot be confirmed by a nasal examination, particu-
larly where endoscopy is not available (3). Ultrasound has also been used,
particularly in Europe, but has similar if not greater limitations compared
to plain sinus films (18).

CT scanning is considered the radiographic modality of choice.
Although limited in differentiating ABRS from a viral URTI (22), CT scans
are very useful in CRS (3) or in assessing the suspected complications of
either ABRS or CRS. MRI scan is generally considered to be of limited
value in the evaluation of rhinosinusitis at this time (3).

Ancillary Tests

There are a number of ancillary tests that may be helpful in assessing the sever-
ity of disease or the response to treatment. These include measures of smell
(such as the University of Pennsylvania Smell Identification Test or UPSIT),
measures of nasal airflow or resistance by acoustic rhinometry or rhinomano-
metry, the Electronic Nose, or various blood tests. As mentioned previously,
allergy testing may be useful, particularly in those with a strong allergic history
or family history, or who have had a poor response to directed therapy.

Outcome Evaluations

An area of great recent interest in many diseases and disorders over the last
few years are the methods to evaluate quality of life (QOL) and outcomes.
Rhinosinusitis has been well studied in relationship to QOL and outcomes,
and a few tools or instruments have been specifically designed to evaluate
this specific entity. Three commonly used instruments are the Rhinosinusitis
Disability Index (RSDI) (23), the Sino-Nasal Outcomes Test (SNOT) (24),
and the Chronic Sinusitis Survey (CSS) (25). The RSDI was specifically
developed to assess rhinosinusitis, although it has more recently been
validated for other nasal and sinus disorders, including allergic and
non-allergic rhinitis. Although there are some differences between these

52 Benninger and Gottschall

instruments, they all serve to establish a level of function for rhinosinusitis
patients and may be used to evaluate the response to treatment.

CONCLUSION

Many symptoms of rhinosinusitis are common to other nasal inflammatory
diseases such as the common cold and seasonal or perennial allergy. The
diagnosis of both pediatric and adult rhinosinusitis is best made based upon
clinical criteria (3), with a large portion of the diagnosis being based upon
the duration of symptoms into acute, subacute, and chronic subtypes. The
duration of symptoms is supported by the number and type of symptoms
as well as physical findings. Thus, the diagnoses are dependent upon estab-
lishing a time frame for the disease and then applying clinical criteria to
assure the diagnosis. Ancillary diagnostic evaluation should be considered
on a case-by-case basis. However, nasal endoscopy or CT scan should be
part of the diagnostic evaluation of CRS. Culture-directed therapy is not
cost-effective in cases of routine ABRS and is not recommended. The phy-
sician should rely on the understanding of the pathophysiology and natural
history of rhinosinusitis to make an accurate diagnosis and institute an
appropriate treatment plan.

REFERENCES

1. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for
acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004; 130(suppl 1):
S1-S50.

2. Ray NF, Baraniuk JN, Thamer M, Rinehart CS, Gergen PJ, Kaliner M,
Josephs S, Pung YH. Healthcare expenditures for sinusitis in 1996: contribu-
tions of asthma, rhinitis, and other airway disorders. J Allergy Clin Immunol
1999; 103:408-414.

3. Benninger MS, Ferguson BJ, Hadley J A, Hamilos DL, Jacobs M, Kennedy DW,
Lanza DC, Marple BF, Osguthorpe JD, Stankiewicz JA, Anon J, Denneny J,
Emanuel I, Levine H. Adult chronic rhinosinusitis: definitions, diagnosis, epide-
miology, and pathophysiology. Otolaryngol Head Neck Surg 2003; 129(3):
S1-S32.

4. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis.
Otolaryngol Head Neck Surg 1997; 117:S41-S49.

5. Kaliner M. Medical management of sinusitis. Am J Med Sci 1998; 316(l):21-28.

6. Fainstein V, Musher DM, Cate TR. Bacterial adherence to pharyngeal cells
during viral infection. J Infect Dis 1980; 141(2):172-176.

7. Gwaltney JM. Acute community-acquired sinusitis. Clin Infect Dis 1996; 23:
1209-1225.

8. Wald ER. Sinusitis. Pediatr Rev 1993; 14(9):345-351.

9. American Academy of Pediatrics. Subcommittee on Management of
Sinusitis and Committee on Quality Improvement. Clinical practice guideline:
management of sinusitis. Pediatrics 2001; 108(3):798-808.

Rhinosinusitis 53

10. Anon JB. Report of the rhinosinusitis task force committee meeting: alexandria,
Virginia, August 17th, 1996. Otolaryngol Head Neck Surg 119;117(3 Pt 2):
S1-S68.

11. Holinger LD. Chronic cough in infants and children. Laryngoscope 1986; 96:
316-322.

12. Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck
Surg 1997; 117:S1-S7.

13. Goldsmith AJ, Rosenfeld RM. Treatment of pediatric sinusitis. Pediatr Clin
North Am 2003; 50:413^126.

14. Cook PR, Nishioka GJ. Allergic rhinosinusitis in the pediatric population.
Otolaryngol Clin North Am 1996; 29:29-56.

15. Parsons DS. Chronic sinusitis: a medical or surgical disease? Otolaryngol Clin
North Am 1996; 29(l):l-9.

16. Phipps CD, Wood WE, Gibson WS, Cochran WJ. Gastroesophageal reflux
contributing to chronic sinus disease in children. Arch Otolaryngol Head Neck
Surg 2000; 126:831-836.

17. Bothwell MR, Parsons DS, Talbot A, Barbero GJ, Wilder B. Outcome of reflux
therapy on pediatric chronic sinusits. Otolaryngol Head Neck Surg 1999;
121:255-262.

18. Benninger MS, Holzer S, Lau J. Diagnosis and treatment of acute bacterial
rhinosinusitis: summary of the Agency on Health Care Policy and Research's
Evidence Based Report. Otolaryngol Head Neck Surg 2000; 122:1-7.

19. Benninger MS, Applebaum PC, Denneny J, Osguthorpe JD, Stankiewicz J,
Zucker D. Maxillary sinus puncture and culture in the diagnosis of acute
bacterial rhinosinusitis: the case for pursuing other culture methods. Otolaryn-
gol Head Neck Surg 2002; 127:7-12.

20. Talbot GH, Kennedy DW, Scheld M, Granito K. Rigid nasal endoscopy versus
sinus puncture and aspiration for microbiologic documentation of acute bacter-
ial maxillary sinusitis. Clin Infect Dis 2001; 33:1668-1675.

21. Gold S, Tami T. Role of middle meatus aspiration culture in the diagnosis of
chronic sinusitis. Laryngoscope 1997; 107(12): 1586-1 589.

22. Gwaltney JM, Phillips CD, Miller RD, Riker DK. Computed tomographic
study of the common cold. N Engl J Med 1994; 330(l):25-30.

23. Benninger MS, Senior B. The development of the rhinosinusitis disability index
(RSDI). Arch Otolaryngol Head Neck Surg 1997; 123:1175-1179.

24. Piccirillo J, Merritt J, Richards M. Psychometric and clinimetric validity of the
20-item sino-nasal outcome test. Otolaryngol Head Neck Surg 2002; 126:
41-47.

25. Gliklich R, Hilinski J. Longitudinal sensitivity of generic and specific health
measures in chronic rhinosinusitis. Qual Life Res 1995; 4:27-32.

Imaging Sinusitis

Nafi Aygun, Ovsev Uzuner, and S. James Zinreich

The Russell H. Morgan Department of Radiology and Radiological Sciences,
The Johns Hopkins Medical Institution, Baltimore, Maryland, U.S.A.

INTRODUCTION

Radiological imaging is complementary to the clinical and endoscopic eva-
luation of patients with rhinosinusitis. The diagnosis of this pathological
entity is made clinically and with the help of endoscopy. Imaging is an
essential part of presurgical evaluation and monitoring of difficult-to-treat,
recurrent, postsurgical disease. In patients in whom there might be clinical
suspicion of a noninflammatory pathology, imaging can be extremely help-
ful in distinguishing the various pathological entities.

AVAILABLE IMAGING MODALITIES

Plain Sinus Radiograph

Plain radiographic evaluation of the paranasal sinuses has fallen out of
favor despite its wide availability and comparatively low cost. The overall
sensitivity and specificity of plain radiographs for sinusitis is 40 to 50%
and 80 to 90%, respectively (1). The sensitivity approaches clinically accep-
table levels only for the diagnosis of maxillary sinus disease (2-4). Generally,
for a comprehensive evaluation, four standard views are obtained: lateral
view, Caldwell view, Waters' view, and sub-mentovertex or base view. The
lateral view shows the bony perimeter of the frontal, maxillary, and sphe-
noid sinus (Fig. 1). The Caldwell view shows the bony perimeter of the

Aygun et al.

Figure 1 Lateral (right) and sub-mentovertical (left) views of the sinuses. Plain
radiographs lack the sensitivity, specificity, and anatomic precision needed for the
evaluation of most patients with sinusitis.

frontal sinus. The Waters' view shows the outlines of the maxillary sinuses, some
of anterior ethmoid air cells, and the orbital outline. The sub-mentovertex
view evaluates the sphenoid sinus and the anterior and posterior walls of the
frontal sinuses (Fig. 1). Evaluation of the ostiomeatal unit (OMU) and the
detail of the ethmoid morphology are precluded by this modality.

Computerized Tomography

Computerized tomography (CT) is the imaging standard for sinusitis (5).
Its ability to display bone, mucosa, and air makes it a perfect tool for the
imaging of the paranasal sinuses. The fine bony architecture of the nasal
cavity and the paranasal sinus drainage pathways is accurately depicted with
CT examination. CT is very sensitive in detection of mucosal hypertrophy
and retained secretions in the paranasal sinuses.

Technique

Single channel CT (SC-CT) scanners use either incremental or helical acqui-
sition schemes for paranasal sinus examination. Coronal images optimally
display the anterior ostiomeatal unit, the relationship of the orbits and brain
to the paranasal sinuses, and also correlate best with the surgical approach.
The slice thickness should be 3 mm or less without interslice gap for optimal
evaluation of the key structures such as OMU and frontal recess. Image
acquisition in the coronal plane requires an extension of the head, which

Imaging Sinusitis 57

may not be possible for very young patients and patients with airway pro-
blems or neck pain. Thin axial images can be reconstructed in the coronal
plane for such patients. Direct sagittal images cannot be obtained with CT.

Multichannel CT (MC-CT) (also called multidetector or multislice
CT) scanners have been recently introduced. The single X-ray detector pre-
sent in SC-CT has been replaced with multiple rows of detectors in MC-CT
scanners that allow registration of multiple channels of data with one rota-
tion of the X-ray tube. For example, 16-slice MC-CT equipment has a
16-fold capacity to collect image data per X-ray tube rotation compared
to a SC-CT. This increased capacity affords much thinner slices from larger
body parts in shorter periods of time. Thin slices permit isotropic data sets
in which the voxels (the smallest elements of a data set) are cuboidal. Cuboi-
dal voxels offer excellent reconstruction of images in essentially any plane
without degradation of quality. Currently, slices as thin as 0.5 mm can easily
be obtained with near-isotropic voxels. Isotropic imaging created a para-
digm shift in CT imaging: we are no longer confined to the plane of acquisi-
tion. Data can be collected from a body part in any desired plane, and
two-dimensional images [multiplanar reconstruction (MPR)] can be dis-
played in any desired plane (Fig. 2). Real-time interactive manipulation of
image data and three-dimensional reconstructions are made possible by
high-performance workstations equipped with special software.

Intravenous contrast administration is not necessary for assessment of
uncomplicated inflammatory sinus disease. Different shades of gray inherently
present in every CT image can be displayed in various "windows" to enhance
visualization of certain tissues (e.g., bones and soft- tissues). A window width
of 2000 Hounsfield units with a level of -200 Hounsfield units is the most
advantageous for inflammatory disease of the paranasal sinuses. These "win-
dow levels" afford best display of the narrow air channels. Window settings
can easily be changed to highlight certain structures and "hard-copy" films
are then printed. Adjustment of window settings is not a post-processing
method and does not change the raw data, whereas bone reconstruction algo-
rithms (also called bone filters) manipulate the raw data to best demonstrate
the bony detail. Images reconstructed using bone algorithm are recommended
for the evaluation of the paranasal sinuses. Evaluation of the soft tissues on
these images, however, is very limited, even when the window settings are
adjusted for soft tissues (Fig. 3).

Radiation Exposure

The increasing number of CT examinations and desire for high-resolution
images inevitably increase the radiation dose to patients. Factors inherent
to the individual CT scanner and the patient greatly influence radiation
dose. Among many operator adjustable scanning parameters that affect
the radiation dose, tube current (milliamper-second, mAs) has the most
direct and profound effect on the final radiation dose received by the

Aygun et al.

(A)

(B)

(C)

Figure 2 Paradigm shift in CT imaging: images in virtually any plane can be recon-
structed from the acquired data set to better demonstrate a certain structure.

(A) Oblique-sagittal reconstruction along the frontal sinus outflow tract (arrow).

(B) Oblique-coronal reconstruction along the ethmoid infundibulum. (C) Recon-
struction along the optic nerve (on) shows dehiscent nerve canal, pneumatized ante-
rior clinoid process (acp) and protrusion of internal carotid artery (ica) to the
sphenoid sinus.

patient. A considerable reduction in radiation exposure can be achieved by
lowering mAs (6-8). LowmAs results in increased image noise and possible
loss of fine detail. A tube current of 50-80 mAs at 120kVp tube voltage is a
reasonable compromise and diagnostic accuracy of paranasal sinus CT is
not affected at these settings compared to higher mAs values (9-13). A very
low-radiation dose CT (even lower than four view radiographs) study can
be performed with 10 mAs and noncontiguous slices for patients who
require multiple repeat studies (8). While the radiation exposure to the lens
from sinus CT examination is well below the threshold level believed to

Imaging Sinusitis

Figure 3 The effect of technical parameters on the appearance of images. (A) Bone
window with soft-tissue algorithm, (B) bone window with bone algorithm, (C) soft-
tissue window with soft-tissue algorithm and (D) soft-tissue window with bone
algorithm. Note that the bone detail is better depicted on image (B) and soft-tissue
is better evaluated on image (C). Patient has CRS and prominent osteitis. Note evi-
dence of prior surgery.

induce cataracts, there is a theoretical risk of stochastic effects (e.g., carcino-
genesis), which is not dependent on a minimum threshold of exposure.
Therefore, judicious use of CT is advised. Multiple examinations with
high-dose protocols should be avoided particularly in young patients.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI)'s exquisite contrast resolution makes it a
perfect tool in the imaging of soft tissues. MRI is extremely sensitive to

60 Aygun et al.

mucosal thickening. In fact, MRFs sensitivity may be too high due to the fact
that small increases in volume and signal intensity of the mucosa in the ethmoid
sinuses and nasal turbinates can be a reflection of physiological nasal cycle (14).
Due to MRFs limited ability to display fine bone detail, its use is limited in
diagnostic and presurgical evaluation of uncomplicated inflammatory sinus
disease. MRI has proven most helpful in the evaluation of regional and intra-
cranial complications of inflammatory sinus disease and their surgical manage-
ment, in the detection of neoplastic processes, and in improved display of
anatomic relationships between the intra- and extra-orbital compartments.
MRI is also useful in the evaluation of mucoceles and cephaloceles.

Tl- and T2-weighted MRI obtained in axial and coronal planes
provide a satisfactory evaluation of the sinuses. Contrast [gadolinium-
diethylenetriaminepentaacetic acid (Gd-DTPA)]-enhanced, fat-saturated Tl-
weighted images are recommended for a more comprehensive examination.

ANATOMY

Understanding of the anatomy of the lateral nasal wall and its relationship
to adjacent structures is essential (15-17). The lateral nasal wall contains
three bulbous projections: superior, middle, and inferior turbinates (con-
chae). The turbinates divide the nasal cavity into three distinct air passages:
the superior, middle, and inferior meati. The superior meatus drains the
posterior ethmoid air cells and, more posteriorly, the sphenoid sinus
(through the sphenoethmoidal recess). The middle meatus receives drainage
from the frontal sinus [through the frontal sinus outflow tract (FSOT)],
maxillary sinus (through the maxillary ostium and subsequently the ethmoi-
dal infundibulum), and the anterior ethmoid air cells (through the ethmoid
cell ostia). The inferior meatus receives drainage from the nasolacrimal duct.
The frontal aeration varies among patients. The frontal sinuses can be
small and only occupy the diploic space of the medial frontal bone, or they
can be large and extend through the floor of the entire anterior cranial fossa,
posterior to the planum sphenoidale. In general, a central septum separates the
left and the right sides. The floor of the frontal sinus slopes inferiorly toward
the midline. The frontal sinus drains through an hourglass-shaped structure.
Some call this entity the frontal sinus outflow tract (FSOT) (Figs. 2A and 4).
The superior portion of this outflow tract is a funnel-shaped narrowing called
infundibulum in the inferior and medial aspect of the frontal sinus, which leads
to the frontal ostium. The frontal ostium forms the waist of the hourglass in
the most medial portion of the frontal sinus. The bottom portion of the hour-
glass is called the frontal recess, the narrowest portion of this outflow tract,
which in turn leads to the superior portion of the middle meatus affording
communication with the anterior ethmoid sinus. The frontal recess is neigh-
bored by the agger nasi cell anteriorly, the ethmoid bulla posteriorly, and unci-
nate process inferiorly (Fig. 4).

Imaging Sinusitis

Figure 4 (A) Axial and (B) oblique sagittal images show the frontal sinus outflow
tract (arrow) which is mildly narrowed due to circumferential mucosal thickening.
Abbreviations: EB, ethmoid bulla; BL, basal lamella; AN, agger nasi cell.

62 Aygun et al.

The agger nasi cell is an ethmoturbinal remnant that is present in
nearly all patients. It is aerated and represents the most anterior ethmoid
air cell. It usually borders the primary ostium or floor of the frontal sinus;
thus, its size may directly influence the patency of the frontal recess and the
anterior middle meatus. The uncinate process is a superior extension of the
lateral nasal wall (medial wall of the maxillary sinus). Anteriorly, the unci-
nate process fuses with the posteromedial wall of the agger nasi cell and the
posteromedial wall of the nasolacrimal duct. Laterally, the free edge of the
uncinate process delimits the ethmoid infundibulum, which is the air passage
that connects the maxillary sinus ostium to the middle meatus. The superior
attachment of the uncinate process has three major variations which deter-
mine the anatomic configuration of the frontal recess and its drainage (18).
These variations are: (1) the uncinate process may extend laterally to attach
to the lamina papyracea or the ethmoid bulla forming a terminal recess of
the infundibulum and the frontal recess directly opens to the middle meatus
(Fig. 5), (2) the uncinate process may extend medially and attaches to the
lateral surface of the middle turbinate, (3) the uncinate process may extend
medially and superiorly to directly attach to the skull base (Fig 5). In the
latter two forms, the frontal recess drains to the infundibulum. Posterior
to the uncinate is the ethmoid bulla (Fig 4b), usually the largest of the ante-
rior ethmoid cells.

The ethmoid bulla is enclosed laterally by the lamina papyracea. The
gap between the ethmoid bulla and the free edge of the uncinate process
defines the hiatus semilunaris. Medially, the hiatus semilunaris communi-
cates with the middle meatus, the air space lateral to the middle turbinate.
Laterally and inferiorly, the hiatus semilunaris communicates with the
infundibulum by the air channel between the uncinate process and the in-
feromedial border of the orbit. The infundibulum serves as the primary
drainage pathway from the maxillary sinus. The structure medial to the
ethmoid bulla and the uncinate process is the middle turbinate. Anteriorly,
it attaches to the medial wall of the agger nasi cell and the superior edge of
the uncinate process. Superiorly, the middle turbinate adheres to the cribri-
form plate. As it extends posteriorly, the middle turbinate emits a number of
laterally coursing bony attachments. The first of these bony leaflets is the
basal or ground lamella that fuses with the lamina papyracea posterior to
the ethmoid bulla. The basal lamella demarcates the anterior ethmoid sinus
from the posterior ethmoid sinus (Fig. 4A).

In most individuals, the posterior wall of the ethmoid bulla is intact.
The air space between the basal lamella and the ethmoid bulla is the retro-
bullar recess or the sinus lateralis, which may extend superior to the ethmoid
bulla forming the suprabullar recess (Fig. 6). The suprabullar recess opens
to the frontal recess. Dehiscence or total absence of the posterior wall of
the ethmoid bulla is common and may provide communication between
these air spaces.

Imaging Sinusitis

Figure 5 Coronal CT. In the most commonly seen anatomic variation, the uncinate
process attaches to the lamina papyracea or the ethmoid bulla. The infundibular
recess (ir) is formed between the uncinate process and the orbit. In this variation
the frontal sinus outflow tract drains to the middle-meatus.

Aygun et al.

Figure 6 The anatomy of the ethmoid and frontal sinus outflow tract on sagittal
CT. Abbreviations: AN, agger nasi cell; FR, frontal recess; EB, ethmoid bulla;
SR, suprabullar recess; BL, basal lamella.

The posterior ethmoid sinus consists of air cells between the basal
lamella and the sphenoid sinus. The number, shape, and size of these air
cells vary significantly among persons (19-21).

The sphenoid sinus is the most posterior sinus (Fig. 7). It is usually
embedded in the clivus and bordered superoposteriorly by the sella turcica.
Its ostium is located medially in the anterosuperior portion of the anterior
sinus wall, which in turn communicates with the sphenoethmoidal recess
into the posterior aspect of the superior meatus (Fig. 8). The sphenoethmoi-
dal recess lies just lateral to the nasal septum and can sometimes be seen on
coronal images, but it is best seen in the sagittal and axial planes.

The relationship between the aerated portion of the sphenoid sinus and
the posterior ethmoid sinus needs to be accurately represented so the surgeon
can avoid operative complications. Usually in the paramedian sagittal plane,
the sphenoid sinus is the most superior and posterior air space. More later-
ally, the sphenoid sinus is located more inferiorly, and the posterior ethmoid
air cells become the most superior and posterior air space. This relationship
is seen well on transverse and sagittal images. The number and position of
the septa of the sphenoid sinus vary. Some septa can adhere to the bony wall
covering the internal carotid artery, which frequently penetrates the sphe-
noid sinus. Note is to be made that all septations are vertically oriented
within the sphenoid sinus. Horizontal bony separations within the area
of the sphenoid sinus represent a bony separation between the posterior
ethmoid sinus cells above and the sphenoid sinus below.

Imaging Sinusitis

Figure 7 The sphenoid sinus and carotid artery. Contrast-enhanced (A) coronal and
(B) sagittal images show protrusion of internal carotid artery (ica) into the sphenoid
sinus with dehiscent carotid canal. Note that on a noncontrast CT displayed with
bone windows this would be indistinguishable from a sphenoid polyp. Arrows: ICA.

Anatomically, the paranasal sinuses are in close proximity to the ante-
rior cranial fossa, cribriform plate, internal carotid arteries, cavernous
sinuses, the orbits and their contents, and the optic nerves as they exit the
orbits (Figs. 2C and 7) (22-24). The surgeon should be cautious when

Aygun et al.

Figure 8 Axial CT image through the sphenoid sinus. The sphenoid ostium is at the
medial and superior aspect of the sphenoid sinus. Note that the left ostium is
obstructed by mucosal thickening.

maneuvering instruments in the posterior direction to avoid an inadvertent
penetration and drainage of these structures (22,23,25,26).

Anatomic Variations and Congenital Abnormalities

The nasal anatomy is unique and similar to the uniqueness of "thumb print."
Although the nasal anatomy varies significantly among patients, certain
anatomic variations are common in the general population and may be seen
more frequently in patients with chronic inflammatory disease (20,21,25-28).
Multiple studies demonstrated an association between some anatomic varia-
tions and sinusitis, but a causal relationship has not been established. It
appears that some of these variations contribute to mechanical obstruction
of the ostiomeatal channels in patients with sinusitis, and need to be addressed
during surgery. The significance of an anatomic variation is determined by its
relationship with the ostiomeatal channels and nasal air passages. The most
common variations are discussed in the following paragraphs. It is stressed
that the high variability of the anatomy necessitates careful presurgical
assessment on an individual basis.

Concha Bullosa

Concha bullosa is defined as an aeration of the middle turbinate (Fig. 9).
Concha bullosa may be unilateral or bilateral. Less frequently, aeration of

Imaging Sinusitis

Figure 9 Concha Bullosa: coronal CT image showing bilateral concha bullosa. The
right concha bullosa is opacified.

the superior turbinate may occur, whereas aeration of the inferior turbinate
is infrequent. A concha bullosa in the middle turbinate may enlarge to
obstruct the middle meatus or the infundibulum. The air cavity in a concha
bullosa is lined with the same epithelium as the rest of the nasal cavity; thus,
these cells can undergo the same inflammatory disorders experienced in the
paranasal sinuses. Obstruction of the drainage of a concha can lead to
mucocele formation.

Nasal Septal Deviation

Nasal septal deviation is an asymmetric bowing of the nasal septum that
may compress the middle turbinate laterally, narrowing the middle meatus.
Bony spurs are often associated with septal deviation. Nasal septal deviation
is usually congenital but may be a post traumatic finding in some patients.
Nasal septal deviation occurs with a similar frequency in asymptomatic
persons with no CT evidence of sinusitis and in patients with sinusitis
(29). When the angle of deviation is high, it may contribute to the mechan-
ical obstruction of the anterior ostiomeatal complex.

Aygun et al.

Paradoxic Middle Turbinate

The middle turbinate usually curves medially towards the nasal septum.
However, its major curvature can project laterally and, thus, narrow the
middle meatus and infundibulum. This variant is called a paradoxic middle
turbinate. The inferior edge of the middle meatus may assume various
shapes with excessive curvature, which in turn may obstruct the nasal cavity,
infundibulum, and middle meatus.

Variations in the Uncinate Process

The course of the free edge of the uncinate process varies. In most cases, it
extends slightly obliquely toward the nasal septum with the free edge sur-
rounding the inferior or anterior surface of the ethmoid bulla. Sometimes,
the free edge of the uncinate adheres to the orbital floor or inferior/anterior
aspect of the lamina papyracea. This variant is usually associated with a
hypoplastic (Fig. 10), and often opacified, ipsilateral maxillary sinus result-
ing from closure of the infundibulum. Due to the small maxillary sinus, the

Figure 1 Hypoplastic maxillary sinus: the uncinate is attached to the floor of the orbit
on this coronal CT image. Also note that the wall of the maxillary sinus is very thick.

Imaging Sinusitis

ipsilateral orbit is more inferiorly located, giving rise to more frequent orbi-
tal complications during surgery (30,31). The posterior edge of the uncinate
process may attach to the lamina papyracea, wall of the ethmoid bulla,
middle turbinate, or skull base. The attachment site of the posterior edge
of the uncinate process determines the drainage site of the frontal recess.

Haller Cells (Infrabullar Recess Cells)

Haller cells are ethmoid air cells that extend along the medial roof of the
maxillary sinus (Fig. 11). Their appearance and size vary. They may cause
narrowing of the infundibulum when they are large. Haller cells may exist
as discrete cells or they may open into the maxillary sinus or infundibulum.

Onodi Cells

Onodi cells are lateral and posterior extensions of the posterior ethmoid air
cells (32). They extend the paranasal sinus cavity very near the optic nerves

Figure 1 1 Haller cell: bilateral extension of ethmoid cells into the maxillary sinuses.
Note the proximity of the Haller cells to the ethmoid infundibulum.

70 Aygun et al.

as they exit the orbits. These cells may surround the optic nerve tract and
put the nerve at risk during surgery.

Giant Ethmoid Bulla

The largest of the ethmoid air cells, the ethmoid bulla may enlarge to narrow
or obstruct the middle meatus and infundibulum.

Extensive Pneumatization of the Sphenoid Sinus

Pneumatization of the sphenoid sinus can extend into the anterior clinoid
processes and clivus, surrounding the optic nerves. When this occurs, the
risk of damage to the optic nerves is increased during surgical exploration.
The carotid canal may protrude into the sphenoid sinus and there could be a
bony dehiscence on the sphenoid sinus wall, increasing the risk of cata-
strophic carotid artery injury.

Medial Deviation or Dehiscence of the Lamina Papyracea

Medial deviation or dehiscence of the lamina papyracea may be a congenital
finding or the result of prior facial trauma. Regardless, the intra-orbital con-
tents are at risk during surgery because of the common dehiscences in the
area and the ease of confusing this medial bulge with the ethmoid bulla.
Excessive medial deviation and bony dehiscence tend to occur most often
at the site of the insertion of the basal lamella into the lamina papyracea,
thus rendering this portion of the lamina papyracea most delicate.

Aerated Crista Gal Ii

Aeration of the crista galli, a normally bony structure, can occur (Fig. 12).
When aerated, these cells may communicate with the frontal recess. Obstruc-
tion of this ostium can lead to chronic sinusitis and mucocele formation. It is
important to recognize this entity preoperatively and to differentiate it from
an ethmoid air cell to avoid extension of surgery into the cranial vault.

Cephalocele and Meningocele

Extracranial herniations of the brain and/or its coverings may be congeni-
tally present or may result from previous ethmoid or sphenoid sinus surgery.
Their presence needs to be considered when dealing with an isolated soft-
tissue mass adjacent to the ethmoid or sphenoid roof, especially if comple-
mented by adjacent bone erosion. The differential diagnosis includes
mucocele, neoplasm, cephalocele, and less likely, a polyp associated with
an adjacent bony dehiscence. Coronal CT will best display the extent of
bony erosion, and sagittal and coronal MRI will be helpful in narrowing
the differential diagnosis. CT cisternography is diagnostic (Fig. 13).

Imaging Sinusitis

Figure 12 Supraorbital ethmoid air cells and pneumatized crista galli demonstrated
on coronal CT image.

Asymmetry in Ethmoid Roof Height

It is important to note any asymmetry in the height of the ethmoid roof
(Fig. 14). The incidence of intracranial penetration during functional endo-
scopic sinus surgery (FESS) is higher when this anatomic variation occurs.
Intracranial penetration is more likely to occur on the side where the posi-
tion of the roof is lower (23).

Acquired abnormalities of the sinus walls such as osteoma and fibrous
dysplasia are relatively common and usually asymptomatic. They can pre-
sent with sinus-related complaints when they interfere with sinus drainage.

IMAGING RHINOSINUSITIS

Acute Rhinosinusitis

Air-fluid levels and complete opacification of a sinus are the imaging
hallmarks of acute rhinosinusitis (ARS) (Fig. 15). More than one sinus
are usually involved, typically the maxillary and the ethmoid sinuses. CT
is much more sensitive than plain radiographs. Air-fluid level is a very

Aygun et al.

Figure 13 Cephalocele: CT-cisternogram in the coronal plane demonstrates CSF
containing sacs in the pterygoid recesses of the sphenoid sinus.

Figure 1 4 Low fovea ethmoidalis: the left cribriform plate is more inferiorly posi-
tioned than the right.

Imaging Sinusitis

Figure 15 Characteristic CT appearance of acute sinusitis on axial contrast-
enhanced image: low attenuation fluid retention in the sphenoid and ethmoid
sinuses with air fluid levels. Also note that the patient has left preseptal cellulitis.

specific sign for ARS in the appropriate clinical setting. Other causes of altered
air-fluid level in a sinus include trauma, prolonged supine position, and intuba-
tion (typical ICU patient), recent nasal irrigation, cerebrospinal fluid (CSF)
leak, and chronic rhinosinusitis (CRS). ARS is diagnosed on the basis of his-
tory, clinical presentation, and physical examination. Imaging is not recom-
mended for diagnosing ARS because of the cost-containment concerns and
radiation exposure, unless the patient is not responding to initial treatment
or there is a complicating factor (33-35). A limited sinus CT consisting of five
to six axial noncontiguous images is utilized in many practices for the initial
diagnosis of ARS. The charge for limited sinus CT is only slightly higher than
the charge for plain radiographs and the radiation dose is reduced, while the
diagnostic accuracy remains reasonably high. The cost-effectiveness of limited
sinus CT exam, which changes with evolving technology and its impact on
treatment plan, has not been well studied (36). When the clinical question is
whether there is sinusitis or not, a limited sinus CT would be adequate. The
reduced cost and radiation dose of limited sinus CT cannot be used as a
justification for imaging of uncomplicated ARS. Authors believe that the
diagnosis of ARS should be made clinically, and that when imaging is
necessary, a "high quality" CT exam should be performed.

ARS is often a self-limited disease and symptoms subside with or even
without treatment; however, in rare instances, catastrophic complications

Aygun et al.

Figure 16 Sub-periosteal abscess: contrast-enhanced coronal CT shows acute sinu-
sitis of the left maxillary and ethmoid with a peripherally enhancing fluid attenua-
tion mass in the left extraconal orbit.

occur. Because of the close proximity of the sinuses to the brain and orbit,
and the naturally present dehiscences and vascular channels in the sinus
walls, infection can spread to the orbit and intracranial compartment.
Sub-periosteal phlegmon and abscess result when the infection is limited
by the intact periorbita (Fig. 16). Penetration of the periorbita allows infec-
tion to spread to the orbital soft tissues causing orbital cellulitis, which may
lead to permanent loss of vision. Intracranial complications such as menin-
gitis, epidural and subdural empyema, brain abscess, and cavernous sinus
thrombophlebitis typically occur in the setting of frontal and sphenoid sinu-
sitis (Fig. 17). Early identification and treatment are essential in preventing
catastrophic results. Contrast-enhanced CT detects most orbital complica-
tions. MRI is the study of choice for intracranial extension.

Subacute Rhinosinusitis

Subacute rhinosinusitis is clinically defined as persistence of symptoms for
more than four weeks and up to 12 weeks. There is no specific radiological
sign for subacute rhinosinusitis and a typical CT study shows some opacifi-
cation of one or more sinuses.

Chronic Rhinosinusitis

The term chronic rhinosinusitis (CRS) is preferred because rhinitis almost
always precedes sinusitis and sinusitis occurs concurrently with inflammation

Imaging Sinusitis

Figure 17 Subdural empyema: axial (A) T2-weighted and (B) post-contrast
Tl -weighted MRI show subdural collections on this patient who was diagnosed with
acute frontal sinusitis one week prior to this MRI.

of the nasal passages (37,38). CRS diagnosis is symptom-based and requires
persistence of patient complaints for more than 12 consecutive weeks. Since
many clinical symptoms of CRS are vague, subjective, and nonspecific,
objective demonstration of mucosal inflammation is necessary to confirm
the clinical diagnosis (37,39-41). Anterior rhinoscopy may not always be able
to confirm the presence of mucosal inflammation, and nasal endoscopy is
required to visualize the middle meatus and ethmoid bulla (41). CT, as
the imaging standard for evaluation of the sinuses, is an excellent tool to
confirm the presence and assess the extent of inflammation in the sinonasal
cavity beyond what is permitted by endoscopy (5,42). The plain radio-
graphs lack the sensitivity, specificity, and anatomic precision needed for
the management of these patients and are simply inadequate. Limited
sinus CT examinations which employ selected, noncontiguous axial slices
may be adequate in some clinical scenarios when the patient had a thor-
ough evaluation of the anatomy with a high quality CT previously. One
has to keep in mind, though, that the limited sinus study is limited not
only in cost and radiation exposure, but in information as well.

Although CT provides excellent information about the extent and
distribution of mucosal disease and status of the nasal air passages, it does
not yield much information about the origin of the changes (e.g., infection,
allergies, granulomatous inflammation, postsurgical scarring, etc.).

The CT signs suggestive of CRS include diffuse or focal mucosal thick-
ening, partial or complete opacification, and bone remodeling and thicken-
ing caused by osteitis from adjacent chronic mucosal inflammation and
polyposis (Fig. 18). The distribution of the inflammatory mucosal changes

Aygun et al.

Figure 18 Diffuse nonspecific CRS: bilateral ethmoid and maxillary opacification.
Note prior uncinectomy, middle turbinectomy, and ethmoidectomy.

in the nasal cavity and sinuses may provide a clue as to the level of mechan-
ical obstruction. Babble et al. (43) defined five recurring patterns of inflam-
matory sinonasal disease including infundibular, OMU, sphenoethmoidal
recess, sinonasal polyposis, and sporadic or unclassifiable disease. In this
study, the infundibular pattern (26% of patients) referred to the focal
obstruction within the maxillary sinus ostium and ethmoid infundibulum
that was associated with maxillary sinus disease. The OMU pattern (25%
of patients) referred to ipsilateral maxillary, frontal, and anterior ethmoid
sinus disease. This pattern was caused by obstruction of the middle meatus.
The frontal sinus is sometimes spared because of the variability in frontal
sinus drainage pathway. The sphenoethmoidal recess pattern (6% of patients)
resulted in sphenoid or posterior ethmoid sinus inflammation caused by
sphenoethmoidal recess obstruction. Diffuse nasal and paranasal sinus
polyps occurred in 10% of the study population (sinonasal polyposis
pattern). One-fourth of the patients in this study did not show a recognizable
pattern. Zinreich and others found middle-meatus opacification in 72% of
patients with chronic sinusitis; 65% of these patients had mucosal thickening

Imaging Sinusitis 77

of the maxillary sinus (20,21,26). The patients with frontal sinus inflamma-
tory disease had opacification of the frontal recess (20,21,26). Frontal sinus
opacification involving the OMU without maxillary or anterior ethmoid
sinus inflammatory disease was rare (20,21,26). Yousem et al. (44) found that
when the middle meatus was opacified, associated inflammatory changes
occurred in the ethmoid sinuses in 82% of patients and in the maxillary
sinuses in 84%. Bolger et al. (45) found that when the ethmoid infundibulum
was free of disease, the maxillary and frontal sinuses were clear in 77%
of patients. Certain anatomic variants, as described, have been implicated
as causative factors in the presence of chronic inflammatory disease. Lidov
and Som (46) found that a large concha bullosa could produce signs and
symptoms by narrowing the infundibulum. However, Yousem et al. (44)
found that the presence of a concha bullosa did not increase the risk of sinu-
sitis. This was corroborated by Bolger et al. (45) who found that concha bul-
losa, paradoxic turbinates, Haller cells, and uncinate pneumatization were
not significantly more common in patients with chronic sinusitis than in
asymptomatic patients. Yousem et al. (44) found that nasal septal deviation
and a horizontally oriented uncinate process were more common in patients
with inflammatory sinusitis. Although these variants may not necessarily pre-
dispose to sinusitis, the size of a given anatomic variant and its relationship to
adjacent structures are important in the development of sinusitis (19).

When sinus secretions are acute and of low viscosity, they are of inter-
mediate attenuation on CT (10-25 Hounsfield units). In the more chronic
state, sinus secretions become thickened and concentrated, and the CT
attenuation increases with density measurements of 30 to 60 Hounsfield
units (Fig. 19) (47).

Sinonasal polyposis has been recognized as a distinct form of
CRS, both clinically and radiographically, although polyp formation is a
nonspecific response to variety of inflammatory stimuli (Fig. 20). There is
an obvious association with asthma, aspirin-sensitivity, and eosinophilia.
The pathogenesis of sinonasal polyposis is very complex and not clearly
understood (48-50). However, high recurrence rate of sinonasal polyposis
is well documented (51-54). Antrochoanal and sphenochoanal polyps
appear as well-defined masses that arise from the maxillary or sphenoid
sinus and extend to the choana through the middle meatus or sphenoeth-
moid recess, respectively (Fig. 21). They can present as nasopharyngeal
masses. It is important to recognize their origin and relation to the maxillary
or sphenoid ostium in treatment planning.

Retention cysts are very common incidental findings in imaging studies
and seen as very well-defined rounded masses, typically in the maxillary sinus
floor (Fig. 22). Their clinical significance is not clear (55). They may become
symptomatic if large enough to interfere with drainage pathways (56).

Mucoceles, a complication of CRS, result from the obstruction of the
sinus drainage and subsequent expansion of the sinus (Fig. 23). Mucoceles

Aygun et al.

Figure 1 9 Right-sided ethmoid and maxillary sinusitis with obstruction of the ostio-
meatal unit is demonstrated on this coronal CT image. The central high attenuation
in the maxillary sinus suggests chronic secretions with high protein content.

are more commonly seen in the ethmoid and frontal sinuses and present
with symptoms secondary to compression of the adjacent structures in addi-
tion to usual symptoms of CRS. Thickening and sclerosis of the bony walls
of the sinuses (Fig. 24) have been traditionally attributed to the secondary
reaction of the bone to a chronic mucosal inflammation. More recent work
suggests that the bone may actually play an active part in the disease process
and that the inflammation associated with CRS may spread through the
haversian system within the bone (57,58). The combination of a surgical
procedure and experimentally induced sinusitis creates an inflammatory
process within bone with the classic histological features of osteomyelitis.
Furthermore, bone inflammation may induce chronic inflammatory changes
in the overlying mucosa at a significant distance from the site of infection.
Identification of bone thickening and sclerosis on CT exam is straightfor-
ward, due to CT's exquisite ability to show the bone detail.

Imaging Sinusitis

Figure 20 Typical CT appearance of sinonasal polyposis in the coronal plane.

On MRI, the appearance of CRS varies because of the changing
concentrations of protein and free water protons (59). Som and Curtin
(47) describe four patterns of MRI signal intensity that can be seen with
chronic sinusitis: (1) hypointense on Tl -weighted images and hyperintense
on T2-weighted images with a protein concentration less than 9%; (2)

Figure 21 Antrochoanal polyp: coronal CT images show a nasopharyngeal mass
that can be followed to the expanded maxillary ostium. The right maxillary sinus
and nasal fossa are opacified.

Aygun et al.

Figure 22 Typical appearance of a retention cyst.

Figure 23 Frontal mucocele. Coronal CT image shows expansion of the left frontal
sinus into the orbit with marked thinning of the sinus wall.

Imaging Sinusitis

Figure 24 CRS and osteitis: marked thickening of the sinus walls.

hyperintense on Tl -weighted images and hyperintense on T2-weighted
images with total protein concentration increased by 20% to 25%; (3) hyper-
intense on Tl -weighted images and hypointense on T2-weighted images with
total protein concentration of 25% to 30%; and (4) hypointense on Tl-
weighted images and T2-weighted images with a protein concentration
greater than 30% and inspissated secretions in an almost solid form. MRI
of inspissated secretions (i.e., those with protein concentrations greater than
30%) may have a pitfall in that the signal voids on Tl- and T2- weighted
images may look identical to normally aerated sinuses.

The correlation between patient symptoms and CT findings is difficult
to determine partly due to the fact that chronic mucosal inflammation may
be present without the findings identified on CT examinations such as muco-
sal hypertrophy and retained secretions and that a modest amount of
inflammation diagnosed by CT may be present in asymptomatic persons.
Several studies failed to show a correlation between symptom severity and
severity of CT findings (40,41,60-62). Particularly, symptoms such as head-
ache and facial pain do not correlate with CT findings at all (63-65). A posi-
tive correlation between the severity of symptoms and CT findings may be
demonstrated when certain symptoms and negative CT exams are elimi-
nated (66,67). The nasal endoscopy findings correlate with CT findings,
though the correlation is less than perfect (41,63,68). The positive predictive
value of abnormal endoscopy for abnormal CT is greater than 90%, whereas
the negative predictive value of normal endoscopy for normal CT is only
70% (41,63).

82 Aygun et al.

To better classify patients into diagnostic and prognostic categories,
various symptom-, CT-, and endoscopy- scoring systems have been used.
The Lund-MacKay scoring system is the most popular method applied to
CT description of sinus disease because of its simplicity and reproducibility
(69). A score of 0, 1, or 2 is given to each of the five sites (anterior ethmoid,
posterior ethmoid, frontal, maxillary, and sphenoid) on both sides of the
sinonasal cavity for normal pneumatization, partial opacification, or com-
plete opacification, respectively (70,71). The ostiomeatal complex receives
either or 2. This yields a maximum score of 12 for one side.

In a small study, the impact of CT on treatment decision was evalu-
ated (36). CT changed the treatment in one-third of the patients and pro-
vided better agreement on treatment plan among ENT surgeons (36).

Fungal Rhinosinusitis

Fungal rhinosinusitis (FRS) differs from bacterial and other types of sinusi-
tis not only in etiology but also in demographics of the effected population,
clinical approach, diagnosis, treatment, and prognosis. There are two main
forms of FRS: invasive and noninvasive (72). Within these categories, five
clinicopathologically distinct entities are defined (73): (i) acute invasive,
(ii) chronic invasive granulomatous form, (iii) chronic invasive nongranulo-
matous form, (iv) fungus ball and (v) allergic fungal sinusitis. It must be
emphasized that FRS is a spectrum of disease and the differences in clinical
presentation are largely determined by the host defense system. Therefore, it
is not uncommon to see overlapping clinical and imaging features.

Acute Invasive FRS

Acute invasive FRS is seen primarily in immunocompromised patients and
is fatal if untreated. A high index of clinical suspicion and biopsy of the mid-
dle turbinate are necessary for early diagnosis, which may be life-saving (74).
CT study obtained early in the disease course may be normal or show non-
specific mucosal thickening indistinguishable from the appearance of bacterial/
viral disease (75) (Fig. 25). Bone destruction and swelling of the soft tissues
adjacent to the paranasal sinuses occur in advanced disease.

Chronic Invasive FRS

Chronic invasive FRS has been associated primarily with immunocompro-
mised patients; however, it does occur in the non-immunocompromised as
well and has a more protracted course with relatively slow progression of
disease, sometimes despite treatment, and high recurrence rate. There is
no apparent difference in clinical and radiological features of the granulo-
matous and nongranulomatous forms. The radiological hallmark of chronic
invasive FRS is bone destruction, which is better depicted with CT, whereas
MRI better defines the soft-tissue extent of disease and brain involvement.

Imaging Sinusitis

Figure 25 Acute invasive fungal sinusitis. On this patient with advanced leukemia
and prior sinus surgery, axial CT shows nonspecific mucosal thickening in the eth-
moid cells. Biopsy proven acute invasive sinusitis.

Foci of increased attenuation (on CT) in the sinus mucosal thickening may
indicate fungal colonization as found in 74% of our patient population (76).
The radiological differential diagnosis of chronic invasive FRS is broad and
includes benign and malignant neoplasms, infectious and idiopathic granu-
lomatous diseases, and allergic fungal sinusitis.

Fungus Ball

Fungus ball refers to a sinus mass that consists of packed hyphae. Patients
with fungus ball are typically immunocompetent and present with varying
nonspecific sinus-related complaints. Serendipitous identification of fungus
balls is not uncommon. Diffuse opacification of a single sinus is the most
common radiographic feature (77). Foci of hyperattenuation in the center of
the sinus mass is seen in approximately 50 to 74% of the patients
(75,77,78). Large calcified concretions are characteristic of the disease but
uncommonly found (Fig. 26). Thickening of the sinus walls is common.
Bone erosion may occasionally be seen.

Allergic FRS

Allergic FRS, an immunologically mediated hypersensitivity reaction to
fungi, is the most common fungal disease of the sinuses (79). A central area
of hyperattenuation on sinus CT is almost always present and corresponds
to markedly decreased T2 signal on MRI. This appearance is due to the
metabolized ferromagnetic elements (primarily iron) and calcium within
the concretion (Fig. 27). Expansion of the involved sinuses with bone remo-
deling or destruction is common.

Aygun et al.

Figure 26 Fungus ball: dense calcification in the center of the completely opacified
left maxillary sinus is shown on this coronal CT image.

Saprophytic Colonization

Saprophytic colonization of the sinonasal mucosa is very common, parti-
cularly in patients who had undergone sinus surgery, and mere presence
of fungi on the mucosa does not necessarily constitute the disease.

PRESURGICAL IMAGING EVALUATION

Using a systematic approach is helpful when interpreting sinus CT
studies. One must identify and describe the important structures of the
paranasal sinuses including the frontal sinus, the FSOT, the agger nasi
cell and anterior ethmoid sinus, the ethmoid roof, the ethmoid bulla,
the uncinate process, the infundibulum, the maxillary sinus, the middle
meatus, the nasal septum and nasal turbinates, the basal lamella, the
sinus lateralis, the posterior ethmoid sinus, the sphenoid sinus, and the
sphenoethmoidal recess.

The symmetry of the ethmoid roof should be noted. If not recognized,
discrepant heights of the ethmoid roof may lead to inadvertent penetration
of the cranial vault during surgery (23).

Imaging Sinusitis

Figure 27 Allergic fungal sinusitis (AFS): axial (A) and coronal (B) CT, axial
T2-weighted and post-contrast coronal Tl -weighted MRI. Predominantly high
attenuation, heterogeneous mass in the right-sided sinuses with erosion into the orbit,
the middle, and posterior cranial fossae. Note that the mass in the sphenoid and parts
of the ethmoid sinuses shows essentially no signal on T2-weighted MRI.

Careful attention should be paid to the status of the lamina papyracea,
and any dehiscence or excessive medial deviation of this bone should be
reported. The relationship of the sphenoid sinus and posterior ethmoid air
cells with the internal carotid artery and optic nerves should be noted. In
particular, extensive expansion of the sinuses around the internal carotid
artery or the optic nerve and bony dehiscences adjacent to either structure
should be noted. The incidence of bony dehiscence around the parasellar

Aygun et al.

portions of the internal carotid artery is 12% to 22% (80). The carotid canal
frequently penetrates the aerated portion of the sphenoid sinus; in many
cases, the sphenoid sinus septa will adhere to the bony covering of the
carotid canal. The surgeon needs to be aware of this variation to prevent
fracture of the sphenoid sinus septum-carotid canal junction and avoid
puncturing the carotid canal. Cephaloceles can be present in the sphenoid
and ethmoid sinuses and mimic inflammatory disease. Any bony dehiscence
should be evaluated with the possibility of encephalocele in mind.

The relationship between the posterior paranasal sinuses and the optic
nerves is important to note to avoid operative complications (Fig. 28).
Delano et al. (81) classified this relationship into four categories depending
on the relationship of optic canal and sphenoid and posterior ethmoid
sinuses. In this study, the optic nerve canal was dehiscent in all cases in which
it traveled through the sphenoid sinus (type 3), in 82% of cases in which the
nerve impressed on the sphenoid sinus wall (type 2), and in 77% of cases in
which the anterior clinoid process is pneumatized. The presence of anterior
clinoid process pneumatization is an important indicator of optic nerve
vulnerability during FESS because of frequent associations with bony dehis-
cence and type 2 and 3 configurations.

Hypoplastic maxillary sinus is usually accompanied by variations in
the lateral nasal wall anatomy and orbital floor, which may give rise to sur-
gical complications, if not recognized (30,31).

The bony outline of the nasal cavity and paranasal sinuses must be
examined with particular attention to absence of bone. Surgical removal of
bone should be documented. Bone erosion or destruction may be secondary

Figure 28 Contrast-enhanced coronal CT image of the sphenoid sinus: aerated
anterior clinoid processes with bulging of the optic nerves into the sphenoid sinus.

Imaging Sinusitis 87

to mucocele or neoplasm; the associated mAss and pattern of bone involve-
ment are helpful clues as to the cause, and MRI may distinguish between
these processes.

POSTSURGICAL IMAGING EVALUATION

The presence or absence of important structures should be identified and
mentioned. The nasal cavity and paranasal sinus boundaries and important
anatomical relationships should be inspected. Areas of bony thickening or
dehiscence should be noted.

The following merit close scrutiny on follow-up CT scan:

The frontal recesses should be identified to determine their patency.
Postoperatively, recurrence of disease is caused by persistent
obstruction in this area, which is the narrowest channel within
the anterior ethmoid complex and is difficult to access surgically.
Therefore, the frontal recess is most likely to be affected with
inflammatory disease in a patient who underwent previous surgery
in the paranasal sinuses. The agger nasi cell (if it remains) should be
noted because of its persistence may continue to narrow the frontal
recess. In patients who had partial middle turbinate resection, one
should look for lateralization of the remnant middle turbinate
which may be the cause of obstruction of the frontal recess, middle
meatus, and/or infundibulum.

The extent of the excision of the uncinate and removal of the ethmoid
bulla should be noted. The course of the infundibulum should be
examined for persistent anatomic narrowing. Careful attention
should be paid to the vertical attachment of the middle turbinate
to the cribriform plate and to the attachment of the basal lamella
to the lamina papyracea. Traction on the vertical attachment and
basal lamella of the middle turbinate during the course of middle tur-
binectomy can fracture the lamina papyracea or the cribriform plate.

The course of the lamina papyracea should be inspected to evaluate
the integrity of this structure. Postoperative dehiscences are com-
monly found posterior to the nasolacrimal duct and may be caused
by the uncinate resection.

Asymmetry in position of the roof of the ethmoid sinus should be
noted. Intracranial penetrations are usually on the side where the
position of the roof is lower.

SURGICAL COMPLICATIONS

In general, complications can be divided into minor and major (22,23,82).
Minor complications include periorbital emphysema, epistaxis, postoperative

88 Aygun et al.

nasal synechiae, and tooth pain. Although these can commonly occur,
they are usually self-limited and do not require postoperative radiological
evaluation.

Major complications are rare but can be severely devastating or fatal
(22). A preexisting loss of integrity of the lamina papyracea can permit
intraorbital fat to herniate into the ethmoid sinuses. Preexisting dehiscence
of the lamina papyracea may be caused by prior trauma or erosion from
chronic sinus disease. Disruption of the lamina papyracea can occur during
resection of the middle turbinate if the basal lamella is resected back to its
attachment to the lamina papyracea.

The medial rectus muscle, superior oblique muscle, or other orbital
contents can be directly damaged if preexisting or intraoperative disruption
of the lamina papyracea occurs (83). If intra-orbital and intraocular pressure
builds up as a result of an expanding hematoma or air being forced into the
orbit from the nasal cavity (through a dehiscent lamina papyracea), then
visual impairment or blindness secondary to ischemia can result (83).

Temporary or permanent blindness caused by injury of the optic nerve
can occur during posterior ethmoidectomy if the bony limit of the sinus is
violated (22,23,82,83). Trauma to the vessels supplying the optic nerve also
can result in visual loss.

Perforation of the cribriform plate can lead to intracranial hematoma,
infection, and cerebrospinal fluid (CSF) leak.

Massive hemorrhage from direct injury to major vessels can occur.
Laceration of the internal carotid artery has been reported and is often fatal
(22,23). Emergent angiography and balloon occlusion of the lacerated artery
have been performed. Patients who report severe postoperative headache or
photophobia or who have signs that suggest subarachnoid hemorrhage
should undergo noncontrast head CT. If subarachnoid blood is found, cere-
bral angiography is recommended to detect vascular injury. Injury to the
nasolacrimal duct can result during anterior enlargement of the maxillary
ostium in the middle meatus. Injury to the membranous portion of the duct
may be self-limited and remit by spontaneous fistulization into the middle
meatus. Stenosis or total occlusion of the nasolacrimal duct can result from
more severe injury (83).

Postoperative CSF leak due to inadvertent penetration of the dura is
another major complication of FESS. A CSF leak may not become clinically
apparent for up to two years after surgery (23). CSF leaks will often close spon-
taneously with conservative measures (e.g., lumbar drain). However, if they
persist, radiological workup is indicated. In many institutions, a radionuclide
CSF study is the initial radiological screening examination in such patients.
Three to four absorbent pledgets are placed on each side of the nasal cavity
and 400 to 500 uCi of indium-Ill (lll-In)-labeled DTP A is instilled into
the subarachnoid space through a cervical or lumbar puncture. Then, the
patient undergoes imaging with a gamma camera at multiple intervals for

Imaging Sinusitis 89

up to 24 hours. Any position or activity known to provoke the leak is encour-
aged. Although images of the head and neck are obtained, evidence of the leak
is unusual on these images. Rather, indirect signs of leaking are sought. Images
over the abdomen are done to search for activity in the bowel, which indicates
that the patient is swallowing CSF as it leaks into the nasal cavity.

At 24 hours, the nasal pledgets are removed and assayed. The results
are compared with 1 1 1-In activity in a serum sample drawn at the same time.
A ratio of pledget activity to serum activity is determined. It is then possible
to predict the general area of the leak based on which pledgets show
increased activity. If none of the pledgets have increased activity but activity
over the abdomen is increased, the radionuclide test is considered positive.

When the radionuclide test is positive (directly or indirectly), a contrast
CT-cisternogram, which involves intrathecal administration of 3-5 ml of
water-soluble contrast media and coronal CT scanning, is done to define
the anatomy and pinpoint the site of leakage.

COMPUTER-AIDED SURGERY

Computer-aided surgery (CAS) is being increasingly utilized in FESS (84).
CAS offers many advantages including real-time correlation of CT images,
surgical field, and position of the surgical devices. Delicate anatomic dissec-
tion, yielding more complete surgeries in difficult places and fewer complica-
tions, is afforded by CAS. Several CAS systems such as SAVANT
(CBYON, Palo Alto, CA), InstaTrak (Visualization Technology, Woburn,
MA), LandMarX (Medtronic Xomed, Jacksonville, FL), and VectorVision
(BrainLab, Tottlingen, Germany) are in use, and they allow projection of
the location of surgical instruments in the operative field on the CT image
data set. The most important components of a CAS system include registra-
tion and tracking units. Registration involves mapping of certain points in
the preoperative image data set to the corresponding points in the operative
field. To accomplish this, certain anatomic landmarks, special headsets, or
radiopaque fiducial markers placed on the patient's skull can be used.
Tracking systems, using electromagnetic or optical sensors, monitor the
ever-changing position of surgical instruments. The position of instruments
is displayed on the image data. The navigational accuracy is dependent on
the accuracy of registration, tracking, and also the quality of CT image data
set. Through technological advancements, a high level of accuracy (usually
within 1 mm) has been achieved (85-91). An inherent limitation of CAS is
that the surgically created changes are not reflected on CT images since there
is no intraoperative image acquisition.

REFERENCES

1. Engels EA, Terrin N, Barza M, Lau J. Meta-analysis of diagnostic tests for
acute sinusitis. J Clin Epidemiol 2000; 53:852-862.

90 Aygun et al.

2. Aalokken TM, Hagtvedt T, Dalen I, Kolbenstvedt A. Conventional sinus
radiography compared with CT in the diagnosis of acute sinusitis. Dentomax-
illofac Radiol 2003; 32:60-62.

3. Chen LC, Huang JL, Wang CR, Yeh KW, Lin SJ. Use of standard radiography
to diagnose paranasal sinus disease of asthmatic children in Taiwan: compari-
son with computed tomography. Asian Pac J Allergy Immunol 1999; 17:69-76.

4. Varonen H, Makela M, Savolainen S, Laara E, Hilden J. Comparison of
ultrasound, radiography, and clinical examination in the diagnosis of acute
maxillary sinusitis: a systematic review. J Clin Epidemiol 2000; 53:940-948.

5. Benninger MS, Ferguson BJ, Hadley J A, Hamilos DL, Jacobs M, Kennedy
DW, Lanza DC, Marple BF, Osguthorpe JD, Stankiewicz JA, Anon J,
Denneny J, Emanuel I, Levine H. Adult chronic rhinosinusitis: definitions,
diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg
2003; 129:S1-S32.

6. Dammann F, Momino-Traserra E, Remy C, Pereira PL, Baumann I, Koitschev A,
Claussen CD. Radiation exposure during spiral-CT of the paranasal sinuses.
Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 2000; 172:232-237.

7. Duvoisin B, Landry M, Chapuis L, Krayenbuhl M, Schnyder P. Low-dose CT
and inflammatory disease of the paranasal sinuses. Neuroradiology 1991;
33:403-406.

8. Hagtvedt T, Aalokken TM, Notthellen J, Kolbenstvedt A. A new low-dose CT
examination compared with standard-dose CT in the diagnosis of acute sinusi-
tis. Eur Radiol 2003; 13:976-980.

9. Hein E, Rogalla P, Klingebiel R, Hamm B. Low-dose CT of the paranasal
sinuses with eye lens protection: effect on image quality and radiation dose.
Eur Radiol 2002; 12:1693-1696.

10. Kearney SE, Jones P, Meakin K, Garvey CJ. CT scanning of the paranasal
sinuses— the effect of reducing mAs. Br J Radiol 1997; 70:1071-1074.

1 1 . Sohaib SA, Peppercorn PD, Horrocks JA, Keene MH, Kenyon GS, Reznek RH.
The effect of decreasing mAs on image quality and patient dose in sinus CT. Br J
Radiol 2001; 74:157-161.

12. Tack D, Widelec J, De Maertelaer V, Bailly JM, Delcour C, Gevenois PA.
Comparison between low-dose and standard-dose multidetector CT in patients
with suspected chronic sinusitis. Am J Roentgenol 2003; 181:939-944.

13. Zammit-Maempel I, Chadwick CL, Willis SP. Radiation dose to the lens of eye
and thyroid gland in paranasal sinus multislice CT. Br J Radiol 2003; 76:418^120.

14. Zinreich SJ, Kennedy DW, Kumar AJ, Rosenbaum AE, Arrington JA,
Johns ME. MR imaging of normal nasal cycle: comparison with sinus patho-
logy. J Comput Assist Tomogr 1988; 12:1014-1019.

15. Zinreich SJBM, Oliverio PS. Sinonasal cavities: CT normal anatomy,
imaging of the osteomeatal complex, and functional endoscopic surgery.
In: Som PCH, ed. Head and Neck Imaging. 3rd ed. St Louis: Mosby, 1996.

16. Hosemann W. Dissection of the lateral nasal wall in eight steps. In: Wigand M,
ed. Endoscopic Surgery of the Paranasal Sinuses and Anterior Skull Base. New
York: Thieme, 1990.

17. Harnsberger HR. Imaging for the sinus and nose. In: Harnsberger HR, ed.
Hand and Neck Imaging Handbook. St Louis: Mosby, 1990.

Imaging Sinusitis 91

18. Daniels DL, Mafee MF, Smith MM, Smith TL, Naidich TP, Brown WD,
Bolger WE, Mark LP, Ulmer JL, Hacein-Bey L, Strottmann JM. The frontal
sinus drainage pathway and related structures. Am J Neuroradiol 2003; 24:
1618-1627.

19. Yousem DM. Imaging of sinonasal inflammatory disease. Radiology 1993;
188:303-314.

20. Zinreich SJ. Imaging of chronic sinusitis in adults: X-ray, computed tomo-
graphy, and magnetic resonance imaging. J Allergy Clin Immunol 1992; 90:
445-451.

21. Zinreich SJ. Paranasal sinus imaging. Otolaryngol Head Neck Surg 1990;
103:863-868; discussion 868-869.

22. Maniglia AJ. Fatal and other major complications of endoscopic sinus surgery.
Laryngoscope 1991; 101:349-354.

23. Hudgins PA, Browning DG, Gallups J, Gussack GS, Peterman SB, Davis PC,
Silverstein Am, Beckett WW, Hoffman JC Jr. Endoscopic paranasal sinus
surgery: radiographic evaluation of severe complications. Am J Neuroradiol
1992; 13:1161-1167.

24. Buus DR, Tse DT, Farris BK. Ophthalmic complications of sinus surgery.
Ophthalmology 1990; 97:612-619.

25. Zinreich J. Imaging of inflammatory sinus disease. Otolaryngol Clin North Am
1993; 26:535-547.

26. Zinreich SJ, Kennedy DW, Rosenbaum AE, Gayler BW, Kumar AJ,
Stammberger H. Paranasal sinuses: CT imaging requirements for endoscopic
surgery. Radiology 1987; 163:769-775.

27. Jones NS, Strobl A, Holland I. A study of the CT findings in 100 patients with
rhinosinusitis and 100 controls. Clin Otolaryngol 1997; 22:47-51.

28. Laine FJ, Smoker WR. The ostiomeatal unit and endoscopic surgery: anatomy,
variations, and imaging findings in inflammatory diseases. Am J Roentgenol
1992; 159:849-857.

29. Collet S, Bertrand B, Cornu S, Eloy P, Rombaux P. Is septal deviation a risk
factor for chronic sinusitis? Review of literature. Acta Otorhinolaryngol Belg
2001; 55:299-304.

30. Erdem T, Aktas D, Erdem G, Miman MC, Ozturan O. Maxillary sinus hypo-
plasia. Rhinology 2002; 40:150-153.

31. Salib RJ, Chaudri SA, Rockley TJ. Sinusitis in the hypoplastic maxillary
antrum: the crucial role of radiology in diagnosis and management. J Laryngol
Otol2001; 115:676-678.

32. Driben JS, Bolger WE, Robles HA, Cable B, Zinreich SJ. The reliability of
computerized tomographic detection of the Onodi (Sphenoethmoid) cell. Am
JRhinol 1998; 12:105-111.

33. McAlister WH, Parker BR, Kushner DC, Babcock DS, Cohen HL, Gelfand MJ,
Hernandez RJ, Royal SA, Slovis TL, Smith WL, Strain JD, Strife JL, Kanda MB,
Myer E, Decter RM, Moreland MS. Sinusitis in the pediatric population.
American College of Radiology. ACR Appropriateness Criteria. Radiology
2000; 215(suppl):81 1-818.

34. Benninger MS, Sedory Holzer SE, Lau J. Diagnosis and treatment of uncom-
plicated acute bacterial rhinosinusitis: summary of the Agency for Health Care

92 Aygun et al.

Policy and Research evidence-based report. Otolaryngol Head Neck Surg 2000;
122:1-7.

35. Snow V, Mottur-Pilson C, Hickner JM. Principles of appropriate antibiotic use
for acute sinusitis in adults. Ann Intern Med 2001; 134:495-497.

36. Anzai Y, Yueh B. Imaging evaluation of sinusitis: diagnostic performance and
impact on health outcome. Neuroimaging Clin North Am 2003; 13:251-263, xi.

37. Hwang PH, Irwin SB, Griest SE, Caro JE, Nesbit GM. Radiologic correlates of
symptom-based diagnostic criteria for chronic rhinosinusitis. Otolaryngol Head
Neck Surg 2003; 128:489-496.

38. Bhattacharyya N. Chronic rhinosinusitis: is the nose really involved? Am J
Rhinol2001; 15:169-173.

39. Chester AC. Symptoms of rhinosinusitis in patients with unexplained chronic
fatigue or bodily pain: a pilot study. Arch Intern Med 2003; 163:1832-1836.

40. Stankiewicz JA, Chow JM. A diagnostic dilemma for chronic rhinosinusitis:
definition accuracy and validity. Am J Rhinol 2002; 16:199-202.

41. Stankiewicz JA, Chow JM. Nasal endoscopy and the definition and diagnosis of
chronic rhinosinusitis. Otolaryngol Head Neck Surg 2002; 126:623-627.

42. Bhattacharyya N, Fried MP. The accuracy of computed tomography in the
diagnosis of chronic rhinosinusitis. Laryngoscope 2003; 113:125-129.

43. Babbel RW, Harnsberger HR, Sonkens J, Hunt S. Recurring patterns of
inflammatory sinonasal disease demonstrated on screening sinus CT. Am J
Neuroradiol 1992; 13:903-912.

44. Yousem DM, Kennedy DW, Rosenberg S. Ostiomeatal complex risk factors for
sinusitis: CT evaluation. J Otolaryngol 1991; 20:419^124.

45. Bolger WE, Butzin CA, Parsons DS. Paranasal sinus bony anatomic variations
and mucosal abnormalities: CT analysis for endoscopic sinus surgery. Laryngo-
scope 1991; 101:56-64.

46. Lidov M, Som PM. Inflammatory disease involving a concha bullosa (enlarged
pneumatized middle nasal turbinate): MR and CT appearance. Am J Neuror-
adiol 1990; 11:999-1001.

47. Som PM, Curtin HD. Chronic inflammatory sinonasal diseases including
fungal infections. The role of imaging. Radiol Clin North Am 1993; 31:33-44.

48. Bachert C, Hormann K, Mosges R, Rasp G, Riechelmann H, Muller R,
Luckhaupt H, Stuck BA, Rudack C. An update on the diagnosis and treatment
of sinusitis and nasal polyposis. Allergy 2003; 58:176-191.

49. Bernstein JM. The molecular biology of nasal polyposis. Curr Allergy Asthma
Rep 2001; 1:262-267.

50. Pawankar R. Nasal polyposis: an update: editorial review. Curr Opin Allergy
Clin Immunol 2003; 3:1-6.

51. Drutman J, Harnsberger HR, Babbel RW, Sonkens JW, Braby D. Sinonasal
polyposis: investigation by direct coronal CT. Neuroradiology 1994; 36:469^172.

52. Subramanian HN, Schechtman KB, Hamilos DL. A retrospective analysis of
treatment outcomes and time to relapse after intensive medical treatment for
chronic sinusitis. Am J Rhinol 2002; 16:303-312.

53. Scadding GK. Comparison of medical and surgical treatment of nasal polypo-
sis. Curr Allergy Asthma Rep 2002; 2:494-499.

Imaging Sinusitis 93

54. 'Rugina M, Serrano E, Klossek JM, Crampette L, Stoll D, Bebear JP, Perrahia M,
Rouvier P, Peynegre R. Epidemiological and clinical aspects of nasal polyposis in
France; the ORLI group experience. Rhinology 2002; 40:75-79.

55. Bhattacharyya N. Do maxillary sinus retention cysts reflect obstructive sinus
phenomena? Arch Otolaryngol Head Neck Sur 2000; 126:1369-1371.

56. Hadar T, Shvero J, Nageris BI, Yaniv E. Mucus retention cyst of the maxillary
sinus: the endoscopic approach. Br J Oral Maxillofac Surg 2000; 38:227-229.

57. Perloff JR, Gannon FH, Bolger WE, Montone KT, Orlandi R, Kennedy DW.
Bone involvement in sinusitis: an apparent pathway for the spread of disease.
Laryngoscope 2000; 110:2095-2099.

58. Khalid AN, Hunt J, Perloff JR, Kennedy DW. The role of bone in chronic
rhinosinusitis. Laryngoscope 2002; 112:1951-1957.

59. Som PM, Dillon WP, Fullerton GD, Zimmerman RA, Rajagopalan B,
Marom Z. Chronically obstructed sinonasal secretions: observations on
Tl and T2 shortening. Radiology 1989; 172:515-520.

60. Stewart MG, Sicard MW, Piccirillo JF, Diaz-Marchan PJ. Severoty staging in
chronic sinusitis: are CT scan findings related to symptoms? Am J Rhinol 1999;
13:161-167.

61. Bhattacharyya T, Piccirillo J, Wippold FJ II. Relationship between patient-
based descriptions of sinusitis and paranasal sinus computed tomographic
findings. Arch Otolaryngol Head Neck Surg 1997; 123:1189-1192.

62. Ashraf N, Bhattacharyya N. Determination of the "incidental" Lund score for the
staging of chronic rhinosinusitis. Otolaryngol Head Neck Surg 2001; 125:483^86.

63. Rosbe KW, Jones KR. Usefulness of patient symptoms and nasal endoscopy in
the diagnosis of chronic sinusitis. Am J Rhinol 1998; 12:167-171.

64. Shields G, Seikaly H, LeBoeuf M, Guinto F, LeBoeuf H, Pincus T, Calhoun K.
Correlation between facial pain or headache and computed tomography in rhi-
nosinusitis in Canadian and U.S. subjects. Laryngoscope 2003; 113:943-945.

65. Mudgil SP, Wise SW, Hopper KD, Kasales CJ, Mauger D, Fornadley JA.
Correlation between presumed sinusitis-induced pain and paranasal sinus com-
puted tomographic findings. Ann Allergy Asthma Immunol 2002; 88:223-226.

66. Kenny TJ, Duncavage J, Bracikowski J, Yildirim A, Murray J J, Tanner SB.
Prospective analysis of sinus symptoms and correlation with paranasal com-
puted tomography scan. Otolaryngol Head Neck Surg 2001; 125:40-43.

67. Arango P, Kountakis SE. Significance of computed tomography pathology in
chronic rhinosinusitis. Laryngoscope 2001; 111:1779-1782.

68. Kennedy DW, Wright ED, Goldberg AN. Objective and subjective outcomes in
surgery for chronic sinusitis. Laryngoscope 2000; 110:29-31.

69. Friedman WH, Katsantonis GP. Staging systems for chronic sinus disease. Ear
Nose Throat J 1994; 73:480-484.

70. Lund VJ, Mackay IS. Staging in rhinosinusitus. Rhinology 1993; 31:183-184.

71. Lund VJ, Kennedy DW. Quantification for staging sinusitis. The Staging and
Therapy Group. Ann Otol Rhinol Laryngol Suppl 1995; 167:17-21.

72. deShazo RD, O'Brien M, Chapin K, Soto-Aguilar M, Gardner L, Swain R.
A new classification and diagnostic criteria for invasive fungal sinusitis. Arch
Otolaryngol Head Neck Surg 1997; 123:1181-1188.

94 Aygun et al.

73. Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am
2000; 33:227-235.

74. Gillespie MB, Huchton DM, O'Malley BW. Role of middle turbinate biopsy in
the diagnosis of fulminant invasive fungal rhinosinusitis. Laryngoscope 2000;
110:1832-1836.

75. DelGaudio JM, Swain RE Jr, Kingdom TT, Muller S, Hudgins PA. Computed
tomographic findings in patients with invasive fungal sinusitis. Arch Otolaryn-
gol Head Neck Surg 2003; 129:236-240.

76. Zinreich SJ, Kennedy DW, Malat J, Curtin HD, Epstein JI, Huff LC, Kumar
AJ, Johns ME, Rosenbaum AE. Fungal sinusitis: diagnosis with CT and MR
imaging. Radiology 1988; 169:439-444.

77. Klossek JM, Serrano E, Peloquin L, Percodani J, Fontanel JP, Pessey JJ.
Functional endoscopic sinus surgery and 109 mycetomas of paranasal sinuses.
Laryngoscope 1997; 107:112-117.

78. Dhong HJ, Jung JY, Park JH. Diagnostic accuracy in sinus fungus balls:
CT scan and operative findings. Am J Rhinol 2000; 14:227-231.

79. Manning SC, Holman M. Further evidence for allergic pathophysiology in
allergic fungal sinusitis. Laryngoscope 1998; 108:1485-1496.

80. Johnson DM, Hopkins RJ, Hanafee WN, Fisk JD. The unprotected parasphe-
noidal carotid artery studied by high-resolution computed tomography.
Radiology 1985; 155:137-141.

81. DeLano MC, Fun FY, Zinreich SJ. Relationship of the optic nerve to the
posterior paranasal sinuses: a CT anatomic study. Am J Neuroradiol 1996; 17:
669-675.

82. Stankiewicz JA. Complications in endoscopic intranasal ethmoidectomy: an
update. Laryngoscope 1989; 99:686-690.

83. Neuhaus RW. Orbital complications secondary to endoscopic sinus surgery.
Ophthalmology 1990; 97:1512-1518.

84. Citardi MJ. Computer-aided frontal sinus surgery. Otolaryngol Clin North Am
2001; 34:111-122.

85. Khan M, Ecke U, Mann WJ. The application of an optical navigation system in
endonasal sinus surgery. HNO 2003; 51:209-215.

86. Kherani S, Javer AR, Woodham JD, Stevens HE. Choosing a computer-
assisted surgical system for sinus surgery. J Otolaryngol 2003; 32:190-197.

87. Olson G, Citardi MJ. Image-guided functional endoscopic sinus surgery. Oto-
laryngol Head Neck Surg 2000; 123:188-194.

88. Han D, Zhou B, Ge W. Application of an image-guidance system in endoscopic
sinus surgery. Zhonghua Er Bi Yan Hou Ke Za Zhi 2001; 36:126-128.

89. Koele W, Stammberger H, Lackner A, Reittner P. Image guided surgery of
paranasal sinuses and anterior skull base — five years experience with the Insta-
Trak-System. Rhinology 2002; 40:1-9.

90. Zinreich SJ, Tebo SA, Long DM, Brem H, Mattox DE, Loury ME, vander
Kolk CA, Koch WM, Kennedy DW, Bryan RN. Frameless stereotaxic integra-
tion of CT imaging data: accuracy and initial applications. Radiology 1993;
188:735-742.

91 . Anon JB, Klimek L, Mosges R, Zinreich SJ. Computer-assisted endoscopic sinus
surgery. An international review. Otolaryngol Clin North Am 1997; 30:389^401.

SECTION II. ANATOMY AND PATHOPHYSIOLOGY

Anatomy and Physiology of the

Paranasal Sinuses

John H. Krouse and Robert J. Stachler

Department of Otolaryngology Head and Neck Surgery, Wayne State University,

Detroit, Michigan, U.S.A.

INTRODUCTION

A thorough understanding of the functional anatomy and physiology of the
nose and paranasal sinuses is essential in approaching the diagnosis and
treatment of sinonasal diseases in children and adults. By considering the
sequential development of the sinuses with maturation and the intricate
anatomic and physiological mechanisms that are involved in the function of
the sinuses in disease and in health, clinicians will be able to apply these
principles in the effective management of sinonasal pathology. The present
chapter will first review the embryology of the developing nose and sinuses,
and discuss their developmental anatomy throughout childhood (Table 1).
It will also present the anatomy of the adult nose and sinuses in detail, with

Table 1 Developmental Anatomy of the Sinuses in Childhood

Sinus

Develops by

Radiographically
present by

Completed
development by

Ethmoid

In fetal life

Soon after birth

Maxillary

In fetal life

Soon after birth

Frontal

Age 1 or 2

Age 3-6

Sphenoid

Age 3 or 4

Age 8 or 9

12 years of age
12 years of age
18 years of age
Young adulthood

96 Krouse and Stachler

a focus on how these anatomical features affect the sinonasal functions.
Finally, it reviews the relevant aspects of the normal physiology of the nose
and sinuses, and discusses how alterations in these normal physiological
mechanisms can result in acute and chronic diseases in children and adults.

EMBRYOLOGY OF THE NOSE AND PARANASAL SINUSES

The first nasal structures are seen as paired lateral nasal placodes and the
midline frontonasal process by the fourth week of fetal life (1). These nasal
placodes will eventually develop into the nasal cavities and their mucosal
linings. The frontonasal process will become the nasal septum. The nasal pla-
codes will invaginate to form pits that will extend back to the nasopharynx
to define the nasal cavities (Fig. 1).

The initial development of the paranasal sinuses is attributable to the
formation of the lateral nasal wall ridges known as ethmoturbinals (2).
These ethmoturbinals develop throughout fetal life into the various pro-
cesses that will form the mature ethmoid bone. In the seventh to eighth week
of development, five to six ridges begin to appear. Three to four of these
ridges will persist in the mature ethmoid bone. The first ethmoturbinal
regresses and its ascending portion form the agger nasi. The descending
portion forms the uncinate process. The second and third ethmoturbinals
form the middle turbinate and the superior turbinate, respectively. The
fourth and fifth ethmoturbinals form the supreme turbinate. In contrast
to the ethmoid structures described above, the inferior turbinate arises from
a ridge, the maxilloturbinal, which is located inferior to those structures. It
is thus formed from the maxillary bone.

The nasal meati and recesses develop from primary furrows that lie
between the ethmoturbinals (Fig. 1). The furrow between the first and second
ethmoturbinals is called the primary furrow. Its anterior segment develops
into a portion of the frontal recess. The posterior (descending) portion deve-
lops into the ethmoid infundibulum, hiatus semilunaris, and the middle
meatus. The maxillary sinus primordium develops from the inferior aspect
of the ethmoid infundibulum. The second and third furrows form the superior
meatus and the supreme meatus, respectively. The ethmoturbinals cross the
ethmoid complex to attach to the lamina papyracea of the orbit and skull base.
There are numerous furrows that become invaginations or evaginations. Ulti-
mately, these furrows will develop into the ethmoid labyrinth. The secondary
concha or accessory concha of the middle meatus are the names given to the
evaginations. Invaginations are called secondary furrows or accessory meati
of the middle meatus. The ethmoid bulla arises from a secondary lateral nasal
wall evagination. The suprabulbar and retrobulbar recesses (sinus lateralis)
arise from secondary furrows forming above and behind the ethmoid bulla.

The maxillary sinus thus develops from a bud of the infundibulum.
The bud continues to enlarge throughout fetal development. At birth, its

Anatomy and Physiology of the Paranasal Sinuses

*-•

i/", .tr

-D

c/3

• -H

[

-4-»

S-,

,<3

5+H

-^-<

Ci— i

•4—'

<<-(

^-h'

5-H

5>«

IE £

Krouse and Stachler

size is estimated to be 6 to 8 cm (Fig. 2). At four to five months after birth,
the sinus can be seen radiographically as a triangular area medial to the
infraorbital foramen. Rapid growth begins and continues until age three
when growth slows until the seventh year. Growth of the maxillary sinus
then accelerates until the sinus approximates adult size at age 12. Complete
development ends in the late teens (Fig. 3) (3).

(A)

Lateral Palatine
Process

(B)

(C)

Philtrum

Medial Primary Palate

Palatine Process of

Secondary Palate

Location of

Primitive Posterior

Choanae

Definitive Nasal
Septum

Upper Lip

Cum

Nasal Septum

Uvula

Figure 2 Nasal development, ventral view, at: (A) six to seven weeks, (B) seven to
eight weeks, and (C) eight to nine weeks. Source: From Ref. 3.

Anatomy and Physiology of the Paranasal Sinuses

■411 § momhi
Brag 1 vcaf
E5s£3 3 vea*s
8 years
12 yewrj

Figure 3 Development of the maxillary and frontal sinuses at various ages. Source:
From Ref. 3.

Frontal sinus and frontal recess development is more varied. Debate
still exists regarding the exact details. Three theories have been promoted.
The frontal sinus may arise (1) from direct extension of the frontal recess,
(2) from an anterior ethmoid cell, or (3) from the anterior superior aspect
of the ethmoid infundibulum. The frontal sinus is barely perceptible at
age one. Development of the frontal sinus does not characteristically begin
until about the fourth year. Its adult size is attained at nearly age 12. The
sinus continues to develop until the late teens.

A cartilage capsule surrounds the primordial nasal cavity and is
responsible for the bony development of this region. The uncinate process
begins to form by the 10th to 12th week as a bud of cartilage. By the 13th
to 14th weeks, a lateral space develops that becomes the ethmoid infundi-
bulum. At 16 weeks, the future maxillary sinus begins to form from the
infundibulum. The cartilage will resorb or ossify, depending on its location.

The ethmoid sinus can be visualized radiographically at birth; how-
ever, its visualization is more difficult than the maxillary sinuses. The
ethmoid and the maxillary sinuses are the only sinuses to be sufficiently
developed at birth to be clinically significant in the pathogenesis of acute
rhinosinusitis. The ethmoid sinuses continue to develop and are more read-
ily seen at one year of age. By age 12, they have reached their adult size.

100 Krouse and Stachler

The sphenoid sinus is the last sinus to develop. The posterior nasal cap-
sule is invaginated by nasal mucosa at three to four months of fetal growth.
This area enlarges to become a pouch or cavity called the cartilaginous cop-
ular recess of the nasal cavity. When the walls around the cartilage ossify, it
is referred to as the ossiculum Bertini. This ossification occurs in the later
months of fetal development. The cavity does not definitely become the sphe-
noid sinus until the cartilage is resorbed as the ossiculum Bertini becomes
attached to the sphenoid in the second to third year. Only in the sixth to
seventh year does the sphenoid become pneumatized. Complete pneumatiza-
tion does not occur until the 9th to 12th years. Further minor modifications
of the sphenoid sinus occur until the late teens or into early adult life (Fig. 4).

ANATOMY OF THE NOSE AND PARANASAL SINUSES

Understanding the relationship of the bony anatomy of the face and the
pneumatized cells within this bony framework is essential in appreciating
the anatomy of the paranasal sinuses. The structures that make up the
framework of the face include the nasal bones and cartilages, the ethmoid
bones, the maxillary bones, and the frontal and sphenoid bones. The outer
structure of the nose is formed by the paired nasal bones, as well as the
upper lateral and lower lateral cartilages inferiorly. These structures provide
prominence to the nasal pyramid, as well as allowing for an aperture to pro-
vide airflow through the nasal cavity (Fig. 5).

The midline of the nose consists of a structure known as the nasal
septum. This structure is composed of both bone and cartilage, and divides
the nasal cavity roughly into two equal halves. The anterior portion of the
nasal septum is composed of the quadrilateral cartilage, while the more
posterior portion of the septum is composed of the perpendicular plate of

-Adult

Figure 4 Development of the sphenoid sinus at various ages. Source: From Ref. 3.

Anatomy and Physiology of the Paranasal Sinuses

101

©WTTC

Figure 5 Coronal view of the paranasal sinuses. 1. Frontal sinuses. 2. Ethmoid
sinuses. 3. Maxillary sinuses. 4. Nasal septum. 5. Superior turbinate. 6. Middle turbi-
nate. 7. Inferior turbinate. 8. Eustachian tube. 9. Middle ear. 10. Nasolacrimal duct.

the ethmoid bone superiorly and the vomer inferiorly. At its posterior limit,
the vomer ends at the posterior choanae of the nose.

The lateral nasal wall consists of bony prominences covered with
respiratory epithelium that project into the nasal cavity. These prominences
are known as the nasal turbinates (Fig. 6). There is a space that exists under
each of these turbinates that is described as the meatus. There are usually
three turbinates and three meati present in the lateral nasal wall bilaterally.
The largest of these turbinates is the inferior turbinate, which arises from the
maxillary bone and projects into the nasal cavity. In the underlying inferior
meatus, the nasolacrimal duct opens into the nose at the valve of Hassner.

The middle turbinate is a projection of the ethmoid bone into the nasal
cavity. The associated middle meatus is important in understanding paranasal
sinus anatomy and physiology because it is into this meatus that the anterior
sinuses communicate with the nose. More superiorly, a small superior turbi-
nate is usually present in the nose, and forms the medial wall of the posterior
ethmoid sinuses. In the associated superior meatus is an area referred to as the
sphenoethmoidal recess, which is an important region in that the posterior eth-
moid sinuses and sphenoid sinuses communicate with the nose in this location.

The superior portion of the nose is bounded by a portion of the skull base
that is referred to as the cribriform plate. This thin bony plate extends from the
sphenoid sinuses posteriorly to the frontal recess anteriorly. The perpendicular
plate of the ethmoid attaches in the midportion of this structure. The cribri-
form plate is perforated by branches of the olfactory nerve that terminate

102

Krouse and Stachler

Middle ear

Frontal sinus— r-M
Sphenoidal sinus

ear i

LardnMi

Auditory
tube (right)l

Figure 6 Sagittal view of the nose, paranasal sinuses, Eustachian tube, and middle ear.

within the nose to provide sensory input to the olfactory cortex. The cribriform
plate is very thin, usually measuring only 1 to 2 mm in thickness (4).

Ethmoid Sinuses

The primary structure that forms the foundation for the bony anatomy of
the face and sinuses is the ethmoid bone. The ethmoid bones are bilateral
and are bound in the midline by the perpendicular plate. The superior
boundary of the ethmoid bones is the cribriform plate, and the lateral
boundary is the lamina papyracea, a thin bony plate that separates the
ethmoid sinuses from the orbits laterally. Inferiorly, the ethmoid bone
includes the middle turbinates and the lateral nasal wall at the area in which
it fuses with the maxillary bone inferiorly.

The lamina papyracea is an important structure in that it forms the
barrier between the ethmoid sinuses and the orbits. This lamina is very thin
and can be compromised by a variety of processes that originate within the
ethmoid sinuses. Acute infections of the ethmoid sinuses can easily cross this
thin bony barrier, resulting in periorbital or orbital cellulitis or abscess
formation. Inflammatory masses of the ethmoid sinuses, such as mucoceles,
mucopyoceles, and neoplasms, can also compromise this barrier through
erosion or expansion, resulting in orbital injury.

The anatomy of the ethmoid sinuses is complex, due to the variable
pneumatization that occurs within the ethmoid bone during early develop-
ment. The ethmoid sinuses can be best conceptualized as a cluster of cells

Anatomy and Physiology of the Paranasal Sinuses

103

that are divided into discrete anatomic regions by a series of vertical bony
partitions. The cluster of cells that occurs within each ethmoid bone
numbers in the range of 12 to 18 cells and is often referred to as the ethmoid
labyrinth. The pneumatized cells of the ethmoid sinuses can be grouped into
two functional units: the anterior ethmoid cells, which are more numerous
and smaller in size and which communicate with the nose in the middle
meatus, and the posterior ethmoid cells, which are less numerous, larger,
and communicate with the nose in the sphenoethmoidal recess. The ethmoid
sinuses are apparent by the third to fourth month of fetal life, and can be
appreciated radiologically during the first year of life.

The anterior ethmoid cells, along with the frontal sinus and the
maxillary sinus, communicate with the nose through an anatomic region
that is referred to as the ostiomeatal complex (OMC) (Fig. 7). The OMC is
important as a structural unit, in that this area is commonly conceptualized
as of primary importance in the normal functioning of the anterior para-
nasal sinuses. When the structural integrity of the OMC is compromised
and the normal ventilation and drainage of the sinuses is adversely affec-
ted, it is common for the associated sinuses to become secondarily infected.

Figure 7 Coronal CT radiograph of the paranasal sinuses with ostiomeatal complex
outlined. 1. Middle meatus. 2. Uncinate process. 3. Middle turbinate. 4. Ethmoid
sinuses. 5. Maxillary sinuses. 6. Frontal recess. 7. Middle turbinate. Dashed lines outline
the area of the infundibulum and OMC. Abbreviation: OMC, ostiomeatal complex.

104 Krouse and Stachler

The posterior ethmoid sinuses are composed only of several larger air
cells. Posteriorly, the ethmoid sinuses are contiguous with the rostrum of the
sphenoid sinus. Occasionally a single large posterior ethmoid cell will pneu-
matize posteriorly and laterally to the sphenoid sinus. This sphenoethmoidal
or Onodi cell is of importance in that the optic nerve travels along its lateral
aspect and can often be dehiscent.

Maxillary Sinuses

The maxillary bones are bilateral structures that form the projection of the
anterior face. The maxilla consists of a main body and four processes: the
frontal, orbital, alveolar, and palatal processes. It forms the midface and
provides support for the maxillary teeth. The opening of the nasal cavity
enters anteriorly through the maxillary bone at the nostrils bilaterally.
The right and left maxillary bones are contiguous in the midline below
the nose, and their palatal processes extend centrally to form the anterior
portion of the hard palate. The oral cavity is separated from the nose and
maxillary sinuses by this process. The alveolar processes of the maxillary
bones contain the roots of the maxillary teeth.

The orbital processes of the maxillary sinuses make up the medial portion
of the floor of the orbit and support the orbital contents inferiorly. The roof of
the maxillary sinuses, therefore, is bilaterally contiguous with the orbital floor.

Within the maxillary bones are the maxillary sinuses, the largest of the
four pairs of paranasal sinuses (Fig. 8). These sinuses are well developed at
birth and are extensively pneumatized. They are apparent by the third to
fourth month of fetal life, and can be appreciated radiologically during
the first year of life. The maxillary sinuses are surrounded on all sides by
bony walls. The medial wall of the maxillary sinus has an opening between
the maxillary sinus and the nose, referred to as the maxillary ostium. This
opening provides the normal communication between the maxillary sinuses
and the nasal cavity, and it is through this small ostium that the maxillary
sinus is both drained and ventilated. The ostium is a small opening into
the ethmoid infundibulum that is located high on the medial wall of the
maxillary sinus, about in the midportion of the anterior-posterior plane.
This ostium is not normally visible, as it is lateral to the uncinate process
of the ethmoid bone. There are also areas in the medial wall of the maxillary
sinuses where there is the absence of bone and a membranous area separates
the nose from the sinuses. These areas are referred to as fontanelles, and
while more commonly found in the posterior portion of the medial wall,
can also be present more anteriorly as well.

Frontal Sinuses

The superior portion of the face and anterior portion of the skull is
composed of a large, flat bone referred to as the frontal bone. The frontal

Anatomy and Physiology of the Paranasal Sinuses

105

Frontal
ifinuttt

Ethmoid

Maxillary
iinuios

Sphenoid
finui

SJV

Figure 8 Coronal view of the four pairs of paranasal sinuses.

bone forms the contour of the forehead and the floor of the anterior cranial
fossa. It is contiguous with the zygoma laterally and forms the roof of
the orbits medially. It divides into two tables in the forehead, the anterior
and posterior tables, which contain the pneumatized space referred to as
the frontal sinus. The anterior table is palpable and visible as the forehead,
while the posterior table forms the anterior wall of the anterior cranial
fossa.

The frontal sinuses are of variable size and development. They are
absent in up to 10% of individuals. While the average size of each frontal
sinus is about 10 cc, an individual sinus can be much larger. The natural
ostia of the frontal sinuses are found inferomedially, near the midline
septum between the right and left sinuses. They communicate with the nose
through an inverted funnel-shaped region known as the frontal recess. This
area can be narrowed by large ethmoid cells that sometimes interfere with
normal ventilation and drainage of the frontal sinuses.

The frontal bones are not pneumatized until the first or second year of
life, and their definitive shape is not apparent until the third year of life. The
frontal sinuses become pneumatized during this period, and are apparent as
discrete structures between three and six years of age. They continue to
enlarge as frontal pneumatization increases through adolescence.

106 Krouse and Stachler

Sphenoid Sinuses

Within the center of the skull is the sphenoid bone. This structure forms the
major portion of the central skull base, as well as portions of the orbit, lateral
skull, and cranial floor. Superiorly to the sphenoid bone is the sella turcica and
middle cranial fossa. Within the midportion of the sphenoid bone are the sphe-
noid sinuses, small pneumatized spaces measuring 5 to lOcc in size, that pneu-
matize in childhood and often do not complete their pneumatization until early
adult life. These sinuses communicate with the nasal cavity in the sphenoeth-
moidal recesses bilaterally. The natural ostium of the sphenoid sinus is located
in the anterior wall of the sphenoid bone at a location near the superior aspect
of the sinus. This opening is at the inferomedial edge of the superior turbinate,
in a narrow space along the sphenoid rostrum and lateral to the nasal septum.
The sphenoid sinuses are the final sinuses to pneumatize. They begin as
an invagination in the nasal capsule, but are not recognizable as discrete
units until age three or four. They are not radiographically apparent until
age eight or nine, and continue to develop into young adulthood as the sphe-
noid bone completes its pneumatization.

PHYSIOLOGY OF THE NOSE AND PARANASAL SINUSES

The function of the nose is to allow inspired air to enter the upper respira-
tory system and to be delivered to the tracheobronchial tree. The presence of
the turbinates on the lateral nasal walls allows this airflow to be turbulent,
creating eddies in flow as the air moves posteriorly from the nostrils to the
posterior choanae. This flow pattern directs the inspired air to come into
contact with a large surface area of the nasal mucosa as it moves posteriorly,
which allows three physiological functions during flow: filtration, warming,
and humidification (5) (Table 2).

The mucosa of the nasal cavity is a respiratory-type pseudostratified
columnar epithelium. This epithelium is contiguous with the paranasal sinuses,
and it is lined with a surface layer of cilia. The ciliated surface is involved in a
variety of processes, including the transport of mucus and particulate matter
from the nasal cavity into the nasopharynx, where it can be swallowed. This
process is known as mucociliary clearance, and is an essential component of
the normal physiology of the nose and paranasal sinuses. As mucus is produced
by goblet cells in the nasal mucosa, this mucus forms a blanket that lines the
surface of the nasal epithelium. This mucous blanket is involved in filtration
of particulate matter as it enters the nose. This particulate population can be
composed of viral and bacterial organisms; foreign proteins such as animal
dander, dust mite debris, and pollen grains; and irritants such as tobacco
smoke. The filtration and transport of this particulate mass is necessary for
normal sinonasal function. When mucociliary clearance mechanisms are
disrupted, as from allergic or infectious rhinosinusitis, changes can occur in
the underlying mucosa that can lead to chronic dysfunction and disease.

Anatomy and Physiology of the Paranasal Sinuses 107

Table 2 Functions of the Nose and Sinuses

Filtration

Removal of particulate matter

Transport of foreign organisms, irritants, and allergens

Prevention of large particles from reaching the lower airway
Warming

Increasing temperature of inspired, cold air

Delivering warm air to the lower airway
Humidification

Increasing humidity of inspired, dry air

Delivering moist air to the lower airway

Mucociliary clearance

Movement of mucus blanket through the sinuses and nose

Transport of mucus blanket to the pharynx
Ventilation

Increases oxygen tension in the sinuses

Allows normal environment for respiratory epithelium

In addition to the filtration function of the nasal cavity, the nose is
involved in both the warming and humidification of inspired air. The inhala-
tion of warm, moist air into the lower respiratory tract is important in
maintaining optimal function of the bronchopulmonary system. When this
important function of the nose is inoperative, cold, dry air can be delivered
to the lungs, which can increase the likelihood of acute bronchospasm, short-
ness of breath, and infection. Chronic nasal dysfunction can contribute signi-
ficantly to lower respiratory diseases such as asthma and chronic bronchitis.

This mucociliary clearance mechanism is also present in the paranasal
sinuses. Since the epithelium is the same throughout the upper respiratory sys-
tem, the mucosa lining the sinus cavities also actively produces mucus that
must be cleared into the nasopharynx and swallowed. Mucociliary clearance
within the sinuses is genetically programmed in such a manner as to direct the
flow of mucus from the sinuses in a predetermined, predictable pattern from
the interior of each sinus to the natural opening or ostium of the sinus, and
into the nose itself (6). Disruptions in the normal clearance of mucus from
the sinus chambers results in mucous stasis within the sinuses, which leads
to a sequence of events that predisposes those sinuses to both acute and
chronic dysfunction and infection. Ventilation of air into the sinuses and drai-
nage of mucus from the sinuses is central in the normal physiologic function
of the sinuses, and interference with this ventilation and drainage is a key
component in the pathogenesis of acute and chronic rhinosinusitis (7).

As was previously discussed, each of the sinuses communicates with
the nasal cavity through a precise anatomical location. The anterior ethmoid
and maxillary sinuses communicate with the nose through a common passage
way, known as the OMC. Since the ethmoid infundibulum is the final space

108 Krouse and Stachler

through which these sinuses communicate with the nose, disease in the ethmoid
is common in most cases of acute and chronic rhinosinusitis. For this reason,
the ethmoid sinuses are often considered to be the "seat of sinus disease.''

The frontal sinuses also communicate with the nose anteriorly, but
their pattern of ventilation and drainage is somewhat variable. In about
two-thirds of individuals, the frontal sinuses communicate with the ethmoid
infundibulum directly, with the frontal recess opening lateral to the bulla
ethmoidalis into the hiatus semilunaris superior. In the remaining one-third
of individuals, the frontal recess communicates medial to the bulla, and
opens directly into the middle meatus just lateral to the attachment of the
middle turbinate. In both of these cases, however, the communication with
the nose is through the middle meatus inferiorly.

Both the posterior ethmoid sinuses and the sphenoid sinus communi-
cate with the nose more posteriorly in an area known as the sphenoethmoidal
recess. This area is in direct communication with the nasopharynx. While
disease in the sphenoethmoidal recess is less frequent than that seen in the
OMC, it is still quite common among patients with acute and chronic sinus
infections.

CONCLUSION

An understanding of the embryology, developmental and adult anatomy,
and physiology of the nose and paranasal sinuses is important in assisting
clinicians with appropriate diagnosis and management of the patient with
nasal and sinus diseases. Ongoing study of the intricate nature of sinonasal
function in disease and in health can provide physicians with a better appre-
ciation of these complex diseases, and can facilitate better outcomes in
children and adults with acute and chronic rhinosinusitis.

REFERENCES

1. Hengerer AS. Embryologic development of the sinuses. Ear Nose Throat J 1984;
63:134-136.

2. Van Alyea OE. Nasal Sinuses: an Anatomic and Clinical Consideration, 2nd ed.,
Baltimore: Williams & Wilkins, 1951.

3. Naspitz CK, Tinkelman DG. Childhood Rhinitis and Sinusitis: Pathophysiology
and Treatment. New York: Marcel Dekker, 1990.

4. Kennedy DW, Bolger WE, Zinreich SJ. Diseases of the Sinuses: Diagnosis and
Management. Philadelphia, BC: Decker, 2001.

5. Abramson M, Harker LA. Physiology of the nose. Otolaryngol Clin North Am
1973; 6:623-635.

6. Stamberger H. Functional Endoscopic Sinus Surgery: the Messerklinger Techni-
que. Philadelphia, BC: Decker, 1991.

7. Corren J, Togias A, Bousquet J. Upper and Lower Respiratory Disease. New
York: Marcel Dekker, 2003.

Pathophysiology of Sinusitis

Alexis H. Jackman and David W. Kennedy

Department of Otorhinolaryngology Head and Neck Surgery,
University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

INTRODUCTION

A complete understanding of the pathophysiology of rhinosinusitis remains
elusive, but several infectious and inflammatory pathways have been iden-
tified. Microbial agents, such as viruses, bacteria, and fungus, are well-
established etiologies of rhinosinusitis, especially in the acute situation,
but numerous host and environmental factors have also been implicated,
either individually or in combination in the chronic disease state. This
chapter will discuss these various factors as well as the individual and sym-
biotic roles they play in the development of rhinosinusitis. Particular empha-
sis will be placed on current hypotheses regarding the etiology of chronic
rhinosinusitis (CRS) and important new areas of research such as biofilms,
superantigens (sags), and osteitis.

Local Paranasal Sinus Defense Mechanisms

The main function of the paranasal sinuses (PNS) is to eliminate foreign
material and defend the body against infection. Essential local factors in
maintaining normal paranasal sinus function include:

• Ostiomeatal complex (OMC) patency

• Mucociliary transport

• Normal mucus production

109

110

Jackman and Kennedy

Ostiomeatal

complex

Middle
turbinate

Inferior
turbinate

Figure 1 The ostiomeatal complex. Source: Kennedy DW. The concept of the ostio-
meatal complex. Diseases of the Sinuses: Diagnosis and Management. Hamilton:
B.C. Decker, 2001:197.

Ostiomeatal complex (OMC) is the common drainage site of the frontal,
ethmoid, and maxillary sinuses. Although a myriad of variations in the size
and architecture of the OMC exist, patency of this area and its respective
outflow tracks is necessary for the removal of mucus and debris and mainte-
nance of sufficient oxygen tensions to prevent bacterial overgrowth. (Fig. 1).

Recently, acknowledgment of an overemphasis on the role of OMC
patency in CRS has been made, but nonetheless the OMC remains one of
the several important factors in normal paranasal sinus function, and osteo-
meatal obstruction remains a common final pathway in sinus disease becom-
ing chronic. Another major factor in PNS function is mucociliary transport
(MCT). MCT is dependent on both ciliary activity and the rheologic proper-
ties of the mucus. Characteristics of the cilia, such as their structure and
population, as well as the coordination of their movement are important in
their ability to function effectively. Likewise, mucus characteristics, such as

Pathophysiology of Sinusitis

111

I
g

Normal CS

35 dyn/cm 2 746 dyn/cm 2

10 1 1C* 103

G' (dyn/cmz)

! 5

Normal CS

1 .79 poise 56 poise

10° 10 1

tf (poise)

Figure 2 Effects of elasticity and viscosity on mucociliary clearance. Source:
Adapted from Ref. 1.

the volume that is secreted and its viscoelastic properties, are known to affect
overall MCT, with maximal velocities being reported for mucus with an elas-
ticity (G') of about 20 dyn/cm and a viscosity (rf) of 2 poise (1) (Fig. 2).

Systemic Paranasal Sinus Defense Mechanisms

Acquired and innate immunity are systemic defense mechanisms against
infection in the sinonasal tract. Humoral immunity, which is a function of
B-lymphocytes, is predominately mediated by IgA antibodies. Normal mucus
contains large amounts of IgA, which detects and initiates the removal of for-
eign material through a process termed opsinization. Additional antibodies
present in nasal mucosa include IgG and IgE. Although IgE is detected in only
trace amounts in normal individuals, large increases in its relative concentra-
tion are observed in atopic patients with CRS, thereby implicating IgE as
a participant in allergic CRS. IgG plays a less prominent role and is present

112

Jackman and Kennedy

only in minimal concentrations. Cell-mediated immunity involves activated
T-lymphocytes, macrophages, and cytokines. Defensins are antimicrobial
cytokines that are present in the airway surface liquid of the paranasal
mucosa. The cationic defensin polypeptide binds to the outer membrane of
target bacterial, viral, or fungal cells, causing membrane disruption, interna-
lization of defensin, and finally cell death (2,3). In a study comparing the level
of expression of defensins in control patients versus patients with chronic
sinusitis, (3-defensins were detected only in patients with sinusitis. Further-
more, levels of p-defensins were significantly higher in nasal polyp (NP) tissue
than in inferior turbinate tissue in these patients, supporting the role of this
inflammatory mediator in the pathophysiology of CRS (4).

Interruption of the normal functions of the PNS changes the physio-
logical milieu and creates an environment that fosters microbial prolifera-
tion and initiates an inflammatory response. A combination of local and
systemic factors are involved in normal sinus function. An example of this
is given by Goldman et al. (5) in their description of the mucosal surface
of the airway as a "chemical shield," with the airway epithelium producing
mucus-containing salt-sensitive defensins and the mucus having a low-salt
(<50mM NaCl) liquid on the surface that renders the defensins active.
Interruption of any one of the many factors, involved in normal sinus func-
tioning can impact other factors often initiating a cascade of events leading
to CRS, with pathological changes in the sinuses that often begin in or are
accompanied by similar changes in the nasal airway (5,6) (Fig. 3).

1 OMC Patency

|P0 2
Mucus stasis

Inflammation

^Mucociliary
Clearance

jCiliary Function

loss of cilia/ciliary damage
|CBF

AMucus Rheology

J, Production
T mucus viscosity

t Bacterial growth

Figure 3 The pathological cycle of CRS.

Pathophysiology of Sinusitis 113

DEFINITIONS OF RHINOSINUSITIS

Rhino sinusitis is an umbrella term that includes a continuum of inflamma-
tory changes in both the nose and sinuses. Rhinosinusitis describes many
different pathological processes that result in mucosal inflammation of the
nose and PNS. In 1996, a multidisciplinary rhinosinusitis task force (RSTF)
was formed in part to develop working definitions to describe the wide spec-
trum of pathological entities represented. The seminal article, "Adult Rhino-
sinusitis Defined," which summarized these proceedings, defined five separate
categories: acute, subacute, chronic, recurrent acute, and acute exacerbation
of CRS. These categories were defined according to specific major and minor
signs and symptoms associated with rhinosinusitis and the time course
over which they occurred without regard to their specific pathogenesis (7)
(Table 1).

Acute rhinosinusitis (ARS) was defined by the presence of specific signs
and symptoms for a duration of up to four weeks. Using similar clinical
criteria, subacute rhinosinusitis was defined as lasting between 4 weeks and
12 weeks, and recurrent acute rhinosinusitis was defined by four or more epi-
sodes of acute sinusitis with complete symptom remission between episodes.
CRS was defined by the presence of several clinical symptoms for duration
of at least 12 weeks, whereas patients with sudden worsening of persistent
symptoms are classified as having an acute exacerbation of CRS. These
definitions put forth by the RSTF are independent of hypothesized etiol-
ogies and associated disease states, reflecting its members' view of CRS as
an inflammatory disease of uncertain etiologies (7).

ACUTE RHINOSINUSITIS

ARS is most commonly associated with an infectious etiology in both chil-
dren and adults. The type and species of microorganism implicated has been
shown to be age-related in several studies. In children, viral agents such as
adenovirus, influenza virus, parainfluenza virus, and rhinovirus predomi-
nate, although bacterial agents are also common with the major pathogens
being Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and
Moraxella catarrhalis (8,9). Similarly, S. pneumoniae, H. influenzae, and
M. catarrhalis were also identified as the predominant microorganisms in
cases of pediatric subacute rhinosinusitis (10). Anaerobic bacteria have
not been shown to play a major role in pediatric rhinosinusitis. Wald
et al. reported that only one of 47 sinus aspirates was positive for anaerobic
bacteria (11). In adults, S. pneumoniae and non-typeable H. influenzae
account for over 75% of cases of community-acquired acute sinusitis, and
two bacterial species in high density were identified in 25% of cases.
Although S. aureus and Streptococcus pyogenes are uncommon causes of
ARS, they have been associated with serious suppurative processes such

114

Jackman and Kennedy

• 1—t
-4— >

• I— <

• «-^

o
d

•d

d
o

• «-^
-*— >

• i—t

CO
CO

<4-4

-*-»

-4->

-4-»

<h-h

S-H

• y—K

C_)

«■

15
o

-4— <
CO

d
o
o

o
d

-d
d

• I-H

S-H
O
S-H

-D

-d

-4- »

• >-H

S-

-4- '

-4— »

CO
l-l

d
d

• t-H

43
J-H

• i-H
U

-4-»

d
o

f-l

<L>
T3

'd
•r^

•—

-4— »

•>
CO

S-H

-4- '

CO
CO

cx
B

<H-H

+->

O
CX

a
>>

<L>
O

13
o

-4— »

o
-d

-4— »

-4— <

d
o

S-l

-4—*

• t-H

• l-H
>

-d

-4-»

<L>

-4-»

• .-H

lplete resolution after effective
edical therapy

d
o

<H-H

S-H

d
o

• t-H
-4-»

S-H

-d

S-l

-4-»

S-H

d
o

d
Q

d
o

•4-»

^3
Q

• r—t

CO
CO

r/i

-4— »

-4— '

"J?

• t-H

s s

'J?

O
'c?

o
d

-4—'

=3
CX

(Tl

(L>

M
VI

-4-<

•s

c^3

-4-»

•4-»

c^S

S-H

S 1

<L>

t4-l

i-i

'-H

o
CX

-4— »

CO'

• r—>
•4-»

■ •— l

co
O

^3
O

Al
bo

d
o

d
d

-4-<

-t—l

Tt"

-4-»
• i— 1

-4—*

symp
rhino

c^3

'—
'—

Pathophysiology of Sinusitis

115

^-H

CD
d

• i-H

o
-t— »

4-"

J-H

-»— »

• I-H

4d
CD

ctf

-<— '

CO)

bfi

W) 4d

i-H

»H

■*-»

•*->

••~r>

ctf

• >-H

s e

5-i

roi

S-h

-t— »

S-h

'c?

i-H

•J?

d>
o

5-H

cd tfH D. d

co
M

V— I

i-H

4d
U

• »-H

bfl

• •— <

co
u

d
d

2 §

P X 43

S « o

43
M

^ fl>

.22 ^

"h-» Ctf
"33 ^

d •*-»

CO £

.a s

43 CD

i-H S-H

o
S-H

-t-»

• t-H

o
S-H

OX) o ^

73 >>

d "O

• i-H

03 ^3

<D (U

(U -t-;

2 .9

0)
50

o
■ ^*

O o3

• i-H

„ B
-d >>

d
o

.A,

r- c3
ed

d
d

<D T3
>h d

d
ex

'3 ij

TD 03

d T3

03 03

d -rt

CO ^

in c

1) 03
s-

— , bO

03 d

03 o

Ti d

>
03
O

03
I

d q o3

> c3

o3 "l

qd
d

d
* d

50
U

50
,A

o3 o«

C/5 CO

cd 2

d d

■*-* Z3

50 *d

o cd

d r

W OX)

<L)

^ cd

a « 9

8 g

3 S

J -°

co fl

^ a
3 §

d S

d
o

bJ)

2 q

d
o

O o3

0:3 S^

CO CU

.. d

03 o3 03

d -d
03 o
Q-

03
to
03

qd 13

* O

>> >• 43

3h .d ^

<tf > 5

,2 5 ft

d u o

43 ^ H "d

° S S

•-H 1^ -*->

tu 03

42 d

bfl

d
>>

•—

co 43
<D ft

5P .

d d

o -3

O 03
— ft

03 -*— '

d d

d ^3
o -

d
bX)

o
d
(-

-<— <

.03

55 'ft CO

o to E

d O 03

*d »h

43 p -rt

ps^ cu S3

re d 03

d oj

co 43

TD -

43 CD

O >

d ,co

116 Jackman and Kennedy

as orbital and intracranial abscesses. Furthermore, anaerobic bacteria are
also rarely implicated in ARS in adults, and when they are, they are almost
always associated with a primary dental pathology (12).

The pathophysiologic reaction to infectious agents in ARS is the initi-
ation of an inflammatory response, the intent of which is to promote the
removal of foreign material, interrupt inflammatory cascade, and restore
normal sinus function. On a macroscopic level, pathologic changes include
mucosal edema with infiltrates of lymphocytes and plasma cells and loss of
cilia from the respiratory epithelium. Luminal exudates are also found,
which consist of primarily neutrophils and limited amounts of eosinophils
(13-15). Several inflammatory cytokines have been demonstrated in
conjunction with these histopathologic changes. Cytokines such as IL-1B,
IL-6, and TNF-oc are important in inducing the expression of adhesion
molecules and activating endothelial cells and T-lymphocytes. Subsequently,
these activated T-lymphocytes release IL-8, a neutrophil chemotaxic factor,
which further enhances the inflammatory response and eventually leads to
evacuation of the initiating organism (16-19). As the infection resolves,
the inflammatory reaction subsides and the physiologic state is restored.

CHRONIC RHINOSINUSITIS

The specific pathogenesis of CRS remains to be determined. Although in
some cases it may result from a persistent acute infection. It is thought to
arise from multiple heterogeneous etiologies either independently, or more
likely, in combination. The latest publications of chronic rhinosinusitis task
force (CRTF) emphasize the position that it is the resulting end-stage
inflammatory state that defines this disease. Furthermore, the concept of
an integrated airway syndrome has been hypothesized along with rhinitis,
rhinosinusitis, and asthma as a spectrum of manifestations of this single
disease state (8).

In contrast to ARS, the etiology of CRS is thought to be more multi-
factorial with the contribution of several systemic host, local host, and
environmental factors. Systemic host factors include genetic predisposition,
immunosuppression, and primary ciliary dyskinesia (PCD). Local host
factors include anatomical sinus obstruction or local tumors or masses
obstructing the sinuses, and localized persistent inflammation, such as that
in the case of bony inflammation. Environmental factors include bacteria,
viruses, and fungi, as well as pollution, smoking, and allergy. Several micro-
organisms, such as bacteria and fungi, are associated with CRS, but
additional research in this area is necessary to more clearly define their
relative roles. Further understanding of these factors may provide new
approaches to diagnosis and treatment of this disease.

The pathological mechanisms involved in CRS share many similarities
with those of ARS, although distinct differences have been demonstrated.

Pa thophysiology of Sinusitis 117

The gross pathological expression of CRS is more variable, and has been
divided into two major categories — CRS with nasal polyps (CRSwNP)
and CRS without nasal polyps (CRSsNP). CRSwNP is characterized by
extensive mucosal edema with goblet cell hyperplasia and mononuclear cell
infiltration, whereas CRSsNP is often noted to have epithelial damage with
very limited neural structures and goblet cell hypoplasia. Fibrosis is com-
mon in both, but occurs to a greater extent in CRSwNP (20,21). An
increased number of eosinophils is the predominant difference in the cellular
infiltrate between CRSwNP and CRSsNP. Also, increased local production
of IgE has been reported (22). A wide variety of inflammatory mediators
have been demonstrated to be increased in patients with CRSsNP and
include IL-1, IL-6, IL-8, TNF-oc, GM-CSF, ICAM-1, MPO (myeloperoxi-
dase), and ECP (eosinophilic cationic protein) (23-26). Patients with nasal
polyposis (NP) have also been shown to have increased amounts of these
mediators, but additional inflammatory mediators in the subset of patients
with NP include a subset of the IL-8 superfamily referred to as regulated on
activiation- normal T expressed and secreted (RANTES) as well as IL-4 and
IL-5, which have been shown to directly activate and increase the survival of
eosinophils (27,28).

ETIOLOGIES OF CHRONIC RHINOSINUSITIS

A myriad of potential factors predispose an individual to the development of
CRS, and several classification schemes have been developed to assist in the
understanding of the relationship between these factors. One approach to the
variety of proposed etiologies is to divide them into three categories: systemic
factors, local host factors, and environmental factors (Table 2).

Systemic Host Factors

Genetic/Congenital Disorders

Several systemic host factors contribute to the development of CRS. Genetic
abnormalities such as cystic fibrosis (CF) and primary ciliary disorders are inti-
mately associated with CRS. Although these diseases are commonly diagnosed
during childhood, adults with a lifelong history of CRS associated with bron-
chial infection, infertility, or situs inversus should be further evaluated (29). In
patients with CRS, diagnosis of a primary ciliary disorder usually requires a
tracheal biopsy because, intranasally, the acquired ciliary deformities associated
with CRS can be difficult to differentiate from the congenital variant.

CF is one of the most common hereditary diseases and affects approxi-
mately 30,000 people in the United States, having a gene frequency of 1 in
20-25 (30,31). The disease was mapped to the long arm of chromosome 7
(7q31), which encodes a protein product that acts as a chloride channel.
Genetic alterations of this protein allow for increased water absorption from

118 Jackman and Kennedy

Table 2 Etiologic Factors in Chronic Rhinosinusitis

Systemic host factors

Genetic/congenital conditions — cystic fibrosis (CF), primary ciliary disorders (PCD)

Immunodeficiencies/immunosuppression — HIV, iatrogenic-s/p transplant,

chemotherapy
Autoimmune —

Granulomatosis (sarcoid, Wegener's)

Vasculitis (SLE)
Idiopathic — Samter's syndrome
Local host factors
Anatomic abnormalities
Bony inflammation
Neuromechanisms
Mucoceles

Neoplasms (benign and malignant)
Environmental factors

Infectious — bacterial, fungal, biofilms, superantigens
Allergy — IgE-mediated, non-IgE-mediated hypersensitivities
Pollutants — pollution, smoke, dust, volatile organic compounds

the respiratory cells, resulting in increased viscosity and impaired mucociliary
clearance (32). Furthermore, bacterial colonization and infection with Pseudo-
monas aeruginosa, H. influenzae, and anaerobes are frequent and thought to
induce cellular changes such as goblet cell hyperplasia, loss of cilia, and squa-
mous cell metaplasia. Gross pathological changes include nasal polyposis,
which is usually noted in early childhood. In contrast to atopic patients, NP
in patients with CF is not associated with a thickened basement membrane
and an eosinophilic infiltrate (33). Other gross pathological changes include
osteomeatal obstruction secondary to local inflammation and tenacious mucus
(34). Recently, there has been significant interest in whether minor CF varia-
tions may be a factor in CRS. At this point, the evidence for this is limited.
However, some patients with homozygous CF do present only with CRS,
and CF should be suspected in any patient who has had an operation before
the age of 18 years (35).

Another group of genetic disorders commonly associated with CRS is
termed primary ciliary disorder (PCD), which include Kartagener's syn-
drome, immotile cilia syndrome, ciliary dysmotility, and primary ciliary
orientation defects. Although it is rare with a prevalence of approxiamately
1:20,000, the effects on the sinonasal tract are significant (36). PCD is
hypothesized to be a genetically heterogeneous condition as several loci
on various chromosomes have been identified. Abnormalities in ciliary
structure resulting in malfunction characterize this disorder and include a
number of ultrastructural alterations in the ciliary architecture, which range
from complete ciliary aplasia to defects in ciliary orientation (37-39).

Pa thophysiology of Sinusitis 119

Resulting mucus stasis leads to pathological mechanisms similar to CF in
the development of CRS.

Immunodeficiency Diseases

Chronic medically refractive CRS is common in patients with congenital and
acquired immunodeficiencies, as well as those who are immunosupressed.
IgG deficiencies are the most common cause of immunodeficiencies asso-
ciated with CRS (40). CRS frequently occurs in patients with the human
immunodeficiency virus, with a reported rate of 68% of patients with this
disease (41). Endoscopic surgery has been advocated as a treatment for
patients who meet the surgical criteria for surgery regardless of their CD4
count (42). CRS is also commonly diagnosed in patients receiving chemo-
therapy and in patients being treated with long-term immunosuppres-
sive therapies, such as in post-transplant recipients. Furthermore, specific
types of immunodeficiency syndromes are associated with certain infectious
pathogens. Patients with antibody deficiencies are known to have a predispo-
sition to infections with encapsulated aerobic gram-positive organisms as
well as gram-negative organisms. In contrast, CRS patients with T-cell
deficiencies is associated with fungal, viral, and protozoal organisms. In
patients with complement deficiencies, aerobic gram-negative organisms
predominate.

Autoimmune/ldiopathic Diseases

CRS is associated with several autoimmune or idiopathic diseases and may
be their presenting illness. Granulomatous disorders frequently associated
with CRS include sarcoidosis and Wegener's granulomatosis (WG). Sarcoi-
dosis, a chronic granulomatosis disease of unknown etiology, can involve
the upper respiratory tract, although lower respiratory tract involvement
is more common. The pathological hallmark of this disease is a chronic
inflammatory response, which includes non-caseating granulomas. Local
tissue changes range in severity from destruction of cilia and mucus-producing
glands to local tissue destruction (43). WG is a necrotizing granulomatosis
of the upper and lower respiratory tract, and is currently classified as one
of the antineutrophil cytoplasmic antibodies (ANCA)-associated small ves-
sel vasculitides. WG is characterized by autoantibodies to proteinase 3, a
component of neutrophil azurophilic granules, although their detection is
not required for diagnosis (44,45). Sinonasal manifestations, and therefore
CRS, is common in this population and can be severe. Other vasculitides
associated with CRS include systemic lupus erythematosus, Churg-Strauss
vasculitis, relapsing polychondritis, and Sjogrens syndrome (46). Samter's
syndrome, the triad of nasal polyps, bronchial asthma, and intolerance to
aspirin, is a condition of unknown etiology, which is associated with an early
onset of CRS. Typically, these patients present between the ages of 20 and 30
years with nasal congestion and polyposis that respond poorly to medical and

120

Jackman and Kennedy

A B

Figure 4 Coronal CT view of frontal sinus and sagittal MRI view of a patient with
Samter's triad. Note: Sinus opacification and erosion of anterior and posterior table
bone.

surgical management, although they may also present with asthma later in
life (47). Although a genetic component of this syndrome has been
suggested, few studies to date have been conducted (Fig. 4).

Local Host Factors

Anatomic Abnormalities

Local host factors can also play a role in the development of CRS. Anatomic
abnormalities of the sinuses, particularly those causing obstruction or narrow-
ing of the OMC either chronically or intermittently due to an acute inflamma-
tory response, can be associated with CRS. Moreover, since the OMC is
immediately adjacent to the site where the majority of inhaled particulate mat-
ter is deposited, it is one of the most common sites for mucosal inflammation.
Obstruction in the area of the OMC will result in secondary obstruction of the
dependent maxillary and frontal sinuses, and persistent inflammation of the
OMC can result in persistent or recurrent infections (Fig. 5).

The relative contribution of anatomic abnormalities to the develop-
ment of CRS is controversial. The rate of structural sinonasal variations
on CT scans has not been shown to correlate with the rates of development
of CRS (48). However, it appears reasonable that anatomical variations,
such as a markedly deviated nasal septum and aerated middle turbinate
(concha bullosa), both of which narrow the OMC, may predispose to muco-

Pathophysiology of Sinusitis

121

Concha
bullosa

Figure 5 Diagram of ostiomeatal complex with concha bullosa. Source: Cummings
CW: Otolaryngology - Head and Neck Surgery, Update 1, Chapter 4: Kennedy DW,
Zinreich SJ: Endoscopic Sinus Surgery, page 83, figure 4-4, CV Mosby Co. 1989.

ciliary obstruction, subsequent infection, and CRS in patients who also have
other risk factors for CRS. Also, it has been demonstrated that certain ana-
tomical abnormalities were associated with the degree and rate of ethmoid,
maxillary, and sphenoid sinus opacification as determined by CT scan dur-
ing an upper respiratory tract infection. These anatomical abnormalities
included septal deviation, horizontal processes of the uncinate, concha bul-
losa, and Haller cell pneumatization (49).

Iatrogenic Anatomic Abnormalities

Previous surgery and sinonasal trauma may also predispose to sinusitis as
a result of malpositioning and scarring of the sinonasal structures, particu-
larly within the region of the OMC. In a review of the causes of failure of
endoscopic sinus surgeries, Richtsmeier reported obstructed natural ostia
and mucus maltransport among the ten most common reasons for persistent
disease (50).

122 Jackman and Kennedy

Sinonasal Cysts, Mucoceles, and Neoplasms

Local obstruction of the PNS by benign cysts, mucoceles, as well as benign
and malignant neoplasms, can result in rhinosinusitis. Although mostly
asymptomatic, mucous retention cysts that result from the blockage of ser-
omucinous glands in the sinus respiratory epithelium can lead to sinus
obstruction and CRS; mucoceles, expanding mucus-filled cysts that are lined
by entrapped respiratory epithelium, are frequently associated with symp-
toms of unilateral CRS such as sinus tenderness and headache. Mucoceles
commonly arise from an obstructed sinus ostium or sinus septation or from
sequestered sinus epithelium a sinus fracture site. If superinfection occurs, a
mucopyocele is produced. Sinus neoplasms, such as juvenile nasopharyngeal
angiofibroma, inverting papilloma, and various carcinomas, typically pre-
sent with unilateral nasal obstruction, but may also present with symptoms
of unilateral CRS or recurrent ARS, sometimes associated with epistaxis.
Accordingly, tumors need to be considered in the differential diagnosis of
etiology of this disease (51,52).

Persistent Inflammation/Osteitis

Persistent inflammatory changes within the paranasal sinus bones is another
local host factor associated with CRS. Investigations into the role that bony
inflammatory changes play in CRS has begun recently. Histological, and
radiographical changes in the bone are commonly termed "osteitic changes,"
and current research focuses on determining whether or not these areas are a
potential source of persistent inflammation. Using histomorphometry and
radioactive labeling bone studies, the rates of bony turnover in patients with
CRS was found to be markedly increased and comparable to that of patients
with osteomyelitis (53) (Fig. 6).

Although these findings raise the possibility that bacteria may be
present in these areas, PCR studies have yet to confirm their presence. In
studies of pseudomonas-induced maxillary sinusitis using a rabbit model,
inflammatory changes in the bone were noted not only in the adjacent
regions but also distally, apparently from spread through the Haversian
canals (54). Additional studies by Khalid et al. using Pseudomonas and
S. aureus-induced maxillary sinusitis have demonstrated similar results of
increased vascularity, inflammatory infiltrates, and later fibrosis occurring
in the canals of the Haversian system (55).

In summary, there is clear evidence that the bone becomes involved in
the disease process in CRS and that, at least in rabbits, the inflammation in
the bone may be present at a site away from the primary infection. The
pathological changes seen are histologically compatible with chronic osteo-
myelitis, but no organisms have been identified within the bone. Although it
appears very likely that this inflammation within the bone contributes
significantly to the refractory nature of the disease process, this has not

Pathophysiology of Sinusitis

123

Figure 6 Bony Remodeling in CRS. Tetracycline-labeled ethmoid bone at the time
of surgery in a control patient without evidence of infection (A) and in patients with
chronic sinusitis (B). Two doses of tetracycline were given 14 days apart. (A) There
is one line labeling, indicating little bone turnover. (B) There is marked separation
of the two lines of fluorescence, indicating significant bone remodeling within the
14-day period. Source: Kennedy DW. Diseases of the Sinuses: Diagnosis and Mana-
gement. Hamilton: B.C. Decker, 2001: 197.

yet been proven. Continuing work in this area will help to better define the
pathophysiology of bony inflammation.

Environmental Factors

Microorganisms

Bacterial infections: Several prospective and retrospective studies have
been conducted to assess the microbiological etiologies of CRS in both
children and adults. Infectious pathogens such as H. influenzae, S. pneumoniae
and M. catarrhalis, account for up to 55% of cases in pediatric CRS. The

124

Jackman and Kennedy

Figure 7 (Caption on facing page)

Pathophysiology of Sinusitis 125

relative contribution of anaerobic bacteria has been debated, and the large
variations in rates of isolation have been attributed to culture techniques.
Brook reported that up to 50% of cases of CRS were culture-positive for anae-
robic bacteria, with the predominance of Prevotella, Fusobacterium, and
Peptostreptococcus spp. (56,57). In adults, infectious CRS is commonly polymi-
crobial, and both gram-positive and gram-negative aerobic and anaerobic bac-
teria are frequently isolated. A wide variety of aerobic bacteria, such as
coagulase negative Staphylococcus, S. aureus, Streptococcus viridans, P. aerugi-
nosa, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter spp. have been
isolated. Also, several different anaerobic species have been demonstrated,
including Prevotella, Fusobacterium, and Peptostreptococcus spp. (56-64).

Biofilms. Biofilms are sessile bacterial microcolonies that are enclosed
in a highly hydrated polysaccharide matrix with interstitial voids in which
nutrients and signaling molecules can be circulated. The structural and func-
tional heterogeneity of bacterial cells within these communities protects
them against the body's natural defenses and provides them with antimicro-
bial resistance. Through genetic alterations, bacteria in biofilms are also able
to transition to the mobile planktonic form, which has been the traditional
model for studying bacterial diseases (65,66). Bacterial biofilms have been
demonstrated on many areas of mucosa in the human body, including the
ear mucosa and tympanostomy tubes removed from patients with chronic
effusions and infections (67,68). It has been hypothesized that biofilms
may play an important role in cases that are refractory to antibiotic therapy,
and antibiotic resistance has been demonstrated to be up to 1000-fold
greater in bacteria in the biofilm form versus the planktonic form
(66-70). Similarities between chronic otitis media and CRS exist. Both of
these disease processes take place in the ciliated respiratory epithelium
and are largely associated with an infectious etiology. The presence of bac-
terial biofilms in CRS patients with culture-positive Pseudomonas has been
demonstrated using scanning electron microscopy (71) (Fig. 7).

Although further work in this area is required, knowledge of the pre-
sence, structural characteristics, and pathological mechanism of biofilms in
CRS may help to identify new treatment modalities.

Super antigens. Another new area of interest in infectious CRS involves
a group of potent mitogens termed superantigens sags. Sags are most com-
monly associated with bacteria, particularly S. aureus and S. pyogenes species,
but can also be produced by viruses and fungi. Unlike conventional antigens
whose activation requires multiple steps in only a limited number of T-lym-
phocytes, sags can directly stimulate a multitude of different T-lymphocytes.

Figure 7 (Facing page) Biofilms in Human CRS. Source: Cyer J, Schipor I, Perloff JR,
Palmer JN. Densely coated sinonasal epithelium with tower-like structures (white
arrows) visible near the top edge of the specimen. Source: From Ref. 71.

126 Jackman and Kennedy

In the traditional pathway, the antigen is phagocytosized by an antigen-
presenting cell (APC), degraded into numerous peptide fragments, which
are then processed for cell surface display in conjunction with a major histo-
compatibility complex (MHC) II receptor. A compatible T-helper cell then
recognizes this MHC II/peptide complex, and an inflammatory response is
initiated. Sags are able to bypass these processing and presenting steps and
bind directly to the outside surfaces of the HLA-DR alpha domain of MHC
class II and V beta domain of the T-cell receptors (picture) (72-75). Through
this mechanism, they are able to stimulate a massive expression of IL-2 at
femtomolar concentrations (76). In turn, IL-2 stimulates the production of
other cytokines such as TNF-oc, IL-1, 11-8, and platelet activating factor
(PAF), leading to an overwhelming inflammatory response. Additionally, sags
also act as traditional antigens, as well as stimulate the production of anti-
superantigen antibodies.

Recently, upregulation of IgE sags antibodies have been demonstrated
in patients with chronic obstructive pulmonary disease (COPD) exacerbation
(77). Likewise, a study by Basher et al. found increased levels of sags in
patients with NP versus control patients (78). Evidence of the roles of super-
antigen-producing bacterial strains in the pathologic mechanism of Kawasaki
disease, atopic dermititis, and rheumatoid arthritis has also been reported, and
a pathophysiological mechanism in which microbial persistence and superan-
tigen-induced T-cell inflammatory responses in CRS has also been proposed
(79). Further studies in this area, as well as in other areas of CRS, may provide
new diagnostic and treatment modalities.

Fungal infections: Fungal species play a variety of roles in chronic
sinusitis from colonization to invasive, life-threatening disease. Invasive
disease is characterized by histopathological evidence of hyphal forms
within the sinus mucosa, submucosa, blood vessels, or bone, and has been
associated with either fulminate or a more indolent chronic course of fungal
rhinosinusitis. In addition, chronic invasive disease may or may not be asso-
ciated with a giant cell response. The pathophysiology of these different
disease courses has been attributed primarily to the host's immune response
to the fungus, although the fungal species also appears to play some role in
the disease course. Fungal species associated with fulminate forms of fungal
sinusitis include Absidia, Aspergillus, Basidobolus, Mucor, and Rhizopus
spp., and most often occur in immunocompromised patients (80). Species
associated with chronic invasive fungal sinusitis include Aspergillus, Mucor,
Alternaria, Curvularia, Bipolaris, and Candida spp., Sporothrix schenckii,
and Pseudallescheria boydii, and can occur in both immunocompetent and
immunocompromised patients (81,82).

Two major forms of non-invasive fungal sinusitis — allergic fungal
sinusitis and sinus mycetoma — exist, with allergic fungal rhinosinusitis
(AFS) forming a distinct subcategory of CRS. Diagnostic criteria for AFS

Pathophysiology of Sinusitis

127

'*•* " *iV^

Figure 8 Hematoxylin and eosin stained nasal tissue demonstrating fungal hyphae,
eosinophils and Charcot-Leyden crystals. Source: Diagnosis of chronic rhinosinusi-
tis. Lanza DC. Annals of Otology, Rhinology, & Laryngology - Supplement.
2004; 193:10-14.

include the demonstration of five characteristics as defined by Bent and Kuhn:
gross production of eosinophilic mucin containing non-invasive fungal
hyphae, nasal polyposis, characteristic radiographic findings, immunocompe-
tence, and allergy to fungus (83). AFS is characterized by a sustained eosino-
philic inflammatory response to colonizing fungi. Mucus secretions, termed
allergic mucin, in AFS are characterized as being highly viscous and contain
branching non-invasive fungal hyphae within sheets of eosinophils and Char-
cot-Leyden crystals (84-88) (Fig. 8).

A non-IgE-dependent association of fungus with CRS has also been
proposed. In 1999, Ponikau et al. reported a fungal colonization in 96% of con-
secutive patients with CRS, using an ultra-sensitive method of fungal identifica-
tion. Additionally, certain fungi were demonstrated to elicit an upregulation of
IL-5 and IL-13 and a resulting eosinophilic inflammatory response. This eosino-
philic response was IgE, and therefore, allergy-independent, which was thought
to indicate a broader role of fungus in CRS than previously hypothesized (89).

Allergy

Environmental allergens are frequently considered as important environmen-
tal factors in CRS, and atopy is identified as a prominent systemic host factor
in CRS. However, the exact contribution of allergy to the development of
CRS is still under investigation. Both pediatric and adult patients with allergic

128 Jackman and Kennedy

rhinitis are more commonly affected with CRS than non-allergic patients (90).
Furthermore, these individuals have been reported to respond more poorly
to medical management and to more frequently undergo endoscopic sinus
surgery (91,92). Inflammatory changes contribute to the development of
CRS in allergic patients. They are stimulated by the production of cytokines,
allergic mediators, and neurogenic stimulation. More specifically, allergen
stimulation of T H 2 cells leads to the production of IL-4, which in turn causes
B-cell activation and IgE antibody production. Subsequent allergen exposure
causes IgE cross-linking and release of inflammatory mediators, such as his-
tamine, leukotrienes, and tryptase, and results in the later phase response-
eosinophil infiltration, mucus hypersecretion, and mucosal edema. Continued
allergen activation, referred to as "priming," further increases the concentra-
tion and magnitude of action of inflammatory cells such as eosinophils and
neutrophils and their associated cytokines. Furthermore, an IgE response
to staphylococcal antigens has been implicated in the development of NPs
in CRS, and this relationship is currently under investigation (8,12,93-95).

Environmental Pollutants

A number of other environmental factors can be linked to the development of
CRS. In a study of 5300 Swedish children, Andrae et al. found a significantly
higher rate of asthma and hay fever in children living near polluting factories
(96). Futhermore, Suonpaa reported an increased incidence of acute sinusitis
and nasal polyposis in southwestern Finland over a decade, which provides
additional evidence for the presence of an environmental impact in CRS
(97). Dust, ozone, sulfur dioxide, volatile organic compounds, and smoke
are just a few of the pollutants that have been implicated in CRS. The major-
ity of these chemicals share a similar pathologic mechanism: they act as nasal
irritants causing dryness and local inflammation with an influx of neutrophils
(98,99). In addition to this mechanism, environmental tobacco smoke has
been shown to cause secondary ciliary disorders, which consist primarily of
micro tubular defects (100). Occupational exposure to nickel, leather, or wood
dust has been associated with epithelial metaplasia as well as carcinoma (101).

SUMMARY

Maintenance of key functional components — ostiomeatal patency, muco-
ciliary clearance, and normal mucus production — of the paranasal sinus is
essential for prevention and recovery from CRS. CRS is a complex disease
process that can result from a single or multiple independent etiologies,
as well as from multiple independent or interdependent etiologies (Fig. 9).
The factors contributing to this disease process can be divided into
systemic host, local host, and environmental factors. Systemic host factors,
such as genetic and autoimmune diseases, are important to identify so that
appropriate treatment modifications can be made, if available. Likewise,

Pathophysiology of Sinusitis

129

Anatomical, mass obstruction (mucoceles, tumors), debris

4 OMC Patency

|P02
Mucus stasis

Inflammation

T Bacterial growth

Infection, Osteitis, Sags, Allergy
AI(Sarcoid, Wegners.SLE)

Immunodeficiency/supression

J, Mucociliary
Clearance

CF, PCD, Pollutants (smoke)
Figure 9 Etiological factors in the pathological cycle of CRS.

local host factors such as anatomic abnormalities and environmental factors
such as infection, allergy, and pollution need to be recognized and appropri-
ately managed.

There is a clear need for further research into the pathophysiology of
this disorder. Current research on biofilms, sags, and osteitis will hopefully
provide us with a better understanding of the role of infection in CRS. Like-
wise, research on allergic CRS and other noninfectious etiologies of CRS
will help to better elucidate the role inflammation plays in this disorder.
A better understanding of both infectious and inflammatory mechanisms
of CRS will provide us with more effective and individualized therapies.

REFERENCES

1. Majima, Y. Mucoactive medication and airway disease. Paediatr Respir Rev
2002; 3:104-109.

2. Lehrer RI, Lichenstein AK, Ganz T. Defensins: antimicrobial and cytotoxic
peptides of mammalian cells. Annu Rev Immunol 1993; 11:105-128.

3. Martin E, Ganz T, Lehrer RI. Defensins and other endogenous peptide
antibiotics of vertebrates. J Leukoc Biol 1995; 58:128-136.

4. Lee SH, Kim JE, Lee HM, Choi JO. Antimicrobial defensin peptides of the
human nasal mucosa. Ann Otol Rhino Laryngol 2002; 111 (2) : 1 3 5— 141.

5. Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson
JM. Human beta-defensin-1 is a salt sensitive antibiotic that is inactivated in
cystic fibrosis. Cell 1997; 88:553-560.

6. Knowles MR, Bouchers RC. Mucus clearance as a primary innate defense
mechanism for mammalian airways. J Clin Investig 2002; 109:571-577.

130 Jackman and Kennedy

7. Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head
Neck Surg 1997; 117:S1-S7.

8. Benninger MS, Ferguson BJ, Hadley, JA, Hamilos DL, Jacobs M, Kennedy
DW, Lanza DC, Marple BF, Osguthrope JD, Stankiewicz JA, Anon J,
Denvey J, Emanuel I, Levine H. Adult chronic rhinosinusitis: definitions, diag-
nosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg 2003;
129:S1-S32.

9. Wald ER, Miloe GJ, Bowen A, Ledesma-Medina J, Salamon N, Bluestone
CD. Acute maxillary sinusitis in children. N Engl J Med 1981; 304:749-754.

10. Wald ER, Byers C, Guerra N, Casselbrandt M, Beste D. Subacute sinusitis in
children. J Pediatr 1989; 115:28-32.

11. Wald ER, Reilly JS, Casselbrant M, Ledesma-Medina J, Milmore GJ,
Bluestone CD, Chipows D. Treatment of acute maxillary sinusitis in childhood:
a comparative study of amoxicillin and cefaclor. J Pediatr 1984; 104:297-302.

12. Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, Nicklas RA.
Rhinosinusitis: establishing definitions for clinical research and patient care.
Otolaryngol Head Neck Surg 2004; 13LS1-S62.

13. Evans FO Jr, Sydnor JB, Moore WE, Manwariring JZL, Brill AH, Jackson RT,
Hanna S, Skaar JS, Holdeman LV, Fitz-Hugh S, Sunde MA, Gwaltney JM, Jr.
Sinusitis of maxillary antrum. N Engl J Med 1975; 293(15):735-739.

14. Berg O, Carenfelt C, Kronvall G. Bacteriology of maxillary sinusitis in
relation to character of inflammation and prior treatment. Scand J Infect
Dis 1988;20:511-516.

15. Pederson M, Sakakura Y, Winther B, Brofeldt S, Mygind N. Nasal mucocili-
ary transport, number of ciliated cells, and beating pattern in naturally
acquired common colds. Eur J Respir Dis Suppl 1983; 128:355-365.

16. Hinni ML, McCaffrey TV, Kasperbauer JL. Early mucosal changes in experi-
mental sinusitis. Otolaryngol Head Neck Surg 1992; 107:537-548.

17. Marks SC. Acute sinusitis in the rabbit model: histologic analysis. Laryngo-
scope 1998; 108:320-325.

18. Rudack C, Hauser U, Wagenmann M, Bachert C, Ganzer U. Cytokine pattern
in various forms of sinusitis. Laryngorhinootologie 1998; 77:34-37.

19. Repka-Ramirez S, Naranch K, Park YJ, Clauw D, Baraniuk JN. Cytokines in
nasal lavage fluids from acute sinusitis, allergic rhinitis, and chronic fatigue
syndrome subjects. Allergy Asthma Proc 2002; 23:185-190.

20. Berger G, Kattan A, Bernheim J, Ophir D. Polypoid mucosa with eosinophilia
and glandular hyperplasia in chronic sinusitis: a histopathological and immu-
nohistochemical study. Laryngoscope 2002; 112:738-745.

21. Kramer MF, Ostertag P, Pfronger E, Rasp G. Nasal Interleukin-5, immuno-
globin E, eosinophilic cationic protein, and soluble intercellular adhesion
molecule- 1 in chronic sinusitis, allergic rhinitis, and nasal polyposis. Laryngo-
scope 2000; 110:1056-1062.

22. Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cawenberge P. Total
and specific IgE in nasal polyps is related to local eosinophilic inflammation.
J Allergy Clin Immunol 2001; 107:607-614.

23. Rhyoo C, Sanders SP, Leopold DA, Proud D. Sinus mucosal IL-8 gene expres-
sion in chronic rhinosinusitis. J Allergy Clin Immunol 1999; 103:395-400.

Pa thophysiology of Sinusitis 131

24. Nonoyama T, Harada T, Shinogi J, Yoshimura E, Sakakura Y. Immunohis-
tochemical localization of cytokines and cell adhesion molecules in maxillary
sinus mucosa in chronic sinusitis. Auris Nasis Larynx 2000; 27:51-58.

25. Bachert C, Wagemann M, Rudack C, Hopken KZ, Hillebrandt M, Wang D,
van Cawenberge P. The role of cytokines in infectious sinusitis and nasal poly-
posis. Allergy 1998; 53:2-13.

26. Rudack C, Stoll W, Bachert C. Cytokines in nasal polyposis, acute and
chronic sinusitis. Am J Rhinol 1998; 12:383-388.

27. Bachert C, Gevaert P, van Cauwenberge P. Staphylococcus aureus enterotox-
ins: a key in airway disease? Allergy 2002; 57:480-487.

28. Hamilos DL, Leung DY, Huston DP, Kamil A, Wood R, Hamid Q.
GM-CSF, 11-5, and RANTES immunoreactivity and mRNA expression in
chronic hyperplastic sinusitis with nasal polyposis. Clin Exp Allergy 1998; 28:
1145-1152.

29. Coste A, Girodon E, Louis S, Pruliere-Escabasse V, Goossens M, Peynegre R,
Escudier E. Atypical sinusitis in adults must lead to looking for cystic fibrosis
and primary ciliary dyskinesia. Laryngoscope 2004; 144:839-843.

30. Varlotta L. Management and care of the newly diagnosed patient with cystic
fibrosis. Curr Opin Pulm Med 1998; 4:311-318.

31. Hulka GF. Head and neck manifestations of cystic fibrosis and ciliary dyski-
nesia. Otolaryngol Clin North Am 2000; 33:1333-1341.

32. Doull JM. Recent advances in cystic fibrosis. Arch Dis Child 2001; 85:62-66.

33. Gysin C, Alothman GA, Papsin BC. Sinonasal disease in cystic fibrosis:
clinical characteristics, diagnosis, and management. Pediatr Pulmonol 2000;
30:481-489.

34. Tandon R, Derkay C. Contemporary management of rhinosinusitis and cystic
fibrosis. Curr Opin Otolaryngol Head Neck Surg. 2003; 11:41-44.

35. Thaler ER. Postoperative care after endoscopic sinus surgery. Arch Otolaryn-
gol Head Neck Surg 2002; 128:1204-1206.

36. Meeks M, Bush A. Primary ciliary dyskinesia. Pediatr Pulm 2000; 29:307-316.

37. Bianchi E, Savasta S, Carligaro A, Beluffi G, Poggi P, Tinelli M, Mevio E,
Martinetti M. HLA haptlotype segregation and ultrastructure study in familial
immotile cilia syndrome. Hum Genet 1992; 89:270-274.

38. Pan Y, McCaskill CD, Thompson K, Hicks J, Casey B, Shaffer LG, Craigen
WJ. Paternal isodisomy of chromosome 7 associated with complete situs inver-
sus and immotile cilia. Am J Hum Genet 1998; 62:1551-1555.

39. Witt M, Wang Y-F, Wang S, Sun C-E, Pawlik J, Rutkiewicz E, Zebrak J,
Diehl SR. Exclusion of chromosome 7 for Kartenger syndrome but suggestion
of linkage in families with other forms of primary ciliary dyskinesia. Am J
Hum Genet 1998; 64:313-318.

40. Berlinger NT. Sinusitis in immunodeficient and immunosuppressed patients.
Laryngoscope 1985; 95:29-33.

41. Rubin J, Honigsberg R. Sinusitis in patients with acquired immunodeficiency
syndrome. Ear Nose Throat J 1990; 69:460^163.

42. Friedman M, Landsberg R, Tanyeri H, Schults RA, Kelanic S, Caldarelli DD.
Endoscopic sinus surgery in patients with HIV. Laryngoscope 2000; 110:
1613-1616.

132 Jackman and Kennedy

43. Long CM, Smith TL, Loehrl TA, Komorowski RA, Tookill TJ. Sinonasal
disease in patients with sarcoidosis. Am J Rhinol 2001; 15:211-215.

44. Hewins P, Tervaert JW, Savage CO, Kallenberg CG. Is Wegner's granuloma-
tosis and autoimmune disease? Curr Opin Rheumatol 2000; 12:3-10.

45. Watts RA. Wegener's granulomatosis: unusual presentations. Hosp Med 2000;
61:250-253.

46. Settipane RA, Lieberman P. Update on nonallergic rhinitis. Ann Allergy
Asthma Immunol 2001; 86:494^507.

47. Beers RF. Intolerance to aspirin. Ann Intern Med 1968; 68:975-983.

48. Jones NS. CT of paranasal sinuses: a review of the correlation with clinical,
surgical, and histopathologic findings. Clin Otolaryngol 2002; 27:11-17.

49. Alho OP. Paranasal sinus bony structures and sinus functioning during viral
colds in subjects with and without a history of recurrent sinusitis. Laryngo-
scope 2003; 113:2163-2168.

50. Richtsmeier WJ. Top 10 reasons for endoscopic maxillary sinus surgery
failure. Laryngoscope 2001; 111:1952-1956.

51. Som PM, Shapiro MD, Biller HF, Sasaki C, Lawson W. Sinonasal tumors and
inflammatory tissue differentiation with MR imaging. Radiology 1988; 167:
803-808.

52. Naranch K, Park YJ, Repka-Ramirez MS, Velarde A, Clauw D, Baranick JN.
A tender sinus does not always mean rhinosinusitis. Otolaryngol Head Neck
Surg 2002; 127:387-397.

53. Kennedy DW, Senior BA, Gannon FH, Montone KT, Hwang P, Lanza DC.
Histology and histomorpholometry of ethmoid bone in chronic rhinosinusitis.
Laryngoscope 1998; 108:502-507.

54. Perloff JR, Gannon FH, Bolger WE, Montone KT, Orlandi R, Kennedy DW.
Bone involvement in sinusitis: an apparent pathway for the spread of disease.
Laryngoscope 2000; 110:2095-2099.

55. Khalid AN, Hunt J, Perloff JR, Kennedy DW. The role of bone in chronic
sinusitis. Laryngoscope 2002; 112(11): 1951-1957.

56. Brook I. Sinusitis — overcoming bacterial resistance. Int J Pediatr Otorhinolar-
yngol 2001; 58:27-36.

57. Brook I, Yoeum P, Shah K. Aerobic and anaerobic bacteriology of concurrent
chronic otitis media with effusion and chronic sinusitis. Arch Otolaryngol
Head Neck Surg 2000; 126:174-176.

58. Doyle PW, Woodham JD. Evaluation of the microbiology of chronic ethmoid
sinusitis. J Clin Microbiol 1991; 29:2396-2400.

59. Hoyt WH III. Bacterial patterns found in patients with chronic sinusitis. J Am
Osteopath Assoc 1992; 92:209-212.

60. Hsu J, Lanza, DC, Kennedy DW. Antimicrobial resistance in bacterial chronic
sinusitis. Am J Rhinol 1998; 12:243-248.

61. Biel MA, Brown CA, Levinson RM, Gavis GE, Paisner HM, Sigel ME,
Tedford TM. Evaluation of the microbiology of chronic maxillary sinusitis.
Ann Otol Rhinol Laryngol 1998: 107:942-945.

62. Brook I, Frazier EH. Correlation between microbiology and previous sinus
surgery in patients with chronic maxillary sinusitis. Ann Otol Rhinol Laryngol
2001; 110:148-151.

Pathophysiology of Sinusitis 133

63. Jiang RS, Lin JF, Hsu CY. Correlation between bacteriology of the middle
meatus and ethmoid sinus in chronic sinusitis. J Laryngol Otol 2002; 1 16:443^146.

64. Finegold SM, Flynn MJ, Rose FV, et al. Bacteriologic findings associated with
chronic bacterial maxillary sinusitis in adults. Clin Infect Dis 2002; 35:428^133.

65. Costerton JW, Vech R, Shirtlift M, Pasmore M, Post JC, Erlich G. The
application of biofilm science to the study and control of chronic bacterial
infections. J Clin Invest 2003; 112:1446-1477.

66. Stewart PS, Costerton JW. Antibiotic resistance of bacterial biofilms. Lancet
2001; 358:135-138.

67. Post CJ. Direct evidence of bacterial biofilms in otitis media. Laryngoscope
2001; lll(12):2083-2094.

68. Ehrlich GD, Vech R, Wang X, Costerton JW, Hayes JD, Hu FZ, Daigle BJ,
Erlich MD, Post JC. Mucosal biofilm formation on middle-ear mucosa in the
chinchilla model of otitis media. JAMA 2002; 287:1710-1715.

69. Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause
of persistent infections. Science 284:318-322.

70. Hoyle BD, Costerton WJ. Bacterial resistance to antibiotics: the role of
biofilms. Prog Drug Res 1991; 37:91-105.

71. Cryer J, Schipor I, Perloff JR, Palmer JN. Evidence of bacterial biofilms in
human chronic sinusitis. ORL 2004; 66:155-158.

72. Choi YW, Kotzin B, Heron L, Callahan J, Marrack P, Kappler J. Interaction
of Staphylococcus aureus toxin "superantigen" with human T cells. Proc Natl
Acad Sci USA 1989; 86:8941-8945.

73. Kappler J, Kotzin B, Herron L, Gelfand EW, Bigler RD, Boylston A, Carrel
S, Posnett DN, Choi Y, Marrack P. V beta-specific stimulation of human T
cells by staphylococcal toxins. Science 1989; 244:811-813.

74. Fraser JD. High-affinity binding of staphylococcal enterotoxin A activated
human T cells. J Immunol 1989; 144:4663-4669.

75. Hong-Geller H, Gupta G. Therapeutic approaches to superantigen-based
diseases: a review. J Mol Recogn 2003; 16:91-101.

76. Carlsson R, Sjogren HO. Kinetics of IL-2 and interferon-gamma production,
expression of IL-2 receptors, and cell proliferation in human mononuclear
cells exposed to staphylococcal entertoxin A. Cell Immunol 1985; 96:175-183.

77. Rodhe G, Gevaert P, Holtappels G, Borg I, Wiethege A, Arinir U, Schultze-
Werninghaus G, Bachert C. Increased IgE-antibodies to Staphylococcus aureus
enterotoxins in patients with COPD. Respir Med 2004; 98:858-864.

78. Bachert C, Gevart P, Holtappels G, Johansson SG, van Crauwenberge P.
Total and specific IgE in nasal polyps is related to local eosinophilic inflamma-
tion. J Allergy Clin Immunol 2001; 107:607-614.

79. Schubet MS. A superantigen hypothesis for the pathogenesis of chronic hyper-
trophic rhinosinusitis, allergic fungal sinusitis, and related disorders. Ann
Allergy Asthma Immunol 2001; 87:181-188.

80. deShazo RD, O'Brien M, Chapin K, Soto-Aguilar M, Gardner L, Swain R.
A new classification and diagnostic criteria for invasive fungal sinusitis. Arch
Otolaryngol Head Neck Surg 1997; 123:1181-1188.

81. Schell WA. Unusual fungal pathogens in fungal rhinosinusitis. Otolaryngol
Clin North Am 2000; 33:375-387.

134 Jackman and Kennedy

82. Stringer S, Ryan MW. Chronic invasive fungal rhinosinusitis. Otolaryngol
Clin North Am 2000; 33:375-387.

83. Bent JP III, Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head
Neck Surg 1994; 111:580-588.

84. Miloshev B, Davidson CM, Gentles JC, Sandison AT. Aspergilloma of
paranasal sinuses and orbit in Northern Sudanese. Lancet 1966; 1:746-747.

85. Stevenson DD, Simon RA, Mathison DA, Christiansen SC Monteleukast is
only partially effective in inhibiting aspirin responses in aspirin-sensitive asth-
matics. Ann Allergy Asthma Immunol 2000; 85:477^82.

86. Miller J, Johnston A, Lamb D. Allergic aspergillosis of the maxillary sinuses.
Proc Scot Thor Soc 1981; 36:710-715.

87. Lamb D, Miller J, Johnston A. Allergic aspergillosis of the paranasal sinuses.
J Pathol 1982; 137.

88. Katzenstein AL, Sale SR, Greenberger PA. Allergic aspergillosis sinusitis:
a newly recognized form of sinusitis. J Allergy Clin Immunol 1983; 72:89-93.

89. Ponikau JU, Sherris DA, Kern EB, et al. The diagnosis and incidence of
allergic fungal sinusitis (AFS). Mayo Clin Proc 1999; 74:877-884.

90. Smith LF, Brindley PC. Indications, evaluation, complications, and results of
functional endoscopic sinus surgery in 200 patients. Otolaryngol Head Neck
Surg 1993; 108:688-696.

91. Benninger MS. Rhinitis, sinusitis and their relationship to allergy. Am J
Rhinol 1992; 6:37^3.

92. Emaneul I, Shah S. Chronic rhinosinusitis: allergy and sinus computed tomo-
graphic relationships. Otolaryngol Head Neck Surg 2000; 123:687-691.

93. Baroody FM, Suh SH, Naclerio RM. Total IgE serum levels correlate with
sinus mucosal thickness on CT. J Allergy Clin Immunol 1997; 100:563-568.

94. Naclerio RM, deTineo ML, Baroody FM. Ragweed allergic rhinitis and the
paranasal sinuses. A computed tomographic study. Arch Otolaryngol Head
Neck Surg 1997; 123:193-196.

95. Suzuki M, Watanabe T, Suko T, Mogi G. Comparison of sinusitis with and
without allergic rhinitis: characteristics of paranasal sinus effusion and
mucosa. Am J Otolaryngol 1999; 20:143-150.

96. Andrae S, Axelson O, Bjorksten B, Fredriksson M, Kjellman NJ. Symptoms
of bronchial hyperreactivity and asthma in relation to environmental factors.
Arch Dis Child 1988; 63:473^178.

97. Suonpaa J, Antila J. Increase of acute frontal sinusitis in southwestern
Finland. Scand J Infect Dis 1990; 22:563-568.

98. Bascom R. Air pollution. In: Mygind N, Naclerio RM, eds. Allergic and
Nonallergic Rhinitis. Copenhagen: Munksgaard, 1993:33-86.

99. Graham D, Henderson F, House D. Neutrophil influx measured in nasal
lavages of humans exposed to ozone. Arch Environ Health 1988; 43:228-233.

100. Afzlius B. Immotile cilia syndrome and ciliary abnormalities induced by infec-
tion and injury. Am Rev Respir Dis 1981; 124:107-109.

101. Zeiger RS. Differential diagnosis and classification of rhinosinusitis. In: Schatz
M, Zeiger RS, Settipane GA, eds. Nasal Manifestations of Systemic Diseases.
Providence, RI: Oceanside Publications, 1991.

SECTION III. MICROBIOLOGY

Infective Basis of Acute and Recurrent

Acute Sinusitis

Ellen R. Wald

Department of Pediatrics and Otolaryngology, University of Pittsburgh School of

Medicine, Allergy, Immunology, and Infectious Diseases,

Pittsburgh, Pennsylvania, U.S.A.

INTRODUCTION

Sinusitis is a common complication of viral upper respiratory infection and
allergic inflammation. Although the paranasal sinuses are believed to be
sterile under normal circumstances, the upper respiratory tract — specifically
the nose and nasopharynx — are heavily colonized by normal flora. Despite
differences in normal nasal flora, the acute bacterial pathogens that cause
acute sinusitis are similar in adults and children.

OBTAINING SPECIMENS

To determine the infective basis of acute or recurrent acute sinusitis, a sample
of sinus secretions must be obtained from one of the paranasal sinuses with-
out contamination by normal respiratory or oral flora (1). The maxillary sinus
is the most accessible of the paranasal sinuses. There are two non-endoscopic
approaches to the maxillary sinus: via either the canine fossa or the inferior
meatus. Both the canine fossa and the nasal vestibule are colonized by patho-
genic bacteria. Accordingly, sterilization of the nasal vestibule and the
mucosa beneath the inferior nasal turbinate or of the mucosa overlying the
canine fossa is recommended if an aspirate of the maxillary sinus is planned.

135

136 Wald

To avoid misinterpretation of culture results, acute infection is defined
as the recovery of a bacterial species in high density, that is, a colony count
of at least 10-10 colony-forming units per milliliter (cfu/mL). This quan-
titative definition increases the probability that organisms recovered from
the maxillary sinus aspirate truly represent in situ infection and not contam-
ination from either the mucosa overlying the canine fossa or beneath the
inferior turbinate. In fact, most sinus aspirates from acutely infected sinuses
are associated with colony counts in excess of 10 4 cfu/mL. If quantitative
cultures cannot be performed, Gram stain of the aspirated specimens
affords semiquantitative data. If bacteria are readily apparent on a Gram
stain, the approximate bacterial density is 10 5 cfu/mL. The Gram stain is
especially helpful if bacteria are seen on the smear and the specimen fails
to grow when using standard aerobic culture techniques. Anaerobic organ-
isms or other fastidious bacteria, such as a bacterial biofilm or partially anti-
biotic-treated infections, should be suspected. Performance of a Gram stain
will also permit an assessment of the local inflammatory response. The pre-
sence of many white blood cells in association with a positive bacterial cul-
ture in high density makes it likely that a bacterial infection is present.
Alternatively, a paucity or absence of white blood cells in association with
the presence of a positive culture in low density suggests that these bacteria
have contaminated the culture rather than have caused infection.

Endoscopic Cultures in Children and Adults

Recently there has been interest in and enthusiasm for obtaining cultures of
the middle meatus endoscopically, as a surrogate for cultures of a sinus aspi-
rate. The endoscopically obtained culture is less invasive and associated with
less morbidity (2). In normal children, unfortunately, the middle meatus has
been shown to be colonized by the same bacterial species such as Streptococcus
pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, as are com-
monly recovered from children with sinus infection (3). Accordingly, middle
meatus cultures are not interpretable. This technique cannot be recommended
for a precise bacterial diagnosis in children with sinus infections.

In three recent studies, cultures of the middle meatus have been
obtained endoscopically from normal adults. The bacterial species recovered
were coagulase-negative staphylococci in 35 to 50% of cultures, Corynebac-
terium spp. in 16 to 23% and Staphylococcus aureus in 8 to 20% (4-6).
The only overlap between commensals and potential pathogens is S. aureus.
While several studies in adults have shown a good correlation between
cultures of the middle meatus and the sinus aspirate in patients with acute
sinusitis (7,8), others have not (9,10). In a retrospective review of the litera-
ture between 1950 and 2000, Benninger et al. concluded that the data were
insufficient to recommend substitution of cultures of the middle meatus for
maxillary sinus aspirates in patients with acute rhinosinusitis (11).

Acute and Recurrent Acute Sinusitis 137

Occasionally, neither a sinus aspirate nor a specimen obtained endos-
copically is sufficient for the diagnosis of a sinus infection. This is especially
true of patients with very protracted symptoms. In this instance, biopsy of
the sinus mucosa for culture and appropriate stains may be required.

MICROBIOLOGY OF ACUTE SINUSITIS IN CHILDREN

The microbiology of paranasal sinus infection can be anticipated according
to the age of the patient, clinical presentation, and immunocompetency of
the host. Despite the substantial prevalence and clinical importance of sinu-
sitis in childhood, study of the microbiology of acute and subacute sinusitis
in children has been relatively limited. Using a study design similar to the
one described by investigators at the University of Virginia (12), an investi-
gation of the microbiology of acute sinusitis in pediatric patients was
reported by the Children's Hospital of Pittsburgh in 1981 (13). Patients were
eligible for this study if they were between 2 and 16 years of age and pre-
sented with one of two clinical pictures: onset with either "persistent" or
"severe" respiratory symptoms.

Sinus radiographs were performed on eligible children. When a
maxillary sinus aspirate was performed on children presenting with clinical
symptoms and significantly abnormal sinus radiographs, bacteria in high
density were recovered from 70% (14). The bacterial isolates in their relative
order of prevalence are shown in Table 1 . S. pneumoniae was most common,
followed closely by H. influenzae and M. catarrhalis. No staphylococci were
recovered. Mixed infection with heavy growth of two bacterial species was
occasionally found. In 25% of patients with bilateral maxillary sinusitis,
there were discordant bacterial culture results. In some cases, one sinus
aspirate was positive, while the other was negative. In the remaining cases,
different bacterial species were recovered from each aspirate.

Table 1 Bacterial Species Cultured from 79 Sinus Aspirates in 50 Children

Single isolates

Multiple isolates

Total

Streptococcus pneumoniae

Moraxella catarrhalis

Haemophilus influenzae

Eikenella corrodens

Group A streptococcus

Group C streptococcus

oc-Streptococcus

Pepto streptococcus

Moraxella spp.

Source. Adapted from Ref. 13.

138 Wald

Viral cultures were also performed on the maxillary sinus aspirates.
Because many children were evaluated after 10 or more days of symptoms,
viruses were recovered infrequently. Adenovirus as the only isolate was
grown from the aspirate of one subject; parainfluenza virus in combination
with a bacterial isolate was recovered from a second (13). In studies of
adults with acute sinusitis, other viruses, including influenza and rhinovirus,
have been recovered from approximately 10% of sinus aspirates (12).
Nucleic acid amplification technology was not available at the time of these
investigations (12,13).

MICROBIOLOGY OF ACUTE COMMUNITY-ACQUIRED
SINUSITIS IN ADULTS

Acute Maxillary Sinusitis

The most elegant work detailing the microbiology of acute sinusitis has been
done at the University of Virginia in Charlottesvile since 1975 (12). Informa-
tion is derived mainly from cultures of specimens obtained by aspiration of
the maxillary sinus because of the accessibility of this particular sinus. In
general, a sinus infection is caused by a single bacterial isolate in high den-
sity. In 25% of cases, two bacterial species, each in high density, will be
recovered.

The two most important causes of acute community-acquired sinusitis in
adults are S. pneumoniae and non-typeable H. influenzae (Table 2) (15,16). One
remarkable change observed by Gwaltney et al. between 1975 and 1991 was
the increase in the prevalence of beta-lactamase producing H. influenzae (16).

Next in frequency were anaerobic bacterial species and streptococci
other than pneumococci. The role of anaerobes in acute community-
acquired disease has been variable. Although anaerobic bacteria have a more
remarkable role in chronic rather than acute sinus disease, they account for
7% of acute cases, some of which arise from a primary dental pathology.
Moraxella and S. aureus account for 4% and 3% of cases, respectively.

Table 2 Community-Acquired Acute Sinusitis in Adults

Streptococcus pneumoniae 41%

Haemophilus influenzae 35%

Anaerobes 7%

Streptococcal species 7%

Moraxella catarrhalis 4%

Staphylococcus aureus 3%

Other 4%

Source: Adapted from Ref. 16.

Acute and Recurrent Acute Sinusitis 139

Acute Sphenoid Sinusitis

Most of the study of the microbiology of acute and recurrent acute sinusitis has
focused on the maxillary sinus. There have been several reports on the micro-
biology of sphenoid sinusitis (17,18), including a recent study of 23 patients
who were cared for between 1975 and 2000 (19). Most of the patients were
adults. All of the specimens for culture were obtained at the time of surgery,
suggesting that the population of patients studied had serious disease. The most
common aerobic isolate in patients with acute disease was S. aureus. Strepto-
coccal species (viridans streptococci, microaerophilic streptococci, S. pneumo-
niae, Group F streptococci, and Streptococcus pyogenes) were next most
common. The predominance of gram-positive coccal species is consistent across
all reports (17-19). There were two isolates of H. influenzae. Anaerobes were
recovered from several patients (Peptostreptococcus spp., Propionibacterium
acnes, Fusobacterium nucleatum, and Prevotella melaninogenica).

Acute Frontal Sinusitis

The microbiology of frontal sinusitis has been evaluated in three studies
(20-22). In a recent review of Brook's experience over a 26-year period,
28 cases of frontal sinusitis were described microbiologically (15 acute and
13 chronic) (22). The primary isolates in patients with acute frontal sinusitis
were S. pneumoniae, H. influenzae, and M. catarrhalis. There was an occa-
sional isolation of anaerobes. These results are similar to those described
by other authors (22,21).

Recurrent Acute Bacterial Sinusitis

There has been relatively little study of the microbiology of recurrent acute
sinusitis. One small series, recently published, reviewed the results for eight
patients (23). Specimens were obtained via maxillary sinus endoscopy under
local anesthesia, through the middle meatus, with calcium alginate-tipped
microswabs. The swabs were placed in 1 mL of media and shaken vigorously
for two minutes, serially diluted, and inoculated. Only bacteria found in
numbers greater than 10 /mL were considered to be pathogens. Not surpris-
ingly, the isolates recovered were S. pneumoniae, H. influenzae, and M. cat-
arrhalis. There was only a single isolate of S. aureus.

Viruses as a Cause of Acute sinusitis

Although we commonly consider acute sinusitis to be a complication of viral
upper respiratory tract infections, several investigators have shown that
radiographic and other imaging abnormalities are very common in both
children and adults with the common cold, suggesting the presence of early
viral sinusitis (24,25). In a study by Puhakka et al., 200 young adults with

140 Wald

the common cold were followed for 21 days. Plain radiographs were
performed on days 1, 7, and 21 of the common cold (26). Patients recorded
their symptoms on a diary card for 20 days, rating symptoms such as watery
rhinitis, purulent rhinitis, nasal congestion, nasal irritation, headache,
cough, sputum, sore throat, and fever on a severity scale of zero to three
(ranging from absent to severe). The etiologic role of 10 viruses (rhino-
virus, adenovirus, coronavirus, enterovirus, influenza A and B viruses,
parainfluenza virus types 1, 2, and 3, and respiratory syncytial virus) was
investigated by virus culture, antigen detection, serology, and rhinovirus
polymerase chain reaction (PCR). Antibody concentrations to five bacteria
(Chlamydia pneumoniae, H. influenzae, M. catarrhalis, Mycoplasma pneumo-
niae and S. pneumoniae) were assayed. Altogether, 57% of the patients had
sinus abnormalities (mucosal thickening, total opacity, air-fluid level, cyst,
or polyp) during the 21 days of the common cold. This compares to 87%
of adult patients with an uncomplicated common cold demonstrating
significant abnormalities when evaluated by computed tomography (24).
Antimicrobial treatment was not provided in this study and all patients
recovered spontaneously, suggesting that there was no substantial compo-
nent of bacterial superinfection (26).

The etiology of the common cold was determined in 69.5% of the sub-
jects. Viral infection was detected in 81.6% of the patients with sinusitis and
in 63.3% of the patients without sinusitis. Rhinovirus was the most frequent
cause of infection, detected in 55.3% and in 48.3% of subjects, respectively.
No significantly increased levels of antibodies to bacteria were detected in
the sinusitis group.

Support for the likelihood that these cases of radiologic "sinusitis"
represent actual virus infection of the paranasal sinuses is found in a study
by Pitkaranta et al. (27). Twenty adult patients with a diagnosis of acute
community-acquired sinusitis were studied between May and July of 1996.
All patients had purulent rhinorrhea, nasal obstruction, and abnormal
radiographs. A nasal swab was obtained from each patient at the area of
puncture below the inferior turbinate. After puncture with a needle, a
bronchoscope brush was passed through the needle into the sinus and
rotated. Cultures and PCR for virus were performed on the nasal swab
and the bronchial brush specimen. Rhinovirus was detected in specimens
from 10 of the patients, including maxillary samples from eight and nasal
swabs from nine by reverse transcription-PCR (RT-PCR). These findings
suggest that viral invasion of the sinus cavity itself may be a common event
during uncomplicated upper respiratory infections. However, a positive
PCR may also have been caused by the presence of virions in the sinus or
viral RNA produced by replication elsewhere in the upper respiratory tract
epithelium and introduced during coughing or sneezing, or potentially even
by RNA from human rhinovirus introduced into the sinus at the time of
puncture.

Acute and Recurrent Acute Sinusitis 141

Fungal Sinusitis

Most cases of fungal sinusitis, especially the allergic forms of fungal
sinusitis, present with very protracted clinical symptoms and therefore are
not considered under the heading of either acute or recurrent acute sinusitis.
The only type of fungal sinusitis likely to present as acute disease is locally
or systemically invasive fungal sinusitis in immunoincompetent patients.

Patients particularly prone to fungal infections of the paranasal
sinuses include diabetics, patients with leukemia and solid malignancies
who are febrile and neutropenic (most of whom will have received broad-
spectrum antimicrobial therapy), patients on high-dose steroid therapy (e.g.,
for connective tissue disease, transplant recipients), and patients with severe
impairment of cell-mediated immunity (e.g., transplant recipients, persons
with congenital T-cell immunodeficiencies) (28).

The most common cause of fungal sinusitis in immunosuppressed
patients is aspergillus. Much less commonly, acute or chronic sinusitis
may be caused by Candida spp. or Mucor spp; the latter agent most
frequently affects diabetic patients. In addition, Pseudallescheria boydii,
Alternaria spp., Exserohilum spp., and Bipolaris spp. have been observed
to cause sinusitis in the immunosuppressed. These infections will be covered
in more detail in the chapters on sinusitis in the immunocompromised host
and fungal sinusitis.

Protozoa

Although protozoan species have not been described as a cause of acute or
chronic sinusitis in normal individuals, a case of acute sinusitis caused by
Cryptosporidium has been reported in a 17-year-old boy with congenital
hypogammaglobulinemia, who presented with a three-week history of
increasingly severe headaches (29). Physical examination showed turbid
nasal discharge, friable nasal mucosa, and facial tenderness over the maxil-
lary sinuses. CT revealed pansinusitis. The maxillary sinus aspirate con-
tained a moderate number of neutrophils and rare Cryptosporidium
oocysts. Extensive culturing for other microbiologic species was negative.
The patient's headache improved after therapy with oral spiramycin and
intravenous 2 difloro-methylornithine HCl-monohydrate.

CONCLUSION

Most cases of clinically important acute and recurrent acute sinusitis are
caused by the bacterial species S. pneumoniae, H. influenzae, and M.
catarrhalis. The most common predisposing event is a viral upper respira-
tory tract infection. Coinfection by viruses and bacteria is likely, as is self-
limited viral infection alone.

142 Wald

REFERENCES

1. American Academy of Pediatrics. Subcommittee on Management of Sinusitis
and Committee on Quality Improvement. Clinical practice guideline: manage-
ment of sinusitis. Pediatrics 2001; 108:798-808.

2. Talbot GH, Kennedy DW, Scheld WM, Granito K. Rigid nasal endoscopy
versus sinus puncture and aspiration for microbiologic documentation of acute
bacterial maxillary sinusitis. Clin Infect Dis 2001; 33:1668-1675.

3. Gordts F, Abu Nasser I, Clement PA, Pierad D, Kaufman L. Bacteriology of
the middle meatus in children. Int J Pediatr Otorhinolaryngol 1999; 48:163-167.

4. Gordts F, Harlewyck S, Pierard D, Kaufman L, Clement PA. Microbiology
of the middle meatus: a comparison between normal adults and children. J
Laryngol Otol 2000; 114:184-188.

5. Klossek JM, Dubreuil L, Richet H, Richet B, Sedallian A, Beutter P. Bacteriol-
ogy of the adult middle meatus. J Laryngol Otol 1996; 110:847-849.

6. Nadel DM, Lanza DC, Kennedy DW. Endoscopically guided cultures in
chronic sinusitis. Am J Rhinol 1998; 12:233-241.

7. Gold SM, Tami TA. Role of middle meatus aspiration culture in the diagnosis
of chronic sinusitis. Laryngoscope 1997; 107:1586-1589.

8. Vogan JC, Bolger WE, Keyes AS. Endoscopically guided sinonasal cultures: a
direct comparison with maxillary sinus aspirate cultures. Otolaryngol Head
Neck Surg 2000; 122:370-373.

9. Winther B, Vicery CL, Gross CW, Hendley O. Microbiology of the maxillary
sinus in adults with chronic sinus disease. Am J Rhinol 1996; 10:347-350.

10. Kountakis SE, Skoulas IG. Middle meatal vs. antral lavage cultures in intensive
care unit patients. Otolaryngol Head Neck Surg 2002; 126:377-381.

11. Benninger MS, Appelbaum PC, Denneny JC, Osguthorpe DJ. Maxillary sinus
puncture and culture in the diagnosis of acute rhinosinusitis: the case for pursu-
ing alternative culture methods. Otolaryngol Head Neck Surg 2002; 127(1):
7-12.

12. Evans FO Jr, Sydnor JB, Moore WE, Moore GR, Manwaring JL, Brill AH,
Jackson RT, Hanna S, Skaar JS, Holdeman LV, Fitz-Hugh S, Sande MA,
Gwaltney JM Jr. Sinusitis of the maxillary antrum. N Engl J Med 1975;
293:735-739.

13. Wald ER, Milmoe GJ, Bowen AD, Ledesma-Medina J, Salmon N,
Bluestone CD. Acute maxillary sinusitis in children. N Engl J Med 1981; 304:
749-754.

14. Wald ER, Reilly JS, Casselbrant M, Ledesma-Medina J, Milmoe GJ,
Bluestone CD, Chiponis D. Treatment of acute maxillary sinusitis in childhood.
A comparative study of amoxicillin and cefaclor. J Pediatr 1984; 104:297-302.

15. Anon JB, Jacobs MR, Poole MD, Ambrose PG, Benninger MS, Hadley J A,
Craig WA. Sinus and allergy health partnership. Antimicrobial treatment
guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg
2004; 130(suppl l):l-45.

16. Gwaltney JM Jr. Acute community-acquired sinusitis. Clin Infect Dis 1996;
23:1209-1225.

17. Lew D, Southwick FS, Montgomery WW, Weber AL, Baker AS. Sphenoid
sinusitis. A review of 30 cases. N Engl J Med 1983; 309:1149-1154.

Acute and Recurrent Acute Sinusitis 143

18. Ruoppi P, Seppa J, Pukkila M, Nuutinen J. Isolated sphenoid sinus diseases:
report of 39 cases. Arch Otolaryngol Head Neck Surg 2000; 126:777-781.

19. Brook I. Bacteriology of acute and chronic sphenoid sinusitis. Ann Otol Rhinol
Laryngol 2002; 111:1002-1004.

20. Suonpaa J, Antila J. Increase of acute frontal sinusitis in southwestern Finland.
Scand J Infect Dis 1990; 22:563-568.

21. Ruoppi P, Seppa J, Nuutinen J. Acute frontal sinusitis: etiological factors and
treatment outcome. Acta Otolaryngol (Stockh) 1993; 113:201-205.

22. Brook I. Bacteriology of acute and chronic frontal sinusitis. Arch Otolaryngol
Head Neck Surg 2002; 128:583-585.

23. Brook I, Frazier EH. Microbiology of recurrent acute rhinosinusitis. Laryngo-
scope 2004; 114:129-131.

24. Gwaltney JM Jr, Phillips CG, Miller RD, Riker DK. Computed tomographic
study of the common cold. N Engl J Med 1994; 330:25-30.

25. Glasier CM, Mallory GB Jr, Steele RW. Significance of opacification of the
maxillary and ethmoid sinuses in infants. J Pediatr 1989; 114:45-50.

26. Puhakka T, Makela MJ, Alanen A, Kallio T, Korsoff L, Arstila P,
Leinonen M, Pulkkinen M, Suonpaa J, Mertsola J, Ruuskanen O. Sinusitis
in the common cold. J Allergy Clin Immunol 1998; 102:408.

27. Pitkaranta A, Arruda E, Molinberg H, Hayden FG. Detection of rhinovirus in
sinus brushings of patients with acute community-acquired sinusitis by reverse
transcription-PCR. J Clin Microbiol 1997; 35:1791-1793.

28. Wald ER. Microbiology of acute and chronic sinusitis in children and adults.
Am J Med Sci 1998; 31:13-20.

29. Davis JJ, Heyman MB. Cryptosporidiosis and sinusitis in an immunodeficient
adolescent. J Infect Dis 1988; 158:649.

Infectious Causes of Sinusitis

Itzhak Brook

Departments of Pediatrics and Medicine, Georgetown University School

of Medicine, Washington, D.C., U.S.A.

INTRODUCTION

The upper respiratory tract, including the nasopharynx, serves as the reservoir
for pathogenic bacteria that can cause respiratory infections including sinusi-
tis (1). During a viral respiratory infection, potential pathogens can relocate
from the nasopharynx to the sinus cavity, causing sinusitis (2). Establishment
of the correct microbiology of all forms of sinusitis is of primary importance
as it can serve as a guide for choosing adequate antimicrobial therapy. This
chapter presents the current information regarding the microbiology of all
forms of sinusitis.

THE ORAL CAVITY NORMAL FLORA

The human mucosal and epithelial surfaces are covered with aerobic and
anaerobic microorganisms (3). The organisms that reside at these sites are
predominantly anaerobic and are actively multiplying. The trachea, bronchi,
esophagus, stomach, and upper urinary tract are not normally colonized by
indigenous flora. However, a limited number of transient organisms may
be present at these sites from time to time. Microflora also vary in different
sites within the body system, as in the oral cavity; the microorganisms
present in the buccal folds differ in their concentration and types of strains
from those isolated from the tongue or gingival sulci. However, the organ-
isms that prevail in one body system tend to belong to certain major

145

146 Brook

bacterial species, and their presence in that system is predictable. The rela-
tive and total counts of organisms can be affected by various factors, such
as age, diet, anatomical variations, illness, hospitalization, and antimicro-
bial therapy. However, these sets of bacterial flora, remain stable through
life, with predictable patterns, despite their subjection to perturbing factors.

Anaerobes outnumber aerobic bacteria in all mucosal surfaces, and
certain organisms predominate in the different sites. The number of ana-
erobes at a site is generally inversely related to the oxygen tension (3). Their
predominance in the skin, mouth, nose, and throat, which are exposed to
oxygen, is explained by the anaerobic microenvironment generated by the
facultative bacteria that consume oxygen.

Knowledge of the composition of the flora at certain sites is useful for
predicting which organisms may be involved in an infection adjacent to that
site and can assist in the selection of a logical antimicrobial therapy, even
before the exact microbial etiology of the infection is known.

The normal flora is not just a potential hazard for the host, but also a
beneficial partner. Normal body flora also serves as protector from coloni-
zation and subsequent invasion by potentially virulent bacteria. In instances
where the host defenses are impaired or a breach occurs in the mucus
membranes or skin, however, the members of the normal flora can cause
infections.

Microbial Composition

The formation of the normal oral flora is initiated at birth. Certain organisms
such as lactobacilli and anaerobic streptococci, which establish themselves at
an early date, reach high numbers within a few days. Actinomyces, Fusobac-
terium, and Nocardia are acquired by the age of six months. Subsequently,
Prevotella, Porphyromonas spp., Leptotrichia, Propionibacterium, and Can-
dida also become part of the oral flora (3). Fusobacterium populations attain
high numbers after dentition and reach maximal numbers at age one year.

The most predominant group of facultative microorganisms native to
the oropharynx are the alpha-hemolytic streptococci, which include Strepto-
coccus mitis, Streptococcus milleri, Streptococcus sanguis, Streptococcus inter-
medius, Streptococcus salivarius, and several others (4). Other groups of
organisms native to the oropharynx are Moraxella catarrhalis and Haemo-
philus influenzae that are capable of producing beta-lactamase and may
spread to adjacent sites causing otitis, sinusitis, or bronchitis. Encapsulated
H. influenzae also induces serious infections such as meningitis and bactere-
mia. The oropharynx also contains Staphylococcus aureus and Staphylococcus
epidermidis that can also produce beta-lactamase and take part in infections.

The normal oropharynx is seldom colonized by gram-negative
enterobacteriaceae. In contrast, hospitalized patients are generally heavily
colonized with these organisms. The reasons for this change in microflora

Infectious Causes of Sinusitis

147

are not known, but may be related to changes in the glycocalyx of the phar-
yngeal epithelial cells or because of selective processes that occur following
the administration of antimicrobial therapy (5). The shift from predomi-
nantly gram-positive to gram-negative bacteria is thought to contribute to
the high incidence of sinus infection caused by gram-negative bacteria in
patients with chronic illnesses.

Anaerobic bacteria are present in large numbers in the oropharynx,
particularly in patients with poor dental hygiene, caries, or periodontal
disease. They outnumber their aerobic counterpart in a ratio of 10:1 to
100:1 (Fig. 1). Anaerobic bacteria can adhere to tooth surfaces and contri-
bute, through the elaboration of metabolic by-products, to the development
of both caries and periodontal disease (4). The predominant anaerobes
are anaerobic streptococci, Veillonella spp., Bacteroides spp., pigmented
Prevotella, and Porphyromonas spp. (previously called Bacteroides melanino-
genicus group), and Fusobacterium spp. (4). These organisms are a potential
source of a variety of chronic infections including otitis and sinusitis, aspira-
tion pneumonia lung abscesses, and abscesses of the oropharynx and teeth.

The microflora of the oral cavity is complex and contains many kinds
of obligate anaerobes. The distribution of bacteria within the mouth seems
to be a function of their ability to adhere to the oral surfaces. The differences
in numbers of the anaerobic microflora probably occur because of consider-
able variations in the oxygen concentration in parts of the oral cavity.

Aerobic/Anaerobic

Nasal Washings:
10-1 071 2 -10 5 /mL

Tooth Surfaces:
10 6 /10 9 -10 1 7mL

Saliva:
10 7 -107l0 8 -107mL

Gingival Scrapings:
lOVlO'-IO'VmL

Cricothyroid Membrane

Figure 1 Oropharyngeal flora.

148 Brook

For example, the maxillary and mandibular buccal folds contain 0.4%
and 0.3% oxygen, respectively, whereas the anterior and posterior tongue
surfaces contain 16.4% and 12.4%. The environment of the gingival sulcus
is more anaerobic than the buccal folds, and the periodontal pocket is the
most anaerobic area in the oral cavity. The ratio of anaerobic bacteria to
aerobic bacteria in saliva is approximately 10:1. The total count of anaero-
bic bacteria is 1.1 x 10 8 /mL (Fig. 1). The predominant anaerobic bacteria
that colonize the anterior nose are P. acnes. Fusobacterium nucleatum is
the main species of Fusobacterium present in the oral cavity. Anaerobic
gram-negative bacilli found in the oral cavity include pigmented Prevotella
and Porphyromonas (previously called black-pigmented Bacteroides),
Porphyromonas gingivalis, Prevotella oralis, Prevotella orisbuccae (rumini-
cola), Prevotella disiens, and Bacteroides ureolyticus.

Fusobacteria are also a predominant part of the oral flora (6), as the
treponemas (7). Pigmented Prevotella and Porphyromonas represent <1%
of the coronal tooth surface, but constitute 4% to 8% of gingival crevice
flora. Veillonellae represent 1% to 3% of the coronal tooth surface, 5% to
15% of the gingival crevice flora, and 10% to 15% of the tongue flora. Micro-
aerophilic streptococci predominate in all areas of the oral cavity, and they
reach high numbers in the tongue and cheek (8). Other anaerobes prevalent
in the mouth are Actinomyces (9), Peptostreptococci, Leptotrichia buccalis,
Bifidobacterium, Eubacterium, and Propionibacterium (10).

Pigmented Prevotella, Porphyromonas, and Fusobacterium species can
also produce beta-lactamase (11). The recovery rate of aerobic and anaero-
bic beta-lactamase producing bacteria (BLPB) in the oropharynx has
increased in recent years, and these organisms were isolated from more than
half of the patients with head and neck infections including sinusitis (11).
BLPB can be involved directly in the infection, protecting not only them-
selves from the activity of penicillins but also penicillin-susceptible organ-
isms. This can occur when the enzyme beta-lactamase is secreted into the
infected tissue or abscess fluid in sufficient quantities to break the penicillin's
beta-lactam ring before it can kill the susceptible bacteria (12) (Fig. 2).

The high incidence of recovery of BLPB in upper respiratory tract
infections may be because of the selection of these organisms following
antimicrobial therapy with beta-lactam antibiotics. Emergence of penicillin-
resistant flora can occur following only a short course of penicillin (13,14).

Obtaining Appropriate Sinus Content Cultures while Avoiding
the Normal Flora

If a patient with sinusitis develops severe infection, is immunocompromised
or fails to show significant improvement or shows signs of deterioration
despite treatment, it is important to obtain a culture, preferably through
sinus puncture, as this may reveal the presence of causative bacteria.

Infectious Causes of Sinusitis

149

p- lactam Antibiotics

["i-lactamase

Producing

Bacteria

p-lactam

Susceptible

Bacteria

Figure 2 Protection of penicillin-susceptible bacteria from penicillin by beta-
lactamase-producing bacteria.

However, obtaining a culture through sinus endoscopy is an alternative
approach.

Sinus aspirates for culture must be obtained free of contamination so
that saprophytic organisms or normal flora are excluded and culture results
can be interpreted correctly. As indigenous aerobic and anaerobic bacteria
are present on the nasopharyngeal mucous membranes in large numbers,
even minimal contamination of a specimen with the normal flora can give
misleading results. The use of sinus puncture is the "gold standard" method
of obtaining such specimens (15). There is, however, data that supports the
use of endoscopically obtained cultures in assessing the microbiology of
infected sinuses (16a-23).

Sinus Puncture

Obtaining sinus aspirates by puncture is the traditional method of specimens
collection. The maxillary sinus is the most accessible of all of the paranasal
sinuses. There are two approaches to the maxillary sinus that use puncture:
via either the canine fossa or the inferior meatus. The nasal vestibule is
often heavily colonized with pathogenic bacteria, mostly S. aureus. There-
fore, sterilization of the nasal vestibule and the area beneath the inferior
nasal turbinate is suggested.

Contamination with nasal flora may, however, occur. To prevent
misinterpretation of the culture results, an infection is defined as the reco-
very of a bacterial species in high density [i.e., a colony count of at least
10 to 10 colony forming units per milliliter (cfu/mL)]. This quantitative
definition increases the probability that microorganisms isolated from the
sinus aspirate truly represent in situ infection and not contamination. Most

150 Brook

aspirates from infected sinuses contain colony counts above 10 4 cfu/mL. If
quantitative cultures cannot be performed, Gram stain of aspirated speci-
mens enables semiquantitative assessment. If bacteria are readily seen on a
Gram stain preparation, the approximate bacterial density is about
10 5 cfu/mL. Of 12 cases in which an antral puncture showed at least
10 5 cfu/mL pathogens, the Gram stain demonstrated either organisms or
white blood cells in all 12 cases, and organisms as well as white blood cells
in 9 of 12 cases (16a). A Gram stain is especially useful if organisms are
observed on smear and the specimen fails to grow using standard aerobic cul-
ture techniques, in which case anaerobic organisms or other fastidious bac-
teria or antibiotic-inhibited flora should be suspected. A Gram stain can
also allow an assessment of the local inflammatory response. The presence
of many white blood cells in association with a positive bacterial culture in
high density makes it probable that a bacterial infection is present. A Gram
stain does not, however, differentiate between neutrophils and eosinophils. In
contrast, a paucity or absence of white blood cells in association with the pre-
sence of a positive culture in low-density suggests bacterial contamination.

Endoscopic Cultures

Recently, there has been an interest in obtaining cultures of the middle
meatus endoscopically, as a substitute or surrogate for cultures of a sinus
aspirate. The endoscopically obtained culture is less invasive and associated
with less morbidity (16a). Unfortunately, the middle meatus in normal chil-
dren is colonized with the same bacterial species, namely, S. pneumoniae, H.
influenzae, and M. catarrhalis, as are commonly recovered from children
with sinus infection (17). Accordingly, this technique cannot be recom-
mended for precise bacterial diagnosis in children with sinus infections.

In three recent studies, the bacterial species recovered from middle
meatal samples obtained from normal adults were coagulase-negative
staphylococci (CNS, 35-50%), Corynebacterium spp. (16-23%), and S.
aureus (8-20%) (18-20). The only overlap between commensals and poten-
tial pathogens is S. aureus.

Several studies in adults have shown a good correlation between
cultures of the middle meatus and the sinus aspirate in patients with acute
sinusitis, especially when purulence is in the middle meatus (16a,2 1,22,25).
However, other studies have not found such a correlation (23,24).

Concordance in the types and concentrations of organisms recovered
by endoscopic aspirates and those isolated during sinus surgery was found
in all six cases in one study (25). Sixteen of the 18 anaerobes isolated from
sinus aspirates were also found in the concomitant endoscopic sample. Five
aerobic isolates were found in both sinus aspirates and endoscopic samples
and their concentration was similar. However, contamination by four aero-
bic gram-positive bacteria (in numbers of <10 4 cfu/sample) were found in
endoscopic samples.

Infectious Causes of Sinusitis 151

CNS is usually interpreted as a nonpathogen in acute sinusitis. Talbot
et al. (16a) correlated the results of endoscopically obtained cultures and the
cultures obtained from maxillary sinus aspirates. They reported no situa-
tions in which the puncture demonstrated CNS in >10 cfu/mL; however, a
swab of the middle meatus grew CNS in 6 of 53 patients. Interpretation of
the pathogenicity of S. aureus is more difficult. Two of 53 patients had
>10 5 cfu/mL, which correlated with the endoscopic swab. However, in an
additional six patients, there was no agreement between sites (16a).

In rare instances, neither a sinus aspirate nor a specimen obtained
endoscopically is sufficient for the diagnosis of a sinus infection. In this ins-
tance, biopsy of the sinus mucosa and broth culture and appropriate stains
may be required to demonstrate the bacterial etiology.

Discrepancies in the Recovery of Bacteria from Multiple Sinuses
in Sinusitis

There are differences in the distribution of organisms in a single patient who
suffers from infections in multiple sinuses that emphasize the importance of
obtaining cultures from all infected sinuses. A recent study has evaluated the
discrepancies among infected sinuses by studying the aerobic and anaerobic
microbiology of acute and chronic sinusitis in patients with involvement of
multiple sinuses (16b). The 155 evaluated patients had sinusitis of either the
maxillary, ethmoid, or frontal sinuses (any combination) and had organisms
recovered from two to four concomitantly infected sinuses. Similar aerobic,
facultative, and anaerobic organisms were recovered from all the groups of
patients. In patients who had organisms isolated from two sinuses and had
acute sinusitis, 31 (56%) of the 55 isolates were found only in a single sinus
and 24 (44%) were recovered concomitantly from two sinuses. In those with
chronic infection, 31 (34%) of the 91 isolates were recovered only from a sin-
gle sinus and 60 (66%) were found concomitantly from two sinuses. Anae-
robic bacteria were more often concomitantly isolated from two sinuses
(50 of 70) than aerobic and facultative (10 of 21, p < 0.05). Similar findings
were observed in patients who had organisms isolated from three or four
sinuses. Beta-lactamase-producing bacteria were more often isolated from
patients with chronic infection (58-83%) as compared to those with acute
infections (32-43%). These findings illustrate that there are differences in
the distribution of organisms in a single patient who suffers from infections
in multiple sinuses, and emphasize the importance of obtaining cultures
from all infected sinuses.

INTERFERING FLORA

The nasopharynx of healthy individuals is generally colonized by relatively
nonpathogenic aerobic and anaerobic organisms (26), some of which

152 Brook

Potential
Pathogens

Norma!
Flora

Figure 3 The role of normal flora in preventing colonization and subsequent
infection by pathogenic bacteria.

possess the ability to interfere with the growth of potential pathogens (27)
(Fig. 3). This phenomenon is called "bacterial interference.'' These organ-
isms include the aerobic alpha-hemolytic streptococci (mostly S. mitis and
S. sanguis) (28) and anaerobic bacteria (Prevotella melaninogenica and
Pepto strep to coccus anaerobius) (29). Many of these organisms produce
bacteriocins, which are bactericidal proteins. Nasopharyngeal carriage of
upper respiratory tract pathogens such as S. pneumoniae, H. influenzae and
M. catarrhalis can, however, occur in healthy individuals, and increases
significantly in the general population of young children during respiratory
illness (30,31). The number of interfering organisms is lower in children
prone to sinusitis (32). The absence of these organisms may explain the
higher recovery of pathogens in these children. The presence of organisms
with interfering potential may play a role in the prevention of colonization
by pathogens and the occurrence of upper respiratory infections.

Administration of antimicrobial agents can influence the composition
of nasopharyngeal flora (33). Members of the oral flora with interfering
capability (e.g., aerobic and anaerobic streptococci as well as penicillin-
susceptible P. melaninogenica strains) can become resistant to amoxicillin,
but stay susceptible to amoxicillin-clavulanate. Beta-lactamase-producing
P. melaninogenica strains are susceptible to amoxicillin-clavulanate. All
these organisms are more resistant to second- and third-generation cepha-
losporin therapy. Therapy with oral second-generation cephalosporins does
not eliminate organisms with interfering capabilities, as do amoxicillin (34)
or amoxicillin-clavulanate.

NASAL FLORA

The origin of organisms that are introduced into the sinuses and may
eventually cause sinusitis is the nasal cavity. The normal flora of that
site is comprised of certain bacterial species, which include S. aureus,

Infectious Causes of Sinusitis 153

S. epidermidis, alpha- and gamma-streptococci, Propionibacterium acnes,
and aerobic diphtheroid (35-37). Potential sinus pathogens have been
isolated from healthy nasal cavity but relatively rarely. These included S.
pneumoniae (0.5-15%), H. influenzae (0-6%), M. catarrhalis (0-4%), Strepto-
coccus pyogenes (0-1%), and anaerobic bacteria [Peptostreptococcus spp.
(7-16%) and Prevotella spp. (6-8%)] (35-37).

The flora of the nasal cavity of patients with sinusitis is different from
healthy flora. While the recovery of Staphylococcus spp. and diphtheroids
is reduced, the isolation of pathogens increases — S. pneumoniae was found
in 36% of patients, H. influenzae in over 50%, S. pyogenes in 6%, and
M. catarrhalis in 4% (38-42).

In many studies of the nasal bacterial flora in sinusitis, a simultaneous
sinus aspirate was not taken (40,41), whereas in other studies, the correla-
tion was found to be poor in some (40,43) but good in others (42,44). A
good correlation was, however, found in one study (38); in this study, when
the sinus aspirate culture yielded a presumed sinus pathogen, the same
organism was found in the nasal cavity sample in 91% of the 185 patients.
The predictive value of a pathogen-positive nasal finding was high for S.
pyogenes (94%), H. influenzae (78%), and S. pneumoniae (69%), but was
low for M. catarrhalis (20%). Despite this encouraging data, nasopharyngeal
culture is not an acceptable alternative to culture through aspiration.

NORMAL SINUS FLORA

It is known that after sinus surgery, the sinus cavities quickly become
colonized with bacteria and are no longer sterile. The question of whether
normal bacterial flora in the sinuses exists is controversial. The communica-
tion of the sinuses with the nasal cavity through the ostia could enable
organisms that reside in the nasopharynx to spread into the sinus. Following
closure of the ostium, these bacteria may become involved in the inflamma-
tion. Organisms have been recovered from uninflamed sinuses in several
studies (45-48). The bacterial flora of noninflamed sinuses was studied for
aerobic and anaerobic bacteria in 12 adults who underwent corrective sur-
gery for septal deviation (45). Organisms were recovered from all aspirates
with an average of four isolates per sinus aspirate. The predominant anae-
robic isolates were Prevotella, Porphyromonas, Fusobacterium, and Pepto-
streptococcus spp. The most common aerobic bacteria were S. pyogenes,
S. aureus, S. pneumoniae, and H. influenzae.

In another study, specimens were processed for aerobic bacteria only,
and thus Staphylococcus spp. and alpha-hemolytic streptococci were isolated
(46). Organisms were recovered in 20% of maxillary sinuses of patients who
underwent surgical repositioning of the maxilla (47). In contrast, another
report of aspirates of 12 volunteers with no sinus disease showed no bacter-
ial growth (48). Jiang et al. evaluated (49) the bacteriology of maxillary

154

Brook

sinuses with normal endoscopic findings. Organisms were recovered from
14 of 30 (47%) swab specimens and 7 of 17 (41%) of mucosal specimens.

Gordts et al. (50) reported the microbiology of the middle meatus in
normal adults. They noted in 52 patients that 75% had the presence of
bacterial isolates, most commonly CNS (35%), Corynebacterium spp. (23%),
and S. aureus (8%). However, only low numbers of these species were present
as compared to previous studies in children where the most common organ-
isms were H. influenzae (40%), M. catarrhalis (34%), and S. pneumoniae
(50%) of children. Nonhemolytic streptococci and Moraxella spp. were
absent in adults.

MICROBIOLOGY OF SINUSITIS

The pattern of many upper respiratory infections including sinusitis evolves
through several phases (Fig. 4). The early stage often is a viral infection that
generally lasts up to 10 days and complete recovery occurs in most indivi-
duals (39). However, in a small number of patients (estimated at 0.5%) with
viral sinusitis, a secondary acute bacterial infection may develop. This is
generally caused by facultative aerobic bacteria (i.e., S. pneumoniae, H. influ-
enzae, and M. catarrhalis). If resolution does not take place, anaerobic bac-
teria of oral flora origin become predominant over time. The dynamics of
these bacterial changes were recently demonstrated by performing serial
cultures in patients with maxillary sinusitis (51).

The Role of Bacterial Superantigens in Sinus Disease

Some microorganisms (bacteria, viruses, and fungi) can produce exotoxins
(also called enterotoxins) that are able to nonspecifically up-regulate

c
a>

100 -t

80 -

60 -

40 -

20 -

Viral

Aerobes

Anaerobes

8-10 Days

3 Months

Time

Figure 4 Microbiological dynamics of sinusitis.

Infectious Causes of Sinusitis 155

T lymphocytes by cross-linking the MHC II molecule on antigen-presenting
cells with the variable beta (Vp) region of the T-cell receptor (TCR). These
exotoxins are called superantigens because they activate in a nonspecific
manner the subpopulations representing up to 30% of T lymphocytes in con-
trast to classical antigens, which activate only <0.01% of T lymphocytes.
Furthermore, superantigens can also act as classical antigens-bringing about
the concomitant generation of antisuperantigen antibodies that are often
IgE isotypes (52).

S. aureus is a common colonizer of the nasal passage of patients with
nasal polyps. S. aureus superantigens may play a role in nasal polyps, as
50% of polyp homogenates contained specific IgE to S. aureus exotoxins.
Polyps associated with IgE to superantigens had significantly greater eosino-
philia and markers of eosinophilic inflammation than controls (53).

Staphylococcal exotoxin-specific serum IgE was present in 5 of 10
(50%) patients with nasal polyposis and in none of 13 control patients.
Patients with IgE to these superantigens have an increase in tissue
eosinophilia and a higher incidence of asthma compared to control patients
(54).

S. aureus was present in 7 of 13 patients with nasal polyps and all
produced exotoxins, namely, staphylococcus enterotoxin A (SEA), toxic
shock syndrome toxin- 1 (TSS T-l), or staphylococcus enterotoxin B (SEB).
A clonal expansion of Vp specific to the isolated exotoxin was observed in
the three patients studied (55).

Viral Infections

Viral illness is the most common predisposing factor for upper respiratory
tract infections, including sinusitis (56). Rhino- and para-influenzae viruses
are the most common causes of sinusitis (57,58). It is uncertain whether the
viral infection precedes or is concurrent with the bacterial infection. The
actual mechanisms by which a virus causes sinus disease are unknown.
The mechanism whereby viruses predispose to sinusitis may involve micro-
bial synergy, induction of local inflammation that blocks the sinus ostia,
increase of bacterial attachment to the epithelial cells, and disruption of
the local immune defense (Fig. 5).

Epithelial cells are often infected with the common respiratory viruses,
which can induce the production of several cytokines (56,59,60). In the
case of rhinoviruses, the virus is transported to the posterior nasopharynx
after deposition in the nose (59,61) and attaches to a specific rhinovirus
receptor (62). Following initiation of the infection, several inflammatory
pathways and the sympathetic nervous system, which generates the classic
symptoms of a cold, are stimulated (63). The common cold involves not
only the nasal passages but also the paranasal sinuses. Sinus computed
tomography (CT) scans of 31 young adults with early common colds

156

Brook

Viruses:

• direct synergy

• anatomy
•^immunity
•Tadherence

• paralysis cilia

Aerobes:

•S. pneumoniae
•H. influenzae
•M. catarrhalis
• others

Anaerobes:

• prevotella
•fusobacteria

• peptostreptococci

Time

Figure 5 Dynamics of upper respiratory tract infection.

showed frequent abnormalities in the sinus cavity (64). Mucosal thickening
is observed in radiographs of 87% of patients with colds (64), probably
because of excess amounts of mucus discharged from goblet cells. These
were observed in the maxillary, ethmoid, frontal, and sphenoid sinuses
in 87, 65, 32, and 39% of the cases, respectively. Similar sinus abnormal-
ities during colds were also observed in adults and children (65,66).

Activation of the inflammatory pathways results in engorgement of
the venous erectile tissue in the nasal turbinates, which leads to leakage of
plasma into the nose and sinuses, discharge of goblet cells and seromucous
glands, sneezing, and sensation of pain.

CT scans show occlusion of the infundibulum in 77% of patients with
viral rhinosinusitis (64). A malfunction in the ability of cilia to move mate-
rial deposits towards the ostia because of the increased amount of viscous
material and their induced slowing and paralysis is also observed (67).
The adverse effect of this dysfunction is compounded by infundibular and
osteomeatal obstruction from mucosal swelling. Some viral infections, such
as influenza, can cause destructive epithelial damage, which enhances bac-
terial adherence.

During a cold, nasal fluid containing viruses, bacteria, and inflamma-
tory mediators is suctioned into the sinus cavities where it produces inflam-
mation and/or infection and is thickened by exocytosis of mucin from the
numerous goblet cells in the sinus epithelium. The CT abnormalities
observed in viral sinusitis could, therefore, be because of an inflammation
alone or a viral infection of sinus epithelium cells. In sinus puncture
studies in patients with acute community acquired rhinosinusitis, 15% of the
sinus aspirates yielded rhinovirus, 5% influenza virus, 3% parainfluenza
virus, and 2% adenovirus (68). Some of the sinus aspirates yielded both
viruses and bacteria.

Infectious Causes of Sinusitis 157

Bacteria in Acute Sinusitis

Bacteria can be isolated from two-thirds of patients with acute infection of
the maxillary, ethmoid, frontal, and sphenoid sinuses (69). The microbio-
logy of acute sinusitis is presented in greater details in Chapter 7. The bac-
teria recovered from pediatric and adult patients with community-acquired
acute purulent sinusitis, using sinus aspiration by puncture or surgery, are
the common respiratory pathogens (S. pneumoniae, M. catarrhalis, H. influ-
enzae, and beta-hemolytic streptococci) and are considered as part of the
normal flora of the nose (S. aureus) (Table 1) (70-72). S. aureus is a common
pathogen in sphenoid sinusitis (72), whereas the other organisms are com-
mon in other sinuses.

The bacteria that cause the infection in children are generally the same
as those found in acute otitis media. S. pneumoniae was isolated in 28% of 50
children with acute sinusitis, and both H. influenzae as well as M. catarrhalis
were isolated in 19% of the aspirates. Beta-lactamase-producing strains of
H. influenzae and M. catarrhalis were found in 20% and 27% of the cases,
respectively.

The infection is polymicrobial in about a third of the cases. Enteric
bacteria are recovered less commonly, and anaerobes were recovered from
only a few cases with acute sinusitis. However, appropriate methods for
their recovery were rarely employed in most studies of acute sinusitis. Anae-
robic bacteria are commonly recovered from acute sinusitis associated with
dental disease, mostly as an extension of the infection from the roots of the
premolar or molar teeth (73,74) (see Chap. 19).

Pseudomonas aeruginosa and other gram-negative rods are common
in sinusitis of nosocomial origin (especially in patients who have nasal tubes
or catheters), the immunocompromised patients with human immune-
deficiency virus (HIV) infection, and patients who suffer from cystic fibrosis
(75).

Bacteria in Chronic Sinusitis

Although the exact etiology of the inflammation associated with this chronic
sinusitis is uncertain, the presence of bacteria within the sinuses in this
patient population has been well documented (76,77). Most clinicians beli-
eve that bacteria play a major role in the etiology and pathogenesis of most
cases of chronic sinusitis and prescribe antimicrobials therapy for its
treatment.

In contrast to the agreement regarding the microbiology of acute sinu-
sitis, there is disagreement regarding the microbiology of chronic sinusitis.
Unfortunately, there are several issues that confound the reliability of many
of these studies and, therefore, contribute to the disparity of their results.
These issues include: various methods used to sample the sinus cavity (i.e.,
aspiration, irrigation, Calginate swab, or biopsy); failure to sterilize the area

158

Brook

o
d

C/5

-*— '

• .-^

-*— »

1/3

• *—t
•*— i

• «-^

• -H
CO

-2

d
o

S-H

X
0Q

S-H

CD ^?

3 II

S-H

CD ^

-4-» l— t
3 II

t--

S-H

fl)

+-»

• »-H

S-H

H— '

OO
CN

r- on Tt vo

>n m iri co

\Q \D \D CN

On (N ^sO SO

•O

OO OO

OO OO -h (N "n

ro en vo ^<

en en o o
m "■* cn

m m m m

'st MD SO ^O

On OO t— CN
IT) ^h t^- OO

IT1 OO IT) h CO

*— « cn cn

•n M ^ oo

^t oo ^o io v© *© m

vo on t-- r- ^o

iO CN ^ t^j-

"vf CN

m cn

OO l> CN

(N CN

nes
tonia

.2 -*—

• «-H

5*.

CJ, ^

•"<.

-4— »

Co Co

tci 3

• >-H
•*— I

G
W

oo o
s -3

^j 5$ .«o

fti fti

si; «s

IT)

OC
OO

«-

Infectious Causes of Sinusitis 159

through which the trocar or endoscope is passed; different sinuses or areas
that are sampled (i.e., ethmoid bulla or maxillary antrum or middle meatus);
lack of assessment of the inflammatory response; lack of quantitation of
bacteria; previous or current use of antibiotics; variable patient selection
(i.e., age, duration, extent of disease, surgical, or nonsurgical subjects), pre-
sence of nasal polyps and time of culture transport and method of culture.

Numerous studies have examined the bacterial pathogens associated
with chronic sinusitis. However, most of these studies did not employ meth-
ods that are adequate for the recovery of anaerobic bacteria. Studies have
described significant differences in the microbial pathogens present in chro-
nic sinusitis as compared with acute sinusitis. S. aureus, S. epidermidis, and
anaerobic gram-negative bacteria predominate in chronic sinusitis. The
pathogenicity of some of the low virulence organisms such as S. epidermidis,
a colonizer of the nasal cavity, is questionable (50,78). The absence of
quantitation or performance of Gram stains in most studies prevents an
assessment of both the density of organisms and the accompaniment of
an inflammatory response. The common resistance of S. epidermidis to anti-
microbials does not prove its pathogenicity. Although S. epidermidis is dis-
counted as a pathogen in sinusitis, its role as a pathogen in other body sites
has been well documented (i.e., neutropenic sepsis, infections of indwelling
catheters, and in burn patients) (79). Their frequent recovery from swabs
obtained from the middle meatus of normal subjects marks them as com-
mensals and likely contaminants. In the unusual situation in which a large
number of white blood cells and gram-positive cocci were present on Gram
stain there was heavy growth of S. epidermidis, proper anaerobic cultures
showed no growth of other organisms, and the possibility of a true infection
by S. epidermidis should be entertained (80).

Gram-negative enteric rods were also reported in recent studies (79-82).
These included P. aeruginosa, Klebsiella pneumoniae, Proteus mirabilis, Enter-
obacter spp., and Escherichia coli. As these organisms are rarely found in
cultures of the middle meatus obtained from normal individuals, their isola-
tion from these symptomatic patients may suggest their pathogenic role.
These organisms may have been selected out following administration of
antimicrobial therapy in patients with chronic sinusitis.

The pathophysiology of chronic sinusitis often differs from that of
acute sinusitis. The exact events leading to chronic sinusitis have been diffi-
cult to identify or prove (83). It has been proposed that chronic sinusitis is
an extension of unresolved acute sinusitis. As mentioned previously, the
etiology of acute sinusitis frequently is viral, which can establish an environ-
ment that is synergistic with the growth of other organisms, both aerobic
and anaerobic. If the infection is not properly treated, the inflammatory
process can persist, which, over time, fosters the growth of anaerobic bac-
teria. Thus, the pathogens in sinusitis appear to evolve over the course of
infection — from viruses to aerobic to anaerobic bacterial growth — as the

160

Brook

symptoms and pathology persist over a period of weeks to months. (Figs. 4
and 5)

The microbiology of chronic sinusitis differs from that of acute
sinusitis (Table 1) (84-87). The transition from acute to chronic sinusitis by
repeated aspiration of sinus secretions using endoscopy was illustrated in
five patients who presented with acute maxillary sinusitis that did not
respond to antimicrobial therapy (51). Most bacteria isolated from the first
culture were aerobic or facultative bacteria — S. pneumoniae, H. influenzae,
and M. catarrhalis. Failure to respond to therapy was associated with the
emergence of resistant aerobic and anaerobic bacteria in subsequent
aspirates. These organisms included F. nucleatum, pigmented Prevotella,
Porphyromonas spp., and Pep to streptococcus spp. (Fig. 6). Eradication of
the infection was finally achieved by administration of effective antimicro-
bial agents and in three cases by surgical drainage.

This study illustrates that as chronicity develops, the aerobic and
facultative species are gradually replaced by anaerobes (51). This may result
from the selective pressure of antimicrobial agents that enable resistant
organisms to survive and from the development of conditions appropriate
for anaerobic growth, which include the reduction in oxygen tension and
an increase in acidity within the sinus (88). These are caused by the persis-
tent edema and swelling, which reduce blood supply, and by the consump-
tion of oxygen by the aerobic bacteria (88). Other factors are the emergence
over time or selection of anaerobes that possess virulence factors such as
capsule (89).

In chronic infections, when adequate methods are used, anaerobes
can be recovered in more than half of all cases; the usual pathogens in acute

H. influenzae
M. catarrhalis

JTIOX

12D

H. influenzae

M. catarrhalis

Peptostrep.

Amox
7D

H. influenzae

Fusobacteria

Peptostrep.

tAmox/clav

S. pneumoniae

Amox
7D

S. aureus

Peptostrep.

Prevotella

S. aureus
Fusobacteria

Clinda

21D

Figure 6 Dynamics of sinusitis. Changes in the microbiology of sinusitis in 2
patients treated with antibiotics. Source: From Ref. 51.

Infectious Causes of Sinusitis

161

sinusitis (e.g., S. pneumoniae, H. influenzae, and M. catarrhalis) are found
with lower frequency (84-87,90). Polymicrobial infection is common in
chronic sinusitis, which is a synergistic infection (89) and may therefore
be more difficult to eradicate with narrow-spectrum antimicrobial agents.
Chronic sinusitis caused by anaerobes is of particular concern, clinically,
because many of the complications associated with this condition (e.g.,
mucocele formation, osteomyelitis, local and intracranial abscess) are
caused by these organisms (91).

That anaerobes play a role in chronic sinusitis is supported by the
ability to induce chronic sinusitis in a rabbit by intrasinus inoculation of
Bacteroides fragilis (92) and the rapid production of serum IgG antibodies
against this organism in the infected animals (93). The pathogenic role of
these organisms is also supported by the detection of antibodies (IgG)
to two anaerobic organisms commonly recovered from sinus aspirates
(F. nucleatum and P. intermedia) (94). Antibody levels to these organisms
declined in the patients who responded to therapy and were cured, but
not in those who failed therapy (Fig. 7).

Aside from their role as pathogens, the production of beta-lactamases
among many gram-negative anaerobes (e.g., Prevotella, Porphyromonas,
and Fusobacterium spp.) can shield or protect other organisms, including
aerobic pathogens, from beta-lactam antibiotics (12,95) (Fig. 2).

Studies in Children

There have been 10 studies of the microbiology of chronic rhinosinusitis in
children between 1981 and 2000 (86,96-104). Four of these studies were

200 i

CO
UJ

100 -

200 n

Failed (n=3)
Cured (n=13)

100 ■

1 2

Time (Months)

1 2
Time (Months)

Figure 7 Serum antibodies to F. nucleatum and P. intermedia in 23 patients with
chronic sinusitis. Source: From Ref. 94.

162 Brook

prospective (96,97,101,103) and six were retrospective. In all but two studies,
the maxillary sinus was sampled by transnasal aspiration. The most
common criteria for evaluation were the symptoms that lasted over 90 days.
An attempt was made to sterilize the nose prior to obtaining the culture only
in five studies, and bacterial quantitation was rarely done. In two of the
studies, normal nasal flora (i.e., S. epidermidis and alpha-hemolytic strepto-
cocci) was recovered. It is difficult to know what pathologic significance
to ascribe to these organisms. In the remaining studies, the usual sinus
pathogens (i.e., H. influenzae, S. pneumoniae, and M. catarrhalis) were
recovered in about 60% of cases. This was especially true when the criteria
for entry included purulent secretions. In the remaining 30 to 40% of
children, contaminants were recovered. Anaerobes were recovered in
three studies, the only one that employed methods for their isolation
(86,96,103).

S. aureus (19%) and alpha-hemolytic streptococci (23%) were the
predominant isolates in ethmoid sinusitis in one study (99), and S. epidermidis
and alpha-hemolytic streptococci were the major ones in another (97).
M. catarrhalis was the most common isolate in a study of children with
allergies, although 25% of the patients had polymicrobial flora (105).
S. pneumoniae and H. influenzae predominated in children with acute
exacerbations (106).

Brook and Yocum (107) studied 40 children with chronic sinusitis. The
sinuses infected were the maxillary (15 cases), ethmoid (13), and frontal (7).
Pansinusitis was present in five patients. A total of 121 isolates (97 anaerobic
and 24 aerobic) were recovered. Anaerobes were recovered from all 37
culture-positive specimens, and in 14 cases (38%) they were mixed with aero-
bes. The predominant anaerobic organisms were gram-negative bacilli (36
isolates), anaerobic gram-positive cocci (28), and Fusobacterium spp. (13).
The predominant aerobic isolates were alpha-hemolytic streptococci (7),
S. aureus (7), and Haemophilus spp. (4).

Brook et al. (96) correlated the microbiology of concurrent chronic
otitis media with effusion and chronic maxillary sinusitis in 32 children.
Two-third of the patients had a bacterial etiology. The most common
isolates were H. influenzae (9 isolates), S. pneumoniae (7), Prevotella spp.
(8), and Pepto streptococcus spp. (6). Microbiological concordance between
the ear and sinus was found in 22 (69%) of culture-positive patients.

Erkan et al. (103) studied 93 chronically inflamed maxillary sinuses in
children. Anaerobic bacteria were isolated in 81 of 87 (93%) culture-positive
specimens, recovered alone in 61 (70%)) cases, and mixed with aerobic or
facultative bacteria in 20 (23%). Aerobic or facultative bacteria were present
alone in six cases (7%). A total of 261 isolates, 19 anaerobes, and 69 aerobes
or facultatives were isolated. The predominant anaerobic organisms were
Bacteroides spp. and anaerobic cocci; the predominant aerobes or faculta-
tives were Streptococcus spp. and S. aureus.

Infectious Causes of Sinusitis 163

Studies in Adults

The presence of anaerobic bacteria in chronic sinusitis in adults was found
to be clinically significant (108,109). In a study of chronic maxillary sinusitis
Finegold et al. (87) found recurrence of signs and symptoms twice as fre-
quent when cultures showed anaerobic bacterial counts above 10 cfu/mL.

Anaerobes were identified in chronic sinusitis whenever techniques for
their cultivation were employed. The predominant isolates were pigmented
Prevotella, Fusobacterium, and Pep to streptococcus spp. The predominant
aerobic bacteria were S. aureus, M. catarrhalis, and Haemophilus spp.
Aerobic and anaerobic BLPB were isolated from over one-third of these
patients (80,84,85,90,109,110). These BLPB were S. aureus, Haemophilus,
Prevotella, Porphyromonas, and Fusobacterium spp.

A summary of 17 studies of chronic sinusitis done since 1974, includ-
ing 1758 patients (133 were children), is shown in Table 2 (85-87,103,110-
123). Anaerobes were recovered in 12% to 93% of patients. The variability
in recovery may result from differences in the methodologies used for
transportation and cultivation, patient population, geography, and previous
antimicrobial therapy.

Brook and Frazier (124), who correlated the microbiology with the
history of sinus surgery in 108 patients with chronic maxillary sinusitis,
found a higher rate of isolation of P. aeruginosa and other gram-negative
bacilli in patients with previous sinus surgery. Anaerobes were, however,
isolated more frequently in patients who did not have prior surgery.

Brook et al. (125) evaluated the microbiology of 13 chronically
infected frontal, seven sphenoid (126), and 17 ethmoid sinuses (127) (Table 1).
Anaerobic bacteria were recovered in over two-thirds of the patients. The
predominant anaerobes included Prevotella, Pep to strep to coccus, and Fuso-
bacterium spp. The main aerobic organisms were gram-negative bacilli
(H. influenzae, K. pneumoniae, E. coli, and P. aeruginosa) .

Nadel et al. (80) also recovered gram-negative rods more commonly in
previous surgery patients or those who had sinus irrigation. P. aeruginosa
was more common in patients who received systemic steroids. Other studies
have also noted this shift toward gram-negative organisms in patients who
have been extensively and repeatedly treated (79,82,128a). The bacterial
flora includes Pseudomonas spp., Enterobacter spp., methicillin-resistant
S. aureus, H influenzae, and M. catarrhalis.

Bacteria in Chronic Maxillary Sinusitis Associated with
Nasal Polyposis

Nasal polyps can impair paranasal sinus ventilation and drainage by
blockage of the ostiomeatal complex. Several studies have shown that in
the majority of cases of chronic sinusitis where nasal polyps are present,
bacterial cultures are negative. Even polymerase chain reaction (PCR)

164

Brook

• f-H

• »-H

(/}

CD
-t-»
O

03
o

• »-H

1-H
43

CD
03

-t-»

d
o

• »-H

-t->

Cm
O

in
-Si

CD
CD

S 2

GO 0)

—

CD
J-h
CD

C/5

J-h

d -a

-4-» J-*

C^3

d w

<o3 »rt

• iH

-t— »

• »-H

d
o

-*— »

-*— '

cmonOncmoonocmonOOsOcooocmcmvoon
'om^HTt'^-TtcNmoocN^oaNOOoo^HCN'^-

»/->OnOcOOOOnC/300

o co o o en co ^

O On On O 7; Z <n

c/3

• .-H
•4— »

• 1-H

• .-H

.-H

1-H
43

CO CO CO CO .22

CO CO CO

CO CO CO CO CO CO

c«
=3

c/o

.2 §

d <u

° ti

43 5 43

U < U

CO CO CO

d d d
d d d

CO CO CO

d d 3

d d d

CO CO CO CO CO CO

• »-H

• •— c

• >-H

• »-H

cyo

S-H

—

• 1-H

Ctf

c^J

■4— •

■ |

p <

. <

■ |

^■^

^— ^

^— «

^— ^

• »-H

• 1-H

OOOOOOOOOOOCJ

Gdddddddddd

ooooooooooo
s^j-is-hs-hs-hj-hs-hs-hs-hs-hj-h

4343434343434343434343

uuuuuuuuuuu<

3 g

• •— (

• i-H

43
O

CD
-*— '
=5
O

• t-H

• »-H

d
d

• »-H
S-H

CO •—!

.a §

"S d

O O

• ^H • f-H

d d

o o

■— u-

43 43

u u

CO CO

oo ^o

C^5

-4— »

O .-3

-*-»

zn
-t-»

-4-»

^f"

en 4^

^ 43

' '

,— '

i-H

O
>0

d «

s-h OX) ^2

« h ^ ^?

-73 *£> ^ ~

d d _; —■

c3 5£ cd ^^

4^ ^

• i— <
J-i

S-H

(1> c3
03

d
U

«=> S £?

o3 ctt 53

13
o

fc > ^ PQ Ph

c--

d cd ^o *-

13 43 OO ^

o o

d 0< 4^ w _ _

O 5 O -*- 1 cd o3

3 X) o 3 ^ ^

c^ H P3 ffi a w

^^ oo

CO f^

CM OO

o3 o3 o3 CJ

73 CD

o <-> d

CD <D

o:
4*i

CD
-*— '

CD O
co bJ3

W ffl w ^ t

— >

o
c

»r

Z
s

Infectious Causes of Sinusitis 165

techniques have failed to demonstrate bacterial infection in most cases
(128b). Hamilos et al. (128c) obtained antral culture in 12 subjects with
chronic maxillary sinusitis with nasal polyps and isolated organisms in only
three patients. However, none of these studies employed methods that were
adequate for the recovery of anaerobic bacteria.

We evaluated aspirates of 48 chronically inflamed maxillary sinuses
from patients who had nasal polyposis that were cultured for aerobic and
anaerobic bacteria (128d). Bacterial growth was present in 46 (96%) spe-
cimens. Aerobic or facultative bacteria were present in 6 (13%) specimens,
anaerobic bacteria alone in 18 (39%), and mixed aerobic and anaerobic bac-
teria in 22 (48%). There were 110 bacterial isolates (2.4 per specimen).

Thirty-nine of the isolates were aerobic or facultative organisms
(0.85 per specimen). The predominant aerobic or facultative organisms were
S. aureus, microaerophilic streptococci, H. influenzae, and M. catarrhalis.
There were 71 anaerobes isolated (1.5 per specimen). The predominant
anaerobes were Pepto streptococcus spp., Prevotella spp., P. asaccharolytica,
Fusobacterium spp., and P. acnes. These findings suggest that the micro-
biology of the maxillary sinus of patients with chronic sinusitis with polyposis
is not different than those who develop chronic sinusitis without this
condition, as the major isolates are polymicrobial aerobic-anaerobic flora.

Bacteria in Acute Exacerbation of Chronic Sinusitis

Acute exacerbation of chronic sinusitis (AECS) represents a sudden worsen-
ing of the baseline chronic sinusitis with either worsening or new symptoms.
Typically, the acute (not chronic) symptoms resolve completely between
occurrences (129). We evaluated the microbiology of acute AECS (130) by
performing repeated endoscopic sinus aspirations in seven patients over a
period of 125 to 242 days. Bacteria were recovered from all 22 aspirates
and the number of isolates varied between two and four. A total of 54
isolates were isolated, 16 aerobic as well as facultatives and 38 anaerobic
bacteria. The aerobic bacteria were seven H. influenzae, three S. pneumoniae,
three M. catarrhalis, two S. aureus, and one K. pneumoniae. The anaerobic
bacteria included pigmented Prevotella and Porphyromonas spp. (19 isolates),
Peptostreptococcus spp. (9), Fusobacterium spp. (8), and acnes (2). A
change in the types of isolates was noted in all consecutive cultures
obtained from the same patients as different organisms emerged and pre-
viously isolated bacteria were no longer recovered. An increase in antimi-
crobial resistance was noted in six instances. These findings illustrate the
microbial dynamics of AECS where anaerobic and aerobic bacteria prevail
and highlight the importance of obtaining cultures from patients with this
infection for guidance in selection of proper antimicrobial therapy.

Brook (131) compared the aerobic and anaerobic microbiology of
maxillary AECS with the microbiology of chronic maxillary sinusitis.

166 Brook

Included in the study were 32 cases with chronic sinusitis and 30 with AECS.
A total of 81 isolates were recovered from the 32 cases (2.5 per specimen) with
chronic sinusitis, 33 aerobic, and 48 anaerobic. Aerobes alone were recovered
in eight specimens (25%), anaerobes only were isolated in 11 (34%), and
mixed aerobes and anaerobes were recovered in 13 (41%). The predominant
aerobic and facultatives were Enterobacteriacaeae and S. aureus. The predo-
minant anaerobic bacteria were Peptostreptococcus spp., Fusobacterium spp.,
anaerobic gram-negative bacilli, and P. acnes. A total of 89 isolates were
recovered from the 30 cases (3.0 per specimen) with AECS, 40 aerobic and
facultatives, and 49 anaerobic. Aerobes were recovered in eight instances
(27%), anaerobes only in 1 1 (37%), and mixed aerobes and anaerobes were
recovered in 11 (37%). The predominant aerobes were S. pneumoniae,
Enterobacteriaceae, and S. aureus. The prominante anaerobes were Peptos-
treptococcus spp., Fusobacterium spp., gram-negative bacilli, and P. acnes.
This study illustrates that the organisms isolated from patients with AECS
were predominantly anaerobic and were similar to those generally recovered
in chronic sinusitis. However, aerobic bacteria that are usually found in acute
infections (e.g., S. pneumoniae, H. influenzae, and M. catarrhalis) can also
emerge in some of the episodes of AECS.

Nosocomial Rhinosinusitis

Patients with nosocomial sinusitis are usually those who require extended
periods of intensive care (postoperative patients, burn victims, and patients
with severe trauma) involving prolonged endotracheal or nasogastric
intubation (132). Nasotracheal intubation places the patient at a substan-
tially higher risk for nosocomial sinusitis than orotracheal intubation (133).
Approximately 25% of patients requiring nasotracheal intubation for
more than five days develop nosocomial sinusitis (134). In contrast to
community-acquired sinusitis, the usual pathogens are gram-negative ente-
rics (e,g., P. aeruginosa, K. pneumoniae, Enterobacter spp., P. mirabilis, and
Serratia marcescens) and gram-positive cocci (occasionally streptococci and
staphylococci) (chap. 16) (133-137). Whether these organisms are actually
pathogenic is unclear, and they usually represent colonization of an environ-
ment with impaired mucociliary transport and foreign body presence in the
nasal cavity.

Evaluation of the microbiology of nosocomial sinusitis in nine
children with neurologic impairment revealed anaerobic bacteria, always
mixed with aerobic and facultative bacteria in 6 (67%) sinus aspirates and
aerobic bacteria only in 3 (33%) (138). There were 24 bacterial isolates,
12 aerobic or facultative and 12 anaerobic. The predominant aerobic iso-
lates were K. pneumoniae, E. coli, and S. aureus (two each) and P. mirabilis,
P. aeruginosa, H. influenzae, M. catarrhalis, and S. pneumoniae (one each).
The predominant anaerobes were Prevotella spp. (5), Peptostreptococcus

Infectious Causes of Sinusitis 167

spp. (4), F. nucleatum (2), and B. fragilis (1). Organisms similar to those
recovered from the sinuses were also isolated from tracheostomy site and
gastrostomy wound aspirates in five of seven instances. This study demon-
strates the uniqueness of the microbiologic features of sinusitis in neurolo-
gically impaired children in which, in addition to the organisms known to
cause infection in normal children, facultative and anaerobic gram-negative
organisms that can colonize other body sites are predominant.

Atypical Organisms

Chlamydia pneumoniae has been isolated from patients with respiratory
infection that included clinical features of sinusitis (139), and serological evi-
dence of its presence in patients with sinusitis was found in only 2% of 103
patients (140). However, as it was only isolated in one case from sinus
aspirate (141), its exact role in sinusitis is uncertain.

Mycoplasma pneumoniae has been suspect as a cause of acute sinusitis,
but no attempts have been made so far to recover it from infected sinuses.
However, serological evidence of an increase in antibody titres suggests a
link between sinusitis and M. pneumoniae infection (142) in purulent bacte-
rial and nonpurulent nonbacterial sinusitis.

One study identified M. pneumoniae-spec'iRc DNA in a small group of
subjects with sinusitis and/or nasal polyposis (143). However, a more recent
study failed to confirm the presence of bacterial-specific DNA sequences for
16S ribosomal RNA (144).

THE ROLE OF FUNGI IN SINUSITIS

Fungal "colonization" of the nose and paranasal sinuses is common in the
normal and inflamed sinuses because of the ubiquitous nature of the
organisms (145-148). Under certain conditions, however, clinically signifi-
cant growth of fungus balls (also called mycetomas) or saprophytic growth
of fungus may occur. This can cause the formation and accumulation of
fungal mycelia within the nose and paranasal sinuses without significant
mucosal inflammation. In such cases, extirpation of the offending fungal
growth is generally sufficient. However, in other forms, the inflammatory
response to the fungi may result in clinically significant disease.

Fungal sinusitis can be either noninvasive or invasive (chap. 20).
Invasive involvement is generally considered as an acute and fulminant
disease. In immunologically deficient patients, however, the invasive fungal
sinusitis is mild or not apparent, and can have a long and chronic course.
Diagnosis is confirmed by histological evidence of nasal or sinus invasive
fungal involvement lasting longer than 12 weeks.

Management of the disease necessitates correction of immunological
deficiency, surgical debridements, and long-term systemic and topical

168 Brook

antifungal treatment. The disease can progress and recur despite aggressive
therapy, and can occasionally be fatal.

Fungi can occasionally cause commonly acquired sinusitis (149). They
are especially common in patients with uncontrolled diabetes, HIV disease,
and those on prolonged immunosuppression therapy (especially transplant
recipients) and courses of antimicrobial therapy. Aspergillus fumigatus is
the most common fungus associated with sinusitis (150), and it can cause
disease in normal as well as the immunocompromised hosts. The organism
is a saprophyte of soil, dust, and decaying organic material. It has
an invasive and a noninvasive form; its portal of entry is the respiratory
tract. Sinusitis caused by aspergillus has been associated with the smoking
of marijuana, as it contaminates the leaves. The organism has a noninvasive,
an invasive, and a disseminated form. The noninvasive form causes chronic
rhinitis and nasal obstruction, and if untreated, can spread to the blood
stream, seeding numerous sites.

Other Aspergillus species have also caused sinusitis in normal hosts
and include Aspergillus jiavus and Aspergillus niger (151,152).

Chronic invasive fungal sinusitis is divided into granulomatous and
nongranulomatous subtypes based on histopathology. Chronic invasive fun-
gal rhinosinusitis has been associated with Mucor, Alternaria, Curvularia,
Bipolaris, Candida, Sporothrix schenckii, and Pseudallescheria boydii. Other
fungi that can cause sinus infection include Schizophyllum commune (153),
Emericella nidulans (154), Pseudoallescheria boydii (155), Paecilomyces
spp., Cryptococcus neoformans, Penicillium melinii, Scedosporium (mono-
sporium), Apiospermum, and Blastomycocis dermatitides (156). Saprophytic
fungi causing infections are Oreschslera spp., Alternaria spp., Curvularia
lunata, and Exserohilum spp. (157). Mucomycosis is caused by fungi of
the Mucurales order. The sinusitis induced occurs mainly in diabetic and
immunocompromised patients.

Allergic sinusitis has been associated with Alternaria, Aspergillus,
Bipolaris, Chrysporium, Dreschlera, and Exserohilum (158). Allergic fungal
sinusitis from Aspergillus spp. is similar to allergic bronchopulmonary
aspergillus with secretions containing eosinophils, Charcot-Leyden crystals,
and fungal hyphe (159). Patients usually have evidence of atopy or asthma.
The sinusitis is protracted and generally involves multiple sinuses.
Myriodontium keratinophelum produces also allergic-like fungal sinusitis
(160). The patients generally suffer from chronic sinusitis, nasal polyps,
and proptosis owing to orbital and ethmoid cell invasion. Allergic fungal
sinusitis was also described to be associated with Dreschslera (161),
Alternaria, and Curvularia (162).

Infectious Causes of Sinusitis 169

CONCLUSION

Sinusitis generally develops as a complication of viral or allergic inflamma-
tion of the upper respiratory tract. The bacterial pathogens in acute sinusitis
are S. pneumoniae, H. influenzae, and M. catarrhalis, whereas anaerobic
bacteria and S. aureus are predominant in chronic sinusitis. P. aeruginosa has
emerged as a potential pathogen in the immunocompromised patients and
in those who have nasal tubes or catheters, or are intubated.

REFERENCES

1. Faden H, Stanievich J, Brodsky L, Benstein J, Ogra PL. Changes in the naso-
pharyngeal flora during otitis media of childhood. Pediatr Infect Dis 1990;
9:623-626.

2. Del Beccaro MA, Mendelman PM, Inglis AF, Richardson MA, Duncan NO,
Clausen CR, Stull TL. Bacteriology of acute otitis media: a new perspective.
J Pediatr 1992; 120:856-862.

3. Socransky SS, Manganiello SD. The oral microflora of man from birth to
senility. J Periodontol 1971; 42:485-496.

4. Gibbons RJ, Socransky SS, Dearaujo WC, Varihoute J. Studies of the predo-
minant cultivable microbiota of dental plaque. Arch Oral Biol 1964; 9:
365-370.

5. Valenti WM, Trudell RG, Bentley DW. Factors predisposing to oropharyn-
geal colonization with gram-negative bacilli in the aged. N Engl J Med
1978; 298:1108-1110.

6. Baird-Parker AC. The classification of fusobacteria from the human mouth.
J Genet Microbiol 1960; 22:458-469.

7. Smibert RM. Spirochaetales: a review. CRC Crit Rev Microbiol 1973; 2:491.

8. Gibbons RJ. Aspects of the pathogenicity and ecology of the indigenous oral
flora of man. In: Balows A, et al. eds. Anaerobic Bacteria, Role in Disease,
Springfield, IL: Charles C Thomas, 1974.

9. Rasmussen EG, Gibbons RJ, Socransky SS. A taxonomic study of fifty gram-
positive anaerobic diphtheroides isolated from the oral cavity of man. Arch
Oral Biol 1966; 11:573-579.

10. Gibbons RJ, Socransky SS, Sawyer S, Kapsimalii B, MacDonald JB. The
microbiota of the gingival

crevice of man: II. The predominant cultivable organisms. Arch Oral Biol
1963; 8:281-289.

11. Brook I. Beta-lactamase producing bacteria in head and neck infection.
Larynscope 1988; 98:428-431.

12. Brook, I. The role of beta-lactamase-producing bacterial in the persistence of
streptococcal tonsillar infection. Rev Infect Dis 1984; 6:601-607.

13. Brook I, Gober AE. Emergence of beta-lactamase-producing aerobic and
anaerobic bacteria in the oropharynx of children following penicillin
chemotherapy. Clin Pediatr 1984; 23:338-341.

170 Brook

14. Tuner K, Nord CE. Emergence of beta-lactamase-producing microorganisms
in the tonsils during penicillin treatment. Eur J Clin Microbiol 1986; 5:
399_404.

15. American Academy of Pediatrics. Subcommittee on management of sinusitis
and committee on quality improvement. Clinical practice guideline: manage-
ment of sinusitis. Pediatrics 2001; 108:798-808.

16a. Talbot GH, Kennedy DW, Scheld WM, Granito K. Rigid nasal endo-
scopy versus sinus puncture and aspiration for microbiologic document-
ation of acute bacterial maxillary sinusitis. Clin Infect Dis 2001; 33:
1668-1675.

16b. Brook I. Discrepancies in the recovery of bacteria from multiple sinuses in
acute and chronic sinusitis. J Med Microbiol 2004; 53:879-885.

17. Gordts F, Abu Nasser I, Clement PA, Pierad D, Kaufman L. Bacteriology of
the middle meatus in children. Int J Pediatr Otorhinolaryngol 1999; 48:
163-167.

18. Gordts F, Harlewyck S, Pierard D, Kaufman L, Clement PA. Microbiology
of the middle meatus: a comparison between normal adults and children.
J Laryngol Otol 2000; 114:18^188.

19. Klossek JM, Dubreuil L, Richet H, Richet B, Sedallian A, Beutter P. Bacter-
iology of the adult middle meatus. J Laryngol Otol 1996; 110:847-849.

20. Nadel DM, Lanza DC, Kennedy DW. Endoscopically guided cultures in
chronic sinusitis. Am J Rhinol 1998; 12:233-241.

21. Gold SM, Tami TA. Role of middle meatus aspiration culture in the diagnosis
of chronic sinusitis. Laryngoscope 1997; 107:1586-1589.

22. Vogen JC, Bolger WE, Keyes AS. Endoscopically guided cultures: a direct
comparison with maxillary sinus aspirate cultures. Oto-HNS 2000; 122:
370-373.

23. Winther B, Vicery CL, Gross CW, Hendley O. Microbiology of the maxillary
sinus in adults with chronic sinus disease. Am J Rhinol 1996; 10:347-350.

24. Kountakis SE, Skoulas IG. Middle meatal vs. antral lavage cultures
in intensive care unit patients. Otolaryngol Head Neck Surg 2002; 126:
377-381.

25. Brook I, Frazier EH, Foote PA. Microbiology of chronic maxillary sinusitis:
comparison between specimens obtained by sinus endoscopy and by surgical
drainage. J Med Microbiol 1997; 46:430-432.

26. Mackowiak PA. The normal flora. N Engl J Med 1983; 307:83-93.

27. Sprunt K, Redman W. Evidence suggesting importance of role of interbacter-
ial inhibition in maintaining balance of normal flora. Ann Intern Med 1968;
68:579-590.

28. Bernstein JM, Sagahtaheri-Altaie S, Dryjd DM, Vactawski-Wende J. Bacterial
interference in nasopharyngeal bacterial flora of otitis-prone and non-
otitis-prone children. Acta Otol Rhinol Laryngol Belg 1994; 48:1-9.

29. Murray PR, Rosenblatt JE. Bacterial interference by oropharyngeal and clin-
ical isolates of anaerobic bacteria. J Infect Dis 1976; 134:281-285.

30. Faden H, Zaz MJ, Bernstein JM, Brodsky L, Stamievich J, Ogru PL.
Nasopharyngeal flora in the first three years of life in normal and otitis-prone
children. Ann Otol Rhinol Laryngol 1991; 100:612-615.

Infectious Causes of Sinusitis 171

3 1 . Brook I, Gober A. Bacterial interference in the nasopharynx of otitis media
prone and not otitis media prone children. Arch Otolaryngol Head Neck Surg
2000; 126:1011-1013.

32. Brook I, Gober AE. Bacterial interference in the nasopharynx and nasal cavity
of sinusitis prone and non-sinusitis prone children. Acta Otolaryngol 1999;
119:832-836.

33. Foote PA Jr, Brook I. Penicillin and clindamycin therapy in recurrent tonsilli-
tis. Effect of microbial flora. Arch Otolaryngol Head Neck Surg 1989; 15:
856-859.

34. Brook I, Foote PA. Effect of antimicrobial therapy with amoxicillin and
cefprozil on bacterial interference and beta-lactamase production in the
adenoids. Ann Otol Rhinol Laryngol 2004; 113:902-905.

35. Brook I. Aerobic and anaerobic bacteriology of purulent nasopharyngitis in
children. J Clin Microbiol 1988; 26:592-594.

36. Savolainen S, Ylikoski J, Jousimies-Somer H. The bacterial flora of the nasal
cavity in healthy young men. Rhinology 1986; 24:249-255.

37. Winther B, Brofeldt S, Gronborg H, Mygind N, Pedersen M, Vejlsgaard R.
Study of bacteria in the nasal cavity and nasopharynx during naturally
acquired common colds. Acta Otolaryngol 1984; 98:315-320.

38. Jousimies-Somer HR, Savolainen S, Ylikoski JS. Comparison of the nasal
bacterial floras in two groups of healthy subjects and in patients with acute
maxillary sinusitis. J Clin Microbiol 1989; 27:2736-2743.

39. Gwaltney JM Jr, Sydnor A, Sande MA. Etiology and antimicrobial treatment
of acute sinusitis. Ann Otol Rhinol Laryngol 1981; 90(suppl 84):68-71.

40. Lystad A, Berdal P, Lund-Iversen L. The bacterial flora of sinusitis with an in
vitro study of the bacterial resistance to antibiotics. Acta Otolaryngol Suppl
1964; 188:390-400.

41. Nylen O, Jeppsson P-H, Branefors-Helander P. Acute sinusitis. A clinical,
bacteriological and serological study with special reference to Haemophilus
influenzae. Scand J Infect Dis 1972; 4:43-48.

42. Bjorkwall T. Bacteriological examination in maxillary sinusitis: bacterial flora
of the nasal meatus. Acta Otolaryngol Suppl 1950; 83:1-32.

43. Catlin FI, Cluff LE, Reynolds RC. The bacteriology of acute and chronic
sinusitis. South Med J 1965; 58:1497-1502.

44. Savolainen S, Ylikoski J, Jousimies-Somer H. Predictive value of nasal bacte-
rial culture for etiological agents in acute maxillary sinusitis. Rhinology 1987;
25:49-55.

45. Brook I. Aerobic and anaerobic bacterial flora of normal maxillary sinuses.
Laryngoscopy 1981; 91:372-376.

46. Su WY, Liu CR, Hung SY, Tsai WF. Bacteriological studies in chronic
maxillary sinusitis. Laryngoscope 1983; 93:931-934.

47. Cook HE, Haber J. Bacteriology of the maxillary sinus. J Oral Maxillofac
Surg 1987;45:1011-1014.

48. Sobin J, Engquist S, Nord CE. Bacteriology of the maxillary sinus in healthy
volunteers. Scand J Infect Dis 1992; 24:633-635.

49. Jiang RS, Liang KL, Jang JW, Hsu CY. Bacteriology of endoscopically
normal maxillary sinuses. J Laryngol Otol 1999; 113:825-828.

172 Brook

50. Gordts F, Halewyck S, Pierard D, Kaufman L, Clement PA. Microbiology
of the middle meatus: a comparison between normal adults and children. J
Laryngol Otol 2000; 114:184-188.

51. Brook I, Frazier EH, Foote PA. Microbiology of the transition from acute to
chronic maxillary sinusitis. J Med Microbiol 1996; 45:372-375.

52. Schubert MS. A superantigen hypothesis for the pathogenesis of chronic
hypertrophic rhinosinusitis, allergic fungal sinusitis, and related disorders.
Ann Allergy Asthma Immunol 2001; 87:181-188.

53. Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P.
Total and specific IgE in nasal polyps is related to local eosinophilic inflamma-
tion. J Allergy Clin Immunol 2001; 107:607-614.

54. Conley DB, Tripathi A, Ditto AM, Grammer LC, Kern RC. Chronic sinusitis
with nasal polyps: staphylococcal exotoxin immunoglobulin E and cellular
inflammation. Am J Rhinol 2004; 18:273-278.

55. Bernstein JM, Ballow M, Schlievert PM, Rich G, Allen C, Dryja D. A super-
antigen hypothesis for the pathogenesis of chronic hyperplastic sinusitis with
massive nasal polyposis. Am J Rhinol 2003; 17:321-326.

56. Subausie MC, Jacoby DB, Richards SM, Proud D. Infection of a human
respiratory epithelial cell line with rhino virus: induction of cytokine release
and modulation of susceptibility to infection by cytokine exposure. J Clin
Invest 1995; 96:549-557.

57. Evans FO Jr, Sydnor JB, Moore WEC, Moore GT, Manwaning Z, Brill AH,
Jackson RT, Hanna S, Skaar JS, Holdeman LV, Fritz-Hugh S, Sande MA,
Gwaltney JM Jr. Sinusitis of the maxillary antrum. N Engl J Med 1975;
293:735-739.

58. Hamory BH, Sande MA, Sydnor A Jr, Seale DL, Gwaltney JM Jr. Etiology
and antimicrobial therapy of acute maxillary sinusitis. J Infect Dis 1979;
139:197-202.

59. Osur SL. Viral respiratory infections in association with asthma and sinusitis:
a review. Ann Allergy Asthma Immunol 2002; 89:553-560.

60. Elias JA, Zheng T, Einarsson O, Landry M, Trow T, Robert N, Panuska J.
Epithelial interleukin-11: regulation by cytokines, respiratory syncytial virus,
and retinoic acid. J Biol Chem 1994; 269:22261-22268.

61. Winther B, Gwaltney JM Jr, Mygind N, Turner RB, Hendley JO. Sites of
rhinovirus recovery after point inoculation of the upper airway. JAMA 1986;
256:1763-1767.

62. Greve JM, Davis G, Meyer AM, Forte CP, Yost SC, Marbov CW, Kamarik ME,
McClelland A. The major human rhinovirus receptor is ICAM-1. Cell 1989;
56:839-847.

63. Gwaltney JM Jr. Rhinovirus infection of the normal human airway. Am J
Respir Crit Care Med 1995; 152:S36-S39.

64. Gwaltney JM Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic
study of the common cold. N Engl J Med 1994; 330:25-30.

65. Puhakka T, Makela MJ, Alanen A, Kallio T, Korsoff L, Arstila P, Leinonen M,
Pulkkinen M, Suonpaa J, Mertsola J, Ruuskanen O. Sinusitis in the common
cold. J Allergy Clin Immunol 1998; 102:403-408.

Infectious Causes of Sinusitis 173

66. Kristo A, Uhari M, Luotonen J, Koivunen P, Ilkko E, Tapiainen T, Alho O-P.
Paranasal. Sinus findings in children during respiratory infection evaluated
with magnetic resonance imaging. Pediatrics 2003; Ill:e586-e589.

67. Sasaki Y, Togo Y, Wagner HN Jr, Hornick RB, Schwartz AR, Proctor DF.
Mucociliary function during experimentally induced rhinovirus infection in
man. Ann Otol Rhinol Laryngol 1973; 82:203-211.

68. Gwaltney JM Jr. Acute community-acquired sinusitis. Clin Infect Dis 1996;
23:1209-1225.

69. Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The microbial etiology
and antimicrobial therapy of adults with acute community-acquired sinusitis:
a fifteen-year experience at the University of Virginia and review of other
selected studies. J Allergy Clin Immunol 1992; 90:457-462.

70. Wald ER, Milmore GJ, Bowen AD, Ledema-Medina J, Salamon N, Bluestone
CD. Acute maxillary sinusitis in children. N Engl J Med 1981; 304:749-754.

71. Wald ER, Guerra N, Byers C. Upper respiratory tract infections in young
children: duration of and frequency of complications. Pediatrics 1991; 87:
129-133.

72. Lew D, Southwick FS, Montgomery WW, Weber AL, Baker AS. Sphenoid
sinusitis. A review of 30 cases. N Engl J Med 1983; 309:1149-1154.

73. Brook I, Frazier EH, Gher ME Jr. Microbiology of periapical abscesses and
associated maxillary sinusitis. J Periodontal 1996; 67:608-610.

74. Brook I, Friedman EM. Intracranial complications of sinusitis in children. A
sequela of periapical abscess. Ann Otol Rhinol Laryngol 1982; 91:41-43.

75. Shapiro ED, Milmoe GJ, Wald ER, Rodnan JB, Bowen AD. Bacteriology of
the maxillary sinuses in patients with cystic fibrosis. J Infect Dis 1982; 146:
589-593.

76. Wald ER. Microbiology of acute and chronic sinusitis in children and adults.
Am J Med Sci 1998; 316:13-20.

77. Biel MA, Brown CA, Levinson RM, Gravis GE, Paisner HM, Siegil ME,
Tedford TM. Evaluation of the microbiology of chronic maxillary sinusitis.
Ann Otol Laryngol Rhinol 1998; 107:942-945.

78. Jiang RS, Hsu CY, Jang JW. Bacteriology of the maxillary and ethmoid
sinuses in chronic sinusitis. J Laryngol Otol 1998; 112:845-848.

79. Hsu J, Lanza DC, Kennedy DW. Antimicrobial resistance in bacterial chronic
sinusitis. Am J Rhinol 1998; 12:243-248.

80. Nadel DM, Lanza DC, Kennedy DW. Endoscopically guided cultures in
chronic sinusitis. Am J Rhinol 1998; 12:233-241.

81. Bahattacharyya N, Kepnes LJ. The microbiology of recurrent rhinosinusitis
after endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg 1999;
125:1117-1120.

82. Bolger WE. Gram negative sinusitis: emerging clinical entity. Am J Rhinol
1994; 8:279-283.

83. Kaliner M, Osguthorpe J, Fireman P, Anon J, Georgitis J, Davis ML,
Naclerio R, Kennedy D. Sinusitis: bench to bedside. Otolaryngol Head Neck
Surg 1997; 116(suppl):Sl-S20.

84. Nord CE. The role of anaerobic bacteria in recurrent episodes of sinusitis and
tonsillitis. Clin Infect Dis 1995; 20:1512-1524.

174 Brook

85. Brook I, Thompson D, Frazier E. Microbiology and management of
chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1994; 120:
1317-1320.

86. Brook I. Bacteriologic features of chronic sinusitis in children. JAMA 1981;
246:967-969.

87. Finegold SM, Flynn MJ, Rose FV, Jousimies-Somer H, Jakielaszek C,
McTeague M, Wexler HM, Berkowitz E, Wynne B. Bacteriologic findings
associated with chronic bacterial maxillary sinusitis in adults. Clin Infect Dis
2002; 35:428^33.

88. Carenfelt C, Lundberg C. Purulent and non-purulent maxillary sinus secre-
tions with respect to P0 2 , PC0 2 and pH. Acta Otolaryngol 1977; 84:138-144.

89. Brook I. Role of encapsulated anaerobic bacteria in synergistic infections. Crit
Rev Microbiol 1987; 14:171-193.

90. Brook I. Bacteriology of chronic maxillary sinusitis in adults. Ann Otol Rhinol
Laryngol 1989; 98:426-428.

91. Brook I. Brain abscess in children: microbiology and management. Child
Neurol 1995; 10:283-288.

92. Westrin KM, Stierna P, Carlsoo B, Hellstrom S. Mucosal fine structure
in experimental sinusitis. Ann Otol Rhinol Laryngol 1993; 102(8 Pt 1):
639-645.

93. Jyonouchi H, Sun S, Kennedy CA, Roche AK, Kajander KC, Miller JR,
Germaine GR, Rimell FL. Localized sinus inflammation in a rabbit sinusitis
model induced by Bacteroides fragilis is accompanied by rigorous immune
responses. Otolaryngol Head Neck Surg 1999; 120:869-875.

94. Brook I, Yocum P. Immune response to Fusobacterium nucleatum and Prevo-
tella intermedia in patients with chronic maxillary sinusitis. Ann Otol Rhinol
Laryngol 1999; 108:293-295.

95. Brook I, Yocum P, Frazier EH. Bacteriology and beta-lactamase activity in
acute and chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg
1996; 122:418^122.

96. Brook I, Yocum P, Shah K. Aerobic and anaerobic bacteriology of concurrent
chronic otitis media with effusion and chronic sinusitis in children. Arch Oto-
laryngol Head Neck Surg 2000; 126:174-176.

97. Orobello PW Jr, Park RI, Belcher L, et al. Microbiology of chronic sinusitis in
children. Arch Otolaryngol Head Neck Surg 1991; 117:980-983.

98. Tinkleman DG, Silk HJ. Clinical and bacteriologic features of chronic sinusitis
in children. Am J Dis Child 1989; 143:938-941.

99. Muntz HR, Lusk RP. Bacteriology of the ethmoid bullae in children with
chronic sinusitis. Arch Otolaryngol Head Neck Surg 1991; 117:179-181.

100. Otten FWA, Grote JJ. Treatment of chronic maxillary sinusitis in children. Int
J Pediatr Otorhinolaryngol 1988; 15:269-278.

101. Otten FWA. Conservative treatment of chronic maxillary sinusitis in children.
Long term follow-up. Acta Otol Rhinol Laryngol Belg 1997; 51:173-175.

102. Don D, Yellon RF, Casselbrant M, Bluestone CD. Efficacy of stepwise proto-
col that includes intravenous antibiotic treatment for the management of
chronic sinusitis in children and adolescents. Otolaryngol Head Neck Surg
2001; 127:1093-1098.

Infectious Causes of Sinusitis 175

103. Erkan M, Ozcan M, Arslan S, Soysal V, Bozdemir K, Haghighi N. Bacteriol-
ogy of antrum in children with chronic maxillary sinusitis. Scand J Infect Dis
1996; 28:283-285.

104. Slack CL, Dahn KA, Abzug MJ, Chan KH. Antibiotic-resistant bacteria in
pediatric chronic sinusitis. Pediatr Infect Dis J 2001; 20:247-250.

105. Goldenhersh MJ, Rachelefsky GS, Dudley J, Brill J, Katz RM, Rohr AS,
Spector SL, Siegel SC, Summanen P, Baron EJ. The microbiology of chronic
sinus disease in children with respiratory allergy. J Allergy Clin Immunol 1990;
85:1030-1039.

106. Wald ER, Byers C, Guerra N, et al. Subacute sinusitis in children. J Pediatr
1989; 115:28-32.

107. Brook I, Yocum P. Antimicrobial management of chronic sinusitis in children.
J Laryngol Otol 1995; 109:1159-1162.

108. Finegold SM. Anaerobic bacteria in human disease. Orlando, FL: Academic
Press, Inc., 1977.

109. Brook I. Pediatric Anaerobic Infections. 3rd. NY: Marcel Dekker Inc, 2002.

1 10. Mustafa E, Tahsin A, Mustafa 6, Nedret K. Bacteriology of antrum in adults
with chronic maxillary sinusitis. Laryngoscope 1994; 104:321-324.

111. Frederick J, Braude AI. Anaerobic infections of the paranasal sinuses. N Engl
J Med 1974; 290:135-137.

112. Van Cauwenberge P, Verschraegen G, Van Renterghem L. Bacteriological
findings in sinusitis (1963-1975). Scand J Infect Dis Suppl 1976; 9:72-77.

113. Karma P, Jokipii L, Sipila P, Luotonen J, Jokipii AM. Bacteria in chronic
maxillary sinusitis. Arch Otolaryngol 1979; 105:386-390.

114. Berg O, Carenfelt C, Kronvall G. Bacteriology of maxillary sinusitis in rela-
tion to character of inflammation and prior treatment. Scand J Infect Dis
1988; 20(5):51 1-516.

115. Fiscella RG, Chow JM. Cefixime for the treatment of maxillary sinusitis. Am J
Rhinol 1991(2,5):193-197.

116. Sedallian AB, Bru JP, Gaillat J. Bacteriologic finding of chronic sinusitis.
(Abstr no. P2.71). The 17th International Congress of the Management of
Infection. Berlin, 1992.

117. Simoncelli C, Ricci G, Molini E, von Garrel C, Capolunghi B, Giommetti S.
Bacteriology of chronic maxillary sinusitis. HNO 1992; 40:16-18.

118. Tabaqchali S. Anaerobic infections in the head and neck region. Scand J Infect
Dis Suppl 1988; 57:24-34.

119. Hartog B, Degener JE, Van Benthem PP, Hordijk GJ. Microbiology of
chronic maxillary sinusitis in adults: isolated aerobic and anaerobic bacteria
and their susceptibility to twenty antibiotics. Acta Otolaryngol 1995;
115:672-677.

120. Ito K, Ito Y, Mizuta K, Ogawa H, Suzuki T, Miyata H, Kato N, Watanabe K,
Ueno K. Bacteriology of chronic otitis media, chronic sinusitis, and paranasal
mucopyocele in Japan. Clin Infect Dis 1995; 20(suppl 2):S214-S219.

121. Erkan M, Asian T, Ozcan M, Koc N. Bacteriology of antrum in adults with
chronic maxillary sinusitis. Laryngoscope 1994; 104(3 Pt 1):32 1-324.

122. Edelstein DR, Avner SE, Chow JM, Ouerksen RL, Johnson J, Ronis M,
Rybak LP, Bierman WC, Matthews BL. Once-a-day therapy for sinusitis:

176 Brook

a comparison study of cefixime and amoxicillin. Laryngoscope 1993;

103:33-41.

123. Klossek JM, Dubreuil L, Richet H, Richet B, Beutter P. Bacteriology of
chronic purulent secretions in chronic rhinosinusitis. J Laryngol Otol 1998;
112:1162-1166.

124. Brook I, Frazier EH. Correlation between microbiology and previous sinus
surgery in patients with chronic maxillary sinusitis. Ann Otol Rhinol Laryngol
2001; 110:148-151.

125. Brook I. Bacteriology of acute and chronic frontal sinusitis. Arch Otolaryngol
Head Neck Surg 2002; 128:583-585.

126. Brook I. Bacteriology of acute and chronic sphenoid sinusitis. Ann Otol
Rhinol Laryngol 2002; 111:1002-1004.

127. Brook I. Bacteriology of acute and chronic ethmoid sinusitis. J Clin Microb
2005; 43:3479-3480.

128a. Bhattacharyya N, Kepnes LJ. The microbiology of recurrent rhinosinusitis
after endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg 1999;
125:1117-1120.

128b. Bucholtz GA, Salzman SA, Bersalona FB, Boyle TR, Ejercito VS, Penno L,
Peterson DW, Stone GE, Urquhart A, Shukla SK, Burmester JK. PCR
analysis of nasal polyps, chronic sinusitis, and hypertrophied turbinates for
DNA encoding bacterial 16S rRNA. Am J Rhinol 2002; 16:169-173.

128c. Hamilos DL, Leung DYM, Wood R, Meyers A, Stephens JK, Barkans J, Bean
DK, Kay AB, Hamid Q. Association of tissue eosinophilia and cytokine
mRNA expression of granulocyte-macrophage colony-stimulating factor and
interleukin-3. J Allergy Clin Immunol 1993; 91:39-48.

128d. Brook I, Frazier EH. Bacteriology of chronic maxillary sinusitis associated
with nasal polyposis. J Med Microbiol 2005; 54:595-597.

129. Clement PA, Bluestone CD, Gordts F, Lusk RP, Otten FW, Goossens H,
Scadding GK, Takahashi H, van Buchem FL, Van Cauwenberge P, Wald
ER. Management of rhinosinusitis in children: consensus meeting, Brussels,
Belgium, September 13, 1996. Arch Otolaryngol Head Neck Surg 1998;
124:31-34.

130. Brook I, Foote PA, Frazier EH. Microbiology of acute exacerbation of
chronic sinusitis. Laryngoscope 2004; 114:129-131.

131. Brook I. Bacteriology of chronic sinusitis and acute exacerbation of chronic
sinusitis. Annals Otolary Head Neck Surg.

132. Bach A, Boehrer H, Schmidt H, Geiss HK. Nosocomial sinusitis in ventilated
patients: nasotracheal versus orotracheal intubation. Anaesthesia 1992;
47:335-339.

133. O'Reilly MJ, Reddick EJ, Black W, Carter PL, Erhardt J, Fill W, Maughn D,
Sado A, Klatt GR. Sepsis from sinusitis in nasotracheally intubated patients: a
diagnostic dilemma. Am J Surg 1984; 147:601-604.

134. Mevio E, Benazzo M, Quaglieri S, Mencherini S. Sinus infection in intensive
care patients. Rhinology 1996; 34:232-236.

135. Caplan ES, Hoyt NJ. Nosocomial sinusitis. JAMA 1982; 247:639-641.

136. Kronberg FG, Goodwin WJ. Sinusitis in intensive care unit patients. Laryngo-
scope 1985; 95:936-938.

Infectious Causes of Sinusitis 177

137. Arens JF, LeJeune FE Jr, Webre DR. Maxillary sinusitis, a complication of
nasotracheal intubation. Anesthesiology 1974; 40:415-416.

138. Brook I, Shah K. Sinusitis in neurologically impaired children. Otolaryngol
Head Neck Surg 1998; 119:357-360.

139. Hahn DL, Dodge RW, Golubjatnikov R. Association of Chlamydia pneumo-
niae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-
onset asthma. JAMA 1991; 266:225-230.

140. Thorn DH, Grayston JT, Campbell LA, Kuo CC, Diwan VK, Wang SP.
Respiratory infection with Chlamydia pneumoniae in middle-aged and older
adult outpatients. Eur J Clin Microbiol Infect Dis 1994; 13:785-792.

141. Hashigucci K, Ogawa H, Suzuki T, Kazuyama Y. Isolation of Chlamydia
pneumoniae from the maxillary sinus of a patient with purulent sinusitis. Clin
Infect Dis 1992; 15:570-571.

142. Savolainen S, Jousimies-Somer H, Kleemola M, Ylikoski J. Serological
evidence of viral or Mycoplasma pneumoniae infection in acute maxillary sinu-
sitis. Eur J Clin Microbiol Infect Dis 1989; 8:131-135.

143. Gurr PA, Chakraverty A, Callanan V, Gurr SJ. The detection of M. pneumo-
niae in nasal polyps. Clin Otolaryngol 1996; 21:269-273.

144. Bucholtz GA, Salzman SA, Bersalona FB, Boyle TR, Ejercito VS, Pinno L,
Peterson DW, Stone GE, Urguhart A. PCR analysis of nasal polyps, chronic
sinusitis, and hypertrophied turbinates for DNA encoding bacterial 16S
rRNA. Am J Rhinol 2002; 16:169-173.

145. Vennewald I, Henker M, Klemm E, Seebacher C. Fungal colonization of the
paranasal sinuses. Mycosis 1999; 42(suppl 2):33-36.

146. Ponikau JU, Sherris DA, Kern EB, Homburger HA, Frigas E, Gaffey TA,
Roberts GD. The diagnosis and incidence of allergic fungal sinusitis. Mayo
Clin Proc 1999; 74:877-884.

147. Catten MD, Murr AH, Goldstein JA, Miatre AN, Lalwani AK. Detection of
fungi in the nasal mucosal using polymerase chain reaction. Laryngoscope
2001; 111:399-403.

148. Stringer SP, Ryan MW. Chronic invasive fungal rhinosinusitis. Otolaryngol
Clin North Am 2000; 33:375-387.

149. Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am
2000; 33:227-235.

150. Gwaltney JM Jr. Microbiology of sinusitis. In: Druce HM, ed. Sinusitis:
Pathophysiology and Treatment. New York: Marcel Dekker, 1994:41-56.

151. Morgan MA, Wilson WR, Neil HB III, Roberts GD. Fungal sinusitis in healthy
and immunocompromised individuals. Am J Clin Pathol 1984; 82:597-601.

152. Jahrsdoerfer RA, Ejercito VS, Johns MME, Cantrell RW, Sydnor JE. Asper-
gillosis of the nose and paranasal sinuses. Am J Otolaryngol 1979; 1:1-14.

1 53. Kern ME, Uecker FA. Maxillary sinus infection caused by the Homobasidiomy-
cetous fungus Schizophyllum commune. J Clin Microbiol 1986; 23:1001-1005.

154. Mitchell RG, Chaplin AJ, MacKenzie DWR. Emericella nidulans in a maxil-
lary sinus fungal mass. J Med Vet Mycol 1987; 25:339-341.

155. Winn RE, Ramsey PD, McDonald JC, Dunlop KJ. Maxillary sinusitis from
Pseudoalles-cheria boydii. Efficacy of surgical therapy. Arch Otolaryngol
1983; 109:123-125.

178 Brook

156. Adam RD, Paquin ML, Petersen EA, Saubolle MA, Rinaldi MG, Corcoran
JN, Solaonya RE. Phaeohyphomycosis caused by the fungal general Bipolaris
and Exserohilum. Medicine 1986; 65:203-217.

157. Zieske LA, Kople RD, Hamill R. Dermataceous fungal sinusitis. Otolaryngol
Head Neck Surg 1991; 105:567-577.

158. Goldstein MF, Dvorin DJ, Dunsky EH, Lesser RW, Heuman PJ, Loose JH.
Allergic rhizomucor sinusitis. J Allergy Immun 1992; 90:394-404.

159. Katzenstein A, Sale SR, Greenberger PA. Pathologic findings in allergic
Aspergillus sinusitis. Am J Surg Pathol 1983; 7:439-443.

160. Maran ACD, Kwong K, Mine LJR, Lamb D. Frontal sinusitis caused by
Myriodontium keratinophilum. Br Med J 1985; 290:207.

161. Friedman GC, Hartwick RW, Ro JY, et al. Allergic fungal sinusitis. Report of
three cases associated with dermataceous fungi. Am J Clin Pathol 1991;
96:368-372.

162. Bartynski JM, McCaffrey TV, Frigas E. Allergic fungal sinusitis secondary to
dermataceous fungi — Curvularia lunata and Alternaria. Otolaryngol Head
Neck Surg 1990; 103:32-39.

SECTION IV. THERAPEUTIC OPTIONS

Antimicrobial Management of Sinusitis

Itzhak Brook

Departments of Pediatrics and Medicine, Georgetown University School of

Medicine, Washington, D.C., U.S.A.

INTRODUCTION

The growing resistance to antimicrobial agents of all respiratory tract bacterial
pathogens has made the management of sinusitis more difficult. This chapter
presents the current information regarding the antimicrobial resistance of the
organisms involved in sinusitis and the approaches to antimicrobial therapy.

ANTIMICROBIAL RESISTANCE

To manage bacterial sinusitis is often a challenging endeavor in which selec-
tion of the most appropriate antimicrobial agents remains a key decision.
This has become more difficult in recent years as all the predominant bacte-
rial pathogens have gradually developed resistance to most of the commonly
used antibiotics.

The observed increase in bacterial resistance to antibiotics is related to
their frequent use. Previous therapy can increase the prevalence of beta-
lactamase-producing bacteria (BLPB). In a study of 26 children who had
received seven days of therapy with penicillin, 12% harbored BLPB in their
oropharyngeal flora prior to therapy (1). This increased to 46% at the
conclusion of therapy, and the incidence was 27% after three months. The
incidence of BLPB was high in siblings and parents of patients treated with
penicillin, who probably acquired these organisms from the patient (2).

179

180 Brook

A greater prevalence of recovery of BLPB in the oropharynx of children
occurs in the winter and a lower one in the summer (3). These changes
correlated with the intake of beta-lactam antibiotics. To monitor the local
seasonal variations in the rate of recovery of BLPB in the community
may help the empirical choice of antimicrobial agents, the proper and judi-
cious use of which may help to control the increase of BLPB.

Risk factors for the development of resistance to antimicrobial agents
include prior antibiotic exposure, day care attendance, age under two years,
recent hospitalization, and recurrent infection (especially in those who are very
young or very old) (4,5).

The variety of organisms involved in sinusitis, increasing levels of
resistance to antibiotic agents, and the phenomenon of beta-lactamase
''shielding" from antibiotic agents all contribute to the therapeutic chal-
lenges associated with the management of acute and chronic sinusitis. Brook
and Gober (5) identified the antimicrobial susceptibility of the pathogens
isolated from patients with maxillary sinusitis who failed to respond to anti-
microbial therapy and correlates it with previous antimicrobial therapy and
smoking. The data illustrated a relationship between resistance to antimicro-
bials and failure of patients with sinusitis to improve. A statistically signifi-
cant higher recovery of resistant organisms was noted in those treated two
to six months previously, and in those who smoked.

Three major mechanisms of resistance to penicillins occur:

1. Porin channel blockage (e.g., used by Pseudomonas spp. to resist
carbapenems)

2. Production of the enzyme beta-lactamase (e.g., utilized by
Haemophilus influenzae and Moraxella catarrhalis).

3. Alterations in the penicillin-binding protein (e.g., used by Strepto-
coccus pneumoniae).

BETA-LACTAMASE PRODUCTION

Bacterial resistance to the antibiotics used for the treatment of sinusitis has
been increased consistently in recent years. Production of the enzyme beta-
lactamase is one of the most important mechanisms of penicillin resistance.
The production of the enzyme beta-lactamase is an important mechan-
ism of virulence of anaerobic gram-negative bacilli as well as other aerobic
and anaerobic bacteria. The production of beta-lactamase can have wider
implication than just protecting the bacteria that produces the enzyme. In
polymicrobial infections BLPB can ''shield'* other co-pathogens that are
penicillin-susceptible (6,7) (Fig. 2 in Chap. 8). It has been hypothesized that
this protection can occur when the enzyme beta-lactamase is secreted into
the infected tissues or sinus fluids in sufficient quantities to break the peni-
cillin's beta-lactam ring before it can kill the susceptible bacteria, thus con-
tributing to treatment failure.

Antimicrobial Management of Sinusitis

181

The emergence and persistence of BLPB after antibiotic therapy has
implications for antimicrobial selection for in treatment of sinusitis as well
as other infections of the upper respiratory tract, particularly chronic condi-
tions in which patients are likely to have had recent antibiotic exposure.

Clinical and laboratory studies provide support for this hypothesis.
Animal studies demonstrated the ability of the enzyme beta-lactamase to
influence polymicrobial infections. Hackman and Wilkins (8) showed that peni-
cillin-resistant strains of Bacteroidesfragilis, pigmented Prevotella and Porphyr-
omonas spp., and Prevotella oralis protected a penicillin-sensitive Fusobacterium
necrophorum from penicillin therapy in mice. Using a subcutaneous abscess
model in mice, Brook et al. (9) demonstrated protection of group A beta-hemo-
lytic streptococci (GABHS) from penicillin by B. fragilis and Prevotella melani-
nogenica. Clindamycin or the combination of penicillin and clavulanic acid (a
beta-lactamase inhibitor), which are active against both GABHS and anaerobic
gram-negative bacilli, were effective in eradicating the infection. Similarly, beta-
lactamase-producing facultative bacteria protected a penicillin-susceptible
P. melaninogenica from penicillin (10).

In vitro studies have also demonstrated this phenomenon. A 200-fold
increase in resistance of GABHS to penicillin was observed when it was
inoculated with Staphylococcus aureus (11). An increase in resistance was also
noted when GABHS was grown with Haemophilus parainfluenzae (12).
When mixed with cultures of B. fragilis, the resistance of GABHS to peni-
cillin increased 8500-fold (13).

Several species of BLPB occur in sinusitis (Table 1). BLPB have been
recovered from over one-third of patients with sinusitis (14,15). H. influenzae
and M. catarrhalis are the predominant BLPB in acute sinusitis, and S. aureus,
pigmented Prevotella, Porphyromonas, and Fusobacterium spp. predominate
in chronic sinusitis.

Table 1 Resistance to Antimicrobial Agents in Bacterial Sinusitis

Bacteria

Incidence (%)

Resistance to penicillin (%)

Acute sinusitis

S. pneumoniae

30-40

H. influenzae*

25-30

M. catarrhalis*

10-15

Chronic sinusitis

S. aureus*

10-35

Pigmented Prevotella*

15-30

and Porphyromonas*

spp.

Fusobacterium* spp.

15^0

20-40
30^0
95

95
10-60

10-60

'Resistance due to beta-lactamase production.

182

Brook

Table 2 Beta-Lactamase Detected in Four Acute Bacterial Sinusitis Aspirates
Obtained from Patients Treated with Amoxicillin

Organism

Patient

S. pneumoniae

M. catarrhalis (beta-lactamase

positive)

H. influenzae (beta-lactamase

positive)

Beta-lactamase activity in pus

+
+

■da

Shielding" of S. pneumoniae by beta-lactamase producers is evident in patients 1 and 2.
Source: Data from Ref. 7.

The actual activity of the enzyme beta-lactamase and the potential of
the presence of the phenomenon of "shielding" were demonstrated in
acutely and chronically inflamed sinus fluids (7). BLPB were isolated in four
of 10 acute sinusitis aspirates and in 10 of 13 chronic sinusitis aspirates
(Tables 2 and 3). The predominant BLPB isolated in acute sinusitis were
H. influenzae and M. catarrhalis, and those found in chronic sinusitis were
S. aureus, B. fragilis, and Prevotella and Fusobacterium spp. (7). "Free" beta-
lactamase was detected in 86% of aspirates that contained these organisms,

Table 3 Beta-Lactamase Detected in Four Chronic Bacterial Sinusitis Aspirates
Obtained from Patients Treated with Amoxicillin

Patient

Organism

S. aureus BL (+)

S. pneumoniae

Peptostreptococcus spp.

Propionibacterium acnes

Fusobacterium spp. BL (+)

Fusobacterium spp. BL (— )

Prevotella spp. BL (+)

Prevotella spp. BL (— )

Bacteroides fragilis group BL (+)

Beta-Lactamase activity in pus

■da

Shielding" is present in all cases.
Abbreviation: BL (+), beta-lactamase-producing organism.
Source: Data from Ref. 7.

Antimicrobial Managemen t of Sinusitis 1 83

and was associated with persistence of even penicillin-susceptible pathogens
despite antimicrobial therapy.

Haemophilus influenzae Resistance to Antimicrobials

Resistance to beta-lactams among strains of H. influenzae has increased
throughout the past three decades. In the 1980s, the prevalence of beta-
lactamase-producing H. influenzae was between 10% and 15% (16,17).
Resistance among strains of H. influenzae increased steadily throughout
the 1990s, and presently approximately 40% of H. influenzae strains are
beta-lactamase producers. Beta-lactamase-producing strains of H. influen-
zae are most prevalent in the northcentral, northeast, and southcentral
regions of the United States (18). Generally, higher doses of beta-lactams
are not effective in overcoming this mechanism of resistance; however, the
addition of a beta-lactamase inhibitor (e.g., clavulanic acid) shifts H. influ-
enzae strains to the susceptible range [e.g., minimal inhibitory concentration
(MIC) <4 u.g/mL], transforming the susceptibilities to those of beta-lacta-
mase-negative strains. Agents that are stable in the presence of beta-lacta-
mases are another option for treating infections caused by this pathogen.

Among the oral beta-lactam antibiotics, amoxicillin/clavulanate (because
of the beta-lactamase inhibitor), cefixime, ceftibuten, cefdinir, and cefpodoxime
are highly active against beta-lactamase-producing H. influenzae (19). Macro-
lides in general have limited activity against H. influenzae', among the three
agents (i.e., erythromycin, clarithromycin, and azithromycin), clarithromycin
is least active against H. influenzae (20). Inhibition of H. influenzae by macrolides
is dependent on the ability to achieve concentrations above the MICs at the
site of infection. Based on pharmacokinetic/pharmacodynamic (PK/PD)
breakpoints, the MICs of virtually all H. influenzae strains in the 1998 surveil-
lance study were below PK/PD breakpoints (i.e., resistant) for erythromycin,
clarithromycin, and azithromycin. Furthermore, azithromycin failed to eradi-
cate 61% of H. influenzae from the middle ear of children with otitis media
(21). Resistance to trimethoprim-sulfamethoxazole (TMP/SMX) was exhibited
among 24% of isolates. Fluoroquinolones, particularly the newer agents, are
very active against H. influenzae, with relatively no resistance according to the
recent surveillance data (20).

Moraxella catarrhalis Resistance to Antimicrobials

Virtually all strains of M. catarrhalis produce beta-lactamase. The 1998 pre-
valence among outpatient isolates for beta-lactamase-producing M. catarrhalis
was 98% (19). At PK/PD breakpoints, 100% of strains were susceptible to
amoxicillin/clavulanate, fluoroquinolones, macrolides, doxycycline, and cefix-
ime. High levels of resistance were exhibited toward TMP/SMX, cefaclor,
loracarbef, cefprozil, and amoxicillin.

184 Brook

Streptococcus pneumoniae Resistance to Antimicrobials

Penicillin Resistance

Resistance among S. pneumoniae strains has been monitored in the United
States since 1979. Prior to the 1990s, resistance to penicillin was not considered
a clinical problem in the United States. Throughout the past decade, the pre-
valence of S. pneumoniae isolates that are either intermediate (i.e., penicillin
MICs 0.12-1.0 |ig/mL) or resistant to penicillin (i.e., MICs>2.0 jig/mL) has
increased, with dramatic increases within the past few years (22). The
incidence of penicillin-resistance in strains of S. pneumoniae approaches
40% in some areas of the United States, and the incidence of high-level resis-
tance has increased by 60-fold during the past 10 years. The mechanism of
beta-lactam-resistance of S. pneumoniae involves genetic mutations that alter
penicillin-binding protein structure, resulting in a decreased affinity for all
beta-lactam antibiotics. About half of the penicillin-resistant strains are
currently intermediately resistant [minimal inhibitory concentration (MIC)
of 0.1-1. Omg/mL] and the rest are highly resistant (MIC > 2.0mg/mL).

It is important to note, however, that this change in MIC does not
confer absolute resistance to all beta-lactams because the pharmacokinetics
of each agent need to be considered. Thus, strains of S. pneumoniae with
penicillin MICs>2 jig/mL (i.e., resistant) are not necessarily resistant to
other beta-lactams (e.g., amoxicillin). Resistance to beta-lactams represents
a pharmacokinetic challenge that can be overcome if a high enough concen-
tration of beta-lactam can be achieved at the site of infection.

Penicillin-resistant strains are often also resistant to other antimicrobial
agents commonly used to treat sinusitis (Table 4). The term drug-resistant
S. pneumoniae refers to strains with penicillin MICs > 0.12 \ig/mL that also
exhibit resistance to at least two other antimicrobial classes. The susceptibility
of S. pneumoniae isolates to other antimicrobials is closely correlated to its
susceptibility to penicillin. However, these strains are susceptible to parenteral
third-generation cephalosporins (i.e., cefotaxime, ceftriaxone), the fluoroqui-
nolones (levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin), vancomycin,
quinupristin with dalfopristin, telithromycin and linezolid. Intermediately
resistant S. pneumoniae are still susceptible in vitro to high doses of penicillin
or amoxicillin (23). Clindamycin and the oral second-generation cephalospor-
ins, especially cefuroxime axetil and cefprozil, are also effective in vitro against
over 95% of intermediately penicillin-resistant strains (24).

The regions of the United States with the highest proportion of
penicillin-, macrolide-, and trimethoprim/sulfamethoxazole-resistant S.
pneumoniae strains are the southcentral and southeast. The reason for
increased resistance in these regions is not currently known, and the varia-
tion is not significant enough to warrant different antimicrobial recommen-
dations for each region. Although penicillin-resistant strains are common in
all age groups, the highest proportions of resistant strains are collected from

Antimicrobial Managemen t of Sinusitis 1 85

Table 4 Cross-Resistance of Penicillin-Resistant S. pneumonl

Cross-resistance (%)

Antimicrobial agent Intermediately resistant a Highly resistant 1

91.9

47.4
80.4

25.3

Trimethoprim-

sulfamethoxazole

Tetracycline

22.8

Macrolides

49.8

Clindamycin

13.1

Third-generation

cephalosporins:

Oral (cefixime,

ceftibuten)

Parenteral (ceftriaxone)

Rifampin

Levofloxacin

2.2

Gatifloxacin

2.1

Telithromyicn

0.1

10
20
2.2
1.9
0.6

a MIC 0.1 2-1.0 mg/mL.
b MIC >2.0 mg/mL.

children younger than two years. In addition, resistant strains are most likely
to be isolated from middle ear (approximately 58% of all S. pneumoniae iso-
lates), sinus (approximately 60% of all S. pneumoniae isolates), and nasophar-
yngeal specimens (approximately 55% of all S. pneumoniae isolates) (25).
Many of these cultures were obtained from treatment failures, however, and
the true prevalence of resistance in specimens isolated from these sites may
be somewhat lower.

Macrolide-Resistance

Macrolide-resistance among S. pneumoniae has escalated at alarming rates
in North America and worldwide. Macrolide-resistance among pneumo-
cocci is primarily due to genetic mutations affecting the ribosomal target site
(ermAM) or active drug efflux (mefE). Ribosomal mutations that confer
high-grade resistance are also cross-resistant to clindamycin, whereas efflux
mutations can likely be overridden in vivo (26). Currently, about a third of
macrolide-resistant strains in North America possess the efflux mutations
mechanism of resistance, and the rest exhibit the ribosomal mutations. This
relationship is reversed in Europe and the Far East, where most resistance is
conveyed through the ribosomal mutations mechanism. Pneumococci resis-
tant to erythromycin (by either mechanism) are also resistant to azithromy-
cin, clarithromycin, and roxithromycin (27). Prior antibiotic exposure is the
major risk factor for amplification and perpetuation of resistance. Clonal

186 Brook

spread facilitates dissemination of drug-resistant strains. Several popula-
tion-based studies noted correlations between the prevalence of macrolide
resistance among S. pneumoniae and overall macrolide consumption in the
region or country (28,29).

Fluoroquinolone-Resistance

The main resistance mechanisms to fluoroquinolones are the efflux pump sys-
tem and specific point mutations. The efflux pump is a mechanism that expells
the antimicrobial agent across the cell membrane, thus reducing the intracel-
lular concentrations to sublethal levels. The pump's action is dependent on
the antimicrobial's ability to bind to the bacterial efflux protein and to be
exported. Some fluoroquinolones, such as moxifloxacin and trovafloxacin,
are not as affected by bacterial efflux mechanisms because of their bulky
side-chain moiety at position 7, which prevents export (30).

The other resistance mechanism involves specific point mutations that
reduce the binding of the antimicrobial to specific enzymatic sites by altering
the target site. In this regard, fluoroquinolones bind to enzymes involved in
DNA replication, including DNA gyrase and DNA topoisomerase IV.
Specific mutations in the genes that code for these enzymes can result in
reduced binding and activity of the fluoroquinolones (31). Different fluoro-
quinolones exhibit weaker or stronger affinity to these enzyme-binding sites.
First- and second-generation fluoroquinolones bind primarily to DNA gyrase
or DNA topoisomerase IV, whereas the third-generation fluoroquinolones
generally bind strongly to both DNA gyrase and DNA topoisomerase IV.
Thus, a single point mutation in DNA gyrase or DNA topoisomerase IV
generally affects first- and second-generation fluoroquinolones to a greater
extent than third-generation fluoroquinolones. Furthermore, the third-genera-
tion C-8 methoxyfluoroquinolones, moxifloxacin and gatifloxacin, appear to
bind different molecular sites within these enzymes, thereby decreasing the
cross-resistance between these agents and the older fluoroquinolones (32).

Microbial resistance to the newer fluoroquinolones (levofloxacin,
gatifloxacin, moxifloxacin and gemifloxacin) is relatively uncommon, cur-
rently occurring in approximately 1% of clinical isolates in North America.
However, increased resistance has been observed in the some countries (33).
These agents can be useful for treatment of bacterial sinusitis, but caution
must be exercised to avoid the potential for selection of widespread resis-
tance, which may occur with indiscriminate use (34).

ANTIMICROBIAL AGENTS

The antimicrobial agents most commonly used to treat acute sinusitis include
amoxicillin (with and without clavulanic acid), oral and parenteral cephalos-
porins, macrolides, and "newer" quinolones (Tables 5 and 6).

Antimicrobial Management of Sinusitis

187

Table 5 Antibiotics Used for Bacterial Sinusitis (PO)

Duration of

therapy for

Pediatric

acute sinusitis

Antibiotic

Adult dosage

dosage (mg/kg)

(days)

Beta-lactams

Cefprozil (Cefzil)

250-500 mg bid

7.5-15 bid

Cefuroxime axetil (Ceftin)

250-500 mg bid

10-15 bid

Cefpodoxime (Vantin)

200-400 mg bid

5 bid

Cefdinir (Omnicef)

300 mg bid

7 bid/ 14 qd

Amoxicillin (Amoxil,

500 mg tid or

20^5 bid

Trimox, Wymox)

875 mg bid

Amoxicillin-clavulanate

500 mg tid a or

22.5 or 45

(Augmentin)

875 mg or
2000 mg (XR)
bid a

(ES600) bid

Ketolides

Telithromycin (Ketek)

800 mg qd

Macrolides

Azithromycin (Zithromax)

250 mg qd

10 day 1, then
5 qd

3 or 5

Clarithromycin (Biaxin)

500 mg bid

7.5 bid

Fluoroquinolones

Levofloxacin (Levaquin)

500 mg qd

Gatifloxacin (Tequin)

500 mg qd

Moxifloxacin (Avelox)

400 mg qd

Others

Clindamycin (Cleocin)

1 50^50 mg
tid or qid

7.5 qid or 6 tid

TMP-SMX (Bactrim,

160mg/800mg

8-12 bid

Septra)

bid

a Based on amoxicillin component.

Abbreviation: NA, not approved for patients <18 years of age.

Amoxicillin is often used for sinusitis therapy and is safe and inexpensive,
and when given in a high dose, it is still the drug of choice for intermediately
penicillin-susceptible S. pneumoniae. However, the growing resistance of
H. influenzae and M. catarrhalis to amoxicillin through the production of beta-
lactamase increases the risk that it will fail to clear the infection. However, the
addition of clavulanic acid (a beta-lactamase inhibitor) to amoxicillin or the
use of antimicrobial agents resistant to beta-lactamase activity is effective against
resistant organisms.

Using higher doses of amoxicillin ± clavulanate (i.e., 4.0g/day in adults
or 90mg/kg/day in children based on amoxicillin component) will help to

188

Brook

CD
-G

=5
G

• »-H

• »-H
S-H
O

-4-»

o
PQ

t/>

-4-»

G
o
60

• »-H

o
u
o

M-H

o
•—
+-»

a.)
c

1 1

CO*

pfj

CD
P-

H-l

P*
I— i

CD
P-

co
a

c
aj
60

• >-H

-H -H -H -H

+ + + -H -H

-M

+ I -H -H

+ + + + +

-H

+ -H -H

-M

G G

o o

• ?-H • f-H

X X

o o

a a

< <

O
• i—t
+-'
CS
U

G
CD
00

cd
U

• >-H

-4— »

S-H

CD
C
CD
60

o
o

C/5

o
o

• »-H

S-h
CD
G
CD
60

ID
1/3

G
O

•F-H

■*-"
C3
U

G
CD
60

C/3

■ — <

cd ^
*-" G

60 g

T3
C

CD
G
CD
60

N
O

S-H

CD
X
CS

• »-^

<H-H

<D *rt

e G

G .2

.2 tS

TO CD

oj G

2h <d

G Of)
CD i

60 TJ

H -G

-H

++++++^^

-H -H

+ + + + +

+ + + +^+^^

73 -G

O .G

CD CD

u u

w G

til ^

CD ^_,

a is

.a x>

X • -3

cG CS

CD CD

u u

CD G

^5 O

h X

o ■ —

G *h

O CD

J u

« X

° 8

N -G
cd

cG «§

3 G
or) c«

a a
o -a

S S

2 S

t.i

Antimicrobial Management of Sinusitis

189

-H -H +

-H

-U

-H -H -H + + -H -H

-H + -H

+ + + +

-H -H + I + + + +

-H -M -H

-H -H -H + + -H

-H

• •— i

• ^^

•*->

-*— »

• fH

—

9 •-
>> o

§1-

-^ b

G -S G

•33 o *rt

£ * y

S o s

G 2 1
43 .& g

G •'- ,

X 42

a s u

-o
• m

CJ
CJ

O
G

99
G

CJ*
CJ
G
cd
-<— »

■ ^h
99

CJ
5-

CJ
Oh

CJ*"

-O

• f-H

• c\

G»

CJ
CJ
99

99
(h

CJ
CJ

• ^H

• i-H

■4-J

G ^

G< p,

U G

99 .G
S Jh

qj :G

> as

« >

+ <

CJ
G
CJ
Gh

-H G

ai CJ

£ o

G S-H

^ G

G *G

•-H j*,
/— s ■*-•

o S3

99 JS

^ • rH

a3 o

X>
+

CJ
CJ

G
TD

O
s-

ft
G

O
G

CJ
99

-t— '

•^H

." «J

>
<

5-H

■4-J

• --

• H

• i-H

^ Gh

190 Brook

ensure adequate eradication of penicillin-resistant S. pneumoniae organisms (34).
Amoxicillin/clavulanate is also active against anaerobic bacteria, which is an
important consideration in patients with chronic sinusitis.

First-generation cephalosporins lack sufficient efficacy against H influen-
zae and many S. pneumoniae strains. Generally, cefaclor and loracarbef are not
considered effective for the treatment of acute sinusitis because of the limited
activity of these agents. The second-generation cephalosporins (cefuroxime axe-
til, cefdinir, cefpodoxime, and cefprozil) are more effective because of their activ-
ity against penicillin-resistant Haemophilus and Moraxella spp. and
intermediately penicillin-resistant S. pneumoniae (24).

Oral third-generation cephalosporins (cefixime and ceftibuten) are most
effective against penicillin-resistant Haemophilus and Moraxella spp., but they
are less effective against S. pneumoniae resistant to penicillin. Parenteral third-
generation cephalosporins (cefotaxime or ceftriaxone) are effective against
H influenzae and M. catarrhalis that produce beta-lactamase, as well as over
95% of intermediately resistant S. pneumoniae. No oral cephalosporin is active
against anaerobes, which is an important consideration for the treatment of
chronic sinusitis.

TMP/SMX has lost efficacy against all major pathogens, including
S. pneumoniae and GABHS. The sulfa component can cause hypersensitivity
reactions.

Of the macrolides, erythromycin is inactive against H influenzae and some
GABHS. Resistance of GABHS to erythromycin and other macrolides occurs in
countries where these agents were overused (e.g., Japan, Finland, Spain, Taiwan
and Turkey) (35). Cross-resistance of GABHS is common among all macrolides.
Azithromycin has improved efficacy against aerobic gram-negative organisms
(H influenzae and M. catarrhalis), while clarithromycin is more efficient than
erythromycin against aerobic gram-positive organisms (36). Recent studies
show, however, increased resistance of S. pneumoniae to all macrolides (up to
35%), and survival of azithromycin-susceptible H influenzae in the middle ear
and sinuses (21, 37). The persistence of the organism in otitis media is believed
to result from accumulation of azithromycin mainly inside the middle ear white
cells, and not in the middle ear fluid where most of the organisms grow.

Clindamycin is effective against anaerobes and aerobic gram-positive
organisms, including most penicillin-resistant S. pneumoniae; however, it
is not effective against aerobic gram-negative pathogens. Vancomycin
(a glycopeptide) and linezolid are effective against penicillin-resistant
S. pneumoniae and methicillin-resistant S. aureus. However, they are not
effective against H influenzae or M. catarrhalis.

Telithromycin is the first ketolide antibacterial to be approved for clin-
ical use. It is structurally related to the macrolides, but has a low propensity to
select for or induce resistance to macrolide-lincosamide-streptogramin anti-
bacterials (38). In vitro, telithromycin is effective against multi-drug-resistant
S. pneumoniae (regardless of the presence of macrolide-resistant determinants

Antimicrobial Managemen t of Sinusitis 191

[erm(B), mef(A)]), GABHS, M. catarrhalis, and H. influenzae. In clinical trials,
it has demonstrated clinical and bacteriological efficacy in the treatment of
acute sinusitis due to penicillin and/or macrolide (erythromycin) resistant
S. pneumoniae as well as H. influenzae or M. catarrhalis (39).

The first-generation fluoroquinolones (e.g., ciprofloxacin, ofloxacin) pro-
vide inadequate S. pneumoniae coverage and are primarily active against aerobic
gram-negative bacilli (including H. influenzae and M. catarrhalis). The second-
generation fluoroquinolone, levofloxacin, is the L-isomer of ofloxacin and
demonstrates somewhat-improved gram-positive activity. However, susceptibil-
ity data show levofloxacin to be less potent than ciprofloxacin against such
gram-negative pathogens as Pseudomonas aeruginosa and certain enterobacter-
iaceae. The third-generation fluoroquinolones include moxifloxacin, gemifloxa-
cin, and gatifloxacin and have improved gram-positive and atypical bacteria
coverage compared with first- and second-generation fluoroquinolones. Some
of the newer fluoroquinolones (e.g., gatifloxacin, moxifloxacin, trovafloxacin)
have activity against oral anaerobes, but their efficacy in chronic sinusitis has
not been proven. In particular, these newer representatives of the fluoroquino-
lone class manifest greater activity against S. pneumoniae (40). A major concern
with the use of these agents, however, is the selection of class resistance to gram-
negative organisms, staphylococci, and pneumococci (19,20). None of the newer
fluoroquinolones is currently approved for use in children.

Pharmacokinetics and Pharmacodynamics (PK/PD)
of Antimicrobials

The goal of antibiotic therapy is to eradicate the causative organism from
the sinus cavity. To achieve this goal, the antibiotic must be active in vitro
against the targeted organisms and must penetrate the sinus cavity in suffi-
cient concentrations. The effect of antibiotics in eliminating the organisms is
an added effect over the natural eradication achieved in time by the host.
The host defenses that participate in this process include activity of inflam-
matory cells, antibody, complement, and other host defense mechanisms.

The environment at the infected sinus never corresponds to the laboratory
in vitro susceptibility testing conditions. The actual performance of an antibiotic
in vivo depends on variables that include the oxygen tension, pH, and protein
binding of an antibiotic.

Several methods are utilized to evaluate the in vitro activity of an anti-
biotic. Most often a MIC or a minimum bactericidal concentration (MBC)
is determined to assess antibiotic activity. The utility and limitations of these
tests should be appreciated. The MIC and MBC are values characterizing an
antibiotic under strict test tube conditions, and clinical interpretation also
requires the consideration of PK/PD issues.

Although standard parameters of antimicrobial activity such as MIC
and minimal bactericidal concentration are helpful, they do not provide

192 Brook

information about the time course or rate of kill relative to concentration or
whether post-antibiotic effects contribute to activity (41). The pharma-
cology of antimicrobial chemotherapy in sinusitis can be divided into two
components (41):

1. pharmacokinetic component — this pertains to the dosing regimen,
drug absorption, distribution, protein binding, bioavailability,
half-life, metabolism, and elimination, which determine the time
course of the drug concentrations in serum, sinus fluid, and sinus
mucosal tissues

2. pharmacodynamic component — this deals with the association
between concentrations of the drug at the site of infection and
its antimicrobial effect

Antibiotics can be divided into two major groups: those that exhibit
concentration-dependent killing and prolonged persistent effects and those
that exhibit time-dependent killing and minimal-to-moderate persistent
effects (41). With drugs that fall into the former group, the area under the
concentration-time curve (AUC) (i.e., quinolones) and peak levels (amino-
glycosides) are the major parameters that correlate with efficacy (Fig. 1).
The ratio of peak concentration to MIC is a measure of potency that also
indicates the efficacy of the drug in these agents. With drugs that exhibit
time-dependent killing and minimal-to-moderate persistent effects, time
above MIC is the major parameter-determining efficacy. Beta-lactam and
macrolide antibiotics belong to this second group.

Time>MIC AUC/MIC

time-dependent activity concentration-dependent activity

Penicillins # Quinolones

Cephalosporins # Aminoglycosides

Macrolides Azithromycin

Clindamycin Ketolides
Optimal profile:

Free serum antibiotic level Optimal profile:

exceeds MIC ^ ree serum AUC/MIC ratio at least

for at least 40-50% 25 " 30 < stre P> other gram-positive)

of dosing interval 125 (gram-negative bacilli)

Figure 1 Predictors of bacterial eradication: pharmacokinetic/pharmacodynamic
profiles.

Antimicrobial Management of Sinusitis 193

Studies in otitis media show that there appears to be a relationship
between the time above MIC in serum and in middle ear fluid (MEF) for
beta-lactam antibiotics. It is predicted that to achieve at least 80% to 85%
bacteriologic cure in otitis media, serum concentrations should exceed the
MIC of pathogens for at least 40% of the dosing interval (42). For the same
cure rate, the peak MEF to MIC ratio should be in the range of 3 to 6. If
the MICs for pathogens are known, it will be possible to predict those
agents for which adequate concentrations can be achieved.

Despite substantial MEF concentrations, some drugs such as the macro-
lides (i.e., erythromycin, azithromycin and clarithromycin) are clinically less
reliable against H. influenzae because the MICs for this organism frequently
exceed the achievable MEF concentrations. In contrast, other drugs such as
the oral third-generation cephalosporins (i.e., cefixime, ceftibuten) that reach
more modest absolute MEF concentrations, but have such low MIC90S for
H. influenzae and M. catarrhalis may be more effective in eradicating this
pathogen. However, these agents are ineffective against penicillin-resistant
S. pneumoniae (41).

Fluoroquinolones demonstrate concentration-dependent killing. The
ratio of the peak concentration (C max ) to the MIC and of the area under the
curve (AUC) to the MIC appear to be the parameters that best correlate with
clinical efficacy. If the free-drug AUC/MIC ratio is >25-30, the probability
of a favorable clinical outcome is quite high (> 100%) for patients infected with
gram-positive organisms (43). Using this cutoff criterion (AUC/MIC ratio,
>25-30), ciprofloxacin fares poorly against gram-positive organisms,
whereas gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin all exceed
this threshold. However, levofloxacin barely achieves the goal, and for isolates
with MICs of >2.0 |ig/mL, levofloxacin is inadequate.

PRINCIPLES OF THERAPY

Selection of the appropriate agent(s) is generally made on an empirical basis,
and the agents should be effective against any potential organisms that may
cause the infection (44). In the empirical choice of antimicrobial therapy for
sinuses, several balances between narrow- and wide-spectrum antimicrobial
agents must be made. If the patient fails to show significant improvement or
shows signs of deterioration despite treatment, it is important to obtain a
culture, preferably through sinus puncture, as this may reveal the presence
of resistant bacteria. Further antimicrobial treatment is based, whenever
possible, on results of the culture. Obtaining a culture through endoscopy
is an alternative approach (45). However, the specimen may be contami-
nated with nasal flora. Surgical drainage may be extremely important at that
time. Culture of nasal pus or of sinus exudate obtained by rinsing through
the sinus ostium can give unreliable information because of contamination
by the resident bacterial nasal flora.

194 Brook

Table 7 Causes for Failure in the Treatment of Bacterial Sinusitis

Viral infection

Noncompliance

Resistant organism(s) as a result of:

Recent treatment with antibiotic agents

Acquisition of resistant organisms (community, day care, school, or nosocomial)

Emergence of resistance during therapy
Inadequate penetration of antibiotics to site
Lack of drainage (anatomical blockage or due to medication)
Persistence of predisposing risk factors
Impaired host defenses

Factors within the sinus cavity that may enable organisms to survive
antimicrobial therapy are inadequate penetration of antimicrobial agents,
a high protein concentration (can bind antimicrobial agents), a high content of
enzymes that inactivate antimicrobial agents (i.e., beta-lactamase), decreased
multiplication rate of organisms that interfere with the activity of bacteriostatic
agents, and reduction in pH and oxygen partial pressure, which reduces the
efficacy of some antimicrobial agents (e.g., aminoglycosides and quinolones)
(46) (Table 7).

Failure to improve on completion of appropriate antibiotic therapy should
prompt consideration of bacterial resistance, noncompliance, or complicated
sinusitis. Antimicrobial agents that achieve good intrasinus concentrations
can, however, fail to eradicate the pathogen(s) if there is impairment of local
defenses (e.g., phagocytosis, ciliary motility) within the sinus environment.

Treatment of Acute Sinusitis

Amoxicillin can be appropriate for the initial treatment of acute uncompli-
cated mild sinusitis (Table 8). However, antimicrobials that are more effec-
tive against the major bacterial pathogens (including those that are resistant
to multiple antibiotics) may be indicated (Table 9) as initial therapy and for
the retreatment of those who have risk factors prompting a need for more

Table 8 Indications for Amoxicillin Therapy (high dose)

Mild illness

No history of recurrent acute sinusitis

During summer months

When no recent antimicrobial therapy has been used

When patient has had no recent contact with patient(s) on antimicrobial therapy

When community experience shows high success rate of amoxicillin

Antimicrobial Management of Sinusitis

195

Table 9 Recommended Antibacterial Agents for Initial Treatment of Acute
Sinusitis or After No Improvement

Factors
prompting
more effective
antibiotics a

At diagnosis

Clinically treatment failure at
48-72 hr after starting treatment

High-dose amoxicillin

Yes

"new"

High-dose amoxicillin/
clavulanate or a
quinolone b or telithromycin b
or cefuroxime-axetil or
cefdinir or cefpodoxime
proxetil

High-dose amoxicillin/
clavulanate or a "new"
quinolone b or telithromycin b
or cefuroxime or cefdinir or
cefpodoxime proxetil

High-dose amoxicillin/
clavulanate or a "new"
quinolone b or telithromycin b
or cefuroxime-axetil or
cefdinir or cefpodoxime
proxetil

a See Table 7.

b Not approved for children (<18 years).

effective antimicrobials (Table 10) and those who had failed amoxicillin
therapy.

These agents include amoxicillin and clavulanic acid, the "newer"
quinolones (e.g., levofloxacin, gatifloxacin, moxifloxacin), telithromycin,
and some second- and third-generation cephalosporins (cefdinir, cefurox-
ime-axetil, and cefpodoxime proxetil).

These agents should be administered to patients when bacterial resistance
is likely (i.e., recent antibiotic therapy, winter season, increased resistance in the
community), the presence of a moderate to severe infection, the presence of
comorbidity (diabetes, chronic renal, hepatic, or cardiac pathology), and when
penicillin allergy is present (Tables 9 and 10). Agents that are less effective
because of growing bacterial resistance may, however, be considered for patients
with antimicrobial allergy. These include the macrolides, TMP-SMX, tetracy-
clines, and clindamycin (47).

A number of antimicrobial agents have been studied in the therapy of
acute sinusitis over the past 25 years, with the use of pre- and post-treatment
aspirate cultures. Those studied were ampicillin, amoxicillin, amoxicillin-
clavulanic acid, cefuroxime axetil, cefprozil, loracarbef, levofloxacin, gati-
floxacin, moxifloxacin, and gemifloxacin. For a 10-day course of therapy,
the success rate was a bacteriological cure over of 80% to 90%. Appropriate
antibiotic therapy is of paramount importance, even though it is estimated
that spontaneous recovery occurs in about half of patients (19,48).

196 Brook

Table 1 Risk Factors Prompting a Need for More Effective Antimicrobials a

Bacterial resistance is likely

Antibiotic use in the past month, or close contact with a treated individual(s)

Resistance common in community

Failure of previous antimicrobial therapy

Infection in spite of prophylactic treatment

Child in day care facility

Winter season

Smoker or smoker in family
Presence of moderate to severe infection

Presentation with protracted (>30 days) or moderate to severe symptoms

Complicated ethmoidal sinusitis

Frontal or sphenoidal sinusitis

Patient history of recurrent acute sinusitis
Presence of comorbidity and extremes of life

Comorbidity (i.e., chronic cardiac, hepatic, or renal disease, diabetes)

Immunocompromised patient

Younger than two years of age or older than 55 years

Allergy to penicillin

Allergy to amoxicillin

a Amoxicillin and clavulanic acid, second- and third-generation cephalosporins, telithromycin,
and the "respiratory" quinolones.

Antimicrobial therapy is beneficial and effective in the prevention of
septic complications (48). The recommended length of therapy for acute
sinusitis is at least 14 days or seven days beyond the resolution of symptoms,
whichever is longer. However, no controlled studies have proved the length of
therapy sufficient to resolve the infection.

Within the last two years, six panels of experts recently presented
reviews and rendered their recommendations on how to diagnose and man-
age sinusitis (19,49-53). The recommendations of three of these guidelines
are summarized in Chapter 10.

Treatment of Chronic Sinusitis

Many of the pathogens isolated from chronically inflamed sinuses are resistant
to penicillins through the production of beta-lactamase (7,54). These include
both aerobic (S. aureus, H. influenzae, and M. catarrhalis) and gram-negative
bacilli anaerobic isolates (all B.fragilis and over half of the Prevotella, Porphyr-
omonas, and Fusobacterium spp.).

Retrospective studies illustrate the superiority of therapy effective
against both aerobic and anaerobic BLPB in chronic sinusitis (54,55).
Amoxicillin-clavulanate (54) or clindamycin (55), both effective against both
aerobic and anaerobic bacteria, were superior to antimicrobials, but were
not active against these organisms.

Antimicrobial Managemen t of Sinusitis 1 97

The choice of antimicrobial agent in chronic sinusitis should provide
coverage for the usual pathogens in acute sinusitis (e.g., S. pneumoniae,
H. influenzae, and M. catarrhalis) as well as beta-lactamase-producing
aerobic and anaerobic organisms. Therefore, treatment with a broad-
spectrum antibiotic that is stable against beta-lactamases and active against
penicillin-resistant S. pneumoniae with anaerobic coverage may be optimal
for the treatment of chronic sinusitis. Antimicrobial agents used for chronic
sinusitis therapy should therefore be effective against both aerobic and anaer-
obic BLPB; these include the combination of a penicillin (e.g., amoxicillin)
and a beta-lactamase inhibitor (e.g., clavulanic acid), clindamycin, chloram-
phenicol, the combination of metronidazole and a macrolide, and the
"newer" quinolones (e.g., trovafloxacin). All of these agents (or similar
ones) are available in oral and parenteral forms. Other effective agents that
are available only in parenteral form are some of the second-generation
cephalosporins (e.g., cefoxitin, cefotetan and cefmetazole), combination of
a penicillin (e.g., ticarcillin, piperacillin, ampicillin) and a beta-lactamase
inhibitor (e.g., clavulanic acid, tazobactam, sulbactam), and the carbape-
nems (i.e., imipenem, meropenem). If aerobic gram-negative organisms such
as P. aeruginosa are involved, parenteral therapy with an aminoglycosides,
a fourth-generation cephalosporin (cefepime or ceftazidime), or oral or
parenteral treatment with a fluoroquinolone (only in postpubertal patients)
is added. Parenteral therapy with a carbapenem (e.g., imipenem) is more
expensive, but provides coverage for most potential pathogens, both anaer-
obes and aerobes.

From a practical point of view, it is not generally recommended or
necessary for clinicians to perform a culture for anaerobic bacteria in these
patients. The tests are very expensive and timely, and most clinicians do not
have access to materials that are necessary to properly culture anaerobic
organisms. They should however, rely, on the data that have demonstrated
the existence of anaerobes (discussed above) in chronic sinusitis. Culture for
anaerobes should, however, be performed in those that do not respond to
therapy and/or develope a complication. Clinicians should consider the
anaerobic activity for the various antimicrobials before selecting an antibio-
tic agent for the treatment of chronic sinusitis.

The length of therapy is at least 21 days, and may be extended up to
10 weeks. Fungal sinusitis can be treated with surgical debridement of the
affected sinuses and antifungal therapy (56). In contrast to acute sinusitis,
which is generally treated vigorously with antibiotics, many physicians
believe that surgical drainage is the mainstay of therapy in chronic sinusitis.
When the patient does not respond to medical therapy, the physician should
consider surgical drainage. Impaired drainage may be a major contribution
to the development of chronic sinusitis, and correction of the obstruction
helps to alleviate the infection and prevent recurrence. The use of antimicro-
bial therapy alone, without surgical drainage of collected pus, may not result

198 Brook

in clearance of the infection. The chronically inflamed sinus membranes with
diminished vascularity may be a poor means of carrying an adequate anti-
biotic level to the infected tissue, even though the blood level may be
therapeutic. Furthermore, the reduction in the pH and oxygen tension
within the inflamed sinus may interfere further with the activity of the anti-
microbial agents, which can result in bacterial survival despite a high anti-
biotic concentration (46).

CONCLUSIONS

Many of the organisms recovered from sinusitis are resistant to penicillins,
either through the production of beta-lactamase (H. influenzae, M. catarrhalis,
S. aureus, Fusobacterium spp., and Prevotella spp.) or through changes in the
penicillin-binding protein (S. pneumoniae). The pathogenicity of beta-
lactamase-producing bacteria is expressed directly through their ability to
cause infections, and indirectly through the production of beta-lactamase.
The indirect pathogenicity is conveyed not only by surviving penicillin ther-
apy, but also by "shielding" penicillin-susceptible pathogens from the drug.
The direct and indirect virulent characteristics of these bacteria require the
administration of appropriate antimicrobial therapy directed against all
pathogens in mixed infections. The oral antimicrobials that are the most effec-
tive in management of acute sinusitis are amoxicillin-clavulanate (given in a
high dose), the newer quinolones (gatifloxacin, moxifloxacin) and the second-
generation cephalosporins (cefuroxime, cefpodoxime, cefprozil, or cefdinir).
The oral antimicrobials that are the most effective in management of chronic
sinusitis are amoxicillin-clavulanate, clindamycin, and the combination of
metonidazole and a penicillin.

REFERENCES

1. Brook I. Emergence and persistence of beta-lactamase-producing bacteria in
the oropharynx following penicillin treatment. Arch Otolaryngol Head Neck
Surg 1988; 114:667-670.

2. Brook I, Gober AE. Emergence of beta-lactamase-producing aerobic and anae-
robic bacteria in oro-pharynx of children following penicillin chemotherapy.
Clin Pediatr (Phila) 1984; 23:338-341.

3. Brook I, Gober AE. Monthly changes in the rate of recovery of penicillin-
resistant organisms from children. Pediatr Infect Dis J 1997; 16:255-256.

4. McCracken GH Jr. Considerations in selecting an antibiotic for treatment of
acute otitis media. Pediatr Infect Dis J 1994; 13:1054-1057.

5. Brook I, Gober AE. Resistance to antimicrobials used for therapy of otitis
media and sinusitis: effect of previous antimicrobial therapy and smoking.
Ann Otol Rhinol Laryngol 1999; 108:645-647.

6. Brook I. The role of beta-lactamase-producing bacteria in the persistence of
streptococcal tonsillar infection. Rev Infect Dis 1984; 6:601-607.

Antimicrobial Managemen t of Sinusitis 1 99

7. Brook I, Yocum P, Frazier EH. Bacteriology and (3-lactamase activity in acute
and chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1996;
122:418^23.

8. Hackman AS, Wilkins TD. In vivo protection of Fusobcicterium necrophorum
from penicillin by Bacteroides fragilis. Antimicrob Agents Chemotherapy
1975; 7:698-703.

9. Brook I, Pazzaglia G, Coolbaugh JC, Walker RI. In vivo protection of group A
beta-hemolytic streptococci by beta-lactamase producing Bacteroides species.
J Antimicrob Chemother 1983; 12:599-606.

10. Brook I, Pazzaglia G, Coolbaugh JC, Walker RI. In vivo protection of penicillin
susceptible Bacteroides melaninogenicus from penicillin by facultative bacteria
which produce beta-lactamase. Can J Microbiol 1984; 30:98-104.

11. Simon HM, Sakai W. Staphylococcal anatagosim to penicillin group therapy
of hemolytic streptococcal pharyngeal infection: effect of oxacillin. Pediatrics
1963; 31:463-469.

12. Scheifele DW, Fussell SJ. Frequency of ampicillin resistant Haemophilus para-
influenzae in children. J Infect Dis 1981; 143:495-498.

13. Brook I, Yocum P. In vitro protection of group A beta-hemolytic streptococci from
penicillin and cephalothin by Bacteroides fragilis. Chemotheraphy 1983; 29:18-23.

14. Wald ER, Milmore GJ, Bowen AD, Ledema- Medina J, Salamon N, Bluestone CD.
Acute maxillary sinusitis in children. N Engl J Med 1981; 304:749-54.

15. Mustafa E, Tahsin A, Mustafa O, Nedret K. Bacteriology of antrum in adults
with chronic maxillary sinusitis. Laryngoscope 1994; 104:321-324.

16. Doern GV, Jorgensen JH, Thornsberry C, Preston DA, Tubert T, Redding JS,
Maher LA. National collaborative study of the prevalence of antimicrobial
resistance among clinical isolates of Haemophilus influenzae. Antimicrob Agents
Chemother 1988; 32:180-185.

17. Jorgensen JH, Doern GV, Maher LA, Howell AW, Redding JS. Antimicrobial
resistance among respiratory isolates of Haemophilus influenzae, Moraxella
catarrhalis, and Streptococcus pneumoniae in the United States. Antimicrob
Agents Chemother 1990; 34:2075-2080.

18. Jacobs MR. Worldwide trends in antimicrobial resistance among common
respiratory tract pathogens in children. Pediatr Infect Dis J 2003; 22(suppl 8):
S109-S1019.

19. Sinus and Allergy Health Partnership: Antimicrobial treatment guidelines for
acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004; 130(suppl 1): IS.

20. Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN, The Alexander
Project Group. The Alexander Project 1998-2000: susceptibility of pathogens
isolated from community-acquired respiratory tract infection to commonly used
antimicrobial agents. J Antimicrob Chemother 2003; 52:229-246.

21. Dagan R, Johnson CE, McLinn S, Abughali N, Feris J, Leibovitz E, Burch DJ,
Jacobs MR. Bacteriologic and clinical efficacy of amoxicillin/clavulanate vs.
azithromycin in acute otitis media. Pediatr Infect Dis J 2000; 19:95-104.

22. Doern GV. Antimicrobial resistance with Streptococcus pneumoniae: much ado
about nothing? Semin Respir Infect 2001; 16:177-185.

23. Dominguez MA, Pallares R. Antibiotic resistance in respiratory pathogens.
Curr Opin Pulmonary Med 1998; 4:173-179.

200 Brook

24. Fung-Tome JC, Huczko E, Stickle T, et al. Antibacterial activity of cefprozil
compared with those of 13 oral cephems and 3 macrolides. Antimicrob Agent
Chemother 1995; 39:533-538.

25. Jacobs MR, Bajaksouzian S, Zilles A, Lin GR, Pankuch GA, Appelbaum PC.
Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to
10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.
S. surveillance study. Antimicrob Agents Chemother 1999; 43:1901-1908.

26. Lynch JP III, Martinez FJ. Clinical relevance of macrolide-resistant Streptococcus
pneumoniae for community-acquired pneumonia. Clin Infect Dis 2002 Mar 1;
34(suppl 1):S27-S46.

27. Klugman KP, Capper T, Widdowson CA, Koornhof HJ, Moser W. Increased
activity of 1 6-membered lactone ring macrolides against erythromycin-resistant
Streptococcus pyogenes and Streptococcus pneumoniae: characterization of
South African isolates. J Antimicrob Chemother 1998; 42:729-734.

28. Granizo J J, Aguilar L, Casal J, Dal-Re R, Baquero F. Streptococcus pneumoniae
resistance to erythromycin and penicillin in relation to macrolide and b-lactam
consumption in Spain (1979-1997). J Antimicrob Chemother 2000; 46:767-773.

29. Cizman M, Pokorn M, Seme K, Paragi A, Orazem A. Influence of increased
macrolide consumption on macrolide resistance of common respiratory patho-
gens. Eur J Clin Microbiol Infect Dis 1999; 18:522-524.

30. Peterson LR. Quinolone molecular structure-activity relationships: what have
we learned about improving antibacterial activity. Clin Infect Dis 2001;
33(suppl 3):S180-S186.

31. Pestova E, Beyer R, Cianciotto NP, Noskin GA, Peterson LR. Contribution of
topoisomerase IV and DN A gyrase mutations in Streptococcus pneumoniae for
resistance to novel fluoroquinolones. Antimicrob Agents Chemother 1999;
43:2000-2004.

32. Lu T, Zhao X, Drlica K. Gatifloxacin activity against quinolone-resistant gyrase:
allele-specific enhancement of bacteriostatic and bactericidal activities by the C-8
methoxy group. Antimicrob Agents Chemother 1999; 43:2969-2974.

33. Scheld WM. Maintaining fluoroquinolone class efficacy: review of influencing
factors. Emerg Infect Dis 2003; 9:1-9.

34. Saravolatz LD, Leggett J. Gatifloxacin, gemifloxacin, and moxifloxacin: the
role of 3 newer fluoroquinolones. Clin Infect Dis 2003; 37(1): 1210—1215.

35. Orden B, Perez Trallero E, Montes M, Martinez R. Erythromycin resistance of
Streptococcus pyogenes in Madrid. Pediatr Infect Dis J 1998; 17:470-473.

36. Spangler SK, Jacobs MR, Pankuch GA, Appelbaum PC. Susceptibility of 170
penicillin-susceptible and -resistant pneumococci to six oral cephalosporins,
four quinolones, desacetylcefotaxime, Ro 23-9424 and RP 67829. J Antimicrob
Chemother 1993; 31:273-280.

37. Brook I, Gober AE. Resistance to antimicrobials used for therapy of otitis
media and sinusitis: effect of previous antimicrobials therapy and smoking.
Ann Otol Rhinol Laryngol 1999; 108:645-647.

38. Clark JP, Langston E. Ketolides: a new class of antibacterial agents for
treatment of community-acquired respiratory tract infections in a primary care
setting. Mayo Clin Proc 2003; 78:1113-1124.

39. Balfour JA, Figgitt DP. Telithromycin. Drugs 2001; 61:815-829.

Antimicrobial Management of Sinusitis 201

40. Phillips I, King A, Shannon K. Comparative in-vitro properties of the quino-
lones. In: Andriole VT, ed. The Quinolones. 3rd ed. San Diego: Academic
Press, 2000:99-137.

41. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for
antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1-10.

42. Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics
in otitis media. Pediatr Infect Dis J 1996; 15:255-259.

43. Schentag J J, Gilliland KK, Paladino J A. What have we learned from pharma-
cokinetic and pharmacodynamic theories? Clin Infect Dis 2001; 32(suppl 1):
S39-S46.

44. Brook I, Frazier EH, Foote PA. Microbiology of the transition from acute to
chronic maxillary sinusitis. J Med Microbiol 1996; 45:372-375.

45. Brook I, Frazier EH, Foote PA. Microbiology of chronic maxillary sinusitis:
comparison between specimens obtained by sinus endoscopy and by surgical
drainage. J Med Microbiol 1997; 46:430-432.

46. Carenfelt C, Eneroth CM, Lundberg C, Wretlind B. Evaluation of the anti-
biotic effect of treatment of maxillary sinusitis. Scand J Infect Dis 1975; 7:
259-264.

47. Gwaltney JM Jr. Acute community-acquired sinusitis. Clin Infect Dis 1996;
23:209-225.

48. Wald ER, Chiponis D, Leclesma-Medina J. Comparative effectiveness of amoxi-
cillin and amoxicillin-clavulanate potassium in acute paranasal sinus infection in
children: a double-blind, placebo-controlled trial. Pediatrics 1998; 77:795-800.

49. Spector SL, Bernstein IL. Parameters for the diagnosis and management of
sinusitis. J Allergy Clin Immunol 1998; 102(suppl):S107-S144.

50. Williams JW Jr, Aguilar C, Makela M, Cornell J, Holleman D, Chiquette E,
Simel DL. Antibiotics for acute maxillary sinusitis. l:Cochrane Database Syst
Rev 2000; (2):CD000243.

51. Benninger MS, Holzer SES, Lau J. Diagnosis and treatment of uncomplicated
acute bacterial rhinosinusitis: summary of the agency for health care policy and
research evidence-based report. Otolaryngol Head Neck Surg 2000; 122:1-7.

52. Brook I, Gooch WM III, Jenkins SG, Pichichero ME, Reiner SA, Sher L,
Yamauchi T. Medical management of acute bacterial sinusitis. Recommenda-
tions of a clinical advisory committee on pediatric and adult sinusitis. Ann Otol
Rhinol Laryngol 2000; 109:1-20.

53. Clinical Practice Guidelines: Managemement of Sinusitis. Pediatrics 2001;
108:798-807.

54. Brook I, Thompson DH, Frazier EH. Microbiology and management of
chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1994;
120:1317-1320.

55. Brook I, Yocum P. Management of chronic sinusitis in children. J Laryngol
Otol 1995; 109:1159-1162.

56. Decker CF. Sinusitis in the immunocompromised host. Curr Infect Dis Rep
1999; 1:27-32.

Medical Management of Acute Sinusitis

Dennis A. Conrad

Division of Infectious Diseases, Department of Pediatrics, University of Texas
Health Science Center at San Antonio, San Antonio, Texas, U.S.A.

INTRODUCTION

The medical management of acute sinusitis remains problematic due to the
inherent contradictions concerning diagnosis and treatment. Although a
significant number of upper respiratory tract infections (URTIs) requiring
evaluation by health care providers occur annually, the ability to precisely
distinguish bacterial sinusitis from viral rhinosinusitis by clinical criteria still
does not exist. Even though the majority of cases of acute bacterial sinusitis
will resolve spontaneously without specific anti-infective therapy, antimicro-
bial treatment shortens the duration of illness and lessens the severity of
symptoms. An increasing prevalence of respiratory pathogens resistant to
traditionally prescribed antibiotics has been documented during the last
decade, yet standard antibacterial regimens still result in acceptably high
cure rates despite probable microbial resistance in vitro.

Current opinion on the management of acute bacterial sinusitis embra-
cing the principles of best practice is to establish the diagnosis of acute bac-
terial sinusitis as accurately as is possible by utilizing clinical information,
and to prescribe and treat the patient with an antibiotic chosen for predicted
probability of success and reduced potential for selection of antimicrobial
resistance (1). In addition, several important analyses of the management
of acute sinusitis have been published within the last seven years that speci-
fically address the evidentiary basis for best clinical practices; synthesis of

203

204 Conrad

this information provides the framework for the management recommenda-
tions contained in this chapter. As has been true for previously published
recommendations, these current recommendations will arise from interpre-
tation of results achieved in clinical trials and from best estimates where
definitive information is lacking.

RATIONALE FOR THE RECOMMENDED MANAGEMENT OF
ACUTE BACTERIAL SINUSITIS

American Academy of Pediatrics

The principles for the judicious use of antimicrobial agents that should be used
to treat acute sinusitis in children were published in 1998 (2). The authors
recommended that the clinical diagnosis of acute bacterial sinusitis in children
required the presence of mild nonspecific symptoms and signs of URTI, such
as purulent rhinitis or cough, which persisted for 10 to 14 days, or the presence
of more severe symptoms and signs, such as high fever and facial fullness or
pain, which were more specific for sinus mucosal inflammation.

The diagnosis of acute sinusitis should be based on clinical finding; the
use of radiographic evaluation was to be limited to episodes of recurrent
sinus disease, when complications of acute sinusitis were suspected, or if
the presumptive clinical diagnosis of bacterial sinusitis was in doubt.

Amoxicillin was appropriate for the initial treatment of acute uncom-
plicated sinusitis, whereas a (3-lactamase-stable (3-lactam antibiotic would be
appropriate to treat recurrent infection and amoxicillin therapeutic-failures.
These recommendations remain useful to date as a guide for current clinical
practice.

American Academy of Allergy and Clinical Immunology

Comprehensive practice parameters on sinusitis addressing diagnosis, anti-
microbial therapy, and adjunctive treatments were published in 1998 (3).
Selected conclusions were that diagnosis of bacterial sinusitis should be
established by a combination of clinical history with physical examination,
nasal cytology, and/or imagining studies, that antibiotics were the primary
therapy for bacterial sinusitis, and that treatment choice should be based on
predicted effectiveness, costs, and potential adverse drug effects.

Critical analyses of the use of the adjunctive therapies of antihista-
mines, oc-adrenergic decongestants, topical and systemic glucocorticosteroids,
saline lavage, mucolytics, expectorants, and nasal endoscopic surgical inter-
vention were also provided and detailed to a degree that merits specific atten-
tion in terms of current clinical practice as regards the non-antibiotic-therapy
aspects of disease management (Table 1).

Medical Management of Acute Sinusitis

205

Table 1 Adjunctive Therapy in the Management of Acute Sinusitis

Adjunctive therapy

Evidence for efficacy

Potential utility

Antihistamines

oc-Adrenergic

decongestants
Topical

glucocorticosteroids
Systemic

glucocorticosteroids

Saline

lavage,mucolytics,

expectorants
Nasal endoscopy

None in acute sinusitis

Prospective studies absent

Useful in reducing mucosal
inflammation and edema
Not adequately studied

No confirmation of specific
efficacy

Subjective improvement in
patients undergoing
procedure

Chronic sinusitis associated

with allergic rhinitis
May reduce mucosal edema

and improve ostial patency
Treatment of rhinitis

accompanying sinusitis
Topical agents preferred

due to reduced risk of

adverse drug effects
Wetting agents may

provide symptomatic

relief
Useful for recurrent

sinusitis due to

ostial obstruction

Source: From Ref. 3.

Agency for Health Care Policy and Research

In 1999, the Agency for Health Care Policy and Research published a com-
prehensive analysis of medical literature evidence concerning the diagnosis
and treatment of community-acquired acute bacterial rhinosinusitis in chil-
dren and adults (4). Utilizing a MEDLINE search of human studies of sinu-
sitis published between 1966 and May 1998, meta-analyses were performed
to evaluate clinical management strategies.

Of the eight research questions posed and subsequently answered by the
review, the observations pertaining to four of the questions are particularly
germane to the current medical management of acute sinusitis (Table 2).
The authors of the report concluded that either symptomatic treatment or
the use of clinical criteria to select patients to be treated with antibiotics were
the most cost-effective strategies to manage patients with uncomplicated acute
bacterial sinusitis, and that the use of either amoxicillin or trimethoprim-
sulfamethoxazole should be the initial therapeutic consideration due to probable
efficacy, adverse events profiles, and treatment cost.

Subcommittee on Management of Sinusitis and the Committee on
Quality Improvement

Due to the limited number of randomized studies of acute bacterial sinusitis
evaluated by the Agency for Health Care Policy and Research, the Sub-
committee on Management of Sinusitis and the Committee on Quality

206 Conrad

Table 2 Results of Meta- Analysis Evaluating Management of Acute Sinusitis

I. What are the values of clinical criteria and imaging for diagnosis of acute bacterial

sinusitis?

A. Clinical criteria may have a diagnostic equivalence to sinus radiography.

II. Are antibiotics effective in resolving the symptoms of acute bacterial sinusitis?

A. Approximately 67% of patients receiving placebo recovered without

antibiotic therapy.

B. Antibiotic therapy increased the number of patients cured and shortened the

duration of symptoms.

III. What is the efficacy and safety of antibiotics in treatment of acute bacterial

sinusitis?

A. Antibiotic treatment reduced the clinical failure rate by one-half when

compared to placebo.

B. Amoxicillin and trimethoprim-sulfamethoxazole were as effective as

newer and more expensive antibiotics.

C. Approximately 4% of patients receiving amoxicillin had adverse effects

causing cessation of therapy; no statistical difference in this percentage
was observed for patients receiving other antibiotics.

IV. Do ancillary therapies benefit the treatment of acute bacterial sinusitis?

A. Difference in the design of individual studies prevented independent analysis
of the benefit of decongestants, antihistamines, topical and systemic
steroids, and surgical drainage and irrigation.

Source: From Ref. 4.

Improvement of the American Academy of Pediatrics partnered with the
Agency for Health Care Policy and Research and family practice and oto-
laryngology colleague organizations to provide a supplement specifically
for the management of acute bacterial sinusitis in children. Utilizing infor-
mation gleaned from nonrandomized pediatric treatment trials that were
published between 1966 and March 1999, in conjunction with the rando-
mized trials that had been reviewed during the Agency for Health Care Pol-
icy and Research study, a technical report (5) and a clinical practice
guideline for the management of sinusitis pertinent to childhood infections
(6) were generated and published in 2001.

Of the four clinical practice guideline recommendations that were for-
mulated following review of these additional studies, three of these recom-
mendations specifically address the medical management of acute bacterial
sinusitis occurring in children (Table 3).

International Journal of Pediatric Otorhinolaryngology
Consensus Opinion

A consensus opinion that was published in 1999 concerning the manage-
ment of rhinosinusitis in children is noteworthy for providing recommenda-
tions concerning the place for surgery in the management of sinusitis (7).

Medical Management of Acute Sinusitis 207

Table 3 Management of Acute Sinusitis in Children

The diagnosis of acute bacterial sinusitis in children is clinical, and is based on either

persistence or severity of upper respiratory tract symptoms.
Imaging studies are not necessary to confirm a clinical diagnosis of sinusitis;

computed tomography of the paranasal sinuses should be reserved for

preoperative evaluation.
Antibiotic therapy is recommended for management of acute bacterial sinusitis;

no recommendations can be made concerning adjuvant therapies, antimicrobial

prophylaxis to prevent recurrent infection, and the use of complementary or

alternative medicine to treat or prevent sinusitis.

Source: From Ref. 6.

The recommended uses of adenoidectomy and antral lavage were limited to
selected cases that could not be characterized as uncomplicated acute bac-
terial sinusitis, and recommendations concerning the absolute and possible
indications for endoscopic sinus surgery were provided (Table 4).

American College of Radiology

The American College of Radiology developed appropriateness criteria for
the evaluation of sinusitis in the pediatric population that were published in
1999 (8). The recommendations that were contained in the report provided
useful guidance concerning the selective use of imaging studies in the man-
agement of acute sinusitis (Table 5).

Table 4 Indications for Surgery in the Management of Acute Sinusitis
Absolute indications Possible indications

Complete nasal obstruction in cystic Persistence of chronic rhinosinusitis

fibrosis patients failing medical management

Antrachoanal polyp

Intracranial complication

Mucocele/mucopyocele

Orbital abscess

Traumatic injury of optic canal

Dacryocystorhinitis resistant to medical
therapy

Fungal sinusitis

Meningoencephalocele

Neoplasm

Source: From Ref. 7.

208 Conrad

Table 5 Use of Radiographic Evaluation in the Management of Acute Sinusitis

The diagnosis of acute and chronic sinusitis is based on clinical finding and not

solely on the basis of imaging studies.
Imaging studies are not indicated for successfully treated acute sinusitis.
Coronal cranial computed tomography should be done if the symptoms of acute

sinusitis persist beyond 10 days of appropriate therapy, and in cases of chronic

sinusitis where imaging evaluation is desired.
Plain radiography in the evaluation of sinusitis is generally unwarranted.

Source: From Ref. 8.

Sinus and Allergy Health Partnership (2000)

In 2000, the Sinus and Allergy Health Partnership published evidence-based
recommendations for the diagnosis and treatment of acute bacterial rhino-
sinusitis (9).

Based on acknowledged limited information available concerning com-
parative clinical trials evaluating diagnostic criteria and antibiotic choices
for the management of sinusitis, the partnership recommended that the
diagnosis of disease was clinical and could be based on the persistence
of upper respiratory tract symptoms that did not improve after a 10-day
duration or worsened during a five to seven-day interval.

Recommended treatment of adult patients with mild disease who were
not exposed to antibacterial therapy in the prior four to six weeks were amoxi-
cillin (lower dose), amoxicillin/clavulanate, cefpodoxime, or cefuroxime. Adult
patients with mild disease who had been exposed to antibacterials within the
prior four to six weeks and those patients with moderate disease should be trea-
ted with amoxicillin (higher dose), amoxicillin/clavulanate, cefpodoxime, or
cefuroxime. Adult patients with moderate disease who had been exposed to anti-
bacterials within the prior four to six weeks should be treated with amoxicillin/
clavulanate, gatifloxacin, levofloxacin, moxifloxacin, or a combination of either
amoxicillin or clindamycin with either cefpodoxime or cefixime. Recommenda-
tions for children with sinusitis paralleled those recommendations for adult
patients, both in terms of prior antibiotic exposure and severity of disease, with
the exception of exclusion of use of fluoroquinolones in this pediatric population.

The sinusitis management recommendations offered by the partnership
were based on predicted efficacy rates that had been mathematically calcu-
lated using in vitro susceptibility data, mechanisms of bacterial killing charac-
teristics for the different antibacterial classes, and predicted pharmacokinetics
of the individual drugs. Limited clinical trail results were available that could
actually substantiate many of the recommendations, although a concern for
the increased prevalence of bacteria which caused URTIs and were resistant
to amoxicillin and trimethoprim-sulfamethoxazole prompted recommenda-
tions to consider broader-spectrum antimicrobials for initial therapy.

Medical Management of Acute Sinusitis 209

Clinical Advisory Committee on Pediatric and Adult Sinusitis

A clinical advisory committee on pediatric and adult sinusitis also published
recommendations for the medical management of acute bacterial sinusitis in
2000 (10). This committee evaluated the importance of individual variables
of patient history, clinical assessment, and diagnostic tests for the initial
diagnosis of acute sinusitis.

The elements of the patient history that were deemed significantly
important to establish the diagnosis of bacterial sinusitis were a "cold" that
had been present for more than 7 to 10 days, "unusually" severe upper
respiratory tract complaints, fever, mucopurulent discharge of greater than
seven-days duration, pain referred to maxillary teeth, and no appreciable
response to decongestant therapy.

Significantly important clinical findings were facial and midface ten-
derness, the appearance of the nasal mucosal surface, intranasal pus, and
the presence of purulent postnasal mucus in the pharynx.

Of the diagnostic tests evaluated, only anterior rhinoscopy, direct
aspiration of the sinus, and bacterial cultures of aspirated material following
sinus puncture were considered significantly important, with the latter two
procedures limited to specific indications.

Antimicrobial therapy recommendations were ranked in a tripartite
hierarchy; agents of first choice were amoxicillin and trimethoprim-
sulfamethoxazole and second-line agents included cefpodoxime, cefprozil,
cefuroxime, cefdinir, and amoxicillin-clavulanate. Recommended third-line
agents were azithromycin, clarithromycin, ciprofloxacin, levofloxacin, gati-
floxacin, moxifloxacin, and clindamycin.

In terms of adjunctive therapies, the committee endorsed the restricted
use of topical decongestants limited to three days, and the use of systemic
decongestants in adult patients.

The committee acknowledged that the optimum management of acute
sinusitis was controversial, but that the primary care physician should
recognize the condition and treat aggressively due to disease impact on
the quality of life for patients with active disease.

American College of Physicians — American Society for
Internal Medicine

The American College of Physicians — American Society for Internal Medi-
cine published clinical practice guidelines in 2001 that outlined the principles
of appropriate antibiotic use to treat acute sinusitis occurring in adults (11);
background information that supported these recommendations was pub-
lished at the same time (12).

Three recommendations concerning management of acute sinusitis
were offered: sinus radiography is not recommended for the diagnosis of
uncomplicated sinusitis; acute bacterial sinusitis does not require antibiotic

210 Conrad

treatment, especially when symptoms are either mild or moderate; and
patients with severe symptoms or those with persistent moderate symptoms
who have specific finding of bacterial infection should receive anti-infective
therapy, preferentially with a narrow-spectrum agent (11).

The companion article provided the rationale that supported the three
recommendations contained in the clinical guidelines, and further observed
that analgesia was an important aspect of management of acute sinusitis and
that topical and oral decongestants may ameliorate some of the nasal symp-
toms associated with infection (12).

Sinus and Allergy Health Partnership (2004)

In 2004, the Sinus and Allergy Health Partnership published antimicrobial
treatment guidelines for acute bacterial rhinosinusitis (13) that updated
the original that were published in 2000 (9). The more recent guidelines
largely reflected those of the original publication; the areas of significant
update included diagnostic modalities, contemporary antibacterial suscept-
ibility profiles, addition of newer antimicrobial agents as recommended ther-
apy, and expansion of the various pharmacodymanic/pharmacokinetic
principles and therapeutic outcomes model (14) used to predict potential
success of the individual agents.

The anti-infective agents recommended for use to treat pediatric and
adult patients with mildly symptomatic sinusitis who had not been exposed to
an antibiotic in the preceding four to six weeks were amoxicillin, amoxicillin-
clavulanate, cefpodoxime, cefuroxime, and cefdinir. Treatment options for
those adult patients with mild sinusitis who had been exposed to an antibiotic
in the previous four to six weeks and those adult patients with moderately symp-
tomatic sinusitis were gatifloxacin, levofloxacin, moxifloxacin, amoxicillin-
clavulanate, ceftriaxone, or a combination of either amoxicillin or clindamycin
and either cefixime or rifampin.

Treatment options for those pediatric patients with mild sinusitis who
had been exposed to an antibiotic in the previous four to six weeks and those
pediatric patients with moderately symptomatic sinusitis were amoxicillin-
clavulanate, cefpodoxime, cefuroxime, cefdinir, ceftriaxone, or a combination
of either amoxicillin or clindamycin and either cefixime or rifampin.

Summary of Varying Recommendations for the Management of
Acute Bacterial Sinusitis

Despite subtle variations in the recently published recommendations for the
management of acute bacterial sinusitis, consistent principles are apparent.
The diagnosis of acute bacterial sinusitis should be made after consideration
of the presence and persistence of symptoms and signs of an URTI without
the use of radiographic or microbiologic evaluation for the majority of
patients, those antimicrobial agents most commonly used to treat respiratory

Medical Management of Acute Sinusitis 211

tract infections are also generally effective in the treatment of acute bacterial
sinusitis as evidenced by clinical trials and treatment experience, selected
adjunctive medicinal therapies may improve symptoms but are not critical
to achieve successful outcome, and surgical intervention is appropriately
restricted to complicated infections. Therefore, current recommendations
for the management of acute bacterial sinusitis may legitimately be an exten-
sion of recent prior recommendations generated by individual investigators,
health care partnerships, and consensus of medical experts on behalf of practi-
tioners, professional societies, and governmental agencies.

CURRENT RECOMMENDATIONS FOR THE MANAGEMENT OF
ACUTE BACTERIAL SINUSITIS

Symptomatic Treatment of URTIs

Children and adults who have a viral URTI may benefit from symptomatic
therapy, largely to improve the quality of life during the acute illness. The
use of normal saline as a spray or lavage may provide symptomatic improve-
ment by liquefying secretions to encourage drainage. The short-term (three-
day) use of topical a-adrenergic decongestants can also provide symptomatic
relief, but use should be restricted to older children and adults due to the
potential for undesirable systemic effects in infants and young children. Topi-
cal glucocorticosteroids may also be useful in reducing nasal mucosal edema,
especially in those cases where a patient who has seasonal allergic
rhinitis develops the complication of an acute URTI. The antipyretic and
analgesic effects of nonsteroidal anti-inflammatory agents may relieve or
ameliorate the associated symptoms of fever, headache, generalized malaise,
and facial tenderness.

Until the clinical diagnosis of acute bacterial sinusitis is established,
management of an URTI should be restricted to either no therapy or symp-
tomatic care alone. Moreover, symptomatic care may prove useful in the
management of acute bacterial sinusitis as adjunctive therapy, but no
adjunct has been shown essential in improving the outcome achieved by
antimicrobial therapy or effective in preventing the development of acute
bacterial sinusitis in persons who have a viral URTI or allergic rhinitis.

Clinical Diagnosis of Acute Bacterial Sinusitis

The presence and persistence of mucopurulent nasal drainage for a mini-
mum duration of time in a person who has an URTI is the most consistent
feature that can establish the diagnosis of acute bacterial sinusitis by clinical
criteria. An adult or a child who has an URTI and who also has persistent
mucopurulent nasal drainage that has not improved during a symptomatic
course of 10-days duration may be considered to have acute bacterial sinu-
sitis for the purposes of initiating anti-infective therapy (Fig. 1).

212

Conrad

Upper respiratory tract infection

Without specific symptoms/signs of sinus mucosal
inflammation

Clear/purulent rhinorrhea

Fever

Headache

Generalized malaise

Pharyngeal irritation

With specific symptoms/signs of sinus mucosal
inflammation

Facial fullness

Midface pain

Percussive tenderness over sinus regions

Maxillary tooth pain

Face pain with sneezing/coughing/bending over

Less than 1 0-day duration

Less than 7-day duration

More than 1 0-day duration

Symptomatic care

Antipyretics/analgesics
Systemic decongestants
Topic decongestants (adult)
Mucosal wetting agents

More than 7-day duration

Symptomatic care

Antipyretics/analgesics
Systemic decongestants
Topic decongestants (adult)
Mucosal wetting agents

Antibacterial therapy

Figure 1 Diagnosis and initial management of acute sinusitis.

The presence of associated symptoms and signs that are suggestive of
sinus mucosal inflammation further supports the clinical diagnosis of acute
bacterial sinusitis. Unilateral or bilateral midfacial tenderness or maxillary
pain, the subjective sensations of facial fullness or nasal congestion, fever,
a persistent cough worsening when the patient is supine, maxillary or peri-
orbital swelling, postnasal drainage, headache, and hyposmia or anosmia
are symptoms and signs that are often associated with acute bacterial sinu-
sitis. In those children and adults who have an URTI and who also have
localizing symptoms and signs of sinus mucosal inflammation, the diagnosis
of acute bacterial sinusitis may be made with reasonable certainty if those
localized findings are present on the seventh day of symptoms of an URTI
as measured from the time of initial onset.

Radiographic Diagnosis of Acute Bacterial Sinusitis

Radiographic evaluation of uncomplicated acute bacterial sinusitis is unneces-
sary to confirm the clinical diagnosis or direct antimicrobial therapy. Imaging
studies should be restricted to patients with symptoms and signs of URTI who
appear acutely ill and in whom the diagnosis of acute bacterial sinusitis is

Medical Management of Acute Sinusitis 213

unclear, patients who have evidence of having an intracranial or intraorbital
complication of acute bacterial sinusitis, patients who fail to respond appro-
priately despite broad-spectrum antimicrobial therapy, patients with recurrent
or chronic sinusitis, and for assessment in anticipation of endoscopic sinus
surgery. In these special circumstances, coronal sinus computed tomography
is the evaluation of choice.

Antimicrobial Therapy

Amoxicillin and trimethoprim-sulfamethoxazole still remain the most cost-
effective antimicrobial agents for the initial treatment of acute bacterial
sinusitis. Recent analyses of the appropriate management of acute bacterial
sinusitis have acknowledged the concern for the increasing prevalence of
bacterial resistance to antimicrobial agents. This increased antibacterial
resistance would have a potentially negative impact on reducing the clinical
efficacy of amoxicillin or trimethoprim-sulfamethoxazole, so recent thera-
peutic recommendations for treatment of acute bacterial sinusitis have been
expanded to include amoxicillin/clavulanate, cefpodoxime, cefuroxime,
cefdinir, and, for adult patients, ceftidoren, gatifloxacin, levofloxacin, and
moxifloxacin (Table 6). If the patient has a history of significant allergy to
P-lactam antibiotics and is not a candidate for fluoroquinolone therapy,

Table 6 Antibacterial Regimens for Treatment of Acute Sinusitis

Antibiotic Pediatric regimen Adult regimen

Amoxicillin 90mg/kg/day bid 3.5gm/daybid

Amoxicillin/clavulanate ES-600 90 mg amoxicillin/kg/day

bid

Amoxicillin/clavulanate XL - 4 gm/day bid

Cefdinir 14mg/kg/day qd-bid 600mg/day qd-bid

Cefixime 8 mg/kg/day qd-bid 400 mg/day qd-bid

Cefpodoxime 10 mg/kg/day bid 400 mg/day bid

Ceftibuten 9 mg/kg/day qd 400 mg/day qd

Ceftidoren - 800 mg/day bid

Cefuroxime 30 mg/kg/day bid 2 gm/day bid

Azithromycin 10 mg/kg/day qd 500 mg/day qd

Clarithromycin 15 mg/kg/day bid 1 gm/day bid

Telithromycin 800 mg/day qd

Clindamycin 20 mg/kg/day tid-qid 1.8 gm/day tid-qid

Gatifloxacin - 400 mg/day qd

Gemifloxacin - 320 mg/day qd

Levofloxacin - 500 mg/day qd

Moxifloxacin - 400 mg/day qd

Trimethoprim/sulfamethoxazole 12 mg/60 mg/kg/day bid 320 mg/ 1.6 gm/day

bid

214 Conrad

then azithromycin or clarithromycin has been proposed as alternative
choices. Even though these recommendations have been validated by differ-
ent mathematical and therapeutic models that have been used to predict the
relative efficacy of these newer antibiotics, no clinical study has yet been
performed that demonstrates the superiority of the extended-spectrum anti-
microbials for the treatment of acute bacterial sinusitis due to penicillin-
resistant Streptococcus pneumoniae and (3-lactamase-producing Haemophilus
influenzae and Moraxella catarrhalis. Therefore, a reasonable approach to
management would be an initial use of amoxicillin in higher dose or tri-
methoprim-sulfamethoxazole for penicillin-allergic patients, reserving the
use of extended-spectrum antimicrobial agents to those patients who fail
initial therapy (Fig. 2).

Patients who have failed initial amoxicillin or trimethoprim-
sulfamethoxazole therapy should be treated with an extended-spectrum anti-
biotic. If no appreciable improvement in symptoms has been noted after three
days of the initial therapy, an anti-infective agent with an enhanced antibac-
terial spectrum should be substituted. For pediatric patients, amoxicillin/
clavulanate, cefpodoxime, cefuroxime, or cefdinir would be a reasonable
choice. These antimicrobials would also be appropriate for adult patients
who have failed initial therapy; in addition, ceftidoren, telithromycin,
gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin could also be used.
In time, fluoroquinolone antibiotics approved for use in adults may also be
approved by the United States Food and Drug Administration for use in
children; until then, however, use in pediatric patients should be restricted
to unusual and special circumstances.

Patients who failed initial antimicrobial therapy and who have an
inadequate response to an extended-spectrum antimicrobial may be mana-
ged either medically or surgically. Medical management would be by use
of an antibiotic regimen that would incorporate those agents with the great-
est activity in vitro against antibiotic-resistant respiratory bacteria. Ceftriax-
one, parenterally administered daily or on alternative days until clinical
resolution of illness, would be one anti-infective option. The second option
would be a combination of two orally administered antibiotics chosen to
maximize activity against gram-positive and -negative bacteria. Clindamy-
cin, in combination with either cefixime or ceftibuten, would be an appropri-
ate regimen. A third option for pediatric patients could be the use of a
fluoroquinolone antimicrobial; with appropriate informed consent and par-
ent approval, the failure of two successive antibacterial regimens may be a
special circumstance justifying use of an agent otherwise currently unap-
proved for use in children.

The duration of antimicrobial treatment of acute bacterial sinusitis
should be for 10 days under most circumstances, as predicated on appreci-
able clinical improvement by the third treatment day. This recommendation
could be modified as the continuation of treatment for seven days beyond

Medical Management of Acute Sinusitis

215

Initial antimicrobial therapy for acute sinusitis
Amoxicillin
Trimethoprim-sulfamethoxazole

Clinical improvement by third treatment day

No/inadequate improvement by third treatment day

Continue antibiotic to complete 1 0-day course

Institute alternative antibiotic

Pediatric patient

Amoxicillin/clavulanate
Cefdinir
Cefpodoxime
Cefuroxime

Adult patient

Levofloxacin

Gatifloxacin

Moxifloxacin

Amoxicillin/clavulanate

Cefdinir

Cefpodoxime

Cefuroxime

Clinical improvement by third treatment day

Continue antibiotic to complete 10-day course

No/inadequate improvement by third treatment day

Institute alternative antibiotic [Option 1]

Surgical intervention [Option 2]

Pediatric and adult patient

Ceftriaxone

Combination therapy
Clindamycin plus
Cefixime or ceftibuten

Endoscopic surgery

Aspiration for culture/antimicrobial susceptibilities
Sinus lavage/irrigation

Clinical improvement by third treatment day

No/inadequate improvement by third treatment day

Continue antibiotic(s) to complete 10-day course

Figure 2 Algorithm for antimicrobial and surgical management of acute sinusitis.

that time where substantial improvement in symptoms following therapy
initiation first occurred. One antibiotic, azithromycin, has been approved
as a three-day regimen for treatment of acute bacterial sinusitis. However,
due to a spectrum of antibacterial activity against the major pathogens

216 Conrad

causing acute bacterial sinusitis that is reduced when compared to (3-lactam
antibiotics and fluoroquinolones, and despite the apparently more favorable
; 'short-course" treatment duration, use of azithromycin should be restricted
to those patients having a history of significant allergy to penicillin and
cephalosporin antibiotics and for whom use of a fluoroquinolone would
be inappropriate.

Use of Surgery in the Management of Acute Bacterial Sinusitis

Endoscopic sinus surgery for aspiration of sinus contents for culture and
susceptibility testing to guide anti-infective therapy could also be an option
for patients who failed initial antimicrobial therapy and who had an inade-
quate response to an extended-spectrum antibiotic. A secondary benefit may
be achieved by endoscopically directed sinus irrigation. Although no evi-
dence would suggest that this intervention is necessary to achieve successful
outcome, many patients will perceive an immediate improvement in the
severity of the symptoms of sinusitis following irrigation.

Endoscopic sinus surgery generally has no place in the management of
uncomplicated acute bacterial sinusitis and should be reserved for patients
who have had a complicated course, such as the failure of medical manage-
ment that was elucidated previously. As well, two additional circumstances
may also justify endoscopic sinus surgery in the management of acute bacterial
sinusitis. If a person with an episode of acute bacterial sinusitis has a history of
frequent episodes of recurring sinusitis, endoscopic sinus surgery performed to
identify a mechanical obstruction prohibiting appropriate sinus drainage may
allow surgical correction to prevent subsequent recurrences. As well, when
acute sinusitis occurs in an immunoincompetent host, knowledge of the infect-
ing pathogen best obtained by fiberoptic sinus endoscopy and aspiration/
lavage can assist in selecting the appropriate anti-infective regimen. However,
even for immunoincompetent hosts, "common things happen commonly;" a
reasonable alternative would be to restrict endoscopic sinus surgery to those
immunoincompetent hosts with acute sinusitis who failed initial empiric
medical management.

REFERENCES

1. Conrad DA, Jenson HB. Management of acute bacterial rhinosinusitis. Curr
Opin Pediatr 2002; 14:86-90.

2. O'Brien KL, Dowell SF, Schwartz B, Marcy SM, Phillips WR, Gerber MA.
Acute sinusitis — principles of judicious use of antimicrobial agents. Pediatrics
1998; 101:174-177.

3. Spector SL, Berstein IL, Li JT, Berger WE, Kaliner MA, Schuller DE, Blessing-
Moore J, Dykewicz MS, Fineman S, Lee RE, Nicklas RA. Sinusitis practice
parameters. J Allergy Clin Immunol 1998; 102(suppl 6, Part 2):S107-S144.

Medical Management of Acute Sinusitis 217

4. Agency for Health Care Policy and Research: Diagnosis and Treatment of
Acute Bacterial Rhinosinusitis. AHCPR Evidence Report/Technology Assess-
ment, Number 9, March 1999 (Rockville, MD).

5. Ioannidis JPA, Lau J. Technical Report: Evidence for the Diagnosis and Treat-
ment of Acute Uncomplicated Sinusitis in Children: A Systemic Overview.
Pediatrics 2001; 108(3). URL:http://www.pediatrics.org/cgi/content/full/
108/3/e57.

6. American Academy of Pediatrics Subcommittee on Management of Sinusitis
and Committee on Quality Improvement. Clinical Practice Guideline: Manage-
ment of Sinusitis. Pediatrics 2001; 108:798-808.

7. Clement PAR, Bluestone CD, Gordts F, Lusk RP, Otten FWA, Goossens H,
Scadding GK, Takahashi H, van Buchem L, van Cauwenberge P, Wald ER.
Management of rhinosinusitis in children. Int J Pediatr Otorhinolaryngol
1999; 49(suppl 1):S95-S100.

8. Expert Panel on Pediatric Imaging. Sinusitis in the pediatric population. ACR
Appropriateness Criteria, Reston, VA: American College of Radiology, 1999.

9. Sinus and Allergy Health Partnership: Antimicrobial treatment guidelines for
acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2000; 123(suppl 1,
Part2):Sl-S32.

10. Brook I, Gooch WM, Jenkins, SG, Pichichero ME, Reiner SA, Sher L, Yamauchi T.
Medical management of acute bacterial sinusitis: recommendations of a clinical
advisory committee on pediatric and adult sinusitis. Ann Otol Rhinol Laryngol
2000; 109:2-20.

11. Snow V, Mottur-Pilson C, Hickner JM. Principles of appropriate antibiotic use
for acute sinusitis in adults. Ann Intern Med 2001; 134:495-497.

12. Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA.
Principles of appropriate antibiotic use for acute rhinosinusitis in adults: back-
ground. Ann Intern Med 2001; 134:498-505.

13. Sinus and Allergy Health Partnership: Antimicrobial treatment guidelines for
acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004; 130(suppl 1):
1S^5S.

14. Poole MD. A mathematical therapeutic outcomes model for sinusitis. Otolaryn-
gol Head Neck Surg 2004; 130(suppl 1):45S^6S.

Medical Management of Chronic

Rhinosinusitis

Alexander G. Chiu

Division of Rhinology, Department of Otorhinolaryngology — Head and Neck
Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Daniel G. Becker

Department of Otorhinolaryngology — Head and Neck Surgery,
University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Sinusitis is one of the most common health problems in the United States,
and accounts for health expenditures in billions of dollars per year. Although
acute sinusitis accounts for the majority of these cases, it is estimated that
chronic rhinosinusitis (CRS) results in 18 to 22 million U.S. physician office
visits annually (1) and causes significant physical, emotional, and functional
impairments (2).

The exact etiology of CRS is still unknown, and therefore a clear defi-
nition and uniform treatment guidelines have not always been agreed upon.
What has come to be known is that CRS represents a cycle of infection and
inflammation. Therapy that fails to address both of these aspects may lead
to inadequate results. There are currently multiple medications and delivery
methods that are used in the medical management of CRS, and a combina-
tion of these therapies is needed in order to manage the multiple factors
involved in the disease state. Before describing the current medical therapy,
we will review the current working definition of CRS and its known inciting
factors.

219

220 Chiu and Becker

DEFINITION OF CRS

The Sinus and Allergy Health Partnership convened a multidisciplinary task
force to develop definitions for CRS that would allow clinicians and research-
ers to accurately diagnose this condition. Their first publication was in 1997
and the definitions were later revised in 2003 (3). The task force defined CRS
as the duration of symptoms for greater 12 consecutive weeks or greater
12 weeks of physical findings. Symptoms include nasal drainage, fatigue,
post-nasal drainage, nasal obstruction, and facial pressure. Physical findings
are erythema and/or edema of the middle meatus by nasal endoscopy, disco-
lored nasal drainage or polyps, and/or abnormal findings on CT or plain
sinus radiographs (3). The criteria not only rely on the duration of symptoms,
but also on the objective evidence of inflammation within the sinonasal pas-
sages. Inflammation can be brought on by a variety of inciting factors.

INCITING FACTORS IN SINUSITIS

The most common causes of acute rhinosinusitis are preceding viral upper
respiratory tract infections and inhalant allergies (4). Both of these inciting
factors result in nasal mucosal edema and resultant blockage of the ostiomeatal
complex, a functional area in which the anterior ethmoid, frontal, and maxi-
llary sinuses drain. This physical obstruction may lead to hypo-oxygenation
of the sinuses and impairment of the mucosal ciliary function. This results in
a stasis of secretions that serves as an ideal environment for bacterial invasion.

The distinction between acute and chronic sinusitis is made on the
length of symptoms and signs of inflammation. The exact etiology behind
CRS is yet unknown, but potential theories have ranged from inadequately
treated acute bacterial infections to native fungus (5) and/or superantigens
of colonizing bacteria (6). Regardless of cause, the final common pathway
is impaired clearance of secretions, damage to the mucosal lining with resul-
tant fibrosis and thickening of the lamina propria (7), and marked tissue eosi-
nophilia (8). Eosinophilic inflammation results in activation of damaging
cytokines and factors to the mucosa, and may result in an end pathway of
nasal polyps and hypertrophic mucosa. A cycle then develops, as greater
mucosal edema and obstruction lead to stasis of secretions and a greater
growth of bacteria, which in turn can perpetuate the inflammatory response.

To break this cycle of infection and inflammation, the ideal medical
management is made by a combination of therapies aimed at reducing muco-
sal inflammation, promoting drainage of the sinuses and the release of secre-
tions, and eradicating the inciting bacterial and/or fungal organisms.

ANTIMICROBIAL THERAPY

The organisms recovered from chronically inflamed sinuses are different
from those of acute infections. While Streptococcus pneumoniae and

Chronic Rhinosinusitis 221

Haemophilus influenzae are the most common isolates in acute sinusitis
(9,10), polymicrobial flora are present in CRS, which includes both aerobic
and anaerobic bacteria. The predominant aerobic isolates include Staphylo-
coccus aureus, coagulase-negative staphylococci, and aerobic gram-negative
bacteria such as Pseudomonas aeruginosa and Stenotrophomonas maltophilia.

Anaerobic bacteria also play a prominent role in CRS. The recovery of
these organisms depends on utilization of appropriate methods for their iso-
lation. Although anaerobes are generally isolated from only 10% of patients
with acute sinusitis, they can be isolated from up to 67% of patients with
chronic infection (11). The predominant species include anaerobic gram-
negative bacilli (e.g., Bacteroides, Prevotella, and Porpyromonas spp.) anaero-
bic gram-positive cocci {Pep to streptococcus spp.), and Fuso bacterium spp. (4).

Many of these aerobic and anaerobic isolates can produce the enzyme
P-lactamase (12), which makes the choice of antimicrobial therapy more
difficult.

The choice of antibiotics should be made based, whenever possible, on
the results of appropriate cultures that led to the recovery of isolates. Sus-
ceptibility testing of these organisms should guide the clinician in the choice
of antibiotics.

Sample collection sites include the middle meatus and the sphenoeth-
moidal recess. The maxillary antral tap and lavage are the recognized gold
standards for obtaining cultures. However, this is an invasive procedure.
Recent studies have shown that endoscopically directed culture swabs and
suction aspirators can lead to comparable results (13,14).

However, it is not always possible to obtain a culture using this
method, as patients may not present with visible purulence. In these cases,
an empirical therapy is chosen.

Empirical antibiotics used for CRS should cover the most common
aerobic and anaerobic bacterial organisms found in this condition. Treat-
ment against both aerobic and anaerobic bacteria was shown to be superior
to treatment against aerobes alone (14). Examples of proper empiric antibio-
tics include the combination of a penicillin- and a P-lactamase inhibitor
(e.g., clavulanic acid), clindamycin, the combination of metronidazole and
a macrolide, or a quinolone also effective against anaerobic bacteria (e.g.,
moxifloxacin) (see Chap. 9 by Brook) (15).

ANTIMICROBIAL AGENTS

The common ^-lactams currently available are the penicillins and the cepha-
losporins. They are time-dependent, and obtaining a concentration above
the MIC into the site of infection for greater than 40% to 50% of the time
ensures the highest degree of bacterial death (16). These antibiotics are com-
monly used in the treatment of acute sinusitis, where they have excellent
activity against penicillin-susceptible S. pneumoniae. In CRS, however, there

222 Chiu and Becker

is a high incidence of multiple drug-resistant S. pneumoniae and (3-lactamase-
producing aerobes and anaerobes. For this reason, amoxicillin in combina-
tion with a (3-lactamase inhibitor (clavulanate) enhances the activity of
amoxicillin against these organisms.

Second-generation cephalosporins have moderate efficacy against
intermediate-level penicillin-resistant pneumococci as well as H. influenzae.
Their use in CRS is limited given their relative lack of activity against aero-
bic and anaerobic gram-negative organisms.

Among the fluoroquinolones, ciprofloxacin is used in CRS to treat aero-
bic gram-negative organisms including Pseudomonas spp. Newer agents, such
as gatifloxacin, moxifloxacin, and gemifloxacin, have activity against gram-
positive and -negative aerobic bacteria as well as some oral anaerobes. The
activity of these antibiotics is concentration-dependent, and they are also used
in for topical preparations.

An effective combination in patients with CRS and osteitic sinonasal
bone, effective against the polymicrobial flora, is clindamycin plus trimetho-
prim-sulfamethoxazole or a third-generation cephalosporin (i.e., cefixime).
Clindamycin has good bone penetration, and is effective against resistant
strains of S. pneumoniae and (3-lactam-resistant anaerobes; trimethoprim-
sulfamethoxazole cefixime are active against aerobic gram-negative organisms.

Macrolides (i.e., erythromycin, clarithromycin, and azithromycin) and
ketolides (e.g., telithromycin) have limited antibacterial use in CRS. There
is increasing resistance to the macrolides by S. pneumoniae and S. aureus,
and both classes have little activity against gram-negative enteric aerobes
and anaerobes. Despite their limited antimicrobial activity, the macrolides
may have a role in the treatment of the inflammatory aspects in CRS.

In vitro studies have shown that macrolides decrease the levels of inflam-
matory cytokines IL-5, IL-8, and G-CSF and have compared their in vitro
effects with that of prednisolone (17). Clinical studies of long-term, low-dose
macrolide therapy following endoscopic sinus surgery, which is typically one-
half of the doses used for antibacterial effect, have shown subjective and objec-
tive improvement as compared to controls (18). More clinical studies are
needed, but long-term macrolide therapy may be a well-tolerated anti-inflam-
matory therapy that can be used to limit the use of steroids in the treatment of
CRS. One concern regarding the use of long-term macrolide therapy is the
possible selection of antimicrobial resistance to this, as well as other classes
of antibiotics.

ANTI-INFLAMMATORY AGENTS

Long-term, low-dose macrolide therapy represents one attempt at control-
ling the inflammation associated with CRS. Agents that possess anti-
inflammatory properties that are well-tolerated are sought to help ease the
reliance on systemic corticosteroids.

Chronic Rhinosinusitis 223

Corticosteroids are powerful anti-inflammatory agents that affect both
the number and function of inflammatory cells. When given systemically,
they reduce circulation of basophil, eosinophil, and monocyte counts to
20% of normal (19). They have multiple effects on the inflammatory
response in CRS. They inhibit the secretion of growth factors and mediators
of inflammatory cell proliferation, the release of arachidonic acid metabo-
lites, the accumulation of neutrophils in the affected tissues, decrease vascu-
lar permeability, and thin mucus by inhibiting glycoprotein secretion from
submucosal glands (20).

When used in a topical form, nasal steroid sprays have been shown to
be safe and effective in alleviating the symptoms of allergic rhinitis (21).
Their use in patients with CRS is important in decreasing the size of nasal
polyps and diminishing sinomucosal edema (22). There are no set guidelines
for the duration of their use, and side effects from long-term use are
unknown. Anecdotally, patients with allergic rhinitis and nasal polyps use
steroid sprays for many years with little side effects.

Studies involving the use of oral steroids in the treatment of CRS were
not done frequently. These agents represent some of our most effective medi-
cations, as they have been shown to decrease the size of nasal polyps, diminish
mucosal edema, and promote drainage of obstructed sinus ostia (23,24). Some
patients with significant and recurrent polyps are maintained on a daily dose
of systemic steroids. This can be deleterious to the patients' overall health
because of significant side effects. Prolonged oral steroid use may result in
muscle wasting and osteoporosis. Bone density scans should be considered
in patients on long-term therapy. Extended use may also result in hyperten-
sion, redistribution of body fat stores, and may even induce long-lasting sup-
pression of ACTH production, which can result in anterior pituitary and
adrenal cortical atrophy. Because of these harmful side effects, steroids are
tapered and given in short courses that may span three to four weeks.

Short-term side effects include water retention, mood shifts, and an
increase in energy, which may result in sleep deprivation. When treating a bout
of CRS, patients are often given a tapering dose of prednisone over a three-
week period. It is imperative that the treating physician warn the patient of
the potential short- and long-term side effects, and some have even resorted
to having patients sign an informed consent form prior to the medical therapy.

ADJUNCTIVE THERAPY

As stated previously, the medical management of CRS rarely depends on a
single medication. In many cases, multiple agents with different mechanisms
of action are given in hopes of ultimately promoting drainage of secretions
and improved oxygenation to obstructed sinus ostia.

One such medication is a decongestant. Decongestants are a-adrenergic
agonists that act to constrict capacitance vessels and decrease mucosal

224 Chiu and Becker

edema. Topical therapy such as oxymetazoline or neosynephrine may be used
in an acute setting, but overuse will result in a rebound effect and rhinitis
medicamentosa. Systemic decongestants can be used for longer periods of
time, but may cause side effects of insomnia and may exacerbate underlying
systemic hypertension (25).

Antihistamines are used in common therapy for patients with underlying
allergic rhinitis, but their use in patients without atopy may cause more harm
than good. They effectively relieve symptoms of itching, rhinorrhea, and sneez-
ing in allergic patients, but in nonallergic patients may result in thickening of
secretions, which may prevent the needed drainage of the sinus ostia.

A well-tolerated medication that thins secretions to facilitate drainage
is a high-dose guaifenesin (glyceryl guaicolate). Given a daily dose of
2400 mg, patients may experience less nasal congestion and thinner post-
nasal drainage (26).

Nasal saline irrigations are also helpful in thinning secretions and may
provide a mild benefit in nasal congestion. Although poorly studied, hyper-
tonic saline irrigations have been found to improve patient comfort and
quality of life, decrease medication use, and diminish the need for surgical
therapy (27,28). This can be done with a 60 cc syringe that is cleaned once
a week with rubbing alcohol and replaced every month to help limit the
chances of contamination and reinfection. There are a number of commer-
cially available delivery methods, including the water pik device and the
netty pot. Nasal irrigations can be used for the duration of symptoms and
also as a daily prophylactic measure in those who suffer from recurrent sinus
infections and allergic symptoms.

Leukotriene inhibitors are systemic medications that block the receptor
and/or production of leukotrienes, potent lipid mediators that increase
eosinophil recruitment, goblet cell production, mucosal edema, and airway
remodeling. Their use in asthma has been well-documented (29), and the
class of medications has been recently approved for the use in allergic rhini-
tis. Their role in CRS and nasal polyposis is much less clear. One case series
documents improved subjective and objective results in patients with nasal
polyposis on anti-leukotrienes (30), but these studies must be better con-
trolled before a judgment can be made on their utility in the management
of CRS and nasal polyposis.

MAXIMAL MEDICAL THERAPY FOR CRS

The definition of maximal medical therapy is not universal. The various medi-
cations used, timing, and doses may vary between practitioners and across the
various specialties that treat this illness. The aim of maximal medical therapy
is, however, uniform to promote drainage of obstructed sinus ostia and
stagnant secretions, decrease mucosal edema, and eliminate inciting bacteria
and/or fungus.

Chronic Rhinosinusitis 225

Table 1 Maximal Medical Therapy for Chronic Sinusitis

Broad-spectrum antibiotic — preferably based on a culture of the middle meatus

Oral prednisone — starting at 60 mg/day and tapered down over three weeks

Nasal hypertonic saline irrigations

Nasal steroid spray

Oral or nasal antihistamine spray if patient has preceding allergic rhinitis

Mucolytic, i.e., guaifenesin

When treating CRS, a CT scan and nasal endoscopy are extremely
useful in the initial patient encounter. Pretreatment objective findings of
mucosal edema radiographically and/or purulent secretions, and mucosal
edema can be used as a baseline to gauge improvement. Quality of life ques-
tionnaires, such as the RSOM-3 1 form or SNOT-20, are also helpful in docu-
menting subjective improvement through the course of therapy.

Once the diagnosis of CRS is made, the treatment regimen consists of a
prolonged course of a broad-spectrum antibiotic, oral steroid, nasal saline irri-
gations, and nasal steroids sprays plus/minus nasal antihistamine sprays based
on evidence of atopy (Table 1). The choice of antibiotic is best made with the
aid of an endoscopically guided culture of the middle meatus. If one is not
attainable, a broad-spectrum antibiotic that covers aerobic gram-positive
and -negative bacteria and anaerobes should be chosen. The exact duration
of therapy varies, but most preferred to treat with an initial three-week course,
with an additional three weeks of therapy for sub-optimal patient response.

The course of antibiotics can be accompanied by a three- week tapering
course of oral steroids. A healthy patient is started with 60 mg of prednisone
a day for four days, followed by 50 mg a day for four days, 40 mg a day for
four days, 30 mg a day for three days, 20 mg a day for three days, and then
finally lOmg a day for three days. During this time period, the patients con-
tinues to flush out their nose twice a day with hypertonic saline irrigations
and nasal steroid sprays. Other adjunctive methods as outlined above may
be tailored to each individual.

After the initial three-week therapy, a repeat CT scan and nasal endo-
scopy is performed. If there is improvement but still significant findings of
sinusitis radiographically or endoscopically, an additional three weeks of
antibiotics may be prescribed. After this, if the patient still has subjective
symptoms and objective findings of sinusitis, the option of endoscopic sinus
surgery is considered.

INFECTIONS FOLLOWING FUNCTIONAL ENDOSCOPIC
SINUS SURGERY

Episodes of rhinosinusitis following functional endoscopic sinus surgery
have a slightly different microbiology profile, but are open to more options

226 Chiu and Becker

Table 2 Alternatives to Oral Antibiotics in the Treatment
of Sinusitis in Previously Operated Patients

Topical antibiotic irrigations
Nebulized antibiotics
Intravenous antibiotics

for medical treatments. Endoscopic cultures are more easily obtained in open
sinus cavities. This is important in the medical management of these patients,
since there is a higher incidence of recovery of aerobic gram-negative organ-
isms and S. aureus from patients who have had previous surgery compared to
non-operated patients (31). Because of the high prevalence of these potentially
antimicrobial-resistant organisms, empirical treatment of bacterial infections
in these patients is not advised. Endoscopic-directed cultures should be
obtained, and antibiotic coverage should be tailored to the corresponding
sensitivities. Rigid nasal endoscopy can be used to direct a cultured swab or
leukens trap to collect mucus directly from the involved maxillary or ethmoid
sinus cavities. Studies have shown equal sensitivity between the different
methods of culture collection and near- equivalence to the maxillary antral
tap (13,14).

Open sinus cavities are not only easier to culture, but they are also
more accessible to topical medications. New alternatives in delivery methods
of antibiotics and anti-inflammatory medications have been employed to
directly administer powerful medications to diseased mucosa, and at the
same time limit the systemic distribution and potential side effects (Table 2).
These methods were ineffective in delivering medicine to the non-operated
sinuses (32), but hold promise in those patients who have cavities that are
widely exposed and easily accessible.

NEBULIZED MEDICATIONS

Nebulized medications have long been known to be an effective delivery
mechanism in management of lower respiratory tract infections (33,34).
Recently, this delivery method is being used to treat acute exacerbations
of CRS in previously operated patients. Intravenous antibiotics are com-
pounded to a nebulized form and delivered to the sinus mucosa through
an aerosilezed machine. The choice of the nebulized antibiotic should be
based on the results of a culture. Studies have shown an increase in disease-
free intervals and greater 75% response over a 12-week follow-up period (35).
Other medications, such as betamethasone, have been tried in an attempt
to deliver a strong course of steroids topically and spare the patient from
the harmful systemic side effects.

Chronic Rhinosinusitis 227

TOPICAL ANTIBIOTIC IRRIGATIONS

Topical preparations share a similar principle as the nebulized medications
in that they represent an attempt to deliver intravenous preparations of anti-
biotics in a topical form directly to the diseased mucosa. Although these
preparations are in widespread use, their use has not yet been well documen-
ted in the medical literature. Many of the commonly used preparations are
directed at aerobic gram-negative organisms commonly seen in patients
who have undergone previous surgery. Ceftazadime (36), gentamicin, and
tobramycin are examples.

Tobramycin preparations have specifically been used in cystic fibrosis
patients awaiting lung transplantation. The sinus and respiratory mucosa of
these patients are frequently colonized with Pseudomonas. Transplant pro-
grams have used antibiotic irrigations as a preventive measure against colo-
nization with Pseudomonas in patients awaiting a lung transplant (37).
Studies examining the use of tobramycin irrigations in children with cystic
fibrosis have shown a significant decrease in revision sinus procedures and
polyp reformation (38).

Topical irrigations aimed at the treatment of S. aureus sinus infections
have their foundation in the vascular access literature. Methicillin-resistant
S. aureus has been increasingly recovered from infected sinuses following sinus
surgery. Mupirocin and betadine nasal irrigations are often being utilized in an
attempt to treat these patients without using intravenous antibiotics.

In addition to topical antibiotics, there are also other medications that
have been used in a topical preparation in the treatment of CRS and nasal
polyps. One case series demonstrated a decrease in the incidence of post-surgical
recurrences of nasal polyps following the topical use of a diuretic (furosemide)
(39). Antifungals are also used in a nasal irrigation. Amphotericin B has been
shown in two prospective, non-controlled trials to decrease nasal polyps. These
studies have a limited follow-up, but have shown the irrigations to be well toler-
ated and have demonstrated good subjective and objective results (40,41). Even
though many of these studies were not randomized or compared to a control
group, they show potential for the management of the difficult-to-treat patients,
where the other options are much more invasive (i.e., intravenous antibiotics
and/or revision surgery).

INTRAVENOUS ANTIBIOTICS

The use of intravenous antibiotics in the treatment of CRS has been tradi-
tionally reserved for orbital and/or intracranial complications of the disease
process. Their use has been well-documented in the management of pediatric
sinusitis as an alternative to sinus surgery, as well as the treatment of pedia-
tric orbital complications from ethmoid sinusitis (42,43). Antibiotics that
cross the blood-brain barrier are used in conjunction with surgical therapy

228 Chiu and Becker

in the management of epidural collections stemming from frontal sinusitis,
and in the management of a Pott's puffy tumor or osteomyelitis of the fron-
tal bone following an acute frontal sinus infection. At least a three-week
course of a culture-based parenteral antibiotic is given. When indicated, this
is followed, by an additional course of oral therapy to complete a total six
weeks, of therapy. If a culture is unavailable, broad-spectrum antibiotics such
as a combination of clindamycin or metronidazole with a fourth generation
cephalosporin (cefepime or ceftazidime) or single therapy with a carbapenem
(i.e., imipenem, meropenem) provide coverage for both anaerobes and aero-
bes. There are some who are advocating the use of intravenous antibiotics
in patients with CRS for patients who have either had unsuccessful surgery,
or who have refused surgery, and base their rationale on comparing the disease
process of this condition to that of osteomyelitis (44).

There is both clinical and experimental evidence to suggest that the bone
underlying the diseased sinus mucosa is involved in CRS. In experimentally
induced sinusitis with P. aeruginosa using an animal model, Bolger et al. (45)
demonstrated bone changes as early as four days after infection of a maxillary
sinus. These changes included a coordinated osteoclasis and appositional bone
formation adjacent to the sinus, as well as subsequent intramembranous bone
formation.

Clinical experience with computed tomography and nasal endoscopy
has shown bone to undergo resorption followed by subsequent hyperostosis.
In addition, studies have shown that ethmoid bone underwent rapid remo-
deling in CRS that was histologically identical to the remodeling seen in
osteomyelitis (46).

Follow-up studies have demonstrated that rabbits inoculated with bac-
terial organisms develop CRS and have histological evidence of chronic
osteomyelitis (47,48). It appears that inflammation spreads through widened
Haversian canal system within the bone and can spread to involve the oppo-
site side. This may help to explain the recalcitrance of severe CRS to medical
and surgical therapy, and the clinical observation for tendency of disease
persistence in localized areas until the underlying bone is removed.

The translation of this research to clinical use where intravenous
antimicrobial therapy was given to patients with CRS has not been as
persuasive. The studies published so far have largely been uncontrolled,
non-randomized case series of a limited number of patients. The majority
of indications are for recalcitrant infections resistant to oral antibiotics.
The efficacy of the treatment varies among the studies (29-89%), but they
are uniform in their relative high rate of complications (14-26%) (49,50)
and have resulted in a relapse rate of 89% at a mean follow-up of 1 1.5 weeks
in one study (51). They range from the benign, such as diarrhea, to the
serious and life-threatening, such as septic thrombophlebitis and neutro-
penia (52). Until more studies are performed, intravenous antibiotic use
should be reserved for those select cases in which orbital and/or intracranial

Chronic Rhinosinusitis 229

complications arise, or in a chronic infection in which there are no other oral
antibiotic alternatives.

ASPIRIN DESENSITIZATION

The classic Samter's triad consists of nasal polyps, asthma, and sensitivity to
aspirin or NSAIDS that exacerbates the above conditions. Recognition of
this disease is not always easily made, since there can be a lag time between
presentation of the components of the triad. Studies of these patients have
shown that an increase in serum leukotrienes with response to aspirin
(ASA) provocation that has a direct result in eosinophil recruitment with
subsequent polyp formation and airway remodeling. Clinically, these
patients are difficult-to-treat, and do relatively poorly following surgery as
compared to non-ASA sensitive patients.

ASA desensitization is the slow introduction of aspirin in a controlled,
monitored setting. In vitro studies have shown a subsequent decrease in
serum leukotrienes to normal levels one year following aspirin desensitiza-
tion (53). Clinical studies have shown significant reductions in prednisone
requirements, polyp reformation, and improvement in pulmonary function
in follow-up as long as six years (54). Patients are often asked to take 650 mg
twice a day for improved nasal breathing, but only 8 1 mg is required to
maintain a desensitized state.

CONCLUSION

The recognition of CRS as a disease of both inflammation and infection is
the first key step in its medical management. There are multiple choices of
antibiotics and anti-inflammatory agents, and a combination of both is
needed for an extended period of time. Infections following sinus surgery
are even more difficult to treat, and antibiotic coverage should be based
on an endoscopically guided culture. There are currently more alternatives
to conventional therapy in these patients in which medications can be
applied topically to the diseased mucosa.

REFERENCES

1. Benninger MS, Holzer SE, Lau J. Diagnosis and treatment of uncomplicated
acute bacterial rhinosinusitis: summary of the Agency for Health Care Policy
and Research evidence-based report. Otolaryngol Head Neck Surg 2000;
122:1-7.

2. Senior B, Glaze C, Benninger MS. Use of the rhinosinusitis disability index in
rhinologic disease. Am J Rhinol 2001; 15:15-20.

3. Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis:
definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head
Neck Surg 2003; 129:S1-S32.

230 Chiu and Becker

4. Taghizadeh F, Hadley J A, Osguthorpe JD. Pharmacological treatments for rhi-
nosinusitis. Expert Opin 2002; 3:305-313.

5. Ponikau JU, Sherris DA, Kern EB, et al. The diagnosis and incidence of allergic
fungal sinusitis. Mayo Clin Proc 1999; 74:877-884.

6. Bernstein JM, Ballow M, Schlievert PM, et al. A superantigen hypothesis for
the pathogenesis of chronic hyperplastic sinusitis with massive nasal polyposis.
Am J Rhinol 2003; 17:321-326.

7. Bolger WE, Leonard D, Dick EJ, et al. Gram negative sinusitis: a bacteriologic
and histologic study in rabbits. Am J Rhinol 1997; 11:15-25.

8. Kaliner MA, Osguthorpe JD, Fireman P, et al. Sinusitis: bench to bedside. Current
findings, future directions. Otolaryngol Head Neck Surg 1997; 1 16:S1— S20.

9. Gwaltney JM. Acute community-acquired sinusitis. Clin Infect Dis 1996; 23:
1209-1225.

10. Brook I. Microbiology and management of sinusitis. J Otolaryngol 1996;
25:249-256.

11. Finegold SM, Flynn MJ, Rose FV, et al. Bacteriologic findings associated with
chronic maxillary sinusitis in adults. Clin Infect Dis 2002; 35:428-433.

12. Brook I, Yocum P, Frazier EH. Bacteriology and [^-lactamase activity in acute
and chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1996;
122:418^122.

13. Nadel DM, Lanza DC, Kennedy DW. Endoscopically guided cultures in
chronic sinusitis. Am J Rhinol 1998; 12:233-241.

14. Brook I, Frazier EH, Foote PA. Microbiology of chronic maxillary sinusitis:
comparison between specimens obtained by sinus endoscopy and by surgical
drainage. J Med Microbiol 1997; 46:430-432.

15. Brook I, Thompson DH, Frazier EH. Microbiology and management of chronic
maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1994; 120:1317-1320.

16. Brook I. Microbiology and antimicrobial management of sinusitis. Otolaryngol
Clin North Am 2004; 37:253-266.

17. Brook I, Yocum P. Antimicrobial management of chronic sinusitis in children.
J Laryngol Otol 1995; 109:1159-1162.

18. Wallwork B, Coman W, Feron F, et al. Clarithromycin and prednisolone
inhibit cytokine production in chronic rhinosinusitis. Laryngoscope 2002;
112:1827-1830.

19. Moriyama H, Yanagi K, Ohtori N, et al. Evaluation of endoscopic sinus
surgery for chronic sinusitis: post-operative erythromycin therapy. Rhinology
1995; 33:166-170.

20. Clerico DM. Medical treatment of chronic sinus disease. In: Diseases of the
Sinuses. London: BC Dekker, 2001.

21. Schleimer RP. Glucocorticoids: their mechanism of action and use in allergic
diseases. Allergy: Principles and Practice. Mosby 2003; 912-914.

22. Nuutinen J, Ruoppi P, Suonpaa J. One dose beclomethasone dipropionate
aerosol in the treatment of seasonal allergic rhinitis. A preliminary report.
Rhinology 1987; 25:121-127.

23. Chalton R, Mackay I, Wilson R, Cole P. Double blind placebo controlled trial
of betamethasone nasal drops for nasal polyposis. Br Med J Clin Res Educ
1985; 291:788.

Chronic Rhinosinusitis 231

24. Mygand N. Effects of corticosteroid therapy in non-allergic rhinosinusitis. Acta
Otolaryngol 1996; 116:164-166.

25. Damm M, Jungehulsing M, Eckel HE, et al. Effects of systemic steroid treat-
ment in chronic polypoid rhinosinusitis evaluated with magnetic resonance
imaging. Otolaryngol Head Neck Surg 1999; 120:517-523.

26. Radack K, Deck CC. Are oral decongestants safe in hypertension? An evalua-
tion of the evidence and a framework for assessing clinical trials. Ann Allergy
1986; 56:396-401.

27. Wawrose SF, Tami TA, Amoils CP. The role of guaifenesin in the treatment of
sinonasal disease in patients infected with the human immunodeficiency virus
(HIV). Laryngoscope 1992; 102:1225-1228.

28. Brown SL, Graham SG. Nasal irrigations: good or bad? Curr Opin Otolaryn-
gol Head Neck Surg 2004; 12:9-13.

29. Rabago D, Zgierska A, Mundt M, et al. Efficacy of daily hypertonic saline
nasal irrigation among patients with sinusitis: a randomized controlled trial.
J Fam Pract 2002; 51:1049-1055.

30. Riccioni G, Santilli F, D'Orazio F. The role of anti-leukotrienes in the treat-
ment of asthma. Int J Immunopathol Pharmacol 2002; 15:171-182.

31 . Parnes SM, Chuma AV. Acute effects on anti-leukotrienes on sinonasal polypo-
sis and sinusitis. Ear Nose Throat J 2000; 79:18-20.

32. Nadel DM, Lanza DC, Kennedy DW. Endoscopically guided cultures in
chronic sinusitis. Am J Rhinol 1998; 12:233-241.

33. Kobayashi T, Baba S. Topical use of antibiotics for chronic sinusitis. Rhinol
Suppl 1992; 14:477-481.

34. Klepser ME. Role of nebulized antibiotics for the treatment of respiratory
infections. Curr Opin Infect Dis 2004; 17:109-112.

35. Cole PJ. The role of nebulized antibiotics in treating serious resp infections.
J Chemother 2001; 13:354-362.

36. Vaughan WC, Carvalho GC. Use of nebulized antibiotics for acute infections in
chronic sinusitis. Otolaryngol Head Neck Surg 2002; 127:558-568.

37. Leonard DW, Bolger WE. Topical antibiotic therapy for recalcitrant sinusitis.
Laryngoscope 1999; 109:668-670.

38. Davidson TM, Murphy C, Mitchell M, et al. Management of chronic sinusitis
in cystic fibrosis. Laryngoscope 1995; 105:354-358.

39. Moss RB, King VV. Management of sinusitis in cystic fibrosis by endoscopic
surgery and serial antimicrobial lavage. Reduction in recurrence requiring
surgery. Arch Otolaryngol Head Neck Surg 1995; 121:566-572.

40. Passali D, Mezzedimi C, Passali GC, et al. Efficacy of inhalation form of
furosemide to prevent postsurgical relapses of rhinosinusal polyposis. J Otorhi-
nolaryngol Rel Spec 2000; 62:307-310.

41. Ricchetti A, Landis BN, Maffioli A, et al. Effect of anti-fungal nasal lavage
with amphotericin B on nasal polyposis. J Laryngol Otol 2002; 1 16(4):261— 263.

42. Ponikau JU, Sherris DA, Kita H, Kern EB. Intranasal antifungal treatment in 51
patients with chronic rhinosinusitis. J Allergy Clin Immunol 2002; 1 10(6): 862-866.

43. Buchaman CA, Yellon RF, Bluestone CD. Alternative to endoscopic sinus
surgery in the management of pediatric chronic rhinosinusitis refractory to oral
antimicrobial therapy. Otolaryngol Head Neck Surg 1999; 120:219-224.

232 Chiu and Becker

44. Sobol SE, Marchand J, Tewfik TL. Orbital complications of sinusitis in
children. J Otolaryngol 2002; 31:131-136.

45. Anand V, Levine H, Friedman M, et al. Intravenous antibiotics for refractory
rhinosinusitis in nonsurgical patients: preliminary findings of a prospective
study. Am J Rhinol 2003; 17:363-368.

46. Bolger WE, Leonard D, Dick EJ, et al. Gram negative sinusitis: a bacteriologic
and histologic study in rabbits. Am J Rhinol 1997; 11:15-25.

47. Hwang P, Montone KT, Gannon FH, et al. Applications of in situ hybridiza-
tion techniques in the diagnosis of chronic sinusitis. Am J Rhinol 1999; 13:
335-338.

48. Khalid AN, Hunt J, Perloff JR, Kennedy DW. The role of bone in chronic
rhinosinusitis. Laryngoscope 2002; 112(11): 195 1-1957.

49. Perloff JR, Gannon FH, Bolger WE, et al. Bone involvement in sinusitis: an
apparent pathway for the spread of disease. Laryngoscope 2000; 1 10:2095-2099.

50. Don DM, Yellon FR, Casselbrant ML, et al. Efficacy of a stepwise protocol
that includes intravenous antibiotic therapy for the management of chronic
sinusitis in children and adolescents. Arch Otolaryngol Head Neck Surg
2001; 127:1093-1098.

51. Gross ND, Mclnnes RJ, Hwang PH. Outpatient intravenous antibiotics for
chronic rhinosinusitis. Laryngoscope 2002; 112:1758-1761.

52. Fowler KC, Duncavage JA, Murray JJ, et al. Chronic sinusitis and intravenous
antibiotic therapy: resolution, recurrent and adverse events. J Allergy Clin
Immunol 2003; lll:s85.

53. Tanner SB, Fowler KC. Intravenous antibiotics for chronic rhinosinusitis: are
they effective? Curr Opin Otolaryngol Head Neck Surg 2004; 12:3-8.

54. Gosepath J, Schaefer D, Amedee RG, et al. Individual monitoring of aspirin
desensitization. Arch Otolaryngol Head Neck Surg 2001; 127:316-321.

55. Stevenson DD, Hankammer MA, Mathison DA, et al. Aspirin densensitization
treatment of aspirin sensitive patients with rhinosinusitis-asthma: long-term
outcomes. J Allergy Clin Immunol 1996; 98:751-758.

Surgical Management

David Lewis

Department of Otolaryngology, Harvard Medical School,
Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.

Nicolas Y. Busaba

Department of Otolaryngology, Harvard Medical School, VA Boston Healthcare
System, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.

INTRODUCTION

The surgical treatment of sinus disease has changed dramatically over the
past 20 years in the United States and nearly 30 years in Europe. In the past,
otolaryngologists relied on using the nasal speculum and a headlight to diag-
nose and treat diseases of the nasal cavity and paranasal sinuses. Such an
examination only allowed for viewing of the anterior components of the
nose, and the observer was unable to adequately view the paranasal sinuses
or their ostia. For improved visualization and more thorough treatment,
open approaches were the only option. There has also been a conceptual
shift away from attempting to surgically exenterate the disease within the
paranasal sinuses to simply opening specific areas in order to improve sinus
function and allow better aeration and drainage. The amount of tissue
removed during sinus surgery is minimized now, and the surgeon relies on
opening key functional areas to restore the normal physiology within the
paranasal sinuses, which thereby helps to reverse the disease.

Since the introduction of nasal endoscopes, the diagnosis and the
treatment of sinus disease have changed remarkably. One now has the abil-
ity to view the anatomy of the nasal cavity, and at times, the paranasal

233

234

Lewis and Busaba

Figure 1 Light source and three 4-mm diameter rigid endoscopes. The endoscopes
have a zero, 30-degree, and 70-degree viewing angles.

sinuses themselves, up close and with remarkable detail (Fig. 1). Nasal endo-
scopes use fiberoptic light cables to transmit light into the nose. Special
optical lenses are used for improved viewing. There are both flexible and
rigid endoscopes; the latter are available in many different angled optics
systems. These scopes allow for excellent visualization of the entire nasal
cavity, both in the office and in the operating room, and all of the key para-
nasal sinus ostia that are involved in sinus disease. The cameras attach to the
eyepiece of the endoscope, allow for easy viewing on a television monitor,
and also offer the added advantage of using endoscopes for video recording
to demonstrate anatomy and pathology to patients in the office, and for
teaching purposes.

DIAGNOSTIC WORK-UP

Medical History

When a patient with sinus complaints is referred to the otolaryngologist, the
evaluation always begins with a thorough history followed by a careful
examination of the nose. (Please refer to the chapter on Clinical Presenta-
tion and Diagnosis for a more detailed review on the evaluation of a patient
with sinus disease). The patient should be asked about symptoms of facial
pain or pressure over individual sinuses, headache, nasal blockage, rhinor-
rhea, postnasal drip, and hyposmia (Table 1). It is very important to ask

Surgical Management 235

Table 1 Medical History

Symptoms

Facial pain or pressure

Headache

Nasal blockage

Rhinorrhea

Post-nasal drip

Hyposmia and/or hypogeusia
Previous treatment attempts

Antibiotics

Steroids

Antihistamines

Allergen avoidance

Previous sinus surgery
Past medical and surgical history
Other medications
Drug allergies
Environmental allergies

Social history including tobacco smoke exposure
Family history
Review of systems

about previous attempts at medical management. What antibiotics have
been used to treat the symptoms and for how long were they used? Did they
improve the symptoms? Is the patient a smoker or exposed to passive smoke
or other irritants? Does the patient have an allergic component to the
disease process? If so, have these issues been maximally treated medically
with antihistamines, nasal steroids, or other medications? Is the patient a
candidate for immunotherapy? Is allergen avoidance a realistic possibility
for the patient? What other comorbidities does the patient have? These
questions are important to ensure that all patients have been given the most
optimal attempt at medical management prior to making any decisions
about surgery.

Physical Examination

As part of the head and neck evaluation, a thorough nasal examination
should be completed in the office. Anterior rhinoscopy using a headlight
or mirror and a nasal speculum should be performed prior to any attempts
at nasal decongestion. Any evidence of mucopurulent discharge, nasal polyps,
enlarged turbinates, nasal septal deviation, or diseased mucosa should be
noted. Using either a rigid or flexible endoscope, one can almost always
view the middle meatus and the sphenoethmoid recess. Decongestion
and anesthesia with a sprayed mixture of 4% lidocaine with phenylephrine

236

Lewis and Busaba

Figure 2 Endoscopic view of an inflammatory polyp in the left middle meatus.

facilitates this part of the examination. The findings noted on anterior rhino-
scopy can be confirmed. Additionally, one might see limited areas of inflam-
mation, mucopurulent discharge, and/or polypoid changes that could not be
seen during the initial rhinoscopic examination (1) (Fig. 2).

Imaging

Based on the history and examination findings, a decision is made whether
or not to obtain a computed tomography (CT) scan. Noncontrast CT scans,
particularly in the coronal plane, can be very helpful both for diagnosis and
pre-operative planning if surgery is indicated. CT scans can confirm sinusi-
tis, and they can offer the surgeon valuable information about the patient's
anatomy that can be used to help avoid complications during surgery. Occa-
sionally, a CT scan can also be useful in ruling out sinus disease in a patient
with convincing sinus complaints but no evidence of disease on exam. Addi-
tionally, the CT scan has become a valuable tool in image-guided sinus
surgery (see following sections).

INDICATIONS FOR PARANASAL SINUS SURGERY

There is currently a wide range of indications for paranasal sinus surgery
(Table 2). The most common indication is for chronic rhinosinusitis (CRS).

Surgical Management 237

Table 2 Indications for Paranasal Sinus Surgery

1. Inflammatory or infectious rhinosinusitis

Chronic rhinosinusitis that failed medical therapy

Recurrent rhinosinusitis

Symptomatic nasal polyposis

Acute or chronic rhinosinusitis with periorbital or intracranial complications

Invasive fungal sinusitis

Fungus ball-mycetoma

2. Sinonasal neoplasm (benign and malignant)

3. Repair of skull base defects

CSF rhinorrhea

Menigoceles or meningoencephaloceles

4. Approach for excision of intracranial pathology

Pituitary tumors

Petrous apex cholesterol granuloma

5. Control of epistaxis

6. Orbital decompression for Graves' ophthalmopathy

7. Removal of sinus foreign bodies

8. Management of nasolacrimal duct obstruction

Patients who continue to have signs and symptoms of rhinosinusitis despite
maximal medical therapy are often candidates for sinus surgery. Maximum
medical therapy has not been standardized, but typically involves four to
six weeks of broad-spectrum oral antibiotics used in conjunction with decon-
gestants and mucolytic agents. Patients with allergies are often also given anti-
histamines and intranasal steroid sprays. Surgery may also be considered in
patients who have repeated episodes of acute rhinosinusitis that clears with
antibiotics. Although there is no agreed treatment algorithm for patients with
recurrent rhinosinusitis, many rhinologists feel that if the frequency and sever-
ity of the patient's symptoms are sufficient to interfere significantly with
school or work, then surgery is a reasonable option (2). Prior to surgery, it
is important to rule out non-sinus causes of a patient's symptoms, i.e., atypi-
cal migraines or other neurologic causes including neuralgia.

Another indication for sinus surgery is to treat patients with sympto-
matic nasal polyposis. The pathophysiology of polyp formation is poorly
understood. However, polyps are commonly associated with asthma and
environmental allergies. On the other hand, it is not unusual to diagnose
polyps in a patient without atopy or asthma. An antral-choanal polyp is
such an example. Unfortunately, medical therapy is rarely sufficient to
control nasal polyposis and surgery is often indicated. Patients should be
counseled about the high recurrence following surgery. Special attention
must be given to those patients with asthma, particularly those with
aspirin-sensitivity (Samter's triad). These patients often require preoperative
corticosteroids and maximal bronchodilator therapy to optimize their

238 Lewis and Busaba

pulmonary status. The corticosteroids may also serve to shrink the polyps
and possibly decrease their risk of recurrence. Aspirin-desensitization may
also be beneficial in these patients. It is important to note that the differen-
tial diagnosis of nasal polyps includes some benign and malignant tumors.
Hence, at the time of surgery, tissue specimens should be sent for permanent
pathology in all cases. Unilateral disease, a rubbery or fleshy, highly vascu-
lar, or ulcerative appearance, or CT evidence of bone destruction should
alert one to the possibility of a neoplasm.

In addition to the more common above-mentioned indications, sinus
surgery can be performed to treat allergic fungal sinusitis and periorbital
and intracranial complications of sinusitis; marsupialize muco(pyo)celes;
control epistaxis; remove maxillary sinus foreign bodies; repair anterior skull
base cerebrospinal fluid (CSF) leaks or meningo(encephalo)celes; decompress
the orbit in patients with Graves' ophthalmopathy; dacrocystorhinostomy;
approach and remove pituitary tumors, petrous apex cholesterol granulomas
or other skull base lesions; resect benign neoplasms (osteomas, inverting
papillomas, or fibrous dysplasia); and decompress the optic nerve (2).

CONTRAINDICATIONS FOR PARANASAL SINUS SURGERY

The only true contraindication to paranasal sinus surgery is the absence of
sinus disease. Patients with migraine headaches or other neurological causes
of facial pain should not be operated on. Additionally, surgery is not a sub-
stitute for medical management; patients with CRS, as mentioned above,
should be given maximum medical therapy prior to being offered surgery.
A bleeding disorder can place a patient at an increased risk for postoperative
hemorrhage, but does not in itself represent a contraindication to surgery.

ENDOSCOPIC (ENDONASAL) SINUS SURGERY

The techniques for performing endoscopic sinus surgery were first described
by Messerklinger during the 1970s. These techniques were later introduced
into the United States during the mid-1980s by Kennedy, who coined the
term "Functional Endoscopic Sinus Surgery" (FESS) to describe a mini-
mally invasive approach to improve drainage of the paranasal sinuses for
the treatment of CRS (3-6). Endoscopic endonasal surgery (EES) or endo-
scopic sinus surgery (ESS) are other terms commonly used to describe the
same operation and can be used interchangeably.

FESS involves opening up narrow areas within the nose and paranasal
sinuses that are responsible for the pathological changes seen in CRS.
Messerklinger studied patterns of mucociliary clearance and noted that in
narrow areas of mucosal contact, mucociliary clearance was disrupted
(6,7). When this occurs, the mucus becomes either stagnant or recirculated

Surgical Management

239

Figure 3 CT image (coronal projection) through the ostiomeatal unit (OMU).

within the affected sinus rather than freely draining into the nasal cavity
and nasopharynx. Stagnant or recirculated mucus predisposes the patient
to infection, which leads to inflammation that further impedes mucociliary
clearance, resulting in increased infection followed by more inflammation,
and then a vicious cycle ensues.

The two primary areas of narrowing that can impair mucociliary
clearance and lead to problems with CRS are the ethmoidal infundibulum
and the frontal recess. These two anatomical points of narrowing are both
located in the anterior ethmoid area within the middle meatus. Many rhinol-
ogists use the term osteomeatal complex (OMC) or osteomeatal unit (OMU)
to describe this functional area where narrowing can occur (Fig. 3). The
ethmoidal infundibulum is a three-dimensional space that is a convergence
point for mucus flowing from the anterior ethmoid air cells, the maxillary
sinus, and the frontal sinus (8). Similarly, the frontal recess is a narrow area
in which mucus from the frontal sinus must pass prior to reaching the
ethmoidal infundibulum (1,6-8). This area can be further narrowed by
projections from the most anterior of the ethmoid air cells, the agger nasi
cells (Fig. 4). FESS aims at opening up these two key areas of narrowing
to allow adequate drainage of the frontal, anterior ethmoid, and maxillary
sinuses. When widespread disease affects all paranasal sinuses, ESS can be
tailored to treat all the involved areas.

There are two primary goals of FESS. The first is to open up the
narrow areas described above. The second is to perform the surgery in as

240

Lewis and Busaba

Figure 4 CT image (coronal projection) showing a right agger nasi cell.

atraumatic a manner as possible (1,6-8). Accordingly, sinus surgeons must
remove the anatomical areas of obstruction without disturbing the sur-
rounding healthy mucosa. In order to open a narrowed ostiomeatal com-
plex, a thin piece of bone called the uncinate process is carefully removed
in its entirety. Additionally, an ethmoid air cell called the ethmoid bulla is
typically removed to allow better drainage (Fig. 3). Any further removal of
tissue is dependent on the extent of disease. Some believe that an uncinect-
omy with an ethmoid bullectomy is all that is necessary during FESS and
coined the term minimally invasive sinus technique (MIST) (9). The major-
ity of rhinologists recommend a more complete ethmoidectomy in addition
to widening of the maxillary ostium and opening of the frontal recess cells.
All agree, however, that any diseased mucosa that is not a direct component
of the osteomeatal complex should not be removed or manipulated because
this surrounding area of disease will eventually revert to normal once there
is a wide open area for drainage and aeration (8). In other words, one does
not need to strip away all of the diseased mucosa because paranasal sinus

Surgical Management

241

Frontal
Recess

Ethmoid
Sinus

Sphenoid
Sinus

Frontal
Sinus

Ethmoid
Bulla

Straight Blakes
Forceps
Inserted
\ Ihtranasally

Maxillary
Ostium

Middle
^Turbinate

Frontal
Recess

Figure 5 Schematic representation of endoscopic sinus surgery. (A) Coronal projec-
tion through the OMU. The shaded area represents the ethmoid sinus. (B) Schematic
drawing of the procedure. (C) Ethmoid sinus cavity at the end of surgery with patent
maxillary antrostomy and frontal recess. Note that the uncinate process has been
removed. Abbreviations: UP, uncinate process; MT, middle turbinate; S, septum.

mucosal pathology can be reversed by improving the ventilation and
drainage of the involved sinus (Fig. 5).

By minimizing mucosal disruption, one can minimize postoperative
scarring. This is very important because some areas of scar tissue formation
can be devoid of the respiratory epithelium required for mucociliary clearance.
If there are large areas of scar, then mucus will stagnate. Additionally, mucosal

242 Lewis and Busaba

Lateral

Nasal
1 Wall

f^k Middle

Turbinate J

Septum

Figure 6 Adhesions in a right ethmoid cavity in a patient with previous endoscopic
ethmoidectomy.

disruption with scarring often results in fibrous adhesions that can re-obstruct
the drainage of mucus resulting in recurrence of sinus disease (Fig. 6). In these
instances, a revision surgery may be required.

The role of several anatomical findings that are noted on CT or nasal
endoscopy in the pathophysiology of rhinosinusitis is controversial (10).
These include Haller cells, agger nasi cells, concha bullosa, and paradoxical
middle turbinate. A Haller cell is an ethmoidal cell that is located along the
floor of the orbit and can narrow the maxillary outflow tract (Fig. 7). An
agger nasi cell is the anterior-most cell of the ethmoid sinus and may repre-
sent pneumatization of the lacrimal bone. Agger nasi cells can narrow the
frontal recess (Fig. 4). A concha bullosa is a pneumatized middle turbinate.
When large, it can conceivably narrow the OMU (Fig. 8). A paradoxical
middle turbinate is convex along its lateral wall instead of the medial wall
(Fig. 9). Similar to a concha bullosa, a paradoxical middle turbinate can
narrow the OMU. All of the above-mentioned anatomical findings are very
prevalent and may be better labeled as anatomical variants, not anomalies.
Surgery is not indicated to treat them in the absence of clinical rhinosinusi-
tis. On the other hand, these anatomical findings need to be addressed
during ESS that is indicated to treat CRS.

The concept of OMU is valid when the pathophysiology of the CRS
is believed to be infectious. More recent theories about the pathogenesis of

Surgical Management

243

Figure 7 Bilateral Haller cells that narrowed the maxillary outflow tract as seen on
a CT scan (coronal projection).

Figure 8 Large left concha bullosa. A smaller concha bullosa can be seen on the
right side. (CT scan; coronal projection).

244

Lewis and Busaba

Figure 9 Paradoxical left middle turbinate. Note that the middle turbinate is convex
on the lateral surface.

rhinosinusitis stress the role of inflammation as the primary event, i.e.,
rhinosinusitis is primarily an inflammatory and not an infectious disease.
The inflammation is believed to be predominantly caused by the inflamma-
tory mediators that are released by eosinophils, usually in response to the
presence of fungi or other superantigens in the nose or sinus mucus (eosi-
nophilic CRS) (11,12). In such a case, the role of ESS is to reduce the
offending antigen load by allowing repeated cleaning of inspissated mucus
from the sinus cavities in the office by opening their ostia, which in turn
can reduce the inflammation. Therefore, ESS in this clinical scenario has
a complementary function, and is not a substitute to medical therapy.

The patients who undergo ESS typically are given perioperative
antibiotics. Coverage is aimed at preventing acute infection by normal flora
that has pathogenic potential, such as Staphylococcus aureus, Streptococcus
pneumoniae, Haemophilus influenzae, or alpha streptococci. A common
choice for an antibiotic would be a first-generation cephalosporin, such as
cephalexin. Other choices include clindamycin or azithromycin, the former
of which covers anaerobes as well. It should be noted that although there
are data to support the use of perioperative antibiotics for other types of
surgery, there is no proven benefit to the use of postoperative prophylactic
antibiotics after ESS (13,14).

When inflammatory rhinosinusits is complicated by chronic infection,
at least 2 weeks of culture driven antibiotics may be used perioperatively
in order to decrease intraoperative bleeding.

Surgical Management 245

The majority of ESSs can be done on an outpatient basis. The surgery
typically takes between 45 minutes and two hours to perform, depending on
the extent of surgery. Although this rarely is a painful surgery, patients are
sent home with a prescription for analgesics, which at times contain a
narcotic. However, many patients only require regular acetaminophen for
analgesia. Like in any other surgery, patients are instructed that they must
avoid aspirin and nonsteroidal anti-inflammatory medications for two weeks
prior to and at least one week after surgery. Patients can often return to work
after a couple of days; however, they are advised to avoid physical exertion for
one to two weeks. Additionally, they are instructed to avoid hot liquids and
spicy foods to prevent intranasal vasodilation that might result in epistaxis.

Postoperative care is of utmost importance. In order to prevent recur-
rence of the disease secondary to scarring, patients must return for intrana-
sal debridements on a routine basis for up to six weeks after surgery. If
intranasal packing was placed for hemostasis, it can be removed on the first
postoperative day. Any material that may have been used to stent open the
middle meatus is typically removed at the first or second office visit. If adhe-
sions are found between the middle turbinate and lateral nasal wall or re-
stenosis is noted of the maxillary antrostomy or frontal recess at any point
during routine follow up, this can often be successfully treated under local
anesthesia in the office. Additionally, irrigation is a very effective method
that patients can use at home to remove crusts and clots. Many surgeons
have their patients started on saline irrigations immediately after surgery
and continue irrigating until the healing process is complete. Using a com-
bination of nasal irrigation and in-office debridements, one can often
prevent complications that might otherwise have resulted in recurrence of
disease and the need for revision surgery (8,15).

COMPLICATIONS OF ENDOSCOPIC SINUS SURGERY

When sinus surgery is performed by experienced surgeons who have a
detailed knowledge of sinus anatomy, complications are extremely rare.
However, complications can and do occasionally occur, even with the most
seasoned of surgeons (Table 3). A small amount of bleeding is expected post-
operatively. Nasal packing, and, at times, hemostasis in the operating room
can control major bleeding. Postoperative infection is uncommon. When an
infection does occur, office debridement and an oral antibiotic which is deter-
mined by culture of the sinus cavity are usually sufficient treatment. As men-
tioned above, scarring with adhesions and restenosis of ostia can occur. If
the office-based treatments fail, then these patients may require a revision
surgery.

The paranasal sinuses are surrounded by a number of important struc-
tures, which can be potentially injured during sinus surgery. Injury to the
anterior skull base can result in a CSF leak. If this is identified during

246 Lewis and Busaba

Table 3 Complications

Bleeding

Infection

Adhesions

Restenosis

CSF leak

Periorbital hematoma

Subcutaneous emphysema

Diplopia

Blindness

Epiphora

surgery, then it can be repaired at the time of the incident. If a CSF leak is
noted postoperatively, then the patient is placed on bed rest with the head
elevated, either with or without placement of a lumbar drain depending
on the severity of the leak. These leaks may close spontaneously. Those that
do not close can be repaired via either an endoscopic or an open approach,
the latter being performed by a neurosurgeon (8,16). Injury to the medial
wall of the orbit can result in a retro-orbital hematoma, diplopia, subcuta-
neous orbital emphysema, or blindness. If the lamina papyracea and perior-
bita are entered, then blood can accumulate in the orbit. Usually this only
results in periorbital ecchymosis; however, patients must be closely moni-
tored for signs of increased intraocular pressure. An ophthalmologist should
be consulted immediately because an elevated intraocular pressure for a pro-
longed interval causes ischemia to the optic nerve, which can result in blind-
ness. Direct injury to the optic nerve along the superior-lateral wall of the
sphenoid sinus or posterior aspect of the lamina papyracea (in the region
of annulus of Zinn) can similarly cause blindness. The presence of an Onodi
cell (a posterior ethmoid air cell that is lateral and at times posterior to the
sphenoid sinus) is associated with an increased incidence of optic nerve
injury since the nerve may be dehiscent and pass through the cell. Such
an anatomic variant can be detected on a preoperative CT (Fig. 10). Blind-
ness can also rarely result from the dissection of local anesthetic containing
decongestants (epinephrine) towards the orbital apex, which can cause
spasm of the central retinal artery. Diplopia can occur if inadvertent entry
into the orbit results in injury to the medial rectus muscle or violation
of the periorbita that results in extensive herniation of intraorbital fat.
Subcutaneous orbital emphysema occurs if there is injury to the lamina
papyracea and the patient inadvertently performs a Valsalva maneuver
during vomiting, sneezing, or nose blowing, which usually resolves sponta-
neously.

Damage to the nasolacrimal duct may occur following sinus surgery,
resulting in epiphora and possibly dacrocystitis. The nasolacrimal duct runs

Surgical Management

247

Figure 10 CT (axial projection) showing a left Onodi cell (a posterior ethmoid cell
that extends lateral and at times posterior to the sphenoid sinus).

anterior to the anteromedial wall of the maxillary sinus. Hence, an aggres-
sive anterior maxillary antrostomy can accidentally damage this duct as it
travels to the inferior meatus (8,16).

Fortunately, these complications are very uncommon. However, patients
must be aware of and understand the implications of each of these complica-
tions prior to consenting to any form of sinus surgery.

IMAGE GUIDANCE SYSTEMS

The advent of image-guided sinus surgery has had a dramatic impact on
ESS. Although it is not a substitute for experience and anatomical knowl-
edge, image-guided surgery has allowed rhinologists to perform challenging
and complicated endoscopic procedures with increased confidence and pre-
cision. Image guidance systems consist of a computer workstation that dis-
plays three-dimensional images of the patient's paranasal sinuses using
information obtained from preoperative CT scans. Either an infrared or
an electromagnetic signal is used to track the position of a probe or surgical
instrument relative to the patient's head (17). Hence, a surgeon can place
the tip of an instrument on, for example, the middle turbinate, and see a

248

Lewis and Busaba

Figure 1 1 Image guidance system. Right upper, left upper, and left lower images are
sagittal, coronal, and axial projections of CT scan with the cross-hairs indicating the
position of the probe during surgery. The probe is inside the right sphenoid sinus. The
right lower image shows a simultaneous endoscopic view into the sphenoid sinus.

real-time representation of the probe in coronal, axial, and sagittal planes.
This can be done to within 2 mm of accuracy (18-20). They can, therefore,
be used to confirm certain anatomical locations that are of interest to the
surgeon, for example, the lamina papyracea, the skull base, the frontal recess,
the sphenoid sinus, or any other area accessible by the probe (Fig. 11). This is
particularly helpful in revision cases where the normal anatomical landmarks
are obscured. The major limitations to widespread use of this technology are
the increased cost and operative time that it requires (18).

MICRODEBRIDERS AND SINUS SURGERY

Mechanical debriders are becoming more and more popular in the field of
ESS. These powered instruments precisely shave tissue using an oscillating
burr connected to a suction machine (Fig. 12). When used correctly, these
mechanical microdebriders can minimize trauma to the tissues and help to

Surgical Management

249

■Hj

Figure 12 A picture of a microdebrider (Diego Microdebrider; Xomed, USA). The
insert is a magnified view of the tip of the microdebrider showing its serrated edges
("aggressive cutter"), which has a 4 mm diameter tip.

preserve normal tissue. In contrast, the use of traditional endoscopic instru-
ments can occasionally tear or strip away healthy mucosa leaving exposed
bone, which results in increased crusting and risk of scarring (21,22). The
microdebrider can remove diseased tissue quickly and efficiently, which is
particularly helpful in cases of nasal polyposis when there can be profuse
intraoperative bleeding. The main disadvantages to this technology are
the cost, the slightly increased set-up time required, and the repeated clog-
ging of the instrument by the resected tissue. Additionally, aggressive use
of a microdebrider through an iatrogenic or disease-related dehiscence of
the lamina papyracea or fovea ethmoidalis (roof of the ethmoid sinus) can
lead to injury of intraorbital or intracranial structures, respectively.

TYPES OF PARANASAL SINUS SURGERY

The type of surgery performed on a patient depends on the extent and nature
of the disease. Now that ESS has become the standard of care for the surgical
management of uncomplicated CRS, open approaches to the sinuses are uti-
lized far less often than in the past. Nonetheless, many open procedures are
still indicated in select cases. Additionally, there are instances when only a
single paranasal sinus needs to be surgically addressed. This section describes
the various surgical approaches specific to each individual paranasal sinus.

Maxillary Sinus Surgery

Antral Puncture and Lavage

This procedure takes approximately 10 minutes and can be performed under
local anesthesia via two approaches: the canine fossa or the inferior meatus.
In the first approach, a small stab incision is made in the upper gingivobuccal
sulcus and the anterior bony wall of the maxillary sinus is then entered. In

250

Lewis and Busaba

Figure 1 3 Schematic representation of the right maxillary sinus. The white rectangle
represents the area in the inferior meatus where antral puncture or inferior nasoantral
window is performed.

the latter approach, the thin bone of the medial maxillary wall is punctured
in the inferior meatus (Fig. 13). Either approach can be performed under
local anesthesia. The maxillary sinus cavity may then be aspirated and the
contents sent for microbiology. The cavity can also be irrigated (lavage) with
saline or antibiotic-containing solution. This procedure is indicated for
symptomatic relief of acute maxillary sinusitis or for obtaining a culture to
guide in the choice of an antimicrobial, usually in the ICU setting or with
immunocompromised patients. The main disadvantages are the discomfort
and the risk of bleeding.

Inferior Nasoantral Window

The technique is similar to antral puncture through the inferior meatus
(Fig. 13). However, in this instance, a wider opening is created in the medial
wall of the maxillary sinus to allow for permanent drainage and aeration.
The procedure can be performed under local or general anesthesia. This pro-
cedure can be particularly helpful in patients with congenital or acquired
ciliary dyskinesia since it provides for gravitational drainage of the maxil-
lary sinus secretions. However, there is a high incidence of stenosis or

Surgical Management 251

complete closure of the window. In addition, maxillary sinus disease may
persist despite a patent inferior nasoantral window since the mucociliary
clearance drives the mucus towards the natural ostium and that may still
be obstructed.

Endoscopic Middle Meatal Antrostomy

As mentioned earlier in this chapter, ESS has become the mainstay of sur-
gical treatment of both chronic and recurrent maxillary rhinosinusitis. In
order to gain endoscopic access to the maxillary sinus, one must surgically
remove the uncinate process in order to open up the ethmoidal infundibu-
lum. Once this is done, the natural maxillary sinus ostium can typically be
seen. This can be enlarged if necessary through the posterior fontanelle
(Fig. 14). Obstructive anatomic abnormalities, such as Haller cells, can also
be addressed. This is usually sufficient to treat the maxillary disease without
the need for stripping the maxillary sinus mucosa. Establishing adequate
aeration and drainage of the maxillary sinus by opening its natural ostium
can reverse the disease in the sinus mucosa. This technique is also utilized
to remove mycotic "fungus balls" or symptomatic mucus retention cysts,
marsupialize muco(pyo)celes of the maxillary sinus, and excise antrochoanal
polyps (23,24) (Fig. 15). In the latter cases, a 30-degree or a 70-degree rigid
endoscope is used to view the entirety of the maxillary sinus cavity to ensure
complete excision, which reduces recurrence. The main advantages in using
an endoscopic approach is that it avoids the need for an incision, it is
relatively quick, and often can be performed on an outpatient basis. The pri-
mary disadvantage is the risk of being unable to fully remove disease in the
most lateral recesses of the sinus or along its floor. This is particularly rele-
vant during excision antrochoanal polyp or maxillary sinus retention cyst
where recurrences following endoscopic approach can be up to 50% (24).
For this reason, many surgeons will often consent select patients for a Cald-
well-Luc procedure (see following section) in case an endoscopic approach
does not provide adequate exposure to sufficiently treat the disease. Clinical
failures of middle meatal antrostomy can be attributed to ciliary dyskinesia
or to its occlusion by scar tissue. Optimal postoperative care with office
endoscopic debridement in the immediate postoperative period can prevent
adhesions in the middle meatus and hence occlusion of the antrostomy.

Caldwell-Luc Procedure

The Caldwell-Luc procedure has been used for over a hundred years to gain
access to the maxillary sinus. The Caldwell-Luc procedure involves opening
up the anterior wall of the maxillary sinus through the upper gingivobuccal
sulcus. A flap of gingiva and periosteum is used to obtain access to the sinus.
Unlike the endoscopic approach, the maxillary sinus mucosa is typically
stripped and removed during a Caldwell-Luc operation. The procedure

252

Lewis and Busaba

Figure 14 (Caption on facing page)

Surgical Management

253

Figure 15 Left antrochoanal polyp. (CT image; coronal projection).

takes approximately one hour. Postoperatively, the patient may or may not
have packing in the sinus depending on the amount of bleeding during the
case. Some surgeons will apply ice to the upper lip or a pressure dressing to
minimize postoperative swelling. Prophylactic antibiotics targeted at normal
oral flora are often given perioperatively for five to seven days. Complica-
tions are relatively uncommon and include facial swelling, bleeding, and
infection. Transient, or rarely permanent, anesthesia of the upper lip and teeth
due to a stretch-on or a transection of the infraorbital nerve can occur. This
typically subsides within weeks to months in the earlier case but is perma-
nent in the latter (25). An oroantral fistula can develop from nonhealing of
the gingivobuccal sulcus incision.

Current indications for the Caldwell-Luc procedure include the
removal of mycotic "fungus balls, ' r symptomatic multiseptate mucoceles
of the maxillary sinus, antrochoanal polyps that cannot be removed in their

Figure 14 (Facing page) Endoscopic intraoperative views during right middle mea-
tal antrostomy. (A) View of the middle meatus showing the uncinate process. (B) An
incision (arrows) is made at the attachment of the uncinate process. (C) The maxil-
lary ostium (arrow) is visualized following the uncinectomy.

254 Lewis and Busaba

Table 4 Indications for Caldwell-Luc

Removal of mycotic "fungus balls"

Symptomatic multiseptate mucoceles of the maxillary sinus

Antrochoanal polyps

Biopsy and/or removal of neoplasms or other masses

Exposure to the pterygopalatine fossa (particularly for epistaxis control)

Oroantral fistula repair

entirety via ESS, and neoplasms (Table 4). Additionally, this procedure
provides excellent exposure to the pterygopalatine fossa and can be used
for closure of oroantral fistula and the biopsy of lesions within the maxillary
sinus that are suspicious for malignancy (26). A relative contraindication to
the procedure involves those pediatric patients with deciduous teeth because
entry into the sinus by this approach may damage the permanent dentition.
The advantage of this procedure is the increased exposure and access to the
maxillary sinus. The disadvantages are the potential risks listed above that
are associated with the procedure and the need for an external incision,
which increases postoperative pain. In addition, maxillary sinus mucoceles
can form several years following the procedure due to entrapment of the
sinus mucosa (27).

Ethmoid Sinus Surgery

Endoscopic Endonasal Ethmoidectomy

As previously mentioned, FESS involves opening the anterior ethmoid air
cells in order to improve aeration and drainage with the paranasal sinuses
(ostiomeatal unit). Depending on the extent of the disease, the amount of
surgery can range from opening up a single ethmoid air cell to opening every
cell. The least extensive surgery involves opening the ethmoid bulla and
removal of the uncinate process. Agger nasi cells, when present, are removed
in patients with frontal sinusitis. Penetrating the basal lamella (insertion of
the middle turbinate along the lateral nasal wall) is needed to gain access to
the posterior ethmoid cells to treat disease in that area. Healthy mucosa in
uninvolved ethmoid cells is preserved. Similarly, the middle turbinate is
commonly preserved (Fig. 5). At times, a partial anterior-inferior middle
turbinectomy is performed to reduce middle meatal adhesions and facilitate
viewing of the middle meatal antrostomy in the office.

Indications for endoscopic ethmoidectomy have been already men-
tioned earlier in this chapter. The advantages are that there is no incision
required and the patients recover quickly with minimal postoperative pain.
The potential complications of the procedure were detailed earlier in the
chapter. In addition, ethmoid mucoceles can form several years following

Surgical Management

255

Figure 16 Endoscopic view of an ethmoid mucocele (arrow) in a patient with
previous endoscopic ethmoidectomy.

the surgery, secondary to entrapment of sinus mucosa (Figs. 16 and 17) (28).
Avoiding trauma to healthy mucosa and repeated postoperative cleaning
and debridement of the ethmoid cavity can reduce the incidence of mucoceles.

External Ethmoidectomy

An external ethmoidectomy requires that a skin incision be made in order to
enter the ethmoid and therefore results in an often barely perceptible scar on
the lateral aspect of the nasal dorsum. This procedure takes one to two hours.
As with other sinus surgeries, prophylactic perioperative antibiotics are often
given. Patients are instructed to place ice over the wound for 24 hours post-
operatively and sutures are removed on postoperative day 5. Intranasal post-
operative care is similar to the endoscopic procedures, as are the potential
complications of the procedure. Additional possible complications include
medial can thai scarring and injury to the trochlea or enopthalmos if too much
bone is removed (27). The main advantage of this procedure is that it provides
excellent visualization and exposure of the medial orbit, ethmoid sinuses, and
anterior skull base. Additionally, when the procedure is performed to treat
acute ethmoiditis with periorbital abscess, a drain that can be used for irriga-
tion of the ethmoid cavity can be placed. The main disadvantage is that it

256

Lewis and Busaba

602 IM.
MPR 3

kV140

GTO.O

Figure 1 7 CT image (coronal projection) showing a left posterior ethmoid mucocele
that formed five years following an endoscopic ethmoidectomy.

requires an incision, that can result in a cosmetic deformity. Additionally, the
incision carries the risk of a sinocutaneous fistula.

External ethmoidectomy continues to have a role in otolaryngology.
Although it no longer is used for the treatment of CRS, it is currently indicated
for the treatment of acute ethmoiditis complicated by a periorbital or orbital
abscess. This approach is also used for the following: for open dacrocystorhi-
nostomy, for complete excision of ethmoid mucocele's with frontal or orbital
extension, for orbital decompression or exanteration, for repair of CSF leak or
anterior skull base meningo(encephalo)celes, and additionally, as an adjunc-
tive procedure to assist with craniofacial resections and medial maxillectomies
(27). Although there are no absolute contraindications to this procedure, one
might argue that it is not an acceptable first-line surgical therapy for CRS
given the widely available and less morbid endoscopic approaches.

Sphenoid Sinus Surgery

Endoscopic Endonasal Sphenoidotomy

Like the maxillary and ethmoid sinuses, the sphenoid sinus can be similarly
opened via an endoscopic approach. The sphenoid sinus can be opened up in
conjunction with an endoscopic ethmoidectomy in cases with pansinusitis.

Surgical Management

257

Figure 18 Endoscopic view of a right sphenoidotomy.

On the other hand, isolated sphenoid sinus disease can be successfully treated
by an endoscopic sphenoidotomy without the need for an ethmoidectomy
(29). In such a case, the sphenoid ostium is accessed between the nasal septum
medially, the roof of the posterior choana inferiorly, and the middle and
superior turbinates laterally. The sphenoid ostium is above the level of the
sinus floor and, therefore, the sphenoidotomy is enlarged in an inferior
and medial direction. The posterior septum (vomer bone) and the intersinus
septum may be drilled for improved drainage and access, if necessary. As is
the case with sinus surgery in general, nondiseased mucosa is preserved
(Fig. 18).

Indications for sphenoidotomy include sphenoid sinusitis with or
without polyposis, especially in patients with symptoms of retro-orbital
headaches or pressure, the removal of or marsupialization of mucoceles
or mucopyeloceles, the removal of mycotic "fungus balls," or to assist neu-
rosurgeons in their approach to removing pituitary lesions or other skull
base lesions (Fig. 19). The management of these patients is the same as
for other endoscopic surgeries; however, it should be noted that the inter-
nal carotid artery and the optic nerve run along the lateral and superior

258

Lewis and Busaba

Figure 19 A patient who presented with occipital and vertex headache and was later
diagnosed with chronic invasive fungal sinusitis based on the clinical presentation
and histopathology. (A) CT scan (axial projection) showing a completely opacified
left sphenoid sinus. (B) Intraoperative endoscopic view of the sinus cavity following
sphenoidotomy. The sphenoid sinus was filled with fungal debris and hyphae.

Surgical Management 259

walls of the sphenoid sinus, and either can be dehiscent. Hence, surgeons
must look carefully for any bony dehiscences on CT scan and be extra
cautious when working in this area. Complications of the procedure
include bleeding, stenosis/closure of the sphenoidotomy, and injury to
the vital structures that are in close proximity to the sinus.

External Spenoethmoidectomy

The majority of sphenoid sinus lesions can be addressed via an endoscopic
approach; however, in select cases, an external sphenoethmoidectomy can
be used to approach this sinus. This involves performing an external
ethmoidectomy and then opening the anterior wall of the sphenoid to gain
access to the sinus. This opening is then connected to the natural ostium.
A middle turbinectomy is also performed for improved access. The main
indication for this approach is for access to skull base tumors or repair
of large defects in the skull base. Similar to an external ethmoidectomy,
the main advantage of an external sphenoidotomy is that it can provide
increased exposure, working room, and if necessary, can be used in con-
junction with a microscope for improved visualization. The disadvantage
is that it requires an external incision with its potential complications
(see external ethmoidectomy).

Frontal Sinus Surgery

Trephination

Frontal sinus trephination involves making an opening in the inferior wall
of the frontal sinus through an incision along the inferior aspect of the
medial eyebrow. The inferior wall of the frontal sinus is devoid of bone
marrow, which averts the risk of developing osteomyelitis in the setting of
frontal sinusitis. The sinus cavity is then irrigated with saline or antibiotic-
containing solution. The entire procedure takes less than 30 minutes. A drain
may be placed for continued irrigation of the sinus. This procedure is indi-
cated in cases of complicated acute frontal sinusitis. Additionally, it can be
used in conjunction with endoscopic approaches to the frontal sinus in
chronic frontal sinusitis or frontal sinus mucoceles, when the trephination
is used to positively identify the frontal duct and pass a catheter through it
into the nasal passage to stent it and prevent its stenosis. The main advantage
to this approach is that it provides fast and easy access to the frontal sinus. It
also affords the surgeon an opportunity to place a drain in the sinus for irri-
gation. Its main disadvantages are its associated scarring, risk of sinocuta-
neous fistula formation, and risk of trochlea injury that can cause diplopia.

Lynch Procedure (External Frontoethmoidectomy)

This procedure is performed via an external ethmoidectomy approach. The
floor of the frontal sinus is entered. The opening is then widened to include

260

Lewis and Busaba

Figure 20 CT image (sagittal projection) through the frontal recess. The "white
square" indicates the area that is opened during a Lynch procedure and endoscopic
approaches to the frontal sinus.

the frontal duct, which is in turn enlarged to establish what is considered an
adequate communication with the anterior ethmoid sinus (Fig. 20). The
surgery takes one to two hours to perform and aims at achieving permanent
drainage and aeration of the frontal sinus. Accordingly, it is indicated to
treat symptomatic frontal sinusitis and frontal sinus muco(pyo)celes. The
procedure is currently very rarely performed due to a high failure rate.
The frontoethmoid opening occludes in up to 50% of cases, leading to recur-
rent disease and formation of frontal sinus mucoceles (30). In addition, the
surgery entails an external incision with the associated cosmetic issues.

Lothrop Procedure

The Lothrop procedure was originally described as an open approach to
treat chronic frontal rhinosinusitis. In this procedure, a common frontal
sinus cavity and recess is created by means of removing the bone that divides
the left and right sinuses as well as the floor of the frontal sinus. In addition,
a portion of the superior nasal septum is resected. The surgery takes one to
two hours to perform. Indications for the Lothrop procedure include the
treatment of patients with recurrence of frontal sinusitis despite surgery
and to remove frontoethmoid mucoceles, osteomas, or inverting papillomas.

Surgical Management

261

This procedure fell out of favor because of a high incidence of restenosis
with recurrence of frontal sinus disease.

Endoscopic Frontal Sinusotomy

An endoscopic anterior ethmoidectomy is first performed. The frontal recess
air cells of the anterior ethmoid are opened to expose the frontal duct
(Fig. 21). This area is anterior to the anterior ethmoid artery as it crosses
along the roof of the ethmoid sinus and just posterior to the anterior
attachment of the middle turbinate. Openings into supra-orbital ethmoid
air cells can at times be confused with the frontal duct, which has a more
medial and anterior location. When present, agger nasi cells are opened to
widen the frontal recess (Fig. 4). What is to be done once the frontal duct
is identified is controversial. Some warn against instrumentation of the duct
itself since this can lead to its stenosis. For these surgeons, opening the fron-
tal recess air cells and treating the anterior ethmoid sinus disease is ade-
quate. On the other hand, others recommend widening the duct by either
removing part of its inflamed mucosa or by drilling the bony walls anteriorly
and along the floor of the frontal sinus with a long handle drill (Fig. 20).

Figure 21 Endoscopic view of the frontal duct and into the frontal sinus following
endoscopic frontal sinusotomy.

262

Lewis and Busaba

In recalcitrant cases of frontal sinusitis or those with fibro-osseous stenosis
of the frontal duct/recess, the floor of the frontal sinus is drilled in addition
to the upper nasal septum, which may then be extended to the floor of
the contralateral frontal sinus (modified Lothrop procedure) (31,32). The
newly created opening is at times maintained by placing a stent for four
to 12 months following the surgery (33). These cases can usually be per-
formed in about two hours. Perioperative antibiotics are typically used,
and postoperative care is similar to that of other endoscopic procedures.
Indications for endoscopic frontal sinus surgery include the treatment of
patients with chronic frontal sinusitis; to remove frontoethmoid mucoceles,
osteomas, or inverting papillomas; or to treat recurrent disease as a salvage
procedure for osteoplastic flap operation failures (see following sections)
(Fig. 22) (32-36).

Most surgeons advocate performing endoscopic frontal sinus proce-
dures with the aid of computer guidance systems (31,34,37). Even so, it
should be noted that these procedures involve working extremely close to
the anterior cranial fossa, medial orbit, and lacrimal sac; hence, only very
experienced surgeons should perform this surgery in order to prevent com-
plications. When they do occur, the complications are typically the same as

Figure 22 CT image (coronal projection) showing soft tissue opacity in the left
frontal recess. This patient suffered from recurrent left frontal sinusitis and was suc-
cessfully treated by an endoscopic frontal sinusotomy.

Surgical Management 263

those with other endoscopic approaches. Additionally, there appears to be a
high incidence of recurrent frontal sinus disease due to restenosis of the
frontal recess (31,32,34-37).

Like the other endoscopic approaches, the advantages are that there is
no incision required and patients recover quickly with minimal postopera-
tive pain. The main disadvantage of the endoscopic approach is that there
appears to be a higher recurrence rate with these procedures when compared
to the osteoplastic frontal sinus obliteration (see following sections). The
area that is opened via the endoscopic approaches, including drilling of
the floor of the frontal sinus, is similar to the one opened by a Lynch or
Lothrop procedure (Fig. 20). Hence, there is no reason to expect a higher
success rate with the endoscopic approaches compared to the external ones.
The success of the endoscopic approach should not be judged until adequate
long-term follow-up is conducted, since frontal sinus mucoceles can form
more than 10 years following the surgery.

Osteoplastic Frontal Sinus Obliteration

The osteoplastic frontal sinus obliteration procedure is an effective means to
eradicate disease in patients who have recurrent or chronic frontal sinusitis
despite attempts at improving drainage via the endoscopic route. The pro-
cedure takes about two hours. Additional indications are frontal sinus
mucoceles, repair of CSF leaks originating from the posterior wall of the
frontal sinus, repair of certain frontal sinus fractures, and repair of frontal
sinocutaneous fistula (30,38). Its main rationale is the high failure rate of
procedures that aim at opening the frontal recess/duct, hence leading to
persistent symptoms and, at times, the formation of mucoceles. Therefore,
the frontal sinus is obliterated to circumvent the consequences of an
occluded frontal recess.

This procedure involves making a skin incision in either the scalp, the
mid-forehead, or the eyebrow. The scalp incision that is made above the
hairline (bicoronal incision) requires longer operative time and increases
intraoperative blood loss but offers superior cosmetics. The supraciliary
incision (above the eyebrow) offers more direct access to the frontal sinus
and hence reduces operative time and blood loss. However, it is associated
with higher incidence of scalp hypesthesia and sometimes long term pain
due to transaction of the supratrochlear and supraorbital nerves. The
mid-forehead incision offers a compromise. This is made along a skin crease
in the forehead and, therefore, has acceptable cosmetics. It also affords
direct access to the anterior wall of the sinus with a short operative time
and minimal blood loss (38). The bone of the anterior wall of the frontal
sinus is then carefully raised in order to open up the sinus. The mucosa of
the sinus is completely removed. A large frontal sinus with extensive lateral
recesses poses a challenge at removing the entire sinus mucosa. The opening
of the frontal duct is then occluded with fascia or other material, such as

264 Lewis and Busaba

bone wax. Fat is harvested from the abdomen and used to obliterate the
sinus cavity. The anterior bony wall is then reflected into position. Drains
are placed under both the scalp and the abdomen incisions for a few days
after the surgery. For this reason, patients typically stay in the hospital as
inpatients until the drains come out. Perioperative antibiotics are given
and there is no intranasal postoperative care. Sutures are removed within
one week.

The main advantage to this procedure is that it has a low failure rate
(30,38). The disadvantages are that this procedure involves a large incision
and is associated with increased length of hospital stay. Permanent frontal scalp
hypesthesia may develop, especially following a supraciliary incision since it
may transect the supraorbital and supratrochlear nerves. Additional complica-
tions include headache, abdominal or scalp wound seroma, hematoma or
abscess, headache, dural laceration, and recurrence of disease (33,37). Despite
these potential complications, this is a safe and very effective procedure, when
done by an experienced surgeon. However, this procedure is not indicated
for patients with uncomplicated frontal sinus disease who are undergoing
surgery for the first time. These patients are better served by endoscopic
procedures.

ANTIBIOTIC COVERAGE IN PARANASAL SINUS SURGERY:
PROPHYLACTIC AND POST SURGERY

The role of prophylactic antibiotic coverage in paranasal sinus surgery is
controversial (13,14). In addition, there is a lack of consensus regarding
antibiotic choice and the duration of such therapy.

It is common practice, however, to put patients on antibiotic coverage
following sinus surgery for a duration ranging from 48 hours to two weeks.
We recommend a 10- to 14-day course. The choice of the antibiotic is dic-
tated by the surgical approach, nature of the disease process, likely bacteria
based on published medical literature, and, when available, preoperative or
intraoperative bacteriology culture results.

The chosen antibiotic should have adequate coverage against skin
flora such as Streptococcus spp. and S. aureus and the likely pathogenic
bacteria in the involved sinus(es) for surgery via an external approach that
require a skin incision. Antibiotic coverage for anaerobic bacteria present in
the oral flora is needed for transoral approaches such as Caldwell-Luc
procedure. In addition, an antibiotic with demonstrated activity against
nasal flora, S. aureus, and likely paranasal sinus pathogens is selected for
endonasal approaches, both conventional and endoscopic procedures.

The antibiotic of choice should preferably have an easy administration
schedule (QD or BID dosing), be well-tolerated, and be available in intrave-
nous as well as equivalent oral formulations. Ability to cross the blood-
brain barrier is essential during surgery in patients with periorbital or

Surgical Management 265

intracranial complications from sinusitis or iatrogenic CSF rhinorrhea
(violation of the base of the skull).

LASERS AND SINUS SURGERY

Presently, lasers have a limited role in sinus surgery. Over the years, various
investigators have attempted to use lasers to aid in the eradication of sinus
disease. For the most part, these attempts have been somewhat successful;
however, the use of lasers is expensive and can be time-consuming. Therefore,
the use of lasers has not gained widespread acceptance.

The C0 2 laser has not been found successful in the treatment of sinus
disease. It has a wavelength that gets absorbed by water, and its thermal
energy is concentrated with very little spread to the surrounding soft tissues.
The principle difficulties in applying the C0 2 laser to sinus disease treatment
is that it requires a relatively dry field for hemostasis, it results in significant
smoke accumulation, and most importantly, its mid-infrared light cannot
travel through a fiberoptic cable. Thus, tissues must be visualized directly
in order to be treated with the C0 2 laser (39).

In contrast, the Nd:YAG, KTP/532, Argon, and Ho:YAG lasers can be
carried through fiberoptic cables. Fiberoptic threads can be passed into
instruments, that are designed for intranasal use. Hence, the instruments that
transmit the laser energy can be handled manually and placed directly onto
tissues with ease and precision. Each of these has advantages and disadvan-
tages related to depth of penetration, scatter of thermal energy, and their abil-
ity to coagulate small blood vessels. These lasers have been used to treat
inferior turbinate hypertrophy with moderate success (39). They can also be
used to remove nasal lesions, such as nasal papillomata, pyogenic granuloma,
and other small superficial lesions (40).

A common application of laser technique is the treatment of hereditary
hemorrhagic telangiectasias. This is an autosomal-dominant disease charac-
terized by telangiectatic lesions primarily in mucosalized areas, such as the
nose, mouth, and gastrointestinal tract. These patients often suffer from
severe bouts of epistaxis throughout their lives. The Nd:YAG and KTP/
532 lasers have each been used successfully to ablate these lesions (39^3).
Patients often require retreatment, however, every four to six months.
Ho:YAG laser with its capability to vaporize bone has been used in intranasal
endoscopic dacryocystorhinostomy. It did not gain widespread popularity
since it does not offer any significant advantage over using cold instruments
to justify the added cost and operative time.

CONCLUSION

Paranasal sinus surgery has several indications; the most common is CRS
that failed medical therapy. The approach and extent of surgery is dictated

266 Lewis and Busaba

by the nature of the disease and the involved sinuses. Endoscopic approaches
that are made possible with the technological advances in flberoptics have
gained widespread use. They offer a minimally invasive technique that has
a low morbidity and high success rate for treating inflammatory paranasal
sinus pathology. The surgery is not risk free, however. Image guidance
systems can make the surgery safer. Surgery is often an adjunct to medical
therapy. A better understanding of the pathogenesis of rhinosinusitis allows
for better delineation of the role of medical therapy and surgery.

REFERENCES

1. Kennedy DW, Zinreich SJ, Rosenbaum AE, Johns ME. Functional endoscopic
sinus surgery. Theory and diagnostic evaluation. Arch Otolaryngol 1985;
111:576-582.

2. Rice DH. Indications for endoscopic sinus surgery. Ear Nose Throat J 1994;
73:461-464, 466.

3. Messerklinger W. Background and evolution of endoscopic sinus surgery. Ear
Nose Throat J 1994; 73:449^50.

4. Stammberger H. The evolution of functional endoscopic sinus surgery. Ear
Nose Throat J 1994; 73:451, 454-455.

5. Vining EM, Kennedy DW. The transmigration of endoscopic sinus surgery
from Europe to the United States. Ear Nose Throat J 1994; 73:456^58, 460.

6. Kennedy DW. Functional endoscopic sinus surgery. Technique. Arch Otolar-
yngol 1985; 111:643-649.

7. Messerklinger W. On the drainage of the normal frontal sinus of man. Acta
Otolaryngol 1967; 63:176-181.

8. Stammberger H, Hasler G. Functional Endoscopic Sinus Surgery: The
Messerklinger Technique. St Louis, MO: Mosby, 1991.

9. Catalano PJ. Minimally invasive sinus technique: what is it? Should we consider
it? Curr Opin Otolaryngol Head Neck Surg 2004; 12:34-37.

10. Kieff DA, Busaba NY. Non-dental related isolated chronic maxillary sinus
opacification does not correlate with ipsilateral intranasal structural abnormal-
ities. Ann Otol Rhinol Laryngol 2004; 113:474-476.

1 1 . Taylor MJ, Ponikau JU, Sherris DA, Kern EB, Gaffey TA, Kephart G, Kita H.
Detection of fungal organisms in eosinophilic mucin using a fluorescein-labeled
chitin-specific binding protein. Otolaryngol Head Neck Surg 2002; 127:
377-383.

12. Ferguson BJ. Categorization of eosinophilic chronic rhinosinusitis. Curr Opin
Otolaryngol Head Neck Surg 2004; 12:237-242.

13. Annys E, Jorissen M. Short term effects of antibiotics (Zinnat) after endoscopic
sinus surgery. Acta Otorhinolaryngol Belg 2000; 54(l):23-28.

14. Hasselgren PO, Ivarsson L, Risberg B, Seeman T. Effects of prophylactic anti-
biotics in vascular surgery. A prospective, randomized, double-blind study. Ann
Surg 1984 Jul; 200(l):86-92.

15. Gross CW, Gross WE. Post-operative care for functional endoscopic sinus
surgery. Ear Nose Throat J 1994; 73:476-479.

Surgical Management 267

16. Stankiewicz JA. Complications of endoscopic sinus surgery. Otolaryngol Clin
North Am 1989; 22:749-758.

17. Parikh SR, Fried MP. Navigational systems for sinus surgery: new develop-
ments. J Otolaryngol 2002; 31(suppl 1):S24— S27.

18. Metson R. Image-guided sinus surgery: lessons learned from the first
1000 cases. Otolaryngol Head Neck Surg 2003; 128:8-13.

19. Metson R, Gliklich RE, Cosenza M. A comparison of image guidance systems
for sinus surgery. Laryngoscope 1998; 108(8 Pt 1):1 164-1 170.

20. Fried MP, Kleefield J, Gopal H, Reardon E, Ho BT, Kuhn FA. Image-guided
endoscopic surgery: results of accuracy and performance in a multicenter
clinical study using an electromagnetic tracking system. Laryngoscope 1997;
107:594-601.

21. Selivanova O, Kuehnemund M, Mann WJ, Amedee RG. Comparison of con-
ventional instruments and mechanical debriders for surgery of patients with
chronic sinusitis. Am J Rhinol 2003; 17:197-202.

22. Bernstein JM, Lebowitz RA, Jacobs JB. Initial report on postoperative healing
after endoscopic sinus surgery with the microdebrider. Otolaryngol Head Neck
Surg 1998; 118:800-803.

23. Busaba NY, Salman SD. Maxillary sinus mucoceles: clinical presentation and
long-term results of endoscopic surgical treatment. Laryngoscope 1999;
109:1446-1449.

24. Busaba NY, Kieff DA. Endoscopic sinus surgery for inflammatory maxillary
sinus pathology. Larynogoscope 2002; 112:1378-1383.

25. Goodman WS. The Caldwell-Luc procedure. Otolaryngol Clin North Am 1976;
9:187-195.

26. Schaefer SD, Gustafson RO, Bansberg SF. Sinus surgery. In: Bailey BJ,
Calhoun KH, eds. Head and Neck Surgery — Otolaryngology. 3rd ed. Philadelphia,
PA: Lippincott Williams and Wilkins, 2001:359-370.

27. Weber R, Keerl R, Draf W. Endonasal endoscopic surgery of maxillary sinus
mucoceles after Caldwell-Luc operation. Laryngorhinootologie 2000; 79:
532-535.

28. Busaba NY, Salman SD. Ethmoid mucocele as a late complication of endo-
scopic ethmoidectomy. Otolaryngol Head Neck Surg 2003; 128:517-522.

29. Kieff DA, Busaba NY. Treatment of isolated sphenoid sinus inflammatory
disease by endoscopic sphenoidotomy without ethmoidectomy. Laryngoscope
2002; 112:2186-2188.

30. Hardy JM, Montgomery WW. Osteoplastic frontal sinusotomy: an analysis of
250 operations. Ann Otol Rhinol Laryngol 1976; 85(4 Pt l):523-532.

31. Wormald PJ, Ananda A, Nair S. Modified endoscopic Lothrop as a salvage
for the failed osteoplastic flap with obliteration. Laryngoscope 2003; 113:
1988-1992.

32. Stankiewicz JA, Wachter B. The endoscopic modified Lothrop procedure for
salvage of chronic frontal sinusitis after osteoplastic flap failure. Otolaryngol
Head Neck Surg 2003; 129:678-683.

33. Neal DG. External ethmoidectomy. Otolaryngol Clin North Am 1985; 18:55-60.

34. Kountakis SE, Gross CW. Long-term results of the Lothrop operation. Curr
Opin Otolaryngol Head Neck Surg 2003; 11:37-40.

268 Lewis and Busaba

35. Gross CW, Harrison SE. The modified Lothrop procedure: indications, results,
and complications. Otolaryngol Clin North Am 2001; 34:133-137.

36. Casiano RR, Livingston JA. Endoscopic Lothrop procedure: the University of
Miami experience. Am J Rhinol 1998; 12:335-339.

37. Samaha M, Cosenza MJ, Metson R. Endoscopic frontal sinus drillout in
100 patients. Arch Otolaryngol Head Neck Surg 2003; 129:854-858.

38. Montgomery WW. State-of-the-art for osteoplastic frontal sinus operation.
Otolaryngol Clin North Am 2001; 34:167-177.

39. Rathfoot CJ, Duncavage J, Shapshay SM. Laser use in the paranasal sinuses.
Otolaryngol Clin North Am 1996; 29:943-948.

40. Shah RK, Dhingra JK, Shapshay SM. Hereditary hemorrhagic telangiectasia: a
review of 76 cases. Laryngoscope 2002; 112:767-773.

41. Parkin JL, Dixon J A. Laser photocoagulation in hereditary hemorrhagic
telangiectasia. Otolaryngol Head Neck Surg 1981; 89:204^208.

42. Levine HL. Lasers in endonasal surgery. Otolaryngol Clin North Am 1997;
30:451-455.

43. Levine HL. Endoscopy and the KTP/532 laser for nasal sinus disease. Ann
Otol Rhinol Laryngol 1989; 98(1 Pt 1):46-51.

Complications of Acute and Chronic
Sinusitis and Their Management

Gary Schwartz and Steve White

Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.

INTRODUCTION

Sinusitis is a common condition that is usually treated uneventfully on an
outpatient basis. Admission to a hospital is rare, as are the complications
stemming from sinusitis (Table 1). Although not exactly known, the inci-
dence of complications from sinusitis is thought to be low. One study found
a 3% incidence of complications in hospitalized patients (1). In addition,

Table 1 Complications of Sinusitis

Local complications

Mucocele

Osteomyelitis (Pott's puffy tumor)
Orbital complications

Inflammatory edema

Orbital abscess

Subperiosteal abscess

Cavernous sinus thrombosis
Intracranial complications

Meningitis

Subperiosteal abscess

269

270 Schwartz and White

other studies from referral centers looking at complications only report
a few patients per year (2). The rarity of this problem can make physicians
complacent about looking for complications and therefore could lead to
significant morbidity and mortality. Morbidities can include blindness and
neurologic deficits.

Complications from sinusitis are caused by the spread of bacteria from
the sinus to the surrounding structures. There are two means by which the spread
of infection can occur. The most common route is through direct spread to
contiguous areas. The spread of infection occurs through either neurovascular
foramina, a defect in the sinus wall from a fracture because of trauma, or a
congenital abnormality. Spread of infection to the bony wall can also lead to
erosions creating an opening through which infection can progress.

PATHOPHYSIOLOGY

Hematogenous route is the other route for an infection to spread. Either
bacteria or septic emboli can get into the bloodstream and reach intracranial
sites separated by a distance from the sinus. To some extent, all sinus veins
drain intracranially and, therefore, have the potential to spread bacteria to the
brain. The frontal sinus, whose venous drainage is almost entirely intracra-
nial, is the most common origin for bacterial spread which can cause intra-
cranial complications. Venous drainage from the sinus runs via the diploic
veins that penetrate the bony sinus lining. The inner table diploic veins
drain directly into the dural venous plexuses and later into the sagital sinus.
The outer table of the sinus drains into both the venous plexuses of the face,
which then drain through the ophthalmic veins in the orbits, and the dural
sinuses. Bacteria from facial skin infections take the same path, which can
lead to intracranial infections. Also draining into the dural sinuses are the
cortical veins from the brain parenchyma. As these veins are without valves,
blood can flow either antegrade or retrograde. Therefore, septic emboli can
start in a frontal sinus, drain into a dural sinus, and flow retrograde into the
brain, leading to an abscess. Septic emboli can also seed structures along the
drainage path, leading to an epidural or subdural empyema.

LOCAL COMPLICATIONS

Osteomyelitis

A sinus infection can spread to the surrounding bony structures leading to
osteomyelitis of either the anterior or posterior walls of the sinus. The spread
of infection can be either by direct extension or by valveless veins draining
into the sinus. Osteomyelitis is most commonly observed in the walls of
the frontal sinuses. Once the bone has become infected, it can erode, allowing
the infection to spread under the subperiostium leading to subperiosteal

Complications of Sinusitis and Their Management 271

abscess formation. The erosion can affect either the anterior or posterior
tables of the sinus, leading to either extracranial or intracranial extension.
If the subperiosteal abscess is adjacent to the anterior table of the frontal
bone, it is called Pott's puffy tumor after Sir Percival Potts, who first
described this condition. This is an extremely rare diagnosis with only 20
cases in the literature (3). Patients with Pott's puffy tumor are always older
than six years because the frontal sinus is not pneumatized until this age.

Etiology

Osteomyelitis of the bone overlying the sinus is caused by the same organisms
that cause sinusitis. The most common are Staphylococcus, Streptococcus, and
anaerobic bacteria (3,4).

Clinical Presentation

Patients who present with osteomyelitis as a complication of sinusitis
frequently present with complaints similar to patients with simple sinusitis.
These include headache, photophobia, and fever. If Pott's puffy tumor is
present, there will also be swelling in the forehead.

Diagnosis

Diagnosis requires radiographic imaging not only to confirm, but also to
rule out any associated intracranial complications. Imaging is most easily
accomplished with a CT scan. Routine blood tests such as complete blood
cell counts are of little value as they are very nonspecific, but an elevated
sedimentation rate may be an indication of osteomyelitis.

Treatment

Treatment for osteomyelitis is by administering intravenous antibiotics for a
prolonged period of time, six to eight weeks. The antibiotics chosen need to
cover both anaerobic and aerobic organisms. An appropriate empiric choice
is a combination of a third-generation cephalosporin (i.e., ceftriaxone) and
metronidazole or clindamycin, with consideration given to adding vancomy-
cin or linezolid (also available orally), if there is a significant Streptococcus
pneumoniae antimicrobial resistance or the involvement of Staphylococcus
spp. Oral therapy with amoxicillin-clavulanate or the combination of cefix-
ime and metronidazole or clindamycin are also appropriate. The choice of
therapy should be adjusted according to adequate cultures. If an abscess
is present, surgical drainage is the treatment of choice.

Mucocele

A mucocele is a chronic, cystic lesion of the paranasal sinuses. It grows slowly,
taking years to become symptomatic, and the symptoms are typically related to
the increasing size of the mucocele. As it enlarges, it can exert pressure on the

272 Schwartz and White

sinus wall which leads to bony erosion. After eroding through the sinus wall,
the mucocele can extend into surrounding structures. Mucoceles most
frequently involve the frontal sinus, followed by the ethmoid and maxillary
sinuses (5). Symptomatic frontal or ethmoid sinus mucoceles can cause head-
aches, diplopia, and proptosis. The proptotic globe is typically displaced
downward and outward. Maxillary sinus mucoceles are usually an incidental
finding on radiographs of the sinus. Mucoceles in this location rarely cause
symptoms because the maxillary sinuses are large and the mucoceles rarely
become large enough to cause bony abnormalities. Maxillary sinus mucoceles
can become symptomatic, if they obstruct the ostium of the maxillary sinus.
Mucoceles can also become symptomatic in any sinus when they become
infected, forming mucopyocele. Diagnosis is usually made by CT of the
sinuses. Symptomatic mucoceles are treated with surgical removal and possi-
ble sinus obliteration.

ORBITAL INFECTIONS

Orbital infections can be caused by penetration of the orbit during either
surgery or trauma; most frequently the result of a bacterial spread is from
an infected sinus. As the orbit is bordered by several sinuses — the frontal,
ethmoid, and maxillary — infection from any of these sinuses can potentially
spread to the orbit. The ethmoid sinus is almost exclusively implicated in the
spread of infection to the orbit. This is related to the thickness of the sinus
wall lining the orbit. The thinner the wall, the easier is for infection to spread
through it. The ethmoid sinus has the thinnest wall, the lamina papyracea,
which lines the lateral wall of the sinus and the medial wall of the orbit.
Most orbital infections are, therefore, on the medial side of the orbit.
Although much less common, the thicker wall sinuses can also be the source
of an orbital infection. Once infection has spread past the sinus wall, the
periosteal lining of the sinus wall serves as an additional barrier to protect
the orbit from the spread of the infection. If an abscess forms between the
wall and periosteum, it is called a subperiosteal abscess. If the periosteum
is violated, then an orbital abscess may form.

Etiology

Many organisms can be isolated in patients with orbital infections (Table 2).
These may be single or multiple organisms, anaerobic or aerobic organisms,
or mixture of both. Frequently, the isolates are the same as those found in
the infected sinus. To best determine the type of organism, patients should
be divided into two groups. The first group consists children of under 9 years
old. These patients typically have single aerobic organisms, which include
alpha and beta hemolytic Streptococcus spp., Staphylococcus spp., non-
Haemophillus influenzae, and Moroxalla catarrhalis (6). The second group

Complications of Sinusitis and Their Management 273

Table 2 Common Organisms Isolated from Patients with Orbital Infections

Aerobic bacteria

Streptococcus spp.: Streptocococcus pneumoniae, Streptococcus viridans, and
Streptococcus viridans

Staphylococcus spp.: Staphylococcus aureus, and Staphylococcus epidermidis

Haemophilus influenzae

Moraxella catarrhalis
Anaerobic bacteria

Gram-negative bacilli (Prevotella, Porphyromonas, and Bacteroides spp.)

Veillonella parvula

Peptostreptococcus spp.

Fusobacterium spp.

Proprionibacterium spp.
Immunocompromised hosts

Pseudomonas aeruginosa

Fungal species: aspergillosis, and mucormycosis

of patients is over nine years old, and typically have complex infections with
mixed aerobic and anaerobic organisms. This is especially true for patients
in their teens or older. Although aerobic organisms are frequently the same
as those found in younger children, the anaerobic organisms are usually oral
flora such as anaerobic gram-negative bacilli, Peptostreptococus spp.,
Fusobacterium spp., and Veillonella parvule. These rules are not absolute,
as there are reports of anaerobic bacteria isolated in young children (7,8).
There are several theories that explain the causes of this transition; they
include the increased incidence of chronic infections in older children and
adults and the relative size of the osteo meatal opening. The relative size
of the osteo meatal opening to the sinus cavity is larger in younger indivi-
duals compared to that of older ones and therefore less likely to become
occluded. Occlusion of the opening blocks the sinus cavity, which becomes
anaerobic and promotes the growth of anaerobic organisms.

Diagnosis

In an article, Chandler described a classification system for orbital infection
that still in use today (9) (Table 3, Fig. 1). The spectrum of orbital infec-
tions is classified into five groups; each represents a progressively more
serious infection. Group 1 is preseptal cellulitis, a simple cellulitis of the
eyelids which manifests as swelling of the eyelids. Infection is limited to the
skin in front of the orbital septum. Group 2 is orbital cellulitis, seen as diffuse
edema of the lining of the orbits. It manifests as eyelid swelling and pain with
extraocular muscle movement. Group 3, subperiosteal abscess, is character-
ized by edema of the orbital lining with a collection of fluid below the

274 Schwartz and White

Table 3 Chandler Classification

Group 1: Periorbital cellulitis

Group 2: Orbital cellulitis

Group 3: Subperiosteal abscess

Group 4: Orbital abscess

Group 5: Cavernous sinus thrombosis.

Source: From Ref. 9.

periosteum usually involving the medical wall of the orbit. Clinically patients
with this condition are similar to Group 2 but proptosis may also be noted.
Group 4, orbital abscess, is characterized as a true abscess in the orbital space.
This may manifest with proptosis, impaired eye movement, and in the worse
case, blindness. Group 5 is cavernous sinus thrombosis with rapidly progres-
sive bilateral chemosis, ophthalmoplegia, retinal engorgement, and loss of
visual acuity, along with possible meningeal signs and high fever.

The most important decision in dealing with a patient with a swollen
eye is determining whether a preseptal or orbital process exists. Obtaining a
thorough history, physical examination, and potentially imaging studies can
very often assist in this. Preseptal cellulitis is most often caused by local
trauma. The history may reveal an insect bite or other trauma to the skin
around the eye, which becomes secondarily infected. This infection is usually
insidious in onset. H. influenzae type B infection causes rapid eyelid swelling
and eyelid closure within hours. With the advent of the H. influenzae type B

Figure 1 (1) Preseptal cellulitis, (2) Orbital cellulitis, (3) Subperiosteal abscess,
(4) Orbital abscess, and (5) Cavernous sinus thrombosis. Source: From Ref. 49.

Complications of Sinusitis and Their Management 275

vaccine, a hematogenous source of infection very rarely is identified as the
cause of preseptal cellulitis (10). Patients with H. influenzae infection typi-
cally develop rapid eyelid swelling with eyelid closure within hours.

As preseptal cellulitis is an inflammatory process, evidence of local eye
inflammation is present. Findings include warmth, redness, induration, and
pain with palpation. In patients with red swollen eyelids which are boggy,
painless to palpation, and not indurated, an allergic reaction or venous con-
gestion because of an underlying sinusitis should be considered. Regardless
of the cause of preseptal cellulitis, there should be no visual problem, no
proptosis, or no significant pain with eye movement.

Orbital infections (group 2-4) are harder to identify and are typically more
insidious in onset. Patients frequently show a history of nasal drainage, head-
ache or pressure, and fever. If infection is in the orbit, visual loss may be present.

Orbital infections may present in a similar way to preseptal infections.
These patients present with evidence of orbital inflammation. The presence
of eyelid swelling is not indicative of inflammation. As space is limited in the
orbit, any inflammatory mass could impact the surrounding structures. A
simple orbital infection exerts pressure on the ocular muscles and causes pain
with eye movement. If a subperiosteal abscess or abscess forms, there may
be pressure placed on the orbit causing proptosis. If the inflammatory pro-
cess pushes on the optic nerve, blindness may result. Early on, the findings
of orbital infection may be minimal, but become more apparent if the infec-
tion is allowed to progress.

Imaging

As there can be an overlap in the symptoms of orbital infection, preseptal
cellulitis, and other causes of eyelid swelling, some clinicians recommend
imaging in all patients with a swollen eye. However, a more common
approach would be to reserve imaging studies for those with nonclassic pre-
sentations of preseptal cellulitis and those with presumed preseptal cellulitis,
who do not improve following one to two days of treatment. All patients
with evidence of orbital cellulitis need an imaging study.

The most frequently used imaging study is a CT scan, with or without
contrast, using thin slices through the orbit with coronal and axial images. A
CT scan is highly sensitive in documenting these infections. Patients with
preseptal cellulitis show evidence of eyelid swelling without orbital involve-
ment. The CT scan images of patients with Chandler group 2 (orbital cellu-
lites) frequently show an opacified ethmoid sinus with an ill-defined mass on
the orbital side of the lamina papyracea (Fig. 2). In addition, there may also
be inflammation of the rectus muscle.

This is the mildest and most common type of orbital infection (Fig. 3).
Group 3 (subperiosteal abscess) shows evidence of inflammation with
periosteum elevation and rim enhancement, rectus muscle displacement,

276

Schwartz and White

Figure 2 Ethmoid sinusitis with inflammation of the medial wall of the right orbit.

and if large enough, some degree of proptosis of the eye (Fig. 3). Findings
for group 4 (orbital abscess) show inflammatory material in the orbital space
with proptosis.

An MRI is possibly a better type of imaging study, but can be proble-
matic since most orbital infections are in young children who will need
sedating for the procedure. An MRI is best reserved for the complicated
infection with intracranial extension, such as cavernous sinus thrombosis
(group 5) or epidural abscess. There is no value in obtaining plain radio-
graphs of the sinuses to diagnose an orbital infection.

Figure 3 Ethmoid sinusitis with subperiosteal abscess in an adolescent who
presented to an emergency department with eyelid swelling and pain with eye
movement.

Complications of Sinusitis and Their Management 277

Treatment

Until the past few years, there has been much disagreement on how to treat
orbital infections. Until recently, surgical drainage was thought to be neces-
sary in the majority of patients. Now medical management is the treatment
of choice in the majority of patients with this type of infection. To success-
fully treat patients with orbital infections, the patients are to be stratified
into low and high risk groups based on likelihood of complications. Low
risk patients have over 90% cure rate with antibiotic therapy alone (11).
Low risk patients are those under 9 years old, who most likely have single aero-
bic organisms causing the infection. In addition to young age, low risk patients
must also have no visual compromise, at most a modest-sized subperiosteal
abscess on the medial side of the orbit, and no evidence of intracranial infection
(Table 4). They also must be able to cooperate with frequent ophthalmolo-
gic examinations. How frequently an exam must be repeated is not known.
Published studies recommend ophthalmic examinations from once a day to
multiple times a day (11,12).

The antibiotics selected should be able to cover aerobic gram-positive
cocci. Adequate choices include a third-generation cephalosporin (ceftriax-
one or cefotaxime) unless there is a high likelihood of recovery of resistant
S. pneumoniae. In these cases, vancomycin should be given. As anaerobic
organisms are rarely seen in young patients, administering antibiotics that
cover these organisms is probably unnecessary. Generally, treatment includes
less than a week of parenteral antibiotics and is followed by a prolonged period
of two to three weeks of oral antibiotic such as high dose of ampicillin/clavu-
lanic acid (90mg/kg/day in children and 4 g/day in adults) (13,14). In addition
to antibiotics, all patients should be started on a nasal decongestant, such as
oxymetazoline. Most patients who fit into this low risk category respond appro-
priately with only antibiotic treatment. However, if the patient's condition
deteriorates, it may be necessary to have the abscess and sinus drained. Indica-
tions for surgery in this low risk group include visual loss, afferent papillary
defect, fever after 36 hours of antibiotic treatment, or absence of clinical
improvement after 72 hours. There is no indication for repeating the CT scan
when deciding whether to perform surgery or not. Findings on the CT scan

Table 4 Low Risk Group for Complications

Age under 9 years old

No visual compromise

At most, modest-size abscess on medial side of orbit

No evidence of intracranial complication

Ability to cooperate with serial ophthalmologic exams

Not immunocompromised

278 Schwartz and White

may worsen before they improve, even in patients who are responding appropri-
ately to antibiotics.

Young children who are not likely to be cured by antibiotics alone
include those with subperiosteal abscess not on the medial side of the orbit
and those with over 2 mm of proptosis (14).

A more aggressive approach is needed to treat older children and adults,
as they have more complex infections that are not as reliably treated with
antibiotics alone. Recommended antibiotics for complex infections are a
second-generation cephalosporin that covers anaerobic and anaerobic organ-
isms (i.e., cefoxitin or cefotetan), clindamycin, or ampicillin/sulbactam. Other
combinations of antibiotics, such as penicillin and metronidazole, can also be
used as long as they cover both aerobic and anaerobes. If there is a high like-
lihood of recovering resistant S. pneumoniae vancomycin can be added. Even
with the administration of appropriate antibiotics, cultures from an infected
sinus or orbital abscess frequently can still grow organisms after several days
of therapy. Until the abscess or infected sinus is sterile, there is a risk of the
infection spreading. For these patients, a trial of antibiotic therapy alone
can be given, but it will likely not cure the infection and place the patient at
a continued risk for complications. Some clinicians will wait for 24 hours to
see how these patients with complex infections respond, whereas others will
proceed to urgent surgery to drain the abscess along with administering
parenteral antibiotics. Surgery can be done either endoscopically or through
an open approach, depending on the location of the subperiosteal abscesses
and the physician's preference.

INTRACRANIAL COMPLICATIONS OF SINUSITIS

Introduction

Intracranial complications of sinusitis are rare, occurring one to three times per
year in major referral centers (15-23). Undoubtedly, the advent of antibiotic
therapy has decreased the incidence of intracranial infectious complications of
sinusitis. Over the three decades spanning 1950-1980, Bradley et al. (24) noted
a four-fold decrease in intracranial abscess arising from sinus infection, despite
improvements in diagnostic modalities which would otherwise have increased
the number of diagnosed cases. Yet, because these intracranial infections repre-
sent the most lethal consequences of diagnostic or treatment failure of sinusitis, it
is imperative for clinicians to understand the clinical presentation, diagnostic
options, and therapeutic approach to treat each of these entities.

Intracranial complications of sinusitis include: (1) meningitis, (2)
epidural abscess, (3) subdural abscess, (4) brain abscess, and (5) dural sinus
thrombosis. In contrast to intraorbital infections, sinusitis underlies only 3%
to 9% of suppurative intracranial infections (15-17,20) and is responsible
for less than 1% of cases of meningitis (17).

Complications of Sinusitis and Their Management 279

However, extra-axial abscesses (subdural and epidural) as discrete
entities are most commonly of sinogenic origin, and epidural abscess is
the most common intracranial complication from sinusitis in some series
(15,16,21), although meningitis is more common in other series (23). Menin-
gitis may be under-represented as lumbar puncture is to be avoided in the
setting of intracranial space-occupying lesions and would likely only be
performed when a CT or MRI scan fails to demonstrate an intracranial
abscess or when an intracranial abscess is not considered. Conversely,
concomitant sinusitis may fail to be diagnosed in patients diagnosed with
meningitis if a neuro-imaging study is not performed, a likelihood in the
management of many patients diagnosed with meningitis.

Dural venous sinus thrombosis/thrombophlebitis (sagittal, transverse,
and cavernous) is the least common complication, absent in some case series
(16,19), and accounting for 3% to 9% of intracranial complications in others
(15,18,23). In most cases, venous sinus thrombosis is not an isolated compli-
cation, but occurs in concert with subdural suppuration.

Patients commonly have more than one intracranial complication,
such as epidural/subdural abscess in association with cerebral abscess
and/or meningitis. Table 5 summarizes the relative frequency of each intra-
cranial complication from data pooled from several recent studies that used
similar inclusion criteria and selection methods.

Most studies have demonstrated a large male predominance (greater than
3:1, male/female) for intracranial suppuration from sinusitis (16-20,22). This
male predominance remains unexplained, but prevails at all age groups and
may suggest sex-related anatomical differences in sinus structure/sinus venous
drainage.

Pathogenesis

The pathogenesis for intracranial suppuration mirrors that of intraorbital
infection. Intracranial infection can develop following direct extension
through sinus wall invasion to contiguous bone, and then to intracranial

Table 5 Relative Frequency of Intracranial Complications 3

Intracranial complication Relative frequency (%, range)

Meningitis 34% (14-54)

Brain abscess 27% (0-50)

Epidural abscess 23% (0-44)

Subdural abscess 24% (9-86)

Dural sinus thrombosis 8% (0-27)
Percent of patients with > 1 intracranial complication 28%

Note: Study reference 30 excluded meningitis cases as a complications.
a Pooled data from 131 patients in eight studies (15-17,19,20,23,30,48).

280 Schwartz and White

structures through either osteitis or congenital or traumatic defects. In contrast
to orbital infections, the more common method of intracranial suppurative
spread is by the propagation of septic emboli via calvarial diploic veins and
the valveless venous system responsible for drainage of the midface and
paranasal sinuses (15,16,20,23).

Although many of these complications arise in the setting of pansinu-
sitis, some intracranial infections are more strongly associated with specific
sinus involvement. Meningitis often arises from ethmoid or sphenoid sinus
involvement (23). Cavernous sinus thrombosis is also associated with sphe-
noiditis and ethmoiditis (25,26), although it was more commonly associated
with frontal sinusitis prior to use of current antibiotic regimens (25). The
frontal sinuses are most frequently implicated in the development of
extra-axial and intracerebral abscesses as well as infection of the remaining
dural sinuses (15,16,21,23).

Clinical Presentation

Because of the shared pathogenic origin, it common for a patient to have more
than one intracranial complication. Therefore, it is difficult to attribute a
presenting symptom to an isolated intracranial cause. Similarly, the signs
and symptoms of rhinosinusitis also overlap to some degree with the presenta-
tion of intracranial infection. Common presenting features will be discussed in
this section, and specific presentations more common or unique to a parti-
cular intracranial pathological entity will subsequently be discussed. Table 6
summarizes presenting symptoms and signs, collated from recent studies with
similar inclusion criteria.

Headache, commonly frontal or retro-orbital, is the overwhelmingly
prominent symptom, occurring in approximately 70% of patients with intra-
cranial infection arising from sinusitis. Most patients have fever (>38.5°C)
as well. As would be expected, many patients have symptoms of sinonasal
disease with purulent rhinorrhea and sinus pressure/pain. Compared to adults,

Table 6 Presenting Symptoms/ Signs of Intracranial Infection Arising from Sinusitis

Headache (%) 69

Fever (%) 60

Altered mental status (ranging from confusion to obtundation; %) 41

Nausea/vomiting (%) 30

Cranial nerve palsy (%) 18

Seizure (%) 14

Other focal neurologic signs (hemiparesis/hemiplegia, aphasia, 14

ataxia, motor/sensory deficits; %)

Nuchal rigidity (%) 10

a Pooled data from 91 patients in seven studies (15-17,19,20,30,48).

Complications of Sinusitis and Their Management 281

children rarely have prominent rhinorrhea or upper respiratory symptoms, and
complications often arise during a more acute course of sinusitis.

Patients also commonly have symptoms of increased intracranial pres-
sure, including alterations in mental function, vomiting, and photophobia.
Arachnoid irritation may be indicated by nuchal rigidity (15-17,19,20).

Later neurological symptoms and signs for intracranial infections
include seizures, focal paresis, and cranial nerve palsies.

Diagnosis

Prior to the advent of computerized cross-sectional neuro-imaging (CT and
MRI), diagnosis of space-occupying intracranial infections was primarily
based on clinical evaluation and judgment (22).

CT and MRI scans are complementary techniques, each of which can
yield diagnostic information helpful in the definitive management of intra-
cranial complications. CT scan is readily available, can demonstrate most
cases of intracranial suppuration, and is a technique of choice to evaluate
bony involvement. CT scanning is the imaging modality of choice for initial
evaluation of complications from sinusitis and for planning sinus surgery
because of its superior ability to delineate air-bone and air-soft tissue
interfaces. MRI, on the other hand, has better resolution for intracranial
pathology and has higher diagnostic accuracy for intracranial infections.
In one study comparing CT and MRI for the diagnosis of suppurative com-
plications from sinusitis, CT scan was diagnostic for 36 of 39 cases (92%)
compared to 100% with MRI. MRI was also able to detect meningitis in
14 cases compared to three for CT scan. CT scanning missed one subdural
abscess and one intracerebral abscess. Both modalities exceeded diagnoses
made on clinical grounds, which had an accuracy of 82% overall (22).

Contrasted CT scan may be contraindicated in patients with renal
insufficiency or those with life-threatening contrast allergies. MRI should
be employed as the first method of evaluation in such cases. If such patients
are unsuitable for MRI because of implanted ferromagnetic devices, pace-
makers, implanted defibrillators, or other contraindications, patients with
renal insufficiency may gain some nephro-protective effect from the adminis-
tration of ^-acetyl cysteine (27) or from hydration with sodium bicarbonate
(28) prior to contrast administration.

Meningitis

Clinical Presentation

Meningitis most frequently presents as headache. The majority of patients
also have fever (>38.5°C) and more than half have neck stiffness/nuchal
rigidity. Other symptoms include vomiting, mental status changes, and less

282 Schwartz and White

commonly, seizures (15,16,20,29). In one series, a patient presented with
facial nerve palsy (30).

Bacteriology

As with other sources for bacterial meningitis, S. pneumoniae is the most
common organism causing meningitis in the setting of sinusitis. Another
causative organism, in order of decreasing incidence, is S. aureus (especially
in sphenoid sinusitis). Rarely, isolates include H. influenzae, Neisseria menin-
gitidis, and gram-negative aerobic bacilli (29). The primary pathogen in
patients with AIDS is Cryptococcus neoformans (29).

Diagnosis

Although meningitis is routinely diagnosed by lumbar puncture and cere-
brospinal fluid analyses, the performance of lumbar puncture in the setting
of a space-occupying lesion risks trans-tentorial uncal herniation, particularly
when the mass is in the temporal fossa (31). As signs and symptoms of space-
occupying infection can be subtle or be obscured by the findings that suggest
meningitis, CT scan should be obtained prior to lumbar puncture when
sinusitis has been diagnosed or clinically suspected. When suspected or
known, space-occupying infection (abscess) or increased intracranial pressure
precludes lumbar puncture; diagnosis of meningitis can sometimes be made on
the basis of contrast-enhanced magnetic resonance imaging. Younis found
MRI diagnostic in 14 of 21 patients with meningitis-complicating sinusitis;
CT was diagnostic in 3 of 21 patients (22). Contrast-enhanced MRI typically
demonstrates dural enhancement along the falx cerebri, tentorium, and dural
convexity. Conversely, CT and unenhanced MRI are usually normal, with the
exception of findings of sinusitis (22).

Treatment

Isolated meningitis, confirmed by absence of space-occupying lesions on CT
scanning or MRI, is treated exclusively with antibiotics. As meningitis can
progress rapidly in a fulminating course, especially with the predominance
of pneumococcus as the primary pathogen, antibiotic therapy should be
initiated as soon as the diagnosis is suspected and prior to neuro-imaging
or lumbar puncture (32). Blood culture, on the other hand, should be
obtained prior to the administration of antibiotics, as blood collection will
not delay therapy.

S. pneumoniae meningitis has a case fatality rate of 20% with significant
morbidity among survivors (33). Dexamethasone, when administered either
before or with first antibiotic dose, has been shown to decrease unfavorable
outcome and mortality (34,35). On the other hand, because vancomycin will
only reach the cerebrospinal fluid (CSF) through inflamed meninges, admin-
istration of dexamethasone may decrease CSF antibiotic penetration (36). In
areas with high prevalence of antibiotic-resistant S. pneumoniae, one must

Complications of Sinusitis and Their Management 283

weigh the potential decrease in sequellae with the possibility of decreased
antibiotic efficacy. Dexamethasone may also be warranted for treatment of
cerebral edema secondary to intracranial infection; however, steroid therapy
may also contribute to immunosuppression and its role in intracranial
suppuration, exclusive of isolated meningitis, has not been rigorously studied.
Choice of initial antibiotic therapy consists of a parenteral third-generation
cephalosporin (cefotaxime or ceftriaxone) combined with vancomycin to
cover resistant S. pneumoniae. Further refinement of antibiotic choice should
then be made upon review of CSF gram stain and again after results of CSF
culture.

In patients with AIDS and contraindication for lumbar puncture, one
would need to initiate intravenous therapy with amphotericin B to cover
cryptococcus.

Brain Abscess

Clinical Presentation

Headache and fever are the initial prominent symptoms. Moreover, nausea
and vomiting are also frequent. Altered mental status — including confusion,
decreased mentation, and/or behavioral changes — is an alarming symptom
which should be a tip-off that a serious intracranial process is occurring
beyond sinusitis or other causes of fever and headache. Intracerebral abscess,
in particular, may be associated with behavioral changes, secondary to asso-
ciated cerebritis. As the majority of brain abscesses from sinusitis occur in
the frontal lobes, relatively neurologically silent, these mental status changes
may be subtle and unlikely to be associated with focal neurologic deficits (20).
Intracerebral abscess also presents a significant risk for seizure development.

Bacteriology

Intracranial and extra-axial abscesses often yield multiple organisms, both
aerobic and anaerobic, including Fusobacterium spp., anaerobic gram-negative
bacilli (Prevotella and Porphyromonas spp.), anaerobic and microaerophillic
streptococci, Propionibacterium spp., Eikenella corrodens, and Staphylococcus
spp. However, intraoperative cultures of intracranial abscess cavities may yield
no identifiable organism. In the majority of such cases, patients have received
oral and/or parenteral antibiotics for the underlying sinusitis. There is often
a correlation between the cultures obtained from the sinuses and from
the intracranial abscess cavities (37,38). Nevertheless, in some patients the
culture results do not correlate between the two sites (15,17). This is likely
because of the different microenvironment of intracranial abscess cavities rela-
tive to the paranasal sinuses. Brook also suggests that variability in collection
techniques, culturing for strict anaerobes, and improper specimen handling to
prevent contamination may account for differences in the final organism

284 Schwartz and White

identification (39). In some cases, however, the presence of sinusitis may be
coincidental and not causative of the intracranial suppuration.

Diagnosis

Computed tomography can demonstrate cerebral abscess on the basis of low
density attenuation of involved parenchyma and mass effect as well as the
later development of ring-enhancement from collagen encapsulation of the
necrosis. However, MRI can also demonstrate the early cerebritis phase
of abscess formation. In addition, MRI T-l weighted images can better
demonstrate sulcus effacement and mass effect (22).

Treatment

Intracranial abscesses are usually treated by three complementary tactics:
(1) immediate initiation of parenteral broad-spectrum antibiotic therapy
(prior to neuro-imaging) with good blood-brain barrier traversal; (2) opera-
tive drainage of intracranial abscess; and (3) drainage of infected sinuses.

The most commonly used empirical antibiotic choices include the com-
bination of a third-generation cephalosporin (cefotaxime or ceftreaxone), a
penicillinase-resistant penicillin, and metronidazole. Vancomycin may sub-
stitute the penicillinase-resistant penicillin to cover resistant S. pneumoniae.
Subsequent antibiotic administration needs to be adjusted based on results
from operative cultures. Intravenous antibiotics should be continued for
four to eight weeks to maintain high CSF drug levels. As healing occurs
and the blood-brain barrier is repaired, adequate drug levels will be
achieved only with parenteral administration (15).

A trial of antibiotic therapy alone may be warranted in a selected subset
of patients who are deemed clinically stable (40,41). This group would include
those in whom the risk of surgery is felt to be inordinately great, either because
of the increased neurosurgical risk inherent in operating on deep, dominant, or
multiple dispersed lesions or because of increased surgical risk from other
health factors. Those patients with early, small abscesses may fall into this
category as well, based on relative risk. Patients forgoing surgical drainage
should be imaged at least weekly for the first two weeks and bi-weekly through
the eight-week course of antibiotic therapy. Clinical deterioration or lack of
clinical improvement would necessitate reconsideration of surgical drainage.

Sinus drainage may be performed by open technique or, more com-
monly, endoscopic technique and should follow intracranial drainage, but
during the same course of anesthesia.

Drainage procedures commence as soon as possible after localization of
the purulent collection. Although small cerebral abscesses can be treated with
a trial of antibiotic therapy, larger ones must be drained either with an open
craniotomy or with CT-localized needle drainage procedures, depending on
abscess location. Because of seizure risk attendant with cerebral abscess,

Complications of Sinusitis and Their Management

285

prophylactic anticonvulsant therapy is warranted and should be initiated as
soon as the diagnosis is established.

Extra-axial Abscess (Subdural and Epidural Abscesses)

Clinical Presentation

Patients with subdural abscess, as with other intracranial infections, usually
present with headaches, fever, and meningismus. Deterioration of neurologic
status can progress rapidly, however, with decreased consciousness and devel-
opment of seizures (42).

Epidural abscess develops more insidiously, and symptoms may be non-
specific and overshadowed by the symptoms of the patient's sinusitis (Fig. 4)
Patients may not present for several weeks, until neurologic deterioration or
seizures prompt CNS imaging (42).

Bacteriology

The bacteriology of subdural and epidural abscesses is similar to that pre-
viously described for intracerebral abscess (39).

Figure 4 Epidural empyema in a teenager being treated for sinusitis who presented
to an emergency department because of new onset seizure.

286 Schwartz and White

Diagnosis

MRI is considered as the imaging modality of choice to diagnose both
epidural and subdural suppurative collections because of its superior ability
to detect abscess not evident on routine CT. In the event that MRI is
unavailable or contraindicated, a contrasted CT scan can still reveal the
diagnosis in most cases.

Treatment

Subdural pus collections are often loculated and extensive over the cerebral
hemisphere and historically have required craniotomy. Multiple burr holes
using CT stereotactic localization are now being employed more frequently (15).

Epidural abscesses have also been traditionally treated with neurosur-
gical drainage. However, a more conservative approach has been suggested
for small epidural abscesses, utilizing endoscopic or trephination for sinus
drainage and intravenous antibiotics for six weeks. Heran et al. (21) used
this approach on a group of four children with epidural abscess with a mean
abscess size of 3 cm x 3 cm x 1 cm, without neurologic deficits. Although two
patients had transient worsening headache and fever over the first 48 hours,
there was no worsening on follow-up imaging, and patients improved over
the subsequent two weeks without neurosurgical intervention. Antibiotic
therapy was continued for six weeks.

In some cases of epidural abscess with frontal sinusitis and osteomyelitis,
exenteration of the frontal sinus (removal of anterior and posterior tables as
well as obliteration of the nasofrontal recess) may be warranted (15).

As with intracerebral abscess, drainage of involved sinuses should be
coordinated with the neurosurgical procedures and antibiotic therapy
should be initiated as soon as possible.

Dural Sinus Thrombosis/Thrombophlebitis

Clinical Presentation

When complicating sinusitis, dural sinus thrombosis rarely occurs in isolation
from other intracranial complications. On the other hand, isolated dural sinus
thrombosis has myriad causes of which facial/head/neck infections account
for only 8%. Patients with major venous sinus thrombosis often appear septic,
with high fever, tachycardia, hypotension, and confusion. Headache is almost
invariably present. Because of associated cerebral edema and ischemic and/or
hemorrhagic infarction, both generalized and focal neurologic symptoms and
signs are often present, including decreased or altered consciousness, seizures,
paralysis, aphasia, and cranial nerve deficits (26,43-45). In one study, patients
who presented with more generalized neurologic impairment, suggesting
intracranial hypertension, actually had more diffuse involvement of venous
sinuses with thrombosis than did patients with a more focal presentation.

Complications of Sinusitis and Their Management 287

Paradoxically, the patients with the intracranial hypertension presentation
had better outcomes than those with focal neurologic impairment (43).

In addition to fever and headache, eye signs will predominate early
in the course of septic cavernous sinus thrombosis. As orbital venous
congestion progresses, chemosis, periorbital edema, and proptosis can
occur. Fundoscopy may reveal papilledema and retinal venous congestion.
Ocular movement may become restricted by intraorbital edema and subse-
quently by oculomotor, trochlear, and abducens nerve palsies. The abducens
nerve in particular may be affected early owing to its course within the
cavernous sinus, and thus lateral nerve palsy may be noted. Although ocular
findings are unilateral initially, progression to bilateral involvement occurs
rapidly, usually within 48 hours (25,26).

Bacteriology

For cavernous sinus thrombophlebitis, the most common offending organ-
ism is S. aureus, accounting for two-thirds of cases (26,46). Other less common
organisms include S. pneumoniae, gram-negative bacilli, and anaerobes (46).

Diagnosis

Venography can be used for diagnosing venous sinus thrombosis, but its use
has largely been supplanted by contrasted MRI with venography (MRV).
Contrasted CT scan can demonstrate filling defects within the venous sinus
(25), if contraindication for MRI or MRI itself is unavailable. Occasionally
the diagnosis is established in the operating room.

Treatment

For septic venous dural sinus thrombosis, management consists of medical
therapy in conjunction with drainage of affected pneumatic sinuses and
associated areas of intracranial purulence. In addition, anticoagulation
has been advocated to facilitate antibiotic penetration, to decrease further
propagation of septic thrombus, and to limit a precipitous rise in intra-
cranial pressure. Others have argued that anticoagulation risks increased
systemic or intracranial bleeding, including intraorbital bleeding and intra-
cranial bleeding from cortical infarcts or from carotid rupture if the carotid
has become infected in it course through the cavernous sinus. Of note, there
have been only two cases of intracranial bleeding secondary to anticoagula-
tion and septic cavernous sinus thrombosis (26,47) and no reported cases of
intraorbital bleeding. There is also a theoretical risk of further propagation
of intracranial infection secondary to a dispersal of septic emboli as the
thrombus breaks down.

However, in a small retrospective series of 31 patients with venous sinus
thrombosis, Soleau and colleagues demonstrated that observation alone
had the poorest results, with clinical improvement in only 2 of 5 patients
and hemorrhagic complications in 4 of 5 with one death, whereas systemic

288 Schwartz and White

anticoagulation resulted in improvement in 75% (8) of patients who were so
treated, with no worsening of hemorrhage even in those patients with pre-
treatment hemorrhage; best results were obtained with a combination of
mechanical endovascular clot dissolution and systemic anticoagulation,
resulting in clinical improvement in 7 of 8 patients and one death. Chemical
thrombolysis (urokinase or tissue plasminogen activator) was successful in
restoring venous sinus patency in 6 of 10 patients, but at a significant rate
of fatal intracranial hemorrhage (30%) (45). These numbers must be consid-
ered in the context of the study limitations inherent with small study size and
retrospective data collection.

Options for anticoagulation include intravenous heparin and low-
molecular weight heparin, which may have a lower risk of bleeding but is
less rapidly reversed. Once the patient becomes stabilized, conversion to oral
anticoagulation can be undertaken. Although degree of anticoagulation has
also not been definitively established, a general guideline would be essen-
tial to maintain an APTT ratio of 1.5 to 2.5 and an INR of 2.0 to 3.0
(26). Duration of anticoagulation should continue until follow-up neuro-
imaging confirms dissolution of the thrombus, about several weeks; long-
term anticoagulation is not required.

REFERENCES

1. Guillen A, Brell E, Cardona E, Claramunt E, Costa J. Pott's puffy tumour: still
not an eradicated entity. Child's Nerv Syst 2001; 17:359-362.

2. Verbon A, Husni R, Gordon SM, Lavertu P, Keys TF. Pott's puffy tumor due
to Haemophilus influenzae: case report and review. Clin Infect Dis 1996; 23:
1305-1307.

3. Laine FJ, Smoker WR. The ostiomeatal unit and endoscopic surgery: anatomy,
variation and imaging findings in inflammatory diseases. AJR 1992; 159:
849-857.

4. Clayman GL, Adams GL, Paugh DR, Koopman CF. Intracranial complications
of paranasal sinusitis: a combined institutional review. Laryngoscope 1991;
101:234-239.

5. Younis RT, Lazar RH, Bustillo A, Anand VK. Orbital infection as a compli-
cation of sinusitis: are diagnostic and treatment trends changing?. Ear Nose
Throat J 2002; 81:771-775.

6. Harris GJ. Subperiosteal abscess of the orbit. Age as a factor in the bacteriology
and response to treatment. Ophthalmology 1994; 101:585-593.

7. Harris GJ, Bair RL. Anaerobic and aerobic isolates from a subperiosteal orbital
abscess in a four year old. Arch Ophthalmol 1996; 114:98-100.

8. Brook I, Friedman EM, Rodriques WJ, Controni G. Complications of sinusitis
in children. Pediatrics 1980; 66:568-572.

9. Chandler JR, Langenbrunner DJ, Stevens ER. The pathogenesis of orbital
complications in acute sinusitis. Laryngoscope 1970; 80:1414-1428.

Complications of Sinusitis and Their Management 289

10. Schwartz GR, Wright SW. Changing bacteriology of periorbital cellulitis. Ann
Emerg Med 1996; 28:617-620.

11. Garcia GH, Harris GJ. Criteria for nonsurgical management of subperiosteal
abscess of the orbit. Analysis of outcomes 1988-1998. Ophthalmology 2000;
107:1454-1458.

12. Uzeategui N, Warman R, Smith A, Howard CW. Clinical practice guidelines for the
management of orbital cellulitis. J Pediatr Ophtalmol Strabismus 1998; 35:73-79.

13. Sobol SE, Marchand J, Tewfik TL, Manoukian JJ, Schloss MD. Orbital
complications of sinusitis in children. J Otolaryngol 2002; 31:131-136.

14. Rahbar R, Robson CD, Petersen RA, DiCanzio J, Rosbe KW, Mcgill TJ.
Management of orbital subperiosteal abscess in children. Arch Otolaryngol
Head Neck Surg 2001; 127:281-286.

15. Gallagher RM, Gross CW, Phillips CD. Suppurative intracranial complications
of sinusitis. Laryngoscope 1998; 108(11 Pt 1):1635-1642.

16. Giannoni CM, Stewart MG, Alford EL. Intracranial complications of sinusitis.
Laryngoscope 1997; 107(7):863-867.

17. Giannoni C, Sulek M, Friedman EM. Intracranial complications of sinusitis:
a pediatric series. Am J Rhinol 1998; 12(3): 173-178.

18. Hytonen M, Atula T, Pitkaranta A. Complications of acute sinusitis in
children. Acta Otolaryngol Suppl 2000; 543:154-157.

19. Ong YK, Tan HK. Suppurative intracranial complications of sinusitis in
children. Int J Pediatr Otorhinolaryngol 2002; 66(1):49.

20. Albu S, Tomescu E, Bassam S, Merca Z. Intracranial complications of sinusitis.
Acta Otorhinolaryngol Belg 2001; 55(4):265-272.

21. Heran NS, Steinbok P, Cochrane DD. Conservative neurosurgical management
of intracranial epidural abscesses in children. Neurosurgery 2003; 53(4):893-897
(discussion 7-8).

22. Younis RT, Anand VK, Davidson B. The role of computed tomography and
magnetic resonance imaging in patients with sinusitis with complications.
Laryngoscope 2002; 11 2(2): 224-229.

23. Younis RT, Lazar RH, Anand VK. Intracranial complications of sinusitis: a
15-year review of 39 cases. Ear Nose Throat J 2002; 81(9):636-638, 40-42, 44.

24. Bradley PJ, Manning KP, Shaw MD. Brain abscess secondary to paranasal
sinusitis. J Laryngol Otol 1984; 98(7):719-725.

25. Amran M, Sidek DS, Hamzah M, Abdullah JM, Halim AS, Johari MR,
Hitam WH, Ariff AR. Cavernous sinus thrombosis secondary to sinusitis. J
Otolaryngol 2002; 3 1(3): 165-1 69.

26. Bhatia K, Jones NS. Septic cavernous sinus thrombosis secondary to sinusitis:
are anticoagulants indicated? A review of the literature. J Laryngol Otol 2002;
116(9):667-676.

27. Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C.
Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet
2003; 362(9384):598-603.

28. Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ,
Bersin RM, Van Moore A, Simonton CA, Rittase RA, Norton HJ, Kennedy TP.
Prevention of contrast-induced nephropathy with sodium bicarbonate: a rando-
mized controlled trial. JAMA 2004; 291(19):2328-2334.

290 Schwartz and White

29. Younis RT, Anand VK, Childress C. Sinusitis complicated by meningitis:
current management. Laryngoscope 2001; 1 1 1(8): 1338—1342.

30. Clayman GL, Adams GL, Paugh DR, Koopmann CF Jr. Intracranial compli-
cations of paranasal sinusitis: a combined institutional review. Laryngoscope
1991; 101(3):234-239.

3 1 . Archer BD. Computed tomography before lumbar puncture in acute meningitis: a
review of the risks and benefits. CMAJ 1993; 148(6):961-965.

32. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial menin-
gitis: risk stratification for adverse clinical outcome and effect of antibiotic
timing. Ann Intern Med 1998; 129(1 1):862-869.

33. Schuchat A, Robinson K, Wenger JD, Harrison LH, Farley M, Reingold AL,
Lefkowitz L, Perkins BA. Bacterial meningitis in the United States in 1995. Active
Surveillance Team. N Engl J Med 1997; 337(14):970-976.

34. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis.
N Engl J Med 2002; 347(20): 1549-1 556.

35. van de Beek D, de Gans J, Mclntyre P, Prasad K. Steroids in adults with acute
bacterial meningitis: a systematic review. Lancet Infect Dis 2004; 4(3): 139-143.

36. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med
1997; 336(10):708-716.

37. Brook I, Frazier EH. Microbiology of subperiosteal orbital abscess and
associated maxillary sinusitis. Laryngoscope 1996; 106(8): 1010-1013.

38. Brook I, Friedman EM, Rodriguez WJ, Controni G. Complications of sinusitis
in children. Pediatrics 1980; 66(4): 568-572.

39. Brook I. Aerobic and anaerobic bacteriology of intracranial abscesses. Pediatr
Neurol 1992; 8(3):210-214.

40. Calfee DP, Wispelwey B. Brain abscess. Semin Neurol 2000; 20(3):353-360.

41. Rosenblum ML, Hoff JT, Norman D, Edwards MS, Berg BO. Nonoperative
treatment of brain abscesses in selected high-risk patients. J Neurosurg 1980;
52(2):217-225.

42. Bockova J, Rigamonti D. Intracranial empyema. Pediatr Infect Dis J 2000;
19(8):735-737.

43. Bergui M, Bradac GB. Clinical picture of patients with cerebral venous thrombo-
sis and patterns of dural sinus involvement. Cerebrovasc Dis 2003; 16(3):21 1-216.

44. Ferro JM, Canhao P, Stam J, Bousser MG, Barinagarrementeria F. Prognosis
of cerebral vein and dural sinus thrombosis: results of the International Study
on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004; 35(3):
664-670.

45. Soleau SW, Schmidt R, Stevens S, Osborn A, MacDonald JD. Extensive experi-
ence with dural sinus thrombosis. Neurosurgery 2003; 52(3):534-544 (discus-
sion 42-44).

46. Ebright JR, Pace MT, Niazi AF. Septic thrombosis of the cavernous sinuses.
Arch Intern Med 2001; 161(22):2671-2676.

47. Southwick FS, Richardson EP Jr, Swartz MN. Septic thrombosis of the dural
venous sinuses. Medicine (Baltimore) 1986; 65(2):82— 106.

48. Rosenfeld EA, Rowley AH. Infectious intracranial complications of sinusitis,
other than meningitis, in children: 12-year review. Clin Infect Dis 1994; 18(5):
750-754.

SECTION V. SINUSITIS AND SPECIFIC DISEASES

Sinusitis and Asthma

Frank S. Virant

University of Washington, Seattle, Washington, U.S.A.

INTRODUCTION

Sinusitis and asthma are commonly seen simultaneously in clinical practice
(1-3). In fact, nearly 50% of asthmatics demonstrate upper airway symptoms
and radiographic evidence of rhinosinusitis (4-11). Chronic sinusitis and
asthma share several pathophysiological features: chemical mediators, e.g.,
histamine, cysteinyl leukotrienes, and prostaglandin D 2 ; cytokines, e.g.,
interleukin-4 (IL-4), IL-5, IL-9, IL-13, and CCL11 (eotaxin); and cellular
mediators, principally eosinophils and T H 2 lymphocytes (12-14). These
observations have led to the concept of "one airway . . . one disease" rather
than the idea of isolated upper and lower airway disorders. At the same time,
numerous clinical studies have demonstrated that aggressive medical or
surgical treatment of sinusitis improves asthma, suggesting that upper airway
inflammation may actually have a causative role in lower airway disease.

This chapter will explore the historical association of sinusitis and
asthma, the common inflammatory basis of these disorders, and evidence
that sinus therapy can improve concomitant asthma. A brief discussion of
possible mechanisms by which sinusitis could exacerbate asthma is followed
by implications for patient management.

HISTORICAL ASSOCIATION OF SINUSITIS AND ASTHMA

About two millennia ago, it was Galen's belief that sinusitis caused asthma;
this assertion was based on the notion that abnormal secretions dripped

291

292 Virant

from the skull into the lungs, inducing irritation and wheezing. This idea
was generally embraced, leading to nasal irrigation and purging to help treat
asthma. Ironically, this notion was abandoned in the mid- 1600s when early
anatomists demonstrated that no direct connection between the skull and
lungs existed (15).

Interest in the association between sinusitis and asthma was revived in
1870 when Kratchmer showed that chemical irritation of animal upper air-
ways with ether, cigarette smoke, or sulfur dioxide caused bronchoconstric-
tion (16). At the beginning of the twentieth century, Dixon and Brodie also
demonstrated that nasal mechanical or electrical stimuli could induce reflex
lower airway obstruction (17).

Clinical observations early in the twentieth century reaffirmed that
upper and lower airway diseases were frequently coexistent. Gottlieb obser-
ved that 31 of 1 17 adult asthmatics also had clinical evidence of sinusitis (4).
Chobot and Weille (5,6) reported that sinus symptoms were present in as
many as 72% of children and adults with asthma. Bullen's review of 400
sinusitis patients revealed a 12% incidence of asthma with many noting that
sinus symptoms preceded the appearance of their asthma (18).

Over the last three decades, several studies in adults and children
demonstrated that 21 to 31% of asthmatics have significantly abnormal sinus
radiographs (mucosal thickening >5mm, air-fluid levels, or opacification)
(7-9,19). In contrast, only 5 to 6% of asymptomatic adults and children
showed such radiographic sinus changes (20,21). Collectively, these reports
suggest that asthmatics are four to six times more likely to display sinus
pathology than healthy non-asthmatics — strong evidence of an association
between these diseases.

CHEMICAL, CYTOKINE, AND CELLULAR MEDIATORS
OF AIRWAY DISEASE

Further evidence of a relationship between sinusitis and asthma is apparent
after comparing chemical, cytokine, and cellular mediators in these diseases
(Table 1).

Chemical Mediators

Levels of histamine, prostaglandin D 2 , and the cysteinyl leukotrienes (LTC4,
LTD 4 , and LTE 4 ) are all elevated in the maxillary sinuses of patients with
chronic eosinophilic sinusitis and in the bronchoalveolar lavage fluid of
patients with asthma (12-14,22).

Cytokine Mediators

Both chronic sinusitis and asthma may demonstrate a variety of common
cytokine mediators, including IL-4, IL-5, IL-9, IL-13, CCL11 (eotaxin),

Sinusitis and Asthma

293

Table 1 Chemical, Cytokine, and Cellular Mediators of Airway Disease

Type

Mediator

Effector functions

Chemical

Cytokine

Cellular

Histamine

Prostaglandin D 2
Leukotriene C 4 , D 4 , E 4

Interleukin 4
Interleukin 5
Interleukin 9
Interleukin 13
CCL 1 1 (eotaxin)
Tumor necrosis factor oe
Eosinophils

T H 2 lymphocytes a

Vasodilation, hypersecretion,

bronchoconstriction
Smooth muscle constriction
Vasodilation, hypersecretion,

bronchoconstriction
Directs B cell to produce specific IgE
Clonal growth factor for eosinophils
T cell, mast cell growth factor
Augments specific IgE secretion
Chemoattractant for eosinophils
Augments inflammation (fever, pain)
Inflammation, airway

hyperresponsiveness
Produce/release IL-4, IL-5, IL-9, IL-13

a T H 2 lymphocytes are a major mediator in allergic rhinosinusitis and allergic asthma; these cells
are a less significant component in non-allergic airway inflammation.

and TNF-a. In patients with underlying allergic disease, all of these media-
tors are present throughout the airway; in non-allergic eosinophilic airway
disease, IL-5, eotaxin, and TNF-a are predominating features (23-26).

Cellular Mediators

Almost 80 years ago, Hansel (27) remarked on the histological similarities
between chronic sinusitis and persistent asthma: marked eosinophilia, gland-
ular hyperplasia, and stromal edema. More recently, Harlin and coworkers
examined the role of the eosinophil in the induction of chronic sinusitis. They
examined sinus tissue for the presence of eosinophils and/or major basic pro-
tein (MBP — a significant eosinophil-derived granule protein) in 26 adoles-
cent and adult patients with chronic sinusitis. All 13 sinus samples from
asthmatics and six of seven samples from allergic rhinitis patients showed sig-
nificant eosinophils and MBP while none of the six patients with chronic
sinusitis without asthma or allergic rhinitis showed significant tissue eosino-
phils (one had MBP) (28).

Hisamatsu and colleagues (29) showed that MBP at physiologic con-
centrations in vitro could cause epithelial damage and ciliary dysmotility
in sinus mucosal tissue. They concluded that eosinophils could play an
important role in increasing the risk for bacterial sinusitis and in the induc-
tion of nasal hyperresponsiveness through cholinergic pathways. Poten-
tially, this effect of upper airway eosinophils could also affect bronchial
hyperresponsiveness through the same neural pathways (30).

294 Virant

IMPACT OF MEDICAL SINUS THERAPY ON ASTHMA

Over the last two decades, several groups have studied the effect of medical
treatment for sinusitis in children with asthma (31). Businco et al. (32) stu-
died 55 asthmatic children with mild to severe maxillary sinus thickening.
After 30 days therapy with either nasal corticosteroid plus antihistamine/
decongestant or ampicillin plus antihistamine/decongestant, all children
showed decreased asthma severity and sinus radiographic improvement. In
1983, Cummings and coworkers compared antibiotics plus nasal corticos-
teroids and decongestants versus placebo in the treatment of asthmatic
children with opacified or markedly thickened maxillary sinuses. Although
pulmonary function and bronchial hyperresponsiveness were not signifi-
cantly changed in either group, the children on active treatment had
reduced asthma symptoms and less need for bronchodilators and oral corti-
costeroids (33). The next year, Rachelefsky et al. (34) treated 48 children
who had at least a three-month history of sinusitis and asthma; treatment
included prolonged antibiotics and, in select cases, antral lavage. Nearly
80% of the subjects were able to discontinue bronchodilators and more
than 50% returned to normal lung function. Independently in 1984, Friedman
and colleagues followed the effect of antibiotic treatment in eight children
with acute sinusitis and asthma exacerbation; seven of the children showed
significant improvement in asthma symptoms. Although pulmonary func-
tion did not statistically improve, response to bronchodilator doubled
compared with pre-study levels (35).

More recently, Oliveira studied 46 allergic and 20 non-allergic children
with sinusitis and asthma. Therapy included 21 days of antibiotics, antihis-
tamines, decongestants, nasal saline irrigation, and five days of oral corti-
costeroids. By the end of the study, only the children who demonstrated
radiographic resolution of their sinusitis had improved pulmonary function
and bronchial hyperresponsiveness (36). Additional evidence that upper air-
way inflammation can affect lower airway disease comes from Corren's
research on patients with seasonal allergic rhinitis/bronchial hyperrespon-
siveness; seasonal nasal corticosteroid treatment alone could prevent
increased bronchial hyperresponsiveness (37,38).

IMPACT OF SURGICAL SINUS THERAPY ON ASTHMA

In contrast to medical treatment, the impact of sinus surgical intervention
on asthma is variable (39). In 1920, Van der Veer published his clinical
observations that asthma was worsened by sinonasal surgery (40). Nearly
a decade later, Francis published a series of 13 patients with surgical inter-
vention for chronic sinusitis; nine demonstrated worsening of their lung
symptoms after operation (41).

In contrast, Weille's 1936 study of 500 asthmatics revealed a 72%
incidence of sinusitis. Ultimately, over half of the 100 subjects who had sinus

Sinusitis and Asthma 295

surgery experienced an improvement in asthma. Ten became totally asymp-
tomatic. At the same time, over 40% of the sinusitis patients who did not
have surgery also had asthma improvement (6). Davison's study in 1969
observed that all but one of his 24 patients had at least a 75% improvement
in asthma symptoms after sinus drainage (42). In the early 1980s, Slavin and
coworkers described similar results in 33 adult sinus surgical patients: 85%
had significantly better asthma control and were able to markedly reduce
their requirement for oral corticosteroids (43). Over a period of months,
though, 40% of those who initially experienced improvement following
surgery demonstrated asthma exacerbations. Werth reported on 22 children
with chronic sinusitis and asthma in 1984; asthma markedly improved in 20
after sinus surgery (44). The same year, Juntunen et al. described 15 children
with persistent chronic sinusitis despite inferior meatal antrostomy and
adenoidectomy; even this degree of surgical intervention appeared to
improve asthma symptoms and lung function (45).

The last decade has spawned numerous additional studies, primarily,
though not exclusively, in adults with nasal/sinus polyps; uniformly, endo-
scopic sinus surgical intervention improved asthma (46-52).

SINUSITIS AS A TRIGGER FOR ASTHMA— MECHANISMS

Nearly 80 years ago, Gottlieb suggested several ways in which sinusitis
might excerbate asthma (Table 2): neural reflexes pathways, nasal obstruc-
tion, sinus inflammatory secretions draining into the lower airway, and
indirect delivery of inflammatory "signals" through the systemic circulation
(4). Recently other researchers have suggested decreased (3-adrenergic
responsiveness as an additional possible mechanism (30,35). Although
controversies remain, the actual process in individual patients is probably
a combination of one or more mechanisms (53).

Neural Reflex Pathways

In the early twentieth century, Sluder proposed that asthma was caused
by reflexes intiated in the nose and sinuses (54). Subsequent animal research

Table 2 Sinusitis as a Trigger for Asthma — Mechanisms

Neural reflex pathways: trigeminal afferents — ► CNS — ► vagal efferents
Nasal obstruction: decreased air filtration, humidification, heating
Sinus inflammatory secretions draining to lower airway: direct effect
Sinus inflammatory mediators exerts systemic effect on lungs: indirect effect
Sinusitis reduces [^-adrenergic responsiveness: unknown pathway

296 Virant

after upper airway "irritation" yielded controversial results, including no
change in lower airway resistance, bronchodilation, and bronchoconstriction.

In 1969, Kaufman et al. (55) studied non-asthmatics with tic doloreux,
inducing increased lower airway resistance by delivering silica into the upper
airway. After surgical treatment of tic doloreux with trigeminal nerve resec-
tion, this response was blocked, leading the authors to postulate a "nasal-
bronchial reflex" mediated through trigeminal affe rents and vagal efferents.
Other groups demonstrated that nasal provocation with cold air, sulfur
dioxide, or petrolatum could also induce pulmonary resistance changes after
exposure (56-58).

Salome demonstrated that histamine nasal challenge in symptomatic per-
ennial allergic rhinitis patients could induce at least a 10% decrease in forced
expiratory volume in one second (FEVi) (59). Three other studies on asympto-
matic seasonal allergic patients failed to show such a change, suggesting that
baseline nasal inflammation was important for this response (60-62).

Corren and coworkers evaluated 10 patients with a previous history
of asthma exacerbation during periods of seasonal allergic rhinitis (37).
Although spirometry was stable, lower airway methacholine responsiveness
increased 30 minutes after nasal radionuclide-labeled nasal antigen chal-
lenge — an effect which lasted for 4 hours. A neural mechanism is suggested
by the rapidity of this change and verification that antigen did not reach the
lower airway.

A decade ago, Brugman et al. (63) studied this issue in rabbits. After
the induction of sterile sinus inflammation, they also found no change in
lung function but did note increased bronchial responsiveness to histamine.
It appeared that these changes could be blocked by preventing inflammatory
exudate from progressing beyond the larynx, suggesting that direct deposi-
tion of mediators into the lungs was an important mechanism for this effect.
Bronchial lavage in "positive reactor" rabbits failed to show histologic signs
of inflammation, however, again raising the possibility of a neural pathway.

Nasal Obstruction

Nasal/sinus edema and increased purulent secretions lead to nasal obstruc-
tion in patients with rhinosinusitis. This is probably an important mechan-
ism for asthma exacerbation in these patients since several important nasal
functions may be bypassed: filtration, humidification, and warming of
inspired air (64). When this occurs, the patient is at risk for increased lower
airway exposure to allergen, irritants, dry air, and cold air — all known trig-
gers for asthma.

Sinus Inflammatory Secretions Draining to Lower Airway

Based on studies nearly a century ago, clinicians speculated that inflamma-
tory material from the upper airway could directly drain into the lower

Sinusitis and Asthma 297

airway and cause symptoms (4-6,18). In recent years, Huxley (65) showed
that nearly 50% of subjects would aspirate upper airway material (radiola-
beled) into the lung during sleep or depressed consciousness. This conclu-
sion was criticized because most aspirators had artificially induced
subconsciousness and perhaps simply could not clear their pharynx nor-
mally. A similar subsequent study by Winfleld failed to show significant
aspiration episodes (66). Bardin et al. (67) examined the pathway of radiola-
beled particles placed in the maxillary sinuses of 1 3 chronic sinusitis patients
(nine with asthma). Although radioactive particles were observed in the nose,
sinuses, pharynx, and esophagus, no material could be seen in the lower
airway. Collectively, these studies suggest that direct aspiration of inflamma-
tory drainage into the lungs is a minor mechanism for asthma at best.

Sinus Inflammatory Mediators Exerting Systemic Effect on Lungs

Bronchial provocation in asthmatics causes an increase in systemic chemotac-
tic factors and it is known that lower airway disease is more common in
patients with systemic inflammatory disorders (68,69). Together, these studies
suggest the possibility that sinus inflammatory mediators could induce asthma
through systemic pathways. Results from the Brugman study, however, seem
to suggest this is unlikely (63). When the rabbits were placed so that inflamma-
tory drainage could not progress past the larynx, lower airway hyper-
responsiveness was not observed. Since the degree of sinus inflammation
was similar in all test rabbits (despite positioning), it would be anticipated that
any systemic mediator effects should also be consistent (and all rabbits would
show an effect). Results suggest that if present, a systemic pathway alone is not
adequate to enhance bronchial responsiveness.

Sinusitis Reduces p-Adrenergic Responsiveness

Friedman et al. (35) observed that asthmatics demonstrated increased
response to (3-adrenergic medication after their sinusitis was successfully
treated. The authors speculated that sinusitis might somehow reduce overall
airway (3-adrenergic responsiveness, possibly down-regulating receptors.
This could be a spurious effect and simply due to an increased use of
(3-adrenergic medication in active asthma (a known down-regulator of
(3-receptors). This postulated mechanism remains a conjecture until further
appropriate (3-adrenergic receptor studies can be performed.

CLINICAL IMPLICATIONS

Given the association between sinusitis and asthma, it is important to
consider both diseases, even when the patient history and complaints focus
only on a single entity (Fig. 1).

298

Virant

Clinical Implications

Acute or chronic sinusitis may serve as a trigger for asthma: consider sinusitis with

prolonged URI symptoms during asthma exacerbation

Treatment leading to resolution of sinusitis will improve asthma

Persistent cough/dyspnea during sinusitis exacerbation may reflect asthma: check

spirometry, response to bronchodilator, methacholine responsiveness

Prevention of sinusitis reduces the need for antibiotics and increased asthma treatment

Figure 1 Association between sinusitis and asthma.

Sinusitis and Asthma 299

Evaluation of Chronic Sinusitis

When the clinical diagnosis of sinusitis is made, careful attention should be
directed to the history of cough, dyspnea, or overt wheezing. If any of these
symptoms is present, lung function should be measured (peak expiratory
flow rate or spirometry). The importance of even subtle lung function
abnormalities can be confirmed by measuring the response to a bronchdila-
tor — significant improvement reflects bronchial hyperresponsiveness. Some
patients with refractory chronic sinusitis demonstrate persistent cough and
normal lung function. In this setting, a bronchial methacholine challenge
can assess whether a component of the patient's cough is due to bronchial
hyperresponsiveness (and thus would respond to appropriate medications).

Evaluation of Chronic Asthma

Sinusitis should always be considered as an important trigger for asthma
exacerbation. The history is examined for a recent prolonged upper respira-
tory tract infection (URTI) (beyond 10 to 14 days), particularly with nasal
congestion and cough. In this setting, nocturnal cough, especially to the
point of vomiting, is suggestive of sinusitis in a child. Supportive evidence
for sinusitis includes nasal cytology with predominance of neutrophils and
radiographic evidence for significant sinus inflammation (opacification,
air-fluid level, or mucosal thickening of greater than 50% of the sinus
volume); these findings are only specific in the context of a clinical history
of prolonged URTI. In children, a Waters' view radiograph is often a useful
screen because it can be easily obtained, is inexpensive, and nearly all new cases
of sinusitis will have a maxillary component. In older patients or when isolated
ethmoid disease is suspected, a coronal sinus CT is more sensitive (70).

Aggressive treatment of suspected bacterial sinusitis includes appropri-
ate antibiotics (based on likely causative microorganisms) and adjunctive
therapy to enhance ostial drainage, e.g., nasal saline, decongestants, and
corticosteroids. Saline lavage and decongestants can be useful, particularly
early in the course of treatment, to aid in symptom relief and promote muco-
ciliary clearance. Nasal and, in severe cases, oral corticosteroids are a crucial
part of treatment in the setting of associated underlying eosinophilic rhinitis
(allergic or non-allergic) and asthma. In addition to reducing upper airway
edema and purulent rhinorrhea, corticosteroids reduce nasal and associated
bronchial hyperresponsiveness.

Prevention of Disease in Patients with Sinusitis and Asthma

When presented with acute sinusitis and asthma, the clinician's first goal is
to normalize the sinuses because this alone will improve the lower airway
disease. Once stable, prevention starts with exploring the possibility of
underlying rhinitis. A baseline evaluation should include nasal cytology to

300 Virant

quantify the degree of inflammation when stable, and appropriate skin
testing to determine allergic triggers. A long-term approach to prevention
begins with environmental control for relevant indoor allergens, e.g., dust
mites, animal danders, or molds. If the underlying rhinitis is mild, addition
of nasal corticosteroids and possibly leukotriene receptor antagonists during
URTIs can often provide a critical reduction in sinus ostial obstruction so
that secretion stasis is avoided. When baseline rhinitis is more moderate
to severe or when the sinus ostia are known to be compromised, the routine
use of nasal corticosteroids and leukotriene receptor antagonists is justified.

CONCLUSIONS

Sinusitis and asthma are frequently encountered simultaneously in patients.
In fact, both diseases share many chemical, cytokine, and cellular mediators,
suggesting a common pathophysiology. Worsening sinusitis can adversely
affect the lower airway. This relationship is apparent from nasal/sinus
challenge studies and aggressive medical or surgical treatment of chronic
sinusitis often results in improvement in concomitant asthma. Although
many ideas have been postulated, the most likely mechanisms for this effect
are neural reflex pathways and nasal obstruction.

The close association of upper and lower airway disease has implica-
tions for clinical management. Spirometry, and in select cases, methacholine
challenge may uncover asthma or bronchial hyperresponsiveness associated
with sinusitis. Unexplained exacerbations of asthma should be scrutinized
for the possibility of sinusitis. Although sinusitis is a clinical diagnosis, nasal
cytology and radiographs may provide supportive evidence.

Ultimately, the key to successful patient management is adequate
attention to the upper airway. The initial step is aggressive medical or even
surgical therapy to normalize the sinuses. Subsequently, based on the degree
of underlying rhinitis, avoidance of environmental triggers and the use of
nasal corticosteroids and leukotriene receptor antagonists is crucial for
prevention of recurrent rhinosinusitis. Success with this approach is the best
way to help the patients control major triggers for their asthma.

REFERENCES

1. Fox RW, Lockey RF. The impact of rhinosinusitis on asthma. Curr Allergy
Asthma Rep 2003; 3:513-518.

2. Borish L. Sinusitis and asthma: entering the realm of evidence-based medicine.
J Allergy Clin Immunol 2002; 109:606-608.

3. Vinuya RZ. Upper airway disorders and asthma: a syndrome of airway inflam-
mation. Ann Allergy Asthma Immunol 2002; 88:8-15.

4. Gottlieb MJ. Relation of intranasal disease in the production of bronchial
asthma. JAMA 1925; 95:105-109.

Sinusitis and Asthma 301

5. Chobot R. The incidence of sinusitis in asthmatic children. Am J Dis Child
1930; 39:257-264.

6. Weille FL. Studies in asthma: nose and throat in 500 cases of asthma. N Engl
J Med 1936; 215:235.

7. Berman SZ, Mathison DA, Stevenson DD, Usselman JA, Shore S, Tan EM.
Maxillary sinusitis and bronchial asthma: correlation of roentgenograms, cul-
tures, and thermograms. J Allergy Clin Immunol 1974; 53:311-317.

8. Rachelefsky GS, Goldberg M, Katz RM, Boris G, Gyepes MT, Shapiro MJ,
Mickey MR, Finegold SM, Siegel SC. Sinus disease in children with respiratory
allergy. J Allergy Clin Immunol 1978; 61:310.

9. Schwartz HJ, Thompson JS, Sher TH, Ross RJ. Occult sinus abnormalities in
the asthmatic patient. Arch Intern Med 1987; 147:2194.

10. Bresciani M, Paradis L, Des Roches A, Vernhet H, Vachier I, Godard P,
Bousquet J, Chanez P. Rhinosinusitis in severe asthma. J Allergy Clin Immunol
2001; 107:73-80.

1 1 . Pfister R, Lutolf M, Schapowal A, Glatte B, Schmitz M, Menz G. Screening for
sinus disease in patients with asthma: a computed tomography-controlled com-
parision of A-mode ultra sonography and standard radiography. J Allergy Clin
Immunol 1994; 94:804-809.

12. Georgitis JW, Matthews BL, Stone B. Chronic sinusitis: characterization of
cellular influx and inflammatory mediators in sinus lavage fluid. Int Arch
Allergy Immunol 1995; 106:416-421.

13. Steinke JW, Bradley D, Arango P, Crouse CD, Frierson H, Kountakis SE,
Kraft M, Borish L. Cysteinyl leukotriene expression in chronic hyperplastic
sinusitis-nasal polyposis: importance to eosinophilia and asthma. J Allergy Clin
Immunol 2003; 1 1 1 :342-349.

14. Creticos PS, Peters SP, Adkinson NF Jr, Naclerio RM, Hayes EC, Norman PS,
Lichtenstein LM. Peptide leukotriene release after antigen challenge in patients
sensitive to ragweed. N Engl J Med 1984; 310:1626-1630.

15. McFadden ER. Nasal-sinus-pulmonary reflexes and bronchial asthma. J Allergy
Clin Immunol 1986; 78:1-3.

16. Kratchmer I [cited by Allen W]. Effect on respiration, blood pressure, and
carotid pulse of various inhaled and insufflated vapors when stimulating one
cranial nerve and various combinations of cranial nerves. Am J Physiol 1928;
87:319-325.

17. Dixon WE, Brodie TG. The bronchial muscles, their innervation and the action
of drugs upon them. J Physiol 1903; 29:97-173.

18. Bullen SS. Incidence of asthma in 400 cases of chronic sinusitis. J Allergy 1932;
4:402^07.

19. Zimmerman B, Stringer D, Feanny S. Prevalence of abnormalities found by
sinus x-rays in childhood asthma: lack of relation to severity of asthma. J
Allergy Clin Immunol 1987; 88:268-273.

20. Kovatch AL, Wald ER, Ledesma-Medina J, Chiponis DM, Bedingfield B.
Maxillary sinus radiographs in children with nonrespiratory complaints. Pedia-
trics 1984; 73:306.

21. Fascenalli FW. Maxillary sinus abnormalities: radiographic evidence in an
asymptomatic population. Arch Otolaryngol 1969; 95:190-193.

302 Virant

22. Borish L. The role of leukotrienes in upper and lower airway inflammation
and the implications for treatment. Ann Allergy Asthma Immunol 2002; 88:
S16-S22.

23. Hamilos DL, Leung DY, Wood R, Bean DK, Song YL, Schotman E,
Hamid Q. Eosinophilic infiltration in nonallergic chronic hyperplastic sinusitis
with nasal polyps is associated with endothelial VCAM-1 upregulation and
expression of TNF-a. 1996; 15:443^50.

24. Bachert C, Wagenmann M, Hauser U, Rudack C. IL-5 synthesis is upregulated
in human nasal polyp tissue. J Allergy Clin Immunol 1997; 99:837-842.

25. Minshall EM, Cameron L, Lavigne F, Leung DY, Hamilos D, Garcia-Zepada EA,
Rothenberg M, Luster AD, Hamid Q. Eotaxin mRNA and protein expression in
chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis.
Am J Respir Cell Mol Biol 1997; 17:683-690.

26. Hamilos DL, Leung DYM, Wood R, Cunningham L, Bean DK, Yasruel Z,
Schotman E, Hamid Q. Evidence for distinct cytokine expression in allergic
versus nonallergic chronic sinusitis. 1995; 96:537-544.

27. Hansel FK. Clinical and histopathologic studies of the nose and sinuses in
allergy. L Allergy 1929; 1:43-70.

28. Harlin SL, Ansel DG, Lane SR, Myers J, Kephart GM, Gleich GJ. A clinical
and pathologic study of chronic sinusitis: the role of the eosinophil. J Allergy
Clin Immunol 1988; 81:867-875.

29. Hisamatsu K, Ganbo T, Nakazawa T, Murakami Y, Gleich GJ, Makiyama K,
Koyama H. Cytotoxicity of human eosinophil granule major basic protein to
human nasal sinus mucosa in vitro. J Allergy Clin Immunol 1990; 86:52.

30. Slavin RG. Nasal polyps and sinusitis. In: Middleton E, Reed CE, Ellis EF,
et al. eds. Allergy, Principles and Practice. 4th ed. St Louis: Mosby, 1992:1455.

31. Scadding G. The effect of medical treatment of sinusitis upon concomitant
asthma. Allergy 1999; 54:S136-S140.

32. Businco L, Fiore L, Frediani T, Artuso A, Di Fazio A, Bellioni P. Clinical and
therapeutic aspects of sinusitis in children with bronchial asthma. Int J Pediatr
Otorhinolaryngol 1981; 3:287-294.

33. Cummings NP, Wood RW, Lere JL, Adinoff AD. Effect of treatment of rhinitis/
sinusitis on asthma: results of a double-blind study. Pediatr Res 1983; 17:373.

34. Rachelsfsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated
reactive airway disease in children. Pediatrics 1984; 73:525-529.

35. Friedman R, Ackerman M, Wald E, Casselbrant M, Friday G, Fireman P.
Asthma and bacterial sinusitis in children. J Allergy Clin Immunol 1984; 74:
185-189.

36. Oliveira CAA, Sole D, Naspitz CK, Rachelefsky GS. Improvement of bronchial
hyperresponsiveness in asthmatic children treated for concomitant sinusitis. Ann
Allergy Asthma Immunol 1997; 79:70-74.

37. Corren J, Adinoff AD, Irwin CG. Changes in bronchial responsiveness to
methacholine following nasal provocation with allergen. J Allergy Clin Immunol
1992; 89:611-618.

38. Corren J, Adinoff AD, Buchmeier AD, Irwin CG. Nasal beclomethasone pre-
vents the seasonal increase in bronchial responsiveness in patients with allergic
rhinitis and asthma. J Allergy Clin Immunol 1992; 90:250.

Sinusitis and Asthma 303

39. Lund VJ. The effect of sinonasal surgery on asthma. Allergy 1999; 54:S141— S145.

40. Van der Veer A Jr. The asthma problem. NY Med J 1920; 112:392-399.

41. Francis C. Prognosis of operations for removal of nasal polyps in asthma.
Practitioner 1929; 123:272-278.

42. Davison FW. Chronic sinusitis and infectious asthma. Arch Otolaryngol 1969;
90:110.

43. Slavin RG. Relationship of nasal disease and sinusitis to bronchial asthma. Ann
Allergy 1982; 49:76-80.

44. Werth G. The role of sinusitis in severe asthma. Immunol Allergy Proc 1984;
7:45.

45. Juntunen K, Tarkkanen J, Makinen J. Cald well-Luc operation in the treatment
of childhood bronchial asthma. Laryngoscope 1984; 94:249-251.

46. Stammberger H. Functional endoscopic sinus surgery. 46. Philadelphia: BC
Decker, 1841991:453-457.

47. Wigand ME, Hosemann WG. Results of endoscopic sinus surgery of the
paranasal sinuses and anterior skull base. J Otolaryngol 1991; 20:385-390.

48. Jankowski R, Moneret-Vautrin DA, Goetz R, Wayoff M. Incidence of
medicosurgical treatment for nasal polyps on the development of associated
asthma. Rhinology 1992; 30:249-258.

49. Nishioka GJ, Cook PR, Davis WE, McKinsey JP. Functional endoscopic sinus
surgery in patients with chronic sinusitis and asthma. Otolaryngol Head Neck
Surg 1994; 110:494-500.

50. Manning SC, Wasserman RL, Silver R, Phillips DL. Results of endoscopic
sinus surgery in pediatric patients with chronic sinusitis and asthma. Arch
Otolaryngol Head Neck Surg 1994; 120:1142-1145.

51. Senior BA, Kennedy DW. Management of sinusitis in the asthmatic patient.
Ann Allergy Asthma Immunol 1996; 77:6-15.

52. Dunlop G, Scadding GK, Lund VJ. Effect of endoscopic sinus surgery on
asthma: management in patients with chronic rhinosinusitis, nasal polyposis
and asthma. Am J Rhinol 1999; 13(4):261-265.

53. Campanella SG, Asher Ml. Current controversies: sinus disease and the lower
airways. Pediatr Pulmon 2001; 31:165-172.

54. Sluder G. Asthma as a nasal reflex. JAMA 1919; 73:589-591.

55. Kaufman J, Chen J, Wright GW. The effect of trigeminal resection on reflex
bronchoconstriction after nasal and nasopharyngeal irritation in man. Am Rev
Respir Dis 1970; 101:768.

56. Nolte D, Berger D. On vagal bronchoconstriction in asthmatic patients by nasal
irritation. Eur J Respir Dis 1983; 64(S):1 10-1 14.

57. Speizer FE, Frank NR. A comparison of changes in pulmonary flow resistance
in healthy volunteers acutely exposed to S0 2 by mouth and by nose. Br J
Industr Med 1966; 23:75.

58. Wyllie JW, Kern EB, O'Brien PC, Hyatt RE. Alteration of pulmonary function
associated with artificial nasal obstruction. Surg Forum 1976; 27:535.

59. Yan K, Salome C. The response of the airways to nasal stimulation in
asthmatics with rhinitis. Eur J Respir Dis 1983; 64:105-108.

60. Hoehne JH, Reed CE. Where is the allergic reaction in ragweed asthma?
J Allergy Clin Immunol 1971; 48:36.

304 Virant

61. Rosenberg GL, Rosenthal RR, Norman PS. Inhalation challenge with
ragweed pollen in ragweed-sensitive asthmatics. J Allergy Clin Immunol 1983;
71:302.

62. Schumacher MJ, Cota KA, Taussig LM. Pulmonary response to nasal-
challenge testing of atopic subjects with stable asthma. J Allergy Clin Immunol
1986; 78:30-35.

63. Brugman SM, Larsen GL, Henson PM, Honor J, Irvin CG. Increased lower
airways responsiveness associated with sinusitis in a rabbit model. Am Rev
Respir Dis 1993; 147:314.

64. Griffin MP, McFadden ER, Ingram RH. Airway cooling in asthmatic and non-
asthmatic subjects during nasal and oral breathing. J Allergy Clin Immunol
1982; 69:354.

65. Huxley EJ, Viroslav J, Gray WR, Pierce AK. Pharyngeal aspiration in normal
adults and patients with depressed consciousness. 1978; 64:564.

66. Winfield JB, Sande MA, Gwaltney JM. Aspiration during sleep. JAMA 1973;
233:1288.

67. Bardin PG, Van Heerden BB, Joubert JR. Absence of pulmonary aspiration of
sinus contents in patients with asthma and sinusitis. J Allergy Clin Immunol
1990; 86:82-88.

68. Lee TH, Toshikazu N, Papageorgiou N, Iikura Y, Kay AB. Exercise-induced
late asthmatic reactions. N Engl J Med 1983; 308:1502.

69. Geddes DM, Corrin B, Brewerton DA, Davies RJ, Turner-Warwick M. Pro-
gressive airway obliteration in adults and its association with rheumatoid dis-
ease. Q J Med 1977; 46(184):427.

70. McAlister WH, Lusk R, Muntz HR. Comparison of plain radiographs and
coronal CT scans in infants and children with recurrent sinusitis. Am J
Roentgenol 1989; 153:1259.

Rhinosinusitis and Allergy

Desiderio Passali, Valerio Damiani, Giulio Cesare Passali,
Francesco Maria Passali, and Luisa Bellussi

Ear, Nose, and Throat Department-University of Siena Medical School,

Viale Bracci, Siena, Italy

EPIDEMIOLOGY

The relationship between rhinosinusitis and allergy has been extensively
investigated. In 1978, Rachelefsky et al. showed that 53% of children with
atopy had abnormal sinus radiographs (1); and in 1988, Shapiro found sinu-
sal radiological alterations in about 70% of children with allergic rhinitis (2).

In 1992, Benninger reported that 54% of outpatients with chronic
rhinosinusitis (CRS) had positive skin-prick tests (3), while Grove et al. found
that 50% of patients listed for sinus surgery had positive skin-prick tests (4).

In a 2000 study on 200 patients undergoing endoscopic sinus surgery
for CRS, Emanuel and Shah reported that allergy was a contributing factor
in 84% of patients; moreover, sensitisation to perennial allergens (house dust)
clearly prevailed in patients with both rhinosinusitis and allergic rhinitis (60%
of patients) (5). However, the type and severity of the allergy did not corre-
late with the degree of changes on computed tomography (CT) scans.

In 2001, in a non-peer reviewed publication, Osguthorpe reported a
higher incidence of rhinosinusitis in the spring and autumn in the Northeast
and South of the United States, which coincides with the pollination of
trees, grasses, and weeds during the spring time (6).

305

306 Passali et al.

More recently (2003), Yariktas et al. showed that 71.2% of patients
affected by allergic rhinitis (both seasonal and perennial) in their sample
had CT findings suggestive of rhinosinusitis, according to the Lund-Mackay
CT-scan staging system. These CT scores were significantly higher among
patients with perennial allergic rhinitis, compared to the seasonal allergic
rhinitis group (p < 0.05) (7).

These and other epidemiological studies lead to the hypothesis that the
mucosa of individuals with allergic rhinitis might be expected to be swollen
and more liable to obstruct the sinusal ostia, thus reducing ventilation and
leading to mucusal retention. These changes produce an intrasinus environ-
ment that might be more prone to becoming infected, with subsequent
development of an infective rhinosinusitis.

In contrast to the above findings, other studies failed to illustrate an
association between infective rhinosinusitis and allergy (8-11). Karlsson
and Holmberg did not find an increase in the incidence of infective rhinosi-
nusitis in the pollen season, although they found that 80% of patients
affected by bilateral maxillary rhinosinusitis were allergic (8). Hinriksdottir
et al. reported that the prevalence of purulent rhinosinusitis was the same in
patients with and without allergic rhinitis (9).

Moreover, Iwens and Clement found that the prevalence and extent of
sinus mucosal involvement as detemined by CT did not correlate with the
patients' atopy (10), and Orobello et al. could not correlate the presence of a posi-
tive bacterial culture obtained by sinusal aspiration with atopy in children (1 1).

These reports highlight the controversy that currently exists regarding
the presence of an association between rhinosinusitis and allergy.

PATHOPHYSIOLOGY

The pathophysiology of allergic rhinitis is characterized by an inflammatory
response at the nasal level. Nasal allergy is believed to be a result of a three-
step process, the first of which is represented by atopy.

Atopy has been defined by the the European Academy of Allergology
and Clinical Immunology (EAACI) Nomenclature Task Force as "' . . . a
personal or familial tendency to produce IgE antibodies in response to
low doses of allergens, usually proteins — ' r In other words, it represents
the genetic predisposition, transmitted as a dominant factor, to become
allergic to a definite number of specific allergens (12).

The second step is the sensitization, which begins when the patient is
exposed to a specific allergen; this molecule is processed at the nasal mucosal
level by the antigen-presenting cells (APCs) and presented, after the migra-
tion of APCs to the lamina propria, to CD4 T-Helper and B cells. Activated
B cells begin to produce IgEs that in turn will bind to high-affinity IgE
receptors of mast cells and basophils and to low-affinity IgE receptors of
macrophages, monocytes, platelets, and eosinophils (13). It is still an enigma

Rhinosinusitis and Allergy 307

why, in this phase, innocuous molecules are recognized by the host as
foreign ones and why the above interactions incite the production of IgE
instead of IgA, IgM, or IgG.

When an allergen to which an individual has already been sensitized
comes in contact with the nasal mucosa for a second time, it interacts with
specific IgEs that coat the surface of mast cells. This incites cellular degranula-
tion and the release of a number of inflammation mediators (i.e., histamine,
leukotrienes, tryptase) (14), leading to the so-called, "early phase response"
of the allergic reaction.

Histamine is the most important mediator of the early phase response:
it stimulates the HI receptors, the sensory nerve endings determining itch-
ing, and it acts on blood vessels leading to plasma extravasation and
congestion that generates the sensation of nasal obstruction.

Leukotrienes also strongly affect the blood vessels of rhinosinusal
mucosa, but their effects on nerve endings or glands are less evident. Tryptase
breaks down kininogen from blood, leading to the generation of kininis, which
in turn causes vasodilatation, edema, and plasma exudation (15).

Moreover, mast cells appear to release some cytokines, namely TNF-oc,
IL-4, IL-5, and IL-13 in this phase. TNF-oc and IL-4 induce the expression of
adhesion molecules on the surface of nasal endothelium; moreover, they seem
to have a direct chemical-attractant effect for inflammatory cells. IL-5 and IL-
13 are strong promoters of activation and survival of eosinophils.

Through the actions of these four molecules (and possibly others that
are not yet well defined), another phase ensues in some patients, 4 to
24'hours after the beginning of the inflammatory process. This phase is
called the, "late phase response" and is characterized by infiltration of cells
and activation at the rhinosinusal mucosal level. Specifically, once inflam-
matory cells, such as eosinophils, basophils, neutrophils, and mononuclear
cells, reach the nasal submucosal tissue, they (by interacting with matrix
proteins) release their own mediators. They reach the nasal submucosal
tissue thanks to the cytokine-induced expression of adhesion molecules on
the endothelium. The inflammatory response is, in this way, perpetuated
and enhanced. Whereas pruritus, sneezing, and itching are the major symp-
toms of the early phase response, the actions of mediators are centered upon
nasal hypersecretion and congestion, in the late phase response (16).

This inflammatory process, if stimulated by repeated exposures to aller-
gens, significantly lowers the threshold of patients to other stimuli. After chronic
allergenic stimulation, allergic patients typically react strongly to low doses of
the causative allergen or to allergens to which they are only mildly sensitised
or to non-specific triggers (cold air, smoke, chemicals, etc.). This phenomenon
was previously called "priming effect" (17). Nowadays, it has been replaced
by the new concept of the "minimal persistent inflammation" (18).

The key element, however, in the development of rhinosinusitis from
an allergic inflammation of the nose is the functional obstruction of the

308 Passali et al.

ostiomeatal complex, which leads to an alteration in the air and secretion
flows to and from the sinuses. In the case of a nasal allergenic challenge
allergic rhinitis contributes to this process by causing, mucosal swelling
and, if the stimulation persists, thickening of the rhinosinusal mucosa.

Nasal hyperreactivity also plays a role in the pathogenesis of rhinosinusitis.
This is mediated by the classical post-gangliar sympathetic and parasympathetic
transmitter, as well as other neurotransmitters such as vasoactive intestinal
peptide (VIP), somatostatin, and neuropeptide Y (19,20).

These substances are released principally by the sensory nervous
endings and represent the effectors of the so-called "neurogenic inflamma-
tory reaction." Independent of the specific cause, the accumulation of
undrainable secretions that are unable to pass through narrowed ostia leads
to further obstruction and to the development of an anaerobic environment
that permits bacterial growth.

Bacterial infection affects mucociliary functionality, which in turn
induces further increase in the thickening of the mucosa and ostial obstruc-
tion. If this vicious circle is not interrupted, the pathology evolves toward
rhinosinusitis, which is the result of continuous rhinosinusal inflammation.

DIAGNOSIS

The process of diagnosing the pathology in the sinus and pharynx in both
adults and children involves three diagnostic steps (Table 1).

The key element of the first phase (step I) is the collection of an accurate
clinical history. The information that is gathered includes the documentation
of nasal and auricular symptoms, the nature of the major triggers, and the
timing of symptoms. These symptoms include itching, sneezing, rhinorrea,
and nasal congestion. They can be the manifestations of all the pathologies

Table 1 Three-Steps Diagnostic Approach

Step I Clinical history

Objective examination

Active anterior rhinomanometry (AAR)

Acoustic rhinometry (AR)

Mucociliary transport time (MCTt)

Allergy tests (PRICK, intradermal)
Step II PRIST

RAST

Eosinophils count

Mastocytes degranulation test
Step III Nasal provocation test (NPT)

Rhinosinusitis and Allergy 309

that involve the rhinosinusal area. The differentiation between an acute attack
of allergic rhinitis from acute rhinosinusitis, or from the coexistence of
both, can be made by comparing the clinical data with the definitions of each
condition.

The next phase involves an objective evaluation of the rhinosinusal
region, which is performed by using rigid or preferably flexible endoscope.

The careful evaluation of rhinosinusal mucosa already may allow for
the differentiation between an allergic and a nonallergic condition. A
reddened mucosa is generally found in an infection or in inflammation of
the rhinosinusal region, whereas a pale and swollen mucosa is typically
present in rhinosinusitis induced by nasal allergy. Crusting of the inflamed
mucosa may suggest atrophic rhinitis. The type, quantity, and location of
secretions should be recorded.

The nasal cavities should be carefully evaluated for the presence of any
anatomical abnormalities (i.e., septal deviation, hypertrophy of turbinates),
polyps, foreign bodies, and tumors.

The objective examination of the rhinosinusal region is complemented
by an instrumental evaluation of the nasal functions, including active anterior
rhinomanometry, acoustic rhinometry, and mucociliary transport time.

Anterior active rhinomanometry is performed in accordance with
the instructions of the Committee on Standardization of Rhinomanometry
(21). This is an instrumental test that enables an objective evaluation of
the patency of the nasal fossae by calculating nasal flows (expressed in cc
per second) and pressures (expressed in Pascal). A specific software calculates
the nasal resistance values that are essential for the assessment of the patho-
physiology of the rhinosinusal region.

Acoustic rhinometry analyzes the sound pulses that are reflected from
the interior of nasal fossa and calculate, in this way, the cross-sectional areas
and volumes of the nasal cavities (22).

However, this relatively new technique requires further standardiza-
tion, especially regarding the method of connecting the nosepiece to nostrils
and the positioning of the patient's head.

When done in conjunction with a nasal decongestion test, these tech-
niques allow for an accurate and sequential quantification of the abnorm-
alities that were induced by the mucosal congestion and their modification
after pharmacological decongestion. The nasal mucociliary function, which
is one of the most important and fundamental defense mechanisms of
the airways against environmental pollutants, can be evaluated in a
specific patient by determining the nasal mucociliary transport time. This
is achieved by measuring the time in which a colored substance, placed on
the head of the inferior turbinate, reaches the pharynx.

One of the testing substances is a mixture of charcoal powder and 3%
saccharine. Charcoal powder is an insoluble tracer, and its use can provide
information about the efficiency of the removal of particles entrapped in the

310 Passalietal.

outer gel layer of nasal mucus. The saccharine, a soluble marker, enables the
determination of times of clearance of the inner sol layer (23). The first diag-
nostic level is completed by allergological tests.

The skin-prick test is the most widely used allergy test, and represents
the primary diagnostic tool for allergy (24). It is simple, inexpensive, and reli-
able in most patients, and, if properly done (with positive and negative con-
trols) and correctly interpreted, allows for the identification of the causative
allergens in most cases.

The second diagnostic level (step II) is aimed at achieving a more thor-
ough evaluation of the allergic problem in the patient. It involves obtaining
laboratory tests that include the total IgE dosages (PRIST), specific IgE
dosages (RAST), the eosinophil count, and the mastocyte degranulation test.

Among second level tests, PRIST lacks specificity, since other condi-
tions can also raise the total serum IgE levels and more than half of the
patients affected by seasonal allergic rhinitis have total IgEs in the physiolo-
gical range. RAST, determined in both serum and nasal secretion, is more
precise and correlates well with the prick test and the nasal challenge results.

The high cost and low sensitivity, compared to those of in vivo tests,
are the main limitations of the step II studies.

The third level test (step III), specifically the nasal specific provocation
test (NPT), is based upon the pathophysiological mechanisms of allergic
sensitization. The symptoms and signs of allergic rhinitis depend mainly
on the prevalent or exclusive localization of previously primed mastocytes
in the shock organ, the nose.

A properly performed NPT is done in this manner: an active anterior
rhinomanometry is done first to exclude any respiratory stenosis (which
could invalidate the results of the test), then lactose (the negative control
substance) is insufflated into the nasal fossa, followed by a control active
anterior rhinomanometry (after lOmin), and thereafter, the administration
of a lower concentration (2.5 A.U.) of the lyophilized allergen into the same
nasal fossa, and last, an active anterior rhinomanometry (after lOmin).

If nasal resistance is not increased, a higher concentration of the allergen
(5, 10, 20, 40, 60, 80 A.U.) is administered and the active anterior rhinomano-
metry is repeated. The NPT is considered positive when an increase of nasal
resistance equal or greater than 100% is registered (25).

The final study is a CT scan. This became the most important diagnostic
radiological investigation for the evaluation of both rhinosinusal and intra-
cranial complications and in the preoperative assessment of patients (26).

TREATMENT

According to the International Rhinosinusitis Advisory Board, the major
objectives in treating rhinosinusitis are to eradicate the infection, to decrease
the duration of the illness, and to prevent the development of complications (27).

Rhinosinusitis and Allergy 311

Although antibiotics remain the mainstay of therapy for sinusitis
(Chap. 9), various general measures, the so-called "adjuvant therapies",
are very important, especially in those individuals where allergy is a major
contribution to the development of rhinosinusal pathology (Table 2).

In addition to controlling the infection, other important goals are to
reduce the mucosal edema, to facilitate the sinusal drainage, to maintain
the ostial patency, and to relieve inflammation and allergic response.

All these goals can be achieved by using adjunctive treatments, namely
topical decongestants, muco-regulators, corticosteroids, antihistamines,
immunotherapy, and nasal irrigation (or douche) with saline solution.

Topical decongestants, administered as nasal drops or sprays, are effi-
cacious only when they are used for a short time (at most, seven days). They
act by stimulating the a-adrenergic receptors of the upper airway mucosa,
with subsequent vasoconstriction of the mucosal capillaries and shrinking
of the edematous mucosa (28). However, after prolonged use these agents
lose their efficacy and can induce a rebound rhinitis (also called rhinitis
medicamentosa). Most topical decongestants are the oximetazoline and
tramazoline nasal sprays and are administered two to three times daily.

Mucolytics, or muco-regulating agents, can be safely used in both the
prevention and treatment of rhinosinusitis, especially in cases where disor-
ders of mucociliary clearance or of mucus glandular production play a major
role in the genesis of the pathology (i.e., cystic fibrosis, immotile cilia
syndrome) (29). These agents act by thinning the mucus, with subsequent
reduction of mucus stasis and promotion of clearance, and are administrated
continuously for four weeks in patients with rhinosinusitis (30).

Oral and parenteral corticosteroids exhibit a strong anti-inflammatory
effect and effectively reduce the inflammatory symptoms. However, they
have the potential of causing serious systemic side effects and are contra-
indicated in several conditions, such as heart disease, hypertension, diabetes,
obesity, and cataracts, which limits their use to only those with an urgent or
severe condition.

Topical nasal steroids act through multiple mechanisms, including
vasoconstriction and reduction of edema, suppression of cytokine-production,
and inhibition of inflammatory cell migration (31). They work best when

Table 2 Support Therapies for Rhinosinusitis

Topical decongestant

Muco-regulators

Corticosteroids (systemic and topical)

Antihistamines

Immunotherapy

Nasal irrigation

312 Passalietal.

taken regularly on a daily basis in a prophylactic regimen, administered once
or twice a day according to the type of steroids administered.

When topical nasal steroids are administered with antibiotic therapy, a
decrease in the number of inflammatory cells, a facilitated regression of the
radiological alterations, and a significant improvement in patients' symp-
toms occur (32).

These agents act by reducing the activity of cholinergic receptors, by
reducing the number of basophils and eosinophils in the nasal mucosa,
and by inhibiting the late phase reaction after exposure to allergens (33).
The most commonly used topical nasal steroids administered as nasal sprays
are beclomethasone dipropionate, budesonide, flutisolide, and fluticasone
dipropionate.

The use of these medications is currently recommended in children
older than five years of age. Prospective, randomized, placebo-controlled
studies in children from 3 to 12 years of age showed that momentasone
has the same rate of side effects as placebo (34,35).

The recommended length of intranasal steroid therapy for acute
rhinosinusitis is three to five weeks, followed by a wash-out period and an
eventual repetition of the treatment (36). The suggested length of therapy
for chronic sinusitis varies from 2 to 16 weeks (37,38).

The untoward effects of these topical drugs include dryness and irrita-
tion of nasal mucosa, epistaxis (in about 5% of patients), and rarely, oral candi-
diasis. These side effects are likely a result of the sterilizing and stabilizing
substances that are added to the solutions such as benzalkomium chloride.

HI -antihistamines are also commonly used as adjunct therapy. These
agents have mild anti-inflammatory activity (39) and significantly reduce
(after four weeks of treatment) sneezing, itching, and rhinorrhea, but their
effects on nasal obstruction is less significant (40).

First-generation antihistamines cannot selectively bind to HI -receptors,
and therefore they also interact with dopaminergic, serotoninergic, and cho-
linergic receptors, leading to untoward effects such as dryness of the mouth
and constipation. Moreover, these drugs, although very efficacious at the
nasal level, easily cross the blood-brain barrier, leading to adverse effects at
the central nervous system level (i.e., fatigue, sedation, dizziness) (41).

Second-generation antihistamines are as efficacious as the former
generation, but, as they are more lipophobic, they do not cross the blood-
brain barrier. Since they selectively bind to HI -histamine receptors (41), they
do not cause somnolence, interfere with performance, or possess an anti-
cholinergic effect. However, when combined with drugs metabolized by the
P-450 Cytochrome, they can produce torsades de pointes and ventricular
arrhythmia (42).

The recently developed third-generation antihistamines have a similar
efficacy as the other two classes without their adverse effects (43), and repre-
sent a promising tool for the management of allergy-related CRS.

Rhinosinusitis and Allergy 313

Numerous uncontrolled clinical reports of immunotherapy, both nasal
and sublingual, suggest that this mode of therapy may have an important
role in the management of allergy-related forms of rhinosinusitis (44).

Although some controversies exist regarding the specific mechanisms of
action of immunotherapy, it produces an increase in allergen-specific Ig G-
blocking antibodies, is associated with an initial increase and subsequent fall
in allergen-specific IgEs levels, and produces a decrease in both the release of
histamine from basophils and in the lymphocyte-cytokine response to aller-
gen challenge (45).

More recently, scientific interest has focused on the allergen-specific
deviation of the immune response from a Th2 to a Thl cytokine phenotype
and on the induction of CD4+/CD25+ T cells that occurs after administra-
tion of immunotherapy (46).

Nishioka observed a significantly better long-term outcome after
endoscopic sinus surgery, compared with allergic patients who underwent
surgery without having preoperative immunotherapy (47).

Krause recently reported that allergic patients with rhinosinusitis and
treated with immunotherapy had a reduced number of infectious episodes
after endoscopic sinus surgery (48).

In conclusion, when properly administered, immunotherapy repre-
sents a valid therapeutic aid in the management of allergic patients affected
by rhinosinusitis. Nasal irrigation (or douche) with saline solution seems to
be able to reduce nasal and rhinosinusal dryness, facilitating the clearing of
thick mucus and crusts (49). The use of nasal irrigations after surgery in
patients operated for CRS has obtained more of a consensus in recent years
because of their moisturizing effects and ability to reduce swelling (50). The
lack of side effects and low price makes the use of saline solutions more
practical.

PREVENTION

The major goal of all the measures taken to prevent rhinosinusitis is to avoid
the negative effects of all the risk and predisposing factors that lead to the
emergence of the rhinosinusal cycle (Chap. 6).

Preventing allergy-related rhinosinusitis involves reducing the chronic
allergic inflammation of rhinosinusal mucosa that can induce a permanent
edematous state, blocking the ostiomeatal complex.

A recent Italian epidemiological analysis (51) found that the probability
of an allergic patient developing rhinosinusitis is 21.5 ± 3.4%. These results
are similar to the 20% risk one noted in the WHO ARIA Document (52).

The concept of "one airway, one disease" in relation to the rhinitis-
rhinosinusitis-asthma relationship is strongly endorsed by the data pre-
sented above. However, although this relationship is well defined from the
theoretical viewpoint, there is paucity of studies that analyze the preventive

314 Passalietal.

effects of different treatments of allergic rhinitis on lowering the risk of
developing rhinosinusitis.

A recent retrospective study that encompassed 20 years of follow-up
found that treatment of nasal allergy can prevent the development of
rhinosinusitis and lower airways pathologies (53). However, no differences
were noted in the preventive effects of the various treatment modalities
(i.e., nasal steroids, antihistamines, immunotherapy).

In conclusion, medical treatment and interference with the early stages
of allergic rhinitis are the most important measures that can prevent the
development of this condition and its complications.

REFERENCES

1. Rachelefsky GS, Goldberg M, Katz RM, Boris G, Gyepes MT, Shapiro MJ,
et al. Sinus disease in children with respiratory allergy. J Allergy Clin Immunol
1978; 61(5):310-314.

2. Shapiro GC. The role of nasal airway obstruction in sinus disease and facial
development. J Allergy Clin Immunol 1988; 82:935-940.

3. Benninger M. Rhinitis, sinusitis and their relationship to allergies. Am J Rhinol
1992; 6:37^3.

4. Grove R, Farrior, J. Chronic hyperplastic sinusitis in allergic patients: a bacter-
iologic study of 200 operative cases. J Allergy Clin Immunol 1990; 11:271.

5. Emanuel IA, Shah SB. Chronic rhinosinusitis: allergy and sinus computed
tomography relationships. Otolaryngol Head Neck Surg 2000; 123(6):687-691.

6. Osguthorpe D. Sinusitis: allergy sufferers more susceptible to sinus disorders;
interview. Sci Health 2001; April 9.

7. Yariktas M, Doner F, Demirci M. Rhinosinusitis among the patients with per-
ennial or seasonal allergic rhinitis. Asian Pac J Allergy Immunol 2003; 21(2):
75-78.

8. Karlsson G, Holmberg K. Does allergic rhinitis predispose to sinusitis? Acta
Otolaryngol Suppl 1994; 515:26-28; discussion 29.

9. Hinriksdottir I, Melen I. Allergic rhinitis and upper respiratory tract infections.
Acta Otolaryngol Suppl 1994; 515:30-32.

10. Iwens P, Clement PA. Sinusitis in allergic patients. Rhinology 1994; 32(2):
65-67.

11. Orobello PW Jr, Park RI, Belcher LJ, Eggleston P, Lederman HM, Banks JR,
et al. Microbiology of chronic sinusitis in children. Arch Otolaryngol Head
Neck Surg 1991; 117(9):980-983.

12. EAACI Nomenclature Task Force. A revised nomenclature for allergy. Allergy
2001; 56:813-824.

13. Van Cauwenberge PB. Nasal sensitisation. Allergy 1997; 52(suppl 33):7-9.

14. Naclerio RM. Allergic rhinitis. N Engl J Med 1991; 325:860-869.

15. Naclerio RM, Proud D, Peters S, Sobotka AK, Lichtenstein L, Norman P. The
role of inflammatory mediators in allergic rhinitis. Ear Nose Throat J 1986;
65:206-212.

Rhinosinusitis and Allergy 315

16. Montefort S, Feather H, Wilson SJ. The expression of leukocyte-endothelial
adhesion cells is increased in perennial allergic rhinitis. Am J Respir Cell Mol
Biol 1992; 7:393-398.

17. Collen JT. Quantitative intranasal pollen challenges. The priming effect in aller-
gic rhinitis. J Allergy 1969; 43:33-44.

18. Ricca V, Landi M, Ferrero P, Bairo A, Tazzer C, Canonica GW, Ciprandi G.
Minimal persistent inflammation is also present in patients with seasonal aller-
gic rhinitis. J Allergy Clin Immunol 2000; 105:54-57.

19. Bousquet J, Chanez P, Vignola AM, Lacoste JY, Michel FB. Eosinopholic
inflammation in asthma. Am J Respir Crit Care Med 1994; 150(suppl):S33-S38.

20. Bonini S, Magrini L, Rotiroti G. Basi biologiche deH'infiammazione allergica
delle vie aeree. In: Passali D, Pozzi E, Olivieri D, eds. Allergia e infiammazione
delle vie aeree:entita parallele o convergenti? Firenze: Scientific Press, 1996:
19-222.

21. Clement PAR. Committee report on standardization of rhinomanometry.
Rhinology 1984; 22:151-155.

22. Hilberg O, Jackson AC, Swift DL. Acoustic rhinometry: evaluation of nasal
cavity geometry by acoustic reflection. J Appl Physiol 1989; 66:295-303.

23. Passali D, Bellussi L, Bianchini-Ciampoli M, De Seta E. Our experiences in
nasal mucociliary transport time determination. Acta Otolaryngol (Stockh)
1984; 97:319-323.

24. Collins-Williams C, Nirami RM, Lamenza C, Chin. Nasal provocative testing
with molds in the diagnosis of perennial allergic rhinitis. Ann Allergy 1972;
30:557-561.

25. Passali D, Anselmi M, Bellussi L, Passali FM, Passali GC. Storia delle meto-
diche utilizzate quali test di provocazione nasale aspecifica (TPNA) alia luce
di esperienze personali. Riv Orl Aud Fon 1999; 3-4:121-130.

26. Lloyd GAS, Lund VJ, Scadding GK. CT of the paranasal sinuses and bronchial
endoscopic surgery: a critical analysis of 100 symptomatic patients. J Laryngol
Otol 1991; 105:181-185.

27. International Rhinosinusitis Advisory Board: Infectious Rhinosinusitis in
adults: Classification, Etiology and Management. ENT J 1997; 76(suppl 12):
1-22.

28. DelaFuente JC, Davis TA, Davis J A. Pharmacotherapy of allergic rhinitis. Clin
Pharmacol Ther 1989; 8:474-485.

29. Davidson TM, Murphy C, Mitchell M, et al. Management of chronic sinusitis
in cystic fibrosis. Laryngoscope 1995; 105:354-358.

30. Yuta A, Baraniuk JN. Therapeutic approaches of airway mucus hypersecretion.
In: Rogers DF, Lethem MI, eds. Airway Mucus: Basic Mechanisms and Clin-
ical Perspectives. Batel: Birkhauser Verlag, 1997:365-383.

3 1 . Meltzer EP, Orgel HA, Backhaus J W, et al. Intranasal flunisolide spray as an
adjunct to oral antibiotic therapy for sinusitis. J Allergy Clin Immunol 1993;
92:812-823.

32. Paurvels R. Mode of action of corticosteroids in asthma and rhinitis. Clin
Allergy 1986; 16:281-288.

33. Mabry RL. Interface of allergy and sinus disease. Dallas Med J 1991; 99:
596-599.

316 Passali et al.

34. Brannan MD, Herron JM, Affrime MB. Safety and tolerability of once-daily
mometasone furoate aqueous nasal spray in children. Clin Ther 1986; 65:
449-456.

35. Nayak AS, Settipane GA, Pedinoff A, Charous BL, Meltzer EO, Busse WW,
et al. Effective dose range of mometasone furoate nasal spray in the treatment
of acute rhinosinusitis. Ann Allergy Asthma Immunol 2002; 89(3):27 1-278.

36. Dolor RJ, Witsell DL, Hellkamp AS, Williams JW Jr, Califf RM, Simel DL.
Comparison of cefuroxime with or without intranasal fluticasone for the treat-
ment of rhinosinusitis. The CAFFS trial: a randomized controlled trial. JAMA
2001; 286(24):3097-3105.

37. Parikh A, Scadding GK, Darby Y, Baker RC. Topical corticosteroids in
chronic rhinosinusitis: a randomized, double-blind, placebo-controlled trial
using fluticasone propionate aqueous nasal spray. Rhinology 2001; 39(2):75-79.

38. Lavigne F, Cameron L, Renzi PM, Planet JF, Christodoulopoulos P, Lamkioued B,
et al. Intrasinus administration of topical budesonide to allergic patients with
chronic rhinosinusitis following surgery. Laryngoscope 2002; 1 12(5): 858-864.

39. Howarth PH. Assessment of antihistamine efficacy and potency. Clin Exp
Allergy 1999; 86:87-97.

40. Braun JJ, Alabert JP, Michel FB, Quiniou M, Rat C, Cougnard J, Czarlewski W,
Bousquet J. Adjunct effect of loratadine in the treatment of acute sinusitis in
patients with allergic rhinitis. Allergy 1997; 52(6):650-655.

41 . Yanai K, Ryu JH, Watanabe T, Iwata R, Ido T, Sawai Y. Histamine HI -receptor
occupancy in human brains after single oral doses of histamine HI -antagonists
measured by positron emission tomography. Br J Pharmacol 1995; 116: 1649-1655.

42. Delpon E, Valenzuela C, Tamargo J. Blockade of cardiac potassium and other
channels by antihistamines. Drug Saf 1999; 1:11-18.

43. Casale TB, Andrade C, Qu R. Safety and efficacy of once-daily fexofenadine
Hcl in the treatment of autumn seasonal allergic rhinitis. Allergy Asthma Proc
1999; 20:193-198.

44. Benninger M, Anon J, Mabry R. The medical management of rhinosinusitis.
Otolaryngol Head Neck Surg 1997; 117:S41-S49.

45. Fireman P. Allergic rhinitis. In: Fireman P, Slavin RG, eds. Atlas of Allergies.
2nd ed. St Louis: Mosby-Wolfe, 1996:141-159.

46. Francis JN, Til SJ, Durham SR. Induction of IL-10+Cd4+Dc25+ T Cells by
grass pollen immunotherapy. J Allergy Clin Immunol 2003; 111:1255-1261.

47. Nishioka GJ, Cook PR, McKinsey JP. Immunotherapy in patients undergoing
functional endoscopic sinus surgery. Otolaryngol Head Neck Surg 1994;
110:406^12.

48. Krause HF. Allergy and chronic rhinosinusitis. Otolaryngol Head Neck Surg
2003; 128:14-16.

49. Nuutinen J, Holopainen E, Haaletela T, et al. Balanced physiologic saline in the
treatment of chronic rhinosinusitis. Rhinology 1986; 24:265-269.

50. Ryan RM, Whittet HB, Norval C, et al. Minimal follow up after functional
endoscopic sinus surgery. Does it affect the outcome? Rhinology 1996;
34:44-45.

51. ARIA: Allergic Rhinitis and its Impact on Asthma, Workshop Report, 2001.

Rhinosinusitis and Allergy 317

52. Passali D, Bellussi L, Damiani V, Passali GC, Passali FM, Celestino D. Allergic
rhinitis in Italy: epidemiology and definition of most commonly used diagnostic
and therapeutic modalities. Acta Otorhinolaryngol Ital 2003; 23(4):257-264.

53. Passali D, Damiani V, Mora R, Passali GC, Bellussi L. Natural history of
allergic rhinitis: our experience in Italy. Clin Exp All Rev 2003; 3:28-32.

Nosocomial Sinusitis

Viveka Westergren and Urban Forsum

Division of Clinical Microbiology, Department of Molecular and Clinical Medicine,
Faculty of Health Sciences, Linkoping University, Linkoping, Sweden

INTRODUCTION

An accurate definition of nosocomial infection identifies "nosocomial" as a
disease or symptom initiated during a period of hospital care and under dif-
ferent states of bacterial presence (1). As such, it describes the two dimen-
sions that together are part of the working definition of the concept of
nosocomial sinusitis. Of the two particular kinds of sinusitis included in this
chapter, however, only one is a "true" nosocomial sinusitis according to the
definition above, and this is the sinusitis of critically ill patients in the inten-
sive care unit (ICU) that is related to mechanical ventilation. On the other
hand, post-sinus surgery refractory sinusitis, which is considered in the last
paragraph of the Introduction section, is not truly a nosocomial sinusitis.
Under each subheading, ventilator-associated sinusitis will be dealt with
first, followed by post-sinus surgery sinusitis.

In the ICU, critically ill patients commonly have dysfunction of one or
more organ systems, including fractures, combined, at least temporarily,
with impaired host-defense. They are subjected to multiple invasive diagnos-
tic and therapeutic procedures. Fever is common, either of infectious or non-
infectious etiology (2), which may be the sign of a complication when all
diagnostic measures are unsuccessful. Devices used for securing the airway
are one of those factors (3) that can induce infection associated with fever.

319

320 Westergren and Forsum

The unique circumstances in the ICU affect the bacterial flora of the
patients, the medical staff, and the ward. The presence and the development
of bacterial resistance to antimicrobials has become a constant problem.
The manner in which antibiotics are utilized regulates the bacterial flora
of the ICU both quantitatively and qualitatively, as well as the pattern of
bacterial antibiotic sensitivity (4).

The diagnosis of bacterial sinusitis is complicated by the concealed
location of the maxillary sinuses, which makes their direct visualization
impossible, and by the difficulty in obtaining an uncontaminated sample for
culture. An infectious sinusitis in the ICU setting is often over-diagnosed, as
most cases of sinus inflammation in this setting are noninfectious reactive
inflammatory sinusitis (5), or an infected artificial ventilation-acquired sino-
pathy. It is quite possible that only a few cases of sinus inflammation in the
ICU setting are truly of infectious etiology.

The first publication regarding sinusitis in the ICU setting was in 1974,
when four cases were reported (6). During the following decade, similar case
reports were published, some of which used purulent nasal discharge or
drainage as the means of diagnosis (7-12). In response to the identified pro-
blem, retrospective studies were conducted. These studies indicated that
infectious sinusitis in the ICU correlated with placement of the nasal tube,
and that bacteria grew in 80% to 100% of aspirated samples (13-18). As
awareness of the diagnostic obstacles of paranasal sinus disease in the
ICU increased, study results have changed over time. In addition to discuss-
ing the diagnosis and management of ICU-associated sinusitis, this chapter
surveys the results of microbiological and other studies that broadened our
understanding of the pathophysiology of this infection.

The post-sinus surgery refractory sinusitis also discussed in this
chapter is not a true nosocomial sinusitis by definition. The major indication
for sinus surgery is chronic sinusitis. Post-surgery sinusitis is a continuous
inflammatory disease of the sinus cavity in which expected healing does not
occur and the bacterial floras may persist or change (19).

ETIOLOGY AND PATHOGENESIS

Numerous factors make the critically ill patient susceptible to infections.
These include the presence of one or more diseases or injuries, a secondary
impaired host-defense, and the need for intensive care in order to survive.
Patients who are already immunocompromised (diabetes, chemotherapy,
undernourished, etc.) are generally at higher risk for infections, while patients
with head injuries and intra paranasal sinus bleeding are at particularly
high risk for infectious sinusitis.

In post-sinus surgery sinusitis, the indication for surgery is generally
chronic sinusitis with an impaired local (the rhinosinus mucosa) host-defense.
Evaluations of short-term endoscopic sinus surgery (ESS) results indicate

Nosocomial Sinusitis 321

"first time" failure rates between 5% and 10%. In long-term follow-ups, new
surgical procedures are necessary in up to 25% of the patients (20,21). Success-
ful ESS provides improvement in the mucosal ciliary beat (22,23), while
scarring with ostial obstruction has repeatedly been identified as a significant
surgical complication at revision surgery (20,23-25).

The Nosocomial Bacterial Flora

The patient's indigenous bacterial flora may cause infections, although the
bacterial reservoir in the ICU represents an even higher potential risk.
Hospitalized patients rapidly become colonized or infected by the ICU flora,
which is strongly influenced by the selective pressure caused by antimicro-
bial agents that are used (26-28). In addition, the therapeutic measures uti-
lized in the patient, such as use of invasive devices and immunomodulating
therapy, may enhance the predisposition to infection. Infectious sinusitis in
this setting is caused by bacteria and occasionally by fungi. However, the
etiology of paranasal sinus during an ICU stay is not only infectious. There
are inflammatory conditions, varying from noninfectious sinusitis that does
not contain bacteria to noninfectious sinusitis with bacteria, that only repre-
sent colonization (29).

Body Position

When lying down, our otherwise upward-directed blood vessels fill better,
since their direction has changed. When a healthy individual assumes a recum-
bent position, the blood vessels in the rhinosinus region become engorged,
thus leading to mucosal edema with a significant reduction in the patency of
the antral ostiae (30,31). An inflammatory reaction in the mucosa due to
allergy or the common cold also increases the nasal airflow resistance up to
three times in the horizontal position as compared to the resistance in a healthy
individual (32,33). The full significance of the general edema in the rhinosi-
nuses of critically ill patients is not fully understood. Even so, it is common
practice in the ICU to position the patient's head at a 30° to 45° elevation to
prevent gastrointestinal aspiration (34) and nasal obstruction.

Biofilm

An inert foreign body in the nose, such as a plastic pearl or a tube, can cause
a localized purulent secretion (35). In an experimental study in rabbits, it
was possible to demonstrate the development of local mucosal reaction with
an increasing number of goblet cells, secretion, and accretion surrounding
the plastic tube, together with a change of bacterial flora (36). The bacterial
accretion of a protective glycocalyx, the formation of biofilm fixed to an
endotracheal tube, is a time-dependent event in the mechanically ventilated
patient (37). Facultative aerobic bacteria with particularly high adhesive

322

Westergren and Forsum

ability and slime production are staphylococci and Pseudomonas aeruginosa,
which are the most common bacteria of the transmeatal maxillary sinus
aspirates in cases of ventilator-associated sinusitis (5). The colonization by
staphylococci and P. aeruginosa comprises the upper airway and the diges-
tive tract, as well as the lower airway, where they are the two most common
bacterial species reported as causative agents of nosocomial pneumonia (1).
How interaction and growth of pathogenic organisms in a biofilm further
trigger an infection has not yet been determined (38).

A biofilm can be defined as an assemblage of microbial cells that is irre-
versibly associated (not removed by gentle rinsing) with a surface and enclosed
in a matrix of primarily polysaccharide material. (Figure 1 is a drawing of the
general biofilm structure, while Figure 2 is a SEM photo of a biofilm.) Biofilms
may form on a variety of surfaces including living tissues, indwelling medical
devices, industrial or potable water system piping, and natural aquatic sys-
tems. The understanding of biofilms has increased during the past decade
through the use of the confocal laser scanning microscope to study biofilm
ultrastructure and to investigate genes involved in cell (bacteria) adhesion
and biofilm formation (38). The course of events from inoculation and sticking
to slime/glycocalyx production and formation of biofilm is complex, with
probable variations among different strains of bacterial species (39).

Schematically, a biofilm formation by Staphylococcus epidermidis can
be divided into three steps, where step 1 is the primary adhesion of indivi-
dual bacteria to a surface, influenced by physical interactions (hydrophobic,
electrostatic) that are in turn possibly influenced by cell surface adhesions.
Step 2 is cellular aggregation mediated by polysaccharide intercellular adhe-
sins. The polysaccharide intercellular adhesins are products of the icaADBC
gene cluster and are virulence factors in the pathogenesis of foreign body
infections (40). The generation of a slime exopoly saccharide encasing the

Figure 1 Organization of a mature biofilm, an organized community of bacteria.
Source: Courtesy of Dr. C. Post, the Center for Genomic Sciences, Allegheny Singer
Research Institute.

Nosocomial Sinusitis

323

Figure 2 Scanning electron microscope image of a "coral reef biofilm. Source:
Courtesy of Dr. C Post, the Center for Genomic Sciences, Allegheny Singer Research
Institute.

surface-bound microorganisms in a gelatinous matrix comprises step 3, the
final step, although it is not crucial for establishing a biofilm (39).

In a P. aeruginosa biofilm formation, step 1 is the primary adhesion of
individual bacteria to a targeted surface and it is dependent on functional
flagellar motility. The next phase, step 2, requires the synthesis of type IV pili,
providing the bacteria with the ability to migrate across the surface and
congregate in microcolonies. The development of the biofilm, step 3, is com-
pleted with the fabrication of an alginic acid-like exopolysaccharide coded
by the algACD gene cluster. Bacteria close to the outer surface may extricate
from the biofilm to migrate and colonize new microenvironments (39).

The established biofilm commonly hosts a mixed flora of bacteria in a
stationary phase in which the single bacteria has transformed from a plank-
tonic cell to a "town-dweller" where the dense bacterial mass participates in
an intercellular signal system. The biofilm coexistence of Klebsiella pneumoniae

324 Westergren and Forsum

and P. aeruginosa can be stable, with P. aeruginosa primarily growing as a base
biofllm while K. pneumoniae forms localized microcolonies in a small part of
10% of the area. The interpretation of this observation is that P. aeruginosa
is competitive in rapidly colonizing the surface and gains long-term advantage,
while K. pneumoniae survives due to its ability to attach to the P. aeruginosa
biofllm, to have a faster growth, and to profit from the surface advantages
of the biofllm (41).

The biofUm-associated bacteria attain resistance to several toxic sub-
stances, such as chlorine and detergents, as well as antibiotics. Several reports
provide reasons and evidence that explain the increased resistance of biofllms
to therapeutic interventions. These include the poor penetration of antibiotic
into the biofllm, decreased growth rate in a biofllm, capacity of biofllm-speciflc
substances such as exopolysaccharide, formation of persister cells, and quorum-
sensing specific effects (42^5). Conjugation (plasmid transfer mechanism)
between bacteria included in a biofllm occurs at a greater rate compared to
bacteria in the planktonic state (46). The plasmids may carry genes for resistance
to multiple antibiotics. Therefore, biofllm-association provides a mechanism
for selection and for promoting the spread of antimicrobial resistance.

The formation of biofllms can apply to all biomedical devices used in
ICU patients, and not only to nasotracheal and nasogastric tubes. However,
these two indwelling devices are mainly used in the rhinosinus area and act
as the local source of bacteria, exposing their additive and unprotected
surfaces to biofllm formation allowing bacterial density not otherwise pos-
sible. The situation is nevertheless hard to avoid, and contamination and
infection are difficult to separate (47).

Nitric Oxide

Mechanical ventilation, as applied today, overrides the ventilation of the
upper airway and thereby sets aside the outflow of nitric oxide from the
maxillary sinuses. The maxillary sinuses were found to be the major endo-
genous origin of airway nitric oxide in 1995 (48). Measured nasal nitric
oxide concentrations are low in newborns with immature sinuses, and there-
after increase and seem to follow the development and pneumatization of
the sinuses to the adult higher levels (48). Nasal nitric oxide of various levels,
possibly related to animal size and comparable to human values, have been
found in several mammals with open paranasal sinuses. In a baboon species
that lack sinuses, the measurable nasal nitric oxide is very low (49). Studies
that utilized ultrastructural immunolocalization determined that the pro-
duction sites of nitric oxide are the sinus epithelial cilia and microvilli
(50). In Kartagener's syndrome, characterized by the derangement of the
cilia and microvilli, an absence of measurable nasally nitric oxide levels
has been ascertained (51). As subjects with immotile cilia syndrome and
cystic fibrosis also show extremely low nasal nitric oxide levels (51,52), it

Nosocomial Sinusitis 325

might be expected that any disorder of the mucosal surface will also have a
negative impact on nitric oxide release.

The nitric oxide pulmonary vasodilating effect that enhances pulmon-
ary oxygen uptake (53), as well as the existence of an endogenous source for
nitric oxide (54), had already been recognized when it was discovered that the
maxillary sinuses are the airway's main endogenous source of nitric oxide.

Nitric oxide has been shown to have an in vivo stimulatory effect on
the mucosa ciliary activity that is part of the local innate rhinosinus defense
system (55). Patients with chronic airway disease, such as chronic sinusitis or
recurrent pneumonia, have low nasal nitric oxide concentrations, as well as
significantly impaired mucociliary function as is measured by the ciliary beat
frequency and saccharin transport time (52). In addition to this mechanical
type of defense, nitric oxide is also involved in other processes that have
antibacterial effects. In the in vitro models, immunomodulatory, cytotoxic,
and antibacterial effects have been demonstrated to be coupled to inducible
nitric oxide synthase (iNOS) released nitric oxide. Experimental results have
indicated that the ability of endothelial cells, after phagocytosis, to kill
Escherichia coli is nitric oxide-dependent, while the effect on Staphylococcus
aureus remains growth-inhibiting (56). Another possible pathway is quinone
compound enhancing of the cytotoxity of phenolic compounds, where nitric
oxide promotes their oxidation (57).

The expression of inflammatory leukocytes in attaining increased num-
bers does not seem to be affected by nitric oxide presence in vivo, but the efficacy
does. In mice with induced K. pneumoniae pneumonia, the nitric oxide-depleted
group had an impairment of phagocytosis and killing function of the bacteria
compared to the control group (58). In an experimental animal bacterial chal-
lenge of iNOS-deficient mice response compared to a wild-type control, an
up-regulated release of polymorphonuclear leukocyte superoxide resulted in a
significantly greater percentage of dead polymorphonuclear leukocytes (59).

The nasal concentrations of nitric oxide output show a significant decrease
if the maxillary sinus ostiae are obstructed as in nonallergic polyposis (60). In a
study of septic ICU patients with radiological sinopathy, the maxillary sinuses
were fenestrated as a measure to reduce a possible origin of sepsis, and the
maxillary nitric oxide output that was found was significantly lower, together
with the iNOS levels, than the levels of the controls (50). However, the decreased
nitric oxide output did not correlate with the presence of infection, as only two
out of six cultures had bacterial growth. Other inflammatory sinus conditions
with decreasing nitric oxide output have been demonstrated by nasal measure-
ments in children with acute sinusitis (61) and in patients with chronic sinusitis,
while common cold subjects exhibit values comparable to the controls (62).

Overall, the number of subjects that were so far included in nitric oxide
studies is small and more studies are needed before we can proceed beyond
hypothetical knowledge and reach the practical level, where the nitric oxide
production in the upper airways would be regulated to the advantage of

326 Westergren and Forsum

critically ill patients as well as chronic sinusitis patients. Joint research recom-
mendations have been published (63) carefully enumerating how measure-
ments should be carried out in order to be able to compare and combine
results of different research groups.

Airway Bypass

Little is known about the local effects on the innate and acquired-host
immune defenses of the sinuses by mechanical ventilation airway bypass,
which brings about a change in gas-compositions in these cavities. When
any nasal medical device is used, it induces traumatic wear and tear of the
mucosa. These, as well other factors such as mucosal sinus surgery trauma,
may enhance the susceptibility of the mucosa to adhesive bacteria, thereby
becoming a receptive surface for biofilm formation. The rapid genetic
exchanges by conjugation among the static biofilm bacteria can effect the
host-microbe interference. The spread of virulence and pathogenicity deter-
minants can turn a nonpathogenic bacterial strain into a pathogenic strain
of the same species (64,65).

Host-Defense

The microbial challenge of the sinus may not be adequately opposed by a
deregulated or a perplexed local defense. Primary immunodeficiencies are
not entirely rare and are commonly underdiagnosed (66). This is particularly
the case among patients with refractory chronic sinusitis who fail to respond
to medical and surgical therapy (67). A study that followed individuals after
ESS revealed that those with a diagnosis of systemic disease had a signifi-
cantly higher frequency of poor surgical outcome as validated by their sub-
jective symptomatic score (20,68). Our inadequate recognition of systemic or
local human immune defense defects is hampering our understanding of
how to improve diagnosis and therapies.

Lactoferrins, avid iron-binding glycoproteins of the transferring family
ubiquitously secreted on mucosal surfaces and within specific granules of
polymorphonuclear leukocytes, have an antimicrobial effect in their unsatu-
rated form. Initially, this was attributed to their ability to sequester iron that
is essential for bacterial growth, but iron-independent antimicrobial activ-
ities that rely upon the direct interaction of lactoferrin with its target have
also been demonstrated (69,70). Even in lower concentrations, lactoferrin
can, by chelating iron, stimulate twitching, a specialized surface motility
of bacteria that keeps them wandering, unable to squat to become sessile
and form biofilms (71).

Antimicrobial peptides are synthesized in granula of phagocytic cells
and are secreted by the epithelia. Once excreted, they avidly bind to many
of the potentially pro-inflammatory molecules released by microorganisms,
such as lipopolysaccharide. Through this inactivation mechanism, the anti-

Nosocomial Sinusitis 327

microbial peptides inhibit the host-cells reactions and restrain undesirable
inflammatory responses. They have inducible and constitutive properties,
and participate in the innate defense of the sinus and the lungs (72).

Mainly known as components of the gastrointestinal region immune
system, (3-defensins provide endogenous antimicrobial activities demonstrated
in vitro, activities against gram-negative bacteria, protozoa, and fungi. |3-
defensins are synergistic with lysoszyme and lactoferrin. They also possess
immunomodulatory functions with memory T-cells and naive dendritic
cells (73).

Increasing levels of locally acting inflammatory mediators can have unto-
ward effects resulting in the production of matrix metalloproteinases (MMPs)
and other components of the hosts' extracellular matrix remodeling machinery.
MMPs, which comprise of more than 20 calcium and zinc dependent enzymes,
can cause persistent pulmonary pathological stromal alterations in asthma,
chronic obstructive pulmonary disease, and emphysema. An increase in the
levels of MMP-9 that exceeds the regulating tissue inhibitor TIMP-1 has been
described in exacerbations of asthma. This is interpreted as an imbalance that
allows temporary matrix damage that is followed by abnormal repair (74). An
increase in the MMP activity also occurs in rhinosinus disease (75). There is a
significant increase within the blood vessel MMP-7-positive epithelial cells in
the nasal polyposis patients as compared to the control and the chronic sinusitis
patients. MMP-9 has a significant up-regulation effect in epithelial cells of both
the nasal polyposis group and the chronic sinusitis group, and some increase in
the stroma. The presence of TIMP-1 -staining cells shows some increase, but this
is not significant in either the nasal polyposis group or the chronic sinusitis group.
However, when the staining results where compared to the ELISA immunoas-
says, the chronic sinusitis group had significantly higher TIMP-1 levels (75).
The difference between the regulations of the MMPs leads to the hypothesis that
there are two different tissue-remodeling patterns in sinus diseases, which offer
possible new therapies.

Another aberrant course of events in the host inflammatory response
seems to occur when the cytokine response increases, possibly becoming un-
controllable, resulting in an enhanced intracellular and extracellular bacterial
growth, as has been shown in vitro (76). This new approach to host-micro-
organism interference is based upon observations in patients with acute
respiratory distress syndrome who had a concomitant ventilator-associated
pneumonia. The observations revealed that nonsurvivors had a heavier bac-
terial, often polymicrobial, load in their bronchoalveolar lavage along with
a more intense local inflammatory response of TNF-oc, IL-ip, and IL-6, than
survivors. This observation reverses the traditional logic that the innate host-
defense is influenced by the microbial pressure and suggests that a cytokine
boom might make bacterial proliferation more abundant. In vitro growth of
the applicable bacterial strains is promoted by adding the cytokines TNF-a,
IL-1 p, or IL-6 to the growth medium (77). These results provide a new insight

328 Westergren and Forsum

into various kinds of difficult rhinosinus diseases, indicating that the presence
of bacteria is only an expression of pathology and not the primary agent.

Additional uncontrollable effects on microorganisms occur due to the
influence of medications that are commonly used in intensive care units, i.e.,
the catecholamine inotropes, norepinephrine, and dobutamin. An associa-
tion between the use of catecholamine injections and an increased rate of
infection was observed 70 years ago. This lead to studies which showed that
epinephrine promotes in vivo growth and virulence of a number of gram-
positive and gram-negative bacteria. An in vitro study of an intravenous
catheter milieu used inotrope concentrations at or below the clinical situa-
tion and a low bacterial inocula of S. epidermidis, attempting to imitate
the situation that occurs at the time of an induction of an opportunistic
infection. The study showed that the inotropes stimulated the growth of
S. epidermidis on the intravenous catheters to form biofilm (78). These stu-
dies demonstrate the effects of inotropes on the bacterial colonization of a
foreign body. Although intravenous catheters are not inserted into the nose
for infusion, this could be a reminder that effects might exist that we do not
see because we do not expect them, and this is also something to be more
aware of, particularly in refractory cases. It could sometimes be worthwhile
to stop the use of pharmaceuticals and only use physiologic saline rinse to
find the basic level of symptomatology.

EPIDEMIOLOGY

Nosocomial Sinusitis

In general, 5% to 1 5% of hospitalized patients contract a nosocomial infection.
This rate is higher in the ICU, where a one-third of the patients will suffer from
a nosocomial infection. Ventilator-associated pneumonia, catheter-related
bloodstream infections, surgical site infections, and urinary-catheter related
infections account for greater than 80% of these infections (79). Among
mechanically ventilated patients, pneumonia has the highest incidence. The
complication of an infection prolongs the length of stay, increases the costs
of hospitalization, and increases the risk of mortality (1).

Epidemiological studies provided the following conclusions regarding
the expected change in the patients' bacterial flora in the ICU setting: (i) In
time all patients are colonized by the nosocomial flora; (ii) colonization rate
is directly related to the seriousness of the patients condition; and (hi) the
same bacterial strains are generally found in the upper as well as the lower
airways of individuals (80-82). Johansson et al. (83) demonstrated over 30
years ago that nosocomial colonization in ICU patients predisposes them
to pneumonias: pneumonia developed in 23% of nosocomially colonized
ICU patients compared to only 3% of noncolonized. Potential pathogenic
bacteria are commonly found within 24 hours of admission in mechani-
cally ventilated patients. In samples taken from oropharynx, gastric fluid,

Nosocomial Sinusitis 329

sub-glottic space, and trachea, most patients in a study harbor enterococci,
S. epidermidis, and Candida spp. In 59% of the patients, anaerobic bacteria
were isolated in the sub-glottic and tracheal samples (84). It has been sur-
mised that colonization starts in the oropharynx, then the stomach, followed
by the lower respiratory tract, and that it then spreads upwards, contami-
nating the tracheal tube (85). Considerable amounts of intraluminal biofllm
(density of up to 10 CFU/cm ) made of hospital-acquired bacterial flora
was found on tracheal tubes used for 24 hours or less (86). This high
microbial load might lead to the development of pneumonia and sinusitis
whenever the opportunity arises. The denser the colonization, the harder
it becomes to obtain adequate maxillary sinus samples. This practical diffi-
culty explains why recent studies included only a smaller number of positive
aspiration cultures (29). A summary of the microbiological findings in speci-
mens obtained by most often the transmeatal route is presented in Table 1.
Overall, the results mirror the hospital-acquired flora, and there were signif-
icant numbers of anaerobic bacteria when proper methods for their collec-
tion and identification were used.

Artificial ventilation-acquired sinopathy is defined as the presence of
signs of sinus disease in a mechanically ventilated patient where bacteria, if
present, are a predisposing factor but cannot be proved as direct agents that
initiate the inflammatory reaction. Indirect imaging pathology is artificial
ventilation-acquired sinopathy until further tests confirm a change of diagno-
sis. In the asymptomatic population, the occurrence rate for sinopathy, such
as mucosal thickening, is present in about 40% of individuals, sinus edema
of the ethmoids is seen in about 30%, and maxillary sinus edema in about
25% (103).

Fassoulaki et al. (104) showed that in 16 patients who were admitted to
the ICU without sinus pathology and were nasotracheally intubated with one
side of the nose free, six (38%) developed sinus X-ray pathology (either muco-
sal thickening, air-fluid levels, or opacification) within 48 to 72 hours. After
eight days, 14 (88%) had only a radiological sinopathy ipsilateral to the naso-
tracheal tube (104). Hansen et al. conducted a similar study and evaluated 12
of 41 patients who underwent CT-scanning because of skull trauma and did
not have sinus pathology on admission. These patients were fit with a naso-
tracheal tube on one side and a nasogastric tube on the other. All had devel-
oped sinopathy in less than two days, in seven cases with the initial changes on
the nasogastric tube side (105). Other comparative studies report 50% sinus
X-ray pathology after five days of mechanical ventilation (106) as compared
to only a 10% imaging pathology in tracheotomized patients (107). Strange
et al. (108) found that significant risk factors were prolonged intubation time,
p < 0.001, and use of nasotracheal tube, p < 0.02, when they observed eight
patients with orotracheal tubes and 12 patients with nasotracheal tubes (108).

All these studies illustrate that radiological sinopathy tends to develop in
any mechanically ventilated ICU patient but faster in patients with nasal

330

Westergren and Forsum

ON
OO

G
G

• l-H

• t-H

H
X

a
§

— '

r--

oo
on

— >
o3

— H

OO
OO

OO C*~> -rt

C-

m cn

>H ^

co m

bfl

• t-H

-*— »

— >

Ih
<D

oo
on

o3
dJ

co co

CD ON CD

g >H - >H

^sO

h- (N m

O ^1"

«n

m cn

vo
Ln

a3
iSl

• l-H

l-H

-*— >
ISl

CO"

c/3

-4— »

(-H

d
o
ih

-4— I

OO
ON

— ->
o3
dJ

o3
Ih

CO ^x

o o

>H O

CO co

>h <N Jh

S-.

■4- '

.2 o

a -d

6<5

s
s

dJ a> U

•5 «H ^

»h & d 3

s |:a 1

>H c3 Q Z

o3
X)

0) <j

o
o
o
o

■a

o3
-*— >

■ ^N

d
dj

d o

U Ch

a a o

o3
O
O

o
o

o r- m <n

ex
in PJ

JU ^> r^

- - 2

co co O

o3 ,.

d ^s

i S

B %

■ ^-

o •»

4_»

j~.

1 )

4— '

• «-H

-O

• -H

dJ
— >
O
o3
X)
O
Ih
dJ

cu .§5

5j
Q
i i
R

.R^

< ^

"d ^

d r &0
Ph ^

O O &3

Ch Gh ^2

co co _£~

co 03 ^
d -G 2 £

Oh CO ^ O

dJ
o3

d
<

CD O

G- 2

co O

co <->

2 E «« ^ co

- § 53 M ^ £

5j C P M ^ P

CQ < O gOO

■4-1

i-
'o

dJ
X

d
d

■*j

Nosocomial Sinusitis

331

<3\

03
■4-J

■4-J

■~-

— '

—

-4-j

'~ H

d
03

C/3

t/l

-4-^

r--

■4-J

CD
■M

CJ
X)

■M

o N
O

</->

m u-) ^t

I/O

o3
— i

:/;

£3

<r>

e^l

fN m

— >

■*->

CD
CQ

</->

OO
OO
On

00 s°

■* .*> s^

■j-.

c/3

.2 o

<U (U <u

— '

s-l

I -a e

.22 3

■4->

-4—'

■4->

■4-1

=> "

2 3

OX) o

— H 0>

(03 >

C/3

o
a

6-5

3
3

o
o

c
o

■£»

■s:

CD
>

■4-1

o3
60

CD
GO

>»

(So

2 o

03
CD

03
O

o
o

-4->

a
13

4-<

bo
^ ft,

a °o Q

o
O
o
O

d
co W

- - 2

co co O

• 1— «

55 .Sh

****

5h fll

!>0

"-««

6<5

B ft

CT -

o ^

— '

M £

O *u

<L>

-4-J .-H

D c«

d 45

"4J

•5

'5 ^

— '

5j
3

C/2 Cd

rt o

1) a3

ft CO ^ O

1/1
O

d
<

CD O

ft 8

c^ ^
(D O

T3 -S

(J --

Ih
(D

.. d
CQ < O

C/D

03
13

c+-

S - I

"g^ d

332

Westergren and Forsum

-G
o

N
■»->

S-H

on ^

o o. &

in
en

oo oo in

>sD O O
CN CN CN

en on in

c--

C--

o
CQ

-4->

o
an

ON 53

^ "* >H

•—

(N ^ 1" 1"

OO
OO

^1-

-4->

— H

o
in

cn en m

VO <N O Tf

-4->

d
o

-g
o

On k « <-•

-4->

»H

(>•

as .o

-4->

-<— '

3
O

-*— >

• - -5

c/5 O
° "S

CD (D <D
Ih & d p

u cd' H 3

-4->

S-H

S-H
3

^H <U

03 >

8
o
o

">*

-G

cj
>

o3
00
1)

>h do Q Z

03
0)

o
03
CJ
CJ

O
o

S 3
5s

g
o

C
Jh

E>3

d
co UJ

^ ^H

03 Sd

■ i-H

co co O

■ i-H
■4-1

bo g

s -§

i s

d ^>

5 ^

o
o

03
O

1> O)

d X)
< 2

Ih
CJ
-<— '
CJ
03
-O

(U CD

.R^

cd -s;

"d °

U 0) 3
&. Oh ^2

So co ^

caj 03 g^

p c _

Oh CO ttj O

— '

• ^n

!>0

■ ™h

t4-(

• f-H

O
Ih

CJ
— <

CJ
03

CO
Ih

-G

■4-J

-4— >

-4-'

— >

Nosocomial Sinusitis

333

o
o

CO
CN

—

— '

On
On

— >

fc/J

o
O

OS
03

-a
o
S

— '

dJ
X>

— '

■4-J

os
•—

•o cn ^t cn

r^ cn

>/-> uo

cn cn

CN
CN

^f O

Xh .9 >h >< m

a ^

</->

>/->

On
On

■M

S-l O-

oo oo 2 ^

OO CN NO VsD >/-> in

>/->

On $

03
Ih

^ ^ s

CN VO

«n

oS
03

NO J3

On g

- 5 I S ^

03
Ih

-3- "■* cn Tf

ON ^ (N -H

Tt — i >T) no Tt CN

no On cn <— ' cn cn

^o o

i— i cn

IT!

■4-J

-3

Ih
=5

-4->

03 ,03

S 'co

^ £ 5 z

S-

o3
CJ

2h ^

.S P

-3 si

O W)

§ 2

-t-> o

a) a

3 o

3
s

B
o
o
o

■a

03
>

>•

— >

r/1

»^

o3
O

CD
C3

03
O

c
o

■4->

•—

q
o

co W

"vH

S ^ w

- - 2

co co O

OS s;

OX) 5

03 »9

8 ^

'SI

C^ ^

o ^

"S 'co

-— _o .^

Ih
dJ

I 1
R

&0 £*>

03 •=:

fJn CIh ■-.
iyj CO „£»

8-3 I*
| g

'70
CJ

3 S

e -5

03 O

S-H

5^ OS

O --H

03 O

^ 2

c« O

2 2

B 2 S r ^ - u

_ j_i m rt _J

^3 1/5
^3 03

£co^O g03<O goo

CO
■ ^^

C*H

o
h

334

Westergren and Forsum

"o3

■4-J

rrt

-4-J

O
O

r/1

■ — H

S-i

>•

CO NO
K~ CN

■4-J

ON
ON

r/1

— H

<4—

03
N

o
oo

c/3

^1"

■M

-t— '

c
a

C4-

2 ^

• •

o
o
O
o

1)
>

03
Ih

• •

•-3
03

03
Ih

co
CO
CN

</">

On OO O

co co ^h

</*> oo

On co

Tf oo

On vo

o co
co o

tj- in v> o

VO CO

° ON °
^h ^ CO

S3 Tt \o vo S3

<D <L) <L>
-rr <h-h _D

>< 0Q Q Z

-*— »

• «— <

-4->

S-H
lH
3

o
_ o
5b o

03 >

..— < ••— i

x> .ti

o to

I ?■

^ 03

O s -

o
o

■4-J

o
>

-t-»
03
bO

Z5
g, 03

CD
03
QJ
O

o
o

c
o

S 2

^ CSh

o
o

•—

a
co W

& &1
is -fe S

co co O

^3 do

03 E»

oo 5

T S

s ^

• ^-

o3
X)

-i— »

•i-s

_£3

Ih
O

<— >

03
X)

•—
o

O
y

"41

O O &o

jS -

r? O

^
Q

< ^ W taq cu co H|

UDhO

Nosocomial Sinusitis

335

•c

■M

— -H

o
o

■*->

C/3

o o o

VsD

S-H

■rf en

oo
m

- ^H

C/5

,/d

•-<
o

-4— '

l-l

-4— »

-4->

-4— •

(L)
O

g ffl < o goo

■4->

C
QJ

■4-1

d
c
■£3

03
03

. d

o ft

~ B

1°

Oh W

(U —

.9 ^

03 03
3 o

o
d

d
o

• »— i

-4-'

d
si

cd "p

a
a

■4-'

-4— '

-o

CO
CO

<L>

TD
P

■~-
C3

a o
8 *

03 M

X) X>

336 Westergren and Forsum

devices. Isolated radiological sinopathy is not an infectious disease; however,
bacterial sinusitis also has radiological sinopathy.

A prospective study of 1,126 intra-nasotracheally intubated patients in
an ICU revealed the presence of bacterial sinusitis in 27 (2%) (98). In another
study where 111 patients were randomized to either orotracheal or nasotra-
cheal intubation and the diagnostic requirements were radiographic sinopathy
and positive protected-brush culture, a 43% frequency of sinus infection was
found in the nasotracheal^ intubated group (94). Additional data about other
clinical studies are discussed in the Diagnosis section.

Post Sinus Surgery Sinusitis

Most operative results represent an improvement (21), but some cases of
chronic sinusitis are refractory to surgery. Some types of chronic sinusitis
heal better than others after surgery, while others do well without surgery.
Facial pain, in particular, is a symptom requiring careful consideration
both when planning primary sinus surgery (109) and even more so when
it persists post surgery (21,109). Differential diagnoses for facial pain
include mid-facial segment pain, tension-type headache, atypical facial pain,
migraine, paroxysmal hemicrania, and cluster headache.

One post-sinus surgery follow-up using scintigraphy to assess mucocili-
ary function noted a difference between cases of sinus cysts and cases with
hyperplastic mucosal generation; the latter took a longer time to recover nor-
mal ciliary function (110). These findings support the hypothesis that there are
different types of inflammatory diseases of the paranasal sinuses. Lavigne
et al. (112) studied 15 consecutive patients with allergy and chronic sinusitis,
all of whom had a rating higher than 12 using the Lund-Mackay staging sys-
tem (111), but no nasal polyposis or any recognized immunodeficiency. At
surgery, mucosa samples were collected and evaluated for lymphocyte subsets
(CD3, CD4, CD8), mast cells, eosinophils, and cells expressing IL-4 and IL-5
messenger RNA. At follow-up two years after surgery, there were seven
patients who were asymptomatic and eight who did not improve. Those
who failed to respond had a significantly increased number of cells expressing
IL-5 messenger RNA in the preoperative ethmoid sinus biopsies, p = 0.007

(112).

Reports on microbiology findings post-sinus surgery are surprisingly
few. Brook and Frazier (113) present a retrospective evaluation of cultures
taken from the patients with chronic sinusitis of whom 33 had surgery and
75 did not have surgery. The recovered bacteria presented as a polymicrobial
flora with anaerobic bacteria, alone or mixed with aerobic bacteria, in more
than 80% of cultures. The post-surgery patients had significantly more often
P. aeruginosa (p < 0.001) and more enteric gram-negative bacilli compared to
those who had no surgery. Bhattacharyya et al. (114) presented a retrospective
study of the aerobic microbiology of 125 patients who relapsed after ESS. No

Nosocomial Sinusitis 337

bacteria grew in cultures from 30% of the patients, which is a frequency similar
to the frequency of cultures with only anaerobic bacteria by Brook and Frazier
(113).

Similar to that study (113), Bhattacharyya et al. (114) recovered
P. aeruginosa, as well as enteric gram-negative bacilli and gram-positive
cocci (mostly S. aureus and S. epidermidis).

The culture results of these two studies resemble those of nosocomial
sinusitis in the ICU setting (Table 1).

Bhattacharyya et al. (115) prospectively investigated whether infections
occurring after ethmoid ESS represent overgrowth of the previous sinonasal
flora or represent a new bacterial infection. Cultures from 113 patients
were obtained endoscopically and processed only for aerobic bacteria. Base-
line postoperative cultures were sterile in 23% of cases, "oral" flora were
recovered in 18%, and 60% were colonized showing commonly gram-positive
cocci (mainly Staphylococcus spp.) in 41%. Twenty acute exacerbations were
cultured in 17 patients during the follow-up period of 14.5 months. All these
cultures yielded bacteria; they were mostly gram-positive cocci (56% of
isolates), half of which were S. aureus and 75% of the strains where new
compared to baseline cultures. These findings illustrate that most infections
arising postoperatively represent a new infection that best requires recultur-
ing to properly select antimicrobial therapy.

Clinical Presentations

It is difficult for critically ill patients to relate symptoms of sinus disease.
While many ordinary people present with nonspecific signs and symptoms
of sinusitis, these are even more common in the ICU patients as they
originate from their critical condition. A decision to search for an infection
is made on an individual basis. Fever can arise from a number of non-
infectious causes in ICU patients. Fever has a variety of features that need
evaluation such as a transient spike, repeated elevations, or persistent fever
(116,117). The symptom of nasal suppuration, discussed under the subhead-
ing Pathogenesis, is not in itself diagnostic of a sinus infection. The observa-
tion of radiographic sinusitis, even accompanied by a positive culture, may
not be diagnostic. This was demonstrated by Borman et al. (118) who fol-
lowed 598 patients; only one of the 26 that required further evaluation
developed an infection. Infectious sinusitis mainly presents itself as an alter-
native cause of a suspected infection in the critically ill patient when other
more common causes have been excluded. The series of Figures 3-9 repre-
sent photographs obtained during antroscopies of ICU patients who were
studied to exclude sinusitis. They illustrate various conditions of normal
maxillary sinuses, different kinds of inflammatory or edematous reactions,
with and without pus, and the presence of adherent plaques probably
representing biofilm.

338

Westergren and Forsum

Figure 3 All images are from antroscopies of ICU patients investigated for
possible infectious maxillary sinusitis from 1991 to 1994 at the University Hospital,
Linkoping, Sweden. (A) Normal mucosa with visible vessels on the right maxillary
sinus. A female patient, 61 years old, had been at the ICU for 21 days with a nasotra-
cheal tube on the left and a nasogastric tube on the right. The left side was unaffected
except for the presence of some serous fluid. The patient had secondary to an
exchange of cerebro ventricular shunts developed meningitis caused by a Pseudomoncis
species and had received antibiotics ceftazidim, piperacillin, and tobramycin. (B)
Panoramic view of the unaffected right maxillary sinus.

Nosocomial Sinusitis

339

Figure 4 A vitreous edema reaction in the left maxillary sinus without bacterial
findings. The patient had had a nasogastric tube for 14 days through the left nasal
cavity and received cefuroxim during this period.

DIAGNOSIS OF AN INFECTIOUS SINUSITIS IN THE ICU

The difficulties in obtaining noncontaminated samples from the involved
sinus makes it difficult to compare results from different studies (119). Sobin
et al. (120) performed a study in healthy people in which they kept the max-
illary samples uncontaminated and showed the sinuses to be free from
bacteria. Another study showed contradictory results, although the patients
were not free from rhinosinus symptoms as sampling was done during sep-
toplasty under general anesthesia, with the occurrence of anaerobic bacteria
in all samples, and mixed with aerobes in some (121). There are indications
that enclosed cavities such as the nose and paranasal sinuses may harbor
different bacterial floras, and that samples of nasal drainage or meatal drai-
nage do not always represent the bacteria that are present within a sinus
itself (122-124).

340

Westergren and Forsum

Figure 5 Polypoid mucosa in the right maxillary sinus in a patient with nasotracheal
tube in the adjacent nasal cavity for 12 days, without bacteria in cultures from secre-
tion and mucosa.

The formation of a biofilm on medical devices is an immense obstacle to
obtaining an uncontaminated maxillary sinus sample via the nose. Some
previous publications used nasal discharge cultures to diagnose sinusitis,
which should be viewed as documentation of nasal biofilm flora.

Most studies performed in ICU sinusitis cases that employed disinfec-
tion prior to transmeatal aspiration failed to document the efficacy of the topi-
cal disinfection. Rouby et al. were able to disinfect the septum in only 50% of
their control samples (95). The biofilms are resistant to disinfection and the
effect of a mechanical surface scrub is temporary (further discussions on bio-
films under heading Etiology and Pathogenesis). The site of sinus penetration
extends more than an inch into the cavity of the inferior meatus. Even the use
of a protected brush combined with a cut off level of >10 CFU/L for asses-
sing the positivity of a sample may not be sufficient if the bacterial density in

Nosocomial Sinusitis

341

Figure 6 Intense red edema in the maxillary sinus.

the route of penetration is unknown and may be >10 CFU/L (96). The
contact of instruments with the mucosa can result in their contaminations in
two-thirds of the samples, and only to refrain from any mucosal contact of
the penetrating instrument eliminated contamination (125). It is, therefore,
prudent to avoid the nasal routes for obtaining sampling from maxillary
sinuses in mechanically ventilated patients. It is, however, important, espe-
cially in the ICU setting, to establish the precise diagnosis of sinusitis without
delay. The use of endoscopic visualization is the most helpful method in a cri-
tically ill patient to diagnose bacterial sinus infection (29,126), preferably, a
protected canine fossa route to avoid nasal contamination. This would allow
obtaining adequate bacterial cultures, which can assist in recovering the
pathogens and selecting the proper antibiotic therapy. The routine study of
the bacterial flora at different body sites of the involved patient, and knowl-
edge of the ICU isolates in general, is necessary to know which antibiotics
to choose from.

342

Westergren and Forsum

Figure 7 Combination of vitreous edema and intense red edema in the left maxillary
sinus. A small amount of serous fluid was removed by suction. The patient had had a
nasotracheal tube in the adjacent nasal cavity for 13 days. The antibiotic cefuroxim
was given for two days before sinoscopy. Bacterial cultures were negative.

MICROBIOLOGY AND CHOICE OF ANTIMICROBIALS

The choice of proper antimicrobial therapy depends upon identification of
the bacteria causing the infection. The validity of the obtained cultures
must be carefully considered, and only after such deliberation has been
made can an informed choice of antimicrobial therapy be made. The
assessments of the bacterial importance of the bacterial isolates in the
ICU setting are presented under previous headings in this chapter
(Etiology and Pathogenesis/The Nosocomial Bacterial Flora/Biofilm/
Nitric Oxide and Epidemiology in Nosocomial Sinusitis).

Table 1 presents published results from studies of maxillary sinus done
in the last 20 years. Since the most common isolate, S. aureus, was usually
recovered through the transmeatal route, its recovery may be due to

Nosocomial Sinusitis

343

(B)

Figure 8 (A) Pus at primary inspection after removing the trocar, right maxillary
sinus. A patient with intracerebral hematoma was nasally intubated for three days,
then tracheotomized for eight days before sinoscopy and free of devices in the right
nasal cavity. The patient was prescribed intravenous cefuroxim since surgery the first
day. Aerobic and anaerobic cultures from the sinuses were negative. (B) At inspec-
tion after suction a red, moderate edema with a biofilm in the form of whitish, sticky
sheets on a surface that could be considered as biofilm.

344

Westergren and Forsum

(A)

(B)

Figure 9 (A) Similar finding as in Figure 6(A) seen in another antroscopy of the left
maxillary sinus, pus at primary inspection after removing the trocar in a female
patient at the ICU for a fortnight and trachetomized after a week. A nasogastric tube
in the adjacent nasal cavity was inserted and the patient had had a high dose of cefur-
oxim for a week. (B) As seen in Figure 7(A) after suction, where a more glassy, red
edema of the mucosa can be seen in areas not covered by biofilm, and not removable
by suction or rinse. Aerobic and anaerobic cultures from pus and mucosa were negative.

Nosocomial Sinusitis 345

specimens contamination rather than causing an infection, since the vestibu-
lum nasi is a normal site of this bacterium.

Gram-negative bacteria emerged as the major pathogens in the studies
that avoided contamination. The isolates most often found are E. coli,
Klebsiella, Acinetobacter, Enter obacter spp., and P. aeruginosa. The com-
bined presence of an Enter obacter iaceae species plus P. aeruginosa is very
common as polymicrobial growth occurs in 59% (Table 1).

Anaerobic bacteria are probably under-represented in most of the studies
as proper method for their collection and transportation were not employed,
and many studies did not include or even attempt to culture them. However,
studies that used proper anaerobic culture illustrated the significance of mixed
anaerobic infection in nosocomial sinusitis. In patients, who had been
previously treated with antibiotics, the role of yeasts needs to be considered.

The empiric selection of a carbapenem (i.e., imipenem) before cultures are
available provides coverage against the aerobic gram-negative species including
most P. aeruginosa as well as anaerobes. A quinolone such as levofloxacin,
providing covering Enter obacter iaceae, P. aeruginosa and several of the aerobic
gram-positive cocci including some resistant strains is an alternative.

Specific therapy can be chosen when culture results become available.
The decision should also take into consideration the bacterial strains recov-
ered from patients and the environment in the specific ICU and their
antimicrobial susceptibility. The choice should be done in consultation with
the hospital infection control unit, and be based upon the need of an
individual patient as well as the control of the nosocomial spread of bacterial
resistance.

TREATMENT

In addition to antimicrobial therapy, surgical drainage may be also needed
to achieve cure of maxillary empyema. Repeated lavages are recommended
along with attempts to shrink the patients' bacterial load. If the patient's
condition permits, the prefered advice is waiting for the identification of
the pathogenic bacteria and their susceptibility to guide the choice or lead
to avoidance of antibiotic therapy. Antibiotics are more effective against
planktonic bacteria (i.e., in the free-floating microbial phase) in the
sinuses (127), as is the case after a lavage, before a new biofilm has a chance
to form. However, once a biofilm has formed, antimicrobial agents usually
do not have effect and assessing bacterial sensitivity by minimum inhibitory
concentration (MIC) may not be applicable. With the help of the Calgary
Biofilm Device, it is possible to measure a minimum biofilm eradication con-
centration (MBEC) (128). Some gram-positive cocci may have identical sen-
sitivity to antibiotics in the planktonic or biofilm state, while P. aeruginosa
strains that are susceptible in the planktonic state become multi-resistant as

346 Westergren and Forsum

a biofilm (129). To use of MBEC to determine antimicrobial susceptibility in
the biofilm is highly recommended.

If the sinusitis is adjacent to a nasal cavity with a medical device, it is
helpful to remove the device to reduce the microbial load in the nose and its
efflux into the sinuses. The utility of re-intubation should be reconsidered, as
this constitutes a risk factor for ventilation-associated pneumonia that may
be due to aspiration of biofilm material (130). Removal of the nasotracheal
tube may be the treatment of choice, however, there are no studies to sup-
port this, though normalization of the condition using ultrasound (131) and
the resolution of fever (118) have been reported. In the authors' experience,
patients generally undergo a decrease in body temperature of 1°C to 2°C one
to two days following antral lavage. These of nasotracheal or the nasogas-
tric tube was not a risk factor in the development of a nosocomial sinusitis,
and a higher statistical significance correlation was found only with nasal
colonization with enteric gram-negative bacteria (p = 0.0007) and Glasgow
coma score < 7 (p = 0.0001) (99).

Weaning the patient off mechanical ventilation so that all medical
devices can be removed is the most effective treatment of sinusitis. Improv-
ing the patient's psychological status increases the upper airway nitric oxide
flow (132) and supports the continuous restoration of normal sinus physiol-
ogy. There are humanitarian aspects in the care of ICU patients, which
might be the key to their improvement.

Some patients with a probable systemic disease may fail both medical
therapy and endoscopic surgery. Using Denker's procedure, a radical sur-
gery, as a last resort in such patients brought about symptomatic improve-
ment (20,133). However, the creation of a widely open sinus cavity destroys
the ciliary transport system and the patients have to rinse their sinuses daily
with saline. The post-Denker sinus cavity is easy to inspect which facilitates
removal of polyps and cysts (20).

COMPLICATIONS

Colonization of the sinuses is common in critically ill patients. The
development of biofilm could shield the undisturbed bacterial communities
that can become the potential origin of the microbial agents of pneumonia
which carries about 50% mortality (130) in the ICU, or sepsis. Although
radiographic sinopathy along with nosocomial colonization can occur prior
to the development of pneumonia (94), the role of sinusitis is still unclear.
Pneumonia is also recognized as carrying a high risk of complication that is
enhanced by the severity of the patient illness, and in the upper airway and
gastric nosocomial colonization (130). Sinusitis is often diagnosed along
with other concomitant infections (118,134). In one study of patients who
had nasotracheal and nasogastric tubes, the patients were randomized to

Nosocomial Sinusitis 347

either receiving extra attention including scheduled sinus CT scans, or to a
control group that was treated and followed routinely. In the study group
of 199, 80 patients developed infectious sinusitis, diagnosed based on CT
findings and positive aspiration culture, and antibiotics were used more
frequently in this group (p = 0.03). No sinusitis was diagnosed in the con-
trol group of 200 patients. The study group developed significantly fewer
pneumonias (p = 0.02) but not significantly fewer septicemias (101).

The other complications of acute and chronic sinusitis, including noso-
comial complications, are presented in Chapter 13.

PREVENTION

Keeping the nasal cavities free of devices is the most effective preventive
measure. Nosocomial sinusitis can also occur in orotracheally intubated
patients, although the frequency is somewhat lower (95). In intensive care
settings, several pros and cons must be considered about the use of nasal
or oral routes for devices (135), and a decision must be made on an indivi-
dual basis. Other preventive strategies involve the use of infection preven-
tion practices that reduce the transfer of nosocomial flora (i.e., careful
handwashing by the staff, the implementation of one team per patient)
and the proper choice of antibiotics to avoid the development of resistance.

Several new avenues of research show promise for newer means of
prevention. Nebulization of gentamicin into tracheal tubes avoids systemic
antibiotics and can reach topical concentrations that exceed the MBEC (136).
Antimicrobial coatings of polyurethane and silicone are being tested (137).
Slow release of nitric oxide coating may have antimicrobial properties that
decrease P. aeruginosa adhesion (138). Oxygen glow discharge that changes
the surface properties of polyvinylchloride endotracheal tubes reduced the
adhesive ability of P. aeruginosa 70% (139). Ongoing experiments with
chemical wet treatments on endotracheal tubes using sodium hydroxide
(NaOH) and silver nitrate (AgN0 3 ) have completely inhibited the adhesion
of P. aeruginosa for a period of 72 hours (140). These results point toward
the potential of future adaptation of respiratory devices which may prevent
their colonization with potential pathogens.

Selective decontamination of the digestive tract showed significantly
decreased mortality in ICU patients (141). This method attempts to preserve
the indigenous intestinal flora, as it possesses protective effect against second-
ary colonization with potentially pathogenic gram-negative bacteria. Nonab-
sorbed topical antibiotics, e.g., polymyxin E, tobramycin, and amphotericin B,
are administered as an oral mixture through the gastric tube. Where oral colo-
nization has already taken place, nebulization is used. A reduction of ventila-
tor-associated pneumonia is difficult to evaluate, and there exists the risk that
enhanced bacterial resistance would result if selective digestive decontamina-
tion was in general use. The method has not yet been validated in a convincing

348 Westergren and Forsum

way, and should be avoided in milieus harboring methicillin-resistant S. aureus,
vancomycin-resistant enterococci, or multi-resistant Acinetobacter spp. (142).

REFERENCES

1. Emori T, Gaynes R. An overview of nosocomial infections, including the role
of microbiology laboratory. Clin Microbiol Rev 1993; 6:428-442.

2. Blech M-F. Impact de l'antibioprophylaxie sur l'ecologie microbienne. Ann Fr
Anesth Reanim 1994; 13:S45-50.

3. Vallandigham JC, Johanson Jr WG. Infections associated with endotracheal
intubation and tracheostomy. In: Bisno AL, Waldvogel FA, eds. Infections
Associated with Indwelling Devices. American Society for Microbiology,
1989:179-197.

4. Cunha BA, Shea KW. Fever in the intensive care unit. Infect Dis Clin North
Am 1996; 10:185-209.

5. Westergren V, Lundblad L, Hellquist HB, Forsum U. Ventilator-associated
sinusitis: a review. Clin Infect Dis 1998; 27:851-864.

6. Arens J, LeJeune Jr F, Webre D. Maxillary sinusitis, a complication of
nasotracheal intubation. Anesthesiology 1974; 40:415-416.

7. Gallagher TJ, Civetta JM. Acute maxillary sinusitis complicating nasotracheal
intubation: a case report. Anesth Analg 1976; 55:885-886.

8. Pope T, Stelling C, Leitner Y. Maxillary sinusitis after nasotracheal intuba-
tion. South Med J 1981; 74:610-612.

9. Knodel AR, Beekman JF. Unexplained fevers in patients with nasotracheal
intubation. JAMA 1982; 248:868-870.

10. O'Reilly MJ, Reddick EJ, Black W, Carter PL, Erhardt J, Fill W, Maughn D,
Sado A, Klatt GR. Sepsis from sinusitis in nasotracheal^ intubated patients.
A diagnostic dilemma. Am J Surg 1984; 147:601-604.

11. Meyer P, Guerin JM, Habib Y, Levy C. Pseudomonas thoracic empyema
secondary to nosocomial rhinosinusitis. Eur Respir J 1988; 1:868-869.

12. Wolf M, Zillinsky I, Lieberman P. Acute mycotic sinusitis with bacterial sepsis
in orotracheal intubation and nasogastric tubing: a case report and review of
the literature. Otolaryngol Head Neck Surg 1988; 98:615-617.

13. Caplan ES, Hoyt NJ. Nosocomial sinusitis. JAMA 1982; 247:639-641.

14. Deutschman CS, Wilton PB, Sinow J, Thienprasit P, Konstatinides FN,
Cerra FB. Paranasal sinusitis: a common complication of nasotracheal intuba-
tion in neurosurgical patients. Neurosurgery 1985; 17:296-299.

15. Kronberg FG, Goodwin WJ. Sinusitis in intensive care unit patients. Laryngo-
scope 1985; 95:936-938.

16. Aebert H, Hiinefeld G, Regel G. Paranasal sinusitis and sepsis in ICU patients
with nasotracheal intubation. Intens Care Med 1988; 15:27-30.

17. Bell R, Page G, Bynoe R, Dunham M, Brill A. Post-traumatic sinusitis.
J Trauma 1988; 28:923-930.

18. Linden B, Aguilar E, Allen S. Sinusitis in the nasotracheally intubated patient.
Arch Otolaryngol Head Neck Surg 1988; 114:860-861.

Nosocomial Sinusitis 349

19. Lund VJ, Draf W, Gwaltney JM Jr, Hoffman SR, Huizing EH, Jones JG,
Jones JK, Kennedy DW, Lusk RP, Mackay IS, Moriyama H, Nacleiro RM,
Stankiewics J A, van Cauwenberge P, Vining EM. Quantification for staging
sinusitis. Ann Oto Rhino Laryngol 1995; 167 (Suppl): 17-21.

20. Wreesman VB, Fokkens WJ, Knegt PP. Refractory chronic sinusitis: evalua-
tion of symptom improvement after Denker's procedure. Otolaryngol Head
Neck Surg 2001; 125:495-500.

21. Palmer JN, Kennedy DW. Medical management in functional endoscopic
sinus surgery failures. Curr Opin Otolaryngol Head Neck Surg 2003; 11:
6-12.

22. Abdel-Hak B, Gunkel A, Kanonier G, Schrott-Fischer A, Ulmer H,
Thumfart W. Ciliary beat frequency, olfaction, and endoscopic sinus surgery.
ORL J Otorhinolaryngol Relat Spec 1998; 60:202-205.

23. Chambers DW, Davis WE, Cook PR, Nishioka GJ, Rudman DT. Long-term
outcome analysis of functional endoscopic sinus surgery: correlation of symp-
toms with endoscopic examination findings and potential prognostic variables.
Laryngoscope 1997; 107:504-510.

24. Chan KH, Winslow CP, Abzug MJ. Persistent rhinosinusitis in children after
endoscopic sinus surgery. Otolaryngol Head Neck Surg 1999; 121:577-580.

25. Richtsmeier WJ. Top 10 reasons for endoscopic maxillary sinus surgery
failure. Laryngoscope 2001; 111:1952-1956.

26. Jarvis WR. The epidemiology of colonization. Infect Control Hosp Epidemiol
1996; 17:47-52.

27. Hanberger H, Hoffmann M, Lindgren S, Nilsson LE. High incidence of anti-
biotic resistance among bacteria in 4 intensive care units at university hospital
in Sweden. Scand J Infect Dis 1997; 29:607-614.

28. Hoth J J, Franklin GA, Stassen NA, Girard SM, Rodriguez RJ, Rodriguez JL.
Prophylactic antibiotics adversely affect nosocomial pneumonia in trauma
patients. J Trauma 2003; 55:249-255.

29. Westergren V, Lundblad L, Forsum U. Ventilator-associated sinusitis: antro-
scopy findings and bacteriology when excluding the contaminants. Acta
Otolaryngol 1998; 118:574-580.

30. Rundcrantz H. Postural variations of nasal patency. Acta Otolaryngol 1969;
68:435-443.

31. Aust R, Drettner B. The patency of the maxillary sinus ostium in relation to
body posture. Acta Otolaryngol 1975; 80:443-448.

32. Rundcrantz H. Posture and congestion of nasal mucosa in allergic rhinitis.
Acta Otolaryngol 1964; 58:283-287.

33. Hasegawa M, Saito Y. Postural variations in nasal resistance and symptoma-
tology in allergic rhinitis. Acta Otolaryngol 1979; 88:268-272.

34. Vincent J-L. Nosocomial infections in adult intensive-care units. Lancet 2003;
361:2068-2077.

35. Baker MD. Foreign bodies of the ears and nose in childhood. Pediatr Emerg
Care 1987; 3:67-70.

36. Westergren V, Otori N, Stierna P. Experimental nasal intubation: a study of
changes in nasoantral mucosa and bacterial flora. Laryngoscope 1999;
109:1068-1073.

350 Westergren and Forsum

37. Sottile FD, Marrie TJ, Prough DS, Hobgood CD, Gower DJ, Webb LX,
Costerton JW, Gristina AG. Nosocomial pulmonary infection: possible etiolo-
gic significance of bacterial adhesion to endotracheal tubes. Crit Care Med
1996; 14:265-270.

38. Donlan RM. Biofilms: microbial life on surfaces. Emerg Infect Dis 2002;
8:881-890.

39. Dunne WM Jr. Bacterial adhesion: seen any good biofilms lately? Clin Micro-
biol Rev 2002; 15:155-166.

40. Rupp ME, Ulphani JS, Fey PD, Bartscht K, Mack D. Characterization of
the importance of polysaccharide intercellular adhesin/hemagglutinin of
Staphylococcus epidermidis in the pathogenesis of biomaterial-based infec-
tion in a mouse foreign body infection model. Infect Immun 1999; 67:
2627-2632.

41. Stewart PS, Camper AK, Handran SD, Huang C-T, Warnecke M. Spatial
distribution and coexistence of Klebsiella pneumoniae and Pseudomonas
aeruginosa in biofilms. Microb Ecol 1997; 33:2-10.

42. Watnick P, Kolter R. Biofilm, city of microbes. J Bacteriol 2000; 182:
2675-2679.

43. Mah TF, O'Toole GA. Mechanisms of biofilm resistance to antimicrobial
agents. Trends Microbiol 2001; 9:34-39.

44. Gilbert P, Allison DG, McBain AJ. Biofilms in vitro and in vivo: Do singular
mechanisms imply cross-resistance? Symp Ser Soc Appl Microbiol 2002;
31:98S-110S.

45. Stewart PS. Mechanisms of antibiotic resistance on bacterial biofilms. Int J
Med Microbiol 2002; 292:107-113.

46. Roberts AP, Pratten J, Wilson M, Mullany P. Transfer of a conjugative trans-
poson, Tn5397, in a model oral biofilm. FEMS Microbiol Lett 1999; 177:636.

47. Bauer TT, Torres A, Ferrer R, Heyer CM, Schultze-Werninghaus G,
Rasche K. Biofilm formation in endotracheal tubes. Association between
pneumonia and the persistence of pathogens. Monaldi Arch Chest Dis 2002;
57:84-87.

48. Lundberg JON, Farkas-Szallasi T, Weitzberg E, Rinder J, Lidholm J,
Anggard A, Hokfelt T, Lundberg JM, Alving K. High nitric oxide production
in human paranasal sinuses. Nature Med 1995; 1:370-373.

49. Lewandowski K, Busch T, Lohbrunner H, Rensing S, Keske U, Gerlach H,
Falke KJ. Low nitric oxide concentration in exhaled gas and nasal airways
of mammals without paranasal sinuses. J Appl Physiol 1998; 85:405^10.

50. Deja M, Busch T, Bachmann S, Riskowski K, Campean V, Wiedmann B,
Schwabe M, Hell B, Pfeilschifter J, Falke KJ, Lewandowski K. Reduced nitric
oxide in sinus epithelium of patients with radiologic maxillary sinusitis and
sepsis. Am J Respir Crit Care Med 2003; 168:265-266.

51. Lundberg JON, Weitzberg E, Nordvall SL, Kuylenstierna R, Lundberg JM,
Alving K. Primarily nasal origin of exhaled nitric oxide and absence in
Kartagerner's syndrome. Eur Respir J 1994; 7:1501-1504.

52. Lindberg S, Cervin A, Runer T. Low levels of nasal nitric oxide (NO) correlate
to impaired mucociliary function in the upper airways. Acta Otolaryngol 1997;
117:728-735.

Nosocomial Sinusitis 351

53. Frostell CG, Blomqvist H, Hedenstierna G, Lundberg J, Zapol WM. Inhaled
nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction
without causing systemic vasodilation. Anesthesiology 1993; 78:427^135.

54. Gerlach H, Rossaint R, Pappert D, Knorr M, Falke KJ. Autoinhalation of
nitric oxide after endogenous synthesis in the nasopharynx. Lancet 1994;
343:518-519.

55. Runer T, Cervin A, Lindberg S, Uddman R. Nitric oxide is a regulator of
mucociliary activity in the upper respiratory tract. Otolaryngol Head Neck
Surg 1998; 119:278-282.

56. Zhang B, Cao GL, Cross A, Domachowske JB, Rosen GM. Differential anti-
bacterial activity of nitric oxide from the isozyme nitric oxide synthase trans-
duced into endothelial cells. Nitric Oxide 2002; 7:42^19.

57. Urion AM, Lopez-Gresa P, Gonzalez C, Primo J, Martinez A, Herrera G,
Escudero JC, O'Connor J-E, Blanco M. Nitric oxide promotes strong
cytotoxicity of phenolic compounds against Escherichia colt the influence of
antioxidant defenses. Free Rad Biol Med 2003; 35:1373-1381.

58. Tsai WS, Strieter RM, Zisman DA, Wilkowski JM, Bucknell KA, Chen G-H,
Standiford, TJ. Nitric oxide is required for effective innate immunity against
Klebsiella pneumoniae. Infect Immun 1997; 65:1870-1875.

59. Gyurko R, Boustany G, Huang PL, Kantarci A, Van Dyke TE, Genco CA,
Gibson FC III. Mice lacking inducible nitric oxide synthase demonstrate
impaired killing of Porphyromonas gingivalis. Infect Immun 2003; 71:
4917-4924.

60. Arnal JF, Flores P, Rami J, Murris-Espin M, Pasto I, Aguilla M, Serrano E,
Didier A. Nasal nitric oxide concentration in paranasal sinus inflammatory
diseases. Eur Respir J 1999; 13:307-312.

61. Baraldi E, Azzolin NM, Biban P, Zacchello F. Effect of antibiotic therapy on
nasal nitric oxide concentration in children with acute sinusitis. Am J Respir
Crit Care Med 1997; 155:1680-1683.

62. Lindberg S, Cervin A, Runer T. Nitric oxide (NO) production in the upper
airways is decreased in chronic sinusitis. Acta Otolaryngol 1997; 117:
113-117.

63. American Thoracic Society. Recommendations for standardized procedures
for the online and offline measurement of exhaled lower respiratory nitric
oxide and nasal nitric oxide in adults and children. Am J Respir Crit Care
Med 1999; 160:2104-2117.

64. Hacker J, Blum-Oehler G, Muhldorfer I, Tschape H. Pathogenicity islands of
virulent bacteria: Structure, function and impact on microbial evolution. Mol
Micro 1997;23:1089-1097.

65. Curtis MA. Summary: Microbiological perspective. Mol Immunol 2003; 40:
477-479.

66. Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiences. Am
Fam Physician 2003; 68:1919, 1923, 1926.

67. Sethi DS, Winkelstein JA, Lederman H, Loury MC. Immunologic defects in
patients with chronic recurrent sinusitis: diagnosis and management. Otolar-
yngol Head Neck Surg 1995; 112:242-247.

352 Westergren and Forsum

68. Sharp HR, Rowe-Jones JM, Mackay IS. The outcome of endoscopic sinus
surgery: correlation with computerized tomography score and systematic
disease. Clin Otolaryngol 1999; 24:39^2.

69. Farnaud S, Evans RW. Lactoferrin — a multifunctional protein with antimi-
crobial properties. Mol Immunol 2003; 40:395-405.

70. Nibbering PH, Ravensbergen E, Welling MM, van Berkel LA, van Berkel
PHC, Pauwels EKJ, Nuijens JH. Human lactoferrin and peptides derived from
its N terminus are highly effective against infections with antibiotic-resistant
bacteria. Infect Immun 2001; 69:1469-1476.

71. Singh PK, Parsek MR, Greenberg EP, Welsh MJ. A component of innate
immunity prevents bacterial biofilm development. Nature 2002; 417:552-555.

72. Devine DA. Antimicrobial peptides in defence of the oral and respiratory
tracts. Mol Immunol 2003; 40:431-443.

73. O'Neil DA. Regulation of expression of P-defensins: Endogenous enteric
peptide antibiotics. Mol Immun 2003; 40:445-450.

74. Cataldo DD, Gueders MM, Rocks N, Sounni NE, Evrard B, Bartsch P,
Louis R, Noel A, Foidart JM. Pathogenic role of matrix metalloproteases
and their inhibitors in asthma and chronic obstructive pulmonary disease
and therapeutic relevance of matrix metalloproteases inhibitors. Cell Mol Biol
2003; 49:875-884.

75. Watelet JB, Bachert C, Claeys C, Van Cauwenberge P. Matrix metalloprotei-
nases MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in
chronic sinusitis vs. nasal polyposis. Allergy 2004; 59:54-60.

76. Meduri GU. Clinical review: A paradigm shift: the bidirectional effect of
inflammation on bacterial growth. Clinical implications for patients with acute
respiratory distress syndrome. Critical Care 2002; 6:24-29.

77. Meduri GU, Kanangat S, Stefan J, Tolley E, Schaberg D. Cytokines IL-ip,
IL-6, and TNF-oc enhance in vitro growth of bacteria. Am J Respir Crit Care
Med 1999; 160:961-967.

78. Lyte M, Freestone PPE, Neal CP, Olson BA, Haigh RD, Bayston R,
Williams PH. Stimulation of Staphylococcus epidermidis growth and biofilm
formation by catecholamine inotropes. Lancet 2003; 361:130-135.

79. Eggiman P, Pittet D. Infection control in the ICU. Chest 2001; 120:2059-2093.

80. Johansson W, Pierce A, Sanford J. Changing pharyngeal flora of hospitalized
patients. New Engl J Med 1969; 281:1137-1140.

81. Schwartz S, Dowling J, Benkovic C, DeQuittner-Buchanan M, Prostko T,
Yee R. Sources of gram-negative bacilli colonizing the trachea of intubated
patients. J Inf Dis 1978; 138:227-231.

82. Donaldsson S, Azizi S, Dal Nogare A. Characteristics of aerobic Gram-
negative bacteria colonizing critically ill patients. Am Rev Respir Dis 1991;
144:202-207.

83. Johansson WG Jr, Pierce AK, Sanford JP, Thomas GD. Nosocomial respira-
tory infections with gram-negative bacilli: the significance of colonization of
the respiratory tract. Ann Intern Med 1972; 77:701-706.

84. Agvald-Ohman C, Wernerman J, Nord CE, Edlund C. Anaerobic bacteria
commonly colonize the lower airways of intubated patients. Clin Microbiol
Infect 2003; 9:397-405.

Nosocomial Sinusitis 353

85. Feldman C, Kassel M, Cantrell J, Kaka S, Morar R, Goolam Mahomed A,
Philips JI. The presence and sequence of endotracheal colonization in patients
undergoing mechanical ventilation. Eur Respir J 1999; 13:546-551.

86. Inglis TJJ, Millar MR, Jones G, Robinson DA. Tracheal biofllm as a source of
bacterial colonization of the lung. J Clin Microbiol 1989; 27:2014-2018.

87. Grindlinger GA, Niehoff J, Hughes SL, Humphrey MA, Simpson G. Acute
paranasal sinusitis related to nasotracheal intubation of head-injured patients.
Crit Care Med 1987; 15:214-217.

88. Guerin JM, Meyer P, Levy C, Reizine D, Habib Y, Tran Ba Huy P,
Segrestaa JM. Sinusites aigues sphenoidales consecutive a l'intubation naso-
tracheals Sem Hop Paris 1987; 63:3671-3674.

89. Humphrey MA, Simpson GT, Grindlinger GA. Clinical characteristics of
nosocomial sinusitis. Ann Otol Rhinol Laryn 1987; 96:687-690.

90. Guerin JM, Meyer P, Segrestaa JM, Reizine D, Levy C. Sinusites nosocomiales
et intubation nasotracheale. Etude prospective a partir de 53 patients. Ann
Med Interne 1989; 140:106-107.

91. Fougeront B, Bodin L, Lamas G, Bokowy C, Elbez M. Sinusites de reanima-
tion. Ann Oto-Lar Chir C-F 1990; 107:329-332.

92. Bowers B, Purdue G, Hunt J. Paranasal sinusitis in burn patients following
nasotracheal intubation. Arch Surg 1991; 126:1411-1412.

93. Michelson A, Schuster B, Kamp H-D. Paranasal sinusitis associated with
nasotracheal and orotracheal long-term intubation. Arch Otolarngol Head
Neck Surg 1992; 118:937-939.

94. Holzapfel L, Chevret S, Madinier G, Ohen F, Demingeon G, Coupry A,
Chaudet M. Influence of long-term oro- or nasotracheal intubation on noso-
comial maxillary sinusitis and pneumonia: Results of prospective, randomized,
clinical trial. Crit Care Med 1993; 21:1132-1138.

95. Rouby J-J, Laurent P, Gosnach M, Cambau E, Lamas G, Zouaoui A,
Leguillou J-L, Bodin L, Do Khac T, Marsault C, Poete P, Nicolas M-H,
Jarlier V, Viars P. Risk factors and clinical relevance of nosocomial maxillary
sinusitis in the critically ill. Am J Respir Crit Care Med 1994; 150:776-783.

96. Bert F, Lambert-Zechovsky N. Microbiology of nosocomial sinusitis in inten-
sive care unit patients. J Infect 1995; 31:5-8.

97. Bert F, Lambert-Zechovsky N. Sinusitis in mechanically ventilated patients
and its role in the pathogenesis of nosocomial pneumonia. Eur J Clin Micro-
biol Infect Dis 1996; 15:533-544.

98. Mevio E, Benazzo M, Quaglieri S, Mencherini S. Sinus infection in intensive
care patients. Rhinology 1996; 34:232-236.

99. George DL, Falk PS, Meduri GU, Leeper KV Jr, Wunderink RG, Steere EL,
Nunnally FK, Beckford, Mayhall CG. Nosocomial sinusitis in patients in the
medical intensive care unit: a prospective epidemiological study. Clin Infect
Dis 1998; 27:463-470.

100. Le Moal G, Lemerre D, Grollier G, Desmont C, Klossek J-M, Robert R.
Nosocomial sinusitis with isolation of anaerobic bacteria in ICU patients.
Intens Care Med 1999; 25:1066-1071.

101. Holzapfel L, Chastang C, Demingeon G, Bohe J, Piralla B, Coupry A.
A randomized study assessing the systematic search for maxillary sinusitis in

354 Westergren and Forsum

nasotracheal^ mechanically ventilated patients. Am J Respir Crit Care Med
1999; 159:695-701.

102. Souweine B, Mom T, Traore O, Aublet-Cuvelier B, Bret L, Sirot J, Deteix P,
Gilain L, Boyer L. Ventilator-associated sinusitis: microbiological results
of sinus aspirations in patients on antibiotics. Anesthesiology 2000; 93:
1255-1260.

103. Yousem DM. Imaging of sinonasal inflammatory disease. Radiology 1993;
188:303-314.

104. Fassoulaki A, Pamaouktsoglou P. Prolonged nasotracheal intubation and
its association with inflammation of paranasal sinuses. Anesth Analg 1989;
69:50-52.

105. Hansen M, Poulsen MR, Bendixen DK, Hartmann-Andersen F. Incidence of
sinusitis in patients with nasotracheal intubation. Br J Anaesth 1988; 61:23 1-232.

106. Pedersen J, Schurizek BA, Melsen NC, Juhl B. The effect of nasotracheal intu-
bation on the paranasal sinuses. A prospective study of 434 intensive care
patients. Acta Anaesth Scand 1991; 35:11-13.

107. Desmond P, Raman R, Idikula J. Effect of nasogastric tubes on the nose and
maxillary sinus. Crit Care Med 1991; 19:509-511.

108. Strange C, Wooten S, Schabel S, Heffner J, Sahn S. Radiographic sinusitis
following endotracheal intubation. Am Review Resp Dis 1988; 137:63.

109. Jones NS, Cooney TR. Facial pain and sinonasal surgery. Rhinology 2003;
41:193-200.

110. Dal T, Onerci M, Caglar M. Mucociliary function of the maxillary sinuses
after restoring ventilation: a radioisotopic study of the maxillary sinus. Eur
Arch Otorhinolaryngol 1997; 254:205-207.

111. Lund VJ, Mackay IS. Staging for rhinosinusitis. Rhinology 1993; 31:183-184.

112. Lavigne F, Nguyen CT, Cameron L, Hamid Q, Renzi PM. Prognosis and
prediction of response to surgery in allergic patients with chronic sinusitis.
J Allergy Clin Immunol 2000; 105:746-751.

113. Brook I, Frazier EH. Correlation between microbiology and previous surgery
in patients with chronic maxillary sinusitis. Ann Otol Rhinol Laryngol 2001;
110:148-151.

114. Bhattacharyya N, Kepnes LJ. The microbiology of recurrent rhinosinusitis
after endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg 1999;
125:1117-1120.

115. Bhattacharyya N , Gopal H V, Lee KH . Bacterial infection after endoscopic sinus
surgery: a controlled prospective study. Laryngoscope 2004; 114:765-767.

116. Cunha BA, Shea KW. Fever in the intense care unit. Inf Dis Clin North Am
1996; 10:185-209.

117. Marik PE. Fever in the ICU. Chest 2000; 117:855-869.

118. Borman KR, Brown PM, Mezera KK, Jhaveri H. Occult fever in surgical
intensive care is seldom caused by sinusitis. Am J Surg 1992: 164:412^416.

119. Rice DH. The microbiology of paranasal sinus infections: diagnosis and man-
agement. Crit Rev CI Lab Sci 1978; 9:105-121.

120. Sobin J, Engquist S, Nord CE. Bacteriology of the maxillary sinus in healthy
volunteers. Scand J Infect Dis 1992; 24:633-635.

Nosocomial Sinusitis 355

121. Brook I. Aerobic and anaerobic bacterial flora of normal maxillary sinuses.
Laryngoscope 1981; 91:372-376.

122. Axelsson A, Brorson JE. The correlation between bacteriology findings in
the nose and maxillary sinus in acute maxillary sinusitis. Laryngoscope
1973; 83:2003-2011.

123. Kountakis SE, Skoulas IG. Middle meatal vs. antral lavage cultures in inten-
sive care unit patients. Otolaryngol Head Neck Surg 2002; 126:377-381.

124. Brook I. Discrepancies in the recovery of bacteria from multiple sinuses in
acute and chronic sinusitis. Med Microbiol 2004; 53:879-885.

125. Westergren V, Forsum U, Lundgren J. Possible errors in diagnosis of bacterial
sinusitis in tracheal intubated patients. Acta Anaesthesiol Scand 1994; 38:
699-703.

126. Westergren V, Lundblad L, Timpka T. Inter-observer variations in assessment
from sinoscopy video recordings. Am J Rhinol 1998; 12:159-165.

127. Westergren V, Nilsson M, Forsum, U. Penetration of antibiotics in diseased
antral mucosa. Arch Otolaryngol Head Neck Surg 1996; 122:1390-1394.

128. Ceri H, Olson ME, Stremick C, Read RR, Morck D, Buret A. The Calgary
Biofilm Device: new technology for rapid determination of antibiotic suscept-
ibilities of bacterial biofilms. J Clin Microbiol 1999; 37:1771-1776.

129. Olson ME, Ceri H, Morck DW, Buret AG, Read RR. Biofilm bacteria:
formation and comparative susceptibility to antibiotics. Can J Vet Res 2002;
66:86-92.

130. Chastre J, Fagon J-Y. Ventilator-associated pneumonia: state of the art. Am J
Respir Crit Care Med 2002; 165:867-903.

131. Weymuller E, Bishop M. Problems associated with prolonged intubation in
the geriatric patient. Otolaryng Clin N Am 1990; 23:1057-1074.

132. Weitzberg E, Lundberg JO. Humming greatly increases nasal nitric oxide. Am
J Respir Crit Care Med 2002; 166:131-132.

133. Kerrebijn JDF, Drost HE, Spoelstra HAA, Knegt PP. If functional sinus sur-
gery fails: a radical approach to sinus surgery. Otolaryngol Head Neck Surg
1996; 114:745-747.

134. Meduri GU, Mauldin GL, Wunderink RG, Leeper KV, Jones CB, Tolley E,
Mayhall G. Causes of fever and pulmonary densities in patients with clinical
manifestations of ventilator-associated pneumonia. Chest 1994; 106:221-235.

135. Holzapfel L. Nasal vs. oral intubation. Minerva Anestesiol 2003; 69:348-352.

136. Adair CG, Gorman SP, Byers LM, Jones DS, Feron B, Crowe M, Webb HC,
McCarthy GJ, Milligan KR. Eradication of endotracheal tube biofilm by neb-
ulised gentamicin. Intens Care Med 2002; 28:426-431.

137. Sodhi RNS, Sahi VP, Mittelman MW. Application of electron spectroscopy
and surface modification techniques in the development of anti-microbial coat-
ings for medical devices. J Electron Spectrosc 2001; 121:249-264.

138. Nablo BJ, Schoenfisch MH. Antibacterial properties of nitric-oxide releasing
sol-gels. J Biomed Mater Res 2003; 67A: 1276-1283.

139. Balazs DJ, Triandafillu K, Chevolot Y, Aronsson B-O, Harms H, Descouts P,
Mathieu HJ. Surface modification of PVC endotracheal tubes by oxygen glow
discharge to reduce bacterial adhesion. Surf Interface Anal 2003; 35:301-309.

356 Westergren and Forsum

140. Balazs DJ, Triandafillu K, Wood P, Chevelot Y, van Delden C, Harms H,
Hollenstein C, Matheiu HJ. Inhibition of bacterial adhesion on PVC endotra-
cheal tubes by RF-oxygen glow discharge, sodium hydroxide and silver nitrate
treatments. Biomaterials 2004; 25:2139-2151.

141. de Jonge E, Schultz MJ, Spanjaard L, Bossuyt PMM, Vroom MB, Dankert J,
Kesecioglu J. Effects of selective decontamination of digestive tract on
mortality and acquisition of resistant bacteria in intensive care: a randomized
controlled trial. Lancet 2003; 362:1011-1016.

142. Bonten MJM, Brun-Buisson C, Weinstein RA. Selective decontamination of
the digestive tract: to stimulate or stifle? Intensive Care Med 2003; 29:672-676.

Cystic Fibrosis and Sinusitis

Noreen Roth Henig

Adult Cystic Fibrosis Center, Advanced Lung Disease Center,
California Pacific Medical Center, San Francisco, California, U.S.A.

INTRODUCTION

Cystic fibrosis (CF) is the most common fatal genetic disease, but with better
understanding of the disease and aggressive treatment, CF patients who
once died as infants are living well into adulthood. CF is an autosomal
recessive disease that results in multisystem dysfunction, including chronic
sino-pulmonary disease, pancreatic exocrine and endocrine insufficiency,
hepatobiliary disease, gastrointestinal dysfunction, and male infertility. The
classic CF phenotype is a patient diagnosed in infancy as a result of failure-
to-thrive or recurrent pneumonias who goes on to have chronic bronchi-
ectasis with difficult-to-treat pathogens and eventually dies of respiratory
failure as an adolescent or young adult. Better genotype diagnosis of the dis-
ease has shown that there is actually a wide range of CF phenotypes that do
not necessarily correlate with the genotype. And, more significantly, better
treatment for the manifestations of CF has led to increased survival. In the
United States, there are about 30,000 CF patients with almost 40% of them
older than 18 years of age. The mean life expectancy is 32 years, and there are
increasing numbers of patients in their fifth or sixth decade of life (1,2).

PATHOPHYSIOLOGY OF CF

CF was initially described in 1938 as cystic fibrosis of the pancreas, and
within the first fifteen years the pulmonary manifestations of the disease

357

358 Henig

were described (3) and the sweat chloride test was developed for making the
diagnosis (4). The myriad of organ involvement in CF, including sinus dis-
ease, relates directly to the underlying genetic defect of CF. CF is caused
by mutations in a large gene on chromosome 7, which encodes for the
1480 amino acid protein now known as the cystic fibrosis-transmembrane
regulator (CFTR) (5). The CFTR is a bidirectional chloride channel that
is a member of the ATP-binding cassette transporter family of membrane
proteins (6). There are now over 1300 mutations of the CFTR described that
fall into five classes of functional defects: (i) premature stop codons, (ii) mis-
folded proteins that cannot escape the endoplasmic reticulum, (hi) improper
activation of the channel once it reaches the cell membrane, (iv) decreased
chloride conductance of the channel, and (v) fewer than normal active
channels expressed on the cell surface (2).

Exactly how disruption of the CFTR results in the sino-pulmonary
manifestations of CF is still under debate. In general, it is accepted that
alterations in ion transport across the cell membrane results in altered ionic
composition and volume of airway surface fluid. It is also generally accepted
that the clinical syndrome is characterized by tenacious respiratory tract
secretions, uncontrolled and damaging inflammation, and chronic infection
with an unusual set of bacterial pathogens. Two competing hypotheses are
proposed for how changes in ionic composition and volume of airway
surface fluid actually result in impaired mucociliary clearance of bacteria
and heightened inflammation in the respiratory tract. The "low volume"
hypothesis contends that water-permeable airway epithelia regulate the
volume of the airway surface layer by isotonic transport to maintain optimal
function of the mucociliary escalator. The "compositional" hypothesis pro-
poses that airway epithelia regulate airway surface layer salt concentration,
which is critical for full function of innate antimicrobial proteins that reside
in the airway surface fluid (2,7).

The vast majority of CF patients develop sinus disease, although the
true incidence of the disease is not known (8). There is also increasing
evidence that suggests that single allelic CFTR mutations are associated
with chronic sinusitis in patients without CF (9). This may reflect the activity
of CFTR in the nasal and sinus passages.

PATHOPHYSIOLOGY OF CF-RELATED SINUSITIS

Pseudostratified ciliated epithelium lines the nasal cavity, paranasal sinuses,
and the tracheobronchial tree. The mucociliary escalator created by this
epithelial cell layer performs vital clearance of inorganic and organic inhaled
particles. The airway surface liquid that lies atop the epithelial cells and
is vital to the mucociliary escalator has two compartments. The sol layer
is a fluid layer of lower viscosity that is high in proteins, many with innate
antibacterial properties, while the other is a gelatinous layer of higher

Cystic Fibrosis and Sinusitis 359

viscosity that traps inhaled foreign particles. In CF, the mucociliary esca-
lator is impaired despite epithelial cells with normal structure, normal ciliary
ultrastructure, and normal ciliary beat frequency. Instead, the underlying
defect of CF is attributed to alterations of the airway surface liquid (7).

Alterations of the airway surface liquid contribute to the thick,
obstructing mucus and chronic infection that characterizes CF. Impaired
chloride conductance from mutated CFTR leads to impaired function of
both the sol and gelatinous layers. This results in altered rheology of the
mucus itself. It also leads to impairment of endogenous antimicrobial func-
tion, possibly by alteration of the osmotic conditions under which the
defense proteins work (10). It is postulated by some that this altered airway
surface liquid may also be proinflammatory (7).

The result of the derangement of the airway surface liquid leads to the
principal components of the pathophysiology of CF: obstruction, inflamma-
tion, and infection. Once a patient with CF has become infected, a patho-
logical cycle ensues where obstructing mucus traps bacterial organisms, a
brisk neutrophilic response is mounted, and the death of both organisms
and inflammatory cells leads to further increase in viscosity of the obstruct-
ing mucus, which further traps organisms and attracts neutrophils.

At the gross anatomical level, these microscopic events lead to the
obstruction of nasal passages and sinus ostia. Frontal sinuses are often
absent or small, attributed to hypopneumatization during formation of the
sinuses. Sinonasal polyposis develops in most, although not all, CF patients.
Obstructing mucus, polyps, and chronic inflammation can deform the lateral
nasal wall, nasal septum, and sinus ostia (11).

Sinonasal polyposis in CF differs from that seen with atopy. In
contrast to atopic polyps, CF polyps have thin basement membranes, lack
submucosal hyalinization, and are neutrophil-rather than eosinophil-laden.
There is also an abundance of acid rather than neutral mucin within CF
mucosal glands. These pathological differences are often the first clue that
a patient may have CF (12).

MICROBIOLOGY

There is a relatively defined group of pathogens which chronically infect
the airways of CF patients (13). These infections are Haemophilus influenzae,
Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas rnalto-
philia, Achromobacter xylosoxidans, and Burkholderia cepacia complex.
There appears to be an age-related prevalence of CF pathogens in both the
lower and upper respiratory tracts (Fig. 1). In addition, it is now accepted
that the bacterial pathogens in the sinuses are the same as those in the lungs
and vice versa. Culturing any of these typical CF organisms from a patient
with chronic sinusitis may increase the level of suspicion for CF as an
underlying diagnosis. The chronic infection with these organisms, especially

360

Henig

IrVES&iH

Vrt y

■*■ .l. ■_* •__ *i ■«*'

Figure 1 Microsopic images comparing histology of nasal polyps. Panels A and B
represent low power and high power magnification of CF; Panels C and D represent
low and high power of allergic sinusitis and Panels E and F represent low and high
power images of chronic sinusitis. Source: Courtesy of Gerald Berrey, M.D.

P. aeruginsosa, is in part achieved by biofilm production by the organisms
themselves. Production of biofilms confers relative resistance against anti-
biotics and allows the organisms to become permanent infections (14).

Nonbacterial pathogens are also frequently found in the respiratory tract
of CF patients. Aspergillus can be found in the transantral aspirates of up to
40% of adult CF patients. Colonization by Aspergillus spp. and other fungi
is increasingly common with increased use of inhaled antibiotics (15). Because

Cystic Fibrosis and Sinusitis 361

patients with CF are immunocompetent, the fungi remain intraluminal and
rarely, if ever, become invasive. Patients with CF-related bronchiectasis are
at risk for infection with non-tuberculous mycobacterium (16,17), although
the rates of sinus infection are unknown. Pediatric CF patients are not more
susceptible to common viral upper respiratory infections than their unaffected
siblings (18). However, viral upper respiratory infections may lead to an acute
exacerbation of chronic bacterial sinusitis.

Historically, it was thought that there was little correlation between
sinus and pulmonary disease (19). The opposite is now believed to be true.
Current microbiology techniques and fingerprinting of bacterial genomes
reveal that the microbiology of the lower and upper respiratory tract is the
same (2). Pathogens that initially infect the upper respiratory tract are
aerosolized and inhaled into the lower tract with each breath. Additional
communication of infectious agents occurs with postnasal drip. Pathogens
that initially infect the lower respiratory tract can infect the upper tract
through the same mechanism of aerosolization and inhalation.

CLINICAL OVERVIEW OF CF SINUSITIS

At baseline, patients with CF have chronic sinusitis and bronchiectasis clini-
cally and radiographically. Many CF patients with radiographic evidence of
sinusitis are symptom-free. However, when patients present with symptoms
of sinusitis, these symptoms are indistinguishable from other etiologies of
sinusitis: pain and pressure in the forehead or over the maxillary sinuses,
orbital pain, chronic headaches, tooth pain, ear discomfort, postnasal drip,
cough aggravated by lying down, persistent need to clear one's throat,
hoarseness, and malodorous breath. Many patients suffer from altered
sensations of taste and smell, and some have true anosmia. CF patients
are chronically infected, often with multiple pathogens. They experience per-
iodic exacerbations of their infections in both their upper and lower respira-
tory tracts. Often, the term acute or chronic sinusitis is used to distinguish
the baseline from symptomatic sinusitis. Exacerbations of infection may
present as increased fatigue and malaise rather than as an increased number
of sinus or pulmonary symptoms such as increased cough or nasal discharge
(20). Fever can occur, but it is often absent in the setting of an acute res-
piratory tract exacerbation.

The true incidence of sinusitis in CF is not known, but current data
suggest that the vast majority of patients develop sinus disease at some
time in their lives (8). Symptoms usually present between the ages of 5
and 14 years, although many older patients have undiagnosed or untreated
sinus disease. Patients often adapt to their symptoms or carry alternative
diagnoses such as migraine headaches. Nasal polyps are the most common
manifestation of sinus disease in younger patients, while chronic headaches
are more common symptoms in the older CF population.

362 Henig

Imaging studies to diagnose CF-related sinusitis are useful. Plain
radiographs can readily identify frontal sinus agenesis or hypoplasia (21).
Computed tomography (CT) scans of the sinuses also show abnormal sinus
findings in almost all of the CF patients, even those who are asymptomatic.
Frontal sinus agenesis and greater than 75% opacification of the maxilloeth-
moid sinus is considered pathognomonic of CF. Similarly, medial bulging of
the lateral nasal wall near the middle meatus and resorption of the uncinate
process is highly suggestive of CF (22,23). Recently, a sinus CT scoring sys-
tem has been proposed, which discriminates between CF and non-CF sinus
disease. Nine criteria highlight the most characteristic sinus abnormalities in
CF patients, which are grouped as paranasal sinus variants, pneumatization
variants, and inflammatory patterns (24) (Table 1). Magnetic resonance ima-
ging (MRI) is useful for both diagnosis and tracking the progression of sinus
disease in CF patients. MRI is thought to be more sensitive than CT for
visualizing and differentiating soft tissues masses in the paranasal sinuses.

Allergic rhinitis may confound the presentation of CF-related sinusitis.
The incidence of allergic rhinitis in CF patients is reportedly the same as in
the general population, 20-40% (25). The subset of CF patients who develop
nasal polyps have an increased incidence of asthma-like reversible broncho-
constriction, airway hyperreactivity, and positive allergen skin tests (26).
However, this is not present in 100% of the CF patients who develop poly-
posis and the connection, if one exists, is poorly understood. Allergic rhinitis

Table 1 Paranasal Sinus Variants Found Commonly in Patients with CF and Used
in a CT Scoring System for Discriminating CF from Non-CF Patients a

Paranasal sinus variants
Frontal sinus aplasia
Frontal sinus hypoplasia
Maxillary sinus hypoplasia
Sphenoid sinus hypoplasia
Pneumatization variants
Absence of all of the following:

Agger nasi cells

Haller cells

Pneumatization of the lamellar or bulbous portion of the middle turbinate, nasal
bone, crista palli, and anterior clinoid or pterygoid process of the sphenoid bone
Inflammatory patterns
Advanced ethmoidomaxillary disease
Bulging of the laternal nasal wall
Sphenoethmoid recess inflammatory pattern

"Revised from Eggesbo HB et al. Proposal of a CT scoring system of the paranasal sinuses in
diagnosing cystic fibrosis.
Source: From Ref. 24.

Cystic Fibrosis and Sinusitis 363

should be diagnosed in addition to CF-related nasal and sinus symptoms in
those who have both as the allergic component should be treated as such.

DIAGNOSIS OF CYSTIC FIBROSIS

If CF is suspected in a patient with chronic sinusitis and/or nasal polyposis,
the patient should be referred for diagnostic studies (27). The gold standard
for making the diagnosis of CF is quantitative pilocarpine iontophoresis, or
the "sweat test. ,r A result of a chloride concentration of >60mmol/L is
diagnostic, while a result of 40-59 mmol/L is considered indeterminate
but likely to represent CF. The sweat test should be obtained at an accre-
dited testing facility where the test is performed frequently.

The other commonly used diagnostic test for CF is genotyping. Mutation
testing is highly specific for CF, but it is not as sensitive as the sweat test. There
are now over 1300 identified mutations of the CFTR gene. Approximately 80-
85% of CF alleles are detected using standard CF gene mutation testing (28).
Testing laboratories may identify the most common 25-29 mutations present
in their local population for the standard screen. There are a number of
national laboratories that perform expanded CF mutation analysis or actually
sequence the gene of the patient suspected of having CF. Increasing the number
of genes screened increases the sensitivity for making the CF diagnosis. For an
expanded screen of 88 mutations, gene detection sensitivity is as follows: 94%
for Caucasians, 97% for Ashkenazi Jews, 72% for Latinos, and 61% for African
Americans (29). Mutation screening is less sensitive for Asian and other non-
Caucasian populations where there is a higher prevalence of rarer mutations.

Nasal potential differences (NPD) are the third accepted diagnostic test
for CF. This test is currently used in research settings primarily, and is only
available at a limited number of accredited sites. NPD can be measured directly
from the middle nasal turbinate. The basal NPD and the effect of a variety
of conductance altering infusates can quite accurately distinguish between
patients with and without CF. There are three main characteristics of the
NPD associated with CF. First, the basal voltage is raised, reflecting enhanced
sodium transport across the relatively chloride-impermeable barrier. Second,
with infusion of amiloride, a sodium channel blocker, a larger inhibition of
NPD occurs, reflecting an inhibition of the accelerated sodium transport.
Third, unlike normal individuals, there is no change in voltage in response to
perfusion of a chloride-free solution with isoproterenol, reflecting the absence
of CFTR-mediated chloride conductance (Fig. 2).

TREATMENT OF CF-RELATED SINUSITIS

The treatment of CF-related sinusitis is not dissimilar from the treatment of
acute and chronic sinusitis in general. As with the pulmonary manifestations
of CF, treatment should target the obstruction, infection, and inflammation
that characterizes the pathophysiology of the disease. Chronic sinusitis is

364

Henig

(A)

time

(min) "\

20 -

10-

-10-

-20-
-30
-40 -j
-50-

-60-

amiloride
1

3 4 5 6 7 8 9 10 11 12 13

J 1 1 1 1 I ! l 1 l l

clfree

Isoproterenol
1

^^-H4-n

(B)

time
(min) 1

2 3 4 5 6 7 8 9 10 11 12 13
J 1 I I ! I I I I I I L

20-
10-

-10-
-20-
-30-
-40-
-50-
-60^

amiloricte
I

cl free
I

Isoproterenol
I

ffWj^tf-jMW

Figure 2 Nasal potential differences in a healthy and a CF patient.

most often treated daily with upper airway clearance and anti-inflammatory
agents. Acute exacerbations of chronic sinusitis are treated with systemic
antibiotics and often more aggressive upper airway clearance, including sur-
gical debridement, if needed.

Upper Airway Clearance

Clearance of the airways is important for both the upper and lower res-
piratory tracts. More attention has been focused on airway clearance of
the lungs than that of the sinuses; however, the ultimate goal, to remove
obstructing mucus, is the same. Upper airway clearance can be achieved
by saline flushes, decongestants and mucolytics, and surgical interventions.
Saline flushing of the nasal passages and sinuses in patients with antro-
stomies can be taught to patients and done frequently, as much as many
times each day. In CF and non-CF sinusitis, symptomatic relief results from

Cystic Fibrosis and Sinusitis 365

mechanical clearance of obstructing mucus (30). It is also suggested that
saline flushes may decrease nasal blood flow, resulting in a decongestant
effect. There is no controlled study of how best to perform saline flushes.
Pre-filled squeeze bottle atomizers are available commercially. Buffered
saline solutions can be prepared at home and used with catheter tipped
syringes, bulb syringes, Water Piks®, or a variety of other devices designed
to create a high flow irrigant. Flushing of maxillary sinuses through catheters
placed following antrostomies is an accepted approach to clearing obstruc-
tion in CF. In the original uncontrolled study of 1 1 CF patients following
lung transplantation, the maxillary sinuses were irrigated with tobramycin,
which effectively reduced contamination of the transplanted lungs (31).
The practice of routine (usually monthly) sinus irrigation with tobramycin
is now also performed in CF patients who are not transplant recipients. This
practice has been shown to reduce the number of pulmonary exacerbations
(32) and the total number of sinus surgeries that patients undergo (33). This
was also shown to improve aeration of the sinuses as assessed by MRI (34).
Although the practice is routine, it is unclear which component of the
monthly flush is most critical — the monthly physician attention to the
sinuses, the act of irrigation, or the irrigant. Other antimicrobial irrigants
have also been used in patients without any supporting data.

The use of decongestants in CF has not been studied, but both oral
and topical decongestants are used in the CF population. Use of deconge-
stants is minimized for fear of rhinitis medicamentosa. Mucolytics such as
guaifenesin are often used for symptomatic relief and are thought not to
be detrimental. Clinically, guaifenesin is more effective for thinning nasal
secretions than pulmonary secretions. Daily use by nebulization of the
mucolyic dornase alpha (recombinant DNase) is recommended for all CF
patients (35). It is unknown what effect, if any, this has on nasal secretions.

Antihistamines, the cornerstone of allergy-induced rhinitis and sinusitis
treatment, were once believed to be contraindicated in patients with CF as they
were believed to further dessicate the already thick secretions (36). Clinically,
this has not been observed and CF patients who also suffer from allergic rhinitis
respond readily to antihistamines. Intranasal cromolyn is used by some practi-
tioners, although there is no data to support its use for CF-related sinusitis.

Antimicrobial Therapy

Antibiotics are the cornerstone of treating infective sinusitis, especially CF-
related sinusitis. Nasal swabs, transantral aspirations, and sputum cultures
can identify infecting pathogens. Because pathogens are never eradicated in
CF, cultures taken months and even years previously are valuable in guiding
the selection of antibiotics. Similarly, in vitro sensitivity-testing with a panel
of antibiotics should be performed. Systemic antibiotics should be at high doses
to increase the concentration of antibiotic in the nares, sinuses, and airways

366 Henig

where the pathogens live. The ideal duration of therapy for acute on chronic
sinusitis is unknown, but the usual treatment is three to six weeks (8,36).

Antibiotics are given systemically or locally via inhalation or maxillary irri-
gation. Systemic antibiotics are preferred since exacerbations of upper and lower
airway disease occur simultaneously. Nebulized aminoglycosides given thrice
weekly are shown to decrease bacterial colonization and decrease inflammation
in non-CF sinusitis patients (37). The recommended treatment for CF patients
chronically infected with P. aeruginosa is twice daily inhalation of tobramycin
solution (TOBI®) (38). It is believed that when used with a jet nebulizer as pre-
scribed, TOBI penetrates the maxillary sinuses. Thus, through the course of
routine CF care, a reduction of pathogens in the maxillary sinuses does occur.

Anti-Inflammatory Agents

Targeting inflammation in CF has been shown to improve lung function and
lower the rate of decline of the forced expiratory volume in one second in the
lungs. To date, systemic agents such as prednisone (39,40) and high dose
ibuprofen (41) have proven to be beneficial, but these specific agents are lim-
ited by toxicity. Nasal steroids are shown to effectively reduce inflammation
in non-CF chronic sinusitis (42), and have had variable results in the CF
population (8,28,43,44). Regular use of nasal steroids is shown to diminish
the size of nasal polyps. Post-polypectomy use of nasal steroids is shown to
prevent recurrent formation of nasal polyps. Although no conclusive data
exist to support the recommendation, use of inhaled nasal steroids is con-
sidered to be a first-line treatment for CF-related sinusitis (36).

Targeting leukotrienes has been another approach to decreasing
inflammation in CF. Patients with CF are recognized as having high circu-
lating leukotriene levels (high LTB4), as well as high cysteinyl leukotrienes
(45). Leukotriene receptor antagonists are a group of anti-inflammatory
agents shown to reduce the symptoms of allergic rhinitis in patients without
CF. These agents are used commonly in patients with CF, especially those
with asthma-like symptoms or allergic rhinitis.

Macrolide antibiotics are shown to have anti-inflammatory properties
distinct from their antimicrobial properties. Regular use of azithromycin in
CF is shown to improve pulmonary function and decrease the number of
pulmonary exacerbations in CF (46). In a non-CF population, macro-
lide antibiotic therapy was shown to shrink nasal polyps and reduce the
concentration of interleukin-8 in nasal lavage (47).

EXPERIMENTAL THERAPIES

A number of experimental therapies are being explored for the treatment of CF,
which will likely benefit the chronic rhinosinusitis as well as the systemic disease.
Gene therapy to correct the underlying CFTR defect is the ultimate solution for
CF, although many obstacles to this type of therapy remain. The nares and sinus

Cystic Fibrosis and Sinusitis 367

cavities are the usual targets of gene therapy transfer studies (48). A variety of
vectors, including adenovirus, liposomes, and adeno-associated virus, have been
explored. In one study of an adeno-associated viral vector with a CFTR cassette
applied to the nasal mucosa, NPD were corrected and the occurrence of sinusitis
was halved during the first month (49). The barriers to gene therapy include rapid
turnover of respiratory epithelium, immunogenic response to the vector, and
appropriate transcription, translation, and expression of the functional gene.

SPECIAL CONSIDERATIONS

Lung Transplantation and CF-Related Sinus Disease

Lung transplantation is the treatment of choice for CF patients with end-stage
lung disease. In general, it is considered a life-extending treatment for carefully
selected patients. Lung transplant recipients are immunosuppressed for life.
Although the historic concern is that immunosuppression could worsen the
chronic sinusitis of CF, experientially most patients with CF do not experience
an increase from baseline in sinusitis symptoms, possibly due to the anti-
inflammatory effects of the drugs. Instead, the concern is that chronic bacterial
infection of the sinuses can result in bacterial infection of the new lungs, and
that repeated injury to the lungs results in chronic allograft rejection, other-
wise known as obliterative bronchiolitis. In the early 1990s, functional endo-
scopic sinus surgery with antrostomies was put forth as a method to prevent
early bacterial infection, and at certain transplant centers, CF patients were
required to undergo sinus evaluation preoperatively (31). This practice is
not universally accepted at all lung transplant centers, although more recent
data from a center that requires aggressive sinus care post-transplantation sug-
gest that attention to the sinuses does result in fewer episodes of tracheobron-
chitis and a trend toward less obliterative bronchiolitis (50).

Anesthesia

CF patients referred for otolaryngologic surgery should undergo the same
preoperative evaluation for general anesthesia as other patients (51). In gen-
eral, it is preferable to avoid general anesthesia with endotracheal intubation,
if feasible. If patients are intubated, every effort should be made to extubate
them as quickly as possible. CF patients can clear their own secretions far
more effectively with cough and expectoration than with endotracheal suc-
tioning. Even patients with advanced lung disease generally tolerate
general anesthesia if proper precautions are taken.

CONCLUSION

In the last 60 years, CF has evolved from an uncharacterized disease of the
pancreas that killed infants to a well-described disease with survival well into

368 Henig

adulthood. This incredible accomplishment resulted from multidisciplinary
science, as well as from multidisciplinary clinical care. There is increasing
recognition of the need to attend to the upper respiratory tract to the same
degree as the lower respiratory tract. Otolaryngologists will likely care for
increasing numbers of CF patients in the coming years as the population
increases and the treatment of sinus disease moves to the forefront.

REFERENCES

1. Cystic Fibrosis Foundation 2003 Registry, www.cff.org.

2. Gibson RL, Burns JL, Ramsey EW. Pathophysiology and management of pulmo-
nary infections in cystic fibrosis. Amer Jo Resp Crit Care Med 2003; 168:918-951.

3. diSant'Agnese PA. The pulmonary manifestations of fibrocystic disease of the
pancreas. Diseases of the Chest 1955; 27:654-670.

4. diSant'Agnese PA, Darling MD, Perera G, Shea E. Abnormal electxolye
composition of sweat in cystic fibrosis of the pancreas. Clinical significance
and relationship to disease. Pediatrics 1953; 12:549-563.

5. Zielenski J, Rozmahel R, Bozon D, Kerem B, Grzelezik Z, Riordan JR, Rom-
mens J, Tsui LC. Genomic DNA sequence of the cystic fibrosis transmembrane
regulator (CFTR) gene. Genomics 1991; 10:214-228.

6. Hyde SC, Emley P, Hartshorn, et al. Structural model of ATP-binding proteins
associated with cystic fibrosis, multidrug resistance, and bacterial transport.
Nature 1990; 346:362-365.

7. Donaldson SH, Boucher RC. Update on pathogenesis of cystic fibrosis lung
disease. Curr Op Pulm Med 2003; 9:486-491.

8. Ramsey B, Richardson MA. Impact of sinusitis in cystic fibrosis. J Allergy Clin
Immunol 1992; 90:547-553.

9. Wang X, Moylan B, Leopold DA, Kim J, Rubenstein RC, Togias A, Proud D,
Zeitlin PL, Cutting GI. Mutation in the gene responsible for cystic fibrosis and
predisposition to chronic rhinosinusitis in the general population. JAMA 2000;
284:1814-1819.

10. Smith J J, Travis SM, Greenberg EP, Welsh MJ. Cystic fibrosis airway epithelia fail
to kill bacteria because of abnormal airway surface fluid. Cell 1996; 85:229-236.

1 1 . Tandon R, Derkay C. Contemporary management of rhinosinusitis and cystic
fibrosis. Curr Op Otolaryng & Head and Neck Surg 2003; 11:41-44.

12. Gysin C, Alothman GA, Papsin BC. Sinonasal disease in cystic fibrosis: Clinical
characteristics, diagnosis, and management. Ped Pulm 2000; 30:481-489.

13. Burns JL, Emerson J, Stapp JR, Yim DL, Kirzewinski J, Louden L, Ramsey
BW, Clauser CR. Microbiology of sputum from patients at cystic fibrosis cen-
ters in the United States. Clin Infect Dis 1998; 27:158-163.

14. Parsek MR, Singh PK. Bacterial biofilms: an emerging link to disease
pathogenesis. Annual Rev. Microbiology 2003; 57:677-701.

15. Bargon J, Dauletbaev N, Kohler B, Wolf M, Poselt HG, Wagner TO. Prophy-
lactic antibiotic therapy is associated with an increased prevalence of Aspergillus
colonization in adult cystic fibrosis patients. Respir Med 1999; 93:835-838.

16. Olivier KN, Weber DJ, Wallace RJ, Faiz AR, Lee JH, Zhang Y, Brown-Elliot
BA, Handler A, Wilson RW, Schecter MS, Edwards LJ, Chakraborti S,

Cystic Fibrosis and Sinusitis 369

Knowles MR, Nontuberculous Mycobacterium in Cystic Fibrosis Study Group.
Nontuberculous mycobacteria I: multicenter prevalence study in cystic fibrosis
lung disease. Am J Respir Crit Care Med 2003; 167:810-812.

17. Olivier KN, Weber DJ, Lee JH, Handler A, Tudor G, Molino PL, Tomashefski
F, Knowles MR, Nontuberculous Mycobacteria in Cystic Fibrosis Study
Group. Nontuberculous mycobacteria I: nested cohort study of impact on cys-
tic fibrosis lung disease. Am J Respir Crit Care Med 2003; 167:835-840.

18. Ramsey BW, Gore EJ, Smith AL, Cooney MK, Redding GJ, Foy H. The effect
of respiratory viral infections on patients with cystic fibrosis. Am J Dis Child
1989; 143:662-668.

19. Shapiro ED, Milmoe GJ, Wald ER, Rodnan JB, Bowen AD. Bacteriology of
the maxillary sinuses in patients with cystic fibrosis. J Infect Dis 1982; 146:
589-593.

20. Rosenfeld M, Emerson J, Williams-Warren J, Pepe M, Smith A, Montgmorey
AB, Ramsey B. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr
2001; 139:359-365.

21. Ledesma-Medina J, Osman MZ, Girdany BR. Abnormal paranasal sinuses in
patients with cystic fibrosis of the pancreas. Pediatr Radiol 1980; 9:61-66.

22. Brihaye P, Clement PA, Dab I, Desprechin B. Pathological changes of the lat-
eral nasal wall in patients with cystic fibrosis. Int J Pediatr Otorhinolaryngol
1994; 141-143.

23. April MM, Zinreich J, Baroody FM, Naclerio RM. Coronal CT scan abnorm-
alities in children with chronic sinusitis. Laryngoscope 1993; 103:985-990.

24. Eggsbo HB, Sovik S, Dolvik S, Eiklid K, Kolmannskog F. Proposal of a CT
scoring system of the paranasal sinuses in diagnosing cystic fibrosis. Eur Radi-
ology 2003; 13:1451-1460.

25. Davidson TM, Murphy C, Mitchell M, Smith C, Light M. Management of
chronic sinusitis in cystic fibrosis. Laryngoscope 1995; 105:354-358.

26. Crockett DM, McGill TJ, Healy GB, Friedman EM, Skalked LJ. Nasal and
paranasal sinus surgery in children with cystic fibrosis. Ann Otol Rhinol Laryn-
gol 1987; 96:367-372.

27. The Diagnosis of Cystic Fibrosis: consensus statement. In: Clinical Practice Guide-
lines for Cystic Fibrosis. Cystic Fibrosis Foundation, Vol. VII, Section I, 1996.

28. Stern RC. The diagnosis of cystic fibrosis. New Engl Jour Med 1997; 7:487^91.

29. Carrier rates and detection rates by ethnic background, www.genzvmegenetics.
com. 2005.

30. Brown CL, Graham SM. Nasal irrigations: good or bad? Current Opinion in
Otolaryngology & Head & Neck Surgery 2004; 12:9-13.

31. Lewiston N, King V, Umetsu D, Starnes V, Marshall S, Kramer M, Thodore J.
Cystic fibrosis patients who have undergone heart-lung transplantation benefit
from maxillary sinus antrostomy and repeated sinus lavage. Transplantation
Proceedings 1991; 23:120-08.

32. Davidson TM, Murphy C, Mitchell M, Smith C, Light M. Management of
chronic sinusitis in cystic fibrosis. Laryngoscope 1995; 105:354-358.

33. Moss RB, King VV. Management of sinusitis in cystic fibrosis by endoscopic
surgery and serial antimicrobial lavage reduction in recurrence requiring sur-
gery. Arch Otolaryngol Head Neck Surg 1995; 121:566-572.

370 Henig

34. Graham SM, Launspach JL, Welsh MJ, Zabner J. Sequential magnetic reso-
nance imaging analysis of the maxillary sinuses: implications for a model of
gene therapy in cystic fibrosis. J Laryngol Otol 1999; 113:329-335.

35. Shak S, Capon D, Hellmis R, Marster SA, Baker CL. Recombinant human
DNase reduces viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA
1990; 87:9188-9192.

36. Hui Y, Gaffhey R, Crysdale WS. Sinusitis in patients with cystic fibrosis. Eur
Arch Otorhinolaryngol 1995; 252:191-196.

37. Kobayashi T, Baba S. Topical use of antibiotics for paranasal sinusitis. Rhinol-
ogy 1992; 14:77-81.

38. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, William-Warren J,
Vasiljev KM, Borowitz D, Bowman CC, Marshall BC, Marshall S, Smith AL.
Intermittent administration of inhaled tobramycin in patients with cystic fibrosis.
Cystic Fibrosis Study Group. N Engl J Med 1999; 340:23-30.

39. Aurbach HS, Williams M, Kirkpatrick JA, Colton HR. Alternate day predni-
sone reduces morbidity and improves pulmonary function in cystic fibrosis.
Lancet 1985; 2:686-688.

40. Konstan MW. Therapies aimed at airway inflammation in cystic fibrosis. Clin
Chest Med 1998; 19:505-513.

41. Konstan M, Byard P, Huppel C, Davis PB. Effect of high dose ibuprofen in
patients with cystic fibrosis. N Engl J Med 1995; 332:848-854.

42. Bateman ND, Fahy C, Woolford TJ. Nasal polyps: still more questions than
answers. J Laryngol Otol 2003; 117:1-9.

43. Cepero R, Smith RJ, Catlin FI. Cystic fibrosis — An otolaryngologic perspec-
tive. Otolaryngol Head Neck Surg 1987; 97:356-360.

44. Hadfield PJ, Rowe-Jones JM, Mackay IS. A prospective treatment trial of nasal
polyps in adults with cystic fibrosis. Rhinology 2000; 38:63-65.

45. Cromwell O, Morris HR, Walport MJ, Taylor GW. Identification of leuko-
triene D and B in sputum from cystic fibrosis patients. Lancet 1981; 2:164-165.

46. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, et al. Azithromycin in
patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa.
JAMA 2003; 290:1749-1756.

47. Yamada T, Fujieda S, Mori S, Yamamoto T, Saito H. Macrolide treatment
decreased the size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol
2000; 14:143-148.

48. Graham SM, Launspach JL. Utility of the nasal model in gene transfer studies
in cystic fibrosis. Rhinology 1997; 35:149-153.

49. Wagner JA, Nepomuceno IB, Shah N, Messner AH, Moran ML, Norbash AM,
Moss RB, Wine JJ, Gardner P. Maxillary sinusitis as a surrogate model for CF gene
therapy clinical trials in patients with antrostomies. J Gene Med 1999; 1:13-21.

50. Holzmann D, Speich R, Kaufmann T, Laube I, Russi EW, Simmen D,
Weder W, Boehler A. Effects of sinus surgery in patients with cystic fibrosis
after lung transplantation: A 10-year experience. Transplantation 2004; 77:
134-136.

51. Karlet MC. An update on cystic fibrosis and implications for anesthesia.
AANA J2000; 68:141-148.

Chronic Rhinosinusitis With and Without

Nasal Polyposis

Joel M. Bernstein

Departments of Otolaryngology and Pediatrics, School of Medicine and

Biomedical Sciences, Department of Communicative Disorders and Sciences,

State University of New York at Buffalo, Buffalo, New York, U.S.A.

INTRODUCTION

Chronic rhinosinusitis (CRS) has been the subject of much debate, as the Rhino-
sinusitis Task Force convened to confront the difficult issues related to rhinosi-
nusitis, including definition, staging, and basic research (1). In general, the
definition of CRS has been based entirely on clinical criteria in which there is evi-
dence of a chronic inflammatory state in the nose and paranasal sinuses for at
least 12 weeks (1). Although in most cases this may be the result of untreated
acute bacterial rhinosinusitis, the diagnostic criteria were still clinical and offered
little explanation of the underlying pathophysiology.

CRS appears to be a clinical syndrome in which a number of factors
play a role. These factors include bacteria, allergy, superantigen, congenital
anatomical factors in the lateral wall of the nose and septum, biofilm, and
fungi (1). The factors associated with CRS can be divided into three cate-
gories, which are outlined in Table 1 . These three categories include systemic
host factors, local host factors, and environmental factors (1). These factors
contribute to the pathogenesis of CRS or are simply associated with CRS.

Chronic inflammation is axiomatic to the definition of CRS. Therefore,
like other chronic inflammatory diseases of, for example, the lung, bowel, and
joints, the development and persistence of chronic inflammation require

371

372

Bernstein

Table 1 Factors Associated with CRS

Systemic host factors

Local host factors

Environmental factors

Allergy

Anatomic

Microorganisms

Immunodeficiency

Neoplasm

Noxious chemicals

Genetic/congenital

Acquired mucociliary
dysfunction

Medications

Mucociliary dysfunction

Trauma

Endocrine

Surgery

Neuromechanism

knowledge of the involvement of inflammatory mediators, cytokines, and
adhesion molecules on the surface of lymphocytes, macrophages, eosinophils,
and neutrophils. The counter receptors on the surface of venules, which result
in attachment of these inflammatory cells to the vascular endothelium, also
need to be identified. Finally, an understanding of chemokines is required to
explain the migration of these inflammatory cells into the milieu of the mucosa
of the paranasal sinuses and nasal polyps.

The 2003 CRS Task Force redefined the clinical definition of the symp-
toms associated with CRS (1), which had already been described by Lanza
and Kennedy (2) in 1997 and divided into major and minor factors that are
summarized in Table 2. The presence of discolored nasal discharge, nasal
polyps or polypoid mucosal swelling associated with other endoscopic find-
ings of edema or erythema of the middle meatus, and edema or erythema of
the ethmoid bulla were the physical findings that may be associated with CRS.

The 2003 CRS Task Force also defined the radiographic findings of
CRS and established that isolated or diffuse mucosal thickening, bone
changes, and air fluid levels had to be present for such a diagnosis (1).
Magnetic resonance imaging (MRI) was not recommended, but plain films,
particularly the Waters' view, demonstrating mucosal thickening of greater
than 5 mm or complete opacification of the maxillary sinuses were deter-
mined to be indicative of CRS.

Table 2 Factors Associated with the Diagnosis of Chronic
Rhinosinusitis

Major factors

Facial pain/pressure
Facial congestion
Nasal blockage
Nasal discharge
Hyposmia/anosmia
Postnasal discharge

Minor factors
Headache
Fever
Halitosis
Fatigue
Dental pain
Cough
Ear pain/fullness

CRS With and Without Nasal Polyposis 373

Many questions regarding CRS have still been unanswered; these
include the necessity of antibiotics, the need for antifungal medication, and
the role of topical applications (i.e., antifungals, antibacterials, and topical
diuretics). The understanding of the inflammatory pathways that may lead
to chronic inflammation of the paranasal sinuses is required so that a logical
form of medical or surgical therapy can be undertaken. The exact mechanism
producing the chronic inflammatory state in CRS is just beginning to become
unraveled. This chapter will summarize the epidemiology, etiology, pathogen-
esis, clinical symptomatology, complications, microbiology, and molecular
biology of CRS with and without nasal polyposis. New ideas for therapeutic
intervention based on principles of pathogenesis and molecular biology asso-
ciated with CRS with massive nasal polyposis are considered. Finally, the
chapter will conclude with a differential diagnosis of nasal masses.

POTENTIAL ETIOLOGIES FOR THE EARLY STAGES OF CRS

The most important initial phase of CRS is mucosal irritation. The sche-
matic representation of the potential alterations in the nasal mucosa that
may occur after insult by bacteria, virus, allergen, air pollution, superanti-
gen, or fungi is shown in Figure 1. These entities may cause upregulation
of intercellular adhesion molecule 1 (ICAM-1) or other cytokines. HLA-DR
molecules may be upregulated on the epithelial surface, which can then play
a role in a specific immune response with the subsequent recruitment of either
TH t or TH 2 cells and the eventual release of specific cytokines.

Granulocyte-macrophage-colony stimulating factor (GM-CSF), inter-
leukin (IL-8), and tumor necrosis factor (TNF-oc) may all be released by
this upregulated epithelium and have an effect on macrophage, mast cells,
eosinophils, and neutrophils. In addition, INF-y released by THi cells may
also enhance the production of ICAM-1 on the surface of the respiratory
epithelium.

The concept of superantigens as a possible cause of the initial triggering
event in the etiology of CRS with massive nasal polyposis has been studied in
our laboratory (3). We have demonstrated that Staphylococcus aureus
accounts for about 60% of cultures of the lateral wall of the nose, even in
the absence of this organism in the nasal vestibule. These organisms always
produce exotoxins, which may act as superantigens. Superantigens may upre-
gulate lymphocytes by attaching to the variable P region of the T cell recep-
tor (TCR) of lymphocytes. Lymphocytes are present in the mucosa of the
lateral wall of the nose. Such upregulation may also result in an increase
of both TH! and TH 2 cytokines, which will be subsequently described in
detail.

Initially, then, the first phase of chronic inflammation of the paranasal
sinuses is an active upregulation of the immune response in the epithelium
of the lateral wall of the nose.

374

Bernstein

Bacteria
ICAM-1

Viruses Allergens

Air pollutants

Fungi Superantigen

ICAM-1

Macrophage Mast cell Eosinophil Neutrophil

Figure 1 Schematic representation of the potential alterations in respiratory epithelium
that may occur after insult by bacteria, virus, allergen air pollution, and fungus. There-
after, upregulation of ICAM-1 or other cytokines may occur. Most importantly, HLA-
DR molecules may be upregulated on the epithelial surface, which can play a role in a
specific immune response with the subsequent recruitment of either TH1 or TH2 cells
and their eventual release of specific cytokines. Abbreviations: GM-CSF, granulocyte-
macrophage-colony stimulating factor; ICAM-1, intercellular adhesion molecule- 1;
IFN-y, interferon-gamma; TNF-a, TNF-oc.

MICROBIOLOGY

The Rhinosinusitis Task Force has reviewed the literature on the microbiology
of CRS, with and without prior surgery (1). Numerous studies of the bacterial
flora in CRS reported the recovery of mixed polymicrobial flora of gram -positive
and gram-negative aerobic and anaerobic bacteria (Chapter 18). However, the
results have varied depending on patient's age and selection criteria, chronicity
of the disease, site of cultures, and specimen transport and culture techniques
(Table 3).

Aerobes represent 50% to 100% and anaerobes 0% to 100% of the micro-
bial isolates (4-8). The predominant aerobes include coagulase-negative
Staphylococcus, S. aureus, Streptococcus pneumoniae, Streptococcus viridans,
Haemophilus influenzae, Corynebacterium, and Moraxella catarrhalis. Fuso-
bacterium, Provotella, Pepto streptococcus, and Propionibacterium spp. are

CRS With and Without Nasal Polyposis 375

Table 3 Bacteriology of Chronic Rhinosinusitis

No prior surgery No prior surgery

Aerobes - 75-100% Anaerobes - 0-25%

Coagulase-negative Staphylococcus Fusobacterium sp.

Staphylococcus aureus Provotella sp.

Streptococcus pneumoniae Peptostreptococcus sp.

Streptococcus viridans Proprionibacterium sp.

Haemophilus influenzae Prior surgery

Corynebacterium sp. Pseudomonas sp.

Moraxella catarrhalis Klebsiella sp.

Enter obacter sp.

Coagulase-negative Staphylococcus
Staphylococcus aureus

Source: Adapted from Ref. 1.

the most common anaerobes. Pseudomonas, Klebsiella, Enterobacter spp.,
coagulase-negative Staphylococcus, S. aureus, and the above anaerobic
bacteria were all recovered from individuals who had prior surgery (5).

There is abundant evidence that anaerobic bacteria play an important
role in both acute and CRS. However, their isolation depended on culture
techniques, and unfortunately most studies have not used optimal techni-
ques for their recovery (4-6).

The role of anaerobic bacteria in CRS has been demonstrated in sev-
eral studies reviewed by Nord (8). The potential ability of beta-lactamase-
producing aerobic and anaerobic bacteria to protect penicillin-susceptible
organisms by the production of beta-lactamase was illustrated by Brook
et al. (9), and Finegold et al. recovered anaerobes from 48% of adults with
chronic maxillary sinusitis (10). Brook et al. illustrated that there are differ-
ences in the distribution of organisms in single patients who suffer from
infections in multiple sinuses, and emphasized the importance of obtaining
cultures from all infected sinuses (11).

Adenovirus and respiratory syncytial virus (RSV) have been demon-
strated in CRS using the polymerase chain reaction (12). Sinus mucosal biopsies
from 20 patients undergoing endoscopic sinus surgery were sterilely collected.

One specimen tested positive for RSV and another for adenovirus by
viral culture and immunofluorescence.

EPIDEMIOLOGY OF CRS WITH MASSIVE NASAL POLYPOSIS

The epidemiology of nasal polyposis has been reviewed by a number of inves-
tigators. Settipane concluded that nasal polyps are found in about 36%
of patients with aspirin-intolerance, 20% of those with cystic fibrosis, 7% of
those with asthma, and 0.1% of normal children (13). Other conditions asso-
ciated with nasal polyps are tabulated in Table 4 and include Churg-Strauss

376 Bernstein

Table 4 Diseases that may be Associated with Massive Nasal Polyposis

With eosinophilia Without eosinophilia

Bronchial asthma Cystic fibrosis

Allergic rhinitis Primary ciliary dyskinesia

Allergic fungal sinusitis Chronic nonallergic rhinitis

Aspirin intolerance Young's syndrome
Churg-Strauss syndrome

syndrome (CSS), allergic fungal sinusitis, ciliary dyskinetic syndrome, and
Young's syndrome.

Settipane demonstrated that nasal polyps were statistically more
common in nonallergic patients than in allergic patients (13). Furthermore,
nasal polyposis was more common in nonallergic asthma versus allergic
asthma patients (13% vs. 5%, p < 0.01). About 40% of patients with surgical
polypectomies had recurrences. Further investigations by this group demon-
strated a family history of nasal polyposis, suggesting a hereditary factor (14).

Similar results were obtained in a recent study that investigated the pre-
valence of nasal polyposis in 3817 Greek patients with chronic rhinitis and
asthma and found nasal polyps in 4.2% of the patients (15). The prevalence
of nasal polyps increased with age in both sexes. Its prevalence was 13% in
patients with nonallergic asthma, 2.4% in patients with allergic asthma,
8.9% in patients with nonallergic rhinitis, and 1.7% in patients with allergic
rhinitis. These results appear to confirm the fact that the absence of IgE-
mediated hypersensitivity is more common in patients with nasal polyps.

Nasal polyps appeared to be present more frequently in nonallergic
patients than allergic patients and in patients with perennial allergy than
patients with seasonal allergy.

Johansson et al. provided the most recent review of the prevalence of
nasal polyps in adults (16). This study comprised 1900 inhabitants over the
age of 20 years stratified for age and gender.

The prevalence of nasal polyps was 2.7%, and the polyps were more
frequent in men, the elderly, and asthmatics.

It appears that most epidemiological studies suggest that nasal polyps
occur in less than 5% of the total population, are frequently associated with
bronchial asthma and tend to increase with age, and are twice as common in
patients who do not have allergy than patients with allergy. There appears
to be some evidence that over the age of 40, bronchial asthma associated
with nasal polyposis is more common in females.

Fritz et al., who sought to understand the basis of nasal polyposis
association with allergic rhinitis, hypothesized that the expression of unique
genes was associated with nasal polyposis phenotype (17). After examining
12,000 human genes transcribed in the nasal mucosa in patients with allergic

CRS With and Without Nasal Polyposis 377

rhinitis with and without nasal polyposis, they identified 34 genes which were
differentially expressed between the patient groups. The greatest differential
expression identified by the array analysis was for a group of genes associated
with neoplasia, including mammaglobin, a gene transcribed 12-fold higher in
patients with polyps compared with control patients with rhinitis alone.
These data suggested that nasal polyposis involves deregulated cell growth
by gene activation in some ways similar to a neoplasm. In addition, mamma-
globin, a gene of unknown function associated with breast neoplasia, might
be related to polyp growth.

THE CLINICAL DIAGNOSIS OF NASAL POLYPOSIS

The most common symptoms of nasal polyposis include nasal obstruction,
hyposmia, nasal discharge, and very often watery rhinorrhea (Table 5).
Although adequate diagnosis cannot be obtained by taking a history alone,
clinical examination of the nose may often reveal nasal polyposis with the
unaided eye. However, endoscopic examination of the nose is imperative
and often reveals nasal polyps in the lateral wall of the nose lateral to the
middle turbinate, as seen in Figure 2.

Polyps appear as pale, gray, watery solid masses, which are signifi-
cantly lighter in color than the normal, vascular pink mucosa of the inferior
and middle turbinates. Nasal polyposis usually is bilateral, although unilat-
eral nasal polyposis is often seen in allergic fungal sinusitis.

Currently, the best imaging procedure of the paranasal sinuses for the
identification of both nasal polyposis and chronic membrane thickening is
computerized tomograph (CT) scanning in both the coronal and axial
planes (Figs. 3 and 4). The basic and supplementary diagnostic tools for the
diagnosis of CRS with or without nasal polyposis are summarized in Table 6.
Although MRI is usually not indicated for the diagnosis of CRS, but in some
cases where a unilateral mass is found in the nose, MRI can be useful to
investigate the presence of mycosis or neoplasm. The presence of abundant
eosinophils in nasal cytology may establish whether or not topical corticos-
teroids would be useful. Nasal biopsy is sometimes indicated, particularly in

Table 5 Symptoms of Nasal Polyposis

Nasal obstruction

Watery rhinorrhea

Postnasal discharge

Anosmia

Nasal pressure

Fatigue

Snoring

378

Bernstein

Figure 2 Endoscopic view of the left and right nasal cavity showing polyposis
extending from the left middle meatus (left) and the right middle meatus (right).
On the left side of the picture, the forceps is pointing at a large polypoid mass in
the lateral wall of the nose completely obstructing the opening of the maxillary sinus.

patients with a unilateral mass in which a neoplasm is suspected. The pre-
sence of a unilateral mass will be reviewed later in this chapter.

The most common location of nasal polyps is the lateral wall of the nose.
Larsen and Tos have emphasized that nasal polyps are truly derived from the
ethmoid portion of the nose, that is, the mucosa lateral to the middle turbinate
(18). Polyps most often arise from the areas of mucosa near the natural ostia
of the maxillary and ethmoid sinuses. As these polypoid inflammatory
growths enlarge, they block the openings of the sinuses and produce total

Figure 3 Normal computerized axial tomogram of the paranasal sinuses showing a
very patent infundibulum on the left and right side with normal ethmoids and normal
maxillary sinuses. There is absolutely no thickened membrane in any of the sinuses.

CRS With and Without Nasal Polyposis

379

Figure 4 A classical case of bilateral ethmoid and maxillary sinusitis with an air
fluid level in the floor of the left maxillary sinus. The ethmoids on the left and the
frontal ethmoidal recess on the left are normal. There is complete obstruction of
the osteomeatal complex on the right side.

obstruction and subsequent development of acute and eventually CRS. Med-
ical or surgical therapy directed at their removal must then be considered.

Although polypoid swellings of the maxillary, ethmoid, frontal, and
sphenoid sinuses may occur, these are less common than the nasal polyps
mentioned earlier, which arise lateral to the middle turbinate.

The potential complications of nasal polyposis include nasal obstruc-
tion, obstructive sleep apnea, epistaxis, anosmia, and the rare case of bone
erosion (Table 7). Hyperteleorism can also result from the benign growth of
nasal polyps into the ethmoids, compressing and destroying the lamina papyr-
acea. Malignant transformation of benign nasal polyposis is extremely rare.

Postnasal discharge, which is a common symptom of obstructive nasal
polyposis, can aggravate bronchial asthma. The mechanism responsible for

Table 6 Basic and Supplementary Diagnostic Tools for Nasal Polyposis

Basic diagnostic tools

Supplementary diagnostic tools

Case history and clinical examination
Endoscopy of the nasal cavity

CT scan in coronal and axial planes

Allergy diagnosis

MRI can for certain diagnoses

(mycosis, tumor)
Nasal cytology
Nasal biopsy

380 Bernstein

Table 7 Complications of Nasal Polyposis

Purulent sinusitis

Epistaxis

Rare bone erosion

Hyperteleorism

Very rare malignant transformation

the development of asthma from CRS has been debated. Triggered nerves
in an affected sinus may result in both parasympathetic stimulation of the
bronchial tree and smooth muscle contraction (19). Removal of nasal polypo-
sis and the resulting improvement in the condition of the paranasal sinuses
often lead to marked improvement in the symptomatology and the treatment
of chronic bronchial asthma (19).

MEDICAL AND SURGICAL THERAPY OF NASAL POLYPOSIS

Because nasal obstruction is a major complaint of patients with nasal poly-
posis, therapy is directed towards relieving nasal obstruction. Furthermore,
knowledge of the specific etiology of nasal polyps, if known, such as an
allergic fungal sinusitis, will determine specific treatment. As nasal polyposis
is the end result of a variety of pathological processes, the goals of treatment
are to relieve nasal blockage, restore olfaction, and improve sinus drainage.

Topical corticosteroids are the mainstay of medical treatment. There is
little evidence that a particular topical steroid has better efficacy than any
other. Oral corticosteroid therapy is also extremely effective, but caution
is advised because of the significant side effects if these oral corticosteroids
are used either too often or for long periods of time. If massive nasal poly-
posis is present, it is most likely that medical therapy will fail. However, oral
steroids occasionally may even be effective in such cases, particularly in
restoring an improved quality of life to the patient. When topical and oral
steroid therapy fail in CRS with massive nasal polyposis, endoscopic surgery
can be very successful, especially when accompanied with aggressive post-
operative treatment with a number of new topical agents (Table 8). The use
of topical steroids, topical diuretics, and topical antibacterial agents can
result in symptom-free patients for many years.

The technique of endoscopic sinus surgery is beyond the scope of this
chapter, but in general, recurrence rates after endoscopic sinus surgery for
severe polyposis may be significant, particularly in patients with asthma.
However, there have been only few studies that correlated the combined
use of topical steroids, topical diuretics, topical antibacterials, and topical
antifungals. Therefore, revision surgery rates and recurrence rates, although
higher in patients with massive polyposis and with bronchial asthma, need

CRS With and Without Nasal Polyposis 381

Table 8 Topical Therapy Following Endoscopic Surgery for Massive Nasal
Polyposis

Topical reagent Mechanism of action

Topical corticosteroids Anti-inflammatory activity

Topical diuretics (amiloride Blocks apical or lateral sodium

or furosemide) channels and decreases water

uptake by mucosal cells

Topical antibacterials Kills bacterial or fungal flora

or antifungals in nasal mucus

Anti-leukotriene drugs Inhibits LTC3 and LTC4 in nasal

(monteleukast) mucosa

Saline irrigation Removes blood or mucous crusts

to be revisited with more aggressive use of postoperative topical agents as
shown in Table 8. In the case of massive nasal polyposis, modern surgical
techniques often have to be performed.

To better understand the chronic inflammatory disease associated with
CRS with nasal polyposis and the efficacy of both medical and surgical
therapy, a thorough knowledge of the molecular biology of the inflammatory
response in CRS with nasal polyposis is required.

The molecular biological events that may lead to the development of
the chronic inflammatory disorder leading to massive nasal polyposis can
be divided into three phases.

PATHOGENESIS OF CRS

Molecular Biology of Nasal Polyposis

Phase 1: Mucosal Irritation

The events that cause initial mucosal irritation in the lateral wall of the nose
involve bacteria, viruses, air pollutants, allergens, fungi, and superantigen
release from various microorganisms.

Structural abnormalities such as markedly deviated septum, Haller
cells, or marked pneumatization of the middle turbinates can also result
in mucosal irritation at the level of the osteomeatal complex. There is
increasing evidence that the airway epithelium, which has traditionally been
regarded as a physical barrier preventing the entry of inhaled noxious par-
ticles into the submucosa, plays an active role as a "metabolically active"
physical-chemical barrier (Fig. 1). It may be capable of expressing and
generating increased amounts of (1) inflammatory eicosanoids, which are
potent cell activators and chemoattractants; (2) pro-inflammatory cyto-
kines, which have profound effect on growth, differentiation, migration,

382 Bernstein

and activation of inflammatory cells; (3) specific cell adhesion molecules,
which play a vital role in "inter-tissue trafficking" of the inflammatory cells;
and (4) major histocompatability complex (MHC, Class II antigens), which
plays an important role in antigen presentation to and subsequent activation
of the T cells (20). More recent studies of the response of airway epithelial
cells to nonallergic stimuli suggested that these may induce synthesis of
inflammatory cytokines. For example, cultured human bronchial epithelial
cells exposed to nitric oxide and H. influenzae demonstrated that these
agents significantly increase synthesis of GM-CSF, IL-8, and TNF-oc by
epithelial cells in vitro (21,22).

Stimulation of epithelial cells by various agents may lead to the generation
of different cytokine profiles and subsequent activation of specific inflammatory
cells. Thus, the very early development of CRS in the lateral wall of the nose, with
or without nasal polyps, may be the result of stimulation of the epithelium by
aerodynamic changes, allowing irritants to metabolically or physically alter or
injure the surface epithelium. Once the surface epithelium is injured, a cascade
of inflammatory changes may occur. The expression of TNF-oc is particularly
important in airway inflammation because it is a cytokine with significant influ-
ence on epithelial cell permeability (23). Expression of IL-8, a major neutrophil
and eosinophil chemotactic factor, and ICAM-1, a member of the immunoglo-
bulin supergene family, may also result from the presence of TNF-oc (24,25).

ICAM-1 has been shown to act as both the ligand and the counter-receptor
for leukocyte function antigen- 1 (LFA-1) expressed on leukocytes (26), and
consequently plays a vital role in the recruitment and migration of inflammatory
cells to the sites of inflammation in the airways. Furthermore, studies of nasal
and bronchial tissues in patients with nasal polyps, perennial-seasonal allergic
rhinitis, and asthma have suggested that the expression of ICAM-1 may be
upregulated in the airway epithelium (27).

Studies investigating the expression of the MHC Class II antigens have
demonstrated that, in accordance with the findings in other cell types, human
airway epithelial cells have the ability to express the HLA-DR antigens and the
genes encoding these antigens (28). The ability of airway epithelial cells to
express HLA-DR antigens, however, suggests that these cells may play a
potentially important role in antigen processing, presentation, or both, and
possibly involve in immunoregulation through recognition, activation, and
proliferation of specific T-lymphocyte types (TH! or TH 2 ), which produce
specific cytokine profiles. These cytokines, such as IL-2, interferon-y, IL-4,
and IL-5, have been demonstrated in nasal polyps (29,30). It is therefore pos-
sible to speculate that the earliest change in the lateral wall of the nose that may
give rise to chronic inflammation or nasal polyposis is the activation or dys-
function of the epithelial cells themselves, resulting in attraction, maintenance,
and activation of various inflammatory cells into the epithelium. It is conceiva-
ble that if the TH 2 cell-associated pathway is activated, then the transcriptional
expression in synthesis of GM-CSF, IL-4, and IL-5 will affect predominantly

CRS With and Without Nasal Polyposis 383

eosinophil, mast cell, and macrophage function. Moreover, nonallergic stimuli
such as air pollutants, bacteria (endotoxin), and viruses can directly affect
epithelial cells to increase synthesis of GM-CSF, ILl-(3 and TNF-oc and also
to promote TH! cell-associated pathways, resulting in decreased synthesis of
IL-3, IL-4, and IL-5 (31). The overall effect would be to enhance migration
and activation of neutrophils in particular, and to attenuate migration and
activation of other inflammatory cell types.

A superantigen hypothesis for CRS and nasal polyposis is appealing
because one of the most common bacterial species found in the nasal mucus
in CRS is S. aureus (32). In all of the cases studied so far, these bacteria pro-
duced enterotoxins, and the corresponding variable- (3 region of the T-cell
receptor was upregulated (32). These data suggest that the initial injury to
the lateral wall of the nose may be the result of toxin-producing staphylo-
cocci. Other microorganisms including fungi may also act as superantigens.
The superantigen may play a role as an initial trigger in the development of
mucosal inflammation in the lateral wall of the nose.

Phase 2: TNF-oc and lnterleukin-1 (3

The second phase in the development of chronic inflammation in the lateral
wall of the nose and nasal polyposis relates to the activity of TNF-oc and IL-
1 (3. The message and the product of these two cytokines are found in the epithe-
lium and endothelium of both nasal polyps and mucosa of CRS (Figs. 5 and 6)
(33). The most important function of these two cytokines is upregulation of the
expression of endothelial adhesion molecules involved in inflammatory reac-
tions. The cytokines and secretagogues that induce self-surface expression of
endothelial adhesion molecules include very late antigen-4 (VLA-4) on the
surface of eosinophils, MAC-1 on the surface of macrophage, and LFA-1 on
the surface of neutrophils (34-36). The corresponding endothelial markers,
which are upregulated and act as counter receptors for these specific adhesion
molecules, are vascular cell adhesion molecule- 1 (VCAM-1) and ICAM-1.
Figure 7 shows a schematic diagram of the attachment of an inflammatory cell
to the endothelial cell of a venule in a nasal polyp.

VLA-4 specifically attaches to VCAM-1, and LFA-1 specifically attaches
to ICAM-1. The movement of the cell along the endothelium from the trailing
edge to the leading edge is shown in Figure 7 and is responsible for migration of
the cell along the endothelial cell border. The aforementioned in vitro studies
and animal experiments have demonstrated that a distinct set of adhesion
molecules is important for adherence of eosinophils to the endothelium and
their subsequent extravasation.

In the multistep model of leukocyte recruitment, it is proposed that
chemoattractants play a dual role by triggering integrin activation and
directing leukocyte migration. Several cysteine-cysteine chemokines, such
as eotaxin and RANTES (regulated upon activation, normal T-cell expressed
and secreted), have been shown to attract and activate eosinophils in vitro and

384

Bernstein

,*.

*♦■

J**

Figure 5 High power photomicrograph (peroxidase-antiperoxidase 400 x) of the
surface epithelium of a nasal polyp. The arrow points to basal cells, which have
the product of TNF-oc. The entire epithelium has the product of TNF-oc. TNF-oc is
also found in eosinophils in the lamina propria. Abbreviation: TNF-oc, tumor necrosis
factor.

to recruit eosinophils into inflammatory lesions with little effect on neutro-
phils (37,38) (Fig. 8).

RANTES also induces selective trans-endothelial migration of eosinophils
in vitro (37,38). Moreover, LFA-1 appears to have a higher affinity for ICAM-1
(39). That these chemoattractants can discriminate between leukocyte subsets
contributes significantly to the understanding of preferential recruitment of
particular cell types in various inflammatory reactions. Finally, increasing
evidence supports the notion that cytokines released from activated CD4 + T cells
are largely responsible for the local accumulation and activation of eosinophils in
allergy-related disorders (40). These T cells produce a particular set of cytokines
(TH 2 profiles); of these, IL-4 and IL-13 are believed to play a role in the prefer-
ential extravasation of eosinophils through selected induction of VCAM-1,
whereas IL-5, GM-CSF, and IL-3 are responsible for eosinophil activation
and prolonged survival (41). The interaction of VLA-4 on eosinophils and
VCAM-1 on venule and endothelial cells is responsible for the specific localiza-
tion of the eosinophil on the vascular endothelial cell in the nasal polyp. The pre-
sence of VLA-4 on the eosinophil and VCAM-1 on the venule endothelial cell

CRS With and Without Nasal Polyposis

385

Figure 6 High-power photomicrograph (peroxidase-antiperoxidase 600 x) of the
lamina propria of a nasal polyp showing the presence of interleukin- 1 (3 in the
endothelial cells (Arrows) of small venules.

Trailing edge
(Loss of attachment)

Migration

Leading edge
(New attachment)

Figure 7 A schematic diagram of the attachment of an inflammatory cell to the
endothelial cell of a venule in a nasal polyp. Very late antigen-4 specifically attaches
to VCAM-1, and leukocyte function antigen- 1 specifically attaches to ICAM-1. The
movement of the cell along the endothelium from the trailing edge to the leading
edge is shown and is responsible for the migration of the cell along the endothelial
cell border. Abbreviations: ICAM-1, intercellular adhesion molecule- 1; VCAM-1,
vascular cell adhesion molecule- 1.

386

Bernstein

RANTES

Figure 8 Photomicrograph of RANTES in the epithelium of a nasal polyp as well
as in eosinophils in the submucosa (peroxidase-antiperoxidase 800 x).

are shown in Figures 9 and 10. Once this slowing of eosinophil migration occurs
in the blood flow of the nasal polyp or the nasal mucosa, the chemokines,
RANTES, and eotaxin are most likely responsible for the trans-epithelial migra-
tion of these eosinophil cells into the lamina propria of the chronic inflammatory
tissue in CRS.

These studies suggest that the eosinophil is the predominant cell in the
nasal polyp where up to 80% of the inflammatory cells are eosinophils (42).
In many tissue sections, there are massive sheets of eosinophils totally filling
the lamina propria as the single or solitary inflammatory cell. (Fig. 11)

One of the most important phenomena that occurs within the lamina
propria of the nasal polyp is the autocrine upregulation of cytokines that
are responsible for the protracted survival of these cells. At least three
cytokines are responsible for the decreased apoptosis of eosinophils (41).
This mechanism has an effect on the long-term survival of eosinophils and
their activation. These three cytokines are IL-3, GM-CSF, and most impor-
tantly IL-5. IL-5 appears to have the most active effect in promoting the
survival of eosinophils in the nasal polyp. In addition to the production
of these eosinophil-promoting cytokines in the epithelium and endothelium
of the nasal polyp, the eosinophil itself can respond by producing similar

CRS With and Without Nasal Polyposis

387

** &*

>•*!>•''

- - i a

Figure 9 High-power photomicrograph of very late antigen-4 (VLA-4) on the surface
of eosinophils in the lamina propria of a nasal polyp (peroxidase-antiperoxidase
600 x).

cytokines in an autocrine-upregulated fashion. This vicious cycle of auto-
crine upregulation enhances the recruitment of even more eosinophils into
the nasal tissue so that the chronic inflammatory state of eosinophilia is
maintained.

Figure 10 High-power photomicrograph of vascular cell adhesion molecule- 1
(VCAM-1) on the tips of the endothelial cells of small venules in the lamina propria
of a nasal polyp (peroxidase-antiperoxidase 800x).

388

Bernstein

Figure 1 1 Lamina propria of a nasal polyp in which Staphylococcus aureus enter-
otoxin was present. High-power photomicrograph showing massive accumulation
of both eosinophils and degranulating eosinophils (magnification, 600 x; hematoxylin
and eosin).

Phase 3: Eosinophils and Major Basic Protein

Most research has concentrated on the potential damage to the epithelium
caused by inflammatory mediators of eosinophils, particularly that of major
basic protein (MBP) (33). Research also focused on the potential role of
MBP on sodium and chloride flux in the epithelium of the polyp epithelial
cell. Eosinophil cationic protein has been shown to stimulate airway mucus
secretion, whereas eosinophilic MBP inhibits the secretion (43). The first
study on the role of MBP and its effect on chloride secretion demonstrated
that MBP increases net chloride secretion (44).

The role of MBP on net sodium and chloride flux in an animal model of a
salt-depleted rat colon demonstrated that MBP significantly increases the net
sodium flux into the interior of the epithelial cell (Bernstein and Choshniak,
personal communication). Although there was a large movement of chloride
both in and out of the cell, there was no significant net flux of chloride. The
short-circuit current appeared to be significantly increased with MBP
compared with the control. In addition, amiloride, a respiratory epithelial
apical sodium channel inhibitor, was able to decrease not only the short-
circuit current, but also the amount of sodium flux into the cell. The results
of these animal studies are summarized in Figure 12. The use of topical
amiloride as an agent in the prevention of edema in recurrent nasal
polyposis might be considered as a possible adjunct to steroids.

CRS With and Without Nasal Polyposis

389

1600
1400

1200

1000

800

600

400

200

0.00

-200

-400

CI" Jne< ■
ISC

r m -~^

Control

MBP

Amiloride

Figure 1 2 The effect of MBP and amiloride on net flux of sodium + and chloride - in
a salt-depleted rat colon model. MBP has a significant effect on net sodium flux and
amiloride has a marked decreased effect on both the sodium flux as well as the short-
circuit current. Abbreviation: MBP, major basic protein.

In addition to the substantial accumulation of eosinophils in chronic
inflammation in the lateral wall of the nose and nasal polyps, the number of
lymphocytes is also significantly increased in CRS inflammation (Fig. 13).
Most of the cells that are found in nasal polyps are T cells (29,30). The TCR

V *

Figure 1 3 High-power photomicrograph of the lamina propria of the nasal polyp in
which Staphylococcus enterotoxin was identified in the adjacent mucus. There is a
massive lymphocytic infiltrate around a small venule. Most of these lymphocytes
are T cells (magnification, 200 x; hematoxylin and eosin).

390 Bernstein

functions in both antigen-recognition and signal transduction, which are
crucial initial steps in antigen-specific immune responses. TCR integrity is
vital to the induction of optimal and efficient immune responses, including
the routine elimination of invading pathogens and the elimination of modified
cells and molecules. It has recently been shown that there is an impairment
of TCR function in T cells isolated from hosts with various chronic patholo-
gies including cancer, autoimmune, and infectious diseases (45). Preliminary
data (Bernstein et al., personal communication) showed that T cells extrac-
ted from nasal polyps also possess a defective TCR in comparison with the
patient's peripheral blood and that of peripheral blood of normal adult
controls.

A common immuno-pathological hallmark of many inflammatory dis-
eases is a T cell invasion and accumulation in the inflamed tissue. Although
the exact molecular and micro-environmental mechanisms governing such
cellular invasion and tissue retention are not known, some key immunologi-
cal principles might be at work. Transforming growth factor- (3 is known to
modulate some of these processes including homing, cellular adhesion,
chemotaxis, and finally T cell activation, differentiation, and apoptosis (46).
The chronicity of T-cell-driven-inflammation may lead to a T cell adaptive
immune response. It is suggested therefore that the T lymphocytes that are
present in the nasal polyp, as in the chronic inflammation associated with
CRS, actually may not be active but may be anergic, which may maintain
the inflammatory response in these tissue sites.

Medical Treatment of CRS with Massive Nasal Polyposis Based
on the Molecular Biology of Inflammation

Eosinophil and lymphocytic infiltration into the lateral wall of the nose are
the characteristic histological findings in patients with CRS and massive nasal
polyposis. The previous description of the phases of inflammation has empha-
sized the interaction of cytokine molecules responsible for the development of
the increased numbers and survival of eosinophils and lymphocytes. There-
fore, a logical approach to the medical treatment of this inflammatory disorder
can only be objectively considered when a complete understanding of this
cytokine network has been established.

Hypothetically, antibodies directed against cytokines responsible for
the accumulation of lymphocytes and eosinophils in chronic inflammation
could be considered in the treatment of CRS with massive nasal polyposis
and other chronic inflammatory disorders in which these cells are present.
These diseases would include allergic rhinitis, bronchial asthma, allergic
fungal sinusitis, Churg-Strauss syndrome (CSS), and, particularly, aspirin-
intolerance, which is associated with CRS with nasal polyposis. The list of
antibodies directed against cytokines that have been used in both human

CRS With and Without Nasal Polyposis 391

Table 9 Anti-Cytokine Antibodies that Have Hypothetical Use in the Treatment
of CRS with Massive Nasal Polyposis

Anti-cytokine Potential mechanism

Anti-TNF-a Downregulates inflammatory cytokines

Anti-ILl-P Downregulates inflammatory cytokines

Anti-VLA-4 Decreases attachment of eosinophils to vascular

endothelium
Anti-VCAM-1 Decreases attachment of eosinophils to vascular

endothelium
Anti-RANTES Decreases attraction of eosinophils into lamina propria

Anti-eotaxin Decreases attraction of eosinophils into lamina propria

Anti-IL-5 51 Decreases survival of eosinophils

Anti-IL-3 Inhibits eosinopoesis

Anti-GM-CSF Inhibits eosinophil survival

Anti-IL-12 52 ' 53 Inhibits TH1 cytokines

and animal experiments are tabulated in Table 9. In these tables, the antic-
ytokine and its potential mechanisms are reviewed.

Although these hypothetical strategies may be interesting for the
researcher and clinician alike, a more practical approach to the medical
treatment of CRS with and without nasal polyposis is depicted in Table 10.
A review of this table is essential for the clinician. Antibiotic therapy using
pharmacokinetic and pharmacodynamic principles is problematic in the
disease that is now called CRS. The presence of bacteria, even though docu-
mented in many cases, does not necessarily prove that they are causing the
inflammation, although it is certainly possible.

As most experts in rhinology agree today that chronic inflammation is
the major problem in CRS with or without nasal polyposis, the use of specific
anti-inflammatory drugs is critical. Corticosteroids are the most commonly
used anti-inflammatory agents in the treatment of CRS, particularly with nasal
polyposis. The mechanism of action of corticosteroids is related to their ability

Table 10 Medical Management of CRS with Massive Nasal Polyposis

Antibiotic therapy using pharmacokinetic-pharmacodynamic principles

Topical and/or systemic corticosteroids

Anti-leukotriene therapy (local or systemic)

Macrolide therapy as anti-inflammatory

Therapy directed against biofilm

Topical diuretic therapy

Anti-allergy therapy (anti-IgE therapy)

392 Bernstein

to enter cells because of their lipophilicity. Following entrance into the cell, the
steroid binds to a steroid receptor where it alters the proteins secreted by that
cell. Therefore, corticosteroids can downregulate the synthesis of proteins that
are synthesized in eosinophils, basophils, mast cells, T cells, B cells, and even
antigen-presenting cells.

Antileukotriene therapy has been considered useful in the treatment
of both allergic rhinitis and nasal polyposis. This drug may be particularly
useful in the aspirin-sensitive patient who has CRS with nasal polyposis.
Although there is an abundant evidence of increasing resistance to macrolides
by S. pneumoniae, erythromycin and clarithromycin have no bactericidal
activity against H. influenzae, and there has been growing evidence supporting
their effect against neutrophils and some inflammatory cytokines. During the
past five decades, there has been an increasing interest in the potential anti-
inflammatory effects of macrolide antibiotics. Low-dose macrolide therapy
has dramatically increased survival in patients with diffuse panbronchiolitis
(47). This has led to further investigation into the potential use of macrolides
in chronic lung diseases with an inflammatory component. The effect of
macrolides in the downregulation of inflammatory mediators and cytokines
in CRS with or without nasal polyposis remains to be established.

Microorganisms are able to adhere to various surfaces and to form a
three-dimensional structure known as biofilm. In biofilms, microbial cells
show characteristics and behaviors different than those of plankton cells.
Once a biofilm has been established on the surface, the bacteria harbored
inside are less exposed to the host's immune response and less susceptible
to antibiotics. There have as yet been very few studies on biofilm in CRS.
However, there have been several studies on the behavior of bacteria on
the mucous membrane of the middle ear in experimental animals suggesting
particularly that nontypable H. influenzae may be involved in biofilm forma-
tion (48). The concept of biofilms in CRS needs more study, but if present,
may be one of the reasons why bacteria continue to colonize the sinuses in
chronic inflammatory disease.

Topical diuretic therapy with furosemide is a beneficial therapy in the
postoperative management of CRS with nasal polyposis (49).

Anti-IgE therapy is a new therapeutic tool used by allergists for the
neutralization of IgE and the inhibition of IgE synthesis (50). Monoclonal
anti-IgE therapy may be a rational approach when allergy is a major trigger
in the patient with IgE-mediated hypersensitivity.

Diseases Associated with Nasal Polyposis

Although nasal polyposis most frequently occurs in adults with bronchial
asthma who have either allergic rhinitis or nonallergic rhinitis, there are other
diseases which can be associated with nasal polyposis. A brief summary of
these diseases is discussed below (Table 4).

CRS With and Without Nasal Polyposis 393

Cystic Fibrosis

Nasal polyposis associated with cystic fibrosis occurs in young children and
young adults. It is the only disease in which nasal polyposis occurs in children
under the age of five. The histopathology of nasal polyposis in cystic fibrosis,
however, is quite different than that in noncystic fibrosis. Lympho-plasmacytic
cells are predominant, and eosinophils, though present, are not common.
Furthermore, the disease arises from the sinuses and encroaches upon the
lateral wall of the nose, which is opposite that of the noncystic fibrosis patient
where the disease arises in the lateral wall of the nose and compresses the sinus
ostia. The prevalence of nasal polyps in cystic fibrosis varies between 20% and
40%. An inverse relationship exists between nasal polyposis in cystic fibrosis
and pulmonary function; a better pulmonary function is generally present in
patients with cystic fibrosis who have nasal polyposis (54).

Allergic Fungal Sinusitis

Allergic fungal sinusitis is probably the only well-documented sinusitis
that is related to fungal elements, specifically those that produce an IgE-
mediated response. McClay et al. reported one of the largest studies of
the clinical presentation of allergic fungal sinusitis in children (55). One of
the characteristic findings in allergic fungal sinusitis is the presence of
obvious bony facial abnormalities, proptosis, unilateral asymmetric sinus
disease, bony extension on CT scan, and fungi on culture. Bipolaris and
curvilaria are equally recovered from both adults and children, whereas
adults have a greater incidence of aspergillus. Children have more obvious
facial skeletal abnormalities, unilateral sinus disease, and asymmetrical
disease than adults. The treatment of allergic fungal sinusitis, in addition
to a combination of surgery and systemic or topical corticosteroids, also
includes immunotherapy to pertinent fungal and nonfungal antigens.

NARES Syndrome

Perennial rhinitis without allergy has recently been named nonallergic rhinitis
with eosinophilia syndrome (NARES). The symptoms include nasal hyper-
reactivity involving sneezing, rhinorrhea, and nasal obstruction. Nasal
endoscopy and sinus CT reveal an evolution towards nasal polyposis in some
patients. In general, this disease is not associated with intolerance to aspirin,
and some investigators suggest that NARES may be a precursor to the triad
of nasal polyposis, chronic sinusitis, and bronchial asthma (56).

Church-Strauss Syndrome (CSS)

CSS is a rare multiple organ disease that belongs to the group of systemic
granulomatous vasculitis. The initial symptoms are often bronchial asthma
and allergic rhinitis; later in the course of the disease, the patients exhibit
lung, heart, and kidney manifestations. There have been approximately

394 Bernstein

200 cases published worldwide. The patients in general are on steroid ther-
apy and often have nasal polyposis and bronchial asthma. Occasionally,
cytotoxic drugs are necessary (57).

Aspirin-Intolerance

Aspirin-intolerance is associated with non-IgE-mediated nasal polyposis,
chronic sinusitis, and bronchial asthma. Occasionally, other drugs can also
be associated with aspirin-intolerance; they include alcohol, metabisulfltes,
benzoates, tartrazine, and codeine. All of these chemicals may be linked
to nonallergic eosinophilic rhinitis with the possible development of nasal
polyposis (58).

Primary Ciliary Dyskinesia

The syndrome of cilia dyskinesia is known as a heterogeneous ciliary
dysfunction caused by morphological defect of the dynein arms, the nexin
links, the radial spokes, and the transposition of micro tubules (59). This
disease is usually associated with chronic broncho-pulmonary infections
and nasal polyposis resistant to therapy and is usually diagnosed by electron
microscopic evaluation of the ultra-structure of the mucosal cilia. Usually it
is associated with disorders of the ciliated epithelium of other parts of the
body and is often misdiagnosed as cystic fibrosis. However, in ciliary dyski-
nesia, unlike cystic fibrosis, there is no evidence of a defect in sodium and
chloride transport along the apical surface of the cell.

Young's Syndrome

Young's syndrome is part of primary ciliary dyskinesia and is characterized
by repeated airway infections and congenital epididymis obstruction (60).
Sperm analyses reveal absence of spermatozoa, although spermatogenesis
in testes biopsies may be normal. Mucociliary clearance is impaired and
patients often have recurrent sino-bronchial disease with rare reports of
nasal polyposis (61).

Differential Diagnosis of Unilateral and Bilateral Masses
in the Nasal Cavity

Although nasal polyps are the most common inflammatory growth in the
nose of adults and some children, the presence of a unilateral nasal mass
should alert the clinician to the many benign sinonasal lesions that can occur
in this area. The nose and sinuses represent one of the regions of greatest
histological diversity in the body with any tissue capable of producing
benign and malignant tumors that can mimic nasal polyposis. In addition,
certain congenital and anatomical conditions may simulate a polyp, empha-
sizing the need for preoperative imaging even when only a biopsy is being
considered.

CRS With and Without Nasal Polyposis 395

Conversely, benign nasal polyposis may be associated with both significant
bone skull base erosion and, in exceptional cases, intracranial invasion.

Benign Lesions in Adults

Anatomic

Pneumatization of the middle turbinate (concha bullosa) can produce a large
mass in the nose which might simulate a fleshy polyp or tumor. This pneuma-
tization may be present on one or both sides, but its true nature can be deter-
mined by palpation and, if any confirmation is required, by CT scanning
(Table 11).

Tumors

Inverted Papilloma

These are the most common true nasal tumors, arising within the middle
meatus from where extension may occur into the nasal cavity and any of
the sinuses (62). The tumor has been a source of concern owing to its report-
edly high recurrence rate and occasional association with malignant transfor-
mation. The recurrence rate may be related to inadequate removal, whereas
the malignant transformation rate ranges from 0% to 55% in the literature,
almost owing to a failure to recognize the presence of squamous cell
carcinoma at the time of removal. The true potential for malignant trans-
formation in large well-done series is less than 5%. However, inverted

Table 1 1 Benign Tumors Simulating Nasal Polyps

Anatomic

Concha bullosa

Tumors
Epithelial

Papilloma (inverted, everted, cylindric)
Minor salivary (pleomorphic adenoma)

Mesenchymal

Neurogenic (meningioma, schwannoma, neurofibroma)

Vascular (hemangioma, angiofibroma)
Fibro-osseous (ossifying fibroma)
Muscular (leiomyoma, angioleiomyoma)

Granulomatous/inflammatory
Wegener's granulomatosis
Sarcoidosis
Crohn's disease

396 Bernstein

papilloma may also occur in association with nasal polyposis, be bilateral,
and infiltrate adjacent bone. This has led to diagnostic and management pro-
blems in the past and reinforces the need for submission of all tissue removed
at surgery for histopathological examination.

Angiofibroma

Juvenile angiofibroma occurs almost exclusively in male children or adolescents
who present with nasal obstruction and epistaxis (63). This may be combined
with dacrocystitis, otitis media with effusion, swelling of the cheek, and, occa-
sionally, visual loss. The tumor arises within the spehnopalatine foramen present
in the nasal cavity and nasopharynx from where it may extend into the sphenoid.
The lesion will spread laterally through the pterygopalatine region compressing
the back wall of the maxillary sinus to dumb-bell into the infratemporal fossa,
and from there may affect the orbit via the infra-orbital fissure. Biopsy of the
lesion may result in life-threatening hemorrhage, but fortunately a combination
of CT and MRI allows both the diagnosis and extent of the lesion to be deter-
mined accurately.

A number of other benign tumors may occur in the nose, all of which
are extremely rare and in which a combination of biopsy and imaging will
determine the histology, extent, and the most appropriate surgical approach
for excision. These benign tumors involve other papillomas and minor sali-
vary gland tumors, for example, pleomorphic adenomas. They may also
involve benign mesenchymal tumors such as fibro-osseous-ossifying fibroma,
vascular hemangioma, schwannomas, neurofibromas, and meningioma.

Inflammatory Granulomatous Conditions

Diseases such as Wegner's granulomatosis (64), sarcoidosis, and very rarely
Crohn's disease (65) may present with granulomatous changes within the
nose and the sinuses. It is exceptional, however, for these to simulate nasal
polyps, and they are usually manifested by a friable granular mucosa asso-
ciated with crusting and bleeding, pansinusitis, and ultimately loss of nasal
structure and support.

Any malignant tumor may mimic nasal polyposis as could mucinous
adenocarcinoma, which may effect both ethmoid labyrinths and produce
bilateral lesions. Squamous cell carcinoma is the most common malignant
neoplasm of the sinonasal region. However, the whole spectrum of histologi-
cal types of tumors may occur of which the most common simulating localized
nasal polyps are adenocarcinoma, olfactory neuroblastoma, and malignant
melanoma (Table 12).

Differential Diagnosis of a Nasal Mass in Children

The differential diagnosis of a unilateral mass in the nose of a child includes
congential lesions such as encephalocoele, glioma, dermoid cyst, and naso-

CRS With and Without Nasal Polyposis 397

Table 1 2 Malignant Lesions Simulating Nasal Polyps

Epithelial

Squamous cell carcinoma

Adenocarcinoma

Adenoid cystic carcinoma

Acinic cell carcinoma

Mucoepidermoid carcinoma

Olfactory neuroblastoma

Malignant melanoma

Metastatic tumors (e.g., kidney, breast, pancreas)
Mesenchymal tumors

Lymphoma

Rhabdomyosarcoma

Chondrosarcoma

Ewing's sarcoma

lacrimal duct cyst and lesions such as craniopharyngioma, hemangioma,
neurofibroma, and rhabdomyosarcoma. Imaging prior to any intervention
is mandatory; optimally a combination of CT and MRI is aimed at defining
the skull base defect and at determining the most appropriate surgical
approach. When true nasal polyposis occurs cystic fibrosis must be suspected
until proven otherwise (Table 13).

CONCLUSIONS

Nasal polyps are common, effecting almost 5% of the population. Their cause,
however, remains unknown and is not the same in all patients. They have
a clear association with asthma, aspirin-intolerance, cystic fibrosis, and chronic,
nonallergic rhinosinusitis. Histologically, they contain large quantities of

Table 1 3 Differential Diagnosis of a Nasal Mass in a Child

Congenital

Encephalocoele
Glioma
Dermoid cyst
Nasolacrimal duct cyst
Neoplasia
Benign

Craniopharyngioma

Hemangioma

Neurofibroma
Malignant

Rhabdomyosarcoma

398 Bernstein

extracellular fluid, mast cell degranulation, and massive eosinophilic infiltration
as well as lymphocytic infiltration. While this appearance suggests an allergic
etiology, there is little conclusive evidence to support this. However, preliminary
evidence suggests that in the absence of systemic allergy, a local allergic process
could be the cause (66).

The definition of CRS with and without nasal polyposis continues to
be evolving and requires understanding of a broader range of etiologies and
pathogenesis in addition to bacterial or viral infections. We need to know
whether the inflammation is of infectious or noninfectious origin. Although
allergic fungal sinusitis is a well-defined clinical entity, the ubiquitous nature
of fungal spores in the nasal mucus makes the role of fungal infection in
patients without allergic fungal sinusitis difficult to determine, and currently
the role of this condition in nasal polyposis remains unclear.

Endoscopic or microscopic sinus surgery of nasal polyps is considered
only after failure of appropriate medical treatment. Excellent results can be
achieved by functional endoscopic sinus surgery that utilizes endoscopic
guidance or three-dimensional microscopic control with microdebriders.
Furthermore, with the use of the currently available therapies, the results of
surgery can be long-lasting.

Therapeutic options include pharmaco-therapies and surgery. The
pharmaco-therapeutic approach includes antibiotics, systemic and topical
steroids, and possibly antifungals and novel anti-inflammatory therapies such
as the use of antibodies directed against a number of inflammatory cytokines,
antileukotrienes, and low-dose macrolide therapy. In the case of massive nasal
polyposis, modern surgical techniques will still have to be performed before
the above-mentioned therapeutic options will be possible.

REFERENCES

1. Benninger ME, Ferguson BJ, Hadley JA, Hamilos DL, Jacobs M, Kennedy DW,
Lanza DC, Marple BF, Osguthorpe JD, Stankiewicz JA, Anon J, Denneny J,
Emanuel I, Levine H. Adult chronic rhinosinusitis: definitions, diagnosis, epide-
miology, and pathophysiology. Otolaryngol Head Neck Surg 2003; 129L:S1-S32.

2. Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck
Surg 1997; 117:S1-S7.

3. Bernstein JM, Ballow M, Schlievert PM, Rich G, Allen C, Dryja D. A super-
antigen hypothesis for the pathogenesis of chronic hyperplastic sinusitis with
massive nasal polyposis. Am J Rhinol 2003; 17:321-326.

4. Brook I. Microbiology and antimicrobial management of sinusitis. Otolaryngol
Clin North Am 2004; 37:253-266.

5. Brook I, Frazier EH. Correlation between microbiology and previous sinus
surgery in patients with chronic maxillary sinusitis. Ann Otol Rhinol Laryngol
2001; 110:148-151.

6. Wald ER. Microbiology of acute and chronic sinusitis in children and adults.
Am J Med Sci 1998; 316:13-20.

CRS With and Without Nasal Polyposis 399

7. Bhattacharyya N. The role of infection in chronic rhinosinusitis. Curr Allergy
Asthma Rep. 2002; 2:500-506.

8. Nord CE. The role of anaerobic bacteria in recurrent episodes of sinusitis and
tonsillitis. Clin Infect Dis 1995; 20:1512-1524.

9. Brook I, Yocum P, Frazier EH. Bacteriology and beta-lactamase activity in
acute and chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg 1996;
122:418-422.

10. Finegold SM, Flynn J, Rose FV, Jousimes-Somer H, Jakielaszek C, McTeague
M, Wexler HM, Berkowitz E, Wynne B. Bacteriologic findings associated with
chronic bacterial maxillary sinusitis in adults. Clin Infect Dis 2002; 35:428-433.

11. Brook I. Discrepancies in the recovery of bacteria from multiple sinuses and
acute and chronic sinusitis. J Med Microbiol 2004; 53:879-885.

12. Ramadan HH, Farr RW, Wetmore SJ. Adenovirus and respiratory syncytial
virus in chronic sinusitis using polymerase chain reaction. Laryngoscope 1997;
107:923-925.

13. Settipane GA. Epidemiology of nasal polyps. Allergy Asthma Proc 1996; 17:
231-236.

14. Greisner WA, Settipane GA. Hereditary factor for nasal polyps. Allergy Asthma
Proc 1996; 17:283-286.

15. Grigoreas C, Vourdas D, Petalas K, Simeonidi S, Demeroutis I, Tsioulos T.
Nasal polyps in patients with rhinitis and asthma. Allergy Asthma Proc 2002;
23:169-174.

16. Johansson L, Akerlund A, Holmberg K, Melen I, Bende M. Prevalence of nasal
polyps in adults: Skovde population-based Study. Ann Otol Rhinol Laryngol
2003; 112:625-629.

17. Fritz SB, Terrell JE, Conner ER, Kukowska-Latallo JF, Baker JR. Nasal
mucosal gene expression in patients with allergic rhinitis with and without nasal
polyps. J Allergy Clin Immunol 2003; 112:1057-1063.

18. Larsen PL, Tos M. Origin of nasal polyps: an endoscopic autopsy study.
Laryngoscope 2004; 114:710-719.

19. Slavin RG. Sinusitis in adults and its relation to allergic rhinitis, asthma, and
nasal polyps. J Allergy Clin Immunol 1988; 82:950-956.

20. Holling TM, Schoote N, vanDenElsen PJ. Function and regulation of MHC
class II molecules in T-lymphocytes: of mice and men. Hum Immunol 2004; 65:
282-290.

21. Opdahl H, Haugen T, Hagberg IA, Aspelin T, Lyberg T. Effects of short-term
nitrogen monoxide inhalation on leukocyte adhesion molecules, generation of
reactive oxygen species, and cytokine release in human blood. Nitric Oxide J
2000;4:112-122.

22. Khair OA, Devalia JL, Abdelaziz MN, et al. Effect of erythromycin on Haemophilus
influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human
bronchial epithelial cells. Eur Respir J 1995; 9:1451-1457.

23. Mitseyama H, Kambe F, Murakami R, Cao X, Ishiguro N, Seo H. Calcium
signaling pathway involving calcineurin regulates interleukin-8 gene expression
through activation of NF-kappa B in human osteoblast-like cells. J Bone Miner
Res 2004; 19:671-679.

400 Bernstein

24. Lu L, Chen SS, Zhang JQ, Ramires FJ, Sun Y. Activation of nuclear factor-
kappa B and its proinflammatory mediator cascade in the infected rat heart.
Biochem Biophys Res Commun 2004; 321:879-885.

25. DeCesaris P, Starace D, Sarace G, Fillippini A, Stefanini M, Ziparo E. Activa-
tion of Jun N-terminal kinase/activated protein kinase pathway by tumor
necrosis factor-oc leads to intercellular adhesion molecule- 1 expression. J
Biochem 1999; 274:278-282.

26. Maeda K, Kai K, Hayashi T, Hasegawa K, Matsumura T. Intercellular adhesion
molecule- 1 (ICAM-1) and lymphocyte function associated antigen- 1 (LFA-1)
contributes to the elimination of equine herpes virus type I (EHV-1) from the lungs
of intranasally infected BALB/c mice. J Comp Pathol 2004; 130:162-170.

27. Rogala B, Namyslowski G, Marowka-Kata K, Gawlik R, Gabriel A. Concen-
tration of s-ICAM-1 in nasal polyp tissue. Med Sci Monitor 2000; 6:1109-1112.

28. Papon JF, Coste A, Gendron MC, Cordonnier C, Wingerstmamm L, et al.
HLA-DR and ICAM-1 expression and modulation in epithelial cells from nasal
polyps. Laryngoscope 2002; 112:2067-2075.

29. Sanchez-Segura A, Brieva J A, Rodriguez C. T lymphocytes that infiltrate nasal
polyps have a specialized phenotype and produce a mixed TH1/TH2 pattern
of cytokines. J Allergy Clin Immunol 1998; 102:953-960.

30. Bernstein JM, Ballow M, Rich G, Allen C, Swanson M, Dmochowski J.
Lymphocyte subpopulations and cytokines in nasal polyps: is there a local
immune system in the nasal polyp? Otolaryngol Head Neck Surg 2004;
130(535):526-535.

31. Khatami S, Brummer E, Stevens DA. Effects of granulocyte-macrophage
colony stimulating factor (GM-CSF) in vivo on cytokine production and
proliferation by spleen cells. Clinical Exp Immunol 2001; 125:198-201.

32. Bernstein JM, Ballow WM, Schlievert PM, Rich G, Allen C, Dryja D. A super-
antigen hypothesis for the pathogenesis of chronic hyperplastic sinvsitis with
massive polyposis. Am J Rhinol 2003; 17:321-326.

33. Bernstein JM. The molecular biology of nasal polyposis. Curr Allergy Asthma
Rep 2001; 1:262-267.

34. Bocchino V, Bertorelli G, D'Ippolito R, Castagnaro A, Zhuo X, Grima P,
DiComite V, Damia R, Olivieri D. The increased number of very late activation
antigen-4-positive cells correlates with eosinophils and severity of disease in the
induced sputum of asthmatic patients. J Allergy Clin Immunol 2000; 105:65-70.

35. Benimetskaya L, Loikej D, Khaled Z, Loike G, Silverstein SC, Cao L, el Koury J,
Cai TQ, Stein CA. Mac-1 (CDllb/CD18) is an oligodeoxynucleotide-binding
protein. Nat Med 1997; 3:412-420.

36. Lum AF, Green C, Lee GR, Staunton DE, Simon SI. Dynamic regulation of
LFA-1 activation and neutrophil arrest on intercellular adhesion molecule- 1
(ICAM-1) in shear flow. J Biol Chem 2002; 277:20660-20670.

37. Kakazu T, Chihara J, Saito A, Nakajima S. Effect of cytokine RANTES on
induction of activated eosinophils. Jpn J Thoracic Dis 1995; 33:1226-1232.

38. Gorski P, Wittczak T, Walusiak J, Palczynski C, Ruta U, Kuna P, Alam R.
Eotaxin but not MCP-3 induces eosinophil influx into nasal fluid in allergic
patients. Allergy 2002; 57:519-528.

CRS With and Without Nasal Polyposis 401

39. Lum AF, Green CE, Lee GR, Staunton DE, Simon SI. Dynamic regulation of
LFA-1 activation and neutrophil arrest on intercellular adhesion molecule
(ICAM-1) in shear flow. J Bio Chem 2002; 277:2660-2670.

40. Douglas IS, Leff AR, Sperling AI. CD4+ T-cell and eosinophil adhesion is
mediated by specific ICAM-3 ligation and results in eosinophil activation. J
Immunol 2000; 164:3385-3391.

41. Carlson M, Peterson C, Venge P. The influence of IL-3, IL-5, and GM-CSF on
normal human eosinophil and neutrophil C3b-induced degranulation. Allergy
1993; 48:437^142.

42. Bernstein JM, Gorfien J, Noble B, Yankaskas JR. Nasal polyposis: immunohistio-
chemistry and bioelectrical findings (a hypothesis for the development of nasal
polyps). J Allergy Clin Immunol 1997; 99:165-175.

43. Lundgren JD, Davey RT Jr, Lundgren B, Mullol J, Marom Z, Logun C,
Baraniuk J, Kaliner MA, Shelhamer JH. Eosinophil cationic protein stimulates
and major basic protein inhibits airway mucus secretion. J Allergy Clin Immu-
nol 1991; 87:689-698.

44. Jacoby DE, Ueki JF, Witticombe JH, Loegering DA, Gleich GJ, Nadel JA.
Effect of human eosinophil major basic protein on ion transport in the dog
tracheal epithelium. Am Rev Respir Dis 1988; 137:13-16.

45. Baniyash M. TCR zeta-chain downregulation: curtailing an excessive inflam-
matory immune response. Nat Rev Immunol 2004; 467:675-687.

46. Luethviksson BR, Gunnlaugsdottir B. Transforming growth factor-P as a
regulator of site-specific T-cell inflammatory response. Scan J Immunol 2003;
58:129-138.

47. Jaff A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Ped
Pulmonol 2001; 31:464-473.

48. Ehrlich GD, Veeh R, Wang X, Costerton JW, Hayes JD, Hu FZ, Daigle BJ,
Ehrlich MD, Post JC. Mucosal biofilm formation on middle-ear mucosa in
the chinchilla model of otitis media. JAMA 2002; 287:1710-1715.

49. Passali D, Bernstein JM, Passali FM, Damiani V, Passali GC, Bellusi L. Treat-
ment of recurrent chronic hyperplastic sinusitis with nasal polyposis. Arch
Otolaryngol Head Neck Surg 2003; 129:656-659.

50. Bez C, Schubert R, Kopp M, Ersfeld Y, Rosewich M, Kuehr J, Kamin W,
Berg AV, Wahu U, Zielen S. Effect of antiimmunoglobulin E on nasal inflam-
mation in patients with seasonal allergic rhino conjunctivitis. Clin Exp Allergy
2004; 34:1079-1085.

51. Leckie MJ. Anti-interleukin-5 monoclonal antibodies: pre-clinical evidence in
asthma models. Am J Respir Med 2003; 2:245-259.

52. Stobie L, Gurunathan S, Prussin C, Sacks DL, Glaichenhaus M, Wu CY,
Seder RA. The role of antigen and IL-12 in sustaining TH1 memory cells in
vitro: IL12 is required to maintain memory/effector TH1 cells sufficient to med-
iate protection to an infectious parasite challenge. Proc Natl Acad Sci USA
2000; 97:8427-8432.

53. Bryan SA, O'Connor BJ, Matti S, Leckie MJ, Kanabar V, Khan J, Warrington SJ,
Renzetti L, Rames A, Bock J A, Boyce MJ, Hansel TT, Holgate ST, Barnes PJ.
Effects of recombinant human interleukin-12 on eosinophils, airway hyper-
responsiveness and the late asthmatic response. Lancet 2000; 356:2149-2153.

402 Bernstein

54. Cimmino M, Cavalieri M, Nardone M, Plantulli A, Orefice A, Esposito V, Raia V.
Clinical characteristics and genotype analysis of patients with cystic fibrosis and
nasal polyposis. Clin Otolaryngol Allied Sci 2003; 48:125-132.

55. McClay JE, Marple B, Kapadia L, Biavatim J, Nussenbaum B, Newcomer M,
Manning S, Booth T, Schwade N. Clinical presentation of allergic fungal sinu-
sitis in children. Laryngoscope 2002; 112:565-569.

56. Moneret-Vautrin DA, Hsieh V, Wayoff M, Guyot JL, et al. Non-allergic rhinitis
with eosinophilia syndrome; a precursor of the triad: nasal polyposis, intrinsic
asthma and intolerance to aspirin. Ann Allergy 1990; 64:513-518.

57. Trittel C, Moller J, Euler HH, Werner J A. A differential diagnosis in chronic
polypoid sinusitis (Churg-Strauss Syndrome). Laryngol Rhinol Otol 1995; 74:
577-580.

58. Moneret-Vautrin DA, Wayoff N, Bonn C. Mechanisms of aspirin intolerance.
Annales I Oto-Laryngologie et de Chirurgie Cervico-Faciale 1985; 102:357-363.

59. Becker B, Morganroth K, Reinhardt D, Irlilch G. The dyskinetic cilia syndrome
in childhood. Modifications of ultra-structural patterns. Respiration 1984; 46:
180-186.

60. Delongh R, Ing A, Rutlend J. Mucociliary function, ciliary ultra-structure, and
ciliary orientation in Young's Syndrome. Thorax 1992; 47:184-187.

61. Balbani AP, Marone SA, Butugan O, Saldiva PH. Young's syndrome: recurrent
respiratory tract infections and azoospermia. Revista DaAssociacao Medica
Brasileria 2000; 46:88-89.

62. Tsunoda R, Takooda S, Nishijima W, Ogawa M, Terada S. Inverted papillo-
mas in the nose and paranasal sinuses. Nippon Jibiinkoka Gakkai Kaiho
(J Otorhinolaryngol Soc Jpn) 1994; 97:912-918.

63. Jamal MN. Imaging and management of angiofibroma. Eur Arch Otorhinolar-
yngol 1994; 251:241-245.

64. Verschuur HP, Struyvenberg PA, van Benthem PP, van Rossum M, Hiemstra I,
Hordijk GJ. Nasal discharge and obstruction as presenting symptoms of
Wegner's granulomatosis in childhood. Ped Otorhinolaryngol 1993; 27:91-95.

65. Ernst A, Preyer S, Plauth M, Jenss H. Polypose pansinusitis als eine ungewohn-
liche-extraintestinale manifestation des morbus Crohn. HNO 1993; 41:33-36.

66. Bachert C, Gevaert P, Holtappls G, Johansson SG, vanCauwenberge P. Total
and specific IgE in nasal polyps is related to local eosinophilic inflammation.
J Allergy Clin Immunol 2001; 107:607-614.

Sinusitis of Odontogenic Origin

Itzhak Brook

Departments of Pediatrics and Medicine, Georgetown University School of

Medicine, Washington, D.C., U.S.A.

John Mumford

Department of Periodontics, Naval Postgraduate Dental School, Bethesda,

Maryland, U.S.A.

INTRODUCTION

Sinusitis of odontogenic source accounts for about one-tenth of all cases of
maxillary sinusitis (1). The maxillary sinus is situated between the nasal and
the oral cavities and is, therefore, the most susceptible of all sinuses to inva-
sion by pathogenic bacteria through the nasal ostium or the oral cavity.
Sinusitis originating from odontogenic source differs in its pathophysiology,
microbiology, and management from sinusitis from other causes. It usually
occurs when the Schneidarian membrane is disrupted by conditions such
as those infections originating from maxillary teeth, maxillary dental trauma,
odontogenic pathology of maxillary bone, or iatrogenic causes such as dental
extractions, maxillary osteotomies in orthognathic surgery, and placement of
dental implants (2). The treatment of sinusitis of odontogenic source often
requires management of the sinus infection as well as the odontogenic source.

PATHOPHYSIOLOGY

The maxillary sinus emerges in the third fetal month and starts growing
into the adjacent maxilla in the fifth fetal month. The final growth of the

403

404 Brook and Mumford

maxillary sinus occurs between 12 and 14 years of age and concurs with the
formation of the permanent teeth and growth of the upper jaw alveolar pro-
cess (3). Before the sinus reaches adult size, there is considerable distance
between the sinus floor and the maxillary teeth apices. However, when the
growth of the maxillary sinus is completed, its volume reaches 15 to 20 mL
and it is surrounded by the orbital floor, the lateral nasal walls, and the
dento-alveolar portion of the maxilla. It can even extend into the palatine
and zygomatic bones.

Continued expansion and pneumatization of the maxillary sinus can
persist throughout the life of dentate individuals, which may induce inferior
displacement of the floor of the sinus in the direction of the maxillary poster-
ior teeth roots (4). The maxillary teeth roots may protrude into the sinus
cavity, resulting in surrounding of the apical aspects of the dental roots
by the sinus mucoperiosteum (5,6).

A significant difference in the height of the sinus floor exists between
dentulous and edentulous individuals. In individuals with maxillary tooth loss,
pneumatization can progress inferiorly and create a recess in the part of the
alveolar bone between the remaining teeth that was occupied before by the lost
tooth. In the completely edentulous person, the sinus can expand and extend
into the alveolar bone, occasionally leaving only thin alveolar bone between
the sinus and the oral cavity (4). The placement of the dental implants in such
patients requires preprosthetic surgical procedures such as alveolar ridge
augmentation with bone grafting and sinus membrane elevation.

The roots of the maxillary premolar and molar teeth are situated
below the sinus floor. The second molars' roots are the closest to the sinus
floor, followed by the roots of the first molar, third molar, second premolar,
first premolar, and canine (1). In contrast, the roots of the central and lateral
incisors are not close to the maxillary sinus. The apex of the maxillary sec-
ond molar root is the closest to the sinus floor (mean distance of 1.97 mm)
and the apex of the buccal root of the maxillary first premolar is the furthest
from the sinus floor (mean distance of 7.5 mm) (7). These short distances
explain the easy extension of an infectious process from these teeth and
the maxillary sinus.

The thickness of the lateral wall of the maxilla, which forms the
anterior wall of the sinus, is 2 to 5 mm. The labial levator and the orbicularis
oculi muscle attach to this wall above the infraorbital foramen and direct the
spread of infection from the maxillary teeth to the maxillary sinus.

The incidence of sinusitis associated with odontogenic infections is very
low despite the high frequency of dental infections. The floors of the sinus
and nose are composed of very dense cortical bone and are most probably
an effective barrier that rarely allows for direct penetration of odontogenic
infections into the maxillary sinus or nasal floor. The weakness of the lateral
wall of the maxilla can be penetrated more readily than the floor of the sinus,
explaining why most odontogenic infections are manifested more often as

Sinusitis of Odontogenic Origin 405

soft tissue vestibular or facial space infections and not as sinusitis. However,
odontogenic infections can drain into the sinus, especially in individuals
whose dental roots are proximal to the floor of the maxillary sinus.

The closeness of the maxillary teeth to the antrum, which is especially
evident in a pneumatized sinus, can sometimes leave only the mucoperios-
teum (Schneidarian membrane) separating the sinus cavity from the roots
of the tooth. The majority of maxillary sinus infections associated with
odontogenic source occur as sequelae of dental caries that lead to pulpitis
and dental abscess formation. Another rare, but possible, origin of pulpitis
may occur as a result of severe periodontal disease. As bone loss progresses,
it may involve a lateral canal or the apex of the tooth. Periodontal patho-
gens may then secondarily infect the pulpal tissues leading to a retrograde
pulpitis (8). The bacterial virulence factors such as the enzymes collagenase,
lysosomes, and toxins can enhance invasion and tissue breakdown. The
odontogenic infections can perforate into the alveolar bone through the
root-tip foramina at the apex of the tooth. The odontogenic infections
can spread through the thin maxillary buccal alveolar bone into the buccal
soft tissue. Infections originating from either the palatal root of the maxillary
molars or the lateral incisor roots can sometimes spread subperiosteal^ and
dissect into the hard palate. Odontogenic infections can also reach the orbit
through the sinus or by alternative routes (9).

Iatrogenic dental causes can also account for maxillary sinusitis. Rou-
tine root canal therapy can initiate periapical inflammation at the floor of
the sinus and instrumentation can even introduce bacteria into the sinus
cavity, both of which can propagate rhinosinusitis (10). Other iatrogenic
causes are displacement of a maxillary tooth root tip into the sinus that
occurs during extraction, extrusion of materials used in root canal therapy
into the sinus, and perforation of the sinus membrane during exodontias,
periodontal surgery, or implant placement. During tooth extraction, signifi-
cant forces are placed on the alveolar bone. Widely divergent roots, carious
teeth, or heavily restored teeth may make the extraction more difficult
because the roots tend to fracture under luxation. The remaining roots
can sometimes be removed only by careful removal of alveolar bone sur-
rounding them; at times, this process may remove thin bone separating sinus
membrane from the oral cavity with a resultant exposure of the sinus.

The apical force employed on the roots during extraction can displace
the root into the maxillary sinus. The presence of a periapical cyst, granu-
loma, or periapical infection that had eroded the surrounding bone can
enable easier displacement of the tooth. An entire tooth can be displaced
into the sinus, especially during removal of a maxillary third molar (wisdom
tooth). Removal of teeth around a lone-standing molar can lead to alveolar
bone resorption resulting in thinning of the alveolar bone between the oral
cavity and the sinus. When that lone-standing molar is eventually extracted,
alveolar bone or maxillary tuberosity fracture with concomitant oro-antral

406

Brook and Mumford

communication can occur. The risk of this occurring may increase if the
tooth is ankylosed to the alveolar bone, where the periodontal ligament
has become mineralized and fused to the bony socket.

Severe intrabony defects between teeth or within the furcation of max-
illary teeth resulting from severe periodontal disease can also encroach on
the sinus floor. The elimination of the periodontal pocket and arresting the
disease process require the removal of periodontal pathogens from the dis-
eased root surfaces and may require osseous resection of the intrabony
defect. The sinus can be inadvertently exposed during resection of the
intrabony defects or instrumentation of the diseased root surfaces within
the involved furcation. Dental implant placement involving sinus lift proce-
dures are becoming more commonplace for the replacement of missing
maxillary posterior teeth. Although the reported incidence of infection is
low, sinusitis can occur as a result of contamination of the sinus cavity by
oral pathogens (11). Figures 1 and 2 demonstrate inadvertent sinus mem-
brane perforation while performing a closed sinus lift in conjunction with
dental implant placement. Other oral and maxillofacial surgery or dental
procedures, such as maxillary orthognathic surgery, preprosthetic surgery,

Figure 1 Maxillary sinusitis secondary to perforation of sinus membrane. Arrow A
demonstrates the extent of the graft material within the maxillary sinus. Arrow B
demonstrates the implant perforation of the sinus membrane. Arrow C demonstrates
the graft material expressed beyond the sinus membrane.

Sinusitis of Odontogenic Origin 407

Figure 2 Perforation of the maxillary sinus during implant placement. Arrow A
demonstrates the floor of the maxillary sinus. Arrow B demonstrates the implant
perforating and extending into the maxillary sinus.

and the placement of implants without sinus lift procedures, have been
implicated as causing sinusitis (12-14).

Oro-antral fistula can also be responsible for the development of
maxillary sinusitis, especially of a chronic nature. These fistula are defined
as an osteo-mucosal communication between the oral cavity and either the
sinus or the nasal cavity. They are generally iatrogenic and occur following
dental procedures such as extractions, removal of an intramaxillary cyst,
or external maxillary sinus surgery. They can also be due to persistent
apico-dental infection that forms a fistula into the antrum, necrosis of a
maxillary tumor, and follow a surgical correction of cleft palates and lips.

MICROBIOLOGY

Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis
are the most common pathogens implicated in acute sinusitis (15), whereas
anaerobic bacteria can be isolated from up to 67% of patients who have chronic
infection (16,17). However, anaerobes were isolated from approximately 5% to
10% of patients with acute sinusitis, mostly from those who developed maxil-
lary sinusitis secondary to odontogenic infection (15). It has been reported
that sinusitis resulting from pathogenic bacteria originating from the oral
cavity most commonly include Streptococci, anaerobic gram-positive cocci

408

Brook and Mumford

(Peptostreptococci), and anaerobic gram-negative rods (fusobacteria, bacter-
oides) (11). We recently described our experience over a 30-year period of
studying the aerobic and anaerobic microbiology of acute and chronic maxil-
lary sinusitis that was associated with odontogenic infection (18). Aspirates of
20 acutely and 28 chronically infected maxillary sinuses that was associated
with odontogenic infection were processed for aerobic and anaerobic bacteria
(Table 1). A total of 37 isolates were recovered from the 20 cases of acute max-
illary sinusitis (1.8 5 /specimen), 16 aerobic and facultatives, and 21 anaerobic.
Aerobic and facultative organisms alone were recovered in two specimens
(10%), anaerobes only were isolated in 10 (50%), and mixed aerobic and
anaerobic bacteria were recovered in eight (40%). The predominant aero-
bes were a-hemolytic streptococci (5), Microaerophilic streptococci (4),
and Staphylococcus aureus (2). The predominant anaerobic bacteria were

Table 1 Predominant Bacteria Recovered from 48 Patients with Maxillary Sinusi-
tis with an Odontogenic Origin a

Number of isolates

Acute sinusitis

Chronic sinusitis

Bacteria

(TV =20)

(TV =28)

Aerobic bacteria

a-Hemolytic streptococci

Microaerophilic streptococci

Streptococcus pneumoniae

Streptococcus pyogenes

Staphylococcus aureus

2(2)

5(5)

Staphylococcus epidermidis

1(1)

Haemophilus influenzae

—

Subtotal aerobes

16(3)

21(6)

Anaerobic bacteria

Pepto streptococcus species

Veilonella parvulla

Euhacterium species

Propionibacterium acne

Fusobacterium species

2(1)

Fusobacterium nucleatum

7(2)

10(4)

Bacteroides species

4(1)

Bacteroides fragilis group

—

2(2)

Prevotella melaninogenica species

12(5)

27 (9)

Porphyromonas asaccharolytica

6(1)

7(4)

Subtotal anaerobes

50 (10)

77 (19)

Total

66 (13)

98 (25)

''Number within parentheses indicates (3-lactamase-producing bacteria.
Source: From Ref. 18.

Sinusitis of Odontogenic Origin 409

anaerobic gram-negative bacilli (22), Peptostreptococcus spp., and Fusobacter-
ium spp. (9). A total of 127 isolates were recovered from the 28 cases of chronic
maxillary sinusitis (4.5 per patient): 50 aerobic and facultatives and 77 anaero-
bic. Aerobes and facultatives were recovered in three instances (11%), anae-
robes only in 11 (39%), and mixed aerobic and anaerobic bacteria were
recovered in 14 (50%). The predominant aerobes were oc-hemolytic strepto-
cocci (7), microaerophilic streptococci (4), and S. aureus (5). The predominant
anaerobes were anaerobic gram-negative bacilli (36), Peptostreptococcus spp.
(16), and Fusobacterium spp. (12). No correlation was found between the
predisposing odontogenic conditions and the microbiological findings.

These findings illustrate the unique microbiology of acute and chronic
maxillary sinusitis associated with odontogenic infection, where anaerobic
bacteria predominate in both types of infections. S. pneumoniae, H. influen-
zae, and M. catarrhalis, the predominate bacteria recovered from acute
maxillary sinusitis not of odontogenic origin (15,19), were mostly absent
in acute maxillary sinusitis that was associated with an odontogenic origin.
In contrast, anaerobic bacteria predominated in both acute as well as
chronic sinusitis. However, the number of both aerobic and anaerobic iso-
lates in infected sinuses associated with odontogenic origin was similar in
chronic sinusitis and acute sinusitis. A higher number of aerobic and anae-
robic organisms per specimen were also found in chronic ethmoid, frontal,
maxillary, and sphenoid sinusitis that were not associated with an odonto-
genic origin as compared to acute infections in these sinuses (19).

The most common anaerobic isolates recovered in this study in acute
and chronic infection were Peptostreptococcus spp., Fusobacterium spp.,
pigmented Prevotella, and Porphyromonas spp., all members of the orophar-
yngeal flora (20). These organisms also predominate in periodontal and
endodontal infection (21-23). The high recovery rate of these anaerobic
bacteria in maxillary sinusitis of odontogenic origin is similar to the findings
in chronic maxillary, ethmoid, frontal, and sphenoid sinusitis where these
organisms also predominate (15-17,19).

Dental infections are generally mixed polymicrobial aerobic and
anaerobic bacterial infections caused by the same families of oral microor-
ganisms made of obligate anaerobes and gram-positive aerobes (21).
Because anaerobic bacteria are part of the normal oral flora and outnumber
aerobic organisms by a ratio of 1:10 to 1:100 at this site (20), it is not
surprising that they predominant in odontogenic infections. There are at
least 350 morphological and biochemically distinct bacterial species that
colonize the oral and dental ecologic sites. The microorganisms recovered
from odontogenic infections generally reflect the host's indigenous oral flora.

The polymicrobial nature of dental infections was evident in many
studies (21-23). A study that evaluated the microbiology of 32 periapical
abscesses highlighted the polymicrobial nature and importance of anaero-
bic bacteria in this infection (Table 2) (22). Seventy-eight bacterial isolates,

410 Brook and Mum ford

Table 2 Predominate Bacteria Isolates Recovered from 32 Perapical Abscesses
Bacteria Number of isolates

Aerobic bacteria

a-Hemolytic streptococcus 1 1

Streptococcus faecalis 3

Streptococcus milleri 3

Staphylococcus aureus 1

Haemophilus parainfluenzae 2

Subtotal aerobes 23

Anaerobic bacteria

Pepto streptococcus species 18

Veilonella parvulla 2

Eubacterium species 2

Fusobacterium species 9

Bacteroides fragilis group 2

Prevotella melaninogenica 3

Prevotella oralis 4

Prevotella oris-buccae 2

Prevotella intermedia 2

Porphyromonas gingivalis 7

Subtotal anaerobes 55

Total 78

Source: From Ref. 22.

55 anaerobic, and 23 aerobic and facultative, were recovered. Anaerobic
bacteria only were present in 16 (50%) patients, aerobic and facultatives
in 2 (6%), and mixed aerobic and anaerobic flora in 14 (44%). The predominant
isolates were Pepto ^streptococcus, Bacteroides, Prevotella, and Porphyromonas
spp., mainly Porphyromonas gingivalis. The major aerobic pathogen was strep-
tococci and there were few gram-negative organisms.

The association between periapical abscesses and sinusitis was estab-
lished in a study of aspirate of pus from five periapical abscesses of the upper
jaw and their corresponding maxillary sinusitis (23). Polymicrobial flora was
found in all instances where the number of isolates varied from two to five.
Anaerobes were recovered from all specimens. The predominant isolates
were Prevotella, Porphyromonas, Pep to strep to coccus spp., and Fusobacterium
nucleatum. Concordance in the microbiological findings between the periapi-
cal abscess and the maxillary sinus flora was found in all instances. These
findings confirm the importance of anaerobic bacteria in periapical abscesses
and demonstrate their predominance in maxillary sinusitis that is associated
with them. The concordance in recovery of organisms in paired infections
illustrates the dental origin of the infection with subsequent extension into
the maxillary sinus. The proximity of the maxillary molar teeth to the floor
of the maxillary sinus allows such a spread.

Sinusitis of Odontogenic Origin 411

Certain organisms were only present at one site and not the other (23).
The discrepancies in isolation of certain organisms generally not recovered
from infected sinuses, such as P. gingivalis, Streptococcus sanguis, and
Streptococcus milleri, suggests that these organisms do not thrive well in the
sinus cavity. These organisms were also not recovered in the infected sinuses
in this report. However, other organisms such as Peptostreptococcus spp.,
Prevotella intermedia, and Fusobacterium spp. were isolated in both sites.
These organisms were also recovered in the infected sinuses in this report.

The higher frequent recovery of anaerobes in chronic sinusitis asso-
ciated with an odontogenic origin may be related to the poor drainage
and increased intranasal pressure that develops during inflammation (24).
This can reduce the oxygen tension in the inflamed sinus (25) by decreasing
the mucosal blood flow and depressing the ciliary action (26). The lowering
of the oxygen content and the pH of the sinus cavity supports the growth
of anaerobic organisms by providing them with an optimal oxidation-
reduction potential (27).

SYMPTOMS

Dental pain, headache, and anterior maxillary tenderness can be present in
conjunction with sinusitis-like symptoms such as nasal congestion and
discharge with or without a postnasal drip. However, there may be minimal
sinusitis symptoms and dental pain because there is no osteomeatal obstruc-
tion and the sinus stay open. This allows for the pressure in the tooth to be
relieved as the infection drains superiorly into an open sinus space. The
clinical symptoms gradually increase as the sinusitis worsens.

Dental symptoms may vary from an acute pain that is associated with
an exposed dental nerve to a dull pain originating from a dental infection
extending into the bone around the apex of a root. The pain can also origi-
nate from periodontal disease, gum disease involving the supporting hard
and soft tissues around teeth. Dental aches and increased sensitivity of
several adjacent maxillary teeth frequently occur on patients with acute sinu-
sitis who do not suffer from an odontogenic problem. What makes the diag-
nosis more difficult is that referred pain from symptomatic teeth to adjacent
structures is also common.

Obtaining history of past sinus disease, oro-antral communication,
allergic rhinitis, or foreign body displacement into the sinus cavity can assist
in making the correct diagnosis. It is often difficult to determine whether the
patient's symptoms originate from the sinus or an odontogenic source, and
this dilemma may lead to the performance of unnecessary root canal therapy
or tooth extraction. Performance of a thorough dental and sinus evalua-
tion that utilizes adequate radiological studies can assist in establishing
the correct diagnosis.

4 12 Brook and Mumford

DIAGNOSIS

The diagnosis of sinus disease of odontogenic origin is based on thorough
dental and medical examinations that include the evaluation of the patient's
symptoms and past medical history, and correlating them with the present
physical findings. Physical examination includes inspection of the buccal soft
tissue, the vestibule for swelling, and the erythema. In addition, determina-
tion of current or past symptoms of a toothache, persistent sensitivity to per-
cussion and/or thermal changes, tooth mobility, recent dental procedures
(including root canals, periodontal surgery, or implant placement), and a
periapical radiograph should be considered, even though this finding is rarely
seen in association with maxillary sinusitis. Soft tissue swelling is rarely
caused by maxillary sinusitis because of the absence of anastomosing veins
connected to the overlying subcutaneous tissue, even though lengthy chronic
sinusitis may eventually erode the wall of the sinus causing a visible intraoral
soft tissue swelling (28).

An apical root that is diseased can be the nidus for a bacterial sinusitis.
Palpation of the anterior maxilla can produce a dull pain and careful percussion
of the maxillary teeth can reveal if the pain can be localized to one or more teeth.
Assessment of the vitality of the teeth using electric or thermal pulp testing can
aid in the diagnosis. Otolaryngological evaluation using rhinoscopy, nasal and
sinus endoscopy, and aspiration of sinus contents for cytological and microbio-
logical assessments can further assist in making the correct diagnosis.

Radiological imaging is an important tool in establishing the correct
diagnosis. Whereas a periapical radiograph is the image preferred in deter-
mining a dental abscess or periodontal disease, the panoramic radiographic
view is very helpful for evaluating the relationship of the maxillary teeth and
periapical pathology to the maxillary sinus (Fig. 3A and B). In addition, the
panoramic view is helpful in identifying the presence of pneumatization,
pseudocysts, and the location of displaced roots, teeth, or foreign bodies
inside the maxillary sinus. A Water's view plain-film radiograph is an accep-
table alternative to a panoramic radiograph. However, the CT scan is the
golden standard for adequate maxillary sinus imaging because of the ability
to visualize bone and soft tissue and obtain thin sections and multiple views.
Axial and coronal sinus CT views can demonstrate the relationship of a
periapical abscess to a sinus floor defect and the diseased tissues and deter-
mine the exact location of a foreign body within the maxillary sinus. Delayed
retrieval of a foreign body from the maxillary sinus may require additional
imaging studies, such as a CT scan, especially when the position cannot be
verified by plain radiographs or if significant sinus disease is involved.

MANAGEMENT

The association between an odontogenic condition and maxillary sinusi-
tis warrants a thorough dental examination of patients with sinusitis.

Sinusitis of Odontogenic Origin

413

Figure 3 (A) Maxillary sinusitis secondary to dental abscess. Arrow A demonstrates
the floor of the maxillary sinus. Arrow B demonstrates the periapical abscess extend-
ing into the maxillary sinus. (B) Enlarged view.

Concomitant management of the dental origin and the associated sinusitis
will insure complete resolution of the infection and may prevent recurrence
and complications.

A combination of medical and surgical approaches is generally
required for the treatment of odontogenic sinusitis. Elimination of the
source of the infection (e.g., removal of an external dental root from the
sinus cavity, removal of failed endosseous implants in communication with

414 Brook and Mum ford

the sinus cavity, extraction, or root canal therapy of an infected tooth) is
necessary to prevent recurrence of the sinusitis.

When displacement of a root or entire tooth into the sinus has
occurred, removal of the root tip through the socket is indicated. However,
if no perforation of the sinus membrane has occurred and the dental root
fragment is not infected and is 3 mm or less, the root can be left in place
(29). Sinus precautions and medical treatment including decongestants and
antibiotics are employed. The patient should be closely monitored for signs
of sinus infection until the anatomical defect heals completely.

Removal of the dental root tip is indicated when it is infected or when
its size is greater than 3 mm (29). The surgical removal is performed by
reflection of a full-thickness mucoperiosteal flap superior to the extraction
socket or in the canine-premolar recess. Bone is removed to form a window
in the buccal alveolar process and the root tip is retrieved. This technique is
advantageous to extraction through widening the extraction socket, espe-
cially in the posterior maxillary areas (second and third molars). Removal
through the extraction socket can result in creating a large oro-antral
communication. If the primary closure with a buccal flap fails, more signifi-
cant flap advancement can be used. In instances where retrieval of the root
or tooth is unsuccessful, treatment with antibiotics and decongestants is
administered, and sinus precaution instructions are employed. Retrieval
can be postponed, and is eventually performed through a modified Cald-
well-Luc approach. A new application of the lateral wall sinus lift surgical
approach to the maxillary sinus can also be used for the retrieval of root
fragments and foreign objects (30).

A low rate of infection is associated with sinus lift procedures, where
bone grafts are placed into the maxillary sinus cavity; however, in patients
who develop sinus infections, removal of the graft material and the implant
is required (11).

Endoscopic techniques have been developed in recent years for the
treatment of chronic maxillary sinusitis of dental origin. The procedure
evolves the creation of an antrostomy window through which the irreversi-
bly diseased tissue, polyps, and foreign materials are removed (31).

The management of oro-antral communication that can complicate
dental surgery includes primary closure of the defect and adequate medical
treatment. A defect smaller than 5 mm will usually heal spontaneously with
normal blood clot formation and routine mucosal healing (32). However,
utilization of a resorbable barrier to cover and protect the defect during
the initial stages of healing may be indicated. Primary closure is necessary
if the defect is greater than 5 mm. Surgery should be performed in a
disease-free sinus environment with the infection under control.

Although odontogenic therapy and surgical drainage are of primary
importance, administration of antimicrobial therapy is an essential part of
the management of patients with serious odontogenic infections and their

Sinusitis of Odontogenic Origin 415

complications. Similarly, the management of sinusitis includes proper anti-
microbial therapy and surgical drainage when improvement is delayed or
absent. Oral administration of antibiotics that are effective against oral flora
and sinus pathogens for 21 to 28 days is required. Additionally administered
are systemic nasal decongestants, local nasal decongestant for two to three
days, moisturizing nasal drops, and saline sprays.

A growing number of anaerobic gram-negative bacilli (i.e., pigmented
Prevotella and Fusobacterium spp.,) have acquired resistance to penicillin
through the production of the enzyme (3-lactamase (33). This has also been
observed in our recent report (18), where 10 (3-lactamase-producing bacteria
(BLPB) were recovered from 7 (35%) specimens of acute sinusitis and
25 BLPB were recovered from 21 patients (75%) with chronic sinusitis.
Penicillin was considered the drug of choice for the therapy of such infec-
tions because of the susceptibility of most oral pathogens; however, the
growing resistance of these strains limits the use of this drug.

The recovery of penicillin-resistant organisms in patients with maxil-
lary sinusitis associated with an odontogenic origin may require the admin-
istration of antimicrobial agents also effective against these organisms.
These include clindamycin, cefoxitin, a carbapenem (i.e., imipenem, merope-
nem), or the combination of a penicillin and a (3-lactamase inhibitor (21).
Metronidazole should be administered with an agent effective against the
aerobic or facultative streptococci. Alternative therapy for penicillin-allergic
patients have been reported and include cefaclor, trimethoprim-sulfa-
methoxazole, and clindamycin (11).

SUMMARY

Odontogenic sinusitis is a well-recognized condition and accounts for appro-
ximately 8% to 12% of cases of maxillary sinusitis. An odontogenic source
should be considered in individuals with symptoms of maxillary sinusitis with
a history of odontogenic infection, dento-alveolar surgery, periodontal sur-
gery, or in those resistant to conventional sinusitis therapy. Diagnosis usually
requires a thorough dental and clinical evaluation including appropriate
radiographs. The most common causes of odontogenic sinusitis include den-
tal abscesses and periodontal disease that had perforated the Schneidarian
membrane, irritation and secondary infection caused by intra-antral foreign
bodies, and sinus perforations during tooth extraction or endosseous implant
placement, with or without sinus lift procedures. An odontogenic infection is
a polymicrobial aerobic-anaerobic infection with anaerobes outnumbering
the aerobes. The most common isolates include anaerobic streptococci and
gram-negative bacilli, and enterobacteriaceae. Surgical and dental treatment
of the odontogenic pathological conditions combined with medical therapy
is indicated. When present, an odontogenic foreign body should be surgically
removed. Surgical management of oro-antral communication is indicated to

416 Brook and Mum ford

reduce the likelihood of causing chronic sinus disease. The management of
odontogenic sinusitis includes a three- to four-week course of antimicrobials
effective against the oral flora pathogens.

REFERENCES

1 . Maloney PL, Doku HC. Maxillary sinusitis of odontogenic origin. J Can Dent
Assoc 1968; 34:591-603.

2. Kretzschmar DP, Kretzschmar JL. Rhinosinusitis: review from a dental per-
spective. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 96:128-135.

3. Abubaker A. Applied anatomy of the maxillary sinus. Oral Maxillofac Clin N
Am 1999; 11:1-14.

4. Sicher H. The viscera of head and neck. Oral Anatomy. St Louis (MO): CV
Mosby, 1975:418-424.

5. Kelley HC, Kay LW. The maxillary sinus and its dental implications. Dental
Practice Handbook. Bristol (UK): John Wright and Sons 1975:1-13.

6. Skillern RH. Maxillary sinus. The Catarrhal and Suppurative Diseases of the
Accessory Sinus of the Nose. Philadelphia: JB Lippincott, 1947:104-125.

7. Eberhardt JA, Torabinejad M, Christiansen EL. A computed tomographic
study of the distances between the maxillary sinus floor and the apices of the
maxillary posterior teeth. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1992; 73:345.

8. Simon J, Glick D, Frank A. The relationship of endodontic-periodontic
lesions. J Periodont 1972; 43:202-208.

9. Mehra P, Caiazzo A, Bestgen S. Odontogenic sinusitis causing orbital cellulitis:
a case report. J Am Dent Assoc 1999; 130:1086-1092.

10. Watzek G, Bernhart T, Ulm C. Complications of sinus perforations and their
management in endodontics. Dent Clin North Am 1997; 41:563-583.

11. Misch C. The pharmacologic management of maxillary sinus elevation surgery.
J Oral Implantol 1992; 18:15-23.

12. Ueda M, Kaneda T. Maxillary sinusitis caused by dental implants: report of
two cases. J Oral Maxillofac Surg 1992; 50:285-287.

13. Timmenga N, Raghoebar GM, Boering G, Weissenbruch RV. Maxillary sinus
function after sinus lifts for the insertion of dental implants. J Oral Maxillofac
Surg 1997; 55:936-939.

14. Regev E, Smith R, Perrott D, Pogrel M. Maxillary sinus complications related
to endosseous implants. Int J Maxillofac Implants 1995; 10:451-461.

15. Nash D, Wald E. Sinusitis. Pediatr Rev 2001; 22:1 1 1-1 17.

16. Brook I. Bacteriology of chronic maxillary sinusitis in adults. Ann Otol Rhinol
Laryngol 1989; 98:426-428.

17. Nord CE. The role of anaerobic bacteria in recurrent episodes of sinusitis and
tonsillitis. Clin Infect Dis 1995; 20:1512-1524.

18. Brook I. Microbiology of acute and chronic maxillary sinusitis associated with
an odontogenic origin. Laryngoscope 2005; 115:823-825.

19. Brook I. Microbiology and antimicrobial management of sinusitis. Otolaryngol
Clin North Am 2004; 37:253-266.

Sinusitis of Odontogenic Origin 417

20. Socransky SS, Manganiello SD. The oral microbiota of man from birth to seni-
lity. J Periodontol 1971; 42:485-496.

21. Brook I. Microbiology and management of endodontic infections in children.
J Clin Pediatr Dent 2003; 28:13-17.

22. Brook I, Frazier EH, Gher ME. Aerobic and anaerobic microbiology of peria-
pical abscess. Oral Microbiol Immunol 1991; 6:123-125.

23. Brook I, Frazier EH, Gher ME. Microbiology of periapical abscesses and asso-
ciated maxillary sinusitis. J Periodontol 1996; 67:608-610.

24. Drettner B, Lindholm CE. The borderline between acute rhinitis and sinusitis.
Acta Otolaryngol (Stockh) 1967; 64:508-513.

25. Carenfelt C, Lundberg C. Purulent and non-purulent maxillary sinus secretions
with respect to p0 2 , pC0 2 and pH. Acta Otolaryngol (Stockh) 1977; 84:
138-144.

26. Aust R, Drettner B. Oxygen tension in the human maxillary sinus under normal
and pathological conditions. Acta Otolaryngol (Stockh) 1974; 78:264-269.

27. Carenfelt C. Pathogenesis of sinus empyema. Ann Otol Rhinol Laryngol 1979;
88:16-20.

28. Rafetto L. Clinical examination of the maxillary sinus. Oral Maxillofac Surg
ClinN Am 1999; 11:35-44.

29. Gonty A. Diagnosis and management of sinus disease. In: Peterson LJ, ed.
Philadelphia: J.B Lippincott 1992:225-266.

30. Uckan S, Buchbinder D. Sinus lift approach for the retrieval of root fragments
from the maxillary sinus. Int J Oral Maxillofac Surg 2003; 32:87-90.

31. Lopatin A, Sysolyatin SP, Sysolyatin PG, Melnikov MN. Chronic maxillary
sinusitis of dental origin: is external surgical approach mandatory? Laryngo-
scope 2002; 112:1056-1059.

32. Laskin D. Management of oroantral fistula and other sinus-related complica-
tions. Oral Maxillofac Clin North Am 1999; 11:155-164.

33. Brook I, Calhoun L, Yocum P. Beta-lactamase-producing isolates of Bacteroides
species from children. Antimicrob Agents Chemother 1980; 18:164-166.

Fungal Sinusitis

Carol A. Kauffman

Division of Infectious Diseases, University of Michigan Medical School,
Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, U.S.A.

INTRODUCTION

Fungal sinusitis spans a wide clinical spectrum that includes acute fulminant
invasive infection in immunocompromised hosts, chronic infection in indivi-
duals who are not immunosuppressed, and allergic disease. Current classifi-
cation schemes separate fungal sinusitis into four categories. The definitions
of the four major forms of fungal sinusitis are as follows:

• Acute invasive fungal sinusitis — rapid invasion of fungi through
the mucosa of the nasal cavity or sinuses into soft tissues and blood
vessels of the face, orbit, and cavernous sinus accompanied by
hemorrhagic infarction and necrosis

• Chronic invasive fungal sinusitis — subacute to chronic infection
characterized by invasion through the mucosa of the sinuses lead-
ing to destruction of the bony structures of the sinuses and orbit
and subsequent spread to the brain

• Mycetoma — masses of fungal hyphae that grow in the sinus cavity
but do not invade through the mucosa, also termed a fungus ball

• Allergic fungal sinusitis — allergic response of the host to coloniza-
tion of the sinuses by certain molds; this is not an infectious process

The fungi causing sinusitis are almost always molds; it is exceedingly
uncommon to see fungal sinusitis caused by yeast-like organisms. The molds

419

420

Kauffman

that cause fungal sinusitis are ubiquitous in the environment; thus, exposure
is quite common and disease is primarily determined by the status of the
host. Local factors, such as nasal polyps and the presence of atopy in the
host, are important in the development of allergic fungal sinusitis. Acute
invasive infection occurs almost entirely in markedly immunosuppressed
patients. The clinical manifestations of the four forms of fungal sinusitis
differ, as might be expected, as does the approach to treatment. Not unex-
pectedly, overlap can occur with these four syndromes in some patients.

EPIDEMIOLOGY

The Organisms

The fungi most commonly found to cause invasive sinusitis belong to the
genus Aspergillus (1-5) (Table 1). Aspergillus fumigatus and Aspergillus
flavus cause most infections, while other species of Aspergillus have uncom-
monly been associated with invasive infection (2,6,7). Patients with chronic
invasive sinusitis in the United States are usually infected with A. fumigatus
(3); however, in the Middle East and India, chronic sinusitis is almost always
due to A. flavus (8,9).

Other hyaline or non-pigmented filamentous fungi, in addition to
Aspergillus species, are the causative agents of all forms of fungal sinusitis.
Typical molds from this group that cause sinusitis include Fusarium species,
Pseudallescheria boydii (Scedosporium apiospermum), and Paecilomyces spe-
cies (2,10-14). In markedly immunosuppressed hosts, especially those who
are neutropenic, acute invasion is the rule. In the older, non-immunosup-
pressed host, chronic invasion occurs with these fungi. Mycetoma and,

Table 1 Fungal Sinusitis: Risk Factors and Most Common Etiological Agents

Clinical syndrome

Risk factors

Usual organisms

Acute invasive fungal
sinusitis

Chronic invasive fungal

sinusitis
Mycetoma (fungus ball)

Allergic fungal sinusitis

Hematologic malignancy
Transplant recipient
Diabetes with ketoacidosis
Deferoxamine therapy
HIV infection
Corticosteroids
Diabetes mellitus

Corticosteroids
Chronic sinusitis
Atopy, nasal polyps

Aspergillus
Zygomycetes

Aspergillus

Aspergillus
Dematiaceous fungi
Dematiaceous fungi
Aspergillus

Fungal Sinusitis 421

rarely, allergic fungal sinusitis have also been described in association with
the won- Aspergillus hyaline molds (15-17).

Dematiaceous or pigmented molds are the major cause of allergic
fungal sinusitis, but can also cause mycetoma, chronic invasive infection,
and uncommonly, acute invasive infection in immunocompromised hosts
(17-20). Infection with these fungi is also known as phaeohyphomycosis.
Organisms in this group include Bipolar is, Curvularia, Alternaria, Exserohi-
lum, and Cladosporium (21,22).

The zygomycetes, Rhizopus, Mucor, Rhizomucor, and less commonly,
Absidia and Cunning hamella, are prominent pathogens causing acute inva-
sive fungal sinusitis (23-25). The zygomycetes rarely cause any of the other
types of fungal sinusitis.

The Host

Almost without exception, acute invasive fungal sinusitis is seen in immuno-
compromised hosts (Table 1). The groups at highest risk include those with
hematological malignancies, those receiving a solid organ or hematopoietic
stem cell transplant, insulin-dependent diabetics, those treated with deferox-
amine for iron overload states or with corticosteroids for a variety of
diseases, and patients with HIV infection (2,4,6,10,12-14,23,26-35).

Patients with hematological malignancies are at risk for invasive
fungal sinusitis primarily while they are neutropenic; those with prolonged
severe neutropenia are at most risk (2,23,26,29). The addition of corticoster-
oids and broad-spectrum antibiotic therapy contribute to the risk of devel-
oping invasive sinusitis. Among those who have received a hematopoietic
stem cell transplant, the greatest risk is in the immediate post-transplant
period before engraftment and late after transplant with the development
of graft-versus-host disease (GVHD) that almost always requires intensive
immunosuppression (4,13,27,30).

Solid organ transplant recipients are at less risk for invasive fungal
sinusitis than those who have received a hematopoietic stem cell transplant.
However, those who require intensive immunosuppression for graft rejec-
tion and those who have concomitant cytomegalovirus (CMV) infection
are at increased risk (33-36). Interestingly, lung transplant recipients who
have higher rates of pulmonary infection with Aspergillus than recipients
of other organs rarely manifest invasive fungal sinusitis (35).

Corticosteroids are a cofactor for fungal invasion in many of the
patients in the risk groups just described, but, when used alone, they also
appear to place patients at risk for acute invasive sinusitis (32).

In addition to the above risk groups, several unique populations have
an increased risk of developing acute invasive sinusitis due to zygomycetes.
Diabetics are especially at risk for infection when they are insulin-dependent
and develop ketoacidosis (25). Ketoacidosis appears to be important because

422 Kauffman

of its detrimental effects on neutrophil chemotaxis, phagocytosis, and killing
(37), essential for defense against the zygomycetes. Use of the iron chelator,
deferoxamine, for removing excess iron that accumulates with multiple
transfusions, places patients at risk for infection with certain zygomycetes,
most notably Rhizopus species (31). Rhizopus is able to link to deferoxamine,
using it as a siderophore to obtain iron, a necessary growth factor.

In contrast to acute invasive sinusitis, most patients with chronic inva-
sive fungal sinusitis are not immunosuppressed. The patients are usually
older and may have non-insulin dependent diabetes mellitus (3,5,18,38).
Corticosteroids are frequently used as initial therapy before the correct diag-
nosis is made and undoubtedly contribute to the progression of disease, but
not to its initial development (38). There is usually no obvious exposure to
the infecting fungus.

Primary paranasal granuloma is a form of chronic invasive fungal
sinusitis that is seen in healthy young men who have no underlying illness.
This disease is described almost entirely from rural semi-arid areas of the
Middle East or the Indian subcontinent (8,9,39).

The situation with sinus mycetoma is similar to that of chronic
invasive fungal sinusitis in that the patients who develop mycetomas are
not immunosuppressed. However, there is almost always a history of recur-
rent episodes of sinusitis and, in some, a history of nasal polyps (1,16,40).

The typical patient with allergic fungal sinusitis is young or middle-
aged and has no underlying immunosuppression or other chronic systemic
diseases. These patients do have a history of atopy manifested by rhinitis
and/or asthma, recurrent sinusitis, and nasal polyposis that can be severe
(17,41).

PATHOGENESIS

Acute invasive sinusitis is characterized by rapid spread into the bony struc-
tures of the sinuses and orbit and subsequent progression in a matter of days
to involve the major vessels in the cavernous sinus and the brain (1,6,23).
The organisms that cause this syndrome have the propensity to invade blood
vessels causing thrombosis, hemorrhage, and tissue infarction. Patients with
neutropenia have a minimal host response and death ensues quickly (42).
Those who are not neutropenic have a more vigorous host response, but
because of host factors such as ketoacidosis or deferoxamine therapy, or
organism factors, especially when a zygomycete is involved, host defenses
are ineffective and thrombosis, tissue necrosis, and rapid death ensue (24,31).
Chronic invasive fungal sinusitis contrasts with the acute form in that
it progresses slowly over weeks to months, and the host response is a
mixture of necrotizing and granulomatous inflammation (1,3,8,18). The dif-
ference in the pathogenesis of this infection from that of acute invasive sinu-
sitis is related to the normal numbers of functioning neutrophils and

Fungal Sinusitis 423

macrophages that are present. The invading fungi, primarily Aspergillus, are
the same in both forms of sinusitis. Destruction of the bony structures of the
sinuses is usual. The mass of hyphae and the inflammatory response fre-
quently extend into the posterior aspect of the orbit, impinge on the optic
nerve, and may extend into the brain.

Primary paranasal granuloma is similar in pathogenesis, but described
mostly in reports from Sudan, other Middle Eastern countries, and India (8,9).
The host response is granulomatous. The few differences that exist between
primary paranasal granuloma and chronic invasive sinusitis probably reflect
the rapidity with which the diagnosis is made, host differences, and perhaps
the dominant role played by A. flavus in primary paranasal granuloma.

Mycetoma formation is similar to that noted in pulmonary mycetomas,
which develop in existing cavitary pulmonary lesions (43). The maxillary
sinuses are almost always involved (40). The fungi are able to grow luxuri-
antly, forming a mass of hyphae that expands and can cause necrosis of
adjacent bony structures. However, invasion through the mucosa and growth
in the bone does not occur. Obstruction of drainage from the sinus creates
many of the symptoms and signs.

The pathophysiology of allergic fungal sinusitis has not been clearly
elucidated. However, it is clear that this disease happens almost entirely
in atopic individuals and that sensitization to fungal antigens is crucial
for the development of symptoms and signs. Two different theories exist.
One theory relates the pathogenesis to a type I immediate hypersensitivity
response involving eosinophils and IgE (44), and the other relates disease
to antigen-antibody complexes, triggering cytokine release (17,41). Which-
ever mechanism initiates the hypersensitivity response, the end result is
edema, which obstructs sinus drainage, thus allowing further proliferation
of fungi and increased inflammatory reaction. Although the condition may
begin in one sinus, frequently many or all sinuses are involved as the
disease progresses.

One of the cardinal features of allergic fungal sinusitis is the production
of allergic mucin, a substance that has been described as peanut butter-like
because of its tenacious character; this substance fills and obstructs the sinuses.
Microscopically, allergic mucin is composed of eosinophils, Charcot-Leyden
crystals, cellular debris, and hyphae (41). Neutrophils and macrophages are
absent.

Clinical Manifestations

Patients with acute invasive fungal sinusitis almost always have sinus or
facial pain that is out of proportion to the physical findings. In addition,
headache, purulent or bloody rhinorrhea, decreased smell and taste, and
visual changes are frequently noted. Fever is common and these patients
appear acutely ill. On physical examination, facial asymmetry, periorbital

424 Kauffman

swelling, and dusky-colored or black lesions on the nasal mucosa or the
palate can be seen; tenderness over the sinuses, hypesthesia of the palate
or nasal mucosa, and absence of bleeding on light abrasion of the nasal
mucosa can be elicited. As the infection progresses, symptoms related to
ophthalmic and central nervous system invasion occur; these include stroke,
mental status changes, cranial nerve palsies, proptosis, ophthalmoplegia,
chemosis, and blindness.

Chronic invasive fungal sinusitis is usually manifested by facial pain
and swelling, but the acuity of the presentation is much less than that noted
with acute invasive sinusitis (3). Fever is usually absent and the patients do
not appear acutely ill. When the orbit is involved, ptosis, blurring of vision,
and diplopia occur. This can progress to the orbital apex syndrome with
proptosis, ophthalmoplegia, and visual loss. Additionally, there may be loss
of smell, nasal congestion, and discharge. Physical examination findings
include unilateral facial swelling, ptosis, proptosis, periorbital edema,
ophthalmoplegia, nasal discharge, and facial tenderness. The major differen-
tial is between tumor and infection.

Patients with mycetoma usually complain of purulent, often foul-
smelling nasal discharge, nasal congestion, and facial pain. The maxillary
sinuses are involved in almost all cases; mycetomas are reported uncom-
monly in the frontal sinuses (16,40). On examination of the nares, nasal
obstruction is sometimes noted and unilateral foul-smelling, purulent nasal
secretions are found.

Most patients with allergic fungal sinusitis have had symptoms of
chronic and recurrent nasal congestion and discharge of semi-solid nasal
crusts for years before the diagnosis is made. They are usually known to
have had recurrent nasal polyposis. Facial pain and fever are uncommon.
Initial consultation may have been sought with an ophthalmologist because
of the development of proptosis or diplopia (45). Children frequently pre-
sent in this manner because the mass of allergic mucin expands more easily
into the orbit in children whose bones are incompletely calcified (46). Exam-
ination of the nares reveals obstruction to the airway and polyps with or
without accompanying changes in the orbit.

DIAGNOSIS

The diagnosis of acute invasive fungal sinusitis in an immunocompromised
patient or diabetic is extremely urgent because death can occur in a matter
of days. Facial pain or other sinus symptoms in the appropriate host should
be considered to be due to invasive fungal infection until proved otherwise.
In the at-risk population, urgent consultation with an otolaryngologist is
essential. For the other forms of fungal sinusitis, consultation is also essen-
tial, but the disease progresses more slowly and the timeliness of diagnosis is
not as urgent. In patients with orbital apex syndrome or other orbital

Fungal Sinusitis 425

Table 2 Criteria for the Diagnosis of Sinus Mycetoma

Sinus opacification on CT scan

Mucopurulent, cheesy mass separate from mucosa present at surgery or endoscopy

Mass composed of hyphae on histopathologic examination; no allergic mucin found

Chronic low-grade inflammation seen in adjacent mucosa

No fungal invasion of mucosa or bone

Source: Adapted from Ref. 16.

complaints, ophthalmological consultation and biopsy of the orbital mass is
essential. Diagnostic criteria have been established in an attempt to standar-
dize the definitions of sinus mycetoma and allergic fungal sinusitis (Tables 2
and 3). However, in the case of allergic fungal sinusitis, there is still no
agreement on exact criteria, especially the requirement for evidence of
IgE-type immune reactivity to fungal antigens.

Imaging studies have proved to be very useful in differentiating invasive
from noninvasive fungal sinusitis and in defining the extent of disease prior to
surgery (24,28,42) (Figs. 1-3). A computed tomography (CT) scan dedicated
to imaging the sinuses and orbits is the imaging study of choice; a magnetic
resonance imaging (MRI) study with gadolinium is more appropriate to
assess the extension of infection into the cavernous sinus, meninges, and
brain.

The CT scan generally demonstrates thickening or opacification of one
or more sinuses and may show air-fluid levels in acute invasive infection.
However, a normal CT scan has been reported in as many as 12% of patients
with acute infection, reflecting the fulminant nature of the disease (28).
Patients with allergic fungal sinusitis usually have opacification of multiple
sinuses. Special attention should be directed to the bony walls of the sinuses,
looking for thinning or destruction. With acute invasion, bony changes
are rarely noted because of the rapidity of spread of the infection; with

Table 3 Criteria for the Diagnosis of Allergic Fungal Sinusitis a

No underlying immunosuppressive condition

Presence of atopy; evidence for IgE-type immune reactivity to fungal antigens

Nasal polyposis

Sinus opacification on CT scan

Allergic mucin found at surgery or endoscopy

Fungal hyphae found with allergic mucin on histopathologic examination

No fungal invasion of mucosa or bone

a The need for demonstration of a type I immune response to fungal antigens or even the previous
existence of atopy and nasal polyposis has been brought into question by some authors. The firm-
est evidence is the demonstration of allergic mucin in material removed from the sinuses.

426 Kauffman

Figure 1 Acute invasive fungal sinusitis due to the zygomycete Rhizopus that
occurred in a young diabetic woman who had ketoacidosis and who developed the
acute onset of facial pain, ptosis, ophthalmoplegia, and loss of vision. Opacification
of the left ethmoid sinus with extension into the orbit can be seen on this MRI scan.

chronic invasive disease, bony changes are common (3). Mycetomas and,
sometimes, allergic fungal sinusitis can cause pressure necrosis of bone
due to the expanding mass of either hyphae or allergic mucin (1).

Endoscopic evaluation is helpful in all patients with fungal sinusitis. In
high-risk immunocompromised patients with facial pain, endoscopic evalua-
tion should be performed urgently, even when the CT scan does not show
clear-cut changes of acute sinusitis. Examination of the involved sinus in
patients with chronic symptoms can help differentiate among invasive
infection, mycetoma, and allergic disease. In the case of mycetoma, the mass
can be separated from the mucosa; the material is either "cheesy" or firm in
consistency. In patients with allergic fungal sinusitis, endoscopic examina-
tion documents the presence of darkly colored, thick, sticky allergic mucin
filling the involved sinuses and usually the presence of nasal polyposis.

If possible during the endoscopic procedure, biopsy material should be
obtained from both mucosa and bone for histopathologic examination and
culture. Histological evidence of tissue invasion is necessary to make a diag-

Fungal Sinusitis

427

Figure 2 Chronic invasive fungal sinusitis in an elderly woman who had no under-
lying illnesses and who developed the gradual onset of worsening facial pain,
followed by orbital apex syndrome. The CT scan shows invasion of tissues posterior
to the orbit and extension into the frontal lobe with abscess formation. Aspergilllus
fumigatus was the responsible pathogen.

nosis of invasive sinusitis. However, this is often difficult in neutropenic
patients who are also thrombocytopenic; in these cases, lavage can be per-
formed for cytological and culture studies. In severely immunocompromised
patients, growth of a mold from the sinus is adequate to make a diagnosis of
acute invasive fungal sinusitis (47). In mycetoma, well-circumscribed masses
of hyphae are present and the integrity of the mucosa is intact. Histopatho-
logical examination of material obtained from patients with allergic fungal
sinusitis shows hyphae within allergic mucin and no invasion of mucosa or
bone (Table 3).

Histopathological examination is very useful in differentiating infection
due to the zygomycetes, which show characteristic broad non-septate hyphae
from infection due to other filamentous fungi with acutely branching septate

428

Kauffman

Figure 3 CT scan of a young man who had a long history of recurrent nasal
discharge and several previous surgical procedures on his sinuses. The CT scan
shows a mass occupying the left frontal sinus with impingement, but no invasion
of the left frontal lobe. Histopathological examination showed allergic mucin and
pigmented hyphae with no invasion into bone. Alternarici species grew in culture
of the material removed at surgery.

hyphae (Figs. 4 and 5). In the case of the zygomycetes, culture of material
from the sinuses often yields no organisms, but the histopathological picture
is distinctive enough to make a diagnosis. However, histopathology alone is
inadequate to differentiate among the septate fungi, especially Aspergillus,
Pseudallescheria (Scedosporium), and Fusarium. Defining the specific organ-
ism causing the infection is essential for choosing the appropriate antifungal
agent when treating acute or chronic invasive infection.

TREATMENT

The treatment of invasive infection combines aggressive surgical debride-
ment with antifungal agents. Specific risk factors, such as iron chelation
therapy or diabetic ketoacidosis, if present, should be eliminated as soon
as possible (25). Surgical debridement must remove all necrotic tissue, includ-
ing the orbit if necessary; the edges of the excision should extend to tissue that
bleeds normally. If aggressive surgical debridement cannot be accomplished,

Fungal Sinusitis

429

** +

Figure 4 Broad non-septate hyphae typical of that of a zygomycete invading through
a blood vessel. This histologic appearance is sufficiently distinctive to make a diagnosis
even if the culture yields no growth.

especially in the imunocompromised patient, the outcome is dismal (2,4,6,10,
14,23,28). However, long-term treatment with antifungal agents sometimes
succeeds in curing chronic invasive sinusitis even when the entire fungal bur-
den cannot be surgically removed (5,38,39). The difference in outcome is
directly related to the relatively intact immune system of the host with chronic
invasive infection in contrast to those with acute invasive infection.

Empiric antifungal therapy should be initiated as soon there is a
reasonable likelihood that acute invasive fungal sinusitis is present (Table 4).
If it is likely that a zygomycete is the cause of the infection, a lipid formula-
tion of amphotericin B should be given (23,48,49). If the likely organism is
a species of Aspergillus, Fusariurn, or Pseudallescheria, voriconazole is the
antifungal agent of choice. Voriconazole is fungicidal for many filamentous
fungi and has shown superiority over amphotericin B for invasive aspergil-
losis (50). Individual case reports document effectiveness for some patients
with infections due to Fusariurn or Pseudallescheria, organisms which are
generally not susceptible to amphotericin B (51-53). In contrast, the zygo-
mycetes are not susceptible to voriconazole. Frequently, in the high-risk
immunocompromised patient, both lipid formulation amphotericin B and
voriconazole are given until the culture results are known.

A variety of adjunctive measures have been tried in addition to surgical
debridement and antifungal therapy in an attempt to cure acute invasive
sinusitis. These include hematopoietic growth factors, such as GM-CSF

430

Kauffman

Figure 5 Thinner, septate hyphae characteristic of hyaline molds such as Asper-
gillus, Pseudallescheria (Scedosporium), and others. The histopathological picture is
not specific for any particular organism, and the diagnosis must be established by
growth of the organism in culture.

and G-CSF, and hyperbaric oxygen (23,54-56). Most importantly, if host
defenses do not return even modestly, as in a profoundly neutropenic patient,
none of the measures used will likely be beneficial.

Chronic invasive fungal sinusitis has a high recurrence rate, and very
frequently, all infected tissue cannot be removed by surgery without
great risk to the patient. For this reason, the management of this disease
involves long-term suppressive azole therapy. Itraconazole was previously
used for this indication (39), but has been mostly supplanted by voricona-
zole, which has better anti- Aspergillus activity, better absorption of the oral
formulation, and superior central nervous system and ocular penetration
than itraconazole (57). In cases of chronic fungal sinusitis due to dematiac-
eous molds, voriconazole is a reasonable choice, but there have been few
patients treated and there is more clinical experience with itraconazole at
this time (58).

The treatment of mycetoma differs greatly from that of invasive fungal
sinusitis. The most important measure to be undertaken is removal of the
obstructing inflammatory mass and drainage of the sinus. Performing these
procedures through endoscopic surgery has gained in popularity in recent
years (40). Radical drainage procedures, previously performed when it was

Fungal Sinusitis

431

4->

-rd

bfi

• t-H

4->

• 1—t

• »-H

4-»

(4-1

S-H

P-h

• f-H

ctf

>— i

•*-»

ctf

f-i

■4-*

4-<

bfl

__i

ctf

• »-H

4->

• »-H

-Si

-Q

!-H

co
3

bfi

S-H

..— i CL
c£ So

—
O

-4-»

bfi

-73

S-H

(4-1
<D

d
o

S-H

bfi

4-»

d
d

bX)

*rd

• F-H

4-J

4^H

• »-H

S-H

C4G

(4-1

CI-

• 1-H

" 8

d
o
o

• i-H
S-H

co
CD
O

cd
d

=5 O

*s -

w ^

CD
co 42

O ID

CD T3

d g

43 <->

• »-H

co bO

<D
O

O
O

■g .a ^

u ™ d

P4 0) <D
X > 4=

% S •

o g -

S-n

bfl

T3 co

^ d

•^ CO

D >

(D d

> o

42 43

« ° 4^

S5 o ^

d (JZ J-H

^30

bD d *d

co * bO

< •- a

CD ^ O

<D O

in ^

• »-H

45 a>

-^ O

d
o
o

o
o

• •— I

S-H

4— »

• >-H
S-H

4— »

'5b .2

d ^

^ ^ a

O «•» S-H

S-H

c U

.d°*s

s^ 4^

4^ Si

4^ '^

TO "^ — ^

c\3
>
G

• «-H

• >-H

G
O
. . u
Jj 43

J s.

>, ^H

* "d

S-H 03

O -u

4*J

C/3

■ ^H

<L>

co
O

0)
41

« ^

> W)

'5b '53

"o o
68 ^

b -d

Ph ^
• ,0

C/3 C4-H

3 .3

rt bo

cd O

c 2

S-( CO

O C3

^H w

O
43

•g 2

s^ ©

O S3

S-H ft)

a >

&'»

S3 S

C/3

o
s3

S3
o

^ o
> >

2 «-<

G O

.9 fc

G ai
u bX)
> «J
bfi c*h

09 O

I-

s^ ro

^ S

co co

TD 4^

g d

O H
43 T3

I I

432 Kauffman

thought that there was a high risk of fungal invasion, are now rarely used.
Antifungal agents appear to have no role in the treatment of mycetoma (16).

Allergic fungal sinusitis is also treated with surgery rather than
antifungal agents. The major goal of surgery is removal of allergic mucin
filling the sinus. Generally, a permanent drainage route is also accomplished
at the time of surgery (41). Surgery is increasingly performed using endo-
scopic procedures. Follow-up endoscopic evaluation is very important; it
is thought that early removal of recurrent polyps and nasal crusts may help
prevent recurrence of the disease.

Follow-up long-term medical management to try to prevent recurrent
disease is very important. However, there is much controversy with regard
to what constitutes appropriate medical management (59-63). Systemic
corticosteroids are of benefit in the postoperative period, but long-term
use, not surprisingly, is associated with more risks than benefits. However,
all patients should receive long-term intranasal corticosteroids. There are
no data showing a benefit in using systemic antifungal agents for this disease.
Intranasal instillation of antifungal agents, such as amphotericin B and
itraconazole, has been advocated, but there are no studies showing a benefit
of this practice. Preparation of solutions of antifungal agents is not standar-
dized; frequently, these solutions are prepared in individual hospital pharma-
cies. It seems unlikely that antifungal activity is maintained in formulations
that are dispensed for the patient to use for sinus irrigation at home. The
role of immunotherapy with specific fungal antigens remains controversial,
but data have been presented which show that immunotherapy can both
decrease reliance on intranasal corticosteroids and decrease the rate of
recurrence (63).

CONCLUSIONS

A broad spectrum of pathological changes and clinical manifestations
constitute fungal sinusitis. Invasive disease is associated with high morbidity
and mortality. The immune status of the host is the most important factor
in the development of invasive infection. Highly immunosuppressed indivi-
duals and diabetics in ketoacidosis are likely to have acute, rapidly pro-
gressive, invasive sinusitis, especially with Aspergillus species and the
zygomycetes. Immediate aggressive surgical debridement and antifungal
therapy are essential for cure. Immunocompetent hosts can develop several
chronic forms of fungal sinusitis. Chronic invasive fungal sinusitis requires
aggressive surgical debridement and antifungal therapy that may have to be
extended to become long-term suppressive therapy. Mycetoma, a localized
non-invasive mass of fungal hyphae, can be removed surgically to effect a
cure. Finally, allergic fungal sinusitis appears to be a hypersensitivity reaction
to fungal antigens rather than actual infection and is treated with surgical
debridement and anti-inflammatory agents rather than antifungal agents.

Fungal Sinusitis 433

REFERENCES

1. deShazo RD, Chapin K, Swain RE. Fungal sinusitis. N Engl J Med 1997;
337:254-259.

2. Iwen PC, Rupp ME, Hinrichs SH. Invasive mold sinusitis: 17 Cases in immuno-
compromised patients and review of the literature. Clin Infect Dis 1997; 24:
1178-1184.

3. Washburn RG, Kennedy DW, Begley MG, Henderson DK, Bennett JE.
Chronic fungal sinusitis in apparently normal hosts. Medicine (Baltimore)
1988; 67:231-247.

4. Drakos PE, Nagler A, Or R, Naparstek E, Kapelushnik J, Englehard D, Rahav G,
Ne'emean D, Slavin S. Invasive fungal sinusitis in patients undergoing bone
marrow transplantation. Bone Marrow Transplant 1993; 12:203-208.

5. Stringer SP, Ryan MW. Chronic invasive fungal rhinosinusitis. Otolaryngol
Clin N Amer 2000; 33:375-387.

6. Talbot GH, Huang A, Provencher M. Invasive Aspergillus rhinosinusitis in
patients with acute leukemia. Rev Infect Dis 1991; 13:219-232.

7. Byard RW, Bonin RA, Haq AU. Invasion of paranasal sinuses by Aspergillus
oryzae. Mycopathologia 1986; 96:41^3.

8. Kameswaran M, Al-Wadei A, Khurana P, Okafor BC. Rhinocerebral aspergil-
losis. J Laryngol Otol 1992; 106:981-985.

9. Panda NK, Sharma SC, Chakrabarti A, Mann SBS. Paranasal sinus mycoses in
north India. Mycoses 1998; 41:281-286.

10. Gucalp R, Carlisle P, Gialanella P, Mitsudo S, McKitrick J, Dutcher J.
Paecilomyces sinusitis in an immunocompromised adult patient: Case report
and review. Clin Infect Dis 1996; 23:391-393.

1 1 . Watters GW, Milford CA. Isolated sphenoid sinusitis due to Pseudallescheria
boydii. J Laryngol Otol 1993; 107:344-347.

12. Anaissie E, Kantarjian H, Ro J, Hopfer R, Rolston K, Fainstein V, Bodey G.
The emerging role of Fusarium infections in patients with cancer. Medicine
(Baltimore) 1988; 67:77-83.

13. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome
of mould infections in hematopoietic stem cell transplant recipients. Clin Infect
Dis 2002; 34:909-917.

14. Hunt SC, Miyamoto C, Cornelius RS, Tami TA. Invasive fungal sinusitis in the
acquired immunodeficiency syndrome. Otolaryngol Clin N Amer 2000; 33:
335-347.

15. Marple BF, Mabry RL. What we now know about allergic fungal sinusitis.
J Respir Dis 2000; 21:23-31.

16. deShazo RD, O'Brien M, Chapin K, Soto-Aguilar M, Swain R, Lyons M,
Bryars WC, Alsip S. Criteria for diagnosis of sinus mycetoma. J Allergy Clin
Immunol 1997; 99:475^85.

17. Ponikau JU, Sherris DA, Kern EB, Homburger HA, Frigas E, Gaffey TA,
Roberts GD. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin
Proc 1999; 74:877-884.

18. Zieske LA, Kopke RD, Hamill R. Dematiaceous fungal sinusitis. Otolaryngol
Head Neck Surg 1991; 105:567-577.

434 Kauffman

19. Dunn JJ, Wolfe MJ, Trachtenberg J, Kriesel JD, Orlandi RR, Carroll KC.
Invasive fungal sinusitis caused by Scytalidium dimidiatum in a lung transplant
recipient. J Clin Microbiol 2003; 41:5817-5819.

20. Ismail Y, Johnson RH, Wells MV, Pusavat J, Douglas K, Arsura EL. Invasive
sinusitis with intracranial extension caused by Curvularia lunata. Arch Intern
Med 1993; 153:1604-1606.

21. Revankar SG, Patterson JE, Sutton DA, PullenR, Rinaldi MG. Disseminated
phaeohyphomycosis: Review of an emerging mycosis. Clin Infect Dis 2002; 34:
467-476.

22. Dixon DM, Polak-Wyss A. The medically important dematiaceous fungi and
their identification. Mycoses 1991; 34:1-18.

23. Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KVI. Zygomycosis in the
1990s in a tertiary-care cancer center. Clin Infect Dis 2000; 30:851-856.

24. Ferguson BJ. Mucormycosis of the nose and paranasal sinuses. Otolaryngol
Clin N Amer 2000; 33:349-365.

25. Sugar AM. Mucormycosis. Clin Infect Dis 1992; 14(suppl 1):S126-S129.

26. Ruess M, Greene JN, Vincent AL, Sandin RL. Invasive Aspergillus involving
the ethmoidal sinuses in cancer patients: Report of four cases and review of
the literature. Infect Dis Clin Pract 1999; 8:323-327.

27. Yuen K-Y, Woo PCY, Ip MSM, Liang RHS, Cjiu EKW, Siau H, Ho P-L,
Chen FFE, Chan T-K. Stage-specific manifestation of mold infections in bone
marrow transplant recipients: risk factors and clinical significance of positive
concentrated smears. Clin Infect Dis 1997; 25:37-42.

28. Gillespie MB, O'Malley BW, Francis HW. An approach to fulminant invasive
fungal rhinosinusitis in the immunocompromised host. Arch Otolaryngol Head
Neck Surg 1998; 124:520-526.

29. Guiot HF, Fibbe WE, van't Wout JW. Risk factors for fungal infection
in patients with malignant hematologic disorders: Implications for empirical
therapy and prophylaxis. Clin Infect Dis 1994; 18:525-532.

30. Ribaud P, Chastang C, Latge J-P, Baffroy-Lafitte L, Parquet N, Devergie A,
Esperon H, Selimi F, Rocha V, Derouin F, Socie G, Gluckman E. Survival
and prognostic factors of invasive aspergillosis after allogeneic bone marrow
transplantation. Clin Infect Dis 1999; 28:322-330.

31. Daly AL, Velazquez LA, Bradley SF, Kauffman CA. Mucormycosis: Associa-
tion with deferoxamine therapy. Am J Med 1989; 87:468-471.

32. Gonzalez-Crespo MR, Gomez-Reino J J. Invasive aspergillosis in systemic lupus
erythematosus. Semin Arthritis Rheum 1995; 24:304-314.

33. Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis
1993; 16:677-688.

34. Kanj SS, Welty-Wolf K, Madden J, Tapson V, Baz MA, Davis RD, Perfect JR.
Fungal infections in lung and heart-lung transplant recipients: Report of 9 cases
and review of the literature. Medicine (Baltimore) 1996; 75:142-156.

35. Flume PA, Egan TM, Paradowski LJ, Detterbeck FC, Thompson JT, Yankas-
kas JR. Infectious complications of lung transplantation: Impact of cystic fibro-
sis. Am J Resp Crit Care Med 1994; 149:1601-1607.

Fungal Sinusitis 435

36. Mehrad B, Paciocco G, Martinez F, Ojo TC, Iannettoni MD, Lynch JP.
Spectrum of Aspergillus infections in lung transplant recipients. Chest 2001;
119:169-175.

37. Chinn RY, Diamond RD. Generation of chemotactic factors by Rhizopus
oryzae in the presence and absence of serum: Relationship to hyphal damage
mediated by human neutrophils and effects of hyperglycemia and ketoacidosis.
Infect Immun 1982; 38:1123-1129.

38. Bradley SF, McGuire NM, Kauffman CA. Sino-orbital and cerebral aspergillo-
sis: cure with medical therapy. Mykosen 1987; 30:379-385.

39. Gumaa SA, Mahgoub ES, Hay RJ. Post-operative reponses of paranasal
Aspergillus granuloma to itraconazole. Trans Royal Soc Trop Med Hyg 1992;
86:93-94.

40. Klossek J-M, Serrano E, Peloquin L, Percodani J, Fontanel J-P, Pessey J-J.
Functional endoscopic sinus surgery and 109 mycetomas of paranasal sinuses.
Laryngoscope 1997; 107:112-117.

41. Marple BF. Allergic fungal rhinosinusitis: Current theories and management
strategies. Laryngoscope 2001; 111:1006-1019.

42. deCarpentier JP, Ramamurthy L, Denning DW, Taylor PH. An algorithmic
approach to Aspergillus sinusitis. J Laryngol Otol 1994; 108:314-318.

43. Judson MA. Noninvasive Aspergillus pulmonary disease. Sem Respir Crit Care
Med 2004; 25:203-219.

44. Manning SC, Holman M. Further evidence for allergic pathophysiology in
allergic fungal sinusitis. Laryngoscope 1998; 108:1485-1496.

45. Carter KD, Graham SM, Carpenter KM. Ophthalmic manifestations of allergic
fungal sinusitis. Am J Ophthalmol 1999; 27:189-195.

46. Goldstein MF, Atkins PC, Cogen FC, Kornstein MJ, Levine RS, Zweiman B.
Allergic Aspergillus sinusitis. J Allergy Clin Immunol 1985; 76:515-524.

47. Ascioglu S, Rex JH, dePauw B, Bennett JE, Bille J, Crokaert F, Denning DW,
Donnelly JP, Edwards JE, Erjavec Z, et al. Defining opportunistic invasive fun-
gal infections on immunocompromised patients with cancer and hematopoietic
stem cell transplants: An international consensus. Clin Infect Dis 2002; 34:7-14.

48. Strasser MD, Kennedy RJ, Adam RD. Rhinocerebral mucormycosis: Therapy
with amphotericin B lipid complex. Arch Intern Med 1996; 156:337-339.

49. Moses AE, Rahav G, Barenholz Y, Elidan J, Azaz B, Gillis S, Brickman M,
Polacheck I, Shapiro M. Rhinocerebral mucormycosis treated with amphoter-
icin B colloidal dispersion in three patients. Clin Infect Dis 1998; 26:1430-1433.

50. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RF, Oestman
J-W, Kern WV, Marr KA, Ribaud P, Lortholary O, et al. Voriconazole versus
amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med
2002; 347:408-415.

51 . Nesky MA, McDougal EC, Peacock JE Jr. Pseudallescheria boydii brain abscess
successfully treated with voriconazole and surgical drainage: Case report and
literature review of central nervous system pseudallescheriasis. Clin Infect Dis
2000; 31:673-677.

52. Munoz P, Marin M, Tornero P, Rabadan PM, Rodriquez-Creixems M, Bouza E.
Successful outcome of Scedosporium apiospermum disseminated infection treated

436 Kauffman

with voriconazole in a patient receiving corticosteroid therapy. Clin Infect Dis
2000;31:1499-1501.

53. Consigny S, Dhedin N, Datry A, Choquet S, LeBlond V, Chosidow O. Success-
ful voriconazole treatment of disseminated Fusarium infection in an immuno-
compromised patient. Clin Infect Dis 2003; 37:311-313.

54. Gaviria JM, Grohskopf LA, Barnes R, Root RK. Successful treatment of
rhinocerebral zygomycosis: A combined-strategy approach. Clin Infect Dis
1999; 28:160-161.

55. Garcia-Diaz JB, Palau L, Pankey GA. Resolution of rhinocerebral zygomycosis
associated with administration of granulocyte-macrophage colony-stimulating
factor. Clin Infect Dis 2001; 32:166-170.

56. Ferguson BJ, Mitchell TG, Moon R, Camporesi EM, Farmer J. Adjunctive
hyperbaric oxygen for treatment of rhinocerebral mucormycosis. Rev Infect
Dis 1988; 10:551-559.

57. Johnson LB, Kauffman CA. Voriconazole: A new triazole antifungal agent.
Clin Infect Dis 2003; 36:630-637.

58. Sharkey PK, Graybill JR, Rinaldi MG, Stevens DA, Tucker RM, Peterie JD,
Hoeprich PD, Greer DL, Frenkel L, Counts GW, Goodrich J, Zellner S,
Bradsher RW, van der Horst CM, Israel K, Pankey GA, Barranco CP. Itraco-
nazole treatment of phaeohyphomycosis. J Am Acad Dermatol 1990; 23:
577-586.

59. Marple BF, Mabry RL. Comprehensive management of allergic fungal sinusi-
tis. Am J Rhinol 1998; 12:263-268.

60. Quraishi HA, Ramadan HH. Endoscopic treatment of allergic fungal sinusitis.
Otolaryngol Head Neck Surg 1997; 117:29-34.

61. Kupferberg SB, Bent JP, Kuhn FA. Prognosis for allergic fungal sinusitis.
Otolaryngol Head Neck Surg 1997; 117:35-41.

62. Ferguson BJ. What role do systemic corticosteroids, immunotherapy, and
antifungal drugs play in the therapy of allergic fungal rhinosinusitis? Arch
Otolaryngol Head Neck Surg 1998; 124:1174-1177.

63. Mabry RL, Mabry CS. Allergic fungal sinusitis. The role of immunotherapy.
Otolaryngol Clin N Amer 2000; 33:433^40.

Sinusitis in Immunocompromised,
Diabetic, and Human Immunodeficiency

Virus-Infected Patients

Todd D. Gleeson and Catherine F. Decker

Division of Infectious Diseases, Department of Internal Medicine,
National Naval Medical Center, Bethesda, Maryland, U.S.A.

INTRODUCTION

Over the past several decades, medical advancements in transplantation and in
the treatment of immunocompromised patients have led to increased survival in
several patient populations including oncology and transplant patients, type 1
diabetics, and human immunodeficiency virus (HlV)-infected patients. Not
surprisingly, these patients are at increased risk for infectious complications. As
the at-risk population continues to grow, sinusitis has become an increasingly
recognized problem in these immunocompromised groups and presents unique
challenges to the clinician in both diagnosis and management. Although each
group differs in its acquired risk and the various impairments in the immune
function, the importance of early recognition, diagnosis, and aggressive
combined modality treatment is common to all immunocompromised patients.
The degree of impairment of the immune system is the most important
host factor in determining the clinical presentation and course of sinusitis.

*The opinions and assertions contained herein are those of the authors and are not to be
construed as official or as reflecting the views of the Department of Defense, the Department
of the Navy, or the naval services at large.

437

4 38 Gleeson and Decker

The spectrum of sinonasal disease varies from a slow, indolent course in the
presence of mild immunocompromise to an acute fulminant course if the
immunocompromised state is severe. For example, one investigator reports
that recurrent or refractory sinusitis in the outpatient setting may in fact be
due to relative immune dysfunction characterized by an unexpectedly high
incidence of low immunoglobulin levels and common variable immuno-
deficiency (1). Conversely, neutropenic patients with invasive fungal rhino-
sinusitis have a devastating outcome with 100% mortality in the absence of
bone marrow recovery (2).

Historically, acute sinusitis has referred to community-acquired bacterial
sinusitis. In immunocompromised groups, acute versus chronic sinusitis
is not as clearly defined . The chronicity of sinusitis in these immunocompromised
groups correlates with immune status and the underlying immunodeficiency.
Generally, chronic sinusitis refers to disease extending beyond four weeks in
duration. Acute fulminant disease can occur over days in patients with signifi-
cant immune system impairment. Severely immunocompromised individuals
receiving therapy for sinusitis may appear to have a chronic disease character-
ized by a course that extends to several weeks. However, if treatment is
withdrawn prematurely, the sinonasal infection may rapidly worsen, often
resulting in a fatal outcome (3,4).

Although sinusitis in the immunocompromised patient may be caused
by common pathogens, such as Haemophilus influenzae and Streptococcus
pneumoniae, it more often results from infection with more unusual organ-
isms. This chapter reviews the clinical presentation, diagnosis, and treatment
of sinusitis in three groups of immunocompromised hosts: neutropenic
patients, diabetic patients, and HIV-infected patients.

SINUSITIS IN NEUTROPENIC PATIENTS

As a result of increasing rates of transplantation and the use of immuno-
suppressive agents over the past several years, the population at-risk for
invasive fungal rhinosinusitis is growing. This disease continues to be a
potentially lethal and dreaded infectious complication of chemotherapy or
bone marrow transplant-induced neutropenia. It occurs in 2 to 4% of
patients undergoing bone marrow transplantation (5,6) and despite therapy,
the majority of cases result in death (7). Recovery of the immune system is
still the major prognostic factor in patients with this infection.

Predisposing Factors

Several risk factors for sinusitis have been identified in neutropenic patients.
Although susceptibility to fungal infections is characteristic of patients
with defects in CD4 mediated function, quantitative or qualitative defects
in neutrophil function also predispose hosts to the development of fungal

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients 439

infections. Absolute neutrophil counts (ANC) below 500 cells/mL are strongly
correlated with the development of invasive fungal disease (8). In bone marrow
transplant (BMT) patients, the critical time period for the development of
fungal rhinosinusitis is approximately three weeks after transplantation (2).
Secondary risk factors include two weeks or more of any of the following:
systemic steroid use (seen in up to 50% of patients with a mean dose of
2.22 mg/kg/day prednisone equivalent) (9,10), ANC<500 cells/mm 3 (11),
and exposure to multiple broad-spectrum antibiotics (9,10,12,13). In addi-
tion, it has been reported that nasal mucosa ciliary dysfunction in BMT
patients predisposes to sinusitis (14).

Etiology

Immunocompetent patients are more often infected by gram-positive bacteria,
and the most common organisms causing sinusitis in neutropenic patients are
gram-negative bacteria, followed by gram-positive bacteria and fungi (15).
Bacteria including Pseudomonas aeruginosa, Enterobacter species, Escherichia
coli, Serratia marcescens, Haemophilus influenzae, Staphylococcus, and Strepto-
coccus species have all been isolated from sinus cultures in neutropenic
patients. Aspergillus species are often the causative organisms of invasive
fungal rhinosinusitis in the neutropenic host, although Mucor, Rhizopus, and
Alternaria species, and other invasive molds have also been implicated (11,16).

Clinical Presentation

The most common presentation of fungal rhinosinusitis, seen in up to 90%
of infected neutropenic patients, is fever unresponsive to 48 hours of appro-
priate broad-spectrum intravenous antibiotics (2). Most patients have fever
and at least one additional finding (17), including sinus tenderness, facial
edema, or rhinorrhea. Headache, facial pain, cranial nerve palsies, and visual
loss are also seen (11,12,17).

Diagnosis

A thorough rigid nasal endoscopic examination should be performed in any
immunocompromised patient with localizing symptoms of sinusitis. Some
centers advocate nasal endoscopy for all febrile neutropenic patients who
do not respond to 48 hours of appropriate broad-spectrum intravenous
antibiotics (12). Endoscopic examination may reveal changes in the nasal
mucosa, including discoloration, granulation, or ulceration (10,16,18).
White discoloration indicates tissue ischemia secondary to fungal invasion
of blood vessels, whereas clinical progression to black discoloration and
ulceration is a later finding of tissue necrosis (10). Decreased sensation
and decreased mucosal bleeding are also ominous signs (12). These findings

440 Gleeson and Decker

on nasal endoscopy may precede rapid facial swelling, nasal symptoms, and
systemic dissemination.

The middle turbinate, which acts as the major filter in the nasal airway, is
most commonly involved in invasive fungal rhinosinusitis (10,19). Local
mucosal disruption, drying secondary to oxygen passing through the nasal
cannula, allergy, or changes in the normal flora that can occur with bacterial
sinusitis may promote fungi to become invasive (10). In most cases, invasive
rhinosinusitis originates in the nasal cavity before extension into the parana-
sal sinuses. Identifying disease early, when it is still confined to the nasal cavity
or middle turbinate, seems to have a positive impact on survival (10).
Performing middle turbinate biopsies in all patients at-risk for invasive fungal
rhinosinusitis, who have fever unresponsive to 48 hours of broad-spectrum
antibiotics or symptoms of rhinosinusitis, or both, may be an effective diag-
nostic technique to help achieve the goal of early detection (19).

Computed tomography (CT) is the preferred imaging modality in
establishing the diagnosis of fungal rhinosinusitis and is more reliable than
plain radiography (16,20,21). A fine cut CT scan of the paranasal sinuses not
only reveals the presence of sinusitis, but also defines bony architecture as
well as intracranial spread or orbital involvement. Although intravenous
contrast helps delineate periorbital or dural inflammation, it is not manda-
tory for most initial evaluations (12). A CT scan showing focal bony erosion
should alert the clinician to invasive fungal disease, although a definitive
diagnosis rests on histological confirmation. In one series, 12% of patients
with invasive fungal rhinosinusitis had a normal CT scan; (12) therefore,
imaging cannot replace careful endoscopic nasal evaluation and biopsy.

Magnetic resonance imaging (MRI) may be even more sensitive than
CT, and is superior to CT in delineating intracranial extension of disease
(8,12). Some postulate that the presence of ferromagnetic elements within
fungal concretions may produce a characteristic signal intensity on MRI (20).

Invasive fungal rhinosinusitis is a histopathological diagnosis and is
characterized by the mucosal infiltration of mycotic organisms from sinus
air spaces to adjacent orbital and intracranial structures. This infiltration
results in tissue necrosis, and invasion of blood vessels produces thrombosis
and infarction. Fulminant invasive disease occurs primarily in neutropenic
patients and BMT recipients, whereas indolent invasive fungal sinusitis is
a more slowly destructive disease seen in immunocompetent hosts, diabetics,
or patients with AIDS. Biopsy and culture provide proper speciation which
can direct therapy, as in the case of infection by Pseudallescheria boydii,
which is resistant to amphotericin B (12).

Treatment

After endoscopic evaluation and antrostomy, if a bacterial etiology of
sinusitis is discovered, gram stain and culture with identification of antibiotic

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients 441

sensitivities of the organism are of major importance for successful treatment
of sinusitis in the neutropenic patient (15). Antibiotics that cover both gram-
negative and gram-positive organisms should be given empirically,
with further modifications directed by culture and sensitivity results of the
aspirate (Table 1).

When a diagnosis of invasive fungal rhinosinusitis is made, immediate
treatment must be instituted. A successful outcome is contingent on both the
recovery of immune function and early medical and surgical intervention
(22). Aggressive surgical debridement to clear margins removes devitalized
tissues that further support fungal growth, enhances the ability of antifungal
drugs to reach infected areas, and provides more time for bone marrow to
recover (12,23). Administration of high-dose systemic amphotericin B at a
dose of >1.5 mg/kg/d, for a total dose of two grams or more, gives the best
chance of survival (10,16,18,20-22). The use of liposomal amphotericin B
should be reserved for patients with renal disease. Despite an aggressive-
combined modality approach, mortality is still 100% in both intracranial
extension of disease and in patients in whom immune function does not
recover (12,22) (Fig. 1).

New antifungal drugs may prove superior to amphotericin B in the
treatment of invasive aspergillosis, including sinonasal disease. One study
reports voriconazole to be superior to amphotericin B in both response rate
and survival in the treatment of invasive aspergillosis. Voriconazole also
caused fewer drug-related adverse events than amphotericin B (24). Some
centers advocate using voriconazole as first-line treatment for invasive
Aspergillus infections (25).

The administration of growth factors also plays a role in the treatment
of neutropenic patients with fungal rhinosinusitis. Patients who respond to
granulocyte colony-stimulating factor (GC-SF) are more likely to have a
favorable outcome. One study demonstrated that responders to GC-SF
were more likely to have contained disease than nonresponders. However,
it is unclear if this outcome reflects response to GC-SF or better underlying
bone marrow status in survivors (10). Granulocyte transfusions have also
been used in invasive fungal rhinosinusitis to enhance immune status and
bridge the interval until hematopoietic regeneration occurs (23,26).

Close follow-up with repeated visualization with rigid nasal endoscopy
is essential. Patients should have repeat endoscopy in 48 to 72 hours if
there is any suspicion for residual disease following the original debridement
(12). Neutropenic patients should continue to receive weekly rigid nasal
endoscopy until resolution of neutropenia and then monthly for six months
thereafter (12). Patients who have had fungal rhinosinusitis are especially
susceptible to relapse or reinfection during future episodes of neutropenia
(10,27). Patients undergoing chemotherapy or bone marrow transplantation
who have had episodes of sinonasal or pulmonary aspergillosis have at least
a 50% risk of developing a recurrence during re-induction chemotherapy

442

Gleeson and Decker

• ■— (

-4— >

J-H

-*- »

• l-H

-4— »

.1>

• l-H

-4— »

-D

• ^H

• l-H

«D

J-h

-4- »

»H

• l-H

• l-H
-4- »

• 1-H

• i-h

•*-»

• l-H

Xfl

<h_

j-i

-O

bX)

5-(

• l-H

• ■—<

-4- »

-Si

-<-»

CD
co

o
[/J

<H_

■d

• i-H

• l-H

d
o

CD
Oh

■4-»
O

• l-H

-4-»

• l-H

•4-4

-4-»

• l-H

-4— »

Cd
13

cd
13

cd
U

cd
u

bX)

^1-

bX)

1-H

i— 1

> ^

HH <N

(j-J^ "d ^ 13 (j 4 J3 T3
bfi kh bX) Er ^ bo

bfl

^ 6«S boS s bag

lAi i-H i-H i-H Tj" i-H

J-H

CX «

•d U

• »-H
f)

• »-H

•—

-*-'

-d £
d *«

d CD

< u

-d
a «=> a

• l-H

'—

a .&u a

c^J

• l-H

^— ^

• l-H

^-^

• i-H

J-H

ctf

J-H

-t— »

CD
-t— »

bfi

c^S

cd
00

d
d

• l-H

5-(
-*— »
=3
CD

-*-•

• l-H

G d

CD .9

^ ° d

J5 '55 d

CD CD _rt
^ ^ gd

w a

CD o

° HH <N

bX)

g/kg/dIV
mg/kg/d
;/kg IV ql

• i-H

,_J

tS>

G (^ d
in c

• i-H

t-h in

d >>J^
•rt hO o

■" ^H N

5-h 13 cvj
CD CD rn

O g §

a^E

a 2

ft CD >

■§ i-i

S^ CD

ITj

o
o

■4-J
(H

' > — «

cd
bX)

J-H

o
CX

13
O O, bX)

_, ^3 \.

-M "-^ in
>5t bX) (N

a ^

cd ^3 d
d "n -g

agd

J-H

•*-»

• i-H

• l-H

(Tl

1/3

>^M

q a

• -H

ID
0)
Ih

-4— I

C/3

id d

X <D

U X)

J-H

'd d

8 2

J-i r,

d w)

Cl) C

G T3

03
O

^^
cr 3

o 8

Ph Oh

bX) -^

a s

o rt
q o

CN >

G -^

-G g

^ G
- qj

1/]

•^H

-4— >
•i-H

C/5

-G

• l-H

-O

CJ
— ^

'.J

i-1

b0 >

a ^

CD G

e>3

o
>

■8

3
W ft 5

QJ Q-,

•G t -
Sh °

.^ G

~* il

5 I

F -d.
Si bo

i 2 *d

O -G
">a

-2^ G

~Q ID
s S

a, pq

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients

443

Immunocompromised State

Neutropenia (BMT or chemotherapy-induced)

Insulin-dependent diabetes mellitus

AIDS

Identify Associated Risk Factors

Broad spectrum antibiotics
Prolonged antibiotic use (>2 wks)
Prolonged neutropenia (>2 wks)
Steroid use (>2 mg/kg/d prednisone)
WBC< 500 cells/mm 3
CD4 count < 50 cells/mm 3
Diabetic ketoacidosis

Symptoms

( 1 ) Fever for 48 hrs despite
broad-spectrum
antibiotics

and/or

(2) Nasal congestion, facial
pain or edema

If history of invasive mycotic
infection, administer empiric
amphotericin B with future
chemotherapy or BMT

Evaluation

(1) Rigid nasal endoscopy with biopsy of suspicious
lesions OR biopsy of middle turbinate if nasal mucosa
appears normal

(2) Antrostomy and lavage for stains and aerobic,
anaerobic and fungal cultures. (Include techniques for
acid-fast bacilli, atypical viruses and parasites in AIDS pts)

(3) Sinus CT or MRI with gadolinium (if intracranial
extension suspected)

Evidence of gross disease and/or
histopathology positive for
invasive fungal elements

No invasive fungal
elements seen on frozen
section biopsy

Weekly rigid nasal
endoscopy until
neutropenia resolves

Treatment

(1) High dose amphotericin B to

total dose of 2 g

(2) Emergent surgical debridement

(3) Correction of DKA

(4) Normalization of glucose

Figure 1 Algorithm for the diagnosis and management of rhinosinusitis in the immu-
nocompromised patient. BMT indicates bone marrow transplant; AIDS, acquired
immunodeficiency syndrome; WBC, white blood cell; DKA, diabetic ketoacidosis

or transplantation (28). Hence, antifungal therapy should be empirically
initiated with further courses of chemotherapy or bone marrow transplan-
tation in these patients (Fig. 1).

Prevention

Few studies have evaluated primary and secondary prophylaxis of invasive
fungal sinusitis with antifungal drugs. One trial of amphotericin nasal spray

444 Gleeson and Decker

in a BMT unit reported an incidence of 1.8% of invasive fungal disease,
compared to 13.8% in historical controls (29,30). A benefit in using intrave-
nous amphotericin to prevent aspergillosis in BMT patients has not been
clearly demonstrated in a sufficient number of controlled trials (30). In
patients who have experienced a previous episode of invasive aspergillosis,
however, prophylactic intravenous amphotericin during re-induction che-
motherapy or bone marrow transplantation decreases the rate of recurrent
aspergillosis (30).

SINUSITIS IN DIABETIC PATIENTS

Patients with diabetes mellitus are at an increased risk of developing a variety
of infections, including sinusitis. Although the underlying condition of
diabetes mellitus cannot be reversed, effective glycemic control improves
multiple factors important in the host response to sinusitis.

Predisposing Factors

The proclivity for diabetic patients to develop infections is not unexpected
given that hyperglycemia produces qualitative immune dysfunction through
impairment of neutrophils. Normalization of glucose and correction of dia-
betic ketoacidosis are essential in treating and preventing infections in these
patients (31,32). Whereas it may be difficult to prove a causal relationship
between hyperglycemia and infection, in vitro and clinical evidence support
such a relationship. The degree of hyperglycemia has been shown to affect
phagocytic function (33), granulocyte adherence (34), chemotaxis (35), and
bactericidal function in vitro (36), all of which improve with aggressive glyce-
mic control (37). Hyperglycemia may also impair complement fixation
and thereby decrease opsonization. Diabetic microangiopathy may also
predispose the diabetic patient to infection (38), however, it has not been
specifically reported as a risk factor for sinusitis.

Etiology

Although fungal rhinosinusitis has been well studied in diabetics, diabetic
patients are also susceptible to acute bacterial sinusitis that may be recalci-
trant if pansinusitis is present. The predominant organisms recovered in
bacterial sinusitis in diabetic patients are streptococci and staphylococcal
organisms, followed by gram-negative bacteria (38). The increased fre-
quency of sinusitis caused by Staphylococcus aureus in this population is
not unexpected given the increased S. aureus carrier state in diabetic patients
requiring insulin (39).

Aspergillus and Zygomycetes species are the most common causes of
fungal sinusitis in this patient group, whereas Candida species are rarely
reported (40). The diabetic patient is particularly susceptible to Rhizopus
infection for many reasons unique to the organism. Rhizopus organisms thrive

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients 445

in high glucose, acidic conditions due to an active ketone reductase system,
making a patient with diabetic ketoacidosis a prime host. In fact, normal
serum inhibits rhizopus growth, whereas serum from patients in diabetic
ketoacidosis stimulates growth (41). In addition, due to impaired transferrin
binding, diabetic patients also have increased free serum iron that may also
promote rhizopus growth (41). The same pathophysiologic mechanism is
responsible for the increased susceptibility to Mucor found in hemodialysis
patients and iron-overloaded patients treated with deferoxamine (42).

Clinical Presentation

The clinical presentation of bacterial sinusitis in the diabetic is not unlike
that of the general population, including symptoms of sinus pain, nasal
congestion, and purulent discharge. However, invasive fungal rhinosinusitis
in the diabetic patient may have as subtle a presentation as in the neutrope-
nic patient, and should be considered in any diabetic who does not respond
to antibiotics for bacterial sinusitis. The most common symptoms and signs
include fever, followed by nasal ulceration and necrosis, and periorbital or
facial swelling. Visual disturbances include decreased vision, cranial nerve
palsy, diplopia, and periorbital pain. While patients may only complain of
facial numbness or epistaxis, palatal or gingival necrosis may be present (43).

Diagnosis

If fungal rhinosinusitis is suspected, early and rapid diagnosis should be
pursued, as in neutropenic hosts, with radiographic and endoscopic exami-
nations. CT is the preferred radiographic modality as it provides more detail
than plain films, including landmarks for possible surgical resection. Early
radiographs may be normal, whereas bony erosion is seen late in the progres-
sion of disease (41). Evidence on CT of infiltration of the periantral fat planes
may be the earliest sign of invasive fungal disease (44). Endoscopy should be
performed with antral aspiration for aerobic, anaerobic, and fungal cultures.
A definitive diagnosis of invasive fungal rhinosinusitis in the diabetic
patient requires histopathological identification of fungal organisms. Mucor-
mycosis may be presumptively diagnosed by identification of ribbon-like
hyphae with few or absent hyphal septations and hyphal branching at right
angles (41). The etiologic agents of mucormycosis may be seen easily with hema-
toxylin and eosin tissue stains, and demonstrate invasion of blood vessels (41).

Treatment

For bacterial sinusitis, oral antibiotics directed against the most commonly
isolated organisms are appropriate for initial treatment in a diabetic patient
without fever, systemic symptoms, or pansinusitis (Table 1). In diabetic
patients with pansinusitis, empiric intravenous antibiotics should be used

446 Gleeson and Decker

with coverage for both streptococci and S. aureus, such as a first- or second-
generation Cephalosporin (38). Treatment should be modified according to
the gram stain and culture after antral aspiration. Dental apicitis may also
be an important nidus of infection of the paranasal sinuses and requires
concurrent treatment for effective cure of sinusitis in the diabetic patient (38).
In invasive fungal sinusitis in the diabetic patient, early recognition
and diagnosis are paramount. As the extent of disease is dependent on the
host response, reversal of diabetic ketoacidosis and glycemic control are
essential medical interventions (45). Immediate surgical consultation with
surgical debridement to clear margins and systemic administration of
amphotericin B optimize chances of recovery.

Prevention

The best preventive strategy for sinusitis in the diabetic population is to
achieve excellent glycemic control in the outpatient setting in order to pre-
vent microcirculation damage and immune system impairment. In the inpa-
tient setting, rapid reversal of diabetic ketoacidosis and normalization of
glucose help limit extent of disease and improves survival.

SINUSITIS IN HIV-INFECTED PATIENTS

Sinusitis is common throughout all stages of HIV infection (46). Historically,
retrospective studies report the incidence of sinusitis in HIV-infected patients
in the range of 10% to 20%. However, more recent prospective studies have
shown the incidence to be twice as high (60-70%) as in the general population
(38.5%) (46-51). Declining immune function marked by decreasing CD4-cell
counts is associated with an increased incidence of sinus disease (52).

Predisposing Factors

A number of factors may predispose the HIV-infected patient to sinonasal
disease. As in BMT patients, mucociliary clearance abnormalities have been
demonstrated in patients infected with HIV (53), particularly with CD4
counts less than 300 cells/mm . IgE-mediated allergic disease is more preva-
lent in HIV-infected patients than in noninfected individuals and can cause
mucosal edema and blockage of sinus ostia, resulting in a secondary bacter-
ial infection. Nasopharyngeal lymphoid hypertrophy occurs in 56 to 88% of
patients in early HIV infection and decreases in size with immune system
impairment (54,55). This local lymphoid hypertrophy may mechanically
alter sinus drainage, predisposing to sinusitis. Finally, qualitative and quan-
titative humoral immunity defects likely predispose HIV-infected patients to
sinusitis (56,57).

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients 447

Etiology

In general, the infecting organisms that cause sinusitis in the HIV-infected
patient vary with the degree of immunosuppression. Of the bacterial
causes of sinusitis, there is a higher prevalence of P. aeruginosa and staphy-
lococcal organisms, which may be due to impaired cellular immunity in HIV
infection (58). Specifically, in two large studies, Pseudomonas was isolated
in 17% of maxillary antral punctures (48,59). Other bacteria recovered
include streptococcal organisms, H. influenzae, Klebsiella pneumoniae,
E. coli, Listeria monocytogenes, Pepto streptococcus and other anaerobes,
and Propionibacterium acnes (46,48,59,60).

While bacterial sinusitis can occur at any stage of HIV infection, sinusitis
caused by opportunistic pathogens such as protozoa, fungi, and atypical viruses
usually occurs with a CD4 count less than 200 cells/mm . A retrospective series
of 12 AIDS patients with CD4 counts less than 100 cells/mm , who underwent
sinus surgery, reported 42% of the patients had unusual or opportunistic infec-
tions (60). The risk of fungal sinusitis generally occurs when the CD4 count
drops below 150 cells/mm 3 (61). Aspergillus is the most common cause of fun-
gal sinusitis in AIDS patients (62,63). Other fungal organisms reported include
Cryptococcus and Rhizopus species. However, given that neutrophil function
remains relatively intact in AIDS patients, mucormycosis is not frequently seen
(41). Other reported opportunistic pathogens include microsporidia, Cryptos-
poridia, cytomegalovirus (CMV), Acanthamoeba, Nocardia, and Mycobacter-
ium kansasii (46,59,60,64—69). In a prospective series, 20 of 54 HIV-infected
patients with evidence of sinusitis on MRI underwent maxillary sinus aspira-
tion. A probable etiologic agent was found in two-thirds of patients. One-third
of the infectious organisms were atypical, including CMV and mycobacteriae,
and one patient had Non-Hodgkin's lymphoma (46).

Clinical Presentation

While sinusitis in HIV-infected patients is frequently asymptomatic, it
can be recurrent and refractory to usual medical management (47,48,70).
Symptoms of sinusitis are often nonspecific and may be attributed to other
causes. Usually, patients experience fever, headache, nasal congestion, and
postnasal drainage. In one retrospective series of HIV-infected patients with
sinusitis, the triad of fever, headache, and nasal congestion was present
in 68% of patients (48). Other symptoms and signs include facial pain or
tenderness, cough, purulent discharge, and cutaneous edema.

Diagnosis

Asymptomatic patients may have incidental radiographic evidence of sinu-
sitis noted on radiographic imaging done for other purposes. Radiographic

448 Gleeson and Decker

findings of sinusitis do not correlate with symptoms and may be just
as severe and extensive in asymptomatic patients as in those with symptoms
(48). One report notes that up to one-third of patients with radiographic
evidence of sinusitis had no symptoms (47). Computed tomography (CT)
and MRI are the most sensitive imaging modalities for sinusitis in the
HIV-infected patient. Radiographically, the majority of cases involve the
maxillary and ethmoid sinuses, followed by sphenoid disease, which often
is not detected by plain radiographs. The extent of radiographic disease
seems to correlate with the degree of immunosuppression. Tarp et al. (46)
prospectively reported the findings of MRIs performed on 54 febrile hospi-
talized HIV-infected patients. Radiographic sinusitis was noted in 54%, with
more extensive changes seen in patients with AIDS (22/32 cases compared
with 16/38 in HIV-infected without AIDS). HIV-infected patients also tend
to have greater opacification of sinuses, as well as multiple sinuses involved.
Unilateral, localized disease is unusual (48).

Recognizing that HIV-infected patients have a high rate of infection
by unusual organisms, it is imperative to perform aerobic, anaerobic,
fungal, viral, and mycobacterial laboratory evaluations and cultures when
a sinus aspiration is performed (71). Early culture avoids delay in
microbe-specific therapy and should be performed if a patient is not improv-
ing with empiric antibiotic therapy for usual bacterial pathogens. Surgical
specimens should be evaluated histopathologically for giant cells and viral
inclusion bodies of invasive CMV infection, and also should prompt
immunohistochemical staining for CMV early antigen (65). In patients
with AIDS and refractory cases of sinusitis, electron microscopy should
be performed on sinonasal tissue to rule out protozoa such as micro-
sporidia (69). Acanthamoeba and Cryptosporidium can also be diagnosed
histologically (67).

Treatment

Initial antibiotic therapy should be directed against the most common
bacterial pathogens and should be modified according to gram stain and
culture or identification of opportunistic pathogens (49,59,60,72). Oral
amoxicillin/clavulanic acid may be used in the outpatient setting, with
escalation of therapy to broad-spectrum intravenous antibiotics if the
symptoms do not improve or worsen (72). The status of the immune system
of the HIV-infected patient should also be taken into consideration when
choosing initial therapy, particularly if the patient has a CD4 count less than
100 cells/mm (72). If the patient shows signs of systemic toxicity, intrave-
nous antibiotics should be the initial treatment, including coverage for
P. aeruginosa (49,59,72). The combination of two antimicrobial agents with
activity against P. aeruginosa has been shown to improve mortality in AIDS
patients with pseudomonas infection compared to monotherapy (12-1 A).

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients 449

A high index of suspicion should be maintained for opportunistic pathogens
as etiologies of sinusitis in AIDS patients, including fungi, protozoa, myco-
bacteria, and viruses, all of which require specific antimicrobial therapy
(Table 1).

Decongestants and mucolytic agents are also effective, as is topical
steroid, which may be used if there is no evidence of opportunistic infection
and if the CD4 count is greater than 50 cells/mm (4). Endoscopic sinus sur-
gery also plays an important role in management, and if necessary can be
safely done in all HIV-infected patients regardless of CD4-cell count. HIV-
infected patients tolerate the procedure well and recover rapidly (4). Initia-
tion of highly active antiretroviral therapy (HAART) and reconstitution of
the immune system and CD4-cell counts is an important adjunct to the sur-
gical and medical management of sinusitis in HIV-infected patients.

Prevention

Although sinusitis is not associated with decreased survival (75), prevention
appears to improve morbidity. Prophylaxis against Mycobacterium avium
and Pneumocystis carinii has the added benefit of prevention of bacterial
sinusitis. In a large prophylaxis trial, trimethoprim/sulfamethoxazole
(TMP/SMX) significantly reduced the risk of bacterial sinusitis (76). TMP-
SMX had the added benefit of reducing the risk of any bacterial infection
compared to dapsone or aerosolized pentamidine (AP). In a prospective
observational study, HIV-infected patients receiving TMP-SMX for
Pneumocystis carinii prophylaxis (PCP) and clarithromycin for prevention
of MAC had a 46% and 44% reduction in the overall risk of infection, respec-
tively. Patients who received both antibiotics decreased the overall risk of
infection even further, though this was not statistically significant (58).

CONCLUSION

While sinusitis is a commonly encountered problem, it can be a very severe
infection in the immunodeficient patient. One of the most immunocompro-
mising conditions is that of chemotherapy or bone marrow transplanta-
tion-induced neutropenia, which can predispose patients to life-threatening
invasive fungal rhinosinusitis. Diabetic patients are also an at-risk population
for this infection. Modification of risk factors, such as normalization of
glucose and reversal of neutropenia, are critical for recovery. Aggressive
surveillance, early diagnosis, surgical debridement, and antifungal agents
are the mainstay of treatment. HIV-infected patients are also predisposed
to sinusitis. The spectrum of their disease may range from asymptomatic to
recalcitrant to treatment. With a greater degree of immunosuppression,
sinusitis is more severe and opportunistic pathogens are frequently recovered.

450 Gleeson and Decker

REFERENCES

1. Chee L, Graham SM, Carothers DG, Ballas ZK. Immune dysfunction in refrac-
tory sinusitis in a tertiary care setting. Laryngoscope 2001; 111:233-235.

2. Kennedy CA, Adams GL, Neglia JP, Giebink GS. Impact of surgical treatment
on paranasal fungal infections in bone marrow transplant patients. Otolaryngol
Head Neck Surg 1997; 116:610-616.

3. Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am
2000; 33:227-235.

4. Gurney TA, Lee KC, Murr AH. Contemporary issues in rhinosinusitis and
HIV infection. Curr Opin Otolaryngol Head Neck Surg 2003; 11:45-48.

5. Choi SS, Milmoe GJ, Dinndorf PA, Quinones RR. Invasive aspergillus sinusitis
in pediatric bone marrow transplant patients. Evaluation and management.
Arch Otolaryngol Head Neck Surg 1995; 121:1188-1192.

6. Drakos PE, Nagler A, Or R, Naparstek E, Kapelushnik J, Engelhard D, Rahav G,
Ne'emean D, Slavin S. Invasive fungal sinusitis in patients undergoing bone
marrow transplantation. Bone Marrow Transplant 1993; 12:203-208.

7. Waitzman AA, Birt BD. Fungal sinusitis. J Otolaryngol 1994; 23:244-249.

8. Lueg EA, Ballagh RH, Forte V. Analysis of the recent cluster of invasive fungal
sinusitis at the Toronto Hospital for Sick Children. J Otolaryngol 1996; 25:
366-370.

9. Rotstein C, Cummings KM, Tidings J, Killion K, Powell E, Gustafson TL,
Higby D. An outbreak of invasive aspergillosis among allergenic bone marrow
transplants: a case-control study. Infect Control 1985; 6:347-355.

10. Gillespie MB, O'Malley BW Jr, Francis HW. An approach to fulminant inva-
sive fungal rhinosinusitis in the immunocompromised host. Arch Otolaryngol
Head Neck Surg 1998; 124:520-526.

11. Iwen PC, Rupp ME, Hinrichs SH. Invasive mold sinusitis: 17 cases in immuno-
compromised patients and review of the literature. Clin Infect Dis 1997; 24:
1178-1184.

12. Gillespie MB, O'Malley BW. An algorithmic approach to the diagnosis and
management of invasive fungal rhinosinusitis in the immunocompromised
patient. Otolaryngol Clin North Am 2000; 33:323-334.

13. Aisner J, Murillo J, Schimpff SC, Steere AC. Invasive aspergillosis in acute
leukemia: correlation with nose cultures and antibiotic use. Ann Intern Med
1979; 90:4-9.

14. Cordonnier C, Gilain L, Ricolfi F, Deforges L, Girard-Pipau F, Poron F,
Millepied MC, Escudier E. Acquired ciliary abnormalities of nasal mucosa in
marrow recipients. Bone Marrow Transplant 1996; 17:611-616.

15. Imamura R, Voegels R, Sperandio F, Sennes LU, Silva R, Butugan O, Miniti A.
Microbiology of sinusitis in patients undergoing bone marrow transplantation.
Otolaryngol Head Neck Surg 1999; 120:279-282.

16. de Carpentier JP, Ramamurthy L, Denning DW, Taylor PH. An algorithmic
approach to aspergillus sinusitis. J Laryngol Otol 1994; 108:314-318.

17. Berlinger NT. Sinusitis in immunodeficient and immunosuppressed patients.
Laryngoscope 1985; 95:29-33.

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients 451

1 8 . Goering P, Berlinger NT, Weisdorf D J . Aggressive combined modality treatment
of progressive sinonasal fungal infections in immunocompromised patients.
Am J Med 1988; 85:619-623.

19. Gillespie MB, Huchton DM, O'Malley BW. Role of middle turbinate biopsy in
the diagnosis of fulminant invasive fungal rhinosinusitis. Laryngoscope 2000;
110:1832-1836.

20. Talbot GH, Huang A, Provencher M. Invasive aspergillus rhinosinusitis in
patients with acute leukemia. Rev Infect Dis 1991; 13:219-232.

21. Washburn RG. Fungal sinusitis. Curr Clin Top Infect Dis 1998; 18:60-74.

22. Rizk SS, Kraus DH, Gerresheim G, Mudan S. Aggressive combination treat-
ment for invasive fungal sinusitis in immunocompromised patients. Ear Nose
Throat J 2000; 79:278-280.

23. Samadi DS, Goldberg AN, Orlandi RR. Granulocyte transfusion in the
management of fulminant invasive fungal rhinosinusitis. Am J Rhinol 2001; 15:
263-265.

24. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE,
Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, et al. Voricona-
zole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl
J Med 2002; 347: 408-415.

25. Link H, Bohme A, Comely OA, Hoffken K, Kellner O, Kern WV, Mahlberg R,
Maschmeyer G, Nowrousian MR, Ostermann H, et al. Antimicrobial therapy
of unexplained fever in neutropenic patients — guidelines of the Infectious
Diseases Working Party (AGIHO) of the German Society of Hematology
and Oncology (DGHO), Study Group Interventional Therapy of Unexplained
Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of
the Deutsche Krebsgesellschaft (DKG-German Cancer Society). Ann Hematol
2003; 82(suppl2):S105-117.

26. Peters C, Minkov M, Matthes-Martin S, Potschger U, Witt V, Mann G,
Hocker P, Worel N, Stary J, Klingebiel T, Gadner H. Leucocyte transfusions
from rhG-CSF or prednisolone stimulated donors for treatment of severe infec-
tions in immunocompromised neutropenic patients. Br J Haematol 1999; 106:
689-696.

27. Mirza N, Lanza DC. Diagnosis and management of rhinosinusitis before sched-
uled immunosuppression: a schematic approach to the prevention of acute
fungal rhinosinusitis. Otolaryngol Clin North Am 2000; 33:313-321.

28. Malani PN, Kauffman CA. Invasive and allergic fungal sinusitis. Curr Infect
Dis Rep 2002; 4:225-232.

29. Trigg ME, Morgan D, Burns TL, Kook H, Rumelhart SL, Holida MD,
Giller RH. Successful program to prevent aspergillus infections in children
undergoing marrow transplantation: use of nasal amphotericin. Bone Marrow
Transplant 1997; 19:43^17.

30. Malani PN, Kauffman CA. Prevention and prophylaxis of invasive fungal
sinusitis in the immunocompromised patient. Otolaryngol Clin North Am 2000;
33:301-312.

31. Rayfield EJ, Ault MJ, Keusch GT, Brothers MJ, Nechemias C, Smith H.
Infection and diabetes: the case for glucose control. Am J Med 1982; 72:
439-450.

452 Gleeson and Decker

32. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in
patients with diabetes mellitus. Infect Dis Clin North Am 1995; 9:1-9.

33. Bagdade JD, Nielson KL, Bulger RJ. Reversible abnormalities in phagocytic
function in poorly controlled diabetic patients. Am J Med Sci 1972; 263:
451-456.

34. Bagdade JD, Stewart M, Walters E. Impaired granulocyte adherence. A rever-
sible defect in host defense in patients with poorly controlled diabetes. Diabetes
1978; 27:677-681.

35. Mowat AG, Baum J. Chemotaxis of polymorphonuclear leukocytes from
patients with rheumatoid arthritis. J Clin Invest 1971; 50:2541-2549.

36. Nolan CM, Beaty HN, Bagdade JD. Further characterization of the impaired
bactericidal function of granulocytes in patients with poorly controlled diabetes.
Diabetes 1978; 27:889-894.

37. MacRury SM, Gemmell CG, Paterson KR, MacCuish AC. Changes in phago-
cytic function with glycaemic control in diabetic patients. J Clin Pathol 1989;
42:1143-1147.

38. Jackson RM, Rice DH. Acute bacterial sinusitis and diabetes mellitus. Otolar-
yngol Head Neck Surg 1987; 97:469-473.

39. Tuazon CU, Perez A, Kishaba T, Sheagren JN. Staphylococcus aureus among
insulin-injecting diabetic patients. An increased carrier rate. JAMA 1975;
231:1272.

40. Dooley DP, McAllister CK. Candidal sinusitis and diabetic ketoacidosis. A brief
report. Arch Intern Med 1989; 149:962-964.

41. Ferguson BJ. Mucormycosis of the nose and paranasal sinuses. Otolaryngol
Clin North Am 2000; 33:349-365.

42. Boelaert JR, de Locht M, Van Cutsem J, Kerrels V, Cantinieaux B, Verdonck A,
Van Landuyt HW, Schneider YJ. Mucormycosis during deferoxamine therapy is
a siderophore-mediated infection. In vitro and in vivo animal studies. J Clin
Invest 1993;91:1979-1986.

43. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-
orbital-cerebral mucormycosis. Surv Ophthalmol 1994; 39:3-22.

44. Strasser MD, Kennedy RJ, Adam RD. Rhinocerebral mucormycosis. Therapy
with amphotericin B lipid complex. Arch Intern Med 1996; 156:337-339.

45. Parfrey NA. Improved diagnosis and prognosis of mucormycosis. A clinico-
pathologic study of 33 cases. Medicine (Baltimore) 1986; 65:113-123.

46. Tarp B, Fiirgaard B, Moller J, Hilberg O, Christensen T, Black F. The
occurrence of sinusitis in HIV-infected patients with fever. Rhinology 2001; 39:
136-141.

47. Zurlo JJ, Feuerstein IM, Lebovics R, Lane HC. Sinusitis in HIV-1 infection.
Am J Med 1992; 93:157-162.

48. Godofsky EW, Zinreich J, Armstrong M, Leslie JM, Weikel CS. Sinusitis in
HIV-infected patients: a clinical and radiographic review. Am J Med 1992; 93:
163-170.

49. Rubin JS, Honigberg R. Sinusitis in patients with the acquired immunodefi-
ciency syndrome. Ear Nose Throat J 1990; 69:460-463.

50. Small CB, Kaufman A, Armenaka M, Rosenstreich DL. Sinusitis and atopy
in human immunodeficiency virus infection. J Infect Dis 1993; 167:283-290.

Sinusitis in Immunocompromised, Diabetic, and HIV-infected Patients 453

51. Lamprecht J, Wiedbrauck C. Sinusitis and other typical ENT diseases within
the scope of acquired immunologic deficiency syndrome (AIDS). HNO 1988;
36:489-492.

52. Decker CF. Sinusitis in the immunocompromised host. Curr Infect Dis Rep
1999; 1:27-32.

53. Milgrim LM, Rubin JS, Small CB. Mucociliary clearance abnormalities in the
HIV-infected patient: a precursor to acute sinusitis. Laryngoscope 1995; 105:
1202-1208.

54. Barzan L, Tavio M, Tirelli U, Comoretto R. Head and neck manifestations
during HIV infection. J Laryngol Otol 1993; 107:133-136.

55. Gurney TA, Murr AH. Otolaryngologic manifestations of human immuno-
deficiency virus infection. Otolaryngol Clin North Am 2003; 36:607-624.

56. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities
of B-cell activation and immunoregulation in patients with the acquired immu-
nodeficiency syndrome. N Engl J Med 1983; 309:453-458.

57. Lane HC, Fauci AS. Immunologic abnormalities in the acquired immuno-
deficiency syndrome. Annu Rev Immunol 1985; 3:477-500.

58. Currier JS, Williams P, Feinberg J, Becker S, Owens S, Fichtenbaum C, Benson C.
Impact of prophylaxis for Mycobacterium avium complex on bacterial infections
in patients with advanced human immunodeficiency virus disease. Clin Infect Dis
2001;32:1615-1622.

59. Milgrim LM, Rubin JS, Rosenstreich DL, Small CB. Sinusitis in human
immunodeficiency virus infection: typical and atypical organisms. J Otolaryngol
1994; 23:450-453.

60. Upadhyay S, Marks SC, Arden RL, Crane LR, Cohn AM. Bacteriology of
sinusitis in human immunodeficiency virus-positive patients: implications for
management. Laryngoscope 1995; 105:1058-1060.

61. Meyer RD, Gaultier CR, Yamashita JT, Babapour R, Pitchon HE, Wolfe PR.
Fungal sinusitis in patients with AIDS: report of 4 cases and review of the
literature. Medicine (Baltimore) 1994; 73:69-78.

62. Teh W, Matti BS, Marisiddaiah H, Minamoto GY. Aspergillus sinusitis in
patients with AIDS: report of three cases and review. Clin Infect Dis 1995; 21:
529-535.

63. Marquez-Diaz F, Soto-Ramirez LE, Sifuentes-Osornio J. Nocardiasis in
patients with HIV infection. AIDS Patient Care STDS 1998; 12:825-832.

64. Marks SC, Upadhyay S, Crane L. Cytomegalovirus sinusitis. A new manifesta-
tion of AIDS. Arch Otolaryngol Head Neck Surg 1996; 122:789-791.

65. Jutte A, Fatkenheuer G, Hell K, Salzberger B. CMV sinusitis as the initial
manifestation of AIDS. HIV Med 2000; 1:123-124.

66. Mylonakis E, Rich J, Skolnik PR, De Orchis DF, Flanigan T. Invasive
Aspergillus sinusitis in patients with human immunodeficiency virus infection.
Report of 2 cases and review. Medicine (Baltimore) 1997; 76:249-255.

67. Dunand VA, Hammer SM, Rossi R, Poulin M, Albrecht MA, Doweiko JP,
DeGirolami PC, Coakley E, Piessens E, Wanke CA. Parasitic sinusitis and otitis
in patients infected with human immunodeficiency virus: report of five cases
and review. Clin Infect Dis 1997; 25:267-272.

454 Gleeson and Decker

68. Rombaux P, Bertrand B, Eloy P. Sinusitis in the immunocompromised host.
Acta Otorhinolaryngol Belg 1997; 51:305-313.

69. Rossi RM, Wanke C, Federman M. Microsporidian sinusitis in patients with
the acquired immunodeficiency syndrome. Laryngoscope 1996; 106:966-971.

70. Del Borgo C, Del Forno A, Ottaviani F, Fantoni M. Sinusitis in HIV-infected
patients. J Chemother 1997; 9:83-88.

71. Belafsky P, Kissinger P, Davidowitz SB, Amedee RG. HIV sinusitis: rationale
for a treatment algorithm. J La State Med Soc 1999; 151:11-18.

72. Hern JD, Ghufoor K, Jayaraj SM, Frosh A, Mochloulis G. ENT manifesta-
tions of Pseudomonas aeruginosa infection in HIV and AIDS. Int J Clin Pract
1998; 52:141-144.

73. Nelson MR, Shanson DC, Barter GJ, Hawkins DA, Gazzard BG. Pseudomonas
septicaemia associated with HIV. AIDS 1991; 5:761-763.

74. Mendelson MH, Gurtman A, Szabo S, Neibart E, Meyers BR, Policar M,
Cheung TW, Lillienfeld D, Hammer G, Reddy S, et al. Pseudomonas aeruginosa
bacteremia in patients with AIDS. Clin Infect Dis 1994; 18:886-895.

75. Belafsky PC, Amedee R, Moore B, Kissinger PJ. The association between sinu-
sitis and survival among individuals infected with the human immunodeficiency
virus. Am J Rhinol 2001; 15:343-345.

76. DiRienzo AG, van Der Horst C, Finkelstein DM, Frame P, Bozzette SA,
Tashima KT. Efficacy of trimethoprim-sulfamethoxazole for the prevention
of bacterial infections in a randomized prophylaxis trial of patients with
advanced HIV infection. AIDS Res Hum Retrovir 2002; 18:89-94.

Index

AAO-HNS guidelines, 24

ABPA. See Allergic bronchopulmonary

aspergillosis.
ABRS. See Acute bacterial

rhinosinusitis.
Abscess, as complication of sinusitis,

285-286
Absolute neutrophil counts, 439
AC ABRS. See Acute community

acquired bacterial rhinosinusitis.
Acoustic rhinometry, 308, 309
ACTH production, 223
Active rhinomanometry, 308-310
Acute American Academy of Allergy

and Clinical Immunology, 204
Acute bacterial rhinosinusitis, 21, 33,

39-41, 208
treatment of, 208, 210
Acute bacterial sinusitis, 18, 23, 33,

204, 444
diagnosis of, 204, 211-212
management of, 205-207, 210-211, 213
surgery for, 216
Acute Committee on Quality

Improvement, 205-206
Acute community acquired bacterial

rhinosinusitis, 22
Acute frontal sinusitis, 139, 259
Acute invasive FRS, 82
Acute invasive fungal sinusitis, 421-429
Acute invasive sinusitis, 421, 422,

424, 429

Acute maxillary sinusitis, 19
Acute rhinosinusitis, 2, 20-24, 41^5,
71-72, 113, 136,220, 237

in children, 32, 33
Acute sinusitis, 10-12, 17-20, 135-139,
181-182, 186-187, 190-191,
194^198,407-411

algorithm for treatment, 215

antibacterial agents, 195

appearance of, 73

bacteria in, 157

current recommendations, 211-216

epidemiology of, 2, 10

medical management of, 203-216

treatment of, 194-196
Acute sphenoid sinusitis, 139
Acute suppurative sinusitis, 17
Acute viral rhinosinusitis, 33
Adenoidectomy, 295
Adrenal cortical atrophy, 223
Adrenergic decongestants, 204, 211
AFS. See Allergic fungal sinusitis.
Agammaglobulinemia, 8
Agency for Health Care Policy and

Research, 205
Agger nasi cell, 60-63, 85, 87, 96, 239,

240, 242, 254, 261
Airway bypass, 326
Airway disease

cellular mediators, 293

chemical mediators, 292

cytokine mediators, 292-293

455

456

Index

Airway epithelium, 381, 382
algACD gene cluster, 323
Allergic aspergillus sinusitis, 29
Allergic bronchopulmonary

aspergillosis, 29
Allergic fungal rhinosinusitis, 126
Allergic fungal sinusitis, 376, 377, 380,

390, 393, 398, 420-427, 432
diagnostic criteria, 24
Allergic mucin, 423-428, 432
Allergic rhinitis, 8, 223, 224,

293, 296, 305-310, 314,

362, 365, 366, 376, 382,

390-393
Allergy, rhinosinusitis and, 10
Allergy-induced rhinitis, 365
American Academy of Allergy and

Clinical Immunology, 204
American Academy of Pediatrics, 204
American College of Physicians-
American Society for Internal

Medicine, 209
American College of Radiology,

207-208
Amiloride, 363, 381, 388, 389
Amoxicillin, 206, 208, 210, 213, 214,

222, 448
Amoxicillin therapy, 194
Amphotericin B, 227, 429, 432, 440-442,

446
Ampicillin, 294
Anaerobic bacteria, 221, 374, 375,

407-410
isolation of, 375
role of, 375
Anatomic abnormalities, 120
Anatomy, of the sinus, 60-7 1
ANC. See Absolute neutrophil

counts.
Anesthesia, 235, 245, 249, 250, 253,

367-368
Angiofibroma, 395, 396
Annulus of Zinn, 246
Anosmia, 22, 26, 361
Anterior ethmoid sinus, 103, 107,

260, 261
Anterior rhinomanometry, 308-310

Anterior rhinoscopy, 48, 75,

235, 236
Anti-IgE therapy, 391, 392
Anti-infective therapy, 211
Anti-inflammatory agents, 222-223,

364, 366, 398
Anti-leukotrienes, 224
Antibiotic irrigations, 227
Antibiotic irrigations, for chronic

rhinosinusitis, 227
Antibiotic therapy, 391, 448
Antifungal therapy, 429, 432
Antigen presenting cell, 126, 306
Antihistamines, 365
Antimicrobial agents, in treatment of

sinusitis, 186-193
Antimicrobial therapy, 180, 183,

193-194, 196-198, 213, 220-221,
365-366
Antral lavage, 294, 346
Antral ostiae, 321
Antral puncture, 249-250
Antrochoanal polyp, 79, 237
Antrostomy, 365, 367, 440
APC. See Antigen presenting cell.
Apical root, 412
Apico-dental infection, 407
ARS. See Acute rhinosinusitis.
Artificial ventilation-acquired sinopathy,

320, 329
Aspergillosis, 441, 444
Aspergillus, 29, 141, 420, 421, 423,
428-432, 439, 441, 444, 447
Aspirators, 297
Aspirin, 237, 238, 245

intolerance, 375, 376, 394, 397
sensitivity, 229, 237
Aspirin desensitization, and chronic

rhinosinusitis, 229
Asthma, 3-5, 8, 10, 291-300
associations with sinusitis, 298
impact of medical sinus therapy,

294
impact of sinus surgery, 294-295
rhinosinusitis and, 10
sinusitis and, 291-300
Atopy, 305, 306, 420, 422, 425

Index

457

Azithromycin, 183, 185, 187, 189-190,

193, 213, 214, 366
Azole therapy, 430

Bacteria

acute sinusitis, 157
chronic sinusitis, 157-163
nasal polyposis, 163-165
Bacterial sinusitis, 8, 10, 203, 293, 299,

320, 336, 412
clinical presentation, 445
Bacterial superantigens, and sinus

disease, 154-155
Bacteriocins, 152
Benzalkomium chloride, 312
Beta-lactamase, 146, 148, 152, 157,

161,221
Beta-lactamase inhibitor (clavulanate),

181, 183, 187, 197, 221, 222
Beta-lactamase producing bacteria, 179,

198
Betadine, 227
Betamethasone, 226
Bilateral maxillary sinusitis, 137
Biopsy, 440
Bipolaris hawiiensis, 29
Blood-brain barrier, 227, 312
BLPB. See Beta-lactamase-producing

bacteria.
BMT. See Bone marrow transplant.
Bone marrow recovery, 438
Bone marrow transplant, 439
Bone wax, 264
Brain abscess, as complication of

sinusitis, 283-285
Broad-spectrum antibiotic, 141, 225,

421, 439-440
Bronchial asthma, 376, 379, 380, 390,

392, 393, 394
Bronchial hyperresponsiveness,

293-294, 299-300
Bronchitis, 3-5

Bronchoalveolar lavage, 292, 327
Bronchoconstriction, 292-293, 296
Bronchodilator therapy, 237, 294
Bulla ethmoidalis, 108

Caldwell-Luc procedure, 251-254,
264, 414

Calgary biofilm device, 345

Calvarial diploic veins, 280

Canine fossa, 50, 135-136, 249, 341

Canine-premolar recess, 414

Carbapenem, 228

CAS. See Computer aided surgery.

Catecholamine, 328

Cefaclor, 183, 190

Cefixime, 210, 213, 222

Cefpodoxime, 208, 210, 213

Cephalexin, 244

Cephalocele, 70, 72

Cephalosporin, 184-186, 190, 193,
195-198, 221, 222

Cerebrospinal fluid (CSF) leaks, 238,
246, 263

Cerebrospinal rhinorrhea, 237, 265

CF mutation analysis, 363

CF sinusitis, 361-363

CF-related bronchiectasis, 361

CF. See Cystic fibrosis.

CFTR. See Cystic fibrosis-
transmembrane regulator.

Choana, 77

Chronic asthma, 299

Chronic eosinophilic sinusitis, 292

Chronic frontal rhinosinusitis, 260

Chronic frontal sinusitis, 259, 262, 263

Chronic invasive FRS, 82-83

Chronic invasive fungal sinusitis, 422,
424, 427, 430, 432

Chronic obstructive pulmonary
disease, 126

Chronic rhinosinusitis, 2, 9, 21, 24, 25,
27, 33,40,41,45,59,73-82, 109,
116, 219, 236-239, 242, 244, 249,
256, 265, 305, 371, 372, 375

Chronic rhinosinusitis, cycle of, 112,
371-398
anti-inflammatory agents, 222-223
antimicrobial therapy for, 220-222
definition of, 220
environmental factors, 123
etiology of, 117-128, 373-374
fungal infections, 126-127

458

Index

[Chronic rhinosinusitis]

inciting factors, 220

intravenous antibiotics, 227-229

local host factors in, 120-123

medical management of, 219-229

microbiology, 374-375

nasal polyposis and, 375-377

nebullized medications, 226

pathogenesis, 381-397

systemic host factors in, 117-120

topical antibiotic irrigations, 227
Chronic sinusitis, 16, 17, 19-22, 25-29,
292-295, 297, 299-300, 312, 320,
325-327, 336, 347, 358-361, 363,
364, 366, 367, 408, 409, 411, 412,
415, 420, 438

bacteria in, 157-163

diagnosis of, 45

treatment of, 196-198
Chronic Sinusitis Survey, 51
Churg-Strauss syndrome, 376, 390
Cilial dysfunction, 8
Ciliary dyskinesia, 250, 251, 376
Ciprofloxacin, 189, 191, 193
Clarithromycin, 449
Clavulanate, 210, 213
Clavulanic acid, 448
Cleft palate, 8
Clindamycin, 221, 222
Clinical Advisory Committee on

Pediatric and Adult Sinusitis, 209
Clinical practice guideline, 32
Clinical rhinosinusitis, 242
Clivus, 64, 70

CMV. See Cytomegalovirus.
CMV infection, 421
Colds, rhinosinusitis and, 8-9
Committee on Quality Improvement,

205
Committee on Standardization of

Rhinomanometry, 309
Common cold and sinusitis, 19, 139-140
Community-acquired disease, 138
Computed tomography scan, 9, 12, 87,

310, 412, 425-428, 440
Computed tomography, radiation
exposure, 57-59

Computer aided surgery, 89
Concha bullosa, 42, 47, 66-67, 77,

242, 243
Confocal laser scanning microscope,

322
Congenital abnormalities, 66-71
COPD. See Chronic obstructive

pulmonary disease.
Corticosteroids, 223, 237, 238, 377, 380,

381, 391, 392, 393, 420-422, 432
Cranial fossa, 105-106
Craniopharyngioma, 397
Cribriform plate, 101-102
Crista galli, 70, 71
Crohn's disease, 395, 396
CRS Task Force, 372
CRS. See Chronic rhinosinusitis.
Cryptosporidium oocysts, 141
CSF leak, 73, 88
CSF rhinorrhea, 237, 265
CSS. See Chronic Sinusitis Survey.
CT. See Computed tomography.
Cultures in nasal endoscopy, 48-51
Cystic fibrosis, 8, 9, 117,227,

357, 358, 363, 375, 376,

393, 394, 397
diagnosis of, 363
Cystic fibrosis, sinusitis and, 357-368
microbiology, 359-361
pathophysiology, 357-359
scoring system, 362
special considerations with treating,

367-368
treatment, 363-366
Cystic fibrosis-transmembrane

regulator, 358
Cysts, 77
Cytokines, 222
Cytomegalovirus, 447

Dacrocystitis, 246
Dacrocystorhinostomy, 238, 256
Debridement, 441, 446
Decongestants, 223, 224
Deferoxamine, 420-422, 445
Deferoxamine therapy, 420, 422

Index

459

Denker's procedure, 346

Dental apicitis, 446

Dental implant, 404, 406

Dermoid cyst, 396, 397

Deviated septum. See Nasal septum

deviation.
Dexamethasone, 282, 283
Diabetes mellitus, 420, 422
Diabetic microangiopathy, 444
Diabetic patients, sinusitis and, 444-446
Diplopia, 246, 259
Dural sinus thrombosis, 286-288
Dural sinuses, 270
Dyspnea, 299

Edema, 8, 12, 43, 44, 46
Edematous mucosa, 3 1 1
EDN. See Eosinophil derived

neurotoxin.
EES. See Endoscopic endonasal

surgery.
EFR. See Eosinophilic fungal

rhinosinusitis.
ELISA immunoassays, 327
Encephalocoele, 86, 396, 397
Endogenous antimicrobial function, 359
Endoscopic cultures, 136, 150-151

for sinusitis, 136-137
Endoscopic endonasal ethmoidectomy,

254-255
Endoscopic endonasal sphenoidotomy,

256-259
Endoscopic endonasal surgery, 238
Endoscopic evaluation, 426, 432
Endoscopic frontal sinusotomy, 261-263
Endoscopic middle meatal antrostomy,

251
Endoscopic sinus surgery, 216, 225, 226,

238-249, 251, 254, 305, 313, 320,

375, 380, 398, 449
complications of, 245-247
infections following, 225-226
Endoscopy, 24, 25, 27, 39, 44, 48, 51, 52,

75, 81, 82, 439, 441
Endoscopy, in diagnosis of sinusitis,

48-49

Endotracheal suctioning, 368

Enterobacteriaceae, 191

Enterotoxins, 32

Eosinophil cationic protein, 388

Eosinophil derived neurotoxin, 31

Eosinophilia, 220, 293, 423

Eosinophilic fungal rhinosinusitis, 31

Eosinophilic mucin rhinosinusitis, 30

Eosinophilic rhinitis, 299

Eotaxin, 292, 383, 386

Epistaxis, 312

Erythromycin, 183, 185, 188-191, 193

Escherichia coli, 325

ESS. See Endoscopic sinus surgery.

Ethmoid bulla, 60-64, 68-70, 75, 84, 87,

240, 254
Ethmoid bullectomy, 240
Ethmoid complex, 96, 103
Ethmoid infundibulum, 96, 99, 104,

107-108
Ethmoid sinus, 99, 101-104, 108,

272, 274
Ethmoid sinus, anatomy of, 64, 78
Ethmoid sinus surgery, 254-256
Ethmoidal infundibulum, 239, 251
Exotoxins, 373

Extended-spectrum antibiotic, 214
External ethmoidectomy, 255-256, 259
External frontoethmoidectomy,

259-260

Facial pain, 336

FESS. See Functional endoscopic sinus

surgery.
Fetal face, development of, 97-100
Fiberoptic sinus endoscopy, 216
Fibrosis, 227
Flexible endoscope, 309
Fluoroquinolone, 186, 208
Fluoroquinolone resistance, 186
Fontanelles, 104
Fovea ethmoidalis, 249
Frontal recess, 239-242, 245, 248,

260-263
Frontal sinus, anatomy of, 64, 104-105
Frontal sinus agenesis, 362

460

Index

Frontal sinus outflow tract, 58, 60, 61,

63, 64
Frontal sinus surgery, 259-264
Frontal sinus trephination, 259
Frontal sinusitis, 228, 254, 259-263
FRS. See Fungal rhinosinusitis.

acute invasive, 82

allergic, 83-84

chronic invasive, 82-83
Fulminent fungal sinusitis. See also

Invasive fungal sinusitis.
Functional endoscopic sinus surgery,

225-226, 238-240, 254
Fungal hyphae, 425, 432
Fungal infections, 126
Fungal organisms, 220
Fungal rhinosinusitis, 82-83, 438, 440
Fungal sinusitis, 141, 197, 419-436

classification of, 28-32

diagnosis, 424-428

epidemiology, 420

pathogenesis, 422-424

treatment, 428-432
Fungi, role in sinusitis, 167-168
Fungus ball, 29, 82-84, 251, 253, 254,

257
Furosemide, 227
Fusobacteria, 148

GABHS. See Group A beta-hemolytic

Streptococci.
Gadolinium-diethylenetriaminepentaacetic

acid, 60
Gd-DTPA. See Gadolinium-

diethylenetriaminepentaacetic

acid.
Gell and Coombs reponse, 30
Gene detection sensitivity, 363
Gene therapy, 367
Genetic/congenital disorders, 117
Gentamicin, 347
GERD. See Gastroesphageal reflux

disease.
Giant ethmoid bulla, 70
Gingivobuccal sulcus, 249, 251, 253
Glandular hyperplasia, 293

Glioma, 396, 397

Glyceryl guaiacolate. See Guaifenesin.

Glycocalyx, 321, 322

GM-CSF, 373, 374, 382-384, 386

Goblet cells, 106, 224

Gram-negative bacilli, 180-181, 191,

336, 337, 409, 415
Gram-negative bacteria, 221, 327, 328,

345-347, 439, 444, 439
Gram-positive cocci, 221, 337, 345, 407
Granulocyte colony-stimulating factor,

441
Granulomatous inflammation, 422, 423
Graves' ophthalmopathy, 237, 238
Group A beta-hemolytic Streptococci,

181
Guaifenesin, 224, 225, 365

HAART. See Highly active

anti-retroviral therapy.
Haemophilus influenzae, 10-12, 221, 274
Haemophilus influenzae resistance, 183
Haller cells, 69, 77, 242, 243, 251, 381
Haversian canal system, 78, 228
Hemangioma, 395, 396, 397
Hematopoietic growth factors, 429
Hematopoietic stem cell transplant, 421
Hemodialysis, 445
Hemolytic Streptococci, 408, 409
Hereditary hemorrhagic telangiectasias,

265
Herniations, 70
Hiatus semilunaris, 62
High-affinity IgE receptors, 306
Highly active anti-retroviral therapy, 11,

449
Histamine, 307, 313
HIV patients, sinusitis and, 11-12,

446-449
Host defense, 320, 326-328
Host-microbe interference, 326
Human airway epithelial cells, 382
Hyperglycemia, 444
Hyperteleorism, 379, 380
Hypertrophic mucosa, 220
Hyphae, 423, 425^130, 432

Index

461

Hypo-oxygenation, 220
Hypoplasia, 362
Hypoplastic maxillary sinus, 86
Hypoplastic maxillary sinus, anatomy
of, 68

Iatrogenic dental causes, 405

IcaADBC gene cluster, 322

ICAM-1, 373, 374, 382, 383, 384

IgEs dosages, 310

Image guidance systems, 247-248

Image-guided sinus surgery, 247-248

Imaging

diagnosis of sinusitis, 51
technical parameters, 59
Imaging, in rhinosinusitis, 51
Immunocompromised patients, 437
Immunocompromised patients, sinusitis

and, 437-449
Immunodeficiency diseases, 119
Immunofluorescence, 375

test for, 375
Immunoglobulin, 438
Indolent fungal sinusitis, 30
Infectious rhinosinusitis, 306
Infectious sinusitis, 320, 321, 337,

339-342, 347
Inferior meatus, 135, 247, 249, 250
Inferior nasoantral window, 250-251
Inferior turbinate, 46, 136, 140
Inflammatory eicosanoids, 381
Infrabullar recess cells, 69
Interleukin, 373
Interleukin-8, 366
International Journal of Pediatric

Otorhinolaryngology, 206-207
International Rhinosinusitis Advisory

Board, 20
Intrabony defects, 406
Intranasal endoscopic

dacryocystorhinostomy, 265
Intranasal examination, 46, 47, 49
Intranasal examination, tools for, 47
Intravenous antibiotics, 227-229
Intravenous antibiotics, for chronic

rhinosinusitis, 227-229

Invasive aspergillosis, 429

Invasive fungal rhinosinusitis, 438, 440

Invasive fungal sinusitis, 421-427, 429,

430, 432
Invasive sinusitis, 420^24, 427, 429, 432
IRAB. See International Rhinosinusitis

Advisory Board.
Iron chelation therapy, 428
Isoproterenol, 363
Itraconazole, 430-432

Kartagener's syndrome, 324
Ketoacidosis, 420-422, 426, 428,

444-445
Ketolides, 222

Ketone reductase system, 445
Klebsiella pneumoniae, 323, 330-334, 345

Labial levator, 404
Lactamase inhibitor, 415
Lactamase-producing bacteria, 408, 415.

See also BLPB.
Lactoferrins, 326
Lamina papyracea, 62, 63, 68-70, 85, 87,

88, 96, 102, 246, 248, 249
Lamina propria, 220
Leukens trap, 226
Leukocyte, 325, 326
Leukocyte function antigen- 1,

382, 385
Leukotrienes, 224, 300, 307, 366
Lothrop procedure, 260-263
Low fovea ethmoidalis, 72
Lumbar puncture, 282
Lund-Mackay CT-scan staging system,

306, 336
Lung transplantation, 365, 367
Lusk guidelines, 32
Lympho-plasmacytic cells, 393
Lymphocyte-cytokine response, 313
Lynch procedure, 259-260

Macrolide, 222

Macrolide resistance, 185-186

462

Index

Magnetic resonance imaging, 59-60, 70,

74, 75, 79, 81-83, 85, 87, 281, 282,

284, 286, 287, 362, 372, 425,

426, 440
Major histocompatibility complex, 126,

382
Malignant melanoma, 396, 397
Mammaglobin, 377
Mastocytes degranulation test, 308
Matrix metalloproteinase, 327
Maxillary antral tap, 221
Maxillary empyema, 345
Maxillary outflow tract, 242, 243
Maxillary rhinosinusitis, 306
Maxillary sinus, 17, 21, 29, 55, 56, 60,

96, 98-99, 103-104, 107, 135-139,

141, 403-410, 412-415
flora, 409, 410, 415
Maxillary sinus, anatomy of, 104
Maxillary sinus endoscopy, 139
Maxillary sinus puncture, procedure for,

50, 55-89
Maxillary sinus secretion, 12
Maxillary sinus surgery, 249-254
Maxillary sinusitis, 2, 12, 154, 160,

162-165, 405^110, 412^15
Maxilloethmoid sinus, 362
Maxillofacial trauma, 46
MBC. See Minimum bactericidal

concentration.
MBEC. See Minimum biofilm

eradication concentration.
MBP. See Major basic protein.
MC-CT. See Multichannel CT scanner.
MCT. See Mucociliary transport.
Meatal antrostomy, 295
Meatus, 60, 62-65, 67, 68, 84,

87, 88
MEF. See Middle ear fluid.
Meningitis, 281-283
Meningocele, 70
Methacholine, 296, 299-300
Metronidazole, 415
MHC. See Major histocompatibility

complex.
MIC. See Minimal inhibitory

concentration.

Microdebriders and sinus surgery,

248-249
Microflora, 145-147
Middle ear fluid, 190, 193
Middle meatal antrostomy, 251, 253, 254
Middle meatus, 136, 139, 235, 236, 239,

245, 251, 253, 362
Middle nasal turbinate, 363, 440
Minimally invasive sinus technique, 240
Minimum bactericidal concentration,

191
Minimum biofilm eradication

concentration, 345-347
Minimum inhibitory concentration, 183,

184, 345
MIST. See Minimally invasive sinus

technique.
MMP. See Matrix metalloproteinase.
Monoclonal anti-IgE therapy, 392
Moraxella catarrhalis resistance, 183
MRI. See Magnetic resonance imaging.
Mucin, 423-428, 432
Mucocele, 60, 67, 70, 77, 80, 87,

253-255, 257, 259, 260, 262, 263,

271-272
Mucocele, frontal, appearance of, 80
Mucociliary clearance, 106-107, 238,

239, 241, 251
Mucociliary transport, 110
Mucoperiosteum. See also Schneidarian

membrane.
Mucormycosis, 445
Mucosa ciliary dysfunction, 439
Mucosal edema, 220, 223, 224, 311
Mucosal sinus surgery trauma, 326
Mucus stasis, 311
Mupirocin, 227
Mutation testing, 363
Mycetoma, 30, 420-427, 430, 432

NARES, 393

Nasal allergy, 306

Nasal anatomy, 66

Nasal corticosteroids, 294, 300

Nasal endoscopy, 39, 44, 48, 52, 226,

242, 439

Index

463

Nasal endothelium, 307

Nasal flora, 152-153

Nasal fossa, 309, 310

Nasal hyper-reactivity, 308

Nasal hypersecretion, 307

Nasal irrigation, 311, 313

Nasal lavage, 366

Nasal mass, 394, 396

Nasal meati, 96

Nasal mucociliary function, 309

Nasal mucosa, 306, 307, 312, 424

Nasal obstruction, 295, 296, 300

Nasal placodes, 96

Nasal polyposis, 26-28, 31, 32, 224, 237,

249, 359, 363, 371, 373, 375-377,

422, 424-426
bacteria in, 163-165
clinical diagnosis, 377-380
medical and surgical therapy for,
380-381
Nasal polyps, 420, 422
Nasal saline irrigations, 224
Nasal septal deviation, 67, 77
Nasal septum, 96, 100, 106
Nasal steroids, 311, 312, 314, 366
Nasal submucosal tissue, 307
Nasal suppuration, 337
Nasal turbinates, 101
Nasal-bronchial reflex, 296
Nasolacrimal duct cyst, 396, 397
Nasopharyngeal lymphoid hypertrophy,

446
Nasopharynx, 42, 43, 47, 48
National Health Interview Survey, 2
Nebulization, 347, 365
Nebulized medications, 226
Nebullized medications, for chronic

rhinosinusitis, 226
Necrosis, 422, 423, 426
Neosynephrine, 224
Netropenic patients, sinusitis and,

438^44
Neural reflex pathways, 295, 300
Neurofibroma, 395, 396, 397
Neurogenic inflammatory reaction, 308
Neurotransmitters, 308
Neurovascular foramina, 270

Neutropenia, 228, 421, 422
Neutrophil, 299, 422, 423, 438,

444, 447
Nitric oxide, 324-326, 342, 346, 347

synthase, 325
Non-Hodgkin's lymphoma, 447
Non-tuberculous mycobacterium, 361
Noninvasive fungal sinusitis, 425
Normal oral flora, 145-151
Nose

embryology of, 96-100

functions of, 107

sagittal view, 102
Nose, physiology of, 96, 106, 108
Nosocomial bacterial flora, 321, 342
Nosocomial colonization, 328, 346
Nosocomial infection, 328
Nosocomial pneumonia, 322
Nosocomial rhinosinusitis, 166-167
Nosocomial sinusitis, 319-328

antimicrobials for, 342-346

complications of, 346-347

epidemiology, 328-338

in the ICU, 339-342

pathogenesis, 320-328

prevention of, 347
NPD. See Nasal potential differences.
NPT. See Nasal specific provocation test.

Odontogenic sinusitis. See also

Sinusitis.
Odotogenic sinusitis, 403-416

diagnosis, 412

management of, 412-415

microbiology, 407-411

pathophysiology, 403-407

symptoms, 411
Olfactory cortex, 102
Olfactory neuroblastoma, 396, 397
OMC. See Ostiomeatal complex.
OMU. See Ostiomeatal unit.
Onodi cell, 69-70, 246, 247
Oral candidiasis, 312
Oral cavity, normal flora of, 145-148
Oral corticosteroids, 294, 295, 299
Orbicularis oculi, 404

464

Index

Oro-antral fistula, 253, 254, 407
Oropharyngeal flora, 409
Osteitic changes, 122
Osteitis, appearance of, 81
Osteoclasis, 228
Osteomyelitis, 228, 270-271
Osteoplastic frontal sinus, 263-264
Osteoplastic frontal sinus obliteration,

263-264
Ostial patency, 3 1 1
Ostiomeatal complex, 8, 103, 110, 220,

239, 240, 308, 313
Ostiomeatal unit, 239, 241, 242
Ostium, 8, 60, 62, 64, 66, 70, 76, 77, 79,

88, 104
Otitis media, 44, 47
Otolaryngologic surgery, 367
Oxidation-reduction potential, 411
Oximetazoline, 224, 277, 311

P-450 cytochrome, 312
Pain, sinus involvement and, 45
Pansinusitis, 141, 256, 444
Paradoxic middle turbinate, 68
Paranasal granuloma, 422, 423
Paranasal sinus, 16, 17, 26, 27, 29, 30,
33, 95-96, 100-101, 103-104,
106-109, 135, 137, 140-141
anatomy and physiology of, 95-108
coronal view, 101, 103
defense mechanisms. 109-111
embryology of, 96-100
sagittal view, 102
systemic defense mechanisms,
111-112
Paranasal sinus surgery, 236-238,

249-264
Paranasal sinus surgery, types of,
249-264
antral puncture and lavage, 249-250
Caldwell-Luc procedure, 251-254
contraindication, 238, 254, 256
inferior nasoantral window, 250-251
middle meatal antrostomy, 251
types of, 249-264
PCD. See Primary ciliary dyskinesia.

PCP. See Pneumocystis carinii

prophylaxis.
Pediatric rhinosinusitis, classification of,

32-34
Penicillin-resistant S. pneumoniae, 185,

190, 193, 197
Perioperative antibiotics. See

Antiobiotic.
Periorbital ecchymosis, 246
Phaeohyphomycosis, 421
Pharyngitis, 5
Pharynx, 297

Plain sinus radiograph, 55-56
Pneumatization, 70, 77, 82, 86
Pneumocystis carinii prophylaxis, 449
Pneumonia, 5, 322, 324, 325, 327-334,

346, 347
Polymerase chain reaction, 375
Polymicrobial flora, 221, 222, 410
Polyposis, 325, 327, 336
Post Denker sinus cavity, 346
Post sinus surgery sinusitis, 320, 336-337
Posterior choanae, 101, 106
Posterior septum, 257
Postnasal discharge, 372, 377, 379
Postsurgical imaging, 87
Pott's puffy tumor, 228, 269, 271
Prednisolone, 222
Prednisone, 366
Presurgical imaging, 84-87
Primary ciliary dyskinesia, 116, 376, 394
Princeton meeting classification, 19, 24
Pruritus, 307

Pseudomonas aeruginosa, 11, 12, 322
Pterygopalatine fossa, 254
Purulent rhinitis, 140, 210
Purulent rhinorrhea, 39, 44, 47, 140
Purulent rhinosinusitis, 306

Quadrilateral cartilage, 100
Quantitative pilocarpine iontophoresis,
363

Radiological imaging, 412
Radiological sinopathy, 325, 329, 336

Index

465

Reactive inflammatory sinusitis, 320
Recurrent acute bacterial sinusitis, 139
Recurrent acute rhinosinusitis, 20, 24, 33
Refractory chronic sinusitis, 326
Refractory sinusitis, 438
Retention cyst, appearance of, 80
Retrograde pulpitis, 405
Reverse transcription-PCR, 140
Rhabdomyosarcoma, 397
Rhinitis, 293, 294, 296, 299, 300
Rhinitis medicamentosa, 224, 311, 365
Rhinitis-rhinosinusitis-asthma

relationship, 313
Rhinomanometry, 51, 308, 309, 310
Rhinorrhea, 18, 19, 26, 33
Rhinoscopy, 412
Rhinosinusal cycle, 313
Rhinosinusal mucosa, 307, 308, 309,

313, 320
Rhinosinusitis Disability Index, 51
Rhinosinusitis Task Force, 43, 113
Rhinosinusitis, 2, 5, 8, 10, 15-17, 21-23,
25-27, 32, 39-53, 71-84, 236, 237,
242, 244, 251, 260, 293, 296, 300,
305-314,405

allergy prevention, 313-314

asthma and, 10

clinical diagnosis of, 43

common cold and, 8-9

definition of, 40-41, 113

pediatric, classification of, 32-34

predisposition to, 5-10

prevalence of, 2

sinusitis vs., 15-16

URTI vs., 42-43
Rhinosinusitis, adult, classifications of,

114-115
Rhinosinusitis, allergy and, 10, 305-314

allergy in, 8, 10

classification of, 15-38

definitions of, 113

diagnosis of, 43-52, 308-310

management of, 205, 206

pathophysiology of, 41-42, 306-308

treatment, 310-313
Rhinovirus, 9, 42, 43, 138, 140
Rhizopus species, 422, 444

RSDI. See Rhinosinusitis Disability

Index.
RSTF. See Rhinosinusitis Task Force.

Saccharine, 309, 310

Samter's triad 41, 42, 44, 229

Saprophytic fungal infestation, 32, 84

Sarcoidosis, 395, 396

Scalp hypesthesia, 263, 264

Schneidarian membrane, 405, 415

Scintigraphy, 336

Sella turcica, 106

Septic emboli, 270

Septoplasty, 339

Seromucous glands, 156

Single channel CT scanner, 56-57

Sinocutaneous fistula, 256, 259, 263

Sinonasal diseases, 106, 108

Sinonasal polyposis, 76, 77, 79

Sinus and Allergy Health Partnership,

208, 210, 220
Sinus aspirate, 136-138, 141
Sinus aspiration 49-51
Sinus aspirations and culture,
in diagnosis of
sinusitis, 49-51
Sinus content cultures

appropriate for diagnosis, 148-151

interfering flora, 151-152

nasal flora, 152-153
Sinus edema, 329
Sinus flora, 153-154
Sinus inflammatory mediators, 295-297
Sinus involvement, pain and, 44
Sinus lateralis, 96
Sinus mucosa, 226, 228
Sinus ostia, 223, 224, 446
Sinus ostium obstruction, 17, 300
Sinus puncture, in specimen collection,

149-150
Sinus radiograph, 55-56, 209, 220
Sinus surgery, 235-265
Sinus X-ray pathology, 329
Sinusal ostia, 306
Sinuses

anatomy of, 60-71

466

Index

[Sinuses]
congenital abnormalities, 66-71
developmental anatomy, 95
frontal, anatomy of, 104-105
functions of, 107
Sinusitis, 1, 2, 10, 40, 41, 45, 51, 135,
137, 140-141, 145-178, 220,
236-238, 250, 254, 257-260, 262,
263, 265, 269, 291-300,
403-417
antimicrobial agents, 186-193
asthma and, 291-300
bacterial resistance, 10-11, 179-180,

181
children, 294
chronic, 19, 20
classification of, 15-34
clinical diagnosis, 18
complications of, 269-288
abscesses, 285-286
brain abscess, 283-285
dural sinus thrombosis, 286-288
intracranial complications,

278-288
local, 270-272
orbital infections, 272-278
pathophysiology, 270
thrombophlebitis, 286-288
cystic fibrosis. See Cystic fibrosis,
definitions, 17-19, 21, 23, 25-27, 32,

40-41
diabetic patients and, 444-446
diagnosis, 439
dynamics of, 160
fungal. See Fungal sinusitis.
HIV and, 11-12,446^49
imaging of, 50, 55-89

postsurgery, 87
immunocompromised patients and,

437-449
in immunocompromised patients, 437
infectious causes of, 135-141, 145-169
maxillary, 2, 12
microbiology of, 137-141, 154-167,

407^11
neutropenic patients and, 438-444
neutropenic patients in, 438

[Sinusitis]

nosocomial. See Nosocomial sinusitis.

obtaining specimens, 135-137

odotogenic origin, 403-416

pathophysiology of, 109-129

postsurgical complications, 87-89

prevalence of, 2-5

radiologic changes, 16

rhinosinusitis vs., 15-16

surgical treatment, 251

symptoms, 411
Skin-prick test, 305, 310
SMS/CQI-AAP guideline, 33
Sphenoethmoidal recess, 101, 103, 106,

108, 221
Sphenoid sinus, 55, 56, 58, 60, 64-66, 70,
72, 74, 77, 84-86, 100, 101, 104,
106, 108
Sphenoid sinus, anatomy of, 65, 66
Sphenoid sinus surgery, 256-259
Sphenoid sinusitis, 139
Spirometry, 296, 299, 300
Squamous cell carcinoma, 395, 396, 397
Staphylococcus aureus, 32, 244, 325,

373, 375
Staphylococcus epidermidis, 322
Streptococcus pneumonia, 10-12, 180,

184^186, 220
Stromal edema, 293
Sub-periosteal abscess, 74
Subacute rhinosinusitis, 23-24, 74
Subacute sinusitis, 17, 19, 26, 33
Subcommittee on Management of

Sinusitis, 205
Subcutaneous orbital emphysema, 246
Subdural empyema, 75
Subperiosteal abscess, 269, 274, 275
Superantigens, 125, 154-155, 373, 383
Supraciliary incision, 263, 264
Surgery, for sinus disease, 233-266

contraindications for, 238

diagnostic work-up, 234-236

endoscopic, 238-245

complications of, 245-247

image-guided, 247-248

indications for, 236-238

medical history, 234-235

Index

467

Surgical complications, 86-89
Surgical drainage, 193, 197

URTI, dynamics of, 156
URTI, rhinosinusitis vs., 42^13

T lymphocytes, 155

Task Force on Rhinosinusitis, 16

TFR. See Task Force on Rhinosinusitis.

TFR guideline, 24-27, 32

Thrombocytopenia, 427

Thrombophlebitis, 228, 286-288

Tic doloreux, 296

Tissue necrosis, 439

TMP/SMX. See Trimethoprim/

sulfamethoxazole.
TOBI(r), 366

Tobramycin, 227, 365, 366
Topical corticosteroids, 377, 380, 381,

393
Topical diuretic therapy, 391, 392
Torsades de pointes, 312
Tramazoline nasal sprays, 3 1 1
Transforming growth factor-O, 390
Transillumination, in diagnosis of

sinusitis, 48
Trephination, 259
Trimethoprim/sulfamethoxazole, 1 84,

209, 213, 214, 222, 449
Tryptase, 307
Tumor necrosis factor, 373, 384

Uncinate process, 60, 62, 63, 68, 69, 77,

84, 96, 99, 104, 362
Uncinectomy, 240, 253
Unicariate process, anatomical

variations, 68-69
University of Pennsylvania Smell

Identification Test, 51
Upper airway clearance, 364-365
Upper respiratory tract infection, 18,

41-43, 46, 51, 203, 299
treatment, 24, 148, 152, 154, 155
URTI See Upper respiratory tract

infection.

Valsalva maneuver, 246

Valve of Hassner, 101

Vancomycin, 184, 190

Vanderbilt Asthma Sinus and Allergy

Program, 24
Vascular cell adhesion molecule- 1, 383,

385
Ventilator-associated pneumonia, 327,

328
Ventilator-associated sinusitis, 322
Vestibulum nasi, 345
Viral infections, in sinus disease,

155-157
Viral rhinosinusitis, 20-21, 33, 203
Viral sinusitis, 139

Viral upper respiratory infection, 140
Virus 139-141

in sinusitis, 138
Vomer bone, 257
Voriconazole, 429-431, 441
Voxels, 57

Water Pik® device, 224
Water's view, 55, 56, 372, 412
Wegner's granulomatosis, 396
Weille's study, 294-295

X-ray examination, 17, 30, 57

Young's syndrome, 376, 394

Zygoma, 105

Zygomycetes, 420^22, 427-429, 43 1
432, 444

DK3789_cover 8/1 1/05 8:39 AM Page 1

Infectious Disease

about the book . .

Filling a gap in the literature, this reference provides concise and practical guidelines for
the diagnosis and management of sinusitis and furnishes an authoritative outline of our
current understanding of the pathophysiology of this condition. Addressing a wide spectrum
of issues related to the identification, epidemiology, and etiology of sinusitis, this guide
presents detailed illustrations and flowcharts to clarify the interactions between the pathological
and physiological processes of sinusitis and illustrate current treatment practices.

Offering step-by-step guidelines for therapy, this guide offers the most recent studies on
the exact diagnosis of sinusitis utilizing clinical and radiological criteria... describes a variety
of antimicrobial and adjuvant agents for treatment... presents an overview of surgical options
available for the management of recurrent and chronic sinusitis, ..contains chapters on
sinusitis and asthma, nosocomial sinusitis, fungal sinusitis, sinusitis in the immunocompromised
patient, radiological diagnosis, and the microbiology of acute and chronic infection... provides
a global overview of the incidence of sinusitis. ..describes the control, prevention, and
treatment of complications related to sinusitis. ..and includes flow diagrams of key steps in
the management of infection, as well as detailed information on antimicrobial therapy.

about the editor . . .

ITZHAK BROOK is Professor of Pediatrics and Medicine at Georgetown University School
of Medicine, Washington D.C; Attending Physician in Infectious Diseases at Georgetown
University Medical Center, Washington D.C. and the National Naval Medical Center,
Bethesda, Maryland; and Senior Investigator for the Armed Forces Radiobiology Research
Institute, Bethesda, Maryland. The author, coauthor, or editor of over 600 journal articles,
book chapters, and books on the role of anaerobic infections in children and adults, he is
considered a world leader in the field. A member of more than 20 professional organizations
and a Fellow of the Infectious Disease Society of America, the Society for Pediatric Research,
and the Pediatric Infectious Disease Society, as well as a member of several consensus and
Advisory Boards on the management of pediatric infection, he is an editorial board member
of the Annals of Otology, Rhinology & Laryngology and a Section Editor on head and neck
infections in Current Infectious Disease Reports. He is a past chairman of the Anti-infective
Drugs Advisory Board for the Food and Drug Administration. He received the M.D. degree
(1 968) from Hebrew University, Hadassah School of Medicine, Jerusalem, Israel, where
he completed his pediatric residency (1974), and the Diploma of Pediatrics (1972), and the
M.Sc. degree (1973) in pediatrics from the University of Tel-Aviv, Israel. He completed
a Fellowship (1976) in pediatric and adult infectious diseases at the University of California
School of Medicine, Los Angeles.

51 it

O I

^ (

[IW

Printed in the United States oj America

Brc

DK37fi^

ISBN D-AE^-E^MA-X

DDDD

Taylor & Francis

Taylor & Francis Group
www.tayIorandfrancisgroup.com

270 Madison Avenue
New York, NY 10016

2 Park Square, Milton Park
Abingdon, Oxon OX 14 4RN, UK

YJIOBEM

7E 1

4fi

Taylor £•

Internet Archive Audio

Featured

Top

Images

Featured

Top

Software

Featured

Top

Books

Featured

Top

Video

Featured

Top

Mobile Apps

Browser Extensions

Archive-It Subscription

Save Page Now

Full text of "كتب في علم الميكروبيولوجي"

See other formats