European Position Paper on Rhinosinusitis and Nasal Polyps 2020

Wytske J. Fokkens1, Valerie J. Lund2, Claire Hopkins3, Peter W. Hellings1,4,11, Rhinology Supplement 29:
Robert Kern5, Sietze Reitsma1, Sanna Toppila-Salmi6, Manuel Bernal-Sprekelsen7, 1 - 464, 2020
Joaquim Mullol8, Isam Alobid9, Wilma Terezinha Anselmo-Lima10, Claus
Bachert11,12, Fuad Baroody13, Christian von Buchwald14, Anders Cervin15, Noam
Cohen16, Jannis Constantinidis17, Ludovic De Gabory18, Martin Desrosiers19,
Zuzana Diamant20,21,22, Richard G. Douglas23, Philippe H. Gevaert24, Anita
Hafner25, Richard J. Harvey26, Guy F. Joos27, Livije Kalogjera28, Andrew Knill29,
Janwillem H. Kocks30, Basile N. Landis31, Jacqueline Limpens32, Sarah Lebeer33,
Olga Lourenco34, Paolo M. Matricardi35, Cem Meco36,37, Liam O’Mahony38, Carl
M. Philpott39,40, Dermot Ryan41,42, Rodney Schlosser43, Brent Senior44, Timothy L.
Smith45, Thijs Teeling46, Peter Valentin Tomazic47, De Yun Wang48, Dehui Wang49,
Luo Zhang50, Adrian M. Agius51, Cecilia Ahlström-Emanuelsson52, Rashid
Alabri53, Silviu Albu54, Saied Alhabash55, Aleksandra Aleksic56, Mohammad
Aloulah57, Mohannad Al-Qudah58, Saad Alsaleh59, Muaid Aziz Baban60, Tomislav
Baudoin61, Tijmen Balvers62, Paolo Battaglia63, Juan David Bedoya64, Achim
Beule65, Khaled M. Bofares66, Itzhak Braverman67, Eliza Brozek-Madry68, Richard
Byaruhanga 69, Claudio Callejas70, Sean Carrie71, Lisa Caulley72, Desderius
Chussi73, Eugenio de Corso74, Andre Coste75, Usama El Hadi76, Ahmed Elfarouk77,
Philippe H. Eloy78, Shokrollah Farrokhi79, Giovanni Felisati80 , Michel D. Ferrari62,
Roman Fishchuk81, Jessica W Grayson82, Paulo M. Goncalves83, Boris Grdinic84,
Velimir Grgic28, Aneeza W. Hamizan85, Julio V. Heinichen86, Salina Husain87, Tang
Ing Ping88, Justinas Ivaska89, Frodita Jakimovska90, Ljiljana Jovancevic91, Emily
Kakande92, Reda Kamel93, Sergei Karpischenko94, Harsha H. Kariyawasam95,
Hideyuki Kawauchi96,Anette Kjeldsen97, Ludger Klimek98, Antoni Krzeski99,
Gabriela Kopacheva Barsova100, Sung Wam Kim101, Devyani Lal102 , José J.
Letort103, Andrey Lopatin104, Abdelhak Mahdjoubi105, Alireza Mesbahi106, Jane
Netkovski107, Dieudonné Nyenbue Tshipukane108, Andrés Obando-Valverde109,
Mitsuhiro Okano110, Metin Onerci111, Yew Kwang Ong112, Richard Orlandi113,
Nobuyoshi Otori114, Kheir Ouennoughy115, Muge Ozkan116, Aleksandar
Peric117, Jan Plzak118, Emmanuel Prokopakis119, Nerayanan Prepageran120,
Alkis Psaltis121, Benoit Pugin122, Marco Raftopulos1,123, Philippe Rombaux124,
Herbert Riechelmann125, Semia Sahtout126, Caius-Codrut Sarafoleanu127, Kafui
Searyoh128, Chae-Seo Rhee129, Jianbo Shi130, Mahdi Shkoukani131, Arthur K.
Shukuryan132, Marian Sicak133, David Smyth134, Kornkiat Snidvongs135, Tanja
Soklic Kosak136, Pär Stjärne137, Budi Sutikno138, Sverre Steinsvåg139, Pongsakorn
Tantilipikorn140, Sanguansak Thanaviratananich141, Thuy Tran142, Jure Urbancic143,
Arunas Valiulis144, Carolina Vasquez de Aparicio145, Dilyana Vicheva146, Paula
M. Virkkula147, Gil Vicente148, Richard Voegels149, Martin Wagenmann150, Retno
S. Wardani151, Antje Welge-Lussen152, Ian Witterick153, Erin Wright154, Dmytro
Zabolotniy155, Bella Zsolt156, Casper P. Zwetsloot157

1. Department of Otorhinolaryngology, Amsterdam University Medical Centres, location AMC, Amsterdam, The Netherlands
2. Royal National Throat, Nose and Ear Hospital, UCLH, London, United Kingdom
3. Ear, Nose and Throat Department, Guys and St. Thomas’ Hospital, London, United Kingdom

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4. Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, KU Leuven, Belgium
5. Department of Otorhinolaryngology - Head and Neck Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
6. Skin and Allergy Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
7. Department Hospital Quironsalud, University of Valencia, Valencia, Spain
8. Rhinology Unit and Smell Clinic, ENT Department, Hospital Clínic, IDIBAPS, Universitat de Barcelona, CIBERES, Barcelona, Catalonia, Spain
9. Rhinology and Skull Base Unit, ENT Department, Hospital Clínic de Barcelona, Universidad de Barcelona, August Pi i Sunyer Biomedical Research Institute, Barce-
lona, Spain
10. Division of Otorhinolaryngology, Department of Ophthalmology, Otorhinolaryngology, Head and Neck Surgery, Ribeirao Preto Medical School-University of Sao
Paulo, Sao Paulo, Brazil
11. Upper Airways Research Laboratory and ENT Department, University Hospital Ghent, Ghent, Belgium
12. Division of ENT Diseases, CLINTEC, Karolinska Institute, University of Stockholm, Stockholm, Sweden
13. Department of Otorhinolaryngology-Head and Neck Surgery, The University of Chicago Medicine and the Comer Children’s Hospital, Chicago, IL, USA
14. Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University, Hospital, Copenhagen, Denmark
15. Department of Otorhinolaryngology, Head and Neck Surgery, Royal Brisbane and Women’s Hospital; Faculty of Medicine, University of Queensland, Brisbane,
Australia
16. 16. Department of Otorhinolaryngology - Head and Neck Surgery, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA
17. 1st Department of ORL, Head and Neck Surgery, Aristotle University, AHEPA Hospital, Thessaloniki, Greece
18. Rhinology and Plastic Surgery Unit, Otorhinolaryngology, Head and Neck Surgery and Pediatric ENT Department, CHU de Bordeaux, Hôpital Pellegrin, Centre F-X
Michelet, Bordeaux, France
19. Department of ORL-HNS, Université de Montréal, Montreal, Canada
20. Dept of Respiratory Medicine and Allergology, Skane University in Lund, Sweden
21. Research Director Respiratory & Allergy, at QPS-Netherlands, Groningen, Netherlands
22. Affiliate to Charles University, Dept of Respiratory Diseases, in Prague, Czech Republic
23. Department of Surgery, The University of Auckland, Auckland, New Zealand
24. Department of Otorhinolaryngology, Ghent University, Ghent, Belgium
25. University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia
26. Rhinology and Skull Base Department, Applied Medical Research Centre, UNSW (Conjoint) and Macquarie University (Clinical), Sydney, Australia
27. Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
28. ENT Department, Zagreb School of Medicine; University Hospital Center “Sestre milosrdnice”, Zagreb, Croatia
29. Patient representative, Opuscomms, London, United Kingdom
30. Department of Inhalation Medicine, Observational Pragmatic Research Institute, Singapore
31. Rhinology-Olfactology Unit, Otorhinolaryngology Department, University Hospital of Geneva, Geneva, Switzerland
32. Medical Information Specialist, Medical Library, Amsterdam University Medical Centres, location AMC, Amsterdam, The Netherlands
33. Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium
34. FCS – UBI Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
35. Department of Pediatric Pneumology and Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
36. Department of Otorhinolaryngology, Head and Neck Surgery, Ankara University, Ankara, Turkey
37. Department of Otorhinolaryngology, Head and Neck Surgery, Salzburg Paracelsus Medical University, Salzburg, Austria
38. Departments of Medicine and Microbiology, APC Microbiome Ireland, National University of Ireland, Cork, Ireland
39. Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
40. ENT Department, James Paget University Hospital, Great Yarmouth, United Kingdom
41. Allergy and Respiratory Research Group, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
42. Optimum Patient Care, Cambridgeshire, United Kingdom
43. Department of Otorhinolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, USA
44. UNC Otorhinolaryngology / Head and Neck Surgery, Division of Rhinology, Allergy, and Endoscopic Skull Base Surgery and Department of Neurosurgery, University
of North Carolina School of Medicine, Chapel Hill, NC, USA
45. Division of Rhinology and Sinus/Skull Base Surgery, Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland,
Oregon, USA
46. Patient representative, Task Force Healthcare, WTC Den Haag, The Netherlands

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47. Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Graz, Graz, Austria
48. Department of Otorhinolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
49. Rhinology Division, ENT Department; Eye and ENT Hospital, Fudan University, Shanghai, China
50. Department of Otorhinolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Beijing, China
51. Department of Medicine and Surgery in the University of Malta
52. ENT-Department, Lund University, Sweden
53. ENT Division, Surgery Department, College of Medicine and Health and Sciences, Sultan Qaboos University, Muscat, Oman
54. Department of Otorhinolaryngology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
55. Department of ENT, Medcare UAE, Dubai
56. ENT Department, University Clinical Centre, University of Banja Luka, Bosnia and Herzegovina
57. ENT Department, King Saud University, Riyadh, Kingdom of Saudi Arabia
58. Department of Otorhinolaryngology, Jordan University of Science & Technology, Irbid, Jordan
59. Department of Otorhinolaryngology - Head and Neck Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
60. Department of Otorhinolaryngology - Head and Neck Surgery, University of Sulaimani, Sulaimayniha, Iraq
61. Dept. of ORL-HNS Sisters of Mercy University Medical Center, School of Medicine University of Zagreb, Croatia
62. Department of Neurology, Leiden University Medical Center (LUMC), LEiden, the Netherlands
63. Division of Otorhinolaryngology, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
64. Department of Otorhinolaryngology, Universidad de Antioquia, Medellín, Colombia
65. Department of Otorhinolaryngology, University Clinic of Munster, Germany
66. Department of Otorhinolaryngology, Omar Al-Moukhtar University, Albyeda, Libya
67. Department of Otorhinolaryngology - Head and Neck Surgery, Hillel Yaffe Medical Center, Israel
68. Department of Otorhinolaryngology, Medical University of Warsaw, Poland
69. Department of ENT, Makerere University, Kampala, Uganda
70. Department of Otorhinolaryngology, Pontificia Catholic University, Santiago, Chile
71. Department of Otorhinolaryngology, Head and Neck Surgery, Newcastle University, United Kingdom
72. Department of Otorhinolaryngology, Head and Neck Surgery, University of Ottawa,Toronto, Canada
73. Department of Otorhinolaryngology, Kilimanjaro Christian Medical University College, Moshi, Tanzania
74. Department of Otorhinolaryngology , La Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
75. ORL et Chirurgie Cervico-Faciale, Université Paris-Est Créteil (UPEC), France
76. Department of Otorhinolaryngology, American University of Beirut, Lebanon
77. Department of Otorhinolaryngology, Cairo University, Egypt
78. Department of ENT, CHU UCL Namur, Yvoir, Belgium
79. Department of Immunology and Allergy, The Persian Gulf Tropical Medicine Research Center; The Persian Gulf Biomedical Research Institute, Bushehr University of
Medical Sciences, Bushehr, Iran
80. Department of Head and Neck, University of Milan, Italy
81. Department of ENT- Organs Microsurgery, Central city clinical hospital of lvano-Frankivsk city council, Ivano-Frankivsk, Ukraine
82. Department of Otorhinolaryngology, Head and Neck Surgery, University of Alabama Birmingham, USA
83. ENT Department, Centro Hospitalar de Entre Douro e Vouga, Santa Maria da Feira, Portugal
84. ENT Department, General Hospital, Pula, Pula, Croatia
85. Department of Otorhinolaryngology, University Kebangsaan, Kuala Lumpur, Malasyia
86. Department of ENT of Hospital de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Asunción, Paraguay
87. Department of Otorhinolaryngology, Head and Neck Surgery, National University of Malaysia, Kuala Lumpur, Malaysia
88. Department ORLHNS, University Malaysia Sarawak, Kuching, Malaysia
89. Clinic of Ear, Nose, Throat and Eye diseases, Vilnius University, Lithuania
90. ENT Department of Medical Faculty, St Cyril and Methodius University of Skopje, North Macedonia
91. Department of Otorhinolaryngology, Head and Neck Surgery, Clinical Centre of Vojvodina, University of Novi Sad, Serbia
92. Department of ENT Surgery, Mulago National Referral Hospital Kampala, Uganda
93. Department of Otorhinolaryngology, Head and Neck Surgery, Cairo University, Egypt
94. ENT Department, Director of Saint Petersburg Research Institute of Ear, Throat , Nose and Speech; Professor and Chairman of First Pavlov State Medical University,

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Saint Petersburg, Russia

95. Department of Allergy and Clinical Immunology, Royal National ENT Hospital, London, United Kingdom
96. Department of Otorhinolaryngology, Shimane University, Matsue, Shimane, Japan
97. Department of Otorhinolaryngology, Head and Neck Surgery, University of Southern Denmark, Odense, Denmark
98. Center of Rhinology and Allergology, Wiesbaden, Hesse, Germany
99. Department of Otorhinolaryngology, Warsaw Medical University, Warsaw, Poland
100. Department of Otorhinolaryngology, University If Medicine, st. Ciril and Methodius, Skopje, North Macedonia
101. Department of Otorhinolaryngology, Head and Neck Surgery, Kyung Hee University, Seoul, South Korea
102. Department of Otorhinolaryngology, Head and Neck Surgery, Mayo Clinic in Arizona, Phoenix, Arizona, USA
103. Department of Otorhinolaryngology, Pontifica Catholic University of Ecuador, Quito, Ecuador
104. Department of Otorhinolaryngology, Policlinic No.1- Senior ENT Consultant and Surgeon; President of Russian Rhinologic Society, Moscow, Russia
105. Clinique Mahabi, Setif, Algeria
106. Department of Facial Surgery, Khodadoust Hospital, Ordibehesht Hospital, Shiraz, Iran
107. Department of Otorhinolaryngology-Head and Neck Surgery, St. Cyril and Methodius, Skopje, Republic of North Macedonia
108. Department of Otorhinolaryngology, University of Kinshasa, Kinshasa, Democratic Republic of Congo
109. Department of Otorhinolaryngology and Surgery, Hospital Mexico, University of Costa Rica, San Jose, Costa Rica
110. Department of Otorhinolaryngology, International University of Health and Welfare, Narita , Japan
111. Department of Otorhinolaryngology, Hacettepe, Ankara, Turkey
112. Department of Otorhinolaryngology, Head and Neck Surgery, University of Singapore, National University Hospital, Singapore
113. Department of Otorhinolaryngology, University of Utah, Salt Lake City, Utah, USA
114. Department of Otorhinolaryngology at The Jikei University School of Medicine,Tokyo, Japan
115. Department of Otorhinolaryngology-Head and Neck Surgery, Saad Dahleb Blida 1, Blida, Algeria
116. Department of Otorhinolaryngology, University of Health Sciences, Ankara City Hospital, Turkey
117. Department of Otorhinolaryngology, Military Medical Academy, Faculty of Medicine, University of Defense, Belgrade, Serbia
118. Department of Otorhinolaryngology, Head and Neck Surgery, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
119. Department of Otorhinolaryngology, University of Crete School of Medicine, Heraklion, Crete, Greece
120. Department of ENT, University Malaya, Kuala Lumpur, Malaysia
121. Department of Otorhinolaryngology, Head and Neck Surgery, University of Adelaide, Adelaide, Australia
122. Department of Health Sciences and Technology, ETH Zürich, Switzerland
123. Royal Australian College of Surgeons, Trainee Representative (Australia)
124. Department of Otorhinolaryngology, University of Louvain, Brussels, Belgium
125. Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ulm, Baden-Wurttemberg, Germany
126. Faculty of Medicine of Tunis, Tunis El Manar University, Tunis, Tunisia
127. ENT&H NS Department, Santa Maria Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
128. Surgery Ear, Nose and Throat Unit, School of Medicine and Dentistry, University of Ghana, Korle-Bu Teaching Hospital, Accra, Ghana
129. Department of Otorhinolaryngology, Head and Neck Surgery, Seoul, Seoul National University, Seoul, Korea
130. Department of Rhinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
131. Department of Otorhinolaryngology, Head and Neck Surgery, Cleveland Clinic Abu Dhabi, United Arab Emirates
132. Department of Otorhinolaryngology, Yerevan State Medical University, Yerevan, Armenia
133. Department of Otorhinolaryngology, Head and Neck Surgery, Central Military Hospital, Slovakia, Slovak Health University Bratislava and Catholic University, Ruzom-
berok, Slovakia
134. Department of Otorhinolaryngology, Head and Neck Surgery, Royal College of Surgeons in Ireland and University College Cork, Waterford, Ireland
135. Department of Otorhinolaryngology, Chulalongkorn University, Bangkok, Thailand
136. University Medical Centre Ljubljana, Department of Otorhinolaryngology and Cervicofacial Surgery, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
137. Department of Otorhinolaryngology, Karolinska University Hospital, Stockholm, Sweden
138. Department of Otorhinolaryngology, Head and Neck Surgery, University of Airlangga, Surabaya, Indonesia
139. Department of ORL, University of Bergen, Norway
140. Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
141. Department of Otorhinolaryngology, University of Khonkaen , Khonkaen, Thailand

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142. Department of ENT Hospital of Ho Chi Minh city, Faculty of medicine of Ho Chi Minh city Vietnam National University, Vietnam
143. Department of Otorhinolaryngology and cervicofacial surgery, UMC Ljubljana, University of Ljubljana, Medical Faculty, Ljubljana, Slovenia
144. Department of Children’s diseases, Vilnius University Medical Faculty, Institute of Clinical Medicine, Vilnius, Lithuania
145. Department of Paediatric Surgery, National Hospital Benjamin Bloom, National University of El Salvador, San Salvador, El Salvador
146. Department of Otorhinolaryngology, Medical University Plovdiv, Bulgaria
147. Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki, University Hospital, Helsinki, Finland
148. Department of Otolaryngology, St. Luke’s Medical Centre, Quezon City, The Philippines
149. Department of Otorhinolaryngology, University of Sao Paulo, Sau Paulo, Brazil
150. Department of Otorhinolaryngology, Dusseldorf University Hospital, Dusseldorf, Germany
151. Department of Otorhinolaryngology Head and Neck Surgery, Dr. Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
152. Department of Otorhinolaryngology, University Hospital Basel, University Basel, Switzerland
153. Department of Otorhinolaryngology, Head and Neck Surgery, University of Ottawa,Toronto, Canada
154. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
155. State Institution of O.S. Kolomiychenko Institute of Othorhnilarungology of National Academy of Medical Sciences of Ukraine, Kiev, Ukraine
156. Department of Otorhinolaryngology, Head and Neck Surgery, University of Szeged, Hungary
157. Department of Neurology, Dijklander Ziekenhuis, Purmerend, The Netherlands

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Summary

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers
published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and
clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on
the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and
addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new
stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the
management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses,
specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using
over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance
for definitions and outcome measurements in research in different settings.
EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated
preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse
disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors,
inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated
respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways.
The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management
of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically
reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount
of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way
to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not
least, advice for patients and pharmacists and a new list of research needs are included.

The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

To cite this article: Fokkens W.J., Lund V.J. , Hopkins C., Hellings P.W., Kern R., Reitsma S., et al. European Position Paper on Rhino-
sinusitis and Nasal Polyps 2020 Rhinology. 2020 Suppl. 29: 1-464.

MeSH keywords: Paranasal Sinus Diseases, Nasal Polyps, Therapeutics, Diagnosis, Asthma, Prevention and Control

Aknowledgements
We thank Polly Chester, Wilfred Germeraad, Julija Keslere and Nina Liberda for the editing and typesetting of the document;
Jacqueline Schaffer, Benoit Pugin and Sietze Reitsma for the beautiful illustrations, and Klementina Avdeeva, Bella Zsolt, Shokrollah
Farrokhi, Eri Mori, Yuan Zhang, for translating papers. We particularly thank the European Rhinologic Society for their generosity in
making EPOS2020 see the light.

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Contents
1.       Executive Summary including management schemes1
1.1. Summary1
1.2. Classification and definitions of CRS1
1.3. Burden of ARS and CRS6
1.4. Acute rhinosinusitis including common cold and recurrent ARS in adults and children9
1.5.      Chronic rhinosinusitis11
1.6.      Management of chronic rhinosinusitis in adults16
1.7.      Paediatric chronic rhinosinusitis21
1.8.      Concomitant diseases in chronic rhinosinusitis22
1.9.      Patient participation, prediction, precision medicine and i mplementation26
1.10 Pharmacist perspective on rhinosinusitis27
1.11 Research priorities in rhinosinusitis27
1.12 Methods used in EPOS202027

2.     Classification, definitions and terminology31

2.1. Defintions31
2.2. Classification of CRS32
2.3. Duration (adults and children)34
2.4. Severity of disease34
2.5. Exacerbation vs. recurrence34
2.6. Control and failure34
2.7. Phenotype35
2.8. Endotype35
2.9. Comorbidities35
2.10. Medical therapy35
2.11. Surgical therapy35
2.12. Precision medicine vs. personalised medicine36
2.13. Burden of rhinosinusitis36
2.14. Age36
2.15. Integrated Care pathways36
2.16. Recalcitrant vs refractory to treatment36
2.17. Nasal douche / lavage / irrigation / rinsing36
2.18. Immunomodulation and Immunotherapy36
2.19. Allergy37
2.20. Duration of antibiotic courses37
2.21 Other definitions37
2.22 Concept of Control of CRS37

3. Burden of acute and chronic rhinosinusitis45

3.1. Quality of life (QOL)45
3.2. Costs of rhinosinusitis47

4. Acute rhinosinusitis including common cold - and recurrent ARS in adults and children53
4.1. Epidemiology of acute rhinosinusitis (ARS)53
4.2. Recurrent ARS (RARS)56
4.3. Factors associated with ARS and RARS57
4.4.  Pathophysiology of ARS59

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4.5. Diagnosis and differential diagnosis of ARS in adults and children63

4.6 Medical management of ARS67
4.6.1.  Introduction67
4.6.2. Management of acute viral rhinosinusitis67
4.6.3. Oral antibiotics – short courses73
4.6.4. Nasal corticosteroid in acute post-viral rhinosinusitis81
4.6.5. Oral corticosteroids87
4.6.6. Antihistamines (oral and local)87
4.6.7. Antileukotrienes89
4.6.8. Nasal decongestants89
4.6.9. Saline90
4.6.10. Steam / heated air90
4.6.11. Physical interventions90
4.6.12. Bacterial lysates90
4.6.13. Homeopathy91
4.6.14. Herbal compounds92
4.6.15. Vaccination94
4.6.16. Sodium hyaluronate94
4.6.17. Mucolytics95
4.7 Complications of acute bacterial rhinosinusitis (ABRS)95

5. Epidemiology, predisposing factors, pathophysiology, and diagnosis of CRS115

5.1. Epidemiology and predisposing factors115
5.2. Pathophysiology of chronic rhinosinusitis with and without nasal polyposis123
5.3. Diagnosis and Differential Diagnosis147
5.3.1. Allergic and non-allergic rhinitis147
5.3.2 Smell disorders147
5.3.3 Facial pain150
5.3.4. Diagnosis and differential diagnosis152
5.3.5. Diagnostic tools153

6. Management of chronic rhinosinusitis in adults205

6.1 Medical Management205
6.1.1. Short term oral antibiotics for chronic rhinosinusitis (CRS) and exacerbations of CRS205
6.1.2.  Long-term antibiotics209
6.1.3. Topical antibiotics213
6.1.4. Intravenous antibiotics216
6.1.5. Intranasal corticosteroids216
6.1.6. Corticosteroid-eluting implants234
6.1.7. Short courses of systemic corticosteroids236
6.1.8. Antihistamines (oral and topical)239
6.1.9. Anti-leukotrienes240
6.1.10. Decongestants242
6.1.11.Saline242
6.1.12. Aspirin treatment after desensitization (ATAD) in N-ERD252
6.1.13. Antimycotics256
6.1.14. Anti-IgE259
6.1.15. Anti-IL5261
6.1.16. Anti-IL4/IL13263

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6.1.17. Probiotics266
6.1.18. Muco-active drugs266
6.1.19.  Herbal treatment267
6.1.20. Traditional Chinese medicine and acupuncture269
6.1.21. Topical furosemide and oral verapamil269
6.1.22. Capsaicin271
6.1.23. Proton-pump inhibitors in patients with GORD272
6.1.24. Bacterial lysates272
6.1.25. Homeopathy273
6.1.26. Phototherapy274
6.1.27. Filgastrim (r-met-HuG-CSF)274
6.1.28. Topical barriers e.g. algae – carrageenans275
6.1.29. Collodial Silver275
6.1.30. Immunotherapy275
6.1.31. New potentials not on the market today275
6.1.32. CRS treatment during pregnancy278
6.2. Surgical Treatment278
6.2.1. Primary endoscopic surgery278
6.2.2. Revision endoscopic surgery300
6.2.3. Indications for external surgery305
6.2.4. Peroperative measures to improve surgical field and outcomes308
6.2.5. Informed consent/patient information in CRS314
6.2.6. Training in surgery316
6.2.7. Peri-operative medication317

7. Paediatric chronic rhinosinusitis349

7.1. Epidemiology, predisposing factors, and comorbidities349
7.2. Pathophysiology354
7.3. Diagnosis and differential diagnosis356
7.4. Management of paediatric CRS and co-morbidities359

8. Concomitant diseases in patients with chronic rhinosinusitis369

8.1. Role of allergy in chronic rhinosinusitis369
8.2. Immunodeficiencies and their role in CRS371
8.3. Lower airway disease including asthma in relation to CRS373
8.4. Cystic fibrosis375
8.5. Primairy ciliary dyskenesia378
8.6. Fungal Rhinosinusitis380
8.7. Vasculitis, granulomatous diseases and their role in CRS392

9.   Patient participation, prediction, precision medicine and implementation413

9.1. Patient participation in CRS413
9.2. What does EPOS 2020 mean for patients?415
9.3.     Prevention of disease416
9.4.     Prediction423
9.5 Precision medicine425
9.6 Implementation426

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 EPOS 2020

10.   Pharmacist perspective on rhinosinusitis433

10.1. Differentiating rhinitis and rhinosinusitis in the community pharmacy setting433
10.2. Dispensing and use of non-prescription antibiotics in URTIs433
10.3. Management of rhinitis and rhinosinusitis in the pharmacy436
10.4 When and how to refer to a physician or to a specialist439
10.5. Advice to pharmacists on explaining to patients how to use medication439

11. Research needs and agenda for the next decade445

11.1. Introduction445
11.2 Classification and definitions445
11.3 Burden of acute rhinosinusitis and chronic rhinosinusitis445
11.4 Acute rhinosinusitis including common cold - and recurrent ARS in adults and children445
11.5 Epidemiology, predisposing factors, pathophysiology, and diagnosis of CRS446
11.6 Management of chronic rhinosinusitis in adults448
11.7 Paediatric Chronic Rhinosinusitis449
11.8 Concomitant diseases in patients with chronic rhinosinusitis449
11.9 Patient participation, prediction, precision medicine and implementation450
11.10 Pharmacist perspective on rhinosinusitis450
11.11 General principles450

12. Methods used in EPOS2020451

12.1. Introduction451
12.2 Search methods to identify RCTs452
12.3 Delphi rounds453
12.4 Dissemination and future updates453
12.5 Editorial Independence454
12.6 Details of search strategies used454

13.    Authors declarations463

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 EPOS 2020

Abbreviations
15LO 15 lipoxygenase CVID Common Variable ImmunoDeficiency
15-HETE 15-Hydroxyeicosatetraenoic acid CXCL11 CXC chemokine ligand
AAO-HNS American Academy of Otolaryngology-Head and cysLTs Cysteinyl leukotrienes
Neck Surgery D Desflurane
ABPA Allergic bronchopulmonary aspergillosis DC Dendritic cell
ABRS Acute bacterial rhinosinusitis DBPC Double-blind placebo-controlled
ACE Angiotensin converting enzyme DBPCT Double blind, placebo controlled trial
ACP Antrochoanal polyp DC Dendritic cell
ACQ-7 Asthma Control Questionnaire-7 dd Daily dosage
ACTH Adrenocorticotropic hormone DRS Dexarhinospray
AD Aspirin desensitizatio DSS Dead Sea salt solution
AdeV Adenovirus EBV Epstein-Barr virus
AE Adverse event EC Epithelial cell
AECRS Acute exacerbation of chronic rhinosinusitis ECP Eosinophil cationic protein
AERD Aspirin-Exacerbated Respiratory Disease eCRS Eosinophilic CRS
AFRS Allergic fungal rhinoSinusitis EESS Extended ESS
AIA Aspirin-induced asthma EMA European Medicines Agency
AIT Allergen-specific immunotherapy EMP1 Epithelium membrane protein 1
anti IgE Anti immunoglobulin E EMT Epithelial to mesenchymal transition
APC Antigen presenting cell eNOS Endothelial NOS
AQLQ Asthma Quality of Life Questionnaire ENT Ear Nose and Throat
AR Allergic Rhinitis EPOS European Position Paper on Rhinosinusitis and Nasal
ARS Acute Rhinosinusitis Polyps
ATA Aspirin-tolerant asthma Eq-5D EuroQol -5D
ATAD Aspirin treatment after desensitisation ESR Erythrocyte sedimentation rate
B-SIT Brief Smell Identification Test  ESS Endoscopic Sinus Surgery
BAFF B-cell activating factor EV Enterovirus
BAL Bronchoalveolar lavage F Fentanyl
BCC Ballon catheter sinuplasty FDA Food and Drug Administration (US)
B.i.d. Twice daily FESS Functional Endoscopic Sinus Surgery
BMT Basement membrane thickening FEV Forced Expiratory Volume
BND Biodegradable nasal dressing FEV1 Forced expiratory volume
BNO 1016 Bionorica 1016 FISH Fluorescence in situ hybridization
BP Blood pressure FNS Furoate nasal spray
BUD Budesonide FOXP3 Forkhead box P3
CBCT Cone beam CT FP Fluticasone propionate
CC16 Clara cell protein 16 FPANS Fluticasone propionate aqueous nasal spray
CCAD Central Compartment Allergic Disease FPND Fluticasone propionate nasal drops
CCCRC The Connecticut Chemosensory Clinical Research FPNS Fluticasone propionate nasal spray
Center FVC Forced vital capacity
CD Clusters of differentiation Ga2LEN Global Allergy and Asthma European Network
CF Cystic fibrosis G-CSF Granulocyte colony-stimulating factor
CSS Chronic Sinusitus Survey GINA Global Initiative for Asthma
CT Computed tomography GM-CSF Granulocyte macrophage colony-stimulating factor
CTL Cytotoxic T lymphocytes GORD Gastro-oesophageal reflux disease

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 EPOS 2020

GP General Practitioners KNHANES Korean National Health and Nutrition Examination

GPCRs G protein-coupled receptors Survey
GWAS Genome wide association study LAR Local allergic rhinitis
H3N2 Influenza A virus subtype LGALS3BP Galectin-3-binding protein precursor
(Aichi/7) LK Lund-Kennedy
HB Hemoglobin LKES Lund-Kennedy endoscopy scoring
HHV-6 Human Herpes Virus-6 LM Lund-Mackay
HLA Human leukocyte antigen LMS Lund-Mackay score
HLA-MHC Human leukocyte antigen - major histocompatibility LR Likelihood ratio
complex LY6E Lymphocyte Antigen 6 Family Member E)
HMPV Human metapneumovirus
MAIT Mucosal associated invariant T
HNS Hypertonic normal saline
MARS Measurement of Acute Rhinosinusitis Instrument
HOCI Hypochlorous acid
MCA2 Minimal cross-sectional area 1
HPA Hypothalamic-Pituitary-Adrenal
MCC Mucociliary clearance
HPF High powered field
MCT Mucociliary clearance time
Hpi Hours post-infection
MD Mean Difference
HPV Human papillomavirus
MDCT Multi-detector CT
HR Heart rate
MF Mometasone furoate
HRQL Health-related quality-of-life
MFNS Mometasone furoate nasal spray
HS Hypertonic saline
M-H Mantel Haenszel
HSV1 Herpes Simplex Virus-1
MID Minimal important difference
I Isoflurane
MII Multichannel intraluminal impedance
I2 measure of heterogeneity
MIST Minimally invasive sinus technique
IA Inhaled anesthesia 
MM Middle meatus
ICAM-1 Intercellular adhesion molecule-1
MMP Matrix metalloproteinase
ICHD International Classification of Headache Disorders
MOH Medication overuse headache
ICOR International Consensus Statement on Rhinosinusitis
MPO Myeloperoxidase
ICP Integrated care pathway
MRI Magnetic resonance imaging
ICU Intensive care unit
mRNA Messenger Ribonucleic acid
IFI6 Interferon Alpha Inducible Protein 6)
MRSA Methicillin-resistant Staphylococcus aureus
IFIH1 Interferon Induced With Helicase C Domain 1
MSCT Multislice detector CT
IFN Interferon
MSS Major symptom score
IFV Influenza virus
MUC5AC Mucin 5AC
IgA Immunoglobulin A
mUV/VIS Mixed ultraviolet and visible light
IgE Immunoglobulin E
N-ERD NSAID-exacerbated respiratory disease
IgG Immunoglobulin G
NAPT Nasal allergen provocation test
IL Interleukin
NAR Non-allergic rhinitis
IL-5Ra Interleukin-5 Receptor Alpha
NARES Non-allergic rhinitis with eosinophils
ILC Innate lymphoid cell
NARESMA Non-allergic rhinitis with eosinophils and Mast-Cells
IMOS Integrated Medicine Outcomes Scale
NARMA Non-allergic rhinitis with Mast-Cells
INCS Intranasal corticosteroids spray
NARNA Non-allergic rhinitis with neutrophils
Inkt Invariant natural killer T
NECs Nasal epithelial cells
iNOS Inducible Nitric oxide
NF Nuclear factor
IOP Intraocular pressure
NIH National Institutes of Health
IP-10 Interferon gamma-induced protein 10
NK Natural killer
IT Immunotherapy
NO Nitric oxide
ITS Internal transcribed spacer
NOSE Nasal Obstruction Symptom Evaluation
ITT Intention to Treat
NP Nasal polyps
i.v. Intravenous
NPS Nasal polyp score

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 EPOS 2020

NS Nasal saline SCCs Solitary chemosensory cells

NSAIDs Non-Steroidal Anti-Inflammatory Drugs sct Saccharine clearance time
NSD no significant difference SCUAD Severe chronic upper airway disease
NSS Nasal and sinus symptom scale SD Standard deviation
O.d. Once daily SF-12 Short Form (12) Health Survey
OERPs Olfactory event-related potentials  SF-36 Short Form (36) Health Survey
OR Odds ratio SHS Second-hand smoke
OUT Operational taxonomic unit SIA Sinus Severity Assessment
P Propofol sIgE Specific IgE
PARP12 Poly(ADP-Ribose) Polymerase SMD Standard mean difference
PCD Primary cilia dyskinesia SNAQ Sino-nasal questionnaire
PCR Polymease chain reaction SNOT Sino-Nasal Outcome Test
PCV7 Pneumococcal conjugate vaccine SNPS Single nucleotide polymorphisms
PD-1 Programmed cell death-1 SOL IL-5Ra Soluble Interleukin-5 Receptor Alpha
PEA phenyl ethyl alcohol SPA Surfactant protein A
PEF Pulmonary expiratory flow SPGB Sphenopalatine ganglion block
PEFR peak expiratory flow rate ssDNA Single-stranded DNA
PG Prostaglandin SSS Sinusitis Severity Score
PIV Parainfluenza virus STT Saccharin transit time
PMN Polymorphonuclear neutrophils t-PA Tissue plasminogen activator
PNAd Peripheral lymph node addressin TAME P-tosyl-l-arginine methyl ester hydrochloride
PND Post-nasal drip (-esterase
PNIF Peak nasal inspiratory flow activity)
TGF Transforming growth factor
POSE Perioperative Sinus Endoscopy score
Th T helper
PROMS Patient reported outcome measures
TIVA Total intravenous anaesthetic
PRRs Pattern recognition receptors
TLR Toll-like receptor
PVR Post-viral rhinosinusitis
TNF Tumor necrosis factor
QOL Quality of life
Treg T regulatory
R remifentanil
TSLP Thymic stromal lymphopoietin
RANTES Regulated upon Activation, Normal T-cell Expressed,
and Secreted TSS Total symptom score
RARS Recurrent Acute Rhinosinusitis UPSIT University of Pennsylvania Smell Identification Test
RAST Radio Allergosorbent Test URTI Upper respiratory tract infection
RCT Randomised controlled trial UVA Ultraviolet A
REAH Respiratory epithelial adenomatoid hamartomas UVB Ultraviolet B
rG-CSF Recombinant human granulocyte colony-stimulating VAS Visual Analogue Scale
factor VCAM Vascular cell adhesion molecule
RIG-1 Retinoic acid inducible gene 1 ZBP1 Zipcode-binding protein 1
RQLQ Rhinoconjunctivitis Quality of Life Questionnaire ZO-1 Zonula occludens-1
RR Relative Risk
RS Rhinosinusitis
RSDI Rhinosinusitis Disability Index
RSOM-31 Rhinosinusitis Outcome Measure-31
RSV Respiratory syncytial virus
RTP4 Receptor Transporter Protein 4
RV Rhinovirus
S Sevoflurane
SBPCT Single blind placebo controlled trial
SBRT Single blind randomised trial

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 EPOS 2020 POSITION PAPER

1. Executive summary including integrated care pathways

1.1. Summary but not least, advice for patients and pharmacists and a new list
of research needs are included.
The European Position Paper on Rhinosinusitis and Nasal Polyps
2020 is the update of similar evidence based position papers 1.2. Classification, definitions and terminology
published in 2005 and 2007 and 2012(1-3). The core objective of
the EPOS2020 guideline is to provide revised, up-to-date and 1.2.1. Introduction
clear evidence-based recommendations and integrated care Rhinosinusitis is a common condition in most of the world,
pathways in ARS and CRS. EPOS2020 provides an update on leading to a significant burden on society in terms of healthcare
the literature published and studies undertaken in the eight consumption and productivity loss(4-7). Acute rhinosinusitis
years since the EPOS2012 position paper was published and (ARS) has a one-year prevalence of 6-15% and is usually the
addresses areas not extensively covered in EPOS2012 such consequence of a viral common cold. ARS is usually a self-
as paediatric CRS and sinus surgery. EPOS2020 also involves limiting disease but serious complications leading to life
new stakeholders, including pharmacists and patients, and threatening situations and even death have been described(8).
addresses new target users who have become more involved It is one of the most common reasons for prescription of
in the management and treatment of rhinosinusitis since the antibiotics and proper management is extremely pertinent in
publication of the last EPOS document, including pharmacists, the context of the global crisis of resistance to antibiotics(9).
nurses, specialised care givers and indeed patients themselves, Chronic rhinosinusitis (CRS) is a significant health problem and
who employ increasing self-management of their condition affects 5-12% of the general population. The major definitions
using over the counter treatments. The document provides are summarized here. For more definitions please refer to
suggestions for future research in this area and offers updated chapter 2.
guidance for definitions and outcome measurements in
research in different settings. 1.2.2. Clinical definition of rhinosinusitis
EPOS2020 contains chapters on definitions and classification
where we have defined a large number of terms and indicated 1.2.2.1. Clinical definition of rhinosinusitis in adults
preferred terms. A new classification of CRS into primary and Rhinosinusitis in adults is defined as:
secondary CRS and further division into localized and diffuse • inflammation of the nose and the paranasal sinuses
disease, based on anatomic distribution is proposed. There characterised by two or more symptoms, one of which
are extensive chapters on epidemiology and predisposing should be either nasal blockage / obstruction / congestion
factors, inflammatory mechanisms, (differential) diagnosis or nasal discharge (anterior / posterior nasal drip):
of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin ± facial pain/pressure
exacerbated respiratory disease, immunodeficiencies, allergic ± reduction or loss of smell
fungal rhinosinusitis and the relationship between upper and and either
lower airways. The chapters on paediatric acute and chronic • endoscopic signs of:
rhinosinusitis are totally rewritten. All available evidence - nasal polyps, and/or
for the management of acute rhinosinusitis and chronic - mucopurulent discharge primarily from middle meatus and/
rhinosinusitis with or without nasal polyps in adults and children or
is systematically reviewed and integrated care pathways based - oedema / mucosal obstruction primarily in middle meatus
on the evidence are proposed. Despite considerable increases and/or
in the amount of quality publications in recent years, a large • CT changes:
number of practical clinical questions remain. It was agreed that - mucosal changes within the ostiomeatal complex and/or
the best way to address these was to conduct a Delphi exercise sinuses
which is a structured communication technique, originally
developed as a systematic, interactive forecasting method 1.2.2.2. Clinical definition of rhinosinusitis in children
which relies on a panel of experts. The EPOS2020 group firstly Paediatric rhinosinusitis is defined as:
prioritised the areas for consideration as a result of which we • presence of two or more symptoms one of which should
have concentrated on diagnostic issues in the first instance. The be either nasal blockage / obstruction / congestion or nasal
results have been integrated into the respective sections. Last discharge (anterior / posterior nasal drip):

1
 EPOS 2020

± facial pain/pressure
± cough 1.2.2.5. Acute rhinosinusitis in children
and either Acute rhinosinusitis in children is defined as:
• endoscopic signs of: sudden onset of two or more of the symptoms:
- nasal polyps, and/or • nasal blockage/obstruction/congestion
- mucopurulent discharge primarily from middle meatus and/ • or discoloured nasal discharge
or • or cough (daytime and night-time)
-oedema / mucosal obstruction primarily in middle meatus for < 12 weeks;
and/or with symptom free intervals if the problem is recurrent;
• CT changes: with validation by telephone or interview.
-mucosal changes within the ostiomeatal complex and/or
sinuses Questions on allergic symptoms (i.e. sneezing, watery
rhinorrhoea, nasal itching, and itchy watery eyes) should be
1.2.2.3. Definition for epidemiology studies and General included.
Practice
For epidemiological studies and general practice, the definition 1.2.2.5. Recurrent acute rhinosinusitis (RARS)
is based on symptomatology usually without ENT examination ARS can occur once or more than once in a defined time period.
or radiology. We are aware that this will give an over estimation This is usually expressed as episodes/year but with complete
of the prevalence due to overlap with allergic and non-allergic resolution of symptoms between episodes.
rhinitis(56-58). Recurrent ARS (RARS) is defined as ≥ 4 episodes per year with
symptom free intervals(42,78).
1.2.2.4. Acute rhinosinusitis (ARS) in adults
Acute rhinosinusitis in adults is defined as: 1.2.2.6. Definition of chronic rhinosinusitis in adults
sudden onset of two or more symptoms, one of which should be Chronic rhinosinusitis (with or without nasal polyps) in adults is
either nasal blockage/obstruction/congestion or nasal discharge defined as:
(anterior/posterior nasal drip): presence of two or more symptoms, one of which should
• ± facial pain/pressure be either nasal blockage / obstruction / congestion or nasal
• ± reduction or loss of smell discharge (anterior / posterior nasal drip):
for <12 weeks; • ± facial pain/pressure;
with symptom free intervals if the problem is recurrent, with • ± reduction or loss of smell;
validation by telephone or interview. for ≥12 weeks;

Figure 1.2.1. Classification of primary CRS (Adapted from Grayson et al(154))

Anatomic distribution Endotype dominance Examples of phenotypes

AFRS
Type 2
Localized
(unilateral)
Non-type 2 Isolated sinusitis

Primary CRS
CRSwNP/eCRS
Type 2 AFRS
Diffuse CCAD
(bilateral)
Non-type 2
Non-eCRS

AFRS, allergic fungal rhinosinusitis; CCAD, central compartment allergic disease; CRSwNP, chronic rhinosinusitis with nasal polyps;
eCRS, eosinophilic CRS.

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 EPOS 2020

with validation by telephone or interview. chosen to indicate that most cases of ARS are not bacterial.
Questions on allergic symptoms (i.e. sneezing, watery However, this term apparently led to confusion and for that
rhinorrhoea, nasal itching, and itchy watery eyes) should be reason we decided in EPOS2012 to choose the term ‘post-viral
included. ARS’ to express the same phenomenon. A small percentage
of the patients with post-viral ARS will have acute bacterial
1.2.2.7. Definition of chronic rhinosinusitis in children rhinosinusitis (ABRS).Chronic rhinosinusitis has traditionally
Chronic rhinosinusitis (with or without nasal polyps) in children been classified into chronic rhinosinusitis with nasal polyps
is defined as: (CRSwNP) and without nasal polyps (CRSsNP). CRSwNP: chronic
presence of two or more symptoms one of which should rhinosinusitis as defined above and bilateral, endoscopically
be either nasal blockage / obstruction / congestion or nasal visualised polyps in middle meatus; and CRSsNP: chronic
discharge (anterior/posterior nasal drip): rhinosinusitis as defined above and no visible polyps in middle
• ± facial pain/pressure; meatus, if necessary following decongestant.
• ± cough; This definition accepts that there is a spectrum of disease
for ≥12 weeks; in CRS which includes polypoid change in the sinuses and/
with validation by telephone or interview. or middle meatus but excludes those with polypoid disease
presenting in the nasal cavity to avoid overlap. Moreover,
1.2.2.8. Definition of difficult-to-treat rhinosinusitis it has become progressively clear that CRS is a complex
This is defined as patients who have persistent symptoms of disease consisting of several disease variants with different
rhinosinusitis despite appropriate treatment (recommended underlying pathophysiologies(10,11). The phenotypes do not
medication and surgery). Although the majority of CRS patients provide full insight into all underlying cellular and molecular
can obtain control, some patients will not do so even with pathophysiologic mechanisms of CRS which becomes
maximal medical therapy and surgery. increasingly relevant because of the variable association with
Patients who do not reach an acceptable level of control despite comorbidities such as asthma and responsiveness to different
adequate surgery, intranasal corticosteroid treatment and up treatments including corticosteroids, surgery and biological
to two short courses of antibiotics or systemic corticosteroids agents(12-15). Better identification of endotypes might permit
in the last year can be considered to have difficult-to-treat individualization of therapy that can be targeted against the
rhinosinusitis. pathophysiologic processes of a patient’s endotype, with
No changes have been made compared to EPOS2012 in the potential for more effective treatment and better patient
definition of severity or in acute versus chronic(3). For acute outcomes.
rhinosinusitis the term ARS comprises viral ARS (common cold)
and post-viral ARS. In EPOS2007, the term ‘non-viral ARS’ was

Figure 1.2.2. Classification of secondary CRS (Adapted from Grayson et al(154)).

Anatomic distribution Endotype dominance Examples of phenotypes

Odontogenic
Fungal Ball
Local pathology Tumour
Localized
(unilateral)
PCD
CF
Secondary CRS
Mechanical
GPA
EGPA
Diffuse Inflammatory
(bilateral)
Selective
Immunity
immunodeficiency

CF, cystic fibrosis; EGPA, eosinophilic granulomatosis with polyangiitis (Churg-Strauss disease); GPA, granulomatosis with polyangiitis (Wegener’s
disease); PCD, primary ciliary dyskinesia.

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 EPOS 2020

Figure 1.2.3. Assessment of current clinical control of CRS.

EPOS 2020: Assessment of current clinical control of CRS (in the last month)

Controlled Partly controlled Uncontrolled

(all of the following) (at least 1 present) (3 or more present)

Present Present
Nasal blockage1 Not present or not bothersome2
on most days of the week3 on most days of the week3

Mucopurulent Mucopurulent
Rhinorrhoea / Postnasal drip1 Little and mucous2
on most days of the week3 on most days of the week3

Not present Present Present

Facial pain / Pressure1
or not bothersome2 on most days of the week3 on most days of the week3

Normal
Smell1 Impaired3 Impaired3
or only slightly impaired2

Sleep disturbance or fatigue1 Not present2 Present3 Present3

Nasal endoscopy Healthy

Diseased mucosa4 Diseased mucosa4
(if available) or almost healthy mucosa

Rescue treatment Need of 1 course of Symptoms (as above) persist

Not needed
(in last 6 months) rescue treatment despite rescue treatment(s)
1 Symptoms of CRS; 2 For research VAS ≤ 5; 3 For research VAS > 5; 4 Showing nasal polyps, mucopurulent secretions or inflamed mucosa

CRS, chronic rhinosinusitis; VAS, visual analogue scale.

1.2.3. Classification of CRS treatment prior to surgery, ‘appropriate medical therapy’

The EPOS2020 steering group has chosen to look at CRS in terms is the preferred option of EPOS2020. Other decisions were
of primary and secondary (Figures 1.2.1. and 1.2.2.) and to divide the preferential use of the terms ‘irrigation’ or ‘rinsing’ when
each into localized and diffuse disease based on anatomic using saline therapy and with respect to duration of antibiotic
distribution. In primary CRS, the disease is considered by courses, the EPOS panel also agreed that four weeks or less
endotype dominance, either type 2 or non-type 2 (see 1.5.2.2.). would be ‘short-term’, accepting that in general practice the
duration is usually <10 days, and >4 weeks would be regarded
Clinically localized primary CRS is then subdivided into two as ‘long-term’. It was also acknowledged that the aim of
phenotypes – allergic fungal rhinosinusitis (AFRS) or an short-term treatment was different from long-term in that
isolated sinusitis. For diffuse CRS, the clinical phenotypes short-term courses are generally given for significant acute
are predominantly eCRS and non-eCRS, determined by the bacterial infection whereas long term courses are given for
histologic quantification of the numbers of eosinophilic, i.e. their immunomodulatory properties. Immunomodulation
number/high powered field which the EPOS panel agreed to be encompasses all therapeutic interventions aimed at modifying
10/hpf (400x) or higher. the immune response and is the preferred over-riding term by
For secondary CRS, again, the division is into localized or diffuse EPOS2020. In the treatment of rhinosinusitis, it encompasses the
and then considered by four categories dependant on local use of biological agents and macrolides as above.
pathology, mechanical, inflammatory and immunological With respect to surgery, functional implies restitution of
factors. Thence a range of clinical phenotypes are included as physiology and is usually, though not exclusively, applied to
shown. endoscopic sinus surgery. It should fulfil the following criteria:
There has been some discussion about a possible umbrella
term of ‘eosinophilic fungal rhinosinusitis’ but it was agreed that • Creates a sinus cavity that incorporates the natural ostium;
‘allergic’ fungal rhinosinusitis should be retained as the principle • Allows adequate sinus ventilation;
term due to common usage, recognising that not all cases have • Facilitates mucociliary clearance;
evidence of an allergic reaction to fungi e.g. a positive skin prick • Facilitates instillation of topical therapies.
and/or specific IgE (see also chapter 8.6).
In contrast, a ‘Full FESS’ is defined as complete sinus opening
1.2.4. Other consensus terms related to treatment including anterior and posterior ethmoidectomy, middle
From the many terms used regarding the sufficiency of medical meatal antrostomies (likely large), sphenoidotomy and frontal

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 EPOS 2020

opening (e.g. Draf IIa ).Extended endoscopic surgery is used as worsening of symptom intensity with return to baseline CRS
in the same context as ‘full’ (e.g. Draf III) but could also include symptom intensity, often after intervention with corticosteroids
extension beyond the confines of sinuses i.e. skull base, orbit, and/or antibiotics. The prevalence varies with the patient cohort
pterygopalatine and infratemporal fossa. Finally, radical also being studied, season, and how the exacerbation was defined.
includes significant removal of inflamed / dysfunctional mucosa. The precise aetiology of acute exacerbation of CRS is still unclear
and is likely to be multifactorial. The role of bacterial infection
1.2.5. Control of disease may have been over-emphasised in the past. Certainly, there is
In EPOS2012 we introduced the concept of control(3). The a lack of bacterial airway pathogens identified in the majority
primary goal of any treatment, especially in chronic diseases, is of patients with exacerbation. It is possible that since many of
to achieve and maintain clinical control, which can be defined these patients have had sinus surgery in the past, postoperative
as a disease state in which the patient does not have symptoms, changes in the microbiome create a new microbial environment
or the symptoms are not impacting quality of life. In the last and other pathogens are in play. Microbial dysbiosis in the form
decade some studies have been performed that attempted to of an altered balance of the bacterial flora rather than a single
validate the EPOS2012 proposed measurement of control(15-17). pathogen may elicit a host inflammatory response.
Based on these validation studies, the EPOS2020 steering Virus infections are perhaps more likely to be a key cause of
group thinks that the current EPOS2012 control criteria might exacerbation of CRS, especially with increasing evidence that
overestimate the percentage of patients being uncontrolled. For rhinovirus infection can drive eosinophilic inflammation and
research purposes we, therefore, recommend using a VAS scale a focus on prevention and management of virus infections
for all symptoms: “not bothersome” can be substituted by ‘VAS ≤ may be more effective than treating secondary infections with
5’, and ‘present / impaired’ by ‘VAS > 5’. Furthermore, we want to antibiotics and eosinophilic flare ups with corticosteroids.
make sure that the symptoms are related to CRS and included However, this remains to be further investigated.
that in the table. For example, a typical migraine headache Firm scientific evidence is still lacking on therapy of AECRS and
should not be taken into account when evaluating control only treatment recommendations based on clinical experience
in CRS. The results of the validation studies also still require and expert opinion are available. However, due to the cyclic
further psychometric validation (including internal consistency, and self-limiting nature of AECRS one should be mindful of the
responsiveness and known group differences) (Figure 1.2.3.). ‘regression to the mean phenomena’. A patient is more likely to
Given the importance of the concept of disease control, from a seek treatment when they are at their worst, the likelihood of
clinical as well as from a research perspective, there still remains improvement is high regardless of treatment, which may distort
a need for a gold standard to assess disease control in CRS. the doctor’s clinical experience as well as rendering clinical
trials lacking a placebo arm rather meaningless. In spite of this
1.2.6. Acute exacerbation of chronic rhinosinusitis (AECRS) confounder, it is likely that steroids and antibiotics will remain
Acute exacerbation of chronic rhinosinusitis (AECRS) is defined the mainstay of treatment for the foreseeable future even

Figure 1.3.1. Prevalence of cardinal symptoms of CRS (25, 26).

Prevalence of cardinal symptoms of CRS

100%

80% Nasal obstruction

60% Change in sense of smell

40% Nasal discharge

20% Facial pain

Unselected CRSwNP CRSsNP CRSwNP in CRSsNP in CRSwNP CRSsNP

patients identified in identified in outpatient clinic outpatient clinic undergoing undergoing
in primary care general general surgery surgery
population population
CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps.

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 EPOS 2020

Figure 1.3.2. Severity of cardinal symptoms of CRS. (25, 26)

Severity of cardinal symptoms of CRS

4 Nasal obstruction

3 Change in sense of smell

2 Nasal discharge

1 Facial pain

CRSwNP in CRSsNP in CRSwNP CRSsNP

outpatient clinic outpatient clinic undergoing undergoing
surgery surgery

CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps.

though the role of antibiotics in the treatment of AECRS is not pain and nasal discharge reported as equally severe as altered
supported by the literature (see chapter 1.6 and 6.1). smell and taste(25, 26) (Figure 1.3.2.). In patients presenting to
ENT clinics, the presence of cardinal symptoms has a positive
1.3. Burden of acute and chronic rhinosinusitis predictive value of 39.9, with high sensitivity but low specificity
for a diagnosis of CRS(27).
Chapter 3 covers the burden of rhinosinusitis, its impact on The overall severity rating of symptoms is obviously highly
quality of life and the costs, both direct and indirect. dependent upon the population being studied. Patients in
secondary care awaiting surgery report mean symptom severity
1.3.1. Quality of life (QOL) scores in the moderate to severe range, with a mean SNOT-22
Both ARS and CRS are associated with significant adverse effects score of 42.0 compared with a control group where a mean
on quality of life using a variety of validated questionnaires score of 9.3 was reported(23). CRSsNP patients had higher pre-
including the general health Eq-5D(18, 19) and SF36(20, 21) and operative baseline scores (44.2) compared with CRSwNP (41.0).
more rhinologic-specific SNOT16(22) and SNOT 22(23). Chronic
rhinosinusitis produces greater quality of life impairment than 1.3.2. Costs of rhinosinusitis
acute(24). Gliklich and Metson first demonstrated the impact Health care spending is significantly greater in rhinosinusitis
of CRS on global quality of life, finding that CRS had a greater than in other diseases such as peptic ulcer disease, acute
impact on social functioning than angina or chronic heart asthma, and hay fever(28). In the USA, the direct costs for the
failure(20). More recently, they have shown that health utility management of CRS are now between $10 and $13 billion
values, measured using the EQ-5D, were lower than the general per year, or $2609 per patient per year. In Europe, Wahid et
population, and comparable to other chronic diseases such as al. reported 2974 GBP on costs for primary and secondary
asthma(19). care extrapolated for a year period compared to 555 GBP
In CRS, the ‘cardinal’ symptoms are nasal obstruction or in the control group and 304 versus 51 GBP out-of-pocket
congestion, nasal discharge (which can be anterior or posterior), expenditure(29). Lourijsen et al. found yearly direct costs of 1501
alteration in sense of smell and facial pain and pressure. These euro per year in a group of patients with CRSwNP(30). Overall
may vary in prevalence between unselected patients in primary CRS leads to an incremental direct healthcare expenditure of
care, CRS patients in the general population, in an outpatient 2500 euro per patient per year. The highest direct costs were
setting and those undergoing surgery and in severity between associated with patients who had recurrent polyposis after
those seen in outpatients and those undergoing surgery (Figure surgery(31). However, whilst surgery is expensive, varying from up
1.3.1). to $11,000 in USA to $1100 in India(32-34), it results in a decrease in
Nasal obstruction and alteration in sense of smell and taste are direct costs in the subsequent two post-operative years(35).
both the most severe and prevalent symptoms in CRSwNP, while The indirect costs of rhinosinusitis are much greater than the
in CRSsNP, nasal obstruction is again the most severe, with facial direct costs. Since 85% of patients with rhinosinusitis are of

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Table 1.4.1. Treatment evidence and recommendations for adults and children with acute viral rhinosinusitis (common cold)*.

Level of
Therapy GRADE recommendation
evidence
Antibiotics 1a (-) There is no evidence of benefit from antibiotics for the common cold or for persisting acute purulent
rhinitis in children or adults. There is evidence that antibiotics cause significant adverse effects in adults
when given for the common cold and in all ages when given for acute purulent rhinitis. Routine use of
antibiotics for these conditions is not recommended.
Nasal corticosteroid 1a (-) The current evidence does not support the use of nasal corticosteroids for symptomatic relief from the
common cold
Antihistamines 1a Antihistamines have a limited short-term (days 1 and 2 of treatment) beneficial effect on severity of over-
all symptoms in adults but not in the mid to long term. There is no clinically significant effect on nasal
obstruction, rhinorrhoea or sneezing
Decongestant (oral / nasal) Ia The current evidence suggests that multiple doses of decongestants may have a small positive effect on
subjective measures of nasal congestion in adults with the common cold. Decongestants do not seem to
increase the risk of adverse events in adults in the short term.
Paracetamol Ia Paracetamol may help relieve nasal obstruction and rhinorrhoea but does not appear to improve other cold
(Acetaminophen) symptoms (including sore throat, malaise, sneezing and cough)
NSAIDs Ia NSAIDs do not significantly reduce the total symptom score, or duration of colds. However, for outcomes
related to the analgesic effects of NSAIDs (headache, ear pain and muscle and joint pain) NSAIDs produce
significant benefits, and malaise shows a borderline benefit, although throat irritation is not improved. Chills
show mixed results. For respiratory symptoms, cough and nasal discharge scores are not improved, but the
sneezing score is significantly improved. There is no evidence of increased frequency of adverse effects in
the NSAID treatment groups.
Antihistamine-decongestant- Ia Antihistamine-analgesic-decongestant combinations have some general benefit in adults and older
analgesic combinations children with common cold. These benefits must be weighed against the risk of adverse effects. There is no
evidence of effectiveness in young children.
Ipratropium bromide Ia The existing evidence suggests that ipratropium bromide is likely to be effective in ameliorating
rhinorrhoea. Ipratropium bromide has no effect on nasal congestion and its use is associated with more
side effects compared to placebo or no treatment although these appeared to be well tolerated and self-
limiting.
Nasal irrigation with saline Ib Nasal saline irrigation possibly has benefits for relieving the symptoms of acute URTIs mainly in children and
is considered an option by the EPOS steering group.
Steam / heated humidified air 1a (-) The current evidence does not show any benefits or harms from the use of heated, humidified air delivered
for the treatment of the common cold.
Probiotics Ia Probiotics may be more beneficial than placebo for preventing acute URTIs. However, the quality of the
evidence was (very) low.
Vitamin C Ia Given the consistent effect of vitamin C on the duration and severity of colds in regular supplementation
studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an
individual basis whether therapeutic vitamin C is beneficial for them.
Vaccines 1b (-) There are no conclusive results to support the use of vaccines for preventing the common cold in healthy
people. This is in contrast to influenza vaccines.
Exercise Ia Regular, moderate-intensity exercise may have an effect on the prevention of the common cold.

Echinacea 1a (-) Echinacea products have not been shown to provide benefits for treating colds, although, there could be
a weak benefit from some Echinacea products: the results of individual prophylaxis trials consistently show
positive (if non-significant) trends, although potential effects are of questionable clinical relevance.
Zinc Ia Zinc administered as zinc acetate or zinc gluconate lozenges at a dose of >=75 mg/day and taken
within 24 hours of onset of symptoms significantly reduces the duration of common cold. For those
considering using zinc it is advised to use it at this dose throughout the cold. Regarding prophylactic zinc
supplementation, currently no firm recommendation can be made because of insufficient data.

Herbal medicine (excluding Ib Some herbal medicines like BNO1016, Cineole and Andrographis paniculata SHA-10 extract have significant
Echinacae) impact on symptoms of common cold without important adverse events. A formal systematic review is
missing.
Fusafungine Ia Fusafungine is an effective treatment of common cold especially when administered early. However,
serious allergic reactions involving bronchospasm although rare have occurred after the use of fusafungine.
For that reason, the medication is no longer on the market.

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Table 1.4.2. Treatment evidence and recommendations for adults with acute post-viral rhinosinusitis.

Level of
Therapy GRADE recommendation
evidence
Antibiotics 1a (-) There is no benefit from prescribing antibiotics for post viral ARS in adults. There is no effect on
cure or duration of disease and there are more adverse events. Based on the moderate level of
evidence and the fact that acute post-viral rhinosinusitis is a self-limiting disease, the EPOS2020
steering group advises against the use of antibiotics for adults in this situation.

Nasal corticosteroids 1a Nasal corticosteroids are effective in reducing total symptom score in adults suffering from
acute post-viral rhinosinusitis. However, the effect is small. Nasal corticosteroids have not been
shown to have an effect on QOL. Acute post-viral rhinosinusitis is a self-limiting disease. Based
on the moderate quality of the evidence and the small effect size the EPOS2020 steering group
advises only to prescribe a nasal corticosteroid when reduction of the symptoms of the acute
post-viral rhinosinusitis is considered necessary.
Systemic corticosteroids 1a Systemic corticosteroids, with or without antibiotics do not have a positive effect on recovery
at 7-14 days. There is a small but significant effect of systemic corticosteroids versus placebo
on facial pain at days 4-7 after start of the treatment. There are no studies comparing systemic
corticosteroids to nasal corticosteroids. The quality of the evidence is low. Based on the
evidence, the numbers needed to treat and the potential harm of systemic corticosteroids,
the EPOS2020 steering group advises against the use of systemic corticosteroids in patients
suffering from acute post-viral rhinosinusitis.
Decongestant (oral / nasal) Ib Nasal decongestants may be effective in improving mucociliary clearance throughout the
acute phase of the disease. No studies have been performed evaluating the effect on resolution
or reduction of symptoms of postviral ARS. Based on the absence of clinically relevant data,
the EPOS2020 steering group cannot advise on the use of decongestants in acute post-viral
rhinosinusitis.
Nasal irrigation with saline Ib One small study did not find a difference between saline nasal spray versus no treatment.
One very small study found a larger effect of high volume versus low volume saline rinsing
on purulent rhinorrhoea and post-nasal drip. Based on the very low quality of the evidence
no strong advice can be given about the use of nasal saline irrigation although on theoretical
grounds saline can be expected to be beneficial rather than harmful.
Homeopathy Ib We found one study evaluating the effect of homeopathy (sinfrontal) showing a significant
reduction of symptoms and radiographic improvement versus placebo. Based on the limited
evidence the EPOS2020 steering group cannot give clear advice on the use of homeopathy in
acute post-viral rhinosinusitis.

Herbal medicine Ib Some herbal medicines like BNO1016 tablets and Pelargonium sidoides drops and Myrtol
(and other essential oil) capsules have significant impact on symptoms of acute postviral
rhinosinusitis without significant adverse events.

ARS, acute rhinosinusitis; QOL, quality of life.

Table 1.4.3. Treatment evidence and recommendations for children with acute post-viral rhinosinusitis.

Level of
Therapy GRADE recommendation
evidence
Antibiotics 1a (-) The use of antibiotics in children with acute post-viral rhinosinusitis is not associated with greater
cure/significant improvement. Based on the moderate level of evidence and the fact that acute
post-viral rhinosinusitis is a self-limiting disease, the EPOS2020 steering group advises against the
use of antibiotics for children in this situation.

Nasal corticosteroids 1a Nasal corticosteroids seem to be effective in reducing total symptom score in children
suffering from acute post-viral rhinosinusitis on top of (ineffective) antibiotics. Acute post-
viral rhinosinusitis is a self-limiting disease. Based on the very low quality of the evidence the
EPOS2020 steering group cannot advise on the use of nasal corticosteroids in children with acute
post-viral rhinosinusitis.
Antihistamines 1b (-) There is one study evaluating antihistamines versus placebo in addition to (ineffective) antibiotics
in children with post-viral ARS showing no additive effect of antihistamines over the treatment
given. Based on the very low quality of the evidence, the EPOS2020 steering group cannot advise
on the use of antihistamines in post-viral ARS.

Bacterial lysates Ib One study has shown benefit in the use of OM-85-BV for shortening the duration of illness.

ARS, acute rhinosinusitis.

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 EPOS 2020

Figure 1.4.1. Integrated care pathway of acute rhinosinusitis.

EPOS 2020: Care pathways for acute rhinosinusitis (ARS)

Two ARS symptoms Check for likely ABRS Self-Care
One of which should be nasal obstruction ≥ 3 of the following:
- • Self-education / e-Health
Pharmacy

and/or discoloured discharge • Fever above 38°C • Decongestants <10 days

Self-Care

• Double sickening • NSAIDs / paracetamol

± facial pain/pressure • Unilateral disease • Herbal medicine
± reduction or loss of smell • Severe pain • Zinc
<10 days • Raised ESR/CRP • Vitamin C
• Consider saline spray / rinses
+ • Avoid antibiotics

Refer to / Treatment by Primary Care

- Appropriate therapy

Check for likely ABRS - Symptoms >10 days or increased after 5 days?
• INCS
• Decongestants <10 days
≥ 3 of the following: + • Herbal medicine
Primary

• Saline spray / rinses

Care

• Fever above 38°C

• Double sickening ≥3 episodes of ABRS last year? • Avoid antibiotics
• Unilateral disease + -
• Severe pain +
• Raised ESR/CRP Consider antibiotics Improvement after
No other investigations 10 days of antibiotics?

Refer to Secondary / Tertiary Care

-
Secondary / Tertiary

PRESENCE OF ALARM SYMPTOMS

Consider and test for differential
diagnosis and treat accordingly • Periorbital oedema/erythema • Severe headache
Care

• Displaced globe • Frontal swelling

(e.g., odontogenic, fungal ball,
• Double vision • Signs of sepsis
bacterial resistance, immunodeficiency) • Ophthalmoplegia • Signs of meningitis
or non-sinus diagnoses • Reduced visual acuity • Neurological signs
(e.g., migraine) IMMEDIATE REFERRAL

ABRS, acute bacterial rhinosinusitis; INCS, intranasal corticosteroids.

working age (range: 18-65 years old), indirect costs such as post-viral ARS and ABRS (acute bacterial rhinosinusitis) was
missed workdays (absenteeism) and decreased productivity at proposed. In the last decade studies have been performed using
work (presenteeism) significantly add to the economic burden this classification. In a recent Dutch paper using the GA2LEN
of the disease(35). As a consequence, rhinosinusitis is one of the questionnaire a prevalence of 18% (17-21%) was found for
top 10 most costly health conditions to US employers(36). Overall, symptoms pointing to post-viral ARS in three different cities
the total indirect costs of CRS were estimated to be in excess of in the Netherlands(38). ABRS is a rare disease with an incidence
$20 billion per year in the USA(37) mainly due to presenteeism. of 0.5-2% of viral ARS (common cold)(2, 39). RARS is defined as
≥ 4 episodes per year with symptom free intervals(40-43). Each
1.4. Acute rhinosinusitis including common cold episode must meet the criteria for acute post-viral (or bacterial)
and recurrent ARS in adults and children rhinosinusitis. The EPOS2020 steering group advises to have at
least one proven diagnosis of post-viral ARS with endoscopy
Chapter 4 describes the epidemiology, pathophysiology, and/or CT scan before a diagnosis of RARS is considered.
diagnosis and differential diagnosis, and management of ARS in
adults and children. Also, a new integrated care pathway based 1.4.2. Predisposing factors for ARS and RARS
on all the evidence is proposed. Predisposing factors for ARS are seldom evaluated. There is
some indication that anatomical abnormalities may predispose
1.4.1. Epidemiology to recurrent acute rhinosinusitis (RARS)(44-47). Active and passive
In EPOS2012 the division of ARS into viral ARS (common cold), smoking predisposes to ARS and there is some evidence that

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 EPOS 2020

Table 1.4.4. Treatment evidence and recommendations for adults with acute bacterial rhinosinusitis (ABRS).

Level of
Therapy GRADE recommendation
evidence
Antibiotics 1a Antibiotics are effective in a select group of patients with symptoms and signs suggestive of ABRS. From the limited
data available (two studies versus one) it seems that amoxicillin/penicillin (beta-lactams) especially are effective
and moxifloxacin (fluoroquinone) is not. The efficacy of beta-lactams is evident at day three where patients
already experience better symptom improvement and continues with a higher number of cures at completion of
treatment. However, careful patient selection for those with ABRS is needed to avoid unnecessary use of antibiotics
and side effects.

Antihistamines 1b (-) There is one study evaluating antihistamines versus placebo in adults with allergic rhinitis and ABRS showing no
effect. Based on the very low quality of the evidence, the EPOS2020 steering group cannot advise on the use of
antihistamines in post-viral ARS and ABRS.
Nasal irrigation with 1b (-) One study comparing hypertonic saline nasal spray, isotonic saline nasal spray and no treatment in addition to
saline antibiotics did not find a difference between the groups. Based on the very low quality of the evidence no advice
can be given about the use of nasal saline irrigation.

Sodium Hyaluronate Ib One study evaluating sodium hyaluronate compared to placebo in a nebulizer ampoule for nasal douching in
addition to levofloxacin and prednisone showed significantly fewer symptoms and better smell threshold in the
sodium hyaluronate group. Based on the very low quality of the evidence no advice can be given about the use of
sodium hyaluronate.

ABRS, acute bacterial rhinosinusitis; ARS, acute rhinosinusitis.

Table 1.4.5. Treatment evidence and recommendations for children with acute bacterial rhinosinusitis (ABRS).

Level of
Therapy GRADE recommendation
evidence
Antibiotics 1a (-) Data on the effect of antibiotics on the cure/improvement of symptoms in ABRS in children are very limited. There
are only two studies with limited numbers that do not show a significant difference over placebo but do show a
significant higher percentage of adverse events. Larger trials are needed to explain the difference between adults
where antibiotics in ABRS has been shown to be effective and this outcome.
Mucolytics 1b (-) Erdosteine as an adjunct to antibiotic was not more effective than placebo
ABRS, acute bacterial rhinosinusitis.

concomitant chronic disease may increase the chance of getting Subjective assessment should take into account the severity
ARS following an influenza infection(48-50). and the duration of symptoms (see above). The recommended
Other potential factors like allergy and GORD do not seem to method of assessing severity of symptoms is with a visual
predispose to ARS(51, 52). analogue scale (VAS) recorded by the patient on a 10cm line
1.4.3. Pathophysiology of ARS giving a score on a measurable continuum of 1 to 10.
The pathophysiology of ARS is systematically evaluated, Bacterial infection may occur in ARS, but in most cases anti-
again trying to organize the literature based on the different biotics have little effect on the course of the illness (see 1.4.5.).
categories of ARS. Since EPOS2012, there have been increasing A number of studies have attempted to provide clinicians with
experimental data supporting the fact that nasal epithelium is combinations of symptoms and signs predicting more severe
the primary portal of entry for respiratory viruses as well as an disease, particularly of a bacterial infection and the likelihood
active component of initial host responses against viral infection. of a response to antibiotics(53). The EPOS2020 steering group
The cascade of inflammation initiated by nasal epithelial cells decided to maintain suggestions made in the earlier EPOS
will lead to damage by the infiltrating cells, causing oedema, versions: at least three of five symptoms of discoloured
engorgement, fluid extravasation, mucus production and discharge, severe local pain, fever, elevated ESR/CRP and
sinus obstruction in the process, eventually leading to ARS or double sickening.
exacerbating ARS (see chapter 4.2.).
1.4.5. Treatment of ARS in adults and children
1.4.3. Diagnosis and differential diagnosis of ARS in adults For EPOS2020 a systematic review was performed evaluating
and children treatment of the different categories of ARS (viral, post-viral or
Post-viral ARS is a common condition in the community, usually ABRS) separately. For acute viral rhinosinusitis we found many
following viral URTI. Most acute viral URTI infections are self- excellent systematic reviews and report on them. For post-viral
limiting, thus post-viral ARS should not be diagnosed before rhinosinusitis and ABRS a systematic review of the literature
10 days’ duration of symptoms unless there is a clear worsening has been performed for children and adults. The different
of symptoms after five days. treatments, levels of evidence and GRADE recommendations are

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 EPOS 2020

reported in Tables 1.4.1-1.4.5. For medication not mentioned in The prevalence of allergy in CRS may vary by phenotype, with
these tables, we could not find RCTs. CCAD and AFRS having a stronger association than CRSwNP and
Based on the systematic review, a new integrated care pathway CRSsNP(59, 60). An important percentage of subjects diagnosed
is proposed (Figure 1.4.1.). In this figure it is emphasized with chronic upper airway disease report alcohol-induced
that the treatment of almost all patients with ARS should be worsening of their symptoms(61).
symptomatic, if needed, combined with local corticosteroids.
The place for antibiotics is very limited and they should only be 1.5.2. Genetics
given in situations pointing to severe disease with symptoms The current knowledge base on the genomics of CRS disease
and signs such as high fever, double sickening, severe pain and offers the promise of identifying new mechanisms of disease
elevated ESR(3). development and markers predicting optimal response
Finally, in chapter 4 the complications of ABRS are discussed. to available therapies. However, for the moment, genetics
Complications of bacterial rhinosinusitis are rare but potentially do not allow prediction of disease or outcome and its uses
serious. However, a number of studies have shown that they are currently restricted to extreme cases to understand the
are not prevented by routine prescribing of antibiotics. A low molecular underpinning of pathologies. It is probable that over
threshold of suspicion must always be maintained for their early the coming years we will identify individual or complex genetic
diagnosis. traits conferring susceptibility to CRS, evolution of disease, and
response to medical or surgical treatment(62, 63).
1.5. Epidemiology, predisposing factors,
pathophysiology , and diagnosis of CRS 1.5.3. The emerging clinical relevance of CRS
pathophysiology
1.5.1. Epidemiology and predisposing factors Research into the aetiology and pathogenesis of chronic
The overall prevalence of symptom-based CRS in the population rhinosinusitis has been largely irrelevant to the clinician, with
has been found to be between 5.5% and 28%(4, 5, 54, 55), CRS minimal impact on management. Historically, CRS has been
is more common in smokers than in non-smokers(4). The divided into two groups based on the presence or absence of
prevalence of self-reported physician-diagnosed CRS is highly polyps and, in rough overview, corticosteroids were commonly
correlated with the prevalence of EPOS-diagnosed CRS(4). When used for CRSwNP and antibiotics for CRSsNP. The rationale for
symptoms are combined with endoscopy or CT scan prevalence these regimens was based on decades-old presumptions that
is reduced to 3-6%(56-58). CRSsNP was the result of an incompletely treated acute bacterial
CRS is associated with asthma, with a prevalence of asthma infection that then became ‘chronic’ and CRSwNP had some
around 25% in patients with CRS compared to 5% in the relationship to local or systemic ‘allergy’. Surgery was the only
general population. CRS is also associated with COPD, option for failures. It has been clear for at least 20 years that this
N-ERD, hypogammaglobulinemia, and GORD (see chapter assessment was simplistic at best. The emerging view was that
5.1). Smoking, air-pollution and occupational exposure are CRS was a syndrome with a multifactorial aetiology resulting
negatively correlated with CRS (symptoms). from a dysfunctional interaction between various environmental

Figure 1.5.1. Aetiology and pathogenesis of CRS.

Etiology and Pathogenesis of CRS

Environment
PHENOTYPE
ENDOTYPE Remodelling Natural history
Outcome
Host

Barrier penetration

Lower airway disease?

Asthma and bronchiectasis

CRS, chronic rhinosinusitis.

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 EPOS 2020

factors and the host immune system. It was, however, very affect treatment recommendations for a patient who has already
unclear which environmental and host factors were important acquired the problem. The accompanying line drawing (Figure
even in the population at large, let alone in an individual CRS 1.5.1.) illustrates a contemporary model of CRS pathogenesis.
patient. Nevertheless, research was undertaken with the initial Rather than analysis of the complex and usually unknown
goal of examining causation of CRS as a route to therapy. Later, factors that cause CRS in an individual patient, interest now is
the results of these efforts shifted emphasis toward the tissue centred on the resulting inflammation that develops in the sinus
effects generated by those causative factors and away from the tissue. The focus is toward the identification of the molecular
factors themselves. The following brief synopsis describes how pathway(s) or endotypes that have been activated. This effort
that 20-year journey is finally beginning to impact how we treat has been aided by recent advances in our understanding of
patients with CRS. the physiologic immune response against pathogens across
Research into the aetiology and pathogenesis of CRS was first mucosal barriers. When the barrier is breached, a self-limited
energized by the work on fungus, which was proposed as immunodefensive response is generated, characterized by
the key aetiologic agent, at least in patients with recalcitrant a cellular and cytokine repertoire targeting one of the three
CRS. This was followed shortly after with Staphylococcus classes of pathogens: type 1 immune responses target viruses;
aureus being proposed as a rival pathogen, perhaps in biofilm type 2 responses target parasites and type 3 target extracellular
format to enable greater resistance. Later, the more general bacteria and fungi, all of which resolve with elimination of the
hypothesis of microbial dysbiosis was proposed, wherein the pathogens and restoration of barrier integrity. In cases of CRS,
collective microbial community was abnormal and pathogenic, barrier penetration results in a chronic inflammatory response
propagating sinonasal inflammation occurred at anatomically that fails to resolve, but still typically utilizes the type 1, 2 or
vulnerable sites. Unfortunately, therapies directed at fungi, 3 pathways alone, or in combinations. Type 2 inflammation
staphyloccus aureus and even the microbiome as a whole have is characterized by cytokines IL-4, IL-5 and IL-13 as well as
been, at best, underwhelming. This suggested the opposite activation and recruitment of eosinophils and mast cells.
therapeutic tactic: shift attention away from antimicrobials and CRS research has revealed that patients with a pure or mixed
towards the goal of correcting any immune dysfunction in the type 2 endotype tend to be much more resistant to current
individual CRS patient. By then it was understood that both therapies, exhibiting a high recurrence rate when compared
the nose and sinuses were not sterile: a process which begins with pure type 1 or 3 endotypes. Furthermore, while type 2 CRS
at birth with the rapid colonization by viruses, bacteria and clearly varies between patients by intensity of inflammation,
fungi. In healthy individuals, the mucosa serves as a relative subtypes may exist wherein discrete aspects of the pathway
barrier modulating interaction with the host immune system, are relatively enhanced (e.g. mast cell activation, eosinophil
promoting tolerance and symbiosis as well as preventing activation, and plasma cells activity). Most importantly, biologic
or limiting inflammation. In patients with CRS, the barrier is agents have now become available that target specific aspects
penetrated with resultant chronic inflammation leading to, in of type 2 inflammation. In the very near future, it may be
many cases, tissue remodeling and clinical symptoms. In theory, possible to offer personalized medicine for CRS patients where
identification of specific genetic or epigenetic variations in the treatment is based on molecular biomarkers for the endotype or
host immune system that permit CRS to develop should be subendotype activated in an individual patient.
possible, providing targets for future therapies. Unfortunately, Remodelling of sinonasal tissues in CRS consists most
outside of cystic fibrosis and CFTR, the genetics of CRS prominently of polyp formation, goblet cell hyperplasia and
appear to be quite complex for the typical patient, involving epithelial barrier abnormalities, which in aggregate, may
multiple genes, each with a small effect size. Moreover, genetic account for many or most of the CRS symptoms. In the case
studies on the large populations necessary to identify these of the barrier remodelling, the result is greater permeability,
genes would be very expensive and have generally not been likely facilitating persistence or recurrence of CRS. All of these
undertaken. Effectively, this approach was rendered impractical changes are most apparent in type 2 CRS, possibly accounting
and therapeutic approaches to manage CRS based on putative for the observed greater symptomatology and higher rate
aetiologies – either host or environment based – have made of treatment failure. The precise relationship between the
relatively little clinical impact. Nevertheless, this entire body of endotype and the remodelling pattern is not completely clear
work revealed a great deal about the nature of the inflammation but recent evidence suggests that it may be cause and effect as
present in the tissue of CRS patients. depicted in Figure 1.5.1. Specifically, the use of biologic agents
The failure of aetiology-based treatments for CRS is, in that suppress the type 2 endotype, also shrink polyps. Reversal
retrospect, not surprising since CRS is typically an adult onset of goblet cell hyperplasia has not yet been documented, but
disorder with diagnosis most commonly in the fifth decade of in vitro studies suggest that barrier-related remodelling is
life. This extended premorbid time course suggests a complex driven directly, in large measure, by canonical type 2 cytokines.
host-environmental interaction, with great variability in nature, Biologic agents that suppress type 2 inflammation may,
sequence and intensity of exogenous stressors including therefore, suppress the inflammation, reverse the remodelling
superimposed stochastic events. Dissecting out the process in and limit recurrence, thereby altering the clinical course of
an individual patient would be a daunting, if not impossible the most severe CRS phenotypes. Further research into type
task that might still not lead to any therapeutic path forward. By 2 inflammation will be extremely helpful in the use of these
analogy, identifying smoking as carcinogenic may help prevent powerful drugs, which have the potential to revolutionize CRS
future cancers through avoidance, but it will not significantly treatment(64).

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 EPOS 2020

Figure 1.6.1. Treatment evidence and recommendations for adults with chronic rhinosinusitis.

EPOS 2020: Care pathways for CRS

Two CRS symptoms Self-Care PRESENCE OF ALARM SYMPTOMS

One of which should be nasal obstruction • Self-education / e-Health • Periorbital oedema/erythema
• Displaced globe
Pharmacy

and/or discoloured discharge • Saline spray / rinses

Self-Care

± facial pain/pressure • INCS (if OTC) • Double vision

± reduction or loss of smell • Avoid antibiotics • Ophthalmoplegia
> 12 weeks • Avoid exacerbating factors • Reduced visual acuity
• Severe headache
- 6-12 weeks:
+ • Frontal swelling
• Signs of sepsis
improvement? • Signs of meningitis
Refer to Primary Care • Neurological signs
• Unilateral symptoms
• Bleeding
• Crusting
Primary care follow-up • Cacosmia
Primary
Care

• Saline rinses + IMMEDIATE REFERRAL

• INCS (if not OTC)
6-12 weeks:
• Educate compliance/technique improvement?
• Avoid antibiotics
• Check treatable traits and comorbidities - +

Refer to Secondary / Tertiary Care

Check treatable traits / comorbidities

History and full ENT exam
Nasal endoscopy

Follow EPOS 2020 management scheme

Diffuse / bilateral CRS
Secondary / Tertiary

on diffuse / bilateral CRS

CT scan
Care

Localized / unilateral CRS

(urgent if suspicion of tumour)

Diagnosis rejected
Reconsider differential diagnosis

Diagnosis confirmed
Surgery likely
Refer if necessary / suspected malignancy

Consider CT scan
No (apparent) CRS Reconsider differential diagnosis

CRS: chronic rhinosinusitis; CT, computed tomography; INCS, intranasal corticosteroids spray; OTC, over-the-counter.

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 EPOS 2020

Figure 1.6.2. EPOS2020 management scheme on diffuse CRS.

Diffuse / bilateral CRS Presence of: Secondary diffuse CRS

• Bleeding / crusting (e.g. vasculitis / immune disorder)
• Severe pain • Serologic investigations
• Tissue loss • Consider biopsy
Primary • Involvement of other organs • CT scan
diffuse CRS • Involve appropriate specialists
to treat underlying disease

ALARM SYMPTOMS
Appropriate medical therapy (AMT) • Periorbital oedema/erythema
• Nasal steroid (drops / spray / rinses) + • Displaced globe
• Saline rinses • Double vision
• Educate technique / compliance 6-12 weeks: • Ophthalmoplegia
• Consider OCS improvement? • Reduced visual acuity

- • Severe headache
• Frontal swelling
Additional work-up: • Signs of sepsis
• Signs of meningitis
CT-scan, SPT, lab; reconsider treatable traits, compliance
• Neurological signs
• Unilateral symptoms
• Bleeding
• Crusting
Non-type 2 Type 2
• Cacosmia
• Main complaint often • Main complaint often smell loss
discharge/facial pain or blockage/congestion AFRS
• Less asthma • N-ERD and/or asthma
• Less atopy • Atopy • Young
• Atopy
NE: purulence NE: polyps, eosinophilic mucin • Warm humid climate
Lab: normal IgE, no eosinophilia Lab: elevated IgE, eosinophilia • Asthma
• SPT: positive for fungi

Consider:
AMT (± longterm antibiotics) AMT (± OCS)
• MRI of sinuses with contrast
or or
• Ophthalmology and
FESS FESS neurosurgery consultation
• Preoperative OCS
+
6-12 weeks: improvement? FESS
• Tailored
Consider: (extended) surgery
- - to remove all debris
• Histopathology
Additional therapy Additional therapy eosinophils, hyphae, CL crystals
Consider: Consider: • Culture fungus
• Xylitol rinses • Biologicals +
• Longterm antibiotics • ATAD in case of N-ERD Saline rinses
• Revision surgery • OCS taper 6-12 weeks: INCS
Additional investigations • Revision surgery improvement? OCS
Consider: Consider immunotherapy
• Secondary diffuse CRS - Repeat imaging with
(e.g. vasculitis / immune disorder)
concern for recurrence

For explanation of (primary and secondary) diffuse CRS see 1.2.3.

AMT, appropriate medical therapy; ATAD, Aspirin treatment after desensitisation; CRS, chronic rhinosinusitis; CT, computed tomography; FESS, func-
tional endoscopic sinus surgery; INCS, intranasal corticosteroid spray; MRI, magnetic resonance imaging; NE, nasal endoscopy; N-ERD, NSAID-exacer-
bated respiratory disease; OCS, Oral corticosteroids; SPT, Skin prick test.

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 EPOS 2020

1.5.4. Differential diagnosis and diagnostic tools scanning may be more cost-effective as compared to extended
courses of antibiotics given empirically and is preferred by
1.5.4.1. Differential diagnosis patients(79-81).Multi-detector CT (MDCT) scanners and cone-
It was decided to include more information in EPOS2020 to beam CT are reducing the radiation dose whilst preserving
better allow differential diagnosis of rhinosinusitis from certain image quality by shortening the scan time and using post-
other conditions and common symptoms, notably allergic processing techniques(82, 83) without compromising anatomical
and non-allergic rhinitis, olfactory loss and facial pain. We also accuracy(84),making them increasingly attractive(85, 86).
include an updated and expanded range of diagnostic tools, In the measurement of health-related quality-of-life (HRQL), a
though many have not substantially changed since 2012. wide range of validated patient reporting outcome measures
Upper airway diseases present with a variable pattern of (PROMS) are available but currently none of the established
common symptoms such as nasal obstruction and discharge, PROMS capture all the desired aspects of CRS; the SNOT-22
making the epidemiological diagnosis of CRS difficult to fails to capture disease duration or medication usage. Current
differentiate from allergic and nonallergic rhinitis based on recommendations include the use of SNOT-22 scores repeated
symptomatic grounds. Combining data from different studies over time, Lund Kennedy endoscopic scores, and additional
leads to a picture of significant overlap in prevalence and questions to evaluate the need for systemic medications or
severity of symptomatology. However, as there are generally progression to surgery, compliance with and side effects of
less inflammatory changes seen on CT sinuses in AR and NAR treatment, additional information on symptom frequency, and
than CRS(65) a combination of symptoms, CT scan and nasal impact on ability to perform normal activities(87).
endoscopy can point in the right direction. Nasal endoscopy remains an essential part of the rhinological
Olfactory loss is one of the cardinal symptoms of CRS but has examination. A recent systematic review analysed the accuracy
a wide differential diagnosis(66). The prevalence of olfactory of nasal endoscopy in diagnosing chronic rhinosinusitis (CRS)
disorders in the general population is estimated to be 3-5 % for compared with paranasal sinus computed tomography (CT).
total smell loss (anosmia) and 15-25 % for partial impairment Sixteen observational or retrospective studies were included
(hyposmia)(67, 68). In CRS the mechanism leading to olfactory resulting in a high correlation (r=0.85; 95% confidence interval
impairment is twofold: inflammatory and purely mechanical [CI][0.78–0.94], p<0.0001, I2 77%) between endoscopy and CT in
due to obstruction of the olfactory cleft(69, 70), which explains why terms of the diagnostic accuracy for CRS(88).
not all patients have an olfactory benefit from surgical removal A clinical history supported with a skin prick test or serum IgE
of polyps alone but also require subsequent anti-inflammatory measuremernt will probably remain the gold standard of the
treatment. However, CRS-related olfactory loss has a good upper airway allergy diagnosis but advances are expected from
success rate of improvement if the CRS is treated even if not the molecular in vitro diagnosis which may change this trend,
always sustained in the long-term. due to improved technology which enables faster diagnosis on
Facial pain is another cardinal symptom of CRS which can a broader panel of allergens(89, 90).
occur in many other conditions(71). However, facial pain when As CRS patients are commonly not fully aware of their olfactory
it occurs alone is rarely caused by CRS and, therefore, when impairment, or are unable to estimate the severity of the loss,
it occurs without other nasal complaints or abnormalities on the use of smell tests is recommended in order to objectively
examination, it should not (primarily) be addressed surgically. evaluate this disorder(91, 92). The most widely used remain the
North American UPSIT(93), its short version (SIT, B-SIT) and the
1.5.4.2. Diagnostic tools European Sniffin’Sticks(94). Although there are many others,
The different imaging modalities in diagnosing rhinosinusitis all have cultural bias and there have been recent advances to
[conventional X-ray, computerized tomography (CT), cone overcome this with culturally unbiased, universally usable smell
beam CT and magnetic resonance imaging (MRI)] have been tests(95).
evaluated(72). Overall CT scan remains the gold standard in the Nasal obstruction is the most significant of the cardinal
radiologic evaluation of rhinologic disease, notably CRS(73-75). symptoms of rhinosinusitis and nasal patency may be
However, in acute rhinosinusitis, the diagnosis is made on objectively evaluated with peak nasal inspiratory flow
clinical grounds and CT is not recommended(3) unless the (PNIF), (active anterior) rhinomanometry (AAR), and acoustic
condition persists despite treatment, or a complication is rhinometry (AR) Newer methods such as computational fluid
suspected(76). Conventional sinus X-rays are no longer indicated dynamics(96) are presently mainly used for research purposes(97, 98)
in either ARS or CRS. but may be of value in the future.
The most commonly used and validated scoring system of In addition to confirming diagnosis, histopathology is becoming
sinonasal inflammatory change remains the Lund-Mackay more important to assist in endotyping of inflammatory
score (LMS) which gives a maximum score of 24 or 12/side(77). disease, thereby directing potential therapies, e.g. biologics.
An LMS of 2 or less has an excellent negative predictive value, Eosinophilic CRS (eCRS) requires quantification of the numbers
and an LMS of 5 or more has an excellent positive predictive of eosinophils, i.e. number/high powered field (HPF (400x) and
value, strongly indicating true disease. In CRS, CT was not EPOS2020 supports 10 or >/HPF. Further stratification may be
normally recommended until after an appropriate course of made between those with10-100 eosinophils per HPF in two
medical therapy had failed(3, 78) and without an intervening or more areas and those with >100 eosinophils per HPF in two
acute episode but more recent studies suggest that early CT or more areas(99). The amount of eosinophilic infiltration and

15
 EPOS 2020

the overall intensity of the inflammatory response are closely Many studies do not make a clear differentiation between
related to the prognosis and severity of disease(100). Until recently CRSsNP and CRSwNP. Very few studies further define CRS
most blood tests in patients with CRS were performed to phenotypes or endotypes in the disease. CRS research has
diagnose immunodeficiencies and vasculitis. However, recently revealed that patients with a pure or mixed type 2 endotype
the options to treat with biologicals has put more emphasis on tend to be more resistant to current therapies, exhibiting a
markers of type 2 disease, although as it stands we are not aware high recurrence rate when compared with pure type 1 or 3
of biomarkers that can predict response to biologicals in CRS(101). endotypes.
For microbiology, in addition to the standard culture-dependant For diffuse, bilateral CRS, local corticosteroids and saline remain
tests, newer culture-independent techniques including next the mainstay of the treatment (Figure 1.6.1.).
generation sequencing may provide significant insight into Furthermore, the integrated care pathway (ICP) advises to check
CRS pathophysiology. This could include sequencing of all DNA treatable traits, to avoid exacerbating factors and advises against
(metagenomics) or all transcribed RNA (metatranscriptomics) the use of antibiotics. In secondary care, nasal endoscopy can
or identification of proteins (metaproteomics) or metabolites confirm disease, point to secondary CRS (e.g. vasculitis) and
(metabolomics), showing not only the true diversity and further differentiate between localized and diffuse disease
structure, but also the full genetic potential and in situ activity of (Figure 1.6.2.).
the mucosa-associated microbiota(102). In addition, emphasis is put on optimum techniques of
EPOS2020 also includes an update on mucociliary testing and medication delivery and compliance. If treatment with nasal
other tests for primary ciliary dyskinesia (PCD), sweat testing steroid and saline is insufficient, an additional work-up with CT
and other tests for cystic fibrosis and advances in genetic scan and endotyping is relevant. Depending on the endotype
testing as well as new diagnostic tools for N-ERD. Finally, the indication, treatment can be tailored to a more type 2 or non-
lower respiratory tract is not forgotten and the full range of type 2 profile. International guidelines differ regarding whether
available investigations are covered from peak expiratory flow to long-term antibiotics and oral steroids should be included as
provocation tests and expired nitric oxide measurement. part of adequate medical therapy (AMT), reflecting conflicting
evidence in the current literature(3, 78, 105), and concerns with
1.6. Management of chronic rhinosinusitis in adults regard to side-effects. There is a lot of debate on the appropriate
moment for surgery for CRS(105). In a recent study for adult
1.6.1. Introduction patients with uncomplicated CRS, it was agreed that ESS could
An important difference compared to EPOS2012 is that we be appropriately offered when the CT Lund-Mackay score was
have decided to move away from differentiating between the ≥1 and there had been a minimum trial of at least eight weeks’
management of CRSsNP and CRSwNP per se. The understanding duration of a topical intranasal corticosteroid plus a short-course
of the last decade of endotyping of CRS and the consequences of systemic corticosteroid (CRSwNP) or either a short-course of a
of endotypes for the management of disease has led to the broad spectrum / culture-directed systemic antibiotic or the use
decision to describe management of CRS based on endotyping of a prolonged course of systemic low-dose anti-inflammatory
and phenotyping. antibiotic (CRSsNP) with a post-treatment total SNOT-22 score
We propose a new clinical classification based on the disease ≥20. These criteria were considered the minimal threshold,
being localized (often unilateral) or diffuse (always bilateral). and clearly not all patients who meet the criteria should have
Both these groups can be further divided into type 2 or non- surgery, but their application should reduce unnecessary
type 2 disease (Figure 1.2.1.). The major challenge is to find surgery and practice variation. A subsequent study applied
reliable biomarkers that define type 2 inflammation and predict these criteria retrospectively to patients recruited to a multi-
reaction to medication. Unfortunately, recent large studies centre cohort study and found that patients where surgery was
with monoclonal antibodies directed at type 2 endotypes deemed ‘inappropriate’ reported significantly less improvement
have not found reliable biomarkers to predict response to in their quality of life postoperatively(106).
treatment(103, 104). For the moment the combination of phenotype It is important to emphasize that CRS is a chronic disease and
(e.g. CRSwNP, N-ERD), response to treatment (systemic ESS a step in the management that is primarily aimed at creating
corticosteroids) and possibly also markers like eosinophils, better conditions for local treatment. After surgery continuous
periostin and IgE either in blood or tissue lead us to the best appropriate medical treatment is mandatory.
estimation of the endotype and reaction to treatment. This If surgery in combination with appropriate medical treatment
is a rapidly evolving field at the moment and we expect that fails, additional therapy can be considered. Options are the
frequent updates will be necessary. use of aspirin treatment after aspirin desensitisation (ATAD)(107),
longer (tapering) treatment with OCS, long term antibiotics( 108)
1.6.2. Management of CRS: an integrated care pathway and/or biologicals when indicated.
For the management of CRS, a full systematic review of the
literature has been performed (see chapter 6 and Table 1.6.1.). 1.6.3. New treatment options with biologicals (monoclonal
Many forms of localised CRS (Figure 1.2.1.) in general, either type antibodies)
2 or non-type 2, are not responsive to medical treatment and The acceptance of dupilumab (anti IL-4Rα) for the treatment
need surgery. For that reason, we advise patients with unilateral of CRSwNP by the US Food and Drug Administration(FDA) and
disease to be referred to secondary care for further diagnosis. European Medicines Agency (EMA) in 2019 has significantly

16
 EPOS 2020

Figure 1.6.3. Indications for biological treatment in CRS.

Indications for biological treatment in CRSwNP

Presence of bilateral polyps in a patient who had ESS*

THREE criteria are required

Criteria Cut-off points

• Evidence of type 2 inflammation Tissue eos ≥10/hpf, OR blood eos ≥250, OR total IgE ≥100
• Need for systemic corticosteroids or ≥ 2 courses per yr, OR long term (>3 months)
contraindication to systemic steroids low dose steroids
• Significantly impaired quality of life SNOT-22 ≥ 40
• Significant loss of smell Anosmic on smell test (score depending on test)
• Diagnosis of comorbid asthma Asthma needing regular inhaled corticosteroids

*exceptional circumstances excluded (e.g., not fit for surgery)

CRS, chronic rhinosinusitis; CRSwNP: chronic rhinosinusitis with nasal polyps; ESS, endoscopic sinus surgery; hpf: high power field (x400); SNOT-22,
sino-nasal outcome test-22.

Figure 1.6.4. Response criteria for biologicals in the treatment of CRS.

Defining response to biological treatment in CRSwNP

Evaluation of 5 criteria Excellent response

5 criteria
• Reduced nasal polyp size
Moderate response
• Reduced need for systemic corticosteroids 3-4 criteria
• Improved quality of life Poor response
• Improved sense of smell 1-2 criteria
• Reduced impact of co-morbidities No response
0 criteria

Evaluate treatment response after 16 weeks

Discontinue
treatment
if no response
Evaluate treatment response after 1 year in any
of the criteria

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 EPOS 2020

Table 1.6.1. Treatment evidence and recommendations for adults with chronic rhinosinusitis.

Level of
Therapy GRADE recommendation
evidence
Short term antibiotics for CRS 1b (-) There are only two small placebo-controlled studies, one in CRS and one in acute exacerbation of CRS. Both show no
effect on symptomatology apart from significantly reduced postnasal drip symptom scores at week 2 in the CRS study.
Seven studies evaluated two different antibiotics regimes, of which only one was placebo-controlled. One out of seven
studies in patients with CRS showed a significant effect on SNOT at 2 and 4 weeks and also one study a significant
improvment in symptoms of infection at day 3 to 5 in one antibiotic versus another in a mixed group of patients with
CRS and with acute exacerbation. The other 5 studies showed no difference in symptomatology. Only two of these seven
studies, both of which were negative, evaluated the effect after one month.
The EPOS2020 steering group, is uncertain, due to the very low quality of the evidence, whether or not the use of a short
course of antibiotics has an impact on patient outcomes in adults with CRS compared with placebo. Also, due to the very
low quality of the evidence, it is uncertain whether or not the use of a short course of antibiotics has an impact on patient
outcomes in adults with acute exacerbations of CRS compared with placebo. Gastrointestinal-related adverse events
(diarrhoea and anorexia) are frequently reported.

Short term antibiotics for acute 1b (-) The EPOS2020 steering group, is uncertain, due to the very low quality of the evidence, whether or not the use of a
exacerbation of CRS short course of antibiotics has an impact on patient outcomes in adults with acute exacerbations of CRS compared with
placebo. Gastrointestinal-related adverse events (diarrhoea and anorexia) are frequently reported.

Longterm antibiotics for CRS 1a (-) The EPOS2020 steering group, due to the low quality of the evidence, is uncertain whether or not the use of long-term
antibiotics has an impact on patient outcomes in adults with CRS, particularly in the light of potentially increased risks of
cardiovascular events for some macrolides. Further studies with larger population sizes are needed and are underway .

Topical antibiotics 1b (-) Topical antibacterial therapy does not seem to be more effective than placebo in improving symptoms in patients
with CRS. However, it may give a clinically non-relevant improvement in symptoms, SNOT-22 and LK endoscopic score
compared to oral antibiotics. The EPOS2020 steering group, due to the very low quality of the evidence, is uncertain
whether or not the use of topical antibiotic therapy has an impact on patient outcomes in adults with CRS compared with
placebo.

Nasal corticosteroids 1a There is high-quality evidence that long term use of nasal corticosteroids is effective and safe for treating patients with
CRS. They have impact on nasal symptoms and quality of life improvement, although the effect on SNOT-22 is smaller
than the minimal clinically important difference. The effect size on symptomatology is larger in CRSwNP (SMD -0.93,
95% CI -1.43 to -0.44) than in CRSsNP (SMD -0.30, 95% CI -0.46). The meta-analysis did not show differences between
different kinds of nasal corticosteroids. Although in meta-analysis higher dosages and some different delivery methods
seem to have a larger effect size on symptomatology, direct comparisons are mostly missing. For CRSwNP, nasal
corticosteroids reduce nasal polyp size. When administered after endoscopic sinus surgery, nasal corticosteroids prevent
polyp recurrence. Nasal corticosteroids are well tolerated. Most adverse events reported are mild to moderate in severity.
Nasal corticosteroids do not affect intraocular pressure or lens opacity. The EPOS2020 steering group advises to use nasal
corticosteroids in patients with CRS. Based on the low to very low quality of the evidence for higher dosages or different
delivery methods and the paucity of direct comparisons the steering committee cannot advise in favour of higher
dosages or certain delivery methods.

Corticosteroid-eluting implants 1a The placement of corticosteroid-eluting sinus implants in the ethmoid of patients with recurrent polyposis after sinus
surgery has a significant but small (0.3 on a 0-3 scale) impact on nasal obstruction but significantly reduces the need
for surgery and reduces nasal polyp score. Based on the moderate to high quality of the evidence the steering group
considered the use of corticosteroid-eluting sinus implants in the ethmoid an option.

Systemic corticosteroids 1a ¸ A short course of systemic corticosteroid, with or without local corticosteroid treatment results in a significant reduction
in total symptom score and nasal polyp score. Although the effect on the nasal polyp score remains significant up to
three months after the start of treatment by that time there is no longer an effect on the symptom score. The EPOS2020
steering group felt that 1-2 courses of systemic corticosteroids per year can be a useful addition to nasal corticosteroid
treatment in patients with partially or uncontrolled disease. A short course of systemic corticosteroid postoperatively does
not seem to have an effect on quality of life. Systemic corticosteroids can have significant side effects.

Antihistamines Ib There is one study reporting on the effect of antihistamines in partly allergic patients with CRSwNP. Although there was no
difference in total symptom score, the days with a symptom score ≤1 was higher in the treated group. The quality of the
evidence comparing antihistamines with placebo was very low. There is insufficient evidence to decide on the effect of
the regular use of antihistamines in the treatment of patients with CRS.

Anti-leukotrienes 1b (-) Based on the very low quality of the available evidence, the EPOS2020 steering group is unsure about the potential
use of montelukast in CRS and does not recommend its use unless in situations where patients do not tolerate nasal
corticosteroids. Also, the quality of the evidence comparing montelukast with nasal corticosteroid is low. Based on the
evidence, the steering group does not advise adding montelukast to nasal corticosteroid but studies evaluating the effect
of montelukast in patients that failed nasal corticosteroids are missing.

Decongestant Ib There is one small study in CRSwNP patients showing a significantly better effect of oxymetazoline combined with MFNS
than MFNS alone without inducing rebound swelling. There was no effect of xylometazoline compared to saline in the
early postoperative period. This review found a low level of certainty that adding a nasal decongestant to intranasal
corticosteroids improves symptomatology in CRS. Although the risk of rebound swelling was not shown in this study, the
EPOS2020 steering group suggests in general not to use nasal decongestants in CRS. In situations where the nose is very
blocked, the temporary addition of a nasal decongestant to nasal corticosteroid treatment can be considered.

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 EPOS 2020

Table 1.6.1. Cont.

Therapy Level of GRADE recommendation

evidence

Nasal irrigation with saline Ia There are a large number of trials evaluating the efficacy of nasal irrigation. However, the quality of the studies is not
always very good which makes it difficult to give a strong recommendation. However, the data show:
Nasal irrigation with isotonic saline or Ringer’s lactate has efficacy in CRS patients.
There is insufficient data to show that a large volume is more effective than a nasal spray.
The addition of xylitol, sodium hyaluronate, and xyloglucan to nasal saline irrigation may have a positive effect.
The addition of baby shampoo, honey, or dexpanthenol as well as higher temperature and higher salt concentration do
not confer additional benefit.
The steering group advises the use of nasal saline irrigation with isotonic saline or Ringer’s lactate with or without the
addition of xylitol, sodium hyaluronate, and/or xyloglucan and advises against the use of baby shampoo and hypertonic
saline solutions due to side effects.

Aspirin treatment after Ia Oral ATAD has been shown to be significantly more effective and clinically relevant than placebo in improving QOL
desensitization (ATAD) with oral (measured with SNOT) and total nasal symptom score in patients with N-ERD. However, the change in SNOT from treating
aspirin in N-ERD with oral ATAD compared to placebo did not reach the clinically important mean difference. ATAD reduced symptoms
after six months compared to placebo. However, ATAD is associated with significant adverse effects, and the risks of not
taking the medication strictly on a daily basis puts a burden on patient and caregiver.
Based on these data, the EPOS2020 steering group suggests that ATAD can be a treatment for N-ERD patients with
CRSwNP whenever there is confidence in the patient’s compliance.

Aspirin treatment after 1b (-) ATAD with lysine aspirin and platelet inhibitors (like Pradugrel) have not been shown to be an effective treatment in
desensitization (ATAD) with nasal CRSwNP patients with N-ERD and are not advised.
lysine aspirin in N-ERD

Low salicylate diet Ib Diets, like low salicylate diet have been shown to improve endoscopic scores and may improve symptoms compared to
a normal diet in patients with N-ERD. However, the quality of the evidence at this moment is not enough to draw further
conclusions.

Local and systemic antifungal 1a (-) Local and systemic antifungal treatments do not have a positive effect of QOL, symptoms and signs of disease in patients
treatments with CRS. The EPOS2020 steering group advises against the use of anti-mycotics in CRS.

Anti-IgE Ib Anti-IgE therapy has been proposed as a promising biologic therapy for CRS. Two RCTs that evaluated anti-IgE monoclonal
antibody did not show impact on disease specific QOL but one study did show an effect on the physical domain of SF-36
and AQLQ. One study demonstrated lower symptom scores (change from baseline in anti IgE group) for nasal congestion,
anterior rhinorrhoea, loss of sense of smell, wheeze and dyspnoea, a significant reduction of NPS on endoscopic
examination, and Lund-MacKay scores on radiologic imaging. Due to the small study population in the existing studies,
further studies with larger population sizes are needed and are underway. The available data are insufficient to advise on
the use of anti-IgE in CRSwNP at this moment.

Anti-Il-5 Ib There is only one large sufficiently powered study with Mepolizumab that showed a significant reduction in patients’ need
for surgery and an improvement in symptoms. Unlike in CRS, there is a significant experience with anti-Il5 in other type
2 driven diseases like asthma that do show a favourable safety profile so far. The EPOS2020 steering group advises use of
mepolizumab in patients with CRSwNP fulfilling the criteria for treatment with monoclonal antibodies (when approved).

Anti IL-4/IL-13 (IL-4 receptor α) Ia At the moment the only anti-Il-4 treatment studied in CRS is dupilumab. Dupilumab is the only monoclonal antibody
that is approved for the treatment of CRSwNP so far. When evaluating all trials with dupilumab, the drug seems to induce
conjunctivitis in trials in patients with atopic dermatitis but not in trials with asthma and CRSwNP. No other adverse
events have been reported in the literature until now. The EPOS steering group advises to use dupilumab in patients with
CRSwNP fulfilling the criteria for treatment with monoclonal antibodies.

Probiotics 1b (-) Although probiotic therapies show theoretical promise, the two studies performed so far did not show any differences
compared to placebo. For this reason, the EPOS2020 steering group advises against the use of probiotics for the treatment
of patients with CRS.

Muco-active agents 1b Data on the effect of muco-active agents in CRS are very limited. The only DBPCT evaluating the addition of
S-carboxymethylcysteine to clarithromycin showed a significantly higher percentage of patients with effective response
and improved characteristics of nasal discharge at 12 weeks. The EPOS2020 steering group considered the quality of the
data insufficient to advise on the use of muco-active agents in the treatment of patients with CRS.

Herbal treatment 1b Of five RCTs evaluating herbal treatment, a large DBPCT, using tablets, showed overall no effect, although a post-hoc
sensitivity analysis, showed a significant benefit in major symptom score at 12 weeks of treatment over placebo in patients
with a diagnosis of CRS for >1 year and a baseline MSS >9 (out of max 15). Of the four studies evaluating different local
herbal treatment, three showed a favourable effect. However, not all studies were blinded and the quality of the studies
was variable.
The treatment does not show significantly more adverse events than placebo. The quality of the evidence for the local
treatment is low. Based on the available data, the EPOS2020 group cannot advise on the use of herbal medicine in CRS.

Acupuncture and traditional 1b (-) There is no evidence that traditional Chinese medicine or acupuncture is more effective than placebo in the treatment of
Chinese medicine CRS. The safety of Chinese medicine is unclear because most of the papers are not (easily) accessible. Minor and serious
adverse events can occur during the use of acupuncture and related modalities, contrary to the common impression
that acupuncture is harmless. For this reason, the EPOS2020 steering group advises against the use of traditional Chinese
medicine or acupuncture.

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 EPOS 2020

Table 1.6.1. Cont.

Therapy Level of GRADE recommendation

evidence

Oral verapamil 1b A very small pilot study showed significant improvement in QOL (SNOT-22), polyp score (VAS), and CT scan (LM-score) of
oral verapamil over placebo. (Potential) side effects limited the dosage.
The quality of the evidence for oral verapamil is very low. Based on the potential side effects the EPOS2020 steering group
advises against the use of oral verapamil.

Nasal furosemide 1b A recent DBPCT study showed significantly reduced QOL (SNOT-22) scores and polyp score (VAS), and significantly
more patients with an NPS of 0 in the furosemide nasal spray treated group versus placebo. There was no indication of a
difference in adverse events between topical furosemide and placebo. However, the quality of the evidence is very low.
The EPOS2020 steering group cannot advise on the use of nasal furosemide.

Capsaicin 1b Capsaicin showed a significant decrease in nasal obstruction and nasal polyp score in two small studies, however data on
other symptoms like rhinorrhea and smell are either non-significant or unreported. The quality of the evidence is low and
the EPOS steering group concludes that capsaicin may be an option in treatment of CRS in patients with CRSwNP but that
larger studies are needed.

Proton-pump inhibitors 1b (-) Proton-pump inhibitors have been shown in one study to be not effective. Moreover, long term use of proton pump
inhibitors has been associated with increased risk of cardiovascular disease. The EPOS2020 steering group therefore does
advise against the use of proton pump inhibitors in the treatment of CRS.

Bacterial lysate 1b There is one DBPCT from 1989 comparing the bacterial lysate Broncho-Vaxom to placebo in a large group of CRS patients
resulting in a significant decrease in purulent nasal discharge and headache over the full six month period compared to
placebo and reduced opacification of the sinus X-ray. Based on this limited evidence, the EPOS2020 steering group cannot
advise on the use of Broncho-Vaxom in the treatment of CRS.

Phototherapy 1b (-) We identified two trials with opposing findings. The quality of the evidence for the use of phototherapy in patients with
CRS is very low. Based on the evidence, the EPOS2020 steering group cannot make a recommendation on the use of
phototherapy in patients with CRS.

Filgastrim (r-met-HuG-CSF) 1b (-) There is one study evaluating Filgastrim compared to placebo in CRS. There was no significant difference in effect on QOL
between the two groups. Based on the evidence, the EPOS2020 steering group cannot make a recommendation on the
use of Filgastrim in patients with CRS.

Collodial silver nasal spray 1b (-) One very small study did not find differences between nasal colloidal silver spray and placebo. Based on the evidence, the
EPOS2020 steering group cannot make a recommendation on the use of collodial silver nasal spray in patients with CRS.

ATAD, Aspirin treatment after desensitisation ; CI, confidence interval; CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps;
CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, double blind placebo controlled trial; LK, Lund Kennedy; MFNS, mometasone fuorate nasal
spray; MSS, major symptom score; N-ERD, NSAID-exacerbated respiratory disease; NPS, nasal polyp score; QOL, quality of life; RCT, randomised con-
trolled trial; SNOT-22, sino-nasal outcome test-22; SMD, standard mean difference.

changed the treatment options in type 2 type CRS and it The response criteria for biologicals have been taken from the
is expected that other monoclonal antibodies will follow. EUFOREA paper (Figure 1.6.4.), although the EPOS2020 group
Until 2019 monoclonal antibodies could only be prescribed also discussed whether there was an indication to repeat
in patients with concomitant (severe) asthma. Within the surgery in patients on biologicals to give them a better starting
EUFOREA setting, the positioning of biologics in the ICP of point. It was decided that we had insufficient data to advise on
CRS with criteria for use and stopping of biologics have been surgery whilst on biologicals before deciding that they are not
published(101). The EPOS2020 steering group made some effective and that this is a research need.
modifications and tightening of these criteria. They concluded
that biologicals are indicated in a patient with bilateral polyps, 1.6.4. Conclusion
who had had sinus surgery or was not fit for surgery and who EPOS2020 provides a full evidence based systematic review of
had three of the following characteristics: evidence of type 2 the management of CRS that has been incorporated into an
disease (tissue eosinopils ≥10/HPF or blood eosinophils ≥250 integrated care pathway (Figures 1.6.1. and 1.6.2.). A significant
OR total IgE ≥100), need for at least two courses of systemic shift in the management of CRS has occurred since EPOS2012.
corticosteroids or continuous use of systemic corticosteroids The options of biologicals in the treatment of type 2 CRS will be
(≥2 courses per year OR long term (>3 months) low dose a paradigm shift in the management of the disease. The exact
steroids OR contraindication to systemic steroids), significantly positioning of this presently very expensive treatment needs
impaired quality of life ( SNOT-22 ≥40), anosmic on smell test to be determined. (Figures 1.6.3. and 1.6.4.).EPOS2020 further
and/or a diagnosis of comorbid asthma needing regular inhaled emphasizes the criteria for (revision) surgery in the disease.
corticosteroids (Figure 1.6.3.).

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1.7.Paediatric chronic rhinosinusitis endotyping.

1.7.1. Epidemiology and predisposing factors 1.7.3. Management of paediatric CRS including integrated
This section has been considerably expanded, reflecting new care pathway
literature. The prevalence of CRS in paediatric patients is now Medical therapy remains the mainstay of management of
estimated to be up to 4%(109).Both passive and active cigarette paediatric chronic rhinosinusitis (Table 1.7.1.). Saline nasal
smoking are associated with chronic rhinitis and rhinosinusitis irrigation is recommended for the treatment of CRS in
in children(110) though a clear and definitive causal relationship children. Addition of nasal antibiotics to saline irrigations is
between allergic rhinitis and CRS has not been established(111). not recommended. There is currently no evidence to support
Evidence suggests that the adenoids may act as a reservoir for treatment of children with CRS with either oral or intravenous
pathogenic bacteria, rather than a source of obstruction(112, antibiotics. There is also no evidence to support the utilization of
113)
whilst the relationship between GORD and CRS in children prolonged macrolide therapy in children with CRS.
remains controversial(114). A large database study suggests a Intranasal steroids are recommended for use in children with
significant familial risk associated with paediatric CRS(115) but CRS despite the absence of good level evidence. This is based
studies on monozygotic twins have not shown that both siblings on safety in children and favourable efficacy data in adults with
always develop polyps, indicating that environmental factors CRS (see chapter 6) and children with rhinitis(117).
are as likely as genetic ones to influence the occurrence of nasal There is hardly any scientific support for other ancillary therapies
polyps. such as antihistamines (intranasal or oral), leukotriene modifiers,
decongestants (intranasal or oral), or mucus thinners and these
1.7.2. Inflammatory mechanisms treatments are not recommended. Exceptions are using ancillary
Multiple studies suggest upregulation of different inflammatory therapies when indicated for concomitant disease such as
substances important in adaptive and innate immunity as well allergic rhinitis or GORD.
as tissue remodelling in sinus tissues, adenoids, nasal lavage, Surgical intervention is considered for patients with CRS who
mucus and serum in children with CRS. Although the evidence have failed appropriate medical therapy (and, less commonly, in
is still scarce, these studies suggest a role for inflammatory complicated acute rhinosinusitis). It seems that adenoidectomy
mechanisms in paediatric CRS. Although many of the markers with / without antral irrigation is certainly the simplest and
parallel those seen in adults, the data is very heterogeneous safest first procedure to consider in younger children with
and does not yet lend itself to endotyping. Inflammatory symptoms of CRS. Evidence suggests that antral irrigation
cytokines are present in sinus tissues of children with CRS and should be considered in addition to an adenoidectomy in
are more abundant when concomitant asthma is present(116). children with asthma who have more severe disease on
Although more evidence is emerging to support upregulation preoperative CT scans. FESS is a safe and possibly effective
of inflammatory markers in paranasal sinus tissues and nasal surgical modality in children with CRS and can be used as
lavages of children with CRS, the data is also relatively limited primary modality or after failure of adenoidectomy in older
and heterogeneous and again does not yet lend itself to children. Decisions on use depends on severity of disease, age

Table 1.7.1. Evidence supporting therapy of CRS in children.

Level of
Therapy GRADE recommendation
evidence
Antibiotics 1b (-) There is no high level evidence to support the efficacy of either short or long term antibiotics for
CRS in children.

Nasal corticosteroids 5 There is no evidence regarding the efficacy of intranasal steroids in the treatment of CRS in
children. Nevertheless the EPOS steering group is supportive of their use in light of their anti-
inflammatory effects and excellent safety record in children.
Systemic Steroids 1b (+) Adding a taper course of systemic steroids to an antibiotic (not effective on its own) is more
effective than placebo in the treatment of paediatric CRS. Judicious use of this regimen is
advised considering systemic side effects.
Saline Irrigation Ib (+) There are a few clinical trials demonstrating the efficacy of saline irrigations in paediatric patients
with CRS. The EPOS steering group is supportive of the use of saline in light of the excellent
safety record in children.
Adenoidectomy 4 Adenoidectomy is effective in younger children with symptoms of CRS. The EPOS steering group
supports adenoidectomy in young children refractory to appropriate medical therapy.
FESS 4 FESS is safe and effective for the treatment of older children with CRS refractory to medical
therapy or previous adenoidectomy.

CRS, chronic rhinosinusitis; FESS, functional endoscopic sinus surgery.

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Figure 1.7.1. Integrated care pathway in paediatric CRS.

EPOS 2020: Care pathways for Paediatric CRS

Two CRS symptoms Self-Care PRESENCE OF ALARM SYMPTOMS

• Periorbital oedema/erythema Differential
One of which should be nasal obstruction
Pharmacy

• Self-education / e-Health
Self-Care

• Displaced globe Diagnosis

and/or discoloured discharge • Nasal hygiene
• Saline spray / rinses • Double vision
± facial pain/pressure Adenoid hypertrophy
• INCS if OTC • Ophthalmoplegia
± cough (non-)Allergic rhinitis
• NSAIDs / Paracetamol • Reduced visual acuity
> 12 weeks Common colds
• Severe headache Primary CRS
• Frontal swelling Secondary CRS
Examination of ears, nose and throat • Signs of sepsis CF
• Signs of meningitis PCD
+ • Neurological signs PID
Suspicion of adenoid hypertrophy? …
• Unilateral symptoms
-
Primary

• Bleeding
Care

INCS • Crusting
+
- 6-12 weeks: improvement?
• Cacosmia
IMMEDIATE REFERRAL

Refer to Primary Care

- Refer to Secondary / Tertiary Care
+

History & full ENT exam; nasal endoscopy

Secondary
Care

Adenoid hypertrophy Primary CRS

Not CRS
Adenoidectomy Consider / test for secondary CRS
and comorbidities
+ 6-12 weeks: - Consider / test for DD and treat
(e.g. CF / PCD / PID)

improvement? (e.g. AR)

Appropriate medical therapy (AMT)
• Nasal steroid (drops / spray / rinses)
+ • Saline rinses
6-12 weeks: Adenoidectomy
Low LMS
improvement? followed by AMT
-
Tertiary

+
- 6-12 weeks:
Care

CT Scan improvement?
Adenoidectomy +/- irrigation
High LMS
followed by AMT Appropriate medical therapy (AMT)
6-12 weeks: + • resolution of symptoms with time
improvement? • check comorbidities / secondary CRS

- In older children: consider FESS

AMT, appropriate medical treatment; CF, cystic fibrosis; CRS, chronic rhinosinusitis; CT, computed tmography; DD, differential diagnosis ; INCS, intrana-
sal corticsteroids; LMS, Lund-Mackay score; NSAIDs, non-steroidal anti-inflammatory drugs; OTC, over the counter; PCD, primary ciliary dyskinesia; PID,
primary immune deficiencies.

and existing co-morbidities. The rate of major complications 1.8. Concomitant diseases in chronic rhinosinusitis
following paediatric FESS was 0.6%, and the rate of minor
complications 2%. Chapter 8 discusses the role of concomitant diseases in CRS.
The systematic review of the literature resulted in an integrated The role of allergy, including central compartment atopic
care pathway for paediatric CRS (Figure 1.7.1.). The differential disease, immunodeficiencies and their role in CRS, a work-up
diagnosis in primary care is broad with the most essential for ENTs before referring to immunologists, lower airway disease
diagnosis in young children being adenoid hypertrophy / including asthma, cystic fibrosis and PCD, fungal rhinosinusitis,
adenoiditis. In secondary and tertiary care, the ICP also advises vasculitis and granulomatous diseases and their role in CRS are
saline irrigation and INCS as first line treatment followed by all discussed.
adenoidectomy with or without sinus irrigation if insufficient.
FESS is reserved for older children who fail adenoidectomy (with 1.8.1. Role of allergy and chronic rhinosinusitis
sinus irrigation). CRS in children may be an indication of severe It has become clear in recent years that the role of allergy in CRS
diseases such as immunodeficiencies, cystic fibrosis or primary depends on different phenotypes / endotypes of CRS. In some
ciliary dyskinesia. Practitioners should be aware of these and phenotypes / endotypes such as AFRS or central compartment
also of serious complications needing immediate referral. atopic disease, allergy seems to play an important role whilst

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Figure 1.8.1. An overview of the interaction of fungi and the human immune response.

Fungi and the human immune response

Allergic fungal Invasive fungal

Fungal ball
rhinosinusitis rhinosinusitis

IMMUNE IMMUNE
IMMUNOCOMPETENT
HYPERSENSITIVITY SUPPRESSION

in others the prevalence does not seem to be higher than in antigens (e.g. tetanus toxoid) and polysaccharide antigens (e.g.
the general population, although even in these patient groups, pneumococcus) and assessing pre- and post-immunization
allergy can be an aggravating factor. Allergic rhinitis (AR) is a antibody levels.
highly prevalent disease and there is a significant overlap in Treatment of patients with primary immune deficiency
symptomatology between CRS and AR. It is not always easy to may consist of long-term antibiotics, often at half dose,
evaluate the role of sensitization to allergens in patients with pneumococcal vaccinations and immunoglobulin replacement
CRS especially in perennial sensitisations. Optimal treatment of therapy.
the allergic rhinitis seems advisable. The prevalence of secondary immune deficiency is
rising due to the increased use of immunosuppressive
1.8.2. Immunodeficiencies and their role in CRS agents such as rituximab, corticosteroids and other drugs
Conditions that are associated with immunodeficiency are and otorhinolaryngologists need to directly ask about
of clinical importance to rhinologists because some patients immunosuppressive agents in their history taking.
who present with CRS are predisposed to their condition by
an underlying immunodeficient state. Immunodeficiency 1.8.3. Lower airway disease including asthma in relation to
conditions may cause CRS patients to respond less favourably CRS
to standard therapies, and some patients require specific Given the epidemiologic and pathophysiologic connection
treatment for their immunodeficiencies in order for their CRS to between CRS and lower respiratory airway disease(11, 118) the
be optimally treated. concept of global airway disease has gained more interest,
Testing of immune function in all patients who present with leading to better diagnosis and therapeutic approaches in
CRS is almost certainly unwarranted as it is likely to produce patients with global airway disease. Lower airway inflammation
more false positive results than true positives. However, it is often co-exists in CRS, with up to two thirds of patients with
recommended that recalcitrance to standard treatments (and CRS affected by comorbid asthma, COPD or bronchiectasis.
particularly rapid recurrence of symptoms after stopping Endoscopic sinus surgery in asthma has been reported to
antibiotics) and association of CRS with lower respiratory improve multiple clinical asthma parameters with improved
tract infections (pneumonia, particularly if recurrent, or overall asthma control, reduced frequency of asthma attacks
bronchiectasis) are used to identify those patients who warrant and number of hospitalizations, as well as decreased use of oral
some form of immune testing. and inhaled corticosteroids.
For CRS patients suspected of having humoral
immunodeficiency because of the characteristics of their 1.8.4. Cystic fibrosis
presentation or their response to treatment, measurement Cystic fibrosis (CF) is a life-shortening genetic condition caused
of serum immunoglobulin levels is the key investigation. by a mutation in the cystic fibrosis transmembrane conductance
If the levels are normal, but the suspicion of humoral regulator (CFTR) gene leading to defective chloride channels,
immunodeficiency is high, referral to a clinical immunologist is which results in secretions with more than double the viscosity
recommended. of secretions of a non-CF individuals. In the Western world
The best approach for confirming a diagnosis of an antibody- national screening programs on specific genetic disorders
deficiency disorder is the measurement of serum-specific including CF have been implemented for newborns. Bilateral
antibody titres (usually IgG) in response to vaccine antigens. nasal polyposis in children may be a clinical indicator of CF.
This approach involves immunizing a patient with protein A major goal in the treatment of patients with CF is thus

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to prevent or delay chronic lung infections. There is a high healthy and diseased sinuses. However, there are several forms
concordance of bacteria cultured from the paranasal sinuses of sinus disease that are associated with fungi as pathogens. In
(based on irrigations, swabs, or mucosal biopsies) and from the these situations, rather than the fungi determining the disease
lungs. process, it is usually the host immune state that determines the
The treatment of CF is currently symptomatic whilst the clinical presentation (Figure 1.8.1).
treatment of the underlying genetic defect, thus curing the There was much prior debate regarding the role of fungi in
disease, has not yet been possible. However, new treatment CRSwNP. Some authors had proposed that a response to fungi
options such as (the combination of ) Ivacaftor, a CFTR might be the basis for most type 2 dominated polypoid forms
potentiator, and Tezacaftor, a selective CFTR corrector, have of CRS. However, subsequent research has not supported this(119,
shown promising results in improving rhinologic QOL in 120)
. Thus, this chapter will discuss these three phenotypes of
patients with CF. ‘fungal’ related CRS but an intentional focus is made on AFRS
Several studies have evaluated the effect of sinus surgery on as a unique phenotype, and its treatment, within the broader
pulmonary function with divergent conclusions. Sinus surgery definition of CRS.
is recommended in CF patients without chronic lung infection A fungal ball is a non-invasive collection of fungal debris.
or with a transplanted lung in an attempt to eradicate gram- Recent studies indicate that anatomic variants are not major
negative bacteria in the paranasal sinuses, thereby avoiding contributors to their formation, which in the maxillary sinus
or preventing re-colonisation of the lungs. Detecting gram- is more often related to dental interventions(121-123). Neo-
negative sinus bacteria at an early stage is an important step osteogenesis of the maxillary sinus wall is common with fungal
towards eradicating the bacteria and avoiding a chronic balls compared to normal patients and is independent of
bacterial sinus infection. The use of topical antibiotics correlates bacterial coinfection(124). Isolated maxillary or sphenoid sinus
with improvement in symptom and endoscopic scoring and is opacification is a marker of neoplasia in 18% and malignancy
safe. in 7-10% of patients presenting with these radiologic findings
so clinicians should be wary of conservative management and
1.8.5. Primary ciliary dyskinesia have a low threshold for early surgical intervention(125). Little
Primary ciliary dyskinesia (PCD) is a collection of rare inherited has changed in the management of fungal balls since 2012
disorders that affects motile cilia and is primarily inherited in which remains surgical, consisting of removal via an adequate
an autosomal recessive manner. Situs inversus (i.e. Kartagener antrostomy. However, persistent dysfunction of the sinus
syndrome) exists in approximately half of all PCD cases. Both cavity with mucostasis was reported to be as high as 18% and,
men and women diagnosed with PCD commonly present therefore, some authors have proposed a medial maxillectomy
with fertility disorders as the reproductive process is largely for some maxillary cases(126). Invasive fungal rhinosinusitis
dependent on ciliary function. PCD has a strong association (IFRS) is almost always associated with immunocompromise,
with history of CRS, being associated with CRSwNP in 15-30% of which diabetes (50%) and haematologic malignancy (40%)
of patients, and is commonly seen in children with CRS. PCD account for 90% of the immunosuppression reported(127). IFRS
also predisposes to bacterial infections commonly including is defined as any state in which fungal hyphae can be seen
H. influenza, S. pneumoniae and P. aeruginosa. In the absence ‘within’ the mucosal tissue, demonstrating classic angio-invasion
of hard clinical and paraclinical criteria for diagnosing PCD, or other infiltrative patterns(128) which result in thrombosis,
confirming the diagnosis with clinical exam alone is a challenge. tissue infarction and necrosis. Although originally several
An electron microscopic analysis of cilia can yield valuable forms of invasive disease were described: granulomatous,
information about ciliary ultrastructure and function. However, chronic and fulminant, they all potentially represent an
it should be noted that cilia may appear normal in patients immunocompromised host reaction to the fungus(129). The
that present with symptoms strongly suggestive of PCD due to most common causative pathogens remain the Zygomycetes
mutations that can result in normal structure. (Rhizopus, Mucor, Rhizomucor) and the Aspergillus species.
A number of studies have shown that exhaled nitric oxide (NO), Unilateral disease on radiology is typical(130, 131) but loss of
particularly nasal NO production levels, are low in PCD patients. contrast enhancement on MRI is more sensitive (86%) than CT
An nNO cut-off value of <77nl/min can allow detection of PCD (69%) in detecting invasive fungal disease(132). Serum analysis via
with a sensitivity and specificity of 98% and >99%, respectively, PCR (serum or whole blood) and/or galactomannan for invasive
after excluding CF and acute viral respiratory infections. aspergillosis can be useful(133).
Prolonged macrolide therapy has been shown to produce There are three principles for treatment:
marked improvement in symptomatology of PCD due to the 1. Systemic antifungals therapy should be started;
anti-inflammatory and immune-mediating properties of the
2. Patients should undergo, at least, endoscopic surgical
antibiotic. Surgical intervention (ESS) may be required when
debridement of necrotic sinonasal tissue, which may
medical therapy has failed. need to be repeated;
3. The patient’s immune suppression should be reduced
1.8.6. Fungal rhinosinusitis
when feasible. 
Fungi are ubiquitous in our environment and with dedicated
assessments they can be found in nasal mucus from almost all Allergic fungal rhinosinusitis (AFRS) is a subset of polypoid

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 EPOS 2020

chronic rhinosinusitis that is characterized by the presence of ENT-related symptom, of which the majority are rhinological.
eosinophilic mucin with non-invasive fungal hyphae within the During the course of the disease, the majority of GPA patients
sinuses and a type I hypersensitivity to fungi. The EPOS2020 experience nasal symptoms with patients experiencing crusting
steering group discussed whether the term ‘eosinophilic fungal (75%), discharge (70%), nasal stuffiness (65%), bleeding (59%),
rhinosinusitis’ would be a better umbrella term but it was reduced sense of smell (52%) and facial pain (33%)(140, 141). ANCA
agreed that ‘allergic fungal rhinosinusitis’ should be retained as tests have become the mainstay of diagnosis in vasculitis.
the principle term due to common usage, recognising that not A positive c-ANCA test and proteinase-3 (PR3) will confirm
all cases have evidence of an allergic reaction to fungi. AFRS the clinical diagnosis of GPA in up to 95% of patients with
accounts for about 5-10% of CRS cases(134). active systemic disease. An ANCA test should be considered
Ideally all five of the major criteria in the original Bent-Kuhn in any patient with suspicious clinical manifestations, in
diagnostic criteria should be met to make the diagnosis as three particular nasal crusting and bleeding, especially if they feel
of the five are common in most cases of CRSwNP. These major disproportionally unwell(142).
criteria consist of the following(135): Cocaine abuse in the form of nasal ‘snorting’ can resemble the
sinonasal symptoms of GPA and can give c-ANCA and PR-3
1. Nasal polyposis;
positivity, making differentiation between the conditions
2. Fungi on staining; difficult(143). Without treatment the mean survival of systemic
3. Eosinophilic mucin without fungal invasion into sinus GPA is five months. Modern immunosuppressive treatment
tissue; following a strategy of combined remission, induction and
4. Type I hypersensitivity to fungi and; maintenance has markedly improved this to a mean survival
of 21.7 years from diagnosis assisted by higher awareness
5. Characteristic radiological findings with soft tissue
and earlier diagnosis. Nasal irrigation, topical intranasal
differential densities on CT scanning and unilaterality or
anatomically discrete sinus involvement. corticosteroid sprays or creams e.g. triamcinolone and/or a
nasal lubricant such as 25% glucose and glycerine drops, honey
The minor criteria include bone erosion, Charcot Leyden ointment or an aqueous gel are usually recommended together
Crystals, unilateral disease, peripheral eosinophilia, positive with regular debridement of the crusts. The possible aetiological
fungal culture and the absence of immunodeficiency or role of Staphylococcus aureus has led to the use of long-term
diabetes(136). CT shows densely packed hyperdensities in the oral co-trimoxazole (trimethoprim-sulfamethoxazole) and
sinuses with expansion and erosion of the bony walls whereas topical anti-staphylococcal creams in the nose. Reconstructive
on MRI signal voids occur on both T1 and T2 sequences(137). surgery has a very limited role and is associated with poor
The mainstay of treatment remains surgery as medical outcomes, increased scarring and adhesions so should be a last
treatment alone is usually ineffective. However, oral steroids resort. Eosinophilic granulomatosis with polyangiitis (EGPA)
both pre- and postoperatively are of benefit(138). Nebulised (previously Churg Strauss Syndrome) is a rare form of vasculitis
topical corticosteroids reduce recurrence(139) and allergen characterised by adult onset asthma, severe rhinitis, nasal polyps
immunotherapy was also helpful in atopic individuals but and other systemic manifestations as a result of widespread
studies are retrospective and underpowered. There is some eosinophilic granulomatous infiltration of tissues(144). EGPA
evidence that oral antifungals may reduce recurrence but do not should be considered in any patient with severe nasal polyposis
improve symptoms. who is not responding to conventional therapy. Active EGPA is
Fungal rhinosinusitis remains an important phenotype of CRS in characterised by marked peripheral eosinophilia (usually >1500
its invasive and non-invasive forms. Clinicians should have a low cells/ul or >10%) and ANCA-positivity is found in a proportion
threshold for seeking its diagnosis, especially in the presence of of the patients. In most patients, disease control is achieved
the immunocompromised. The mainstay of treatment remains with immunosuppressant therapy, usually oral prednisolone +/-
surgical though may be combined with medical therapies in cytotoxic drugs such as pulsed cyclophosphamide, azathioprine,
invasive and allergic forms. See Figure 1.6.2. which includes an mycophenolate mofetil and methotrexate dependent on
integrated care pathway for AFRS although the steering group the severity of the disease at presentation. Sarcoidosis is
realized that diagnosis in primary and secondary care can be a chronic multi-system inflammatory disease of unknown
difficult. aetiology characterised by non-caseating granuloma. There is
no definitive test for sarcoidosis other than a positive biopsy.
1.8.7. Vasculitis Blood tests may include raised serum and urinary calcium levels,
ANCA-associated vasculitis includes GPA, EGPA and microscopic raised alkaline phosphatase and raised serum angiotensin-
polyangiitis (MPA) and frequently affect the upper respiratory converting enzyme (SACE) but none are diagnostic (sensitivity
tract and specifically the sinonasal region where they may be 60%; specificity 70%). Systemic steroids remain the mainstay of
mistaken for more common forms of chronic rhinosinusitis. treatment in sarcoidosis, though hydroxychloroquine, steroid-
Classically GPA affects the nose, lungs and kidneys but can sparing cytotoxic agents such as methotrexate and TNF-alpha
present in any system and limited forms of the disease are antagonists such as infliximab are being used.
recognised. Two thirds of patients initially present with an

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 EPOS 2020

1.9. Patient participation, prediction, precision Co-morbidities such as allergy, asthma and GORD should be
medicine and implementation considered. Genetic and microbiological factors will likely
become of greater importance. Early diagnosis and selection
1.9.1. Patient participation in CRS of the optimal treatment is central to secondary prevention.
Patient participation in rhinosinusitis can relate on an individual Optimising medical treatment and consideration of the timing
basis to participation of the patient in the design and/or and extent of surgery can improve outcomes. In tertiary
discussion of the treatment plan, or to participation in the prevention, a careful review of ongoing treatment, technique
follow-up after medical or surgical treatment(145). There is limited and compliance with medication should be undertaken.
research on the impact of patient participation on outcomes of Growth in digital healthcare and patient apps may encourage
treatment in CRS. self-management and increase compliance. There are a small
Patient involvement, moreover, is recognized as a key number of studies using big data sets that suggest that
component of clinical practice guideline development with endoscopic sinus surgery for CRS reduces the yearly incidence
important implications for guideline implementability(146). of new asthma diagnoses. Those patients who have later
Aspects of patient participation are covered for the first time surgery may develop higher rates of asthma than those who
in EPOS2020 because patient involvement is essential in undergo surgery at an earlier timepoint. Finally, the prevention
the development of their future care. Patients were actively of recurrent disease is important. Continued use of intranasal
involved in the development of EPOS2020. Recent mobile health corticosteroids after surgery has been shown to improve
initiatives to educate patients on CRS, on correct medication use postoperative endoscopic scores in all CRS patients and, in
and treatment options have been implemented in certain areas those with CRSwNP, reduce risk of recurrence. Adherence
in Europe with success(147). Whilst they allow a more proactive with prescribed postoperative medications dropped to only
follow-up of patients with remote monitoring of symptoms by 42% at 12 months after surgery in one study, despite regular
physicians(147, 148) the impact of e-health on CRS outcomes still telephone contact; strategies to improve this such as utilizing
needs to be defined and proven. digital technology will likely be important in future. One can
For individual patients, shared decision-making is one of the also imagine that other forms of ensuring the application of
four cardinal principles of Precision Medicine(149). In order postoperative medication, e.g. by drug eluting stents, may solve
to improve compliance, it is important to explain the aim the problem of compliance. A small number of studies have
of ongoing usage or any maintenance treatments to both found that ongoing occupational exposure to irritants may
control symptoms and reduce need for recurrent interventions. increase risk of recurrence. Any factors thought to be involved
Information on the safety of treatment and instructions for use in the underlying aetiology of CRS in each individual patient
must be provided in all necessary languages. While physicians should be addressed where possible to reduce risk of recurrence.
are likely to understand the chronic nature of sinus disease In contrast to the large number of studies evaluating changes
in many patients and the need for ongoing treatment, it is in HRQOL after treatment, few studies have evaluated patient
essential to share this with the patient from the outset. The aim satisfaction with outcomes of treatment, and only following
of treatment is to achieve adequate control of symptoms with as surgical interventions. Although data is limited, it appears that
little need for intervention as possible; for many this will involve pre-treatment counselling to ensure that a patient has realistic
ongoing usage of intranasal treatments and in some, repeated expectations of treatment outcomes is important to avoid a
need for systemic treatments or surgical interventions. Some dissatisfied patient. This is in respect to improvement overall
patients will remain inadequately controlled despite receiving and in those symptoms deemed to be most important to the
optimum current evidence-based care. Cure, with an absence patient, as well as optimizing outcomes with respect to their
of symptoms in the setting of no ongoing medication usage, nasal symptoms.
is unusual in CRS with the exception of localized sinus disease
where there has been a curable cause, such as an odontogenic 1.9.3. Prediction
source. There are no studies evaluating the natural history of untreated
CRS although there is some evidence for the adverse effects
1.9.2. Primary, secondary and tertiary disease prevention in of delayed surgical treatment(151). Notwithstanding ethical
CRS considerations, there is clearly an urgent need for more
Prevention may be considered as primary, secondary and research in this area. Similarly, there are very few studies
tertiary(150). Primary prevention aims to reduce incidence of predicting outcomes of medical treatment. When predicting
disease by reducing exposure to risk factors or triggers. CRS outcomes following sinus surgery, a number of studies have
is a heterogeneous disease, where inflammation, mucociliary shown that the preoperative symptom score such as SNOT-22
dysfunction and changes in the microbial community interact is the best predictor of outcome(152, 153). Primary surgery has
with differing influences to cause disease; the aetiology is likely better outcomes than revision. When loss of smell is a major
multifactorial, and opportunities to prevent targeting specific symptom, response in olfactory function to oral corticosteroids
causes will likely vary between subgroups. Occupational and (OCS) predicts the outcome of surgery. Prediction of recurrent
environmental factors, especially exposure to tobacco smoke, disease involves many factors including age, gender, ethnicity,
are of increasing importance in primary prevention and the co-morbidities, and duration of disease. Both blood and tissue
effects of global warming should be carefully monitored. eosinophil levels can be measured with little additional expense

26
 EPOS 2020

and may be used to help predict risk of recurrence and need for social circumstances. A full implementation plan will be written
targeted postoperative care. separately to the EPOS2020 document in the near future.

1.9.4. Precision medicine 1.10. Pharmacist perspective on rhinosinusitis

In 2015 President Obama launched the precision medicine Chapter 10 gives the pharmacist’s perspective on rhinosinusitis
initiative: “delivering the right treatment at the right time, every and offers specific advice to pharmacists on how to differentiate
time, to the right person”. The principles of precision medicine and treat the various forms of ARS (common cold, post-viral
can be implemented within existing adult treatment algorithms rhinosinusitis and acute bacterial rhinosinusitis) and CRS in
for CRS(149). At the time of diagnosis, prediction of success of the contradistinction to allergic rhinitis. Special emphasis has
initiated treatment as well as patient participation in decisions been placed on the avoidance of antibiotics in the treatment
regarding the treatment plan can be undertaken. Precision of rhinosinusitis and the role that the pharmacist can have in
medicine allows real-time clinical decision support at the point advising patients on the correct use of nasal sprays.
of care with implementation of harmonized care based on
quality criteria and allows patients to be treated and monitored 1.11. Research priorities in rhinosinusitis
more precisely and effectively to better meet their individual Chapter 11 gives an overview of research priorities. In many
needs. It brings together clinicians from many inter-related areas of rhinosinusitis, evidence is still of low quality and most
specialities, scientists and above all patients in a collaborative subchapters in EPOS2020 originally ended with: ‘more research
effort to provide the most efficient and effective management. is needed to provide high quality evidence’. We decided,
therefore, to remove the majority of these exortations and to
1.9.5. Implementation collate the most urgent questions in this final chapter.
The implementation of high-quality guidelines and position
papers is essential to improve clinical practice and public health. 1.12 Methods used in EPOS2020
We tried to make EPOS2020 implementable by writing a clear In chapter 12 the methods used in EPOS2020 are discussed.
and concise executive summary with extensive chapters with We describe the development strategy used in EPOS2020
all the evidence behind it. We hope that the executive summary has been published before we started the work(155). We did
will be translated in all necessary languages. Furthermore, we a full systematic review of the literature and used GRADE
reached out to many key opinion leaders all over the world methodology for recommendations. On a large number of
to review and comment on the document and included their practical clinical questions with no or or very low level of
suggestions in the final text. We do realize that not all advice evidence we conducted a Delphi exercise.
in EPOS2020 can be followed in all health care systems and

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126. Nomura K, Asaka D, Nakayama T, et al. Sinus with nasal polyposis: a comparative study. 152. Hopkins C, Rudmik L, Lund VJ. The predictive
fungus ball in the Japanese population: clinical Otolaryngol Head Neck Surg. 2007;136:252-7. value of the preoperative Sinonasal Outcome
and imaging characteristics of 104 cases. Int J 139. Dai Q, Duan C, Liu Q, Yu H. Effect of nebulized Test-22 score in patients undergoing endoscopic
Otolaryngol. 2013;2013:731640. budesonide on decreasing the recurrence of sinus surgery for chronic rhinosinusitis.
127. Turner JH, Soudry E, Nayak JV, Hwang PH. allergic fungal rhinosinusitis. Am J of otolaryngol. Laryngoscope. 2015;125:1779-84.
Survival outcomes in acute invasive fungal 2017;38:321-4. 153. Rudmik L, Soler ZM, Hopkins C. Using
sinusitis: a systematic review and quantitative 140. Gottschlich S, Ambrosch P, Kramkowski D, et postoperative SNOT-22 to help predict the
synthesis of published evidence. Laryngoscope. al. Head and neck manifestations of Wegener’s probability of revision sinus surgery. Rhinology.
2013;123:1112-8. granulomatosis. Rhinology. 2006;44:227-33. 2016;54:111-6.
128. Trief D, Gray ST, Jakobiec FA, et al. Invasive fungal 141. Srouji IA, Andrews P, Edwards C, Lund VJ. Patterns 154. Grayson JW, Hopkins C, Mori ES, B. Contemporary
disease of the sinus and orbit: a comparison of presentation and diagnosis of patients with Classification of Chronic Rhinosinusitis: Moving
between mucormycosis and Aspergillus. Br J Wegener’s granulomatosis: ENT aspects. The J of beyond CRSwNP and CRSsNP. JAMA Otolaryngol
Ophthalmol 2016;100:184-8. Laryngol and otology. 2007;121:653-8. Head Neck Surg. 2020; in press.
129. deShazo RD, O’Brien M, Chapin K, Soto-Aguilar 142. Bossuyt X, Cohen Tervaert J-W, Arimura 155. Fokkens W, Desrosiers M, Harvey R, et al.
M, Gardner L, Swain R. A new classification and Y, et al. Position paper: Revised 2017 EPOS2020: development strategy and goals
diagnostic criteria for invasive fungal sinusitis. international consensus on testing of ANCAs for the latest European Position Paper on
Arch. of Otolaryngol. -- Head & Neck Surgery. in granulomatosis with polyangiitis and Rhinosinusitis. Rhinology 2019;57:162-8.
1997;123:1181-8. microscopic polyangiitis. Nature reviews
130. Wandell GM, Miller C, Rathor A, et al. A multi- Rheumatol. 2017;13:683-92.
institutional review of outcomes in biopsy- 143. Trimarchi M, Bertazzoni G, Bussi M. Cocaine
proven acute invasive fungal sinusitis. Int Forum induced midline destructive lesions. Rhinology.
Allergy Rhinol. 2018;8:1459-68. 2014;52:104-11.
131. Payne SJ, Mitzner R, Kunchala S, Roland L, 144. Greco A, Marinelli C, Fusconi M, et al. Clinic

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 EPOS 2020 POSITION PAPER

2. Classification, definitions and terminology

2.1. Defintions

2.1.1. Sinusitis vs. rhinosinusitis [*It is recognised that symptoms have high sensitivity, but low
specificity hence the need for objective findings.]
Rhinosinusitis recognises that rhinitis and sinusitis co-exist and
that physiologically and pathophysiologically it is difficult to 2.1.2.2. Children
make a distinction between the nose and sinuses although one Rhinosinusitis = inflammation of the nose and paranasal sinuses
area may be more evidently affected than another. This term characterised by two or more symptoms, one of which should
was first used in the early 1990s and has been widely adopted be either nasal blockage/obstruction/congestion or nasal
internationally(1-9). discharge (anterior/posterior nasal drip):
In primary care, GPs may distinguish between rhinosinusitis • ± facial pain
and rhinitis, in secondary care ENT surgeons may distinguish • ± cough(16)
between phenotypes of rhinosinusitis and in tertiary care, rhino-
logists may distinguish between rhinosinusitis endotypes. and either
In primary care, patients with symptoms of nasal obstruction, • endoscopic signs of:
discharge, pressure, pain, lack of barotrauma and often retained - nasal polyps and/or
sense of smell are likely to have rhinitis only(10). Additionally, - mucopurulent discharge primarily from middle meatus
those who are younger (<35 years) with seasonality, distinct and/or
allergen exacerbations and involvement of other sites (conjunc- - oedema/mucosal obstruction primarily in middle meatus
tiva, lung, skin) are likely to have rhinitis(11-13).
and/or
2.1.2. Clinical definition • CT changes:
- mucosal changes within the ostiomeatal complex and/or
2.1.2.1. Adults sinuses
Rhinosinusitis = inflammation of the nose and paranasal sinuses
characterised by two or more symptoms*, one of which should 2.1.3. Definition for epidemiology studies and General
be either nasal blockage/obstruction/congestion or nasal Practice
discharge (anterior/posterior nasal drip): For epidemiological studies and general practice, the definition
• ± facial pain/pressure is based on symptomatology usually without ENT examination
• ± reduction or loss of sense of smell or radiology.
and either
2.1.3.1. Acute rhinosinusitis (ARS) in adults
• endoscopic signs of: Acute rhinosinusitis in adults is defined as:
- nasal polyps and/or sudden onset of two or more symptoms, one of which should be
- mucopurulent discharge primarily from middle meatus either nasal blockage/obstruction/congestion or nasal discharge
and/or (anterior/posterior nasal drip):
- oedema/mucosal obstruction primarily in middle meatus • ± facial pain/pressure,
• ± reduction or loss of smell
and/or for <12 weeks;
• CT changes: with symptom free intervals if the problem is recurrent, with
- mucosal changes within the ostiomeatal complex and/or validation by telephone or interview.
sinuses
[Minimal thickening, involving only 1 or 2 walls and not the 2.1.3.2. Acute rhinosinusitis in children
ostial area is unlikely to represent rhinosinusitis(14, 15)] Acute rhinosinusitis in children is defined as:

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 EPOS 2020

sudden onset of two or more of the symptoms: 2.1.4.1. Definition of chronic rhinosinusitis when no earlier
• nasal blockage/obstruction/congestion sinus surgery has been performed
• or discoloured nasal discharge Chronic rhinosinusitis with nasal polyps: bilateral, endoscopi-
• or cough (daytime and night-time) cally visualised in middle meatus.
for < 12 weeks; Chronic rhinosinusitis without nasal polyps: no visible polyps in
with symptom free intervals if the problem is recurrent; middle meatus, if necessary following decongestant.
with validation by telephone or interview. This definition accepts that there is a spectrum of disease in CRS
which includes polypoid change in the sinuses and/or middle
Questions on allergic symptoms (i.e. sneezing, watery rhinor- meatus but excludes those with polypoid disease presenting in
rhoea, nasal itching, and itchy watery eyes) should be included. the nasal cavity to avoid overlap.

2.1.3.3. Recurrent acute rhinosinusitis (RARS) 2.1.4.2. Definition of chronic rhinosinusitis when sinus sur-
ARS can occur once or more than once in a defined time period. gery has been performed
This is usually expressed as episodes/year but with complete Once surgery has altered the anatomy of the lateral wall, the
resolution of symptoms between episodes. presence of polyps is defined as bilateral pedunculated lesions
Recurrent ARS (RARS) is defined as ≥ 4 episodes per year with as opposed to cobblestoned mucosa >6 months after surgery
symptom free intervals(3, 17). on endoscopic examination. Any mucosal disease without overt
polyps should be regarded as chronic rhinosinusitis without
2.1.3.3. Definition of chronic rhinosinusitis in adults nasal polyps.
Chronic rhinosinusitis (with or without nasal polyps) in adults is
defined as: 2.1.4.3. Co-morbidities for sub-analysis in research
presence of two or more symptoms, one of which should be The following conditions should be considered for sub-analysis:
either nasal blockage / obstruction / congestion or nasal dischar- 1. NSAID-exacerbated respiratory disease (N-ERD). Aspirin
ge (anterior / posterior nasal drip): sensitivity based on positive oral, bronchial, or nasal provo-
• ± facial pain/pressure; cation or an obvious history;
• ± reduction or loss of smell; 2. Asthma / bronchial hyper-reactivity / chronic obstructive
for ≥12 weeks; pulmonary disease (COPD) / bronchiectasies based on
with validation by telephone or interview. symptoms, respiratory function tests;
3. Allergy based on specific serum specific immunoglobulin E
Questions on allergic symptoms (i.e. sneezing, watery rhinor- (IgE) or Skin Prick Test (SPT);
rhoea, nasal itching, and itchy watery eyes) should be included. 4. Total IgE in serum (treatment effects may be influenced by
IgE level);
2.1.3.4. Definition of chronic rhinosinusitis in children 5. Eosinophil levels in blood and tissue.
Chronic rhinosinusitis (with or without nasal polyps) in children
is defined as: 2.1.4.4. Exclusion from general studies
presence of two or more symptoms one of which should be Patients with the following diseases should be excluded from
either nasal blockage / obstruction / congestion or nasal dischar- general studies, but may be the subject of a specific study de-
ge (anterior/posterior nasal drip): pending on phenotype:
• ± facial pain/pressure; 1. Cystic fibrosis based on positive sweat test or DNA alleles;
• ± cough; 2. Gross immunodeficiency (congenital or acquired);
for ≥12 weeks; 3. Congenital mucociliary problems (e.g. primary ciliary dyski-
with validation by telephone or interview. nesia (PCD));
4. Non-invasive fungal balls and invasive fungal disease;
2.1.4. Definition for research 5. Systemic vasculitis and granulomatous diseases;
For research purposes acute rhinosinusitis is defined as per the 6. Cocaine abuse;
clinical definition. Bacteriology (antral tap, middle meatal cul- 7. Neoplasia.
ture) and/or radiology (CT) are advised, but not obligatory.
For research purposes chronic rhinosinusitis is defined as per 2.2. Classification of CRS
the clinical definition and should be based on phenotypes and
endotypes, with and without previous surgery. It may include The EPOS2020 steering group have chosen to look at CRS in
sub-analysis for other co-morbidities. terms of primary and secondary (Figures 2.2.1. and 2.2.2.) and to

32
 EPOS 2020

Figure 2.2.1. Classification of primary CRS (Adapted from Grayson et al(154))

Anatomic distribution Endotype dominance Examples of phenotypes

AFRS
Type 2
Localized
(unilateral)
Non-type 2 Isolated sinusitis

Primary CRS
CRSwNP/eCRS
Type 2 AFRS
Diffuse CCAD
(bilateral)
Non-type 2
Non-eCRS

AFRS, allergic fungal rhinosinusitis; CCAD, central compartment allergic disease; CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosi-
nusitis with nasal polyps; eCRS, eosinophilic CRS; OMC, ostiomeatal complex.

Figure 2.2.2. Classification of secondary CRS (Adapted from Grayson et al(154)).

Anatomic distribution Endotype dominance Examples of phenotypes

Odontogenic
Fungal Ball
Local pathology Tumour
Localized
(unilateral)
PCD
CF
Secondary CRS
Mechanical
GPA
EGPA
Diffuse Inflammatory
(bilateral)
Selective
Immunity
immunodeficiency

CRS, chronic rhinosinusitis; PCD, primary ciliary dyskinesia.; CF, cystic fibrosis; GPA, granulomatosis with polyangiitis (Wegener’s
disease); EGPA, eosinophilic granulomatosis with polyangiitis (Churg-Strauss disease).

divide each into localized and diffuse disease based on anato- minantly eCRS and non-eCRS, determined by the histologic
mic distribution. In primary CRS, the disease is considered by quantification of the numbers of eosinophilic, i.e. number/high
endotype dominance, either type 2 or non-type 2 (see 1.5.2.2.). powered field which the EPOS panel agreed to be 10/hpf or
Clinically localized primary CRS is then subdivided into two higher.
phenotypes – allergic fungal rhinosinusitis (AFRS) or an isolated For secondary CRS, again, the division is into localized or diffuse
sinusitis. For diffuse CRS, the clinical phenotypes are predo- and then considered by four categories dependant on local pa-

33
 EPOS 2020

thology, mechanical, inflammatory and immunological factors. separate term to describe patients with prolonged acute rhino-
Thence a range of clinical phenotypes are included as shown. sinusitis was not necessary because the number of patients who
have such a prolonged course is small and there are very little
2.3. Duration (adults and children) data on which to offer evidence based recommendations on
how to manage these patients.
2.3.1. Acute <12 weeks with sudden onset and complete re-
solution of symptoms (<4 weeks in ICOR)(4, 7-9) (Figure 2.3.1.) 2.4. Severity of disease

EPOS recognises acute viral, acute post-viral and 2.4.1. Severity

acute bacterial rhinosinusitis. • Mild = VAS 0-3
• Moderate=VAS >3-7
2.3.1.1. Common cold • Severe = VAS >7-10
Acute viral rhinosinusitis: duration of symptoms <10 days Based on VAS 0-10 (not troublesome to worst thinkable trou-
blesome)(19)
2.3.1.2. Acute post-viral VAS >5 affects patient QOL (validated in adult CRS only)
Increase in symptoms >5 days or persistent symptoms >10 days VAS degree of severity correlates with SNOT 22(20, 21)
with <12 weeks duration
2.4.2. SCUAD: Severe Chronic Upper Airway Disease(22)
2.3.1.3. Acute bacterial Patients whose symptoms are inadequately controlled despite
Defined by at least three symptoms / signs: adequate (i.e. effective, safe, acceptable) pharmacologic treat-
• discoloured mucus; ment based on guidelines. Includes severe uncontrolled allergic
• severe local pain; rhinitis, nonallergic rhinitis, chronic rhinosinusitis, N-ERD or
• fever >38°C; occupational airway diseases. Defined by impaired quality of life
• raised CRP/ESR; (QoL), social functioning, sleep, school/work performance.
• ‘double’ sickening.
It was noted that in many cases of acute bacterial rhinosinusitis, 2.4.3. Acute complications
the disease is unilateral(18). Sudden onset of disease beyond local site.
(See chapter 4 for extensive discussion.)
2.5. Exacerbation vs. recurrence
2.3.2. Prolonged acute rhinosinusitis Exacerbation: aggravation [Oxford English Dictionary (OED)] –
We recognise that in general, acute rhinosinusitis will usually implies increase of a problem against background of disease(23)
last a maximum of a few weeks. In the literature a number of dif- as in acute exacerbation of chronic rhinosinusitis (AECRS) (See
ferent classifications have been proposed. In the past the term also 5.1.3.) Recurrence: come back, return, repeat, occurring
‘subacute’ was sometimes used to fill the gap between acute again (OED), – implies a disease episode after a period without
and chronic rhinosinusitis. However, the EPOS group felt that a the problem.

Also, in the literature the term ‘acute on chronic’ can be found.

Figure 2.3.1. Definition of acute rhinosinusitis.
The EPOS steering group felt that the term
‘exacerbation of CRS’ was more appropriate and
Increase in symptoms after 5 days, or persistent symptoms after 10 days also consistent with the term used in other
with less than 12 weeks duration respiratory diseases, such as asthma.
Common Post-Viral Acute Rhinosinusitis Signs of potential
Cold
Increase in symptoms after 5 days
acute bacterial
rhinosinusitis
2.6. Control and failure
Symptoms

At least 3 of:
2.6.1. Control: dominate, command, hold in check, regulate
• Fever above 38°C
• Double sickening (OED) (see section 2.22.)
• Unilateral disease
Persistent symptoms after 10 days • Severe pain A disease state in which the patients do not have symptoms, or
• Raised ESR/CRP
the symptoms do not adversely affect quality of life, if possible
5 10 15 combined with a healthy or almost healthy mucosa and only
Days
need for local medication.

34
 EPOS 2020

In asthma, the Global Initiative for Asthma (GINA) guidelines 2.10. Medical therapy
have defined the term ‘control’ as effective management of 2.10.1. Maximal
the clinical characteristics of the disease, including symptoms, The most possible, greatest.
nocturnal awakening, reliever use, limitation of activity, and
lung function, as well as future risk of adverse outcomes. Three 2.10.2. Appropriate
levels of asthma control have been established (well controlled, The most suitable in the circumstances.
partially controlled, and uncontrolled)(24).
2.10.3. Adequate
2.6.2. Failure: uncontrolled Satisfactory or suitable in amount, just enough to produce the
Using a VAS of 0-10, partially or uncontrolled patients will have desired effect.
symptoms of nasal blockage, discharge, facial pain/pressure, re-
duced sense of smell and sleep disturbance of >5 in addition to 2.10.4. Sufficient
nasal endoscopy findings and the need for rescue medication. The same as adequate.

2.6.3 Difficult-to-treat rhinosinusitis 2.10.5. Tailored

Patients who have persistent symptoms of rhinosinusitis despite Specific or adapted for a particular condition or person (as in
appropriate treatment (recommended medication and surgery). precision / personalised medicine).
Although the majority of CRS patients can obtain control, some
patients will not do so even with the maximal medical therapy 2.10.6. Best
and surgery. Finest, greatest, top, foremost, leading, pre-eminent, premier,
Patients who do not reach an acceptable level of control despite prime, first, chief, principal, supreme, of the highest quality, su-
adequate surgery, intranasal corticosteroid treatment and up perlative, unrivalled, second to none, without equal, nonpareil,
to two short courses of antibiotics or systemic corticosteroids in unsurpassed, unsurpassable, peerless, matchless, unparalleled,
the last year can be considered to have difficult-to-treat rhinosi- unbeaten, unbeatable, unexcelled, optimum, optimal, ultimate,
nusitis. surpassing, incomparable, ideal, perfect (OED).

2.7. Phenotype 2.10.7. Optimal

An organism distinguishable from others by clinical features e.g. As for ‘best’!
N-ERD using symptoms, endoscopy ± NPs, ± CT.
Of these terms, ‘appropriate medical therapy’ is
2.8. Endotype the preferred option of the EPO2020
Features within an individual e.g. raised IgE, IL-5, eosinophilia, steering group.
periostin and based on a pathophysiological mechanism.
2.11. Surgical therapy
2.9. Comorbidities
2.11.1. Polypectomy
2.9.1. Comorbidity Removal of polyps from the nose or post-surgical cavity without
Comorbidity is the presence of one or more additional diseases altering the bone anatomy.
or disorders co-occurring with a primary disease or disorder
or any distinct additional entity that has existed or may occur 2.11.2. Minimal
during the clinical course of a patient who has the index disease Least tissue removal compatible with clinical improvement,
under study. In chronic rhinosinusitis these are divided into conservation of mucosa.
respiratory and other systemic conditions.
2.11.3. Full as in ‘Full FESS’
2.9.2. United airway disease Complete sinus opening including anterior and posterior
A pathological continuum due to the interaction between upper ethmoidectomy, middle meatal antrostomies (likely large),
and lower airways in allergy, asthma, infection and inflamma- sphenoidotomy and frontal opening (e.g. Draf IIa ).
tion(25).
2.11.4. Extended
Used in same context as ‘full’ (e.g. Draf III) but could also include
extension beyond confines of sinuses i.e. skull base, orbit, pte-

35
 EPOS 2020

rygopalatine and infratemporal fossa. 2.14.3. Adult

A legal adult is a person who has attained the age of majority
2.11.5. Radical and is therefore regarded as independent, self-sufficient, and
Also used in same context as ‘full’ but could include significant responsible, e.g. >18 years in UK.
removal of inflamed /dysfunctional mucosa’.
2.15. Integrated care pathways
2.11.6. Functional An integrated care pathway (ICP) is a multidisciplinary outline of
Implies restitution of physiology and is usually, though not anticipated care, placed in an appropriate timeframe, to help a
exclusively, applied to endoscopic sinus surgery. It should fulfil patient with a specific condition or set of symptoms move pro-
the following criteria: gressively through a clinical experience to positive outcomes.
• Creates a sinus cavity that incorporates the natural ostium;
• Allows adequate sinus ventilation; 2.16. Recalcitrant vs. refractory to treatment
• Facilitates mucociliary clearance;
• Facilitates instillation of topical therapies. 2.16.1 Recalcitrant
Difficult to manage or operate; not responsive to treatment.
2.12. Precision medicine vs. personalised medi-
cine 2.16.2. Refractory
Resistant to cure.
2.12.1. Precision medicine According to the OED, recalcitrant and refractory are synony-
Medical care designed to optimize efficiency or therapeutic be- mous.
nefit for particular groups of patients, especially by using gene-
tic or molecular profiling by tailoring therapy to the individual. The EPOS steering group prefers ‘recalcitrant’.

2.12.2. Personalised medicine 2.17. Nasal douche / lavage / irrigation / rinsing

A type of medical care in which treatment is customized for an
individual patient. 2.17.1. Douche
A stream of water applied for cleansing purposes.
2.13. Burden of rhinosinusitis
2.17.2. Lavage
2.13.1. Quality of life The therapeutic washing out of an organ.
The standard of health, comfort, and happiness experienced by
an individual or group. 2.17.3. Irrigation
Washing out or flushing a wound or body opening with a stream
2.13.2. Outcomes of water.
Results – subjective / objective; patient / provider; generic /
disease-specific. 2.17.4. Rinsing
To cleanse by washing with fluid.
2.13.3. Cost
Direct and Indirect (costs that are directly or not directly accoun- The EPO2020 steering group prefers ‘irrigation’
table to the treatment itself (can be fixed or variable)). or ‘rinsing’.

2.14. Age 2.18. Immunomodulation and immunotherapy

2.14.1. Child 2.18.1. Immunomodulation

A young human being below the age of puberty or below the Immunomodulation encompasses all therapeutic interventions
legal age of majority i.e. a minor. aimed at modifying the immune response and is the preferred
over-riding term by the EPO2020 steering group. In the treatment
2.14.2. Paediatric of rhinosinusitis, it encompasses the use of biological agents
Medical care of infants, children and adolescents. Maximum age and macrolides.
varies e.g. up to 21 years in USA.

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 EPOS 2020

2.18.2 Immunotherapy 2.20.2. Long-term

Treatment to stimulate or restore the ability of the immune sys- >2 weeks i.e. 4, 6, 8, 10, 12, etc. up to years.
tem to fight infection and disease OR treatment or prevention of
disease (such as an autoimmune disorder, allergy, or cancer) that The EPO2020 steering group agreed that four
involves the stimulation, enhancement, suppression, or desen- weeks or less would be ‘short-term’, accepting that
sitization of the immune system. Generally, this term is used in in general practice the duration is usually <10
relation to the treatment of allergy. days, and >4 weeks would be regarded as
‘long-term’.
2.18.3. Biological therapy
A type of treatment that uses substances made from living orga- They also acknowledged that the aim of short-
nisms to treat disease. term treatment was different from long-term.
Short-term courses are generally given for acute
2.19. Allergy bacterial infection whereas long term courses are
given for their immunomodulatory properties.
2.19.1. Allergy
A damaging immune response by the body to a substance, 2.21. Other definitions
especially a particular food, pollen, fur, or dust, to which it has
become hypersensitive. 2.21.1. Eosinophilic fungal rhinosinusitis vs. ‘allergic’ fungal
rhinosinusitis
2.19.2. Allergic rhinitis The EPO2020 steering group discussed this umbrella term for
A symptomatic IgE-driven inflammation of the nasal mucosa(26). fungal rhinosinusitis but it was agreed that ‘allergic’ fungal
An IgE-mediated inflammatory nasal condition resulting from rhinosinusitis should be retained as the principle term due to
allergen introduction in a sensitized individual(27). common usage, recognising that not all cases have evidence
of an allergic reaction to fungi e.g. a positive skin prick and/or
2.19.3. Entopy or local allergic rhinitis (LAR) specific IgE.
A phenotype of allergic rhinitis characterised by a localised nasal
allergic response in patients with negative skin prick testing to It was agreed that ‘allergic’ fungal rhinosinusitis
inhalant allergens and non-detectable serum specific IgE antibo- should be retained as the principle term due to
dies. Diagnosis is based on a positive response to nasal allergen common usage.
provocation(28-30).
2.21.2. Eosinophilic rhinosinusitis (eCRS)
2.19.4. Atopy Requires quantification of the numbers of eosinophils, i.e. num-
Atopy refers to the genetic tendency to develop allergic ber / high powered field which varies in the literature [8-12/hpf
diseases such as allergic rhinitis, asthma and atopic dermatitis (400x)](32, 33).
(eczema). Atopy is typically associated with heightened immune
responses to common allergens, especially inhaled allergens The EPO2020 steering group prefers 10/hpf.
and food allergens(26).
A genetic disposition to develop an allergic reaction (as allergic 2.21.3. Central compartment disease
rhinitis, asthma, or atopic dermatitis) and produce elevated A variant of CRS with polypoid changes of the entire central
levels of IgE upon exposure to an environmental antigen and sinonasal compartment (i.e. the middle and superior turbinates,
especially one inhaled or ingested. and the posterosuperior nasal septum), while the lateral sinus
An inherited predisposition to produce IgE antibody(27). mucosa remains relatively normal, likely due to allergy(34).

2.19.5. Atopic march 2.22. Concept of Control of CRS

The progression from atopic dermatitis in infants and children to
allergic rhinitis and/or asthma(31). 2.22.1. Introduction
The primary goal of any treatment, especially in chronic disea-
2.20. Duration of antibiotic courses ses, is to achieve and maintain clinical control, which can be
defined as a disease state in which the patient does not have
2.20.1. Short-term symptoms, or the symptoms are not impacting quality of life
Applied to anything from 2-3-5-7-10-14 days in the literature. (QoL)(35).

37
 EPOS 2020

Figure 2.22.1. Assessment of current clinical control of CRS.

EPOS 2020: Assessment of current clinical control of CRS (in the last month)

Controlled Partly controlled Uncontrolled

(all of the following) (at least 1 present) (3 or more present)

Present Present
Nasal blockage1 Not present or not bothersome2
on most days of the week3 on most days of the week3

Mucopurulent Mucopurulent
Rhinorrhoea / Postnasal drip1 Little and mucous2
on most days of the week3 on most days of the week3

Not present Present Present

Facial pain / Pressure1
or not bothersome2 on most days of the week3 on most days of the week3

Normal
Smell1 Impaired3 Impaired3
or only slightly impaired2

Sleep disturbance or fatigue1 Not present2 Present3 Present3

Nasal endoscopy Healthy

Diseased mucosa4 Diseased mucosa4
(if available) or almost healthy mucosa

Rescue treatment Need of 1 course of Symptoms (as above) persist

Not needed
(in last 6 months) rescue treatment despite rescue treatment(s)
1 Symptoms of CRS; 2 For research VAS ≤ 5; 3 For research VAS > 5; 4 Showing nasal polyps, mucopurulent secretions or inflamed mucosa

A number of tools are currently being used in daily clinical The EPOS expert committee proposed to combine the severity
practice and research context, to evaluate different aspects of of patients’ symptoms, aspect of nasal mucosa and medical
disease control in chronic rhinosinusitis (CRS). These include QoL intake as parameters of control. The proposed CRS control test
and symptom severity questionnaires, but also more objective takes into account the presence and severity of the four major
measurements such as endoscopic scoring systems. sinonasal symptoms, sleep disturbance and/or fatigue, nasal
However, the concept of control of disease is relatively new in endoscopic evaluation and need for oral medication. Based on
the field of chronic rhinosinusitis (CRS). The European Position the presence of none, one or more items of this list, patients are
Paper on Rhinosinusitis (EPOS) 2012 incorporated criteria for divided into those with controlled, partly controlled and uncon-
the assessment of CRS control, to address the lack of unifor- trolled rhinosinusitis.
mity in the application and interpretation of existing tools in
the context of disease control (Figure 2.22.1). Such staging 2.22.2. Validation of the EPOS 2012 criteria for disease
system can be useful in clinical practice to evaluate burden of control
disease, to guide management and to assess quality of care, Since the criteria for CRS control proposed by the EPOS expert
especially since there is still a significant group of patients with panel in 2012 are largely based on opinion rather than data-
CRS who remain uncontrolled despite receiving a combination driven, further validation was required.
of adequate medical treatment and endoscopic sinus surgery A systematic literature search on control in CRS produced three
(ESS) following evidence-based guidelines(35, 36). A variety of papers summarized in Table 2.22.1.
factors can be associated with inadequate disease control and In a study of van der Veen et al. 19.5% of patients (n=389) met
it is important to first define this group of patients in order to the criteria of well controlled CRS when being evaluated 3-5
identify and address these contributing factors and to optimize years after ESS, whereas 36.8% had partly controlled and 43.7%
CRS management(36). had uncontrolled CRS(37). Very stable results were recorded in
Furthermore, the concept of control can be used in a research the smaller (n=47), prospective 12 year follow-up study by Calus
context to better characterize patient populations or as an out- et al., where 40% of patients was uncontrolled 6 years after
come measurement for preventive or therapeutic interventions. ESS, 44% was partially controlled and only 16% was control-
The primary goal of any treatment, especially in chronic disea- led(38). Although the percentage of uncontrolled patients after
ses, is to achieve and maintain clinical control, which can be surgery was similar in both studies, it was surprisingly high as
defined as a disease state in which the patient does not have the perception of success of FESS is currently estimated higher
symptoms, or the symptoms are not impacting quality of life. with reported success rates of up to 80%(39). It is important to

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Table 2.22.1. Overview of clinical studies that used the EPOS control criteria (March 2012 – June 2019).

Study Objectives Methods

Snidvongs, To develop a chronic rhinosinusitis (CRS) Design: Prospective study
2014(41) disease control staging system that predicts Population: Adult CRS patients undergoing ESS were recruited from a tertiary referral
patient and physician opinion. This in- clinic.
volved exploring the predictive capacity of Method: Patients (n = 106) returned at 6 months and 12 months after ESS.
the proposed European Position Paper on Symptoms, endoscopy score, and systemic medication used were collected at each
Rhinosinusitis (EPOS) 2012 staging system visit along with physician’s and patient’s report of their condition as either "controlled,
and other potential scoring systems based "partly controlled," or "uncontrolled". Ordinal regression was used for modelling a sta-
on patient symptoms and objective criteria. ging system. The EPOS criteria and various combinations were assessed. Kappa agree-
ments between the staging systems and patient/physician reports were analysed.
van der To study the degree of CRS control using Design: Cross-sectional study
Veen, novel EPOS control criteria at 3–5 years Population: Adult CRS patients who had undergone bilateral FESS for chronic inflam-
2017(37) after a functional endoscopic sinus matory sinonasal disease 3–5 years prior to the study were included.
surgery (FESS) and correlate these data to Method: Patients received a postal questionnaire asking for control items according
symptoms scores (VAS & SNOT-22). to EPOS control criteria, visual analogue scale (VAS) scores for total and individual
To study the influence of performing nasal sinonasal symptoms, sinonasal outcome test (SNOT)-22 and Short Form (SF)-36
endoscopy on defining patients’ level of questionnaires.
control based on EPOS criteria. 389 of the 560 patients included in the study returned a filled questionnaire (69,0%
response rate). Among patients who responded, 81 (20.8%) accepted the invitation
for a voluntary outpatient visit where nasal endoscopy was performed.
Calus, To monitor recurrence and revision surgery Design: Prospective study, however EPOS control criteria were evaluated retrospecti-
2019(38) over 12 years after endoscopic sinus sur- vely.
gery in CRSwNP patients. Population: Adult patients (n = 47) with CRSwNP, undergoing primary or revision
To validate EPOS 2012 control criteria extended endoscopic sinus surgery, were followed.
Method: Clinical symptoms, total nasal endoscopic polyp score and inflammatory
markers in tissue, nasal secretions and serum were evaluated before, 6 years and 12
years after surgery.

note that patients included in the studies by van der Veen et difficult-to-treat group of patients. Aspirin intolerance was also
al. and Calus et al. had been treated in a tertiary referral centre associated with lower percentages of CRS control after FESS(37).
for rhinologic diseases, causing a bias towards the more severe A first comparison was performed between EPOS assessment of
spectrum of disease. Also, the success rate in other studies was CRS control with both VAS global symptom scores and SNOT-
defined as symptomatic improvement after FESS and belon- 22 scores(37). The average VAS total nasal symptom scores of
ging to the uncontrolled group does of course not exclude a controlled, partly and uncontrolled groups were 0.8, 2.7 and
beneficial effect of surgery. This is also shown in the study of 5.7 respectively. The average SNOT-22 scores were 9.7, 22.2 and
van der Veen et al., where 10 out of 21 patients (47.6%) who 44.8, respectively(37).
were telephoned and asked how they perceived CRS control Van der Veen et al. also evaluated the added value of nasal
after FESS, regarded themselves as having controlled CRS. When endoscopy for defining disease control in CRS patients. In 95.1%
EPOS criteria were applied on these patients, only four of them of the cases, performing a nasal endoscopy did not cause a shift
(19.1%) met the criteria of being controlled(37). Calus et al. also in the control category that was defined by just the presence of
focused on how patients appraised their condition. Twelve years symptoms and use of systemic medication(37). Although nasal
after FESS, 97.4% of patients reported general therapeutic relief endoscopy is described as optional (‘if available’) in the EPOS
(21.1% reported a complete, 36.8% a marked, 26.3% a moderate control criteria, this might have been a barrier to apply them in
and 13.2% a slight relief over time)(38). Regarding the distribution some study protocols, as this was also explicitly mentioned by
of patients over the 3 EPOS categories of control, a significant the authors of one of the studies reviewed(40). This is especially
change towards more control was found 6 (p = 0.001) and 12 the case in large-scale studies and/or studies involving non-ENT
years (p < 0.001) after surgery, when compared to the distribu- practitioners.
tion prior to FESS(38). Due to its cross-sectional design, improve- Snidvongs et al. conducted a prospective trial in which 106
ment of disease control could not be evaluated by van der Veen patients undergoing ESS were evaluated at 6 and 12 months
et al., since there were no data available from before surgery. after surgery to investigate if the EPOS 2012 CRS control staging
They did see a significant higher proportion of women compa- system, or any modification of this system, correlates with both
red to men in the uncontrolled group. Patients that had revision patient and physician reports of disease(41). They selected a mo-
FESS were less frequently controlled compared to the ones dified staging system using Nasal Obstruction, Systemic medica-
that had primary FESS, suggesting that they might form a more tion and Endoscopic inflammation (‘NOSE’) based on predictive

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 EPOS 2020

strength. More specifically, they evaluated which symptoms 2.22.3. Alternative tools for (indirect) assessment of CRS
were, as a single factor, associated with patient’s report (nasal control
obstruction p = 0.02) and which nasal endoscopy features were, All clinicians involved in the treatment of CRS aim to achieve cli-
as a single factor, associated with physician’s report of disease nical control in their patients. Nevertheless, the methods used to
progression (endoscopic mucosal inflammation p < 0.001 and assess CRS control in daily practice are still very heterogeneous
thick and/or purulent discharge p = 0.01). Unfortunately, data and the idea of controlled disease can differ between physicians.
concerning the use of EPOS control criteria is rather limited and Uniformity in the routine application and interpretation of
no comparison can be made with results from the other studies, the existing tools for assessment of CRS control is lacking as a
e.g. on patients’ distribution in the different EPOS control cate- consensus on assessment criteria has not yet been reached. This
gories before and (six and 12 months) after surgery. is in contrast to asthma control assessment criteria in the GINA
After analysis of kappa agreements between the staging (Global Initiative for Asthma) guidelines, which are widely accep-
systems and the patient’s and physician’s reports, they arrived ted and are recommended as good clinical practice(43).
to the conclusion that both the EPOS and the NOSE criteria Apart from the CRS control criteria proposed by the EPOS
for control had significant agreement with these reports. They 2012, numerous other tools for assessing (elements of ) control,
propose the NOSE system, as a modified version of the EPOS disease severity and/or Quality of Life are already being used in
criteria, since it has fewer criteria (i.e. fewer symptoms) to assess clinical practice and research. In 2017, a Core Outcome Set for
and they found better agreement with physician and patient four key domains of CRS was selected by the CHROME-study.
rated control in their study. It is not entirely clear from the article For the domain ‘control of disease’ they proposed three measu-
how the criteria used in these patients’ and physicians’ reports of rement tools: need for systemic medication (steroid or antibio-
disease control were established. This is an important considera- tic), progression to surgery and the Lund-Kennedy endoscopic
tion to make, since they largely determine the primary outcome score(44).
of this study, namely the kappa agreement between these The SNOT-22 and VAS for total as well as individual sinonasal
reports and the different investigated disease control staging symptoms are both validated tools that are widely known
systems. among clinicians and researchers in the field of CRS and used for
Two other studies mentioned the EPOS control criteria but did assessing Quality of Life and symptom severity respectively(45,
not use them in real-life studies with CRS patients and are for 46)
. More recently, in this age of big data and precision medicine,
that reason not listed in Table 2.22.1. mobile health technology has been emerging and mobile ap-
The first was an article published by Hellings et al. in 2013(36). plications are being developed for numerous diseases, including
They reviewed the state of the art on control of both allergic CRS(42). Sedaghat et al. investigated chronic rhinosinusitis control
rhinitis and CRS, emphasizing the importance of this concept to from the patient and physician perspectives in 209 patients.
define those patients with poorly controlled disease. They pro- Participants were asked to rate their global level of CRS control
pose a treatment algorithm for CRS in relation to the categories as “not at all,” “a little,” “somewhat,” “very,” and “completely”(47). This
of control provided in EPOS 2012, with proposed treatments 5 scale control scores by patients and physicians were compa-
based on the EOS 2012 treatment algorithms. Secondly, they red to the SNOT-22(48) and also reported the number of sinus
describe the wide variety of factors that can contribute to a lack infections, CRS-related antibiotic courses taken, CRS-related oral
of control and divide them into four categories: disease-related corticosteroid courses taken, and missed days of work or school
factors, diagnosis-related factors, treatment-related factors and due to CRS, all in the last 3 months. While both patients and
patient-related factors. physicians rely on the burden of CRS symptomatology, patients
Another article published by Doulaptsi et al. in 2018 correlates consider primarily nasal symptoms while physicians include
VAS and SNOT-22 scores in 180 CRS patients(40). They mention nasal and extra-nasal symptoms of CRS in determining CRS
the EPOS 2012 criteria for CRS control, but decided that apply- control. Physicians also independently consider CRS-related an-
ing them was not feasible in their postal questionnaire survey. tibiotic use, as a reflection of acute bacterial CRS exacerbations,
Instead they used VAS total nasal symptom score to assess and CRS-related oral corticosteroid use in the determination of
disease control, using follow cut-off points: well controlled (VAS global CRS control.
≤ 2), partly controlled (VAS >2 and ≤5), uncontrolled (VAS > 5).
These cut-off values were based on the study of van der Veen et 2.22.3.1. SNOT-22
al. and have also recently been used in a mobile app for patients The SNOT-22 questionnaire is a 22-item, disease-specific, health-
with CRS, developed by the European Forum for Research and related questionnaire assessing quality of life in CRS patients,
Education in Allergy and Airway diseases (EUFOREA)(37, 42). that has been validated in multiple languages (see 5.3.4.2).
Van der Veen et al. showed significant differences in SNOT-22
scores between the three stages of control based on the EPOS

40
 EPOS 2020

control criteria(37). More prospective studies comparing these dif- In addition, the 36-item Short Form (SF-36), the 12-item Short
ferent scoring systems are needed to validate these results. Form (SF-12) and the EuroQol-5Dimension-5Level (EQ-5D-5L)
Considering its ability to predict CRS control status, it is impor- are health questionnaires that are designed to assess general,
tant to note that some variables of SNOT-22, e.g. ear symptoms health-related QoL and to be applied to all health conditions.
and emotional disorders, are not disease-specific. The SF-36 was also included in the study of van der Veen et al.
and, as was the case for VAS and SNOT-22 scores, SF-36 scores
2.22.3.2. VAS were significantly different when comparing the 3 categories of
The VAS is widely used by rhinologists both in research and in CRS control based on EPOS criteria(37).
daily practice. Patients quantify the severity of their symptoms
on a 10-cm scale, with 0 meaning total absence of symptom(s) 2.22.4. Recommendations and future needs
and 10 being the worst thinkable severity (46) (see 5.3.4.2). Based on the results of van der Veen et al., showing a mean
VAS for total nasal symptoms is already being used in clinical VAS of 5.5 for total nasal symptoms, the EPOS2020 steering
practice, based on the EPOS guidelines, to classify CRS into mild, group think that the current EPOS2012 control criteria might
moderate and severe disease(49) and has also been incorporated overestimate the number of patients being uncontrolled. For
and validated in several mHealth apps(42, 50). research purposes we therefore recommend using a VAS scale
Van der Veen et al. compared VAS scores to the EPOS control cri- for all symptoms: “not bothersome” can be substituted by ‘VAS
teria and the three categories of CRS control showed significant < 5’, and ‘present/impaired’ by ‘VAS ≥ 5. This is in keeping with
differences in mean total and individual VAS scores, as was also the VAS score of 5 or more that has already been proposed to
the case with the SNOT-22 scores(37). Another interesting finding evaluate symptom control in allergic rhinitis(51).
in this study, was that only uncontrolled patients had VAS scores The fact that only one feature has to be present for a patient to
higher than 5. The mean VAS score for total nasal symptoms in be classified as partly controlled, is something else that we think
this uncontrolled group was 5.5, which is relatively low when should be reconsidered. This is especially important since sleep
comparing to the cut-off values used to classify CRS severity(35). disturbance and/or fatigue and also, but to lesser extent, rhinor-
Based on these findings, Doulaptsi et al. created new cut-off rhoea, facial pain, loss of smell and even nasal obstruction can
points for VAS TNSS to define the level of disease control: well all possibly be attributed to other medical conditions. Based on
controlled (VAS ≤ 2), partly controlled (VAS > 2 and ≤ 5), uncon- the results of van der Veen et al., we have changed the criteria so
trolled (VAS > 5) (7). Using these cut-off points, 10% of patients that these symptoms must be related to CRS (37). For example, a
were classified as well controlled, 28.3% as partly controlled, and typical migraine headache should not be taken into account.
61.7% as uncontrolled(40). Generally, there is a need for additional, large-scale studies, pre-
Recently, these same cut-off points have also been used in the ferably with long follow up to confirm the high percentage of
mySinusitisCoach app to assess CRS control(42). Taking into ac- uncontrolled patients after surgery as shown by Calus et al. and
count its ease of use and its applicability in mHealth tools, the van der Veen et al. and to further evaluate the responsiveness of
role of VAS in assessment of disease severity, monitoring disease the EPOS criteria to treatment(37, 38).
and maybe also assessment of disease control might become These studies will help to explore differences in disease control
even more prominent in coming years. (based on EPOS criteria) between men and women, patients
However, regarding its use in assessment of CRS control, it undergoing primary or revision FESS, and between different
is important to consider that these VAS scores are patient- phenotypes e.g. with or without nasal polyps, AR, asthma, AERD,
reported outcomes, lacking any form of objective support such and endotypes based on inflammatory patterns. Such data
as medication use or nasal endoscopic evaluation. Also, VAS will likely prove to be valuable in predicting patients at risk of
scores for individual symptoms might not all be equally useful having uncontrolled disease.
in predicting disease control, as e.g. rhinorrhea, facial pain or
hyposmia may also be caused by numerous other conditions. 2.22.5. Conclusion
Since the third EPOS update was published in 2012, only a few
2.22.3.3. Other questionnaires studies have applied the proposed criteria for assessment of cur-
Over the course of years, many other questionnaires have been rent disease control and the results of these studies still require
used to evaluate CRS symptoms and/or their impact on QoL further psychometric validation (including internal consistency,
and general health status (see 5.3.4.2) These include the Sinus responsiveness and known group differences).
Control Test (SCT) the 31-Item Rhinosinusitis Outcome Measure Given the importance of the concept of disease control, from a
(RSOM-31), the 20-Item Sino-Nasal Outcome Test (SNOT-20), clinical as well as from a research perspective, there still remains
the Sinonasal questionnaire (SNAQ-11) and the Rhinosinusitis a need for a gold standard to assess disease control in CRS.
Disability Index (RSDI)15.

41
 EPOS 2020

The results of previous studies and the recommendations for fu- this process of validation in the coming years, together with the
ture research described in this document can hopefully facilitate arrival of mHealth technologies.

• The criteria have been revised in EPOS2020 for defining controlled, partly controlled and uncontrolled CRS.
• Since the third EPOS update was published in 2012, only a few studies have applied the proposed criteria for assess-
ment of current disease control and the results of these studies still require further psychometric validation (including
Keyand
internal consistency, responsiveness points
known|group
What’s new since EPOS 2012
differences).
• Given the importance of the concept of disease control, from a clinical as well as from a research perspective, there still
remains a need for a gold standard to assess disease control in CRS.
• The results of previous studies and the recommendations for future research can hopefully facilitate validation in future
years, together with the arrival of mHealth technologies.

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 EPOS 2020 POSITION PAPER

3. Burden of acute and chronic rhinosinusitis

3.1. Quality of life (QOL)

3.1.1. The burden of ARS

Few studies have measured the impact of ARS on quality of life, There are two validated disease-specific quality of life instru-
in contrast to the myriad of studies reporting on both direct and ments for use in ARS. The Measurement of Acute Rhinosinusitis
indirect costs. This may reflect the short-lived duration of illness, Instrument (MARS) demonstrates significantly higher scores
with patients usually returning to their pre-morbid health status. in patients with ARS than healthy controls. The SNOT-16, a
Of studies that do report on symptoms, many fail to differentiate derivative of the RSOM-31 instrument originally developed and
between ARS and ABRS. validated in a chronic rhinosinusitis cohort, has also been valida-
In a prospective study of 150 adult patients with ARS, 88% ted for use in ARS(6).
patients reported pain and discomfort, and 43% had difficulties
performing normal daily activities at the onset of an episode 3.1.2. The burden of CRS
of ARS, measured using the Eq-5D(1). By day 15 only 31.5% CRS is associated with a wide range of symptoms, across sino-
reported pain or discomfort and all but 1.4% had fully returned nasal, aural, sleep and general domains. The ‘cardinal’ symptoms
to normal daily activities. A study of 1585 adults diagnosed are considered to be nasal obstruction or congestion, nasal
with acute rhinosinusitis, found the most common presenting discharge (which can be anterior or posterior), alteration in
symptoms were moderate-to-severe nasal obstruction (80.4%), sense of smell and facial pain and pressure.
facial pain (74.5%), rhinorrhoea (70.4%), and headache (63.6%) Population studies show that symptoms of nasal obstruction
(2)
. Symptoms were indicated as having a moderate to very and discharge are common. In a survey of unselected patients
significant effect on activities of daily living (71.6% of patients), in primary care (Figure 3.1.1.)(7), 11.9% of adults sampled fulfilled
leisure (63.1%), and professional/school activities (59.2%). In the EPOS criteria for rhinosinusitis. With repeated review at six
contrast, in children, cough is the most prevalent symptom in months, symptoms were persistent in 4.7% of the cohort(8), sug-
both presumed URTIs and ARS(3). gesting the presence of CRS.
A prospective study of 2610 patients diagnosed with ARS accor- Using EPOS criteria to identify CRS in responses from a ran-
ding to the EPOS 2012(4) criteria separated patients into viral ARS dom sample of the general population, thereby preferentially
(36%) and post-viral ARS (63%). Assessment of the severity of selecting those with nasal obstruction and /or discharge shows
symptoms using a VAS found that 2% reported mild symptoms a high prevalence of cardinal symptoms but provides only
at baseline, 51% moderate symptoms and 44% reported limited insight into the severity of patients with CRS successfully
symptoms to be severe. There was no significant difference in managed in a primary care setting(9), as selection bias will likely
the frequency of nasal obstruction (98 vs. 97%), rhinorrhoea (95 identify more severe patients in secondary care.
vs 94%) facial pain and pressure (76 vs. 77%) or loss of smell (59 The majority of studies evaluating the prevalence and severity
vs. 63%) comparing viral and post-viral groups. Disease severity of symptoms analyse responses in patients referred to secon-
measured using a VAS did not differ at baseline between groups dary care, or those undergoing sinus surgery, therefore selecting
(6.98 for viral vs. 7.13 for post viral ARS). Disease specific QOL those with symptoms more resistant to treatment in primary
measured with the SNOT-16 found statistically higher baseline care. Surveys of patients seen in ENT outpatient clinics(10) and
scores in the post-viral group (38.7 vs. 36.0 in the viral ARS those electing sinus surgery(11) show that the cardinal symptoms
group), however, this difference is not clinically significant, are reported as the most severe and prevalent. Nasal obstruc-
A comparative study performed using the SF-36 found that pa- tion and alteration in sense of smell and taste are both the most
tients with acute rhinosinusitis (which was not clearly defined) severe and prevalent symptoms in CRSwNP, while in CRSsNP,
reported impaired quality of life compared with a control popu- facial pain and nasal discharge are reported as equally severe as
lation, but were not as severely affected as patients with chronic altered smell and taste, with nasal obstruction again being the
rhinosinusitis(5). most severe (Figures 3.1.1. and 3.1.2.). Fatigue and waking up

45
 EPOS 2020

Figure 3.1.1. Prevalence of cardinal symptoms of CRS in unselected patients in primary care, and CRS patients in the general population, in an outpa-
tient setting and those undergoing surgery.

Prevalence of cardinal symptoms of CRS

100%

80%

60%

40%

20%

Unselected CRSwNP CRSsNP CRSwNP in CRSsNP in CRSwNP CRSsNP

patients identified in identified in outpatient clinic outpatient clinic undergoing undergoing
in primary care general general surgery surgery
population population

Nasal obstruction Change in sense of smell Nasal discharge Facial pain

tired are also highly prevalent and bothersome. When a group dependent upon the population being studied. When asked
of CRS patients (not differentiated by polyp status) were asked how bothersome their symptoms were overall, the CRS patients
what symptoms they felt were the most important to experience identified in the general population study reported mean scores
improvement in after surgery, nasal obstruction was rated as of 8.2 and 7.8 for CRSwNP and CRSsNP respectively, on a VAS
"extremely" or "very" important by 93% of patients, followed by scale of range 0-10. Patients in secondary care awaiting surgery
smell/taste, thick nasal discharge, need to blow nose, postnasal report mean symptom severity scores in the moderate to severe
discharge, and sleep symptoms (range 61-72%)(12). range, with a mean SNOT-22 score of 42.0(17), compared with
In patients presenting to ENT clinics, the presence of cardinal a control group where a mean score of 9.3 was reported. The
symptoms has a positive predictive value of 39.9, with high median score of 7.0 was proposed as a threshold for normal
sensitivity but low specificity(13) for a diagnosis of CRS. Similarly, scores(18); CRSsNP patients had higher pre-operative baseline
when patients undergoing CT imaging for non-sinogenic condi- scores (44.2) compared with CRSwNP (41.0).
tions were surveyed, 50% of those who reported CRS symptoms CRS has been shown to impact on patients’ health related qua-
were found to have normal CT scans (Lund-Mackay =0)(14). lity of life. Significant differences are found in all domains of the
Asymptomatic changes are commonplace on CT imaging(14). SF-36 compared with healthy controls(19). In a landmark paper,
Individual symptoms cannot be used to reliably differentiate Gliklich and Metson first demonstrated the impact of CRS on
between CRS and other conditions, although the presence of global quality of life, finding that CRS had a greater impact on
hyposmia is predictive of CRS(15), while facial pain is negatively social functioning than angina or chronic heart failure(20). More
predictive(16). recently, they have shown that health utility values, measured
The overall severity rating of symptoms is obviously highly using the EQ-5D, were lower than the general population, and

46
 EPOS 2020

Figure 3.1.2. Severity of cardinal symptoms of CRS in patient cohorts seeking outpatient care and undergoing surgery.

Severity of cardinal symptoms of CRS

CRSwNP in CRSsNP in CRSwNP CRSsNP

outpatient clinic outpatient clinic undergoing undergoing
surgery surgery

Nasal obstruction Change in sense of smell Nasal discharge Facial pain

comparable to other chronic diseases such as asthma(21). This is tion with long-term ramifications with regard to both medical
further discussed in the section on PROMS (see section 5.3.1.4.). and surgical treatments, associated total cost, as well as the
Symptom severity has been shown to be influenced by gender, impact of disease on patient productivity and quality-adjusted
with females reporting greater symptom severity and impact on life years(24). Total costs are often divided between direct and
their quality of life, when measured with disease specific instru- indirect costs where direct costs primarily refer to traditional
ments or with global measures, such as the SF-36 or Eq-5D(19, 21). healthcare costs such as physician visits, prescription medical
Co-morbid depressive illness is associated with worse CRS-speci- therapy and surgery while indirect costs refer primarily to lost
fic quality of life(22). Symptom severity may be in part determined productivity in those suffering rhinosinusitis(25). Conservative
by severity of disease but is further modified by intrinsic patient estimates suggest that for CRS, total costs are in excess of $30
features (gender, ethnicity, religious and cultural beliefs), co- billion per year in the USA with $20 billion accounted for in
existing illnesses and extrinsic features such as socio-economic indirect costs(26).
factors, and support systems. This likely explains the mismatch
commonly found between objective and patient rated disease 3.2.1. Direct costs
severity scales, such as has been found with radiological staging
and symptom scores(23). 3.2.1.1. Direct costs of chronic rhinosinusitis
In 2009, Bhattacharyya published an assessment of the eco-
3.2. Costs of rhinosinusitis nomic disease burden of rhinosinusitis(27). Data were extracted
Research concerning the socioeconomic impact of rhinosinusitis from the National Health Interview Survey over a 10-year period
is a nascent field. In particular, CRSw/sNP is a common condi- of 1997-2006 in the USA. One-year disease prevalence showed

47
 EPOS 2020

that one quarter (23%) of patients with CRS visited an emergen- an assessment of the additional disease burden of nasal polyps
cy department, one third (34%) saw a medical specialist, more in CRS(35). Patients were included according to the Rhinosinusitis
than half (56%) spent $500 or more per year on health care. Symptom Inventory (Task Force on Rhinosinusitis criteria) and
Health care spending was significantly greater in rhinosinusitis by findings with nasal endoscopy and on CT (Lund MacKay
than that of other diseases such as peptic ulcer disease, acute score). Three groups were composed: one with CRS without
asthma, and hay fever. In Europe two studies reported on direct nasal polyps (CRSsNP), a second group with CRS with nasal po-
costs of CRS, Wahid et al. reported £2974 on costs for primary lyps (CRSwNP) and a third with CRS with recurrent nasal polyps
and secondary care extrapolated for a year period compared to after surgery. While the groups with and without nasal polyps
£555 in the control group and £304 versus £51 out-of-pocket ex- showed a clear difference in phenotype, this did not trans-
penditure (28). Lourijsen et al. found yearly direct costs of €1501 late into a difference in expenditures for physician visits and
per year in a group of patients with CRSwNP(29). medication costs between the first two groups. However, there
was a difference in total medication costs for the last group with
Health care spending was significantly greater in recurrent polyps after surgery with a higher cost for this group
rhinosinusitis than in other diseases such as peptic of $866 compared to the $570 for Group 1 and $565 for Group
ulcer disease, acute asthma, and hay fever. 2. Further study of the differences in cost in patients with polyps
were studied by Bhattacharyya et al. in 2019 using the Truven
Direct costs of CRS, over and above inflation, appear to be incre- Health MarketScan US claims database(36). Annual incremental
asing in the USA where most estimates originate. In 1999, Ray et costs were $11,507 higher for patients with CRSwNP versus
al. estimated the total direct cost in the USA at nearly $6 billion those without CRS. Costs were higher in subgroups of patients
per year(30). In 2011, Bhattacharyya estimated direct costs to be with CRSwNP undergoing functional endoscopy sinus surgery
$8.6 billion(31). In 2017, Rudmik established that the overall direct (FESS), with a comorbid diagnosis of asthma, receiving oral corti-
costs of CRS had increased to between $10 and $13 billion(26). costeroids, or macrolides versus the overall CRSwNP group. This
study did not include, generally speaking, patients treated with
In the USA, the direct costs for the management biologics. The authors concluded that patients with CRSwNP
of CRS have risen in recent years and are now with high clinical burden had higher overall costs than CRSwNP
between $10 and $13 billion per year, or $2609 per patients without.
patient per year.
The highest direct costs were associated with
While total direct costs are important, in 2002, Murphy et al. exa- patients who had recurrent polyposis after
mined the direct costs of an individual patient with CRS in the surgery.
USA per year(32). These patients accounted for 43% more outpa-
tient and 25% more urgent care visits than patients without CRS. Evaluating incremental direct costs is important to determine
Patients with CRS filed 43% more prescriptions but had fewer the cost directly attributable to the management of CRS. In
inpatient hospital stays. The direct cost of treating an individual 2011, an evaluation calculated the incremental health care
patient with CRS was $2,609 per year, 6% more than the average utilization and expenditure for CRS in the USA(31). Patient data
adult. In Europe, a study executed by van Agthoven established were extracted from the Medical Expenditure Panel Survey. For
that the direct costs of a patient treated in a university hospital utilization of health care, data show that CRS patients incurred
for severe chronic rhinosinusitis were €1861/year(33). 3.5 additional office visits and 5.5 additional prescriptions com-
The impact of nasal polyps on direct costs has also been a pared to patients without CRS. This extra utilization of health-
subject of interest. In Sweden, Berggren evaluated the costs care evokes higher expenditures; a patient with CRS would have
of a scenario treating CRSwNP with budesonide following by a substantial incremental increase in health care expenditures
sinus surgery when indicated versus direct surgery followed by of approximately $800 per year consisting of $346 (±$130) for
budesonide(34). For the surgical intervention a comparison was office-based expenditures, $397(±$88) for prescription expendi-
made between in-patient FESS, in the office polypectomy under tures and $90 (±$24) for self-expenditures.
sedation or in the office polypectomy under local anaesthesia.
The scenario of treating CRSwNP with budesonide following by CRS leads to an incremental direct healthcare
sinus surgery was due to the high success of the nasal cortico- expenditure of 2500 euro per patient per year.
steroid treatment alone (yearly costs €409-602) , significantly
less expensive than the scenarios that started with surgery: Direct costs associated with severe CRS that eventually requires
from €67 for the polypectomy in local treatment to €976 for the surgery have received additional attention. Bhattacharyya et al.
in-patient FESS. In the US, Bhattacharyya’s 2009 study provided reported the costs of managing CRS in the year prior to and fol-

48
 EPOS 2020

lowing endoscopic sinus surgery (ESS)(37). Data from the Market $210 for antibiotics, $452 for other sinus-related prescriptions,
Scan Commercial Claims and Encounters Database from 2003 to $47 for imaging and $382 for other visit costs.
2008 were evaluated. Patients with nasal polyps were excluded
from this study. All sinus-related healthcare utilization costs 3.2.2. Indirect costs for ARS and CRS
were rolled into the study (medication, office visits, diagnostic The studies of direct medical costs of rhinosinusitis demonstrate
assessment with radiology and endoscopy). Results show that a tremendous socioeconomic burden. Interestingly, the indirect
in the year prior to ESS, costs increase to approximately $2,500 costs of rhinosinusitis are much greater than the direct costs.
with a clear increase in the six months directly preceding ESS; Since 85% of patients with rhinosinusitis are of working age
the first three months account for $361 and final three months (range: 18-65 years old), indirect costs such as missed workdays
account for $1,965. This is due to an increase in office visits, (absenteeism) and decreased productivity at work (presentee-
diagnostic investigations and medication use. The increase in ism) significantly add to the economic burden of the disease(43).
prescription medication is primarily due to a higher antibiotic
use; from $75 in the first three months to $225 in the second Rhinosinusitis is one of the top 10 most costly
three months. The ESS-procedure and the 45-day post proce- health conditions to US employers.
dure period account for $7,726 ($7,554 – $7,898). In the first year
following ESS, costs drop by $885 to an average of $1,564 per Goetzel et al. attempted to quantify the indirect costs of rhi-
year. In the second year post procedure they drop an additional nosinusitis(44). Their 2003 study resulted in rhinosinusitis being
$446 to $1,118 per year. This decrease was mostly due to fewer named one of the top 10 most costly health conditions to US
physician visits; there was only a minor change in the costs of employers. A large multi-employer database was used to track
anti-inflammatory medication. insurance claims through employee health insurance, absentee
days, and short-term disability claims. Episodes of illness were
Endoscopic sinus surgery is expensive but results linked to missed workdays and disability claims, accurately cor-
in a decrease in direct costs in the subsequent two relating absenteeism to a given disease. In a large sample size
post-operative years. (~375,000 employees), total healthcare payments per employee
per year for rhinosinusitis (both acute and chronic) were found
Surgery for CRS represents a substantial direct cost and depends to be $60.17, 46% of which came from the cost of absenteeism
on geography(37-39). Based on the literature, the direct costs of and disability. These figures approximate the cost to employers,
ESS in the USA range between $8,500 and $11,000. However, disregarding the cost incurred by other parties, and therefore
direct costs are lower in Canada ($3,700), Taiwan ($1,900), and tremendously underestimate the entire economic burden of the
India ($1,100), all of these direct costs measured in 2016 USD. disease.

Patients with recurrent acute rhinosinusitis have Indirect costs account for a majority of the total
average direct health care costs of $1,091/year costs of rhinosinusitis.
(USA 2012).
Ray et al. estimated by the 1994 National Health Interview
3.2.1.2. Direct costs of acute rhinosinusitis Survey that the number of missed workdays due to rhinosi-
While most ENT specialists spend much of their clinical time nusitis was 12.5 million and restricted activity days was 58.7
treating CRS, acute rhinosinusitis also presents in both non-re- million days(45). In his 2003 study, Bhattacharyya used patient-
current (acute bacterial rhinosinusitis, ABRS) and recurrent forms completed surveys from 322 patients to estimate the direct and
(recurrent acute rhinosinusitis, RARS)(40). Much less is known indirect costs of chronic rhinosinusitis(46). Patients completed
about the costs related to RARS. In 2004, Anand estimated that a survey assessing symptoms of disease, detailing medication
there were approximately 20 million cases of ABRS yearly in use, and quantifying missed workdays attributable to CRS.
the USA(41). However, RARS is more commonly treated by the The report concluded that the cost of treating CRS per patient
rhinologist and it is estimated that 1 in 3,000 adults suffer from totalled $1,539 per year with 40% of these costs due to indirect
RARS(42). In 2012, Bhattacharyya found that RARS required an costs of missed work; the mean number of missed workdays in
average of 5.6 health care visits/year and 9.4 prescriptions filled this sample of 322 patients was 4.8 days/year (95% CI: 3.4 - 6.1).
(40% antibiotic). Only 20% of patients had either nasal endo- The study was followed up in 2009 and 2012 using data from
scopy or CT scan annually, indicating that it is likely that only a the National Health Interview Survey between 1997 and 2006
small proportion of these patients are referred for ENT-specialist encompassing nearly 315,000 individuals and reported that
evaluation. The individual patient annual direct healthcare costs patients with rhinosinusitis missed on average 5.7 days of work
of recurrent acute rhinosinusitis (RARS) averaged $1,091/year: per year(27). These cohorts report on all patients with CRS and

49
 EPOS 2020

therefore include less severe forms of the disease that are likely Yip reported in the patients in a Canadian tertiairy care centre
never referred for ENT-specialist management. Stankiewicz et an average of 20.6 workdays missed over a 12-month period(50).
al. reported on the rates of absenteeism and presenteeism in In Europe Wahid reported a total number of missed workdays
a population of 56 patients undergoing surgical intervention of 18.7 per patient per year(28). Lourijsen found a total of missed
for chronic rhinosinusitis. Prior to surgery, they reported a 6.5% workdays of 10.6, work-related productivity loss of 30.4 days
rate of absenteeism (i.e. 6.5% of work time missed) and 36% and unpaid work productivity loss of 23.7 days leading to total
rate of presenteeism (reduction of on-the-job effectiveness). indirect costs of €5659 per patient/year(29).
When combined, the rate of absenteeism and presenteeism
yielded a 38% work productivity loss in the study population, A major component of the indirect costs results
but no dollar value was placed on this figure(47. Supporting this, from absenteeism and presenteeism and is in
Stull et al. reported that nasal congestion alone resulted in poor excess of $20 billion per year in the USA.
sleep, increased fatigue, and daytime sleepiness contributing to
decreased work productivity(48). In 2014, Rudmik et al. specifi- More recent data has emerged which demonstrate changes in
cally evaluated recalcitrant CRS in 55 patients and found that productivity costs after treatment of chronic rhinosinusitis, with
patients with this more severe form of CRS had mean annual differential changes across symptom domain and severity(51-56).
presenteeism and absenteeism rates of 25 - 39 days per patient While patients who were considered candidates for ESS who
per year equating to an average indirect cost of over $10,000 per elected to continue medical therapy showed no improvement
patient per year(49). Overall, the total indirect costs of CRS were in average measures of productivity, patients who elected ESS
estimated to be in excess of $20 billion per year in the USA(26). showed substantial improvement in productivity.

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34. Berggren F, Johansson L. Cost effectiveness in 1996: contributions of asthma, rhinitis, L. What drives productivity loss in chronic
of nasal budesonide versus surgical treat- and other airway disorders. J Allergy Clin rhinosinusitis? A SNOT-22 subdomain analy-
ment for nasal polyps. Pharmacoeconomics Immunol 1999;103:408-14. sis. Laryngoscope 2018;128:23-30.
2003;21:351-6. 46. Bhattacharyya N. The economic burden and 56. Smith KA, Rudmik L. Medical therapy, refrac-
35. Bhattacharyya N. Assessing the additional symptom manifestations of chronic rhinosi- tory chronic rhinosinusitis, and productiv-
disease burden of polyps in chronic rhi- nusitis. Am J Rhinol 2003;17:27-32. ity costs. Curr Opin Allergy Clin Immunol
nosinusitis. Ann Otol Rhinol Laryngol 47. Stankiewicz JA, Lal D, Connor M, Welch K. 2017;17:5-11.
2009;118:185-9. Complications in endoscopic sinus surgery

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4. Acute rhinosinusitis including common cold - and

recurrent ARS in adults and children

4.1. Epidemiology of acute rhinosinusitis (ARS) Figure 4.1.1. Definition of acute rhinosinusitis.

4.1.1. Common cold, post-viral rhinosinusitis and acute

bacterial rhinosinusitis Increase in symptoms after 5 days, or persistent symptoms after 10 days
Many patients consult their primary care clinician or pharmacist with less than 12 weeks duration

with problems associated with upper respiratory infections. The Common Post-Viral Acute Rhinosinusitis Signs of potential
majority are self-limiting and can be classified as common colds. Cold acute bacterial
Increase in symptoms after 5 days rhinosinusitis
Common colds are defined as acute viral rhinosinusitis with Symptoms
At least 3 of:
a duration of symptoms of <10 days (but less than 12 weeks)
• Fever above 38°C
(Figure 4.1.1). • Double sickening
• Unilateral disease
When symptoms increase after five days, or when symptoms are Persistent symptoms after 10 days • Severe pain
• Raised ESR/CRP
persistent for more than 10 days, with less than 12 weeks dura-
tion, then EPOS classifies this as acute post-viral rhinosinusitis. 5 10 15

Only a minority of acute rhinosinusitis is from bacterial origin. Days

Acute bacterial rhinosinusitis if defined by EPOS by at least three

symptoms/signs of the five below: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
• Discoloured mucus
• Severe local pain (often unilateral)
• Fever > 38°C Fig 4.1.2. The incidence of different forms of ARS: Common cold, postvi-
• Raised CRP/ESR ral rhinosinusitis and acute bacterial rhinosinusitis (ABRS). Antibiotics are
• ‘double’ sickening only indicated in a small part of the patients with ABRS.

This chapter describes the epidemiology and predisposing

factors for different forms of acute rhinosinusitis (ARS).
Acute Bacterial
Rhinosinusitis
4.1.2. Incidence of ARS in the population
ARS is a common problem, the precise incidence of which is Common Cold Post-Viral
Rhinosinusitis
difficult to estimate. The incidence of acute viral rhinosinusitis Acute Bacterial
Rhinosinusitis
(common cold) is very high, as previously described(1) and as Needing Antibiotics

summarised in Table 4.1.1. It has been estimated that adults

suffer two to five episodes of viral ARS (or colds) per year and
school children may suffer seven to 10 colds per year(1, 2). In a re-
cent Dutch paper using the GA2LEN questionnaire a prevalence
of 18% (17-21%) was found for symptoms pointing to post-viral/
ABRS ARS in three different cities in the Netherlands(3). cation of (post)viral ARS, a recent review described a collection
Approximately 0.5-2% of viral upper respiratory tract infections of factors which make this outcome more likely (Table 4.1.2.)(6).
are complicated by bacterial infection(1, 4)(Figure 4.1.2.). It is also important to understand the natural history of a bout of
ARS and the spectrum of symptoms which accompany it (Figure
4.1.2.1. Incidence of acute bacterial rhinosinusitis (ABRS) 4.1.3). It can be seen that the majority of the symptom complex
The precise incidence of ABRS is not known. This has been has resolved by day 7 but that nasal discharge and cough may
placed at 0.5-2.% of all viral infections(5). To develop acute bacte- last for a further three or four days (Figure 4.1.3.). It is clear that
rial rhinosinusitis it is reasonable to assume that this is a compli- most symptoms, however, resolve by day 5 and that in general it

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Table 4.1.1. Acute rhinosinusitis (ARS) incidence and prevalence in primary care studies.

Study Author, year Evidence Type of study

Hoffmans Prevalence of (post-viral and ABRS) ARS based on the EPOS criteria 18% (17- Prospective population study
2018(3) 21%)
Hoffmans Incidence of (acute) rhinosinusitis in primary care in the Netherlands Retrospective primary care morbidity
2015(17) 18.8/1000 patient years registration
Uijen Incidence of acute rhinosinusitis during 2002 to 2008: Retrospective, population study
2011(374) 0-4 years: 2/1000 per year in all years.
5-14 years: 7/1000 in 2002 reducing to 4/1000 in 2008 (p<0.001)
12-17 years: 18/1000 per year in all years.
Oskarsson Incidence of ARS is 3.4 cases per 100 inhabitants per year, or 1 in 29.4 patients Retrospective population study
2011(375) visit their GP due to acute rhinosinusitis.
Wang 6-10% of patients present at GP, otolaryngologist or paediatric out-patient Multi-national questionnaire survey
2011(176) practices with ARS
Bhattacharyya Point prevalence of 0.035% for recurrent acute rhinosinusitis during 2003- Retrospective cohort study
2011(31) 2008.
Meltzer, Kaliner, Kaliner 1 in 7 adults affected by rhinosinusitis in USA Guidelines
2011, 1997, 1997(168, 376)
Neumark 7.5% of consultations for respiratory tract infections (or 1 in every 13.3) were Prospective population study
2009(45) attributable to sinusitis. Expanding to all primary care consultations, 19.3
consultations/1000 patients were attributable to sinusitis.
Bhattacharyya For 1997-2006, 1-year prevalence of sinusitis (all forms) was 15.2% Retrospective cohort study
2009(50, 377)
Fokkens For 1999, 8.4% of the Dutch population reported at least one episode of acute Guideline
2007(378) rhinosinusitis.
van Gageldonk-Lafeber Incidence of acute respiratory tract infection (including ARS) during 2000- Prospective case-control study
2005(15) 2003 was 54.5 cases /1000 patient-years, or 1 in every 18.3 consultations
Cherry In the USA, upper respiratory tract infection is third most common cause of a National Survey
2005(379) primary care consultation, of which a third is attributable to ARS.
Louie In US study conducted during January to March 2002, 9% of previously heal- Prospective study
2005(380) thy patients presented with acute sinusitis.
Varonen, Rautakorpi During 1998-1999, 12% of patients were diagnosed with ARS. 12% of consulta- Cross-sectional multi-centre
2004, 2001(381, 382) tions for infection (all cause) over this time period were attributable to ARS. epidemiological survey
Bachert Between July 2000 and June 2001 6.3 million separate diagnoses of acute Review
2003(2) sinusitis were identified in Germany, resulting in 8.3 million prescription

ABRS, acute bacterial rhinosinusitis; ARS, acute rhinosinusitis; GP, general practitioner.

is impossible to differentiate between bacterial and non-bacteri- over-diagnosed with concomitant overuse of both diagnostic
al before this time, although the possibility of bacterial infection tools and of antibiotics, with up to 60% receiving a course of
increases if there is deterioration in symptoms after day 5(6). antibiotics on day 1 of an event(9-11). Furthermore, early adminis-
However, some guidelines state that symptoms should go on tration of antibiotics appears to have little or no bearing on the
for longer before bacteria are implicated(7). A recent review and development of complications of ARS(12-14).
meta-analysis suggests that the percentage of bacterial infection
is somewhat higher than has previously been thought, but 4.1.3. Health seeking in ARS
recognises the complexity of the diagnosis in both radiograp- Patients with common cold and post-viral rhinosinusitis will
hical diagnosis, with abnormal findings being associated with often seek help from their GP.
the presence of non-pathogenic bacteria and bacterial sampling In a three-year case-control study of the Dutch population, van
techniques which may suggest differing levels of infection or Gageldonk-Lafeber estimated that annually, 900,000 individual
contamination. They found that even when the strictest clinical patients (545/10,000 patient years) consulted their primary care
and radiologic criteria are applied, only 53% of cultures are posi- physician for acute respiratory tract infection and that the most
tive for pathogenic bacteria. They recommend further research common aetiology was viral infection(15).
is needed(8). In the USA, between 2000-2009, acute rhinosinusitis was
What is very clear is that bacterial rhinosinusitis is greatly diagnosed in 0.5% (95% confidence interval (CI), 0.4%-0.5%) of

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Table 4.1.2. Predisposing factors for acute bacterial rhinosinusitis. diagnostic criteria differ from place to place and environment.
Primary care, by its very nature sees the vast majority of patients
Dental: infections and procedures
with acute respiratory infections, however, diagnostic labelling
Iatrogenic causes: sinus surgery, nasogastric tubes, nasal packing,
mechanical ventilation
and subsequent coding is not always accurate with failure to dif-
ferentiate between acute and chronic rhinosinusitis(17). Similarly
Immunodeficiency: human immunodeficiency virus infection, im-
munoglobulin deficiencies Impaired ciliary motility: smoking, cystic patients presenting to academic centres of excellence appear
fibrosis, Kartagener syndrome, immotile cilia syndrome to have lower diagnostic rates, probably due to a more rigorous
Mechanical obstruction: deviated nasal septum, nasal polyps, hyper- diagnostic approach(20). Thus any estimation of incidence and
trophic middle turbinates, tumour, trauma, foreign body,
granulomatosis with polyangiitis prevalence has to be largely inferred from examining data col-
Mucosal oedema: preceding viral upper respiratory infection, allergic lected retrospectively while providing routine clinical care, or
rhinitis, vasomotor rhinitis collected prospectively.
A recent study suggests that both prevalence of viruses and
climatic factors influence the expression of influenza type
all outpatient visits among adults, averaging 19.4 visits (95% CI, illness, suggesting that fluctuations in variability of numbers
16.5-22.3) per 1000 adults and this did not change during the of presentations are to be expected(21). Studies of prescribing
study period(16). A recent Dutch paper found a comparable figure habits may also shed light as to what the real prevalence of
using two different Dutch GP registries; an incidence of con- patients with ARS seeking medical attention might be in the
sultations for acute rhinosinusitis of 18.8- 28.7 per 1000 patient general population. A retrospective study of 3.7 million patients
years. Because these registries do not make a clear differentia- revealed that 74,359 patients had had a consultation for ARS
tion between ARS and CRS a proportion of these consultation over a two-year time span suggesting a consultation rate of 1%
might have been for CRS. Medication was prescribed in over of the population per annum(22). A longitudinal study of 856 pri-
90% of cases(17). mary care trainees in Australia (108.759 individual consultations
A global analysis reveals that unspecified Upper Respiratory with 169,303 problems/diagnoses) resulted in a prevalence of
Tract Infection (URTI) is the most common cause for consulta- 0.9% of acute rhinosinusitis of all problems or 1.39% of indivi-
tion in the developing world and the second most common dual consultations(23).
reason for consultation. In contrast, acute rhinosinusitis was A cross-sectional study including GPs from two Nordic coun-
not specified by clinicians although patients rated it as the tries, two Baltic countries and two Hispano-American countries
thirteenth most common cause for seeking medical help(18). A registered patients with respiratory tract infections (RTIs) during
very detailed study of activity in Australian primary care demon- three weeks in January 2008. In total, 618 participating GPs
strated that acute /chronic rhinosinusitis accounted for 0.8% of registered 33.273 patients with RTIs, of whom 1150 (3.46%) were
total problems but was encountered in 1.3% of consultations considered to have acute post-viral or acute bacterial rhinosinu-
(in primary care patients frequently consult with more than one sitis as defined by EPOS. Over 50% of the patients with acute rhi-
clinical problem)(19). nosinusitis had symptoms for <5 days and most had no fever(24).
It is, however, difficult to be precise concerning prevalence: The wide variability in diagnostic rates may also indicate geo-
graphical factors, the cost or ease of accessing healthcare, diag-
nostic norms in differing countries, patient expectations, patient
FIgure 4.1.3. Common cold symptoms. worries, concerns or beliefs, and clinical expertise(24).
This problem is further compounded and confounded with
70%
misdiagnosis especially regarding migraine headaches(25-27).
Nasal discharge
60%
4.1.4. Conclusion
50%
In summary, it is difficult to give a precise estimate of the pre-
40% valence of ARS. Viral ARS (common cold) is very common and
Cough it has been estimated that adults suffer two to five and school
30%
children may suffer seven to 10 episodes per year. The only
20% available prospective population study evaluating EPOS defined
Headache post-viral ARS (and ABRS) points to a prevalence of 18%(3) and
10%
Fever Nasal obstruction (post-viral and ABRS) ARS is likely to be responsible for 1-2% of
0%
consultations in primary care. Carefully constructed prospective
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
epidemiological studies with valid diagnoses of ARS may give a
Days of illness
clearer picture of the real burden of ARS.

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 EPOS 2020

Figure 4.2.1. Delphi: In the diagnosis of recurrent acute rhinosinusitis do you Figure 4.2.4. Delphi: In the diagnosis of recurrent acute rhinosinusitis: Is it
rely on: History alone? essential to examine the patient with a CT sinuses during (or shortly after)
an acute episode if endoscopy has been performed and is normal?

Figure 4.2.2. Delphi: In the diagnosis of recurrent acute rhinosinusitis do you Figure 4.2.5. Delphi: In the diagnosis of recurrent acute rhinosinusitis: Is it
rely on: History + positive objective findings, i.e. endoscopy and/or CT? essential to examine the patient with a CT of sinuses during (or shortly after) an
acute episode if endoscopy has been performed and is abnormal?

Figure 4.2.3. Delphi: In the diagnosis of recurrent acute rhinosinusitis: Is it 4.2. Recurrent ARS (RARS)
essential to examine the patient with a CT-sinuses during (or shortly after)
an acute episode if endoscopy has not been performed? RARS is defined as ≥4 episodes per year with symptom free in-
tervals(7, 28-30). Each episode must meet the criteria for acute post-
viral (or bacterial) rhinosinusitis. Recurrent ARS may be conside-
red distinct from ARS and CRS. Using data from a medical claims
database for 13.1 million patients from 2003 to 2008, the point
prevalence of recurrent ARS has been reported to be 0.035%,
considerably lower than that of ARS(31). However, in the study by
Hoffmans et al. only four out of 5574 ARS patients visiting their
GP met this categorisation(17). Whether RARS should be conside-
red a form of acute or CRS requires further discussion.
Lee et al. (32) underlined the diagnostic challenge when it comes
to RARS, and this is due to the relative lack of awareness and
also the sporadic diagnosis by different healthcare providers.
Most of the time, endoscopy is clear and CT sinuses do not show

56
 EPOS 2020

any significant mucosal thickening(33). The EPOS2020 steering acquiring an acute respiratory illness was 2.9 (95% CI: 2.8- 3.0) in
group advises to have at least one proven diagnosis of post-viral January to March, 1.8 (95% CI: 1.7-1.9) in October to December
ARS with endoscopy and/or CT scan before a diagnosis of RARS and 1.4 (95% CI: 1.3-1.5) in April to June. In an audit of compli-
is considered (Figures 4.2.1.-4.2.5.) . cations of ARS, Babar-Craig et al. reported that 69% of patients
were admitted during the winter months of November to
4.3. Factors associated with ARS and RARS April(12). Similar patterns have been reported in acute exacerba-
tions of CRS(46) and upper respiratory tract infections(47). Climate
There appear to be many factors which impact upon ARS, and variations have been reported to induce facial pain similar to
it is likely that many people suffering from a bout of ARS have ARS. Chinook or Föhn winds are weather events in which a
more than one contributing factor. In a recent questionnaire- rapidly moving warm, high-pressurised wind enters a specific
based study from the Netherlands, the factors which predis- location. The pressure changes that occur during the Chinook
posed to increased likelihood of ARS were: a doctor-diagnosis of may induce facial pain similar to that experienced in rhinosinu-
CRS, allergic rhinitis, female gender, eczema, itchy rash and smo- sitis pain. Rudmik et al. report that compared to controls, the
king. Increasing age was a protective factor(3). In the Netherlands presence of concha bullosa and spheno ethmoidal cell (Onodi
non-Caucasian ethnicity was also a protective factor, but this cell; p=0.004), and larger maxillary sinus size (right, p=0.015; left,
clearly depends on other factors as, for example, in a study from p=0.002) are all associated with complaints of Chinook heada-
the USA, being Caucasian was protective(34), suggesting that che(47, 48). However, as the Lund-Mackay (LM) score was higher in
risk factors have different impacts in different locations. There the control group, the authors conclude that CRS is unlikely to
is limited evidence on predisposing factors in RARS(35) though it be associated with the Chinook induced facial pain. Exposure to
appears that the majority of episodes follow viral ARS and some air pollution(49-51), irritants used in the preparation of pharmaceu-
patients are immunodeficient(36, 37), mainly IgA deficient and tical products(52), during photocopying(53) and forest fire smoke(54)
common variable immunodeficient(38-40). have all been associated with an increase in the prevalence of
symptoms of ARS. Of importance in seasonality of ARS is the
4.3.1. Environmental exposures presence of CRS which seems to predispose to ARS especially
Using a matched case-control study design conducted in a in the winter months, whereas ARS was more common in those
Dutch population over the period 2000 to 2003, van Gageldonk- without CRS in the spring months(55). This study also quantified
Lafeber et al.(41) reported that exposure to an individual(s) with the effect of no previous past history of CRS compared to those
respiratory complaints, inside or outside of the immediate who had a previous and current history of CRS, demonstrating
household was an independent risk factor for attending their an increasing incidence gradient also shown for never, former
GP with an acute respiratory tract infection (adjusted odds ratio (1.01) and current smokers (1.53), the presence of asthma
(OR)=1.9 and adjusted OR=3.7, respectively). In contrast, pa- symptoms, a diagnosis of hay fever (1.36), migraine (1.55), anxi-
tients with children in secondary education, who had dampness ety (0.96-1.29), sinus surgery (1,46-1.74), being Caucasian (1.5)
or mould at home, or had exposure to passive smoking were and female gender (1.35). Broadly similar results were found
less likely to visit their GP compared to those without children, in a study from the Netherlands(3). A review of the literature by
mould or dampness or passive smoking exposure respectively. De Sario et al. described how the role of our changing climate,
Increased levels of dampness, but not mould, in the home outdoor pollution, temperature, wild-fires, and desert storms
has been associated with rhinosinusitis(42). Seasonal trends in may act synergistically to present a challenge to those suffering
occurrences of ARS have been reported. This is of course to be from respiratory disease(44).
expected and is common knowledge that does not need to be
over-elaborated as acute viral infections are the most common 4.3.2. Anatomical factors
cause of upper respiratory tract infections including acute rhino- Abnormalities on radiology are often seen in the healthy popu-
sinusitis(43). What has become clear is that weather patterns are lation. Two recent studies, one in Japan and one in the Nether-
increasingly variable which will impact on many of the currently lands reported on radiology in healthy populations and found
identified risk factors(21, 44). significant percentages that could be misinterpreted as abnor-
In a study of respiratory tract infections, Neumark et al. reported malities pointing to ARS or CRS. The Dutch study showed some
seasonal variation in the incidence rate of rhinosinusitis from abnormality (LM>0) in 43% of the population and 14% had a LM
1999 through to 2005, with increased incidence in the first score ≥ 4 pointing to ARS or CRS(56). The Japanese study was in
quarter of each year(45). For acute respiratory illnesses in 2000 an elderly population and found 17% LM>0 and 7.4% LM score
to 2003, van Gageldonk-Lafeber et al. reported similar seasonal ≥ 4 respectively(57).
trends to those of Neumark(15). Compared to July to September, It has been suggested that anatomical variation is more likely
van Gageldonk-Lafeber et al. reported that the relative risk of to be of causal significance in patients with RARS(33, 58-60) with

57
 EPOS 2020

infraorbital cells and concha bullosa most often cited. In a small episodes of ARS, or bacteriological and radiological findings
retrospective study on CT in 36 patients with RARS versus 42 suggesting that the presence of allergy may be incidental.
controls, the LM score was 2.25 in the RARS group compared In a comparative case-control study of Israeli air force pilots, Ula-
with 1.27 in the controls, notably related to the presence of novski reported that 33% of pilots with a history of AR and 21%
infraorbital cells(58). However, the presence of an anatomic vari- of the control group had one or more episodes of ARS (p=0.09)
ant did not correlate with the pattern of inflammation in a small (72)
. In 2009, Pant et al. undertook a review of allergy in rhinosi-
retrospective study(60). Endoscopy and CT were shown to be nusitis. In agreement with the above literature, they concluded
undertaken less frequently than in CRS, 9.2% in the first three that insufficient evidence exists to confirm seasonal or peren-
years and 40% in the first four years, respectively(31). nial AR as a significant predisposing factor for ARS(73). Lin et al.
In conclusion, there are limited data correlating anatomical reported that children with atopy were more likely to develop
factors to (recurrent) ARS. Abnormalities seen on radiology are ARS(74). They reported that atopic children with ARS reported sig-
also common in a healthy population. nificantly higher symptoms (including dizziness, sneeze, snore,
itchy or burning eyes, eye congestion and tearing) as well as
It has been suggested that anatomical variation is significantly higher levels of anxiety, dyspnoea, chest tightness,
more likely to be of causal significance in patients and lower nasal peak inspiratory flow than non-atopic children
with RARS patients. with ARS. A more recent study in children demonstrated that
although ARS was common in the studied population, there was
4.3.3. Odontogenic infections no difference in incidence between those sensitised to grass
Odontogenic infections, or infections arising from dental pollen and those not sensitised but that the most common risk
sources, causing acute maxillary sinusitis have been reported factor was an acute viral infection(75). We are not aware of studies
in the literature. Bomeli et al. reported that oroantral fistula and evaluating the role of allergy in RARS.
periodontal disease plus either a projecting tooth root or peri- In summary, there appears to be little to support the presence of
apical abscess were significantly identified as sources of acute allergic rhinitis as a risk factor for developing ARS.
maxillary sinusitis(61). Furthermore, they demonstrated that the
greater the extent of fluid opacification and mucosal thickening, There appears to be little to support the presence
the greater the likelihood of an identifiable dental infective of allergic rhinitis as a risk factor for developing
source. In a computed tomography (CT) radiological study of ARS.
the maxillary sinus in elderly dentate and edentulous patients,
Mathew et al. reported an increased prevalence of mucosal 4.3.5. Ciliary impairment
thickenings (74.3 versus 25.6; p<0.05 ) and mucous cysts (2.1% Ciliary impairment has been demonstrated to be a feature of
versus 0) in dentate patients compared to edentate controls, both viral and bacterial rhinosinusitis(1). This includes both the
but most of these abnormalities can be considered chronic(62). A loss of cilia and ciliated cells as well as a disruption of normal
recent retrospective analysis from Finland suggests that some mucociliary flow. Smoking and allergy have been implicated in
15% of ARS may be odontogenic in nature(63). the disruption of cilia function. Indeed, impaired mucociliary
clearance in AR patients predisposes patients to ARS(76).
In patients with (recurrent) ARS, odontogenic Ciliary impairment has also been associated with cigarette smo-
sources of infections should be considered. king. In vitro studies have demonstrated that cigarette smoke
condensate and cigarette smoke extract impair ciliogenesis in a
4.3.4. Allergy dose-dependent manner(77). Clinical studies have also reported
The role of allergy in ARS is the subject of much debate with that exposure to passive smoking increases the levels of matrix
literature both supporting and disputing a role for allergy in metalloproteinase 9 (MMP-9), a gelatinase associated with tissue
predisposing for ARS(64). Schatz et al. reported that the odds of modelling which is significantly increased in nasal secretions of
developing an episode of ARS was 4.4 times higher in patients children(78) exposed to passive smoking. As increased production
with rhinitis than in healthy controls(65). The major difficulty is of MMP-9 has been found in the acute allergic response in the
the high prevalence of around 30% depending on the location nose and lungs, the implications for the involvement of MMP-9,
of allergy in the population worldwide(66-70). In 1989, Savolainen ciliary function, allergic response, and smoking in ARS needs
reported that 25% of 224 patients with acute maxillary sinusitis further exploration.
had allergy, as verified by allergy questionnaire, skin testing and
nasal smears, with a further 6.5% of patients having probable 4.3.6. Smoking
allergy(71). However, upon comparison of those with and without Limited research exists on the impact of smoking on ARS. Using
allergy, no differences were found in the number of previous data from the 1970 US National Health Interview Survey, and

58
 EPOS 2020

after excluding families with children with chronic respiratory 4.3.8. Anxiety and depression
illness, Bonham and Wilson reported that children from house- Poor mental health or anxiety and depression have been signifi-
holds with one or more adult cigarette smokers had significantly cantly associated with ARS. In a study of 47,202 college students
more restricted activity and bed-disability days than children aged 18 to 24 years, Adams et al. reported that the prevalence of
from families with non-smoking adults(79). This difference was acute infectious illness, which included bronchitis, ear infection,
found to be due to children from families with active smokers rhinosinusitis, and strep throat, ranged from 8% to 29%, while
having more episodes of acute respiratory illness (including the prevalence of anxiety and depression ranged from 12% to
ARS). Comparable significant results were found when families 20%, respectively(88). It is important to recognise the confoun-
in which 45 cigarettes or more were consumed per day were ding impact of smoking as smoking contributes to ARS but also
compared to families with non-smoking adults. The authors to anxiety/depression. Those who stop smoking demonstrate an
concluded that higher cigarette consumption was associated improvement in mood and quality of life with reduced levels of
with increased predisposition for acute respiratory illness. In anxiety and depression(89).
a paediatric characterisation study of 76 patients with acute
rhinosinusitis aged 4-18 years, Eyigör and Başak reported that 4.3.9. Concomitant chronic disease
51.3% (39 patients) were exposed to second-hand smoke and Concomitant chronic disease (bronchitis, asthma, cardiovascu-
2.6% (two patients) were active smokers(80). Based on their lar disease, diabetes mellitus, or malignant cancer) in children
population, the authors concluded that exposure to primary has been associated with an increased risk of developing ARS
or second hand smoke were predisposing factors for ARS. In a secondary to influenza. Loughlin et al. reported that the overall
study characterising the respiratory symptoms of adult postal incidence rate of developing ARS following influenza ranged
workers in Zagreb, Croatia, the prevalence of rhinosinusitis in from 0.9 to 1.3 in children aged 0 to 14 years. While the inci-
active smokers was 53.1% compared to 26.4% in non-smokers, dence of ARS subsequent to influenza in healthy children aged
although no information was available on whether the rhinosi- 5-14 years was 1.2 (95% CI: 0.9 – 1.5), this increased to 3.1 (95%
nusitis was recurrent acute or chronic in nature(81). CI: 1.5 – 5.8) in children with chronic disease (rate ratio: 2.7 (95%
Active and passive smoking has been shown to alter the normal CI: 1.5 – 5.4). Increased monitoring of children with chronic
bacterial flora present in the nasopharyngeal spaces, resul- disease who develop influenza maybe necessary(90).
ting in the colonisation of more potential pathogens than in
non-smokers(82). Following smoking cessation, the microbial 4.3.10. Conclusion
population has been shown to revert back to that found in Predisposing factors for ARS are seldom evaluated. There is
non-smokers(83). The impact of smoking cessation programmes some indication that anatomical abnormalities may predispose
on the incidence and prevalence of ARS is unknown. In vitro and for RARS. Active and passive smoking predisposes to ARS and
in vivo studies have recently shown increased MMP-9 produc- there is some indication that concomitant chronic disease may
tion in children exposed to passive smokers(78) and increased increase the chance of getting ARS following an influenza infec-
complement activation in human respiratory epithelial cells and tion. Other potential factors like allergy and GORD do not seem
mice exposed to cigarette smoke extract(84). Whether increased to predispose to ARS.
MMP-9 production or complement activation due to exposure
to cigarette smoke predisposes to ARS is unknown and requires 4.4 Pathophysiology of ARS
further investigation. More recent studies confirm the negative
impact of smoking(55). ARS can be divided into acute viral rhinosinusitis, post-viral rhi-
nosinusitis and acute bacterial rhinosinusitis. ABRS is frequently
Active and passive smoking predisposes to (R)ARS. preceded by acute viral rhinosinusitis or common cold(91). In
addition to the strain and virulence of individual viruses, the se-
4.3.7. Laryngopharyngeal reflux verity and pathogenesis of ARS is highly dependent on the host
Little is known about the association of ARS and laryngopha- factors or predisposing conditions, such as age, host defence
ryngeal reflux. As reviewed by Pacheco-Galván et al., epidemio- parameters or immune deficiency, previous infection or immuni-
logical studies conducted between 1997 and 2006 have shown zation, pre-existing mucosal inflammation caused by exposure
significant associations between gastro-oesophageal reflux to allergens, pathogens or other environmental risk factors, and
disease (GORD) and rhinosinusitis(85). However, in a recent syste- anatomic deformity of the nose and sinuses.
matic review, Flook and Kumar showed only a poor association The pathogenesis and pathophysiology of ARS is incompletely
between acid reflux, nasal symptoms, and ARS(86). The role of understood. This is mainly due to the lack of prospective clinical
reflux in ARS remains unclear(87). and laboratory studies in patients being performed during the
natural course of ARS. In the literature, most reported studies

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were carried out using human volunteers, in vitro study of Figure 4.4.1. Nasal epithelium is the primary portal of entry for respi-
human tissue or cell lines, and experimental animals. These ratory viruses as well as an active component of initial host responses
results have yet to be validated in human patients with naturally against viral infection. The cascade of inflammation initiated by nasal
acquired viral infection and ARS. epithelial cells will lead to damage by the infiltrating cells, causing
ARS can theoretically be divided into viral (common cold) and oedema, engorgement, fluid extravasation, mucus production and sinus
post-viral rhinosinusitis. A small subgroup of ARS is caused by obstruction in the process, eventually leading to postviralARS or even
bacteria (ABRS). The pathogenesis and inflammatory mecha- ABRS.
nisms of viral and post-viral infection, and ABRS (if it occurs) can
considerably overlap as can their clinical presentation.

ARS can theoretically be divided into viral

(common cold), post-viral rhinosinusitis and a
small subgroup of acute bacterial rhinosinusitis.

4.4.1. Viral rhinosinusitis

Viral rhinosinusitis (or the common cold) is, by definition, an
acute rhinitis induced by respiratory viruses, such as rhinovi-
rus (RV), respiratory syncytial virus (RSV), influenza virus (IFV),
coronavirus (CorV), parainfluenza virus (PIV), adenovirus (AdeV)
and enterovirus (EV)(35, 91, 92). RV and CorV are the most common
viruses isolated from adult ARS, accounting for approximately
50% of viral ARS diagnosis(93). In children, there is a wider variety
of responsible viruses, i.e. besides rhinoviruses and coronaviru-
ses, one can also expect to find RSV, parainfluenza viruses and
adenoviruses. Geographically, there are also other viruses isola- The nasal epithelium is the primary portal of entry
ted from patients with ARS, e.g. human bocavirus is frequently for respiratory viruses and immediate target for
isolated from ARS cases(94). With the new development of more viral replication in the airway. It serves as a
sensitive and high-throughput viral detecting and screening mechanical barrier to protect from
techniques, multiple viruses can be detected. It is, however, environmental factors, microorganisms, and
relatively difficult to identify key viruses that cause or exacerbate toxins, but also participates in both innate and
ARS in clinical practice. adaptive immune responses.

Post-viral ARS and ABRS are frequently preceded RV infection can upregulate the expression of ICAM-1 via IL-1β
by acute viral rhinosinusitis or common cold. and nuclear factor (NF)-κB-dependent mechanisms, directly
enhancing infectivity and promoting inflammatory cell infiltra-
4.4.1.1 Nasal epithelium tion(100, 106, 107). In nasal polyp epithelium, higher expression of
Receptors α-2,3-SA and α-2,6-SA will lead to the entry of more avian and
The nasal epithelium is the primary portal of entry for respi- seasonal influenza virus infection than normal nasal mucosa(108).
ratory viruses and immediate target for viral replication in the In in vitro culture of differentiated nasal, tracheal and bronchial
airway(95-98). It is also an active component of initial host respon- cells, the α-2,3-SA and α-2,6-SA receptors were located in cilia-
ses against viral infection. Nasal epithelial cells express various ted and non-ciliated cells, respectively(109). Therefore, influenza
receptors recognizing specific viruses, such as intercellular ad- virus likely targets non-ciliated cells in the nose, as the α-2,6-SA
hesion molecule-1 (ICAM-1)(99, 100), toll-like receptor 3 (TLR3)(101), receptor is expressed in both the nose and trachea(110).
α-2,3-linked sialic acid (α-2,3-SA)/α-2,6-SA containing receptor
(102)
, retinoic acid inducible gene 1 (RIG-1, also known as DDX58) Immune responses
(101, 103)
, and MDA4 (also known as IFIHI)(103). Upon infection the The nasal epithelium not only serves as a mechanical barrier to
virus enters by receptor-mediated endocytosis, followed by ex- protect from environmental factors, microorganisms, and toxins,
pression and replication of the viral genome within hours after but also participates in both innate (non-specific) and adap-
infection(99, 104, 105) (Figure 4.4.1.). tive immune responses. The pseudostratified airway surface
epithelium can be damaged in different degrees depending
on the type of viruses and can also regenerate to restore its

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defence functions. Therefore, the interactions between the nasal viral infections. For example, rhinoviruses tend to express much
epithelium and invading pathogens play key roles in the disease weaker signatures compared to influenza infection(97); and infec-
progression and subsequent immune responses against the tions such as RSV tend to elicit a sustained response following
virus, thus contributing to both disease burden and combating infection compared to other viruses(124). Therefore, studies to
infection of the nasal epithelium. differentiate the pathogenic mechanism of different respiratory
Many studies indicate that the nasal epithelium actively trig- viruses are pivotal to understand their differential symptoms
gers innate immune responses and also modulates adaptive and severity in ARS, further highlighting the need for viral detec-
immunity against these viruses(95, 96, 111). Nasal epithelial-specific tion for symptom management of ARS.
transcriptomic signatures may significantly influence the down-
stream immune responses and homeostasis that define the Motile cilia
pathology of respiratory infection and complications(97, 112-114). In In an early study, a significant and long-lasting (up to 32 days)
addition, respiratory viruses are also implicated to disrupt cilia impairment of nasal mucociliary clearance functions such as a
and tight junction integrity in airway epithelial cells through fall in the number of ciliated cells and a moderate and short-
the modulation of ZO-1, claudin-1 and occludin in the airway lasting change in beating frequency and intracellular synchrony
epithelial barrier(115-117). were observed in patients with common cold(125). More recent
Nasal epithelial cells elicit their own repertoire of immune studies have further confirmed that impaired ciliogenesis was
responses and actively prevent pathogens from damaging the prominent following viral infections(126), consistently leading to
airway(111, 118). Upon infection, they not only release anti-micro- loss of cilia and ciliated cell ultrastructural abnormalities (i.e.,
bial surfactants and mucus to delay pathogen transmission in cytoplasmic blebbing, swollen mitochondria)(97, 111, 127, 128).
the airway(114, 119), but also express and secrete various cytokines In vitro studies from human nasal epithelial cell models de-
and chemokines to drive immune responses against invading monstrated that downregulation of ciliogenesis marker Foxj1
pathogens in the airways(120, 121). In an in vitro study, H3N2 (Ai- and upregulation of goblet cell marker Mucin5AC indicated the
chi/7) infection of human primary nasal epithelial cells, showed: altered muco-ciliary function due to RV infection (clone RV16)
1) highly efficient viral replication dynamics starting as early (97)
. In another study, RSV was found to infect preferentially the
as four hours post-infection (hpi); 2) upregulation of four main ciliated cells in human primary nasal epithelium. A portion of
pathogen recognition receptors (PRRs) RIG-I, NLRP3, TLR3 and the RSV proteins (F and G) were trafficked into the cilia between
TLR7; 3) exponentially elevated IFN-α2, IFN-β, IL-28A and IL-29 (8 24 and 48 hour-post-infection followed by extensive cilia loss
to 72 hpi) at both intracellular mRNA and secreted protein levels; at five days-post-infection(129). For influenza, the infection was
4) a rapid production and release of chemokines IP-10, CXCL11, followed by apoptotic and necrotic cell death causing the loss of
and RANTES and inflammasome markers including IL-1α, IL- epithelium including ciliated cells, impacting ciliary function(111).
1β, IL-6, IL-8, TNFα and TGFβ after 24-72 hpi; 5) indices of cell
damage and death showed a steady decline in viability, integrity Goblet cells
and survival rate from 16 to 72 hpi. These findings demonstrated The mucosal lining of the nasal cavity is coated by a mucus
quantitatively virus-host relationship, transmission capacity and layer 10 to 15 µm thick. Mucus is supplied by goblet cells in the
virulence of the respiratory viruses in the upper airway(111). epithelium and submucous seromucous glands. Sinus secreti-
ons are a mixture of glycoproteins, other glandular products,
Transcriptomic signatures and plasma proteins. Secretions are rich in lysozyme, lactoferrin,
The transcriptomic changes of infected nasal epithelial cells albumin, secretory leukoprotease inhibitors, and mucopro-
revealed differential regulation of 11 targets (CD38, HERC5, teins(130). In an ideal scenario, immediately after viral infection,
HERC6, IFI6, IFIH1, LGALS3BP, LY6E, MX1, PARP12, RTP4, ZBP1) a timely immune response is elicited, culminating in early viral
creating influenza-specific signatures(122). Hence, these key elimination with minimal damage to the host. However, the
transcriptomic signatures during influenza are nasal-initiated, cascade of inflammation initiated by the epithelial cells normally
underscoring the potential application of nasal epithelial leads to damage by the infiltrating cells, causing oedema,
responses in rapid and sensitive molecular-based diagnostics to engorgement, fluid extravasation, mucus production and sinus
improve influenza detection(98). In addition, recent studies have obstruction, eventually leading to ARS or exacerbating ARS(131).
highlighted the strong expression of interferon lambda (IFN-λ, It has been reported that common cold symptoms may result
including IL-28A and IL29) as an important factor for limiting from release of inflammatory mediators, such as bradykinin
influenza viral spread, and potentially other viruses(97, 98, 111, 123). and TAME-esterase activity (but not histamine), into the nasal
On the other hand, while other viruses express highly similar mucosa and secretions(132). There is a luminal entry of plasma,
transcriptomic signatures exerting antiviral effects, the magni- including large binding proteins such as fibrinogen and α2 –ma-
tude and response-time of the signatures may differ between croglobulin, which may bind and transport a variety of cytokines

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in both the common cold and allergic rhinitis(133). In addition, Post-viral rhinosinusitis is not an indicator of
it has been shown that rhinovirus infection induces mucus development of bacterial infection as only a small
hypersecretion, which may contribute to a progress from watery percentage of the patients with ARS
rhinorrhoea to mucoid discharge during the common cold(134). will have ABRS.
Viral interaction with goblet cells may also contribute to
symptoms and aggravation of ARS. For example, MUC5AC 4.4.3. Acute bacterial rhinosinusitis
production from goblet cells increased following RV and RSV Acute bacterial rhinosinusitis (ABRS) is an uncommon compli-
infection(97, 135), while MUC5B was found to increase following in- cation of viral upper respiratory tract infections that may cause
fection with human metapneumovirus (hMPV) in epithelial cell mucosal damage and bacterial super-infection. Damage or
lines(136). With influenza virus, goblet cells produce sialic acid rich disruption of mucociliary function due to viral infection is pro-
glycoprotein decoys in the mucus layer to prevent influenza bin- bably a major cause of super- or secondary bacterial infection.
ding to the epithelial cells(137, 138). However, the virus circumvents Bacterial and fungal infections are normally accompanied by
the sialic acid rich mucus layer via neuraminidase mediated viral infections, as observed in the common cold (RV-infection),
cleavage of the sialic acids(138). This interaction also contributes and recurrent or chronic rhinosinusitis(144-146). Streptococcus pneu-
to secondary bacterial aggravation of ARS with cleaved sialic moniae, Hemophilus influenzae and Moraxella catarrhalis are the
acid serving as additional nutrient sources for bacteria such as S. most frequent bacteria in rhinosinusitis(146). RV-1b infection
pneumoniae(139). Hence, the role of goblet cells in the pathoge- can promote the internalization of Staphylococcus aureus into
nesis of ARS is complex and multifaceted requiring controlled non-fully permissive cultured pneumocytes with a mechanism
studies with appropriate models to establish their roles with that involves the virus-induced release of IL-6 and IL-8, and the
different viruses. overexpression of ICAM-1(145). RV infection also promotes expres-
sion of cell adhesion molecules and bacterial adherence to
Other factors primary human respiratory epithelial cells(147-149). Furthermore, in
Other factors such as soluble chemical factors, kinins, nitric RV-infected nasal epithelial cells (NECs) from the nasopharynx,
oxide, nerve stimulation and neuromediators, may play im- TNF-α expression was increased by Aspergillus infection(150).
portant roles in the pathophysiology or pathogenesis of viral Viral infection of the nasal mucosa may trigger an inflammatory
rhinosinusitis have been previously reviewed in EPOS 2012(91). cascade thought to be responsible for the cold symptoms, but
Additionally, membrane tethered mucins (including MUC1, also forming the basis for immunological defence. The process
MUC3A, MUC3B, MUC4, MUC12, MUC13, MUC15, MUC16, of clearing the virus generates dead epithelial and infiltrating
MUC17, MUC20, and MUC21) that are expressed by the mucosal cells that contribute to the pathology of ARS. Such nasal epithe-
epithelium unlike secreted mucins expressed by goblet cells, lial-specific transcriptomic alterations may significantly influence
may also play a role in viral ARS(140, 141). For example, MUC1 has the downstream immune responses and homeostasis that de-
been implicated in influenza infection and its subsequent fine the pathology of respiratory infection and complications(97,
inflammatory responses(142, 143); while MUC4 and MUC16 may 98, 112, 114)
. It also creates an environment suitable for secondary
also play a role in forming a protective barrier against invading bacterial infections (such as Staphylococcus aureus and Strepto-
pathogens(141). coccus pneumoniae), representing another factor exacerbating
ARS symptoms initiated by a viral infection(95, 139, 151, 152).
4.4.2. Post-viral rhinosinusitis
In EPOS 2012 the term ‘post-viral ARS’ has been recommended Viral infection of the nasal mucosa may trigger an
in order to express the phenomenon of increase of symptoms inflammatory cascade thought to be responsible
after 5 days or persistent symptoms after 10 days with less than for the cold symptoms, but also forming the basis
12 weeks duration(91). It is not an indicator of development of for immunological defence.
bacterial infection as only a small percentage of the patients
with ARS will have ABRS. It has been suggested that respiratory virus infection induces
The pathophysiology and pathogenic mechanisms of post-viral the production of type I interferons (IFNs), inhibiting both the
rhinosinusitis remain unclear. Viral infection of the nose and recruitment of circulating neutrophils and macrophages to the
sinuses induces multiple changes, which include infiltration and lung following bacterial challenge and the differentiation of
activation of various inflammatory cells in the sinonasal mucosa antibacterial T helper 17 (TH17) cells from naive T cells or other
and defects in the host and adaptive immune defence functions, T helper (TH) cell types (such as TH1 and TH2 cells). This then
as well as increase the risk of bacterial superinfection. Therefore, potentiates host susceptibility to secondary bacterial infection(95,
in most patients, this is a time frame for recovery from a single 153)
. Interleukin-10 (IL-10) production by influenza virus-specific
episode of ARS to complete resolution. effector T cells may inhibit the ability of innate immune cells,

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in particular macrophages, to kill bacteria. Finally, the direct response against invading viruses, especially in the context of
interaction and/or infection of innate immune cells — such as influenza(111). Furthermore, the nasal cells could initiate cross-talk
macrophages, neutrophils and natural killer (NK) cells — with between innate and adaptive immunity via strong production
influenza virus suppresses the ability of these cells to take up of adaptive immune-activating cytokines and chemokines. A
and kill bacteria(95). recent study showed that H3N2 infection of the nasal epithe-
S. pneumoniae infection is commonly associated with the aggra- lium was associated with significant increase in interferons
vation of viral infections(154). Studies have shown that influenza (IFN-α, IFN-γ, IL-29), pro-inflammatory cytokines (TNF-α, BDNF,
infection alters the gene expression of S. pneumoniae promoting IL-3) and viral-associated chemokines (IP-10, MCP-3, I-TAC, MIG),
dispersal from biofilms on the nasal mucosa(154, 155). As respiratory detectable as early as 24h post infection(158). This translates into
viruses induce a similar antiviral repertoire in the nasal epithe- rapid monocyte, NK-cell and innate T-cell (MAIT and γδ T-cells)
lium, these viruses can cause similar dispersal of S. pneumoniae activation, evident with CD38+ and/or CD69+ upregulation(158).
into the airway mucosa. Therefore, an understanding of the predominant type and
underlying mechanisms of mucosal inflammation triggered by
4.4.4. Host defence mechanism common viral infections will allow us to identify targets for bet-
The anti-viral immune response involves innate and specific ter management of chronic airway inflammatory diseases.
components and requires the coordinated actions of many diffe- There are also critical down-regulated functions in nasal epithe-
rent cell types including neutrophils, macrophages, eosinophils, lium related to multiple metabolic and DNA damage responses
dendritic cells, epithelial cells, mast cells, natural killer cells and against influenza that are not observed in blood or serum
B- and T-lymphocytes. Coordination of this response involves samples(98, 159-163). Such reductions in metabolic function and
numerous cytokines and chemokines. related metabolites at the primary influenza infection site may
It is often speculated that the T-helper 1 (Th1) response is be an interesting area for future investigation to understand
initiated from the epithelial innate immune response via toll- their relationships with viral replication and immune functions.
like receptors 3, 7 and 9 (TLR 3, TLR7 and TLR9) due to the virus In addition, these changes in the metabolic and homeostatic
infection(111, 156). Depending on the type of virus, the pathogen- pathways are unique to the nasal epithelium.
sensing molecules in turn activate the production and secre-
tion of nuclear factor-κB (NF-κB), interferon-β (IFN-β), tumour
necrosis factor-α (TNFα) and interleukins-1β, 6 and 8 (IL-1 β, IL-6 Key points | What’s new since EPOS 2012
and IL-8), which are potent inducers or recruiters of neutrophils
and macrophages(92, 95). The initial action of neutrophils against
virus-infected cells usually contributes to the early symptoms of
an acute respiratory virus infection. Following this, the further Since EPOS 2012, there has been increasing experimental data
secretion of TNFα and interferon-γ (IFN-γ) increases the recruit- supporting the fact that nasal epithelium is the primary portal
ment of Th1 cells and cytotoxic T-cells leading to the clearance of entry for respiratory viruses as well as an active component of
of the viral pathogens and viral-infected cells. initial host responses against viral infection. The cascade of in-
IFNγ production by influenza virus-specific effector T cells flammation initiated by nasal epithelial cells will lead to damage
decreases the expression of macrophage receptor with collage- by the infiltrating cells, causing oedema, engorgement, fluid
nous structure (MARCO) by alveolar macrophages and inhibits extravasation, mucus production and sinus obstruction in the
the ingestion of bacteria by these cells. It is known that through process, eventually leading to postviral ARS or even ABRS.
secretion of type I IFNs (IFN-α/β), the first line innate immunity
defence in the infected cells, the neighbouring uninfected cells
would be alerted to trigger its antiviral mechanisms. IFN-β is
involved in the upregulation of antiviral proteins, induction of 4.5. Diagnosis and differential diagnosis of ARS in
apoptosis to inhibit the viral replication, and removal of infected adults and children
cells in the normal airways upon RV infection(157).
In addition, type III IFNs (IL-28A and IL-29) are shown to be 4.5.1. Update from EPOS 2012
strongly responsive to H3N2 infection, particularly their respon- Although the diagnosis and differential diagnosis of ARS has not
ses were found as early as 4 hpi and peaked at 24-48 hpi(111). It is, changed substantially, there is more evidence on the prevalence
therefore, important to look at the antiviral responses shown by of symptoms and the predictive value of individual and com-
IFNs where we will be able to assess viral pathogenesis differen- bined symptoms on the diagnosis of (bacterial) acute rhinosinu-
ces in the nasal epithelium. sitis. This update reflects that new information.
Naïve epithelial cells evoke an appropriate type-1 inflammatory

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Post-viral ARS is a common condition in the ARS is sub-divided into ‘acute viral rhinosinusitis’ (synonymous
community, usually following viral URTI. with the ‘common cold’), in which the duration of symptoms is
less than 10 days, usually a self-limiting condition that frequent-
4.5.2. Introduction ly does not present to clinicians, ‘acute post-viral rhinosinusitis’,
ARS is a common condition and is usually self-limiting. Many defined by an increase in symptoms after five days or persisten-
patients will self-manage or use over the counter remedies, so ce beyond 10 days(176) and ‘acute bacterial rhinosinusitis’ defined
will not seek medical care or have a formal diagnosis made. by at least three symptoms/signs – discoloured mucus, severe
When medical care is sought, most patients will consult with a local pain, fever>38’, raised CRP/ESR, ‘double’ sickening.
primary care physician, although in some health systems may
directly access specialist services. Although educational efforts 4.5.3.1. Assessment of ARS symptoms
have been made to familiarize General Practitioners (GPs) with
the concepts of rhinosinusitis and the diagnostic criteria for the Most acute viral URTI infections are self-limiting,
diagnosis of ARS(164), ‘sinusitis’ is commonly used as a diagnos- thus post-viral ARS should not diagnosed before
tic label, and as this is frequently considered by GPs an acute 10 days duration of symptoms unless there is a
bacterial rather than inflammatory condition(165), antibiotics are clear worsening of symptoms after five days.
extensively prescribed(166, 167). The dissemination of the EP3OS(1)
and other recent guidelines(168, 169) emphasizing the inflammatory The subjective assessment of ARS in adults is based on the pres-
nature of ARS and providing standardization of diagnostic crite- ence and severity of symptoms.
ria and use of investigations has led to more rational diagnosis • Nasal blockage, congestion or stuffiness
and management in some(167, 170) but not all(171, 172) settings. In • Nasal discharge or postnasal drip, often mucopurulent
addition to misunderstandings concerning the inflammatory • Facial pain or pressure, headache, and
nature of ARS(171), concern over the risk of septic complications • Reduction/loss of smell
from untreated bacterial disease may be a factor in the ongoing
high use of antibiotics in ARS. Observational evidence indicates, Besides these local symptoms, distant and systemic symptoms
however, that complications are rare(13, 173) usually manifest early may occur. Associated symptoms are pharyngeal, laryngeal, and
in the course of the illness with severe symptoms(174, 175), and that tracheal irritation causing sore throat, dysphonia, and cough,
antibiotic treatment of ARS in general practice does not prevent and general symptoms including drowsiness, malaise, and
complications(12, 13). fever. There is little reliable evidence of the relative frequency of
different symptoms in ARS in community practice. Individual va-
Observational evidence indicates that antibiotic riations of these general symptom patterns are many(177-181). Only
treatment of ARS in general practice does not a small proportion of patients with purulent rhinosinusitis, wit-
prevent complications. hout coexisting chest disease, complain of cough(178). In patients
with a suspicion of infection, facial or dental pain (especially
Guidelines agree that in uncomplicated cases, ARS is diagnosed if unilateral) have been found to be predictors of acute maxil-
on clinical criteria and supplementary investigations are not re- lary sinusitis, when validated by maxillary antral aspiration(178)
quired(168). In particular patient groups and in those with severe or paranasal sinus radiographs(179). The symptoms of ARS occur
or atypical symptoms, additional diagnostic procedures may be abruptly without a history of recent nasal or sinus symptoms. A
needed, as discussed below. ARS is frequently an isolated clinical history of sudden worsening of pre-existing symptoms suggests
event and a self-limiting condition, although may be recurrent an acute exacerbation of chronic rhinosinusitis, which should be
in some cases. diagnosed by similar criteria and treated in a similar way to ARS.
In children acute rhinosinusitis is defined as a sudden onset of
4.5.3. Clinical diagnosis in primary care two or more of the following symptoms: nasal blockage/ob-
struction/congestion or discoloured nasal discharge or cough
ARS is diagnosed by the acute onset of typical (daytime and night-time) for <12 weeks.
symptoms that include nasal blockage, discharge, Subjective assessment should take into account the severity and
facial pain or pressure and reduction in smell. the duration of symptoms (see above). The recommended me-
thod of assessing severity of symptoms is with the use of a visual
In the primary care setting (and for epidemiological research), analogue scale (VAS) recorded by the patient on a 10cm line
ARS is defined by symptomatology without detailed ENT exa- giving a score on a measurable continuum of 1 to 10. Disease-
mination or imaging. ARS is defined by the presence of relevant specific questionnaires measuring quality of life impairment
symptoms for up to 12 weeks (see Chapter 2). are available(182, 183) but not commonly used in clinical practice; a

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good clinician will, however, informally assess the impact of ARS 4.5.3.3. Clinical examination
on their patient as part of a full clinical assessment. The VAS can Anterior rhinoscopy
be used to assess overall and individual symptom severity (see Although anterior rhinoscopy alone is a very limited investiga-
below) or patients can be asked to simply rate their symptoms tion, it should be performed in the primary care setting as part
as absent, mild, moderate or severe. of the clinical assessment of suspected ARS as it may reveal
Patient reported purulence of nasal discharge has been recom- supportive findings such as nasal inflammation, mucosal oe-
mended as a diagnostic criterion for acute bacterial rhinosinusi- dema and purulent nasal discharge, and can sometimes reveal
tis(169), and is prioritized by GPs as a feature indicating the need previously unsuspected findings such as polyps or anatomical
for antibiotics(167). However, the positive likelihood ratio for (pu- abnormalities.
rulent) nasal discharge as a symptom (LR+ 1.3) and on physical
examination (LR+ 0.88) do not support using purulent discharge Temperature
to identify bacterial origin(184). The presence of a fever of >38°C indicates the presence of a
Facial or dental pain, especially when unilateral, has been found more severe illness and the possible need for more active treat-
to be a predictor of acute maxillary sinusitis. Retained sinus ment, particularly in conjunction with more severe symptoms. A
secretions in patients with suspected bacterial infection can be fever of >38°C is significantly associated with the presence of a
confirmed by maxillary antral aspiration(178) or paranasal sinus positive bacteriologic culture, predominantly S. pneumoniae and
radiographs(179). Pain on bending forwards and toothache in the H. influenzae, obtained by sinus aspiration or lavage(185).
upper jaw, particularly when unilateral, are often interpreted
by GPs as indicative of more severe disease and the need for Inspection and palpation of sinuses
antibiotics(167), although with limited supporting evidence. The Acute rhinosinusitis does not lead to swelling or redness of
presence of toothache in the upper jaw has a positive likelihood maxillofacial area unless there is a dental origin when the diag-
ratio for the presence of acute bacterial rhinosinusitis of 2.0, nostic odds ratio is 0.97. Data on local tenderness are inconclu-
which ranks this symptom as one of the highest predictors(184). sive(184).

Bacterial infection may occur in ARS, but in most Nasal endoscopy

cases antibiotics have little effect on the Nasal endoscopy is not generally available in routine primary
course of the illness. care settings and is not required in the clinical diagnosis of ARS
in these circumstances.
4.5.3.2. Clinical rules for the prediction of bacterial disease
A number of studies have attempted to provide clinicians with C-reactive protein (CRP)
combinations of symptoms and signs predicting more severe CRP is a haematological biomarker (available as rapid assay
disease, particularly of a bacterial infection and the likelihood of near-patient testing kits) and is raised in bacterial infection. Its
a response to antibiotics. A recent meta-analysis tried to com- use has been advocated in respiratory tract infection(186) as an
bine all these studies(184). However, in such a meta-analysis it is aid to targeting bacterial infection and thus limiting unnecessa-
very important for the prediction to choose the right population ry antibiotic use. A low or normal CRP may identify patients with
(primary care patients with at least 10 days of symptoms or in- a low likelihood of bacterial infection and who are unlikely to
crease of symptoms after five days in which the GP felt antibio- need or benefit from antibiotics. CRP guided treatment has been
tics were needed) and the right gold standard. The EPOS group associated with a reduction in antibiotic use without any impair-
in 2007 decided to base their advice on the study of Lindbaek(186) ment of outcomes(187) and CRP levels are significantly correlated
who chose an air fluid level or total opacification at CT scan as with changes in CT scans(188) and a raised CRP is predictive of a
the gold standard in a population of primary care patients in positive bacterial culture on sinus puncture or lavage(185, 189).
which the doctor suspected ARS requiring antibiotics. We do not
believe abnormalities on CT scan in general or abnormalities at Procalcitonin
sinus X-ray or ultrasound are good gold standards, neither do Procalcitonin has also been advocated as a potential haema-
we consider patients sent in for an antral puncture to the ENT tological biomarker indicating more severe bacterial infection
the ideal population. For that reason, we decided to stick to and investigated as a tool for guiding antibiotic prescribing in
suggestions as made in the earlier EPOS versions: at least three respiratory tract infections in the community. A recent review re-
of five symptoms of discoloured discharge, severe local pain, vealed two randomised controlled trials (RCTs) aiming to reduce
fever, elevated ESR/CRP. We appreciate that a study is required antibiotic prescription with procalcitonin as guiding marker(190).
to determine the best clinical predictors in a carefully selected These studies did show reduced antibiotic prescriptions without
population. detrimental effects on outcomes.

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Erythrocyte sedimentation rate (ESR) and plasma viscosity The differentiation of AR from ARS is made mainly on the basis
Markers of inflammation such as ESR and plasma viscosity are of a prior history of allergy and atopy, and exposure to an aller-
raised in ABRS, may reflect disease severity and can indicate gen (usually an aeroallergen) to which the patient is sensitized.
the need for more aggressive treatment in a similar way to CRP. Ocular symptoms are common in AR, in particular in patients
ESR levels are correlated with CT changes in ARS(251) with an allergic to outdoor allergens, but not in ARS. Mucopurulent
ESR of >10 predictive of sinus fluid levels or sinus opacity on CT rhinorrhoea, pain, nasal obstruction without other symptoms
scans(189). Raised ESR has a positive likelihood ratio for rhinosi- and anosmia are uncommon in AR. Diagnostic tests for AR are
nusitis of 2,61 and a negative likelihood ratio of 0,68(187), with based on the demonstration of allergen-specific IgE in the skin
higher ERS levels increasing the likelihood of the presence of (skin tests) or the blood (specific IgE), and may be considered to
rhinosinusitis. Additional investigations such as imaging, micro- clarify the diagnosis, particularly in those with severe or persis-
biology and nasal nitric oxide measures are not required in the tent symptoms.
diagnosis of ARS in routine practice.
Orodontal disease
4.5.3.4. Differential diagnosis of ARS in clinical practice Patients with orodontal disease may present to primary care
The symptoms of ARS are non-specific and may overlap with a physicians with ill-defined facial pain, with or without fever and
number of other conditions, from which it should be differenti- toothache. The absence of other ARS-associated symptoms such
ated. as rhinorrhoea, nasal discharge and smell disturbance will make
ARS a less likely diagnosis, although in some cases doubt may
Viral upper respiratory tract infection (URTI) persist. A dental assessment and dental radiography may be
The symptoms of the common cold and of self-limiting viral required to clarify the diagnosis. ARS may occur more frequently
URTIs overlap with those of post-viral ARS. Indeed, most epi- and have overlapping symptoms in patients with orodontal
sodes of postviral ARS will start as a viral URTI but manifest a disease(61).
prolonged illness beyond 10 days or with worsening symptoms
after five days. Most common colds are associated with rhinovi- Rare diseases
rus infection with symptoms peaking by three days(191), and the Facial pain syndromes
majority of patients not seeking medical care. The diagnosis is A number of conditions can present acutely with facial pain and
clinical and supportive advice, symptomatic treatment and reas- nasal symptoms, including migraine and cluster headaches. The
surance are generally the only interventions required. differential diagnosis of facial pain is discussed in Chapter 5.3.3.

Allergic rhinitis (AR) Vasculitis

AR is a common global condition affecting at least 10-20% of Autoimmune vasculitides such as granulomatosis with polyangi-
the adult population(192). AR is the most common form of non-in- itis, eosinophilic granulomatosis with polyangiitis or sarcoidosis
fectious rhinitis and is associated with an IgE-mediated immune may involve the nose and sinuses and on rare occasions may
response against allergens. Since the nasal mucosa is conti- present acutely. The presence of other suggestive symptoms
nuous with that of the paranasal sinuses, congestion of the ostia and an atypical clinical course can alert the clinician to alterna-
may result in rhinosinusitis, which does not exist without rhini- tive diagnoses. (See Chapter 8.7.)
tis, so AR may be part of an allergic rhinosinusitis with similar
symptoms to those of ARS (and CRS). Symptoms of AR include Acute invasive fungal rhinosinusitis
rhinorrhoea (non-purulent), nasal obstruction, nasal itching, and In immunosuppressed patients and in (uncontrolled) diabetics,
sneezing, which are reversible spontaneously or with treatment. acute invasive fungal rhinosinusitis may present in a similar way
AR is subdivided into “intermittent” or “persistent” disease. Inter- to ARS, but with severe and rapidly progressive symptoms(193, 194).
mittent rhinitis may occur suddenly in response to exposure to When this diagnosis is suspected, a more aggressive diagnos-
a specific allergen, and so cause diagnostic confusion between tic approach is required as a delay in diagnosis worsens the
AR and ARS. Seasonal AR is related to a wide variety of outdoor prognosis. (See Chapter 8.6.)
allergens such as pollens or moulds, and sudden exposure to
such aeroallergens or to others (e.g. cat and dog dander in sen- CSF leak
sitized individuals) can cause acute onset of symptoms. In AR, Unilateral watery rhinorrhoea is uncommon and should raise
there will usually be a history of similar symptoms in response suspicion of cerebrospinal fluid leakage(195).
to similar exposures, often with a seasonal pattern. Non-specific 4.5.3.5. Warning signs of complications of ABRS
irritants such as air pollution and viral infection may aggravate Septic complications of ABRS represent a potential medical
symptoms in symptomatic AR patients. emergency and require prompt recognition by generalists and

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immediate referral to secondary care for assessment (Chapter Table 4.5.1. Warning symptoms of complications in ARS requiring imme-
4.7; Table 4.5.1.). Observational surveys suggest that these diate referral / hospitalization.
complications occur rarely but early in the course of the disease, Periorbital oedema/erythema
and that outcomes are not influenced by the use or non-use of Displaced globe
antibiotics in primary care(13, 175).
Double vision
Ophthalmoplegia
Complications of ARS are uncommon, but vital Reduced visual acuity
to identify early. They occur early in the course of
Severe unilateral or bilateral frontal headache
the illness and primary care clinicians need to be
Frontal swelling
vigilant for the danger signs and symptoms.
Signs of meningitis
Neurological signs
4.5.4. Diagnosis of ARS in specialist care
Reduced consciousness
Although uncomplicated ARS is more likely to present to
primary care physicians, in some health systems patients may
present acutely to specialists or may be referred early for a
specialist assessment, usually to a rhinologist or ENT specialist. diagnosis and treatment with open or endoscopic sinus surgery
Generally, the diagnosis may be made clinically using the same (see Chapter 8.6.). The diagnosis is usually histopathological, so
criteria outlined above, but sometimes more detailed diagnostic early endoscopic evaluation is indicated, with open biopsy if
investigations may be applied. Immediate referral and/or hospi- doubt remains(193, 194).
talization are indicated for any of the symptoms listed in Table
4.5.1. These investigations include nasal endoscopy and imaging 4.5.6. Conclusion
(see Chapters 5.3.4.1., 5.3.4.3.). Acute rhinosinusitis may be divided into a viral common cold,
post-viral or acute bacterial rhinosinusitis depending on the
4.5.5. Diagnosis of ARS in specific settings duration and severity of the symptoms. There have been some
recent studies supporting the symptom base, but more are
4.5.5.1. Diagnosis for research required to reduce the inappropriate use of antibiotics.
In research settings, a more formal diagnosis may be required.
In such settings, a variable combination of symptoms, ima- 4.6. Medical management of ARS
ging findings, examination findings, and bacteriology samples
(obtained from middle meatus or from sinus puncture) may be 4.6.1. Introduction
required for confirmation of the diagnosis as specified in the As mentioned before, ARS is divided into acute viral rhinosinusi-
study protocol. The diagnostic criteria used must be specified in tis, acute post-viral rhinosinusitis and acute bacterial rhinosinu-
research studies to allow comparison of results between studies. sitis. For the definitions see Chapters 2 and 3.
In recent years a large number of systematic reviews and meta-
4.5.5.2. Diagnosis of ARS in the intensive care unit analyses have covered the significant parts of the management
ABRS is common in ICU (with risk factors including naso-gastric of acute viral rhinosinusitis (often called common cold and/or
tubes, mechanical ventilation, failure of defence mechanisms upper respiratory tract infection). For that reason, this chapter
and pronged supine posture), and is associated with poor contains a short overview of these systematic reviews and meta-
outcomes. Sepsis may involve multiple sinuses(196). As a conse- analysis. For acute post-viral rhinosinusitis and acute bacterial
quence, more aggressive diagnostic processes may be appro- rhinosinusitis new systematic reviews and meta-analysis are
priate such as CT scanning to confirm the diagnosis(197), and performed in this chapter.
sinus puncture which is safe in skilled hands and can provide
important microbiological information to confirm the diagnosis 4.6.2. Management of acute viral rhinosinusitis (common
and guide therapy(196). cold)
In recent years a large number of systematic reviews and meta-
4.5.5.3. Diagnosis of ARS in immunosuppressed patients analyses have covered the significant parts of the manage-
Immunosuppressed patients are much more vulnerable to com- ment of acute viral rhinosinusitis. For that reason, this chapter
plications of ABRS, and a more aggressive diagnostic approach contains a short overview of the systematic reviews and meta-
is required. Acute invasive fungal rhinosinusitis(290) is a serious analysis published after 2012. For the search performed please
disease with high mortality and morbidity and requires prompt see Chapter 11.

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4.6.2.1. Antibiotics was no difference between antihistamines and placebo in the

Eleven randomized controlled trials compared any antibiotic mid-term (three to four days) to long term (six to 10 days). When
therapy against placebo in people with symptoms of common evaluating individual symptoms such as nasal congestion, rhi-
cold(198). Participants receiving antibiotics for the common cold norrhoea and sneezing, there was some beneficial effect of the
did no better in terms of lack of cure or persistence of symptoms sedating antihistamines compared to placebo (e.g. rhinorrhoea
than those on placebo (risk ratio (RR) 0.95, 95% CI 0.59 to 1.51, on day 3: mean difference (MD) -0.23, 95% CI -0.39 to -0.06 on
(random-effects)), based on a pooled analysis of six trials with a four- or five-point severity scale; sneezing on day 3: MD -0.35,
a total of 1047 participants. The RR of adverse effects in the 95% CI -0.49 to -0.20 on a four-point severity scale), but this ef-
antibiotic group was 1.8, 95% CI 1.01 to 3.21, (random effects). fect is clinically non-significant. Adverse events such as sedation
Adult participants had a significantly greater risk of adverse ef- were more commonly reported with sedating antihistamines
fects with antibiotics than with placebo (RR 2.62, 95% CI 1.32 to although the differences were not statistically significant. Only
5.18) (random effects) while there was no greater risk in children two trials included children and the results were conflicting. The
(RR 0.91, 95% CI 0.51 to 1.63). The pooled RR for persisting acute authors concluded that antihistamines have a limited short-term
purulent rhinorrhoea with antibiotics compared to placebo was (days 1 and 2 of treatment) beneficial effect on severity of over-
0.73 (95% CI 0.47 to 1.13) (random effects), based on four studies all symptoms in adults but not in the mid to long term. There is
with 723 participants. There was an increase in adverse effects in no clinically significant effect on nasal obstruction, rhinorrhoea
the studies of antibiotics for acute purulent rhinitis (RR 1.46, 95% or sneezing(200).
CI 1.10 to 1.94). The authors concluded that there is no evidence
of benefit from antibiotics for the common cold or for persisting 4.6.2.4. Decongestants
acute purulent rhinitis in children or adults. There is evidence In 2016, Deckx et al. published a Cochrane review on the ef-
that antibiotics cause significant adverse effects in adults when ficacy, and short- and long-term safety, of topical and/or oral
given for the common cold and in all ages when given for acute decongestants used in monotherapy to alleviate symptoms of
purulent rhinitis. Routine use of antibiotics for these conditions the common cold in adults and children(201).The authors inclu-
is not recommended. ded 15 trials with 1838 participants. In six studies the interven-
tion was a single dose and in nine studies multiple doses were
4.6.2.2. Nasal corticosteroids used. Eleven studies used oral decongestants; four studies used
The anti-inflammatory effects of nasal corticosteroids may be topical decongestants. Nine studies used pseudoephedrine
beneficial in the common cold. In 2013, a Cochrane review was and three studies used oxymetazoline. Nine studies compared
published to compare nasal corticosteroids versus usual care multiple doses of topical or oral decongestants with placebo.
for the common cold on measures of symptom resolution and Subjective measures of congestion were significantly better for
improvement in children and adults. Three trials (353 partici- the treatment group compared with placebo approximately
pants) were included. Two trials compared nasal corticosteroids three hours after the last dose (SMD 0.49, 95% CI 0.07 to 0.92;
to placebo and one trial compared nasal corticosteroids to usual p=0.02); seven studies reported adverse events (six oral and one
care. In the two placebo-controlled trials, no benefit of nasal topical decongestant); meta-analysis showed that there was
corticosteroids was demonstrated for duration or severity of no statistical difference between the number of adverse events
symptoms. The authors concluded that the current evidence in the treatment group compared to the placebo group. The aut-
does not support the use of nasal corticosteroids for symptoma- hors concluded that the current evidence suggests that multiple
tic relief from the common cold(199). doses of decongestants may have a small positive effect on sub-
jective measures of nasal congestion in adults with the common
4.6.2.3. Antihistamines cold. Due to the small number of studies that used a topical
To assess the effects of antihistamines on the common cold nasal decongestant, they were unable to draw conclusions on
the authors of a Cochrane review included 18 RCTs, which the effectiveness of oral versus topical decongestants. Decon-
were reported in 17 publications (one publication reports on gestants do not seem to increase the risk of adverse events in
two trials) with 4342 participants (of which 212 were children) adults in the short term.
suffering from the common cold, both naturally occurring
and experimentally induced. The interventions consisted of 4.6.2.5. Paracetamol (acetaminophen)
an antihistamine as monotherapy compared with placebo. In To investigate the effectiveness of paracetamol RCTs comparing
adults there was a short-term beneficial effect of antihistamines paracetamol to placebo or no treatment in adults with the com-
on severity of overall symptoms: on day 1 or 2 of treatment 45% mon cold four RCTs involving 758 participants were evaluated
had a beneficial effect with antihistamines versus 38% with pla- in a Cochrane review(202). Participants treated with paracetamol
cebo (odds ratio (OR) 0.74, 95% CI 0.60 to 0.92). However, there had significant improvements in nasal obstruction in two of the

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four studies. One study showed that paracetamol was superior 4.6.2.8. Ipratropium bromide
to placebo in decreasing rhinorrhoea severity but was not su- A Cochrane review was published in 2013 to determine the
perior for treating sneezing and coughing. Paracetamol did not effect of ipratropium bromide versus placebo or no treatment
improve sore throat or malaise in two of the four studies. Results on severity of rhinorrhoea and nasal congestion in children
were inconsistent for some symptoms. Two studies showed and adults with the common cold(205). Seven trials with a total
that headache and achiness improved more in the paracetamol of 2144 participants were included. Four studies (1959 partici-
group than in the placebo group, while one study showed no pants) addressed subjective change in severity of rhinorrhoea.
difference between the paracetamol and placebo group. None All studies were consistent in reporting statistically significant
of the included studies reported the duration of common cold changes in favour of ipratropium bromide. Nasal congestion was
symptoms. Minor side effects in the paracetamol group were reported in four studies and was found to have no significant
reported in two of the four studies. One of them used a combi- difference between the groups. Two studies found a positive res-
nation of pseudoephedrine and paracetamol. The authors con- ponse in the ipratropium bromide group for the global assess-
cluded that paracetamol may help relieve nasal obstruction and ment of overall improvement. Side effects were more frequent
rhinorrhoea but does not appear to improve some other cold in the ipratropium bromide group, OR 2.09 (95% CI 1.40 to 3.11).
symptoms (including sore throat, malaise, sneezing and cough). Commonly encountered side effects included nasal dryness,
blood tinged mucus and epistaxis. The authors concluded that
4.6.2.6. NSAIDs for people with the common cold, the existing evidence sug-
Non-steroidal anti-inflammatory drugs (NSAIDs) have been gests that ipratropium bromide is likely to be effective in amelio-
widely used for the treatment of pain and fever associated rating rhinorrhoea. Ipratropium bromide had no effect on nasal
with the common cold. A Cochrane review performed in 2009 congestion and its use was associated with more side effects
includes nine RCTs, describing 37 comparisons: six were NSAIDs compared to placebo or no treatment although these appeared
versus placebo, and three were NSAIDs versus NSAIDs(203). A total to be well tolerated and self-limiting.
of 1064 patients with the common cold were included. The aut-
hors reported that NSAIDs did not significantly reduce the total 4.6.2.9. Nasal irrigation with saline
symptom score, or duration of colds. However, for outcomes Nasal irrigation with saline is often employed as an (adjunct)
related to the analgesic effects of NSAIDs (headache, ear pain treatment for URTI symptoms. The Cochrane review publis-
and muscle and joint pain) NSAIDs produced significant bene- hed in 2015 identified five RCTs that randomised 544 children
fits, and malaise showed a borderline benefit, although throat (three studies) and 205 adults (exclusively from two studies). All
irritation was not improved. Chills showed mixed results. For res- included studies compared saline irrigation to routine care or
piratory symptoms, cough and nasal discharge scores were not other nose sprays, rather than placebo. Most outcome measures
improved, but the sneezing score significantly improved. They differed greatly between included studies and, , could not be
found no evidence of increased frequency of adverse effects in pooled. Most results showed no difference between nasal saline
the NSAID treatment groups. The authors recommended NSAIDs treatment and control. However, one larger trial, conducted
for relieving discomfort or pain caused by the common cold. with children, did show a significant reduction in nasal secre-
tion score (MD -0.31, 95% CI -0.48 to -0.14) and nasal breathing
4.6.2.7. Antihistamine-decongestant-analgesic combinations (obstruction) score (MD -0.33, 95% CI -0.47 to -0.19) in the saline
To assess the effectiveness of antihistamine-decongestant-anal- group. The trial also showed a significant reduction in the use
gesic combinations in reducing the duration and alleviating the of decongestant medication by the saline group. Minor nasal
symptoms of the common cold in adults and children 27 trials discomfort and/or irritation was the only side effect reported
(5117 participants) of common cold treatments were evaluated by a minority of participants. The authors concluded that nasal
in a Cochrane review(204). Fourteen trials studied antihistamine- saline irrigation possibly has benefits for relieving the symptoms
decongestant combinations; two antihistamine-analgesic; six of acute URTIs(206).
analgesic-decongestant; and five antihistamine-analgesic-
decongestant combinations. In 21 trials the control intervention 4.6.2.10. Steam / heated humidified air
was placebo and in six trials an active substance. The evidence Background: Heated, humidified air has long been used by com-
in this systematic review suggests that antihistamine-analgesic- mon cold sufferers. The theoretical basis is that steam may help
decongestant combinations have some general benefit in adults congested mucus drain better and heat may destroy cold virus
and older children. These benefits must be weighed against the as it does in vitro. The Cochrane review in 2017 included six trials
risk of adverse effects. There is no evidence of effectiveness in from five publications involving a total of 387 participants(207).
young children. The authors reported that it is uncertain whether heated, hu-
midified air provides symptomatic relief for the common cold,

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as the fixed-effect analysis showed evidence of an effect (OR 4.6.2.12. Vitamin C

0.30, 95% CI 0.16 to 0.56; two studies, 149 participants), but the In 2013, a Cochrane review on the use of vitamin C for preven-
random-effects analysis showed no significant difference in the ting and treating the common cold appeared(209). In the review
results (OR 0.22, 95% CI 0.03 to 1.95). No studies demonstrated 29 placebo-controlled trials evaluating 11,306 participants
an exacerbation of clinical symptom scores. One study conduc- contributed to the meta-analysis on the RR of developing a
ted in the USA demonstrated worsened nasal resistance, but an cold whilst taking vitamin C regularly over the study period. In
earlier Israeli study showed improvement. One study examined the general community trials involving 10,708 participants, the
viral shedding in nasal washings, finding no significant diffe- pooled RR was 0.97 (CI interval 0.94 to 1.00). Five trials involving
rence between treatment and placebo groups (OR 0.47, 95% CI a total of 598 marathon runners, skiers and soldiers on subarc-
0.04 to 5.19). As judged by the subjective response to therapy tic exercises yielded a pooled RR of 0.48 (95% CI 0.35 to 0.64).
the number of participants reporting resolution of symptoms Thirty-one comparisons examined the effect of regular vitamin
was not significantly higher in the heated humidified group (OR C on common cold duration (9745 episodes). In adults the du-
0.58, 95% CI 0.28 to 1.18; two studies, 124 participants). There ration of colds was reduced by 8% (3% to 12%) and in children
was significant heterogeneity in the effects of heated, humidi- by 14% (7% to 21%). In children, 1-2 g/day vitamin C shortened
fied air on different outcomes, therefore, the authors graded colds by 18%. The severity of colds was also reduced by regular
the quality of the evidence as low. Some studies reported minor vitamin C administration. Seven comparisons examined the
adverse events (including discomfort or irritation of the nose). effect of therapeutic vitamin C (3249 episodes). No consistent
The authors concluded that the current evidence does not show effect of vitamin C was seen on the duration or severity of
any benefits or harms from the use of heated, humidified air colds in the therapeutic trials. The authors concluded that the
delivered for the treatment of the common cold. failure of vitamin C supplementation to reduce the incidence of
colds in the general population indicates that routine vitamin
4.6.2.11. Probiotics C supplementation is not justified, yet vitamin C may be useful
In 2015, a Cochrane review assessing the effectiveness and for people exposed to brief periods of severe physical exercise.
safety of probiotics (any specified strain or dose), compared with Regular supplementation trials have shown that vitamin C redu-
placebo, in the prevention of acute URTIs in people of all ages, ces the duration of colds, but this was not replicated in the few
who are at risk of acute URTIs was published(208). therapeutic trials that have been carried out. Nevertheless, given
The authors included 13 RCTs, although they could only extract the consistent effect of vitamin C on the duration and severity
data to meta-analyse 12 trials, which involved 3720 participants of colds in the regular supplementation studies, and the low
including children, adults (aged around 40 years) and older peo- cost and safety, it may be worthwhile for common cold patients
ple. We found that probiotics were better than placebo when to test on an individual basis whether therapeutic vitamin C is
measuring the number of participants experiencing episodes beneficial for them. Further therapeutic RCTs are warranted.
of acute URTI (at least one episode: OR: 0.53; 95% CI=0.37-0.76, In 2018 and 2019, four systematic reviews investigated effects
p<.001, low quality evidence; at least three episodes: OR: 0.53; of vitamin C on common cold(210-213). However, none of these
95% CI=0.36-0.80, p=.002, low quality evidence); the mean du- systematic reviews included newer studies than included in the
ration of an episode of acute URTI (MD: -1.89; 95% CI = -2.03 to Cochrane review(209). So these reviews were not considered.
-1.75, p<.001, low quality evidence); reduced antibiotic prescrip-
tion rates for acute URTIs (OR: 0.65; 95% CI = 0.45-0.94, moderate 4.6.2.13. Vaccines
quality evidence) and cold-related school absence (OR: 0.10; In 2017, a Cochrane review was published to assess the clinical
95% CI=0.02-0.47, very low quality evidence). Probiotics and effectiveness and safety of vaccines for preventing the common
placebo were similar when measuring the rate ratio of episodes cold in healthy people(214). The development of vaccines for the
of acute URTI (rate ratio: 0.83; 95% CI=0.66-1.05, p=.12, very low common cold has been difficult because of antigenic variability
quality evidence) and adverse events (OR: 0.88; 95% CI=0.65- of the common cold virus and the indistinguishable multiple
1.19, p=.40, low quality evidence). Side effects of probiotics were other viruses. There is uncertainty regarding the efficacy and
minor and gastrointestinal symptoms were the most common. safety of interventions for preventing the common cold in
The authors concluded that probiotics were better than placebo healthy people.
in reducing the number of participants experiencing episodes of The review includes only one RCT dating from the 1960s with an
acute URTI, the mean duration of an episode of acute URTI, an- overall high risk of bias. The authors found no conclusive results
tibiotic use and cold-related school absence. This indicates that to support the use of vaccines for preventing the common cold
probiotics may be more beneficial than placebo for preventing in healthy people compared with placebo.
acute URTIs. However, the quality of the evidence was low or
very low(208).

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4.6.2.14. Exercise 88%), school absence (p=0.0003) and prescription of antibiotics

In 2014, Lee et al. published a systematic review and meta-ana- (p<0.00001) was lower in the zinc group. Overall adverse events
lysis to determine the effects of exercise on prevention of the (OR 1.58, 95% CI 1.19 to 2.09) (p=0.002), bad taste (OR 2.31, 95%
common cold(215). Four randomized controlled trials with a total CI 1.71 to 3.11) (p<0.00001) and nausea (OR 2.15, 95% CI 1.44 to
of 281 participants were included. The effect of exercise on the 3.23) (p=0.002) were higher in the zinc group. The very high he-
prevention of the common cold had a relative risk (RR) of 0.73 terogeneity means that the averaged estimates must be viewed
(95% CI, 0.56 to 0.95; I(2) =7%). The mean difference of mean with caution. Authors' conclusions: Zinc administered within 24
illness days between exercise group and control group was -3.50 hours of onset of symptoms reduces the duration of common
(95% CI, -6.06 to -0.94; I(2) =93%). The authors concluded that cold symptoms in healthy people, but some caution is needed
regular, moderate-intensity exercise may have an effect on the due to the heterogeneity of the data. As the zinc lozenges
prevention of the common cold. formulation has been widely studied and there is a significant
reduction in the duration of cold at a dose of >= 75 mg/day, for
4.6.2.15. Echinacea those considering using zinc it would be best to use it at this
To assess whether there is evidence that Echinacea preparations dose throughout the cold. Regarding prophylactic zinc sup-
are effective and safe compared to placebo in the prevention plementation, currently no firm recommendation can be made
and treatment of the common cold Karsch-Volk et al. included because of insufficient data. When using zinc lozenges (not as
24 double-blind trials with 4631 participants including a total syrup or tablets) the likely benefit has to be balanced against
of 33 comparisons of Echinacea preparations and placebo in a side effects, notably a bad taste and nausea(217). Based on the
Cochrane review(216). Ten trials with 13 comparisons investiga- same studies additional meta-analysis were performed. Hemila
ted prevention and 15 trials with 20 comparisons investigated et al. evaluated whether the allergy status and other characteris-
treatment of colds (one trial addressed both prevention and tics of common cold patients modify the effects of zinc acetate
treatment). None of the 12 prevention comparisons reporting lozenges and concluded that since the effects of zinc acetate lo-
the number of patients with at least one cold episode found a zenges were consistent between the compared subgroups, the
statistically significant difference. However, a post hoc pooling overall estimates for effect seemed applicable over a wide range
of their results, suggests a relative risk reduction of 10% to 20%. of common cold patients(218). Hemila furthermore compared the
Of the seven treatment trials reporting data on the duration of efficacy of zinc acetate lozenges with zinc gluconate and exa-
colds, only one showed a significant effect of Echinacea over mined the dose-dependency of the effect and concluded that
placebo. The authors concluded that Echinacea products have properly composed zinc gluconate lozenges may be as effective
not shown to provide benefits for treating colds, although, there as zinc acetate lozenges. Moreover, he found no evidence that
could be a weak benefit from some Echinacea products: the zinc doses over 100mg/day might lead to greater efficacy in the
results of individual prophylaxis trials consistently show positive treatment of the common cold. Finally, the same group estima-
(if non-significant) trends, although potential effects are of ques- ted using individual patient data (IPD) meta-analysis the effect
tionable clinical relevance. of zinc acetate lozenges on the rate of recovery from colds and
found a three-fold increase in the rate of recovery from the com-
4.6.2.16. Zinc mon cold(219). From these meta-analyses it can be concluded that
To assess whether zinc (irrespective of the zinc salt or formu- zinc administered as zinc acetate or zinc gluconate lozenges at
lation used) is efficacious in reducing the incidence, severity a dose of >=75 mg/day and taken within 24 hours of onset of
and duration of common cold symptoms placebo-controlled symptoms significantly reduces the duration of common cold. It
trials using zinc for at least five consecutive days to treat, or for is advised for those considering using zinc to use it at this dose
at least five months to prevent the common cold. included 16 throughout the cold. Regarding prophylactic zinc supplementa-
therapeutic trials (1387 participants) and two preventive trials tion, currently no firm recommendation can be made because
(394 participants). Intake of zinc was associated with a signifi- of insufficient data.
cant reduction in the duration (days) (MD -1.03, 95% CI -1.72
to -0.34) (p=0.003) (I² statistic =89%) but not the 4.6.2.17. Herbal medicine (excluding Echinacae)
severity of common cold symptoms (MD -1.06, 95% CI -2.36 to We are not aware of a systematic review analysing the effecti-
0.23) (p=0.11) (I² statistic = 84%). The proportion veness of herbal medicine in common cold. A recent review of
of participants who were symptomatic after seven days of Koch et al. included patients with symptoms and signs indi-
treatment was significantly smaller (OR 0.45, 95% CI 0.20 to 1.00) cative of viral rhinosinusitis (common cold), post-viral rhinosi-
(p=0.05) than those in the control, (I²statistic = nusitis and maybe a few patients with ABRS although in most
75%). The incidence rate ratio (IRR) of developing a cold (IRR studies high fever and/or severe illness were excluded(220) and,
0.64, 95% CI 0.47 to 0.88) (p=0.006) (I² statistic = therefore, could not be used. However, studies including large

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number of patients have been done evaluating the effectiveness with influenza with one study with patient with common cold.
of herbal medicine for common cold and, therefore, a short The study evaluating patients with common cold did not show a
summary is given here. Four papers describe the effectiveness significant effect(229).
of BNO1016 (Sinupret) in patients with symptoms indicative of In conclusion, some herbal medicines like BNO1016, cineole
common cold(221-224). The two papers by Jund are both double and andrographis paniculata SHA-10 extract have significant im-
blind placebo controlled trials (DBPCTs) and the study described pact on symptoms of common cold without important adverse
in the 2012 papers has also been included in the 2015 paper. events. A formal systematic review is missing.
BNO1016 is an extract of five herbal drugs (gentian root, primula
flower, sorrel herb, elder flower, and verbena herb) that has 4.6.2.18. Fusafungine
demonstrated antimicrobial and antiviral activity. The herbal Fusafungine displays bacteriostatic activity and has anti-
drug combination was assessed for efficacy and tolerability in inflammatory properties. Lund et al. described a pooled analysis
600 patients with acute viral rhinosinusitis in two DBPCT trials(221, of three randomised double-blind placebo-controlled parallel-
222)
. A significant higher response to treatment, and significantly group studies in 532 patients with identical objectives design
more improvement in SNOT-20, major symptoms score, rhinor- and dosage(230). The percentage of responders (patients with
rhoea, postnasal drip headache and facial pain were found at nasal symptom score improvement from day 0 to day 4) was
day 14 in favour of BNO1016. No serious adverse events were re- 61.5 ± 2.9% with fusafungine versus 46.8 ± 3.1% with placebo
ported in either trial. In a study of 64 patients with common cold (p=0.009) with an odds ratio of 1.8 (p=0.01) in favour of fusaf-
Sinupret for eight days on top of antibiotic was evaluated(223). ungine. The nasal symptom score distribution at day 4 showed
The Sinupret group had shorter duration of headache, impaired an odds ratio of 1.56 (p=0.011) also in favour of fusafungine.
breathing, nasal discharge and olfactory impairment and faster For patients treated early the percentage of responders was
resolution of clinical findings at rhinoscopy. Finally, a recent trial 65.9 ± 4.1% with fusafungine versus 38.3 ± 4.0% with placebo
evaluated Sinupret syrup three times daily in a group of 184 (p=0.022) with an OR of 3.08 (p=0.033) in favour of fusafun-
children (mean age 8.4 (6-11)) on top of saline and symptomatic gine. The authors concluded that fusafungine is an effective
medication(224). The children’s self-assessment of their condition treatment of common cold especially when administered early.
during the first 10 days of the treatment for three symptoms However, serious allergic reactions involving bronchospasm alt-
(rhinorrhoea, facial pain, and headache) was significantly better hough rare have occurred after the use of fusafungine (https://
in the Sinupret group than placebo on days 5-8. The physicians www.ema.europa.eu). For that reason, the medication is no
had a similar assessment. longer on the market.
Two studies investigated cineole, an extract from eucalyptus
oil with anti-inflammatory properties, in 302 patients with 4.6.2.19 Homeopathy
symptoms and signs indicative of viral rhinosinusitis, one versus A systematic review by Hawke aimed at assessing the effec-
placebo(225) and one versus an alternative herbal preparation(226). tiveness and safety of oral homoeopathic medicinal products
Both studies found a greater reduction in symptom scores, indi- compared with placebo or conventional therapy to prevent and
vidual symptom scores and rhinoscopy findings in the cineole treat acute respiratory infections in children (402). After the analy-
group than in the control group after seven days of treatment. sis of eight RCTs including 1562 children, the authors reported
It can be concluded that the herbal medicine preparations no significant benefit of homoeopathic products compared to
BNO1016 and possibly also cineole have a significant impact on placebo on infection recurrence or cure rates in children. No
symptoms of common cold without important adverse events. similar study was found for the use of homoeopathic products
Two studies evaluated the effectiveness of andrographis panicu- in adults with respiratory tract infections.
lata SHA-10 extract (1200 mg/day) for five days in one study(227)
and Kan Jang (85 mg standardized extract of andrographis pani- 4.6.2.20. Conclusion
culata SHA-10 and 10 mg of eleutherococcus senticosus extract) In recent years a number of systematic reviews, many perfor-
four tablets, three times daily, for five days(228) in reducing the med within the Cochrane collaboration have been performed
prevalence and intensity of symptoms and signs in respectively evaluating the effectiveness of medication for the prevention
158 and 200 patients with common cold as compared with a and treatment of acute viral rhinosinusitis (common cold). The
placebo. A significant decrease in the intensity of symptoms was authors of these reviews concluded that to prevent common
observed for the Andrographis paniculate group compared to colds probiotics were better than placebo in reducing the
placebo in both studies. No adverse effects were observed or number of participants experiencing episodes of acute URTI and
reported. Finally, Hawkins et al. published a systematic review that also moderate-intensity exercise may have an effect on the
about the potential use of black elderberry (sambucus nigra) for prevention of the common cold.
common cold. But they combined three studies with patients It was concluded that the failure of vitamin C supplementation

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to reduce the incidence of colds in the general population nefits or harms for the treatment of the common cold.
indicates that routine vitamin C supplementation is not justified, Finally, it was concluded that Echinacea products have not
yet vitamin C may be useful for people exposed to brief periods been shown to provide benefits for treating colds, although,
of severe physical exercise. And finally, no conclusive results there could be a weak benefit from some Echinacea products.
supported the use of vaccines for preventing the common cold However, some herbal medicine like BN1016, Cineole and
in healthy people compared with placebo. Andrographis paniculata SHA-10 extract seem to have a signifi-
For the treatment of acute viral rhinosinusitis, the authors of cant impact on symptoms of common cold without important
these reviews concluded that there is no evidence of benefit adverse events.
from antibiotics for the common cold or for persisting acute
purulent rhinitis in children or adults and that there is evidence 4.6.3. Oral antibiotics – short courses
that antibiotics cause significant adverse effects in adults when
given for the common cold. Although the treatment has no 4.6.3.1. Short courses of oral antibiotics in adult patients with acute
significant adverse effect it was also concluded that the current bacterial rhinosinusitis (ABRS)
evidence does not support the use of nasal corticosteroids for 4.6.3.1.1. Summary of the evidence
symptomatic relief from the common cold. There is however ABRS involves a small portion of patients with ARS. ABRS is
some low / very low-quality evidence that probiotics were bet- considered to be present when three or more of the following
ter than placebo in reducing the mean duration of an episode of criteria are present: discoloured discharge, severe (unilateral
acute URTI, antibiotic use and cold-related school absence. dominance) facial pain, high fever (>38°C), double sickening or
For symptomatic medication, it was concluded that antihistami- raised ESR / CRP(231). Antibiotics are thought to be useful in at
nes have a limited short-term (days one and two of treatment) least part of the patients with ABRS but poor patient selection
beneficial effect on severity of overall symptoms in adults but increases the risk of unwanted antibiotics resistance. There is a
not in the mid to long term. There is no clinically significant ef- need to assess the efficacy of antibiotics among patients who
fect on nasal obstruction, rhinorrhoea or sneezing, that multiple fulfil the criteria for ABRS. In this section, studies which com-
doses of decongestants may have a small positive effect on pared antibiotics with placebo for the treatment ABRS were
subjective measures of nasal congestion in adults with the com- assessed.
mon cold without increasing the risk of adverse events in adults Studies which involved adults and adolescents (12 years and
in the short term. Moreover, it was concluded that paracetamol above) with symptoms that fulfilled the criteria for ABRS were
may help relieve nasal obstruction and rhinorrhoea but does not included. Studies without a placebo arm, involving children
appear to improve some other cold symptoms (including sore (under 12 years old), participants with other respiratory tract
throat, malaise, sneezing and cough), NSAIDs relieve discomfort infection (such as otitis media, tonsillitis or pharyngitis) or inclu-
or pain caused by the common cold and it was suggested that ding participants with symptoms lasting more than 12 weeks,
antihistamine-analgesic-decongestant combinations have some were excluded. Only randomized controlled trials were conside-
general benefit in adults and older children. These benefits must red. The outcomes evaluated were the percentage of patients
be weighed against the risk of adverse effects. The authors also that achieved cure or improvement during or at the end of the
concluded that ipratropium bromide is likely to be effective treatment period.
in ameliorating rhinorrhea in common cold but had no effect Three studies were included(232-234), two double blinded placebo
on nasal congestion and its use was associated with more side controlled randomized trials(232, 233) and one open labelled ran-
effects compared to placebo or no treatment although these domized trial(234) (Table 4.6.1.). All studies involved participants
appeared to be well tolerated and self-limiting. who had symptoms and/or signs suggestive of ABRS. Lindbaek
It was also concluded that because there is a consistent effect of et al.(232) recruited patients with ABRS symptoms and abnorma-
vitamin C on the duration and severity of colds in supplementa- lities at CT scan (total opacification or fluid level in any sinus). A
tion studies, and the low cost and safety, it may be worthwhile score of one point was given for: symptoms lasting longer than
for common cold patients to test on an individual basis whether seven days before the first visit, unilateral facial pain, pain in
therapeutic vitamin C is beneficial for them. The same holds for upper teeth, pain worsening on bending forward, two phases
zinc administered as zinc acetate or zinc gluconate lozenges at of disease, rhinorrhoea, nasal obstruction, sinus pain, malaise,
a dose of >=75 mg/day and taken within 24 hours of onset of fever above 38°C and hyposmia or anosmia and two extra points
symptoms significantly reduces the duration of common cold. for purulent secretion resulting in a maximum severity score
When using zinc lozenges the likely benefit has to be balanced of 13 points. The participants in this study had a severity score
against side effects, notably a bad taste and nausea. Also, nasal between 7.8 to 8.8 which meant they would have at least six
saline irrigation has possible benefits for relieving the symptoms of the 11 symptoms assessed, and , therefore, would fulfil the
of acute URTIs contrary to steam which does not show any be- criteria for ABRS. Hadley et al.(233) included adults diagnosed by

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Table 4.6.1. Antibiotics vs. placebo in acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Garbutt DBPCRT Adults with maxillary pain/ • Amoxycillin 1500mg • Mean difference between • SNOT-16 score was lower
2012(5) sinus tenderness, purulent 3 times daily for 10 days groups (SNOT-16) day 3, 7, at day 7 in antibiotics group
secretions and rhinosinusitis (n=85) 10 and 28 but no difference at day 3
symptoms which did not • Placebo (n=81) • Symptom improvement/ and 28
improve/worsened after cure at day 3, 7, 10 and 28 • More patients in antibiotic
7-28 days. • Days unable to perform group had symptoms
usual activity improvement at day 7 but
• Relapse or recurrence at not at day 3, 10 or 28
day 28 • No difference in other
• Adverse event outcomes
Meltzer DBPCRT Adults (≥12y), clinical • Amoxicillin 500 mg three • Mean symptoms score • No difference in symptom
2005(6) diagnosis acute sinusitis times daily for 10 days (diary)between day 2 to 15 score between antibiotics
(7-28 days) (n=251) • Global response at day 15 and placebo
• Placebo (n=252) • Treatment failure during • No difference in global
• MFNS 200 mg once daily treatment response
with placebo spray in the • Adverse event • Treatment failure in 7.2%
evening (n=243) antibiotics and 10.7%
• MFNS 200 mg twice daily placebo
(n=235) • No difference in adverse
event
Merenstein DBPCRT Adult (18y) with at least • Amoxycillin 1 g twice daily • Patient reported improve- • No difference in improve-
2005(7) 1symptom of sinusitis for 10 days (n=67) ment at day 14 ment at day 14
(purulent d/c, facial pain, • Placebo twice daily for 10 • Likert scale for feeling sick • No difference in likert
pus in nasal cavity) for at days (n=68) (0-10) at day 3, 7 and 14 score at day 3, 7 and 14
least 7 days • Days to improvement • Antibiotic group improved
• Adverse event earlier (8.1 vs. 10.7 days)
Haye DBPCRT Adults (28-70y), GP practice, • Azithromycin 500mg once • Cure or improvement, at • No difference in overall
1998(8) purulent nasal secretion daily for 3 days (n=87) day 3-5, day 10-12 days and cure or improvement at day
(10-30 days) AND maxillary • Placebo (n=82) day 23-27 23-27 but more patients
sinus pain/tenderness • Relapse at day 27 with improvement in antibi-
• Adverse event otics group at day 10-12
• No difference in relapse
• No difference in adverse
effect
Lindbaek DBPCRT Adults with clinically • Penicillin V 1,320 mg 3 • Number restored or much • No difference in number
1998(9) diagnosed acute sinusitis times daily for better at day 10 restored or much better
AND mucosal thickening 10 days (n=20) • Mean VAS score for sinus between groups
(≥5mm) on CT scan (exclude • Amoxycillin 500 mg 3 symptoms at day 10 • No difference in VAS
opacification). (Duration times daily for 10 days • Duration of illness (feeling between groups at day 10
illness median 10-13 days (n=22) sick) • No difference in duration
from results.) • Placebo (n=21) of illness
Stalman DBPCRT Adults (15y) with symptoms • Doxycycline 100mg once • Days to cure (no pain) • No difference in time to
1997(10) of URTI at least 5 days. Pres- daily for 10 days (n=98) • Cure or improvement day recover
ence of 2 out of 3 symptoms • Placebo (n=94) 10 and day 42 • No difference in numbers
(common cold, purulent • Side effect cures or improvement at
discharge, pain in maxillary day 10 or day 42
sinus when bending) • 17 in antibiotics and 2 in
placebo group reported
side effects
Van Bu- DBPCRT Patients with maxillary • Amoxycillin 750mg 3 times • Cure or greatly decreased • No difference in cure
chem sinusitis (acute onset of a daily for 7 days (n=108) symptoms at 2 weeks • No difference in symptoms
1997(11) common cold with sickness, • Placebo (n=106) • Mean change symptom score
headache, nose obstruction, score after 2 weeks (scale • Normal radiographs at 2
discharge and tapping pain 1-5) weeks were similar in both
of the maxillary sinus) AND • Normal radiograph at 2 groups
abnormal radiograph on weeks • More side effects in antibi-
Caldwell or water’s view • Relapse after 1 year otics group
(mucosal thickness >5mm, • Side effects • No difference in relapse
air fluid level, opacification). after 1 year
Mean symptom duration 2.2
weeks.

CT, computed tomography; DBPCRT, double blind placebo controlled randomised trial; y, years; GP, general practitioner; MFNS, mometasone furoate
nasal spray; SNOT-16, Sino-nasal Outcome Test-16; URTI, upper respiratory tract infection; VAS, visual analogue scale.

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clinical symptoms of rhinosinusitis [two major (purulent anterior 4.6.3.2. Short courses of oral antibiotics in children with ABRS
or posterior nasal discharge and unilateral facial pain or malar 4.6.3.2.1. Summary of the evidence
tenderness) or one major and one minor symptom (frontal Studies which involved children (<12 years of life) with
headache or fever >37.5oC axillary temp)] lasting between seven symptoms that fulfilled the criteria for ABRS were included. Only
and 28 days and presence of air-fluid levels and/or opacification randomized controlled trials were considered. The outcomes
on water’s view of a sinus X-ray and positive bacterial culture evaluated were the percentage of patients that achieved cure or
from a sinus puncture. Høsøien et al.(234) included patients with improvement during or at the end of the treatment period.
facial pain, purulent discharge, double sickening within 10 days Two small double blinded placebo controlled randomized trials
initial improvement and neutrophilia. were included(235, 236). Both studies involved at least partly child-
Three different types of antibiotics were used (moxifloxacin ren who had symptoms and/or signs suggestive of ABRS (Table
400mg daily)(233), penicillin V 1320mg three times daily(232) and 4.6.2.).
amoxycillin 500mg three times daily(232, 234) for the duration of Wald et al.(235) included 56 children from one to 10 years of age
five to 10 days. Two studies used matched placebos while one (average five years) with ARS including one of three features
study used ultrasound as comparison(234). Cure was defined as (persistent symptoms >10 days, acutely worsening symptoms
resolution of signs or symptoms after completion of treatment after day 5, or severe symptoms with fever ≥102F and purulent
which did not need further intervention(233), or self-rated as discharge for three consecutive days). In 24 (43%) children, the
either feeling restored or much better(232). Improvement was illness was classified as mild, whereas in the remaining 32 (57%)
defined as improved clinical symptoms during the treatment children it was severe. Children were randomly assigned to
phase. Hadley et al.(233) did not report any difference in improve- receive either amoxicillin (90 mg/kg) with potassium clavula-
ment or cure between antibiotics and placebo while Lindbaek nate (6.4 mg/kg) or placebo. Children’s conditions were rated as
et al.(232) reported significantly better improvement and cure rate cured, improved, or failed according to scoring rules. Of the 28
for the antibiotics group. Høsøin et al.(234) compared antibiotics children who received the antibiotic, 14 (50%) were cured, four
with ultrasound therapy and found little or no difference in the (14%) were improved, four (14%) experienced treatment failure,
pain reduction between groups. Although this study reported and six (21%) withdrew. Of the 28 children who received pla-
a larger decrease in pain score at day 4 in the ultrasound group, cebo, four (14%) were cured, five (18%) improved, and 19 (68%)
the difference in pain reduction between the groups was small experienced treatment failure. Children receiving the antibiotic
(1.5 out of 10). were more likely to be cured (50% versus 14%) and less likely to
Two studies could be combined into a meta-analysis. In the have treatment failure (14% versus 68%) than children recei-
study of Lindbaek two antibiotics were assessed and evaluated ving the placebo. There was no division between the mild and
separately(232). At completion of treatment (day 6 to 10), the anti- severe patients. Adverse events were reported in 44% children
biotics group (two studies (three arms), 289 patients) showed a receiving antibiotics and in 4 14% children receiving the placebo
higher cure rate than placebo RR 1.36 (95% CI 1.16-1.59, I2=23%) (p=.014). The most common adverse event was diarrhoea,
(Figure 4.6.1.). The antibiotics group (two studies, 289 patients) which, in general, was self-limited.
also had more patients with improved symptoms at day three Ragab(236) included 53 children (<12 years, average five years)
of treatment compared to placebo (RR 1.68 95% CI 1.04-2.71, with URTI symptoms >10 days <28 days with at least three
I2=84%) (Figure 4.6.2.). Meta-analysis of adverse events did not symptoms/signs pointing to ABRS (discharge (with unilateral
quite reach significance in terms of more adverse events in the predominance) and purulent secretion in the middle meatus,
antibiotics group in these studies (RR 1.27 95% CI 0.87-1.86, I2 severe local pain (with unilateral predominance), fever (>38o8C),
64%) (Figure 4.6.3.). and double sickening) in a DBPCT comparing amoxicillin 100
mg/kg/day to placebo. All patients were on saline irrigation.
4.6.3.1.2. Conclusion In the amoxicillin group clinical cure was observed in 83.9% in
Antibiotics are effective in a select group of patients with comparison to 71% patients in the placebo group (p=0.22). The-
symptoms and signs suggestive of ABRS. From the limited data re were also no differences between both groups in the repor-
available (two studies versus one) it seems that especially am- ted nasal symptom scores, total symptoms scores improvements
oxicillin / penicillin (beta-lactams) are effective and moxifloxacin at day 7 (p=0.09 and 0.65) and day 14 (p=0.29 and 0.14), and
(fluoroquinolone) is not. The efficacy of beta-lactams is evident the mean total PRQLQ values after the two weeks of treatment
at day three where patients already experience better symptom (p=0.06). Saline with placebo has less reported adverse effects
improvement and continues to have a higher number of cures than amoxicillin and nasal saline irrigations (p=0.005).
at completion of treatment. However, careful patient selection The studies could be combined into a meta-analysis considering
for those with ABRS is needed to avoid unnecessary use of anti- cure at 14 days. Although both studies favoured antibiotics,
biotics and side effects. there was no significant difference over placebo (RR 1.45 95% CI

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Figure 4.6.1. Forest plot of the effect of antibiotic versus placebo for cure at completion of intervention (day 6-10) in adult patients with acute bacte-
rial rhinosinusitis.

CI, confidence interval; M-H, Mantel Haenszel.

Figure 4.6.2. Forest plot of the effect of antibiotic versus placebo to assess improvement at day 3 of treatment of adult patients with acute bacterial
rhinosinusitis

CI, confidence interval; M-H, Mantel Haenszel.

Figure 4.6.3. Forest plot of the effect of antibiotic versus placebo for adverse effects during treatment of adult patients with acute bacterial rhinosi-
nusitis

CI, confidence interval; M-H, Mantel Haenszel.

Figure 4.6.4. Forest plot of the effect of antibiotic vs placebo for improvement at completion of intervention (day 14) in children with acute bacterial
rhinosinusitis

CI, confidence interval; M-H, Mantel Haenszel.

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Table 4.6.2. Double blind placebo controlled RCT on antibiotics in presumed ABRS in children.

Study Methods Participants Interventions Outcomes Results

Ragab DBPCRT Children (<12y average 5y) with URTI • Amoxicillin 100 mg/ • Clinical cure at day • No difference in clinical
2015(236) symptoms kg/day three times 14 cure
>10 days <28 days. At least 3 daily with normal sa- • Mean total nasal • No difference in TNSS
symptoms/signs (discharge (with line irrigation (n=41) symptoms score • No difference in PRQOL
unilateral • Placebo with normal (TNSS) day 0-7 and 7 score at day 7 and 14
predominance) and purulent secretion saline irrigation only • PRQOL score • No difference in neutrophil
in the middle meatus, severe local pain (n=43) • Neutrophil counts on count at day 7 and day 14
(with unilateral predominance), fever cytology • More adverse event in
(>38,8oC), and double sickening). • Adverse event antibiotic group
Wald DBPCRT Children 1 to 10y (average 5y) (n=56, • Amoxicillin (90 mg/ • Cured (defined • Children receiving the anti-
2009(235) 50 evaluated) with a clinical presen- kg) with potassium as clinical severity biotic were more likely to be
tation compatible with ABRS. One of clavulanate (6.4 mg/ score <2) or improved cured (50% vs. 14%, p=0.01)
three features (persistent symptoms kg) (n=22) (unclear (score decrease at • More adverse event in
>10 days, acutely worsening how many days) least 50%) at day 14 antibiotics group
symptoms after day 5, or severe • Placebo (n=28) • Adverse event
symptoms with fever ≥102F and puru-
lent discharge for 3 consecutive days).

ABRS, acute bacterial rhinosinusitis; DBPCRT, double blind placebo controlled randomised trial; PRQOL, patient rated quality of life; TNSS, total nasal
symptoms score; y, years.

0.83-2.53, p=0.19, 2 RCT, n=118, I2=66%) (Figure 4.6.4.). 4.6.3.3. Short course of oral antibiotics in adult patients with acute
The children on antibiotics had significantly more adverse post viral rhinosinusitis
events compared to the placebo (RR 2.50 95% CI 1.43-4.37,
p=0.001, 2 RCT, n=118, I2=0%) (Figure 4.6.5.). 4.6.3.3.1. Summary of the evidence
Acute post viral rhinosinusitis is defined as having symptoms
4.6.3.2.2. Conclusion of acute rhinosinusitis (ARS) persisting for more than 10 days
Data on the effect of antibiotics on the cure/improvement of or worsening after five days(231). This section aims to assess the
symptoms in ABRS in children are very limited. There are only efficacy of antibiotics in the post viral ARS group. Studies were
two studies with limited numbers that do not show a significant included which involved adults with ARS with symptoms of at
difference over placebo but do show a significant higher percen- least five days but less than 12 weeks (to exclude chronic rhi-
tage of adverse events. Larger trials are needed to explain the nosinusitis). Only double-blind placebo-controlled randomized
difference between adults where antibiotics in ABRS has been trials were included.
shown to be effective (see paragraph 4.6.3.1.) and this outcome. Studies were excluded if the study population fulfilled the
Systematic reviews or meta-analysis of antibiotic use need to criteria for acute bacterial rhinosinusitis (ABRS) or if more than
pay careful consideration to the different classes of antibiotics 20% of the study population had symptoms for less than five
that target different bacterial molecular mechanisms, similarly days. The minimum duration of five days was used as a cut-
to how different biologics will target different host molecular off to exclude patients with common cold. Studies without a
mechanisms (Figure 4.6.6.). placebo arm, involving children (under 12 years old) or involving
participants with other respiratory tract infection (such as otitis
media, tonsillitis or pharyngitis) were also excluded. The primary

Figure 4.6.5. Forest plost of percentage of patients on antibiotics vs placebo for adverse effects during treatment for children with acute bacterial rhi-
nosinusitis.

CI, confidence interval; M-H, Mantel Haenszel.

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Figure 4.6.6. Antibiotic classes and molecular targets. of acute rhinosinusitis which fulfilled the EPOS criteria for at
least at least five days. There were three studies which required
Cell wall inhibition
participants to have symptoms for at least seven days prior
Bacterial β-lactamase
Cell wall β-lactams β-lactamases inhibitor to randomization(237-239) while one study required 10 days(240).
Membrane Lindbaek et al.(241) did not specify duration of symptoms prior to
recruitment but the median duration of illness for participants
Cell division Protein synthesis

Macrolides
after randomization was 10 to 13.5 days after treatment indica-
Fluoroquinolones
ting post viral ARS.
Ribosome 50S
Garbutt et al.(237) reported higher improvement in the antibio-
DNA mRNA 30S tics group on day seven of treatment compared to the placebo
Gyrase / group. However, this difference was not significant at comple-
Topoisomerase
Tetracyclines
tion of treatment at day 10. Haye et al.(240) assessed azithromycin
for three days and reported more improvement in the antibio-
e.g. Penicillin, Amoxicillin, Cefuroxime, Cefaclor e.g. Clarithromycin, Roxithromycin, Azithromycin tics group at day 10-12. However, this difference was not seen
e.g. Clavulanate e.g. Doxycycline at day 3 or 28. The other five studies(238, 239, 241-243) did not find any
e.g. Ciprofloxacin
difference in improvement of symptoms or achievement of cure
Beta-lactams (e.g. Penicillin, Amoxicillin, Cefuroxime, Cefaclor) target between groups at any time point.
peptidoglycan crosslinking in the cell wall. Beta-lactamase inhibitors
All but one of the studies could be combined into a meta-
(e.g. Clavulanate) target bacterial beta-lactamases that break down
beta-lactam antibiotics. Fluoroquinolones (e.g. Ciprofloxacin) target analysis to determine the cure rate at day 10-14 (931 patients in
DNA gyrase and Topoisomerase IV, thereby blocking DNA separation seven studies)(237, 239-243). The use of antibiotics was not associated
and cell division. Tetracylines (e.g. Doxycycline) target the 30s ribosomal
submit thereby blocking protein synthesis. Similarly, macrolides (e.g. with greater cure at day 10-14 (RR 1.06 95% CI .98-1.14, I2=0%)
Clarithromycin, Roxithromycin, Azithromycin) target the 50s ribosomal (Figure 4.6.7).
submit thereby blocking protein synthesis.
There were three studies(239, 241, 243) which reported on the num-
ber of days needed to achieve cure after treatment. Only Meren-
stein et al.(239) reported an earlier cure for the antibiotics group
outcome is number of patients who obtained cure. Cure was (median: eight versus 12 days, p=0.04). The other two studies
defined as clinical resolution or significant improvement of did not report significant differences in the number of days to
symptoms which did not require any further intervention. The cure between the antibiotics and the placebo group(241, 243).
secondary outcomes assessed were number of days to cure and Two studies(239, 242) including 233 patients could be pooled to
adverse effects. assess the number of days to achieve cure. The use of antibiotics
Seven studies were included(237-243) (Table 4.6.1). Most studies in post-viral ARS was not associated with earlier cure (SMD -0.43,
evaluated amoxycillin(237-239, 241, 243) and three studies evaluated 95% CI -1.02—0.16, I2=73%) (Figure 4.6.8.).
penicillin V(241), doxycycline(242) or azithromycin(240), respectively. Improvement of symptoms was assessed at day 3 of treatment
The antibiotics were taken for seven to ten days except for in four studies. This was defined as complete/partial disappea-
azithromycin (three days)(240). All participants had symptoms rance of symptoms(240), patient reporting feeling a lot better/no

Figure 4.6.7. Forest plot of the effect of antibiotic versus placebo for cure at completion of the intervention (days 10-14) in adult patients with acute
post-viral acute rhinosinusitis.

CI, confidence interval; M-H, Mantel Haenszel.

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 EPOS 2020

symptoms(237), not feeling ill at day 3 of treatment(241) or without al.(237) found that the SNOT-16 score was lower in the antibiotics
treatment failure (worsening or no improvement of symptoms) group at day 7 of treatment, but this was not significant upon
at day 3 of treatment(238). completion of treatment. Studies which assessed symptoms of
Four studies, including 907 patients could be pooled to assess rhinosinusitis(238, 239, 241, 243) assessed for common nasal symptoms
improvement at day 3-4 of treatment(237, 238, 240, 241). There was a such as rhinorrhea, nasal congestion, facial pain and feeling
trend that the use of antibiotics was associated with greater im- sick. These symptoms were either scored on a visual analogue
provement at day 3-4 of treatment compared to placebo but it scale or on an ordinal scale. There were no differences in the
just did not reach significance (RR 1.06, 95% CI 1.00-1.12, I2=0%) mean overall change in symptoms score(238, 241) from baseline
(Figure 4.6.9). between antibiotics and placebo. There was also no difference
There were five studies(237-241) which used patient reported out- in the mean individual symptoms score between antibiotics
come measures such as SNOT-16(237), questionnaire or symptoms and placebo(239, 243). It was not possible to combine data into a
score(238-241) to measure severity of nasal symptoms either scored meta-analysis. This indicates that the use of antibiotics does not
daily in a diary, or upon baseline and follow up visits. Garbutt et significantly reduce the symptoms burden of post viral rhinosi-

Figure 4.6.8. Forest plot of the effect of antibiotic versus placebo to assess the difference (mean difference) in the number of days to achieve cure after
treatment in adult patients with acute post-viral acute rhinosinusitis

CI, confidence interval; M-H, Mantel Haenszel.

Figure 4.6.9. Forest plot of the effect of antibiotic versus placebo to assess improvement at day 3 of treatment of adult patients with acute post-viral
acute rhinosinusitis.

CI, confidence interval; M-H, Mantel Haenszel.

Figure 4.6.10. Forest plot of the effect of antibiotics vs. placebo for adverse effects during treatment of adult patients with acute post-viral acute rhi-
nosinusitis.

CI, confidence interval; M-H, Mantel Haenszel.

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Table 4.6.3. Double blind placebo controlled RCT on antibiotics in post-viral ARS in children.

Study Methods Participants Interventions Outcomes Results

Khoshdel RCT Children (4–15y, mean age • Amoxicillin (80 mg/kg/day) in • Cure at day 3 and 14 • Cure better in amoxi-
2014(246) 7.6±2.86) with a clinical presen- 3 divided doses for 14 days with (Children visited at home cillin group at day 3
tation of mild - moderate post- saline nasal irrigation (for 5 days) and examined for com- (85 vs. 37.5%, p<0.01)
viral acute rhinosinusitis (recent and 0.25% phenylephrine (for 2 plete absence of sinusitis but no difference at
upper respiratory infection, days) (n=50) signs and symptoms). other time points.
postnasal discharge and/or nasal • Saline nasal irrigation (for 5
congestion) for 10-30 days. days) and 0.25%
phenylephrine (for 2 days) (no
placebo tablet) (n=50)
Kristo DBPCRT Children (4–10y) with acute • Cefuroxime axetil in 125mg • Cure, improve, unchan- • No difference in
2005(245) respiratory symptoms <3 weeks capsules twice daily for 10 days ged or deteriorate based % cure or improve
(average 8.4±5.6 days) sugges- (n=41) on clinician assessment between groups at
tive of post-viral rhinosinusitis • Placebo twice daily for 10 days and parents’ opinion at day 14
(nasal discharge and obstruc- (n=41) day 14 • No difference in
tion, sneezing, cough) and an • 14-day diary nasal symptom score
abnormal ultrasound finding symptoms score (total between groups at
of at least one maxillary sinus 0-6) from day 1 to 14
(mucosal thickening or fluid) • Adverse effect • No difference in
adverse effect
Garbutt DBPCRT Children (1 to 18 years, average • Amoxicillin 40 mg/kg/d three • Improvement (little or a • No difference in im-
2001(244) age 8y) with persistent sinus times daily (n=58) for 14 days lot better) at day 14 provement at day 14
symptoms and a clinical diagno- • Amoxicillin-clavulanate am- • Change in sinus • No difference in S5
sis of acute post-viral rhinosinu- oxicillin 45 mg/kg/d twice daily symptoms score using S5 sinus symptoms score
sitis for 10 to 28 days (n=48) for 14 days score (0-3) at day 14 at day 14
• Placebo twice daily for 14 days • Adverse effects of • No difference in
(n=55) treatment adverse event

DBPCRT, double blind placebo controlled randomised trial; RCT, randomised controlled trial; y, years.

Figure 4.6.11. Forest plot of the effect of antibiotic versus placebo to assess improvement at day 10-14 of treatment of children with acute post-viral
acute rhinosinusitis

CI, confidence interval; M-H, Mantel Haenszel.

Figure 4.6.12. Forest plot of the effect of antibiotics vs. placebo for adverse effects during treatment of children with acute post-viral acute rhinosi-
nusitis.

CI, confidence interval; M-H, Mantel Haenszel.

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nusitis. p=0.44, 2 RCT (3 arms) , n=296, I2=0%) (Figure 4.6.12.).

Finally, the antibiotics group had significantly more adverse
events compared to the placebo group although there was a 4.6.3.4.2. Conclusion
significant heterogeneity (1341patients, RR 1.28 95% CI 1.06- The use of antibiotics in children with acute post-viral rhinosinu-
1.54, I2=79%) (Figure 4.6.10). sitis is not associated with greater cure/significant improvement.
Although the two studies that could be combined did not show
4.6.3.3.2. Conclusion significantly more side effects than placebo, studies in adults
In conclusion, there is no benefit of prescribing antibiotics for (see 4.6.3.3) did show significantly more side effects. Based on
post viral ARS in adults. There is no effect on cure or duration of the moderate level of evidence and the fact that acute post-viral
disease and there are more adverse events. Based on the mode- rhinosinusitis is a self-limiting disease, the EPOS2020 steering
rate level of evidence and the fact that acute post-viral rhinosi- group advises against the use of antibiotics for children in this
nusitis is a self-limiting disease, the EPOS2020 steering group situation.
advises against the use of antibiotics for adults in this situation.
4.6.3.5. Methods that could change inappropriate prescription of
4.6.3.4. Short course of oral antibiotics in children with acute post antibiotics
viral rhinosinusitis Antibiotic resistance is a major public health problem. A major
risk factor is irrational antibiotic use, e.g., in patients with com-
4.6.3.4.1. Summary of the evidence mon respiratory tract infections(247-250). Prescription of antibio-
This section aims to assess the efficacy of antibiotics in the tics in in Europe varies greatly; the highest rate in 2016 was in
post viral ARS group in children. Studies were included which Greece (36.3 DDD per 1000 inhabitants daily(251)) and the lowest
involved children with ARS with symptoms of at least five days was in the Netherlands (10.4 DDD per 1000 inhabitants daily)(247,
but less than 12 weeks (to exclude chronic rhinosinusitis). Only 248)
. Higher rates of antibiotic resistance are shown in high antibi-
DBPCTs were included. otic consuming countries (Figures 4.6.13 and 4.6.14). It has been
Studies were excluded if a significant proportion of the study shown that individuals prescribed an antibiotic in primary care
population fulfilled the criteria for ABRS or if more than 20% for a respiratory or urinary infection develop bacterial resistance
of the study population had symptoms for less than five days. to that antibiotic. The effect is greatest in the month immedia-
The minimum duration of five days was used as a cut-off to tely after treatment but may persist for up to 12 months(252).
exclude patients with common cold. Studies without a placebo But even in countries in Northwest Europe substantially higher
arm, and/or involving adults were also excluded. The primary proportions of consultations result in an antibiotic prescription
outcome is number of patients who obtained cure/significant than was deemed appropriate according to what has been ad-
improvement at 10-14 days. The secondary outcomes assessed vised in guidelines, and presumed acute rhinosinusitis is one of
were number of days to cure and adverse effects. the diseases where discrepancies are largest. In a study in the UK
Three studies were included: Garbutt, 2001; Kristo, 2005; and 88% of the consultations for rhinosinusitis resulted in an antibi-
Khoshdel, 2014(244-246). The Garbutt study contained three arms. otic prescription where experts deemed 11% appropriate(22). The
Two studies evaluated amoxicillin(244, 246), one amoxicillin with same was true in the Netherlands where 34% of the interviewed
clavulanic acid(244) and one cefuroxime(245). The antibiotics were primary care physicians chose an antibiotic as treatment for a
taken for 10-14 days. All participants had symptoms of acute patient with moderate severe acute rhinosinusitis(171). Substan-
post-viral rhinosinusitis which fulfilled the EPOS criteria for at tial variation between practices is found(22, 253).
least at least five days (Table 4.6.3.). A number of studies have evaluated measurements that could
Khoshdel et al.(246) found a higher cure rate in the amoxicillin help to decrease the inappropriate prescription of antibiotics
group at day 3 (85 vs. 37.5% , p<0.01) but no difference at other for acute rhinosinusitis(254-259). Most studies emphasize training
time points. The other two studies did not find a significant dif- of physician communication skills on the use of antibiotics(255,
ference between antibiotics and placebo(244, 245). 256)
, accountable justification and peer comparison(255, 256, 259) and
The studies could be combined into a meta-analysis to deter- training of physicians(256, 258). The use of a point-of-care C-reactive
mine the cure rate at day 10-14 (366 patients in three studies) protein testing did not reduced antibiotic prescription in child-
(244-246)
. The use of antibiotics was not associated with greater ren with (non-severe) acute respiratory infections(254, 257).
cure/significant improvement at day 10-14 (RR 1.02 95% CI .96-
1.08, I2=0%) (Figure 4.6.11.). 4.6.4. Nasal corticosteroid in acute post-viral rhinosinusitis
Two studies could be combined and could not show that the pa-
tients on antibiotics did have significantly more adverse events 4.6.4.1. Nasal corticosteroid in acute post-viral rhinosinusitis in
compared to the placebo group (RR 1.29 95% CI 0.69-4.38, adults

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Figure 4.6.13. Consumption of antibiotics for systemic use in the com- Figure 4.6.14. Proportion of macrolide Resistant (R) Streptococcus pneu-
munity by antibiotic group in 30 EU/EEA countries, 2013 (expressed in monia isolates in participating countries in 2013(250).
DDD per 1000 inhabitants and per day(251).

in symptoms. Three studies reported a reduced time to cure/

reduced symptoms(261, 264, 265), the other two did not. The data
were insufficiently reported to meta-analyse. Three studies(263, 264)
evaluated the SNOT-20 score. The SNOT-20 is not validated for
ARS but may give some impression of quality of life also in acute
disease. The meta-analysis showed no significant difference
4.6.4.1.1. Summary of the evidence between treatment with nasal corticosteroids and placebo alt-
This section aims to assess the efficacy of nasal corticosteroids hough the data showed significant heterogeneity (MD 0.13, 95%
in adults with post-viral ARS. There are no studies evaluating the CI -0.04 to 0.31, p=0.14; 4 RCTs, n = 1120; Figure 4.6.14.).
effect of nasal corticosteroids on ABRS. Studies were included Four studies reported on total symptom score(238, 260, 265, 266).
if they involved adults with ARS with symptoms of at least five The studies could be combined into a meta-analysis. Both the
days but less than 12 weeks (to exclude chronic rhinosinusitis). analyses of the studies where nasal corticosteroid was the single
Only double-blind placebo-controlled randomized trials publis- treatment (SMD 0.32, 95% CI 0.15 to 0.50, p=0.0003; two (two
hed after the year 1990, assessing the effects of nasal cortico- arms) RCTs, n = 1860; Figure 4.6.14.) and where nasal corticoste-
steroids for patients who fulfilled the criteria of post-viral acute roid was added to an antibiotic (that on its own has shown to be
rhinosinusitis are included. Patients with common cold and not effective (see paragraph 4.6.4.3.)) showed a significant effect
acute bacterial rhinosinusitis (ABRS), are excluded. Nasal corti- over placebo (SMD 0.21, 95% CI 0.11 to 0.30, p<0.00001; two
costeroids delivered into the nose and the paranasal sinuses by RCTs, n=1699; Figure 4.6.16.).
any delivery methods generally available in clinical practice are Some studies reported on separate symptoms where nasal
included. Outcomes included in this analysis are time to cure, congestion was often found to be significantly improved in the
quality of life, symptoms and adverse events. nasal corticosteroid group compared to placebo. No meta-ana-
Of the eight studies included in this section, five studies(238, 260-263) lysis was performed.
were placebo-controlled trials assessing the effects of nasal cor- There was no difference in adverse events and/or in patients
ticosteroids alone (Table 4.6.4.) and three were studies(264) evalu- needing antibiotics in the studies that evaluated that parameter
ating the effect of the addition of nasal corticosteroids to treat- (Tables 4.6.6.-4.6.7.).
ment with antibiotics (Table 4.6.5.). The papers of Bachert(263) and Finally, Svensson et al.(267) used a cost-effectiveness model to
Meltzer 2012(261) are post-hoc analyses of the data from Meltzer analyse the cost-effectiveness of mometasone furoate nasal
2005(238). All studies mainly evaluated patients meeting the EPOS spray (MFNS) compared with amoxicillin or placebo in the
criteria for acute post-viral rhinosinusitis although in the study treatment of post-viral rhinosinusitis. Costs were reduced and
of Dolor(264) duration of disease was not indicated. A number of quality-adjusted life years were increased with MFNS 200 µg
studies evaluated more than one dosage of nasal corticoste- twice daily compared with amoxicillin 500 mg three times daily.
roids. These are analysed separately in the meta-analysis. MFNS was cost-saving or cost-effective compared with amoxicil-
Five studies(260-262, 264, 265) reported on time to cure or reduction lin or non-active treatment in the sensitivity analyses regardless

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Table 4.6.4. Nasal corticosteroids compared to placebo in adult patients with acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Keith DBPCT 737 patients (age >12y) • FFNS 110μg once daily During 1 month: Treatment with FFNS vs.
2012(260) with acute post-viral (n=240) for 2 weeks • SNOT-20 placebo resulted in:
rhinosinusitis • FFNS 110μg twice daily • Daily major symptom • No significant reduction
(n=252) for 2 weeks score (a composite in SNOT-20
• Placebo (n=245) for 2 score of three indivi- • Significant reduction in
weeks dual symptoms (nasal major symptom score
congestion/stuffiness, • Significant reduction in
sinus headache/pressure congestion
or facial pain/pressure, • No significant difference
postnasal drip), each in time to symptom
using a scale of 0–3. improvement
These assessments were • No difference in need
conducted twice daily, for antibiotics
before the morning and • No difference in adverse
evening dose) events
• Individual symptoms
• The first time to
symptom improvement
(defined as reduction
of individual symptom
scores of nasal con-
gestion/stuffiness, sinus
headache/pressure or
facial pain/pressure, and
postnasal drip)
• Need of antibiotics
• Adverse events
Meltzer DBPCT 728 patients (age >12y) • MFNS 200µg twice daily • MSS Treatment with MFNS
2012(261) with post-viral ARS for 15 days (n=234) • The percentage of compared to placebo
Post hoc analysis of • MFNS 200µg once daily days with minimal MSS resulted in:
Meltzer 2005(238) for 15 days (n=243) (defined as average am / • Significantly reduced
• Amoxicillin 500mg 3 pm MSS ≤4) for 1 month mean rhinosinusitis
times daily for 15 days • The percentage of days major symptom score
(n=248) with minimal congestion • Significantly reduced
• Placebo for 15 days (≤1) for 1 month percentage of days with
(n=246) • Time to first day with minimal MSS
minimal symptoms • Significantly reduced
percentage of days with
minimal congestion
• Significantly reduced
time to first day with
minimal symptoms
Williamson DBPCT 240 adults post-viral ARS • 500mg of amoxicillin 3 • Proportion of patients No significant effect in
2007(262) (207 analysed) times per day for 7 days having symptoms lasting any treatment group
and 200µg budesonide in 10 days or more compared to placebo for
each nostril once per day • Time to cure (graph) all outcomes
for 10 days (n=46) • % cured at day 10
• 500mg of amoxicillin 3 • Total symptom score
times per day for 7 days
(n=54) 200µg budeso-
nide in each nostril
once per day for 10 days
(n=56)
• Placebo (n=51)
Bachert Post hoc analysis of 340 patients (331 ana- • MFNS 200µg twice daily • SNOT-20 Treatment with MFNS
2007(263) Meltzer 2005(238) lysed) with post-viral ARS for 15 days (n=81) • Global scores compared to placebo
although the dosa- • MFNS 200µg four times resulted in:
ge indicated here daily for 15 days (n=84) • Significant improve-
are twice as high • Amoxicillin 500mg 3 ment in SNOT-20
as in the original times daily for 10 days • Significant improve-
paper (200µg twice (n=84) ment in global response
and four times daily • Placebo nasal spray and to treatment
compared to once tablets (n=82)
and twice daily in
Meltzer 2005(238)

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Table 4.6.4. Nasal corticosteroids compared to placebo in adult patients with acute post-viral rhinosinusitis. (continued)

Study Methods Participants Interventions Outcomes Results

Meltzer DBPCT Post-viral ARS (n=981) • MFNS 200µg once daily • Mean am / pm MSS over • MFNS 200mg twice daily
2005(238) for 15 days (n=243) days 2 to 15 of the treatment produced significant symp-
• MFNS 200µg twice daily phase tom improvements versus
for 15 days (n=235) • Mean major symptom score, amoxicillin and placebo
• Amoxicillin 500mg 3 total symptom score, and • MFNS 200mg once daily pro-
times daily for 10 days individual scores (average duced significant symptom
(n=251) of am / pm scores) for each improvements versus placebo
• Placebo nasal spray and symptom averaged weekly • The incidence of treatment-
tablets (n=252) and daily emergent adverse events was
• Safety assessments included similar among the treatment
disease recurrence during groups
follow-up and adverse event
monitoring
ARS, acute rhinosinusitis; DBPCT, double blind placebo controlled trial; FFNS, fluticasone furoate nasal spray; MFNS, mometasone furoate nasal spray;
MSS, Mean Rhinosinusitis Major Symptom Score; SNOT-20, Sino-nasal Outcome Test-20; y, years.

Table 4.6.5. Nasal corticosteroid as addition to oral antibiotics in adult patients with acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Nayak DBPCT 967 post-viral rhinosinusitis • MFNS 400µg nasal spray • Mean improvement in Treatment with MFNS 400
2002(265) patients twice daily for 21 days daily symptom scores (0-3) and 200 twice daily compa-
(n=324) for total symptoms, heada- red to placebo resulted in a
• MFNS 200µg nasal spray che, facial pain, congestion, significantly:
twice daily for 21 days purulent rhinorrhoea, • Larger mean reduction in
(n=318) postnasal drip, and cough total symptom scores and
• Placebo nasal spray for 21 over 15 days congestion than placebo
days (n=325) • Overall therapeutic • Larger mean reduction in
response to treatment (0-5) facial pain, rhinorrhoea and
All patients: amoxicillin/cla- at day 21 post-nasal drip than placebo
vulanate potassium 875mg, • Onset of relief • Significantly better overall
twice daily, for 21 days • CT scan at day 21 therapeutic response at day
• Adverse events 21 compared to placebo
• Co-syntropin-stimulation • Significant faster onset of
plasma cortisol relief
• Comparable adverse events
No differences in CT scans,
adverse events and plasma
cortisol
Dolor DBPCT 95 ARS patients with acute • FPNS 2 puffs twice daisy • Time to clinical success Patients using FPNS had:
2001(264) sinonasal symptoms and • Placebo nasal spray in (patient reported cured or • Significantly shortened time
history of recurrent rhino- each nostril once daily for much improved) to clinical success
sinusitis or chronic rhinitis 21 days (n=48) • Sinus symptoms score • Significantly shorter time to
(92 analyzed) (duration of • SNOT-20 clinical success
disease unclear) All received 250mg of ce- • SF-12 • Improved work performance
furoxime axetil twice daily • Mean work performance • No significant differences in
for 10 days and 2 puffs of rhinosinusitis symptom
xylo zoline hydrochloride
in each nostril twice daily
for 3 days
Meltzer DBPCT 407 post-viral ARS patients • MFNS 400µg, twice daily • Daily symptom scores • Significantly greater decre-
2000(266) (n=200) (0-3) for headache, facial ase in total symptom score
• Placebo spray twice daily pain, congestion, purulent and headache, congestion,
for 21 days (n=207) rhinorrhoea, postnasal drip, and facial pain compared
and cough with placebo.
All patients: • Overall therapeutic • No differences in other
Augmentin, 875 mg twice response to treatment (0-5) outcomes
daily at day 21 • No difference in therapy-
• CT scan at day 21 related local adverse events
• Adverse events

CT, computed tomography; DBPCT, double blind placebo controlled trial; FPNS: fluticasone propionate nasal spray; MFNS, mometasone furoate nasal
spray; SF-12, Short Form-12 (12-item short form QOL survey; SNOT-20, Sino-nasal Outcome Test-20.

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Figure 4.6.15. Forest plot of the effect of intranasal corticosteroids versus placebo on change from baseline SNOT-20 score in acute post-viral rhinosi-
nusitis.

CI, confidence interval; M-H, Mantel Haenszel.

Figure 4.6.16. Forest plot of the effect of intranasal corticosteroids versus placebo on change from baseline of total symptom score in acute post-viral
rhinosinusitis.

CI, confidence interval; M-H, Mantel Haenszel.

of the HRQOL measurement used. 4.6.4.2.1. Summary of the evidence

This section aims to assess the efficacy of nasal corticosteroids in
4.6.4.1.2. Conclusion children with post-viral ARS. There are no studies evaluating the
Nasal corticosteroids are effective in reducing total symptom effect of nasal corticosteroids on ABRS. Studies were included if
score in adults suffering from acute post-viral rhinosinusitis. they involved children with ARS with symptoms of at least five
However, the effect is small. Nasal corticosteroids have not been days but less than 12 weeks (to exclude chronic rhinosinusitis).
shown to have an effect on QOL. We downgraded the evidence We identified two studies, one DBPCT and one single blind(268,
because of high heterogeneity. Acute post-viral rhinosinusitis 269)
. Both evaluated the use of nasal corticosteroids on top of
is a self-limiting disease. Based on the moderate quality of the antibiotics. Both studies found a significantly larger decrease in
evidence and the small effect size the EPOS2020 steering com- symptoms and in one study more children were cured (21/50
mittee advises only to prescribe a nasal corticosteroid when versus 2/50) (Table 4.6.8.).
reduction of the symptoms of the acute post-viral rhinosinusitis
is considered necessary. 4.6.4.2.2. Conclusion
Nasal corticosteroids seem to be effective in reducing total
4.6.4.2. Nasal corticosteroid in acute post-viral rhinosinusitis symptom score in children suffering from acute post-viral
in children rhinosinusitis on top of (ineffective) antibiotics. Acute post-viral
rhinosinusitis is a self-limiting disease. Based on the very low

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Table 4.6.6. Bacterial lysates in children with acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Barreto DBPCT Children aged 18m-9y with • OM-85-BV (3.5mg) (n=26) • Improvement • OM-85-BV group improved
1998 (283) ARS • Placebo (n=30) daily for • Convalescence sooner than the placebo group
10 days (5.56±4.98 vs. 10±8.49; p<0.05).
Both groups received • OM-85-BV had significantly shor-
amoxicillin/clavulanic acid ter convalescence time compared
(40/10mg/kg) daily in 3 to the placebo group (15.38±8.91
doses for 21 days. vs. 20.28±7.17; p<0.05)

DBPCT, double blind placebo controlled trial; m, months; OM-85-BV, oral bacterial extract; y, years.

Table 4.6.7. Homeopathy for acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Zabolotnyi DBPCT Adults with radio- Sinfrontal (n=57) vs. Assessed at day 0, 7, 14, • There was a significant reduction
2007(285) graphic confirmed placebo (n=56); one tablet and 21 in the SSS compared to placebo
acute maxillary sinusitis every hour until first im- • SSS (5.8±2.3[6.0] point vs. 2.3 ± 1.8[2.0]
(n=133). provement (max 12 tablets • Radiographic cure points; p<0.0001).
per day). After first sign of • Clinical cure • At 3 weeks, 68.4% of those on me-
improvement or day 3, two • Improvement in health dication had complete remission
tablets three times daily. state (EQ-VAS) of symptoms compared to 8.9% of
Tablets had to be melted • Ability to work or do placebo patients.
slowly in the mouth at least usual activities • Substantial radiographic impro-
30 minutes before or after • Treatment outcome vement was noted in significantly
meals. more patients in the sinfrontal
group compared to placebo (77.2%
vs. 21.4%, p<0.0001).
• By day 7, 52.6% of patients in the
sinfrontal group were able to carry
out daily activities compared to the
17.9% in the placebo group.
• The mean change for the EQ-VAS
was significantly different for the
sinfrontal group compared to
the placebo group (17.3±9.1 vs.
6.2±8.1, p<0.01).
DBPCT, double blind placebo controlled trial; EQ-VAS: Euroqol visual analoque score; SSS, sinusitis severity score.

Table 4.6.8. Nasal corticosteroid as addition to oral antibiotics in children with acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Rahmati SBRT 100 children with mostly • Amoxicillin 80 to 100 mg/ At 10-14 days: In the group receiving am-
2013(268) post-viral ARS (2 to 14 kg/ day with FPNS 50 µg • Cure oxicillin and FPNS compared
years) per nostril twice daily for 14 • Total symptom score to the groups with amoxicil-
days (n=50) (0-50) lin alone:
• Amoxicillin 80 to 100 mg/ • Significantly more patients
kg/ day for 14 days (n=50) were cured
• Symptom score was signifi-
cantly lower
Barlan DBPCT 151 (89 evaluated) children • Budesonide nasal spray Evaluation in first 3 weeks: The budesonide group com-
1997(269) with mostly post-viral ARS bid, 50µg, to each nostril for • Daily record card (filled pared to the placebo group
(mean age 7y) 3 weeks (n= 43) in by parents) symptom showed:
• Placebo nasal spray bid, scores including purulent • Significant larger impro-
50µg, to each nostril for 3 nasal discharge, cough vement in cough and nasal
weeks (n=46) and presence of fever and discharge scores at the end
All patients received amoxi- headache (0-3). of second week but not 1st
cillin-clavulanate potassium, or 3rd week.
40mg/kg/d three times daily
for 3 weeks

ARS, acute rhinosinusitis; DBPCT, double blind placebo controlled trial; FPNS, fluticasone propionate nasal spray; SBRT, single blind randomised trial;
y, years.

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quality of the evidence the EPOS2020 steering committee can- facial pain at days 4-7 after start of the treatment. There are no
not advise on the use of nasal corticosteroids in children with studies comparing systemic corticosteroids to nasal corticoste-
acute post-viral rhinosinusitis. roids. The quality of the evidence is low. Based on the evidence,
the numbers needed to treat and the potential harm of systemic
4.6.5. Oral corticosteroids corticosteroids, the EPOS2020 steering group advises against
the use of systemic corticosteroids in patients suffering from
4.6.5.1. Summary of the evidence acute post-viral rhinosinusitis. There is insufficient data in pa-
Systemic corticosteroids could be effective by attenuating the tients with ABRS to advise on treatment of ABRS.
inflammatory response. Systemic administration of cortico-
steroids may have advantages over nasal use, such as quicker 4.6.6. Antihistamines (oral and local)
onset of action, higher therapeutic levels and no risk of poor
deliverance because of nasal congestion/sinus blockage. In 2014 4.6.6.1. Summary of the evidence
a Cochrane review of systemic corticosteroid therapy for acute While there has been some data showing efficacy of antihistami-
rhinosinusitis suggested that oral corticosteroids in combination nes in common cold (see 4.6.2.), we found one study in children
with antibiotics may be modestly beneficial for short-term relief evaluating the addition of nasal oxymetazolone and oral syrup
of symptoms in acute rhinosinusitis(270). containing brompheniramine and phenylpropanolamine versus
We analyzed four DBPC studies evaluating the effect of 3-7 days placebo to oral amoxicillin for 14 days. Responses to treatment
of systemic corticosteroids (varying dose) in patients with main- were similar between the two groups. The authors concluded
ly post-viral rhinosinusitis (Table 4.6.9.)(271-274). In three studies the that decongestant antihistamine need not be given to the child
systemic corticosteroid was combined with antibiotics(272-274), in with acute maxillary sinusitis(275). In addition, one such study in
one it was given without antibiotics(271). adults has been completed in acute bacterial rhinosinusitis.
The inclusion criteria were not very clear in most studies but Braun and colleagues(276) evaluated the use of antihistamines in
most resembled post-viral rhinosinusitis, although the study of acute bacterial rhinosinusitis (Table 4.6.10.). This study involved
Klossek included patients with less than five days of symptoms 139 patients with a history of allergic rhinitis who were diag-
(common cold). nosed with acute bacterial rhinosinusitis. This diagnosis was
Two studies looked at recovery at 7-14 days and found no dif- made upon visualization of purulent rhinorrhoea or purulence
ference(271, 274). noted from the middle meatus on exam. These patients were
Three studies evaluated the proportion of patients with resolu- randomized to receive either Loratadine (10mg) or placebo for
tion of facial pain at day 4-7 after start of the treatment, these 28 days. Each group was also given the following: 14 days of
studies could be combined into a meta-analysis, showing a RR antibiotics and 10 days of corticosteroids. Outcomes were eva-
of 1.17 (95% CI 1.05-1.30), RD of 0.11 (0.03-0.18), 633 patients luated at the end of treatment, and the addition of antihistami-
(Figure 4.6.17.) and showed a significant higher resolution of fa- nes significantly decreased nasal obstruction (MD=−0.58; 95%
cial pain 4-7 days after start of systemic corticosteroid treatment CI =−0.85- −0.31, p<0.01), but did not reduce total symptom
than placebo. The differences were however, small and notably scores (MD=−1.25; 95% CI=−2.77-0.27, p=0.11), or rhinorrhoea
almost two-thirds of the patients had no symptoms after pla- symptoms (MD=−0.06; 95% CI=−0.37-0.25, p=0.71). Similar
cebo treatment (197/316). The effect of systemic corticosteroids results were noted at day 14 with the addition of antihistamines,
compared to placebo was not found at 10-14 days after start of there was significantly decreased nasal obstruction (MD=−0.34;
the treatment. 95% CI=−0.64- −0.04, p=0.02), but did not reduce total symptom
Two studies could be combined to evaluate the proportion of scores (MD= −0.26; 95% CI=−3.11-0.59, p=0.18) or rhinorrhoea
patients with resolution of nasal discharge at day 4-7 after start symptoms (MD=−0.12; 95% CI=−0.39-0.15, p=0.39).
of the treatment showing no significant differences in resolution
of nasal discharge at day 4-7 ( RR of 1.24 (95% CI 0.88-1.74), 387 4.6.6.2. Conclusion
patients (Figure 4.6.18.)). Also here, spontaneous recovery was In conclusion, there are two studies evaluating antihistamines
high (72%). versus placebo in addition to antibiotics; one in adults with
ABRS the other in children with post-viral ARS. Both studies
showed no additive effect of antihistamines over the treat-
4.6.5.2. Conclusion ment given. Based on the very low quality of the evidence, the
In conclusion, post-viral rhinosinusitis is a self-limiting disease. EPOS2020 steering group cannot advise on the use of antihista-
Systemic corticosteroids, with or without antibiotics do not have mines in post-viral ARS and ABRS.
a positive effect on recovery at 7-14 days. There is a small but
significant effect of systemic corticosteroids versus placebo on

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Table 4.6.9. Studies comparing systemic corticosteroids versus placebo in patients with mainly acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Venekamp DBPCT 185 patients with post- • Prednisolone 30mg/d for 7 • The proportion of patients No clinically relevant bene-
et al. viral rhinosinusitis (174 days (n=88) with resolution of symptoms ficial effects
2012(271) evaluated) • Placebo for 7 days (n=86) (facial pain or pressure, nasal
congestion or blockage, post-
nasal discharge, runny nose,
poor sleep, cough and redu-
ced productivity) on day 7
• SNOT-20 on days 1, 7 and 14
• Median duration of symp-
tom
Ratau DBPCT 42 patients with post-viral • Betamethasone 1mg orally • Change in treatment effects Bethamethasone versus
2004(272) rhinosinusitis once a day for 5 days (n=21) for the duration of therapy placebo resulted in:
• Placebo tablets for 5 days expressed as slope values • Significantly larger reduc-
(n=21) based on a daily symptom tion in headache (none/
score card (headache, facial mild versus moderate se-
All patients received pain, nasal congestion and vere) and facial pain, nasal
amoxicillin-clavulanic acid dizziness) for 5 days congestion and dizziness
625mg orally, three times • Percentage of patients with (none versus symptoms)
daily for 5 days percussion tenderness and • Significantly less patients
nasal secretions on day 6 with percussion tenderness
• Use of paracetamol for 6 and nasal secretions on
days day 6
• No significant difference
in paracetamol taken
Klossek DBPCT 289 patients with common • Prednisone (40-60kg • Mean pain intensity dif- Prednisone versus placebo
2004(273) cold/acute rhinosinusitis bodyweight: 40mg, 60-80kg ference, nasal obstruction resulted in:
with symptoms for <5 bodyweight: 60mg >80 kg (VAS) compared to baseline • Significant reduction in
days (prednisone n=142, bodyweight: 80mg), for 3 on day 1-3 mean pain intensity dif-
placebo n=147) days (n=142) • Paracetamol use in day 1-3 ference, nasal obstruction
• Placebo (n=147) and use of paracetamol at
Both groups treated with day 1-3
cefpodoxime 100 mg twice
daily for 10 days
Gehanno DBPCT 417 adult patients with • 8mg of methylprednisolone • Clinical and/or radiological 24mg methylprednisolone
2000(274) mainly post-viral rhinosi- 3 times daily (n=208) for 5 recovery at day 14 versus placebo resulted in:
nusitis days • Craniofacial pain, nasal • No difference in recovery
• Placebo 3 times daily discharge at day 4 • Significant reduction in
(n=209) for 5 days craniofacial pain but not in
All patients received 500mg nasal discharge at day 4
of amoxicillin-clavulanate
3 times daily for 5 days and
half received 10 days

DBPCT, double blind placebo controlled trial; VAS, visual analogue scale..

Figure 4.6.17. Proportion of patients with resolution of facial pain after 4-7 days of systemic corticosteroid treatment versus placebo.

CI, confidence interval; M-H, Mantel Haenszel.

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Figure 4.6.18. Proportion of patients with resolution of nasal discharge after 4-7 days of systemic corticosteroid treatment versus placebo.

CI, confidence interval; M-H, Mantel Haenszel.

4.6.7. Antileukotrienes post-viral ARS (as described in the paper although the authors
There is no evidence from RCTs for the use of anti-leukotrienes speak about ABRS) on mucociliary clearance (MCC). The final
in common colds, post-viral ARS or ABRS. MCC score of the oxymetazoline group, taken after three weeks,
was not significantly different to any other intervention. In the
4.6.8. Nasal decongestants oxymetazoline group, however, there was a significant impro-
vement in MCC scores throughout the duration of treatment.
4.6.8.1. Summary of the evidence Interestingly, regardless of intervention, patients with post-viral
Decongestants are commonly recommended by primary health ARS continued to have significantly poorer MCC scores com-
care physicians, as well as otorhinolaryngologists, as part of pared to healthy controls after three weeks of treatment. This
the treatment for ARS. Although the current evidence suggests study was limited in that the baseline MCC scores between
that multiple doses of decongestants may have a small positive groups were significantly different. The baseline MCC score in
effect on subjective measures of nasal congestion in adults with the oxymetazoline group was significantly higher than the other
the common cold(201), their use in ARS has had limited investiga- groups , therefore, any improvements noted in this group could
tion. We systematically reviewed nasal decongestants/vasocon- be attributed to a type 1 error.
strictors in ARS. Studies that included either ABRS or post-viral
rhinosinusitis were included. The common cold was excluded. 4.6.8.2. Conclusion
We identified one randomised controlled (RCT) study that In adult acute post-viral rhinosinusitis nasal decongestants may
evaluated the impact of nasal decongestants on the clinical be effective in improving mucociliary clearance throughout the
outcome of adult acute post-viral ARS. Inanli et al.(277) examined acute phase of the disease but further RCTs are required. No
the effect of several different topical agents in 60 patients with studies are performed evaluating the effect of resolution or re-

Table 4.6.10. Antihistamines in ABRS and post-viral ARS.

Study Methods Participants Interventions Outcomes Results

Braun RCT, 130 adults with allergic • Loratadine (10mg) four times Assessed at 28 days: At 28 days:
1997(276) placebo- rhinitis and ABRS daily) for 28 days (n=71) • Total symptom score • No significant reduction in
control • Placebo four times daily for • Nasal obstruction total symptom scores
28 days (n=68) • Rhinorrhoea • Significant decreased
All patients received: Aug- • Sneezing nasal obstruction
mentin (2g/day) x 14 days + • Nasal itching • No significant decrease in
prednisone 40mg four times • Cough other symptoms
daily x 4 days and 20mg for
4 days
McCormick DBPCT 68 children (age 6 (6-16) • Nasal oxymetazolone and Assessed at day 3 and 14: No differences between the
1996(275) with acute post-viral oral syrup containing bromp- • Mean symptom score treatment groups.
rhinosinusitis heniramine and phenylpro-
panolamine (age dependent
dosage) (n=34)
• Placebo (n=34)
All children received amoxicil-
lin three times daily dosage
depending on weight

ABRS, acute bacterial rhinosinusitis; RCT, randomised controlled trial

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duction of symptoms of ARS. Based on the absence of clinically saline irrigation in ABRS or post-viral ARS.
relevant data, the EPOS2020 steering group cannot advise on
the use of decongestants in acute post-viral rhinosinusitis. 4.6.10. Steam / heated air
Steam inhalation has been proposed as an adjunct in the
4.6.9. Saline treatment of ARS. A systematic review identified two RCTs that
examined the role of steam inhalation however both of these
4.6.9.1. Summary of the evidence papers were excluded. Little et al.(281) examined the role of steam
Saline irrigation and sprays are commonly recommended by pri- and analgesia in patients with respiratory tract infections. This
mary health care physicians, as well as otorhinolaryngologists, paper was excluded as the patients were grouped into lower
as part of the treatment for ARS. respiratory tract infections (LRTI) and non-LRTI cohorts. Patients
We identified three RCTs evaluating the impact of nasal saline with specific ARS symptoms were not specifically examined.
irrigations/sprays on clinical outcomes in adult patients with Little et al.(282) compared the effectiveness of steam inhalation
ARS. Studies that included either ABRS or post-viral rhinosinusi- and nasal irrigation for CRS or recurrent ARS. This study was
tis were included. The studies were different in design, duration excluded because the first follow up assessment was three
and outcome measurements. Both studies reported no effect months after the intervention which is beyond the timeframe
(Tables 4.6.11. and 4.6.12.). for assessment in patients with ARS.
Adam et al.(278) examined 75 adults with ABRS in a partially In conclusion, there are no studies evaluating the effect of steam
blinded RCT. Hypertonic and normal saline nasal spray three / heated air in post-viral ARS and ABRS.
times daily were compared. The study found no difference in
symptoms between the groups on day 3 of their illness and 4.6.11. Physical interventions
no difference between the groups in the duration of recovery. We identified one study evaluating the effect of ultrasound
Rabago et al.(279) examined in a non-blinded RCT the use of daily, treatment in comparison to amoxicillin in the treatment of 48
high volume (150ml per side), hypertonic saline on patients with patients (42 analysed) with presumed ABRS(234). The experimen-
post-viral ARS and CRS. Eighty percent of the study population tal group received four consecutive days of ultrasound and the
had a diagnosis of post-viral ARS, so this study was included. control group received a 10-day course of amoxicillin. There
Outcomes were measured at six weeks, three months and six were no differences between the treatment groups, apart from
months. Results at six weeks are included as this is closest to a significant larger decrease in pain around the nose at day 4.
the relevant ARS symptom time frame. The intervention group There were no other differences between the groups in terms of
had no significant improvement in their Rhinosinusitis Disability satisfaction with intervention, number of side-effects, or num-
Index (RSDI), single-Item Sinus Severity Assessment (SIA) and SF- ber of relapses. Due to the lack of a placebo group no relevant
12 score. Gelardi et al.(280) evaluated the difference between the conclusions can be drawn from this study.
efficacy of two irrigation systems in 20 patients with acute (pre-
sumed post-viral) rhinosinusitis and who were further treated 4.6.12. Bacterial lysates
with levofloxacin 500 mg/day for 10 days and topical naphazo-
line (two puffs in each nostril) twice daily for seven days. Patients 4.6.12.1 Summary of the evidence
were randomly assigned to either a nasal syringe (10mL saline Barreto et al.(283), evaluated the efficacy of OM-85-BV (3.5mg)
solution, three times daily for 14 days) or a high volume (250ml) versus placebo for 10 days, in addition to amoxicillin/clavula-
warm saline irrigation system twice daily for 14 days. Nasal high nic acid (40/10mg per kg for 21 days) in children with acute
volume warm saline irrigation compared to 10ml saline resulted rhinosinusitis. They evaluated children from 18 months to nine
in significantly less patients with purulent rhinorrhoea at seven years old with at least 30 days of the following symptoms:
days, and significantly less post-nasal drip at seven and 14 days. post-nasal discharge, nasal congestion, halitosis, facial pain and
There were no differences in nasal obstruction of rhinomano- pressure, nasal mucosa irritation, fevers, retro-orbital headache
metry. and radiographic evidence of sinus opacification or oedema of
bilateral paranasal sinuses. Patients were assessed on days 0, 3,
4.6.9.2. Conclusion 15, 21, 30, 60, 90, and 180 for improvement of current infection
Two relatively small studies, one in ABRS(278), one in post-viral and recurrent respiratory infections. Patients who received
ARS(279) did not find a difference between saline nasal spray OM-85-BV had significantly shorter time to improvement when
versus no treatment. One very small study found a larger effect compared to the placebo group (5.56±4.98 vs. 10±8.49; p<0.05).
of high volume versus low volume saline rinsing on purulent The convalescence time was significantly shorter in the OM-85-
rhinorrhoea and post-nasal drip. Based on the very low quality BV group when compared to the placebo group (15.38±8.91 vs.
of the evidence no advice can be given about the use of nasal 20.28±7.17; p<0.05). There was one adverse event, a rash, that

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Table 4.6.11. Nasal saline spray in adult ABRS.

Study Methods Participants Interventions Outcomes Results

Adam RCT, partial Adults with ABRS (n=75) • HNS spray; 2 sprays per • Nasal symptom score on • No significant difference
1998(278) blinding nostril, 3 times per day for day 3 between the groups in:
10 days (n=26) • Day of well-being (day of • Day 3 nasal symptom
• NS spray; 2 sprays, each symptom resolution) scores
nostril, 3 times per day for • Day of well-being
10 days (n=23) between the groups
• No treatment (n=26)
All patients received antibi-
otics (unclear which one)

ABRS, acute bacterial rhinosinusitis; RCT, randomised controlled trial; HNS: hypertonic nasal saline; NS: nasal saline

Table 4.6.12. Saline use in adult post-viral ARS.

Study Methods Participants Interventions Outcomes Results

Gelardi RCT, non- 20 adults with (post-viral?) ARS • High volume (250ml) At 7,14 and 21 days: The high volume warm
2009 (280) blinded warm saline irrigation sys- • Symptoms saline irrigation compared
tem twice daily for 14 days • Nasal endoscopy to 10 ml saline resulted in:
• Saline applied with a 10ml • Rhinomanometry • Significantly less patients
syringe 3 times daily for with purulent rhinorrhoea
14 days at 7 days
All patients received • Significantly less post-
levofloxacin 500 mg/day for nasal drip at 7 and 14 days
10 days and topical napha- • No difference in rhinoma-
zoline 2 puffs in each nostril nometry
twice daily for 7 days.
Rabago RCT, non- 76 adults with 2 episodes of • 2.0% saline with baking Baseline, 6w, 3m, 6m: No significant difference in
2002 (279) blinded ARS or 1 episode of CRS per soda 150ml per nostril daily • SF-12 the reported outcomes.
year, for 2 consecutive years (n=52) • RSDI
63 with diagnosis post-viral ARS • No treatment • SIA
• Compliance diary

ARS, acute rhinosinusitis; CRS, chronic rhinosinusitis; m, months; RCT, randomised controlled trial; RSDI, Rhinosinusitis Disability Index; SF-12, Short
Form-12 (12-item short form QOL survey); SIA, Sinus Severity Assessment; w, weeks.

disappeared three days after drug discontinuation (Table 4.6.6.). solubilis Hahnemanni (Trit. D6)). in acute maxillary sinusitis. This
study consisted of 22 days of treatment with sinfrontal versus
4.6.12.2. Conclusion a placebo and patients were evaluated at four time points over
One study has shown benefit in the use of OM-85-BV for shor- the course of the study (day 0, 7, 14, and 21). There was a post-
tening the duration of illness in post-viral rhinosinusitis. Further observational phase of eight weeks where the patients were no
studies should be conducted to determine efficacy in patients longer on the study medication. Outcome measures included
with post-viral and ABRS. the sinusitis severity score (SSS) which consisted of the sum
score of the following six symptoms: headache, maxillary pain,
4.6.13. Homeopathy maxillary pain worsening on bending forward, percussion, or
pressure; nasal obstruction, purulent nasal secretion, purulent
4.6.13.1. Summary of the evidence nasal discharge visualized in the middle meatus of purulent
Two studies(284, 285) evaluated the use of homeopathy in acute post-nasal discharge. Each symptom was scored on a 0-4 scale
post-viral rhinosinusitis. The study of Friese et al.(284) is excluded (0 – not present, 4 – very severe). Each patient underwent sinus
from this analysis because the patients had symptoms for three- radiography which was scored on a modified version of the sys-
eight days at the beginning of the trial and thus did not fulfil the tem used by van Buchem(243) from not assessable (NA) to a score
criteria for post-viral rhinosinusitis. of 6 for an air-fluid level. A response was defined as a SSS of < 10
There was one study(285) evaluating the use of sinfrontal (Cin- point on day 7 and a reduction of the SSS ≥ 4 points from day 0
nabaris (Trit. D4), Ferrum phosphoricum (Trit. D3), Mercurius to day 7 and a clinical cure was defined as complete remission

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 EPOS 2020

of signs and symptoms (SSS=0) or substantial improvement de- clude post-viral patients are the studies by Pfaar et al. evaluating
fined as reduction of signs and symptoms (each symptom SSS≤1 the effectiveness of Cyclamen europaeum nasal spray versus
point). There was a significant reduction in the SSS compared placebo as an adjunct to amoxicillin(290) and the study from Ba-
to placebo (5.8±2.3[6.0] point vs. 2.3±1.8[2.0] points; p<0.0001). chert evaluating pelargonium sidoides versus placebo(291).
Patients in the sinfrontal group met criteria as responders The frozen, dried, natural fluid extract of the cyclamen euro-
significantly more than the placebo group (66.7% vs. 5.4%, paeum plant delivered intranasally is thought to have beneficial
p<0.0001). Substantial radiographic improvement was noted in effects in relieving congestion by facilitating nasal drainage
significantly more patients in the sinfrontal group compared to and has an anti-inflammatory effect. Cyclamen europaeum
placebo (77.2% vs. 21.4%, p<0.0001). By day 7, 52.6% of patients nasal spray as an adjunct to medical therapy (amoxicillin 500mg
in the sinfrontal group were able to carry out daily activities three times daily for days) was compared to placebo in 99
compared to the 17.9% in the placebo group. The mean change patients with post-viral rhinosinusitis(290). There was no diffe-
for the EQ-VAS was significantly different for the sinfrontal group rence between the groups for change mean rhinosinusitis visual
compared to the placebo group (17.3±9.1 vs. 6.2±8.1, p<0.01). analogue scale scores of total symptom, nasal obstruction,
Seven patients (6.3%) had adverse events during the study. Six facial pain or pressure, smell dysfunction, mucous secretions or
patients (10.5%) in the active medication group and one (1.8%) sleep quality after 5-7 days. Similar trends were observed at day
in the placebo group had adverse events and these were most 12-15. Of note, a reduction in facial pain significantly favoured
commonly gastrointestinal complaints. The events were most cyclamen europaeum (MD: -1.20, [-2.32, -0.08]; p=0.04) for the
often connected to symptoms from lactose exposure as this was per protocol-population after five to seven days. Endoscopic
one of the main constituents of sinfrontal and the placebo. This evaluation demonstrated that mucus oedema or nasal obstruc-
study was also evaluated from a health economic perspective. tion was reduced to a significantly greater extent with cyclamen
Sinfrontal led to incremental savings of 275 euros (95% CI 433, europaeum than placebo after 5-7 days (MD: -0.76, [-1.44 to
103) per patient compared with placebo over 22 days, essential- -0.08]; p<0.03). There were no significant between group diffe-
ly due to the markedly reduced absenteeism from work (7.83 vs. rences for mucopurulent secretion scores in the middle meatus
12.9 workdays). Incremental utility amounted to 0.0087 QALYs at any time points evaluated. No patients needed additional
(95% CI 0.0052, 0.0123), or 3.2 quality-adjusted life-days (QALDs) treatment for rhinosinusitis during the study, and there were no
(286)
(Table 4.6.7.). medical complications associated with progression of ARS. Ad-
verse events were reported by 67% of the cyclamen europaeum
4.6.13.2. Conclusion group and 29% of placebo recipients but no serious adverse
We found one study evaluating the effect of homeopathy (sin- events were reported. A DBPC study of cyclamen europaeum
frontal) and showing a significant reduction of symptoms and versus placebo in a subgroup of 29 patients with presumed
radiographic improvement versus placebo. Based on the limited (post)viral rhinosinusitis showed a comparable improvement
evidence the EPOS2020 steering cannot give clear advice on the in total symptom scores but a significant difference between
use of homeopathy in acute post-viral rhinosinusitis. treatment groups in change in percent of sinus opacification in
favour of cyclamen. More treatment-related adverse events were
4.6.14. Herbal compounds reported in the placebo group (37.5%) than in the cyclamen
group (15%). As the two studies were very different no meta-
4.6.14.1. Summary of the evidence analysis could be performed.
Herbal compounds have been extensively explored in the treat- Pelargonium sidoides (P. sidoides), is an herbal remedy thought
ment of upper respiratory tract diseases. Numerous randomized to be effective in the treatment of upper respiratory infecti-
studies, of varying quality, have been performed to assess the ons(292). Only one RCT has evaluated its efficacy in 103 patients
efficacy and safety of herbal compounds in the treatment of vi- with presumed post-viral ARS(291). Patients were randomized to
ral, post-viral and acute bacterial ARS. However, in many studies receive P. sidoides 60 drops orally three times daily or a matched
it is unclear which groups of ARS patients have been studied. placebo for a maximum of 22 days. The mean decrease in the
We found six DBPC randomized studies of the efficacy of herbal sinusitis severity score at day 7 was 5.5 points in the P. sidoides
compounds in the treatment of presumed post-viral ARS (Table group and 2.5 points in the placebo group (between group dif-
4.6.13.). Of these six trials, in four trials it is however unclear ference of 3.0 points; 95% CI [2.0 to 3.9]; p<0.0001). Significant
what the exact ARS phenotype of the patients was(228, 287-289). treatment effects were also observed for SNOT-20 (0.6 vs. 0.2;
In these studies the duration of the symptoms after the acute p< 0.0001), EQ-VAS (18.1±14.1 vs. 5.1±11.0; p<0.0001) by day 7
onset was often not indicated and some patients were included in the P. sidoides group versus placebo. Similarly, the duration
that had signs that could point to ABRS such as high fever, or of days patients were unable to work (8.7±6.4 vs. 15.9±11.8;
severe unilateral pain(228, 287). The only two studies that clearly in- p=0.002), the number of patients able to work or engage in

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Table 4.6.13. Herbal compounds versus placebo in acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Pfaar DBPCT Adults with acute post-viral • Cyclamen europaeum • TSS on day 5-7 (VAS) Compared to placebo, cyclamen
2012(290) rhinosinusitis (n=99) nasal spray (1.3mg) once • Individual symptom europaeum resulted in:
daily each nostril for 15 scores (nasal congestion, • Improvement in mean patient
days (n=48) mucus secretion, facial (p=0.03) and investigator-satis-
• Placebo for 15 days (n=51) pain, impairment of smell) faction scores (p=0.04)
All patients received on day 5-7 and 12-15 (VAS) • No difference for change mean
Amoxicillin 500 mg 3 times • Endoscopic findings on TSS, nasal obstruction, facial
daily for the first 8 days day 5-7 and 12-15 pain or pressure, sleep quality
• Treatment failure/need for (VAS), or endoscopic mucopuru-
additional treatment lent secretions
• Onset of medical compli- • Improvement in endoscopic
cations of rhinosinusitis scores for nasal obstruction/mu-
• Sleep quality cus oedema at 5-7 days (p=0.03)
• Overall patient- and • No patients needed additional
investigator-assessed treat- treatment for rhinosinusitis
ment satisfaction during the study, medical
• Safety assessment complications associated with
progression of ARS
• Adverse events were reported
by 67% of the cyclamen euro-
paeum group and 29% of pla-
cebo recipients but no serious
adverse events were reported.

Ponikau DBPCT Adults with acute (post) • Cyclamen europaeum • Percent sinus opacifica- • Significant improvement in
2012(287) viral rhinosinusitis (n=29) nasal spray (2.6mg) once tion on CT scans at days 15, percent of sinus opacification in
daily each nostril for 7 days 29 or endpoint favour of cyclamen (p=0.045).
(n=24) • Reduction in TSS at • Comparable improvement in
• Placebo spray sterile endpoint total symptom scores.
water, once daily for 7 days • Endoscopic inflammation • More treatment-related
(n=24) at day 7 adverse events in the placebo
group (37.5%) vs. cyclamen
group (15%).

Bachert DBPCT Adults with mostly • Pelargonium sidoides (P. • SSS at day 7 Compared to placebo, P. sidoi-
2009(291) symptoms of acute (post) sidoides) 60 drops orally • Radiographic cure at day des demonstrated:
viral rhinosinusitis although three times daily for maxi- 21 • Greater reduction in sinusitis
some of the patients could mum 22 days (n=51) • SNOT-20 at day 7 severity score (p<0.0001) SNOT-
have had ABRS (n=103) • Matched placebo three • EQ-VAS on day 7 20 score (p<0.0001)
times daily for maximum 22 • Activity level on day 7 • Decrease in duration of inabi-
days (n=52) • Ability to work or engage lity to work (p=0.002)
in usual activities on day 7 • Increase in subjects able to
• General well-being on work or engage in usual activi-
day 7 ties (p=0.003), and subjects as-
• Patient and investigator- sessed as a ‘major improvement’
reported treatment on IMOS (p <0.0001) on day 7
outcome on the IMOS • Radiographic improvement in
• Safety assessment the maxillary sinuses (p=0.002)
• No significant radiographic
improvement in the frontal or
ethmoid sinuses at day 21

Federspil Rando- Patients with acute • Myrtol standardized 4 • Difference in symptoms • Myrtol standardized and the
1997(288) mized, (post(viral) rhinosinusitis capsules of 300mg daily, for score before and after treat- other essential oil proved to be
double- (n=331) 6±2 days (n=109) ment at 14 days significantly superior to placebo
blind, • Essential oil (unregistered) • Tolerance was slightly better
double- 4 capsules of 300 mg daily, for myrtol standardized in com-
dummy, for 6±2 days (n=110) parison to the essential oil
trial • Matched placebo, 4
capsules daily for 6±2 days
(n=111)
All patients received xylo-
methazoline 4dd2 puffs

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Table 4.6.13. Herbal compounds versus placebo in acute post-viral rhinosinusitis (continued)..

Study Methods Participants Interventions Outcomes Results

Neubauer DBPCT Patients with acute • Sinupret 2 tablets three • Patient assessment of the Compared to placebo, Sinupret demon-
1994 (289) (post(viral) rhinosi- times daily for 14 days therapy (three categories: strated
nusitis (n=160) (n=81) asymptomatic/good ef- • Greater improvement in patient-repor-
• Placebo (sugar-coated fect/no effect) at 14 days ted complete resolution of symptoms
tablets) 2 tablets three • Clinical symptoms of (p=0.0002)
times daily for 14 days rhinosinusitis at 14 days • Improvement in radiographic findings
(n=79) • Radiographic finding after 14 days of treatment (p=0.02)
All patients received (completely opaque/sha- • Effect on nasal obstruction and mucous
doxycycline and xylome- dowed/nothing abnormal) swelling
talzoline • No difference in response rates for
nasal patency, nasal discharge or
headaches.

ABRS, acute bacterial rhinosinusitis; ARS, acute rhinosinusitis; DBPCT, double blind placebo controlled trial; EQ-VAS: Euroqol visual analoque score;
IMOS, ‘Integrated Medicine Outcomes Scale’; SNOT-20, Sino-nasal Outcome Test-20; SSS, Sinusitis Severity Score; TSS, total symptom scores.

usual activities (32 [63%] vs. 19 [37%]), and the number of headaches (0.15 [0.00, 0.3]). The efficacy of Sinupret was com-
patients improved from sleep disorders (40 [82%] vs. 27 [54%]; pared in one study to fluticasone furoate (Table 4.6.14.)(293). Sixty
p=0.003) on day 7 favoured P. sidoides. The investigator assessed patients with ARS were randomized to Sinupret or intranasal
the treatment outcome as a ‘major improvement’ in 15 (30%) in fluticasone furoate for 14 days. No differences between the two
the P. sidoides group, compared to three (5.8%) patients in the groups were found, most likely due to type II error. No adverse
placebo group (p< 0.0001) and treatment outcome assessment events were reported in the Sinupret group. Among the patients
by the patients yielded to a similar pattern in favour of the P. that received fluticasone furoate, three patients reported minor
sidoides group. Results also indicated a statistically significant adverse events (epistaxis and nasal itching).
superiority of P. sidoides for radiographic improvement in the
maxillary sinuses (24 [69%] vs. 22[44%]; p=0.002). Six patients 4.6.15. Vaccination
(11.8%) reported non-serious adverse events in the P. sidoides There are no RCTs which demonstrate a direct effect of vacci-
group compared to two patients (3.8%) in the placebo group. nation on post-viral ARS. A systematic review which examined
Federpil et al.(288) studied the efficacy of myrtol, an herbal extract inactivated parental influenza virus vaccination reported 59%
from essential oils, as a therapeutic alternative for acute rhino- efficacy in preventing confirmed influenza (RR 0.41 95% CI 0.36-
sinusitis (n=331), in comparison to placebo and other essential 0.47)(294). The pneumococcal vaccine also led to decrease in inva-
oils. The results showed a statistically significant improvement of sive diseases (meningitis, bacteremia) and acute otitis media(295)
total rhinosinusitis symptoms score in the myrtol standardized but there was no data on decrease of ABRS or post-viral ARS(296).
group and the other essential oils group compared to placebo There has been a shift in the organisms involved in ARS after
at 14 days (10.5 vs. 9.2 points) without difference between the the Heptavalent conjugate pneumococcal vaccine (PCNV7) was
myrtol and the other essential oils. introduced with decreased isolated streptococcus pneumoniae
BNO 1016 (Sinupret), an extract of five herbal drugs (gentian but increased in isolated Haemophilus influenza culture among
root, primula flower, sorrel herb, elder flower, and verbena herb) adults with acute maxillary sinusitis(297). How this will impact oc-
that has demonstrated antimicrobial and antiviral activity, has currences of ABRS is still under speculation(296, 298).
been investigated in common cold (see Chapter 4.6.17.). One
study from Neubauer et al.(289) randomized 160 patients with 4.6.16. Sodium hyaluronate
symptoms and signs indicative of acute post-viral rhinosinusitis One study evaluated 48 patients with ABRS following EPOS
into Sinupret or placebo in addition to doxycycline and xylome- criteria that were treated with high molecular weight sodium
tazoline. A greater percentage of patients in the Sinupret group hyaluronate (3%) plus saline solution (3mL sodium chloride-
reported complete resolution of symptoms (60.3% vs. 25.0%; NaCl-0.9 %) versus placebo using a nebulizer ampoule for nasal
p=0.0002) and were observed to have improvement in radio- douching twice a day(299). All patients received Levofloxacin
graphic findings after 14 days of treatment (84.0% vs. 68.4%; (500mg for 10 days) and Prednisone (50mg for eight days, 25mg
p=0.02) than in the placebo group. While Sinupret demonstra- for four days and 12, 5mg for four days). The hyaluronate group
ted a small but significant effect on nasal obstruction (difference compared to placebo had significantly fewer symptoms and
in response rates: 0.23, [0.09, 0.39]) and mucous swelling (0.32 better smell threshold (Table 4.6.15.).
[0.17, 0.46]), there was no difference in response rates for nasal In conclusion, sodium hyaluronate may have an additive effect
patency (0.10 [-0.05, 0.26]), nasal discharge (0 [-0.17, 0.20]) or to antibiotics in patients with ABRS.

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Table 4.6.14. Herbal compounds versus corticosteroids in acute post-viral rhinosinusitis.

Study Methods Participants Interventions Outcomes Results

Passali Randomi- Adults with acute • Sinupret Forte 1 tablet • MSS according to the investiga- • No statistical analyses
2015(293) zed, pros- (post)viral rhinosinu- 3 times a day for 14 days tor at day 3, day 7, 10, and 14 performed.
pective, sitis (n=60) (n=30) • SNOT- 20 score at day 3, day 7, • Comparable mean major
open-label • FFNS 55 µg in each nos- 10, and 14 symptom score, SNOT-20
study tril, once a day for 14 days • Concomitant medication for the score, and percentage of
(n=30) treatment of acute rhinosinusitis patients at 14 days.
• Premature termination due • No adverse events were
to antibiotic therapy for acute reported in the Sinupret
rhinosinusitis group.
• Percentage of patients with MSS • Three patients in the FFNS
≤1 at day 14 treatment group reported
• Percentage of patients with MSS minor adverse events (epis-
>1 at day 14 taxis and nasal itching).
• Safety assessment

MSS, major symptom scores; SNOT-20, Sino-nasal Outcome Test-20.

Table 4.6.15. Sodium hyaluronate versus placebo in ABRS.

Study Methods Participants Interventions Outcomes Results

Ciofalo DBPCT Adults with ABRS (EPOS • Sodium hyaluronate (3%) At 14–18 days and 30–35 The hyaluronate group compared
2017(299) criteria, details not plus saline solution (3mL days: to placebo had:
given) (n=48) sodium chloride-NaCl-0.9 • Symptoms (0-3) • Significantly less nasal obstruc-
%) twice daily (n=24) • Smell (0-3) tion at 14 days
• Placebo using a nebulizer • Smell test (threshold, dis- • Significantly less nasal discharge
ampoule for nasal douche crimination, identification)• at both time points
twice a day (n=24) Mucociliary clearance time • Better smell (0-2) at 14 days but
All patients received not at 30 days
levofloxacin (500 mg for • Significantly better median
10 days) and prednisone threshold smell score at both time-
(50 mg for 8 days, 25 mg points but no other differences in
for 4 days and 12, 5 mg for smell testing
4 days) • Significantly better mucociliary
clearance time at both timepoints

ABRS, acute bacterial rhinosinusitis; DBPCT, double blind placebo controlled trial.

Table 4.6.16. Mucolytics versus placebo in ABRS.

Study Methods Participants Interventions Outcomes Results

Unuvar DBPCT Children (8.5 ± 3.2y) (81 • Erdosteine (5-8mg/kg/ • Cure at day 14 • No difference between
2010(300) evaluated) with ABRS day) (n=49) • Daily general impression the treatment groups
(n=92) • Placebo (n=43) for 14 days
All patients received antibi- • Daily symptoms for 14
otics, dosage and duration days
unclear

ABRS, acute bacterial rhinosinusitis; DBPCT, double blind placebo controlled trial.

4.6.17. Mucolytics 4.7. Complications of acute bacterial rhinosinusitis

To evaluate whether mucolytic agents have an adjuvant role (ABRS)
with antibiotics in the treatment of children with ABRS, Unuvar
et al. evaluated the effectiveness of Erdosteine (5-8 mg/kg/day) The complications of ABRS refer to periorbital, endocranial
versus placebo as an adjunct to antibiotic in 92 children (age 8.5 and osseous clinical conditions which are uncommon poten-
± 3.2 years) with ABRS(300). They found no significant difference tially life-threatening events. The periorbital complications
between the groups (Table 4.6.16.). include preseptal cellulitis, orbital cellulitis, subperiosteal and
intraorbital abscess; rapid diagnosis and treatment (including

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intravenous antibiotics and / or surgical drainage) is imperative per year (see Table 4.7.1.) despite very different utilization of
to avoid long-term morbidity and mortality. The endocranial antibiotics in the various countries and this number has not
complications include epidural empyema, subdural empyema, been reduced by the advent of widespread antibiotic prescri-
brain abscess, meningitis, encephalitis, superior sagittal and bing. In patients who are hospitalized with ABRS, the reported
cavernous sinus thrombosis. These may present with non- rate of complications varies from approximately 3% to 20%(12,
specific signs and symptoms and diagnosis requires high clinical 320, 321)
, although there is selection bias and thus existing series
suspicion from practitioners, especially in children. Osseous likely overestimate the incidence of those complications. The
complications result from osteomyelitis and may present as a highest number of admissions occurs from January to March(173,
subperiosteal frontal bone abscess (Potts Puffy tumour) or a 310)
. Seven studies (until 2019), attempting to collect nationwide
frontocutaneous fistula. The quantity and quality of high-quality or large-scale data were identified and the incidence results are
studies is restricted, in part due to the frequency and emergen- briefly summarized below (Table 4.7.1.). In the majority of these
cy nature of many of the problems. studies, males are significantly more frequently affected than
females and ABRS was more often the precipitating factor in
There are still cases in which acute bacterial sinus children, whereas CRS with or without NP was more important
infection is associated with complications which in adults(173, 301, 322, 323). In all studies, the orbital complications are
can be due to sporadic, untreated or treated the most frequent while osseous appear to be relatively uncom-
microbial infections. mon (Table 4.7.1.).

4.7.1. Introduction The incidence of ABRS complications has been

Despite the advent and broad use of antibiotic therapy during shown to be approximately three per million of the
the last six decades, complications of rhinosinusitis still cause population per year despite very different
substantial morbidity and occasionally mortality. Due to con- utilization of antibiotics in the various countries
temporary diagnostic modalities [mainly CT and Magnetic Reso- and this number has not been reduced by the
nance Imaging (MRI)] and improved surgical techniques (mainly advent of widespread antibiotic prescribing.
endoscopic sinus surgery) incidence and related morbidity and
mortality from complications of bacterial rhinosinusitis have With regard to age predeliction, orbital complications seem to
dramatically decreased. However, there are still cases in which be more common in small children while intracranial complicati-
acute bacterial sinus infection is associated with complications ons can occur at any age, with a preponderance of young adults
which can be due to sporadic(12), untreated or treated microbial around their 20th birthday(301, 324). The course of ABRS complica-
infections(301-303) or they could be overlooked due to lack of avai- tions has been reported to become more prolonged in parallel
lability of contemporary diagnostic and therapeutic modalities with the age of the patients(311, 323).
in certain populations(304, 305). Other cases include those patients It is important to note that three studies in ABRS patients(301, 311,
in whom prescription of oral antimicrobial agents is contraindi- 322)
did not record any benefit for history of oral antimicrobial
cated such as pregnant women(306-308). Complications of ABRS are drug usage prior to the development of the complications. In
typically classified as orbital (approximately 60-80%), intracra- this regard the study by Babar-Craig(12), which was based on
nial (approximately 15-20%) and rarely osseous (approximately returned questionnaires by members of the British Rhinology
5%)(302, 309-317) (Table 4.7.1.).though occasionally some unusual Society also showed that prescribing of antimicrobials for ABRS
complications can develop (see below and Table 4.7.5.)(302, 303, does not prevent the occurrence of complications. These facts,
318, 319)
. Recently a cohort study even associated acute bacterial together with the risk of antibiotic resistance and possible
rhinosinusitis with an increased risk for stroke(318). Although a masking of intracranial complications argue strongly against
cohort design is adequate to document causality, more studies the routine use of antibiotics in ABRS(302). These studies also
are necessary to classify stroke as a complication of chronic or emphasise the need to be constantly vigilant for complications
untreated rhinosinusitis(318). irrespective of whether antibiotics are being taken or not and
4.7.2. Epidemiology of complications complications may occur before the patient is seen in primary
Evidence with regard to the incidence and prevalence of the care.
complications of rhinosinusitis is patchy and there is no consen-
sus on the exact prevalence of the different types of complicati- Taking oral antibiotics did not provide any
ons. Furthermore, the causal link between the microbial sinus in- advantage in the prevention of complications.
fection and the reported complications is rarely if ever reported
in the literature. The incidence of ABRS complications has been
shown to be approximately three per million of the population

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Table 4.7.1. Epidemiological data of complications in ABRS.

Author, Country Age Disease Patients (Incidence per Orbital Intracra- Bone Soft
year, ref. million population nial tissue
per year)
Dennison Sweden Children ABRS 29 100%
2019(328)
El Mograbi Israel Adults ABRS + 70 100% 2.8%
2019(322) CRS (70) concur-
rent (2)
Hamill USA Children ABRS 250 61.6% 11.6%
2018(364) (154) (29)
Scholin Ask Sweden Children ABRS + 213 3.6 (orbital only) 80%
2017(323) CRS Hospitalization boys 171
5.3, girls 3.6
Nicoli Finland Adults / ABRS 3.2 (intracranial 6
2016(383) children only)
Chaiyasate China Adults / ABRS 1655 85 patients with 41 24 2 3
2015(312) children complications
Capra USA Children ABRS 0.738 children in
2015(320) 2000 and 0.605 in
2009
Miah UK Adults / ABRS 31/248 21 9
2015(314) children
Sedaghat USA Children ABRS 696 90.2% 9.8%
2014(317)
Hansen Netherlands (Natio- Adults / ABRS 48 (48/16.3 million=3 ) 67% 33%
2012(301) nal Database 2004) children (32) (16)
Piatt USA – National in- Children ABRS 695 2.7 – 4.3
2011(384) patient database
(1997, 2000, 2001,
2003, 2006)
Babar-Craig UK – national Adults / ABRS 78 N/A 76% 9% 5%
2010(12) ques-tionnaire children
Stoll 2006(14) France (2001-2003) Adults and ABRS 43 (30/12 million= 2.5) 35% 37% 18%
adolescents (15) (16) (8)
Oxford USA Children ABRS/CRS 104 N/A 91% 16% 3%
2005(316) (95) (17) (3)
Eufinger Germany Adults / ABRS 25 N/A 88% 20% 2 pat.
2001(313) children (22) (5) (had
both)
Mortimore South Africa Adults / ABRS/CRS 63 N/A 81% 13% 10% 24%
1997(315) children (51) (8) (6) (15)

ABRS, acute bacterial rhinosinusitis; CRS, chronic rhinosinusitis; N/A, not applicable.

4.7.3. Orbital complications of AΒRS symptoms so it is mandatory to have a high level of clinical sus-
picion for the possibility of orbital complications in children with
4.7.3.1. Classification ABRS. Hospital admission due to acute rhinosinusitis in children
Orbital complications, the most commonly related to ABRS, decreased after the introduction of pneumococcal conjugate
involve (in decreasing frequency) the ethmoid, maxillary, frontal vaccine but there was no parallel decrease in the incidence of
and rarely the sphenoid sinuses (Table 4.7.2.). The infection orbital complications(328, 329).
spreads directly via the thin and often dehiscent lamina pa- Despite the fact that the Chandler’s classification is widely
pyracea or a pre-existing anatomical abnormality in cases of used, it does present some problems. The orbital septum is the
recurrent periorbital cellulitis or through venous return(302, 303, anterior limit of the orbit, therefore it has been suggested that
309)
. Orbital complications commonly affect children(322, 323, 325-327) pre-septal cellulitis should be classified as an eyelid, rather than
a population which is known to express fewer clinical signs and an orbital infection(302). In this regard it has been argued that

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pre-septal cellulitis is infrequently associated with rhinosinusitis dacryocystitis or skin infection while rhinosinusitis is an uncom-
and its clinical picture, its management and its prognosis dif- mon cause(302, 315, 326). Pre-septal cellulitis presents with orbital
ferentiate it from all other orbital infections(302). It has been sug- pain, eyelid oedema, erythema and fever. On clinical examina-
gested that orbital involvement (more appropriately: post-septal tion there may be no evident proptosis and no limitation of eye
cellulitis) presents with swelling, exophthalmos and impaired, movement. Of note these signs of proptosis and limited eye
painful extra-ocular eye movements with diplopia. With the ex- movement can be difficult to assess in paediatric patients(325, 326,
ception of swelling, these features are not present in pre-septal 337)
. Most cases of pre-septal cellulitis respond to oral antibiotic
cellulitis and differentiate it from true orbital infections(302). Ad- therapy but if not timely and appropriately treated, they can
ditionally, cavernous sinus thrombosis, as has been suggested spread beyond the orbital septum(334, 335, 338). In most cases, pre-
by Mortimore in 1997(315) is an intracranial complication and not septal cellulitis is a clinical diagnosis and due to the superficial
necessarily the end stage of orbital infection, while it is more nature of the inflammation, CT scan is not necessary(302, 336).
often associated with sphenoid rather than ethmoid or frontal
sinus infection(302). 4.7.3.3. Orbital cellulitis
According to Chandler’s classification, orbital complications may Orbital cellulitis, orbital abscess and subperiosteal abscess are
be divided into five stages based on their clinical and radiologi- all complications that are more commonly associated with acute
cal findings(309): rhinosinusitis, in contrast with pre-septal cellulitis which more
commonly occurs following upper respiratory tract infections
• Stage 1: pre-septal cellulitis (see above)(302). As the inflammation spreads through the orbit,
• Stage 2: orbital cellulitis proptosis (a protruding eyeball) develops together with some
• Stage 3: subperiosteal abscess limitation of ocular movement (diplopia can present in extreme
• Stage 4: orbital abscess gaze) indicating orbital cellulitis. Other typical signs of orbital
• Stage 5: cavernous sinus thrombosis cellulitis are chemosis (conjunctival oedema), ocular pain and
tenderness, as well as ophthalmoplegia (restricted and painful
Because Chandler’s classification remains the most commonly ocular movement) of the extraocular muscles(302). This com-
used and because we attempted to summarize the evidence plication requires immediate and aggressive treatment with
from a number of papers, past and present, we still employ this intravenous antibiotics and should be referred for detailed CT
classification in Table 4.7.2., although it was also debated in scan with contrast of the sinuses to distinguish between orbital
EPOS 2012(302). cellulitis, intraorbital or subperiosteal abscess(336). However, there
Periorbital or orbital cellulitis may result from direct or vascu- should be close monitoring for progression with a low threshold
lar spread of the sinus infection(330-335). As the spread of sinus for surgical intervention as the few who do not respond to anti-
infection through the orbit follows a well-described pattern, the biotic therapy can progress rapidly over 24–48 h. In cases where
initial manifestations are oedema and erythema of the medial a concomitant intracranial complication is also suspected, MRI
aspects of the eyelid. Spread of infection from the maxillary scan better diagnose orbital complications(313, 338-340). All three
or the frontal sinus results in initial presentation with swelling complications (orbital cellulitis, subperiosteal and intraorbital
of the lower or upper eyelid, respectively. Consultation with abscess) cause eyeball proptosis and limit ocular movement.
an ophthalmologist, in some cases twice daily, should always Evidence of an abscess on the CT scan, progressive orbital
be sought for clinical and medicolegal reasons and objective findings or visual deterioration after initial intravenous (i.v)
assessment of proptosis (exophthalmometer), orbital pres- antibiotic therapy should be considered as indications for orbital
sure (tonometer), visual acuity, colour vision (an important and exploration and drainage (see below). Repeated ophthalmologic
early sign of deterioration) and eye movements should always examinations of visual acuity should take place and i.v. antibio-
be clearly documented(302, 315, 319). Snellen charts can be easily tic therapy may be converted to oral when the patient has been
downloaded as free-of-charge android applications and are a afebrile for 48 hours and the ophthalmological symptoms and
quick and reproducible way of assessing visual acuity and colour signs are resolving(302, 337, 341, 342).
vision by the non-expert. Indications for surgical intervention in orbital complications of
ABRS:
4.7.3.2. Preseptal cellulitis • Evidence of subperiosteal or intraorbital abscess in CT or
Preseptal cellulitis refers to the inflammation of the eyelid and MRI (with potential exception for small volume abscesses).
conjunctiva and involves the tissues anterior to the orbital sep- • Reduced visual acuity/reduced colour vision/affected af-
tum. It can be identified on the CT scan as soft tissue swelling. ferent pupillary reflex or inability to assess vision.
The MRI T2 sequence is better in presenting the inflammation • Progression or no improvement in orbital signs (diplopia,
in the soft tissues(336). It can occur as a complication of a URTI, ophthalmoplegia, proptosis, swelling, chemosis) after 48

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Table 4.7.2. Orbital complications of ABRS.

Author, N Age Disease Type of Management

year, ref. complications
Tachibana 21 Adults / children ABRS/CRS Preseptal cellulitis (4) Surgical (23.8%)
2019(311) Postseptal orbital cellulitis (8)
Subperioteal abscess (9)
Trivic 61 Children ABRS Preseptal cellulitis (50.0%) Medical and Surgical
2019(346) Orbital cellulitis (50%)
El Mograbi 70 Adults ABRS/CRS Preseptal/orbital cellulitis (61.5%) Medical only
2019(322) Orbital cellulitis (23%) Medical only
Subperiosteal abscess (11%) Surgical, ESS (5), ESS & EXS (2)
Orbital abscess (3%) Surgical, ESS (1), ESS & EXS (1)
Cavernous sinus thrombosis (1.5%) Surgical, ESS (1)
Jabarin 123 Children ABRS Preseptal cellulitis (57%) Medical only
2019(344) Orbital cellulitis (1.5%) Medical only
Subperiosteal abscess (41.5%) Medical (29), Surgical (24)
Gavriel 37 Adults ABRS Preseptal cellulitis (49%) Medical only
2018(341) Subperiosteal abscess (51%) Medical (12), Surgical (7)
Scholin Ask 203 Preschool children ABRS Preseptal cellulitis (96.5% ) Medical only
2017(323) Orbital cellulitis/Subperiostal abscess (2.0%) Medical only
Orbital abscess (1,5%) Medical (2), Surgical (1)
Chang 71 Adults / children ABRS/CRS Preseptal cellulitis (47%) Surgical (13)
2017(334) Orbital cellulitis (9.6%) Surgical (3)
Subperiosteal abscess (19.3) Surgical (13)
Orbital abscess (9.6%) Surgical (6)
Li 28 Children Preseptal cellulitis (1) Medical only (8)
2017(385) Orbital cellulitis (9) Medical and Surgical (20)
Subperiosteal orbital abscess (13)
Orbital abscess (5)
Wan 31 Children ABRS Preseptal cellulitis (4 ) Medical (16)
2016(325) Orbital cellulitis (14) Surgical (15)
Subperiosteal abscess (13)
Miah 31 Adults / children ABRS Periorbital cellulitis (16)
2015(314) Orbital abscess (6)
Intracranial abscess (9)
Radovani 35 Adults / children ABRS Preseptal cellulitis (15) Medical (12)
2013(335) Orbital cellulitis (10) Medical + surgical (3)
Subperiosteal abscess (6) Surgical
Orbital abscess (3) Surgical
Cavernous sinus thrombosis (1) Surgical
Surgical
Al-Madani 35 Adults / children ABRS Preseptal cellulitis (26) All medical
2013(333) Orbital cellulitis (8) Surgical (1)
Orbital abscess (2)
Huang 64 Children ABRS Subperiosteal/intraorbital abscess 56% (36) Medical only: 53% (34)
2011(343) Preseptal/orbital cellulitis 44% (28) Medical and surgical: 47% (30)
Georgakopoulos 83 Children ABRS/CRS Preseptal cellulitis 83% (69) Medical only: 95% (79)
2010(326) Orbital cellulitis 12% (10) Surgical and medical: 5% (4)
Subperiosteal abscess 5% (4)
Siedek 127 Adults / children ABRS/CRS Preseptal cellulitis 36% (46) Medical only: 51% (65)
2008(345) Orbital cellulitis 44% (56)
Subperiosteal abscess 6% (8) Surgical: 49% (62)
Intraorbital abscess 14% (17)
Eviatar 52 Children ABRS Preseptal cellulitis 92% (48) Medical only: 98% (51)
2008(338) Subperiosteal abscess 8% (4) Surgical: 2% (1)
Mekhitarian 25 Children ABRS Preseptal cellulitis 96% (24) Medical only: 92% (23)
2007(327) Subperiosteal abscess 4% (1) Surgical: 8% (2)
Oxford 43 Children ABRS Subperiosteal abscess 100% (43) Medical only: 42% (18)
2006(348)

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Table 4.7.2. Orbital complications of ABRS continued

Author, N Age Disease Type of Management

year, ref. complications
Mortimore 51 Adults / children ABRS Preseptal cellulitis 55% (28) Not stated
1997(315) Orbital cellulitis 10% (5)
Subperiosteal abscess 33% (17)
Intraorbital abscess 2% (1)

ABRS, acute bacterial rhinosinusitis; CRS, chronic rhinosinusitis.

hours intravenous antibiotics. abscess has been reported to be approximately 80% which rises
• Progression or no improvement in the general condition to approximately 90% with the addition of CT imaging. MRI may
(fever, infection parameters) after 48 hours of intravenous be useful in cases of diagnostic uncertainty after a CT scan or
antibiotics. when intracranial complications are suspected(348, 349).
Subperiosteal abscess in children is not an absolute indication
4.7.3.4. Subperiosteal and orbital abscess for immediate surgical intervention. Conservative measures
A subperiosteal abscess forms between the periorbita and the can be safe and effective if appropriately used, depending
sinuses and is located outside the ocular muscles (or extraconal). on patient characteristics, exam findings, clinical course, and
The clinical features of a subperiosteal abscess are oedema, imaging(350). An ophthalmologist should check visual acuity from
erythema, chemosis and proptosis of the eyelid with limitation the early stages of the illness. Intravenous antimicrobial therapy
of ocular motility and as a consequence of extra-ocular muscle should cover aerobic and anaerobic pathogens. Evidence of an
paralysis, the eyeball becomes fixed (ophthalmoplegia) and vi- abscess on the CT scan or absence of clinical improvement after
sual acuity diminishes. In most case series, high fever and raised 24-48 hours of i.v. antibiotics are indications for orbital explora-
leucocyte count as well as left shift (an increase in the number of tion and drainage(349). Depending on the radiographic volume of
immature leucocytes in the peripheral blood, particularly neu- the abscess, the decision to surgically explore may be prioritized
trophil band cells) have been reported as strongly associated if the volume appears to be large. In contrast, in small abscesses
with (subperiosteal or intraorbital) abscess formation(309, 311, 321, 322, the most prudent decision would be to continue i.v. antibiotics
325, 326, 333-335, 339, 341, 343-346)
. and monitor the patient(351). A current guideline mandates that
An orbital abscess is contained within the space defined by pre-septal and orbital cellulitis should be treated with antibi-
the ocular muscles and the eyeball ie intraconal and genera- otics while subperiosteal and intraorbital abscesses require
lly results from diagnostic delay, inappropriate antimicrobial surgical exploration which should include not just the drainage
treatment or immunosuppression of the patient(335, 341, 347) with of the abscess but also of the paranasal sinuses(302) as cellulitis
a frequency of between 1.5% and 14% (Table 4.7.2.) in paedia- can be expected to improve with proper antimicrobial therapy
tric studies of orbital complications. The clinical or radiological while drainage is the mainstay of treatment for any abscess.
evidence of an abscess or the lack of clinical improvement after The guideline recommends an endoscopic approach to open
24-48 hours of i.v. antibiotics are indications for prompt surgical the lamina papyracea and draining the abscess after complete
exploration and drainage, preferably via endoscopic approa- ethmoidectomy. External approaches to lateral and medial
ches. orbital abscesses (lateral and medial orbitotomy) can also be
As previously noted, a detailed CT scan of the sinuses with used if necessary. However, there have been a number of recent
contrast and possibly with 3D reconstruction may help to studies showing good outcomes with i.v. antibiotics in children
distinguish between cellulitis and orbital or subperiosteal with subperiosteal abscesses(302, 345, 347, 349). In such cases, and
abscess. In the case of a subperiosteal abscess, the CT usually provided there is(302): clear clinical improvement within 24-48
reveals oedema of the medial rectus muscle, lateralization of the hours; no decrease in visual acuity; small (<0.5-1 ml in volume);
periorbita and lateral downward displacement of the eyeball(336, medially located subperiosteal abscess; no significant systemic
337, 342)
. In cases where the CT scan shows obliteration of the involvement; the decision might be to withhold surgical drai-
detail of the extraocular musculature and of the optic nerve by nage and closely monitor the patient(341, 342). Importantly, it has
a confluent mass, the orbital cellulitis has progressed to an intra- recently been reported that the same conservative approach is
orbital abscess, in which case there may sometimes be air in the also valid for adult patients with orbital abscesses. Gavriel et al.
orbit due to the presence of anaerobic bacteria. The diagnostic reported a similar prognosis between conservative medical and
accuracy of clinical examination alone to determine an orbital surgical approach in the treatment of orbital abscesses for adult

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patients(341). Therefore, based on this evidence, adult patients . lnflammatory complications of the brain start as inflamma-
361)

may also be candidates for watchful waiting instead of endo- tion (ie encephalitis), which progresses to necrosis and lique-
scopic drainage. Blindness may result from central retinal artery faction of brain tissue, with a reactive connective tissue capsule
occlusion, optic neuritis, corneal ulceration, or panophthalmitis. forming around the brain abscess.
It is not infrequent for sepsis to spread intracranially as well as A CT scan with contrast, as a minimum, is required for diagnosis
anteriorly into the orbit(302, 303, 319). Patients with delayed admis- as it allows for precise definition of osseous tissue involvement.
sion and additional risk factors have a higher risk of irreversible MRI is considered to be the “gold-standard” as it is more sensitive
blindness(352). than CT and should be the imaging modality of choice where
available; further it has additional diagnostic value to exclude
Subperiosteal abscess in children is not an or confirm cavernous sinus thrombosis and also in cases with
absolute indication for immediate surgical soft tissue involvement(336, 357). Studies show a high incidence
intervention. Conservative measures can be safe of anaerobic organisms or mixed aerobic-anaerobic in patients
and effective if appropriately used, depending with endocranial complications. In cases where meningitis is
on patient characteristics, exam findings, clinical suspected and provided that any intracranial abscess has been
course, and imaging. definitely excluded by imaging, a lumbar puncture can be
performed to properly determine the underlying pathogens
4.7.4. Endocranial complications and to customize antimicrobial therapy(357). Pathogens most
Endocranial (or intracranial) complications of ABRS are epidural commonly isolated following lumbar puncture are Streptococ-
or subdural empyema, brain abscess, meningitis, cerebritis and cus and Staphylococcus species including methicillin-resistant ­
superior sagittal and cavernous sinus thrombosis (Table 4.7.3.). (MRSA) and anaerobes(363-365). High dose long-term i.v. antimi-
These complications may present with non-specific symptoms crobial therapy followed by neurosurgical burr hole drainage,
and signs of a systematic inflammatory response (high fever, craniotomy for evacuation of the abscess or image guided
headache, lethargy, reduced consciousness) or with specific aspiration, are usually required for successful treatment(312, 349, 354,
central nervous system signs due to focal neurologic damage or 359, 361)
. Current treatment involves joint neurosurgical drainage
increased intracranial pressure. Of note, it is not uncommon for procedures and drainage of the paranasal sinuses (most often
any of these complications to either present with non- specific the frontal sinus) can be performed endoscopically(359, 362, 366). The
symptoms including high fever accompanied by headache, or rationale is to evacuate the intracranial collection and manage
even to be silent(315). Although an intracranial abscess can be re- the source of infection using a rhinological approach which will
latively asymptomatic, subtle affective and behavioural changes provide microbiological samples. Lack of early sinus drainage
are not uncommon; these are signs of altered neurologic func- has been associated with the need for repeated craniotomies(357,
tion, orientation and cognitive state. Gait instability and severe, 366)
. The prognosis of intracranial complications of acute bacterial
progressive headache have also been reported to be common rhinosinusitis depends on the severity of neurological signs and
symptoms(302). The majority of the endocranial complications of on the delay in diagnosis and management(354, 366). The mortality
ABRS however, present with more specific signs and symptoms rate varies from 0% up to 19%(312, 361, 362, 367), (Table 4.7.3.), and
that suggest the intracranial inflammatory involvement, such as is related to cortical veins thrombosis and to cerebral vascular
nausea and vomiting, neck stiffness and altered mental state(301, infarction (357, 366).
312, 324, 347, 353-358)
. The clinical expression of subdural and epidural
empyema is different. Subdural empyema often presents with 4.7.5. Cavernous sinus thrombosis
neurologic symptoms as an emergency case. In contrast epidu- Cavernous sinus thrombosis is a rare complication and has been
ral empyema is more often diagnosed on imaging studies(359). estimated at a rate of less than 10% of all the intracranial com-
Intracranial abscesses often become apparent through signs of plications (Table 4.7.3.)(353, 356). The highly anastomotic venous
increased intracranial pressure, meningeal irritation and focal system of the paranasal sinuses allows retrograde spread of
neurologic deficit mainly of the third, sixth or seventh cranial infection to the cavernous sinus causing sepsis and multiple
nerves(301, 305, 316, 330, 347, 349, 360, 361). cranial nerve involvement(316, 330, 353, 356, 362, 368). Proptosis, ptosis,
Endocranial complications are usually associated with frontoet- diplopia, chemosis, involvement of the eye motor nerves and
hmoidal or sphenoid rhinosinusitis(312, 324, 354, 355, 357, 361, 362). Infecti- impairment in the ophthalmic and maxillary branches of cranial
ons can proceed from the paranasal cavities to the endocranial nerve V(1) (ophthalmic nerve neuralgia) papilloedema and signs
structures by two different routes: (a) haematologically – patho- of meningeal irritation associated with spiking fevers and pros-
gens can pass through the diploic veins to reach the brain; (b) tration establish the diagnosis(301, 356, 361). Symptoms start in one
tissue continuity spread – pathogens can reach the intracranial eye and progress to the other.
structures by eroding the thin osseous walls of the sinuses(354-356, Full blood count may show increased white blood cell count

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Table 4.7.3. Endocranial complications in ABRS.

Author, N Complications Management (all had Mortality / further defects

year, ref. medical therapy)
Mulvey 43 Meningitis (10) ESS (43) No mortality. 14 patients (16%)
2019(367) Epidural empyema (28) NS (23) were readmitted for worsening
Subdural empyema (19) symptoms or complications of
Intracerebral abscess (2) treatments.
Schupper 16 Epidural abscess (10) Simultaneous ESS and NS as first No mortality
2018(361) Subdural abscess (9) procedure (16)
Intracerebral abscess (3)
Multiple abscesses in 6 cases
Cavernous sinus thrombosis (2)
Kou 22 Subdural empyema (10) ESS (19) No mortality
2018(362) Epidural abscess (10) NS (8) Neurologic deficits 4.5% (short
Meningitis (5) Simultaneous ESS and NS (6) follow up average: 7 months)
Cerebral abscess (5)
Cavernous sinus thrombosis (2)
Patel 27 Epidural empyema (14) ESS (11) No mortality
2015(358) Subdural empyema (9) ESS and NS (18) Neurologic deficits cognitive/per-
Cerebral abscess (4) Only NS (3) sonality changes 33% (6 months
follow up)
Garin 17 Subdural empyema (9) ESS and NS (15) No mortality
2015(359) Epidural empyema (8) Only ESS (2) Cognitive and schooling problems:
subdural empyema 67%, epidural
empyema 29%
Khamassi 23 Subdural empyema (11) Medical therapy only (3) Mortality 8.7%
2015(366) Epidural empyema (7) NS (19) Morbidity 34.7%
Intracerebral abscess (5) ESS (1)
Cerebral thrombophlebitis (4)
Chaiyasate 24 Meningitis (13) Mortality 11.3%
2015(312) Brain abscess (5) Morbidity 25.3%
Cavernous thrombosis (8)
transverse sinus and sigmoid sinus
thrombosis (2)
superior sagittal sinus (1)
Deutschmann 50 Meningitis (23) Medical therapy only (23) No mortality
2013(365) Epidural abscess (10) NS (14) Morbidity 6%
Subdural abscess (8) ESS (8)
Intracerebral abscess (3) Other (5)
Cavernous sinus thrombosis (2)
Other (4)
Hansen 16 Subdural empyema (9) Mortality 19%
2012(301) Meningitis (3) Morbidity 19%
Epidural abscess (2)
Intracerebral abscess (2)
Encephalitis (1)
Superior sagittal sinus thrombosis (1)
DelGaudio 23 Epidural empyema (8) Only medical therapy (3) Mortality 4%
2010(355) Subdural empyema (10) ESS (1) Morbidity 12%
Intracerebral abscesses (2) NS (18)
Meningitis (3)
Bayonne 25 Epidural empyema Sequelae 16%
2009(354) Subdural empyema Mortality 0%
Meningitis
Germiller 25 (mean Epidural empyema (13) ESS (21) Morbidity 8%
2006(357) age 13y) Subdural empyema (9) EXS (7) Mortality 4%
Meningitis (6) NS (13)
Encephalitis (2)
Intracerebral abscess (2)
Cavernous sinus thrombosis (2)
Quraishi 12 (mean Frontal lobe abscess (2) Mortality 8%
2006(305) age 14 y) Subdural empyema (8) Morbidity 16 %
Cavernous sinus thrombosis (2)

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Table 4.7.3. Endocranial complications in ABRS (continued).

Author, N Complications Management (all had Mortality / further defects

year, ref. medical therapy)
Oxford 18 (mean Epidural empyema (7) No mortality
2005(316) age 12 y) Subdural empyema (6) Morbidity 11%
Intracerebral abscess (2)
Meningitis (2)
Cavernous sinus thrombosis (1)
Younis 39 Epidural empyema (7) Medical therapy only (21) Sequelae 10%
2002(349) Subdural empyema (4) NS (15) No mortality
Meningitis (21) EXS (4)
Intracerebral abscess (4) ESS (2)
Superior sagittal sinus thrombosis (1)
Jones 47 Subdural empyema 38% NS (47) Mortality 2%
2002(347) Meningitis 2% EXS (17) Morbidity 19%
Epidural empyema 23% ESS (6)
Intracranial abscess 30%
Albu 16 Meningitis (6) Mortality 6%
2001(353) Frontal lobe abscess (6) Morbidity 25%
Epidural empyema (5)
Subdural empyema ($)
Cavernous sinus thrombosis (2)
Gallagher 15 Meningitis 18% Mortality 7%
1998(356) Cerebral abscess 14% Morbidity 13%
Epidural empyema 23%
Clayman 24 Meningitis 29% Mortality 4%
1991(324) Cerebral abscess 46% Morbidity 33%
Epidural empyema 5%
Subdural empyema 8%
Cavernous sinus thrombosis 8%
Sagittal vein thrombosis 4%

ABRS, acute bacterial rhinosinusitis; CRS, chronic rhinosinusitis; ESS, endoscopic sinus surgery; EXS, external sinus surgery; NS, neurosurgical proce-
dures.

with left shift, C-reactive protein (CRP), erythrocyte sedimenta- no evidence of severe bleeding risk or current hemorrhage by
tion rate (ESR,) and D-dimer while lumbar puncture may show history, exam, and imaging) but the anticoagulation remains
elevated opening pressure and pleocytosis even in culture ne- controversial. Retrospective reviews suggest a possible decrease
gative samples whilst blood cultures are frequently positive(353, in mortality and reduction in neurologic morbidity when anti-
356)
. Screening for thrombophilia may give false results during coagulation is combined with antibiotics for septic cavernous
anticoagulation therapy and should be delayed until after treat- sinus thrombosis but without support from prospective clinical
ment is completed. trials(302) due to a lack of cases. Corticosteroids are often given
The cornerstone of diagnosis is an MR venogram, demonstrating with antibiotics but without proven efficacy. The potential be-
absence of venous flow in the affected cavernous sinus. High- nefit would be decreased inflammation and vasogenic oedema
resolution CT scan with contrast can also show filling defects(336, surrounding cranial nerves and orbital structures. Immediate
337)
. Previous articles described an approximate mortality rate endoscopic drainage of the affected sinus (almost always the
of 30% and a morbidity rate of 60% in the adult population but sphenoid) is mandatory.
more recent articles report better results(369). Lize et al. reported
seven patients who were treated for septic cavernous sinus 4.7.6. Osseous complications
thrombosis secondary to acute bacterial rhinosinusitis. All ABRS can also affect the bony sinus walls causing osteomyelitis
patients were treated with high dose i.v antibiotics, anticoagu- and subperiosteal abscess, eventually involving the brain and
lation therapy and endoscopic sinus drainage of the infected the nervous system. Even though the most frequent intracranial
sinuses. They described a mortality rate of 0% but one patient route of spread is from the frontal sinus, any sinus infection can
developed permanent unilateral visual loss and four permanent lead to osseous complications. The most common osseous com-
neurologic deficits(370). Most experts recommend anticoagula- plications is osteomyelitis of the maxillary (typically in infancy)
tion, in the absence of strong contraindications (only if there is or the frontal bones(330, 336, 365, 371).

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The frontal sinus infection can cause osteitis and osteomyelitis 4.7.7. Unusual complications of rhinosinusitis
of the frontal sinus walls and may develop into a subperiosteal A number of unusual complications have been reported in cases
abscess with soft tissue swelling and a doughy pitting oedema of patients with ABRS. These are presented in Table 4.7.4. It is
on the anterior wall (Pott's puffy tumour). A sino-cutaneaous important to note that the management of ABRS complications
fistula is a rarer presentation. Since the inflammatory process should always be multidisciplinary and close cooperation with
also extends posteriorly from the frontal sinus, directly or via other different specialties as ophthalmologists, neurologists/
thrombophlebitis of the valveless diploic veins, patients may neurosurgeons, paediatricians, radiologists and microbiologists
have concomitant complications, such as meningitis, epidural is mandatory.
and subdural empyema and brain abscess(316, 371, 372).
Leong(316, 371, 372) reviewed 29 cases of Pott’s puffy tumor (PPT) and 4.7.8. Follow-up of complications
the most common aetiology was acute frontal sinusitis (62%). ABRS complications may occasionally appear simultaneously
Bony complications develop in 3-10% of complicated ABRS (for example subperiosteal frontal abscess and intracranial ex-
cases(316, 371, 372). tension, orbital and intracranial complications) and intracranial
Signs and symptoms of intracranial involvement are soft tissue complications may have neurologic deficits. Therefore, a long
oedema (especially of the superior eyelid), high fever, severe term follow-up of 6-12 months is indicated for such patients in
headache, meningeal irritation, nausea and vomiting, diplopia, order to monitor for complete resolution of the disease as well
photophobia, papillary oedema, coma and focal neurological as to exclude any disease recurrence or complication of treat-
signs. Ocular signs can appear contralaterally as well. Contrast- ment. Meticulous care of the sinuses should be the first priority.
enhanced CT scan is needed to confirm the diagnosis. A lumbar
puncture is not indicated if the intracranial pressure is elevated, 4.7.9. Conclusion
but in certain cases it can also be of diagnostic value. Therapy Complications of bacterial rhinosinusitis are rare but potentially
originally included a combination of i.v. broad-spectrum antibio- serious. However, a number of studies have shown that they
tics administration and surgical debridement of sequestered are not prevented by routine prescribing of antibiotics so a low
bone and drainage(302, 321, 373). There is a growing body of evidence threshold of suspicion must always be maintained for their early
that uncomplicated PPT can be managed successfully via an en- diagnosis.
doscopic approach/minimal external drainage, combined with
long-term antibiotics(316, 371, 372).

There is a growing body of evidence that

uncomplicated PPT can be managed successfully
via an endoscopic approach/minimal external
drainage, combined with long-term antibiotics.

Table 4.7.4. Unusual complications of ABRS.

Author, year (ref.) Type of complication Outcome

Abou-Al-Ahaar 2019 (386)
Clival osteomyelitis with VI, XII nerve palsy Complete recovery after medical and surgical therapy
Fabre 2018 (387)
Acute Stroke Complete recovery after medical therapy and ESS
Righini 2009(388) Acute ischemic stroke Minimal neurologic sequelae after medical therapy and ESS
Sanan 2017 (340)
Stable ophthalmologic findings after medical therapy and
Intra-optic nerve abscess with vision loss
ESS
Korkmaz 2017(389) Isolated unilateral upper lid ptosis Complete recovery after medical therapy
Huth 2015(390) Thrombophlebitis temporal vein (without cavernous
Complete recovery after medical therapy and ESS
sinus thrombosis)
Tien 2016(391) Nasal septal abscess (5 cases) No morbidity after medical and surgical therapy
Zielnik-Jurkiewicz 2005 (392)
Nasal septal and palatine process abscess No morbidity after medical and surgical therapy
Gradoni 2010(393) Nasal septal abscess No morbidity after medical and surgical therapy
Nomura 2014 (394)
Orbital hematoma Complete recovery after medical therapy and ESS

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Table 4.7.4. Unusual complications of ABRS, continued.

Author, year (ref.) Type of complication Outcome

Nomura 2014 (394)
Complete recovery after medical therapy, ESS and superior
Orbital hematoma
orbitotomy
Yim 2013(395) Orbital abscess secondary to contralateral rhinosinu- Complete recovery after medical therapy, ESS and superior
sitis orbitotomy
Chan 2009(396) Toxic Shock Syndrome Complete recovery after medical therapy and ESS
Chen MC 2019(330) Septic shock Complete recovery after medical therapy and ESS
Rimal 2006 (332)
Septicaemia Complete recovery after only medical therapy
Suzuki 2005(360) Internal carotid artery aneurysm with multiple cranial Partial recovery of visual disturbance after endovascular coil
nerve palsy placement of the aneurysm
Patel 2003(397) Lacrimal gland abscess Complete recovery after medical therapy and drainage
Mirza 2001 (398)
Lacrimal gland abscess Complete recovery after medical therapy and ESS
Sidwell 2001(399) Pyoderma gangrenosum of the eyelid Scarring of the eyelid after medical therapy
Sahjpaul 1999 (400)
Pituitary abscess and cavernous sinus thrombophle- Blind right eye and pituitary insufficiency after medical
bitis therapy and ESS

ESS, endoscopic sinus surgery.

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344. Jabarin B, Marom T, Gavriel H, Eviatar E, Pediatric sinogenic epidural and subdural prescribing and referrals 2002-2008. Scand J
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345. Siedek V, Kremer A, Betz CS, Tschiesner U, of multiple cranial nerve palsy due to Laeknabladid 2010;96:531-5.
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orbital complications due to rhinosinusitis. aneurysm. Auris Nasus Larynx 2005;32:415- al. Sinusitis: bench to bedside. Current
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380. Louie JK, Hacker JK, Gonzales R, et al. Eur Ann Otorhinolaryngol Head Neck Dis Reconstr Surg 2013;29:e142-3.
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381. Varonen H, Rautakorpi UM, Huikko S, et al. 389. Korkmaz M, Güven M, Asil K. An Unusual Lacrimal gland abscess complicating acute
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386. Abou-Al-Shaar H, Mulvaney G, Alzhrani G, Endoscopic drainage of orbital subpe- 402. Hawke K, van Driel ML, Buffington BJ,
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5. Epidemiology, predisposing factors, pathophysiology ,

and diagnosis of CRS

5.1. Epidemiology and predisposing factors of scopy, and a symptom-based definition to be used in epide-
CRS miologic research, without radiologic imaging or endoscopic
examination(1). Due to the overlap of symptoms between CRS,
5.1.1.Epidemiology of CRS acute rhinosinusitis and (non-)allergic rhinitis, it can be difficult
The number of papers on epidemiology of chronic rhinosinusitis or maybe impossible to discriminate between these diagnoses
(CRS) is limited compared to papers on treatment. based on symptoms alone.
Surveys with questionnaires are the most common way to The addition of nasal endoscopy or computed tomography (CT)
explore the field of CRS in order to screen the population and scan makes the diagnosis more reliable. Two studies evaluating
to determine the prevalence of CRS in the general population. the use of nasal endoscopy to make a clinical diagnosis of CRS in
It probably overestimates the prevalence of CRS due to overlap a population study showed reduction of the prevalence to 1.2%
with other rhinologic diseases. (88 of 7,343)(5) and 6.8%(9). Interestingly in the paper from Tomas-
In recent years a number of population-based studies have been sen et al., 38% of symptom-negative patients had a positive
performed with questionnaires evaluating the prevalence of endoscopy. The reason for the discrepancies between these two
CRS based on the epidemiological definition from the EPOS2012 papers is unclear. Both papers used the EPOS criteria of clinical
document(1). CRS: the presence of polyps, presence of oedema in the middle
Earlier studies in the USA in 2009 based on the National Health meatus or presence of thick purulent discharge in the middle
Interview Survey found 13% of adults to have “sinusitis”(2). meatus to define endoscopy positive CRS.
The first of these studies was part of The Global Allergy and Also, two studies evaluated the use of CT scan to make a clinical
Asthma European Network (GA2LEN). It consisted of a postal diagnosis of CRS in a population study. In one study a group of
questionnaire sent to a random sample of adults aged 15-75 subjects who underwent a computed tomographic or magne-
years in 19 centres in Europe. Participants reported symptoms tic resonance imaging scan of the head for any non-rhinologic
of CRS, and doctor diagnosed CRS, allergic rhinitis, age, gender indication were asked to fill in the GA2LEN survey including the
and smoking history. Information was obtained from 57,128 CRS questions(10). The scans were evaluated according to the
responders living in 12 countries. The overall prevalence of CRS Lund-Mackay (LM) scoring system. Eight hundred and thirty-four
was 10.9% with a wide variation between countries ranging subjects were included, and 107 (12.8%) had epidemiologically
from 6.9 in Finland to 27.1 in Portugal. CRS was more com- based CRS according to EPOS. Of these subjects, 50% had an LM
mon in smokers than in nonsmokers (odds ratio (OR) 1.7: 95% score of 0, 26% had an LM score of 1 to 3, and 23% had an LM
confidence interval (CI) 1.6-1.9). The prevalence of self-reported score of 4 or greater. Twenty-five (3.0%) subjects had clinically
physician-diagnosed CRS within centres was highly correla- based CRS (based on LM score >/=4), and 53 (6.4%) subjects had
ted with the prevalence of EPOS-diagnosed CRS. Subsequent clinically based CRS (based on LM score >0). In subjects who
studies following roughly the same method showed a preva- did not report upper airway symptoms, 57% had an LM score
lence of 5,5% in Brazil(3), 8% in China(4),11% in South Korea(5) and of 0, 30% had an LM score of 1 to 3, and 12% had an LM score
12% in the USA(6),16% in the Netherlands(7) and 28% in Iran(8). of 4 or greater. The authors found a prevalence of 3.0% to 6.4%
In a second phase of the GA²LEN Survey each centre invited of clinically based CRS (depending on an LM cut-off point; i.e.,
120 randomly selected subjects with asthma, 120 with CRS, 40 LM ≥ 4 or LM > 0, respectively) in a relatively randomly selected
with asthma and CRS and 120 with neither asthma or CRS for a group of subjects. The other study(11) collected questionnaires
clinical study visit with further investigations among which was and sinus CT scans from 646 participants selected from a source
a questionnaire including the same questions as for the postal population of primary care patients. Symptom status was based
survey. Of the patients having an epidemiological diagnosis of on guideline criteria, and radiology was based on the LM score
CRS in the first phase, EPOS provides two definitions of CRS: a using cutoff points of ≥ 3, 4, or 6. The authors found a preva-
clinical diagnosis based on symptoms, supported by signs of lence of 11.1%, 9.9%, and 5.7% among woman respectively, and
mucosal inflammation found on imaging or with nasal endo- 16.1%, 14.6%, and 8.7% among men for the different LM cutoff

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points. When combining with symptomatology, the proportion 5.1.1.1. CRS: difference between CRSwNP and CRSsNP
of clinically based CRS was 1.7%, 1.6%, and 0.45% among wo- CRS can be classified into CRS with nasal polyps (CRSwNP) and
men and 8.8%, 7.5%, and 3.6% among men. The figures of these CRS without nasal polyps (CRSsNP). Data on the prevalence of
two studies are very comparable, pointing to a prevalence of CRSwNP are limited. Two early Scandinavian studies(17, 18)
CRS based on symptoms and CT scan of around 3%. investigated the prevalence of nasal polyps in an adult popu-
Finally, prevalence of CRS can be estimated from databases lation. A random sample of 1,900 inhabitants over the age of
based on the diagnosis by physicians. Health care administrative 20 years, stratified for age and gender, was drawn from the
databases allow for population-based cohort studies to generate municipal population register in Skövde, Sweden, in December
large sample sizes with small financial and time expense. Howe- 2000. The subjects were called to clinical visits that included
ver, the risk of inaccurate cohort identification can lead to biased questions about rhinitis, asthma, and aspirin intolerance and
outcomes. Lui et al. showed that in 27 studies obtaining CRS- examination by nasal endoscopy. In total, 1,387 volunteers (73%
specific data from a health records database, eight different CRS of the sample) were investigated. The prevalence of nasal polyps
case definitions were identified and 13 administrative databases was 2.7% (95% confidence interval, 1.9-3.5), and polyps were
were evaluated. The most commonly used CRS case definition more frequent in men (2.2 to 1), the elderly (5% at > or =60 years
was the ICD-9 473.x code alone(12). The CRS case definition of of age), and asthmatics(18). Similar data were found in Denmark
>/=2 claims with a CRS ICD-9 code (471.x or 473.x) within two where over a 6-year period all polyp patients diagnosed for the
years of the reference case provides a balanced validity with a first time (n=252; 174 males, 78 females) were prospectively
sensitivity of 77% and specificity of 79%(13). The data that can be registered at the study clinic and compared to an estimated
used to evaluate prevalence and doctors’ visits are limited. background population. The mean estimated incidences for all
In the year 2000, 2405 residents of Olmsted County were given age groups were 0.86 and 0.39 patients per thousand per year
an ICD-9 diagnosis code for CRS. Among these, 1627 (67.7%) for males and females, respectively. With a disease duration of
were female and 778 (32.3%) were male. The overall age- and estimated 20 years, this would lead to a prevalence of 1.92 and
sex-adjusted prevalence per 100,000 was 1955 (1.96%)(14). 0.78 for males and females. Using a validated questionnaire/
The mean age- and sex-standardized incidence of diagnosed algorithm (90% specificity and sensitivity) in a population-
CRS in Canada was reported to be 2.5 (range, 2.3-2.7) per 1000 based random sample, Klossek et al. estimated a prevalence of
population. The estimated prevalence based on age-specific 2.11% (95% CI 1.83-2.39). CRSwNP patients (n=212, 45% males)
incidence varied between 18.8 (95% CI, 18.7-18.9) and 23.3 (95% were aged 49.4 ± 17.6 years. No gender preponderance was
CI, 23.1-23.5) per 1000 population during 2004-2005 to 2013- observed, but NP tended to increase with age. Mean duration of
2014, and no obvious growing trend was found. There was high nasal symptoms was 22.4 ± 15.7 years.
geographic variation in the diagnosed incidence and prevalence Tan et al. sought to determine incidence for CRSsNP and
of CRS(15). CRSwNP using electronic health records data from 446,480
Studies from [general practitioner (GP)] databases often suffer Geisinger Clinic primary care patients(19). The average incidence
from suboptimal differentiation between ARS and CRS. Hof- of CRS was 83 ± 13 CRSwNP cases per 100,000 person-years and
fmans et al. showed that GPs often do not differentiate between 1048 ± 78 CRSsNP cases per 100,000 person-years. Between
the two diseases(16). 2007 and 2009, 595 patients with incident CRSwNP and 7523
Xiao et al. (845) retrospectively reviewed a random sample of adult patients with incident CRSsNP were identified and compared
patients diagnosed with CRS in 2016, based on ICD-10 codes with 8118 control subjects. Compared with control subjects and
from primary care and otorhinolaryngology departments. The patients with CRSsNP, patients with CRSwNP were older and
percentage of patients fullfilling the criteria of the American more likely to be male. Finally Won et al. found a prevalence of
Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) CRSsNP and CRSwNP of 3.5 ± 0.2% and 2.5 ± 0.2% (mean ± SE),
was very low from GP patients (0.97) and low from otorhinola- respectively. When classified by age group, the prevalence of
ryngologists’ patients (28.9%). Symptom duration <12 weeks CRSwNP increased with age in adults (≥18 years of age), which
was higher in primary care (81.6% vs. 53.6%, p<0.0001), as was was particularly evident after 40 years of age and CRSsNP was
lack of evidence of inflammation (97.4% vs. 50.0%, p<0.0001). more prevalent in subjects younger than 40 years. Those with
Having <2 of the required symptoms was significantly higher CRSwNP were significantly more likely to be men, to have higher
in otorhinolaryngology (63.8% vs. 50.8%, p=0.013). The most BMI, to smoke cigarettes, and to have asthma than the CRSsNP
commonly unevaluated symptom was decreased sense of smell or no-CRS group.
(97.7% in primary care, 69.1% in otorhinolaryngology encoun- CRSwNP was significantly associated with adult-onset asthma
ters). There is an obvious need for clear criteria to do research on (onset after 18 years of age) or late-onset asthma (onset after 40
CRS in healthcare. years of age), whereas CRS without nasal polyps was related to
childhood-onset asthma (onset before 18 years) or early-onset

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asthma (onset before 40 years) in adults. The 2 CRS subgroups mendation is that allergy testing and treatment are an option in
showed significant associations with current asthma but not CRSwNP and CRSsNP. Since 2014, a few noteworthy studies have
with past asthma. However, the comorbid asthma rate was been published. A more recent non-systematic review points to
lower than 10% among subjects with CRS(20). the fact that different phenotypes/endoptypes of CRS may have
Soler et al.(21) in 2012 evaluated the role of gender and race in a variable associations with allergy. The authors point to allergic
surgical outcomes for patients with CRSwNP and asthma. In his fungal rhinosinusitis (AFRS) (see 8.6) and central compartment
study, African Americans with CRSwNP had less improvement atopic disease (CCAD)(25)(see 8.1.2.1.) This point was also made
after endoscopic sinus surgery than Caucasians. This difference in a recent study from the UK that analysed differences between
according to ethnicity must be proven because it could be different phenotypes of CRS and controls in secondary care(26).
confused by other socio-economic factors such as access to The analysis included 1470 study participants: 221 controls, 553
healthcare in this population. This study also shows that the CRSsNPs, 651 CRSwNPs and 45 AFRS. The prevalence of inhalant
prevalence of CRS was lower in the Asian (7%) and Hispanic allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust
population (8.6%) than in the black population (13.3%) or the mite allergy was significantly higher in CRSwNPs (16%) compa-
Caucasian population (prevalence around 13% too). red to CRSsNPs (9%) in this study.
However, there is no significant difference regarding the gender. In conclusion, the prevalence of allergy in CRS may vary by phe-
This is confirmed by the study of Hirsch et al.(6) in 2017 that notype, with CCAD and AFRS having a stronger association than
found that women are more likely to have acute rhinosinusitis CRSwNP and CRSsNP. Large studies evaluating relationships in
but that there is no sex ratio for CRS. Hoffmans et al.(7) had the different settings like the Philpott paper are needed.
same conclusions regarding ethnicity and gender in his study
including 8,347 adults in the Netherlands in 2017. 5.1.2.2. Asthma and other lower airway diseases
Brescia et al.(22) in 2016 examined the difference in CRS preva- Unlike for allergy and CRS, the relationship between CRS and
lence between elderly and young people. After endoscopic asthma is indisputable.
sinus surgery, nasal polyps recurred less often in the elderly, The prevalence of asthma is around 25% in patients with CRS
maybe because in CRS in the elderly, there is less eosinophilic compared to 5% in the general population(27). GA2LEN(28) studied
infiltration which is known to increase the risk of recurrence. over 52,000 adults aged 18-75 years living in 19 centres in 12
Furthermore, the proportion of patients with allergy was signi- countries and concluded that there is a strong association
ficantly higher in young people than in the elderly population, between asthma and CRS. The association with asthma was
but there was no difference in the prevalence of asthma in both stronger in those reporting both CRS and allergic rhinitis. In
populations. Cho et al.(23) found the same result in his study, sug- the earlier mentioned UK study(26), the prevalence of asthma
gesting that when CRS appears in the elderly the pathogenesis was 9.95% in controls, 21.2% in patients with CRSsNP, 44.9% in
is different, less linked with allergy and eosinophilic infiltration, CRSwNPs and 73.3% in patients AFRS. A subgroup of the earlier
but more with nasal polyp formation. mentioned GA2LEN cohort, with and without asthma and CRS
of 3337 participants were further analysed for decline in lung
5.1.2. Predisposing factors of CRSwNP and CRSsNP function. Participants with asthma had lower forced expiratory
flow per second (FEV) and a steeper slope of FEV1 against age
5.1.2.1. Allergy equivalent to smoking 1-2 packs of cigarettes per day. Those
The relationship between atopy and CRS has been well studied with atopy had a slope equivalent to controls, but neither CRS
and resulted in many reviews. A systematic review was perfor- nor atopy alone were associated with such decline(29).
med by Wilson in 2014(24). A total of 24 articles were found that Chen et al.(30) identified patients newly diagnosed with asthma
met the inclusion criteria; 18 articles examined the relations- in Taiwan and analyzed the incidence of CRS in that population.
hip between allergy and CRSwNP, with 10 articles showing an After adjustment for gender, age and medical comorbidities,
association, seven articles showing no association, and one they showed that asthma is an independent predictor of CRS,
article showing a possible association. Nine articles examined with or without nasal polyps (OR: 2.58 for CRSsNP). The chrono-
the relationship between allergy and CRSsNP, with four articles logy of developing asthma or CRS first is variable.
showing an association and five articles showing no association. A Japanese study shows that there is no significant difference
Four studies directly compared the role of allergy in CRSwNP in onset times between the two diseases(31). Wheezing and
and CRSsNP, and, again, the results were mixed. No articles respiratory discomfort are present in 31 to 42% of patients
examined the outcomes of CRSsNP or CRSwNP following allergy with CRSwNP, and asthma is reported by 26% of patients with
treatment. The authors concluded that the role of allergy in CRSwNP, compared to 6% of controls(32). On the contrary, 7% of
CRSwNP and CRSsNP continues to be controversial, with the asthmatic patients have nasal polyps with a prevalence of 13%
level of evidence poor. Based on the available data, the recom- in non-atopic asthma and 5% in atopic asthma and they have

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more nasal symptoms than patients that have CRS without respiratory reactions to NSAIDs was higher in participants with
asthma(33). In asthmatic CRS patients, a sizeable portion of CRS CRS symptoms and asthma symptoms in last 12 months but
impact on QOL is indirectly mediated through the effect of was not associated with allergic rhinitis(43). In the previously
CRS on poorer asthma control which may then drive decreased mentioned UK analysis(26) the prevalence of self- reported aspirin
QOL(34). sensitivity was 2.3 in the control group, 3.3 in CRSsNP patients,
Several authors reported on the higher incidence of CRS in 9.6 in CRSwNP patients and 40% in the AFRS group. In this same
chronic obstructive pulmonary disease (COPD) patients(35). The study the AFRS and CRSwNPs group and to a lesser extent also
figures depend mostly on the definition of CRS applied in a the CRSsNP group were significantly more likely than controls
study. Upper airway symptom frequency among COPD patients to report symptom exacerbation due to ingestion of food
may be as high as 88%(33) but when more objective tests were groups with higher potential dietary salicylate content(44). The
applied for CRS diagnosis (such as CT scans), lower numbers prevalence of N-ERD among patients with CRSwNP in a tertiary
were reported (53%). CRS symptoms significantly impair COPD referral centre was 16%(45). Patients with aspirin-exacerbated
patients’ quality of life. Smoking should be considered an impor- respiratory disease (AERD) had undergone two-fold more sinus
tant risk factor of CRS(35). surgeries (p<.001) and were significantly younger at the time
Within the GA2LEN network a multicentre cross-sectional case- of their first surgery than were patients with CRSwNP without
control study recruited 935 adults (869 eligible for analysis: N-ERD.
237 CRSsNP; 445 CRSwNP; 187 controls). Comorbidities such Upper airway disease in N-ERD patients is usually CRSwNP. On
as asthma, allergy, eczema, food allergy, urticaria, and chronic average, upper respiratory symptoms are worse, extent of opaci-
obstructive pulmonary disease were significantly more frequent fication on CT scan and recurrence of nasal polyps after surgery
in CRS patients(36). Another chronic pulmonary disease has been are more frequent in N-ERD than in NSAIDs-tolerant CRSwNP
studied thanks to a National database analysis in Taiwan(37). They patients(39, 45).
followed 68,058 patients and found 569 patients that developed Diagnosis is mainly based on patient history and aspirin provo-
CRS during the five years of follow-up. After adjustment COPD cation tests are only needed when the history is not clear (see
was an independent predictor of CRS without nasal polyps. also 5.3.4.14).
Bronchiectasis is a chronic bronchial disease with permanent
and irreversible destruction and dilatation of the bronchial wall, 5.1.2.4. Immune deficiencies
leading to retained secretions and recurrent infections. More There is good evidence that immune deficiencies are more com-
than 50% of bronchiectasis are idiopathic but as it is a respira- mon in patients with CRS. A meta-analysis, which included 1418
tory tract disease, some researchers studied the link between it individuals with CRS from 13 studies, found that 23% of patients
and CRS. Guilemany et al.(38) found that 77% of bronchiectasis with difficult- to-treat CRS and 13% of individuals with recurrent
patients have CRS and 26% of them have nasal polyps; in both CRS had immunoglobulin deficiencies(46). A recent study shows
idiopathic and post-infective bronchiectasis. Some authors that the prevalence of immune deficiencies could be up to 50%
suggest that in bronchiectasis there is an impairment of ciliary in “difficult to treat” cases of CRS and that immunological tests
function such as in Kartagener’s syndrome, explaining these should be undertaken in these cases(47). Other authors suggest
results and the sinonasal symptomatology. integrating systematically immunological tests when exploring
a diagnosis of CRS, particularly when it does not respond to
5.1.2.3. Non-steroidal anti-inflammatory drug (NSAID)-exa- standard treatment or have an impact on morbidity or quality
cerbated respiratory disease (N-ERD) of life(48).
Non-steroidal anti-inflammatory drug (NSAID)-exacerbated The most frequent immune deficiency found in these cases is
respiratory disease (N-ERD) is a chronic eosinophilic, inflam- Common Variable ImmunoDeficiency (CVID) (10 % cases) and
matory disorder of the respiratory tract occurring in patients Selective immunoglobulin A (IgA) deficiency (6% cases)(49).
with asthma and/or CRS with nasal polyps (CRSwNP), symptoms Selective IgA deficiency is the most common immunodeficiency
which are exacerbated by NSAIDs, including aspirin(39). with a prevalence of one in 600 individuals, but usually people
The pathogenesis of N-ERD is related to dysregulation of eicosa- are asymptomatic(47). However, many of the patients diagnosed
noid synthesis(40) leading to an eosinophilic inflammation of the in the series included in the meta-analysis had subclass or spe-
nasal and sinus membranes and an increased leukotriene pro- cific antibody deficiency. The laboratory criteria for diagnosing
duction that is further accentuated by cyclooxygenase (COX)-1 these conditions, and the clinical implications once the diagno-
inhibitor (aspirin or NSAIDs)(41). ses are made, are not uniformly accepted. Many of the studies of
Respiratory symptoms following NSAID intake have been the meta-analysis were performed in tertiary referral centres and
reported by 1.8% of the general European population and this may have biased the population of patients studied toward
by 10% - 20% of patients with asthma(42). The prevalence of having underlying immune defects. These reservations aside, it

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is likely that the prevalence of hypogammaglobulinemia in CRS recurrent and aggressive CRS. This suggests that there could be
patients is significantly higher than in the general population. a benefit of giving an anti-reflux treatment to a patient with CRS
even if he has no symptoms of GORD. However, it has not yet
5.1.2.5. Gastro-oesophageal reflux disease (GORD) been shown that reducing gastroesophageal reflux symptoms
Gastro-oesophageal reflux disease (GORD) is a common correlates with a reduction of CRS symptoms (see also 6.1.23.1).
gastrointestinal disorder that affects approximately 10% of
western populations and has been hypothesized to be one 5.1.2.6. Nasal anatomic variations
of the possible factors that induces CRS and contributes to its Anatomic variants have been studied because the obstruction
worsening. However, the relationship between GORD and CRS of the ostiomeatal complex has been suggested as a risk factor
remains indeterminate due to its complexity, and it is not clear for developing CRS(33). A systematic review analyzing the role of
that an anti-reflux treatment would be indicated for patients septal deviations in CRS demonstrated a significant association
with recurrent CRS. A recent meta-analysis(50) in 2016 gathered of septal deviation and rhinosinusitis. However, the clinical ef-
32 publications that assessed the prevalence or incidence of CRS fect was modest and interestingly in all studies that examined
in a GORD population or vice-versa. the laterality of rhinosinusitis associated with septal deviation,
In a recent systematic review, Leason et al. included studies inflammation was found bilaterally(56). A recent study(57) analyzed
(n=32) that consisted of studies reporting pathogenic factors CT and nasal endoscopies in patients with CRS and found that
(n=20), epidemiological association (n=8), prognostic interac- 88.2% of patients had a deviated nasal septum and 76.4% had
tions (n=3), and a combination of these outcomes (n=1). They concha bullosa. However, these numbers were close to those
concluded that the potential pathogenic roles for GORD in CRS found in retrospective trials in the general population and are
were supported; CRS subjects had greater prevalence of intrana- not significant.
sal Helicobacter pylori and acid reflux than subjects without CRS. Sedaghat et al.(58) studied CT scans of patients with CRS and
A more recent study also showed that CRS patients had signifi- found that sinonasal anatomic variants such as infra-orbital cells
cantly higher incidences of gastro-oesophageal reflux measured and frontal inter-sinus cells are related to faster progression of
with 24-h multichannel intraluminal impedance (MII)-pH mo- CRS, but this prevalence has not been compared to a population
nitoring compared with asymptomatic controls(51). CRS is more without CRS. Although patients with CRS do not necessarily
prevalent in GORD sufferers than those without GORD. Evidence have higher rates of specific anatomic variations, it appears that
is conflicting for GORD as a factor in CRS treatment failure. they can affect the progression of the disease.
A second systematic review included 12 papers and found
eight cross-sectional articles that suggested a relation between 5.1.2.7. Microbiology
CRS and GORD, especially in CRS that is refractory to clinical or
surgical treatment(52). However, the authors concluded that the 5.1.2.7.1. Bacteria and biofilms
groups are small and methodologies different. The pathophysiology of CRS is multifactorial but mostly consi-
The association between GORD and CRS seems to be two-way dered an inflammatory disease of the upper airways analogous
and Leason et al. suggest that direct nasopharyngeal reflux to asthma in the lower airways. It is a multifactorial condition
leads to gastric acid and pepsin reflux directly in the nasal cavity, in which the microbiota may play a pathogenic role. Because
mostly in a lying position, inducing nasal inflammation that the nose is not sterile, a culture of the sinus obtained via the
worsens CRS. Another hypothesis is the intranasal presence of nose will always grow microbes, and causality in CRS is not
H. pylori, a bacteria which has in fact been found in the nasal established by a positive culture. Trying to determine the role
cavity(53); and as it is known for its aggression and its role in the of infection based on a response to antibiotic treatment is also
pathogenicity of gastric ulcers, gastritis and gastric cancers, it difficult. CRS in general also does not have a favorable reaction
is reasonable to suggest the same pathogenicity in the nasal to treatment with either short term or long term antibiotics (see
cavity. Furthermore, as nasal pepsin, gastric acid and local 6.1.). Studies of the microbiology of CRS have demonstrated
eosinophilic infiltration are more prevalent in the nasal cavity a variety of bacteria depending on geographic location, prior
in GORD patients(54) with CRS, the induced nasal inflammation surgery, and recent antibiotic use. Staphylococcus aureus (SA) is
is more important and explains the results of studies(55) finding a frequent colonizer in humans, and it is considered to be asso-
that patients with GORD and CRS had more symptomatic CRS ciated with chronic airway diseases including CRS and asthma.
[higher Sino-Nasal Outcome Test (SNOT)-22 score, more CRS In studies of general populations, nasal SA colonization had
medication, more endoscopic sinus surgery] than patients with significant relationships with asthma prevalence. In studies of
CRS without GORD. patients with CRS, positive associations were also found but had
Another hypothesis is that corticosteroids and antibiotics given a considerable heterogeneity and the results were comparable
in CRS medication could induce or worsen GORD, mostly in between CRS with and without nasal polyps(59). Recent improve-

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ments in the microbiological techniques have greatly advanced supports the role of the transient viral infection as the initial
our understanding of the complex nature of this interaction. inflammatory stimulus in the pathogenesis of acute exacerbati-
The nature of the interaction between the microbiota and the ons in CRS.
local immune system is very complex and has not been fully
elucidated. The role played by microbiomes in CRS is difficult to 5.1.2.7.3. Fungal infection
be clearly defined at the current time due to the difficulties in Chronic fungal rhinosinusitis may represent a wide spectrum
the laboratory techniques and small studies with limited sample of disease ranging from the mild form of superficial coloniza-
size. It is likely that bacterial and fungal airway microbiomes are tion (saprophytic fungal infestation and fungal ball), allergic
dynamic and experience natural shifts in diversity with time. manifestations (AFRS) to chronic granulomatous invasive fungal
The underlying reasons for these shifts appear to be a combi- rhinosinusitis (see 9.6).
nation of changes in environmental climate and host factors. A
small core community that persisted throughout the two year 5.1.2.8. Ciliary impairment
sampling period was identified: Corynebacterium, Propionibac- Motile ciliary disorders have been extensively investigated in
terium and Staphylococcus, and one type of fungus, Malassezia primary ciliary dyskinesia (pcd), a rare and under-recognized
restricta(60). genetic disease characterized by impaired mucociliary clea-
The presence of biofilms in CRS patients was first demonstrated rance (see 9.5). Defective mucociliary clearance, evidenced by
in 2004 via scanning electron microscopy of the nasal mucosa of impaired ultrastructure and/or function of respiratory cilia, have
CRS patients(61). A biofilm comprises any syntrophic consortium also been implicated in CRS.
of microorganisms in which cells stick to each other and often In healthy individuals, mucociliary clearance (MCC) is part of the
also to a surface. These adherent cells become embedded with- innate defense mechanism and functions to protect the airways
in a slimy extracellular matrix that is composed of extracellular by trapping inhaled ambient pathogens within the mucus
polymeric substances. Because they have three-dimensional layer of epithelial surfaces and propelling it out of the airways
structure and represent a community lifestyle for microorga- through coordinated cilia movement. Normal functioning of
nisms, they have been metaphorically described as cities for MCC consists of two equally important components: mucus
microbes. Microbes form a biofilm in response to various dif- production and mucus transport. When MCC is compromised,
ferent factors which may include cellular recognition of specific airways become vulnerable to a vicious cycle of infection and
or non-specific attachment sites on a surface, nutritional cues, or obstruction. Extrinsic factors such as pollutants and microbes
in some cases, by exposure of planktonic cells to sub-inhibitory can directly and indirectly impact normal cilia function. This
concentrations of antibiotics. A cell that switches to the biofilm phenomenon is evident in patients with CRS who experience
mode of growth undergoes a phenotypic shift in behaviour relentless cycles of infection and inflammation, resulting in
in which large suites of genes are differentially regulated(62). ciliary loss and a hyperviscous mucus blanket generating dys-
Since the advent of biofilm detection in CRS, multiple bacterial functional mucociliary coupling. In addition to direct ciliary loss,
organisms have been implicated including Staphylococus aureus, cilia surviving the microbial and/or inflammatory insults appear
Pseudomonas aeruginosa, Haemophilus influenza and Moraxella not to function normally(68). Although the literature is conflicting
catarrhalis. Of these, SA biofilms have the greatest association regarding ciliary impairment and its changes in patients with
with severely recurrent and recalcitrant cases of CRS possibly be- CRS, recent work has suggested that a subset of patients with
cause of their potential to produce antigens(63). Estimated rates CRS have a blunted ciliary response to environmental stimuli
of biofilm formation in patients with CRS range from 29 to 72%. that is reversible once the tissue is removed from the infected or
CRS patients with biofilm have more severe disease preope- inflamed sinonasal environment. This finding suggests that local
ratively and persistence of postoperative symptoms, ongoing exogenous factors can negatively modulate the ciliary dynamic
mucosal inflammation, and infections(64, 65). response to stimuli.
Multiple environmental and exogenous factors alter the normal
5.1.2.7.2. Virus physiological state, and the resultant inflammatory cytokines
The role of viral infections in inducing or exacerbating CRS has secondarily exacerbate the impaired mucociliary clearance(69).
been studied and coronavirus was identified via molecular
sequencing as the most common virus in patients with CRS(66). 5.1.2.9. Smoking
Parainfluenza virus has been identified as a major cause of post- Smoking should be considered an important risk factor of
infectious olfactory dysfunction and could have a potential role CRS(35). The GA2LEN survey showed that current smoking and
in the pathogenesis of CRS(67). Acute exacerbations of CRS have ex-smoking are significantly associated with CRS(70). Tobacco is
been increasingly recognized as an important disease entity toxic to the nasal mucosa and cigarette smoking plays a signifi-
with a significant impact on the quality of life. Current evidence cant role in diseases of the upper airway because pollutants and

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toxins in cigarette smoke are pro-inflammatory and create oxi- is not clear and further larger prospective studies are needed.
dative stress of the mucosa, leading to symptoms such as nasal
obstruction, increased nasal secretion and mucosal dryness. 5.1.2.12. Metabolic syndrome and obesity
Recent systematic reviews found a strong correlation between Using to the Korean National Health and Nutrition Examination
active and passive cigarette smoke with the prevalence of CRS. Survey (KNHANES), Lee et al.(83) analyzed 12,015 individuals and
Paediatric patients exposed to secondhand smoke appear to found that the prevalence of CRS in patients with metabolic
have particularly poor outcomes(71, 72). syndrome (high triglyceride level, reduced high-density lipopro-
tein level and elevated blood pressure) was significantly higher
5.1.2.10. Pollution than in patients without metabolic syndrome (14.15 vs. 10.16%;
The consequences of the World Trade Centre attack have clearly p<0.05). This database was also used to show that obesity(84) is
shown the relation between pollution and CRS. The enormous an independent factor in developing CRS (OR,1.46; 95%CI, 1.16-
dust exposure of the firefighters resulted in a significant increase 1.84; p=0.001). The hypothesis is that there is a pro-inflamma-
in prevalence of CRS that was correlated to the amount of inha- tory condition secondary to excessive adipose tissue favouring
lation and did not diminish by time since exposure(73). Recently the development of inflammatory diseases such as CRS. This
air pollutants were shown to correlate with CRS symptom association needs further study.
severity that may be influenced by exposure levels, with a more
pronounced impact on CRSsNP patients(74). Geramas et al.(75) also 5.1.2.13. Vitamin D (VD3)
concluded in their 2018 review that living in poor, crowded or There now is substantial literature to indicate that VD3 acts as
old housing is associated with increased prevalence of CRS. an immunomodulator of adaptive and innate immunity locally
Until quite recently, the current state of the literature allowed within the respiratory epithelium.
us to make very few conclusions about the role of hazardous Stokes et al. included seven articles (four prospective and three
occupational in CRS(76). However, some recent studies show asso- retrospective studies), with a total of 539 patients in a systematic
ciations between occupational exposure to paper dust, cleaning review. There were significantly lower VD3 levels in the polypoid
agents, metal dust, animals, moisture/mould/mildew, poisonous phenotypes of CRS compared with controls. Low VD3 levels
gas and physically strenuous work(77-79). A recent Portuguese were often associated with an increased degree of inflammati-
study(79) found an important correlation between occupational on(85). The authors conclude that the available evidence indicate
dust exposure and nasal polyps’ occurrence in textile workers that there is a significant relationship between low VD3 levels
and Mady et al.(74) suggest that exposure to air pollutants cor- and polypoid CRS phenotypes. The association between VD3
relates with CRS symptom severity in CRSsNP. levels and disease severity and VD3 potential for drug therapy
remains unclear, which warrants further research in the area.
5.1.2.11. Obstructive sleep apnoea (OSA)
Patients with undiagnosed obstructive sleep apnoea (OSA) 5.1.2.14. Alcohol
often present to an otorhinolaryngologist with symptoms of An important percentage of subjects diagnosed with chronic
CRS. In a retrospective analysis of adult patients at an academic upper airway disease report alcohol-induced worsening of their
practice with a rhinologic chief complaint, the authors showed symptoms.
that OSA and CRS have significant overlap in symptom profiles The highest prevalence of nasal and bronchial alcohol hyper-
and that the SNOT-22 can help identify those with undiagnosed responsiveness is observed in patients with N-ERD, followed by
OSA. OSA should be suspected in patients who report a sleep- patients with CRSwNP, and less frequent in CRSsNP, and healthy
related item as a most important symptom and display higher controls. Alcohol hyper-responsiveness is significantly more
psychological and sleep domain scores(80). prevalent in CRSwNP patients suffering from recurrent disease
A retrospective study found that obstructive sleep apnoea(81) is and in patients with severe symptomatology(86).
an independent factor of risk for developing CRS [hazard ratio
(HR) of 3.44 for males and 2.63 for females]. 5.1.3. Acute exacerbations of CRS (AECRS)
In a Taiwanese study evaluating patients who underwent FESS,
38% complained of daytime sleepiness, and this sleep problem 5.1.3.1. Epidemiology and predisposing factors
was correlated with the symptom of nasal obstruction. Obstruc-
tive sleep apnoea syndrome (OSAS) was diagnosed in 64.7% of 5.1.3.1.1. Epidemiology
the patients, but there was no correlation with the severity of Acute exacerbation of chronic rhinosinusitis (AECRS) is defined
rhinosinusitis. Nasal polyps did not worsen sleep problems in as worsening of symptom intensity with return to baseline CRS
the CRS patients(82). symptom intensity, often after intervention with corticosteroids
The exact relationship between these two overlapping diseases and or antibiotics. Exacerbation of nose and sinus symptoms,

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often considered as a bacterial infection, may in reality have a nasal polyps, which was negatively associated with the risk of
more complex background and depend on multiple factors. It exacerbation(90).
could be due to a worsening of allergic rhinitis, an acute viral
respiratory infection, exacerbation of asthma or other stress 5.1.3.2. Pathophysiology
factors including depression.
Nasal symptoms are common in the general population and 5.1.3.2.1. Viruses
without prior sinus CT it is difficult to precisely ascertain if an Over 160 serotypes of rhinoviruses have been identified and
exacerbation of nasal symptoms was on a background of CRS. are considered important contributors or triggers of airway
Large scale epidemiologic studies have , therefore, previously inflammation both in the upper and lower airway. It is believed
not been available. A recent epidemiologic study has tried to that the rhinovirus initiates primary epithelial damage which
overcome this by studying acute exacerbation of nasal and is followed by secondary damage by the host anti-viral inflam-
sinus symptoms from a general population of 200 769 subjects, matory response. This should ideally be timely and self-limiting,
7847 were selected and mailed questions on nose and sinus avoiding permanent inflammatory change in the sinonasal
symptoms according to EPOS2012 every four months over 16 mucosa(91). The inflammatory response starts with activation of
months. Subjects were classified into; current long-term CRS, Toll like receptors (TLR 3,7 and 9) to initiate a cellular response,
current recent, past or never CRS. Prescription of oral antibiotics which induce the expression of interferons and cytokines, which
and or orals steroids were considered as a proper event of exa- in turn leads to recruitment of innate responders such as macro-
cerbation. Prevalence peaked in the winter months and peaking phages and neutrophils. More recently evidence has emerged
among long-term current CRS subjects, where 25.9% of patients that eosinophils are involved in anti-viral activities and are
had at least one exacerbation in the last 12 months compared to recruited to the site of rhinovirus infections explaining among
7.9% in the never CRS group(87). other things asthma exacerbations seen during viral respiratory
Another study has followed 209 CRS patient from a tertiary tract infections(92).
care rhinology clinic monitoring the number of CRS infections, A recent comprehensive review found 147 publications studying
CRS-related antibiotic prescription and CRS-related oral corti- the effect of rhinoviruses in CRS patients and concluded that; 1)
costeroids taken. Ninety patients reported zero exacerbations, rhinovirus infections have a higher prevalence in CRS patients
whereas 119 patients had three or more episodes during the than in the general population, 2) humans challenged in vivo
prior 12 months(88). with rhinoviruses will elicit a local inflammatory response evi-
In 108 asthmatic patients with CRS (69.9% with CRSwNP) the dent by elevated cytokines (IL-6, IL-8) in nasal lavage and muco-
mean number of exacerbations of CRS was in the past 3 months sal changes on MRI, and 3) in vitro challenge of nasal epithelial
0.8 episodes, it is unclear if this refer to a specific season, but cells will produce a robust cytokine response mimicking the one
if extrapolated it would suggest 2.4 episodes per year in this found in vivo supporting the causality(93).
particular group of patients(89). The same study showed that Rhinoviruses may also disturb the balance of the residential
frequency of acute exacerbation of CRS have a negative impact microbiome. A study where healthy participants were inocula-
on asthma control. ted with rhinoviruses revealed a shift in the resident microbiome
A study on the effect of quality of life from acute exacerbations where the abundance of Haemophilus parainfluenzae, Neisseria
of CRS found that in 85 patients with a mean SNOT score of 36.8 subflavia and Staphylococcus aureus increased. This change in
the patients had taken a mean of 1.5, SD=1.9 courses of antibio- the microbiota could help explain why virus infections predispo-
tics related to CRS in the past 12 months(90). ses to secondary bacterial infections(94).
Thus, the prevalence varies with the patient cohort being stu- To sum up, virus infections are likely to be the main trigger for
died, season, and how the exacerbation was defined. acute CRS exacerbations, where host response initiates or accen-
tuates an inflammatory reaction in the nose and sinus mucosa,
5.1.3.1.2. Predisposing factors including eosinophils, and has a potential to shift the residen-
According to the previously mentioned epidemiologic study tial microbiome towards an increased abundance of microbial
an increased prevalence of AECRS is more likely to be seen; in airway pathogens.
younger white, female, on medical assistance or having greater
Charlson comorbidity index. Other risk factors identified in 5.1.3.2.2. Bacteria
this study were CRS status, increased BMI, asthma, hay fever, The microbiology of exacerbations of CRS has been studied by
migraine and history of sinus surgery(87). Brook using traditional culture. He found that in the majority of
The study by Phillips et al. identified an exacerbation prone phe- cases the bacterial flora was similar to the one found in stable
notype associated with high sinonasal burden (SNOT score over CRS patients, although Haemophilus influenzae was significantly
24) and comorbid asthma and interestingly patients without more prevalent in the exacerbation group (9 positive cultures

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of 30 patients with exacerbation, compared to 2 of 32 in stable notype(99). Indeed, for schizophrenia, a well described disease
CRS)(95). entity with distinctive symptoms, was found to be associated
A more recent study using 16S ribosomal RNA for bacteria revie- with variations in almost one hundred different genes(100).
wed the sinus microbiotia during acute exacerbation of CRS in Compounding this difficulty was the genes identified are often
134 patients (65 CRSsNP, 55 CRSwNP and 14 AFRS). Of the bac- at first glance difficult to integrate into mechanistic models – for
teria identified, those with the highest relative abundance were example, one of the main associations in schizophrenia was with
Staphylococcus spp (21.3%), Pseudomonas (15.0%), Streptococcus a gene coding for C4, an element of the complement casca-
(14.4%), and Staphylococcus aureus (12.4%). No consistent dif- de(101). Additionally, identified genetic factors may not so much
ferences among subgroups were noted and all various bacterial modify the structure of an organ or a cellular organelle, but may
taxa and species were present in all clinical subgroups(96). instead increase susceptibility to an environmental influence,
In 50 patients with a history of previous sinus surgery with acute such as infection or colonisation with undesirable bacteria(102). It
exacerbation of CRS, most were found to have Staphylococcus may then be the bacterial presence that contributes to persis-
aureus and S. epidermidis with six patients positive for Hae- tence or maintenance of disease. While this complicates the
mophilus influenzae and 5 for Pseudomonas aeruginosa(97). This direct transposition of genetic results to the clinic, the field
once again demonstrates that common airway pathogens only of genomics is again progressing, and mathematical approa-
explain a small number of clinical exacerbations. ches being developed to make predictions based on multiple
In summary, virus infections are likely to be the main trig- variations, rather than relying on a single one. A glimpse into the
ger for AECRS, where host response initiates or accentuates future is afforded by a recent commercial venture which analy-
a symptomatic inflammatory reaction in the nose and sinus ses combinations of SNPSs from the DNA of fertilised embryos
mucosa. Furthermore, rhinoviruses have the potential to shift to predict the fittest ones for implantation in vitro fertilisation
the residential microbiome towards an increased abundance of (https://genomicprediction.com). This nevertheless may be of
microbial pathogens. Significant microbiological changes are, limited usefulness, as a simulation exercise using real GWAS data
however, only identified in a small number of exacerbations sug- from large families showed that simulated embryos selected to
gesting other mechanisms may be responsible. be the smartest and tallest were only around 2.5 IQ points and
2.5 centimetres above average. Screening human embryos for
Virus infections are likely to be the main trigger for AECRS and polygenic traits has limited utility(103).
rhinoviruses have the potential to shift the residential microbio- CRS is nevertheless benefitting from the ‘genetics revolution’. For
me towards an increased abundance of microbial pathogens. example, in studies from the group of Desrosiers identification
of candidate genes associated with epithelial and basement
5.2. Pathophysiology of chronic rhinosinusitis membrane structure and function led to exploration of barrier
with and without nasal polyposis function in epithelial cells from CRS patients. This culminated
in the recent identification of a defect in tissue repair in CRS(104),
5.2.1. Genetics and epigenetics of CRS opening up the possibility of new drug treatments, confirming
that there is value in the genetics arena. Other insights still wai-
5.2.1.1. Genetics of CRS ting to bear fruit may become clearer as we better understand
The study of DNA via the Human Genome Project in the late the role and functions of identified putative candidate genes.
1990s was supposed to revolutionise medicine genes, allowing
new understandings of implicated mechanisms and identifying 5.2.1.2. Genetics: an overview
new drug targets, with future treatments based on personalised The term ‘genetics’ encompasses transmissible gene variations
genetic makeup(98). However, despite the considerable advances causing or predisposing to development of disease or pheno-
in technology and radical cost reductions of genotyping, early type in question. Transmissible variations in gene function may
experience with use of association genetics was disappointing. also be induced by exposure to outside agents in a process ter-
Monogenic gene disorders, where transmission of variation(s) in med epigenetic regulation, or epigenetics. In a newer challenge,
the makeup of a single gene produce disease via well-described previously ignored short sequences of the genome called ‘mi-
mechanisms (such as the Cystic Fibrosis Transmembrane Con- croRNAs’ have been found to play important roles in regulation
ductance Regulator (CFTR) gene responsible for cystic fibrosis), of gene function, and transmission of de-novo genetic material
were almost never found. Instead, for complex traits (such as via bacterial viruses termed ‘bacteriophages’ may also modulate
height, intelligence, creativity), and traits for complex diseases genetic makeup.
(such as schizophrenia, diabetes and asthma) were found to be The identification of a genetic basis to a disease may be dif-
associated with a dizzying number of variations in wide variety ficult. Sinus physiology is a complex system, with multiple steps
of genes, all offering minor contributions to the observed phe- involved in even a single process such as pathogen recognition

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and initiation of initial defensive responses. Variations in func- comparisons between two or more groups, usually separated
tion of a number of different genes or regulatory elements may according to the element under study. Markers of genetic
lead to dysfunction within this system, ultimately yielding the variation (‘microsatellites’ or single nucleotide polymorphisms
same common disease phenotype. In addition, different genetic (SNP)), single genes or multiple genes of a pathway are compa-
variations within a same gene may produce variable degrees of red to identify differences in frequency of identified traits. The
dysfunction. modern era was ushered in by the introduction of ‘chips’ which
The earliest identified genetic disorders were discovered allowed the simultaneous analysis of 100,000+ SNPs simulta-
because they showed a clear pattern of heritability, with well- neously, interrogating the entire genome in a hypothesis-free
defined disease phenotype or by using markers such as the fashion (Genome wide association study (GWAS)). More recently,
sweat chloride test used in cystic fibrosis (CF). These well-cha- whole-genome sequencing has been used, however, bioin-
racterised genetic disorders implicated a single gene with a high formatic analysis of results remains a rate-limiting step. For
penetrance and strong effects, which made the search for the validation, find­ings must be validated via replication in a second
genetic underpinnings of the disease much simpler. In contrast, population and/or associated with genotype-specific variation
most chronic disease such as asthma and CRS are considered in a biologic mechanism or in outcome. For a number of genetic
‘complex diseases’ where multiple genes are believed to parti- findings, biological plausibility may not be evident as the role
cipate in disease development, with each genetic factor having these genes play in normal function may not yet be described.
weak effects and thereby making only a partial contribution. In One particular problem for CRS is difficulties with statistical
addition, the genetic basis may not be immediately obvious. For methods required in genetic association studies; the size of re-
example, while it may seem obvious that an immune deficiency quired populations and the cost of studies. Analysing the typical
may predispose to chronic infection with bacteria, a defect one million different genetic variations simultaneously increases
in a gene involved of the epithelial barrier may lead to poor the risk of spurious association. Thus large, well-characterised
epithelial regeneration following viral insult, thereby facilitating populations (1,000-10,000 subjects) are required, with their at-
bacterial sub-epithelially and thereby yielding the same result. tendant costs. Caution must be thus be used when interpreting
Despite the considerable difficulties posed by the multiplicity the results from CRS genetic studies in the literature.
of factors implicated in CRS pathogenesis, strong evidence
nevertheless supports that there is nonetheless a hereditary 5.2.1.3. Implications of genetic association studies of CRS
component to CRS. A classic example is CF, where homozygous Despite these challenges, genetic assessments of CRS are sug-
mutations in the CFTR gene lead to defects in chloride transport gesting links with exiting concepts of pathophysiology and
and yield the clinical manifestations of the disease. CRS, prefe- extending the tantalizing promise of future results down the
rentially affecting the maxillary sinuses, is a consistent feature of road. Published genetic association studies in CRS have incre-
CF. Other examples of well-characterised genetic diseases which ased in number over the past decade, increasing the number
include CRS in their phenotype include the forms of ciliary of potential gene candidates (Table 5.2.1.), and also repeatedly
dyskinesia which can be coded for by at least 31 different genes implicating certain genes, supporting their relevance to disease
implicated in coding a different portion of the structural arm of (Table 5.2.2.). Increased numbers allowed us to categorise gene
the cilia(105). candidates according to location or function. In both groups,
More recent work by Oakley et al. assesses the heritability of candidate genes group loosely into regulation of immune func-
CRSwNP and CRSsNP in a more general population. In a study tion, barrier function, and a variety of SNPs in genes whose func-
of 1638 patients with CRSwNP and 24,200 CRSsNP patients, tions are unknown or difficult to integrate into our current vision
they identify that first-degree family members of affected of CRS pathophysiology. Note that the high percentages of iden-
subjects are 4.1 times more likely to develop CRSwNP and 2.4 tified genes related to immune function may reflect a selection
times more likely to develop CRSsNP(106). However, despite the bias of candidate genes studied rather than their actual level of
demonstration of a heritable component, they still suggest an implication. As an example, barrier structure and function genes
environmental factor as spouses of an affected patient are also were not suspected in CRS, but were identified with ‘agnostic’ or
2.0 times more likely to develop CRSsNP as well. This is comple- ‘hypothesis-free’ genome-wide approaches. Subsequently, dys-
mented by work from Sweden. Relatives of patients with nasal function of the epithelial barrier has been confirmed in in vitro
polyposis were screened for CRSwNP. 13.4% of the relatives had models as a novel pathway for CRS development and persisten-
nasal polyps (compared to 2.7% in a control group randomly ce. This improves our understanding of the disease process and
selected from the Swedish population). Thus the relative risk of opens potential new targets and approaches for therapy.
the first-degree relatives having nasal polyps when compared to
the control group was 4.9(107). 5.2.1.4. Epigenetics in CRS
Techniques used to identify the genetic basis of disease involve Epigenetics deals with changes in organisms brought about by

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Table 5.2.1. List of genes associated with CRS in more than one study. Genes are grouped according to putative biological role: a. immune system
related; b. epithelial barrier related; c. difficult to categorize.

a. Immune system

Gene Reference
ALOX5AP Al-Shemari et al. 2008(804); Henmyr et al. 2014(805)
AOAH Bossé et al. 2009(806); Zhang et al. 2012(807)
IL1A Karjalainen et al. 2003(846); Erbek et al. 2007(808); Mfuna Endam et al. 2010(809)
IL1B Erbek et al. 2007(808); Bernstein et al. 2009(810)
IL10 Kim et al. 2009(811); Bernstein et al. 2009(810); Zhang 2012(812)
IL22RA1 Endam 2009(813); Henmyr 2014(805)
IL33 Buysschaert 2010(814); Kristjansson 2019(436)
IRAK-4 Tewfik et al. 2009(815); Zhang et al. 2011(816)
NOS1 Castano et al. 2009(817); Zhang et al. 2011(816); Henmyr et al. 2014(805)
NOS1AP Zhang et al. 2011(816); Henmyr et al. 2014(805)
TAS2R38 Adappa et al. 2014(116); Mfuna Endam et al. 2014(111); Purnell et al. 2019(117)
TGFB1 Henmyr et al. 2014(805)
TNFA Erbek et al. 2007(808); Bernstein et al. 2009(810); Batikhan et al. 2010(818)
b. Barrier and structural
Gene Reference
None None
c. Not easily categorised
Gene Reference
DCBLD2 Pasaje et al. 2012(819); Henmyr et al. 2014(805)
PARS2 Bossé et al. 2009(806); Henmyr et al. 2014(805)
RYBP Bossé et al. 2009(806); Zhang et al. 2011(816); Cormier et al. 2014(102)

modifications in gene expression not resulting directly from al- 5.2.1.5. Clinical uses of genetics and genotyping in CRS
teration of DNA sequences(108). This can lead to the modification
of gene expression which can then be transmitted both intra- 5.2.1.5.1. Characterisation of unexplained immune deficien-
generationally and inter-generationally. “Epigenetics” denote cies
the way that genes interact with the environment in order to Immune deficiencies frequently present as a clinical portrait or
produce each individual phenotype. It is of significant interest phenotype, where an immune defect is suspected but which
that factors associated with increased risk of severity of disease may not be specifically elucidated by common blood tests(114).
such as cigarette smoking or Staphylococcus aureus are both However, sequencing suspect genes may identify the nature
implicated in epigenetic modification. of the defect and allow for specific corrective therapy. A recent
Evidence of epigenetics in vivo is still limited, but nevertheless, example of this has been the novel description of TLR3 receptor
the concepts suggested by these studies are intriguing and hold dysfunction first identified by sequencing patients with herpes
promise for the future(109-113). Most studies assessing blood or simplex encephalitis(115).
nasal epithelia obtained from brushing or raised nasal epithelial
cultures derived from patients have identified that epigenetic 5.2.1.5.2. Assessment and selection of therapy for cystic
changes are more pronounced in epithelium than in circulating fibrosis (CF)
blood, supporting the importance of contact with the external CFTR genotyping is not recommended routinely in CRS patients
environment for their development. This suggests that patho- but is instead performed only following demonstration of CFTR
gens might be playing a role in adapting the environment for gene function impairment via sweat testing. In patients with
evolutionary advantage, and underlines that genetics co-exist positive test (high sweat chloride), this will be followed by gene
with environment, compounding the difficulties in finding a testing for a panel of standard mutations then possibly gene
‘single-gene’ solution to the problem of CRS. sequencing. Type of mutation identified does not predict evo-

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Table 5.2.2. Genes reported in a single study. Genes are grouped according to putative biological role: a. immune system-related; b. epithelial barrier
related; c. difficult to categorize.

a. Immune system CACNG6 Lee et al. 2010(831)

Gene Reference CDH23 Cormier et al. 2014(102)
ALOX15 Kristjansson et al. 2019 (436)
K6IRS2 Cormier et al. 2014(102)
ALOX5 Al-Shemari et al. 2008(804) KCNAM1 Purkey et al. 2014(786)
BDKRB2 Cormier et al. 2014 (102)
KCNQ5 Purkey et al. 2014(786)
CD58 Pasaje et al. 2011(819) K6IRS4 Cormier et al. 2014(102)
CD8A Alromaih et al. 2013(820) LAMA2 Bossé et al. 2009(806)
CIITA Bae et al. 2013 (821)
LAMB1 Bossé et al. 2009(806)
CNTN5 Cormier et al. 2014(102) LF Zielinska-Blizniewska et al. 2012(827)
COX2 Sitarek et al. 2012(822) MMP9 Wang et al. 2010(832)
CYSLTR1 (X)* Al-Shemari et al. 2008 (804)
MSRA Bossé et al. 2009(806)
FOXP1 Kristjansson et al. 2019(436) MUSK Bossé et al. 2009(806)
HLA-DQA1 Kristjansson et al. 2019 (436)
NARF Cormier et al. 2014(102)
HLA-DQB1 Schubert et al. 2004(823) NAV3 Bossé et al. 2009(806)
HLA-DRA Bohman et al. 2017(824) RPGR Bukowy-Bieryłło et al. 2013(833)
IGFBP7 Cormier et al. 2014 (102)
c. Not easily categorised
IL1RL1 Castano et al. 2009 (817)
Gene Reference
IL1RN Cheng et al. 2006(825) C13orf7 Cormier et al. 2014(102)
IL18R1 Kristjansson et al. 2019 (436)
CYP2S1 Kristjansson et al. 2019(436)
IL4 Zhang et al. 2012(807) DPP10 Kim et al. 2015(834)
MET Sitarek et al. 2012(822) FAM79B Cormier et al. 2014(102)
MET1 Castano et al. 2010 (826)
GFRA1 Cormier et al. 2014(102)
OSF-2 (POSTN) Zielinska-Blizniewska et al. 2012(827) GNB2 Purnell et al. 2019(117)
PDGFD Cormier et al. 2014 (102)
HLCS Bohman et al. 2017(824)
PRKCH Cormier et al. 2014(102) KIAA1456 Bossé et al. 2009(806)
RAC1 Cormier et al. 2014(102) MYRF Kristjansson et al. 2019(436)
SERPINA1 Kilty et al. 2010 (828)
PHF14 Cormier et al. 2014(102)
TAS2R19 Purnell et al. 2019(117) PIGT Cormier et al. 2014(102)
TNFAIP3 Cormier et al. 2009(829) SLC13A3 Cormier et al. 2014(102)
TP73 Tournas et al. 2010 (830)
SLC22A4 Kristjansson et al. 2019(436)
TSLP Kristjansson et al. 2019 (436)
SLC5A1 Bohman et al. 2017(824)
VSIR Bohman et al. 2017(824) TOMM34 Cormier et al. 2014(102)
b. Barrier and structural TRHDE Cormier et al. 2014(102)
Gene Reference TRIP12 Bossé et al. 2009(806)
BICD2 Bohman et al. 2017 (824)
UBE3A Cormier et al. 2014(102)
CACNA1I Bossé et al. 2009 (806)
UBE3C Pasaje et al. 2011(819)
CACNA2D1 Cormier et al. 2014(102) 10p14 Kristjansson et al. 2019(436)

lution, as the overall clinical picture is believed to be secondary 5.2.1.5.3. Predictive genetics in CRS
to other ‘modifier’ genes. However, certain genotypes may Given the multiplicity of implicated factors, it is unclear that
predict response to Ivacaflor, a new drug enhancing CFTR gene genetic polymorphisms alone will allow planning of success
function. vs. failure following therapy. However, a number of markers are
already predicting type of bacteria likely to be recovered, which
offers a beginning of a classification of CRS patients.

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Table 5.2.3. Genetic polymorphisms associated with S. aureus carriage in may also play role or have predictive value in CRS, notably the
CRSwNP patients .
(102)
taste receptor TAS2R19 (rs10772420)(111, 117). This remains to be
validated and replicated in other populations.
a. Immune system 5.2.1.6. Staphyloccus aureus carriage in CRSwNP
Gene Genes associated with culture-positivity for S. aureus in CRSwNP
BDKRB2 patients has been assessed in an agnostic ‘hypothesis-free’
CNTN5 fashion using a pooling-based Genome-wide Association study
IGFBP7 (102)
. Presence of S. aureus in CRSwNP patients is associated with
PDGFD a number of genes loosely organised along reduced engulfment
PRKCH of bacteria, modulation of inflammatory response, and genes of
RAC1 barrier elements (Table 5.2.3.). This supports that CRS patients
colonised with S. aureus may be subject to immune impairment
b. Barrier and structural
and dysfunction of the epithelial barrier and may thus be exqui-
Gene
sitely sensitive to low level chronic bacterial infection with S. au-
CACNA2D1
reus. Attempts to predict S. aureus carriage in individual patients
CDH23
implicates several genes acting together to provide additive
GFRA1
effects (Figure 5.2.1.). This supports the concept of multiple ge-
K6IRS2 nes in a pathway interacting to yield a common final phenotype
K6IRS4 (S. aureus carriage) and aligns well with our current concepts of
TOMM34 disease pathogenesis. Given the ubiquity of S. aureus in CRS and
c. Not easily categorised its association with a difficult evolution, having the capacity to
Gene identify patients at risk of S. aureus carriage prospectively might
C13orf7 allow selection of patients for specific anti-S. aureus therapy.
FAM79B
NARF 5.2.1.7. Summary and future perspectives
The current knowledge base in genomics of CRS disease of-
PHF14
fers the tantalizing promise of identifying new mechanisms
PIGT
of disease development and of markers predicting optimal
RYBP
response to available therapies. However, for the moment,
SLC13A3
genetics do not allow prediction of disease or outcome and its
TRHDE
uses are currently restricted to extreme cases to understand the
UBE3A molecular underpinnings of disease. Nevertheless, simultaneous
ongoing revolutions in our understanding of CRS and the dis-
section of implicated mechanisms will complement increased
appreciation of genetic changes. Diagnosis of particular forms of
5.2.1.5.4. Taste receptors: predicting Gram-negative carri- disease or identification of particular predisposing factors may
age help predict evolution and better tailor therapy. Identification of
TAS2R38 polymorphisms have been associated with CRS(116). novel pathogenic mechanism may lead to increased scrutiny of
TAS2R38 codes for a type of bitter taste receptor, which is genes in unsuspected novel pathways.
expressed in the airway and is implicated in innate immune As knowledge regarding and our appreciation of interactions
defence. Activation of T2Rs by bitter stimuli are followed by se- of immune system / microbiome / epithelial barrier improves,
cretion of antimicrobial peptides, production of nitric oxide, and we may be able to develop multi component predictive models
increased ciliary beat frequency. The protective genotype codes that integrate all of the interaction components and allow more
for ability to detect phenylthiocarbamide (PTC), which can be rational administration of therapy and improved clinical care.
assessed by simple taste testing. Interestingly, in CRSsNP, the It will be essential to continue to collect genetic material as a
non-tasting (or non-protective) TAS2R38 genotype is associated component of clinical trials to be able to verify whether iden-
with a higher rate of gram-negative bacterial carriage and a tified factors and factors remaining to be discovered influence
poor outcome. To this end, many physicians now profile taste as response to therapy and can be used for pharmacogenomic
part of patient assessment, however, this does not yet identify purposes.
optimal therapy. Additionally, there is a concern that the effect
may not be similar in patients with CRSwNP. Also, taste receptors

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Figure 5.2.1 Physiologic immune responses across mucosal boundaries Figure 5.2.2. This figure is a proposed model of the Type 1 immune
are tailored to address particular classes of inciting pathogens. Type response in CRS. ILC1 cells and dendritic cells set the process in motion.
1 responses, depicted on the left, are directed against intracellular The Type 1 CRS has not been extensively studied and many of the
pathogens, most commonly viruses. The canonical cytokine is IFN-γ. molecular details have not been confirmed at the protein level. The
Type 2 responses, in the center, are directed against large, extracel- degree of barrier damage, conceptually viewed as a form of tissue
lular parasites. The canonical cytokines are IL-4, IL-5 and IL-13. Type 3 remodeling, is variable. In this figure, neutrophil activity is depicted as
responses are directed against extracellular bacteria and fungi and the the primary driver of barrier damage but other factors such as Type 1
canonical cytokines are IL-17 and IL-22. Each type of response utilizes a cytokines may play a role. Further study is necessary. Other forms of
rapid response mediated by an innate lymphocyte subset (ILC1, 2 and 3 remodeling such as nasal polyposis are less common than seen in Type
respectively) that is linked to a corresponding delayed T helper subset 2 CRS and the pathways less certain. Emerging evidence however, sug-
(Th1, Th2 and Th17 respectively). In CRS, these pathways are typically co- gests that Type 1 polyps are composed of fibrin matrix, similar to Type 2
opted with chronic activation of one or more of these responses in the polyps.
sinonasal tissue.

5.2.1.8. Conclusion 5.2.2. Inflammatory mechanisms of CRS

It is probable that over the coming years we will identify
individual or complex genetic traits conferring susceptibility to The inflammatory mechanisms of chronic rhinosinusitis (CRS)
CRS, evolution of disease, and response to medical or surgical are the molecular pathways leading to the establishment of the
treatment. Given that in other disease areas, genetic traits have mucosal inflammation and tissue remodeling that characterizes
already been identified which allow administration of appropri- this broad syndrome. Multiple inflammatory mechanisms are
ate therapy while minimizing side effects, it is certainly intri- operative, interacting dynamically, and resulting in variable pat-
guing to explore what role genetic variations may play in CRS terns of tissue inflammation that roughly correlate with clinical
diagnosis and therapy. phenotype. Recent attempts have been made to subdivide CRS
As knowledge regarding and our appreciation of interactions into inflammatory endotypes, defined as distinct pathobiolo-
of immune system / microbiome / epithelial barrier improves, gical mechanisms, that may vary in time and between diffe-
we may be able to develop multi component predictive models rent sinonasal anatomic sites in individual patients. From the
that integrate all of the interaction components and allow more standpoint of aetiopathogenesis, the prevailing, as yet unpro-
rational administration of therapy and improved clinical care. ven, hypothesis is that these diverse inflammatory mechanisms
It will be essential to continue to collect genetic material as a are driven by dysfunctional interactions at the mucosal surface
component of clinical trials to be able to verify whether iden- between the host and environmental stressors. From the host
tified factors and factors remaining to be discovered influence standpoint, genetic and epigenetic variation of the muco-
response to therapy and can be used for pharmacogenomic sal immune system is believed to play a key role in CRS, but
purposes. multiple genes are likely involved and thus far, very few have
been associated with a large effect-size. The key environmental

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Figure 5.2.3. This figure is a proposed model of the Type 2 immune Figure 5.2.4. This figure is a proposed model of the Type 3 immune
response in CRS. ILC2 cells and dendritic cells set the process in motion. response in CRS. ILC3 cells and Th17 cells are key, as well as IL-17, IL-22
Type 2 CRS has been been the most extensively studied subset of CRS, and IL-23. Type 3 CRS has not been extensively studied and many of the
and many of the molecular details have been confirmed at the protein details have not been confirmed at the protein level. The degree of bar-
level. The degree of tissue remodeling is greatest in Type 2 CRS, particu- rier damage, conceptually viewed as a form of tissue remodeling, is vari-
larly in terms of fibrin mesh formation and barrier damage. These are able. In this figure, neutrophil activity is depicted as the primary driver
shown in the figure as driven by IL-13 although other factors likely play of barrier damage but other factors such as Type 3 cytokines may play a
a role as well. Inhibition of t-PA (tissue plasminogen activator) results in role. Further study is necessary but the neutrophil response is particu-
the deposition of a fibrin mesh that forms the tissue matrix of polyps. larly strong in Type 3 immunity. Fibrin deposition and polyp formation
Fibrin mesh deposition and polyp formation is less common in Type 1 occurs, but with less frequency than in Type 2 CRS.
and Type 3 CRS, but also appears to involve t-PA suppression. Barrier
damage in Type 2 CRS is often severe, and this may be a key driver of
treatment failure. Factors driving barrier damage include autoimmunity
and complement activation as well as a chronically immature state of
epithelial differentiation driven by IL-13 amongst other factors. (See text
for more details.)

agents also remain largely unctableertain, but cigarette smoke, Type 1 canonical cytokines include IFN-gamma (IFN-g) and IL-12
fungi, viruses, bacteria, pollutants and allergens have all been with the response geared towards addressing viral pathogens
implicated. The most commonly discussed microbial agent (Figure 5.2.2.). Canonical Type 2 cytokines are IL-4, IL-5, and
is Staphylococcus aureus, but some evidence also implicates IL-13, which promote anti-helminth immunity and regulate
dysbiosis of the microbial community as a whole, rather than a tissue regeneration following injury (Figure 5.2.3.). Type 3
specific dominant pathogen. cytokines include IL-17A and IL-22 with immunologic effects
Although the host-environment interactions are complex and directed against extracellular bacteria and fungi (Figure 5.2.4.).
begin very early in life, perhaps in utero, it is important to bear Each immune response pathway is orchestrated by unique in-
in mind that CRS is predominantly an adult onset disorder. This nate lymphoid (ILC) and T helper (Th) subsets that secrete the
suggests that duration, intensity and sequence of exposure, majority of the key cytokines. Importantly, in vivo responses are
including stochastic events such as viral infection, may be key often mixed, with significant plasticity in the ILC and Th subsets
components of pathogenesis in an individual CRS patient. In as well as a self-limited time course. In cases of CRS, mucosal
conditions of health, the sinonasal mucosa acts as a relative barrier penetration by environmental agents also invokes Type
barrier, modulating environmental stimulation including com- 1, 2 and 3 pathways; however, in contrast to the specific, self-
mensal organisms with a specific, self-limited response. In cases limited, pathogen-directed response associated with physio-
of pathogen penetration, single or combined Type 1, 2 and 3 logic host defence, the CRS response is chronic and polyclonal,
immunological response pathways are invoked, generating directed against an array of thus far poorly characterized targets
cytokine, chemokine, innate cellular and T helper (Th) respon- including self-antigens in some severe cases. The resulting tissue
ses designed to eliminate the identified class of pathogen with inflammation is of a mixed pattern and intensity, potentially in-
minimal collateral tissue damage (Figure 5.2.1.). volving multiple endotypes and exhibiting variability in clinical

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presentation (phenotypes), natural history, comorbidities and ons, respectively. A systematic review of all of these publications
outcome. was undertaken for EPOS 2020. This chapter will update the
CRS with Type 2 cytokines is most commonly associated with current understanding of CRS aetiology and pathogenesis. The
asthma and resistance to current therapies. The tissue inflam- environmental factors and host immune elements implicated in
mation is often associated with remodeling patterns including CRS will be reviewed first. The last section will discuss a current
fibrosis, polypoid oedema, fibrin deposition and barrier failure. It concept of aetiopathogenesis and endotypes resulting from
is unclear if factors associated with barrier failure mediate initial host-environment interactions.
barrier penetration, but failure may promote a feed forward pro-
cess whereby the loss of barrier results in greater antigenic sti- 5.2.2.2. Environmental factors
mulation and more inflammation, further damaging the barrier Microbial agents are generally viewed as the most important
and potentially fostering chronicity. Future challenges include a environmental drivers of CRS. Molecular sequencing techniques
better understanding of: 1) the aetiologic factors that drive CRS are evolving in power and are now being applied to study the
with a goal towards prevention; 2) the pathophysiologic inflam- total and relative microbial abundance of the sinonasal tract and
matory mechanisms and relevant endotype biomarkers with a the functional activity of microbiota in health and disease. Acute
goal toward targeted therapy; 3) the molecular mechanisms of viral infection has been implicated in both the initial develop-
barrier and tissue remodeling that may play a role in persistence ment and subsequent exacerbations of asthma, yet the role of
and recurrence. viruses in CRS pathogenesis remains unclear. Studies on bacteria
have revealed the abundance and diversity of bacterial genera
5.2.2.1. Introduction present in the nose and sinuses, further suggesting alterations
Chronic rhinosinusitis (CRS) is a clinical syndrome, rather than in association with the presence of CRS. In particular, the pres-
a specific disease, characterized by persistent symptomatic ence of S. aureus has been hypothesized to potentiate certain
inflammation of the nose and paranasal sinus mucosa for more inflammatory mechanisms of CRS. Fungi seem to affect CRS at
than 12 weeks. This definition is purposely broad and says least in some sporadic cases. Allergens and an array of other
nothing about aetiology, pathogenesis, clinical presentation environmental agents also pay a role in CRS. The final part of this
or natural history. In a small subset of patients, CRS syndrome section will address other environmental factors such as aller-
occurs in association with a known systemic disorder or local gens and air pollutants, which have been little studied in CRS.
process. For the vast majority, aetiology is uncertain although
multiple environmental and host genetic factors have been 5.2.2.2.1. Viruses
implicated. From the standpoint of pathogenesis, these host An RNA virus has RNA as its genetic material. Usually it is single-
and environmental factors interact over time to trigger one stranded RNA (ssRNA) but it may be double-stranded RNA
or more mechanistic pathways (endotypes) of chronic tissue (dsRNA). RNA viruses that contribute to respiratory infections
inflammation that lead to the clinical presentation (phenotype). include rhinovirus, respiratory syncytial virus and influenza.
This chapter will review the host and environmental factors RNA viruses have high mutation rates compared to DNA viruses
implicated in this process and the mechanistic pathways that because viral RNA polymerases lack the proofreading ability
ensue. Overall, while this remains an area of active research, of DNA polymerases(118). The common cold is caused by RNA
relative consensus has emerged on three points: 1) CRS is viruses and is the most common viral disease. Ex vivo studies
typically an antegrade process with the mucosal inflammation of mucosal tissue have shown that rhinovirus infection can be
triggered by a dysfunctional interaction between exogenous linked with exacerbations of CRS, including increased bacterial
agents inhaled through the nose and the host immune system; adhesion; increased susceptibility to secondary microbial infec-
2) specific causal factors likely vary in importance in individual tion (by bacteria, fungi, or other viruses), reduction of epithelial
patients leading to different types or patterns of tissue inflam- barrier integrity, respiratory exacerbations (as in asthma, CF and
mation (endotypes); 3) the clinical characteristics (phenotypes), bronchiectasis subjects); epithelial damage, including necrosis;
natural history and response to treatment will depend on 1 and ciliary dysfunction; and impairment of mucociliary clearance
2. Since the last EPOS document, much research has been done and mucus overproduction(119, 120). A study group evaluated the
to better characterize both the host immune response and the prevalence of rhinovirus and respiratory syncytial virus by per-
environmental stressors that interact in CRS. A Literature search forming PCR to mucus specimens that were collected from 56
covering January 2012 to May 2019 produced 1202 publicati- CRSwNP and 23 CRSsNP patients in Iran undergoing ESS(121). The
ons in English concerning pathomechanisms of human CRS. prevalence of at least one virus was 33%, which is higher than
The most frequently existing search words were “eosinophil” that reported in the literature in healthy adults suffering from
in 401/1202 publications, “epithelium” in 370, “bacteria” in 184, the common cold (10%)(122). Cadherin-related family member 3
“type 2” in 180, “IL-25”in 132 and “lymphocyte” in 87 publicati- gene (CDHR3) is a rhinovirus receptor and its rs6967330 risk al-

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lele (A) has been shown to be associated with childhood asthma 5.2.2.2.2. Bacteria
with severe exacerbations(123) and adult CRS, suggesting a role Bacteria can be classified into five groups according to their
for aberrant rhinovirus effects in the pathogenesis of both disea- shapes (such as cocci) or to their metabolism (such as anaero-
ses(124). Carlson-Jones showed virus-like particles and bacterial bes). This classification has been replaced by an operational
populations by performing flow cytometry to five sinus flush taxonomic unit (OTU), in which bacteria are grouped by DNA
samples(125). Virus infection activates TLR3 and TLR7-9 signaling sequence similarity of a specific taxonomic marker gene, especi-
in human airway epithelium. Tengroth et al. showed defects in ally when analyzing small subunit 16S ribosomal RNA (16S rRNA)
the TLR9 mediated microbial defence close to anatomical origin marker gene sequence datasets(132). 16S rRNA is the component
of polyp, which might explain virus induced polyp growth(126). of the 30S small and highly conserved subunit of a prokaryotic
Golebski exposed epithelial cells from CRSwNP patients to vari- ribosome and thus 16S rRNA -genes are used for quantitation of
ous TLR-specific triggers and detected a higher TSLP- gene and different sinonasal bacteria. Metatranscriptomics is a functional
protein expression in polyp compared to control epithelium, technique profiling gene expression of complex microbial com-
suggesting that this could reflect contribution of viral infections munities enhancing our understanding of the complex com-
to CRSwNP pathogenesis(127). Rowan et al. performed PCR- munity behavior of the microbiome(132). In addition to expres-
based sequencing on sinus samples of 21 CRS patients and 14 sion profiling, the place and timing of sampling are important
controls and detected positive screens in four CRSsNP patients, to consider when investigating host-microbial events of CRS
one CRSwNP patient and none of the controls(66). Coronavirus pathogenesis. Still the greatest challenge remains in identifying
was the most common virus detected. Liao et al. performed causality in microbial contribution to natural homeostasis and
PCR of nine common viruses from middle meatal scrapings of CRS. Acute exacerbations of CRS have been more closely linked
53 controls and 128 CRS patients who were without common to specific bacteria, perhaps following a viral infection, but it
cold(128). Overall about 70% of subjects had viral infections and remains unclear whether the presence or abundance of particu-
there were no significant differences between subject groups by lar bacteria are a cause or a consequence of CRS development.
virus profiles, nor were there associations of viral infection with Commensals likely play important roles in immune priming
symptoms, computed tomography or endoscopic scores(128). and development of healthy sinus mucosa and most microbial
A DNA virus has DNA as its genetic material and replicates using colonies are benign or even beneficial. The resident microbiota
a DNA-dependent DNA polymerase. The nucleic acid is usually imbedded in the respiratory mucus effectively provide the first
double-stranded DNA (dsDNA) but may also be single-stranded line of defence in that commensal organisms prevent coloniza-
DNA (ssDNA), which is usually expanded to double-stranded in tion or proliferation of pathogens and also likely provide certain
infected cells. Notable DNA-viruses in the head and neck region local metabolites that enhance mucosal health. Bacterial com-
under normal conditions and during cancer pathogenesis are munities vary more between subjects than between sites within
human herpes virus Epstein-Barr virus (EBV), and human papil- a subject, although significant regional differences also exist in a
lomavirus (HPV), yet their role in CRS pathogenesis still needs given individual(133).
more evidence from research. Ioannidis et al. detected with Dysbiosis is a term indicating microbial imbalance and some
quantitative PCR a trend that EBV and Human Herpes Virus-6 evidence suggests that it is associated with the sinonasal
(HHV-6) associated with nasal polyps specimens compared microbiome of CRS patients(134-141). Lal et al. performed 16S
to controls(129), whereas Ha et al. did not detect EBV-positive rRNA gene sequencing and showed that microbiome profile of
lymphoid cells in the nasal mucosa of 420 patients who had CRSsNP subjects exhibited decreased diversity and anaerobic
undergone surgical resection of lesions with various diagnoses enrichment(142). The size of an antrostomy(143), as well as comor-
such as CRS(wNP), AR, papilloma, cyst, or septal deviation(130). bid asthma and purulence affect resident bacterial communities
Wang et al. infected cultured inferior turbinate and nasal polyp and may predict surgical outcome(144). Moreover, the sinonasal
samples with either Herpes Simplex Virus-1 (HSV1) or S. aureus bacterial microbiomes are significantly different between heal-
alone or a combination of both(131). Epithelial damage scores thy individuals in general(136), and between sinonasal anatomic
were significantly higher for HSV1 and S. aureus co-infected ex- subsites of an individual patient. Some evidence suggests that
plants compared with control explants or S. aureus only-infected CRS phenotypes are associated with distinct microbiomes(135, 142,
explants, and significantly correlated with HSV1-invasion scores, 145)
and the microbiomes change, at least transiently, after sinus
thus suggesting that HSV-1 infection facilitates invasion of S. surgery(146). Copeland et al. detected that Escherichia was over-
aureus(131). Taken together, virus infection might contribute to represented in CRS sinuses, and that sinus samples were supe-
development and exacerbations of CRS, via damaged airway rior to middle meatal samples as they have less intra-patient
barrier, though further studies are needed. variation(137). Cope et al. performed 16S rRNA gene sequencing
for intraoperative sinus brushings from 59 CRS patients and
10 controls, and detected that CRS patients fall into clusters

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based on co-colonization pattern of Streptococcaceae, Pseu- the precise nature of any dysbiosis remain limited, but these
domonadaceae, Corynebacteriaceae, or Staphylococcaceae(147). newer techniques are only now being applied to large numbers
Each pathogenic microbiota was functionally distinct and was of patients using standardized protocols. The largest study to
associated with distinct host immune responses(147). date did not indicate any key role for a specific organism but did
Traditional culture techniques, as opposed to the newer show that the depletion of two genera (Corynebacterium and
molecular techniques, typically reveal only the most rapidly Peptonophilus) was associated with CRS. It is possible that stu-
growing organisms. Nevertheless, large scale studies have been dies using narrow CRS patient groups may reveal associations
done over the years. Liu et al. performed bacterial culture from with characteristic microbiomes or even the presence of specific
middle meatal swabs of 165 CRSwNP, 76 CRSsNP and 44 control organisms. Nevertheless, this would only be the first step to-
subjects and detected coagulase-negative staphylococci to wards validating the microbiome hypothesis as the association
be closely associated with all three subject groups, whereas S. of a more specific microbial signature with a specific endotype
aureus, Streptococcus, Haemophilus, Enterobacter and Corynebac- or phenotype may not be causative.
terium species were associated with CRSwNP(148). The prevalence A biofilm consists of bacterial colony embedded within an
of Gram-negative aerobic and facultative anaerobic bacteria extracellular matrix of polymeric substances, which makes it
was high in the non-eosinophilic CRSwNP subgroup(148). Another resistant to environmental stress, host defences and antimicro-
study performed middle meatal cultures of 136 CRSwNP, 66 CRS- bial treatment(155). Biofilm layers can be detected by staining and
sNP, and 49 control subjects and revealed that the isolates were light microscopy but characterization of bacterial species and
similar in all three groups, the commonest being coagulase- dynamics of biofilms require advanced optical technology such
negative staphylococcus, Corynebacterium and Staphylococcus as electron microscopy, confocal laser scanning microscopy,
epidermidis and S. aureus(149). The CRSwNP group presented with fluorescent tagging and in-situ hybridization(156). Pathogens
high relative abundance of Citrobacter and the eosinophilic such as Haemophilus influenzae, Streptococcus pneumoniae,
CRSwNP group presented with S. aureus(149). Tabet et al. perfor- Pseudomonas aeruginosa, Moraxella catarrhalis and S. aureus can
med culture of middle meatal swabs from 337 CRS patients and all form sinonasal biofilms in CRS patients, some of which have
showed that S. aureus (33%), Corynebacterium diphtheria (26%), been associated with a worse prognosis. The bacterial compo-
coagulase-negative staphylococci (51%), and Pseudomonas aeru- sition of biofilms vary between the ethmoid bulla and middle
ginosa (7%) were the most frequently recovered organisms(150). turbinate(157). An uncontrolled study detected bacteria in 29/30
Relative abundance of the Bacteroidetes phylum in CRS has been postoperative paranasal sinus specimens and 23/62 strains were
shown to be associated with increased severity of histopatholo- coagulase-negative Staphylococcus epidermidis and 6/62 strains
gical inflammation and the presence of mucosal ulceration(150). were Escherichia coli(155). 58/62 strains were used to assess biofilm
PCR studies have not detected DNA of Helicobacter pylori in na- formation, of which about 30% were moderate to strong biofilm
sal polyp tissue(151), nor C. pneumoniae or M. pneumonia in sinus producers(155). In a Chinese study 13 out of 19 CRSwNP patients
aspirates(152) or nasal polyp tissue(153). Hauser et al. showed that and none of the controls had biofilms, which were associated
culture of ethmoid samples from CRS patients identifies only with increased mucosal inflammatory signs(158), purulent nasal
about 50% of the taxa compared to 16S rRNA gene sequencing, discharge, preoperative Lund-Kennedy scores, serum total IgE,
and 12% of isolates detected by culture were not identified by and previous ESS(159). An uncontrolled study showed that 39/84
16S rRNA gene sequencing, highlighting the need for replica- CRS patients had both ethmoidal osteitis and bacterial biofilms,
tion by several methods(154). and their extent correlated(160). In a study by Marcinkiewicz et
In summary, traditional culture techniques are still used in the al. biofilms were found by scanning electron microcopy in 3/10
setting of acute exacerbations, but their clinical utility and samples from CRSwNP patients undergoing ESS; S. epidermidis
pathophysiologic relevance in CRS has greatly diminished in was the primary isolated bacteria and, biofilm-associated neu-
recent years. The newer molecular microbiome data has provide trophil infiltration was detected with compromised antimicrobi-
support for the hypothesis that dysbiosis of the community as a al activity(161). Arjomandi et al., visualized sinonasal biofilms in 15
whole, as opposed to individual organisms, may trigger mucosal of 20 patients with CRS confirmed by microbial presence using
inflammation(132). From this perspective, the resident microbiota fluorescence in-situ hybridization, and was associated with host
embedded in the respiratory mucus effectively provide the first inflammatory response involving plasma cells and eosinophil
line of defence. Commensal organisms would prevent coloniza- recruitment(162). Overall, the literature indicates an association
tion of pathogens and also likely provide certain local meta- between the presence of biofilm-forming pathogens and CRS.
bolites that enhance mucosal health. The results vary greatly, This suggests the hypothesis that biofilms are potentially an im-
however, depending on the number of subjects, sampling me- portant factor in CRS pathogenesis explaining resistance to con-
thodology, techniques used, depth of sequencing, phenotype ventional therapy. Moreover, the emergence of biofilms due to
and prior treatments. As a result, any firm conclusions about one or more stochastic events could possibly address the ques-

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tion of aetiology, serving as a potential initiating event. It should and upstream from any superantigen effects(170-172). A recent
be kept in mind however, that the simple presence of biofilms report has demonstrated large amounts of locally expressed
does not indicate pathology since the sinonasal tract likely IgE in some Type 2 polyp patients, targeting common resident
exhibits commensal and pathologic biofilms in both health and nasal bacteria including S. aureus, Streptococcus pyogenes and
disease. Detection of the relative abundance of commensal and Hemophilus influenza(172). While the mechanism is unclear, this
pathogenic biofilms would be challenging and any results very study indicates that the Type2-skewing detected in CRSwNP is
difficult to interpret. Moreover, biofilms are a survival adaptation not solely directed against antigens derived from S. aureus.
and the presence of pathogenic biofilms may reflect a response Taken together, implementation of 16s rRNA gene sequencing
to stress (e.g. antibiotics). Lastly, the presence of pathogenic technology on a small scale has suggested that some degree of
biofilms may reflect variation in the host immune response that bacterial dysbiosis may be associated with CRS pathogenesis,
is unrelated to CRS causation. In summary, the role of biofilms in although it is not yet known whether it is a primary or secon-
the aetiology and pathogenesis of CRS remains unclear. dary event. The composition of microbiota varies based on age,
S. aureus is the microbe most commonly associated with CRS. stochastic events, prior treatment, anatomic subsite and, most
Using conventional culture techniques, this organism has been importantly, individual variation. This necessitates very large,
shown to colonize the nasal cavity of one-third of the general well-controlled studies, which, for the most part, have yet to be
population but affects a higher percentage of patients with(163) done. While a large proportion of CRS patient heterogeneity
eosinophilic CRS, specifically CRSwNP patients with asthma(59, could be explained by the composition of their sinus bacterial
164)
. This organism also has the capability to reside within nasal microbiota and related host immune response, it is unclear
epithelial cells, the presence of which in CRS appears to confer a if direct manipulation of the microbiome can be an effective
poor prognosis(102, 151, 152, 165, 166). Some molecular studies support a treatment modality(147). Implementation of hypothesis-free and
key role for staphylococcus as well, indicating a greater abun- functional (such as meta-transcriptomics) approaches may be
dance of S. aureus and altered microbial composition in CRS vs. useful in addressing both causation and therapy.
controls. The largest molecular study on the sinonasal micro-
biome thus far undertaken however, did not suggest a key role 5.2.2.2.3. Fungi
for S. aureus in CRS in general. At this point, aggregate evidence Commensal fungi are present over all mucosal surfaces of the
would suggest that S. aureus is most closely associated with a body, with potentially important roles in CRS. Initial studies
subpopulation of CRS patients, specifically severe CRSwNP and suggesting that fungi were the key drivers of CRS have not been
asthma patients exhibiting high tissue eosinophilia(160). High validated, but their presence, nevertheless, almost assuredly im-
tissue eosinophilia is typically associated with high levels of pacts mucosal health. Similar to bacteria, fungi are also capable
cytokines IL-4, IL-5 and IL-13, which are also known as Type 2 cy- of forming biofilms and secreting toxins but the relevance to
tokines(167). (See section 5.2.2.3 for a more complete description CRS pathogenesis is uncertain. Fungi can be difficult to detect,
of Type 1, 2 and 3 inflammation.) as traditional cultures are not particularly sensitive. Molecular
The precise nature of the association between S. aureus and techniques (such as 18S rRNA gene sequencing) are now being
Type 2 cytokine signaling is however, unclear. The presence applied however, and the knowledge gained should eventually
of Type 2 inflammation should independently favor S. aureus expand our understanding of fungi in both health and CRS.
colonization since Type 2 inflammation suppresses aspects Nuclear ribosomal internal transcribed spacer (ITS) region serves
of the normal immune response directed against S. aureus. In a universal DNA barcode marker for fungal species(173). Hoggard
addition this organism also has the capacity to secrete supe- et al. performed middle meatal ITS2 marker amplicon sequen-
rantigenic toxins that can directly alter the immune response cing of 106 CRS and 38 control subjects and data demonstrated
of the host, in part, triggering locally produced polyclonal IgE. that there is high abundance of Malassezia spp, and while fungal
This is supported by a large, multi-institutional European study, communities vary seasonally, they vary little between subject
which revealed the presence of staphylococcal superantigen groups(174).
effects in a subpopulation of severe, Type 2 CRSwNP patients(153). Zhao et al. estimated fungal biomass by extracting DNA and
Polyp samples from Asian CRSwNP patients, which tend to have measuring ITS amplicon concentration using fluorometry of
lower expression levels of Type 2 cytokines than Western polyps, middle meatal swabs of 63 CRS and 27 control subjects(138). Fungi
show little evidence of superantigen effects(168, 169). Viewed were identified in 14% CRS patients by conventional techniques
conservatively, these findings would suggest that superantigens (culture and histology)(138). This fungus-identified group had a
accentuate but do not initiate Type 2 inflammation. Challenging significantly higher average ITS concentration and a significantly
this perspective are recent papers suggesting that S. aureus lower Shannon's diversity index compared to the other two
is a key player actually driving Type 2 inflammation primarily groups(138). The most abundant organism sequenced was Asper-
via a specific pattern recognition receptor (TLR2) unrelated to, gillus(138). Cleland et al. performed 18S rRNA gene sequencing

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of middle meatal swabs from 23 CRS and 11 control subjects, clearly present in CRS and many have the capability to stimulate
and detected ubiquitous and rich (a total of 207) fungal genera, an inflammatory response, at least in vitro. Any generalizable
Malassezia being the most abundant(175). Fungal richness did not relevance to CRS pathogenesis is, however, quite uncertain as
correlate with QOL and it decreased postoperatively(175). Aurora fungal directed therapies were ineffective. Much more work,
et al. sequenced bacterial 16S and fungal 18S rRNA genes of using large numbers of patients and standardized techniques,
middle meatal lavage samples from 30 CRS and 12 control will be necessary before any firm conclusions can be made
subjects and detected quantitative increase in most bacterial about the fungal microbiome in health and CRS. Although a
and fungal species, and also host secreted IL-4, IL-5, IL-8, and broad role in pathogenesis is uncertain, fungi almost certainly
IL-13, eosinophils and basophils in CRS relative to controls(176). play key roles in two CRS subtypes: fungal balls and allergic
Yet the microbiomes of CRS patients were qualitatively similar fungal rhinosinusitis (AFRS). Aspergillus can cause a fungal ball,
to the controls(176). Hirotsu et al. performed culture, microscopy which is usually unilateral, and is more prevalent in middle aged
and PCR on 35 middle meatal nasal polyps and 15 sphenoidal to elderly females. Histologically, fungal balls are characterized
mucosal samples of controls(177). No microbiological growth or by entangled masses of fungal organisms or masses of fungi
fungal bodies were observed, whereas 16/35 samples showed embedded in fibrinous, necrotic exudate, with minimal mucosal
amplification of fungal DNA (such as C. parapsilosis, R. mucilagi- inflammatory reaction without tissue invasion or granulomatous
nosa and Aspergillus sp), which was associated with enhanced inflammation.
tissue eosinophils(177). Mohammadi et al. performed PCR and Allergic fungal rhinosinusitis was classically defined over 20
clinical examination of sinonasal samples obtained intraoperati- years ago as: 1) Type 1 hypersensitivity; 2) nasal polyposis; 3)
vely from various locations from 100 patients with a suspicion of characteristic CT changes; 4) eosinophilic mucus; 5) presence
noninvasive fungal rhinosinusitis, and showed that the propor- of non-invasive fungus in sinus contents(185). We now know that,
tion of fungal rhinosinusitis was 27% (such as Aspergillus flavus, when using special techniques, fungi can be detected in the
Penicillium chrysogenum and Candida glabrata species complex), nose and sinuses of all patients with and without CRS, indicating
of these 41% were housekeepers by way of occupation(178). that the fifth requirement needs revision. In contrast to normal
Fungi have the capacity to stimulate significant host responses patients and routine CRS, patients with fungal rhinosinusitis
in vitro, suggesting a role in CRS pathogenesis. Using ELISA, have large amounts of fungi that are readily detectable by
Sproson et al. studied cytokines in nasal polyp tissue, challenged routine histologic techniques. The EPOS steering group agreed
ex vivo by Alternaria alternata, Aspergillus niger, Cladosporium that allergic fungal rhinosinusitis (AFRS) should be regarded as
sphaerospermum and Penicillium notatum. Results indicated a subgroup of eosinophilic fungal rhinosinusitis and reserved
that Aspergillus niger stimulation increased pro-inflammatory for subjects with evidence of an allergic reaction to fungi e.g. a
cytokines TNF-α, GM-CSF and IL-6(179). In contrast, stimulation positive skin prick and/or specific IgE.
with Cladosporium sphaerospermum, Alternaria alternata and In comparison to typical CRSwNP patients, AFRS patients tend
Penicillium notatum reduced pro-inflammatory cytokines TNF-α to be younger, express consistently high serum IgE, and have
and IL-6, but induced a dose-dependent increase in remode- milder asthma in general. AFRS is also more common in humid
ling cytokines TGF-b1 and bFGF, which suggests a possible climates with a tendency to present unilaterally(186). Despite
disease-modifying role for fungi in CRS(179). Shin et al. performed the phenotypic differences, distinguishing AFRS and generic
PCR to primary nasal polyp fibroblasts(180, 181), epithelium(182) that CRSwNP has been problematic at the molecular level(187). More
were co-cultured with Alternaria and Aspergillus. They detec- recent work has suggested that an innate immune defect
ted induction of IL-6, IL-8, TLR2, TLR5 and extracellular matrix (possibly in TLR4) may account for fungal accumulation in the
in fibroblasts(180, 181) and fungi and RV-16 induced mucin gene sinonasal cavities of AFRS patients(186). Fungi have intrinsic
expression in epithelial cells(182). Rai et al. performed ELISA of se- protease effects that induce Type 2 cytokine signaling leading to
rum samples for 40 CRSwNP and 20 control subjects and PCR of the accumulation of eosinophilic mucin, which is histologically
nasal lavages for CRSwNP group and detected that serum levels characterized by sloughed epithelial cells, eosinophils, Char-
of IL-1β, IL-17, IL-21, and TGF-β were higher in CRSwNP group cot–Leyden crystals, and scattered fungal hyphae. Furthermore,
compared to controls(183). The proportion of Aspergillus flavus these same protease effects should foster a type 2 response as
positive CRSwNP patients was 78%, and they had increased risk well, favoring local and systemic IgE responses to fungal anti-
of elevated serum IL-17(183). Lawrence et al. co-cultured sinus gens(188, 189). The corollary of this hypothesis would be that fungi
epithelial cells with Aspergillus and Alternaria, from nine CRSwNP drive AFRS, with T and B cells targeting the fungi as a major
and seven control subjects and demonstrated by performing component of the disease. Secondary barrier damage may, ho-
ELISA of cell supernatants that fungi increased IL-6 and IL-8 wever, lead to the targeting of many other colonizing microbes
production in both CRSwNP and control groups, which was thereby blurring the distinction between AFRS and CRSwNP as
decreased by superoxide dismutase(184). In overview, fungi are the process evolves.

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5.2.2.2.4. Other environmental factors with control and non-eosinophilic CRS groups(195). This suggests
Immune responses against airborne allergens with or without that an imbalance of proteases and protease inhibitors within
co-existing CRS are common in Western individuals. The relati- the epithelial barrier may contribute to the pathogenesis of
onship between allergic rhinitis (AR) and chronic rhinosinusitis Type 2 diseases in general(196). As we advance our understanding
has been studied for decades and remains controversial and of the interactions between barrier immunity and the environ-
while many large studies have demonstrated an association, the ment as a function of time, the relationship between allergens
significance is unclear(190). Allergic rhinitis occurs through host and CRS pathogenesis should become clearer.
sensitization to foreign proteins (allergens) across a mucosal Exposure to tobacco smoke alters sinonasal mucosa. Xie et al.
barrier via dendritic cells and naive CD4-positive lymphocytes, performed microscopy and ELISA on polyps obtained from 28
with the generation of antigen-specific type 2 lymphocytes and non-smoking and 21 smoking CRSwNP patients and detected
IgE-secreting plasma cells. The sensitizations patterns for air- that cigarette smoke exposure downregulates expression levels
borne allergens vary significantly by geography, genetics, living of E-prostanoid receptors and stimulates the production of pros-
conditions and climate, amongst other factors(191-193). taglandin E2, IL-8 and TNF-α(197). Mulligan et al. isolated polyp/
Regardless, subsequent allergen challenge across the nasal mucosal dendritic cell subsets from CRSwNP and control sub-
mucosa of sensitized individuals results in cross-linking of IgE jects and detected by flow cytometry that in general, exposure
bound to the surface of mast cells with degranulation, mediator, to tobacco smoke alters the sinonasal composition of dendritic
chemokine and cytokine release, leading to the recruitment cells(198). Tharakan et al. grew sinonasal epithelial cells from con-
of other inflammatory cells. In the unoperated state, allergens trol patients at the air-liquid interface and were able to demon-
should have limited access to the sinus mucosa, but they can strate that cigarette smoke extract stimulation caused disrup-
certainly trigger inflammation of the nasal cavity reducing sinus tion of the epithelial junctional proteins and transepithelial
drainage. An ‘allergic phenotype of CRS’ has been proposed electrical resistance, whereas barrier dysfunction was reversible
by two separate groups of investigators, with primarily central by an antioxidant (Nrf2) activation(199). Huang et al. performed
intense nasal inflammation and milder signs of inflammation in PCR on the nasal tissues of 40 asthmatic patients with/without
the dependent sinuses(194). Further study is necessary to validate CRS and detected that cigarette smoke was associated with IL-
whether an allergic phenotype of CRS is a significant discrete 17A activation and lesser improvement of asthma control after
entity. sinonasal surgery(200). Kule et al. performed polyp microscopy in
Severe CRS is, in general, not regarded as an allergic disease, but 30 smoking and 47 non-smoking CRSwNP patients and showed
co-existing allergic rhinitis will accentuate Type 2 inflammatory no differences between the groups in basement membrane
mechanisms of CRS. There is limited epidemiological evidence thickness, goblet cell hyperplasia, subepithelial oedema, submu-
of an association with nasal polyposis and it has been inter- cous glands, tissue leukocyte subsets, squamous cell metaplasia,
preted that allergy does not increase the probability of CRSwNP. or stromal cell atypia(201). Shin et al. stimulated nasal fibroblasts
A recent study in the Chinese population showed distinct muco- with cigarette smoke extract which had a stimulatory effect on
sal immunopathologic profiles in atopic and nonatopic CRSsNP vascular endothelial growth factor mRNA and protein expres-
patients, suggesting that in the Chinese population the comor- sion through the TLR4, ROS, MAPK and NF-kappaB signaling
bid CRSsNP and AR might be more related to Type 2 mechanis- pathways(202).
ms, whereas the phenotype CRSsNP without AR exhibits more Ozone is an air pollutant with known proinflammatory effects
non-Type 2 mechanisms(187). Clearly, there is significant overlap on exposed epithelia. Zhu et al. cultured polyp/mucosa from
between AR and CRS in terms of Type 2 cytokines. While the CRSwNP ±ASA intolerance and control subjects and exposed
initiating events in CRS are unknown, allergen sensitization is, in these in vitro to ozone(203). They showed by immunohistoche-
part, related to complex interactions with the epithelial surface. mistry and ELISA that after ozone exposure, Cox1/2 expression
Allergens typically possess intrinsic protease activity that can remained unchanged in all groups, yet PGE(2) release was
interact with epithelial cells through three principle pathways: lowered more in ASA tolerant than in ASA intolerant patients
direct effects on junctional proteins, reaction with cell surface after ozone exposure(203). Clara cell protein 16 (CC16) is produced
protease-activated receptors and toll-like receptor 4 (TLR4)- by non-ciliated Clara cells in the respiratory epithelium and has
dependent epithelial activation(186). Protease activity of allergens an anti-inflammatory role in chronic upper and lower airway eo-
may elicit the release of epithelial-derived Type 2-driving cytoki- sinophilic inflammations(204). Decreased levels of CC16 are found
nes and chemokines, some of which have also been implicated in the nasal secretions and plasma of patients with chronic eosi-
in CRS. In terms of potential overlap between AR and CRS pa- nophilic inflammatory disorders, such as asthma, allergic rhinitis
thogenesis, Kouzaki et al. showed lower host expression of two and CRSwNP and CRSsNP, as well as in people exposed to high
protease inhibitors (cystatin A and SPINK5) in the nasal epithelial levels of air pollutants(204). Tissue metal levels are increased due
cells extracted from patients with eosinophilic CRS compared to smoking, environmental and occupational exposure. Khlifi

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et al. studied blood concentrations of heavy metals, cadmium ting and recruited phagocytes (monocytes and neutrophils), in-
and nickel, in 90 CRSwNP and 171 control Tunisian subjects nate lymphoid cells, NK cells, as well as non-cellular components
and higher heavy metal concentrations were associated with (e.g. complement system). The major functions of the sinonasal
CRSwNP, with tobacco consumers and with CRSwNP patients innate immune system include phagocytosis, recruiting im-
with occupational exposure(205). Among risk factors, shisha con- mune cells to sites of infection, activation of the complement
sumption, environmental exposure and occupational exposure cascade to identify and clear off bacteria, antibody complexes
presented the most significant association with CRSwNP(205). The or dead cells, identification and removal of foreign substances,
same study group measured cadmium, chromium, nickel and ar- and activation of the adaptive immune system through antigen
senic by atomic absorption spectrometry of polyp/nasal mucosa presentation.
from 55 CRSwNP subjects and they detected increased heavy
metal levels in polyp tissue compared to non-polyp tissue from Epithelial barrier
the same patient, suggesting a role of heavy metal exposure in The sinonasal tract is covered by ciliated pseudostratified
CRSwNP pathogenesis(206). Yamin et al. stimulated with cigarette columnar, olfactory, and to lesser extent layered squamous
smoke extract or dsRNA cultured polyp/mucosa from CRSsNP, epithelium (in the nostril area). Airway epithelium plays a critical
CRSwNP and control subjects and detected increased TGF-β1 role in conducting and humidifying air, responding to trigeminal
and activin A in CRSwNP patients, suggesting that cigarette and olfactory stimuli, and host defence. Airway epithelial barrier
smoke and viral infection might contribute to polyp remode- comprises ciliated cells, olfactory cells (in olfactory epithelium)
ling(207). mucus-secreting goblet cells, and basal cells which are consi-
There is limited knowledge of the effects of nutrition on CRS dered progenitor cells(210). More recently, solitary chemosensory
pathogenesis. Vitamin D and its receptors might be involved cells (SCCs) have also been reported in the sinonasal epithelium,
in the regulation of the immune system and may play role in playing a significant role in IL-25 production contributing to
CRS. Tomaszewska et al. performed immunohistochemistry of Type 2 immunity(211).
ostiomeatal complex tissue from 52 CRSsNP, 55 CRSwNP and 59 Transcriptomics of healthy middle turbinate epithelium showed
control subjects and detected a decrease in vitamin D receptor that about three quarters of protein coding genes are expressed,
nuclear staining in CRS patients as compared to controls(208). suggesting nasal epithelium is a very active organ(212). Both
Vitamin D3 deficiency has been shown to cause changes in epithelial specification and terminal differentiation are critical
murine sinonasal immunity as measured by tissue immune cell to epithelial homeostasis. Environmental and mucosal signals
infiltrate and nasal lavage cytokine levels(209). regulate epithelial stem-cell self-renewal under normal conditi-
ons(213) and in CRS(112). Under physiological conditions environ-
5.2.2.3. Host factors mental and intrinsic signals are able to alter the composition
The function of the immune system is to maintain homeostasis and function of epithelium rapidly. Hence investigating the role
and to prevent or eradicate infections, but chronic activation of differentially expressed epithelial genes or proteins between
can also be seen in a range of disorders. Host defences are CRS and controls in a cross-sectional set-up is challenging.
grouped under innate immunity which provides immediate Single cell transcriptomics detect cell subtypes exhibiting
protection against microbial invasion, and adaptive immunity distinct gene expression profiles and are able to trace cell
which provides a delayed but more specialized defence against transitions in development and disease. Ordovas-Montanes et
infections. The innate and adaptive immune systems are presen- al. performed single cell transcriptomics of polyp/scraping epi-
ted in this section as discrete functional entities, but they largely thelium from 12 CRSwNP and 9 control subjects and detected
overlap in nature. The initial portion of this section will discuss differences in expression of antimicrobial genes by secretory
the cells and molecules that are related to innate immunity cells, a loss of glandular cell heterogeneity, and that polyp basal
responses. Next the adaptive immune responses are discussed. progenitor cells were locked by a Type 2 memory(112). Epithelial
The final part of this section will address other host factors, such basal progenitor cells are able to migrate and proliferate into
as remodeling, which is presumably driven by the presence of ciliated and goblet cells in injured regions. Epithelial cells may
the chronically activated immune response. also de-differentiate through squamous metaplasia or epithelial
to mesenchymal transition (EMT), which describes a rapid and
5.2.2.3.1. Innate immunity normally reversible modulation of the epithelial phenotype
Innate immunity is present in healthy individuals at baseline, toward mesenchymal cells(214). Epithelial cells undergoing EMT
prepared to block the entry of microbes and to rapidly eliminate lose cell-cell polarity and adhesion to become migratory and
microbes entering the host tissues. The components of innate usually downregulate junctional proteins (such as E-cadherin)
immune system include epithelial barrier, sentinel mucosal cells while acquiring mesenchymal features such as alpha-smooth
(resident macrophages, dendritic cells, mast cells etc.), circula- muscle actin, vimentin, matrix metalloproteinases (MMPs), and

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the transcription factors. Studies on polyp and control tissue stasis and inflammation(247). Kim et al. performed immunofluo-
show that CRSwNP may be associated with elevated expression rescence microscopy and qPCR to sinus mucosa biopsies from
levels of MMP-1(215, 216), MMP-2(215), TIMP-1(217, 218), MMP-7(219, 220), 11 CRS and 7 control subjects and detected increased gene and/
MMP-9(215, 217-219, 221-224), and suppressed TIMP-2(221) and E-cadher- or protein expression of connexins in CRS compared to con-
in(225-227) expression. Periostin binds to several integrin molecules, trols(247). The relevance to CRS pathogenesis remains unclear.
including αVβ1, αVβ3, and αVβ5 on the epithelial cell surface to Cilia are microtubule-based hair-like organelles that are funda-
support adhesion and migration of epithelial cells, and elevated mental to the development and physiology of many organs.
airway mucosal periostin may be useful in detecting Type-2 Mucociliary clearance (MCC) and apical junctional complexes
CRSwNP(228-238) and asthma(239). Kim et al. suggested that a main between epithelial cells comprise a mechanical barrier between
cellular source of periostin in eosinophilic CRSwNP are mast host and environment, which provides the first line of host
cells(240). Regardless, it has been proposed that abnormalities of defence for the nose and sinuses. Coordinated ciliary beating
epithelial turnover and maturation may result in an immature, transports debris-laden mucus from respiratory passages
leaky barrier with significance in CRS pathogenesis(230). This will towards the oropharynx(248). Genetic and acquired defects in
be discussed further in section 5.2.2.3.3. mucociliary flow with increased mucus viscosity are associated
Epithelial physical barriers are maintained by intercellular with a high incidence of CRS(69, 249). Li et al. detected structural
junctions, especially tight junctions (TJs). TJs are located most and functional abnormalities in the cilia obtained from CRSwNP
apically, are linked to cytoskeleton, and inhibit solute and water patients(250, 251). The cytokines IFN-γ and IL-13, but not IL-17
movement through the paracellular space, thus establishing decrease differentiation of ciliated epithelial cells and secon-
cell polarity(214). TJ molecules and epithelial barrier function in dary reduction in ciliary beat frequency(251). Ma et al. cultured
CRS may be modulated by various internal and external factors sinonasal epithelial cells and found that cilia loss and decreased
such as inhaled allergens, microbial or viral infections, cytokines, expression of WDPCP, a ciliogenesis protein, are associated with
hypoxia, or zinc deficiency(241). Several genes/molecules, such as CRScompared to controls(252). Overall, these studies indicate that
SPINK5, S100A7, S100A8/9, PCDH1, NDRG1, SPRR, and p63 are CRS is commonly associated with ciliary dysfunction.
involved in modulating the physical barrier function in CRS(241). Cilia are coated with membrane-spanning mucins and tethered
Epithelium membrane protein 1 (EMP1) is a TJ protein media- mucopolysaccharides that exclude mucus from the periciliary
ting cell proliferation and its gene and protein expression has space and promote formation of distinct mucus layers(214). Secre-
been shown to be lower in nasal polyp epithelium compared tory cells produce a different class of mucins, the polymeric gel-
to control nasal mucosa(242). Soyka et al. detected a decreased forming mucins. The two major airway gel-forming mucins are
trans-tissue resistance in biopsy specimens from patients with MUC5AC and MUC5B. Some secretory cells, known as mucous
CRSwNP along with decreased TJ proteins(243). Suzuki et al. mea- or goblet cells, produce mucins and store them within easily
sured electrical impedance in vivo using a tissue conductance visualized collections of mucin granules, whereas other cells
meter and performed microscopy and qRT-PCR, detecting that produce and secrete mucins (especially MUC5B) but lack pro-
electrical impedance did not differ between the turbinate and minent granules(214). Gel-forming mucins are secreted into the
polyp tissue(244). The polyp tended to show higher expression of airway lumen and are responsible for the characteristic viscoe-
claudin-1 but showed lower expression of tricellulin than the lastic properties of the mucus gel layer. Tipirneni et al. identified
turbinate(244). Jiao et al. assessed transepithelial resistance in ALI- that dynamic mucus strand velocities from submucosal glands,
cultured polyp/mucosal samples from 17 eosinophilic CRSwNP, a major component of MCC, were significantly decreased in CRS
15 noneosinophilic CRSwNP and 20 control subjects and detec- patients compared to controls(253).
ted that integrity of epithelial TJ barrier in the nasal epithelium Surfactants are compounds that lower the surface tension.
is compromised in Chinese patients with eosinophilic and El-Anwar et al. performed PCR and immunohistochemistry on
noneosinophilic CRSwNP, and that TGF-β1 plays an important inferior turbinate and sinus mucosal biopsies from 30 CRS, 30
role in inducing TJ barrier defects(245). Li et al. showed that the primary atrophic rhinitis and 20 control subjects, and demon-
expression of epithelial ZO-1, claudin-1, DSG1 and DSG2 in the strated that Surfactant protein A gene expression was increased
CRSwNP patient group and the expression of claudin-1, DSG1 in CRS and decreased in primary atrophic rhinitis patients com-
and DSG2 of the CRSsNP patient group was significantly lower pared to controls(254).
compared to that of the control group(246). Overall, these data Pattern recognition receptors (PRRs) rapidly detect microbial
suggest that the mechanical barrier is more susceptible to pene- and other foreign molecular patterns and either maintain
tration in patients with CRS. homoeostasis or induce immune responses. Toll-like receptors
Epithelial cell communication is mediated via, for example Gap (TLR1-TLR10), NOD receptors, RIG-like receptors and dectins are
junction channels, which are formed by connexin proteins and among the best-known pattern recognition molecules(214). Ten-
they facilitate communication between adjacent cells in homeo- groth et al. demonstrated that nasal apical epithelium expresses

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abundant TLR3, TLR7, TLR9, RIG-I, and MDA-5, and that TLR- Innate lymphoid cells
agonist-stimulation leads to upregulation of several secreted Innate lymphoid cells (ILCs) are lineage and antigen receptor-
cytokines(255). The group detected defects in the TLR9-mediated negative lymphocytes including natural killer (NK) cells and at
microbial defence in the turbinates of CRSwNP patients, which least three distinguishable cell subsets (ILC1, ILC2, ILC3)(167) that
could in part explain virus-induced polyp growth(126). Studies rapidly produce cytokines (IFN-γ, IL-5, IL-13, IL-17A, IL-22) upon
on polyp and control tissue show that CRSwNP may be related activation(273). As such, ILCs can act as first-line defenders in
to increased epithelial expression levels of TLR 2(256) and 4(256-258). the airway epithelial barrier. ILC1, ILC2 and ILC3 correspond to
Nasal polyp fibroblast activation may occur via TLR 2(181, 259, 260), the Th1, Th2, and Th17 subsets of CD4+ T cells, respectively(274).
TLR 4(261, 262), TLR 5(181), and TLR 9(263) might be related to polyp B The development of ILC2s, the best studied of ILC subsets, is
cell activation(264). controlled by the GATA-3 transcription factor and they pro-
NOD family PRRs form a major component of the inflam- duce IL-5 and IL-13(275). In response to tightly regulated local
masome, which is a multiprotein oligomer that maturates and environmental cues, ILCs can generate characteristics of other
secretes pro-inflammatory cytokines interleukin 1β (IL-1β) and subtypes, a process known as plasticity(275). ILC2s can promptly
interleukin 18 (IL-18). This results in pyroptosis, a form of pro- shift to functional IFN-γ-producing ILC1s or IL-17-producing
grammed pro-inflammatory cell death distinct from apoptosis. ILC3s, depending on the cytokines and chemokines produced
Jardeleza et al. performed microscopy and PCR of polyp/mu- by antigen presenting cells or epithelial cells. Due to as yet
cosal samples of CRS patients with/without S. aureus biofilms, unknown triggers, this complex network of signals may become
and detected involvement of inflammasome complexes and dysregulated(275). Several distinct ILC precursors (ILCP) with pan-
their signaling pathways in biofilm positive CRSwNP(265). Lin et ILC (giving rise to all ILCs) or subset-restricted potentials have
al. performed microscopy and ELISA of polyp/mucosal samples been described(273). How and where these different ILCPs give
from CRSwNP and control subjects and detected that NLRP3 rise to more mature tissue-resident ILCs remains unclear. Re-
(NACHT, LRR and PYD domains-containing protein 3) and cently, environmental signals have been shown to epigenetically
caspase-1 were overexpressed in eosinophilic CRSwNP, and that influence canonical ILC differentiation pathways, generating
the inflammasome signaling pathway was augmented by LPS substantial functional plasticity(273). Although there is significant
but suppressed by glyburide, suggesting that inflammasome is intergroup plasticity, each ILC group appears to have a distinct
playing a pro-inflammatory role in eosinophilic CRSwNP patho- physiologic role and cytokine profile described as Type 1, 2 and
genesis(266). 3 inflammation respectively(276). ILC1 cells respond to viruses and
Bitter taste receptors (T2Rs), also present on epithelial cells, intracellular bacteria, fostering a Th1 lymphocyte response and
function as non-classical PRRs. They are G protein-coupled release various cytokines including IFN-g which is considered
receptors (GPCRs), which are widely expressed in host airway the canonical Type 1 cytokine. ILC2 cells target parasites, assist in
epithelial membranes. Airway T2R-mediated immune responses tissue repair and also mediate allergy. They foster type 2 respon-
are activated by bacterial quinolones as well as acyl-homoserine ses and are associated with the canonical Type 2 cytokines IL-4,
lactones(267) secreted by gram-negative bacteria, including Pseu- IL-5 and IL-13. ILC3 cells target extracellular organisms, foster
domonas aeruginosa(268). Linkage studies have demonstrated Th17 responses and release IL-17 and IL-22, canonical Type 3
associations between taste receptor genetics and CRS(269). cytokines(277, 278). ILC2 cells are the best studied in CRS, playing
Both mucosal and glandular epithelium secrete a large ar- a significant role in eosinophilic CRSwNP, and possibly all CRS
ray of host defence molecules (such as surfactant, lactoferrin, that exhibits Type 2 inflammation. ILC2s are likely an important
defensin) that are known to kill or neutralize microorganisms. source of Type 2 cytokines that drive tissue inflammation. On
Disruption of this antimicrobial action might lead to the risk of the other hand, while canonical Type 1 and Type 3 cytokines are
colonization or infection by microorganisms, which might be clearly present in the tissue of some CRS patients, the impor-
associated with the pathogenesis of chronic airway inflamma- tance and contribution of ILC1 and ILC3 cells to this process is
tion. Baseline levels are secreted into the mucus and production unclear. From the standpoint of epithelial signaling to ILCs in
is increased with PRR stimulation. Some evidence suggests that CRS, the key upstream epithelial cytokines thus far identified
decreased secretion of some host defence molecules is asso- include IL-25(279-281), IL-33(279-281), and thymic stromal lymphopoie-
ciated with CRS(270). Studies on polyp and control tissue show tin (TSLP)(127, 279, 280, 282-284). They activate ILC2 cells as well as other
that CRSwNP may be related to decreased expression levels of cell types, which is the physiologic response to parasites. A more
PLUNC, possibly secondary to loss of glands, as well as increased comprehensive knowledge of the molecular mechanisms that
surfactant-B and alpha-defensin expression(265, 267, 271, 272). Protease regulate ILC development and effector functions may allow for
inhibitors regulate environmental proteases that might compro- better understanding of their role in CRS.
mise barrier and they have been discussed in the earlier section
on allergens (5.2.2.4).

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Neutrophils early stages of epithelial repair but excess amounts or the dimi-
Neutrophils, also known as polymorphonuclear leukocytes, are nished follow up signals have been associated with defective
the most abundant leukocytes in the blood and are important barrier regeneration(292, 295), helping to drive Type 2 CRS(293).
in the early phagocytosis and killing of extracellular mucosal
microbes(274). Neutrophil recruitment is driven in large part by Monocytes
microbial stimulation (via pattern recognition receptors) or tis- Monocytes are less abundant in the blood than neutrophils, and
sue damage signals, and epithelial release of IL-8(285). In response they also ingest microbes in the blood and tissues(274). During in-
to bacterial or fungal infection, the production of neutrophils flammation, monocytes extravasate into the tissue and differen-
from bone marrow increases, rapidly leading to their increased tiate into macrophages, which may survive for a long time, even
levels in blood(274). Neutrophils typically live for only 1-2 days, years(274). Macrophages exist in all connective tissue and organs
expressing receptors for products of complement activation and of the body, having diverse roles that include removal of particu-
for antibodies that coat microbes(274). These receptors increase lates, primary response to pathogens, tissue homeostasis, coor-
the ability of the neutrophils to kill ingested microbes. The role dination of the adaptive immune response, inflammation and
of the neutrophil in CRS pathophysiology remains unclear, but tissue repair(296). There are two types of activated macrophages,
they are found in all or nearly all cases, with the highest tissue M1 and M2. M1 macrophages are the dominating phenotype
levels seen in CF patients(286). For other forms of CRS, differences observed in the early stages of inflammation, and the activation
appear to depend on ethnicity as well as on the presence or is driven by Type 1 cytokines that trigger a proinflammatory res-
absence of nasal polyps. In Caucasians, neutrophilic infiltration ponse necessary to kill intracellular pathogens. The alternative
can be demonstrated in CRS, with slightly lower levels observed pathway is driven by Type 2 cytokines in the local milieu, which
in CRSsNP than in CRSwNP. Nevertheless, in general, the degree leads to activation of M2 macrophages; this process is important
of neutrophilic infiltrate is comparable between CRSsNP and in the defence against helminths, in humoral immunity, and
CRSwNP as opposed to the eosinophilic infiltrate, which is in tissue repair. Conversion to M2 status may be important in
significantly less in CRSsNP. As a corollary, it has been suggested Type 2 CRSwNP and CCL23 may be the key chemokine for the
that CRSsNP is more distinctly a neutrophilic process, whereas recruitment of macrophages into the polyp, which then convert
CRSwNP is more eosinophilic, based on the relative degree of to M2 in the Type 2 cytokine milieu(297). These M2 macrophages
tissue infiltration(286). In the subpopulation of CRSwNP patients appear to have an impaired ability to phagocytose and also
with relatively low eosinophilic infiltration, it has been sug- secrete high levels of CCL18, a cytokine known to be chemotac-
gested that neutrophils may be the major pathologic driver tic for dendritic cells, naïve T cells, and Th2 cells — all of which
of disease, analogous to ‘neutrophilic’ asthma(287). In studies of may contribute to the pathogenesis of CRSwNP(298). M2 macro-
polyps from Chinese patients, although both neutrophilic and phages are also important sources of factor XIII-A in Caucasian
eosinophilic infiltration are decreased compared with polyps CRSwNP patients, which induces excessive fibrin deposition and
in Caucasian patients, the degree of eosinophilia reduction secondary tissue oedema in nasal polyps(299-302). In relationship
is much more pronounced, which suggests these polyps are to CRSsNP, macrophages have not been extensively studied, but
relatively neutrophilic(288, 289). Immunologic profiling of Asian they are often elevated, presumably play a central role in Type 1
CRSsNP demonstrated strong Type 2 and 3 inflammation with CRS inflammation. Macrophages may also recruit both eosinop-
dominant neutrophil-related markers, which were associated hils and neutrophils to the site of inflammation(299, 303, 304).
with disease extent(290). Neutrophils are driven most strongly by
Type 3 cytokines and their infiltrates often co-exist with Type-2 Basophils
cytokine-driven eosinophils, suggesting the possibility that Basophils are granulocytes found mainly in the circulation
this tissue neutrophilia may reflect a superimposed physiologic and are known to have a role in allergic disease and immunity
response against microbiota in CRS patients(286, 290-292). Clinically, against parasites. They have been implicated in Type 2 respon-
this may explain some degree of corticosteroid resistance seen ses in general, possibly serving as an early source of IL-4 driving
in some forms of CRS(293). polarization in the Th2 direction (see below)(167). They are parti-
The role of neutrophils in CRS pathogenesis is uncertain, but cularly elevated in aspirin tolerant polyps as opposed to N-ERD
these cells are capable of degranulation with tissue damage polyps. Their significance in CRSwNP remains unclear.
including some loss of barrier integrity. In addition, similar to
macrophages(286, 291), neutrophils can differentiate from the N1 Mast cells
phagocytic type, into the N2 form of neutrophils in the presence Mast cells are present in all connective tissues, especially under
of Type 2 cytokines. Among other factors, N2 neutrophils release epithelia, and adjacent to blood vessels with physiologic roles in
oncostatin M (OSM), which is important in epithelial repair and innate immunity and wound healing(305). They can be activated
homeostasis(291, 293, 294). OSM is believed to be operative in the by microbial products binding TLRs and by components of the

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complement system as part of the innate immunity or by an these cells in CRS, recent studies have demonstrated that tissue
antibody-dependent mechanism in adaptive immunity. Mast eosinophilia correlates with a relatively poor outcome indepen-
cell granules contain vasoactive amines such as histamine that dent of the presence or absence of polyps(323, 324). Consequently,
cause vasodilation and increased capillary permeability, as whereas eosinophils are not essential for CRS to exist, they ap-
well as proteolytic enzymes, lipid mediators, chemokines and pear to be a biomarker for severe, recalcitrant disease, and may
cytokines, which provide a defence against helminths, other still be the cell that mediates this relatively poor prognosis(325, 326).
pathogens and animal venoms, and which are also responsi- Systemic or tissue biomarkers for eosinophilic CRS could have,
ble for early onset allergic symptoms via antigen-driven IgE therefore, a significant clinical role(327, 328).
cross-linking(305). Overall, the downstream effects of this process The overall process of eosinophil recruitment, activation and
include tissue oedema, degradation of the ECM, and diminished survival in CRS is driven largely by epithelial cytokines, exoge-
barrier integrity. In CRS, interest has centred on a role for mast nous proteases, complement proteins, eicosanoids, stem cell
cells in nasal polyposis, in part as a result of the potential to in- factor and Type 2 cytokines(198, 284, 329-331). The critical upstream
duce, augment and maintain eosinophilic inflammation through cellular sources of the Type 2 cytokines in eosinophilic CRS in-
IgE-dependent and IgE-independent processes(306). Specifically, clude ILC2 and Th2 cells(332). Although the pathological effects of
local IgE class switching directed against common aeroallergens eosinophil activity in CRS are unclear, presumably degranulation
may mediate mast cell activation and contribute to subsequent causes tissue oedema, epithelial sloughing and possbily some
eosinophilic inflammation in CRSwNP, but non-IgE mediated ac- fibrosis, as has been reported in asthma(333, 334). Eosinophils have
tivation mechanisms such as CD30L may also be play a role(307). also been shown to exert a host defence effect against bacteria
Mast cells, along with platelets (see below), may be sources at sites of barrier damage via the formation of extracellular traps,
of proinflammatory leukotrienes (cysLTs) and prostaglandins which may have collateral negative effects on barrier integrity
(PGD2) in CRSwNP and N-ERD(308, 309). Mast cells in CRSwNP are as well(335). The mechanism for eosinophil degranulation in CRS
localized near the glandular tissue of polyps, but the clinical is unclear, but data from other tissues suggest that cross-linking
significance is unclear(310-312). Recent clinical trials using anti-IgE of receptors for IgA is an important trigger(336). High levels of IgA
for CRSwNP have also demonstrated efficacy independent of have been identified in nasal polyps, which suggests that this
systemic allergy, which suggests the potential importance of immunoglobulin may play a key role in vivo(337, 338).
the mast cell in at least a subtype of CRSwNP patients with local The association of eosinophilia with refractory disease makes
IgE production(313). Overall, however, the relative importance of this cell a potentially important target in CRS. Eosinophils are
mast cells versus other cell types in the pathogenesis of CRSwNP steroid responsive, which likely explains at least some of the
remains unclear(314). therapeutic effects of glucocorticoids in CRS(339). A double-
blinded trial using oral corticosteroids demonstrated clinical
Eosinophils efficacy and reduced IL-5 and eosinophilic cationic protein in
Eosinophils have a significant role in tissue repair and immune nasal secretions(340). Unfortunately, systemic steroids have broad
defence, in particular against helminths(274). Eosinophils are also tissue effects resulting in significant morbidity. A more directed
an important cell type in asthma, AR and CRS; and CRS was approach has been suggested by recent papers which identified
at one time considered by many to be a purely eosinophilic specific features of activated eosinophils, variations that could
disease. Eosinophilic damage to the sinonasal mucosa was be- potentially be targeted to reduce tissue eosinophilia(328). This
lieved to be the central pathophysiologic mechanism of CRS and concept has been utilized in early clinical trials using anti–IL-5
the hallmark of the disorder(315, 316). It was always clear, however, and in CRSwNP with evidence for reduced polyp eosinophilia
that non-eosinophilic forms existed, and some cases of CRS de- as well as clinical efficacy(341). Although the majority of CRSwNP
monstrated relatively minimal eosinophilia with a predominant in Western countries demonstrate a Type 2 cytokine profile
influx of other cell types(317). Notably, separation of CRS tissue with polyp eosinophilia(342-344), only about half demonstrated
specimens into CRSsNP and CRSwNP demonstrated that tissue significant polyp shrinkage with anti-IL-5 mAb therapy(341). In
eosinophilia was much higher on average in polyps(318, 319). This addition, a recent study utilizing the oral anti-eosinophil drug,
close association, independent of atopy, suggested that eosi- dexpamipexole, demonstrated a >90% decrease in both blood
nophils may be critical to polyp formation, but the relationship and polyp eosinophils in CRSwNP patients without significant
between CRSwNP and mucosal eosinophilia is not maintained improvement in symptoms or polyp shrinkage(345). These results
in Asian polyps or in a demonstrable minority of Western/Cau- suggest that despite being a predictive marker for disease-se-
casian polyps(320, 321) in comparison to most Caucasian polyps(322). verity, eosinophils may account for only a portion of Type 2 CRS
Taken together, these studies indicate that eosinophils are not pathophysiology.
absolutely necessary for nasal polyposis or CRS to be present.
Although this might appear to diminish the importance of

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Natural killer cells the development of the aspirin-induced reactions.

Natural killer (NK) cells are a type of cytotoxic lymphocyte
critical to the innate immune system. NK cells recognize infected 5.2.2.3.2. Mechanisms of adaptive immunity
and stressed cells and respond by killing these cells and by The separation of the innate and the adaptive immune respon-
secreting the macrophage-activating cytokine IFN-γ(274). NK cells ses into distinct compartments is artificial; in vivo, these two
do not express immunoglobulins or T cell receptors, the antigen arms of the immune response are mutually supportive and
receptors of B and T lymphocytes. On activation by (virus-) distinctions have been blurred. Nevertheless, the separation is
infected cells, NK cells empty their cytoplasmic granules(274). The useful for mechanistic and temporal explanations of immune
granule proteins enter infected cells and induce apoptosis. Kim defence across mucosal barriers. Specifically, if penetration of
et al. peformed flow cytometry on peripheral blood mononu- the mechanical and innate defences is sufficiently strong, an
clear cells from 18 CRS and 19 control subjects, and detected adaptive immune response will be initiated and maintained;
that compared to the controls, impaired ability of NK cells to the overall response will be specialized to address both the
degranulate and to produce cytokines such as IFN-γ and TNF-α specific nature and the strength of the insult. Cytokine crosstalk
was associated with CRSwNP, concomitant asthma and perip- between epithelial cells (ECs), innate lymphocytes (ILCs), and
heral blood eosinophilia(346). The study group also showed that dendritic cells (DCs) plays a key role in matching the appropriate
compared with healthy controls, eosinophil apoptosis mediated adaptive response to foreign stimuli. In health, this maintains
by NK cells was significantly decreased in CRS patients(347). Smith mucosal homeostasis with 1) tolerance of potential allergens
et al. performed flow cytometry to peripheral blood mononu- and commensals and 2) defence against pathogens without the
clear cells and to polyp/mucosal samples from eight CRSsNP, development of chronic inflammation. Adaptive immunity is
eight CRSwNP and eight control subjects, and detected that typically divided into a T-cell response and a B-cell response, and
compared to controls, sinonasal markers of cytotoxity, gran- these will be discussed as they relate to CRS.
zyme B and perforin, CD8+ T cells, but not the NK cells, were
decreased in CRSsNP group(331). Invariant natural killer T (iNKT) Antigen presentation, dendritic cells and T cell activation
cells and mucosal associated invariant T (MAIT) cells express T The initiation of T cell responses requires that naïve T cells re-
cell receptors of very limited diversity(327). iNKT and MAIT cells cognize antigens presented by dendritic cells under conditions
recognise antigens presented by the MHC class 1-like mono- that require multiple receptors and co-stimulatory molecules.
morphic molecules CD1d and MR1, respectively. Both iNKT cells Antigen presentation is a transition phase from the innate to the
and MAIT cells have been identified in the skin and airways and adaptive response and is mediated mainly by DCs(274). DCs can
can rapidly produce cytokines after activation(327). Luukkainen et activate both innate and adaptive immunity via antigen capture,
al. stimulated with H3N2-virus a co-culture of peripheral blood presentation of antigen to immature T cells, and secretion of
mononuclear cells and nasal epithelium, differentiated from soluble inflammatory mediators. DCs are influenced by the col-
stem/progenitor cells, and detected rapid activation of mono- lective cytokine response from ECs and ILCs, and this is believed
cytes, NK-cells and innate T-cells (MAIT and γδ T cells) bridging to be pivotal in shaping T-cell differentiation(277). Plasmacytoid
systemic models and possibly enabling the development of tar- dendritic cells are decreased in patients with a more severe type
geted immunomodulatory therapies(328). Taken together, innate 2 profile, suggesting an important role of the cytokines milieu
immunity is crucial to maintain sinonasal homeostasis, and most in their functional response or that plasmacytoid dendritic cell
probably disrupted homeostasis between microbiota and host could mitigate the inflamed process found in polypoid tissue(349,
innate immune system is a key event in CRS. 350)
. Zheng et al. showed increased expressions of IL-17RB and
ST2 on myeloid DCs associated with enhanced local type 2
Platelets inflammation in polyp(351). Shi et al. detected distinct subsets
Platelets are cytoplasmic fragments that primarily function in of lesional DCs in eosinophilic and noneosinophilic CRSwNP,
haemostasis. In addition, since they are rapidly deployed to sites which could prime Th2 cells, and Th1/Th17 cells respectively in
of injury, they may potentially modulate inflammatory proces- these endotypes(352). Lin et al. investigated the functional status
ses by interacting with effector cells and secreting mediators(274). of dendritic cells (DCs) in polyp/mucosa from 30 CRSwNP and
Platelets are activated and a major source of proinflammatory 10 control subjects and detected infiltration of DCs in NP, with
leukotrienes (cysLTs) and prostaglandins (PGD2) in CRSwNP the majority being mature DCs, and that DCs are able to interact
and, in particular N-ERD(348). Based on released microparticles, with T cells via the CD40/CD40L co-stimulatory factor(353).
which may indicate signs of cell injury or pathology, platelets, as Antigen presentation is regulated by co-stimulatory molecules.
well as mast cells and basophils, were more highly activated in Programmed cell death-1 (PD-1) is a negative regulator of T-cell
patients with N-ERD than in patients with CRS. However, overall responses(354). Kortekaas Krohn et al. measured expression of
it is not yet clear whether platelet activation plays a direct role in PD-1 pathway molecules by RT-qPCR on tissue from 21 CRSwNP

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and 21 control subjects and detected higher PD-1 expression 17A, IL-17F, and IL-22.
in CRSwNP compared to controls independently of atopic sta- CD4+ T cells differentiate and acquire distinct functions to com-
tus(354). In accordance with this, high PD-L1 levels were associa- bat specific pathogens but can also adapt their functions in res-
ted with Asian eosinophilic CRSwNP compared to controls(355). ponse to changing circumstances(358, 360). Although this phenoty-
Overall however, at this point, only limited evidence exists to pic plasticity can be potentially deleterious, driving pathology,
support the hypothesis that defects in antigen presentation are the T-cell flexibility also provides important benefits that have
significant in CRS pathogenesis. led to its evolutionary preservation(360). Studies of the human
T cell response to microbes have advanced our understanding
T cells of CD4+ T cell functional heterogeneity, in particular with the
T cells have multiple roles in immune defence including defence discovery of a distinct Th1 subset involved in the response to
against intracellular and extracellular infection(274). T cells acti- Mycobacteria and the characterization of two types of Th17 cells
vate and recruit effector cells including phagocytes, kill infected specific for extracellular bacteria or fungi(356).
cells and provide help for B cells in immunoglobulin production. In CRS, the protective adaptive pathways go awry, usually with
Memory T cells are active as a durable form of innate activity at an excessive and prolonged response(361). In support of this, the
barrier surfaces such as the sinus mucosa. numbers of regulatory T cells (Tregs) are generally reduced in
A major role of CD4+ T helper cells is to send signals to other CRS and this has been interpreted as diminished Treg activity
types of immune cells, including CD8+ killer cells(274, 356). Loss leading to chronicity(362). For the other Th subsets however,
of T-helper cell function leaves the body vulnerable to a wide elevated numbers have been associated with CRS(363). Elevated
range of infections as have been detected in untreated HIV numbers of Th2 cells and eosinophils have been reported with
infection(274). CD4+ T cells may differentiate into different subsets Western CRSwNP, while increased Th1/Th17 and neutrophilia
of effector cells that produce distinct sets of cytokines that as- are associated with Asian CRSwNP and CF polyps(343, 344, 363). There
sist in defence against various types of microbial infections in is emerging evidence to suggest that the prevalence of Type
tissues, and a fourth subset that activates B cells in secondary 2 CRS is increasing in Asia however(322). The aetiologic factors
lymphoid organs: Th1, Th2, Th17 and follicular helper T cell(274). underlying this shift are both unknown and likely complex.
A fifth T subset are T regulatory (Treg) cells that help turn the Nevertheless, the speed of the process suggests changes in
process off. Activated CD4+ cells produce a mixture of the cha- environmental exposures with secondary epigenetic variation as
racteristic cytokines(274). The Th1 subset is induced, with the help a root cause. Importantly, an overall increase in T2 diseases was
of ILC1s, by microbes that are ingested by phagocytes (primarily observed in Western countries beginning in the early 20th cen-
macrophages)(356). Th1 cells stimulate phagocyte-mediated tury, and the changes in Asia appear to be manifesting in those
killing of ingested microbes via secretion of interferon-γ (IFN-γ) areas adopting a more Western life style. Further study of these
and tumor necrosis factor -α and –β (TNF-α and TNF–β), leading real-time changes in Asian CRS may be useful in identifying key
to macrophage activation and enhanced antigen presentation, environmental determinants that, with avoidance, could lead to
B-cell help and class switching to production of IgG subclasses a reduction in the incidence of CRS.
and local tissue inflammation and neutrophil activation(356, 357). CD4+ T cells that express Foxp3 and with immune suppres-
Th2 cells are induced by parasitic worm infections and promote sive activity are known as CD4+Tregs(274). Tregs develop in the
IgE-, mast cell-, and eosinophil-mediated destruction of these thymus or peripheral tissues on recognition of self-antigens
parasites with the help of ILC2 cells(274, 358). Th2 cells secrete the and suppress the activation of potentially harmful lymphocytes
Type 2-cytokines IL-4, IL-5, and IL-13, which have important specific for these self-antigens. They are also essential for main-
protective effects that include eosinophil effector mechanisms, taining tolerance and immune homeostasis(364-369). As mentioned
immunoglobulin class switching to IgE and IgG4 and mucus above, Tregs appear to be reduced in CRS and autoantibodies
production(359). The Type2-cytokines also stimulate the alter- have been reported. Studies show that multiple Th subsets may
native pathway of macrophage activation and shut down the be activated in the same CRS patient, that the cytokines produ-
classical pathway mentioned above. This terminates prolonged ced may suppress or augment the other subsets, and this may
and potentially damaging reactions. Alternative M2 macropha- be part of normal immunoresponse, or may affect development
ges secrete growth factors that act on fibroblasts to increase or clinical presentation of CRS, or may affect treatment course(342,
collagen synthesis and induce fibrosis fostering tissue repair. 370)
.
Th17 cells develop in response to extracellular bacterial and CD8+ cells activated by antigen and other signals differentiate
fungal infections and induce inflammatory reactions destroying into cytotoxic T cells (CTL, T-killer cell) that are able to kill infec-
these organisms. Th17 stimulate recruitment of neutrophils and ted (particularly with viruses) cells expressing the antigen(274).
monocytes and the production of defensins via secretion of IL- CTLs also kill malignant and other damaged cells(274). Memory
T cells recirculate from the tissues to the peripheral blood. As

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mentioned above, T cell levels are higher in CRS but the CD8+/ of 7-21 days. IgG has several effector functions: it neutralizes
CD4+ T cell ratio is also higher, indicating particular enhance- microbes and toxins; opsonizes antigens; activates the classical
ment of the cytotoxic T cell population(371, 372). Any specific role pathway of the complement system; is responsible for NK cell
for cytotoxic T cells in CRS pathogenesis, however, remains cytotoxicity events and feedback inhibition of B cells(274). IgD is
unclear(372). an enigmatic antibody isotype best known when co-expressed
Cell adhesion molecules located on the cell surface are involved with IgM on naive B cells. Class switching to IgE is regulated
in binding with other cells or with the extracellular matrix. by Type 2 cytokines and this immunoglobulin plays several
Adhesion molecules on leukocytes, fibroblasts and vascular important physiologic roles that include antigen presentation,
endothelium, enabling leukocyte extravasation from vessels and increased mast cell survival, mucosal homeostasis, and defence
migration to sites of inflammation(373). Increased expression of against viruses, bacteria, fungi and parasites(312, 348, 379-383). The Fc
intercellular adhesion molecule-1 (ICAM-1) in activated eosinop- portions of IgE and IgA are often mounted on mast cells and
hils is associated with eosinophil extravasation and infiltration eosinophils, respectively(274). The antigen selective portions can
into NP tissue, and seems to initiate also mucosal remodeling of bind parasites, sterically inhibiting their ability to invade and
NP(374). Fibroblasts´ expression of vascular cell adhesion molecule also leading to degranulation, which may trigger inflammation
(VCAM) has been shown to attract eosinophils and mast cells and some degree of tissue damage.
contributing to Type 2 cytokine skewing, while ICAM attracts B cells and immunoglobulins have been implicated in CRS and
neutrophils and to a lesser degree, eosinophils(375). VCAM expres- antibody defects are the most common immunodeficiencies,
sion was lowest in controls, higher in CRSsNP, and highest in typically associated with CRSsNP(384). Low immunoglobulin pro-
CRSwNP, while ICAM expression was elevated in both CRS sub- tection can lead to recurrent acute sinus infection and ultimately
types(375). The L-selectin ligand, peripheral lymph node addressin CRSsNP(385). Most cases of CRSsNP do not have an immunoglo-
(PNAd), was preferentially induced in the nasal vasculature of bulin deficit however, and in fact, a subset of CRSsNP patients
eosinophilic CRS facilitating tissue recruitment from blood(376). It has high tissue levels of IgD, although any role in pathogenesis
is not clear if primary defects in cell adhesion markers in parti- remains uncertain.
cular or effector recruitment in general, play any key role in CRS B cell activation with excessive local antibody production has
pathogenesis. Specifically, the above findings may simply be the more commonly been associated with CRSwNP(369-371, 386). Polyp
predicted secondary effect of the tissue inflammation present in tissue from CRSwNP patients has been found to contain high
the sinus mucosa of the CRS patient. Regardless, this may lead to levels of B cells, plasma cells, follicles that resemble germinal
innovative treatments via limiting the influx of eosinophils and centres, and high levels of IgA, IgM, IgG and IgE that indicate
neutrophils into the sinus tissues. local production of immunoglobulins(337, 369-372, 387, 388). Antibody
Humoral immunity is the type of host defence mediated by anti- production in CRSwNP is driven in part by elevated levels of the
bodies, which are produced and secreted by B cells and plasma BAFF cytokine (B-cell activating factor) in nasal polyp tissue(389).
cells, functioning both in circulation and in peripheral tissues In addition to B-cell proliferation, BAFF has also been associ-
such as sinonasal mucosa(274). Antibodies use their antigen bin- ated with isotype class switching to IgE and IgA as well as the
ding regions (Fab) to bind and block harmful effects of microbes development of autoimmune immunoglobulins. Tan et al. was
and toxins. Heavy-chain isotype (class) switching and affinity the first to demonstrate this, with anti-dsDNA IgG and IgA auto-
maturation enhance the protective functions of antibodies(274). antibodies at increased levels in nasal polyps in comparison with
The major functions of antibodies are to block or neutralize controls, suggesting a role for autoimmunity in the more seve-
the infectivity of microbes, coat microbes and promote their rely affected CRSwNP patients(344). One specfic target appears
ingestion by NK-cells, to activate (IgE) mast cell and eosinophil to be the self protein BP180, which is a key anchoring protein
mediated reactions against helminthic parasites, and activation in the skin and the nasal mucosa. Anti-BP180 antibodies were
of the complement system vs. Physiologically tonic secretion of elevated in CRSwNP patients, suggesting autoimmune targeting
secretory IgA works in concert with other innate protective fac- of the epithelial barrier(343).
tors and mucociliary flow to limit mucosal colonization without Local IgE has been the most commonly implicated antibody
tissue-damaging inflammation(377). This IgA is of low affinity and in the pathophysiology of CRSwNP. Elevated IgE levels in nasal
generated by a T cell independent process by extrafollicular B polyps have been shown to be independent of systemic atopy,
cells. In the case of an active breach of the respiratory mucosa, driven by BAFF with local class switching, predict poor progno-
higher-affinity IgA secretion may increase and, in combination sis and correlate with the presence of IgE against staphylococcal
with help from IgG, a robust inflammatory response ensues(378). superantigenic toxins. These toxins have the capacity to act as
These are high affinity, T dependent immunoglobulins produced both B and T cell superantigens in nasal polyps, fostering a poly-
by follicular B cells and plasma cells. IgG is the most common clonal IgE response(390). Studies have demonstrated that the IgE
circulating antibody with four subclasses (IgG1-4) and a half-life in nasal polyps is polyclonal and can trigger mast cell degranula-

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tion, suggesting a significant role for IgE in the pathophysiology many forms of CRS, leading to increased permeability to foreign
of this subset of CRSwNP patients(391). The therapeutic potential material suggesting this as an early factor in CRS pathogene-
of anti-IgE for nasal polyposis has recently been demonstrated sis. While specific areas of weakness have been identified (see
in CRSwNP patients as well(313, 384). section 5.2.2.43.1.), the underlying cause(s) are uncertain. Some
Similar to IgE, IgG4 is a minor IgG subtype whose production is evidence exists suggesting genetic and epigenetic factors, early
also regulated by Type 2 (IL-4 and IL-13) cytokines. Local IgG4 stage environmental insults including an abnormal microbiome
expression is high in serve eosinophilic CRS, with higher ILC2, or viral injury, and possibly systemic hormone signaling defects,
plasma cells, B cells and activated CD8+ T cells(362, 363). which could all serve as permissive factors in CRS pathoge-
The complement system is a collection of circulating and cell nesis(218, 400). Once established, the inflammatory cytokines of
membrane proteins that play important roles in host defence CRS also trigger increased barrier permeability, an effect most
against microbes and in antibody-mediated tissue injury(274). closely associated with Type 2 inflammation but which likely oc-
Complement assists the antibody-mediated lysis of microbes curs in other types as well(240, 243, 401, 402). None of the above would
but can result in tissue injury, particularly in cases of autoimmu- be considered remodeling but epithelial cells undergo turnover
nity. At this point, there is only weak evidence to support a com- and repair after injury through a process involving interplay with
plement defect associated with CRS pathophysiology(366-368). The fibroblasts, termed epithelial to mesenchymal transition (EMT).
evidence for excessive complement activation in CRS is stronger, Under healthy conditions, this results in maintenance of a nor-
suggesting the importance of antibody-mediated events in CRS mal barrier but in some forms of CRS, the process is abnormal,
pathophysiology possibly related to autoimmunity(384). resulting in epithelial remodeling toward acanthosis, acan-
tholysis and a very leaky barrier(400). The EMT process is driven
5.2.2.3.3. Other inflammatory mechanisms by an array of factors including WNT, reactive oxygen species,
Remodeling is defined as abnormal restitution of damaged proteases, HIF1, IL-13 Epiregulin, Oncostatin M, and IL-1 among
tissues and these processes have been widely described in others(207, 230, 373, 374, 377, 403). There is some evidence that stem cells
lower airway diseases. In CRS, remodeling also takes place in the epithelium maintain a memory for the chronic immature
and observed changes include fibrosis, basement membrane EMT state in severe Type 2 CRS(228). This form of remodeling may
thickening (BMT), goblet cell hyperplasia, epithelial barrier lead to barrier failure with markedly increased antigen access
abnormalities and polyp formation, osteitis and angiogenesis(392, suggesting the possibility of a feed forward mechanism, such
393)
. The remodeling patterns were thought to separate based on that barrier failure leads to more inflammation accelerating bar-
the presence or absence of polyps, but clear distinctions have rier damage and then accelerating inflammation(404). This con-
been difficult to clearly demonstrate(394). This finding illustrates cept of a remodeled, immature, very leaky barrier is most closely
the limitations of this classification and CRS is now viewed as associated with Type 2 CRS and may account for the higher
a heterogeneous disorder driven by an array of inflammatory treatment failure rate using conventional therapy. Directly targe-
mechanisms or endotypes. The underlying working hypothesis ting the failed barrier may be necessary to limit recurrence(405).
in upper airway disease is that the inflammation leads to remo- Nasal polyposis is associated with marked tissue oedema,
deling with cytokines, mediators, enzymes and other factors diminished collagen and extracellular matrix degradation,
determining the remodeling pattern. Essentially, the duration possibly due to imbalances in metalloproteinase activity(406).
and type of inflammation would determine the outcome. The Abnormalities of the coagulation cascade have also been as-
alternative hypothesis, that inflammation and remodeling are sociated with polyp formation including Factor X, tissue factor
independent, remains viable although currently unsubstantia- and thrombin(407-409). Supportive studies have indicated that a
ted at least in the upper airway(395). crosslinked fibrin matrix is the key component of polyps. It has
Studies have attempted to associate cytokines and other tissue been proposed that this matrix draws in fluid, accounting for
markers with remodeling changes in CRS. Periostin has been the polyp mass. The pathway begins with inflammation, which
suggested as a marker for BMT and fibrosis(238). BMT has also results in the leakage of fibrinogen, amongst other plasma pro-
been related to the duration of inflammation independent of teins, out of the vasculature into the tissues, where components
the presence of tissue eosinophilia(393, 396). TGF-b has been most of the coagulation cascade catalyze formation of a fibrin matrix
closely linked to fibrosis, but IL-13 and osteopontin have also ‘clot’. Under normal circumstances, plasminogen is activated
been implicated in BMT and fibrosis(395, 397-399). Fibrosis may also by t-PA (tissue plasminogen activator) to form plasmin, which
be secondary to surgical trauma, confounding interpretation of enzymatically degrades the fibrin matrix into dimers. Type 2
results. cytokines inhibit t-PA activity so in the presence of high levels
Remodeling changes in the epithelial barrier have engendered of Type 2 inflammation, the matrix will be retained and grow(300).
much interest since the last EPOS publication. As discussed The intrinsic levels of t-PA vary in the tissue and they are particu-
in 5.2.2.3.1., the epithelial barrier appears to be weakened in larly low in the ethmoid sinuses, a possible explanation for this

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site as the most commonly observed origin of nasal polyps. The mune system. Dysfunctional innervation might contribute to
coagulation factor XIII-A has also been shown to induce exces- the pathogenesis of CRSwNP and could in part explain olfactory
sive fibrin depostion in nasal polyps and M2 macrophages are loss. Wu et al. detected that axonal guidance signaling and neu-
the probable source(302). Eosinophils may also play a role in fibrin ral growth factor pathway proteins are significantly suppressed
deposition in N-ERD patients through the expression of L-selec- in eosinophilic CRSwNP(422). Elevated TRPV1 levels in comorbid
tin(410). Thus far, fibrin deposition has only been demonstrated asthma and allergy may have a function in CRSwNP(259). Sub-
in polyps from patients with Type 2 inflammation. Very recent stance P was released from the sensory neurons and human/
studies have indicated that a broad reduction in the fibrinolytic murine nasal epithelial cells within 15 minutes of local TLR7 sti-
pathways via protease inhibition accounts for accumulation of mulation(423), highlighting a novel role for sensory neuropeptides
the fibrin matrix in CRSwNP(411). as acute and local mediators of pathogen-driven inflammation,
Tissue angiogenesis is a complex phenomenon that results in rapidly priming innate immune defences in the airway. Neuro-
the growth of new blood vessels from the microcirculation. This trophin-3, a neurotrophic factor, was associated with CRSwNP
process has been known to play a crucial role in tumour growth compared to controls(424). Neuronal dysfunction has been pro-
as well as several benign diseases(412) and could be conside- posed as an endotype for chronic rhinitis, but it is also likely that
red a form of remodeling in CRS. Angiogenesis is regulated these mechanistic pathways play a role in CRS as well(425).
by infection and immune cells VEGF, VEGFR-1, Ang-1, Ang-2,
Tie-2A, Tie-2B, SDF-1α and SDF-1β mRNA expression to be 5.2.2.4. Conclusions and future needs
significantly higher in CRSwNP patients compared to the control A wide array of exogenous agents are inhaled through the nose
group(412). Luukkainen et al. performed immunohistochemistry and interact with the sinonasal mucosa, a process that begins
and counted lymphatic vessel density of sinus mucosa and at birth with rapid colonization by viruses, bacteria and fungi.
polyp tissue of 120 subjects and detected that low, absolute In healthy individuals, the mucosa serves as a relative barrier
and relative density of vessels and of lymphatic vessels was limiting and regulating environmental interaction with the host
associated with CRSwNP and antrochoanal polyp (ACP) tissues immune system, a process that is likely beneficial to the host in
compared to control inferior turbinate(413). This was observed a number of ways including development of tolerance, gene-
also in the inflammatory hotspot area. Higher lymphatic vessel ration of important metabolites and competitive inhibition of
density seems to associate with polyp recurrence(413). In contrast, pathogens(136). In healthy patients, when the barrier is breached,
Mostafa et al. have detected a high density of lymphatic ves- a specific, self-limited physiologic immune response is genera-
sels in the transitional area between the sinus mucosa and the ted, characterized by a cellular and cytokine repertoire targeting
pedicle of the ACPs, compared to the control group(414). Regar- the pathogen(s). Although the in vivo response is much more
ding other growth factors, differences existed in EGF pathways complex, at the basic level Type 1 immunity targets viruses,
in CRS patients and normal subjects as well as in CRSsNP and Type 2 parasites and Type 3 extracellular bacteria and fungi,
CRSwNP(415)). GF-1 induced MUC8 and MUC5B expression is resolving with elimination of the pathogens and restoration of
regulated by activation of the ERK1 and p38 MAPK signaling barrier integrity. In cases of CRS, the current working hypothesis
pathway in human airway epithelial cells(416). PDGF systems play is that barrier penetration, possibly by an alternate mechanism,
important roles in polyp pathogenesis. Fibroblast-derived PDGF results in a chronic inflammatory response that still utilizes the
may be more important than MNC-derived PDGF in the polyp Type 1, 2 or 3 pathways alone, or in combinations. CRS immune
developing process(417). responses are: a) dynamic and heterogeneous, likely exhibiting
Osteitis has been described in eosinophilic CRSwNP and putati- plasticity; b) not self-limiting (remaining active for months to
vely results from infection and biofilm production(418). Downre- years); c) not clearly matched to the inciting agents; and d) often
gulated pro-osteoblastic mucosal BMP signaling is strongly and associated with various types of tissue remodeling, presumably
significantly associated with increased osteitis in CRSwNP(419, linked to the pattern of inflammation. There is no evidence at
420)
. There are phenotypic differences in adhesion and minerali- this point for a specific dominant pathogen and, based on the
zation between osteoblasts in patients with CRS compared to limited evidence currently available, the immunologic response
controls(419). Different signaling pathways are involved in osteitis is polyclonal, targeting antigens derived from multiple orga-
in CRS and are activated by the TGF-β/Smad signaling pathway nisms, including nasal bacteria(168, 172). In some severe, recurrent
in CRSwNP versus the TGF-β/Smad-independent signaling pa- CRS cases, self antigens are also targeted but the development
thway in CRSsNP(418, 420). Taken together, pathways closely related of autoimmunity is mostly viewed as a phenomenon secondary
to mucosal inflammation have been much less studied than the to the chronic process(367).
immune system. It is possible that they have a role in CRS and Many questions remained unanswered including the mecha-
would be worthy of further investigation. nism for initiation of CRS, but presumably this results from a
Neural function is closely related to infection(421) and the im- combination of environmental stressors, genetic susceptibility

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and stochastic events that collectively promote barrier penetra- mation tend to be resistant to treatment with a high recurrence
tion. While the nature, intensity and sequence of the exposures rate. In theory, this could relate to remodeling changes in the
are likely significant in triggering CRS, evidence supporting a epithelium that persist despite treatment(112, 400, 404).
role for specific environmental agents remains largely indirect, The extensive pre-morbid time course, complexity of environ-
as no widely accepted animal model of CRS exists. Host genetic mental exposures and lack of many strong genetic signals has
variation, particularly governing the sinonasal epithelium and diminished current enthusiasm for studies on CRS aetiology
immune response, also plays a major role but given that age and pathogenesis. Moreover, therapies focused on addressing
of onset of CRS is typically in the fifth decade, environmental proposed environmental agents have not been very successful
and epigenetic effects likely dominate from the standpoint of in CRS management. As a result, interest has shifted to study
causation. Relatively few high-quality genetic studies have been the mechanistic pathways (endotypes) that result within the
performed to this point, but using adult onset asthma as a mo- sinus mucosal tissue itself, as opposed to searching for putative
del, multiple genes are involved, each typically conferring a rela- causes. This shift has been accelerated by the recent availabi-
tively small effect size and most having functional implications lity of biologic agents that target molecules operative in these
for the epithelial barrier and immune response(426). CF, with mu- pathways. In theory, the intensity and nature of the endotype
tation of the CFTR gene, is a notable exception demonstrating a should play a key role in determining the observed phenotype,
strong association of the homozygous mutation with childhood clinical course, response to therapy, remodeling pattern in
onset CRS(427). Presence of the heterozygous CFTR mutation is the tissue and possibly the presence of co-morbid pulmonary
also associated with a CRS signal albeit less than clinical CF, and disease. The first large study attempting to define the endotypes
usually presenting in adulthood(428). The impaired mucociliary of CRS with tissue data used a modified cluster analysis of pre-
flow seen with CFTR mutations is presumed to intensify micro- selected tissue biomarkers including Type 1, 2 and 3 canonical
bial exposure driving the process(429). The importance of CFTR in cytokines, neutrophilic markers, IgE to staphylococcal superan-
childhood onset CRS suggests that other barrier-related genes tigens, albumin, TGF-beta, IL-6 and IL-1b. Results indicated 10
may play a role in CRS initiation. endotypes including four that were characterized as IL-5 nega-
The identity of the antigens triggering CRS is another area tive and six as IL-5 positive. Of these six, three were considered
where we have little information. The limited data available sug- high IL-5 and had the strongest association with asthma and the
gests that common nasal bacteria, including S. aureus, are tar- presence of polyps(153, 166, 439). There was a correlation between
geted by the host immune system in CRSwNP(172). In AFRS, fungi the Type 2 intensity and the presence of asthma and nasal
are likely targeted as well. Both nasal bacteria and fungi should polyps but data on symptoms, natural history and response the-
induce a Type 3 immune response, yet nearly 90% of Western rapy were unavailable. A second large scale attempt to define
CRSwNP patients (and over 50% of surgical CRSsNP patients) endotypes and tissue patterns was based on the Type 1, 2 and 3
exhibit a significant if not predominant Type 2 cytokine profile. inflammatory patterns alone(342). The various possible combina-
indicating that interactions between host and bacteria are not tions of the three types of inflammation yields eight endotypes.
solely driven by Type 3 mechanisms(153, 342, 400, 430-434). Although the In this study, smell loss was associated with Type 2 inflammation
reason for Type 2 skewing is very unclear, it suggests that some as previously shown. The presence of Type 1 inflammation was
of the inter-related hypotheses which have been used to explain protective against facial pain while the presence of pus was
atopy including dysbiosis, may be operative in Type 2 CRS as associated with Type 3 inflammation. These two classifcation
well. Alternatively, it has been proposed that S. aureus, via mul- schemes are the first steps towards identifying the precise
tiple pathobiologic mechanisms including superantigens, is ca- mechanistic pathways potentially relevant and active in an in-
pable of shifting the immune response in a Type 2 direction(170). dividual patient. Type 2 inflammation is the best studied in CRS,
Some evidence also suggests that environmental proteases and and it is likely that subendotypes exist that vary beyond simply
host anti-proteases interact at the mucosal surface, setting a disease-intensity. Overall, the mechanistic pathways of Type 2
threshold for barrier penetrance as well as skewing the immune inflammation in CRS tissue are more likely to reflect an intercon-
response in the Type 2 direction(196, 400, 435). One key pathway nected lattice network as opposed to a linear progression(404).
for Type 2 skewing may include the gene ALOX15, as a loss of As a consequence, the mechanism that results in the N-ERD phe-
function variation protects against nasal polyposis(436). This gene notype may be a distinct Type 2 subendotype with accentuated
encodes the enzyme 15LO (15 lipoxygenase), which is up-regu- prostaglandin/leucotriene activity. AFRS as well as SE-IgE+ pa-
lated by IL-13 and promotes eoxtaxin 3 expression by epithelial tients may be subendotypes that are more closely tied to local
cells, presumably driving tissue eosinophilia in CRSwNP(437). This polyclonal IgE production. As a corollary, it is very possible that
pathway has also been implicated in epithelial remodeling and these subendotypes, if verified, would respond differently to the
establishment of chronically immature, leaky barrier(438). Lastly, various Type 2 biologics currently available. Lastly, both of these
beyond Type 2 skewing, patients with severe Type 2 inflam- CRS endotype classification schemes had one endotype (>10%)

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of surgical CRS patients that had no measured inflammatory literature evaluating symptom prevalence and severity in CRS,
markers that were significantly greater than background control AR and NAR.
levels. The CT and symptoms scores were, however, similar to
other endotypes(344). Although the mechanism is unclear in this 5.3.1.2. CT scan in allergic rhinitis versus CRS
group, the symptoms and the mucosal oedema in the group In a group of 216 CRS patients, the patients with a positive spe-
appear to be driven by a mechansim distinct from the traditio- cific in vitro allergen test result did not have higher overall rates
nal inflammatory pathways associated with CRS. Neuroimmune of radiographic sinus inflammation(446). Moreover, in patients
dysfunction involving neuropeptides and ion channels, already with allergic rhinitis alone, asthma alone or both, the group with
proposed as an endotype of non-allergic rhinitis, could also be allergic rhinitis and asthma, 58% had some abnormalities on CT
operative in CRS(425). scan versus 74% of the patients with only asthma, 67% with only
Although much has been accomplished since the last EPOS rhinitis versus 20% in a control group. In the group with allergic
document, many questions still remain regarding aetiology, rhinitis CTscan abnormalities were seen significantly more often
pathogenesis and relevant inflammatory mechanisms. Future in the “blockers” (90%) than the “sneezers” (52%)(447).
challenges include a better understanding of: 1) the aetiolo- A central radiological pattern of mucosal disease may be as-
gic factors that drive CRS with a goal towards prevention; 2) sociated with inhalant allergen sensitization. This group may
the pathophysiologic inflammatory mechanisms and relevant represent a CCAD subgroup of patients with mainly allergic
endotype biomarkers with a goal towards targeted therapy; 3) aetiology(194) (see also CCAD). The prevalence of allergy in CRS
the molecular mechanisms of barrier and tissue remodeling that may vary by phenotype, with CCAD and AFRS having a stronger
may play a role in persistence and recurrence. association than CRSwNP and CRSsNP (see 5.1 and 8.1).

5.3. Diagnosis and differential diagnosis 5.3.1.3. Differentiating AR, NAR and CRS
Combining data from different studies in one table (Table 5.3.1.)
5.3.1. Allergic and non-allergic rhinitis although incomplete, leads to a picture of a significant overlap
Upper airway diseases present with a variable pattern of in symptomatology for prevalence and severity of symptomato-
common symptoms such as nasal obstruction and discharge, logy.
making the epidemiological diagnosis of CRS difficult to diffe- Koskinen et al.(448) compared diagnostic accuracy of symptoms,
rentiate from allergic and nonallergic rhinitis based on symp- endoscopy and imaging signs of CRSsNP and allergic rhinitis
tomatic grounds only. Moreover, not all patients presenting patients and made a prediction model for CRSsNP. They also
with symptoms meeting CRS criteria have evidence of disease if concluded that there is a significant overlap in symptoms. The
diagnosis is complemented with nasal endoscopy and CT. highest area under curve value (0.93) was demonstrated for a vi-
sual analogue scale score of facial pain / pressure ≥4/10 showing
5.3.1.1. Allergic and non-allergic rhinitis 60% sensitivity and 95% specificity for detecting the CRSsNP
Allergic rhinitis (AR) is clinically defined as a symptomatic group (p<.001). The radiologic sign of an obstructed ostiomeatal
disorder of the nose induced after allergen exposure by an IgE- complex showed 100% specificity and 38% sensitivity for de-
mediated inflammation of the nasal membranes. The symptoms tecting the CRSsNP group (p<.001). In this study endoscopy had
include rhinorrhoea (anterior or posterior), nasal congestion, no added value.
nasal itching, and sneezing. There is no uniform definition for
epidemiological studies. Different definitions have been used in 5.3.1.4. Conclusion
questionnaires in previous studies. It can be very difficult to discriminate between AR, NAR and
Allergic rhinitis is a very prevalent disease(440-443). CRS. The combination of symptoms, CT scan and maybe also
In a Dutch study using the GA2LEN questionnaire 29% of the nasal endoscopy can point in the right direction but significant
population had allergic rhinitis, based on the question “Do you overlap in diseases occur.
have any nasal allergies including hay fever?” and 16% CRS
based on the EPOS criteria. In this study the risk of CRS was sig- 5.3.2. Smell disorders
nificantly higher in respondents with a doctor’s diagnosis of CRS
(OR 6.83), AR (OR 2.87), asthma (OR 2.36), an adverse response 5.3.2.1. Symptoms
after taking painkillers (OR 2.34), itchy rash (OR 1.71), or active Olfactory impairment, like facial pain is part of the four main
smoking (OR 1.45). CRS symptoms. Similar to facial pain and in contrast to nasal
Data on the prevalence of non-allergic rhinitis are less abundant obstruction and rhinorrhoea, olfactory impairment may not
with figures of 10-19%(444, 445). exclusively be related to sinonasal disease and thus has a wide
As far as we are aware there are no comparative studies in the differential diagnosis(449). Olfactory impairment as a symptom

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Table 5.3.1 Prevalence and severity of symptoms in CRS, AR and NAR (data from different studies).

Symptom Chronic rhinosinusitis Allergic rhinitis Non-allergic rhinitis

Prevalence (%) Severity Prevalence (%) Severity Prevalence Severity

Nasal obstruction 92 6.8 92$ 2.7# 5.8#

Rhinorrhoea / discharge 80 5.8 86 $
3.6 #
4.3#
Post-nasal drip 80 6.0 65$ 5.3$
Loss of smell 84 6.8 30@
0&
Facial pain / pressure / headache 67 5 0.5&
Nasal / palatal itch 81$ 6.8$
Itchy eyes 45 3.2 63 $
2.4# 2.3#
Sneezing 56 3.6 80$ 4.2# 4.0#
*All values recalculated to a scale of 10; $ Data from Jaruvongvanich 2016(835); @ Data from Stuck 2015(836); # Data from Segboer 2018(837); & Data from
Koskinen(448). Empty cells: no data available.

can be roughly subdivided into distortions (qualitative disor- from general ENT outpatient clinics. The reports from speciali-
der), decrease or total loss (quantitative disorders). Patients may zed clinics underreport the frequency of CRS- related olfactory
present with only a qualitative, quantitative or both complaints. disorders, whereas this seems to be the most frequent cause
Identifying the exact symptom by means of inquiry and mea- encountered by the average ENT physician.
surement(450) (see section 5.3.5.5) is essential for establishing a
correct diagnosis. 5.3.2.4. Olfactory (dys-) function in CRS
Olfactory function in CRS has a very variable degree of clinical
5.3.2.2. Epidemiology manifestation, ranging from no impairment to total loss. The
The prevalence of olfactory disorders in the general popula- literature also shows that the extent of olfactory dysfunction
tion is estimated to be 3-5 % for total smell loss (anosmia) and depends on the underlying form of sinonasal disease. CRS
15-25 % for partial impairment (hyposmia)(451, 452). These studies with nasal polyps is more severely and more often associated
provide reliable data on how often, but not why and for what with olfactory impairment than any other form of sinonasal
reason people have impaired olfactory function. Some of these disease(449, 463-467). The mechanism leading to olfactory impair-
epidemiological follow-up studies suggest a link between ment in CRS is twofold: inflammatory and purely mechanical
altered olfactory function and increased mortality or develop- with obstruction of the olfactory cleft(468, 469). Inflammation that
ment of neurodegenerative diseases(453, 454). This underlines the characterises CRS also modifies the olfactory epithelium(468) with
potential biomarker function of olfactory measurement. consecutive functional impairment. Mechanical blockage to the
olfactory cleft also decreases olfaction(469). In most CRS patients
5.3.2.3. Causes and frequency with olfactory impairment both mechanisms are present and a
In a patient with an olfactory disorder, the most important mechanistic view of olfactory impairment is inadequate. It ex-
question is the cause of the smell problem. Many methods have plains why not all patients per se have an olfactory benefit from
been proposed to classify olfactory disorders such as conductive surgical removal of polyps alone, but also require subsequent
versus sensorineural or peripheral versus central. The short- anti-inflammatory treatment.
comings of these classifications are that they suggest that the CRS related olfactory dysfunction has some distinct clinical
place and mechanism of the disorder is known, which is not features that should be looked for during assessment since
supported by the current knowledge in the field. The olfactory they may help to identify the olfactory impairment as sinonasal
literature is very consistent with the suggestion that one should versus other causes. The first particularity mainly found in CRS-
classify olfactory disorders currently according to the putative related olfactory dysfunction is fluctuation of the olfactory com-
cause(449, 455-462). The most frequently identified causes of olfactory plaint(470-473). Fluctuation is hardly ever found in post-traumatic,
disorders are listed in Table 5.3.2. post-infectious, and congenital or neurodegenerative causes.
The table shows that the four most frequent causes, post- The second finding that can be seen more often in CRS related
traumatic, post-infectious, CRS-related and idiopathic olfactory olfactory impairment is a gap between ortho- versus retronasal
disorders occur in very different frequencies whether they are olfactory function(474-476). Although not consistently present,
reported from specialized smell and taste outpatient clinics or certain CRS patients have well preserved retronasal olfactory

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Table 5.3.2. Details and characteristics of olfactory symptoms and their occurrence in CRS.

Quantitative disorder Definition / characteristics

Parosmia / troposmia Distorted smell triggered by an odour source. Mostly after post-infectious / post-traumatic olfactory
impairment. Very rarely in CRS.
Phantosmia / olfactory hallucination Distorted smell occurring independently of an odour source. Wide differential diagnosis including post-
infectious / post-traumatic but also tumour, psychiatric or idiopathic olfactory impairment. Rare but not
impossible in CRS.
Qualitative disorder Definition / characteristics
Normosmia Normal olfactory function
Hyposmia Decreased olfactory function. Smell perceived if odours are strong / concentrated. Very frequent in CRS.
Anosmia Total loss of olfactory function. No smell perception even if odours are very strong. Wide differential diag-
nosis but frequently encountered in severe forms of CRS.
Hyperosmia Increased, over average good olfactory function. Subjectively reported in migraine, pregnancy and mul-
tiple chemical sensitivity but rarely confirmed by psychophysical / objective measures. Literature scarce.
Not reported in CRS.
Specific anosmia Selective loss / inability to smell certain odours while all other odours are perceived normally. Physiologi-
cal state due to variable olfactory receptor expression in humans. All of us have certain specific anosmias.
Not related to CRS.

Table 5.3.3. Most frequent causes of olfactory dysfunction according to their putative cause(449, 455-462, 473, 838, 839) and depending on where the patient was
seen (specialized outpatient clinic or in a general ENT department).

Cause Frequency (observed in special- Frequency (in general ENT Presence of distortions
ized smell and taste clinics) consultations) (parosmia / phantosmia)
CRS related (sinonasal) 6 - 21 % 72 % rare
Post-infectious (URTI) 26 – 40 % 11 % very frequent
Post-traumatic 16 – 39 % 5% frequent
Idiopathic 14 – 22 % 6% variable
Neurological-neurodegenerative 1–2% n/a variable
Congenital 4 – 10 % 1% almost never
Other rare causes (e.g. toxic exposure) 9 – 15 % 5% variable

URTI, upper respiratory tract infection.

function and express that as intact flavour perception whereas sinonasal symptoms, possible fluctuation, distortions and events
their orthonasal olfaction is decreased or absent. The most likely preceding the olfactory deficit (e.g. trauma or URTI) in order to
explanation is a partially preserved retronasal access to the delimit the major causes of olfactory deficits (Table 5.3.3.). Mea-
olfactory cleft. Third, if testing is performed with tests that have suring olfactory function as completely as possible (see chapter
thresholds and identification (see chapter 5.3.5.5) CRS- related 5.3.5.5) should be done in order to assess the measurable olfac-
olfactory impairment often shows a characteristic pattern of tory function since purely asking is not representative of what
low threshold and preserved identification scores(464, 477). Finally, eventually may be measured(482-484). Finally, a thorough nasal
CRS- related olfactory impairment shows a steroid-dependent endoscopy is mandatory. If after these steps, the putative cause
reversal(478), which is a clear indicator of inflammatory related ol- remains unclear and before stating that it might be an idiopa-
factory impairment. Olfactory dysfunction that is reversible with thic problem, a short systemic steroid trial and imaging (CT and
systemic steroids has also been found to be a reliable predictor MRI) to rule out any hidden intranasal inflammation (especially
of post-surgical olfactory outcome(479-481). in the olfactory cleft) and intracranial elements that explain the
olfactory dysfunction should be undertaken.
5.3.2.5. Diagnosis and assessment
Diagnosing an olfactory deficit comprises several steps: the 5.3.2.6. Treatment
patient’s history is crucial and one should look for all the Treating CRS-related olfactory dysfunction is synonymous with
above-mentioned elements, such as the duration, concomitant treating CRS and is discussed elsewhere in the position paper.

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The current literature shows that olfaction mostly improves with advised when facial pain is the main symptom, as it has a strong
varying degrees of reported success rates(463, 485). For post-infec- negative predictive value to rule out sinogenic pain(494).
tious, post-traumatic, neurodegenerative and congenital olfac- In patients with an indication for endoscopic sinus surgery, the
tory disorders no real curative treatment exists. However, smell prevalence of facial pain is higher. In a surgical cohort of pa-
training, a regular and conscious exposure to odours has been tients with CRSwNP, roughly half was found to report moderate
shown to significantly improve olfactory function, especially in to severe facial pain pre-operatively, with marked improvement
post-infectious and to a lesser extent post-traumatic olfactory after several weeks(495) up to seven months postoperatively(496).
dysfunction(486). Studies with mixed surgical cohorts of patients with CRSsNP or
CRSwNP also showed sustained improvement of facial pain after
surgery(497, 498).
Key points | What’s new since EPOS 2012 Interestingly, there seems to be a difference in the prevalence or
severity of headache/facial pain between patients with CRSwNP
and those with CRSsNP. Studies show that both groups have
comparable total symptom scores, but those without polyps
• Olfactory dysfunction is frequent in the general population have increased scores for headache and facial pain, while the
• The most frequent cause of olfactory dysfunction encoun- other cardinal symptoms of CRS are more prevalent in patients
tered by ENT physician is related to CRS with nasal polyps(499, 500). Moreover, the tendency for CRSsNP
• CRS-related olfactory impairments have a good success rate patients to report more severe facial pain can even be used to
of improvement if the underlying CRS is treated distinguish them from allergic rhinitis patients(501).
• CRS-related olfactory impairments show some distinct There is no correlation between the location of facial pain and
clinical features that should be looked for since they help to abnormalities (if any) of anatomically related sinuses upon
accurately diagnose the olfactory dysfunction imaging, both for CRSsNP and CRSwNP(502, 503). Patients reporting
facial pain as their main symptom have less abnormalities upon
imaging than those reporting the other cardinal symptoms that
constitute CRS(504). Moreover, in CRSsNP patients, facial pain sco-
5.3.3. Facial pain res are negatively correlated with CT sinus abnormalities(505). As
Like all the cardinal symptoms that constitute the diagnosis of such, routine CT scanning in patients with facial pain is not ad-
CRS, facial pain has a broad differential diagnosis. Unlike the vised, as most will have no relevant findings(506). Proper history-
other symptoms, however, causes for facial pain should often taking can eliminate the need for imaging in most patients(507).
be sought in areas beyond the nose. Unfortunately, ‘common Taken together, facial pain should only be ascribed to CRS if
sense’, often strengthened by the judgement of primary care there are other nasal symptoms and concordant abnormalities
physicians, indicates that facial pain must derive from sinonasal upon nasal endoscopy and/or imaging. Ideally, the pain and
disease. As such, ENT-surgeons regularly encounter patients its intensity have a temporal relationship with the intensity of
referred for facial pain but will only diagnose CRS in the minority the other nasal symptoms (also indicated in the third edition of
of them(487). Therefore, having a basic understanding of the va- the Int Classification of Headache Disorders (ICHD), see https://
rious causes of facial pain is pivotal to determine the right diag- ichd-3.org). With the absence of any of these findings, a primary
nosis and management. Too often patients undergo treatment, headache syndrome should be considered as cause of the facial
including surgery, aimed at supposed sinonasal disease, when pain (Table 5.3.4.).
proper history-taking would have revealed a non-sinonasal
cause to be far more likely(488). 5.3.3.2. Nasal complaints in primary headache syndromes
Unfortunately, patients with a primary headache syndrome also
5.3.3.1. Facial pain in CRS report nasal symptoms. In a retrospective chart review, these
Facial pain is usually a mild complaint in CRS (see section 3.1). patients were found to report items as nasal congestion, rhinor-
Small studies with both CRSwNP and CRSsNP patients suggest rhea and sneezing in the majority of cases(508). When compared
that they report more facial pain than controls (although the to healthy controls, patients with either midfacial segment pain
controls groups were really small, <10 subjects per study)(489, or CRS both have increased SNOT scores(508, 509). However, the
490). In patients with CRSwNP, 16-18% report moderate to se- pattern in the subdomains is different. CRS patients have higher
vere facial pain, with only a good correlation between pain and scores for the rhinological domain, while midfacial segment
sinus disease in those with purulent discharge(491, 492). Conversely, pain patients score higher in the ear/facial domain (including
in patients with purulent secretions from the paranasal sinu- facial pain)(510). As such, a ratio of ear/facial domain over rhino-
ses, only 29% report facial pain(493). As such, nasal endoscopy is logical domain scores > 0.66 was found to be a strong negative

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Table 5.3.4. Most frequent primary headache syndromes giving facial pain.

Trigeminovascular headache Tension-type Midfacial

headache segment pain

Migraine Trigeminal Paroxysmal Cluster headache

neuralgia hemicrania

Paroxysmal Paroxysmal Paroxysmal Paroxysmal Paroxysmal or Paroxysmal or

continuous continuous
Location Usually frontotem- In the distribution(s) Orbital, supraorbital Orbital, supraorbital, Entire vertex The midface alone
poral, facial of one or more and/or temporal, temporal, facial (bridge of the nose,
divisions of the facial paranasal, and/
trigeminal nerve or peri-orbital) in
midfacial segment
pain.
Side Mostly unilateral Unilateral Unilateral Unilateral Usually bilateral, Usually bilateral,
symmetrical symmetrical
Duration 4-72h Fraction of a second 2-30min 15 min-3h Continuously pre- Continuously pre-
– 2 min sent to some extent sent to some extent
(30 min – 7 days if
paroxysmal)
Quality Pulsating (throb- Severe, electric Severe pain, bur- Very severe pain, Pressing, tightening Pressing, tightening
bing, piercing, shock-like, shooting, ning, piercing burning, piercing, (non-pulsating). (non-pulsating).
stabbing) stabbing or sharp pressing
Accompa- Nausea, vomiting, Mild autonomic Any or several of Any or several of Hyperaesthesia
nied by photophobia, symptoms such as ipsilateral nasal ipsilateral nasal Increase of
phonophobia lacrimation and/ congestion, rhinor- congestion, rhinor- complaints when
or redness of the rhea, lacrimation, rhea, lacrimation, bending over
ipsilateral eye may conjunctival injec- conjunctival injec-
be present tion, eyelid edema, tion, eyelid edema, A sense of nasal
facial sweating, facial sweating, obstruction
miosis or ptosis, miosis or ptosis,
sense of restlessness sense of restlessness
or agitation or agitation
Others Prodromal state, Attacks can be Rare condition, Rare condition, Often patients
aura precipitated by mostly males. Fre- mostly males. Most overuse analge-
innocuous stimuli quent attacks (>5 often comes in sics without clear
within the affected daily); a chronic bouts that last benefit; if nasal
trigeminal distri- form exists as well; weeks to months surgery is perfor-
bution. There may absolute response med, it typically
be concomitant to indometacin relieves complaints
continuous pain of for several months
moderate intensity only

For a full overview of neuropathies and facial pain syndromes see: https://ichd-3.org; midfacial segment pain is not yet recognized in this list as a
separate headache syndrome, but is established as a clinical entity.

predictor of CRS(511). The relevance for this chapter is that a patient referred for sinus
disease because of headache or facial pain, might also be suf-
5.3.3.3. Medication overuse headache fering from MOH in addition to a primary headache syndrome.
Patients with a primary headache syndrome are prone to use
analgesic medication in an increasing frequency. This might trig- 5.3.3.4. Pragmatic approach
ger a concomitant form of headache, which is termed medica- When a patient’s main complaint is facial pain:
tion overuse headache (MOH). According to the ICHD diagnostic • Invest in taking a proper history, including:
criteria, it occurs 15 or more days per month, in a patient with a • the presence of (other) rhinosinusitis symptoms
primary headache syndrome using medication for more than 10 • the correlation between the pain and other symptoms
or 15 days per month (depending on the medication group) for • medication use (especially analgesics)
more than three months. More detailed information on this form • other nasal conditions than CRS (e.g., allergic rhinitis)
of headache can be found in a recent review by Diener et al.(512). • the response of the facial pain/headache to previouna-

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sal treatments such as nasal and oral corticosteroids,

antibiotics and/or surgery. Key points | What’s new since EPOS 2012

• Perform nasal endoscopy to exclude CRS or other rhinologi-

cal causes for the facial pain • Many studies have explored further the relation between
• Use CT imaging only when in doubt. facial pain and CRS, showing that facial pain alone is rarely
caused by CRS.
If CRS is expected as the explanation for the facial pain: • Patterns in the different domains of disease-specific surveys
• First treat medically such as the SNOT-22 help discern sinonasal facial pain from
• Check whether the pain improves together with the other other causes.
signs and symptoms of CRS. • There is no relation between the location of facial pain and
• If so, surgery might be helpful when medication alone abnormalities upon imaging.
fails to gain control of disease • A pragmatic approach to the patient with facial pain is
• If not, reconsider the diagnosis or at least consider provided.
overlap with a primary headache syndrome or MOH • Facial pain without other nasal complaints or abnormali-
and consider referral to a specialized neurologist ties on examination should not (primarily) be addressed
surgically.
If the facial pain is not likely caused by CRS (or any other rhinolo-
gical condition):
• Counsel the patient that the sinuses are not involved
• Try to further clarify the pain according to the cha- 5.3.4.2. Viral exacerbation
racteristics in Table 5.3.4. Episodic/paroxysmal pain Point of care viral assays are available and are now starting to be
alludes to a primary headache disorder. used clinically. The impact of these tests on antibiotic prescrip-
• It is up to the treating physician / rhinologist to what tion and clinical outcomes in exacerbation of airway disease is
extent the treatment is carried out personally. Always currently being evaluated(519). It is too early to form an opinion
consider referral to a specialized neurologist. For treat- on the role of viral assays in the diagnosis of exacerbations of
ment, current literature suggests (a trial of ) treatment CRS but they may play a role in the future.
with amitriptyline and/or triptans(513-516), while others
report success by offering a team-based approach(517). 5.3.4.3. Bacterial exacerbation
A nasal swab with ensuing culture is often inconclusive. Ho-
Treating a primary headache syndrome might be challenging wever, if positive, it will allow targeted antibiotic treatment. A
and might need multiple medication regimes to succeed. repeated positive result is also informative and may suggest an
For example, in a small retrospective cohort of patients with antibody deficiency associated with encapsulated micro orga-
midfacial segment pain, success was achieved in 50% within nisms such as Streptococcus Pneumonia, Haemophilus Influenzae
18 months. Most patients used a combination of drugs at that and Moraxella Catarrhalis(520).
time(518). As such, it is advised to consult a specialized neurologist
dedicated to neuropathies, headache and facial pain whenever 5.3.4.4. Biomarkers
the first-line treatment (such as amitriptyline) fails. No unique biomarkers have been identified to diagnose an
acute exacerbation of CRS. Point of care CRP or ESR have proved
5.3.4. Diagnosis and differential diagnosis to be of limited value in acute rhinosinusitis(521).

5.3.4. 1. Host factors 5.3.4.5. Differential diagnosis

As with all difficult to treat CRS patients, evaluation of the pa- Conditions of recurrent or cyclic nature such as migraine are
tient’s immune system is warranted (see also 8.2). Basic testing more likely to be mistaken for AECRS. Many migraine sufferers
would include a full blood count including eosinophils, specific have nasal symptoms with congestion, rhinorrhoea, fullness
IgE for common airway allergens and serum IgE. Immune in cheek and forehead and which easily lead to the diagnosis.
deficiency has to be considered if the patient’s history suggests AECRS(522). Flare-ups of allergic rhinitis or non-allergic rhinitis are
frequent infections and is more common in patients with exa- also easily confounded with AECRS and having a full under-
cerbation of CRS than in the healthy population, up to 11% in standing of the patient’s airway history and immune system
recurrent acute CRS according to a recent review(46). Revision sur- including allergy testing is helpful in identifying this.
gery should be considered if the sinus anatomy is unfavourable. Other possibilities are similar to the differential diagnosis in

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Figure 5.3.1. Delphi: Is it essential to do CT of the sinuses at initial presenta- Figure 5.3.2. Delphi: Is it essential to do CT of the sinuses at initial presenta-
tion to ENT secondary care with highly suggestive symptoms of CRS and tion to ENTsecondary care in patients with highly suggestive symptoms of
abnormal mucosa at endoscopy ? CRS but normal endoscopy ?

difficult-to-treat CRS including; dental infection, GORD, cystic CT with contrast or MRI is used (if there is no contraindication)
fibrosis, primary ciliary dyskinesia, vasculitis and sarcoidosis. (530)
. However, a recent study from Spain suggested that CT
Conditions of recurrent or cyclic nature are more likely to be continues to be over-used in this context(531). MRI and CT with
mistaken for AECRS such as migraine. contrast are also indicated if neoplasia or invasive fungal rhino-
sinusitis are suspected or in the further investigation of olfactory
5.3.5. Diagnostic tools loss(525, 526, 532).
This subchapter discusses diagnostic tools most relevant for It was unclear from the responses of the EPOS2020 steering
CRS. For more extensive discussion of diagnostic tools in rhino- group whether it was essential to do a CT of the sinuses at
logy please refer to the European position paper on diagnostic initial presentation to ENT / secondary care in a patient with
tools in rhinology(450). symptoms highly suggestive of CRS irrespective of whether the
mucosa was abnormal or normal at endoscopy (Figures 5.3.1.,
5.3.5.1. Diagnostic imaging in rhinosinusitis 5.3.2.).
However, the majority of the EPOS2020 steering group conside-
5.3.5.1.1. Rationale red it was essential to do CT in CRS after failure of appropriate
Imaging is used to assess: medical or surgical treatment in secondary care with continued
• Corroboration of clinical symptoms and endoscopic fin- symptoms and abnormal endoscopy (Figure 5.3.3.).
dings Many attempts have been made to semi-quantify the changes
• Anatomy and anatomical variants observed on CT scan using scoring and staging systems of
• Pathology varying complexity. The most commonly used of these is the
• Diagnosis Lund-Mackay system which is based on the degree of opacifi-
• Extent(523, 524) cation for the maxillary, anterior and posterior ethmoids, frontal
and sphenoid sinuses (0-none; 1-partial; 2-complete) and OMC
5.3.5.1.1. Tests (0 or 2) giving a maximum score of 24 or 12/side(533). This scoring
The different imaging modalities in diagnosing rhinosinusitis system has been validated in several studies(534, 535). Modifications
(conventional X-ray, computerized tomography (CT), cone beam of the LMS have been proposed but have not shown significant
CT and magnetic resonance imaging (MRI)) have been evaluated improvement in correlation with symptom severity scores or
(525) of which overall CT scan remains the gold standard in the HRQOL impairment(536-538).
radiologic evaluation of rhinologic disease, notably CRS(526-528). In CRS after failure of appropriate medical or surgical treatment
The first guidelines that recommended CT sinus imaging and/or in secondary care with continued symptoms and abnormal
nasal endoscopy for confirmation of the symptoms-only based endoscopy, the EPOS2020 steering group regarded a total Lund-
diagnosis of chronic rhinosinusitis were the EPOS guidelines in Mackay score of 0 as irrelevant, the relevance of a score of 1 or 2
2005(529). due to mucosal thickening in 2 sinuses to be unclear and scores
However, in acute rhinosinusitis, the diagnosis is made on clini- of 2 due to complete obstruction of one sinus, or a score of 3 or
cal grounds and CT is not recommended(1) unless the condition greater, whether uni- or bilateral to be clinically relevant (Figures
persists despite treatment, or a complication is suspected when 5.3.4. - 5.3.10.).

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Figure 5.3.3. Delphi: Is it essential to do CT in CRS after failure of appropriate based diagnosis of CRS may have normal CT and endoscopy re-
medical or surgical treatment in secondary care with continued symptoms sults(9, 10). The accuracy of CT in the diagnosis of CRS was tested,
and abnormal endoscopy ? comparing CT scores with histopathologic grade of inflamma-
tion and including a control group without CRS, utilizing well
designed criteria(543). By using the ROC method, the sensitivity of
CT was found to be 94% and specificity 41% using an LMS score
cut-off value for CRS of greater than 2. If the value of “normal”
LMS scores (i.e. >4) was applied, specificity increased to 59%.
Using the same method in paediatric rhinosinusitis, taking an
LMS of at least 5 to indicate real disease, CT sensitivity was 86%
and specificity 85%(546). Thus, an LMS of 2 or less has an excellent
negative predictive value, and an LMS of five or more has an ex-
cellent positive predictive value, strongly indicating true disease.
Weak but significant correlations were found in a small cohort
of CRS patients between CT stage and scores on patient-based
questionnaires in the CRSwNP subgroup but not with the CRS
patient group as a whole(547). In a similar study using 271 CRS
When deciding if the changes are clinically relevant, the patients comparing SNOT-22 and VAS with LMS CT score, no
EPOS2020 steering group felt that the importance of the fol- association was found between total SNOT-22 score and LMS
lowing were unclear: overall or in CRSsNP(505). However, again some independent
• Degree of mucosal thickening associations were shown with the LMS in CRwNP and both
• Number of sinuses affected SNOT-22 and VAS (p<0.001). There was no correlation between
• Status of the ostiomeatal complex inflammation on CT and facial pain especially in CRSwNP(504,
However, the presence of complete opacification of any sinus 505)
and in CRSsNP the higher the SNOT-22 facial pain score, the
was considered by the majority as clinically positive (Figures lower the LMS (p=0.022) . The only symptom that significantly
5.3.11., 5.3.12., 5.3.13., 5.3.14.). correlates with CT scores is olfaction(465, 548). On the other hand,
For the purposes of both medical and surgical treatment in CT scores were found to significantly correlate with the stage
secondary care/ENT, the EPOS020 steering group considered of inflammation in histopathological analysis of sinus mucosal
it was acceptable to use a previously performed CT scan of the samples in CRS, most notably in CRSsNP(549, 550).
sinuses which has been done up to six months earlier. They In comparison to CT, plain sinus radiographs have shown poor
were unclear regarding the acceptability of a scan performed >6 sensitivity and specificity, so that even low irradiation does not
months-3 years earlier but considered one performed >3 years justify their use. Correlation of CT scans with plain sinus radio-
earlier to be unacceptable for the purposes of medical treat- graphs for maxillary sinusitis was reasonable (78%) but was only
ment of CRS (Figures 5.3.15.-5.3.24.). 52% for the ethmoids(551) and CT out-performed ultrasonograp-
How and when the scan is done will influence the results(450). hy(521). However, CT cannot confirm acute bacterial rhinosinusitis
Marked inflammatory changes may be observed following a as compared to antral puncture with positive bacteriology(552, 553).
viral cold which can persist for a number of weeks(539, 540) which CT is also extremely sensitive in demonstrating ‘abnormalities’
probably accounts for the high percentage of normal asympto- in the sinonasal region. A wide range of anatomic variations are
matic adults who have evidence of mild mucosal thickening on observed which are generally unrelated to the development of
CT (~18%)(10, 541). disease(541, 554) but are highly significant for ‘safe’ surgery e.g. the
Thus, on CT a “normal” Lund-Mackay score (LMS) for adults is presence of a sphenoethmoidal cell(555). The high resolution of
4.26 (95% CI, 3.43 to 5.10)(542) and for children it is 2.81 (95% con- modern CT and the use of detailed three planar reconstruction
fidence interval, 2.40 to 3.22), with only 19.3% having a score of has significantly improved our appreciation of the complex
0(543). The LMS can also be applied to MRI and does not appear anatomy particularly in the frontal recess and led to Int efforts
to overstage inflammatory disease(544). to agree a classification of the area(523, 524). Thus, preoperative CT
CRS studies comparing symptoms with CT and endoscopic fin- is mandatory for sinus surgery in most countries and should be
dings have shown good correlation between CT and endoscopy available in the operating theatre(556, 557) providing an anatomical
but generally not between symptoms and CT. When comparing roadmap often augmented by navigation systems and other
concordance between endoscopy and CT staging in CRS, the techniques such as fusion of CT and MRI.
correlation was 65% for positive and 71% for negative results(545). Whilst CT is the principle modality for diagnosis in rhinosinusitis,
However, more than 40% of patients who fulfil the symptom- extent of disease does not necessarily equate with prognosis(527,

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Figure 5.3.4. Delphi: What do you regard as a clinically relevant total Figure 5.3.5. Delphi: What do you regard as a clinically relevant total LM
LundMackay score for CRS in this situation ? 0 score for CRS in this situation? 1

Figure 5.3.6. Delphi: What do you regard as a clinically relevant total LM Figure 5.3.7. Delphi What do you regard as a clinically relevant total LM
score for CRS in this situation? 2 complete obstruction of one sinus score for CRS in this situation? 2 mucosal thickening in 2 sinuses

Figure 5.3.8.: Delphi What do you regard as a clinically relevant total LM Figure 5.3.9.: Delphi What do you regard as a clinically relevant total LM
score for CRS in this situation? 3 or more uni or bilateral score for CRS in this situation? 4 or more uni or bilateral

. In a multicentre prospective study of patients undergoing

534)
(coeff=0.24, p=0.02), complication rate (odds ratio (OR) 1.08,
surgery for CRS with nasal polyps (CRSwNP) and without (CRS- 95% confidence interval (CI) 1.06-1.1) and revision rates (OR
sNP), the LMS was correlated with a range of parameters in 1.03, 95% CI 1.001-1.06) but showed no correlation with SNOT-
1840 CT scans(558). This showed as expected that the higher the 22 scores. In another large multicentre cohort of refractory
score, the higher the grade of polyp and the more extensive CRS patients, patients with low stage LMS are not significantly
the surgery. The score also correlated with symptom reduction different than high stage LMS and did not show any difference

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Figure 5.3.10. Delphi: What do you regard as a clinically relevant total LM Figure 5.3.11. Delphi: When deciding if the changes are clinically relevant,
score for CRS in this situation? 5 or more uni or bilateral. how important are the following in your decision, Degree of mucosal thick-
ening ?

Figure 5.3.12. Delphi: When deciding if the changes are clinically relevant, Figure 5.3.13. Delphi: When deciding if the changes are clinically relevant,
how important are the following in your decision. Number of sinuses how important are the following in your decision. Status of the ostiomeatal
affected? complex?

Figure 5.3.14. Delphi: When deciding if the changes are clinically relevant, Figure 5.3.15. Delphi: For the purposes of medical treatment in secondary
how important are the following in your decision: Presence of complete care/ENT is it acceptable to use the previously performed CT scan which has
opacification of any sinus ? been done: < 3months ago.

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Figure 5.3.16. Delphi: For the purposes of medical treatment in secondary Figure 5.3.17. Delphi: For the purposes of medical treatment in secondary
care/ENT is it acceptable to use the previously performed CT scan which has care/ENT is it acceptable to use the previously performed CT scan which has
been done 3-6 months ago been done 6-12 months ago?

Figure 5.3.18. Delphi: For the purposes of medical treatment in secondary Figure 5.3.19. Delphi: For the purposes of medical treatment in secondary
care/ENT is it acceptable to use the previously performed CT scan which has care/ENT is it acceptable to use the previously performed CT scan which has
been done 1 3 years ago been done longer then 3 years ago ?

Figure 5.3.20. Delphi: For the purposes of surgical treatment in secondary Figure 5.3.21. Delphi: For the purposes of surgical treatment in secondary
care/ENT is it acceptable to use the previously performed CT scan which has care/ENT is it acceptable to use the previously performed CT scan which has
been done < 3months ago? been done 3-6 months ago?

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Figure 5.3.22. Delphi For the purposes of surgical treatment in secondary in level of improvement after endoscopic sinus surgery(559). In
care/ENT is it acceptable to use the previously performed CT scan which has contrast, a more recent study showed that the preoperative LMS
been done 6-12 months ago ? in 665 patients with medically recalcitrant CRS correlated signi-
ficantly with preoperative extranasal and rhinologic symptom
severity on the SNOT-22 and that the LMS was an indicator of
postsurgical quality of life (QOL) outcomes(560). The LMS mea-
sures a different aspect to ‘subjective’ symptom scores as it cor-
relates well with other markers of disease severity, the nature of
surgery offered and its outcome. Its main value lies in diagnosis,
determining extent of disease and providing inclusion criteria
for studies.
The pattern of inflammation may also be important. A central
radiological pattern of mucosal disease is likely associated with
inhalant allergen sensitization - the so-called ‘black halo’ sign(194).
The radiological pattern defined by centrally limited changes in
all of the paranasal sinuses was associated with allergy status
and predicted atopy with 90.82% specificity, 73.53% positive
Figure 5.3.23. Delphi For the purposes of surgical treatment in secondary predictive value, likelihood positive ratios of 2.16 and diagnostic
care/ENT is it acceptable to use the previously performed CT scan which has OR of 4.59.
been done 1 - 3 years ago ? Other radiologic features such as the degree of neo-osteoge-
nesis in CRS may have important prognostic implications(561-563).
Scoring systems have been developed to evaluate this on sinus
CT based on bone thickness (Kennedy osteitis score: 0-3(564);
Global osteitis scoring system: 0-5)(565).
In CRS, CT imaging is the primary modality, but it is not normally
recommended until after an appropriate course of medical the-
rapy has failed(1, 566) and without an intervening acute episode.
It should be noted that other studies suggest that early CT
scanning may be more cost-effective as compared to exten-
ded courses of antibiotics given empirically and is preferred by
patients(567-569). This is especially pertinent in patients with rhinitis
or atypical facial pain(504, 570, 571) and may be facilitated by the avai-
lability of lower radiation protocols and/or cone beam.
Hitherto, CT has not been used as an outcome measure due
Figure 5.3.24. Delphi For the purposes of surgical treatment in secondary to ethical issues with additional radiation exposure but the
care/ENT is it acceptable to use the previously performed CT scan which has technology and processing abilities of multi-detector CT (MDCT)
been done longer then 3 years ago? scanners have continued to evolve and there has been a drive to
reduce radiation dose whilst preserving image quality by shor-
tening the scan time and using post-processing techniques(572,
573)
. Cone beam CT (CBCT), historically used for dental imaging, is
also being utilised in sinonasal imaging producing high resolu-
tion images, but the longer scan time, subsequent susceptibility
to motion artefact and the lack of soft tissue differentiation can
be a drawback resulting in loss of some pathological detail such
as the hyperdensities seen in sinonasal fungal disease(574).
However, ionizing radiation has been significantly reduced with
multi-slice detector CT (MSCT) utilising low dose protocols,
which reduce the dose to 0,07 mSv, 10 times lower than the
standard protocol(575). Low dose protocols have been shown
to significantly shorten the duration of the procedure without
compromising anatomical accuracy(575) making them increasin-

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gly attractive as an objective outcome measure in therapeutic 5.3.5.2.2. HRQOL measures in ARS
studies(576, 577). Perhaps reflecting the self-limiting nature of ARS, and its relati-
vely short duration, there are very few studies evaluating HRQOL
5.3.5.2. Health-related quality-of-life (HRQOL) measures in ARS and a paucity of validated measures. The SNOT-16(584),
a derivative of the RSOM-31 questionnaire, which was initially
5.3.5.2.1. Rationale developed for patients with CRS, has been validated for use in
Patient reporting outcome measures (PROMs) are question- primary care patients with ARS. It has been shown to have high
naires or instruments, developed and validated according to internal consistency and sensitivity to change, with a mean item
defined methods, that are designed to quantify patients' sub- score reported between 0-3 and an MCID of 0.5.
jective perception of the severity of their disease in terms of the Trials of treatments in ARS report variable outcomes, but
impact on quality of life. They may be disease specific or reflect usually present 'cure' rates (described as complete resolution
global QOL. While not intended as diagnostic tools, PROMS of symptoms, but not otherwise defined) or report scores for
will normally discriminate between those with and without the individual symptoms of facial pain, congestion, rhinorhoea,
disease in question, and for many 'normal' population scores post-nasal drip or headache. The heteregeneity in reporting of
have been defined. However, they are best used as repeated outcomes precludes meta-analysis. There is no core outcome set
measures to detect changes in HRQOL over time, or in response for ARS.
to medical or surgical intervantion. The EPOS2020 steering group were unclear whether a QOL
Early reports of sinus surgery focused in clinician rated measures instrument was important for the management of acuterhinosi-
such as endoscopy or radiological scores, although since the nusitis (ARS) (Figure 5.3.25.).
mid 90s there has been a growing focus in the use of symtoms For a General Health-related quality of life instrument in ARS,
scores and PROMS, reflecting the primary aim of treatment the EPOS2020 steering group used a wide range of possibilities.
being the improvement in the general well-being of the patient Of these the SF36 was the most popular but the SF12 was also
and their quality of life. CRS related quality of life has been suggested (Figure 5.3.26.).
shown to drive patient's decision-making regarding treatment When using a specific rhinologic health-related quality of life
options and predicting post-operative outcomes. instrument in ARS, the majority of the EPOS2020 steering group
proposed the SNOT22 (Figure 5.3.27.).
5.3.5.2.2. Tests
Instruments which measure health-related quality-of-life (HR- 5.3.5.2.3. HRQOL measures in CRS
QOL) are generally divided into generic HRQOL instrument and Chronic rhinosinusitis (CRS) has a significant impact on HRQOL
disease specific ones. and may affect different domains of HRQOL in addition to
Generic questionnaires are designed to measure different rhinological symptoms, such as fatigue, sleep quality, pain and
domains of physical, psychological and social functioning across emotional impairment (like anxiety and depression, productivity
all health conditions. These instruments may be used to com- and social functioning.
pare healthy and diseased subjects, and may also be used to A number of HRQOL evaluating instruments have been deve-
estimate the impact of different diseases on general well-being loped during past few decades. The key features of the most
of patients in comparison with other diseases patients(578), but commonly used PROMs are summarised in Table 5.3.5.
are also used to measure QOL in CRS patients(36, 579-582). The EQ-5D The Chronic Sinusitis Survey (CSS)(585) evaluated six item severity
responds well to changing CRS symptomatology(583). and duration based specific outcomes, primarily related to
Disease-specific instruments may be composed of different do- rhinosinusitis symptoms, pain and medication use. Rhinosinu-
mains of general health affected in a given disease but also mea- sitis Disability Index (RSDI)(586) is a similar HRQOL instrument
sure the severity of the specific symptoms of the disease. Such asking 30 questions in 3 domains, covering also some generic
instruments are developed having identified the most common questions. The Rhinosinusitis Outcome Measure (RSOM-31), de-
symptoms or impairments when questioning the patients about veloped in 1995(587) is a HRQOL questionnaire evaluating seven
the problems they experience related to the disease. These in- domains in 31 questions. RSOM-31 was reduced to SNOT-20
struments may measure both the severity and frequency of the in 2002, and then modified into SNOT-22 in 2009. The SNOT-
impairment. Specific questionnaires seem to discriminate better 22 is now regarded as the most appropriate instrument in the
between those with and without disease than generic PROMS, evaluation of HRQOL impairment in CRS patients, according to
and better evaluate the impairment within the domains of a a recent systematic review of 15 CRS related PROMs which were
specific disease and their interactions, such that they are more analyzed using Consensus-based Standards for the selection
relevant to clinical practice. They are of less value in comparison of Health Measurement Instruments(588). The SNOT-22 includes
with other conditions. evaluation of the severity of major and most of the minor CRS

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Figure 5.3.25. Delphi: Is a QoL instrument important for the management symptoms with a nasal domain, and includes additional items in
of ARS ? subdomains relating to sleep disturbance, emotional / psycho-
logical and aural/ facial pain domains(588, 589). Patients score each
of 22 items on a Likert 6 points scale, or 0 to 5, with a total score
range of 0-110. SNOT-22 scores are influenced significantly with
several demographic confounders and comorbid disorders, like
gender, smoking, asthma and mental illness, including anxiety
and depression(511, 590, 591).
The SNOT 22 questionnaire was validated in 2009 relying on the
data from a UK multicentric prospective cohort study in over
3000 patients followed pre- and postoperatively after sinus
surgery(592, 593). The SNOT-22 can be stratified into ‘mild’ being
defined on the SNOT-22 score as 8-20, ‘moderate’ as >20-50
and ‘severe’ as >50(594). It has been validated in several foreign
languages(595-599), for children(600, 601) and it has been used as an
outcome measure in several multicentric cohort studies(36, 590, 602).
Patients with non-sinogenic headache have distinct SNOT-22
Figure 5.3.26. Delphi: If you use a general healthrelated quality of life instru- score patterns compared with patients with CRS. A domain 3
ment which would you use for ARS? (Ear/facial)/domain 1 (Rhinologic) ratio greater than 0.66 is a
strong negative predictor of CRS, which can be used to aid in
SF-36 9 (36%) patient counseling and potentially limit the use of unnecessary
SF12 5 (20%) sinonasal therapeutics(511).
I don't use one 5 (20%) With regards to changes in HRQOL in the setting of chronic
2 (8%) + 1 (4%) in a research setting disease, many patients may experience improvement after
EuroQOL
only
intervention but many may have ongoing symptoms. Repeated
A short one (e.g.NOSE) 1 (4%)
measures allow change in HRQOL to be monitored over time.
SF-36 or SF-12 (generic not
1 (4%) It may also facilitate cohort studies where the effectiveness
general)
of interventions can be analysed. In order to determine if a
I don’t see ARS patients 1 (4%)
change at individual or population level is clinicaly significant,
SNOT-16 1 (4%)
the minimal clinically important difference (MCID) can be used.
VAS 1 (4%)
This is the smallest change in a given outcome measure that
EVA 1 (4%)
can be detected by a patient as a perceptible change. The MCID
Multiple options given by some respondants. can be calculated using a number of different methods; using
anchor-based methodology in a large surgical cohort the MCID
has been shown to be a change in 8.9 points on the SNOT-22,
Figure 5.3.27. Delphi: If you use a specific rhinologic healthrelated quality of while for patients undergoing medical intervention, an MCID of
life instrument, which would you use for ARS? 12 has been proposed(603). Scores for the SNOT-22 subdomains
have also been defined(603, 604). It can be used to help define a
SNOT-22 12 (48%) minimum threshold for ‘success’ or response rate for any given
intervention. A limitation of the MCID is that it is a population-
SNOT20 3 (6%) derived score and the threshold for perceived benefit may vary
I don't use 3 (6%) between individuals. Individualized outcome measures, howe-
ver, are complex to use and preclude comparative studies.
NOSE 1 (4%)
Based on the large number of outcome measures and hete-
I don’t see ARS patients 1 (4%) rogeneity of outcomes measured in the current published
literature, a Core Outcome Set (COS) for assessing outcomes
EVA 1 (4%)
in CRS has been proposed(605). A COS is a standardized group
SNOT unspecified 1 (4%) of outcome measures that may be included in future trials to
facilitate data comparisons and future meta-analyses. For the
Not all participants answered. CRS COS, items in four domains were identified as imperative:
patient reported symptoms and QOL, control of disease, impact

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Table 5.3.5. Characteristics of validated patient reported outcome measures for chronic rhinosinusitis.

QoL Year Type No. of No. of No. of Score Domains assessed Minutes MCID
Measure developed patients in questions domains range to
validation complete
study
CSS 1995 HRQoL 104 6 2 0-100 CRS symptoms; 5 9.75
medication use
RSOM-31 1995 HRQoL 142 31 7 0-155 Nasal; eye; ear; sleep; gene- 15
ral; emotional; functional
RSDI 1997 HRQoL 87 30 3 0-120 Physical; functional; 5-10 10.35
emotional
SNOT-16 1999 HRQoL 47 16 0 0-48 NA 5

SNOT-20 2002 HRQoL 102 20 0 0-100 NA 5 16.0

RSI 2003 Symptom 322 20 3 0-100 CRS symptoms; medication 5

score use; work and social
Rhino- 2005 HRQoL 49 17 3 0-100 Symptom severity; bother- 7 3.8-6.1
QoL someness; impact scale
RSTF 2007 Symptom 201 14 0 0-140 NA 3
score
SNOT-22 2009 HRQoL 2803 22 0 0-110 Rhinologic; extranasal 7 8.9
rhinologic; ear/facial;
psychosocial; sleep
SNQ 2009 Sinusitis 59 5 0 0-35 NA <2
screen
DyNa- 2012 HRQoL 759 78 6 0-780 Nasal obstruction; anterior 15
Chron rhinorrhea; posterior
rhinorrhea; sense of smell
difficulty; facial pain; cough
QOD 2012 HRQoL 102 25 3 0-57 Negative items; positive 7-10 2.6 – 8.6
items; social items
DSS 2013 HRQoL 48 6 2 0-32 Symptoms; HRQoL <2

EQ-5D 2015 Generic QoL/ 350 15 5 0-100 Mobility; self-care; usual <2
Health state activity; pain/discomfort;
utility anxiety/depression
SCT 2015 CRS-specific 50 4 3 0-16 Symptoms; productivity; 1
control rescue medication use

Data from Rudmik et al. 2015(588). CSS, Chronic Sinusitis Survey; CRS, chronic rhinosinusitis; DSS, Disease Severity Score; DyNaChron,
Dysfonctionnement Nasal Chronique Questionnaire; EQ-5D, EuroQoL Five-dimensional Questionnaire; HRQoL, health related quality of life; NA, not
available/applicable; QOD, Questionnaire of Olfactory Disorders;QoL, quality of life; RhinoQoL,Rhinosinusitis Quality of Life questionnaire; RSDI,
Rhinosinusitis Disability Index; RSI, Rhinosinusitis Severity Inventory; RSOM-31, 31-item Rhinosinusitis Outcome Measurement; RSTF, Rhinosinusitis
Task Force; SNOT, Sinonasal Outcome Test; SCT, Sinonasal Control Test; SNQ, Sinonasal 5-item questionnaire.

on daily activity, and acceptability of treatment and side effects. The EPOS2020 steering group were unanimous that a QOL
Currently none of the established PROMS capture all the desired instrument was important for the management of CRS (Figure
aspects of CRS; the SNOT-22 fails to capture disease duration or 5.3.28.).
medication usage. Current recommendations include the use The General Health-related quality of life instrument which was
of SNOT-22 scores repeated over time, Lund-Kennedy (LK) en- used by the majority of the EPOS2020 steering group in CRS was
doscopic scores, and additional questions to evaluate the need the SF36 but the SNOT22 and EQ-5D were also popular (Figure
for systemic medications or progression to surgery, compliance 5.3.29.).
with and side effects of treatment, additional information on When using a specific rhinologic health-related quality of life
symptom frequency, and impact on ability to perform normal instrument in CRS, the vast majority of the EPOS2020 steering
activities(605) (Table 5.3.6.). group used a SNOT22 (Figure 5.3.30.).

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Table 5.3.6. Core Outcome Set.

Domain Item Proposed measurement tool

Patient-reported symptoms and QOL Overall symptom severity SNOT-22 repeated over time
Frequency of symptoms Additional question required to address fre-
Duration of symptoms quency of symptoms
Duration of treatment effect
Sense of smell
Runny nose/nasal discharge (anterior or posterior)
Nasal obstruction/blockage/congestion
Disease-specific quality of life
Control of disease Overall control of disease Need for systemic medication (steroid or
Need for surgery antibiotic)
Endoscopic appearances (including presence/ Progression to surgery
quality of pus, presence and size of polyps, edema, Lund-Kennedy score
crusting, inflammation)
Impact on daily activity Ability to perform normal activities SNOT-22 (or specific measures of productivity)
Compliance with treatment Measurement of compliance and side effects
Acceptability of treatment and side effects Acceptability of treatment
Side effects of treatment (including medical and
surgical)

5.3.5.3. Nasal endoscopy Figure 5.3.29. Delphi :If you use a general health-related quality of life
instrument, which would you use for CRS *?
5.3.5.3.1. Rationale
Nasal endoscopy is an essential part of the rhinological exami- SF-36 12 (48%)
nation of the nasal cavity, middle meatus, sphenoethmoidal
SNOT-22 6 (24%)
recess and postnasal space, and is an essential part of the rhino-
logical examination(450). It allows identification of oedema, pus EQ-5D 6 (24%)
and/or polyps, assessment of sinus cavities following surgery
SF12 4 (16%)
and facilitates postoperative debridement or microbiological
sampling when needed(606). It can be used to evaluate the res- None 1 (4%)
ponse to both medical and surgical treatment and allows photo
VAS 1 (4%)
/ video-documentation. It is a useful educational tool for both
junior staff and patients, and is generally well-tolerated.
*Multiple options given by some respondants.
5.3.5.3.2. Test
The standard three-pass technique for rigid nasendoscopy was
Figure 5.3.30. Delphi: If you use a specific rhinologic healthrelated quality of
life instrument, which would you use for CRS *?
Figure 5.3.28. Delphi: Is a QoL instrument important for the management
of CRS ? SNOT-22 21 (84%)

SNOT unspecified 2 (8%)

CRS-PRO 1 (4%)

SNOT20 1 (4%)

RSDI 1 (4%)

VAS 1 (4%)

*Not all participants answered.

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 EPOS 2020

originally described using a 4mm 30 degree endoscope, but on the allergen, from 40% (cockroach) to 87-89% (grass, mites)
it can be performed with a 2.7mm endoscope and/or a zero of the positive SPT reactions (wheal size ≥3 mm) are associated
degree endoscope instead(607). The patient should be upright, with patient-reported clinical symptoms when exposed to the
and topical decongestant/anaesthetic spray may be used if ne- respective allergen. The risk of allergic symptoms increased
cessary. The first pass is made along the floor of the nose to the significantly with larger wheal sizes for 17 of the 18 allergens
nasopharynx, looking at the general anatomy, septum, inferior tested(618).
turbinates and nasal mucosa.The second pass runs above the In exceptional circumstances in the diagnosis of CRS, mainly
inferior turbinate to the middle meatus then medial to the mid- when occupational allergies are involved, allergy testing may be
dle turbinate into the sphenoethmoidal recess.The third pass is done with nasal or conjunctival allergen provocation(619). Nasal
made as the endoscope is withdrawn, when it may be possible allergen challenge tests may be performed by direct application
to roll it laterally into the middle meatus. Flexible endoscopes of allergen extract solution sprayed into the nostril or by the ex-
can be used instead, and are particularly useful if the larynx and posure to the inhalation of allergen in the allergen provocation
pharynx need to be assessed as well, but additional procedures chamber. Unlike in skin tests, where allergen is applied uniform-
cannot be performed(608). ly, nasal challenges are based on the search of the allergen dose
Endoscopy improves diagnostic accuracy compared to anterior responsible for a verified allergic response, starting with lower
rhinoscopy alone, up to 69.1% - 85%(609, 610). It is highly specific, dose of allergen, and increasing the dose several times until the
with several studies reporting specificities of up to 95%(567, 609, response is reached. Several guidelines for the standardization
611)
. It is less sensitive, ranging from 30% to 73%(609, 610). Various of nasal allergen challenge tests have been published, the latest
endoscopic scoring systems have been described, such as the being the EAACI position paper in 2018, which are suggesting
Lund-Kennedy system and modifications thereof(612-614). Inter- standardized application and outcome measures to prove posi-
rater reliability is variable, with some aspects of the examination tive response to allergen(620). The conjunctival provocation test is
scoring highly and others less so, although overall inter-rater also an option to prove allergic response in the target organ, as
agreement is good(615). the eye is also often involved in the response to allergen(621). The
Recently, a systematic review analysed the accuracy of nasal diagnostic efficacy of conjunctival provocation test was 89% in
endoscopy in diagnosing chronic rhinosinusitis (CRS) compa- a trial where nasal allergen challenge with house dust mite was
red with paranasal sinus computed tomography (CT). Sixteen used as a standard reference, irrespective of whether the patient
observational or retrospective studies were included resulting had ocular symptoms in natural exposure(622).
in a high correlation [r= 0.85; 95% confidence interval (CI) Diagnosis of allergy in vitro is primarily based on the detection
(0.78–0.94), p<.0001, I277%) between endoscopy and CT in of serum specific IgE to airborne allergens, which may confirm
terms of the diagnostic accuracy for CRS. The sensitivity and SPT results and the presence of clinical symptoms. The other in
specificity were 0.73 [95%CI (0.58–0.83)] and 0.77 [95% CI vitro method is the basophil activation test. In vitro methods are
(0.69–0.85)], respectively. In a subgroup analysis of studies using not sensitive to patients’ medication with antihistamines, have
a Lund–Kennedy endoscopic score threshold ≥2, the area under no risk of systemic reactions to allergens, and are more comfor-
the summary curve was 0.881, and the sensitivity and specificity table for the patients, as they do not result in side effects seen
were 0.84 [95% CI (0.78–0.93)] and 0.79 [95% CI (0.37–0.96)], after SPT and after nasal or conjunctival challenges. This is very
respectively(616). important for the diagnosis of allergy in children.
In conclusion: nasal endoscopy is is an essential part of the Serum specific IgE usually correlates with SPT results, and this
rhinological examination and correlates quite well with CT scan correlation is stronger in patients with more severe symptoms
of the sinusses in patients with CRS. and higher total IgE serum concentration. However, SPT is more
sensitive than specific IgE in serum, and in most trials SPT is used
5.3.5.4. Allergy testing as a standard reference, when testing diagnostic accuracy of
sIgE. Specific IgE assays which are commercially available are not
5.3.5.4.1. Rationale completely compatible, and results using different assays may
The potential role of allergy in CRS has been discussed in 5.1.2.1. differ in sensitivity and specificity, as well as for the producer,
and the allergener(623). Different companies also produce diag-
5.3.5.4.2. Test nostic panels of specific IgE, to improve the speed and reduce
Sensitisation in the regular clinical practice can be measured the cost of the diagnosis if many allergens have to be tested.
with skin prick testing or serum specific IgE(450). It is important Such mixture panels for the most common airborne allergens
to realize the difference between sensitization to aero-allergens have been used for years and their sensitivity and specificity
and allergic rhinitis. Around 60% of the total amount of sensiti- may be moderate to high (70.8 and 90.7, respectively)(624). This
zations to aero-allergens are clinically relevant(617). Depending will probably be even more pronounced in the future, as current

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EU regulations are likely to produce a reduction in commercially ased smell loss and less fluctuation is associated with the increa-
available diagnostic allergens for SPT or ICT(625). This will proba- sing severity of sinonasal disease. For that reason, it is important
bly induce a switch to a broader panel of in vitro sIgE diagnos- to evaluate sense of smell both subjectively and objectively
tics. Further development of in vivo molecular diagnostics is in CRS patients. As they are commonly not fully aware of their
expected through the component resolved diagnosis (CRD). impairment, or at least they are not able to estimate the severity
CRD allows us to identify single allergen molecular components of smell loss, the use of smell tests is recommended in order to
responsible for the allergic reaction. It may help in distin- objectively evaluate this disorder(450, 630, 631). The tests may also be
guishing clinical symptoms resulting from allergen exposure useful during the follow-up of the CRS patient, primarily to mo-
from those which can be attributed to cross-reactivity. nitor the outcomes of anti-inflammatory or surgical treatment.
Total serum IgE is not of much value in diagnosing allergic Many olfactory tests are available but very few are well validated
rhinitis and but might be useful to discriminate patients that are or used on a regular basis with a high number of observations
eligible for anti-IgE treatment. In chronic urticaria and asthma over the last decades, especially in CRS patients(463). The most
total serum IgE levels and their change seems to predict the widely used are the North American UPSIT(629), its short version
response to treatment with omalizumab(626, 627). (SIT, B-SIT) and the European Sniffin'Sticks(632). Numerous other
The basophil activation test (BAT) is a flow-cytometry based IgE tests exist(449). Most tests used worldwide are pure identification
functional test which detects basophil activation in the presence tests (e.g. UPSIT) or composite tests where identification is com-
of allergen and specific IgE. The BAT measures the expression of plemented by a discrimination task and an olfactory threshold
activation markers on the basophil surface which are activated (e.g. Sniffin'Sticks extended version). They also differ significantly
due to cross-linking of IgE antibodies bound to the high-affinity in time consumption (4-25 minutes) which is mainly dependent
IgE receptor (FcεRI). It imitates the conditions leading to type I on the number of items and aspects tested(633). For most of these
hypersensitivity reaction. The use of the BAT in the diagnosis of tests, test-retest reliability is high and the cost of the test set
allergy in CRS is limited. more or less the same(634, 635). All identification tests have cultural
To summarize, clinical history supported with the SPT will pro- biases, which is the main reason for the large number of dif-
bably remain the golden standard of the upper airway allergy ferent tests. There have been recent advances to overcome this
diagnosis, for some time, as it has acceptable sensitivity and spe- with culturally unbiased, universally usable smell tests(636).
cificity. The advances which are expected from the molecular in However, in the patient with symptoms suspicious of CRS who
vitro diagnosis may change trend, due to improved technology complains of smell impairment, the diagnostic approach to
which enables faster diagnosis on a broader panel of allergens. olfactory assessment should also include rigid endoscopy of the
On the other hand, complications related to the availability of nose, which may differentiate between potential causes for in-
diagnostic allergen extracts or molecules may also shift diagnos- flammatory olfactory loss. Polyp presence or endonasal tumour
tic preference towards in vitro diagnostics. For the cases which detected at endoscopy may help explain the smell decline, or it
are difficult to diagnose, nasal and conjunctival provocations may be only obstructive or inflammatory. However, due to inter-
test as in vivo procedures, and BAT as an in vitro procedure, may action of sensory epithelia with inflammation in the nose, the
help in establishing the final diagnosis, however in the diagnosis exact aetiology and level of smell impairment may be mixed and
of CRS these tests are seldom necessary. not always entirely due to inflammation, mechanical obstruction
or olfactory epithelial damage due to repeated inflammation. If
5.3.5.5. Assesment of smell the subjective and psychophysical level of smell loss does not
correlate with the endoscopic finding, it may raise suspicion of a
5.3.5.5.1. Rationale sinonasal or skull base tumour which was not seen on endo-
Smell loss has been reported in 60 to 80% of CRS patients(463, scopy. Such suspicion should lead to CT and MRI imaging of the
467)
. Olfactory impairment is significantly worse in patients with skull base and brain and if there is an olfactory complaint, regar-
CRSwNP and smell loss is associated with higher eosinophilic dless of the endoscopy, there needs to be psychophysical tes-
inflammation in nasal polyp tissue (which was not shown in the ting. Imaging with MRI or CT may exclude olfactory and pituitary
CRSsNP phenotype)(628). Besides nasal polyps, asthma, N-ERD, tumours and aneurysms and may detect reduced olfactory bulb
previous surgery and age have been shown to be predisposing volume and reduced olfactory sulcus depth in congenital smell
factors for a greater smell loss(465, 629). loss(637-639). Regarding parosmia, different studies show morpho-
logic(640, 641) and functional differences on MRI and functional MRI
5.3.5.5.2. Tests scans(642). However, there is no tool yet available to reliably assess
Smell impairment is a symptom which differentially affects CRS the presence of olfactory distortions in a single patient apart
patients in terms of severity of smell disorder than is the case from some questionnaires(643).
with rhinitis or other inflammatory sinonasal disease(470). Incre- Smell tests are classified into threshold (liminar) and supra-

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threshold (supraliminar) tests(644). In threshold tests the subjects Compared to one or two decades ago, there are many well
detect the minimum concentration of the tested odorant. Such validated and especially widely used psychophysical tests availa-
tests most commonly use phenyl ethyl alcohol and n-butanol as ble(651, 652). It is generally admitted that the value of an individual
the odorant substance but can be done for any substance. The test score obtained for a single patient is more meaningful the
test time in detection threshold test for a person with normal better the test used was. It is thus important to test whenever
smell is about 15 minutes and tends to be lower for subjects possible with standardized psychophysical tests and use a suf-
with impaired smell. The test is done starting with lower concen- ficient amount of odours.
trations with a stepwise increase until the minimally perceived A lower number of test odours may reduce the cost and time
dose is reached, which has to be confirmed several times. A less spent. However, it introduces, based on the distribution of the
common type of threshold test is the recognition threshold test, normative data, a certain degree of unreliability. Such short tests
where perception threshold is combined with recognition of should be used for screening purposes only(653, 654).
odour. The olfactory discrimination test includes examination Identification tests should be exclusively used with a previously
with three odour challenges, where two are the same, and the described forced choice paradigm for two reasons: hyposmic
third is different ("find the odd one" principle). The test subject subjects perform better and it potentially gives hints about
has to recognize the different odour in the set. Threshold tests malingering or aggravation.
can be useful in patients with CRS, where the patients with Retronasal testing is combining the test of smell and taste,
higher threshold concentration may still be performing well in which is close to testing flavour. Such tests apply test substan-
the suprathreshold tests. In composite tests such as the Snif- ces transorally, or on the tongue. Retronasal olfaction is often
fin'Sticks, a pattern of test results with low threshold but normal better preserved in CRS with polyps compared to orthonasal
suprathreshold scores have been repeatedly identified as quite olfaction(476). Using retronasal olfaction may give supplemen-
typical for CRS-related olfactory impairment(464, 645). tary information for a possible inflammatory related olfactory
Suprathreshold tests are used much more commonly than thres- impairment. Although many reports have been published, as
hold and they are based on identification of different odours in yet there is no commercially available retronasal test available.
much higher concentrations then the threshold. However, there has been a recent European attempt for a self-
These tests are usually developed as a panel of different odours, built retronasal test(655).
which stimulate either olfactory or trigeminal response. Panels Objective measurement of olfactory function can be done with
of odours contain from 8-40 odours and in some tests they are olfactory-event related potentials. This diagnostic tool is able to
applied to both nostrils. Time consumption depends primarily confirm the absence of olfactory specific brain responses to a
on the number of odours in the panel, and varies from 4 to 30 given olfactory stimulus and thus suspected anosmia. However,
minutes. Tested subjects recognize the odour through a forced OERPs are not part of the routine work-up and rather time-con-
choice response(646). The examiner tests the subject with a suming. Their use is largely restricted to research and medical
sequence of known odour stimuli which are presented to the expertise.
tested subject, who has to recognize the right odour between
several descriptors offered as response. The examiner usually The EPOS2020 steering group were unclear as to whether it
offers 3-4 different distractors as a response to the presented was essential to do a smell test at initial presentation to ENT/
odour, and the subject has to choose a single response. The secondary care with highly suggestive symptoms of CRS and
smell test has to be culturally adjusted, which means that abnormal mucosa on endoscopy (Figure 5.3.31.).
odours in the panel tested and offered responses have to be It was not essential to do a smell test at initial presentation to
recognized and familiar to the vast majority of the population ENT / secondary care with highly suggestive symptoms of CRS
that will be tested. Only a few of the smell tests integrate liminar and normal mucosa on endoscopy (Figure 5.3.32.).
and supraliminar tests (Sniffin'Sticks full version, Connecticut The EPOS2020 steering group were unclear as to whether it was
Chemosensory Clinical Research Center Test, Barcelona Smell essential to do a smell test in CRS after failure of appropriate
Test-24, T&T olfactometer)(647-649). medical or surgical treatment in ENT / secondary care with con-
Several trials have tested the compatibility or the correlation of tinued symptoms and abnormal mucosa on endoscopy (Figure
the results of the different smell tests in the same individuals 5.3.33.).
(normal and hyposmic). These studies confirm compatibility of
the results with different tests. The commonly used European 5.3.5.6. Objective measures of nasal airflow and patency
tests managed to differentiate tested individuals into anosmic,
hyposmic and normosmic categories, with some discrepancies 5.3.5.6.1. Rationale
within the hyposmic group, however, all the tests Chronic rhinosinusitis is characterized with chronic nasal ob-
were able to differentiate anosmic from normosmic well(650). struction and HRQOL impairment in CRS is also often related to

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 EPOS 2020

sleep disturbance and chronic fatigue(656), which may be related Figure 5.3.31. Delphi: Is it essential to do a smell test at initial presentation
to sleep disorders. On the other hand, other upper airways disor- to ENT secondary care with highly suggestive symptoms of CRS and abnor-
ders have symptoms which overlap with CRS, such as enlarged mal mucosa on endoscopy ?
adenoids (nasal obstruction, smell disorders) and laryngopha-
ryngeal reflux (postnasal drip, chronic cough). In nasal obstruc-
tion, sleep disorders and laryngopharyngeal reflux, investigation
of the upper airways may help distinguish each disorder and
their comorbidities.

5.3.5.6.1. Evaluation of nasal patency

Besides nasal endoscopy (see 5.3.5.2.) nasal patency may be
objectively evaluated with peak nasal inspiratory flowmetry
(PNIF), (active anterior) rhinomanometry (AAR), and acoustic
rhinometry (AR). All of these methods have been standardized
for years and their outcomes related to subjective sensation of
nasal patency(450, 657-660). Newer methods are computational fluid
dynamics(661) that at the moment is mainly used for research
purposes(661-664).
The different tests are extensively discussed in the European Figure 5.3.32. Delphi: Is it essential to do a smell test at initial presentation
position paper on diagnostic tools in rhinology(450). to ENT secondary care in patients with highly suggestive symptoms of CRS
The simplest objective method for nasal patency measurement but normal endoscopy ?
is peak nasal inspiratory flowmetry(665-668). It measures simulta-
neously one or both nostrils during maximal inspiration and
the best of the three attempts is taken as the objective measure
of nasal patency. This measure correlates best with subjective
nasal patency(669, 670) and QOL after FESS(645). PNIF and AAR have
a similar and significant power to discriminate pathologic from
healthy subjects(671, 672). PNIF also correlates well with AR(673). Besi-
des that, this method has the advantage of being the cheapest
and the most functional, in the sense that it measures real life
exposure challenges, like exercise(674), aspirin(675-677) or allergen
challenge(620). The weakness of PNIF method is that it does not
locate the narrowest point of nasal obstruction (like acoustic
rhinometry). It is also influenced by collapsibility of the nasal
valve, which may occur only in maximal airflow.
Objective airway testing has been used to evaluate nasal pa-
tency in patients with CRS in the diagnostic phase(678, 679) as in the Figure 5.3.33. Delphi: Is it essential to do a smell test in CRS after failure of
evaluation of treatment(670, 680-682). appropriate medical or surgical treatment in ENTsecondary care with con-
tinued symptoms and abnormal mucosa on endoscopy ?
5.3.5.7. Histopathology tests

5.3.5.7.1. Biopsies

5.3.5.7.1.1. Rationale
To confirm diagnosis, to assist in endotyping of inflammatory
disease and for research purposes.
To provide tissue uncrushed and suitable for analysis.
To explore the differential diagnosis (inflammation, respiratory
epithelial adenomatoid hamartoma (REAH), infection, granu-
loma / vasculitis, tumour).
To confirm potential aetiologic or pathogenic mechanisms (type

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 EPOS 2020

and severity of inflammation, cellular composition e.g. eosinop- diagnostic discrepancy was found in 1.1% of CRSsNP and 4.5%
hils, bacterial and fungal elements. of CRSwNP and routine examination of nasal polyp tissue was
To determine nature of relationship e.g. invasive or non-invasive recommended.
fungus. However, two more recent studies [from Canada (prospective)
To direct potential therapies e.g. biologics. and the Netherlands (retrospective)] found only <0.5% had an
unexpected histopathological diagnosis after routine endosco-
5.3.5.7.1.2. Technique pic sinus surgery for CRS(691, 692). Yeh et al. calculated that 217 ca-
Nasal biopsies can be performed in an outpatient clinic under ses had to be screened to discover one unexpected pathology,
local anaesthesia or in the operating theatre(450). The choice the cost of which was >$19,000. Van der Boer et al. considered
depends on a number of factors including the reason for per- material from 1944 operations of which only two yielded an
forming the biopsy and the size of the biopsy required. For re- unexpected diagnosis (inverted papilloma in each case) and
search purposes, the biopsy must be easily performed, painless questioned the need for routine histology.
and with a minimal complication rate. For clinical diagnosis the A systematic review was conducted by Wong et al. to assess
need for sufficient sample size has to be balanced with the bur- the usefulness of routine histopathology in CRSwNP which
den for the patient. It is important that the biopsy is not crushed included six studies of which only Yeh et al. was prospective. Of
either by surgeon or scrub nurse. This can be achieved with spe- the 3772 patients, 3751 had a pre-operative clinical and post-
cific Fokkens forceps(683) or fenestrated punch forceps(684) or in the operative pathological diagnosis of inflammatory nasal polyps
operating theatre with scissors(685). Small biopsies for research with an agreement proportion of 99.44 %. Overall there were 18
purposes can be taken from the inferior turbinate after local unexpected benign and three unexpected malignant diagnoses
anaesthesia(683, 684). For light microscopic evaluation, the biopsy identified (0.48 and 0.08 % respectively). The number needed to
specimens can be embedded in Tissue-Tek II OCT compound screen was 210 and 1258, respectively, and the cost to pick up
in a gelatin capsule and frozen immediately. It has been shown one unexpected benign diagnosis was $14,557 and $87,204 for
that biopsies can safely be taken from the olfactory mucosa one unexpected malignancy. Despite this low yield, the authors
without affecting nasal function or the sense of smell(686). concluded that there was no compelling evidence to cease
With the advent of microdebrider powered instrumentation, routine histological examination(693).
there were initial concerns that tissue would be unsuitable for Therefore, should representative tissue removed at surgery
histological analysis. However, Zweig et al. showed in a small in apparently uncomplicated CRS be subjected to biopsy and
prospective blinded study (15 cases covering a range of patho- histopathology or only in cases that raise suspicions such as
logies) that there was no significant loss of morphologic features unilateral disease, friable mucosa, crusting, serosanguinous
in tissue passed through the debrider(687). discharge?
In rhinosinusitis, where clinical diagnosis is based on well esta- Evidence from the literature is not strong but in cases of bila-
blished criteria in specialist care (defined symptoms + endosco- teral CRS with no other concerning clinical features, clinicians
py and/or imaging), histopathological confirmation of inflam- should exercise judgment in submitting polyp specimens for
mation in surgically removed sinus mucosa is very high though histopathology rather than routinely sending all polyps every
there are few high quality studies. Two retrospective studies time. However, there are sound medicolegal reasons to confirm
from the UK published 20 years ago evaluated histopathological the initial diagnosis in all cases and tissue may be increasingly
findings from CRSwNP (n=344 and 2021 respectively)(688, 689) and important for endotyping with its therapeutic implications. For
confirmed the diagnosis in 95% and 98,5%. example, to assess eosinophils in tissue especially when consi-
Misdiagnoses included inverted papillomas, granulomatous dering biologics.
disease, and malignancy in <1%. Diamantopoulos et al recom- Subphenotyping and endotyping by degree of eosinophilic infil-
mended routine histology in all cases on the grounds that the tration and other histological criteria is gaining attraction(694-697)
medicolegal costs outweighed the service costs whilst Kale et and has led to the development of institutional protocols for
al. concluded only first-time bilateral polyps and any unilateral sampling, storing and processing samples in close collabora-
polyps should undergo histology but that by implication, subse- tion with histopathologists. Eosinophilic CRS (eCRS) requires
quent routine histology was not required (688, 689). quantification of the numbers of eosinophils ie number/high
A similar retrospective cohort from the USA analyzed 380 con- powered field (HPF) which varies in the literature (8-12/hpf ).
secutive patients (unilateral and microdebrider cases excluded), Sampling has been described as ‘approximately the three most
comprising 180 CRSsNP and 200 of CRSwNP(690). Two cases of dense collections of eosinophils in the stroma’(694) or ‘the mean
apparent CRSsNP had sinonasal sarcoidosis and in the CRSwNP number of eosinophils in the mucosa counted at HPF (×400)
group, there were five inverted papillomas, two carcinomas, in the three densest areas with cellular infiltrate beneath the epi-
one invasive fungal rhinosinusitis, and one sarcoidosis. Thus thelial surface”(698). Further stratification may be made between

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 EPOS 2020

those with 10-100 eosinophils per HPF in two or more areas and but PCR may be helpful if fungal elements cannot be detected
those with >100 eosinophils per HPF in two or more areas(694). In by histopathology(709). A recent study involving 76 patients with
a systematic review of 11 articles reporting high tissue eosinop- suspected fungal rhinosinusitis, including the chronic invasive
hilia associated with recurrence, a cut-off value of >55 eosinop- forms, showed that histopathology in these cases had a sensi-
hils / HPF showed the highest sensitivity (0.87; 95%CI, 0.82-0.91), tivity of <20%, whereas PCR had a sensitivity of 35%. However,
specificity (0.97; 95% CI, 0.93-0.99), and Diagnostic Odds Ratio fungal disease was proven in less than half of suspicious cases,
(232.7; 95% CI, 91.0-595.1)(699). This was not affected by other and the result was calculated after considering all the diagnostic
factors considered in a meta-regression analysis and was , there- procedures (staining, culture, histopathology and PCR)(709).
fore, proposed as a useful tool for the diagnosis of eCRS. The EPOS2020 steering group did not consider it essential to do
A systematic review of 71 articles considering the histopatho- histopathology / biopsy at initial presentation to ENT / seconda-
logy of human sinus mucosa collected in vivo in patients with ry care with highly suggestive symptoms of CRS irrespective of
CRS was undertaken to determine if there were specific histo- whether the mucosa was abnormal or normal on endoscopy but
pathological markers of inflammation that help to distinguish their responses were unclear regarding whether this was essen-
between the various subgroups of CRS and if such markers tial after failure of appropriate medical or surgical treatment in
could serve as prognostic indicators(700). Techniques used for ENT / secondary care with continued symptoms and abnormal
the analysis included light microscopy, immunohistochemistry, mucosa on endoscopy (Figures 5.3.34., 5.3.35., 5.3.36.).
in-situ hybridization, reverse-transcription polymerase chain
reaction, immunoassays, Western blot, and flow cytometry. 5.3.5.7.2. Other nasal sampling
Twenty-eight considered histopathological findings that
might be prognostic indicators in CRS and forty-four evaluated 5.3.5.7.2.1. Rationale
inflammatory biomarkers in the various subgroups of CRS. The In addition to sinonasal tissue, nasal secretions and cells can
amount of eosinophilic infiltration and the overall intensity of also provide diagnostic and therapeutic information. The most
the inflammatory response were closely related to the prognosis common techniques are nasal lavage fluid, nasal suctioning,
and severity of disease, information that is quantifiable by light insertion of nasal packs, nasal brushing or scraping, the choice
microscopy alone and does not require any specific immuno- being determined by whether inflammatory markers, nasal cells
histochemistry techniques. There were discrepancies in the for cytology or culture, or ciliary function are required.
methodologies and results of the immunohistochemistry so a
meta-analysis of the inflammatory markers was not possible,
but the authors concluded that future studies were needed to 5.3.5.7.2.2 Techniques
determine their role as indicators of prognosis or targets for Nasal blown secretions are the easiest method to collect nasal
tailored therapy. secretions is by simply blowing the nose and collecting the
Close collaboration between surgeon, radiologist and histopa- mucus in sterile containers directly or by letting the participants
thologist underpins optimal tissue sampling, especially when blow in tissues(710). This method is useful in children, but the
there is co-existent pathology in CRSwNP e.g. inverted papil- sample is often small.
loma or respiratory epithelial adenomatoid hamartomas (REAH) In nasal lavage, fluid is introduced into the nose for a certain
(701, 702)
. amount of time and then recollected, with its associated nasal
A range of specific staining techniques, immunohistochemistry secretions. It is easy to perform and well tolerated. Usually
and confocal scanning laser microscopy (CSLM) coupled with a 2-10mL of saline, 0.9% sodium chloride (NaCl) at body tempe-
fluorescence in-situ hybridization (FISH) probe can assist in more rature, is instilled with a syringe and the patient is asked not to
refined analyses(697, 703, 704). For research purposes also more ad- swallow the fluid while the head is reclined. After approxima-
vanced techniques like (RT)PCR an micro-arrays are be used(282, tely 10 seconds(711-714) the head is bent forward and the lavage
705, 706)
. fluid collected in sterile containers. Smaller volumes of iso- to
The distinction between invasive and non-invasive forms of mildly hypertonic saline (0.9–1.8%) can be instilled with a nasal
fungal rhinosinusitis depends on the presence or absence of spray(712). Inflating the cuff of a paediatric tracheostomy tube
fungal hyphae in the mucosa (section 9.6). Special fungal stains into the nostril has been described to reduce loss of lavage
of the secretions may be required e.g. Gomori methenamine sil- fluid(715).
ver combined with the presence of Charcot Leyden crystals and Sterile nasal suctioning devices with a reservoir are also availa-
marked eosinophilia in AFRS(707). In acute invasive fungal forms ble The mucus can be suctioned out and directly frozen at -80 to
frozen section biopsy can assist confirmation, with a sensitivity -90°C before further processing or a known quantity of phosp-
of 87.5% and 100% specificity(708). Granulomatous and chronic hate buffered saline (PBS) or similar agents can be applied which
invasive fungal disease should be confirmed by histopathology stop chemical activity such as proteolysis in the mucus(716). The

168
 EPOS 2020

Figure 5.3.34. Delphi: Is it essential to do histopathologybiopsy at initial technique is well tolerated, has the advantage of minimal sti-
presentation in secondary care with highly suggestive symptoms of CRS and mulation and/or trauma to the mucosa and can be done under
abnormal endoscopy ? endoscopic control(717).
Nasal packing can be used to soak up nasal secretions from
different areas of the nasal cavity (e.g. inferior or middle meatus)
being weighed before and after insertion into the nose. The
packs are left in-situ for five minutes and are then placed in a co-
nical tube, washed in NaCl and mechanically squeezed out (e.g.
with a syringe), then washed again and centrifuged at 1500 g
for 10 min at 4°C to obtain all secretions(717). An advantage of this
method is clear discrimination of sides as compared to lavage
techniques but the technique is uncomfortable and irritates
the mucosa. Another technique uses reticulated polyurethane
foam packs (at 60 and 110 pores per inch (PPI)) that may absorb
secretions better than standard packs with less stimulation of
the mucosa(718).
Nasal brushing can be performed with a soft sterile brush (bron-
chial brush) in the middle or inferior meatus and then placed in
Figure 5.3.35. Delphi: Is it essential to do histopathologybiopsy at initial tubes containing an appropriate growth medium. The material
presentation in secondary care in patients with highly suggestive symptoms is dislodged by oscillation and the contents centrifuged at 400 g
of CRS but normal endoscopy ? for 10 minutes. A specimen of cells is obtained and the superna-
tant can be discarded or the mucus it contains may be used for
further analysis(719). Nasal scraping may also be obtained using
a small disposable plastic cup (Rhinoprobe) which is more com-
fortable for the patient and more accurate than swabbing(720).
The material can be spread onto a slide, fixed and airdried fol-
lowed by staining, usually with Wright-Giesma or Cresol-Red-O.
Specimens obtained by brushing or with the Rhinoprobe can
also be used to measure ciliary beat frequency or perform elec-
tron microscopy of particular importance in the diagnosis of pri-
mary ciliary dyskinesia (see 5.3.5.9). Several abnormalities may
be observed in the ciliary ultrastructure including total or partial
absence of dynein arms, aberrant organization of the dynein
arms and/or disorientation but may also be observed in some
cases of secondary ciliary disease. Therefore, EM evaluation may
support diagnosis of PCD but is not 100% sensitive or specific.
Figure 5.3.36. Delphi: Is it essential to do histopathologybiopsy in CRS after The EPOS2020 steering group did not consider it essential to do
failure of appropriate medical or surgical treatment in ENTsecondary care cytology (either brushings or lavage) at initial presentation to
with continued symptoms and abnormal mucosa on endoscopy ? ENT/ secondary care with highly suggestive symptoms of CRS
irrespective of whether the mucosa was abnormal or normal on
endoscopy but their responses were unclear regarding whether
this was essential after failure of appropriate medical or surgical
treatment in ENT/secondary care with continued symptoms and
abnormal mucosa on endoscopy (Figure 5.3.37., 5.3.38., 5.3.39.).

5.3.5.8. Blood tests

5.3.5.8.1. Rationale
Until recently most blood tests in patients with CRS are to
diagnose immunodeficiences and vasculitic disease with sinona-

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 EPOS 2020

sal manifestations. However, recently the options to treat with Figure 5.3.37. Delphi: Is it essential to do cytology brushings or lavage at
biologicals has put more emphasis on markers of type 2 disease initial presentation in secondary care with highly suggestive symptoms of
although until today we are not aware of biomarkers that can CRS and abnormal endoscopy ?
predict response to biologicals in CRS(721).
Immunodeficiencies can be the cause or a contributing factor in
CRS (see 5.1.2.4. Immune deficiencies and 9.2 Immunodeficien-
cies and their role in CRS). The testing of immune function in all
patients who present with CRS is almost certainly unwarranted
as it is likely to produce more false positive results than true
positives. However, it is recommended that the clinical features
listed below are used to identify those patients who warrant
some form of immune testing for testing.
The most common immunoglobulin deficiency in the general
population is IgA deficiency with a prevalence between 1:173
and 1:3024(722). Most patients are asymptomatic, but a deficiency
of IgA would appear to predispose patients to rhinosinusitis and
allergies(723).
CRS secondary to hypogammaglobulinaemia may present to
a rhinologist in a manner identical to idiopathic CRS. There are Figure 5.3.38. Delphi: Is it essential to do cytology brushings or lavage at
some clinical features that may elevate suspicion: association initial presentation in secondary care in patients with highly suggestive
with lower respiratory tract infections (pneumonia, particularly symptoms of CRS but normal endoscopy ?
if recurrent, or bronchiectasis) and recalcitrance to standard
treatments (and particularly rapid recurrence of symptoms after
stopping antibiotics).

5.3.5.8.2. Tests

5.3.5.8.2.1. Markers of type 2 disease

The main biomarkers used at the moment to define type 2
disease are eosinophils, IgE levels, and in some more specialized
centres periostin. Other biomarkers are currently under investi-
gation and may provider further guidance in the future.
There is quite some evidence showing that eosinophils are a
reasonable surrogate marker for type 2 disease, and that blood
eosinophils are a reasonable biomarker to predict eosinophilic
CRS with or without nasal polyps(695, 724, 725). Blood eosinophil
counts were found to be significantly correlated with the Lund– Figure 5.3.39. Delphi: Is it essential to do cytology brushings or lav-
Mackay CT and Lund–Kennedy endoscopic scores in patients age in CRS after failure of appropriate medical or surgical treatment in
with nasal polyps (r=0.353, p=0.010 and r=0.444, p=0.001, ENTsecondary care with continued symptoms and abnormal mucosa ?
respectively)(724).
Receiver operating characteristic curve analysis predicted high
tissue eosinophilia at blood eosinophil levels above 0.24109/L
[sensitivity 70.9%, specificity 78.4%, area under the curve (AUC):
0.792, p<0.01]. eCRS was predicted at eosinophil above 4.27%
of total WCC (sensitivity 64.1%, specificity 88.5%, AUC 0.797;
p<0.01; positive predictive value 89.2%, negative predictive
value 62.4%, positive likelihood ratio 5.57, and diagnostic odds
ratio 13.71)(695). A cut-off point of blood eosinophils >0.24 109/L
or eosinophil ratio >4.27% of total WCC was proposed by Ho et
al.(695).
The EPOS2020 steering group were unclear as to whether it was

170
 EPOS 2020

essential to evaluate blood eosinophilia either at initial presen- Figure 5.3.40. Delphi: Is it essential to evaluate blood eosinophilia at initial
tation to ENT / secondary care with highly suggestive symptoms presentation to ENT/secondary care with highly suggestive symptoms of
of CRS irrespective of whether the mucosa was abnormal or CRS and abnormal mucosa on endoscopy ?
normal on endoscopy or after failure of appropriate medical
or surgical treatment in ENT / secondary care with continued
symptoms and abnormal mucosa on endoscopy (Figure 5.3.40.,
5.3.41., 5.3.42.).
Anti-IgE treatment has been shown to be effective in the treat-
ment of CRSwNP (see 6.1.14). There is an association between
increased levels of total IgE, specific IgE, and eosinophilic
inflammation in NPs, which may be of relevance in the pathop-
hysiology of nasal polyposis(726). Increased serum IgE has been
described in a subset of patients with N-ERD(727). A serum
IgE cut of value of 96 kU/L was shown to be a bad predictor of
CRSwNP (44% in CRSwNP group versus 28% in CRSsNP and 30%
in controls)(728).
The EPOS2020 steering group were unclear as to whether it was
essential to measure total IgE either at initial presentation to
ENT / secondary care with highly suggestive symptoms of CRS Figure 5.3.41. Delphi: Is it essential to evaluate blood eosinophilia at initial
irrespective of whether the mucosa was abnormal or normal on presentation to ENT/secondary care in patients with highly suggestive
endoscopy or after failure of appropriate medical or surgical tre- symptoms of CRS but normal endoscopy ?
atment in ENT / secondary care with continued symptoms and
abnormal mucosa on endoscopy (Figure 5.3.43., 5.3.44., 5.3.45.).
Periostin is both an extracellular matrix protein and matricel-
lular protein that is capable of activating cells by linking integrin
molecules to cell receptors, promoting tissue remodeling. It may
be an important biomarker for type 2 immunity and airway aller-
gic inflammation exacerbations(729). It has been established that
periostin is a downstream molecule of interleukin (IL)-13, and
that asthmatic patients with high serum periostin react more
favourable to anti-IL-13 antibodies (lebrikizumab) and anti-IgE
antibodies (omalizumab)(730). Methylprednisolone and omali-
zumab significantly reduced serum periostin levels in CRSwNP
patients(731).
Serum periostin was found to be the sole biomarker among
those tested for detecting the presence of nasal polyps and it
significantly correlated with Lund-Mackay score in patients with Figure 5.3.42. Delphi: Is it essential to evaluate blood eosinophilia in CRS
chronic rhinosinusitis and asthma(732). Mean serum periostin after failure of appropriate medical or surgical treatment in ENT/secondary
levels were markedly elevated in patients with CRS versus con- care with continued symptoms and abnormal mucosa on endoscopy?
trols. In addition, mean periostin levels were significantly higher
in CRS patients with nasal polyps as compared with those wit-
hout polyps(728, 733). In the study of Maxfield et al. periostin levels
did not correlate with sex, smoking history, N-ERD, oral steroid
use within 1 month of surgery, use of topical steroid nasal spray
or number of prior sinus operations(733).

5.3.5.8.2.2. Immunoglobulin
It is not clear how much of the immunological testing should
be undertaken by the rhinologist before referral to an immuno-
logist, and this decision may reflect the individual knowledge
and expertise of the rhinologist. For CRS patients suspected

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 EPOS 2020

of having humoral immunodeficiency because of the charac- Figure 5.3.43. Delphi: Is it essential to measure total IgE at initial presenta-
teristics of their presentation or their response to treatment, tion to ENT/secondary care with highly suggestive symptoms of CRS and
measurement of serum immunoglobulin levels (IgA and IgG) abnormal mucosa on endoscopy ?
is the key investigation. The best approach for confirming a di-
agnosis of an antibody-deficiency disorder is the measurement
of serum-specific antibody titers (usually IgG) in response to
vaccine antigens. This approach involves immunizing a patient
with protein antigens (e.g., tetanus toxoid) and polysaccharide
antigens (e.g., pneumococcus) and assessing pre- and post-
immunization antibody levels(734). If the levels are normal, but
the suspicion of humoral immunodeficiency is high, referral to
a clinical immunologist is optimal. Further studies, such as flow
cytometry can then be organized by an expert in the interpreta-
tion of these tests.
The EPOS2020 steering group did not consider it essential to do
an objective test of immunodeficiency at initial presentation to
ENT/ secondary care with highly suggestive symptoms of CRS
irrespective of whether the mucosa was abnormal or normal on Figure 5.3.44. Delphi: Is it essential to measure total IgE at initial presenta-
endoscopy. tion to ENT/secondary care in patients with highly suggestive symptoms of
Their responses were unclear regarding whether this was es- CRS but normal endoscopy ?
sential after failure of appropriate medical or surgical treatment
in ENT/secondary care with continued symptoms and abnormal
mucosa on endoscopy (Figure 5.3.46., 5.3.47., 5.3.48.).

5.3.5.8.2.3. Testing for vasculitis

Vasculitic diseases with sinonasal manifestations usually but not
always involve multiple organs. Rhinitis, sinusitis, septal perfora-
tion and epistaxis are the most common nasal features related
to these diseases. There are two relatively common vasculitides
in the sinunasal tract:
Granulomatosis with polyangiitis (GPA, formerly Wegener’s
granulomatosis) and Eosinophilic granulomatosis with polyan-
giitis (EGPA, formerly Churg–Strauss syndrome). Patients with
granulomatosis with polyangiitis (GPA) affecting the sinonasal
cavity usually have persistent bleeding, crusting and obstruc-
tion, and may develop a septal perforation. Sometimes the Figure 5.3.45. Delphi: Is it essential to measure total IgE in CRS after failure
manifestations of this vasculitic condition are limited to the of appropriate medical or surgical treatment in ENTsecondary care with
sinonasal cavity. GPA is strongly associated with anti-neutrophil continued symptoms and abnormal mucosa on endoscopy ?
cytoplasmic antibodies (ANCA), and the more widespread and
severe the presentation, the more likely the serum ANCA is to be
positive(735). In cases limited to the sinonasal tract the ANCA can
be negative, making the diagnosis challenging. The combina-
tion of clinical features, positive ANCA serology, necrotizing
vasculitis and granulomatous inflammation on biopsy esta-
blish the diagnosis(736). However, nasal biopsies often do not
have enough features specific to this condition to confirm the
diagnosis, and so biopsies from other involved organs may be
required. Eosinophilic granulomatosis with polyangiitis (EGPA,
formerly Churg–Strauss syndrome) is a necrotizing vasculitis
of small and medium-sized vessels. Among a wide spectrum
of non-pulmonary symptoms, nasal and sinonasal features are

172
 EPOS 2020

common and part of the diagnostic criteria for EGPA(737). This Figure 5.3.46. Delphi: Is it essential to do an objective test of immunodefi-
condition typically develops in patients with adult onset asthma ciency at initial presentation in secondary care with highly suggestive symp-
and the sinonasal manifestation is chronic rhinosinusitis with toms of CRS and abnormal endoscopy ?
eosinophilic nasal polyps. Many of these patients also have mid-
dle ear disease(738).
Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of
autoantibodies, mainly of the IgG type, against antigens in the
cytoplasm of neutrophil granulocytes and monocytes. They are
detected as a blood test in a number of autoimmune disorders,
but are particularly associated with systemic vasculitis, so called
ANCA-associated vasculitides. ANCAs are associated with small
vessel vasculitides including granulomatosis with polyangiitis,
microscopic polyangiitis, primary pauci-immune necrotizing
crescentic glomerulonephritis (a type of renal-limited microsco-
pic polyangiitis), eosinophilic granulomatosis with polyangiitis
and drug induced vasculitides. PR3 directed c-ANCA is present
in 80-90% of granulomatosis with polyangiitis, 20-40% of
microscopic polyangiitis, 20-40% of pauci-immune crescentic
glomerulonephritis and 35% of eosinophilic granulomatosis Figure 5.3.47. Delphi: Is it essential to do an objective test of immunodefi-
with polyangiitis. c-ANCA (atypical) is present in 80% of cystic ciency at initial presentation in secondary care in patients with highly sug-
fibrosis (with BPI as the target antigen) and also in inflammatory gestive symptoms of CRS but normal endoscopy ?
bowel disease, primary sclerosing cholangitis and rheumatoid
arthritis (with antibodies to multiple antigenic targets). p-ANCA
with MPO specificity is found 35% of eosinophilic granulomato-
sis with polyangiitis. p-ANCA with specificity to other antigens
are associated with inflammatory bowel disease, rheumatoid
arthritis, drug-induced vasculitis, autoimmune liver disease,
drug induced syndromes and parasitic infections.
Cocaine and levamisole, which is a common adulterant of co-
caine, can cause an ANCA positive vasculitis(739-741).
The EPOS2020 steering group did not consider it essential
to do an objective test for vasculitis at initial presentation to
ENT/ secondary care with highly suggestive symptoms of CRS
irrespective of whether the mucosa was abnormal or normal on
endoscopy but their responses were unclear regarding whether
this was essential after failure of appropriate medical or surgical
treatment in ENT/secondary care with continued symptoms and Figure 5.3.48. Delphi: Is it essential to do an objective test of immunodefi-
abnormal mucosa on endoscopy (Figure 5.3.49., 5.3.50., 5.3.51.). ciency in CRS after failure of appropriate medical or surgical treatment in
ENT/secondary care with continued symptoms and abnormal mucosa ?
5.3.5.8.2.4. Testing for sarcoidosis
Sarcoidosis is a complex disease with manifold clinical manifes-
tations. A case suspicious for sarcoidosis requires clinical, radio-
logical and histological evidence of non-caseating granulomas.
Serum soluble interleukin-2 (sIL-2R), angiotensin converting
enzyme (ACE) and lysozyme levels have become useful tools in
the diagnosis of sarcoidosis and for evaluating disease activity,
in addition to fluorodeoxyglucose-positron emission tomograp-
hy (FDG-PET). Serum ACE is the most widely used laboratory test
for the investigation of sarcoidosis(742). Elevated serum levels of
ACE, IL-2R, and lysozyme are usually associated with more ag-
gressive disease and multiple-organ involvement(743).

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5.3.5.8.2.5. Testing for N-ERD Figure 5.3.49. Delphi: Is it essential to do an objective test for vasculitis at
Oral provocation test with aspirin is the most common inves- initial presentation in secondary care with highly suggestive symptoms of
tigation used to identify hypersensitivity reactions to aspirin CRS and abnormal endoscopy ?
(see 5.3.5.14). For details how to perform see the recently
published EAACI position paper: Diagnosis and management
of NSAID-Exacerbated Respiratory Disease (N-ERD)(39). However,
for those patients who have a higher risk of severe reactions,
flow cytometry-assisted basophil activation testing (FAST) and
functional-eicosanoid-test (FET) can be helpful tools to elucidate
the diagnosis, if they are available(744, 745).

5.3.5.9. Microbiology

5.3.5.9. 1. Rationale
Sinonasal microbiological sampling is important in the diagnos-
tic work-up of patients with rhinosinusitis. The importance of
microbes in the aetiology of acute bacterial rhinosinusitis (ABRS)
is well recognized(553) whereas the situation in CRS is less clear
but is of increasing interest, facilitated by improved identifica- Figure 5.3.50. Delphi: Is it essential to do an objective test for vasculitis at
tion techniques(746, 747). initial presentation in secondary care in patients with highly suggestive
symptoms of CRS but normal endoscopy ?

5.3.5.9.2. Tests

5.3.5.9.2.1. Culture-dependent Techniques

Sinus aspirates
A maxillary sinus tap (MST) has historically been the gold
standard technique for obtaining sinus cultures by providing
a representative specimen of the antral contents with minimal
nasal contamination(748, 749). It can be performed under local
anaesthesia via the inferior meatus or canine fossa but is often
associated with discomfort, potentially risks orbital, dental and
nerve injury and only provides information on the maxillary
sinus(748).
The sphenoid sinus can also be approached directly to obtain an
aspirate for culture(750). In the past the frontal sinus has also been Figure 5.3.51. Delphi: Is it essential to do an objective test for vasculi-
‘punctured’ through the anterior wall to obtain a sample(751) but tis in CRS after failure of appropriate medical or surgical treatment in
this is of greater magnitude, usually requires a general anaes- ENTsecondary care with continued symptoms and abnormal mucosa on
thetic and is generally part of a therapeutic surgical procedure endoscopy ?
rather than being purely diagnostic(752).
Nasal swabs
Nasal swabs are the most commonly used sampling method
in the nasal cavity as they are easy to use, non-invasive and
generally well tolerated without the need for local anaesthesia.
However, there is a poor correlation between undirected nasal/
nasopharyngeal and endoscopically directed middle meatal
(EDMM) culture swabs, largely due to contamination from the
nasal vestibule and cavity. EDMM swabs show a high concor-
dance with maxillary sinus aspirates and cultures(753-758) and thus
have become the mainstay of microbial sampling in patients
with rhinosinusitis (Table 5.3.7.). A meta-analysis confirmed that

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Table 5.3.7. Bacteriology of rhinosinusitis. Correlation of middle meatus versus maxillary sinus.

Author, year, (ref) Number of Type of rhinosi- Technique Concordance

samples nusitis
Joniau 2005(756) 26 ARS Endoscopic swab (MM) vs. maxillary sinus tap 88.5%
Casiano 2001(755) 29 ARS (intensive care) Endoscopic tissue culture (MM) vs. maxillary sinus tap 60.0%
Talbot 2001 (840)
46 ARS Endoscopic swab (MM) vs. maxillary sinus tap 90.6%
Vogan 2000(754) 16 ARS Endoscopic swab (MM) vs. maxillary sinus tap 93.0%
Gold and Tami 1997 (841)
21 CRS Endoscopic tap (MM) vs. maxillary aspiration during ESS 85.7%
Klossek 1996(757) 65 CRS Endoscopic swab (MM) vs. maxillary aspiration during ESS 73.8%

EDMM is a highly sensitive and accurate culture method for sinus penetration in an unoperated patient. These issues may be
ABRS and may be more sensitive than maxillary sinus taps (MST) circumvented by direct sinus lavage through an endoscopically
given the presence of pathogenic bacteria not found on antral placed maxillary sinus catheter. Studies comparing direct sinus
lavage(759). For known pathogenic bacteria for ABRS and in com- lavage to EDMM swabs have demonstrated higher bacterial
parison to MST, EDMM had a sensitivity of 80.9%, a specificity of yields and increased recovery of anaerobic pathogens using the
90.5%, a positive predictive value of 82.6%, a negative predictive former technique(762, 763) and this sampling technique could be
value of 89.4%, and an overall accuracy of 87.0% (95% confi- facilitated by balloon technology as many devices have inbuilt
dence interval, 81.3%-92.8%). catheters that can be used for lavage drainage and antibiotic
The more recent meta-analysis by Smith et al. showed that bac- irrigation. The clinical relevance of the anaerobic organisms and
terial pathogens are recovered by sinus puncture or EDMM cul- the targeted culture and treatment of isolated infected sinuses
ture in 53% of patients with suspected ABRS, based on studies remain to be studied.
requiring patients to meet clinical criteria, with most studies also
requiring radiographic and/or endoscopic confirmation. 5.3.5.9.2.2. Culture-independent techniques
There is limited research on how representative middle meatal Standard culture approaches offer only a limited range of de-
swabs are for the remaining sinuses. Although not a direct com- fined conditions for microbial growth and , therefore, omits taxa
parative study, a recent retrospective study by Miller et al.(760) de- that require alternative conditions, including slower-growing
monstrated different pathogens in two or more of the swabs of organisms that are outcompeted for a limited range of nutrient
40% of patients undergoing multiple sinus cultures. While only sources or those that depend upon cooperation to survive in
5% of the patients in this study received clinical benefit from vivo (such as cross-feeding relationships). The disparity between
changing the antibiotic, it does suggest that bacterial cultures the identification of microbes by culture and those (viable but
from the middle meatus may not be entirely representative of all nonculturable or difficult to culture) identified by molecular
the sinuses. methods has been termed “the great plate count anomaly,” with
EDMM culture swabs have become the mainstay of microbial estimates of the nonculturable portion of microbial communi-
sampling in patients with rhinosinusitis. ties ranging between 25% and 99%(764, 765).

Nasal blown secretions Next generation sequencing

Nasal blown secretions may be readily obtained in primary care, Next generation sequencing techniques have enabled identifi-
particularly for paediatric patients as it avoids the discomfort of cation of micro-organisms previously unidentifiable on routine
a nasal swab. The few comparative studies comparing expel- culture studies(450). Samples can be obtained using guarded,
led mucus to standard culture swab techniques suggest a high flocculated microbial swabs or by tissue biopsy with high con-
concordance rate (>90%) for the detection of common upper cordance noted between the two (Bassiouni). DNA is extracted
airway pathogens when nasal secretions are present, but as from the obtained specimens and sequenced using primers
might be expected, this rate reduces to less than 50% but in the specific for conserved genetic regions within bacterial or fungal
absence of obvious secretions(710, 761). micro-organisms. Sophisticated bio-informatic pipelines that
reference known microbial libraries then allow identifica-
Nasal and sinus lavage tion and relative quantification of all the organisms present.
Nasal lavage is not an accurate technique for the culturing of Initially a research tool, such technology is now commercially
sinus contents due to contamination by nasal flora and minimal available for clinical use. Studies comparing culture-directed

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analysis with next generation sequencing have shown signifi- procedures, including microbiology, can be performed.
cant discordance, with sinus culture poorly predicting resident The role of microbial sampling in CRS remains unclear. Pros-
microbiota(154). In direct comparisons between results of culture pective trials are needed to examine the relevance of routine
and sequencing approaches, the dominant bacteria identified in microbiologic cultures and antibiotic treatment in CRS patients
most patients by sequencing were identified by culture only ap- before sound recommendations can be made.
proximately half of the time. Of those taxa present at a relative It is possible that the incorporation of modern culture-indepen-
sequence abundance of 1%, only about 5% were also identified dent techniques into clinical practice may improve treatment
by culture, revealing the extent of information on lower-abun- outcomes, but further research is required. The EPOS2020 stee-
dance taxa missed by standard clinical culturing. This may in ring group did not consider it was essential to do microbiology
part explain poor treatment response despite culture-directed at initial presentation to ENT/ secondary care with highly sug-
antibiotic therapy. It is possible that the incorporation of mo- gestive symptoms of CRS irrespective of whether the mucosa
dern culture-independent techniques into clinical practice may was abnormal or normal on endoscopy.
improve treatment outcomes, but further research is required. However, they were unclear as to whether it was essential to do
Future techniques, particularly in the microbiology research on microbiology in CRS after failure of appropriate medical or surgi-
inflammatory mucosal diseases such as CRS include sequencing cal treatment in ENT/secondary care with continued symptoms
of all DNA (metagenomics) or all transcribed RNA (metatrans- and abnormal mucosa on endoscopy (Figures 5.3.52., 5.3.53.,
criptomics) or identification of proteins (metaproteomics) or 5.3.54.).
metabolites (metabolomics) which should provide greater
insights into the true diversity and structure, as well as the full 5.3.5.10. Mucociliary clearance testing
genetic potential and in-situ activity, of the mucosa-associated
microbiota(746). 5.3.5.10.1. Rationale
By their coordinated movement, the cilia lining the respiratory
Outcomes epithelium transport the mucus layer with entrapped inhaled
There is no evidence that microbiological assessment of nasal particles from the nasal cavity towards the hypopharynx.
or sinus samples has any impact on outcomes in rhinosinusi- Normal mucociliary transport (MCT) isssential for the mainte-
tis. 80% of individuals with ABRS typically improve within two nance of healthy sinonasal cavities. With infection or congenital
weeks without treatment(766) and there is no evidence showing dysfunction of the cilia as in PCD, MCT is inadequate or ab-
superiority of culture-directed antibiotic therapy over empi- sent. In PCD, lack of MCT may lead to CRS and bronchiectasis.
ric treatment for this condition. Although low-level evidence Mucostasis, hypoxia, microbial products and toxic inflammatory
suggests a possible role for culture-directed antibiotic therapy mediators in CRS may induce secondary ciliary changes, i.e.
in the treatment of acute exacerbations of CRS, no high-level secondary ciliary dyskinesia (SCD), with subsequent inadequate
evidence studies exist supporting the use of antibiotics in CRS. MCT(450).
Furthermore, there is a paucity of literature comparing outco- The mucociliary clearance (MCC) time is considered to be nor-
mes of culture-directed versus empirical antibiotic treatment for mal below 15 minutes and should be less than one hour.
this condition. The saccharine test evaluates the time taken to experience a
Microbial sampling for uncomplicated ABRS is not routinely sweet taste after placement of a 1-2mm particle of saccharine
recommended. on the inferior turbinate mucosa, 1cm from the anterior end. The
There is no evidence that microbiological assessment of nasal patient must sit quietly with the head bent forward and without
or sinus samples has any impact on outcomes in rhinosinusitis. sniffing, coughing, sneezing, drinking or eating during the in-
Although antibiotics provide a small but significant benefit for vestigation. Alternatively, one can monitor the time needed for a
clinical outcomes in adults and children with ABRS (see 4.4.3.1. dye such as methylene blue to be transported from the mucosa
and 4.4.3.2.) most patients suffer from post-viral ARS where of the anterior third of the nasal cavity towards the hypopha-
antibiotics are not helpful (see 4.4.3.3. and 4.4.3.4). Furthermore, rynx. Other substances including technetium- 99m-labeled iron
there are no studies ishowing superiority of culture-directed oxide have also been used.
antibiotic therapy over empiric treatment for this condition. As the MCC time can only be measured in cooperative patients
with patent nasal cavities and in the absence of severe mucosal
Recommendations disease, it has limited diagnostic value in certain patients. It also
Microbiological assessment is not routinely recommended in has low sensitivity and specificity and requires significant time
the diagnosis of rhinosinusitis. In ABRS non-responsive to empi- investment. In the context of the clinical relevance of MCT, it has
rical antimicrobial treatment and topical nasal steroids, referral recently been demonstrated that nasal lavages, a commonly
is recommended to an ENT specialist where further diagnostic recommended treatment for many sinonasal conditions, reduce

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Figure 5.3.52. Delphi: Is it essential to do microbiology at initial presenta- the MCC time(767).
tion to ENT secondary care with highly suggestive symptoms of CRS and The EPOS2020 steering group did not consider it essential to do
abnormal mucosa on endoscopy ? an objective test of mucociliary function at initial presentation
to ENT / secondary care with highly suggestive symptoms of
CRS irrespective of whether the mucosa was abnormal or nor-
mal on endoscopy but their responses were unclear regarding
whether this was essential after failure of appropriate medical
or surgical treatment in ENT/secondary care with continued
symptoms and abnormal mucosa on endoscopy (Figures 5.3.55.,
5.3.56., 5.3.57.).

5.3.5.11. Nasal nitric oxide

5.3.5.11.1. Rationale
Nitric oxide (NO) is a colourless, odourless gas that is present in
air exhaled through the mouth or nose. NO is produced from
arginine and oxygen by nitric oxide synthase (NOS). Constituti-
vely expressed neuronal and endothelial forms exist as well as
Figure 5.3.53 Delphi: Is it essential to do microbiology at initial presentation an induced form, iNOS, which appears to be upregulated within
in secondary care in patients with highly suggestive symptoms of CRS but the respiratory tract in response to pro-inflammatory signals.
normal endoscopy ? Exhaled NO (eNO) levels are raised in eosinophilic asthma and
measurement of this has become a standardised, but not yet
widespread, tool in the diagnosis and management of asthma.
It can potentially provide a rapid, low cost objective measure of
lower airway inflammation. Most NO is produced in the sinuses,
far less by the nasal mucosa and the lower respiratory tract(450).
NO and its metabolites are toxic to micro-organisms and likely
form part of the innate defence mechanism of the respiratory
tract. NO may also stimulate ciliary beat frequency within the
epithelium and regulate nasal vascular tone.

5.3.5.11.2. Diagnostic accuracy

Nasal NO (nNO) can be measured in either nostril and shows
no diurnal variation. The measurement is quick, reproducible,
feasible and best assessed with an aspiration flow of 700 ml/min
during breath-holding for 10 seconds(768). Humming during nNO
Figure 5.3.54 Delphi: Is it essential to do microbiology in CRS after failure of measurement initially increases levels considerably in healthy
appropriate medical or surgical treatment in ENTsecondary care with con- subjects. If low values are obtained, measuring nNO during
tinued symptoms and abnormal mucosa on endoscopy ? humming can increase the specificity of the measurement(768).
Healthy controls usually have nNO levels above 300ppb(769).
Nasal NO testing using palatal closure manoeuvres has diag-
nostic accuracy similar to electron microscopy and/or genetic
testing for primairy ciliairy dyskinesia when cystic fibrosis has
been ruled out(770). Nasal NO values below 77 ppb are very sug-
gestive of PCD but higher values are occasionally found. CF also
has generally low values (70-300 ppb), and the presence of nasal
polyps is associated with significantly lower nNO levels than in
CF patients without nasal polyps(771) due to obstruction of the
sinuses. Thus, in nasal polyps, patients may paradoxically have
low nNO and normal or high eNO from the chest.
Nasal NO is a sensitive and specific test for PCD in cooperative

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Figure 5.3.55 Delphi: Is it essential to do an objective test of mucociliary patients (generally over five years old) with a high clinical suspi-
function at initial presentation in secondary care with highly suggestive cion for this disease. To a lesser extent it may also be a useful ad-
symptoms of CRS and abnormal endoscopy ? junct in a potential diagnosis of CF. Whilst not commonly used
as a specific diagnostic tool in CRS, it may be used to monitor
the response to treatment in these conditions.

5.3.5.12. Other tests for PCD

5.3.5.12.1. Rationale
No ideal test is available for the diagnosis of PCD in routine
practice(772). In cases of suspected PCD in a patient with CRS
since birth, a family history of PCD and/or associated features of
Kartagener syndrome (situs inversus and infertility), one should
consider diagnostic tests of ciliary function by evaluation of
ciliary beat frequency (CBF), EM evaluation of the dynein arms
of the cilia and/or evaluation of the cilia after ciliogenesis in
vitro(450). Harvested epithelial cells can be evaluated for ciliary
beat frequency (CBF) and the ciliary wave form analysed in
Figure 5.3.56 Delphi: Is it essential to do an objective test of mucociliary detail by digital high-speed video imaging. The evaluation of the
function at initial presentation in secondary care in patients with highly CBF as well as assessment of their coordinated movement can
suggestive symptoms of CRS but normal endoscopy ? be performed by computerized programs using a Fast Fourier
analysis. Normal values of CBF vary depending on the metho-
dology used, the age of the patient and the culture conditions.
The demonstration of normal CBF and beat pattern excludes the
diagnosis of PCD. Recently, a novel technique for quantification
of CBF has been reported using phase-contrast microscopy
images, estimating ciliary motion by means of an optical flow
algorithm(773). In a tertiary referral centre, one third of patients
referred with suspected PCD were eventually diagnosed with
the condition(774).
As these techniques are not available in routine ENT practice,
one should rely on measuring nNO levels in cases of suspected
PCD; low nNO levels have been associated with PCD and , there-
fore, represent an excellent screening tool (see above). In ad-
dition, screening for genetic mutations known to be associated
with PCD, as well as genetic counselling, is recommended(775).
Figure 5.3.57 Delphi: Is it essential to do an objective test of mucociliary
function in CRS after failure of appropriate medical or surgical treatment in 5.3.5.13. Sweat testing
ENT/secondary care with continued symptoms and abnormal mucosa ?
5.3.5.13.1. Rationale
Cystic fibrosis (CF), caused by mutations in the CF transmem-
brane conductance regulator (CFTR) gene, continues to present
diagnostic challenges. It is recommended that diagnoses as-
sociated with CFTR mutations in all individuals, from newborn
to adult, be established by evaluation of CFTR function with a
sweat chloride test(776). Sweat chloride testing should be perfor-
med according to approved procedural guidelines published
in established, Int protocols such as the CLSI 2009 Guidelines
(https://clsi.org).

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Figure 5.3.58 Delphi: Is it essential to do an objective test for cystic fibrosis 5.3.5.13.2. Advice of the Consensus Guidelines from the
at initial presentation in secondary care with highly suggestive symptoms of Cystic Fibrosis Foundation
CRS and abnormal endoscopy ? Newborns with a positive CF newborn screen, to increase the
likelihood of collecting an adequate sweat specimen, should
have the test performed bilaterally and when the infant weighs
>2 kg, and is at least 36 weeks of corrected gestational age.
Newborns greater than 36 weeks gestation and >2 kg body
weight with a positive CF newborn screen, or positive prenatal
genetic test, should have sweat chloride testing performed as
soon as possible after 10 days of age, ideally by the end of the
neonatal period (four weeks of age).
In infants with presumptive CF identified through NBS, CF
treatment should not be delayed while efforts to establish a
diagnosis of CF are initiated. Sweat chloride analysis should be
performed within a few hours of sweat collection. In individuals
presenting with a positive newborn screen, clinical features
consistent with CF, or a positive family history, a diagnosis of CF
Figure 5.3.59 Delphi: Is it essential to do an objective test for cystic fibrosis can be made if the sweat chloride value is ≥60 mmol/L.
at initial presentation in secondary care in patients with highly suggestive In individuals with a positive newborn screen, a sweat chloride
symptoms of CRS but normal endoscopy ? <30 mmol/L indicates that CF is unlikely.
Individuals with clinical features that may be consistent with CF
who have a sweat chloride <30 mmol/L indicates that CF is less
likely. It may, however, be considered if evolving clinical criteria
and/or CFTR genotyping support CF and not an alternative di-
agnosis. Individuals presenting with a positive newborn screen,
symptoms of CF, or a positive family history, and sweat chlo-
ride values in the intermediate range (30-59 mmol/L) on two
separate occasions may have CF. They should be considered for
extended CFTR gene analysis and/or CFTR functional analysis.
Individuals who are screen-positive and meet sweat chloride
criteria for CF diagnosis should undergo CFTR genetic testing
if the CFTR genotype was not available through the screening
process or is incomplete(776).
The EPOS2020 steering group did not consider it essential to do
an objective test for CF at initial presentation to ENT/ secondary
Figure 5.3.60 Delphi: Is it essential to do an objective test for cystic fibro- care with highly suggestive symptoms of CRS irrespective of
sis in CRS after failure of appropriate medical or surgical treatment in whether the mucosa was abnormal or normal on endoscopy but
ENTsecondary care with continued symptoms and abnormal mucosa on their responses were unclear regarding whether this was essen-
endoscopy ? tial after failure of appropriate medical or surgical treatment in
ENT / secondary care with continued symptoms and abnormal
mucosa on endoscopy (Figures 5.3.58., 5.3.59. and 5.3.60.).
5.3.5.13.3. Indications and possibilities of genetic testing
Genetic testing is mainly used for CF, Primary Ciliary Dyskinesia
(PCD) and to a lesser extent in chronic rhinosinusitis (CRS)(777).
CF results from mutations in the cystic fibrosis transmembrane
conductance regulator (CFTR) which is located on the long
arm of chromosome 7. Normally a 6.5-kb mRNA encodes CFTR
which is a 1490-amino acid integral membrane protein. It is an
ion channel responsible for chloride exchange in epithelial cells.
To date more than 2000 CFTR variants have been described(778).
Newborn screenings date back to 1979 in New Zealand and

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are performed by serial, two-tiered, or, more recently, three- receptors are currently tested for the phenotype of patients as
tiered/hybrid-based methods(778). The screenings are based on either supertasters, intermediate or non-tasters.
immunoreactive trypsinogen (IRT). There are three approaches:
1) one starts with the measurement of IRT where measurements 5.3.5.14. Lower respiratory tract assessment
above a defined cut-off are followed up by genetic analysis to
determine specific mutations in the CFTR gene (IRT/DNA); 2) An 5.3.5.14.1. Rationale
initial IRT measurement with defined cut-offs is followed by IRT A significant number of patients with rhinosinusitis have invol-
measurement on a second specimen collected two weeks later vement of the lower respiratory tract embodied in the concept
(IRT/IRT); 3) Pancreatitis-associated protein is used following of the 'united airways'. A patient's own assessment of their chest
an increased IRT (IRT/pancreatitis-associated protein method). symptoms (wheeze, shortness of breath, chest tightness, and
Direct sandwich immunoassays with either monoclonal or cough) and severity is often poor or they may even be unaware
polyclonal antibodies are used and may also be multiplexed. The that the lower respiratory tract is affected so objective assess-
advantage is to test multiple samples in a patient at a relati- ment is necessary(34).
vely low cost. The genetic analysis (from blood or oral mucosal
scrapings) are done by Sanger sequencing and quantitative 5.3.5.14.2. Techniques
methods. Nowadays new high throughput approaches such as Peak flow
Next Generation Sequencing, targeted deep sequencing (TDS) This is a simple test in which the individual stands and blows
and Droplet Digital PCR technologies are used(779). Recently, as hard as possible through a disposable filtered mouthpiece
Zeevi et al.(780) proposed a new method called allele sensitive into a peak flow meter. The best of three attempts is taken and
proliferation sequencing (ASP-SEQ) which is more sensitive than compared with charts of normative data for sex, age and height.
targeted deep sequencing or digital PCR methods. If the result is not within the normal range, it can be repeated
PCD is a genetically heterogeneous autosomal-recessive motile 15 minutes after administration of a bronchodilator such as
ciliopathy associated with 32 genes. Clinical manifestations are salbutamol, to assess reversibility. A 20% increase and absolute
situs inversus, neonatal respiratory distress, progressive bron- improvement of 60l/min is suggestive of asthma though the
chiectasis, and respiratory failure in young adulthood(781). Tests diagnosis cannot be made on a single test. Alternatively, an
include including nNO, high speed videomicroscopy analysis exercise test such as running for 10-15 minutes followed by peak
(HSVA), transmission electron microscopy (TEM), immunofluo- flow measurements every 5 minutes which show a decrease of
rescent tests of ciliary proteins and genetic testing. Structural >10% or >200ml from baseline of FEV1 for adults or a fall in PEF
abnormalities can be confirmed by genetic testing of biallelic of >15% in children is also indicative of asthma(788-792).
mutations in known PCD(782). The most prevalent mutations Patients can be prescribed a peak flow meter and chart on
occur in five genes (DNAH5; DNAH11; DNAI1; CCDC39; CCDC40) which they can record their daily measurements, ideally perfor-
(783). Genetic tests combining Intron-exon level copy number med at the same time morning and evening. They can be asked
variations (CNVs) and whole-exome sequencing (WES) seem to to keep the record over several weeks and to bring the chart
be the most efficient approach(781). to their next outpatient visit. Average daily diurnal variation is
For CRS genomic analysis the most studied targets are bitter calculated as the day’s highest PEF minus the day’s lowest PEF,
taste receptors especially T2R38(784) which are analysed by eg. divided by the mean PEF for the day and then averaged over the
reverse transcription polymerase chain reaction with 7900HT course of a week. A variability of >10% in adults and >13% in
fast using allele-specific probes and primers(785) or single nu- children is suggestive of asthma(792-794).
cleotide polymorphisms (SNPs)(117). Other genetic approaches
target single nucleotide polymorphism genotypes in potassium Spirometry
channels (eg. by Illumnia Human-Hap550 BeadChip or Illumina This technique provides additional information in the outpatient
Human610-Quad BeadChip)(786). A more recent genome-wide as- setting (Table 5.3.8.). The individual is asked to blow as hard as
sociation study investigated the role of ALOX15 in CRS(436). More possible into a tube through a filtered disposable mouthpiece
targeted analyses eg. for methylated genes like FZD5 playing a and expiratory effort continued as long as possible. Again, the
role in CRSwNP can be detected using methyl-CpG-binding do- best of three attempts is used to derive the following values:
main sequencing (MBD-seq) and validated using methylation- • Forced expiratory volume in one second (FEV1)
specific polymerase chain reaction(787). • Forced vital capacity (FVC)
In summary, many potential genes influencing CRS have been • Ratio of FEV1/FVC. This should be >70-80% in healthy
investigated but for diagnosis or confirmation of the latter adults and >90% in healthy children(305, 788-791).
genetic testing has only been routinely established for CF and Comparative normative data are available. Various abnormal
PCD. Despite promising targets for future research bitter taste patterns may be seen.

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Table 5.3.8. Comparison of peak expiratory flow and spirometry in the assessment of possible asthma (Scadding and Lund 2004(842))

Setting Advantages Disadvantages

Spirometry Outpatients Most reliable Snapshot
Reproducible Expense
Results in 15-30 mins Trained operator
Pre- and post-bronchodilator Patient compliance
Peak flow Outpatients / Home Sensitive Less reliable than FEV1
Easy Patient compliance
Cheap Snapshot or wait ~ 4 weeks for home values

1) Obstruction: FEV1 is low, FVC normal and FEV1/FVC <70-80% 5.3.5.15. Diagnosis of N-ERD
or below the lower limit of normal (lowest 5% of the reference
population)(305, 789). 5.3.5.15.1. Rationale
This is characteristic of asthma and likely reversible with a NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosi-
beta-agonist eg salbutamol, albuterol . The likelihood of a false nophilic, inflammatory disorder of the respiratory tract occur-
negative result is increased if a short-acting beta-agonist was ring in patients with asthma and/or chronic rhinosinusitis with
administered within 4 hours of the test, or if a long-acting beta nasal polyps (CRSwNP), symptoms of which are exacerbated by
agonist was administered within 15 hours of the test. NSAIDs, including aspirin. As the condition is likely under-diag-
An increase of FEV1 by >12% from baseline (in adults and child- nosed and outcomes are worse in these patients, it is important
ren) or an increase of >200ml after a short-acting bronchodilator to identify the hypersensitivity. It is also important so that af-
(in adults) indicates significant reversibility. fected patients can be warned about avoidance, whilst enabling
Caution is advised with the use of a fixed FEV1/FVC ratio as a the non-sensitive to use therapeutic aspirin and NSAIDs and to
cut-point, as it results in false-positive diagnoses of obstruc- allow consideration of the option of aspirin desensitization in
tion in older adults and potentially false-negative diagnoses of those who are sensitized(797).
obstruction in younger adults, given a natural decline in FEV1
with age(795, 796). 5.3.5.15.2. Diagnosis
2) Restriction: FEV1 and FVC are low with a normal FEV1/FVC. Diagnosis of N-ERD is mainly based on a patient history of at
This is characteristic of a fibrosis or granulomatous process such least one documented reaction to aspirin or NSAIDs though it is
as sarcoid and is not reversible with bronchodilators. To confirm recognised that history alone is not always reliable, especially as
restriction a measurement of lung volumes (total lung capacity, asthmatic patients are often warned to avoid these drugs(798).
residual volume) is necessary. Thus, aspirin provocation tests are needed when the history is
not clear (Figure 5.3.61.).
Spirometry post-initiation of controller therapy Aspirin provocation tests are needed when the history is not
In adults, if after four weeks of anti-inflammatory, controller clear.
therapy (such as an inhaled corticosteroid or combined inhaled
corticosteroid and long-acting beta agonist), FEV1 has improved 5.3.5.15.3. Techniques
by over 12% and over 200 mL (or PEF by over 20%), this can also A provocation test may be undertaken via oral, bronchial or na-
be seen as supportive of a diagnosis of asthma in the appropri- sal routes (Table 5.3.10.). An oral provocation test with aspirin is
ate clinical context(792). the most common investigation used but is not without poten-
If not already involved, the presence of abnormal measure- tial risk. Oral or bronchial challenge starts with a very low dose,
ments or high clinical suspicion should prompt referal to a chest usually around 30 mg aspirin, which is then given in gradually
physician. They also have at their disposal other investigati- increasing doses(799). Although bronchial challenge can take only
ons including bronchial provocation testing, with or without four hours to perform(800), both these methods can result in se-
pharmacologic agents and fractional exhaled nitric oxide as vere symptoms in over 50% of subjects, especially in asthmatics,
well as imaging of the chest. The availablility of expired nitric and may necessitate emergency treatment, hospital admission
oxide measurement to rhinologists as well as pulmonologists and close monitoring. Since the reaction can be delayed, the
has improved diagnosis and reduced the use of peak flow as this challenge often requires more than 1 day and and subsequent
provides immediate confirmation of inflammation in the lower overnight admission.
(and upper) respiratory tract (see 5.3.5.9.; Tables 5.3.8.; 5.3.9.). Nasal provocation with lysine aspirin (LAS), a truly soluble form
of aspirin, is an approach that has gained popularity as it can

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Table 5.3.9. Diagnostic testing of lower respiratory tract (Brigham et al. 2015(843)).

History of variable respiratory symptoms

Confimed variable expiratory airflow limitation
Peak expiratory flow (repeated measures)
Basic measurements
Spirometry (repeated measures)
Positive exercise challenge test
Spirometry pre-bronchodilator and post-bronchodilator
Assessment of a response to treatment
Spirometry post-initiation of a controller therapy ie inhaled steroid
Nonpharmacologic: exercise or eucapnic voluntary ventilation
Bronchial provocation
Pharmacologic: hypertonic saline, mannitol, or methacholine
Allergy testing
Other supportive tests
Exhaled nitric oxide

be performed in severe asthmatics due to the rarity of systemic lation test (CAST) but a study showed that whilst the leucocytes
reactions. It has been standardized, is reproducible(801) and may of patients with N-ERD produced increased amounts of cysteinyl
be done in the outpatient setting but it should still be perfor- leukotrienes, the assay had a low sensitivity (25%), a specificity
med under medical supervision with resuscitation equipment of 92.3%, a positive predictive value of 28.7% and a negative
available. The reaction does not begin until about 45 minutes value of 90.7% which limit its usefulness(803).
after the nasal application and may persist for many hours. If The EPOS2020 steering group was unclear whether one or two
nasal provocation proves negative, oral challenge should be episodes of a respiratory reaction to aspirin or NSAIDs wasves-
considered. In a cohort of 150 difficult-to-treat CRSwNP patients, sential for the diagnosis AERD in a patient with CRS and whether
100 proved positive on nasal challenge, and 31 who were ne- an objective test was essential to diagnose aspirin exacerbated
gative went on to oral LAS challenge of which a further 14 gave
positive results(802).
Medication which must be stopped prior to the provocation Table 5.3.10. Different challenges to assess aspirin sensitivity
test: (Nizankowska 2000(844)).
• Oral and intranasal corticosteroids (at least seven days);
History +/- Challenge
• Antileukotrienes (at least seven days);
• Antihistamines (three days); Sensitivity (%) Specificity (%)
• Decongestants and cromones (one day). Oral 77 93
Bronchial 77 93
Lysine-aspirin solutions at 0.1, 1 and 2M are instilled in the Nasal 73 94
nose at 45-minute intervals and the effects assessed by clinical
symptoms (VAS), objective nasal airway assessment (acoustic
rhinometry, anterior rhinomanometry) and pulmonary function. Figure 5.3.62 Is an objective test to diagnose aspirin exacerbated respira-
A positive response is taken either as a 25% or greater decrease tory disease essential for the diagnosis AERD in a patient with CRS?
in the nasal airway (represented by a reduction of cross-secti-
onal area: Amin or volume 0– 12 cm) as assessed by acoustic
rhinometry or a 40% decrease in nasal inspiratory peak flow(799).
However, nasal inspiratory peak flow monitoring has been
shown to be less sensitive to obstruction caused by aspirin than
acoustic rhinometry(802). On pulmonary function, a drop of 20%
FEV1 is considered positive.
If nasal provocation proves negative, oral challenge should be
considered.
However, for those patients who have a higher risk of severe
reactions, flow cytometry-assisted basophil activation testing
(FAST) and functional-eicosanoid-test (FET) can be helpful tools
to elucidate the diagnosis, if they are available(744, 745). Another
alternative to aspirin provocation is the cellular antigen stimu-

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Figure 5.3.61. Diagnosis of N-ERD (adjusted from Kowalski, 2019).

Respiratory symptoms after NSAID -

• Rhinorrhoea, nasal congestion, dyspnoea

History of respiratory CRSwNP ± asthma?

+ +
reaction to NSAID? • Recurrence of NP Diagnosis
• Loss of smell
• >1 reaction reported
• Reaction to 2+ NSAIDs • Moderate to severe asthma of N-ERD
• Latest reaction < 5 years • Intolerance to alcohol
• Blood eosinophilia

? ?
+

Check non-respiratory Confirm/exclude the Oral, bronchial or nasal

reaction to NSAID presence of CRS and asthma challenge with aspirin
• CRS: ENT consultation,
endoscopy, CT-scan
• Asthma: respiratory function
test, bronchial hyperreactivity
-
N-ERD
excluded

Figure 5.3.63. Is a clinical history of two episodes of respiratory reaction Figure 5.3.64 Is a clinical history of one episode of respiratory reaction to
to aspirin or NSAIDs essential for the diagnosis AERD in a patient with aspirin or NSAIDs essential for the diagnosis AERD in a patient with CRS?
CRS?

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 EPOS 2020

respiratory disease for the diagnosis AERD in a patient with CRS quired to make the diagnosis of N-ERD though history alone is
(Figures 5.3.62., 5.3.63. and 5.3.64.). not always reliable. Aspirin provocation tests are needed when
the history is not clear.
5.3.5.15.4. Recommendations Nasal challenge with lysine aspirin is a good alternative to oral
All patients with CRS should be asked about reactions to aspirin and bronchial methods, in terms of safety, sensitivity and specifi-
and NSAIDs. city.
At least one documented reaction to aspirin or NSAIDs is re-

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with nasal polyp pathogenesis in asth- Desrosiers M. Polymorphisms in the tumour ability. Arch Otolaryngol Head Neck Surg
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822. Sitarek P, Zielinska-Blizniewska H, Dziki L, et ic rhinosinusitis. J Otolaryngol Head Neck of olfactory disturbance. Acta Otolaryngol
al. Association of the -14C/G MET and the Surg 2009;38:133-41. Suppl 1998;538:197-201.
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the risk of chronic rhinosinusitis with nasal A, Grenier JP, Desrosiers M. A pooling-based Granito K. Rigid nasal endoscopy versus
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biology 2012;31:1258-66. the p73 gene in chronic rhinosinusitis. J biologic documentation of acute bacte-
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6. Management of chronic rhinosinusitis in adults

6.1. Medical Management between-group-differences on Visual Analog Scale-Severity

Scoring Assessment [nasal secretion: mean difference (MD)
-2 (-16.1, 12.1), p=0.44; nasal obstruction: MD – 6.6(−10.6, 24),
6.1.1. Short-term oral antibiotics for chronic p = 0.78]. There was no difference between nasal endoscopy
rhinosinusitis (CRS) and exacerbations of CRS scores at day 14 between the groups (total endoscopy score,
p=0.88; nasal polyps, p=0.58; oedema, p=0.36; nasal secretion,
6.1.1.1. Summary of the evidence p=0.42). The quality of life (Sino-nasal Outcome Test, SNOT-22)
Short-term courses of antibiotics are prescribed at high rates improvement was similar between groups after three months
in patients with chronic rhinosinusitis (CRS) in primary and [MD -2.7 (-20.36, 14), p=0.75]. Bacterial eradication was observed
secondary care(1, 2). There is a need for stronger evidence on the in 29% of those treated with amoxicillin/clavulanate compared
role of antibiotics in CRS management. In this review, short-term to 9% of those in the placebo group, but no significant statistical
antibiotic treatment is defined as a treatment duration of four difference was observed between groups (p=0.37). Although
weeks or less. To date, there have been two randomized clinical no severe adverse events were reported in either group, two
trials published that utilized a placebo control investigating patients who received amoxicillin/clavulanate complained of
the effect of short-term antibiotics in CRS(3, 4). A single-centre mild abdominal colic and diarrhoea.
placebo-controlled trial(3) of 32 patients with acute on chronic Van Zele et al.(4) conducted a double-blinded placebo-controlled
exacerbation of CRS (Table 6.1.1.1). Acute exacerbation of CRS randomized controlled trial (RCT) of the effect of doxycycline
was defined as an acute worsening of sinonasal symptoms in the in treatment of CRS with nasal polyps (CRSwNP) in 28 patients.
last four weeks (nasal secretion, nasal obstruction/congestion, Doxycycline treatment significantly reduced postnasal drip
sense of smell, and/or facial pain) in patients with underlying symptom scores at week 2 (p=0.044) and showed a trend for
CRS. Patients were randomized to receive amoxicillin/ reduction in rhinorrhoea at week 8 (p=0.058) (no corrections
clavulanate vs. placebo for two weeks. Although both groups for multi-testing). Doxycycline had no significant effect on
had significant symptom improvement in nasal secretions and nasal congestion, or loss of sense of smell during the study
nasal obstruction compared to baseline, there was no significant period nor on postnasal drip and rhinorrhoea at the other time

Table 6.1.1.1. Short-term antibiotics for the treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results
Sabino DBPCT 32 patients (>18 • Amoxicillin-clavu- • Visual Analog Scale-Se- • No significant difference in symptoms scores, SNOT-
years of age) with lanate 875 mg/125 verity Scoring of clinical 22, endoscopy scores or bacteriologic eradication
2017(3) acute on chronic mg, orally, twice symptoms at 2 wks at day 14 compared to baseline in the 2 treatment
exacerbation of daily for 14 days • Nasal endoscopy at 2 wks groups
CRSsNP (n=12) or (n=21) • Middle meatus swab at • No significant differences in SNOT-22 at 3 months
CRSwNP (n=20) • Placebo twice daily 2 wks
for 14 days (n=11) • Lund-Kennedy scores at
2 wks
• SNOT-22 at 2 wks and 3
months

Van Zele DBPCT 47 patients with • Oral methylprednis- • Nasal symptoms (anterior Doxycycline treatment compared to placebo resulted in:
recurrent bilateral olone (32 mg/d on rhinorrhoea, nasal obstruc-
2010 (4) nasal polyps days 1-5; 16 mg/d tion, postnasal drip, and • Significantly reduced postnasal drip symptom scores
after surgery or on days 6-10; and 8 loss of sense of smell) at 1, at week 2 (p=0.044)
massive bilateral mg/d on days 11- 2, 4, 8, and 12 weeks • Trend of reduction in rhinorrhoea at 8 wks (p=0.058)
nasal polyps 20) (n=19) • Total nasal polyp score • No significant differences in all other symptoms and
(grade 3 or 4) • Oral doxycycline (0-8) at 1, 2, 4, 8, and 12 time points.
(200 mg on day 1, weeks • Small (0.5 on scale of 8) but significant reduction in
100 mg/d on days • Nasal peak inspiratory flow nasal polyp size for 3 months compared to placebo
2-20) (n=14) at 1, 2, 4, 8, and 12 weeks (p=0.015).
• Placebo for 20 days • Serum eosinophil counts • No significant increase in PNIF over the entire study
(n=14) and serum ECP period for doxycycline- treated group.
• IL-5, IgE, MMP-9, MPO and • Significant reduction in MPO in nasal secretions for 2
ECP in nasal secretions months and MPP-9 for 2 weeks

CRSwNP, chronic rhinosinusitis with nasal polyps; CRSsNP, chronic rhinosinusitis without nasal polyps; DBPCT, double-blind placebo
controlled trial; ECP, eosinophil cationic protein; MPP-9, Matrix metalloproteinase; MPO, myeloperoxidase; PNIF, peak nasal inspirato-
ry flow; SNOT, Sino-nasal Outcome Test.

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points. The doxycycline group was noted to have a small but recruited for the study. Clinical symptom improvement was
significant reduction in nasal polyp size (0,5 on a scale of 8) found to be comparable between amoxicillin/clavulanate and
for three months compared to placebo (p=0.015). There were clarithromycin for PND (40.7% vs. 46.7%; p=0.802), headache
no significant differences in peak nasal inspiratory flow (PNIF). (40.7% vs. 50.0%; p=0.626), cough (48.1% vs. 43.3%; p=0.626),
Although a significant decrease in serum IL-5Ra levels was rhinorrhoea (48.1% vs. 43.3%; p=0.502), epistaxis (14.8% vs.
observed at one month in the doxycycline group compared to 10.0%; p=0.473), facial pain or pressure (55.6% vs. 56.7%;
placebo (p=0.01), this decrease was not sustained throughout p=0.995), and nasal congestion (81.5% vs. 63.4%; p=0.255),
the study period. Doxycycline had no effect on serum eosinophil respectively. The authors reported no significant difference
counts or serum eosinophil cationic protein (ECP) levels in the rates of adverse events between both groups, with
compared to placebo. A significant decrease in ECP levels in diarrhoea (10.3%) observed most commonly in the amoxicillin/
nasal secretions was observed at one month in the doxycycline clavulanate group and anorexia (10.0%) reported in the
groups (p=0.032), but the significance of this difference was clarithromycin group.
likely resultant from an increase in the mediator in the placebo
group. Similarly, a significantly lower level of immunoglobulin Fan et al.(7), conducted an open label study in 43 patients with
E (IgE) in nasal secretions was observed in the doxycycline chronic rhinosinusitis without nasal polyps (CRSsNP) comparing
treatment groups at four weeks compared to placebo (p=0.003), the effects of low versus high dose clarithromycin for 14 days.
while an increase in this mediator was observed in the placebo Patients recruited for the study demonstrated at least 12 weeks
group. Levels of IL-5 in nasal secretions progressively increased of two or more clinical symptoms (including nasal obstruction,
during the treatment period for the doxycycline treatment nasal secretion, postnasal drip, facial pain or pressure, headache
group (significance of change compared to placebo not and reduction or loss of sense of smell), visible secretions in
reported). Doxycycline treatment demonstrated significantly the middle nasal meatus and/or olfactory cleft on endoscopic
reduced level of myeloperoxidase in nasal secretions compared examination, and no nasal polyps. Patients on low dose
to placebo during the study period (week 8; p=0.022), clarithromycin did not experience any significant changes in
suggestive of a reduction in neutrophilic activity. A significant median visual analogue scale scores of nasal congestion (5.4
decrease in levels of matrix metalloproteinase 9 (MMP-9) was vs. 5.4), rhinorrhoea (6.8 vs. 6.8), PND (4.5 vs. 4.3) or loss of smell
observed in the doxycycline group compared to placebo at after four weeks compared to baseline. However, those in the
week 1 (p=0.025) and week 2 (p=0.028). high-dose group had sustained improvement in MVAS scores up
to week 4 for nasal congestion (3.8 vs. 5.7; p<0.025), rhinorrhoea
There were seven randomized studies identified that provided (2.0 vs. 6.5; p<0.025), PND (1.6 vs. 3.9, p<0.025), and loss of
a parallel comparison of various antibiotic therapies (Table smell (1.0 vs. 2.2, p<0.025) compared to baseline. There was also
6.1.1.2). One multi-centre, double-blind, double-placebo significant improvement in both SNOT 20 and endoscopic Lund-
study(5) evaluated the effects of short-term ciprofloxacin and Kennedy scoring for the high-dose group at two and four weeks
amoxicillin/clavulanate in CRS. CRS was defined as unilateral compared to baseline, as well as when compared to the low-
or bilateral inflammation without nasal polyps of at least dose group (p<0.025). Significant differences in nasal symptom
three months duration. Overall, both treatment groups had scores were also observed between the low-dose and high
similar clinical cure rates (58.6% vs. 51.2%) and bacteriologic dose groups at week 2 and week 4 (statistical significance not
clearance rates (88.9% vs. 90.5%). However, patients with a reported). Interleukin-8 (IL-8) decreased significantly following
positive culture who received ciprofloxacin were more likely low and high dose antibiotic therapy at two and four weeks
to maintain bacteriologic clearance at 40 days post-treatment (p<0.025). The high dose treatment group also significantly
(83.3% vs. 67.6%, p=0.043). Endoscopy at the end of treatment decreased levels of IL-5 at two and four weeks compared to
showed purulent discharge in the middle meatus had cleared in baseline and levels of IL-5 and IL-8 when compared to the low
a higher proportion of ciprofloxacin-treated patients (p=0.05), dose group (p<0.025).
while inflammatory reaction resolved in a higher proportion of
amoxicillin/clavulanate-treated patients (p=0.04). Ciprofloxacin Namyslowski et al.(8)investigated 14 days of amoxicillin/
was better tolerated during the study period with only 12.4% clavulanate vs. cefuroxime in 115 patients with clinical and
of patients reporting at least one adverse event, compared radiographic features of CRS. CRS was defined as clinical
to 25% in the amoxicillin/clavulanate recipients (p=0.012). symptoms of headache, facial pain, presence of purulent or
Gastrointestinal-related events were the most common mucopurulent nasal discharge or PND, nasal obstruction and
complaints in both treatment groups and all adverse events objective findings including X-ray documentation of sinus
resolved by the end of treatment. There was no placebo arm. opacification, air-fluid levels or mucosal thickening. The authors
In a single-centre, clinical trial(6), 59 patients with CRS were focused on unilateral or bilateral chronic maxillary rhinosinusitis,
randomized to receive clarithromycin versus amoxicillin/ performing maxillary punctures to evaluate microbiologic status
clavulanate. Patients that demonstrated clinical symptoms and bacteriologic eradication post-treatment. There was no
of chronic rhinosinusitis [headache, rhinorrhoea, coughing, significant difference in the observed rates of clinical cure in the
post-nasal drip (PND), feeling of facial fullness, and nasal amoxicillin/clavulanate group as compared to the cefuroxime
congestion for more than 12 weeks] with at least one CT finding group (98.2% vs. 91.1%, p=0.2) or efficacy of bacteriologic
(sinus opacity, air-fluid level or thickening of mucus layer) were eradication (rates for this outcome variable not specified). One

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Table 6.1.1.2. Comparison of various short-term antibiotics for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Fan Open-label, 43 patients • Clarithromycin At 2 and 4 weeks: High-dose group demonstrated:
2014 (7) parallel-group (>20 years 250 mg daily for
randomized of age) with 14 days (n=20)
• Nasal symptom assessment • Significant improvement in nasal symptom
clinical trial CRSsNP • Clarithromycin • Endoscopic inspection scores, Lund-Kennedy and SNOT-20 at weeks 2
(Lund–Kennedy scores) and 4 compared with the baseline values and
500mg twice dai-
ly for 7 days, then
• SNOT-20 low dose group
250mg twice
• Interleukin-5 levels in nasal • IL-8 levels in nasal secretions were significantly
secretions decreased at weeks 2 and 4 compared with the
daily for 7 days
(n=23)
• Interleukin-8 levels in nasal baseline values and low-dose group values
secretions • IL-5 levels were significantly decreased at
weeks 2 and 4 compared with the baseline val-
ues and the low-dose group values

Amini Parallel-group 59 CRS • Clarithromycin • Clinical efficacy at 7, 17, 21, • No statistically significant differences in clinical
2009 (6) randomized patients 500 mg daily for 3 28, 42 and 56 days improvement of symptoms or adverse events
clinical trial weeks (n=30) • Radiographic status at 8 between treatment groups
• Amoxicillin-clavu- weeks
lanate 625 mg • Adverse effects
three times
daily for 3 weeks
(n=29)
Jareoncharsri Open, 60 patients • Levofloxacin 300 • Clinical response at day 4 • Mean total symptom score at 21 days, radio-
2004 (12) parallel-group (>16 years mg daily for 14 and 21 logic improvement, bacteriologic eradication,
randomized of age) days (n=34) • Plain film radiologic laboratory tests, vital signs and adverse events
clinical trial with acute • Amoxicillin clavu- evaluation at day 14 at 14 days were comparable between both
maxillary lanate 625 mg • Bacteriologic efficacy at day groups.
sinusitis three times daily 14 • Subgroup analysis of chronic sinusitis group
(N=48) for 14 days (n=26) • Adverse drug reactions at not performed
and acute day 14
exacerbation • Laboratory tests at and 14
of CRS (N=12) • Vital signs at day 14
Namyslowski Open, 231 patients • Amoxicillin • Clinical response at day 3 to 5, • No significant difference in clinical cure rates
2002 (9) parallel-group (>18 years clavulanate 15 to 18, week 2 to 4 or bacteriologic eradication between the
randomized of age) with 875/125mg twice • Treatment compliance at day amoxicillin-clavulanate treatment group vs. the
clinical trial CRS or acute daily for 14 days 15 to 18 cefuroxime treatment group at day 15-18.
exacerbation (n=115) • Bacteriologic response at day • Significant improvement in symptoms of infec-
of CRS • Cefuroxime 15 to 18 tion at day 3 to 5 in the amoxicillin clavulanate
500mg twice • Global severity of infection group compared to cefuroxime (81% vs 56%;
daily for 14 days week 2 to 4 p=0.0137)
(n=116) • Adverse events • Persistent, purulent nasal discharge following
treatment was noted to be significantly higher
in the cefuroxime group at day 3-5(3% vs. 12%;
p=0.036).
• Clinical relapse at week 2 to 4 was significantly
higher in the cefuroxime group in the clinically
evaluable patients (0% vs. 8%; p=0.0049) and
the intention-to-treat population (0.09% vs. 7%;
p=0.03).
• Adverse events were comparable between the
2 treatment groups. Diarrhoea was the most
common adverse event observed in both
treatment groups.
Namyslowski Parallel-group 115 patients • Amoxicillin • Clinical efficacy evaluated at • No significant difference in the observed rates
1998(8) randomized (>18 years clavulanate week 2 to 4 of clinical cure or bacteriologic eradication in
clinical trial of age) with 875/125mg twice • Bacteriologic response the amoxicillin-clavulanate group as compared
unilateral or daily for 14 days evaluated at week 2 to 4 to the cefuroxime group at week 2 to 4
bilateral CRS (n=55) • Adverse events (that is, diarrhoea) were com-
• Cefuroxime • Adverse events parable between the 2 treatment groups.
500mg twice
daily for 14 days
(n=56)

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Study Methods Participants Interventions Outcomes Results

Legent Double-blind, 251 patients • Ciprofloxacin • Clinical efficacy at day 10 • Ciprofloxacin and amoxicillin clavulanate had
1994(5) parallel-group, (>18 years 500mg twice and 40 similar clinical cure rates (58.6% vs. 51.2%) and
double-placebo of age) with daily for 9 days • Bacteriologic eradication at bacteriologic clearance rates (88.9% vs. 90.5%).
randomized unilateral (n=122) day 10 and 40 • Endoscopy at day 10 showed purulent
clinical trial or bilateral • moxicillin clavula- • Clinical tolerance at day 10 discharge in the middle meatus had cleared
CRSsNP nate 500mg three • Adverse events in a higher proportion of ciprofloxacin-treated
times daily for 9 patients (p=0.05)
days (n=129) • Inflammatory reaction on endoscopy at day 10
resolved in a higher proportion of amoxicillin
clavulanate-treated patients (p=0.04).
• Patients with a positive culture who received
Ciprofloxacin were more likely to maintain bac-
teriologic clearance at 40 days post-treatment
(83.3% vs. 67.6%, p=0.043).
• Ciprofloxacin-recipients had lower adverse
events (12.4% vs. 25%, p=0.012)

Huck Parallel-group 56 acute • Cefaclor 500mg • Clinical evaluation at day 2, • No significant differences between the groups
1993(11) randomized rhinosinusitis, twice daily for 10 16 to 18 in the CRS group
clinical trial 25 recurrent days (n=5)
rhinosinusitis, • Amoxicillin • Sinus X-rays at day 16 to 18
15 chronic 500mg 3 times • Adverse events
maxillary daily for 10 days
sinusitis (n=10)

CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; IL, interleukin; SNOT, Sino-nasal Outcome Test.

patient from each of the study arms interrupted treatment due All other signs and symptoms including inflammation of the
to diarrhoea. sinuses (6% vs. 6%), fever (11% vs. 0%), headache (6% vs. 13%),
and molar tenderness (5% vs. 9%) were not reported to be
In a second study from Namyslowski et al.(9), 231 participants significantly different between the amoxicillin/clavulanate
with either chronic rhinosinusitis or an acute exacerbation of treated and cefuroxime treated patients. Bacterial eradication
CRS were randomized to receive amoxicillin/clavulanate or rates were similar for amoxicillin/clavulanate and cefuroxime
cefuroxime for 14 days. CRS was defined as at least one major in the bacteriologically evaluable population (66% vs. 68%;
symptom (including post-nasal discharge, rhinorrhoea, cough) p=0.85; MD 95% CI= -18% to 15%) and the intention-to-treat
and constitutional symptoms (including headaches, facial pain, population (42% vs. 40%). Clinical relapse was observed to be
tooth pain, halitosis, sore throat, earache, increased wheeze significantly higher in the cefuroxime group in the clinically
or fever) plus an abnormal X-ray (including opacification, evaluable patients (0% vs. 8%; p=0.0049) and the intention-to-
abnormal air-fluid level or greater than 5 mm swelling of treat population (0.09% vs. 7%; p=0.03). Adverse events were
mucosa) lasting for at least three months. Acute exacerbation observed in 7% of the amoxicillin/clavulanate treated group and
of CRS was defined as the presence of inflamed sinuses on 9.5% in the cefuroxime-treated group. Diarrhoea was the most
X-ray associated with two or more symptoms (including common adverse event observed in both treatment groups.
purulent nasal discharge, headache, molar tenderness and Seven patients discontinued treatment due to amoxicillin/
fever) lasting ≤ four weeks, and a patient history of at least two clavulanate-related adverse events, compared to four patients
episodes of acute rhinosinusitis requiring antibiotic treatment in the cefuroxime-treated group. It was unclear if the second
during the 12 months prior to study inclusion. It is unclear study from Namyslowski et al.(9) represented longitudinal patient
how many patients had an acute exacerbation. All patients recruitment from the first Namyslowski et al. study(10). Given
had a maxillary sinus puncture confirming infection. There the similarities in the two studies and the lack of clarity in their
was no significant difference in clinical cure rates between the patient recruitment, a meta-analysis of the study outcomes
amoxicillin/clavulanate treatment group versus the cefuroxime was not attempted. Huck et al.(11) evaluated cefaclor versus.
treatment group in the clinically evaluable patients (95% vs amoxicillin over 10 days. The study included patients with:
88%; p=0.07; MD 95% CI =0.6% to 15% ) or the intention-to-treat acute rhinosinusitis (ARS) (n=56), defined as patients with
populations (92% vs 86%; p=0.15; MD 95% CI= -2% to 14%). rhinosinusitis symptoms for fewer than 14 days with no previous
At the day 3-5 assessment, the amoxicillin/clavulanate group episodes in the previous year; recurrent rhinosinusitis, defined
showed improvement in symptoms of infection, compared as more than one episode per year with improvement between
the cefuroxime group (81% vs. 56%, p=0.0137). Persistent, episodes (n=25); and CRS defined as non-resolving sinus disease
purulent nasal discharge following treatment was noted to be (n=15). While 40% of the patients on amoxicillin and 20% of the
significantly higher in the cefuroxime group at day 15 to 18 (3% patients on cefaclor were found to have improvement post-
vs. 12%; p=0.036). therapy, these numbers were too small for statistical analysis.
Jareoncharsri et al.(12) investigated the role of levofloxacin and

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amoxicillin/clavulanate in patients with acute maxillary sinusitis antibiotics which have had promising results with decreases
and acute exacerbation of CRS. Patients with acute rhinosinusitis in inflammatory markers, changes in mucus consistency, or
were defined based on symptoms and signs of rhinosinusitis, endoscopic and radiographic scoring systems(15-21). Macrolide
including obstruction, purulent nasal discharge, postnasal drip, antibiotics at a low-dose are thought to express an immune-
loss of smell, foul smell and headache, lasting less than four modulating effect and their use has been incorporated into
weeks and acute exacerbation of CRS was defined as acute standard cystic fibrosis (CF) care(22-24). However, there are studies
worsening of chronic symptoms lasting less than four weeks. comparing nasal steroid sprays to macrolide antibiotics without
The authors demonstrated comparable symptom improvement evidence of improvement in the macrolide group over the
(68.7% vs. 69.8%), radiological improvement (61.8% vs. 61.5%), use of a nasal steroid spray(25, 26). Two meta-analysis containing
bacteriologic eradication (78.5% vs. 70.0%, p>0.05) and adverse studies in the Chinese literature have been published recently,
events (8.6% vs. 7.7%) in levofloxacin recipients as compared to however the authors indicated that none of the studies not
amoxicillin/clavulanate amongst patients with acute maxillary reviewed here were double blind, placebo controlled trials
sinusitis and acute exacerbation of CRS. However, the sample (DBPCT)(21, 27).
size in the subgroup of patients with acute exacerbation of CRS
(n=12) was small. Two studies(13, 14) ( 6.1.2.1.) have completed placebo-controlled
trials of the effects of long-term macrolide therapy on signs,
It is uncertain whether or not the use of a short symptoms, and patient reported quality of life outcomes. Both
course of antibiotics has an impact on patient studies evaluated 12-week treatment, however Wallwork et
outcomes in adults with CRS compared with al. evaluated roxithromycin at 150mg daily, while Videler et al.
placebo. evaluated azithromycin (AZM) 500mg per week. Wallwork and
colleagues showed significant improvement in SNOT-20 scores,
6.1.1.2. Conclusion saccharin transit time, and nasal endoscopy. Once the groups
The EPOS2020 steering group, due to the very low quality of were sub-divided into low and high IgE levels (<200µg/L vs.
the evidence, is uncertain whether or not the use of a short > 200µg/L), the low IgE group had significant improvement
course of antibiotics has an impact on patient outcomes in in saccharin transit time, endoscopy, and nasal lavage of
adults with acute exacerbations of CRS compared with placebo. IL-82. However, Videler et al. did not show any improvement
Also, due to the very low quality of the evidence, it is uncertain in their outcomes and IgE was not measured so no subgroup
whether or not the use of a short course of antibiotics has an analysis was possible. At the end of the studies, Videler and
impact on patient outcomes in adults with CRS compared with colleagues had an improvement in 51% of patients on AZM and
placebo. Gastrointestinal-related adverse events (diarrhoea 35% of the placebo group without significance. Interestingly,
and anorexia) are frequently reported. There is a need for larger when the groups were re-evaluated by phone 12 weeks after
high-quality trials, especially to evaluate the use of short courses completion of the antibiotics, 50% of the AZM group reported
of antibiotics in acute exacerbations of CRS. “improvement/cure” compared to 9% in the placebo group. This
was statistically significant (p=0.017). Wallwork and colleagues
6.1.2. Long-term antibiotics had a response rate in the roxithromycin group of 67%
compared to 22% in the placebo group.
6.1.2.1. Long-term treatment with systemic macrolide While these studies had similar study sizes (60 vs. 64), their
antibiotics vs. placebo in CRS inclusion criteria were different. Wallwork et al. included only
For this systematic review, long-term antibiotic treatment was patients without nasal polyps, while Videler included patients
defined as a treatment duration longer than four weeks. While both with and without nasal polyps. As stated above, the
treatment with antibiotics is common practice in the treatment Wallwork et al. study sub-analyzed patients based upon low
of acute rhinosinusitis, there have been few placebo-controlled and high IgE levels. The high IgE group had the larger majority
studies on the effects of this practice. There are two such of non-responders. It is possible that sub-group analysis of the
studies that evaluate the outcomes after long-term treatment Videler study would have shown a high proportion of elevated
with macrolide antibiotics(13, 14). There have been multiple IgE patients. These two studies highlight the importance of
open studies evaluating the effects of long-term macrolide appropriate patient selection when using macrolide therapy.

Figure 6.1.2.1. Forest plot of the effect of macrolides versus placebo on responder scores in CRS patients.

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Figure 6.1.2.2. Forest plot of the effect of macrolides versus placebo on SNOT scores in CRS patients.

Furthermore, the once weekly dosing regime utilised by taken for assessment (i.e. SNOT-22 scores were divided by 22
Videler et al may have compromised the study in comparison and SNOT-20 scores were divided by 20) (Figure 6.1.2.3).
with low dose daily dosing by Wallwork et al. Further studies
on the efficacy of macrolide therapy have evaluated different 6.1.2.3. Long-term antibiotic in CRS vs. surgery
biochemical markers in those who do and do not respond to Two studies(31-33) evaluated treatment with long-term antibiotics
macrolide therapy, while some have identified lower levels of versus surgical intervention for patients with and without nasal
IgE to be significantly associated with response to macrolides(28), polyps. One study(32, 33) evaluated patients with and without
others have not shown this direct correlation polyps, while the other study(31) only evaluated patients with
Pooled data analysis of the responder score (Table 6.1.2.1.; polyps (Table 6.1.2.3.) The studies could not be combined in a
Figure 6.1.2.1.) and the SNOT scores (Figure 6.1.2.2) did not meta-analysis due to the differences in design.
show any significant benefit in the macrolide group [responder Ragab et al. reported on the same group of CRS patients
score: 0.45 (-1.32, 0.43), p=0.32, two trials, 120 patients], [SNOT with and without polyps19,20. The long-term antibiotic group
score: standard mean difference (SMD) 0.08(-1.14, 0.97), p=0.88, received erythromycin for 12 weeks in addition to nasal saline
two trials, 120 patients]. Both analyses showed significant irrigations and intranasal corticosteroids (INCS). The surgical
heterogeneity. group underwent surgery followed by short-term post-
operative antibiotics (erythromycin), nasal saline irrigations,
6.1.2.2. Long-term antibiotics in CRS vs. topical Dexarhinospray (DRS) for two weeks, followed by INCS. The
corticosteroids patients were assessed at three, 6 and 12 months. There was
Two double blind studies(29, 30) evaluated long-term antibiotics significant improvement in visual analogue scale (VAS), SNOT-
in comparison with topical corticosteroids in patients with and 20, Short Form 36 Health Survey (SF36), saccharin clearance
without nasal polyps (Table 6.1.2.2.) time, and nitric oxide (NO) in each group with no significant
Haxel et al. assessed erythromycin plus fluticasone furoate differences between the two subgroups. Endoscopy scores
in CRS patients with or without NP. All patients were treated increased at six and 12 months from baseline with no significant
post-surgery. There was no significant improvement in SNOT- difference between groups. Subgroup analysis found no
20, olfaction, saccharin trasit time, endoscopy scores, or nasal significant difference between patients with and without
health between the groups (29). Subgroup analysis determined polyps except in total nasal volume. Patients with CRSsNP had
that CRSsNP patients trended towards significant improvement significant improvement in nasal volume in the surgery group
in the erythromycin group, however, only the endoscopy scores (%∆; 57.3±37.6v41.8±42.8; p<0.01).
were significant. Amali et al.(30) evaluated azithromycin plus
fluticasone versus fluticasone in patients with and without nasal One study(31) compared clarithromycin plus endoscopic sinus
polyps. There was significant improvement in SNOT-22 scores in surgery (following eight weeks of antibiotics) to endoscopic
the azithromycin group when compared to fluticasone. sinus surgery alone in patients with CRSwNP. Patients were
Pooled data analysis of SNOT scores showed no significant evaluated at the completion of antibiotic treatment as well
benefit in the macrolide over topical corticosteroids [SMD as six- and 12-months post-surgery for endoscopic and nasal
0.21(-1.28, 2.09), p=0.83, two trials, 118 patients]. The I2was 96%, symptom scoring. Both groups had a significant decrease in
suggesting a little heterogeneity (X2=22.94, df=1, p<0.01). For nasal symptom score post-treatment (antibiotics vs. surgery).
this analysis, mean scores from SNOT-20 and SNOT-22 were Both groups also had an increase in nasal symptom score

Figure 6.1.2.3. Forest plot of the effect of macrolides versus nasal corticosteroids on SNOT scores in CRS patients.

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Table 6.1.2.1. Long-term antibiotic for the treatment of patients with CRS.
Study Methods Participants Intervention Outcomes Results
Videler DBPCT 60 CRSwNP • Azithromycin All assessed at 6, 12, 14 weeks No significant
2011(13) and CRSsNP 500mg weekly for effects
12 weeks (n=29) • Patient response rating scale (1-5, 1 desperately worse, four cured)
• Placebo weekly for • SNOT-22
12 weeks (n=31) • VAS (nasal obstruction, rhinorrhea, PND, facial pain, smell reduc-
tion, general health, headache, toothache, tear, coughing, nasal
bleeding, crusts, fatigue, nausea, vomiting/diaorrhea)
• SF36
• Endoscopy scores
• PNIF
• Olfaction
• Cultures

Wallwork DBPCT 64 CRSsNP • Roxithromycin All at 12 weeks Significant effect

2006(14) 150mg daily for 12 on SNOT-20,
weeks (n=29) • Patient Response rating Scale (1-6, 1 completely improved, 6 endoscopy,
• Placebo daily for 12 much worse) saccharin transit
weeks (n=35) • SNOT-20 time. Subgroup
• PNIF analysis on
• Saccharin transit time low vs high IgE
• Olfaction levels found 93%
• Endoscopy improvement in
• IL8, fucose, alpha2-macroglobulin the low IgE group

CRSwNP, chronic rhinosinusitis with nasal polyps; CRSsNP, chronic rhinosinusitis without nasal polyps; DBPCT, Double-blind place-
bo-controlled trial; IL, interleukin; IgE, immunoglobulin E; PND, post-nasal drip; PNIF, peak nasal inspiratory flow; SF-36, Short-Form 36;
SNOT, Sino-nasal Outcome Test; VAS, visual analogue scale.

Table 6.1.2.2. Long-term antibiotics versus topical corticosteroids for the treatment of patients with CRS.

Study Methods Participants Intervention Outcomes Results

Amali DBPCT 66 CRSwNP • Azithromycin 250 mg once daily • SNOT-22 at 12 weeks Significant improvement in SNOT 22
2017(30) and CRSsNP (60 for 12 weeks (n=20) scores in Azithromycin group over
analysed) • Placebo once daily for 12 weeks fluticasone
(n=40)
All patients received fluticasone
proprioanate 100 mcg twice daily
Haxel DBPCT 58 CRSsNP • Erythromycin 250mg once daily Assessed at 12 and 24 weeks No significant improvement in
2015(29) andCR SwNP for 12 weeks (n=29) SNOT20, olfaction, STT, endoscopy
• ECP
postoperatively • Placebo 250mg once daily for 12 • MPO scores, or nasal health. Trend towards
weeks (n=29 improvement in CRSsNP subgroup
• SNOT-20
on erythromycin, but only endoscopy
All patients received • Olfaction
score was significant.
• Saccharin transit time
fluticasone fuorate 27.5 mcg once • Nasal endoscopy score
daily • Nasal health self-rate

CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, Double-blind placebo-
controlled trial; ECP, eosinophil cationic protein; MPO, Myeloperoxidase ; SNOT, Sino-nasal Outcome Test; STT, Saccharin Transit Time.

from six to 12 months post-surgical intervention, but this 6.1.2.4. Long-term antibiotics versus Chinese herbal medicine
was not significant between the two groups. Patients in the One study(34) compared the effect of Chinese herbal medicine
clarithromycin plus surgery group had significant improvement (CHM), specifically Tsang-Erh-San extract granules and
in endoscopy scores post-antibiotic treatment and post-surgical Houttuynia extract powder to erythromycin 250mg bid for
treatment. The surgical arm also had significant improvement eight weeks in patients with CRSsNP. The groups were assessed
of endoscopic scores. In both groups, there were patients with with the Taiwanese SNOT-20 (TWSNOT-20), endoscopy scores,
polyp recurrence at six and 12 months. This was significantly saccharin transit time, and bacterial culture. In both groups,
higher in the surgery only group at six (27.5%v50%; p=0.034) there was significant decrease in TWSNOT20, with no significant
and 12 months (35%v62.5%; p=0.029). differences between groups (Table 6.1.2.4.). Both groups also
had a decrease in endoscopy scores, however, this did not reach
significance. Mucociliary clearance improved more significantly

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Table 6.1.2.3. Long-term antibiotics versus surgery for the treatment of patients with CRS.
Study Methods Participants Intervention Outcomes Results
Peric, RCT 80 CRSwNP • Clarithromycin 500mg daily x 8 Assessed at 2 weeks, 6 months, and Significant improvement in
weeks followed by surgery (n=40) 12 months after surgery NSS and Endoscopy score.
2014(31)
• Surgery alone (n=40) • Nasal polyp sizeNasal symptom Surgical group with significantly
score higher polyp recurrence post-
operatively.
Ragab RCT 90 CRSwNP • Erythromycin 500mg bid x 2 weeks Assessed at 6 and 12 months Significant effect on SNOT-20,
and then 250mg bid + alkaline douche + • VAS (nasal blockage, nasal SF36, SCT and NO in both groups.
2004, discharge, olfaction, facial pain,
CRSsNP (89 intranasal corticosteroid x 10 weeks No difference between groups
2010(32, evaluated) (n=45) headache, overall discomfort)
33) • Surgery + erythromycin 250mg • SNOT-20
bid x 2 weeks + alkaline douche • SF-36
+ intranasal corticosteroid (after 2 • NO
weeks) (n=44) • STT
• Acoustic rhinomanometry
• Endoscopy

RCT, randomised controlled trial; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal pol-
yps; NO, nitric oxide; NSS, Nasal and Sinus Symptom scale ; SCT, Saccharine Clearance Time ; SF36, Short-Form 36; SNOT, Sino-nasal
Outcome Test.

in the CHM group than erythromycin with improvement in in contrast to Svanstrom et al.(48). The apparent discrepancies
saccharin transit time. between this study and others(38, 40, 41, 43, 48) may be because
these have predominantly investigated associations in general
6.1.2.5. Comparison of long-term antibiotics in CRS populations with a potentially greater prevalence of pre-existing
One study(35) compared one macrolide antibiotic to another in heart conditions and other morbidities in contrast to a CRS
a single blinded study. The clarithromycin group was found to population. Clarithromycin should not be given to patients with
have improved efficacy over erythromycin (Table 6.1.2.5.) history of QT prolongation (congenital or documented acquired
QT prolongation) or ventricular cardiac arrhythmia, including
6.1.2.6. Cardiovascular risks of macrolide antibiotics torsades de pointe or hypokalaemia (risk of prolongation of
In common with a number of other drug groups, macrolides QT-time).
are known to prolong the QT interval, potentially increasing the Concomitant administration of clarithromycin and astemizole,
short-term risk of arrhythmia(36, 37). Since the CLARICOR study(38) cisapride, pimozide and/or terfenadine is contraindicated as
there have been a number of studies exploring cardiovascular this may result in QT prolongation and cardiac arrhythmias,
events in associations between macrolides, in particular including ventricular tachycardia, ventricular fibrillation,
clarithromycin, some of which have found increased risks of and torsades de pointe. Also, concomitant administration
cardiovascular events up to a year beyond the exposure to of clarithromycin and ergotamine or dihydroergotamine is
the antibiotic(39-41) whereas this has not been demonstrated contraindicated, as this may result in ergot toxicity. Concomitant
in a number of large observational studies(42-46), though some administration with ticagrelor or ranolazine is contraindicated.
found evidence of short-term increases in risk(43-46). A meta- Furthermore, clarithromycin should not be used concomitantly
analysis published by Wong et al.(47), demonstrated that the with HMG-CoA reductase inhibitors (statins) that are extensively
short-term risk of cardiovascular outcomes associated with metabolized by CYP3A4 (lovastatin or simvastatin), due to the
macrolides in observational studies was estimated at 1.79 excess increased risk of myopathy, including rhabdomyolysis. As with
myocardial infarctions per 1000 patients (95% confidence other strong CYP3A4 inhibitors, Clarithromycin should not be
interval (CI): 0.88 to 3.20). This risk was not observed in RCTs used in patients taking colchicine. Clarithromycin should not
but these trials were likely underpowered to detect this. No be used in patients who suffer from severe hepatic failure in
long-term cardiovascular risk (ranging from 30 days to three combination with renal impairment.
years) associated with macrolides was observed. Williamson et
al.(46) in an observational cohort of 66,331 adult CRS patients “As always a full clinical and drug history should
receiving 320,798 prescriptions for a macrolide or penicillin, be undertaken to cover these aspects and
compared prescriptions for macrolide antibiotics to penicillin. potential drug interactions”.
Outcomes were all-cause mortality, cardiac death, myocardial
infarction, stroke, diagnosis of peripheral vascular disease, 6.1.2.7. Summary
and cardiac arrhythmia. A non-statistically significant trend The two placebo-controlled studies were conducted with
towards increased risk of myocardial infarction during the first macrolide antibiotics. One study(13) did not find any significant
30 days following macrolide prescription was observed. No improvement in a mixed group of patients (with and without
statistically significant short- or long-term risks were observed nasal polyps). The other study(14) found improvement in
for macrolide prescription nor for clarithromycin in particular, SNOT-20 scores, nasal endoscopy, and saccharin transit time

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Table 6.1.2.4. Long-term antibiotics vs. Chinese herbal medicine for the treatment of patients with CRS.
Study Methods Participants Intervention Outcomes Results
RCT 83 (53 evaluated) CRSsNP • Erythromycin Assessed at 8 weeks • Saccharin transit time improved significantly
Jiang (34) 250mg bid x 8 more in the Chinese herbal medicine group
weeks (n=26) • Taiwanese SNOT-20 than erythromcycin group.
• Chinese herbal • Nasal endoscopy • No significant difference between the
medicine (n=27) • Nasal swab groups for all other measurements.
• Saccharin transit time
CRSsNP, chronic rhinosinusitis without nasal polyps; RCT, randomised controlled trial; SNOT, Sino-nasal Outcome Test.

Table 6.1.2.5. Long-term clarithromycin vs. erythromycin for the treatment of patients with CRS.
Study Methods Participants Drug Outcomes Results
(35)
Hashiba 1997 Single 59 CRS Clarithromycin 400mg twice Efficacy assessed (symptoms Clarithromycin was significantly
blind daily vs. erythromycin 600mg and endoscopic signs) after 2, more effective when compared to
three times daily for 8-12 weeks 4, 8 and 12 weeks. erythromycin

CRS, chronic rhinosinusitis.

in CRSsNP patients treated with macrolides. Patients with comparing erythromcyin versus Chinese Herbal Medicine(34).
low IgE were noted to have more significant improvement There are indications that the use of macrolides have increased
with macrolide treatment. The meta-analysis did not show a risks of cardiovascular events up to a year beyond the exposure
significant effect of macrolides over placebo for responder to the antibiotic although this has not been shown in patients
score and SNOT score. While both studies used macrolides, with CRS(46).
they utilized different dosages and schedules that may have
affected the results. These two studies also did not look at the 6.1.2.8. Conclusion
same subtypes of CRS. Larger placebo-controlled trials are A small number of randomized (placebo) controlled trials
warranted, in addition to more microbiological studies on the have evaluated the potential of long-term macrolides in the
underlying difference in the nasal microbiome of CRSwNP and treatment of CRS. No difference has been shown compared to
CRSsNP and these are presently on-going in several European placebo, nor could any differences compared to other proven
countries(49). Both studies evaluating the efficacy of antibiotics effective treatments like nasal corticosteroids or surgery be
over topical corticosteroids used macrolide antibiotics in a found. There is some indication that macrolides might be more
population of patients with CRSwNP and CRSsNP(29, 30). In meta- effective in patients with low IgE. Macrolides have been shown
analysis, macrolide antibiotics had no significant benefit over to have some potentially serious side effects at normal full
topical steroids for SNOT scores. Further studies on individual dosage and the risk of these side effects and specifically cardiac
CRS subtypes would be useful to determine which patients toxicity should be considered when considering the prescribing
would benefit from long-term antibiotics and more specifically these drugs. The EPOS2020 steering group, due to the low
macrolide antibiotics. quality of the evidence, is uncertain whether or not the use
of long-term antibiotics has an impact on patient outcomes in
The EPOS2020 steering group, due to the low adults with CRS, particularly in the light of potentially increased
quality of the evidence, is uncertain whether risks of cardiovascular events. There is a need for the larger high-
or not the use of long-term antibiotics has an quality trials that are presently being undertaken in Europe.
impact on patient outcomes in adults with CRS,
particularly in the light of potentially increased 6.1.3. Topical antibiotics
risks of cardiovascular events. There is a need for
the larger high-quality trials that are presently 6.1.3.1. Summary of the evidence
being undertaken in Europe. The rationale of treating patients with recalcitrant difficult-
to-treat rhinosinusitis with local antibiotics is the potential
Both studies(31-33) comparing long-term antibiotics treatment role of biofilm. These patients have wide open sinuses that
versus surgical treatment reported similar improvement. are perfectly accessible for local treatment but despite rinsing
However, Peric et al. reported more durable polyp control post- with saline, anti- inflammatory corticosteroid treatment and/
surgical intervention in patients who received pre-operative or systemic antibiotics, the sinus mucosa remains inflamed.
long-term antibiotics. Two reports on the same study(32, 33) found Often (biofilm-forming) Staphylococcus aureus or Pseudomonas
similar benefit from the use of long-term macrolide therapy aeruginosa is cultured from these sinuses(50), but more recent
when compared to surgical treatment. molecular microbiome studies point towards various other
Alternative medicinal treatments have been used routinely micro-organisms being possibly involved(51). Culture-dependent
in Eastern culture and are being used more often in Western studies need to be carefully interpreted since micro-organisms
culture. There was no significant difference in a small study such as S. aureus and P. aeruginosa can easily overgrow culture

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Table 6.1.3.1. Topical antibiotics for the treatment of patients with difficult-to-treat CRS.

Study Methods Participants Interventions Outcomes Results

Sykes DBPCT CRSsNP defined as • Dexamethasone- • Daily symptom diary card • No significant impact on
chronic mucopurulent tramazoline-neomycin nasal • Sinus radiograph symptoms, sinus radiograph,
1986(53) rhinorrhoea (50), nasal spray 1 application to each • Nasal mucociliary clearance nasal mucociliary clearance
blockage (28/50) and/ nostril 4 times daily for 2 measured by the modified
or facial pain (15/50), weeks (n = 20) saccharin method
abnormalities at sinus • Dexamethasone-tramazo • Nasal airways resistance
radiograph (25/50), line nasal spray 1 application measured by active anterior
abnormalities at to each nostril 4 times daily rhinomanometry
nasendoscopy (28/50) for 2 weeks (n = 20)
• Placebo spray 1 application
to each nostril 4 times daily
for 2 weeks (n = 10)

Desrosiers DBRCT 20 patients with • 3-times daily applications • Symptoms pain, congestion, • No benefit from the addition
(55)
refractory rhinosinusitis of 4 mL of a 20 mg/mL PND (VAS) 0, 2, 4 and 8 weeks of tobramycin on symptoms,
2001 who had failed tobramycin-saline solution after start of treatment quality of life and/or mucosal
maximal surgical and as a 4-week course of • Quality of life (RQLQ) oedema or secretion
medical therapies large-particle nebulized • Mucosal oedema and secretion
without immune aerosol therapy (n=10?) evaluated by nasal endoscopy
deficiencies • 3-times daily applications 0, 2, 4 and 8 weeks after start of
of 4 mL of saline solution treatment (0-3)
as a 4-week course of
large-particle nebulized
aerosol therapy (n=10?)

Videler DBPC 14 patients with • 8 ml solution of bacitracin/ • Severity of symptoms (rhinor- • No difference in severity of
(56)
cross- recalcitrant CRSsNP colimycin (830/640 μg/ rhoea, postnasal drip, crusts, symptoms measured by VAS,
2008 over [symptomatology and ml) twice daily for 8 weeks headache, facial pain, smell disease specific symptom
study a positive nasal culture (n=14) disturbance, nasal pain, nose score, SF-36 or nasal endo-
for Staph. aureus • 8 ml placebo solution bleeds, fever, malaise, tired- scopic findings
returned, despite 2 (n=14) ness) measured using VAS
previous attempts to • Disease-Specific Symptom
treat the disease with Score
appropriate antibiotics • SF-36 questionnaire
(at least 2 weeks) and • Nasal endoscopic findings
nasal saline irrigation]

Jervis DBRCT 25 Stap. aureus- • 125 mg mupirocin in a in • Change from baseline SNOT-20 • Change from baseline SNOT-20
positive CRSwNP 200 ml proprietary buffered (28 days) just not significant (0.06)
Bardy patients but no frank salts blend (MUP group) + • Change from baseline VAS • Change from baseline VAS
2012(57) polyps at moment of 3dd placebo tablet for 28 battery (summation of 5 battery: not significant
trial with ongoing signs days (n=9) individual symptom scores plus • Significantly better LK score in
and symptoms of CRS • 200 ml proprietary buffered an overall symptomatology mupirocin treated group -4.0
despite complete ESS salts blend and 3dd 625 score; total score range, 0–60) (-7.0 to -1.3) than Augmentin
Augmentin (n=13) for 28 (28 days) 3.0 (-1.0 to 4.0).
days • Change from baseline Lund- • Significantly better bacterial
Kennedy endoscopic score) (28 eradication
days)
• Bacteriological culture at 28
days

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Table 6.1.3.1. Topical antibiotics for the treatment of patients with difficult-to-treat CRS (continued).
Study Methods Participants Interventions Outcomes Results
Shikani DBRCT 35 adult patients • Topical regimen group • Lund-Kennedy symptoms score • No comparisons are given
with refractory CRS (13 CRSwNP, 12 CRSsNP) • Lund-Kennedy endoscopic between treatment groups
2013(58) (CRSwNP and CRSsNP) daily self-administered but in the CRSsNP there
appearance scores
that had undergone topical nebulisation of • Histological response to appears to be no difference
prior endoscopic sinus culture-directed antibiotics treatment between treatments. In the
surgery (tobramycin, vancomycin, CRSwNP topical treatment
mupirocin and levofloxacin) significantly reduced both
and of mometasone using a LK symptom score and LK
commercial nebuliser for 6 endoscopic appearances and
weeks (n=25, 13 CRSwNP, 12 oral treatment did not
CRSsNP) • The improvement
• Oral regimen group in histological score
consisting of culture- (inflammation, oedema,
directed oral antibiotics epithelial attenuation,
and commercially available epithelial hyperplasia,
mometasone spray for 6 squamous metaplasia, fibrosis
weeks (n=10, (5 CRSwNP, 5 and goblet cell hyperplasia)
CRSsNP) was significant for the CRSwNP
group treated with topical
therapy but not for CRSsNP.
No comparison between
treatment groups was made
Bonfils DBPCT 72 adults CRSwNP • A solution of 150 mg • Bacteriological eradication • Significantly better bacterio-
(59)
post-surgery (55 tobramycin for inhalation • Congestion, anterior or poste- logical eradication with active
2015 evaluated) by nebulization in a single treatment
rior rhinorrhea, sneezing, facial
dose of 3 ml medium pain or olfactory impairment • No significant impact on
(150mg/3ml) administered (VAS) symptoms
by the Easynose®mesh • Early withdrawal
nebulizer (n= 32 evaluated) • Adverse effects
twice daily for 7 days
• Same treatment with 3 ml
saline (n= 23 evaluated)

CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, double blind placebo
controlled trial; LK, Lund-Kennedy; PND, post-nasal drip; VAS, visual analogue scale; Short-Form 36; SNOT, Sino-nasal Outcome Test.

plates(52). Videler et al. investigated the effect of nasal irrigation with

In this systematic review, we identified seven randomized bacitracin/colimycin or placebo after two weeks of levofloxacin
trials(53-59) with topical antibiotics in difficult-to-treat CRS of 500 mg twice daily for two weeks in a randomised, double
which four were placebo (or saline)-controlled studies(53, 55, 56, blind, cross-over study in 14 patients with recalcitrant CRS in
59)
(Table 6.1.3.1.) The design and outcome parameters of the spite of surgery with positive S.aureus culture. Both groups
studies were too different to allow for meta-analysis. improved and there was no difference in SF-36 and endoscopic
The four placebo controlled studies (n=141) did not appearance(56).
show significant improvement in symptoms by using Bonfils et al. showed in 59 patients with CRSwNP with symptoms
topical antibiotics (nebulization or spray) compared to after surgery that inhalation by nebulization of a solution
the treatment without antibiotics(53, 55, 56, 59). Sykes et al. of 150 mg tobramycin twice daily for seven days eradicated
compared dexamethasone, neomycin and tramazoline with bacteria based upon post-treatment culture significantly
dexamethasone without neomycin and a placebo group in 50 better than placebo. Bacteriological analysis was performed
patients with CRSsNP with vehicle alone and showed significant on day 0 and day 10, following Day et al.(61) studying the
effect of the dexamethasone/tramazoline compared to placebo presence of pathogenic strains in culture and their antibiotic
but no additive effect of neomycin(53). susceptibility, with cytological analysis of the presence and
Desrosiers et al. investigated 20 recalcitrant CRS patients concentration of leukocytes (D0 and D10). Pre-treatment
(CRSsNP and CRSwNP) in a randomized, double-blind trial of and day 10 post-treatment bacterial isolates were compared.
tobramycin-saline solution or saline with quinine as control, Presence of leukocytes and sensitivities to antimicrobials were
administered thrice daily by means of a nebulizer for four weeks, also evaluated. However, there was no significant impact on
followed by a four-week observation period. Both patient symptoms(59).
groups experienced improvement in signs and symptoms but Of the non-placebo controlled randomised trials (RTs) Jervis-
the addition of tobramycin appears of no benefit (55). The bitter- Bardy et al.(57) evaluated the effect of 125 mg mupirocin in a200
masking quinine used for the placebo in this trial is now being ml proprietary buffered salts blend (MUP group) + 3dd placebo
used therapeutically to stimulate taste receptors and potentially tablet for 28 days (n=9) with Augmentin 200 ml proprietary
to clear gram-negative bacteria(60). buffered salts blend and 3dd 625 Augmentin (n=13) for 28 days

215
 EPOS 2020

in 25 CRSwNP patients but no frank polyps at the time of trial However, it may give a clinically non-relevant improvement in
with ongoing signs and symptoms of CRS despite complete symptoms, SNOT-22 and LK endoscopic score compared to oral
endoscopic sinus surgery (ESS). The MUP treatment eradicated antibiotics. The EPOS2020 steering group, due to the very low
S. aureus significantly more effectively than Augmentin at quality of the evidence, is uncertain whether or not the use of
one month and five patients remained S. aureus negative for topical antibacterial therapy has an impact on patient outcomes
a period of two months after the treatment, based on middle in adults with CRS compared with placebo.
meatus swab cultures. The Lund-Kennedy (LK) endoscopic
score change from baseline was significantly better in the MUP 6.1.4. Intravenous antibiotics
treated group -4.0 [-7.0 to -1.3] vs. Augmentin 3.0 [-1.0 to 4.0].
The change from baseline in the SNOT-20 scores approached There are no randomized studies evaluating the effectiveness of
significance (MUP -7.0 [-10.0 to -1.0] vs. Augmentin -1.0 [-4.5 intravenous (IV) antibiotics in CRS.
to 3.0], P 0 .06), whereas the VAS scores were not significantly There is one uncontrolled case series of 45 patients reporting
different. a significant improvement in symptoms in patients receiving
Finally, Shikani 2013(58) conducted a randomized study in 35 home IV antibiotics when previous oral antibiotic treatment
patients with refractory chronic rhinosinusitis (CRSwNP and and/or surgery had failed(62).
CRSsNP) that had undergone prior endoscopic sinus surgery.
Twenty-five patients (13 CRSwNP, 12CRSsNP) daily self- 6.1.4.1. Conclusions
administered topical nebulisation of culture-directed antibiotics Due to the very low quality of the evidence, it is uncertain
(tobramycin, vancomycin, mupirocin and levofloxacin) and whether or not the use of intravenous antibiotics therapy has an
mometasone using a commercial nebuliser for six weeks. The impact on patient outcomes in adults with chronic rhinosinusitis
control group of 10 patients (five CRSwNP, five CRSsNP) received compared with placebo.
culture-directed oral antibiotics and commercially available
mometasone spray for six weeks. No comparisons are given 6.1.5. Nasal corticosteroids
between treatment groups but in the CRSsNP there appears to
be no difference between treatments, in the CRSwNP topical 6.1.5.1. Summary of the evidence
treatment significantly reduced both LK symptom score and In this analysis, DBPCT trials after the year 1990, assessing
LK endoscopic appearances whereas oral treatment did not. the effects of nasal corticosteroids for patients with chronic
The improvement in histological score (inflammation, oedema, rhinosinusitis, both with and without polyps are included.
epithelial attenuation, epithelial hyperplasia, squamous Diagnostic criteria for CRS should meet the current EPOS
metaplasia, fibrosis and goblet cell hyperplasia) was significant criteria for chronic rhinosinusitis(63). Patients with allergic fungal
for the CRSwNP group treated with topical therapy but not for rhinosinusitis, cystic fibrosis, immunodeficiency, primary ciliary
CRSsNP. No comparison between treatment groups was made. dyskinesia, fungal balls, granulomatosis with polyangiitis are
excluded. Corticosteroids delivered into the nose and the
Topical antibacterial therapy does not seem to paranasal sinuses by any delivery methods generally available in
be more effective than placebo in improving clinical practice are included. Trials administering corticosteroids
symptoms in patients with CRS. However, it may via catheter(64, 65) and polyp injection(66) are excluded. Outcomes
give a clinically non-relevant improvement in analysed in this analysis are symptoms, quality of life, endoscopy
symptoms, SNOT-22 and LK endoscopic score polyp size, polyp recurrence and adverse events.
compared to oral antibiotics. Of the 42 studies included in this review (43 articles), 40 studies
were placebo-controlled trials assessing the effects of nasal
6.1.3.2. Conclusion corticosteroids (Table 6.1.5.1.). Four studies compared different
There are six RCTs evaluating the efficacy of topical antibacterial delivery methods of nasal corticosteroids (Table 6.1.5.2.)(67-70).
therapy in recalcitrant CRS. The four placebo controlled studies One article(71)included data of a previously published article(72)for
(n=141, 3 in CRSsNP, 1 in CRSwNP) did not show significant re-analysis. Thirty-two studies evaluated patients with CRSwNP,
improvement in symptoms compared to the treatment without five studied patients with CRSsNP and the other five studied a
antibiotics(53, 55, 56, 59). mixed population. In 24 trials most patients had previous sinus
High-volume rinsing with mupirocin seems able to eradicate surgery and in 14 trials most had no surgery. Patients’ sinus
S. aureus significantly better than oral Augmentin and LK surgery status was not mentioned in four trials. A variety of nasal
endoscopy score and SNOT-22 showed (near) significant corticosteroids was used such as triamcinolone, mometasone
improvement compared to Augmentin(57). Also, topical furoate, hydrocortisone, budesonide, FP, and dexamethasone.
nebulisation of culture-directed antibiotics seemed to be more Corticosteroids were delivered using nasal spray in 26 trials,
effective than oral treatment especially in CRSwNP patients(58). nasal drop in seven trials, nebulizer in two trials, aerosol in three
The latter two studies lack a placebo group and have significant trials, nasal irrigation in 4 trials and turbuhaler in two trials. Four
other methodological issues reducing the certainty of the trials used a bi-directional exhalation device which generated
findings. airflow in the nose after patients blew through the device. In
Topical antibacterial therapy does not seem to be more effective 13 trials postoperative nasal corticosteroids were administered.
than placebo in improving symptoms in patients with CRS. Endoscopic sinus surgery was not performed in 29 trials.

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Table 6.1.5.1. Nasal corticosteroids for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Leopold DBPCRCT 323 CRSwNP, • FP using exhalation • Disease specific quality • At 16 weeks, greater number of responders
27% previous delivery system 93µg of life (SNOT-22) at 16, in symptoms and polyp score reduction
2019(73) b.i.d. for 16 weeks 24 weeks significantly favoured FP versus placebo
sinus surgery
(n=81) • Proportion of respond- • SNOT-22, symptoms, polyp grade were
• FP using exhalation ers at 16 weeks significantly improved in each FP group at
delivery system 186µg • Symptom score weeks 8, 12, 16
b.i.d. for 16 weeks improvement (0-3, 4 • There were no differences between active/
placebo groups in intraocular pressure and
(n=80) symptoms) at 4 weeks
cataract
• FP using exhalation • Polyp score (0-3)
• Serious AEs were reported in 1 patient
delivery system 372µg reduction at 4, 8, 12, 16, receiving placebo (meningitis and
b.i.d. for 16 weeks 24 weeks sinusitis) and 1 patient receiving 372mg FP
(n=82) • Adverse events (positional vertigo)
• Placebo for 16 weeks • Local adverse events were more common in
(n=80) FP (epistaxis and nasal septal ulcer)

Kobayashi DBPCRCT CRSwNP, 35% • Beclomethasone dipro- • Disease specific quality • At 4 weeks, greater number of responders in
previous sinus pionate metered-dose of life (SNOT-22) at 4 polyp score reduction significantly favoured
2018(74)
surgery inhaler, inhalation weeks beclomethasone dipropionate versus
through the mouth • Proportion of respond- placebo
followed by exhalation ers at 4 weeks • At 4 weeks, SNOT-22 improved significantly
through the nose for 4 • Polyp score (0-4) reduc- in the beclomethasone dipropionate group
weeks (n=11) tion at 4 weeks • At 4 weeks, beclomethasone dipropionate
reduced polyp size significantly
• Placebo for 4 weeks
(n=12)

Tait 2018(81) DBPCRCT 74 CRS • Budesonide irrigation • Quality of life (SNOT-22 • The SNOT-22 scores at 4 weeks were not
(25%CRSwNP), 1000µg o.d. in 240ml (0-110) at 4 weeks) different between the 2 groups
28% previous bottle for 4 weeks • Symptoms (Likert scale • Symptoms at 4 weeks were not different
sinus surgery (n=29) of improvement 1-7, • LKES change at 4 weeks was not different
(61 analyzed) • Saline irrigation with scale at 4 weeks) There were no related adverse events.
placebo (lactose) for 4 • Endoscopy score (LKES
weeks (n=32) (0-20) at 4 weeks)
• Adverse event

Venkatesan DBPCRCT 22 CRSwNP, • Fluticasone fuorate • Symptom score (0-3, 5 • At 12 weeks, improvement by corticosteroid
without sinus nasal spray 110µg o.d. symptoms) improve- treatment over placebo on symptom scores
2016(107)
surgery for 12 weeks (n=18) ment at 12 weeks and the polyp score were not significant
• Placebo nasal spray for • Polyp score (0-3) reduc-
12 weeks (n=2) tion at 12 weeks

Zhou DBPCRCT 748 CRSwNP, • MFNS 200µg b.i.d. for • Proportion of respond- • At 16 weeks, a greater number of
(106) 24% previous 16 weeks (n=375) ers at 16 weeks responders was significant for MFNS
2016
sinus surgery • Placebo spray for 16 • Symptom score (0-3, 4 compared to placebo
weeks (n=373) symptoms) improve- • MFNS was significantly effective in
ment at 4, 8, 12, 16 symptom improvement over placebo. Nasal
weeks obstruction, anterior rhinorrhoea, smell
• Polyp score (0-3) improvements were significant at 4, 8, 12, 16
weeks. It was significant for postnasal drip at
reduction at 4, 8, 12, 16
8, 12 weeks.
weeks
• Change from baseline in total polyp size
score was significantly greater for MFNS vs.
placebo at 4, 8, 12, 16 weeks

Dixon DBPCRCT 388 CRSsNP • MFNS 200µg/day for • Disease specific quality • At 24 weeks, there was no difference
(75) (237 adult and 24 weeks (n=189) of life (SNOT-22) at 24 between corticosteroid and placebo in
2015
151 children) • Placebo for 24 weeks weeks SNOT-22
without sinus (n=199) • Symptom score (1-60) • At 24 weeks, there was no difference
surgery improvement at 24 between groups in symptom improvement
weeks

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 EPOS 2020

Table 6.1.5.1. Nasal corticosteroids for the treatment of patients with CRS (continued).
Study Methods Participants Interventions Outcomes Results
Wang DBPCRCT 57 CRSwNP, • Budesonide 1000µg • Symptom (4 symp- • At 2 weeks, budesonide transnasal
without sinus b.i.d. transnasal neb- toms) improvement at nebulization significantly improved total
2015(85)
surgery ulization for 14 days 2 weeks nasal symptoms and 4 individual symptoms
(n=29) • Polyp score (0-3) reduc- • At 2 weeks, budesonide transnasal
• Placebo nebulization tion at 2 weeks nebulization significantly reduced polyp size
for 14 days (n=28) • Adverse events compared with placebo
• Morning plasma cortisol levels showed no
significant difference between the initial
treatment and the end of treatment. There
was no symptom of adrenal suppression in
any of the participants.
• No serious adverse events were reported

Rawal SBPCRCT 50 CRSwNP • Budesonide irrigation • Quality of life (SNOT-22 • SNOT-22, RSOM31, and RSDI scores were not
postoperative 500µg in 240ml bottle. (0-110), RSOM-31 (0- different between 2 arms at all 3 timepoints
2015(82)
(42 analyzed) 60ml/nostril b.i.d. for 155), RSDI (0-120) at 2 (2 weeks, 3, 6 months).
24 weeks (n=24) weeks, 3, 6 months)
• Saline irrigation alone
for 24 weeks (n=18)

Nordin DBPCRCT 60 CRSwNP, • Peri-operative FPND • General quality of life, • At 5 weeks, both groups increased in
(76) postoperative 400µg b.i.d. for 14 using General Well general quality of life score to a similar
2013
weeks (n=26) Being Schedule (0-110, extent without difference
• Peri-operative placebo 14 questions with a
b.i.d. for 14 weeks 6-point scale and 4
(n=34) questions with an
11-point scale) at weeks
4 and 5

Vento DBPCRCT CRSwNP, • Postoperative triam- • Symptom score (0-3, 10 • There was no difference in symptom
postoperative cinolone acetonide symptoms) improve- improvement
2012(105)
nasal aerosol 220µg ment at month 3, 6, 9 • At 3 months, triamcinolone acetonide
⁄ day as 2 actuations • Polyp score (0-3) reduc- reduced polyp size and prevented regrowth
of 55µg, each for 9 tion at month 3, 6, 9 of nasal polyps significantly in acetylsalicylic
months (n=30) • Polyp recurrence at 9 acid-tolerant patients, but it was not
• Postoperative placebo months significant at 6 and 9 months. It was not
significant in acetylsalicylic acid-intolerant
spray for 9 months • Adverse events
patients
(n=30)
• No serious adverse events reported.
There was no difference in blood in nasal
secretions.

Mosges DBPCRCT 59 CRSsNP, • MFNS 200µg b.i.d. for • Proportion of respond- • At 16 weeks, greater number of responders
(90) without sinus 16 weeks (n=29) ers at 16 weeks significantly favoured MFNS over placebo
2011
surgery • Placebo for 16 weeks • Symptom score (0-3, 5 • At 16 weeks, symptom score was
(n=30) symptoms) improve- significantly improved by MF
ment at weeks 1, 4, 8, • At 16 weeks, the LK endoscopy score
12, 16 showed a significant difference between
• LK endoscopy score at the MFNS group and the placebo group
weeks 1, 4, 8, 12, 16
• No serious adverse events reported. No
difference between groups in non-specific
• Adverse events complaints

Rotenberg DBPCRCT 64 CRSwNP • Budesonide irrigation • Quality of life (SNOT-21 • SNOT-21, LKES, and LM score results of both
(N-ERD) 60ml/nostril 500µg (0-105) at 6,12 months) intervention groups were not different from
2011(83)
postoperative b.i.d. (total 1000µg) for • Endoscopy score (LKES placebo group at both 6 and 12-month
(60 analyzed) 52 weeks (n=20) (0-12) at 6,12 months) timepoints (significant level was defined at
• Saline irrigation • CT score (LM score (0- p < .0167)
60ml/nostril and 24) at 6,12 months) • IOP and ACTH level were not changed at
budesonide spray • Ocular events (IOP at both 6 and 12-month timepoints
64µg/nostril b.i.d. 6,12 months)
(total 256µg) for 52 • HPA axis (ACTH (nor-
weeks (n=19) mal/abnormal) at 6,12
• Saline irrigation alone months)
for 52 weeks (n=21)

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 EPOS 2020

Table 6.1.5.1. Nasal corticosteroids for the treatment of patients with CRS (continued).

Study Methods Participants Interventions Outcomes Results

Hansen DBPCRCT 20 CRSsNP, all • FPNS 400µg b.i.d. • Proportion of respond- • At 12 weeks, a significantly greater
previous sinus using a bi-directional ers at 12 weeks number of responders reported symptom
2010(78)
surgery exhalation delivery • Symptom improve- improvement in the FP group than in the
device for 12 weeks ment at 4, 8, 12 weeks placebo group.
(n=10) • Disease specific quality • Combined symptom score was significantly
• Placebo b.i.d. using a of life (RSOM-31) at 4, 8, improved by FP compared to placebo at
bi-directional exhala- 12 weeks 8, 12 weeks
tion delivery device • LK endoscopy score at • Overall RSOM-31 score and nasal subscale
were not different at 12 weeks but nasal
for 12 weeks (n=10) 4, 8, 12 weeks
subscale was significantly improved with FP
compared to placebo at 4, 8 weeks
• Endoscopy score showed a significant
improvement of FP in oedema at 4, 8, 12
weeks but no difference for nasal discharge.

Olsson DBPCRCT 68 CRSwNP, • Perioperative FPND • Health related quality • At 5 weeks after sinus surgery no effect on
postoperative 400µg twice daily. for of life (SF-36, 0-100, total SF36 but significant improvement in
2010(77)
10 weeks (n=30) 8 health domains) the FPND group of the mental component
• Perioperative placebo at week 5 after sinus summary and 3 domains (role physical,
b.i.d. for 10 weeks surgery vitality, social functioning).
(n=38)

Ehnhage DBPCRCT 68 CRSwNP, • Perioperative FPND • Symptom score (3 • There was no difference between FP and
postoperative 400µg b.i.d. for 10 symptoms, each score placebo in symptom improvement and
2009(95)
weeks (n=100) 0-3) improvement at 10, nasal polyp score reduction at 10 and 17
• Perioperative placebo 17 weeks weeks
b.i.d. for 10 weeks • Nasal Polyp score (0-3) • No difference in adverse events
(n=47) reduction at 4, 6, 10, 17
weeks
• Adverse events

Jankowski DBPCRCT 245 CRSwNP, Flluticasone dipro- • Symptom score (0-3, At 4 weeks, FPNS 400 µg/ day was significantly
without sinus pionate nasal spray 3 symptoms), VAS im- more effective than placebo
2009(99)
surgery 200µg bid for 8 provement at 4 weeks • in reduction of intensity of three symptoms
months (n=81) • Polyp score (0-3) reduc- • polyp reduction
• FP nasal spray 200µg tion at 4 weeks
bid for 1 month
followed by FP NS
200µg daily for 7
months (n=83)
• Placebo spray for 2
months followed by
FP NS 200µg bid for 6
months (n=81)

Jorissen DBPCRCT 91 CRS (45% • Postoperative • Symptom score (4 • At 6 months, there was no difference
CRSwNP), mometasone fuorate symptoms and overall between MF and placebo in symptoms
(93)
2009 nasal spray200µg bid discomfort, 0-10 VAS) • At 6 months, endoscopy scores were
postoperative
for 6 months (n=46) improvement at reduced in both groups without difference
• Postoperative placebo months 1, 2, 4, 6 • Serious adverse events were rare without
bid for 6 months • Endoscopy score (0-2, difference between MFNS and placebo
(n=45) 8 characteristics) at
days 7, 14 and months
1, 2, 4, 6
• Adverse events

Stjarne DBPCRCT 162 CRSwNP • Postoperative • Time to relapse for • At 24 weeks follow-up, postoperative use
postoperative mometasone fuorate polyp recurrence at 24 of mometasone furoate, 200 µg once daily,
(114)
2009 nasal spray200µg o.d. weeks provided a statistically significant longer
for 8 weeks (n=80) • Adverse events time to relapse with nasal polyps than with
• Postoperative placebo placebo
for 8 weeks (n=82) • The frequency of AEs with mometasone and
placebo was comparable.

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Table 6.1.5.1. Nasal corticosteroids for the treatment of patients with CRS (continued).

Study Methods Participants Interventions Outcomes Results

Vlckova DBPCRCT 109 CRSwNP • FP 400µg b.i.d. using • Proportion of respond- • At 4, 8, 12 weeks, a greater number of
(65% previous a bidirectional exha- ers at 4, 8, 12 weeks responders was significant for FP compared
2009(72) lation delivery device • Polyp score (0-3) reduc- to placebo.
sinus surgery)
for 12 weeks (n=54) tion at 4, 8, 12 weeks • At 4, 8, 12 weeks, a significantly greater
Djupesland • Placebo b.i.d. for 12 • Adverse events reduction in polyp score was observed for
weeks (n=55) FP
2010(71) • No serious adverse events reported.
Epistaxis occurred in 11% subjects treated
with FP and none in the placebo group.
Morning plasma cortisol concentrations
were unchanged.

Stjarne DBPCRCT 274 CRSwNP, • MFNS 200µg o.d. for • Symptom score (0-3, 4 • At 4 months, both o.d. and b.i.d. doses of MF
sinus surgery 16 weeks (n=94) symptoms) improve- significantly improved in nasal obstruction
2006a(104) • MFNS 200µg b.i.d. for ment at months 1, 2, score and anterior rhinorrhoea compared
status not
16 weeks (n=93) 3, 4 to placebo. At 4 weeks, only the b.i.d. dose
mentioned
• Placebo for 16 weeks • Polyp score (0-3) reduc- significantly improved postnasal drip.
(n=87) tion at months 1, 2, 3, 4 • At 4 months, MF significantly produced
• Adverse events greater reductions in bilateral polyp grade
than placebo
• Most adverse events were mild or moderate
in severity without difference among 3
groups.

Stjarne DBPCRCT 298 CRSwNP • MFNS 200µg o.d. for • Proportion of respond- • At 16 weeks, a greater proportion of
(26% previous 16 weeks (n=153) ers at 16 weeks the MFNS-treated group than the
(80)
2006b • Placebo for 16 weeks • Symptom score (0-3, 3 placebo group experienced a significant
sinus surgery)
(n=145) symptoms) improve- improvement in 3 symptoms of nasal
ment at 12, 16 weeks obstruction, rhinorrhoea and sense of smell
• Polyp score (0-3) reduc- • At 16 weeks, polyp size reduction
tion at 12, 16 weeks significantly favoured MFNS.
• Quality of life (4 items,
• At 16 weeks, MFNS significantly improved
quality of life in nose breathing, daily
1-3 for 2 items and 0-3
activities, sleep disturbance. It was not
for 2 items) at 12, 16 significant for taste and smell.
weeks • Most adverse events were mild or moderate
• Adverse events in severity without difference between
groups.

Aukema DBPCRCT 54 CRSwNP, • FPND 400µg/day for • Proportion of respond- • At 12 weeks, the number of responders who
(83% previous 12 weeks (n=27) ers at 12 weeks did not require surgery was significantly
(110)
2005 • Placebo nasal drops • Symptom score (VAS greater with FPNS versus placebo
sinus surgery )
for 12 weeks (n=27) 0-10) at 2, 6, 12 weeks • Nasal blockage scores were significantly
• Polyp volume estimat- lower with FPNS at 6, 12 weeks
ed by endoscopy using • Polyp volume was significantly reduced in
VAS at 2, 6, 12 weeks the FPNS group at 12 weeks

Rowe- DBPCRCT 109 CRS (71% • Postoperative FPNS • Symptom score (VAS, 6 • At 5 years, ‘How do you feel overall’ VAS
CRSwNP), 200µg b.i.d. for 6 symptoms) improve- favoured FPNS significantly but total VAS
Jones weeks (n=55) ment at week 6 and was not different.
postoperative
2005(92) • Postoperative placebo year 1, 2, 3, 4, 5 • At 1 year, improvement in polyp score was
spray for 6 weeks • Polyp score (0-2) reduc- significantly better by FPNS but it was not
(n=54) tion at week 6 and year different at 5 years
1, 2, 3, 4, 5 • There was no difference in endoscopy
oedema and discharge score at 1 and 5
• LK endoscopy score at
years.
week 6 and year 1, 2,
3, 4, 5

Small DBPCRCT 354 CRSwNP, • MFNS 200µg o.d. for • Symptom score (0-3, 4 • At months 1, 2, 3, 4, MF significantly
sinus surgery 16 weeks (n=115) symptoms) improve- improved nasal obstruction, loss of smell,
2005(103) • MFNS 200µg b.i.d. for ment at day 8 and anterior rhinorrhoea, and postnasal drip
status not
16 weeks (n=122) months 1, 2, 3, 4 • At 4 months, improvement in polyp grade
mentioned
• Placebo for 16 weeks • Polyp score (0-3) was significantly better by MF
(n=117) reduction at day 8 and • Most adverse events were mild or moderate
months 1, 2, 3, 4 in severity without difference among 3
groups. 24-hour urinary free cortisol was not
• Adverse events
different between groups

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Table 6.1.5.1. Nasal corticosteroids for the treatment of patients with CRS (continued).
Study Methods Participants Interventions Outcomes Results

Dijkstra DBPCRCT 162 CRS (42% • Postoperative FPNS • Number of patients • No difference in percentage of recurrence of
CRSwNP) 400µg b.i.d. for 1 year with recurrence of at disease between the groups
(111)
2004 (n=53) 1 year • The incidence of epistaxis was similar
postoperative
• Postoperative FPNS • Adverse events between FP ANS and placebo
800µg b.i.d. for 1 year
(n=53)
• Postoperative placebo
b.i.d. for 1 year (n=56)

Lund DBPCRCT 167 CRSsNP, • Budesonide nasal • Proportion of respond- • At 20 weeks, greater number of responders
without sinus spray 128µg b.i.d. for ers at 20 weeks significantly favoured Budesonide over
(112)
2004 20 weeks (n=81) • Disease specific quality placebo
surgery
• Placebo for 20 weeks of life (CSS) at 20 weeks • At 20 weeks, CSS was not different between
(n=86) • Symptom score (0-3, 4 groups
symptoms) improve- • At 20 weeks, BUD significantly improved
ment at 20 weeks combined symptom score compared to
placebo.
• Adverse events
• There were no serious adverse events
reported. Minor effects were not different
between groups.

Gulati DBPCRCT 63 CRSwNP, • Postoperative • Proportion of respond- • At 12 weeks, greater responder of symptom
postoperative Budesonide nasal ers at 12 weeks improvement in the Budesonide group
(859)
2001 sprays 400µg/day for • Symptom improve- than placebo group was significant for
12 weeks (n=38) ment (4 symptoms) at rhinorrhoea and sneezing.
• Postoperative saline 12 weeks • At 12 weeks, Budesonide treated patients
nasal sprays for 12 • Polyp recurrence at 12 had significantly lower rate of polyp
weeks (n=25) weeks recurrence.

Jankowski DBPCRCT 183 CRSwNP, • Budesonide nasal • Symptom score (0-4, 4 • Combined symptom scores improved
(98) all previous spray 128µg daily for 8 symptoms) improve- significantly in all Budesonide-treated
2001
sinus surgery weeks (n=48) ment at 4, 8 weeks groups at 4, 8 weeks.
• Budesonide nasal • Polyp score (0-3) reduc- • Budesonide nasal spray (all regimens)
spray 128µg bid for 8 tion at 4, 8 weeks significantly reduced polyp size at 4, 8
weeks (n=48) • Adverse events weeks.
• Budesonide nasal • Budesonide nasal spray was well
tolerated. The adverse events reported
spray 256µg daily for 8
more frequently with Budesonide nasal
weeks (n=42)
spray treatment were blood-tinged nasal
• Placebo spray for 8 secretions.
weeks (n=45)

Parikh DBPCRCT 22 CRS • FPNS 200µg b.i.d. for 8 • Symptom score (VAS, 9 • There was no difference between FP and
(18%CRSwNP), weeks (n=9) symptoms) improve- placebo in symptoms and endoscopy score.
2001(91)
>50% • Placebo for 8 weeks ment at 8 weeks
previous sinus (n=13) • LK endoscopy score at
surgery 8 weeks

Filiaci DBPCRCT 157 CRSwNP, • Budesonide turbuhal- • Proportion of respond- • At 8 weeks, substantial control of symptoms
41% previous er 140µg b.i.d. for 8 ers at 8 weeks was significantly superior in patients
2000(96)
sinus surgery weeks (n=39) • Symptom score (3 receiving Budesonide (70%) than placebo
• Budesonide turbu- symptoms, each score (45%)
haler 280µg o.d. for 8 0-3) improvement at 8 • At 8 weeks, the mean reduction in total
weeks (n=40) weeks polyp score was significantly greater in the
• Budesonide turbu- • Polyp score (0-40) group receiving Budesonide, 140 µg twice
daily, than in the placebo group
haler 140µg o.d. for 8 reduction at 8 weeks
• Budesonide was well tolerated, and the
weeks (n=41) • Adverse events proportion of patients reporting adverse
• Placebo for 8 weeks events were similar in the four treatment
(n=37) groups.

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Table 6.1.5.1. Nasal corticosteroids for the treatment of patients with CRS (continued).
Study Methods Participants Interventions Outcomes Results
Keith DBPCRCT 104 CRSwNP, • FPNS 400µg daily for • Proportion of respond- • At 12 weeks, number of responders
(100) 69% previous 12 weeks (n=52) ers at 12 weeks significantly favoured FP nasal spray over
2000
sinus surgery • Placebo for 12 weeks • Symptom score (0-3, placebo in reduction of nasal blockage
(n=52) nasal blockage, overall • At 12 weeks, symptom score reduction
rhinitis, smell) improve- significantly favoured FP nasal spray in nasal
ment at 4, 8, 12 weeks blockage and overall rhinitis but smelling
• Polyp score (0-3) reduc- score was not significant
tion at 12 weeks
• At 12 weeks, number of responders was
not statistically significant in polyp size
• Adverse events reduction
• No serious adverse events. More patients
reported epistaxis in the FPNS group
(19%) than in the placebo group (4%). No
individual’s serum cortisol level fell below
the lower threshold limit.
Pentilla DBPCRCT 142 CRSwNP, • FPNS 400µg o.d. for 12 • Proportion of respond- • At 12 weeks, greater number of responders
71% previous weeks (n=48) ers at 12 weeks significantly favoured FPNS over placebo
(102)
2000 sinus surgery • FPNS 400µg b.i.d. for • Symptom score • At 12 weeks, nasal blockage showed
12 weeks (n=47) (0-3, nasal blockage significant improvements with both doses
• Placebo for 12 weeks and overall rhinitis) of FP nasal spray over placebo, but overall
(n=47) improvement at weeks rhinitis showed significant improvement
4, 8, 12 only for FPNS 400 µg o.d.
• Polyp score (0-3) reduc- • At 4, 8, 12 weeks, polyp size was reduced
significantly by FP nasal spray 400 mg b.i.d.
tion at weeks 4, 8, 12
as compared with placebo
• Adverse events • There were no serious adverse events. There
was no difference in side effects between
groups.

Holmstrom DBPCRCT 100 CRSwNP • FPNS 400µg/day for • Proportion of respond- • At 26 weeks, a greater number of
without sinus 12 weeks (n=49) ers at 12 weeks responders in polyp score reduction was
1999(97)
surgery • Placebo spray for 12 • Polyp score (0-3) reduc- found with FP versus placebo
weeks (n=51) tion at 26 weeks • No serious adverse events reported
• Adverse events
Lund DBPCRCT 29 CRSwNP, • FPNS 200µg b.i.d. for • Symptom score (0-4, 4 • At 12 weeks, the overall symptom score
66% previous 12 weeks (n=10) symptoms) improve- was lower for both treatment groups, it
1998(79) did not reach statistical significance when
sinus surgery • Beclomethasone ment at 12 weeks
dipropionate 200µg • Polyp score (0-3) reduc- compared with placebo
b.i.d. for 12 weeks tion at 12 weeks • At 12 weeks, the polyp score reduction was
(n=10) • Adverse events significant in the FP ANS-treated group
• Placebo for 12 weeks but not significant in the beclomethasone
group
(n=9)
• No serious adverse events. No drug related
adverse events.

Tos 1998(69) DBPCRCT 138 CRSwNP, • Budesonide aqua • Proportion of respond- • The proportion of responders after 6 weeks
all previous spray 128µg b.i.d. for 6 ers at 6 weeks treatment was not significantly different
sinus surgery weeks (n=46) • Symptom score (0-3, 3 between the Aqua and Turbuhaler-treated
• Budesonide turbuhal- symptoms) improve- groups
er 200µg b.i.d. for 6 ment at 6 weeks • At 6 weeks, Budesonide aqua spray showed
weeks (n=45) • Polyp score (0-3) reduc- a significantly superior efficacy over
• Placebo aqua spray for tion at 6 weeks turbuhaler for blocked nose, runny nose and
sneezing
6 weeks (n=24) • Adverse events
• At 6 weeks, there was no statistical
• Placebo turbuhaler for difference between aqua and turbuhaler in
6 weeks (n=23) polyp size reduction
• No serious adverse events
Holmberg DBPCRCT 55 CRSwNP, all • FPNS 400µg/day for • Proportion of respond- • At 26 weeks, greater responder of symptom
previous sinus 26 weeks (n=15) ers at 26 weeks improvement in the corticosteroids group
1997(109)
surgery • Beclomethasone • Symptom improve- than in the placebo group, but it was
dipropionate aqueous ment (0-3, 5 symptoms) significant only for beclomethasone
nasal spray for 26 at 4, 8, 26, 38 weeks • At 26 weeks, symptom score improvement
weeks (n=16) • Polyp score (0-4) was significantly greater than placebo only
• Placebo nasal spray for reduction at 4, 8, 26, 28 for beclomethasone
26 weeks (n=11) weeks
• Reduction in polyp size at 26 weeks
was only statistically significant for
• Adverse events beclomethasone
• A drug related adverse event was
epistaxis. No serious adverse events were
experienced.

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Table 6.1.5.1. Nasal corticosteroids for the treatment of patients with CRS (continued).
Study Methods Participants Interventions Outcomes Results
Lildholdt DBPCRCT 126 CRSwNP, • Budesonide turbuhal- • Proportion of respond- • At 4 weeks, greater number of responders
(101) sinus surgery er 200µg b.i.d. for 4 ers at 4 weeks significantly favoured Budesonide over
1995
status not weeks • Symptom score (0-3, 3 placebo
mentioned • Budesonide turbuhal- symptoms) improve- • At 4 weeks, significant improvement of
er 400µg b.i.d. for 4 ment at 4 weeks symptom score and polyp score in BUD
weeks • Polyp score (0-3) reduc- group
• Placebo for 4 weeks tion at 4 weeks • No serious adverse events reported.
• Adverse events
Johansen DBPCRCT 86 CRSwNP, • Budesonide nasal • Symptom score (0-3, 3 • After 4 weeks, both BUD spray and aerosol
(70) sinus surgery spray 100µg bid for 3 symptoms) improve- were significantly effective in patients with
1993
status not months ment weekly up to 12 small and medium sized polyp symptoms
mentioned • Budesonide aerosol weeks • At 4, 8, 12 weeks, BUD reduced polyp size
100µg bid for 3 • Polyp score (0-3) reduc- significantly
months tion at 4, 8, 12 weeks • Few side effects were reported without
• Placebo for 3 months • Adverse events difference between groups.

Qvarnberg DBPCRCT 40 CRSsNP, all • Budesonide aerosol • Proportion of respond- • At 12 weeks, the number of responders was
previous sinus 200µg b.i.d. for 12 ers at 12 weeks not different
(868)
1992 surgery weeks (n=20) • Symptom score (0-3, 4 • At 12 weeks, facial pain and facial sensitivity
• Placebo for 12 weeks symptoms) improve- were significantly improved by Budesonide
(n=20) ment at weeks 1, 2, 12 but not nasal blockage, nasal discharge and
postnasal drip.
Ruhno DBPCRCT 36 CRSwNP, • Budesonide spray • Symptom score (0-4, 6 • At 4 weeks, effect on mean symptom score
previous 400µg b.i.d. for 4 symptoms) improve- was not significant. Only improvement in
(113)
1990 sinus surgery weeks (n=18) ment at week 4. blockage significantly favoured BUD
unclear • placebo spray for 4 • Adverse events • No serious adverse events reported.
weeks (n=18)

ACTH, Adrenocorticotropic Hormone ; AE, Adverse Event ; b.i.d., twice daily;BUD, Budesonide ; CSS, Chronic Sinusitus Survey ; CRSsNP, chronic rhinosi-
nusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCRCT, double blind placebo controlled randomised controlled trial;
FPND, Fluticasone Propionate Nasal drops ; FPNS, Fluticasone Propionate Nasal spray ; HPA, Hypothalamic Pituitary Adrenal ; IOP, intraocular pressure;
LK, Lund-Kennedy; LKES, Lund-Kennedy endoscopy scoring ; LM, Lund-Mackay; MFNS, Mometasone fuorate nasal spray; N-ERD, NSAID-exacerbated
respiratory disease ; o.d., once daily; RSOM-31, Rhinosinusitis Outcome Measure-31 ; RSDI, Rhinosinusitis Disability Index; SNOT, Sino-nasal Outcome
Test.

6.1.5.2. Impact of nasal corticosteroids on quality of life significant(84). When general QOL was measured with SF-36,
(QOL) in patients with CRS nasal corticosteroids significantly improved the Mental subscale
There were twelve studies assessing quality of life (QOL)(73-80)(67, but not the Physical subscale at five weeks(77). However, when
81)(82, 83)
. Of the 12 studies, 10 assessed disease-specific quality psychological well-being was measured with General Well
of life(73-75, 78-80)(67, 81)(82, 83) and two studies assessed general Being Schedule, improvement in general QOL was not different
health-related quality of life(76, 77). Disease-specific quality of life between nasal corticosteroids and placebo(76).
questionnaires used were the Sinonasal Outcome Test-22 (SNOT-
22)(73-75)(67, 81)(82, 83), Rhinosinusitis Outcome Measure (RSOM-31)(78) 6.1.5.3. Impact of nasal corticosteroids on symptoms in
(82)
, the Chronic Sinusitis Survey (CSS)(79), Rhinosinusitis Disability patients with CRS
Index (82), and a questionnaire designed by the investigators(80). Eighteen studies evaluating symptoms could be combined
in a meta-analysis (Figures 6.1.5.2-6.1.5.3). The meta-analysis
Nasal corticostereoids have a positive impact on favoured nasal corticosteroids over placebo in the improvement
disease specific and general QOL in patients with in symptoms for both symptom score [SMD -0.63, 95%
CRS confidence interval (CI) -0.89 to -0.37, p<0.01; 12 randomised
controlled trials (RCTs), n = 1690; Figure 6.1.5.2] and the
The studies evaluating the Sinonasal Outcome Test-22 were proportion of responders (RR 0.66, 95% CI 0.59 to 0.73, p<0.01;
combined in a meta-analysis although the treatment time 12 RCTs, n = 1646; Figure 6.1.5.3).
evaluated was quite different (from four weeks(74) to 24 weeks(73).
The meta-analysis favoured nasal corticosteroids over placebo When subgroup analysis by CRS subtype was performed, the
in the improvement of disease specific quality of life (MD magnitude of beneficial effects of nasal corticosteroids in the
--5.46, 95% CI -8.08 to -2.84, p<0.001; 6 RCTs, n = 715; Figure symptoms score improvement was significantly greater (p<0.01)
6.1.5.1). Although statistically significant, the effect size of 5.46 in patients with polyps (SMD -0.93, 95% CI -1.43 to -0.44, p<0.01;
with 95% CI of -8.08 to -2.84 is smaller than the MCID (minimal 6 RCTs, n= 1096), than patients without nasal polyps (SMD -0.30,
clinically important difference) of 8.9 and may ne not clinically 95% CI -0.46 to -0.14, p<0.01; 6 RCTs, n= 594; Figure 6.1.5.4) but

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the proportion of responders was similar (Figure 6.1.5.5). -1.42; 95%CI [-2.70, -0.14] versus SMD -0.39; 95%CI [-0.52, -0.26]),
Patients who had previous sinus surgery had similar change in p=0.12) and the proportion of responders (RR 0.63; 95%CI [0.51,
symptoms score and proportion of responders than patients 0.77] versus RR 0.64; 95%CI [0.55, 0.75]), p=0.84).
without sinus surgery (RR 0.63, 95% CI 0.47 to 0.84, p<0.01; 5
RCTs, n = 298 versus RR 0.67, 95% CI 0.59 to 0.77, p<0.01; 6 RCTs, 6.1.5.5. Delivery methods
n = 1264; Figure 6.1.5.6). Devices affect the beneficial effects of nasal corticosteroids over
placebo in the improvement in symptoms score.
6.1.5.4. Regimes varied across studies One study reported on the delivery via a nebulizer and showed
When the impact of type of corticosteroids on symptoms was the largest effect (SMD -2.79, 95% CI -3.53 to -2.05, p<0.001; 1
assessed, benefits in symptom improvement were found in RCT, n = 57), followed by a study reporting on turbuhaler (SMD
all types without difference. Beneficial effects on symptom -1.06, 95% CI -1.58 to -0.55, p<0.01; 1 RCT, n = 47), bi-directional
scores reduction favoured fluticasone propionate (SMD -0.50; exhalation device (SMD -0.68, 95% CI -0.92 to -0.44, p<0.01; 3
95%CI [-0.76, -0.23]), budesonide (SMD -1.35; 95%CI [-2.60, RCTs, n = 285) and nasal spray (SMD -0.30, 95% CI -0.41 to -0.19,
-0.11]) and mometasone furoate (SMD -0.37; 95%CI [-0.53, p<0.01; 7 RCTs, n = 1281) (Figure 6.1.5.9.). Data from trials using
-0.22]) significantly over placebo without difference among nasal drops could not be pooled. Differences are statistically
corticosteroids type (p=0.24) (Figure 6.1.5.7). significant for both three-subgroup comparison and pair
Corticosteroid dosages varied across studies. In general, nasal comparisons (p<0.01 for all comparisons). However, there was
corticosteroids were administered with dosages not higher no difference between subgroups in proportion of responders.
than doubling rhinitis dosages. Nevertheless, there were studies Four studies compared different delivery methods of nasal
giving higher dosages (e.g. fluticasone propionate >400 µg corticosteroids directly(Table 6.1.5.2). Corticosteroid nasal spray
per day; budesonide >512 µg per day; mometasone furoate was compared to corticosteroid nasal drops(68), corticosteroid
>400 µg per day)(72, 73, 78, 85). When impact of different dosages irrigation(67), corticosteroid aerosol(70) and corticosteroid
of nasal steroids on symptoms in CRS patients compared to turbuhaler(69). Data favoured corticosteroid drops and
placebo was assessed, there was a trend toward greater effects corticosteroid nasal irrigation over corticosteroid spray. Demirel
in the subgroup of studies giving higher dosages (SMD -1.20; and colleagues(68) randomized 34 patients with CRSwNP to
95%CI [-2.06, -0.33]) than regular dosages (SMD -0.35; 95%CI receive fluticasone propionate in the form of aqueous nasal
[-0.50, -0.20]). However, this difference did not reach statistical spray 100μg twice daily, or nasal drop 400μg once or twice
significance (p=0.06) (Figure 6.1.5.8). daily for 12 weeks and they found that corticosteroid drop
brought the greatest effects in decreasing nasal polyp size,
Long term treatment with nasal corticosteroids is and improving symptoms. Harvey and colleagues performed
effective and safe in patients with CRS. a double-blind placebo-controlled randomized trial by giving
post-operative 2mg mometasone delivered by either spray
Duration of treatment varied across studies from four weeks or irrigation to 44 patients with CRS(67). The corticosteroid
to 52 weeks. Of the 42 studies included in this review, there nasal irrigation group showed greater improvement than
were 13 studies giving nasal corticosteroids for less than 12 corticosteroid spray in nasal blockage, drainage, total visual
weeks and there were three studies giving nasal corticosteroids analogue scale, endoscopy score and radiological score at 12
for as long as 52 weeks. As nasal corticosteroids are aimed months.
for controlling chronic inflammatory process of CRS so that, Nasal corticosteroid irrigation is an alternative delivery
in general they are administered for a period of 12 weeks or method which aims to increase the exposure of corticosteroid
greater. Nevertheless, when impact of duration of nasal steroids onto the sinus mucosa. Harvey and colleagues investigated
treatment on symptoms in CRS patients compared to placebo total paranasal sinus distribution in 10 cadaver heads after
was assessed, there was no difference between the duration nasal irrigation and nasal spray with water-soluble iodinated
of treatment of <12 weeks and ≥12 weeks in symptoms (SMD radiopaque contrast medium. Blinded scan assessment showed

Figure 6.1.5.1. Forest plot of the effect of nasal corticosteroids versus placebo on disease specific quality of life (SNOT-22) in patients
with CRS.

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Figure 6.1.5.2. Forest plot of the effect of nasal corticosteroids versus placebo on change in symptom score in patients with CRS
compared to placebo.with CRS.

Figure 6.1.5.3. Forest plot of the effect on the proportion of responders versus placebo of treatment with nasal corticosteroids in
patients with CRS.

significantly greater total sinus distribution by nasal irrigation patients with CRSwNP (82), one trial studied a mixed population
with netipot and squeeze bottle than pressurized spray(86). of CRS with a majority of CRSsNP(81), one trial studied a mixed
When a human study to define the fluid dynamics during nasal population of CRS with a majority of CRSwNP(67)and one trial
irrigation was conducted by the same group, the data revealed studied patients with aspirin exacerbated respiratory disease(83).
the exposure of fluid onto the sinus mucosa with retention All studies used a sinus rinse bottle kit as a device for nasal
of fluid of around 2.5% or 5.8mL for the 240mL irrigations(87). corticosteroid irrigation. However, volumes of corticosteroid
In addition, these two studies also assessed the impact of irrigation varied. Two studies utilized a volume of 60ml on each
endoscopic sinus surgeryon fluid distribution and showed that nostril twice daily(82, 83), while the other two studies used a higher
sinus surgery greatly enhanced the delivery of nasal solutions. volume of 240ml once daily(67, 81). Three trials administered nasal
Apart from the general therapeutic goals of topical corticosteroid irrigation after ESS(67, 82, 83) and one trial used it
management in providing pharmaceutical delivery, without sinus surgery(81 ). Regarding extension of surgery, one
simultaneous mechanical lavage by nasal corticosteroid study explicitly stated it would perform a complete full-house
irrigation enhances the mechanical removal of mucus, ESS(67) while one study stated that basic functional endoscopic
inflammatory products, and bacteria/ biofilm(87). sinus surgery (FESS) was performed(83)and one study did
To assess the effects of nasal corticosteroid irrigation compared not provide information(82). The study of nasal corticosteroid
to control, four RCTs were identified (Table 6.1.5.3).There were irrigation without sinus surgery stated that the majority (77%)
three double-blind (67, 81, 83) and one single-blind randomized of patients were un-operated patients(81 ). Three studies followed
controlled trial(82). Of a total of four RCTs, one trial studied the patients up for more than three months (12 months for two

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Figure 6.1.5.4. Forest plot of the effect of nasal corticosteroids versus placebo on the change in symptom score in subgroups of CRS
patients.patients with CRS.

Figure 6.1.5.5. Forest plot of the effect of nasal corticosteroids versus placebo on the proportion of responders in patients with
subgroups of CRS with (CRSwNP) and without (CRSsNP) nasal polyps compared to placebo.with CRS.

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Figure 6.1.5.6. Forest plot of the effect of nasal corticosteroids versus placebo on the proportion of responders in subgroups of CRS
patients with and without sinus surgery.

Figure 6.1.5.7. Forest plot of the effect of nasal corticosteroids versus placebo on change in symptom score in CRS.

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trials(67, 83) and six months for one trial(82)). One study assessed the the mometasone irrigation group had significantly greater
outcome at four weeks(81). improvement than spray in symptoms improvement and
Three RCTs compared nasal corticosteroid irrigation with endoscopic score reduction.
placebo irrigation. There were heterogeneities across studies When meta-analysis was performed to assess the impact of
regarding patient population, surgical status and the volume corticosteroid irrigation on SNOT improvement at six months,
of corticosteroid irrigation. Tait et al. performed a double blind data were pooled from two RCTs(82, 83). A study by Tait et al.(81)was
RCT giving nasal corticosteroid irrigation without sinus surgery not included because SNOT was assessed at four weeks. A study
to patients with CRS with a majority of CRSsNP. At the short by Harvey et al.(67)was not included because the control group
term of four-week irrigation, disease-specific quality of life and received mometasone nasal spray. Meta-analysis showed no
endoscopy scorewere not different when compared to saline difference between nasal corticosteroid irrigation and placebo
irrigation with placebo(81). in SNOT improvement at six months (SMD -0.17, 95% CI -0.61
Rawal et al. performed a single blind RCT studying patients with to 0.26, p=0.44; 2 RCTs, n = 83). (Figure 6.1.5.10.) It is not clear
CRSwNP. They gave nasal corticosteroid irrigation after ESS. why benefits of corticosteroid irrigation over saline irrigation
Although a total volume of 240ml was rinsed per day, a volume are not shown yet by meta-analysis. Patients with high tissue
of 60ml was used per nostril for each irrigation. At 24 weeks, eosinophilia are the most corticosteroid responsive and should
disease-specific quality of lifewas not different when compared be favourable cases(88). Various factors impact corticosteroid
with control. Rotenberg et al. performed a double blind RCT penetration and influence the effectiveness of corticosteroids.
studying postoperative patients with aspirin exacerbated These factors include patients’ surgical status with a wide access
respiratory disease. Likewise, a volume of 60ml was used per for topical medical therapy and delivery methods using high
nostril for each irrigation and disease-specific quality of life pressure and large volume(89). It is notable that trials reporting
and endoscopic score were not different when compared with no benefit used budesonide irrigation 1000µg per day in a
control at one-year timepoint(82). 240ml bottle with a volume of 60ml after a basic FESS(82, 83) while
One trial compared nasal corticosteroid irrigation with nasal a trial reporting benefits used mometasone irrigation 2000µg
corticosteroid spray. Harvey et al. performed a double blind, per day in a 240ml bottle with a volume of 240ml after a full-
double dummy, placebo-controlled RCT studying patients house FESS(67).
with CRS (77% CRSwNP). They established a neo-sinus cavity
that could be managed with topical medication by creating a 6.1.5.6. Impact of nasal corticosteroids on nasal endoscopy
complete spheno-ethmoidectomy, wide antrostomy with either Endoscopy score was assessed in six studies. Lund-Kennedy
a complete DrafIIa or DrafIII. Nasal corticosteroid irrigation was endoscopy score was assessed in six studies evaluating
administered using a squeeze bottle to deliver a total volume discharge, oedema, crusting, polyp and scars or adhesions(78,
of 240ml. When compared to corticosteroid spray at one year, 90-92)(81, 83)
. Jorissen and colleagues used their own scoring system

Figure 6.1.5.8. Forest plot of the effect of different dosages of nasal corticosteroids versus placebo on symptoms in CRS patients.

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assessing sinus ostia stenosis, polypoid change, synechia, or medial to the middle turbinate) was used in 18 studies(69-73,
remucosalized areas, secretions, inflammation, oedema and 80, 95-106)
. NPS on a 4-point scale (0-3), described by Lund et al.(79)
crusts(93). The standardized mean difference was used for (0=no nasal polyps; 1= nasal polyps within the middle meatus;
data analysis. When data were pooled for endoscopy score 2= nasal polyps outside the middle meatus; 3= completely
assessment, nasal corticosteroids were effective in decreasing obstructive nasal polyps) was used in 3 studies(79, 85, 107). NPS on a
endoscopy scores over placebo (SMD -0.49, 95% CI -0.73 to 5-point scale (0-4), described by Meltzer et al.(108). (0= no visible
-0.25, p<0.01; 6 RCTs, n = 286; Figure 6.1.5.11). nasal polyps; 1= small amount of polypoid disease confined
Nasal polyp size reduction was assessed in 25 studies. NPS on within the middle meatus; 2= multiple nasal polyps occupying
a 3-point scale (0-2) per side (0-4 for both sides), taken from the middle meatus; 3= nasal polyps extending beyond the
endoscopic score described by Lund and Mackay(94) was used in middle meatus, within the sphenoethmoid recess but not totally
one study Rowe-Jones 2005(92). NPS on a 4-point scale (0-3) per obstructing, or both; 4= nasal polyps completely obstructing the
side (0-6 for both sides), described by Johansen et al.(70) (0 = no nasal cavity) was used in one study. Kobayashi 2018(74). NPS on a
polyps; 1 = polyps in the middle meatus, not reaching below the 5-point scale (0-4) (0= No nasal polyps; 1= small nasal polyps not
inferior border of middle turbinate; 2 = nasal polyps reaching requiring polypectomy; 2= medium nasal polyps not requiring
below the inferior border of the middle turbinate, but not the polypectomy; 3= large nasal polyps requiring polypectomy; 4=
lower border of the inferior turbinate; 3 = nasal polyps reaching completely obstructive nasal polyps requiring polypectomy)
lower than the inferior border of the inferior turbinate and/ was used in one study. Holmberg 1997 (109). Visual analogue scale

Table 6.1.5.2. Comparison of different delivery methods of nasal corticosteroids for the treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results
Harvey DBPCRCT 44 CRS (77% • Mometasone spray and Quality of life (SNOT-22) • At 1 year, there was no difference in SNOT-
2018(67) CRSwNP), placebo irrigation for 1 at 1 year 22 between the mometasone irrigation and
postoperative year (n=23) Symptom score (VAS total mometasone spray groups
• Mometasone irrigation and 10 symptoms) at 1 • At 1 year, the mometasone irrigation group
and placebo spray for 1 year had significantly greater improvement than the
year (n=21) Endoscopy score (MLKS) mometasone spray group in total VAS, nasal
0-6 for inflammation, 0-2 blockage and nasal drainage
for mucus, 0-2 for pus, • A significantly greater improvement on
assessment of 10 cavities) endoscopy score in the mometasone irrigation
at 1 year group was revealed at 1 year.
Adverse events • There were no medication reactions observed
in either group

Demirel DBRCT 34 CRSwNP, • FPNS 100μg nasal spray Symptom score (0-3, 4 • At 12 weeks, FPNS showed significantly greater
2008(68) postoperative twice daily for 12 weeks symptoms) improvement efficacy than FPNS in improving rhinitis
(13/34 (n=11) at 12 weeks symptoms, smelling and nasal blockage,
patients had • FPNS 400μg nasal drops Polyp score (0-3) reduc- • At 12 weeks, FPNS showed significantly greater
polypectomy) once daily for 12 weeks tion at 12 weeks efficacy than FP NS in decreasing nasal polyp
(n=10) size and increasing total nasal volume.
• FPNS 400μg nasal drops
twice daily for 12 weeks
(n=13)

Tos DBPCRCT 138 CRSwNP, • Budesonide aqua spray Proportion of responders • The proportion of responders after 6 weeks
1998(69) postoperative 128µg twice daily for 6 at 6 weeks treatment was not significantly different
weeks (n=46) Symptom score (0-3, 3 between the Aqua and Turbuhaler-treated
• Budesonide turbuhaler symptoms) improvement groups
200µg twice daily for 6 at 6 weeks • At 6 weeks, Budesonide aqua spray showed a
weeks (n=45) Polyp score (0-3) reduc- significantly superior efficacy over turbuhaler
• Placebo aqua spray for 6 tion at 6 weeks for blocked nose, runny nose and sneezing
weeks (n=24) Adverse events • At 6 weeks, there was no statistical difference
• Placebo turbuhaler for 6 between aqua and turbuhaler in polyp size
weeks (n=23) reduction
• No serious adverse events
Johansen DBPCRCT 86 CRSwNP, • Budesonide nasal spray Symptom score (0-3, 3 • BUD spray and aerosol were not different
1993(70) sinus surgery 100µg twice daily for 3 symptoms) improvement in symptom improvement and polyp size
status not months weekly up to 12 weeks reduction
mentioned • Budesonide aerosol 100µg Polyp score (0-3) reduc- • Few side effects of BUD spray and aerosol were
twice daily for 3 months tion at 4, 8, 12 weeks reported without difference between groups.
• Placebo for 3 months Adverse events

CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCRCT, double blind placebo controlled randomised controlled trial;
DBRCT, double blind randomised controlled trial; FPNS, Fluticasone Propionate Nasal spray ; MLKS, Modified Lund-Kennedy Score; SNOT, Sino-nasal
Outcome Test; VAS, visual analogue scale.

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Table 6.1.5.3. Nasal corticosteroid irrigation in CRS patients.

Study Methods Participants Interventions Outcomes Results
Harvey DBPCRCT 44 CRS (77% CRSwNP), • Mometasone irrigation • Quality of life (SNOT-22 • SNOT-22 changes at 12 months
2018(67) postoperative 2000µg in 240ml saline (0-110) at 52 weeks) are not different between
(35 analyzed) and placebo spray for 52 • Symptoms (VAS (0-100) at mometasone irrigation and spray
weeks (n=15) 52 weeks) • Total VAS scores at 12 months
• Mometasone spray • Endoscopy score (MLKS significantly favoured
2000µg and placebo (0-100) at 52 weeks) mometasone irrigation over spray
irrigation 240ml for 52 • CT score (LM score (0-24) • Endoscopy scores at 12
weeks (n=20) at 52 weeks) months significantly favoured
• Adverse event mometasone irrigation over spray
• CT scores at 12 months
significantly favoured
mometasone irrigation over spray
• No treatment-related adverse
event was observed.
Tait DBPCRCT 74 CRS (25%CRSwNP), • Budesonide irrigation • Quality of life (SNOT-22 • The SNOT-22 scores at 4 weeks
2018(81) with 28% history 1000µg once daily in 240ml (0-110) at 4 weeks) were not different between 2
of prior ESS (61 bottle for 4 weeks (n=29) • Symptoms (Likert scale of groups
finally analysed) • Saline irrigation with pla- improvement 1-7, scale at • Symptoms at 4 weeks were not
cebo (lactose) for 4 weeks 4 weeks) different
(n=32) • Endoscopy score (LKES • LKES change at 4 weeks was not
(0-20) at 4 weeks) different
• Adverse event • There were no related adverse
events.
Rawal SBPCRCT 50 CRSwNP, with 100% • Budesonide irrigation 500µg • Quality of life (SNOT-22 • SNOT-22, RSOM31, and RSDI
2015(82) postoperative in 240ml bottle. 60ml/nostril (0-110), RSOM-31 (0-155), scores were not different between
(42 finally anal- twice daily for 24 weeks RSDI (0-120) at 2 weeks, 3, 2 arms at all 3 timepoints (2 weeks,
ysed) (n=24) 6 months) 3, 6 months).
• Saline irrigation alone for 24
weeks (n=18)
Rotenberg DBPCRCT • 64 CRSwNP (Samter’s • Budesonide irrigation 60ml/ • Quality of life (SNOT-21 (0- • SNOT-21, LKES, and LM score
2011(83) triad), with 100% nostril 500µg twice daily 105) at 6,12 months) results of both intervention groups
postoperative (basic (total 1000µg) for 52 weeks • Endoscopy score (LKES were not different from placebo
FESS) (60 finally (n=20) (0-12) at 6,12 months) group at both 6 and 12-month
analysed) • Saline irrigation 60ml/nostril • CT score (LM score (0-24) timepoints (significant level was
and budesonide spray 64µg/ at 6,12 months) defined at p< .0167)
nostril twice daily (total • Ocular events (IOP at 6,12 • IOP and ACTH level were not
256µg) for 52 weeks (n=19) months) changed at both 6 and 12-month
• Saline irrigation alone for 52 • HPA axis (ACTH (normal/ timepoints
weeks (n=21) abnormal) at 6,12 months)
ACTH, Adrenocorticotropic Hormone ; CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCRCT, double blind placebo
controlled randomisedcontrolled trial; FESS, functional endoscopic sinus surgery; HPA, Hypothalamic Pituitary Adrenal ; IOP, intraocular pressure;
LKES, Lund-Kennedy endoscopy scoring ; LM, Lund-Mackay; MLKS, Modified Lund-Kennedy Score; SBPCRCT, single blind placebo controlled ran-
domised controlled trial; SNOT, Sino-nasal Outcome Test; VAS, visual analogue scale; RSDI, Rhinosinusitis Disability Index; RSOM-31, Rhinosinusitis
Outcome Measure-31 .

was assessed in one study(110). included in this review (43 articles), adverse events of nasal
Nasal corticosteroids reduced polyp score (SMD -0.87, 95% corticosteroids compared to placebo were assessed in 26
CI -1.17 to -0.57, p<0.01; 2 RCTs, n = 184; Figure 6.1.5.12) and studies(67, 69, 70, 72, 73, 79-81, 83, 85, 90, 93, 95, 96, 98, 100-105, 109, 111-114). All these
brought greater proportion of responder over placebo in polyp studies found that nasal corticosteroids were well tolerated
size reduction (RR 0.45, 95% CI 0.36 to 0.57, p<0.01; 7 RCTs, n = and safe. Drug related major adverse events were not reported.
889; See Figure 6.1.5.13). Minor adverse events (if any) had mild to moderate severity.
In addition, when nasal corticosteroids were administered after Of the 26, 18 studies found that adverse events (including
endoscopic sinus surgery, they prevented polyp recurrence epistaxis) caused by nasal corticosteroids were not different
significantly better than placebo (RR 0.73, 95% CI 0.56 to 0.94, from placebo(69, 70, 79, 80, 85, 90, 93, 95, 96, 101-105, 111-114). Five studies reported
p<0.01; 3 RCTs, n = 256; Figure 6.1.5.14). that a greater number of patients in the nasal corticosteroid
Patients who had previous sinus surgery had significantly group had epistaxis than in the placebo group(72, 73, 98, 100, 109).
greater change of polyp size reduction than placebo (RR 0.31, When data were pooled for meta-analysis, nasal corticosteroids
95% CI 0.20 to 0.49, p<0.01; 3 RCTs, n = 307 versus RR 0.54, 95% resulted in increase in the risk of epistaxis compared to placebo
CI 0.41 to 0.70, p=0.04; 4 RCTs, n = 582; Figure 6.1.5.15). (RR 3.49, 95% CI 2.42 to 5.05; 16 RCTs, n=2021; Figure 6.1.5.16).
Nasal septal ulcer was reported more frequently in the nasal
6.1.5.7.Adverse events of nasal corticosteroids corticosteroid group in one study(72, 73). The hypothalamic–
Of the 42 double-blind randomized controlled studies pituitary–adrenal axis suppression assessed in four studies

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Figure 6.1.5.9. Forest plot of the effect of different delivery methods of nasal corticosteroids versus placebo on symptoms scores in
CRS patients.

Figure 6.1.5.10. SNOT score at six months after steroid irrigation versus saline irrgation in CRS compared to placebo.CRS patients.

Figure 6.1.5.11. Forest plot of the effect of nasal corticosteroid versus placebo on nasal endoscopy score in patients with CRS.

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Figure 6.1.5.12. Forest plot of the effect of nasal corticosteroid versus placebo on nasal polyp score in patients with CRSwNP.

Figure 6.1.5.13. Forest plot of the effect of nasal corticosteroid versus placebo on the proportion of responders in nasal polyp score
reduction.

Figure 6.1.5.14. Forest plot of the effect of nasal corticosteroid versus placebo on the prevention of nasal polyp recurrence after sinus
surgery in CRSwNP patients

found that serum cortisol(72, 85, 100) and 24-hour urinary free improvement, although the effect on SNOT-22 is smaller the
cortisol(103) were unchanged with no difference from the minimal clinically important difference. The effect size on
placebo group. No patients in both groups had clinical adrenal symptomatology is larger in CRSwNP (SMD -0.93, 95% CI -1.43
insufficiency. Nasal steroids did not increase intraocular pressure to -0.44) than in CRSsNP (SMD -0.30, 95% CI -0.46). The meta-
and did not cause cataract(73). This is concordance with a analysis did not show differences between different kinds of
systematic review that also concluded that nasal corticosteroids nasal corticosteroids. Although in meta-analysis higher dosages
do not affect intraocular pressure or lens opacity: a systematic and some different delivery methods seem to have a larger
review of controlled trials(115). There was no difference between effect size on symptomatology direct comparisons are mostly
nasal steroids and placebo in asthma exacerbation(95), and acute missing. For chronic rhinosinusitis with nasal polyposis, nasal
bacterial rhinosinusitis(95, 116). although one study did describe corticosteroids reduce nasal polyp size. When administered
more infections(117). after endoscopic sinus surgery, nasal corticosteroids prevent
polyp recurrence. Nasal corticosteroids are well tolerated.
6.1.5.7.Conclusion Most adverse events reported are mild to moderate in severity.
There is high-quality evidence that long term use of nasal Nasal corticosteroids do not affect intraocular pressure or lens
corticosteroids is effective and safe for treating patients with opacity. The EPOS2020 steering committee advises to use nasal
CRS. They have impact on nasal symptoms and quality of life corticosteroids in patients with CRS. Based on the low to very

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Figure 6.1.5.15. Forest plot of the effect of nasal corticosteroid versus placebo on the proportion of patients with nasal polyp score
reduction in subgroups of CRS patients with and without sinus surgery.

Figure 6.1.5.16. Forest plot of the effect of nasal corticosteroid versus placebo on the proportion of CRS patients with epistaxis.

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low quality of the evidence for higher dosages or different 6.1.6.2. Corticosteroid-eluting implants in office, summary
delivery methods and the paucity of direct comparisons the of the evidence
steering committee cannot advise in favour of higher dosages In addition to the postoperative studies, two studies evaluated
or certain delivery methods. the effect of placement of a corticosteroid-eluting sinus implant
delivering 1350µg of mometasone furoate (MF) in the ethmoid
6.1.6. Corticosteroid-eluting implants of patients with recurrent polyposis after sinus surgery over
approximately 90 days(118, 119), as well as the follow-up of Han(120).
6.1.6.1. Corticosteroid-eluting implants following Both the treated and the placebo group also used 200µg
endoscopic sinus surgery, summary of the evidence mometasone furoate nasal spray once daily (Table 6.1.6.1.)
Steroid-eluting stents, spacers and dressings can improve local Some of the parameters could be combined for the two studies:
drug delivery immediately following endoscopic sinus surgery the change from baseline to day 90 in nasal obstruction/
or be placed in office in postoperative patients. The placement congestion score (0-3), evaluated for seven days before clinic
immediately after surgery will be discussed in chapter 6.2.7.4. visits, showed MD 0.28 (95% CI 0.09, 0.48); 366 participants; two

Figure 6.1.6.1. Forest plot of the effect of corticosteroid-eluting implants versus placebo on the change from baseline to day 90 in
nasal obstruction/congestion score in patients with CRS.

Figure 6.1.6.2. Forest plot of the effect of corticosteroid-eluting implants versus placebo on the change from baseline to day 90 in
bilateral Nasal Polyp Score (NPS) in patients with CRS.

Figure 6.1.6.3. Forest plot of the effect of corticosteroid-eluting implants versus placebo on the reduction of indicated sinus surgery
at day 90 (%).

Figure 6.1.7.1. Forest plot of the effect of short course of systemic corticosteroid therapy versus placebo on total symptom score 2-3
weeks after start of the therapy in CRS patients.at day 90 (%).

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Table 6.1.6.1. Corticosteroid-eluting implants for the in the office treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results

Kern DBRPCT 301 CRSwNP • Bioabsorbable drug-eluting • Change from baseline to day 30 and day 90 in • All outcomes
patients stent releasing 1350μg of nasal obstruction/congestion score (0-3) significant better in
2018(118)
mometasone furoate over • Change from baseline to day 90 in bilateral the mometasone
approximately 90 days for 60 polyp grade (0-8), as determined by indepen- furoate stent group
days and 200µg mometasone dent, blinded panel than the placebo stent
furoate nasal spray once daily • Patients indicated for sinus surgery at day 90 group but facial pain.
(n=201) (%)
• Bioabsorbable drug-eluting • Change from baseline to day 90 of ethmoid • No difference in
placebo stent and1350µg sinus obstruction (0-100) by independent, adverse events.
mometasone furoate nasal blinded panel
spray once daily (n=100) • Change from baseline to day 90 in sense of
smell (0-5) and facial pain (0-5)
• Adverse events

Forwith DBRPCT 100 CRSwNP • Bioabsorbable drug-eluting • Change from baseline to day obstruction/ At 6 months, treated
patients stents releasing 370μg of congestion score (0-3) (subset of patients) at patients compared to
2016(120)
(Follow- mometasone furoate over 6 months placebo patients had:
approximately 30 days (n=53) • Change from baseline in bilateral polyp grade
up of Han • Placebo stents (n=47) (0-4) at 6 months • Significant reduction
• Patients indicated for sinus surgery at 6 in ethmoid snus
2014(119)) obstruction (p < 0.001)
months (%)
• Change from baseline of ethmoid sinus and bilateral polyp
obstruction (0-100) at 6 months grade (p = 0.018)
• Adverse events • Significantly smaller
change of sinus
surgery

Han DBRPCT 100 CRSwNP • Bioabsorbable drug-eluting • Change from baseline to day obstruction/ • Significant reduc-
(119) patients stents releasing 1350μg of congestion score (0-3) (subset of patients) at tion in obstruction/
2014
mometasone furoate over day 7, 14, 30,45,60, and 90 congestion (day
approximately 90 days for 60 • Change from baseline in bilateral polyp grade 30 and 90), polyps
days and 200µg mometasone (0-4) at day 7, 14, 30,45,60, and 90 grade, ethmoid sinus
furoate nasal spray once daily • Patients indicated for sinus surgery an inter- obstruction
(n=53) vention at day 90 (%) • No significant
• Bioabsorbable drug-eluting • Change from baseline of ethmoid sinus ob- differences in adverse
placebo stent and 1350µg struction (0-100) at day 7, 14, 30,45,60 and 90 events or ocular safety
mometasone furoate nasal • Adverse events
spray once daily (n=47) • Ocular safety

CRSwNP, chronic rhinosinusitis with nasal polyps; DBRPCT, double blind randomised placebo controlled trial.

studies (I2 = 43%), lower = better, indicating less symptoms of treated with corticosteroid-eluting sinus implant compared with
nasal obstruction/congestion in the patients that were treated the placebo. No differences in facial pain scores were found.
with corticosteroid-eluting sinus implant than the placebo
(Figure 6.1.6.1). 6.1.6.3. Safety of corticosteroid-eluting implants
The change from baseline to day 90 in bilateral polyp grade (0- Most of the safety studies have been performed directly after
8/0-4), showed an SMD 0.40 (95% CI 0.19, 0.61); 392 participants; surgery and the full safety data are discussed in chapter 6.2.7.3.
two studies; I2 = 0%), lower = better, indicating less disease in None of the studies showed impact on ocular safety(119, 121,
the patients that were treated with corticosteroid-eluting sinus 122)
. Local (drug related) adverse events were limited and not
implant than the placebo (Figure 6.1.6.2). reported more often in the local corticosteroid group than the
placebo group.
The patients indicated for sinus surgery at day 90 (%) showed an
OR of 0.37 (95% CI 0.23, 0.61); 398 participants; two studies (I2 6.1.6.4. Conclusion
= 0%), indicating less likelihood that the patients treated with The placement of corticosteroid-eluting sinus implants in the
corticosteroid-eluting sinus implant than the placebo would ethmoid of patients with recurrent polyposis after sinus surgery
need sinus surgery (Figure 6.1.6.3). has a significant but small (0.3 on a 0-3 scale) impact on nasal
obstruction but is significantly reduced the need for surgery
In one study(118) sense of smell (scale 0-5) and facial pain (scale [odds ratio (OR) 0.34] and reduced nasal polyp score. Based on
0-5) were also evaluated. There was a significant improvement the moderate to high quality of the evidence the steering group
in smell MD - 0.46 (95% CI -0.85;-0.06) in the patients that were considered the use of corticosteroid-eluting sinus implants

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in the ethmoid an option. Larger studies including long term systemic corticosteroids using a DBPCRT design are included.
safety data are needed. Different forms of systemic corticosteroids were used (Table
6.1.7.1. for comparison of corticosteroids) although most
6.1.7. Short courses of systemic corticosteroids studies used prednis(ol)one. In seven DBPCRCTs a short course
of systemic corticosteroids, sometimes combined with local
A short course of systemic corticosteroid, with or corticosteroids, was compared to placebo (4, 123-128)(Table 6.1.7.2.).
without local corticosteroid treatment results in a All studies were done in patients with CRSwNP. We are not aware
significant reduction in total symptom score and of any RCTs with systemic corticosteroids in CRSsNP. Five studies
nasal polyp score in patients with CRSwNP. evaluated the effect of oral (methyl)prednis(ol)one in dosages
ranging from 25-60 mg for 7-20 days(4, 124, 126-128). Three studies
6.1.7.1. Summary of the evidence only used the systemic corticosteroids(4, 124, 128) and two studies
Short courses of systemic corticosteroids (7-21 days), usually used a form of local corticosteroids after the systemic course(126,
combined with local corticosteroids, are a widely used 127)
. All five studies measured some form of symptom score
treatment for chronic rhinosinusitis with nasal polyps. Systemic 2-4 weeks after the start of the treatment (for Hissaria we took
corticosteroids reduce the inflammatory response and may the nasal domain of the Rhinosinusitis Outcome Measure-31
reduce the size of nasal polyps. Interestingly especially (RSOM-31)) and the meta-analysis showed a significant effect
inflammation of the olfactory mucosa is reduced often resulting on total symptom score (SMD -1.51 (95% CI -1.08, -1.57); 266
in a rapid improvement in olfaction (days) without visual change participants; four studies; I2 = 0%)(p<0.00001) (Figure 6.1.7.1).
in polyp volume. However, at 10-12 weeks after the start of the treatment the
In this analysis, only studies comparing a short course of difference was no longer significant SMD –0.13 (95% CI -0.41,

Figure 6.1.7.2. Forest plot of the effect of short course of systemic corticosteroid therapy versus placebo on total symptom score 10-
12 weeks after start of the therapy in CRS patients.

Figure 6.1.7.3. Forest plot of the effect of short course of systemic corticosteroid therapy versus placebo on polyp score 2-3 weeks
after start of the therapy in CRS patients.

Figure 6.1.7.4. Forest plot of the effect of short course of systemic corticosteroid therapy versus placebo on polyp score 10-12 weeks
after start of the therapy in CRS patients.

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Figure 6.1.7.5. Forest plot of the effect on SNOT-22 of postoperative short course of systemic corticosteroid therapy versus placebo
2-3 months after surgery in CRS patients.

Table 6.1.7.1. Short courses of systemic corticosteroids for the treatment of patients with CRSwNP.

Author Methods Participants Interventions Outcomes Results

Shen DBPCT, 100 patients with • Oral prednisolone • Symptoms head fullness, smell, • No differences in symptoms and
2019(123) postoperative bilateral CRSwNP 15mg twice a day for 2 cough, nasal obstruction, head- SNOT-22 at 1, 3 and 6 months
postoperatively weeks combined with a ache, foul odor, facial pressure, • LKES: trend (0,05) at 6 months
(82 included) nasal spray of 100μg of post nasal drip, and rhinorrhoea for whole group, significantly
stratified by mometasone furoate once (VAS) lower in prednisolone group for
stratification daily (n=35) • SNOT-22 at 1, 3 and 6 months the high eosinophils group at 3
by tissue • Placebo twice a day for postoperatively months and trend at 6 months
eosinophils 2 weeks combined with • LKESs 2 weeks and 2, 3 and 6 (no correction for multi-testing)
(> 10 tissue a nasal spray of 100μg of months postoperatively.
eosinophils/HPF) mometasone furoate once • Safety and side effects assess-
daily (n=47) ment

Ecevit DBPCT 23 patients with • Prednisolone 60 mg (60 • Symptoms (VAS) at day 15-17 • Significantly more improvement
2015(124) bilateral CRSwNP tablets) for 7 days, then • Sense of smell (CCCRC) butanol in the corticosteroid group
reduced to 10mg taken olfactory threshold test) day compared to placebo in disease
every other day, stopping 15-17 severity, smell, and PNIF
on day 17 (n=11) • Nasal polys score (0-6) • No differences in adverse events
• Placebo (6 tablets) for 7 PNIF day 15-17
days, then reduced to 1 • Adverse events
tablet every other day,
stopping on day 17 (n=12)

Dautremont DBPCT 36 CRSwNP • Prednisone 30 mg daily for • Endoscopy (LK score) at 1 week, • No significant differences
2014(125) patients 7 days and 1 dissolvable 3 weeks, and 2 months postop- in mean endoscopic scores
postoperatively spacer soaked with 2ml eratively. or SNOT-22 ant any of the
triamcinolone (40mg/ • SNOT-22 at 1 week, 3 weeks, and timepoints.
ml) and high-volume 2 months postoperatively.
budesonide irrigation
once daily (1mg in 240 ml
of saline (n=18)
• Placebo daily for 7 days
and 1 dissolvable spacer
soaked with 2ml triam-
cinolone (40mg/ml) and
high-volume budesonide
irrigation once daily (1mg
in 240 ml of saline (n=18)

Kirtsreesakul DBPCT 3:2 117 CRSwNP • Oral prednisolone 50 mg • Disease severity (added symp- The prednisolone treated group
2012(126) randomization (114 included) daily for 14 days followed tom score (0-7) for blocked showed compared to placebo:
by mometasone furoate nose, runny nose, sneezing, na- • Significantly greater improve-
nasal spray (MFNS) at 200 sal itching, hyposmia, postnasal ments in all nasal symptoms,
micrograms twice daily for drip, cough and sinonasal pain nasal airflow, and polyp size at
10 weeks (n=67) at 2, 7 and 12 weeks 2 weeks
• Placebo for 14 days • Nasal polyp score (0-6) • Significantly greater improve-
followed by MFNS at 200 • PEFR ments in most symptoms, nasal
micrograms twice daily for • Adverse events airflow, and polyp size at 7 weeks
10 weeks (n=47) • Significantly greater improve-
ments in smell, nasal airflow, and
polyp size at 12 weeks

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Table 6.1.7.1. Short courses of systemic corticosteroids for the treatment of patients with CRSwNP (continued).
Author Methods Participants Interventions Outcomes Results
Vaidyanathan DBPCT 60 CRSwNP (51 • Prednisolone tablets, • RQLQ at 2 weeks and 6 months Oral corticosteroid therapy
2011(127) included) 25 mg/day for 2 weeks • total nasal symptoms score at 2 followed by topical steroid therapy
followed by fluticasone weeks and 6 months compared to nasal corticosteroid
propionate nasal drops, • nasal polyps score (0-6) alone resulted in a significant larger
400µg twice daily, for 8 • PNIF reduction in:
weeks then fluticasone • Responders at 28 weeks (im- • % responders at 28 wks
propionate nasal spray, provement more that MID) • RQLQ at 2 wks
200µg twice daily for a • Serum eosinophil-derived • Total nasal symptom score at
further 18 weeks (n=27) neurotoxin 2 wks
• Placebo tables for 2 • High-sensitivity C-reactive • Nasal polyp score at 2 and 10
weeks followed by protein levels wks
fluticasone propionate • Overnight urinary free cortisol • PNIF at 2 wks
nasal drops, 400µg twice and corrected for creatinine
daily, for 8 weeks then • 08:00 am serum cortisol
fluticasone propionate • Low-dose 1µg adrenocortico-
nasal spray, 200µg twice tropic hormone-simulation test
daily for a further 18 • Markers of bone turnover
weeks (n=24)
Van Zele DBPCT 33 CRSwNP • Oral methylprednisolone • Disease severity, measured by Oral corticosteroids compared to
2010(4) (32mg/day on days 1 to patient-assessed symptoms placebo for 20 days resulted in:
5; 16mg/day on days 6 to (anterior rhinorrhoea, nasal • Reduced symptoms for 4 weeks
10; 8mg/day on days 11 obstruction, post-nasal drip • Reduced polyp score and PNIF
to 20) (n=14) and loss of sense of smell) at 20 for 55 days
• Placebo, 20 days (n=19) days and 12 weeks.
• Nasal polyp score (0-8)
• PNIF
• Blood eosinophils
• Serum ECP, soluble IL-5rα
• ECP, IL-5, IgE, MMP9 and MPO in
nasal secretion
• Need for rescue surgery/ nasal
steroids
• Adverse events
Hissaria DBPCT 40 CRSwNP • 50mg of prednisolone • Nasal symptoms Significantly better results of
2006(128) once daily for 14 days • RSOM-31, and nasal domain of systemic corticosteroid compared
(n=20) RSOM-31 at 2 weeks to placebo for:
• Placebo once daily for 14 • Polyp score • Symptoms of stuffy/blocked
days (n=20) • MRI nose, runny nose, sneezing,
• Responders at 2 weeks decreased sensation of smell,
and postnasal drip showed
significant improvement after
treatment with corticosteroids
(p<.05) as opposed to placebo
• RSOM-31 and nasal domain of
RSOM-31

CCCRC, The Conneticut Chemosensory Clinical Research Centre ; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, double blind placebo
controlled trial; ECP, eosinophil cationic protein; IgE, immunoglobulin E; IL-5, interleukin-5; LK, Lund-Kennedy; LKES, Lund-Kennedy Endoscopic
Scores; MFNS, Mometasone furoate nasal spray; MID, Minimal important difference ; MMP9, matrix metalloproteinase 9; MPO, Myeloperoxidase ; MRI,
magnetic resonance imaging; PEFR, Peak Expiratory Flow Rate ; PNIF, peak nasal inspiratory flow; RSOM-31, Rhinosinusitis Outcome Measure-31 ;
RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire ; SNOT, Sino-nasal Outcome Test; VAS, visual analogue scale.

0.15); 200 participants; 3 studies; I2 = 0%), (p=0.38) (Figure 6.1.7.2). Two studies (118 postoperative CRSwNP patients) evaluated the
Four studies could be included in a meta-analysis on nasal postoperative use of systemic corticosteroids(123, 125). Both studies
polyp score at 2-3 weeks after the start of the corticosteroid reported no significant differences in SNOT-22 in the first 2-3
therapy. The meta-analysis showed a significant effect of oral months after surgery (Figure 6.1.7.5) and in Shen et al. even six
corticosteroid treatment over placebo: SMD -1.51 (95% CI -2.12, months after surgery. Shen et al.(123) found a significantly lower
-0.90); 237 participants; four studies; I2 = 70%; p<0.00001) Lund-Kennedy endoscopy score in the prednisone group for
(Figure 6.1.7.3). the high eosinophils group at three months and a trend at six
At 10-12 weeks after the start of the treatment the difference months (no correction for multitesting).
was still significant SMD –0.51 (95% CI -0.80, -0.21); 203
participants; three studies; I2 = 4%), (p=0.0007) (Figure 6.1.7.4). The adverse effects of short courses of systemic corticosteroids

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Table 6.1.7.2. Corticosteroid dose equivalents(869-872)

Equivalent Dose Steroid
1.2mg Betamethasone (long-acting)
1.5mg Dexamethasone (long-acting)
8mg Methylprednisolone (intermediate-acting)
8mg Triamcinolone (intermediate-acting)
10mg Prednisone (intermediate-acting)
10mg Prednisolone (intermediate-acting) [4,5]
40mg Hydrocortisone (short-acting)
50mg Cortisone (short-acting)

can include insomnia, mood changes and gastrointestinal The role of sensitisation in CRSsNP is unclear (see 5.1.2). It is
changes. Short-term courses of systemic corticosteroids are tempting to speculate that allergic inflammation in the nose
generally safe, but there have been reports of associated predisposes the atopic individual to the development of CRS.
avascular necrosis and a few cases of fatal varicella-zoster in However, papers evaluating atopy as a risk factor to CRS are
immunocompetent patients(129). It is not clear from the literature conflicting.
whether the dose or duration of the systemic corticosteroids are Notwithstanding the lack of hard epidemiologic evidence for
important. In the lower airways, evidence is not strong enough a clear causal relationship between allergy and CRS, there is
to reveal whether shorter or lower-dose regimens are generally some indication that failure to address allergy as a contributing
less effective than longer or higher-dose regimens in asthma factor to CRS diminishes the probability of success of a surgical
or indeed that the latter are associated with more adverse intervention(133). In a real life retrospective study among allergy
events(130) although in chronic obstructive pulmonary disease patients undergoing immunotherapy, those who felt most
(COPD) there is data that shorter courses are equally effective(131). helped by immunotherapy were the subjects with a history of
When given over the longer term, or through many repeated recurrent rhinosinusitis, and about half of the patients who had
short courses, it is possible to develop osteoporosis(132). had sinus surgery before believed that the surgery alone was
not sufficient to completely resolve the recurrent episodes of
6.1.7.2. Conclusion infection(133).
A short course of systemic corticosteroid, with or without local In a large German retrospective database, both ENT specialists
corticosteroid treatment results in a significant reduction in total (3.5%) and GPs (2.2%) prescribed low rates of antihistamines in
symptom score and nasal polyp score. Although the effect on patients with CRSsNP and slightly higher rates in CRSwNP (5.4%
the nasal polyp score remains significant up to three months and 3.1%, respectively)(134).
after the start of treatment by that time there is no longer an There are no studies evaluating the effect of antihistamines in
effect on the symptom score. The EPOS2020 steering group patients with CRSsNP(135).
felt that 1-2 courses of systemic corticosteroids per year can be There is one study evaluating the effect of antihistamines in
a useful addition to nasal corticosteroid treatment in patients patients with CRSwNP(135, 136)
with partially or uncontrolled disease. A short course of systemic Haye et al. in a DBPCT randomised 45 patients with CRSwNP (of
corticosteroid postoperatively does not seem to have an effect which 16 were allergic) to receive either 20 mg of cetirizine or
on quality of life. placebo for three months (Table 6.1.8.1). The authors reported
that cetirizine reduced days with a score for nasal sneezing and
6.1.8. Antihistamines (oral and topical) rhinorrhoea lower than one from 70-80% (rhinorrhoea) and 80-
90% (sneezing) in the placebo group to 90-100% in the cetirizine
6.1.8.1. Summary of the evidence treated group(136) at all time points). However, data for patients

Table 6.1.8.1. Antihistamines for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Haye 1998 (136)
DBPCT 45 patients • 20 mg of cetirizine • Total symptom score at 4, 8 and 12 • No difference in total symptom score
with CRSwNP for 3 months (n=23) weeks • Cetirizine significantly reduced days
• Placebo for 3 • Days with a symptom score ≤1 for na- with a score for nasal sneezing and
months (n=22) sal obstruction, rhinorrhoea, sneezing rhinorrhea ≤1 at all time points and
at 4, 8 and 12 weeks nasal obstruction at week 8
• Polyp score at 4, 8 and 12 weeks • No change in polyp score

CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, double blind placebo controlled trial.

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with allergies and those without were not reported separately. studies comparing montelukast to nasal corticosteroids showed
There was no effect of the cetirizine on nasal polyp size(136). similar improvement compared to baseline for both treatments
(Table 6.1.9.1.).
6.1.8.1. Conclusion Two studies have been performed after the publication of the
The quality of the evidence using GRADE comparing Wentzel review(137) both of which were prospective RCTs, adding
antihistamines with placebo was very low. Evidence was oral montelukast to regular treatment. Suri et al.(143) randomized
downgraded because of the small number of studies and 40 consecutive adult CRSwNP patients into two groups. Subjects
because the most important measures of efficacy were not were treated with oral prednisolone for 14 days and budesonide
reported. There is insufficient evidence to decide on the effect nasal spray for eight weeks with or without additional oral
of the regular use of antihistamines in the treatment of patients montelukast. Subjects treated with additional oral montelukast
with CRS. reported a statistically significant improvement in overall
symptom score, sense of smell, and sneezing after eight weeks
6 .1.9. Anti-leukotrienes which remained for the four weeks after stopping the treatment
(Table 6.1.9.2.).
6.1.9.1. Summary of the evidence Van Gerven et al.(144) evaluated the efficacy of montelukast as
Cysteinyl leukotrienes (CysLT) are a class of inflammatory an add-on treatment to intranasal corticosteroids spray (INCS)
mediators synthesized by eosinophils and mast cells through in 72 postoperative CRSwNP patients for one year. They found
the breakdown of arachidonic acid. CysLT are known to play a no significant differences between the two treatment arms in
role in the pathophysiology of rhinitis, asthma and possibly also total symptom score, nasal polyp score and LMK score. They
CRSwNP, promoting bronchoconstriction, mucus production, concluded that the addition of montelukast to INCS should not
oedema and chemotaxis of eosinophils and neutrophils. be recommended in the treatment of postoperative CRSwNP
Overproduction of CysLTs and upregulation of the receptor has patients.
been demonstrated in allergic rhinitis, asthma, and CRS with
nasal polyposis (CRSwNP) (5.1.2). The EPOS2020 steering group does not advise
There are no data on the efficacy of CysLT in CRSsNP adding montelukast to nasal corticosteroid but
There are limited data on the efficacy of CysLT in CRSwNP, mainly studies evaluating the effect of montelukast in
on montelukast. There are no RCTs performed in patients with patients that failed nasal corticosteroids are
CRSwNP with other CysLT inhibitors such as zafirlukast, zileuton missing.
(-lipoxygenase inhibitor) and pranlukast.
Wentzel et al.(137) performed a systematic review in 2013 We performed a meta-analysis of the three studies evaluating
describing two placebo-controlled RCTs of which only one the addition of montelukast to INCS either postoperatively or
was double blind(138, 139) and three non-placebo controlled after systemic corticosteroid treatment for eight weeks. There
RTs(140-142) which included a total of 179 CRSwNP patients. The was no significant additional effect from adding montelukast
study by Mostafa indicates that it was double blind but no to intranasal corticosteroids after either surgery(144) or systemic
explanation of how the blinding was done is given, the other corticosteroids for two weeks(141, 143) (Figure 6.1.9.1.).
two studies were not blinded. The non-placebo controlled Various neuropsychiatric events have been reported as adverse
RCTs compared montelukast to intranasal corticosteroids(140, events of anti-leukotrienes; however, the evidence of the
142)
postoperatively and the combination of montelukast and association is conflicting(145-148).
nasal corticosteroids versus nasal corticosteroids alone after a
course of oral steroids(141). They concluded that both placebo- 6.1.9.2. Conclusion
controlled RTs showed significant improvements in symptoms The quality of the evidence using GRADE comparing
and local inflammatory mediators over the four- to six-week montelukast with placebo was very low. Evidence was
course of treatment compared to placebo. It was not possible downgraded because of the small number of studies and
to combine the two studies in a meta-analysis. The two small patients in the studies and because only one study was double

Figure 6.1.9.1. Forest plot of the effect of the added effect of montelukast on intranasal corticosteroids at 12 weeks in CRSwNP
patients

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 EPOS 2020

Table 6.1.9.1. Montelukast for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Schaper, SBPCT 24 CRSwNP • Montelukast 10 • Nasal symptoms (0-12) • Total symptom score improved from 5.9 to 1.75 in
(139)
crossover patients and mg 1dd for 6 • Nasal endoscopy montelukast group and not in placebo. No direct
2011 asthma (12 weeks (n=24) • Anterior rhinomanometry comparison. No data for placebo
with N-ERD) • Placebo 1dd for 4 • Olfactometry • Significant reduction in oedema, hypersecretion,
weeks (n=24) • Mediators in nasal secretion blockage compared to placebo at nasal endoscopy
and blood • Significant improvement in nasal airflow
• Lung function • Significant reduction in inflammatory mediators
and eosinophils in nasal secretion
• Significant improvement in lung function
Pauli, 2007 (138)
DBPCT 30 CRSwNP • Montelukast 10 • HRQL (health related quality • Significant reduction in most domains of HRQL
patients mg 1dd for 4 of life questionnaire) at 4 • No significant difference in nasal endoscopy score
weeks (n=20) wks or ECP in nasal secretion
• Placebo 1dd for 4 • Nasal endoscopy at 4 wks
weeks (n=10) • ECP in nasal secretion at
4 wks

CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, double-blind placebo-controlled trial; ECP, eosinophil cationic protein; HRQOL, health relat-
ed quality of life; N-ERD, NSAID-exacerbated respiratory disease; SBPCT, single-blind placebo-controlled trial.

Table 6.1.9.2. Montelukast added to intranasal corticosteroids for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Van Gerven RCT 72 CRSwNP • CRSwNP Montelukast 10 mg 1dd together with • T5SS (T5SS) at 3, 6 • No significant difference
postoperative mometasone furoate 200 µg 2 times a day for and 12 months between the treatments for any
2018(144)
1 year (n=36) • Nasal polyp score outcome measured
• CRSwNP mometasone furoate 200 µg 2 times a (NPS) at 3, 6 and
day for 1 year (n=36) 12 months
• LMS at 3, 6 and 12
months
• BAST 24 at 3, 6 and
12 months
Suri RCT 40 CRSwNP • Montelukast 10 mg for 8 weeks+ prednisolone Total symptoms • Significant better effect of
35 mg reducing by 5 mg every second day and nasal blockage, montelukast group for total
2015(143) over 14 days+ budesonide nasal spray 2 me- headache, facial symptoms (8 and 12 wks),
tered doses to each nostril for 8 weeks (n=20) pain, sense of smell, headache (12 wks), sense
• Prednisolone 35 mg reducing by 5 mg every nasal discharge and of smell (8 and 12 wks) and
second day over 14 days+ budesonide nasal sneezing (0-10) at 8 sneezing (8 wks)
spray 2 metered doses to each nostril for 8 and 12 weeks
weeks (n=20)
Stewart RCT 38 CRSwNP • Montelukast 10 mg for 8 weeks+ prednisolone • Total symptoms • Significant better effect of
(35 analysed) 35 mg reducing by 5 mg every second day over and nasal block- montelukast group for facial
2008(141)
14 days+ budesonide nasal spray 2 metered age, headache, pain (8 wks) headache (8 wks),
doses to each nostril for 8 weeks (n=20) facial pain, sense sneezing (8 wks)
• Prednisolone 35 mg reducing by 5 mg every of smell, nasal dis- • No significant difference
second day over 14 days+ budesonide nasal charge, sneezing between the treatments for any
spray 2 metered doses to each nostril for 8 at 8 and 12 weeks outcome measured at 12 wks
weeks (n=20) • SF36 • No significant difference in SF36

BAST-24, Barcelona Smell Test 24 odours; CRSwNP, chronic rhinosinusitis with nasal polyps; LMS, Lund-McKay score; RCT, randomized clinical trial; SF-
36, short form 36; T5SS; Total 5 Symptom Score.

blinded. Based on the available evidence, the EPOS2020 steering evaluating the effect of montelukast in patients that failed nasal
group is unsure about the potential use of montelukast in CRS corticosteroids are missing.
and does not recommend its use unless in situations where
patients do not tolerate nasal corticosteroids. Also, the quality of 6.1.10. Decongestants
the evidence comparing montelukast with nasal corticosteroid
is low. Based on the evidence, the steering group does not 6.1.10. 1. Summary of the evidence
advise adding montelukast to nasal corticosteroid but studies The use of topical decongestants has the theoretical potential

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Table 6.1.10.1. Nasal decongestants for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Kirtsreesakul, DBPCRCT 68 CRSwNP • Oxymetazoline plus MFNS 2 sprays per • Symptoms, • Combination of oxymetazoline
patients nostril twice daily, with an interval of 5 • Nasal patency plus MFNS significantly more
2016(152).
minutes between each medication for • Nasal polyp size effective than MFNS alone on:
4 weeks followed by 2 weeks of MFNS • NMCCT was evaluated at • Symptoms of nasal blockage
only (n=34) 4 and 6 weeks and smell at 4 and 6 wks
• Placebo plus MFNS, 2 sprays per nostril • Adverse events • Nasal patency at 4 wk
twice daily, with an interval of 5 minutes • Nasal polyp size at 4 and 6 wks
between each medication for 4 weeks • NMCCT at 4 and 6 wks
followed by 2 weeks of MFNS only • No signs of rebound swelling
(n=34)
Humphreys, DBPCT 47 CRS • Xylometazoline hydrochloride 0.1% • Symptom scores at day • No differences between the
(155) patients adult nasal spray (n=24) 10 postoperatively groups
2009
postoperative • A physiological sterile saline aerosol
(n=23)

DBPCRCT, double-blind placebo-controlled randomized clinical trial; MFNS, mometasone furoate nasal spray; NMCCT, nasal mucocil-
iary clearance time.

to reduce mucosal oedema by inducing vasoconstriction(149). decongestant, xylometazoline, to a saline spray in 47 patients
However, prolonged use can lead to rhinitis medicamentosa in the FESS early postoperative period(155). Postoperative VAS
and worse symptoms of nasal obstruction upon decongestant symptom scores for nasal obstruction, rhinorrhoea, pain, loss of
discontinuation(150). sense of smell and bleeding assessed at day 10 postoperatively
Nasal decongestion per se does not have effect on nasal polyp did not show any difference between the groups.
size(151).
Two RCTs have been performed evaluating the effect of local 6.1.10.2. Conclusion
decongestants in the treatment of CRS (Table 6.1.10.1). There is one small study in CRSwNP patients showing a
Kirtsreesakul et al. evaluated in a DBPCT the additive effect of significantly better effect of oxymetazoline combined with
oxymetazoline administration on nasal steroid therapy and MFNS than MFNS alone without inducing rebound swelling(152).
whether rebound congestion develops after oxymetazoline This is consistent with effects seen in the treatment of allergic
treatment in 68 CRSwNP patients(152). Patients were randomly rhinitis where the combination of nasal corticosteroid with
assigned in a 1:1 ratio to receive either oxymetazoline plus decongestant also seemed to prevent rebound swelling(153, 154).
mometasone furoate nasal spray (MFNS) or placebo plus There was no effect of xylometazoline compared to saline in
MFNS, two sprays per nostril twice daily, with an interval of the early postoperative period(155). This review found a low level
five minutes between each medication for four weeks. All the of certainty that adding a nasal decongestant to intranasal
patients were then treated with MFNS, two sprays per nostril corticosteroids improves symptomatology in CRS. Although
twice daily for two weeks. At four weeks after beginning the the risk of rebound swelling was not shown in this study, the
treatment, the oxymetazoline-MFNS group showed significantly EPOS2020 steering group suggests in general not to use nasal
greater improvement in blocked nose, hyposmia, peak nasal decongestants in CRS. In situations where the nose is very
inspiratory flow (PNIF), nasal mucociliary clearance time blocked, the temporary addition of a nasal decongestant to the
(NMCCT) and total nasal polyps score (NPS) than the placebo- nasal corticosteroid treatment can be considered.
MFNS group. During the two weeks in which all patients were
only treated with MFNS both groups showed continuing 6.1.11. Saline
improvement in all outcome variables but the oxymetazoline-
MFNS group still showed significantly greater improvement in 6.1.11.1. Summary
blocked nose, hyposmia, NMCCT and total NPS, but not PNIF, Nasal saline irrigation is considered to be an important aspect
than the placebo-MFNS group at the end of the study. There of the management of CRS. Saline nasal irrigation may
was no evidence of rebound congestion after four weeks of improve nasal mucosa function through several physiological
oxymetazoline treatment. This lack of rebound congestion when effects including mechanical removal of mucus and crusts,
nasal decongestants are combined with nasal corticosteroids improvement in mucus clearance, enhanced ciliary beat activity,
has also been shown in two studies in allergic rhinitis where 2-4 disruption and removal of antigens, biofilms and inflammatory
weeks’ treatment with the combination of nasal decongestant mediators, and increases hydration of the sol layer. Also, saline
and corticosteroid was more effective than nasal corticosteroid can be the carrier to supply sufficient volume to transport
alone and did not show rebound swelling(153, 154). medication into the sinus. There is however little consensus on
In the second trial Humphreys at al. compared topical the best method of irrigation and the tonicity (concentration)

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Table 6.1.11.1. Saline nasal irrigation versus no irrigation for the treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results
Giotakis RCT not blinded 174 CRSwNP • 250ml of 1,175% Emser Salt® solution At 3, 6, 9 and 12 • Significantly better results in
(163) patients (158 (EmsSalt) (n=59) twice daily for one year months: nasal symptoms and RQLQ
2016
evaluated), • 250ml of isosmotic mineral salt mixture • Nasal symptoms between irrigation and no
postoperative (IsoMix) (n=58) twice daily for one year • RQLQ irrigation
• No irrigation (n=57) for one year • Missed work days • No significant difference
• Postoperative condi- in missed work days and
All patients were allowed to use mucosa
budesonide nasal spray in limited doses tion of the mucosa
• No significant differences
in the first 6 months and corticoid and between Emser Salt and
antibiotic nasal ointment in the first 14 the isosmotic mineral salt
days. mixture
Nikakhlagh RCT not blinded 185 CRS After 3 weeks of antibiotics patients After 3 months: • Isotonic was more effective
patients received: than hypertonic, hypotonic
2016(165) • Percentage of
• Hypertonic lavage (volume and and no lavage
patients with symp-
frequency unclear) for 3 months
toms of headache,
• Isotonic lavage for 3 months
discharge from nose
• Hypertonic lavage for 3 months
and throat, nasal ob-
• No lavage for 3 months struction, coughing,
olfaction, feeling of
fullness in the face
Jiang RCT, no blinding, 185 patients EAW for nasal irrigation daily for 2 months Two months after FESS: • No significant differences
postoperative undergoing starting 1 months after FESS (n=36) in postoperative SNOT-20
2014(179) • SNOT-20
FESS (110 Neutral NS daily for 2 months starting 1 scores, mean MCA , smell
evaluated) months after FESS (n=35)
• Mean MCA2 2
threshold, UPSIT-TC scores,
• Smell threshold saccharine transit time, and
No nasal irrigation after surgery (n=39) • UPSIT-TC endoscopic scores among
• Saccharine transit the three groups.
time
• Endoscopic score
Freeman, Within-subject, 22 CRS patients • 2ml isotonic saline via a mucosal atomi- At 3 weeks and 3 • Significant positive effect of
single- sation device one side of the nose, three months: saline atomisation on dis-
2008 (158)
blinded RCT times per day for 6 weeks • Adhesions, charge, no other differences
postoperatively • No saline other side of the nose discharge, polyps,
crusting, oedema (0-
3) at endoscopy
Liang RCT, no blinding, 77 patients • Pulsatile nasal irrigation for 3 months At 2 weeks and 1, • No significant effect of
2008(175) postoperative undergoing • No treatment 2 and 3 months nasal irrigation for the whole
FESS postoperatively: group
• Symptom score • Significant positive effect of
• Endoscopy score nasal irrigation in patients
with mild CRS but not with
severe CRS (based on CT
scan > LM >12)
Pinto Postoperative, 60 patients • NS (n=20) four times per day, two puffs For 5 days: • Significantly more nasal
2006(178) RCT, double with histories on each side, for the first 5 postoperative discharge in hypertonic
blinded for of frequent days. • Symptoms (nasal saline group compared to
sprays sinusitis after obstruction/conges- the other groups
FESS • Buffered HS (n=20) 4 times per day, 2 tion, nasal discharge/
puffs on each side, for the first 5 postop- postnasal drip, pain/ • No other significant differ-
erative days. pressure, headache, ences
• Or no spray (n=20) and trouble sleep-
ing/insomnia) (0-4)
• Pain medication
Heatley RCT, no blinding 150 CRS • Nasal irrigation with bulb syringe with • RSOM-31 at 2 weeks • No significant differences
2001(177) patients (128 hypertonic saline for 2 weeks between the groups
completed the • SF-36 at 2 weeks
study) • Nasal irrigation with nasal irrigation pot
with hypertonic saline for 2 weeks • Use of medication at
2 weeks
• Reflexology massage for 2 weeks

CRS, chronic rhinosinusitis; CRSwNP, Chronic Rhinosinusitis with nasal polyps; CT, computed tomography; EAW, electrolyzed acid water ; FESS, func-
tional endoscopic sinus surgery; HS, hypertonic saline; LM, Lund-Mackay; NS, normal saline; RCT, randomised controlled trial; RSOM-31, Rhinosinusitis
Outcome Measure-31; SF-36, Short Form 36.

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of the saline solution, nor on the volume (low or high), pressure effective in reducing symptoms and signs of CRS.
(low or high), and frequency, devices, and head position when
rinsing. Nasal irrigation with isotonic saline or Ringer’s
This systematic review identified 33 RCT studies (14 in the lactate is an effective treatment in CRS patients.
postoperative phase after FESS) evaluating the impact of nasal
saline irrigations/spray on clinical outcomes in adult CRS (Tables 6.1.11.3. What is the best content?
6.1.1.1- 6.1.11.10). The studies were very different in design, Six studies evaluated the differences between hypertonic and
duration and outcome measurements. Twenty studies reported normal saline(157, 161, 163, 165, 178, 184) (Table 6.1.11.3). Three studies
a positive effect of some form of saline irrigation(156-175). (325 patients) found, in general, better results with isotonic than
Eight reported no effect (158, 176-182)and in five studies the effect hypertonic saline(157, 165, 178). Two studies (248 patients) found no
compared to baseline was not mentioned(183-187). difference(161, 163) and one study (60 patients) showed hypertonic
Six studies evaluated the effect of a form of saline irrigation nasal spray to have significantly better results on congestion
versus a form of no irrigation of the nose (Table 6.1.11.1). The and cough than isotonic saline(184).
studies could not be combined in a meta-analysis. Four studies Two studies(156, 159) evaluated the differences between Dead
showed no or hardly any (e.g. on one symptom) effect of Sea salt and other hypertonic saline irrigation alone(156) or in
saline irrigation. The two most recent studies((163, 165) did show combination with fluticasone dipropionate(159). The studies
significant positive effect of isotonic saline irrigation versus no showed that hypertonic saline alone was less effective than the
irrigation. The differences between the positive and negative other two treatments. One study in 74 CRS patients directly after
studies are not very clear but potential reasons for them could FESS evaluated the differences between isotonic saline irrigation
be the length of the treatment/evaluation (the positive studies (n=25) with lactated Ringer’s irrigation (n=26) and hypertonic
had a mean duration of 7.5 months (3-12 months), the negative saline nasal irrigation (n=23) for six weeks(161). Lactated Ringer’s
ones of six weeks (1-13 weeks). resulted in a significantly larger reduction in SNOT and VAS total
In conclusion, studies evaluating a form of saline irrigation symptom score over six weeks than the other two irrigations.
versus a form of no irrigation of the nose do not lead to a In conclusion, in general, studies do not show that rinsing with
concurrent conclusion. More studies are necessary to further hypertonic saline is more effective than with isotonic saline.
analyse this important question for patients and professionals. There is one postoperative study showing that irrigation with
lactated Ringer’s solution is more effective than both isotonic
6.1.11.2. What is the best method? and hypertonic saline irrigation(161).
Two studies evaluated different methods of applying saline. A
prospective, cross-over study evaluated the effectiveness of 6.1.11.4. What is the best temperature?
three methods of nasal irrigation (nasal spray, nebulisation with One study compared a single saline irrigation at room
RinoFLow and nasal douching while kneeling with the head temperature with irrigation with saline at 40
on the floor) on distribution of saline to the nasal cavity and degrees Celsius on mucociliairy transit time and nasal
paranasal sinuses(188). The authors showed that nasal douches obstruction and found no differences(164) (Table
are more effective in distributing irrigation solution to the 6.1.11.4).
maxillary sinus and frontal recess, but all techniques were able
to reach the anterior and posterior nasal cavity in patients post- 6.1.11.5. Will additions help?
FESS and healthy subjects. The spray and the nebulizer were
unable to penetrate any of the sinuses or the frontal recess in 6.1.11.5.1. Antiseptic/mucolytic/baby shampoo
the controls. However, effect on symptoms was not measured. Three studies evaluated the addition of antiseptic/mucolytic/
One study in 86 CRS patients compared a squeeze bottle with baby shampoo solution and showed little or no differences
a nasal spray for one month and found no differences between between the groups but the baby-shampoo group was reported
the SNOT-22, Nasal and Sinus Symptom Scale (NSS) or Peri- to have significantly more side effects and had more patients
Operative Sinus Endoscopy (POSE) score between the two ways stop the solution(160, 174, 183) (Table 6.1.11.5). Moreover, it has been
of administration(162). Although the study showed a significant shown in healthy persons to create congestion and reversible
improvement in both groups there was no difference between smell loss (190).
patients treated with the squeeze bottle compared to saline
nasal spray (Table 6.1.11.2). The same was shown by Salib et 6.1.11.5.2. Sodium hyaluronate in CRS patients (both
al. who evaluated a low-volume high-pressure nasal spray and CRSsNP and CRSwNP).
high-volume low-pressure saline application system following Six Italian DBPCT or single blind (blinding often not clearly
functional endoscopic sinus surgery and found no differences described) studies evaluated the addition of 9mg of sodium
in SNOT-22 and only one timepoint difference for the LK score hyaluronate to saline(166-168, 185, 186, 191). Five studies evaluated
in favour of high volume(189). The studies could not be combined nebulisation with a small volume(167, 168, 185, 186, 191) and one study
into a meta-analysis because of insufficient data. rinsing with 250ml. The five studies evaluating nebulization
To conclude, although nasal douches have been shown to be in general reported positive outcomes, the study evaluation
more effective in distributing irrigation solution to the sinuses, addition of sodium hyaluronate to saline rinsing found in
there are no studies that show that nasal douches are also more general no significant effect (Table 6.1.11.6).

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In conclusion, sodium hyaluronate might have a positive effect Three studies(169, 170, 176) evaluated the addition of honey to saline
on postoperative symptoms when compared to a saline spray. irrigation(169, 176) or spray(170). None of the studies did find any
Adding sodium hyaluronate to saline rinsing postoperatively did relevant differences between the honey treated group and the
not show an effect in one study. placebo group (Table 6.1.11.7). However, in all studies patients
also received oral antibiotics and/or nasal corticosteroids which
6.1.11.5.3. Honey in nasal saline irrigation reduces the possibility of finding significant differences.
Honey is a viscous, supersaturated sugar solution derived from
nectar gathered and modified by the honeybee, Apis mellifera. The addition of Xylitol, sodium hyaluronate, and
Honey has been used since ancient times as a remedy in wound xyloglucan to nasal saline irrigation may have a
care. Honey appears to heal partial thickness burns more quickly positive effect.
than conventional treatment (which included polyurethane film,
paraffin gauze, soframycin-impregnated gauze, sterile linen and 6.1.11.5.4. Xylitol nasal irrigation
leaving the burns exposed) and infected post-operative wounds Xylitol is a five-carbon sugar alcohol that occurs naturally in
more quickly than antiseptics and gauze(192). In otolaryngology, many fruits and vegetables and is used widely in the food
studies have investigated the effect of honey and other bee industry as a sweetener. It has gained extensive attention in
products like propolis and royal jelly in oral infections, infections the past decade as a natural antibacterial agent and more
of the respiratory tract, in rhinosinusitis, tonsillectomy and head recently as an anti-biofilm agent , particularly in periodontics.
and neck surgery(193). It decreases the salt concentration of human airway surface
liquid that contains many antimicrobial substances, which can

Table 6.1.11.2. Methods of nasal irrigation for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Macdonald Single blind RCT 86 CRS patients • Saline squeeze bottle (n=43) for 1 month • SNOT-22 • Significant improvement
(162) postoperative (55 CRSwNP) • Saline nasal spray (n=43) for 1 month • POSE in both groups for SNOT-
2015
directly • Nasal and 22, POSE, NSS
postoperatively sinus symp- • No difference between
tom scale treatment groups
(0-15)

TM
Salib Single blind RCT 31 CRS patients • Sterimar Isotonic two sprays three times At 2, 4 and At 2, 4 and 12 weeks:
postoperative directly daily in one nostril for a period of 12 weeks 12 weeks • No difference in SNOT-22
2013(189)
postoperatively after surgery (n=24). following at any timepoint
TM
(24 evaluated) (17 • Sinus Rinse 120ml three times daily in one surgery: • Statistical difference for
CRSwNP) nostril for a period of 12 weeks after surgery. • SNOT-22 LK score at 4 weeks and
All patients received 1-week course of antibiotics, • LK score trend at 2 weeks
topical nasal steroids, and a 10-day course of
oral steroids in patients with nasal polyposis.

CRS,Chronic Rhinosinusitis; Single blind RCT, Single Blind Randomised Controlled Trial; CRSwNP, Chronic Rhinosinusitis with nasal
polyps;SNOT-22, Sino-Nasal Outcome Test-22; POSE, Perioperative Sinus Endoscopy score; NSS, Nasal and Sinus Symptom scale; LK
score, Lund-Kennedy score;

Table 6.1.11.3. Hypertonic versus isotonic saline irrigation for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Giotakis 2016 (163)
RCT not 174 CRSwNP • 250ml of 1,175% Emser Salt® solution At 3,6,9 and 12 months: • Significantly better
blinded patients (158 (EmsSalt) (n=59) twice daily for one • Nasal symptoms results in nasal
evaluated), year • RQLQ symptoms and RQLQ
postoperative • 250ml of isosmotic mineral salt • Missed work days between irrigation and
mixture (IsoMix) (n=58) twice daily • Postoperative condi- no irrigation
for one year tion of the mucosa • No significant differ-
• No irrigation (n=57) ence in missed work
• All patients were allowed to use days and mucosa
budesonide nasal spray in limited • No significant differ-
doses in the first 6 months and corti- ences between Emser
coid and antibiotic nasal ointment in Salt and the isosmotic
the first 14 days. mineral salt mixture

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Table 6.1.11.3. Hypertonic versus isotonic saline irrigation for the treatment of patients with CRS (continued).

Study Methods Participants Interventions Outcomes Results

Giotakis RCT not 174 CRSwNP • 250ml of 1,175% Emser Salt® solution At 3,6,9 and 12 months: • Significantly better
(163) blinded patients (158 (EmsSalt) (n=59) twice daily for one • Nasal symptoms results in nasal
2016
evaluated), year • RQLQ symptoms and RQLQ
postoperative • 250ml of isosmotic mineral salt • Missed work days between irrigation and
mixture (IsoMix) (n=58) twice daily • Postoperative condi- no irrigation
for one year tion of the mucosa • No significant differ-
• No irrigation (n=57) ence in missed work
• All patients were allowed to use days and mucosa
budesonide nasal spray in limited • No significant differ-
doses in the first 6 months and corti- ences between Emser
coid and antibiotic nasal ointment in Salt and the isosmotic
the first 14 days. mineral salt mixture
Nikakhlagh RCT not 185 CRS After 3 weeks of antibiotics patients After 3 months: • Isotonic was more
blinded patients received: effective than hypertonic,
2016 (165)
• Hypertonic lavage (volume and • Percentage of patient hypotonic and no lavage
with symptoms of head-
frequency unclear) for 3 months
ache, discharge from
• Isotonic lavage for 3 months
nose and throat, nasal
• Hyptonic lavage for 3 months
obstruction, coughing,
• No lavage for 3 months olfaction, feeling of
fullness in the face
Low DBRCT 74 CRS • Normal saline irrigation (n=25) for After 6 weeks: • All groups showed signifi-
postoperative patients directly 6 wks cant improvement over 6
2014 (161)
postoperative • Lactated Ringer’s irrigation (n=26) • SNOT-20 wks for SNOT and VAS
for 6 wks
• Symptom scores (VAS) • Lactated Riner’s was
• Mucociliary clearance significantly better over
• Hypertonic saline nasal irrigation (MCC)
(n=23) for 6 wks 6 wks than the other two
irrigations
• No differences in MCC
Friedman Double blind 145 CRS • 20 ml hypertonic DSS solution 2dd At 4 weeks • Significant improvement
RCT patients (114 and DSS nasal spray (n=59) for 4 wks in SNOT-20 in both groups
• 20 ml hypertonic saline irrigation 2dd • SNOT-20
(159)
2012
evaluated) • No significant differences
and nasal spray + 1dd fluticasone 50
• UPSIT between the groups
μg (n=57) for 4 wks
• Nasal endoscopy • No significant difference
• Acoustic rhinometry compared to baseline or
between the groups for
UPSIT, nasal endoscopy or
acoustic rhinometry
Culig RCT 60 CRS patients • Hypertonic nasal spray (2,12%) (Steri- After 1 and 2 wks: • Hypertonic nasal spray
mar) 3-6 times daily for 2 weeks had significant better
• Normal saline nasal spray (Sterimar) • Rhinorrhea, congestion,
(184)
2010
results on congestion (1
cough, headache and
3-6 times daily for 2 weeks and 2 wks) and cough (at
sinus region sensitivity
2 wks) than normal saline
on palpation after 1 and
2 wks
Hauptman Double blind 80 patients with • Buffered hypertonic saline (3%) 1ml • Acute effect on: • Normal saline resulted in
(157) RCT CRS (10 pufs of 100 microliter) in the most • Symptoms of nasal stuffi- significantly less stuffiness,
2007
obstructed nasal cavity once ness, nasal obstruction nasal obstruction and
• Normal saline (3%) 1ml (10 pufs and nasal burning/irrita- burning/irritation than
of 100 microliter) in the most tion (0-10) hypertonic saline
obstructed nasal cavity once • Acoustic rhinometry • MCT was significantly
• (Change in) MCT better after normal saline
but change in MCT sign.
Better after hypertonic,
• MCA2 significantly better
after normal saline
Friedman DBPCT 57 patients • Hypertonic Dead sea salt (DSS) solu- • RQLQ • RQLQ and total symptom
with CRS (42 tion 2dd (n=22) for 1 month • Total symptoms score score significantly better
2006(156)
evaluated) • Hypertonic saline irrigation 2dd (0-48) for DSS than hypertonic
(n=20) for 1 month saline

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Table 6.1.11.3. Hypertonic versus isotonic saline irrigation for the treatment of patients with CRS (continued).

Pinto Postoperative, 60 patients • Normal saline (NS; n = 20) 4 times • Symptoms (nasal • Significantly more nasal
(178) RCT, double with histories per day, two puffs on each side, for obstruction/congestion, discharge in hypertonic
2006
blinded for of frequent the first 5 postoperative days. nasal discharge/postna- saline group compared to
sprays sinusitis after • Buffered hypertonic saline (HS; n = sal drip, pain/pressure, the other groups
FESS 20) 4 times per day, two puffs on headache, and trouble • No other significant
each side, for the first 5 postoperative sleeping/insomnia) (0-4) differences
days. for 5 days
• Or no spray (n = 20) • Pain medication for 5
days

CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, double blind placebo controlled trial; DBRCT,
double blind randomised controlled trial; dd, daily dosage; DSS, Dead Sea Salt solution; FESS, functional endoscopic sinus surgery;
HDSS, Hypertonic Dead sea salt; HS, hypertonic saline; MCA2, Minimal cross-sectional area 1; MCT, mucociliary clearance time; NS,
normal saline; RCT, randomised controlled trial; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire .

Table 6.1.11.4. Temperature of nasal saline for irrigation for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Nimsakul RCT not 23 CRS patients • 250ml saline at room temperature (n=9) • Saccharin transit time (STT) • Significant im-
blinded • 250ml saline at 40o C (n=12) • PNIF provement in STT
2018(164)
• Total nasal resistance measured in both groups
by anterior rhinomanometry • No differences
• Total nasal volume measured by between the
acoustic rhinometry groups
• Nasal obstruction score (0-5) • No differences in
• Breathe-comfort score (0-5) other outcomes
• Adverse events.

CRS, chronic rhinosinusitis; PNIF, peak nasal inspiratory flow; RCT, randomised controlled trial; STT, saccharin transit time.

Table 6.1.11.5. Saline irrigation with addition of antiseptic/mucolytic/baby shampoo solution for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Yu 2016(174) DBPCT 43 CRS patients • Low-concentration HOCl At 1,2,4 and 8 weeks: Low-concentration HOCl versus saline
(39 evaluated) 30 ml twice daily using a • SNOT-20 resulted in significantly reduced
Salicid device • RSDI • SNOT-20 at 2 and 4 weeks
• Saline 30 ml twice daily • Endoscopy (LK score) • None of the other outcomes
using a Sham Salicid • Adverse events • No treatment related adverse events
device

Farag 2013(160) Single 40 CRS patients • 120ml Hypertonic Saline • RSOM-31 • Significant decreases in scores for
blind RCT directly solution 3dd until 4 • SNOT-22 both the SNOT-22and RSOM-31
postoperative postoperative months postop • Olfaction with phenyl overtime for both treatments but no
• 120ml of 1% baby sham- ethyl alcohol (PEA) difference between the treatments
poo solution3dd until 4 threshold test • PEA thresholds showed improve-
months postop • Adverse events ment but no difference between
the treatments
• The baby-shampoo group reported
significantly more side effects and
had more patients stop the solution

Pigret 1996(183) Single- 20 CRSwNP • Pressurized seawater (vol- • Residual nasal crusts No significant differences although
blind RCT patients after ume unclear) (n=10) 3dd weight at 21±2 days the mean residual crust weight was
postoperative endoscopic • 10ml of saline plus benzo- secretions after 21±2 higher in the pressurized seawater
endonasal dodecinium (antiseptic) days group (1,756±688mg) than in the
ethmoidectomy plus oleosorbate (mucol- • Visual analogue scale antiseptic/mucolytic saline group
ytic) (n=10) 3dd for nasal obstruction, (932±414mg)
rhinorrhoea, cacosmia
and facial pain

DBPCT, double blind placebo controlled trial; LK, Lund-Kennedy; PEA, phenyl ethyl alcohol; RSDI, Rhinosinusitis Disability Index;
SNOT, Sino-nasal Outcome Test; RCT, randomised controlled trial; RSOM-31, Rhinosinusitis Outcome Measure-31

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Table 6.1.11.6. Saline irrigation with addition of Sodium hyaluronate for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Mozzanica DBPCT 56 CRSsNP • 250ml saline plus 9mg sodium At 3 and 6 weeks • No differences in SNOT-22, NOSE,
patients hyaluronate twice daily for 6 postoperatively: symptoms and total LK score at 6
2019(166)
postoperatively weeks (n=26) • SNOT-22 weeks
• Saline twice daily for 6 weeks • NOSE • Significantly better result of NOSE
(n=30) • Symptoms (VAS) score at 3 weeks in sodium hyaluronate
• LK score group
• Significantly better result for headache
and smell alteration at three weeks in
sodium hyaluronate group
• Significantly reduced scar formation (3
and 6 weeks), crusting (3 weeks) and
secretion (6 weeks)
Cantone DBPCT 80 CRS patients • 9 mg (3 mL) of high-molecular- At 3 months: Significantly better result of sodium
(40 allergic and weight sodium hyaluronate • SF-36 hyaluronate than saline on top of MFNS
2016(191)
40 non-allergic) in 2 ml saline solution • SNOT-22 for:
administered twice a day for 15 • Obstruction (VAS) • SF36
consecutive days per month for • Nasal discharge (VAS) • SNOT-22
3 consecutive months by using • LK score • Obstruction (VAS)
a nebulizer ampoule for nasal • Nasal discharge (VAS)
douche (n=40) • LK score
• 2 ml saline solution
administered twice a day for 15
consecutive days per month for
3 consecutive months by using
a nebulizer ampoule for nasal
douche (n=40)

All patients used Mometasone

fuorate nasal spray200µg o.d. for
3 months
Cantone DBPCT 124 CRSwNP • Intranasal nebulization of 9mg At 30 days postoperatively: Significantly better result of sodium
(122 evaluated) sodium hyaluronate (3mL) plus • SF-36 hyaluronate than saline for:
2014 (185)
postoperatively saline solution (2mL) twice daily • SNOT-22 • SF36
for 30 days (n=62) • Symptoms (VAS) • SNOT-22
• Intranasal nebulization of saline • Endoscopic score • Total symptoms (VAS)
(5ml) twice daily for 30 days • Endoscopic score
(n=60)
Casale, RCT 33 CRS patients • Nebulization of 3ml containing At 2 and 4 weeks • VAS score of hyaluronate significantly
(single postoperatively 9mg sodium hyaluronate nasal postoperatively: lower than saline at 2 and 4 weeks
2014 (167)
blind?) washes plus saline twice daily • CRS questionnaire • CRS score significantly lower than
for 1 month (n=18) • Visual analogic scale (VAS) saline at 2 and 4 weeks
• Nebulization of 5mL saline • Nasal endoscopy • Significantly less crusts and oedema
twice daily for 1 month (n=15) and secretions
Gelardi RCT 36 CRSwNP • Intranasal nebulization of At 30 days postoperatively: Sodium hyaluronate group had
(single postoperative sodium hyaluronate 9mg in • Nasal obstruction, burning, compared to saline:
2013(186)
blind?) 3ml twice daily for 30 days dryness of the mucosa • Significantly faster mu-cociliary
(n=19) (VAS) clearance
• Intranasal nebulization saline • Presence or absence of • Lower incidence of rhinorrhoea
5ml twice daily for 30 days rhinorrhoea • Less nasal obstruction
(n=17) • Mucociliary clearance time • A lower incidence of exudate on
• Presence of exudate at endoscopy
endoscopy • Better tolerability
Macchi DBPCT 46 CRSwNP • Nebulization of 6ml containing At 3 months postoperatively: Significantly better result of sodium
patients 9mg sodium hyaluronate nasal • Prevalence of symptoms hyaluronate than saline for:
2013 (168)
postoperatively washes plus saline for 15 days/ • Endoscopy • Nasal dyspnea (obstruction?)
mo over 3 months (n=23) • Cytology • Normal mucosa
• Nebulization of 6mL isotonic • Biofilm • Absence of secretion
saline for 15days/mo over 3
months (n=23)

CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps;
DBPCT, double blind placebo controlled trial; LK, Lund-Kennedy; MFNS, Mometasone fuorate nasal spray; NOSE, Nasal Obstruction
Symptom Evaluation; RCT, randomised controlled trial; SF 36, Short Form 36; SNOT, Sino-nasal Outcome Test; VAS,
visual analogic scale.

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Table 6.1.11.7. Saline irrigation with addition of honey for the treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results
Ooi Single blind 25 recalcitrant • 14 days of twice-daily 16.5% Manuka Honey + At 14 days: • No significant
(investigator) CRS patients 1.3mg/mL augmented methylglyoxal sinonasal • SNOT-22 differences
2019(176)
placebo rinses • Symptom scores (VAS) in SNOT-22,
controlled • 14 days of twice-daily saline sinonasal rinses • UPSIT symptoms,
trial Both groups received 10 days of culture-directed • Endoscopy (LK score) UPSIT, LK score,
antibiotic therapy • Microbiology microbiology or
• Adverse events adverse events

Lee Single blind 49 CRS patients • 120ml saline containing 12mg of manuka honey At 30 days: • No significant
(169) (investigator) (42 analysed) twice daily for 30 days • SNOT-22 differences
2016
placebo postoperatively • 120ml saline twice daily for 30 days • LK endoscopy score between the
controlled • All patients received culture-directed oral antibi- • Bacterial culture groups
trial otic, and/or oral steroids for up to 3 weeks, and/ • In the subgroup
or high-volume topical steroid sinus irrigations not using
(budesonide 0.5mg/2mL vial or 0.6mg/2mL cap- antibiotics manuka
sule, 0.5 bottle to each nasal cavity twice daily) honey significantly
polyps or inflammation for 30 days. reduced bacteria
• The dose of budesonide was determined when
the patient filled the prescription; if insur-
ance covered it, then the vial version at the
0.5mg/2mL dose was used, and if not covered,
then the capsule version at the 0.6mg/2mL dose
was used.
Hashemian DBPCT 64 CRS patients • Thyme/honey nasal spray 2 puffs per nostril At 60 days: • No significant
postoperatively twice daily (n=27) • SNOT-22 differences
2015(170)
(53 analysed) • Placebo nasal spray 2 puffs per nostril twice daily • CT-scan between the
(n=26) • Endoscopy score (0-8) groups
All patients received cefixime 400mg daily for 10
days postoperatively and were instructed to
rinse their nasal cavity initially with saline three
times daily, and then use fluticasone nasal spray
(50mcg) twice daily.

CRS, chronic rhinosinusitis; LK, Lund-Kennedy; SNOT, Sino-nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification
Test; VAS, visual analogic scale.

Table 6.1.11.8. Saline irrigation with addition of Xylitol for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

DBPCT 30 CRS • 240 ml of water containing 12 g Xylitol At 30 days: At 30 the Xylitol group
Lin patients (25 once daily for 30 days (n=13) had significant better
2017(180) • SNOT-22
evaluated) • 240 ml of saline once daily for 30 days • VAS (symptoms) result than the saline
• 3 days washout between treatments (n=12) • Nasal NO group for:
• iNOS mRNA in the right max- • SNOT-22
illary sinus • VAS (symptoms)
• Nasal NO
• Induction of iNOS
DBPC 20 CRS • 240ml of water containing 12g Xylitol once • Change in SNOT-20 versus Significant larger
Weissman crossover patients (15 daily for 10 days (n=20) baseline reduction in SNOT-20 in
2011(181)
study evaluated) • 240ml of saline once daily for 10 days 3 days • Change in VAS (how you think the xylitol group versus
washout between treatments (n=20) your nose/sinuses are feeling the saline group
overall) versus baseline No differences in VAS
score

CRS, chronic rhinosinusitis; DBPC, double blind placebo controlled; DBPCT, double blind placebo controlled trial; iNOS, inducible
Nitic Oxide; mRNA, messenger Ribonucleic Acid; NO, nitric oxide; SNOT, Sino-nasal Outcome Test; VAS, visual analogue scale.

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Table 6.1.11.9. Saline irrigation with addition of Dexpanthenol for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Tantilipikorn DBPCT 50 CRS patients • Dexpanthenol nasal spray 4 • % of patients with symp- • Majority of symptoms and signs did
postoperatively times a day for 6 weeks (n=25) toms at 2, 4 and 6 wks not show significant differences
2012(171)
• Saline nasal spray 4 times a • % of patients with endo- • Dexpanthenol nasal spray has
day for 6 weeks (n=25) scopic abnormalities at 2, 4 superior efficacy compared
and 6 wks with normal saline nasal spray
• Mucociliiary clearance time on improvement of mucociliary
at 6 wks clearance and smell at 6 wks and
inferior effect on nasal discharge
Fooanant RCT 128 CRS • Dexpanthenol (5%) in sea • At 1, 2, 3, 4, 6 and 12 weeks: • No significant differences in total
patients (110 water nasal spray 2 puffs per nasal symptom score, nasal crusts
2008(187)
evaluated) nostril, twice a day for 4 weeks
• Total nasal symptom score
(but at wk 2 less in saline group),
postoperatively • Saline nasal irrigation (volume • Symptoms
mucociliary clearance (but for
unclear) twice a day for 4
• Nasal crusts
subgroup of CRSwNP)
weeks
• Mucociliary clearance (only
at 4 wks)

CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT, double blind placebo controlled trial; RCT,
randomized controlled trial.

Table 6.1.11.10. Saline irrigation with addition of Hyaluronate for the treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results
Mozzanica DBPCT 56 CRSsNP • 250ml saline plus 9mg sodium At 3 and 6 weeks • No differences in SNOT-22, NOSE,
patients hyaluronate twice daily for 6 weeks postoperatively: symptoms and total LK score at 6 weeks
(166)
2019 postoperatively (n=26) • SNOT-22 • Significantly better result of NOSE score
• Saline twice daily for 6 weeks (n=30) • NOSE at 3 weeks in sodium hyaluronate group
• Symptoms (VAS) • Significantly better result for headache
• LK score and smell alteration at three weeks in
sodium hyaluronate group
• Significantly reduced scar formation (3
and 6 weeks), crusting (3 weeks) and
secretion (6 weeks)

Cantone DBPCT 80 CRS patients • 9 mg (3 mL) of high-molecular- At 3 months: Significantly better result of sodium
(40 allergic and weight sodium hyaluronate in 2 ml • SF-36 hyaluronate than saline on top of MFNS for:
2016 (191) 40 non-allergic) saline solution administered twice • SNOT-22 • SF36
a day for 15 consecutive days per • Obstruction (VAS) • SNOT-22
month for 3 consecutive months by • Nasal discharge • Obstruction (VAS)
using a nebulizer ampoule for nasal (VAS) • Nasal discharge (VAS)
douche (n=40) • LK score • LK score
• 2 ml saline solution administered
twice a day for 15 consecutive days
per month for 3 consecutive months
by using a nebulizer ampoule for
nasal douche (n=40)

All patients used MFNS 200µg once

daily for 3 months
Cantone DBPCT 124 CRSwNP • Intranasal nebulization of 9mg At 30 days Significantly better result of sodium
(122 evaluated) sodium hyaluronate (3mL) plus saline postoperatively: hyaluronate than saline for:
2014(185) postoperatively solution (2mL) twice daily for 30 days • SF-36 • SF36
(n=62) • SNOT-22 • SNOT-22
• Intranasal nebulization of saline (5ml) • Symptoms (VAS) • Total symptoms (VAS)
twice daily for 30 days (n=60) • Endoscopic score • Endoscopic score

Casale, RCT 33 CRS patients • Nebulization of 3ml containing 9mg At 2 and 4 weeks • VAS score of hyaluronate significantly
(single postoperatively sodium hyaluronate nasal washes postoperatively: lower than saline at 2 and 4 weeks
(167)
2014 blind?) plus saline twice daily for 1 month • CRS questionnaire • CRS score significantly lower than saline
(n=18) • Visual analogic at 2 and 4 weeks
• Nebulization of 5mL saline twice daily scale (VAS) • Significantly less crusts and oedema and
for 1 month (n=15) • Nasal endoscopy secretions

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Table 6.1.11.10. Saline irrigation with addition of Hyaluronate for the treatment of patients with CRS (continued)

Study Methods Participants Interventions Outcomes Results

Gelardi RCT 36 CRSwNP • Intranasal nebulization of sodium At 30 days Sodium hyaluronate group had compared
2013(186) (single postoperative hyaluronate 9mg in 3ml twice daily postoperatively: to saline:
blind?) for 30 days (n=19) • Nasal obstruc-tion, • Significantly faster mu-cociliary clearance
• Intranasal nebulization saline 5ml burning, dryness of • Lower incidence of rhinorrhoea
twice daily for 30 days (n=17) the mucosa (VAS) • Less nasal obstruction
• Presence or ab- • A lower incidence of exudate on endos-
sence of rhinor- copy
rhoea • Better tolerability
• Mucociliary clear-
ance time
• Presence of exu-
date at endoscopy
Macchi DBPCT 46 CRSwNP • Nebulization of 6ml containing 9mg At 3 months Significantly better result of sodium
2013(168) patients sodium hyaluronate nasal washes postoperatively: hyaluronate than saline for:
postoperatively plus saline for 15 days/mo over 3 • Prevalence of • Nasal dyspnea (obstruction?)
months (n=23) symptoms • Normal mucosa
• Nebulization of 6mL isotonic saline • Endoscopy • Absence of secretion
for 15days/mo over 3 months (n=23) • Cytology
• Biofilm

CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps; DBPCT,
double blind placebo controlled trial; LK, Lund-Kennedy; MFNS, Mometasone fuorate nasal spray; NOSE, Nasal Obstruction Symptom
Evaluation; RCT, randomized controlled trial; SF-36, Short Form-36; SNOT, Sino-nasal Outcome Test; VAS, visual analogue scale.

Table 6.1.11.11. Thermal water for the treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results
Ottaviano DBPCT 80 CRS • Sulfurous, salty, bromic, iodic (SSBI) At 1 month: • No significant differences
patients thermal water (5mL, 4 times daily for between thermal water and
2011(197) one month (n=40) • Nasal endoscopy saline
• Saline 5mL, 4 times daily for one month • Rhinomanometry
(n=40)

Salami DBPCT Eighty • Sulphurous thermal water from The At 12 days and 3 months: At 12 days and 3 months the
patients with Tabiano SPA Mineral Water applied as thermal water compared to placebo
2010(873) CRS warm inhalation (38°C, at a distance • Symptoms (VAS) significantly reduced
of 20 cm from the patient’s face for 10 • Clinical parameters of
min) combined with nasal irrigations recurrence • Symptoms (VAS)
with the same water for 6 minutes for • Nasal resistance measured • Clinical parameters of recurrence
12 days (n=40) with anterior active rhino- • Nasal resistance measured with
• Placebo water (saline made white and manometry anterior active rhinomanometry
with Sulphur) applied as warm inhala- • Mucociliary clearance • Mucociliary clearance
tion (38°C, at a distance of 20 cm from
the patient’s face for 10 min) combined
with nasal irrigations with the same
water for 6 minutes for 12 days (n=40)

Passali RCT 55 CRS • Thermal (salt-bromine-iodic) water At 4 weeks: At 4 weeks a significant reduction in
patients or nasal spray 4 times daily (n=30) for the thermal water nasal spray versus
2008(198) patients with 4 weeks • Symptoms of headache, saline in:
recurrent RS • Saline nasal spray (n=25) for 4 weeks rhinorrhoea, hyposmia • Symptoms
(0-3) • Nasal endoscopy
• Nasal endoscopy • Rhinomanometry
• Nasal resistance measured • Mucociliary clearance
with anterior active rhino-
manometry
• Mucociliary clearance
Passali RCT 120 CRS • Crenotherapy treatment (vapour At 2 weeks: At 4 weeks a significant reduction in
patients or inhalation, aerosol and nasal douching) the thermal water nasal spray versus
2008(199) patients with with thermal (salt-bromine-iodic water) • Symptoms of nasal saline in:
recurrent RS water for 14 days at Salsomaggiore obstruction, rhinorrhoea, • Symptoms
Thermal baths nightly awakenings • Nasal endoscopy
• Nasal douching and aerosol with saline • Percent of patients with • Mucociliary clearance
twice a day for 14 days at the Rhino- hyposmia • No difference in percentage of
logic Centre of the ENT Clinic of Siena • Nasal endoscopy (conges- patients with hyposmia
University. tion, secretion)
• Mucociliary clearance
CRS, chronic rhinosinusitis; DBPCT, double blind placebo controlled trial; RCT, randomised controlled trial; SPA, ; VAS, visual analogue scale.

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contribute to the improvement of the innate immune system, 6.1.11. 7. Conclusions

and thereby prevent airway infections. Moreover, through There are a large number of trials evaluating the efficacy
disruption of the glucose cell-wall transport and intracellular of nasal irrigation. However, the quality of the studies is
glycolysis, Xylitol can inhibit bacterial growth. not always very good which makes it difficult to give a
Two small studies analysed the efficacy of Xylitol rinsing in the strong recommendation. However, the data show:
treatment of patients with CRS(180, 181). Both studies reported Nasal irrigation with isotonic saline or Ringer’s lactate
a significant better effect of Xylitol compared to saline in the has efficacy in CRS patients.
reduction of SNOT and total symptoms visual analogue scale There is insufficient data to show that a large volume is
(VAS). The studies could not be combined into a meta-analysis more effective than a nasal spray.
because of missing data (Table 6.1.11.8). The addition of Xylitol, sodium hyaluronate, and
xyloglucan to nasal saline irrigation may have a positive
6.1.11.5.5. Dexpanthenol in nasal saline irrigation effect. The addition of baby shampoo, honey, or
Dexpanthenol is an analog of pantothenic acid, which has been Dexpanthenol as well as higher temperature and higher
claimed to promote wound healing(194). It has been shown to salt concentration do not confer additional benefit.
improve symptoms in patients with atrophic rhinitis(195). Two The steering group advises the use of nasal saline
studies evaluated the effect of Dexpanthenol in saline(171, 187). irrigation with isotonic saline or Ringer’s lactate
Both studies showed no effect on the majority of symptoms and potentially with the addition of Xylitol, sodium
endoscopy but a superior efficacy over placebo on mucociliary hyaluronate, and xyloglucan and advises against the
clearance (in the Fooanant study only in patients with CRSwNP) use of baby shampoo and hypertonic saline solutions
(Table 6.1.11.9). due to side effects.

6.1.11.5.6. Xyloglucan in nasal saline irrigation 6.1.12. Aspirin treatment after desensitization
Xyloglucan, a natural polysaccharide derived from tamarind (ATAD) in N-ERD
seeds, possesses a “mucin-like” molecular structure that confers
mucoadhesive properties, allowing xyloglucan formulations 6.1.12.1. Summary of the evidence
to act as a barrier capable of reducing bacterial adherence Non-steroidal anti-inflammatory drug (NSAID)‐exacerbated
and invasion and to preserve tight junctions and paracellular respiratory disease (N-ERD) is a chronic eosinophilic,
flux, as observed in different in vitro and in vivo studies(196). inflammatory disorder of the respiratory tract occurring in
There is one study(182) evaluating the effect of xyloglucan nasal patients with asthma and/or CRSwNP, symptoms of which
spray compared to saline that indicated that xyloglucan spray are exacerbated by NSAIDs, including aspirin. Upper airway
resulted in a significant reduction in symptoms and signs of disease in N-ERD patients is usually CRSwNP. On average, upper
disease (Table 6.1.11.10) and saline did not. However, no direct respiratory symptoms are worse, extent of opacification on
comparison between the groups was made. computed tomography (CT) scan and recurrence of nasal polyps
In conclusion there is limited evidence that xyloglucan nasal after surgery are more frequent in N‐ERD than in NSAIDs‐
spray may have a positive effect on symptoms and signs of tolerant CRSwNP patients(200, 201).
disease in patients with CRS [level 2b (downgraded because of The management options are essentially based on strict
quality of the study. avoidance of the culprit drug and cross‐reactive drugs. Patient
education is important, since NSAIDs respiratory symptoms are
6.1.11.5.7. Thermal water not limited to a specific drug, but may appear after the intake
Three Italian studies evaluated the use of thermal water, as nasal of other, strong cyclooxygenase (COX)-1 inhibitors. Weak COX-1
irrigation (197), nasal spray (198) or as a combination treatment inhibitors (paracetamol) as well as preferential (meloxicam,
(vapour inhalation, aerosol and nasal douching)(199) (Table nimesulide) and selective (celecoxib and etoricoxib) COX-2
6.1.11.11). Only one study was double blind (197). inhibitors are usually well tolerated by most N-ERD patients(201).
The double blind study of Ottaviano showed no significant In N-ERD patients, aspirin may induce a period lasting 24 to
differences between the treatments (calculated from data 72 hours, in which patients are refractory to repeated aspirin
given). The other two studies showed significant improvement challenges and experience clinical improvement(202). Based on
of symptoms, nasal endoscopy and nasal mucociliairy this observation, several oral and nasal aspirin desensitization
clearance. The studies were of very low-quality making protocols were developed. Most widely used is the Scripps-
conclusions difficult. clinics oral aspirin desensitization protocol, in which, following
a stepwise dose increase, 625mg aspirin is orally administered
6.1.11.6. Adverse effects twice daily(203). Desensitization procedures can be performed
Adverse effects of saline irrigations are rare, but include local in both outpatient and hospital settings and should be
irritation, ear pain, nosebleeds, headache, nasal burning, and supervised by an experienced physician, but to ensure safety
nasal drainage are mentioned. The use of baby-shampoo has and effectiveness of desensitization, it is advised that one of
been shown to create congestion and reversible smell loss. the well-established protocols is followed with gradual dose
increase, with at least 90-120 min intervals between doses(203).

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Table 6.1.12.1. ATAD in the treatment of CRS patients with N-ERD.

Study Methods Participants Interventions Outcomes Results

Mortazavi DBPCT 41 CRSwNP • 650 mg of aspirin twice • SNOT-22 at 6 months In the aspirin treated group
(204)
(38 analysed) every day for 1 month • Symptom Score (0-27) at 6 months compared to placebo at 6
2017 with aspirin and 325 mg of the same months:
• Medication Score at 6 months
intolerance twice daily for the next 5 • CT scan (LM score) at 6 months • Decreased SNOT, symptom
months (n=19) • Serum IL-4 and IL-5 score, medication score
• Placebo (n=19) • Asthma exacerbations • Higher FEV1
• Lower serum IL-5

Esmaeilzadeh, DBPCT 34 CRSwNP • 650 mg of aspirin twice • SNOT-22 at 1 and 6 months In the aspirin treated group
(205)
(32 analysed) every day for 1 month • Symptom Score at 1 and 6 months compared to placebo at 6
2015 with aspirin and 325 mg of the same months:
• Medication Score at 1 and 6 months
intolerance twice daily for the next 5 • CT scan (LM score) at 6 months • Decreased SNOT and symptom
months (n=16) • FEV1 at 1 and 6 months score
• Placebo (n=16) • Serum IL-10, IFN-γ and TGF-β at 6 • Higher FEV1
months • No significant difference in
• Asthma exacerbations other parameters measured
• Adverse events • 1 patient in aspirin groups had
severe intestinal bleeding

Świerczyńska- DBPCT 34 CRSwNP • 624 mg of aspirin 1dd • Nasal symptoms monthly • Only the patients with AIA
(206)
[20 aspirin for 6 months [n=18 (12 • SNOT20 monthly subjected to AD reported
Krępa 2014 intolerant AIA)] improvements in smell and
• PNIF monthly
(AIA), 14 • Placebo for 6 months • Asthma Control Questionnaire (ACQ) reductions in sneezing and
aspirin [n=16 (8 AIA)] monthly nasal blockade
tolerant (ATA)] • Spirometric parameters (and PEF) • The SNOT20 and Asthma
monthly Control Questionnaire scores
• Blood eosinophilia monthly of these patients decreased,
• Corticosteroid doses monthly and their peak nasal inspiratory
• Urinary leukotriene E4 and the (PG) flows increased
D2 metabolite 9a,11b-PGF2 after 1, 3, • The dosages of inhaled
5 and 6 months. corticosteroids were reduced
• No changes in leukotriene E4
or 9a,11b-PGF2 levels after AD

Fruth DBPCT 6 70 CRSwNP • After desensitization • QOL (Rhinosinusitis Disability Index In aspirin treated group compared
(207) wks post- with N-ERD maintenance dose of questionnaire) at 6, 12, 24 and 36 to placebo at 36 months:
2013
operative (30 evaluated) 100 mg daily for 36 months • Significantly better Quality-of-
months (n=18) • Symptoms scores (0-4) for nasal life score
• After desensitization airway obstruction, postnasal drip, • Significantly lower total
maintenance dose of cephalgia, impairment of olfactory symptom score
placebo daily for 36 function • Lower quality-of-life
months (n=13) • Coughing and sneezing (0-2) impairment by nasal and
• Total symptom score (0-20) paranasal complaints
• Smell (Sniffin’ Sticks) at 6, 12, 24 and • Lower overall nasal and
36 months paranasal complaints, quality-
• Nasal polyp score (0-3) of-life impairment by nasal
• Overall nasal and paranasal com- and paranasal complaints and
plaints [1 (best)-7 (worst)] general health condition
• Quality-of-life impairment by nasal • Less revision sinus surgery
and paranasal complaints (1-7)
• General health condition (1-7)
• Revision sinus surgery

ACQ, Asthma Control Questionnaire; ; AD, Aspirin Desensitizatio ; AIA, Aspirin-induced Asthma ; ATA, Aspirin-tolerant Asthma ; CRSwNP,
chronic rhinosinusitis with nasal polyps; CT, computed tomography; DBPCT, double blind placebo controlled trial; FEV1, forced expirato-
ry volume 1; IFN, interferon; IL, interleukin; LM, Lund-Mackay; N-ERD, NSAID-exacerbated respiratory disease ; PEF, Pulmonary Expira-
tory Flow ; PG, Prostaglandin ; PNIF, peak nasal inspiratory flow; QOL, quality of life; SNOT, Sino-nasal Outcome Test; TGF, Transforming
Growth Factor .

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Table 6.1.12.2. Nasal lysine aspirin solution for the treatment of CRS patients with N-ERD.

Study Methods Participants Interventions Outcomes Results

Parikh 2005(211) DBPC 22 aspirin- • Incremental doses of lysine aspirin • Nasal and pulmonary symptom • No significant
cross-over sensitive patients solution (LAS) until a dose of 16 mg scores differences
trial (19 CRSwNP), 11 was tolerated followed by LAS every • Peak expiratory flow rate (PEFR) between the
completed the 48 hours for 6 months (n=11) • Nasal inspiratory flow (PNIF), groups
full study (2 one • Incremental doses of lysine aspirin • Acoustic rhinometry
phase of cross- solution (LAS) until a dose of 16 mg
over) was tolerated followed by placebo
every 48 hours for 6 months (n=11)

DBPC, Double Blind Placebo Controlled ; CRSwNP, Chronic Rhinosinusitis with nasal polyps; LAS, lysine aspirin solution; PEFR, peak
expiratory flow rate; PNIF, peak nasal inspiratory flow

Table 6.1.12.3. Low salicylate diet for the treatment of CRS patients with N-ERD.
Study Methods Participants Interventions Outcomes Results
Sommer Crossover 14 aspirin-sensitive • 6 weeks low-salicylate • SNOT-22 • No significant differences
2015(874) RCT patients (10 (n=10) • Nasal Symptom Severity Score (NSSS) apart from POSE
evaluated) • 6 weeks normal diet • Lund-Kennedy score
(n=10) • POSE
• ACQ-7
Sommer Partially 30 aspirin-sensitive • 6 weeks low-salicylate • SNOT-22 • All parameters significantly
2016(875) single blind patients (27 (n=30) • Nasal Symptom Severity Score (NSSS) better in patients on low-
crossover evaluated) including • 6 weeks normal diet • Lund-Kennedy score salicylate diet
RCT the patients (n=30) • POSE
from(874) • ACQ-7

RCT, Randomised Controlled Trial ; SNOT, Sino-Nasal Outcome ; NSSS, Nasal Symptom Severity Score; LK, Lund-Kennedy; POSE,
Perioperative Sinus Endoscopy score ; ACQ, Asthma Control Questionnaire

Table 6.1.12.4. Prasugrel for the treatment of CRS patients with N-ERD.
Study Methods Participants Interventions Outcomes Results
Laidlaw DBPC 46 aspirin- • Prasugrel 5 mg/d for patients weigh- • Change in the provocative dose of aspirin • No
crossover sensitive patients ing <60 kg or Prasugrel 10 mg/d for at 4 weeks significant
(876)
2018 trial (40 evaluated), patients weighing _>60 kg after a 60- • Changes in lung function, urinary eicosa- differences
unclear how many mg loading dose) for 4 weeks (n=40) noids, plasma tryptase, platelet-leukocyte
had CRS • Placebo for 4 weeks n=40) aggregates, and platelet activation at 4
weeks
CRS, Chronic Rhinosinusitis; DBPC, Double Blind Placebo Controlled

6.1.12.2. Aspirin treatment after desensitization with oral Aspirin treatment after desensitization (ATAD)
aspirin with oral aspirin is effective in improving QOL and
Since EPOS2012 four DBPCTs with ATAD have been performed total nasal symptom score in patients with N-ERD.
(Table 6.1.12.1)(204-207). Three of these studies could be meta-
analysed to show that ATAD results in a significant and clinically The study by Fruth(207) was interesting in that it had a 36 months
relevant reduction of the SNOT score of 11,9 points (based on follow-up. Unfortunately, 39 out of 70 patients, 18 of the aspirin
SNOT-22)(204-206). Pooled data analysis of the SNOT score showed and 21 of the placebo group, discontinued the treatment in that
significant benefit in the ATAD group over placebo (MD -0.54[- period, although none because of side effects of the aspirin.
0,76, -0,31], p=0.00001, three trials, 85 patients). The I2 was 0%. In the patients that completed the full follow-up period there
For this analysis, mean scores from SNOT-20 and SNOT-22 were was a trend to less recurrences of polyps in the ATAD group
taken for assessment (i.e. SNOT-22 scores were divided by 22 compared to placebo and the ATAD groups showed significantly
and SNOT-20 scores were divided by 20) (Figure 6.1.12.1.). fewer overall nasal and paranasal complaints, less quality-of-
Also, two studies from the same group reported on a significant life impairment by nasal and paranasal complaints, and better
reduction in total symptoms. general health condition.
Pooled data analysis of the total symptoms score (total score
27) showed significant benefit in the ATAD group over placebo 6.1.12.3. Aspirin treatment after desensitization with nasal
(MD -3.51 [-5.2-, -1.81], p=0.0001, two trials, 70 patients) (Figure lysine-aspirin
6.1.12.2.) and Forced Expiratory Volume 1 (FEV1) (MD 6.43 [3.26-, Nasal administration of lysine-aspirin reduces the risk of severe
9.61], p=0.0001, two trials, 70 patients) (Figure 6.1.12.3.). hypersensitivity reactions and the frequency of gastrointestinal

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Figure 6.1.12.1. Forest plot of the effect of ATAD versus standard treatment alone on the SNOT score
six months after start of the treatment in patients with CRSwNP.

Figure 6.1.12.2. Forest plot of the effect of ATAD versus standard treatment alone on the symptom score
six months after start of the treatment in patients with CRSwNP.

Figure 6.1.12.3. Forest plot of the effect of ATAD versus standard treatment alone on the FEV1 six months after start of the treatment
in patients with CRSwNP.

side effects associated with oral aspirin desensitization. Some high omega-3/low omega-6 diet for the treatment of aspirin
retrospective studies reported clinical benefit from nasal exacerbated respiratory disease (AERD)(212). The authors
lysine-aspirin treatment(208-210). In a randomized, double-blind concluded that a high omega-3/low omega-6 diet may be an
placebo-controlled cross over trial, N-ERD patients with positive appropriate adjunct treatment option for patients with AERD.
nasal lysine-aspirin challenge received either 16mg nasal lysine
aspirin or placebo every 48 hours for six months. Of 22 patients 6.1.12.5. Prasugrel
entering the trial, 11 were eligible for analysis. Multivariate Finally, a DBPC crossover trial was performed with Prasugrel.
analysis of measured parameters did not reveal a significant Prasugrel is a platelet inhibitor and an irreversible antagonist
clinical benefit to patients receiving topical lysine-aspirin of P2Y12 ADP receptors. The study showed no significant effects
compared with placebo(211) (Table 6.1.12.2). on change in aspirin provocation dose or lung function (Table
6.1.12.4).
6.1.12.4. Diets
Recently two crossover RCTs evaluated the effect of a low 6.1.12.6. Side effects of ATAD
salicylate diet on sinus (SNOT-22) and asthma (ACQ-7) quality ATAD is associated with adverse effects (mostly gastrointestinal),
of life. The second study contained the data of the first study. and the incidence of adverse symptoms related to aspirin intake
The second study showed significant and clinically relevant ranges from 0% to 34%(201). In order to reduce the prevalence of
improvement in SNOT22 (15.5 points) and ACQ-7 (5 points). adverse effects associated with aspirin treatment, appropriate
Also, the Nasal Symptom Severity Score, the Lund-Kennedy preventive measures (Helicobacter pylori eradication, PPI, and
score and the POSE showed significantly better results with the H2blockers) should be introduced and continued during the
low salicylate diet than with the normal diet (Table 6.1.12.3). treatment(201).
Moreover, a cohort study was performed on the effect of a

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6.1.12.7. Conclusions 6.1.13. Antimycotics

Oral ATAD has been shown to be significantly more effective and
clinically relevant than placebo in improving QOL (measured 6.1.13.1 Introduction
with SNOT) and total nasal symptom score in patients with Although the aetiology of chronic rhinosinusitis is not fully
N-ERD. However, the change in SNOT from treating with understood, it may involve abnormalities in the host response to
oral ATAD compared to placebo did not reach the clinically irritants, commensal and pathogenic organisms and allergens.
important mean difference (CIMD) (MD -0.54[-0,76, -0,31], There is much debate regarding the role of fungus in the
p=0.00001, three trials, 85 patients). ATAD reduced symptoms aetiology of chronic rhinosinusitis. Intranasal fungus can be
after six months compared to placebo (with MD -3.51 [-5.2-, demonstratedin nearly all diseased and normal sinuses(213-215).
-1.81], p=0.0001, two trials, 70 patients on a scale of 27), the Although fungi are ubiquitous in our environment, there are
FEV1 showed a significant reduction compared to placebo several forms of sinus disease that are associated with fungi
and the data were consistent. However, ATAD is associated as pathogens. However, rather than the fungi determining
with significant adverse effects, and the risks of not taking the the disease process, it is usually the host immune state that
medication strictly on a daily basis puts a burden on patient determines the clinical presentation. The role of antifungal
and caregiver. Based on these data, the EPOS2020 steering therapies in the setting of established fungal-related CRS is
group suggests that ATAD can be a treatment for N-ERD patients summarised in Fungal associated RS (Chapter 9.6). This chapter
with CRSwNP whenever there is confidence in the patient’s summarises the role of antimycotics in the setting of CRSwNP
compliance. and CRSsNP.
Lysine aspirin and platelet inhibitors (like Pradugrel) have not Based on fungal detection and the presence of allergic mucus
been shown to be an effective treatment in CRSwNP patients in almost all patients with chronic rhinosinusitis, Ponikau
with N-ERD and are not advised. Diets, like low salicylate diet and co-authors proposed that CRS is generally caused by a
were shown to improve endoscopic scores and may improve dysregulated, but IgE independent immune response to fungal
symptoms compared to a normal diet in patients with N-ERD. elements present on the mucosal surface(213).
However, the quality of the data at this moment is not enough Consequently, reduction of fungus load should influence
to draw further conclusions.

Figure 6.1.13.1. Forest plot of the effect of local antifungal treatment versus placebo on SNOT score in patients with CRSwNP after 2-3
months of treatment.

Figure 6.1.13.2. Forest plot of the effect of local antifungal treatment versus placebo on total symptom score in patients with CRSwNP
after 2-3 months of treatment.

Figure 6.1.13.3. Forest plot of the effect of local antifungal treatment versus placebo on nasal endoscopy score in patients with
CRSwNP after 2-3 months of treatment.

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Figure 6.1.13.4. Forest plot of the effect of local antifungal treatment versus placebo on CT scan score in patients with CRSwNP after
2-3 months of treatment

Table 6.1.13.1. Local antifungal treatment for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Jiang DBPCT 79CRS • 50 ml of 200 μg/mL of amphotericin • Taiwanese SNOT-22 at 2 No significant difference for any
2018(227) patients (26 B per nostril (daily dose 20 mg) once months outcome
CRSwNP) (73 a day (n=37) for 2 months • Endoscopy at 2 months
completed the 50 ml of saline (n=36) • Smell test at 2 months
trial) starting • Saccharine transit test at 2
1 month months
postoperative • Bacterial culture at 2 months
FESS

Yousefi DBPCT 80 CRS patients • 10 ml (5 ml per nostril) of 200 μg/ • RSOM-31 at 3 months No significant difference for
2017(226) (40 CRSwNP) mL amphotericin B twice daily (daily • VAS symptom score (for nasal any outcome apart from facial
dose 8 mg) for 3 months congestion, post-nasal drip, pain that was better in the
• 10 ml placebo (5 ml per nostril) reduction in the sense of smell amphotericin-treated group
twice daily for 3 months and facial pain) at 3 months
• Nasal endoscopy at 13 weeks
• Blood levels of IgE, IL- 4, IL-
5,and IL-13
• CT and MRI
Hashemian DBPCT 54 CRS patients • 12 drops per day, 2 times a day of • SNOT-20 at 8 wks No significant difference for any
2016(219) (21 CRSwNP) fluconazole nasal drops (0.2%,) (daily • Endoscopy at 8 wks outcome
(48 completed dose 1.2 mg) for 8 wks (n = 27) • CT scan at 8 wks
the study) • Placebo nasal drops (12 drops per • Adverse effects
day, 2 times a day) for 8 wks (n = 27)

Jiang DBPCT 87 CRS • 50 ml of 100 μg/mL of amphotericin • Taiwanese SNOT-22 at 2 No significant difference for any
2015(225) patients (33 B per nostril (daily dose 20 mg) once months outcome
CRSwNP) (77 a day (n=37) for 2 months • Endoscopy at 2 months
completed the • 50 ml of saline (n=36) • Smell test at 2 months
trial) starting • Saccharine transit test at 2
1 month months
postoperative • Bacterial culture at 2 months
FESS

Gerlinger DBPCT 33 CRSwNP • Amphotericin B (5 mg/ml), nasal • CT scan at 8 wks No significant difference for any
2009(224) patients (30 spray, 2 puffs per nostril (100 µl per • SNAQ-11(877) at 8 wks outcome
completed the nostril), twice daily (total daily dose • Nasal endoscopy at 8 wks
trial) directly = 4.8mg) for 8 wks (n=16)
postoperative • Placebo nasal spray (0.2 µg/ml
FESS acriflavin chloride solution ) for 8
wks (n=17)

Liang DBPCT 70 CRSsNP (64 • 250 ml of amphotericin B • Chinese RSOM-31 at 2 and No significant difference for any
2008(223) completed the (containing 10 mg of amphotericin 4 wks outcome
study) B) per nostril once daily (total daily • Endoscopy
dose = 20 mg) for 4 wks (n=35) • Fungal and bacterial cultures
• 250 ml of placebo per nostril once
daily (total daily dose = 20 mg) for 4
wks (n=35)

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Study Methods Participants Interventions Outcomes Results

Ebbens DBPCT 116 CRSwNP • 25 ml of amphotericin B (100 µg/mL) • RSOM-31 at 13 weeks No significant differences in any
2006(222) patients (111 in 2.5% glucose applied to each nos- • Total VAS symptom score (the parameter measured
completed the tril twice daily for 13 weeks (n=59) sum of VAS for nasal block-
study) (daily dose 10 mg) age, rhinorrhoea, facial pain,
• 25 ml of placebo nasal lavage (3.4 postnasal drip and anosmia) at
mL/L Cernevit in 2.5% glucose) 13 weeks
applied to each nostril twice daily for • SF36 at 13 weeks
13 weeks (n=57) • Endoscopy at 13 weeks
• PNIF at 13 weeks
• Levels of pro-inflammatory
cytokines, chemokines and
growth factors and albumin
• Adverse effects
Ponikau DBPCT 30 CRS patients • 20 mL amphotericin B solution (250 • SNOT-20 at 3 and 6 months • No significant differences in
2005(221) (24 completed µg/mL) per nostril twice daily for 6 • Endoscopy at 3 and 6 months. SNOT-20 at 3 and 6 months
the study) months (n=15) (daily dose 20 mg) • CT scan at 6 months • Significant better change
• 20 mL placebo solution per nostril • Adverse effects from baseline for endoscopy
twice a day for 6 months (n=15) at 3 and 6 months and for
CT scan at 6 months in
the amphotericin B group
compared to placebo
• 2 patients in the amphotericin
B group complained of
burning
Weschta DBPCT 78 CRSwNP • Amphotericin B (3 mg/mL), nasal • Rhinosinusitis quality of life No significant differences in any
2004(220) patients (60 spray, 2 puffs per nostril (200 µLper score (RQL) (0-36) at 8 wks parameter but symptom scores
completed the nostril), 4 times daily (total daily dose • VAS for nasal blockage, facial that were better in the placebo
study) = 4.8mg ) for 8 wks (n=39) pain, smell, nasal discharge treated group than in the
• Placebo nasal spray: saline solution sneezing at 8 wks amphotericin B treated group
containing tartrazine, chinin sulfate, • Endoscopy at 8 wks
1-(4-sulfo-1-phenylazo)-2-naphthol- • CT scan at 8 wks
6-sulfo acid, choline in 5% glucose • Adverse events
solution, 2 puffs per nostril, 4 times
daily for 8 wks (n=39)
CRS, Chronic Rhinosinusitis; CRSsNP, Chronic Rhinosinusitis without nasal polyps ; CRSwNP, Chronic Rhinosinusitis with nasal polyps; DBPCT, Double
Blind Placebo Controlled Trial ; SNOT, Sino-Nasal Outcome ; RSOM-31, Rhinosinusitis Outcome Measure-31 ; VAS, Visual Analogue Scale ;anti IgE,
anti-immunoglobulin E ; IL, Interleukin; CT, computed tomography; MRI, Magnetic Resonance Imaging; SNAQ, Sino-nasal Questionnaire ; SF-36, Short
Form 36 ; PNIF, Peak Nasal Inspiratory Flow ; RQL, Rhinosinusitis quality of life score.

disease severity in all subtypes of CRS. This hypothesis led to a 9.6.5.4). Seven studies (437 participants) were included that
series of investigations, as proof of this concept of fungal-driven used amphotericin B (six studies; 383 participants). The authors
inflammation in CRS. In these studies, patients complying with concluded that due to the very low quality of the evidence, it is
the AAO-HNS or EPOS definitions of CRS were included(216, uncertain whether the use of topical or systemic antifungals has
217)
irrespective of the presence of eosinophilic mucus and/or an impact on patient outcomes in adults with CRS compared
fungus detection. In this systematic review studies of patients with placebo or no treatment. In terms of adverse effects, they
fulfilling the AAO-HNS or EPOS definitions of CRS (with or concluded that topical antifungals may lead to more local
without nasal polyps) are evaluated. Subgroup analyses explore irritation compared with placebo.
potential differences where possible.
Local and systemic antifungal treatments do not
6.1.13.2. Topical amphotericin B have a positive effect of QOL, symptoms and signs
In most trials with antifungals in CRS, amphotericin B was of disease in patients with CRS.
applied topically, either as a nasal spray or as a nasal irrigation.
The majority of patients included in these trials suffered from We systematically reviewed the literature and included nine
CRSwNP. However, the presence of nasal polyps was not studies [627 CRS patients (373 CRSwNP; 567 CRS patients)
explicitly reported in all trials. Recently a Cochrane review has completed the trials], local antifungal treatment, eight studies
been published evaluating the effect of topical amphotericin comparing amphotericin B and in one study, fluconazole nasal
B in CRS with or without NP but not in patients that recently drops(219)with placebo (usually yellow coloured saline)(219-227)
had surgery(218). The authors included eight studies (490 adult (Table 6.1.13.1.). Three studies involved patients with CRSwNP(220,
participants). No studies that specifically investigated the effect 222, 224)
, one study(223) involved patients with CRSsNP, and the other
of antifungals in patients with AFRS were included (Chapter studies were either mixed populations or it was not clear what

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kind of CRS patients were included. to the subcutaneous administration of four to eight doses of
The volumes and total daily dose of local antifungal treatment omalizumab or placebo. Total serum IgE levels were between
varied and we also included three studies(224, 225, 227) that were 20 and 700 kU/mL. The subcutaneous administration of four to
performed postoperatively. eight doses of omalizumab was not found to result in significant
None of the studies showed a significant difference for total reduction in RSOM-31 or SF-36. But the physical domain of
symptoms or QOL in favour of the antifungal. SF-36 and the Asthma Quality of Life Questionnaire (AQLQ)
Three studies using SNOT (SNOT-22 or SNOT-20) could be demonstrated a significant improvement in the omalizumab
combined in a meta-analysis (Figure 6.1.13.1). group, whereas no significant changes were seen in the placebo
The analysis showed a trend for placebo to have a better impact group. Anti-IgE resulted in significantly lower symptoms scores
on SNOT score than local fungal treatment. for nasal congestion (p=0.003), anterior rhinorrhoea (p=0.003),
Two studies could be combined in a meta-analysis, showing a loss of sense of smell (p=0.004), wheeze (p=0.02) and dyspnoea
more favourable outcome in symptomatology for placebo than (p=0.02) compared to baseline. Cough and spirometric results
for oral antifungal treatment (Figure 6.1.13.2). did not improve with anti-IgE treatment.
Five studies(219, 222, 225-227) could be combined into a meta-analysis A linear mixed model demonstrated a lower total nasal polyp
evaluating the effect of local antifungal on nasal endoscopy. score (NPS) in the omalizumab group compared to the placebo
The analysis showed no difference between local antifungal group throughout the study period (p=0.2). Lund-MacKay scores
treatment and placebo (Figure 6.1.13.3). were significantly better in the omalizumab group compared
Finally, five studies could also be meta-analysed concerning to placebo (p=0.04) on radiologic imaging. The clinical and
the effect of local antifungal treatment on CT scan radiographic improvements following use of anti-IgE therapy
opacification(219-221, 224, 226). Also, in this analysis no significant were seen independent of serum IgE levels. At 16 weeks, a
difference was found between the two options (Figure 6.1.13.4). decrease in total NPS was seen in allergic (-2.57; p= 0.03) and
non-allergic patients (-2.75; p=0.06). An improvement in Lund-
6.1.13.3. Systemic antifungal treatment Mackay CT scan scores was observed in the allergic patients
One study evaluated the effect of systemic antifungal treatment (22.61, p=0.04), but this was not observed in nonallergic patients
with terbinafine vs. placebo (53 participants) and reported that (20.66, p=0.75). By contrast, the total AQLQ score demonstrated
there was little or no difference between the groups in disease- an improvement in the nonallergic group (259.4, p=0.03), but
specific health-related quality of life or disease severity score not in the allergic group (212.3, p=0.12). At least one adverse
(both low-quality evidence)(886). Systemic antifungals may lead event was observed in 22 of 23 (95.7%) included patients. The
to more hepatic toxicity events (RR 3.35, 95% CI 0.14 to 78.60) most commonly reported adverse event was a common cold in
but fewer gastrointestinal disturbances (RR 0.37, 95% CI 0.04 the omalizumab group which occurred at a higher rate in the
to 3.36), compared to placebo, although the evidence was of treatment group compared to the control (p=0.02). One patient
low quality. This study did not find a difference in CT scan score developed fatal lymphoblastic lymphoma in the omalizumab
between the groups. Generic health-related quality of life and group one year following the study. Of note, four of eight (50%)
nasal endoscopic score were not measured. of patients in the control group were excluded from the analysis.
Pinto et al.(230) conducted a randomized, double-blind, placebo-
6.1.13.3. Conclusions controlled trial of anti-IgE for CRS in 14 patients (12 of 14
Local and systemic antifungal treatments do not have a positive with CRSwNP) refractory to standard treatment. Participants
effect of QOL, symptoms and signs of disease in patients with were required to have a serum total IgE between 30 - 700 IU/
CRS. The EPOS2020 steering group advises against the use of ml. All patients received omalizumab, 0.016 mg/ kg per IU
these treatments in patients with CRS. The EPOS2020 steering subcutaneously, or placebo injections every two to four weeks
group advises against the use of anti-mycotics in CRS. for six months. There was no significant net difference in SNOT-
20 scores across treatments (median omalizumab –5.5, placebo
6.1.14. Anti-IgE –2.3, p < 0.60). The median change in SNOT-20 scores across
the study period was consistent with a clinically significant
6.1.14. 1. Summary of the evidence improvement (defined as at least 0.8) in the omalizumab group
The pathophysiology of CRSwNP is characterized by prominent and no clinically significant change in the placebo group
local production of IgE that may contribute to chronic (-1.05 vs. -0.20, p<0.78). There were no significant differences
inflammation by continuously activating mast cells(228). Two between treatments for any domain except for vitality
randomized clinical trials(229, 230) have investigated the role of (omalizumab 9.4, placebo 12.5, p < 0.05). Similarly, there were
omalizumab, a recombinant humanized monoclonal antibody, no statistical differences in total University of Pennsylvania Smell
in CRS management (Table 6.1.14.1). The mechanism of action Identification Test (UPSIT) score, nasal endoscopy scores, sinus
of omalizumab involves its selective binding to free circulating opacity in CT scan, median change in percent eosinophils in
IgE which decreases the expression of IgE receptors on mast nasal lavage, median PNIF), and median total nasal symptom
cells, basophils and dendritic cells, and interferes with activation scores between the omalizumab and placebo groups. Patients
of these effector cells(229, 231, 232). on omalizumab used fewer courses of steroids over the trial
In the study by Gevaert et al.(229), 24 patients with CRSwNP and (median 0 vs. 1, p<0.043) and less use of antibiotics (0 vs. 1,
comorbid asthma for more than two years were randomized p<0.32) compared to placebo. No side effects or adverse events

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Table 6.1.14.1. Anti-IgE therapy for the treatment of patients with CRSwNP.
Study Methods Participants Interventions Outcomes Results
Gevaert et al. Double-blind 24 patients • Omalizumab At 16 weeks: Anti-IgE compared to placebo resulted in:
placebo (>18 years) every 2 weeks/8
2013 (229)
controlled with CRSwNP injections in
• Quality of life question- • No significant impact on QOL but significant
naires (RSOM-31, AQLQ, improvement compared to baseline of anti-IgE
randomized total or every
SF-36) treated group for AQLQ, physical domain of SF-36
clinical trial 4 weeks/4 in-
jections in total
• symptoms score and some subdomains of RSOM-31
based on total
• Total endoscopic polyp • Lower symptoms scores (change from baseline
score in anti IgE group) for nasal congestion, anterior
serum IgE levels
and body weight
• Lund-Mackay CT score rhinorrhea, loss of sense of smell, wheeze and
(maximum
• Spirometric results dyspnea
dose of 375mg)
• Adverse events • Reduction of polyp size on endoscopic exam-
ination
(n=16)
• Placebo (n=8) • Improvement in Lund-MacKay scores
• Increased common colds (p=0.02)
• One event of fatal lymphoblastic lymphoma in 1
year following the study

Subgroup group analysis of allergic vs non-allergic

patients demonstrated:
• A decrease in total polyps score in allergic (-2.57;
p= 0.03) and non-allergic patients (-2.75; p=0.06).
• Improvement in Lund-Mackay CT scan scores
was observed in the allergic patients (22.61,
p=0.04), but not observed in nonallergic patients.
• Improvement in total AQLQ score in the nonaller-
gic group (259.4, p=0.03), but not in the allergic
group (212.3, p=0.12)
Pinto et al. Double-blind, 14 patients 7 patients received • SNOT 20 at month 1, 2, Omalizumab compared to placebo resulted in:
placebo- with CRS omalizumab (0.016 3, 4, 5, 6
2010 (230)
controlled, (12 CRSwNP, mg/kg per IU total • SF-36 at 6 months
• No significant difference in SNOT-20 or SF-36
randomized 2 CRSsNP) serum IgE/mL • Total nasal symptom
• Increased median change in sinus opacity in
coronal CT scans
clinical trials subcutaneously) score (nasal obstruction,
7 patients received nasal discharge, facial
• Fewer courses of steroids over the trial (median 0
vs 1, p<0.043)
placebo injections pain, hyposmia, 0-4 each)
at 6 months
• Less use of antibiotics (0 vs 1, p<0.32)
• UPSIT at 6 months
• No significant net difference in SNOT-20 No side
effects or adverse events in either treatment
• Sinus CT % opacification
group
at 6 months
• Nasal endoscopy polyp
score at 6 months
• PNIF at 6 months
• Use of rescue medica-
tions at 6 months
• Nasal lavage for eosino-
phil counts at 6 months
• Adverse events at 6
months
CRSwNP,Chronic Rhinosinusitis with nasal polyps; RSOM-31, Rhinosinusitis Outcome Measure-31; AQLQ, Asthma Quality of Life Ques-
tionnaire; SF-36, Short Form 36; QOL, Quality of Life; IgE, Immunoglobulin E; CRS, Chronic Rhinosinusitis; CRSsNP, Chronic Rhinosi-
nusitis without nasal polyps; SNOT, Sino-Nasal Outcome; UPSIT, University of Pennsylvania Smell Identification Test; PNIF, Peak Nasal
Inspiratory Flow.

occurred during the study. The investigators were limited by experience with anti-immunoglobulin-E (IgE) treatment
poor subject recruitment due to perceived risk of placebo, high indicating a very small chance of anaphylaxis(233) but some
time commitment, high patient volume not meeting study indication of an association with arterial and venous
inclusion criteria and a U.S. Food and Drug Administration thromboembolic events leading to cardiovascular and
(FDA)-issued warning about anaphylaxis associated with cerebrovascular accidents(234).
omalizumab. Recent unpublished data point to a significant
impact on baseline in nasal polyp score and change from 6.1.14.2. Conclusion
baseline in average daily nasal congestion score, SNOT-22 and Anti-IgE therapy has been proposed as a promising biologic
sense of smell. therapy for CRS. Two RCTs that evaluated anti-IgE monoclonal
Concerning side effects, at this moment there is a vast antibody included patients with serum IgE levels between 20

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kU/mL and 700 kU/mL and compared omalizumab (0.016 mg/ other QOL, symptoms, and lung function were also completed.
kg per IU total serum IgE/mL; max dose of 375 mg) to placebo. One-hundred-and-five patients were initially included and
Both these small studies (<30 patients) did not show impact 74 ultimately completed treatment through to week 25 for
on disease specific QOL but one study did show an effect assessment. More patients in the mepolizumab group no longer
on the physical domain of SF-36 and AQLQ(229). One study(229) met the criteria for surgery when compared to those in the
demonstrated lower symptom scores (change from baseline in placebo group at week 25 (ITT, 16(30%) vs. 5 (10%);p=0.006).
anti IgE group) for nasal congestion, anterior rhinorrhoea, loss There were also significant differences in VAS scores for
of sense of smell, wheeze and dyspnoea, a significant reduction rhinorrhoea, nasal blockage, mucus, and loss of smell (treatment
of NPS on endoscopic examination, and Lund-MacKay scores difference: -2.3(-3.4 to -1.2); p<0.001, -1.8(-2.9 to -0.7); p=0.002,
on radiologic imaging. Due to the small study population in the -2.1(-3.2 to -1.0); p<0.001, -1.9(-2.9 to -0.9);p<0.001). SNOT-22
existing studies, further studies with larger population sizes are scores also significantly improved in the mepolizumab group
needed and are underway. The available data are insufficient to at weeks 25 (treatment difference: -13.2(-22.2 to -4.2); p=0.005).
advise on the use of anti-IgE in CRSwNP at this moment. There was statistical benefit in PNIF at 25 weeks (treatment
difference: 26.7(3.1 to 50.2); p=0.027), but no statistical
6.1.15. Anti-IL5 difference in olfaction or pulmonary function testing. There
were no significant differences in adverse events.
6.1.15.1. Summary of the evidence Gevaert et al.(239) performed a double blind, placebo-controlled
Previous treatment of CRS has included both topical and trial evaluating the effect of mepolizumab on nasal polyposis
systemic corticosteroids, long-term antibiotics, and surgical in 30 patients with grade 3 or 4 polyps or those who had
intervention. However, some patients have recalcitrant disease recurrence following surgery. Patients received either 750mg
despite utilization of best practices. Interleukin 5 (IL-5) is of mepolizumab or placebo via IV injection 28 days apart from
essential for final differentiation into an eosinophil and prolongs two doses. Patients were assessed for changes in symptom
survival of the mature cell in the tissue(235). IL-5 has been noted scores, NPS, CT scores, PNIF, and biological activity (defined
to be elevated in nasal polyp tissue, and therefore has made it as blood eosinophil counts, cytokine measurements in nasal
a potential target for the management of patients with non- secretions). Safety and adverse events data was also collected.
allergic asthma and CRSwNP(236, 237). A few drugs have undergone The mepoluzimab group showed no significant difference in
testing and been available on the market, for the purpose of symptoms but had a greater change from baseline polyp score
this review we will discuss mepolizumab and reslizumab, both resulting in a significant treatment difference when compared to
blockers of free IL-5, as they have undergone randomized placebo (-1.30(1.51); p=0.028). There was a significant reduction
controlled trial testing. RCT studies on benralizumab, a blocker in the mepolizumab treated group when compared to placebo
of IL-5Rα, are ongoing. in blood eosinophil counts, serum eosinophil cationic protein
Three placebo-controlled studies(238-240) evaluating anti-IL5 (ECP) levels, and serum IL-5Rα between the groups (raw data not
monoclonal antibodies were identified. Two of these studies available). There was no difference in the nasal ECP, IL-5, or total
evaluated mepolizumab(238, 239), while one study evaluated IgE levels.
reslizumab(240). Despite, these studies being placebo-controlled Gevaert et al.(240) performed a double blind, placebo-controlled,
trials, the data was unable to be pooled for meta-analysis, two-centre safety and pharmacokinetics study evaluating
therefore each paper will be discussed below (Table 6.1.15.1.). reslizumab in 24 patients with CRSwNP. Biologic activity of
Bachert et al.(238)evaluated the efficacy of mepoluzimab in the monoclonal antibody was assessed via endoscopic NPS,
patients with CRSwNP who were also on INCS (FPNS 200µg). sinosal symptoms, peripheral eosinophils, peripheral and local
All patients were given an infusion every four weeks for a total eotaxin levels, ECP, and IL5 levels. Patients (n=24) were divided
of six doses of either mepolizumab 750mg or placebo. Efficacy into three groups: receiving 1mg/kg of reslizumab, 3mg/kg of
was measured as the number of patients who no longer needed reslizumab, or a placebo via IV for one dose. Adverse events and
revision surgery based upon VAS scores of CRS severity and NPS safety data were also obtained. Twenty-three (95.8%) subjects
following the implementation of mepolizumab. Assessments of reported at least one adverse event, which was most often a

Figure 6.1.15.1. Forest plot of the effect of anti-IL-5 biologics versus placebo on adverse events in patients with CRSwNP.CRSwNP after
2-3 months of treatment.

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Table 6.1.15.1. Anti-IL-5 for the treatment of patients with CRSwNP.

Study Methods Participants Interventions Outcomes Results

Bachert DBPCT 105 Severe Mepolizumab 750 Assessed at 25 weeks • Patients in the Mepo group no longer met
2017(238) CRSwNP mg IV q 4 weeks x • Number of patients no longer criteria for surgery compared to placebo (ITT<
6 months (n=54) v needing revision surgery 16(30%) vs 5(10%);p=0.006)
placebo infusion q • VAS polyp severity (0-10), • Significant improvement in the Mepo group for
4 weeks x 6 months • Endoscopic polyp score (0-8) VAS scores (rhinorrhoea, mucus, nasal block-
(n=53) • Symptom scores - VAS symp- age, and loss of smell, in SNOT22 (28.8(22) vs
toms - (rhinorrhoea, mucus, nasal 38.2(24.5), and PNIF (mean difference, 26.7(3.1-
blockage, loss of sense of smell), 50.2), p=0.027)
SNOT22, EQ-5D, PNIF, olfaction • Significant improvement in the Mepo group over
(0-12) placebo in nasal polyp severity VAS scores (mean
• Eosinophils change; -1.8(-2.9-0.8), p=0.001
• FEV1/FVC/PEFR • Blood eosinophils decreased in the Mepo group,
but not placebo group.
• No difference in EQ-5D scores, smell scores, or
lung function between the groups.
Gevaert DBPCT 30 Severe Mepolizumab Assessed at 8 weeks • No significant changes in symptom scores
2011(239) or recurrent 750mg IV q4weeks • Nasal polyp score (0-8) • Significant improvement in total polyp score at
CRSwNP x 2 doses (n=20) v • CT scan (improved, worse, no week 8 (treatment difference of -1.3(SD, 1.51),
placebo q4weeks x change) p=0.028) with increased improvement in the
2 doses (n=10) • PNIF Mepo group (60% v 10%, OR 13.5, p=0.018)
• Symptom score - anterior rhinor- • Improved change from baseline in PNIF in Mepo-
rhoea, nasal obstruction, PND, loss lizumab group compared to placebo (raw data
of smell (0-12) not available)
• Biological activity (peripheral • Significant reduction in blood eosinophil counts,
blood eosinophil counts, serums serum ECP levels, and serum IL5Rα in the mepoli-
ECP, serum IL5Rα, nasal ECP, IL5, zumab group, but not in nasal ECP, IL5, or IgE
IgE).
Gevaert DBPCT 24 CRSwNP Reslizumab 3mg/ Assessed at 4 weeks • No significant improvement in symptom scores
2006(240) kg (n=8) or 1mg/ • Endoscopy polyp size (0-8) or nasal peak inspiratory flow
kg (n=8) x 1 dose v • Symptoms (anterior rhinorrhoea, • Nasal polyp score was significantly decreased
placebo (n=8) nasal obstruction, PND, loss at 1 time point for 1mg/kg group (raw data not
of sense of smell) (scoring not available)
obvious) • Significant decrease in blood eosinophils, serum
• Nasal peak inspiratory flow ECP, and soluable IL5Rα (raw data not available)
• Eosinophil count (local and pe-
ripheral), ECP (local and peripher-
al), eotaxin (local and peripheral),
IL5 (local and peripheral)

CRSwNP, Chronic Rhinosinusitis with nasal polyps; PND, post nasal drip, ECP, eosinophil cationic protein; PNIF, peak nasal inspiratory flow; DBPCT,
double blind placebo controlled trial; OR, Odds ratio; SD , Standard deviation;FEV1, forced expiratory volume 1; FVC, Forced Vital Capacity, PEFR, Peak
Expiratory Flow Rate; SNOT, Sino-Nasal Outcome.

URI. There was no significant difference in symptom scores or anti-IL-5 monoclonal antibody group (SMD 0.72(0.29,1.77),
peak nasal inspiratory flow in both treatment groups compared p=0.48, two trials, 129 patients) (Figure 6.1.15.1.).
to placebo. The NPS was only significantly less at week 12 in the Unlike in CRS, there is a significant experience with anti-Il5 in
1mg/kg treatment group compared to baseline values. However, other Th2 driven diseases like asthma that do show a favourable
this study was not powered to determine differences in efficacy safety profile for the time used until now(241-244). In all these
variables. Reslizumab caused a significant decrease in blood studies, patients had previously undergone conventional
eosinophil counts in both treatment groups when compared therapy including sinus surgery and topical corticosteroid
to the placebo group. These results were evident as early as 12 irrigations with these medications reserved as a treatment
hours following administration. Similar findings were also true of option for patients who are considered recalcitrant despite best
serum ECP and IL5Rα, however, eosinophil counts did undergo efforts. This is an important adjunct to our armamentarium for
significant rebound in both treatment groups at week 24 and 32 treatment of these difficult to control CRS patients. The relative
following treatment administration. position of the different monoclonal antibodies one to another
has to be determined.
6.1.15.2. Safety
The only data that was able to be pooled for meta-analysis was 6.1.15.3. Conclusion
the number of patients who suffered from an adverse event. At the moment the only anti-Il-5 treatment studied in CRS is
There was no statistical significance between the placebo and mepolizumab. There is only one large sufficiently powered study

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that showed a significant reduction in patients’ need for surgery with dupilumab significantly improved SNOT-22, rhinosinusitis
and an improvement in symptoms. The EPOS2020 steering disease severity (VAS), nasal blockage, UPSIT smell score, NPS,
group advises use of mepolizumab in patients with CRSwNP LMS, and asthma outcomes (FEV1 and control) compared to
fulfilling the criteria for treatment with monoclonal antibodies control.
(245)
(see chapter 1). There was one study from Wenzel et al.(249) evaluating SNOT-22 in
a group of patients with persistent, moderate-to-severe asthma
Dupilumab is the only monoclonal antibody that and eosinophilia. Unfortunately, it was not evaluated whether
is approved for the treatment of CRSwNP at the these patients actually had CRS so we could not include the
moment. The panel advises to use dupilumab study. Four posthoc studies have been performed that are not
in patients with CRSwNP fulfilling the criteria for taken into account in this meta-analysis(250-253).
treatment with monoclonal antibodies. The Bachert studies were very much done in the same way and
could be combined into a meta-analysis of the three studies
6.1.16. Anti-IL4/IL13 evaluating dupilumab added to standard-of-care treatment to
patients with CRSwNP(247, 248).
6.1.16.1. Summary of the evidence The SNOT-22 score (scale 0-110) at 4-6 months showed a
IL-4 and IL-13 are potent mediators of type 2 immunity with significant and clinically relevant decrease of MD - 19.61 (95% CI
both overlapping and distinct functions. IL-13 and IL-4 partly -22.53 - -16.69); 784 participants; two studies; I2 = 0%), (Figure
share the same receptor and signalling pathways and both 6.1.16.1).
are deeply involved in IgE synthesis, eosinophil activation,
mucus secretion and airways remodelling. IL-4 is a major The Rhinosinusitis disease severity (VAS) at 4-6 months showed
differentiation factor driving a TH2 type response by initiating T a significant and clinically relevant decrease of MD – 2.54 (95%
cell differentiation toward the TH2 subtype. IL-4 also induces the CI -2.84 - -2.23); 784 participants; two studies; I2 = 40%), (Figure
production of type 2 associated cytokine and chemokines such 6.1.16.2).
as IL-5, IL-9, IL-13, TARC and fotaxin. Furthermore, IL-4 and IL-13 The nasal congestion/obstruction score at 4-6 months showed
are primarily responsible for isotype class switching of B cells to a significant and clinically relevant decrease of MD – 0.86 (95%
produce Ig(246). CI -0.98 - -0.75); 784 participants; two studies; I2 = 0%), (Figure
6.1.16.3).
6.1.16.1.1. Dupilumab Smell was evaluated using the UPSIT. The UPSIT score at 4-6
There is recent data on the efficacy of dupilumab in CRSwNP months showed a significant and clinically relevant decrease of
(table 6.1.16.1). Dupilumab is a fully human monoclonal MD 10.83 (95% CI 9.59 – 12.08); 784 participants; two studies; I2
antibody to the IL-4 receptor a subunit, which inhibits signaling = 0%), (Figure 6.1.16.4).
of IL-4 and IL-13 that is given as a subcutaneous injection. The nasal polyp score was the primary endpoint in these studies.
There are no other RCT’s performed in patients with CRSwNP The mean nasal polyp score in these studies was around 6
with the other anti-IL-4/IL-13 agents such as Tralokinumab and indicating severe polyp disease. The nasal polyp score at 4-6
Lebrikizumab-IL-13. months showed a significant decrease of MD -1.79 (95% CI
Bachert et al.(247) performed a proof of concept double blinded, -2.01 – -1.56); 784 participants; two studies; I2 = 65%), (Figure
placebo controlled parallel group study in 2013, which 6.1.16.5).
randomized 60 adult CRSwNP into two groups. After a four- The Lund-Mackay score (scale 0-48) at 4-6 months showed a
week run-in period of treatment with mometasone, patients significant decrease of SMD -1.50 (95% CI -1.84 – -1.16); 784
were randomly allocated to add-on therapy with subcutaneous participants; two studies; I2 = 71%), (Figure 6.1.16.6).
dupilumab (600mg loading followed by 15 weekly doses of Finally, there was a significant impact on ACQ and FEV1. Because
300mg) or matched placebo for 16 weeks. Patients treated ACQ5 and ACQ6 were used, the data could not be combined
with dupilumab had significant improvement in SNOT-22, into a meta-analysis but both studies showed a significant
rhinosinusitis disease severity (VAS), nasal blockage, UPSIT smell improvement over placebo. The FEV1 could be combined into a
score, nasal polyp score (NPS), and CT score (LMS), and asthma meta-analysis and showed a significant improvement in FEV1 (l)
outcomes (FEV1 and control) compared to placebo. at 4-6 months of MD 0.21 (95% CI 0.20 – 0.22); 488 participants;
Bachert et al.(248)published the results of two randomised two studies; I2 = 0%), (Figure 6.1.16.7).
double-blind, multicentre, placebo-controlled, parallel
group phase 3 trials which evaluated dupilumab added to The most common adverse events (nasopharyngitis, worsening
standard-of-care in adults with severe CRSwNP. In the liberty nasal polyps and asthma, headache, epistaxis, injection-site
NP SINUS-24 study, patients were randomized 1:1 to 24 weeks erythema) were more frequent with placebo. When evaluating
subcutaneous dupilumab 300mg or placebo every two weeks. all trials with dupilumab the drug seems to induce conjunctivitis
Liberty NP SINUS-52, patients were randomized 1:1:1 to 52 in trials in patients with atopic dermatitis but no trials with
weeks dupilumab 300mg every two weeks, 24 weeks every two asthma and CRSwNP(254). No other adverse events have been
weeks then 28 weeks dupilumab 300mg every four weeks, or reported in the literature up until now.
52 weeks placebo every two weeks. In both studies, treatment

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Figure 6.1.16.1. Forest plot of the effect of Dupilumab versus placebo on SNOT-22 score in CRSwNP patients at 4-6 months.

Figure 6.1.16.2. Forest plot of the effect of Dupilumab versus placebo on the rhinosinusitis disease severity (VAS) in CRSwNP patients
at 4-6 months.

Figure 6.1.16.3. Forest plot of the effect of Dupilumab versus placebo on the change in nasal congestion/obstruction score in
CRSwNP patients at 4-6 months.

Figure 6.1.16.4. Forest plot of the effect of Dupilumab versus placebo on UPSIT score in CRSwNP patients at 4-6 months.

Figure 6.1.16.5. Forest plot of the effect of Dupilumab versus placebo on the change in nasal polyp score in CRSwNP patients at 4-6
months.

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Figure 6.1.16.6. Forest plot of the effect of Dupilumab versus placebo on the Lund-Mackay score in CRSwNP patients at 4-6 months.

Figure 6.1.16.7. Forest plot of the effect of Dupilumab versus placebo on the change in FEV1 in CRSwNP patients at 4-6 months.

Table 6.1.16.1. Dupilumab for the treatment of patients with CRSwNP.

Study Methods Participants Interventions Outcomes Results

Bachert 2x DBPRCT SINUS-24: SINUS-24: At 24 and 52 weeks: Dupilumab resulted in significant
2019(248) 276 CRSwNP • Dupilumab (300mg q2w) for 24 weeks • SNOT-22 improved outcomes in both studies
patients (n=143) • Rhinosinusitis disease compared to placebo at 24 and 52
SINUS-52: • 1 placebo for 24 weeks (n=133) severity (VAS) weeks:
448 CRSwNP • Nasal congestion • SNOT 22
patients SINUS-52: • Smell (UPSIT) • Rhinosinusitis disease severity (VAS)
pts • Dupilumab 300mg every 2 week for 52 • Nasal polyp score (NPS) • Nasal congestion
weeks (n=150) • CT scan (LMS) • Smell (UPSIT)
• Dupilumab 300mg every 2 week for 24 • ACQ5 • NPS
weeks then 300 mg every 4 weeks for • FEV1 • LMS
28 weeks (n=145) • ACQ5
• Placebo every 2 week for 52 weeks • FEV1
(n=153)
• Both studies 4 weeks run-in and during
the trial mometasone nasal spray 100
μg in each nostril twice daily
Bachert DBPRCT 60 CRSwNP • Dupilimab (600mg loading, 300mg At 16 weeks: Dupilumab resulted in significant
2016 (247) patients weekly) (n=30) • QOL (SNOT-22) improved outcomes in both studies
refractory to • Placebo (n=30) • Rhinosinusitis disease compared to placebo at 16 weeks:
INCS • 4 weeks run-in and during the trial severity (VAS) • SNOT 22
mometasone nasal spray 100μg in • Nasal congestion • Rhinosinusitis disease severity (VAS)
each nostril twice daily • Smell (UPSIT) • Nasal congestion
• Nasal polyp score (NPS) • Smell (UPSIT)
• CT scan (LMS) • NPS
• ACQ6 • LMS
• FEV1 • ACQ6
• FEV1

DBPRCT, Double Blind Placebo Controlled Trial; CRSwNP, Chronic Rhinosinusitis with nasal polyps; pts,patients; SNOT, Sino-Nasal
Outcome; VAS, Visual Analogue Scale; UPSIT, University of Pennsylvania Smell Identification Test; NPS, Nasal Polyp Score; LMS,
Lund-Mackay Score; ACQ5, Asthma Control Questionnaire 5 ; FEV1, Forced Expiratory Volume; INCS, Intranasal corticosteroids spray;
QOL, Quality of Life; ACQ6, Asthma Control Questionnaire 6;

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Table 6.1.17.1. Probiotics for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Martensson DBPC 21 CRSsNP • Nasal spray containing LAB (a mixture of 9 • SNOT-22 • No significant
crossover patients lactobacilli and 4 bifidobacteria) for 14 days • Microbiology differences in any
2017(258)
trial with at • Placebo nasal spray for 14 days • Inflammatory mediators in parameter evaluated
least 4 wks nasal lavage fluid
washout

Mukerij DBPCT 77 CRS • Probiotic Lactobacillus rhamnosus R0011 At 4 and 8 weeks: • No significant
patients strain (500 million active cells/tablet) twice differences between
2009(257) • SNOT-20
daily for 4 weeks (n = 39) probiotic and placebo
• Oral placebo treatment twice daily for 4 • Symptoms
weeks (n = 38)

CRS, Chronic Rhinosinusitis; CRSsNP, Chronic Rhinosinusitis without nasal polyps ; DBPC, Double blind placebo controlled; DBPCT,
Double Blind Placebo Controlled Trial ; SNOT-22, Sino-Nasal Outcome Test-22 ; SNOT-20, Sino-Nasal Outcome Test-20.

6.1.16.2. Conclusion 6.1.18. Muco-active drugs

Dupilumab is the only monoclonal antibody that is approved for
the treatment of CRSwNP at the moment. The panel advises to 6.1.18.1. Summary of the evidence
use dupilumab in patients with CRSwNP fulfilling the criteria for Mucoactive drugs are regularly used as a therapeutic
treatment with monoclonal antibodies(245). option for mucus alteration, including hypersecretion. The
drugs can be divided into expectorants (like hypertonic
6.1.17. Probiotics saline), mucoregulators that regulate mucous secretion (like
carbocisteine and anticholinergic agents), mucolytics that
6.1.17.1. Summary of the evidence decrease mucous viscosity (like N-acetylcysteine, erdosteine
A locally disturbed commensal microbiome might be an and DNase) and mucokinetics: drugs that increase mucociliary
aetiological factor in chronic rhinosinusitis. Despite significant clearance by acting on the cilia (like bronchodilators and
heterogeneity in study design, tissue sampling, processing surfactants).
and bioinformatics analysis, consistent findings have emerged Evaluation in the lower airways has shown that treatment
from the recent literature. Healthy individuals and CRS patients with mucolytics may produce a small reduction in acute
have similar overall bacterial burden of disease and share exacerbations and a small effect on overall quality of life in
many common phyla. CRS patients, however, routinely show patients with chronic bronchitis or COPD(259). Small benefits of
reductions in markers of biodiversity. Both medical and surgical mannitol, inhalation of normal and hypertonic saline has been
treatments appear to influence the sinonasal microbiome, found in patients with chronic lung diseases outside CF(260).
with certain bacterial strains associated with better treatment Adverse effects of rhDNase on lung function suggest this should
outcomes. The presence of microbial dysbiosis in CRS is now not be administered in non-CF bronchiectasis(260).
supported by numerous studies. Whether this dysbiosis is a Data in CRS patients are very limited (Table 6.1.18.1.). There is
cause or rather an association of the disease process remains one RCT evaluating the addition of S-carboxymethylcysteine
unclear(255, 256). (1500mg/day) to clarithromycin (200mg/day)(261). The authors
We identified two studies on probiotic therapy, one oral(257) and found no significant differences in effect on SNOT-20 or CT scan
one evaluating a nasal spray(258) (Table 6.1.17.1.). Both studies at 12 weeks but a significantly higher percentage of patients
evaluated SNOT and showed no significant difference between with a remarkably effective symptomatic response at 12 weeks,
probiotic and placebo. The study of Mukerji et al. showed a but not at four and eight weeks and also a significantly higher
significant reduction in SNOT-20 and symptoms after four weeks percentage of patients with improved characteristics of nasal
of treatment in the probiotic group and not the placebo group discharge and reduced post-nasal discharge. There were slightly
compared to baseline, but the differences between the groups more adverse events than with clarithromycin alone, but none
were not significant and the change from baseline was not were serious.
found after eight weeks. A second study is a non-randomized prospective non-
Also, no differences in the bacteria cultured or inflammatory interventional study evaluating the effect of erdosteine(262).
mediators were found. Erdosteine was originally developed as a mucolytic agent.
Moreover, it has also been shown to have anti-bacterial, anti-
6.1.17.2. Conclusion oxidant and most importantly anti-inflammatory effects(262, 263).
Although probiotic therapies show theoretical promise, the
two studies performed so far did not show any differences 6.1.18.2. Conclusion
compared to placebo. For this reason, the EPOS2020 steering Data on the effect of muco-active agents in CRS are very limited.
group advises against the use of probiotics for the treatment of The only DBPCT showed a significantly higher percentage of
patients with CRS.

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Table 6.1.18.1. Muco-active drugs for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Hoza Non- 60 CRSwNP • Erdosteine 300mg twice • SNOT-22 • After 3 months the erdosteine only
2013(262) randomized patients a day for the period of 3 • NPS group compared to the erdosteine and
prospective months (n=33) • Adverse events mometasone groups had significantly
non- • Erdosteine 300mg twice better change in SNOT-22 and polyp
interventional a day combined with score
post- mometasone nasal spray • There was no difference in adverse
authorisation (dosage unknown) for the events and adverse events were mild
study period of 3 months (n=27)
Majima RCT 425 CRS • Clarithromycin (200mg/day) • SNOT-20 at 12 weeks • No significant difference in effect of
2012 (261) (318 for 12 weeks (n=213) • CT scan at 12 weeks SNOT-20 or CT scan at 12 weeks
analysed) • Clarithromycin (200mg/ • % of patients with remark- • Significantly higher % of patients
day) and S-carboxymeth- ably effective or effective with remarkably effective or effective
ylcysteine (1500mg/day; response at 4, 8 and 12 response at 12 weeks, but not at 4 and
combination group) for 12 weeks 8 weeks
weeks (n=212) • % of patients with im- • Significant higher % of patients with im-
provement of endoscopy proved characteristics of nasal discharge
• Adverse events and reduced post-nasal discharge
• No serious adverse events

CRS,Chronic Rhinosinusitis; CRSwNP, Chronic Rhinosinusitis with nasal polyps; SNOT-22, Sino-Nasal Outcome Test-22; NPS, Nasal
Polyp Score; SNOT-20, Sino-Nasal Outcome Test-20; RCT, Randomised Controlled Trial;

patients with effective response and improved characteristics reported by 528 (57.0%) patients during the treatment period,
of nasal discharge at 12 weeks. The EPOS2020 steering group most of mild to moderate intensity. A relationship with the
considered the quality of the data insufficient to advise on the study drug was suspected in 18 patients (5.9%) treated with
use of muco-active agents in the treatment of patients with CRS. the 480mg Sinupret extract, 14 patients (4.4%) treated with
240mg and in 12 patients (3.9%) who received placebo. The
6.1.19. Herbal treatment most common drug-related adverse events reported for the
480mg, 240mg and placebo were upper abdominal pain (1.3%,
6.1.19.1. Summary of the evidence 1.3%, 0.7%), diarrhoea (0.3%, 0.6%, 1.3%) and headache (1.3%,
Herbal medicine represents a relatively frequently used 0.3%, 0.7%). Adverse events led to discontinuation in 20 patients
complementary and alternative treatment for CRS. However, the (total 2.2%, 1.6% in placebo group, 2.0% in 240mg and 3.0%
safety and efficacy of herbal medicine for the treatment of CRS is in 480 mg). Serious adverse events were noted in 11 patients
currently uncertain. Most of the studies are not randomized. (1.2%) during the treatment period; no causal relationship with
We found five RCTs: four with a local application(264-267)and one the study medication was seen for all of these. No medically
very large study with the tablet BNO 1016(268). relevant differences in laboratory parameters or vital signs were
BNO 1016 has been established for use in patients with observed for patients treated with Sinupret extract compared to
acute rhinosinusitis and is marketed under the brand name placebo.
‘Sinupret extract CT’. It contains the dry extract of five herbal Of the four local studies, three measured quality of life with
drugs, namely gentian root, primula flower, sorrel herb, elder SNOT(264-266), two symptoms severity(265, 267)and two CT scan(264,
flower, verbena herb, in a ratio of 1:3:3:3:3. The efficacy in acute 266 )
. The studies were too different to combine into a meta-
rhinosinusitis has been demonstrated in a randomised, placebo- analysis. One study found a significant improvement in the
controlled trial(269). group treated with Nigella Sativa nasal spray versus saline in
A DBPCT with 929 patients examined BNO 1016 (Sinupret SNOT-20, endoscopy and CT scan at four weeks’ treatment. Two
extract) in CRS. Two different Sinupret extract doses (240mg studies compared to treatment with FPNS. One showed no
or 480mg daily) were compared to placebo, with a treatment difference compared to fluticasone diproporanate nasal spray
period of 12 weeks. The primary endpoint was the mean (FPNS) but in the other comparing intranasal administration of
Major Symptom Score (MSS) in weeks 8 and 12 of treatment. sinupium (P. anisium) drops to FPNS, interestingly, the intranasal
Secondary endpoints included symptom severity by VAS, administration of P. anisium led to a significantly greater
work activity and QOL (SNOT-20 score). Sinupret extract was improvement (p=0.012) in SNOT-22 score when compared to
not superior over placebo regarding the primary endpoint. FPNS. However, the lack of blinding increases performance
However, in patients with a diagnosis of CRS for >1 year and a bias(266). Sinupim was well tolerated by patients. There were no
baseline MSS >9 (out of max 15) a post-hoc sensitivity analysis serious adverse effects in either group.
showed a significant benefit in MSS and work activity (WPAI:GH) 6.1.19.1. Conclusion
at 12 weeks of treatment with the use of Sinupret extract when Of five RCTs evaluating herbal treatment, a large DBPCT,
compared to placebo(268). In total, 1,215 adverse events were although a post-hoc sensitivity analysis, showed a significant

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Table 6.1.20.1. Traditional Chinese Medicine for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Jiang DBPCT 53 CRSsNP • Chinese Herbal Medicine (2g of Tsang-Erh- • SNOT-20 • No significant differ-
2012(34) patients San extract granules and 1gm of Houttuyn- • Endoscopic score ence in any endpoints
ia extract powder twice daily for 8 weeks) • Saccharin transit test between the groups
with erythromycin placebo (n=26) • Bacterial culture rate before and
• Erythromycin (250mg twice daily for 8 at 8 weeks of treatment
weeks) with CHM placebo (n=27)
Liang DBPCT 97 CRS • Chinese Herbal Medicine (2g of Tsang-Erh- • RSOM-31 • No significant differ-
2011(271) postoperative San extract granules and 1gm of Houttuyn- • Endoscopic score ence in any endpoints
ia extract powder twice daily for 8 weeks) • Acoustic rhinometry between the groups
with 4 weeks of amoxicillin placebo (n=33) • Nasal swabs at 8 weeks post-
• Amoxicillin (250mg three times dailly for operative
4 weeks and CHM placebo for 8 weeks • CT (LM-scoreat 12 weeks post-
(n=34) operative
• Placebo (n=30)
CRS, Chronic Rhinosinusitis;CRSsNP, Chronic Rhinosinusitis without nasal polyps ; DBPCT, Double Blind Placebo Controlled Trial ;
CHM, Chinese Herbal Medicine ; SNOT-20, Sino-Nasal Outcome Test-20 ; RSOM-31, Rhinosinusitis Outcome Measure-31 ; CT, comput-
ed tomography; LM, Lund-Mackay

Table 6.1.20.2. Acupuncture for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Stavem RCT 66 CRSsNP (49 • Traditional Chinese Acupuncture • CSS • No significant difference in any endpoints
2008(272) (Investigator evaluated) (10 treatments over 4 weeks) (n=17) • SF-36 at baseline between the groups
not blinded. • Sham acupuncture (10 treatments and 12 weeks
Patient’s over 4 weeks) (n=15)
partially • Medical management (xylometazo-
blinded.) line and normal saline irrigation
for 1 week, oral corticosteroids for
14 days, and antibiotics – either
cephalexin 1,500mg daily for 10
days or azithromycin 500mg for 7
days) (n=17)

Rössberg RCT 55 CRS patients • Traditional Chinese acupuncture 10 • SF-36 at 12 • Conventional treatment improved CT
2005(274) (49 evaluated at treatments with bilateral acupoints weeks scan at 4 weeks contrary to both acu-
4 weeks, 37 at over a period of 4 weeks (n=25) • QOL (VAS) at 12 puncture groups
12 weeks and • Minimal acupuncture at non-acu- weeks • Total symptom score at 4 weeks trend to
29 at 1 year) points 10 treatments with bilateral • Total symptom improvement (p=0.06) compared both
acupoints over a period of 4 weeks score at 4, 12 acupuncture groups
(n=19) and 52 weeks • Significant improvement in SF-36 and
• Conventional medical therapy • CT scan at 4 QOL (VAS) at 12 weeks for conventional
consisting of xylometazoline weeks treatment contrary to both acupuncture
saline locally for 1 week, and oral groups
corticosteroids for 14 days (n=21). • After 12 months, 15 patients reported
In addition, cefalexin 1500 mg daily having had surgical intervention for
for 10 days (n=14) or azithromycin chronic sinusitis (conventional group 5,
500 mg for 7 days (n=6) acupuncture 6, sham 4), and there was lit-
tle difference in symptom score between
the groups (p = 0.32).

CSS, Chronic sinusitis survey ;CRS,Chronic Rhinosinusitis; CRSsNP, Chronic Rhinosinusitis without nasal polyps ; RCT, Randomised
Controlled Trial ; SF-36, Short form 36; QOL, Quality of Life ; VAS, Visual Analogue Scale ; CT, computed tomography.

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benefit in major symptom score at 12 weeks of treatment over 6.1.20.3. Conclusion

placebo in patients with a diagnosis of CRS for >1 year and a There is no evidence that traditional Chinese medicine or
baseline MSS >9 (out of max 15) showed overall no effect(268). Of acupuncture is more effective than placebo in the treatment
the four studies evaluating different local herbal treatment three of CRS. The safety of Chinese medicine is unclear because most
showed a favorable effect. However, not all studies were blinded of the papers are not ready accessible(275). Minor and serious
and the quality of the studies was variable. adverse events can occur during the use of acupuncture and
The treatment does not show significantly more adverse events related modalities, contrary to the common impression that
than placebo. The quality of the evidence for the local treatment acupuncture is harmless(276). For this reason, the EPOS2020
is low. steering group advises against the use of traditional Chinese
Based on the available data, the EPOS2020 group cannot advise medicine or acupuncture.
on the use of herbal medicine in CRS.
6.1.21. Topical furosemide and oral verapamil
6.1.20. Traditional Chinese medicine and
acupuncture 6.1.21.1. Summary of the evidence
While surgical intervention has often been the mainstay in
Complementary and alternative medicine (CAM) is commonly treatment of nasal polyps, the propensity for some patients to
inquired about and often used by patients with CRS(270). relapse has led to further investigations with therapies aimed at
Many different CAM therapies are available including herbal preventing recurrence. Two of these medications are verapamil
medications, homeopathy and traditional Chinese medicine. We and furosemide.
identified five RCTs for review. Verapamil is a non-dihydropyridine Ca+-channel blocker, given
orally, and an inhibitor of P-gp and can block IL-5, IL-6, and
6.1.20.1. Traditional Chinese Medicine thymic stromal lymphopoietin (TSLP) secretion. One double
Two studies examined the use of Traditional Chinese Medicine blind placebo-controlled trial(277) evaluated the use of oral
in CRS. One study in 53 CRSsNP compared the Chinese Verapamil for treatment of patients with CRSwNP. Patients were
herbal medicine (CHM) Tsang-Erh-San with Houttuynia with treated with either 80mg of Verapamil three times per day
an erythromycin control group(34)(Table 6.1.20.1). At eight versus placebo for eight weeks.
weeks both groups had a significant improvement in their Patients were evaluated at two, four and eight weeks for
SNOT-20 score, however there was no significant difference changes in quality of life (SNOT-22), symptoms (VAS), or changes
between the two groups. Neither intervention influenced the in CT scan (LMS). Patients were also evaluated for side effects
endoscopic score or bacterial culture rate. The validity of these from the medication. There was significant improvement from
improvements is unclear due to the lack of placebo control. baseline to week eight in SNOT-22 scores (MD -27.7 95%CI[-
Another study in 97 postoperative CRS patients compared the 49.36 to -6.05], p=0.01) and VAS scores (MD -37.97 95%CI[-
same CHM (Tsang-Erh-San with Houttuynia) with amoxicillin 60.01 to -15.93], p=0.001) in the verapamil group compared to
and placebo(271). All three groups had significant improvements placebo. There was also improvement in Lund-Mackay score
in their RSOM-31 and endoscopic score at eight weeks post- in the verapamil group with an absolute mean difference of
operatively, however there was no significant difference -5.20 (95% CI, -9.66 to -0.74; p=0.02). There were also significant
between the three groups. There was no significant difference decreases in total Lund-Kennedy score in the verapamil group
post-operatively between the three groups on their acoustic at week four with an LSM difference of -2.8 (95%CI, -4.3 to
rhinometry and CT scores. -0.98; p=0.003). This trend continued to week eight but was
no longer statistically significant. Patients with higher BMIs
6.1.20.2. Traditional Chinese acupuncture had less improvement with verapamil and this is thought to
In some countries acupuncture is used to treat CRS although be due to higher required doses that would otherwise be
there is hardly any documentation on the effect. We found supratherapeutic (Table 6.1.21.1). Studies with local verapamil
two studies from the same group evaluating health-related are ongoing (https://ichgcp.net/clinical-trials-registry/
quality of life comparing traditional Chinese acupuncture, sham NCT03102190).
acupuncture, and 2-4 weeks of medication with antibiotics, Furosemide, in contrast, is a loop diuretic that acts on Na+ and
corticosteroids, 0.9% sodium chloride solution, and local K+ channels and can increase absorption of these ions, as well
decongestants(272, 273). Change in health-related quality of life as water. This dehydrates the respiratory epithelial surface. A few
was assessed over 4-52 weeks using the Chronic Sinusitis Survey studies have been completed evaluating their efficacy in the
(CSS), Short form 36 (SF-36) questionnaires, total symptom prevention of nasal polyp recurrence (Table 6.1.21.2).
scores and CT scan. One study(274) in general showed better Hashemian et al.(219) conducted a double-blind, placebo-
effect of the conventional treatment than both traditional controlled trial assessing the efficacy of topical furosemide
Chinese acupuncture and sham acupuncture, the other did on nasal polyps. Patients were randomly assigned to receive
not show difference in effects on CSS or SF-36 between the either postoperative nasal spray, two puffs twice daily for two
traditional Chinese acupuncture and the sham acupuncture months of either 300μg of furosemide per day or placebo.
groups (Table 6.1.20.2). Patients were assessed six months after surgery for NPS (Meltzer

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Table 6.1.22.1. Capsaicin for the treatment of patients with CRSwNP.

Study Methods Participants Interventions Outcomes Results
Zheng DBPCRCT CRSwNP post- • Capsaicin (3x10 mol,
-6
Assessed at 9 months: At 9 months there was no difference in
2000(282) polypectomy dissolved in 70% ethanol) • Nasal blockage (0-5) subjective rhinorrhoea in either group.
(n=51) (n=29) • Rhinorrhoea (0-5) • The capsaicin group at 9 months group had
• vehicle alone (70% etha- • NPS (0-6) a significant decrease in NR compared to
nol) (n=22) once a week the vehicle group
times 5 weeks • NPS data?
Filiaci DBPCRCT CRSwNP (n=30) • Capsaicin 0.1mL (30μmol) Assessed at 1 and 3 months: At 1 and 3 months when comparing the
1996(281) in each fossa once weekly • Nasal symptoms: obstruc- capsaicin group versus the controls, the
for 5 weeks (after anes- tion, secretion, itching, capsaicin group had:
thetizing the nasal cavity) sneezing (0-5) • A significantly larger decrease in all nasal
(n=15) • NPS (0-6) symptoms
• 0.1mL physiologic solution • Nasal resistance (active • A significant larger decrease difference in
(n=15) in each fossa once anterior rhinomanometry) NPS
weekly for 5 weeks • Specific nasal hyperreactivi- • Significantly larger improvement in nasal
ty (provocation testing with resistance
cold water with rhinoma- • Significantly improved nasal hyperreactivity
nometric assessment) • Significantly increased nasal tissue eosin-
• Nasal tissue eosinophils ophils

CRSwNP, Chronic Rhinosinusitis with nasal polyps; DBPCRCT, Double Blind Placebo Controlled Randomised Controlled Trial ; NPS, Nasal Polyp Score.

Figure 6.1.22.1. Forest plot of the effect of capsaicin versus placebo on nasal obstruction in CRSwNP patientsmonths.

score), CT scoring (LMS), QOL (SNOT-22), and VAS polyp scoring. to 2.0±0.8, p<0.001; furosemide: 2.2±0.9 to 1.7±0.9; p<0.001).
Eighty-four patients completed treatment and were able to be There was no significant difference between the two groups.
evaluated, with 42 patients in each group (n=84). During the Given the small sample size, this may be considered to be a
study time, there were no clinically significant adverse effects. type 2 error. The steroid group had significant improvement
After treatment, significantly more patients in the furosemide in polyp eosinophil counts (50-2.35±392.66 to 190.65±291.41;
group had a polyp score of 0, compared to the placebo p<0.01), while the furosemide group did not (280.95±364.58 to
group (79% vs 38%; p<0.01). There was a significant effect of 382.80±370.60; p=0.185). Neither group had significant changes
furosemide on SNOT-22 scores (MD, 8.05; 95%CI, 3.24-12.85) and in oedema or tissue mastocytes.
VAS scores (MD, 0.81; 95%CI, 0.22-1.39) compared to placebo. Passali et al.(279) conducted a pseudo-randomized trial on
However, the Lund-Mackay score did no show significant patients with CRSwNP following surgery. Patients were
differences (MD, 2.52; 95%CI, -0.35-5.39). randomized to either receive topical furosemide, no treatment,
Kroflic et al.(278) evaluated the efficacy of oral or topical mometasone furoate nasal spray (MFNS) post-
methylprednisolone (1mg/kg/day) or inhalation of 6.6mmol/l operatively after either anterior or full ethmoidectomy. For six
furosemide solution/10 min through a jet nebulizer—i.e., max. years (1991-1997) patients were randomized between topical
20mg/day furosemide for seven days on patient reported furosemide and no treatment and after 1997 randomization
symptoms (nasal obstruction, nasal hypersecretion, loss of was done between furesomide and MFNS. No details about
smell (0-3), postnasal drip, snoring, sneezing, cough, swelling, the randomization process are given. Follow-up ranged from
epistaxis, headache (0-1), fatigue, temperature, previous surgery 1-9 years over the group as a whole. Patients in the furosemide
(0-1) adding up to a total symptom score of 20), NPS (Malm 0-6), group received two puffs per day per nostril (each puff= 50µg)
and histomorphometric analysis of eosinophils, mastocytes, for 30 days, then one month of no treatment and then repetition
and edema. Both groups showed significant improvement of the furesomide treatment until a total of four months per
in subjective symptom scores (pre-steroid mean 15.5±3.4 to year. The MFNS group received two puffs per day per nostril
post-steroid 9.5±3.6, p<0.001; pre-furosemide 15.6±3.9 to (puff= 100µg) for 30 days then following a similar regimen to
post-furosemide 9.8±3.7, p<0.001) and NPS (steroid: 2.4±0.7 the furosemide group, and the no treatment group received no

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further intervention following surgery. Patients were assessed capsaicin 0.1mL (30μmol) in each fossa versus 0.1mL physiologic
for relapse. Relapse was based on acoustic rhinometry active solution in each fossa once weekly for five weeks. Patients were
anterior rhinomanometry, and the presence of nasal polyp then assessed at three months for nasal symptoms, including
recurrence. Acoustic rhinometry and nasal endoscopy was obstruction, itching, and sneezing, endoscopic polyp scoring,
assessed every six months in each patient. NPS was as follows: nasal resistance, specific nasal hyperreactivity, and eosinophils
stage 0, no nasal polyps seen; stage 1, nasal polyps confined to in nasal polyp tissue. The capsaicin group had a significant
the middle meatus, with acoustic rhinometry values within the decrease in all nasal symptoms compared to placebo (p<0.01).
normal range (24.5±1.5cm3); stage 2, nasal polyps prolapsing There was a significant difference in the nasal polyp scores (NPS)
beyond the middle turbinate, with less than a 10% reduction between the capsaicin and control group at one month (p<0.05)
of nasal volumes (per AR); and stage 3, sub-obstructive and three months (p<0.01). There was significant improvement
nasal polyps requiring another operation (>50% reduction in nasal resistance in the capsaicin group compared to the
of nasal volumes). The no treatment group had a significant control group at three months post-treatment (p<0.01). There
worsening of nasal volumes at the end of their six-year follow- was a significant difference in nasal hyperreactivity between
up (16.6±1.3cm3; p= 0.02). More patients in the untreated the capsaicin and control group at three months (p<0.01). Nasal
group had relapse compared to furosemide or mometasone tissue eosinophils were significantly increased in the patients
(30%v17.5%v24.2%; no p value available). Patients without undergoing capsaicin treatment at one and three months
treatment had a significantly higher NPS of polyp recurrence (<0.01).
compared to furosemide and mometasone fuorate nasal spray Zheng et al.(282), also conducted a double blind, placebo-
(20% vs 2% vs 3%; p<0.05). controlled trial comparing capsaicin (3x10-6mol, dissolved in
Another report of Passali(280) appears to report on a subgroup of 70% ethanol) versus vehicle alone (70% ethanol) once a week
the patients of the 2003 study(279). for five weeks, following nasal polypectomy. Patients were
assessed at nine months for nasal resistance (0-5), rhinorrhoea
6.1.21.2. Conclusion (0-5), and NPS (0-6 unilateral). The capsaicin group had a
There is some indication that verapamil might have anti- significant decrease in nasal resistance compared to the vehicle
inflammatory effects. A very small pilot study showed significant group. (p<0.01). There was no difference in subjective rhinorrhea
improvement in QOL (SNOT-22), polyp score (VAS), and CT scan in either group. Patients treated with capsaicin had lower nasal
(LMS) of oral verapamil over placebo. (Potential) side effects polyp score when compared to the control group (stage 0: 41%
limited the dosage. vs 4.5%, p<0.01). Adverse events were not mentioned in both
There is some indication that topical furosemide might have a studies but are know from studies in NAR to be mostly limited to
beneficial effect on symptoms and signs of CRSwNP. A recent local irritation(283).
DBPCT study showed significantly reduced QOL (SNOT-22) Pooled data analysis of the nasal obstruction measurement
scores and polyp score (VAS), and significantly more patients (0-5) showed significant benefit in the capsaicin group (SMD
with an NPS of 0 in the furosemide nasal spray treated group -0.68 [-1.05, -0.31], p<0.0003, two trials, 81 patients). The I2 was
versus placebo. There was no indication of a difference in 0%, suggesting no heterogeneity (X2=0, df=1, p=0.98) (Figure
adverse events between topical furosemide and placebo. 6.1.22.1).
The quality of the evidence for oral verapamil and topical Pooled data analysis of nasal polyp score showed significant
furosemide is very low. Based on the potential side effects benefit in the capsaicin group (SMD -1.82[-2.93, -0.7],
the EPOS2020 steering group advises against the use of oral p<0.01, two trials, 81 patients). The I2 was 0%, suggesting no
verapamil. The group also cannot advise on local furosemide. heterogeneity (X2=0, df=1, p=0.98) (Figure 6.1.22.2).
Further placebo-controlled studies on both local furosemide
and local verapamil are needed to determine efficacy and 6.1.22.2. Conclusion
appropriate patient selection. Two small double-blind placebo-controlled studies(281, 282)
have evaluated the efficacy of capsaicin. Capsaicin showed a
6.1.22. Capsaicin significant decrease in nasal obstruction and nasal polyp score,
however data on other symptoms like rhinorrhea and smell are
6.1.22.1 Summary of the evidence either non-significant or unreported. The data were consistent
Neuropeptides and parasympathetic nerves in the nasal over the two studies, but we downgraded for imprecision and
mucosa are thought to potentially play a role in the formation risk of bias. It has to be mentioned that blinding of capsaicin
of nasal polyps. Therefore, capsaicin, a medication that can be treatment is very difficult/impossible. The quality of the
applied topically has been considered for possible prevention evidence is low and the EPOS steering group concludes that
of nasal polyp recurrence. Capsaicin, which acts upon the C Capsaicin may be an option in treatment of CRS in patients with
fibers, is thought to neuromodulate nasal hyper-reactivity CRSwNP but that larger studies are needed.
and potentially prevent nasal polyp recurrence. Two studies
completed double blind, placebo-controlled, randomized trials
(Table 6.1.22.1).
Filiaci et al.(281), evaluated 30 patients, with half of them receiving

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Table 6.1.23.1. Omeprazol for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results
Anzic DBPCT 60 CRS • Omeprazol 20mg once At 8 weeks: No significant differences at 8 weeks
2018(287) patients with daily (n=33) for 8 weeks • CRS symptom score (0-48) between Omeprazole and placebo apart
GORD • Placebo once daily (n=27) • Nasal endoscopy score from reflux finding score
for 8 weeks • RSI score
• RFS

CRS,Chronic Rhinosinusitis; DBPCT, Double Blind Placebo Controlled Trial ; GORD, Gastro-oesophageal reflux disease ; RSI, Reflux symptom index; RFS,
Reflux finding score.

6.1.23. Proton-pump inhibitors in patients with significantly different from each other at baseline. The long-term
GORD use of proton pump inhibitors is not without risk and has been
associated with increased risk of cardiovascular disease and
6.1.23.1. Summary of the evidence morbidity(288, 289).
There is some of evidence demonstrating an association
between gastro-oesophageal reflux disease (GORD) and CRS. 6.1.23.1. Conclusion
GORD is defined by reflux of gastric contents, resulting in There is one DBPCT trial evaluating the effect of omeprazole
troublesome symptoms and/or complications. CRS patients 20mg once daily for eight weeks in 60 patients that was ill-
have been shown to have significantly higher incidences of matched at baseline making evaluating of the results difficult.
gastro-oesophageal reflux compared with asymptomatic At the end of the eight weeks treatment period there were no
controls(284). differences in CRS and nasal endoscopy scores. Moreover, long
CRS is more prevalent in GORD sufferers than those without term use of proton pump inhibitors has been associated with
GORD although the diseases have overlapping symptoms increased risk of cardiovascular disease. The EPOS2020 steering
like the feeling of mucus in the throat(285). While CRS is a group therefore does advise against the use of proton pump
multifactorial process, the evidence suggests that GORD inhibitors in the treatment of CRS.
may play a role in CRS, at least in some patients. Potential
pathogenic roles for GORD in CRS could be a greater prevalence 6.1.24. Bacterial lysates
of intranasal Helicobacter pylori and acid reflux into the nose/
nasopharynx. Evidence is conflicting for GORD as a factor in CRS 6.1.24.1. Summary of the evidence
treatment failure(286). Bacterial lysates are constituted by a mixture of bacterial
There is one DBPCRCT evaluating the role of proton-pump antigens derived from different respiratory bacterial species.
inhibitors in CRS(287) (Table 6.1.23.1). Sixty patients (28 women, Different antigens are mixed and excipients are added in
aged 19-87 years) with CRS and GORD were treated with eight order to prepare lysate tablets. Bacterial lysates have both
weeks of omeprazole 20mg once daily (o.d.). Although the a specific and non-specific immunostimulating properties.
authors conclude that CRS symptom score, nasal endoscopy Broncho-Vaxom® (OM-85 BV) is a lysate of 21 strains of 8
score, reflux symptom (index) score, and reflux finding scores bacteria(Staphylococcus aureus, Haemophilus influenzae,
were significantly reduced after eight weeks omeprazole Streptococcus pyogenes, Moraxella catarrhalis, Klebsiella
treatment compared to placebo using ANOVA for repeated pneumoniae, Klebsiella ozaenae, Streptococcus viridans and,
measurements or McNemar’s test, only the reflux finding score Diplococcus pneumoniae), that is used as an immunostimulant
showed a significant difference between the groups at the for the prevention and treatment of upper and lower airway
eight weeks measurement. Unfortunately, the matching of infections and has the ability to enhance mucosal barrier
the groups at baseline was not good as the CRS and RSI were function and regulate immune responses(290, 291).A recent meta-

Table 6.1.24.1. Bacterial lysates for the treatment of patients with CRS.
Study Methods Participants Interventions Outcomes Results
Heintz 1989(294) DBPCT 284 CRS patients • Broncho-Vaxom, 1 capsule • Symptom score (0-4) • Significant reduction in
(some patients had daily for a period of 10 days per for headache, purulent symptoms
persistent RS after month during 3 consecutive nasal discharge, cough • Significant reduction in
sinus puncture) (258 months (n=127) and expectoration opacification of X-ray sinus
analysed) • Placebo 1 capsule daily for a • X-ray sinus • No difference in adverse
period of 10 days per month • Adverse events events
during 3 consecutive months
(n=121)

CRS,Chronic Rhinosinusitis; DBPCT, Double Blind Placebo Controlled Trial ; RS, Rhinosinusitis

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Table 6.1.26.1. Phototherapy for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results

Dulguerov DBPCT 50 CRSsNP • Mixed visible and At the end of 3 wk treatment and • No significant difference in any outcome
2017(296) patients ultraviolet (UVA and one month after treatment: measured except carbon monoxide
UVB) light source ap- • RSDI • Significant increase in carbon monoxide
plication for 3 weeks • symptom severity (nasal obstruc- production in the treatment group as
(n=26) tion, sense of smell, rhinorrhoea, compared to controls at the end of treat-
• Low intensity visible and facial pain) (VAS) ment (5.24 vs. 3.88, p=0.048), however no
light alone for 3 weeks • Rhinomanometry significant difference at 1 month following
(n=24) • Olfactory thresholds treatment (5.25 vs. 4.07, p=0.13)
• Nasal Nitric Oxide
• Carbon monoxide

Kiricsi et al. RCT 87 subjects • intranasal mUV/VIS At week 12, week 16 and 26 weeks Patients that received phototherapy
2017(300) (76 evaluated) phototherapy 3 times • NOSE questionnaire demonstrated significant improvement in:
CRSwNP per week for 12 weeks • Nasal symptom score (total nasal • NOSE (p < 0.001) at week 12, 16 and 26
patients and MFNS 200μg symptom score and separate • Total nasal symptom score and in nasal con-
twice daily for 12 symptom) gestion, discharge at week 12, 16 and 26
weeks (n=52) • Nasal endoscopy and polyp size • Smell threshold test (p<0.001) at week 12,
• MFNS 200μg twice (0-5) 3 16 and 26
daily for 12 weeks • PNIF • PNIF at week 26
(n=24) • Acoustic rhinometry 3 • Nasal polyp size at week 16 and 26
• Smell threshold • No significant change in acoustic rhinome-
• Exhaled nasal NO try or exhaled nasal NO
• In control group, no significant changes
were measured at week 12, 16 and 26
• NO statistics between groups performed

CRSsNP, Chronic Rhinosinusitis without nasal polyps ;CRSwNP, Chronic Rhinosinusitis with nasal polyps; DBPCT, Double Blind Placebo Controlled
Trial ; RCT, Randomised Controlled Trial ; mUV/VIS, Mixed ultraviolet and visible light; UVA, Ultraviolet A; UVB, Ultraviolet B; MFNS, Mometasone
Furoate Nasal spray ; RSDI, Rhinosinusitis Disability Index; VAS, Visual Analogue Scale ; NOSE, Nasal Obstruction Sympton Evaluation ; PNIF, Peak Nasal
Inspiratory Flow ; NO, Nitric Oxide.

analysis showed that Broncho-Vaxom was positively correlated better in the Broncho-Vaxom treated group than the placebo
with a reduction in the frequency of respiratory infection group. No major side effects were reported, with comparable
[MD=-2.33, 95% CI (-2.75, -1.90), P<0.00001] compared to the and good tolerability for OM-85 and placebo.
control group. The Broncho-Vaxom group was more effective
than control groups in relation to the duration of antibiotics 6.1.24.2. Conclusion
course, infections, fever, cough, and wheezing, increasing serum There is one DBRCT from 1989 comparing the bacterial lysate
immunoglobulin levels (IgG, IgA or IgM), and T-lymphocytes Broncho-Vaxom to placebo in a large group of CRS patients
subtype (CD3+, CD4+, or CD8+)(292). OM-85 BV has resulting in a significant decrease in purulent nasal discharge
ciliostimulatory and immunogenic properties in an epithelial and headache over the full six months period compared to
cell culture system that may be partially responsible for its placebo and reduced opacification of the sinus X-ray. Based
observed efficacy as a respiratory therapeutic. These responses on this limited evidence the EPOS2020 steering group cannot
were NO-dependent and consistent with T2R activation(293). advise on the use of Broncho-Vaxom in the treatment of CRS.
Oral administration of Broncho-Vaxom(R) (OM-85 BV) was also Larger studies of longer duration are needed with proper
shown to alleviate allergic rhinitis symptoms and to improve patient characterization and outcome evaluation.
the overall mucosal immunity via restoring and maintaining
the normal Th1/Th2 cytokine balance as an underlying cellular/ 6.1.25.   Homeopathy
signaling mechanism(290).
There is one DBRCT in adults with potential CRS patients 6.1.25.1. Summary of the evidence
although the population has been insufficiently described and Homeopathy is an alternative medicine. Its practitioners, called
some patients had persistent RS after sinus puncture(294) (Table homeopaths, believe that a substance that causes symptoms
6.1.24.1). Broncho-Vaxom or placebo (one capsule daily for a of a disease in healthy people would cure similar symptoms in
period of 10 days per month during three consecutive months) sick people. Homeopathic preparations are termed remedies
was administered to 284 patients presenting with chronic and are made using a process of homeopathic dilution, in
purulent rhinosinusitis. Patients were clinically examined before which a chosen substance is repeatedly diluted in alcohol or
admittance to the study and at one, two, three and six months water, typically until nothing of the original substance remains
after treatment initiation Broncho-Vaxom therapy resulted in a in the product. Homeopathy in CRS involves treating both
significant decrease in purulent nasal discharge and headache the underlying disease and its predominant symptoms with
over the full six months period compared to placebo. Also, the dilutions of substances that create/start the disease. There is
effect on the opacification of the sinus X-ray was significantly much debate as to whether these dilutions actually contain any

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molecules of the original substance and hence whether any dose-dependent increase of eosinophil and T-cell apoptosis(298,
clinical effect is attributable to a placebo effect or study bias. 299)
. Kiricsi and colleagues conducted a randomized clinical trial
comparing a combination therapy of mixed ultraviolet/visible
6.1.25.2. Conclusion light phototherapy and intranasal corticosteroids and intranasal
We could not retrieve RCTs on homeopathy in CRS published steroids in 87 subjects with CRSwNP(300). The authors used a
after 1990. Based on the available evidence, the steering group mixed ultraviolet/visible light device containing 5% ultraviolet
of EPOS2020 cannot advise on the use of homeopathy in the B, 25% of ultraviolet A and 70% of visible light, with the
treatment of CRS. spectrum between 280 and 650 nm. Mixed ultraviolet/visible
light phototherapy led to a significant improvement in nasal
6.1.26. Phototherapy congestion, nasal discharge, total nasal score, Nasal Obstruction
Symptom Evaluation (NOSE) score and sense of smell (p<0.001).
6.1.26.1. Summary of the evidence The authors observed a significant improvement in nasal
The immunomodulative effect of phototherapy has been endoscopic scores in staging of polyps on the left and right side
investigated as a potential therapeutic target for CRS patients. (p<0.001 and p<0.008, respectively). There was no significant
Ultraviolet phototherapy has been found to have a profound improvement in these parameters in the control group. There
immunosuppressive effect with reduction of Langerhans cell was no significant improvement in acoustic rhinometry scores
number and function, induction of apoptosis in infiltrating T or exhaled nasal NO in the phototherapy or control groups. No
cells, and induction of immune-modulatory cytokines such comparisons were made between the two groups.
as TNF-α and IL-10(295). Two RCT have been performed (Table
6.1.26.1.). Dulguerov et al. (2017)(296) conducted a randomized, 6.1.26.2. Conclusion
blinded and placebo-controlled study of mixed visible and Two randomized clinical trials of phototherapy in CRS has shown
ultraviolet light therapy (310-600 nm light spectrum) as variable results. The DBPCT trial did not show any effect. The
compared to visible light alone in 50 patients with CRS without non- blinded RCT in CRSwNP patients with phototherapy on top
nasal polyps according to the EPOS diagnostic criteria(297). of nasal corticosteroid treatment showed a significant reduction
Patients in the treatment group did not demonstrate a in NOSE scale, symptomatology, smell and polyp score in the
significant improvement in quality of life (QOL) (RSDI; 0.71 vs. phototherapy group and not in the nasal corticosteroid only
0.72; p=0.84), nasal obstruction (4.87 vs. 4.56, p=0.63), sense of group. However, no comparisons between the groups were
smell (3.78 vs. 4.25; p=0.54), rhinorrhoea (5.56 vs. 4.18; p=0.09), made.
facial pain (3.76 vs. 3.78, p=0.43), total nasal resistance (0.65 vs.
0.67, p=0.88), total nasal resistance after vasoconstrictor (0.56 vs. The quality of the evidence for the use of phototherapy in
0.44, p=0.12), difference in total nasal resistance before and after patients with CRS is very low. Based on the evidence the
vasoconstrictor (0.09 vs. 0.24, p=0.21), or nitric oxide production EPOS2020 steering group cannot make recommendation on the
(571.45 vs. 656.85, p=0.21) as compared to the controls at the use of phototherapy in patients with CRS.
end of treatment. Similar findings were observed at one month
post-treatment. The authors observed an increase in carbon 6.1.27. Filgastrim (r-met-HuG-CSF)
monoxide production in the treatment group as compared
to controls at the end of treatment (5.24 vs. 3.88, p=0.048), The proliferation and differentiation of neutrophils are
however this difference was not sustained at one month promoted by the administration of recombinant human
following treatment (5.25 vs. 4.07, p=0.13) granulocyte colony-stimulating factor (rG-CSF). Clinical studies
in subjects who are non-neutropenic indicate that rG-CSF may
Studies of mixed ultraviolet/visible light have demonstrated be beneficial as adjunctive therapy for treatment of serious
the penetrative effect of this light therapy into polyp tissue bacterial and opportunistic fungal infections in patients who are
to reach the inflammatory cells in the stroma and induce a nonneutropenic, including those with alterations in neutrophil

6.1.27. Filgastrim (r-met-HuG-CSF) for the treatment of patients with CRS.

Study Methods Participants Interventions Outcomes Results
Van Agthoven DBPCT 56 CRSsNP • Filgastrim 300mg subcutaneously once a day for • At 4,8,12 and 24 weeks: • No significant
2001(301) patients with the first 14 days and every other day for another • SF-36 differences between
recalcitrant 10 weeks • EuroQol the groups
CRS • Placebo subcutaneously once a day for the first • McGill pain question-
14 days and every other day for another 10 weeks naire

All patients were treated at the beginning of the trial

with a combination of 500–750mg of ciprofloxacin
twice daily and 450–600mg of clindamycin three
times a day for 14 days.

CRS, Chronic Rhinosinusitis ;CRSsNP, Chronic Rhinosinusitis without nasal polyps ; DBPCT, Double Blind Placebo Controlled Trial ; SF-36, Short Form 36.

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function. Van Agthoven et al. evaluated in a double-blind cytokines, alarmins, markers on effector cells, and novel options
placebo-controlled randomized clinical trial, the influence of that are considered as new potential treatments at the moment.
filgastrim administration on QOL using the EuroQol, the Short
Form (SF)-36, and the McGill pain questionnaire of 56 refractory 6.1.31.2. GATA-3 DNAzyme
chronic rhinosinusitis patients who did not respond to regular It is obvious that type 2 immune reactions are the most clinically
treatments during a 24-week trial(301). There was no significant relevant immune deviations in nasal polyposis as type 2 is
difference in effect on QOL between the two groups. associated with comorbid asthma and recurrent disease after
sinus surgery and comorbid asthma(308). Clinical relevance
6.1.28. Topical barriers e.g. algae – carrageenans has been underscored by, current Phase 3 trials with anti-IgE,
anti-IL-5 or IL-5 receptor alpha strategies, or anti-IL-4 receptor
One alternative approach to prevention and treatment of alpha (see chapter 6.1.13 – 6.1.15 for more details.) Future
infections of the nasal mucosa is the creation of a protective concepts using more upstream targets, including GATA-3,
physical barrier in the nasal cavity with carrageenans, high focus even more on type 2 immune responses, as GATA-3 is the
molecular weight sulphated polysaccharides derived from red transcription factor essential for Th2 and ILC2 development
seaweed (Rhodophyceae). Several randomized clinical trials and function(309). DNAzymes are single-stranded catalytic
have investigated carrageenans as a potent antiviral agent in DNA molecules that bind and cleave specific sequences in a
the management of upper respiratory tract infections(302-305). target mRNA molecule, such as GATA3 mRNA; this prevents
To date, there have been no randomized clinical trials of topical the development of Th2 and ILC2 cells(310). Their potential as
carrageenans in CRS. novel therapeutic agents has been demonstrated in a variety of
disease models, including allergic asthma(310, 311) and COPD(312).
6.1.29. Collodial Silver As compared to baseline, GATA3-specific DNAzyme attenuated
the late asthmatic airway response in subjects with allergic
Colloidal silver (CS), a widely used naturopathic agent, has asthma and sputum eosinophilia by on average 34% and the
shown anti-biofilm properties both in vitro and within a early asthmatic response by on average 11%(313). The study also
rhinosinusitis animal model. A study in 22 patients evaluated the showed penetration of the drug into nasal polyp tissue and
efficacy of CS as a topical nasal spray in patients with refractory specifically into Th2 cells, underscoring its potential in CRSwNP.
CRSsNP and found no meaningful subjective or objective At the same time, the treatment was well tolerated. There is
improvements(306). No participants experienced negative health potential to develop a local nasal therapy for CRSwNP, as it has
effects directly attributable to the administration of intranasal CS. been demonstrated for asthma.

6.1.31.3. Anti-siglec-8
6.1.30. Immunotherapy Eosinophils, mast cells, and basophils selectively express sialic
acid-binding immunoglobulin-like lectin (Siglec) 8, which
A systematic review evaluating the effect of immunotherapy (IT) is highly expressed in healthy and diseased subjects. As its
found no RCTs. Lower level evidence resulted in seven studies of activation may cause cell death, Siglec-8 represents a potential
which three were prospective(307). therapeutic target(314). Siglec-8 engagement in short-term IL-5-
The authors concluded that symptom scores improved in activated eosinophils causes reactive oxygen species production
patients treated with IT when compared with baseline data and Src family kinases phosphorylation: both are essential in
and control patients. Objective endoscopic exam measures mediating Siglec-8-induced cell death(315). A proof-of-concept
improved with IT treatment in short-term studies. Significant study with the antibody AK001 however failed to show efficacy
improvements were observed in radiographic assessments, (unpublished). Presently, new antibodies against Siglec-8 are in
and there was a decreased necessity for revision surgery, early clinical development.
interventional office visits, and intranasal and oral steroid use.
After highlighting the paucity of the data, they concluded that 6.1.31.4. Anti-OX40L
there is weak evidence to support the use of IT as an adjunctive In severe asthma, anti-OX40L may be a potential therapeutic
treatment in CRS patients, particularly in the postoperative target(316), as it allows the development of regulatory T (Treg)
period. We are not aware of studies published after this cells, which might suppress inflammatory T cells. However, the
systematic review. combination of two monoclonal antibody therapies (anti-OX40L
and anti-TSLP) on Treg frequency using a human model of
allergic asthma failed to deliver the expected suppression(317).
6.1.31. New potentials not on the market today In addition, despite anti-inflammatory efficacy, decreasing
serum IgE (by 17%) and sputum eosinophils (by 75%), treatment
6.1.31.1. Introduction with anti-OX40L monoclonal antibodies failed to attenuate the
Many cytokines, alarmins, markers on effector cells, and novel early and late airway response to inhaled allergen(318). So far, no
options (like DNAzyme and biophages) that could potentially studies with anti-OX40L have been performed in CRSwNP.
be used as therapeutic targets have been discussed in chapter
5.2.2. and more details can be found there. Here we focus on

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6.1.31.5. Anti-TNF alpha a phase 1 study of CSL311 in mild asthma has commenced
In addition to type 2 inflammatory components, also non- (https://clinicaltrials.gov/ct2/show/NCT04082754).
type2/type 2-low or type 1, bacteria or endotoxins-triggered,
neutrophilic responses may comprise future targets for 6.1.31.9. Anti-TSLP
monoclonal antibody therapy in CRS(319). In a placebo-controlled Upon stimulation of the airway epithelium, several alarmins may
study in healthy volunteers comparing anti-TNF with oral be released, including thymic stromal lymphopoietin (TSLP),
corticosteroids (OCS), the endotoxin-induced neutrophilic IL-33, and IL-25 which may induce downstream type 2 responses
response in sputum was significantly modulated by anti-TNF in both via the innate and adaptive pathways. These cytokines
contrast to OCS and control treatment(319). Therefore, anti-TNF may serve as targets for future treatment of type 2 disease(331).
could have potential in patients with neutrophilic COPD without TSLP is a cytokine that triggers dendritic cell-mediated TH2
infectious cause(320), but also in mixed T1/T2 immune responses inflammatory responses, enhances IL-1-dependent TH2 cytokine
in severe asthma(321, 322). Theoretically, also in CRS anti-type 1 production in mast cells and together with IL-33 or IL-25
strategies may be useful, but no trials have been performed activates ILC2s. Exposure of nasal polyp-derived epithelium to
yet. As a caveat: in several studies, anti-TNF treatment was a virus, in contrast to healthy control epithelium, triggers the
associated with serious side effects, especially infections(323). production of TSLP(332). Although increased levels of TSLP mRNA
have been found in nasal polyps of CRSwNP patients compared
6.1.31.6. Anti-IL-17 alpha to uncinate tissue from patients with CRS or control subjects, the
Neutrophilic inflammation in CRSsNP, as well in as in NP from TSLP protein was significantly decreased, obviously degraded
patients with cystic fibrosis (CF) is predominantly driven by IL- by tissue proteases(333). A relatively small double-blind, placebo-
17, with ILC3s being an important source of IL-17, while its role controlled trial in 31 patients with mild allergic asthma was
in CRSwNP with or without asthma is questionable(324). Findings performed using three monthly doses of AMG 157 (700 mg) or
from early clinical studies with anti-IL-17 agents, including placebo intravenously(334). AMG 157 attenuated allergen-induced
brodalumab, secukinumab, and ixekizumab provide strong early and late asthmatic responses, and decreased blood and
evidence for the role of IL-17 signaling in the pathophysiology sputum eosinophils. Whether anti-TSLP therapeutics will have
of a range of inflammatory diseases(325). However, data from a clinical value in CRSwNP remains to be demonstrated
pivotal randomized, placebo-controlled double-blind trial with
brodalumab in 300 patients with moderate to severe asthma, 6.1.31.10. Anti-IL-25
appeared rather disappointing(326). Studies in CRSsNP and CF As mentinoned above, upon stimulation of the airway
patients with CRSwNP should be performed to understand the epithelium, several alarmins may be released, including IL-25
potential of this approach in this disease. which may induce downstream type 2 responses both via the
innate and adaptive pathways and may thus serve as targets
6.1.31.7. Anti-CXCR2 receptor for future treatment of type 2 disease. IL-25 expression has also
Another therapeutic strategy in neutrophilic airway been found to be upregulated in the mucosa of patients with
disease targets the IL-8 receptor CXCR2 to reduce airway CRSwNP versus healthy controls and to positively correlate
neutrophilia(327). Two placebo-controlled studies with CXCR2 with the expression of several inflammatory markers, including
antagonists have been conducted in patients with uncontrolled GATA3 (see above), TGF-β1, and TGF-β2. Anti-IL-25 treatment
severe (neutrophilic) asthma(328, 329). Despite reductions in reduced the number of nasal polyps and mucosal thickness
sputum and blood neutrophils in one study(328), substantial due to oedema as well as the infiltration of inflammatory cells
clinical effectiveness was not obtained in either study. In line in a mouse model of CRSwNP(335). Based on these data, it has
with the negative outcomes in clinical studies targeting IL17RA, been speculated that IL-25 antagonism could be specifically
these findings challenge a crucial role of neutrophils as potential promising in Asian nasal polyposis.
therapeutic targets in asthma, while so far no studies in CRS
targeting neutrophils have been conducted. 6.1.31.11. Anti-IL33
Interleukin 33 is a key upstream mediator of type 2
6.1.31.8. Anti-GM-CSF/IL-3/IL-5 inflammation within the airways. This alarmin binds to a
Granulocyte-macrophage colony stimulating factor (GM- heterodimeric cell-surface receptor consisting of a IL-1 receptor
CSF), IL-3 and IL-5 stimulate pro-inflammatory activities of accessory protein and ST2 on immune cells, such as TH2 cells,
haematopoietic cells, through interaction with the receptor ILC2s, basophils, eosinophils, mast cells, dendritic cells (DCs)
complex incorporating the shared β common (βc, CD131) and others, activating intracellular signaling pathways and thus
receptor(330). These cytokines are critical mediators in the supporting the allergic airway inflammation. Direct exposure
pathogenesis of inflammatory airway disease. A novel human of airway epithelium to S. aureus increases the expression
monoclonal antibody (CSL311) may interact with all three of IL-33 and TSLP, and consecutively of IL-5 and IL-13 in nasal
cytokines at the same time, specifically targeting eosinophil polyp tissue, accompanied by elevated expression levels of
survival. In an ex vivo study, CSL311 inhibited the survival of TSLP and IL-33 receptors(336). In mice, repeated intratracheal
inflammatory cells in induced sputum from allergic asthmatic exposure to SplD, a staphylococcal protein, led to IL-33 and
subjects undergoing allergen bronchoprovocation(330). Presently, eotaxin production, eosinophilia, bronchial hyperreactivity,

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and goblet cell hyperplasia in the airways. Blocking IL-33 via the cyclooxygenase (COX) pathway and a key mediator in
activity with a soluble ST2 receptor significantly decreased the the pathophysiology of allergic rhinitis, chronic rhinosinusitis
numbers of eosinophils in this model(337). Furthermore, IL-33 and asthma(351). PGD2 exerts its bio-active activities through
may induce mucus overproduction in human epithelial cells(338). interaction with the DP1 receptor and DP2 or chemoattractant
In CRSwNP, ILC2s were found to be increased versus control receptor-homologous molecule on Th2 cells (CRTH2), located
and CRSsNP tissue , spontaneously releasing type 2 cytokines on several structural and inflammatory cells. Through DP2
including IL-5 and IL-13(339). ILC2s can be found specifically in receptors located on Th2 cells, innate lymphoid type 2 cells
high numbers in CRSwNP patients with comorbid type 2 disease (ILC2), and eosinophils, PGD2 interlinks the adaptive and innate
such as asthma(340, 341). The regulation of IL-33 and thus the effect immune pathways and, hence, seems an attractive target for
of serine-protease like proteins (SPLS) in tissue are strongly type2 disorders(352, 353). CRTH2 antagonists represent a category
dependent on the regulation of proteases and anti-proteases(342). of small molecules (SM) currently under development for
This regulation, as well as specific antibodies to IL-33 or its the treatment of asthma and related syndromes(354, 355). In the
receptor, may be used for therapeutic intervention in CRSwNP in initial proof of concept studies, CRTH2 antagonists showed an
the future. overall modest protection against allergen-mediated airway
responses of the upper(356) and lower respiratory tract(357, 358).
6.1.31.12. Biphasic antibodies When given as monotherapy or on top of standard controllers
Novel highly potent bispecific antibodies, e.g. anti-TSLP/IL13 to patients with mild to moderate asthma for four to 12 weeks, a
antibodies, that concurrently inhibit the signaling of two or similarly modest effectiveness was observed on clinical indices
more cytokines, e.g. anti-IL4Ralpha/anti-IL5, may be designed such as symptom scores, disease control, lung function and
and developed for human airway disease(343). inflammatory markers(359-362). Until recently, in studies of allergic
airway disease, the overall therapeutic effectiveness of CRTH2
6.1.31.13. Anti-IL7R (CD127) antagonists compared to antihistamines(356) and leukotriene
Interleukin (IL)-7 is a cytokine that is constitutively produced by receptor antagonists (LTRA)(362), while some studies showed
stromal cells in non-haematological tissues, by lymphoid tissue improved effectiveness in selected patient populations(361, 363).
(thymus and bone marrow), and by lymphatic endothelial cells. While previous data showed upregulation of the PGD2 pathway
An increasing body of both pre-clinical and clinical evidence and CRTH2 in (more) severe uncontrolled type 2 asthma(364),
suggests that elevated levels of IL-7 and/or the IL-7 receptor 12 weeks of treatment with a dual DP/CRTH2 antagonist
(IL-7R, CD127) are associated with various disease/inflammatory (AMG853) failed to show clinical effectiveness in patients with
states. In inflamed tissues, several cell types, including moderate to severe asthma uncontrolled by corticosteroids(365).
macrophages, dendritic cells, and fibroblasts produce IL-7. IL-7 Alternatively, in a similar study population, another CRTH2
primarily acts on T cells and ILCs, which are increased at the receptor antagonist, fevipiprant, on top of corticosteroids for
inflammatory sites that abundantly express CD127(344). 12 weeks, reduced airway eosinophils and improved clinical
Although IL-7R signalling is crucial to most T lymphocytes and physiological parameters in patients with moderate-severe
and ILCs, most predominantly ILC2 and ILC3s(345), regulatory T asthma with sputum eosinophils(366).
cells (Tregs) exhibit low - to - undetectable expression of the
receptor. It was hypothesized that blocking IL- 7R signalling may Although, no data have been published on CRTH2 antagonists
selectively spare Tregs function while exerting inhibitory effects in CRSwNP so far, based on their mechanism of action, it is
on other potentially pathogenic T cell types (346). plausible to assume that these SM may have clinical potential
The substantial amelioration of inflammation and in patients with type2 disease despite different clinical
immunopathology in experimental animal models for these presentations which include severe eosinophilic and/or
diseases by blocking IL-7(receptor) supports this role of IL-7 and corticosteroid-resistant asthma and CRSwNP. Future studies of
demonstrates that IL-7 and its receptor represent novel targets CRTH2 antagonists or combinations with LTRA or biologicals on
for immunotherapy(347). top of corticosteroids should provide the evidence(367).
CD127 is also a component of TSLPR and is required for efficient
TSLP signalling(348). Furthermore, TSLPR complex-mediated 6.1.31.15. Bacteriophages and anti-biofilm agents
inflammation has been associated with a number of allergic As antibiotic treatment may not be effective or may lead to
inflammatory diseases(349). resistance of germs, alternative therapeutic strategies against
To date, one double-blind (a study of a single intravenous S. aureus and other frequent germs in the nose and paranasal
infusion of anti-CD127 mAb) has been performed(350). Therapy sinuses may be useful. Theoretically, viruses targeting and
was well tolerated and blocked IL-7 receptor signalling upon full killing germs (called bacteriophages) have been proposed to
target engagement. Although there was no discernible impact kill even multidrug resistant S. aureus(368). In addition, a cocktail
on peripheral T cell subsets in healthy subjects, anti-CD127 of bacteriophages could possibly reduce biofilm formation in
may effectively modulate the autoinflammatory activity of vitro(369, 370). This approach may be enforced by targeting the
pathogenic T cells/ILCs in diseased tissues. essential iron metabolism for bacterial growth, survival and
pathogenesis(371). In an ex-vivo experiment using nasal polyp
6.1.31.14. Anti-DP2 or CRTH2 mucosa, it was shown that a S. aureus-bacteriophage could kill
Prostaglandin D2 (PGD2) is a metabolite of the arachidonic acid naturally occurring nasal S. aureus and reduce the S. aureus

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driven IL-5 synthesis(372). However, no clinical studies have been foetus for ABRS or acute exacerbations of CRS. Penicillin and
performed yet in human airway disease, while potential safety cephalosporin are the safest classes, and can be given when
issues need to be addressed first. endoscopic evidence of purulence is present. Antibiotics that
put the foetus at risk such as tetracyclines, aminoglycosides,
During pregnancy it is advised to continue nasal trimethoprim-sulfamethaxazole and fluoroquinolones should
corticosteroid sprays for CRS maintenance. not be used during pregnancy, nor long-term macrolide or
doxycycline.
6.1.32. CRS treatment during pregnancy The panel advises to avoid anti-leukotrienes for CRS
maintenance during pregnancy because of the low-quality
6.1.32.1. Summary of the evidence evidence of efficacy of anti-leukotrienes in CRS (see 6.1.9.2.).
A recent systematic review evaluating CRS treatment during However, montelukast can be continued / initiated for
pregnancy found no relevant level 1, 2, or 3 studies(373). A recalcitrant asthma during pregnancy, especially in those
panel of experts formulated a number of recommendations. with prior response. Furthermore, they advised to avoid oral
They advised to continue using nasal corticosteroids because decongestants and first-generation antihistamines should be
modern nasal corticosteroids including budesonide, fluticasone avoided given their sedative and anticholinergic properties.
and mometasone should be safe to use for CRS maintenance Allergen immunotherapy is likely safe to continue during
during pregnancy at recommended doses. The off-label use of pregnancy. However, initiation or build-up of immunotherapy
budesonide irrigations or CCS nasal drops is not recommended. should be not be conducted during pregnancy. Aspirin therapy
There is fairly good evidence for the safety of inhaled CCS for AERD should be discontinued during pregnancy.
in asthma during pregnancy. Budesonide is category B in
pregnancy and remains the agent for which the preponderance 6.1.32.2. Conclusion
of safety data exists(374). Newer generation sprays have negligible Expert panel recommendations for rhinosinusitis management
systemic absorption and may be safe to use, but evidence that during pregnancy included continuing nasal corticosteroid
these medications during pregnancy are not associated with any sprays for CRS maintenance, using pregnancy-safe antibiotics for
untoward risks is lacking. acute rhinosinusitis and CRS exacerbations, and discontinuing
aspirin desensitization for aspirin exacerbated respiratory
The panel concluded that oral corticosteroids in short bursts disease.
may be safe after the first trimester. Use is better justified in
severe CRS, especially if causing exacerbation of asthma. They 6.2. Surgical treatment
advised consultation with patient’s obstetrician.
Based upon the asthma literature, oral corticosteroids use 6.2.1 Primary endoscopic surgery
would be expected to be associated with slightly increased risk
of cleft lip with or without cleft palate, increased incidence of 6.2.1.1 Preoperative CT scanning – is the timing of the scan
preeclampsia, and the delivery of both preterm and low birth prior to the operation important?
weight infants. Oral corticosteroids cause hyperglycaemia and To date, previous iterations of EPOS and other guidelines have
can lead to/worsen diabetes, causing additional maternal- not stipulated clear guidance on timing, although the current
foetal risks. Patients should undergo diabetes testing prior American College of Radiology (ACR) appropriateness criteria
to use, especially if a longer course of corticosteroids is describe CT scanning without contrast as the imaging modality
being considered. First trimester use has the greatest risk of of choice for diagnosing CRS3. A CT scan may or may not have
potential teratogenicity. The risks of oral corticosteroids use already been performed as part of the diagnostic work-up for
are outweighed by risks of undertreated asthma, but this CRS patients; for those where endoscopic findings confirm the
justification is less so in CRS and clinical judgment must be diagnosis, the CT scan may be reserved until the point at which
exercised. Oral corticosteroids are considered to be compatible surgical intervention is being contemplated, unless concerns
with breastfeeding. exist at first presentation about any unusual features such as a
The panel advised to use oral antibiotics that do not harm the mucocoele(375).

Figure 6.2.1.1. Effect of preoperative use of corticosteroids versus placebo on surgical blood loss.

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Figure 6.2.1.2. Effect of perioperative use of corticosteroids versus placebo on the quality of the surgical field.

Figure 6.2.1.3. Effect of preoperative use of corticosteroids versus placebo on duration of surgery.

Table 6.2.1.1. Effect of preoperative corticosteroids on sinus surgery.

Study Methods Participants Interventions Outcomes Results

Ecevit DBPCT 23 CRSwNP pa- • 60 mg prednisolone once daily for 7 • Blood loss (ml) Treatment with topical corticoid
2015(124) tients having FESS days followed by 10 mg predniso- • Surgical field quality compared to placebo resulted in
(22 evaluated) lone every other day for 8-10 days (Boezaart, 0-5) significantly:
preoperatively • Operation time • Reduced blood loss
• Placebo once daily for 7 days fol- • Hospital stay • Improved surgical field quality
lowed by placebo every other day
for 8-10 days preoperatively • Decreased operation time
• Hospital stay

Gunel DBPCT 65 CRSwNP pa- • Oral prednisolone (1 mg/kg), once • Blood loss (ml) Treatment with oral corticoid
2015(379) tients having FESS daily for 2 days and then tapered • Surgical field quality compared to placebo resulted in
down until day 10 (n=36) preoper- (VAS) • No difference in blood loss or
atively surgical field quality
• Placebo once daily for 2 days and
then tapered down until day 10
(n=29) preoperatively

Albu DBPCT 70 CRS (33 CRSwNP) • Mometasone nasal spray 200 mcg • Blood loss (ml) Treatment with topical corticoid
2010(380) patients having FESS twice daily 4 weeks preoperatively • Surgical field quality compared to placebo resulted in
(n=35) (Boezaart, 0-5) significantly:
• Placebo nasal spray twice daily 4 • Operation time • Reduced blood loss
weeks preoperatively (n=35) • Improved surgical field quality
• Decreased operation time

Wright DBPCT 26 CRSwNP patients • Oral prednisolone 30 mg daily for 5 • Blood loss (ml) Treatment with oral corticosteroid
2007 (381) having FESS days preoperatively • Operation time compared to placebo resulted
and then 30 mg daily for 9 days in no difference in blood loss or
preoperatively (n=11) surgical field quality
• Placebo once daily for 5 days pre-
operatively
and for 9 days preoperatively (n=15)

DBPCT, Double Blind Placebo Controlled Trial; CRSwNP, Chronic Rhinosinusitis with nasal polyps; VAS, Visual Analogue Scale; FESS,
Functional Endoscopic Sinus Surgery.

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A CT scan is mandatory prior to surgery, both to Four DBPCT studies evaluated the effect of corticosteroids
confirm the presence and extent of disease. during the surgery(124, 379-381) (Table 1). Two of these studies used
systemic corticosteroids 5-15 days before the surgery(124, 379).
A scan is mandatory prior to surgery, both to confirm the One study used systemic corticosteroids five days before the
presence and extent of disease, and to identify any anatomical surgery and nine days after surgery(381), and one a corticosteroid
features that may predispose to the risk of complications. nasal spray for four weeks before the surgery(380). All studies
Multiplanar images are required to fully assess the anatomy. evaluated surgical blood loss. One study did not report
There are a number of systems published to facilitate systematic standard deviations(381) and one did not estimate blood loss.
preoperative interpretation of the images; the CLOSE mnemonic Three studies(124, 379, 380)could be combined into a meta-analysis
is widely used (376). showing a significant but rather small mean reduction of blood
loss of -54 ml (CI -100 - -7). There was a significant heterogeneity
C Cribriform niche – depth and asymmetry should be evaluated
(I2 74%) so data are presented as SMD (SMD -0.81 (CI -1.19 -
-0.43), three studies, 120 patients (Figure 6.2.1.1.).
L Lamina papyracea – examined for dehiscence
Two studies evaluated the quality of the surgical field using the
O (Onodi) spheno-ethmoidal cells Boezaart scale (0-5)(382) and could be combined into a meta-
S Sphenoid sinus – examined for dehiscence of bone overlying analysis(124, 380 ). It showed a significant impact on the quality of
the optic nerve and carotid artery the surgical field of the use of preoperative corticosteroids (MD
E Ethmoidal arteries – the position of the anterior and posterior -0.98 (CI -1.37 - -.059, two studies, 55 patients) (Figure 6.2.1.2.).
ethmoid artery relative to the skull base should be assessed Finally, data were pooled from two out of four studies which
evaluated the effect of corticosteroids on the duration of the
surgery(124, 380). Corticosteroids resulted in a significant reduction
Provided no surgical procedures have been of surgery time of almost 14 minutes (MD -13.84 CI -21.02 - -6.68,
performed in the interim period, it is not essential 2 studies, 55 patients) (Figure 6.2.1.3.).
to repeat CT imaging. Interestingly there does not seem to be a difference between
four weeks of local corticosteroids or 15 days of systemic
Provided no surgical procedures have been performed in corticosteroids. It is not always clear whether the systemic
the interim period, it is not essential to repeat CT imaging if corticosteroids were given on top of local corticosteroids or
a scan has been performed at an earlier date. Only one study separate. The study of Ecevit(124) giving systemic corticosteroids
has evaluated this to date; Huang et al. identified 56 patients after local steroids failed, but it was not disclosed whether the
undergoing repeated imaging prior to ESS, with a median local corticosteroids were continued.
interval of 782 days. There was no significant difference in In conclusion: The use of perioperative corticosteroids reduces
radiological extent of disease measured using Lund-Mackay blood loss and operation time and improves the quality of the
scores and the repeat scan did not change the proposed extent surgical field. This effect was shown to occur in one study with
of surgery. nasal corticosteroids and three with systemic corticosteroids.
Whether there is an additive effect on systemic corticosteroids
6.2.1.2.Preoperative medication – what should this consist on top of nasal corticosteroids is unclear. The EPOS steering
of to optimise the surgical field and outcome? group advises to use (nasal) corticosteroids before endoscopic
Excess bleeding during sinus surgery may result in an increase sinus surgery.
in operative time, difficulty of surgery and potentially serious There are no other medications that have been shown to
complications. Bleeding during FESS is evaluated by measuring improve the surgical field and outcome. Antibiotics are not
the amount of blood loss, although this is quite a crude method, helpful (see also 6.1.1.)
assessment of the surgeon of the quality of the surgical field and Peroperatively a number of measures can be taken to improve
the operating time. the surgical field. For a review of those please see 6.2.4.
Methods to reduce bleeding are the pre-operative stopping of
medication that can cause bleeding like anti-coagulants and/ 6.2.1.3. Indications for surgery – what evidence do we have
or aspirin/NSAIDS although we are not aware of any studies in for when to operate?
endoscopic sinus surgery showing a difference. However, for The principle that sinus surgery should be considered only in
tonsillectomy a meta-analysis on reoperation for postoperative patients with sinus disease refractory to a trial of primary medical
haemorrhage reveals a 7.2-fold increased risk in the aspirin therapy has been upheld since endoscopic surgery was first
group(377). introduced(383). However, there is a lack of clarity regarding what
constitutes an adequate trial of medical therapy (both in terms
6.2.1.2.1. Corticosteroids of therapeutic classes, modes of delivery and duration), the
It has been shown that increased inflammation increases importance of patient compliance with treatment and how to
bleeding during surgery(378). The use of preoperative determine failure of this approach. This likely contributes to wide
corticosteroids improves the quality of the surgical filed, the variations in surgical intervention rates, found in North America
duration of the surgery and the operation time. and Europe, both between states and between countries. In
the USA, a mean adjusted rate of 0.94 was found per 1000

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population in 2015, with a four-fold difference between highest of patients undergoing surgery have CT scores, measured
(1.8) and lowest rates (0.5)(384). In the UK the mean adjusted using the Lund-Mackay score, within the range of the normal
rate is nearly half; 0.53 per 1000 population, with a five- fold population; in the 2006 UK comparative audit of surgery, a
difference between highest and lowest regions(https://www. prospective study enrolling 3128 patients undergoing sinus
england.nhs.uk/rightcare/products/atlas/). Mean annual adjusted surgery in 87 different hospitals(393), 35% patients with CRSsNP
rates in Alberta, Canada are 0.33/1000(385) and in Finland(386) had a LMS<=4, as did 8% CRSwNP. There is a poor correlation
the nationwide annual rate of ESS is 0.71 per 1000 people, but between preoperative LMS and quality of life measures(394),
variation remains very high. In Finland hospital district rates nonetheless, evidence of at least some disease on CT scan
varied from 0.25/1000 (95% CI 0.18 to 0.32) to 1.15/1000 (95% CI would be desirable. In a small study of patients with low-stage
1.09 1.21). In the Canadian study, the mean extremal quotient CRS on CT (LMS1-3) by Rudmik et al., improvements in QOL
for health status areas was 6.9, indicating a seven-fold difference were comparable to those with more extensive disease(395). In a
between the highest and lowest regions. Overall, there has been a 2017 publication evaluating the severity of disease in patients
progressive increase in intervention rates, despite declining rates undergoing balloon sinus dilation, 57% had LMS <=4, with 19%
of CRS diagnoses being recorded(387), and increases in the number of the total study cohort having no opacification or mucosal
of sinus procedures being performed. Geographical variation oedema in any sinus. In contrast to the study in low-stage
in disease prevalence, access to healthcare and varying patient disease, a randomised trial of balloon dilatation in patients with
preferences may account for some of the variation, but in each no evidence of sinus disease (LMS=0), surgery was no better
study areas of high variation were found immediately adjacent to than a sham procedure in terms of improving QOL or headache
areas of low variation. A recent study shows that variation persists severity(396).
when separating CRS according to polyp status(388). An early paper on indications for sinus surgery summarised
“if the patient has an appropriate history, appropriate physical
There is a lack of clarity regarding what constitutes findings, and appropriate CT, endoscopic sinus surgery
an adequate trial of medical therapy (both in typically will be indicated and beneficial”(383). In the 25 years
terms of therapeutic classes, modes of delivery and following publication there has been little to further refine that
duration), the importance of patient compliance description. In an attempt to define evidence-based indications
with treatment and how to determine failure of for surgery, Rudmik utilised the RAND/UCLA appropriateness
this approach. methodology, with an international, multidisciplinary panel
of 10 experts in CRS who completed two rounds of a modified
There are few attempts in the literature to standardise Delphi ranking process along with a face-to-face meeting(397).
indications for surgery. A systematic review of studies reporting A total of 624 clinical scenarios were ranked, 312 scenarios
outcomes from ESS identified 387 published studies in a five- each for CRS with and without nasal polyps. For adult patients
year period, however only 21% reported medical treatment with uncomplicated CRS with nasal polyps, it was agreed that
employed prior to surgical intervention(389). Medical therapy ESS could be appropriately offered when the CT Lund-Mackay
regimens reported included topical intranasal corticosteroids score was >/= 1 and there had been a minimum trial of at least
in 91% studies (mean duration eight weeks), systemic eight weeks’ duration of a topical intranasal corticosteroid
corticosteroids in 61% (18 days), oral antibiotics in 89% (23 plus a short-course of systemic corticosteroid with a post-
days), saline irrigations in 39% and oral antihistamines in 11%. treatment total SNOT-22 score >/= 20. For adult patients
with uncomplicated CRS without nasal polyps, ESS could be
As the aim of surgery is to improve the severity appropriately offered when the CT Lund-Mackay score is >/=
of patient’s symptoms, the decision to operate 1 and there had been a minimum trial of at least eight weeks’
should only be made in patients with symptomatic duration of a topical intranasal corticosteroid plus either a
disease, with the exception of patients with actual short-course of a broad spectrum/culture-directed systemic
or impending complications. antibiotic or the use of a prolonged course of systemic low-
dose anti-inflammatory antibiotic with a post-treatment total
One study to evaluate factors (including demographics, SNOT-22 score >/= 20. These criteria were considered the
clinical measures, social support and personality type) that minimal threshold, and not all patients who meet the criteria
influence a patient’s choice to pursue surgery found that only should have surgery, but application should reduce unnecessary
their preoperative symptom severity, measured using the surgery and practice variation. A subsequent study applied
Sino-Nasal Outcome Test (SNOT)-22, predicted the choice for the criteria retrospectively to patients recruited to a multi-
surgical intervention(390). Preoperative symptom scores are centre cohort study and found that patients where surgery was
predictive of postoperative improvement and the chance of deemed ‘inappropriate’ reported significantly less improvement
achieving a clinically significant change in symptom scores(84, 391). in their quality of life(398).
Furthermore, postoperative changes in symptom scores can also As there are strong recommendations for use of intranasal
predict need for revision surgery(392). corticosteroids and saline irrigation, based on high-quality level
As previously mentioned, a CT scan is considered mandatory 1 evidence(399, 400), guidelines are consistent in recommending
prior to undertaking sinus surgery for surgical planning. usage prior to offering surgery. In contrast, international
However, there is evidence that a relatively high proportion guidelines are conflicted regarding whether long-term

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antibiotics and oral steroids should be included as part of in a prospective cohort of 3128 patients undergoing sinus
adequate medical therapy (AMT), reflecting conflicting evidence surgery, Hopkins et al.(393) found the preoperative SNOT-22 score
in the current literature(297, 397, 401), and concerns with regards to to be a strong predictor of postoperative SNOT-22, with those
side-effects. having higher preoperative scores achieving greater reductions
in symptom scores but having persistently higher scores
6.2.1.4. Prediction of the success of surgery postoperatively. Older patients achieved greater improvement,
Brooks et al. studied whether Lund-McKay CT score (LMS) was patients with asthma less improvement. Male patients reported
predictive of postoperative QOL outcomes in adult patients lower scores at all time points, but there was no difference in the
with medically recalcitrant CRS (n = 665) in a prospective, overall amount of symptom improvement by gender.
observational cohort study(402). It showed a significant More recently, a systematic review and meta-analysis with
association of preoperative CT scores with preoperative meta-regression analysis identified the variables among 3048
SNOT-22 scores and postoperative SNOT-22 scores, driven by patients that significantly correlated with an improved SNOT-22
extranasal and rhinologic subdomains of the QOL questionnaire. outcome(405) namely: older age, asthma, prior ESS, and a high
Patients in the lowest preoperative LMS quartile had the lowest preoperative SNOT-22 score. It seems obvious that a higher
mean change in SNOT-22 scores at 12 months (16.8 points; 95% SNOT-22 at baseline is more likely to be reduced after surgery.
confidence interval [CI], 12.2-21.3). Patients in the second and This association applied to older patients as well, who reported
third lowest preoperative LMS quartiles had mean changes at 12 a higher SNOT-22 score preoperatively. Current tobacco use
months of 21.1 points (95% CI, 16.7-25.4) and 23.1 points (95% status and the length of follow-up correlated with poorer SNOT-
CI, 18.3-27.9). Patients in the highest preoperative LMS quartile 22 outcomes.
had the greatest improvement in SNOT-22 scores after FESS
(29.9 points; 95% CI, 24.9-34.8). The difference in QOL change In summary, the preoperative symptom score has consistently
at 12 months between the highest and lowest preoperative been shown to the best predictor of success of surgery with
LMS quartiles was 13.1 points (95% CI, 6.0-20.2; p<0.001). The those with higher preoperative scores achieving greater
key limitation of this study may be the setting, as this was improvement in symptoms scores.
conducted in a large tertiary otolaryngology setting and thus
may not be transferable to wider practice. The preoperative symptom score has consistently
Lal et al. tried to assess retrospectively features that might been shown to the best predictor of success of
predict outcomes from endoscopic sinus surgery (ESS) with surgery with those with higher preoperative scores
the help of clinical and endotypic features, CT, histopathology achieving greater improvement in symptoms
and the SNOT-22 in 146 adults that underwent ESS(403). They scores.
were able to differentiate severity grades of CRSsNPs as clusters
from middle burdened (cluster D) to severely burdened (cluster 6.2.1.5. Timing of the surgery relevant to the duration of the
A), the latter with high scores in all four domains. Asthma disease – does this affect outcome?
burden and eosinophilia were significantly higher in cluster C In order to evaluate the impact of timing of surgery on
(p=0.03) and three months after ESS, all groups had significantly outcomes, data from both the UK prospective audit of surgery
improved (p<0.0001). At six months, patients in cluster C tended for CRS and electronic datasets were analysed by Hopkins et
to worsen. al.(406). Patients were classified according to the duration of their
In a prospective, observational multi-centre study on 690 CRS until their first surgical intervention for CRS. Three cohorts
patients with CRS, Soler et al. tried to identify clusters of patients of patients were defined: early cohort – less than 12 months;
based on three common clinical variables(404). SNOT-22 was mid cohort – 12-60 months; and late cohort – more than 60
completed at baseline and 18 months after continued medical months of symptoms. In the UK Audit 1493 patients having
or surgical treatment (according to patient preferences). Forty- primary surgery were identified; 11.5% in the early group, 50.2%
two percent (289/690) of patients had undergone prior sinus in the mid group and 38.2% in the late group. Patients in the
surgery and comorbidities, such as allergy (25%, 172/690), early group had not only a greater percentage improvement in
asthma (37%, 255/690), and nasal polyps (37%, 254/690) were their symptoms, but the improvement was better maintained
common. To assess factors associated with achieving a minimal over five years. At five years there was a significantly higher
clinically important difference (MCID) for each QOL measure proportion of patients in the early group maintaining a clinically
after either medical or surgical treatments, controlling for significant improvement over baseline (71.5%) than in either the
baseline value and follow-up duration, a logistic regression mid (57.3%) or late (53.0%) groups. Using healthcare interactions
was performed. Three variables were shown to allow a as a proxy for symptomatic improvement in CPRD (assuming
discrimination of patients: preoperative SNOT-22 score, age and that higher frequency of healthcare visits and prescription
missed productivity. Extent of the surgery was, however, left medications reflect a poorer outcome from surgery), a similar
to the criterion of each treating surgeon, which does not allow pattern was found. Patients having early surgery saw their GP
one to draw conclusions about the potential effect of various less frequently and received fewer prescription medications
extensions of the surgical procedure. each year after surgery than the mid or late cohorts. These
results were further replicated in a US based electronic dataset,
Using a similar regression to determine risk adjusted outcomes MarketScan(407).

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Perhaps of even greater interest to the population as a whole, Wadwongtham and Aeumjaturapat studied differences in the
the impact of ESS on the subsequent development of asthma patency rate between a large middle meatal antrostomy and
was also analysed. It was found, using both UK and US datasets, an undisturbed maxillary ostium in endoscopic sinus surgery
that ESS was associated with a reduction in the incidence of new for CRSwNP in 60 cases with a similar extent of polyposis in
asthma diagnoses following surgery, and that the reduction was a randomized setting(415). The patency rate of a large middle
greatest in those having early surgery(408). meatal antrostomy was 71.7-85% compared to 61.7-65% of the
Other groups have subsequently studied the impact of timing undisturbed maxillary ostium cases. There was a statistically
of surgery. A prospective study in Sweden found that patients significant difference only in early phase evaluation between the
with less than 12 months of sinus disease derived greatest two surgical techniques (p-value = 0.002). Thirty-six of 60 cases
benefit after ESS(409). In contrast, a multi-centred cohort study (60%) had good results with adequate drainage openings, no
in the US found that improvements in QOL were greater in infection and no recurrent polyps at the final evaluation. Early
those with longer pre-operative symptom duration. The most and small nasal polyps (grade I polyp) was the main correlation
recently published study evaluated the effect of surgical wait factor to the success of endoscopic sinus surgery for CRSwNP
times and found that prolonged wait times were associated with (p= 0.017). Patency was strongly dependent on the recurrence
detrimental outcomes(410). rate of the polyposis causing blockage.
Although the timing of surgery has not been formerly evaluated
in a randomised trial, there is a growing body of evidence Albu and Tomescu conducted a prospective randomised
suggesting that lengthy delays in intervention are detrimental controlled study on 133 patients to assess whether the size
to symptom improvement. The mechanism for this is not yet of a small middle meatal antrostomy (<6mm) or a large
clear. Reduction in type 2 inflammation and prevention of one (>16mm) had an influence in relieving the symptoms
irreversible remodeling of the mucosa by facilitating improved of rhinogenic chronic maxillary rhinosinusitis (obstruction,
access to topical therapies are potentially disease-modifying headache, and nasal discharge). The postoperative size of the
benefits of surgery. ostia did not correlate with the clinical outcome. However,
persistent accessory maxillary ostia and scarring within the
There is a growing body of evidence suggesting ethmoid cavity/sinuses were statistically significant predictors of
that lengthy delays in intervention are detrimental poor surgical outcome(416).
to symptom improvement.
Similarly, Kim et al. studied 98 patients with CRSwNPs
6.2.1.6. Does the type or extent of surgical procedure affect undergoing a maxillary antrostomy where 32 patients (group
outcomes? A), had the inflamed/polypoid mucosa radically (but not
Many acronyms have been applied to FESS since its inception completely) removed with a powered microdebrider, 28 patients
in the 1980s to characterise extent of the surgical procedure. (group B), where only part of the mucosa was removed (mucosa
First reported in 1996, minimally invasive sinus technique in the inferior half of the sinus was preserved), and 38 patients
(MIST) is a conservative approach involving simple ventilation (group C), where only enlargement of the maxillary ostium
of the lower sinuses and has been considered to settle cases was performed without any removal of mucosa(417). Pre- and
even when severe disease is present some advocating its use in postoperative changes in symptoms, endoscopic polyp grade,
current practice(411, 412); however, it is likely that selecting cases and Lund-Mackay CT score were compared between the
with less aggressive endotypes of CRS may be the appropriate three groups. After twelve months follow up, the study found
for the use of MIST. A key advocate of MIST in the literature no significant differences in symptoms (on VAS), endoscopic
is Peter Catalano at Massachusetts, USA who first published 4-point grading of the sinus mucosa or CT scores (LMS) between
a case series of 85 patients undergoing MIST in 2003(413). The the three groups.
series included a diverse age range from four to 81 years old but
with an equal male/female divide. Using the Chronic Sinusitis In a prospective, randomized, single-blinded study Myller
Survey, patients were followed up for two years on average. The et al. compared sides of the nose for either preservation or
mean CSS symptom score showed 124% improvement, with enlargement of the maxillary sinus ostium(418). In 30 patients
a 30% improvement in the mean CSS medication score and a with CRSsNP they performed ESS with uncinectomy on one
62% improvement in the mean CSS total score (all p-values < side and an additional maxillary antrostomy on the other
0.00001). Thirteen percent of patients were symptomatically side. On the enlarged side, the natural ostium was widened
worse and 8% were unchanged. By the end of the follow up posteriorly to double its size; of note 25 of the 30 patients
period, 6% had had revision MIST surgery and were reported to also had a bilateral ethmoid bullectomy. LMS and the ostial
have improved afterwards. diameters were analysed with 1mm slice thickness CT scans
taken preoperatively and nine months post-operatively and
6.2.1.6.1. Maxillary sinus were used for comparison of the two operative techniques. Also,
After the anterior ethmoid sinuses, the maxillary sinus is most the correlation between CT findings and subjective outcomes
frequently targeted in all forms of sinus surgery, regardless of was studied with simple questionnaires using a total symptoms
extent(393) with a historic principle of the value of addressing score out of 16 points; intervals for the latter were one month
this sinus to improve OMC functionality or vice versa(414). pre-operatively and one, 9 and 36 months postoperatively.

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Comparison of the preoperative and postoperative CT scans scores for purulent discharge, foul odour, and postnasal drip at
revealed a significant reduction of LM score was achieved on six and 12 months were observed in the CFP group compared
both sides, regardless of the type of procedure performed. The with the MMA group which was attributed to the removal
postoperative area of the ostium remained significantly larger of severe maxillary mucosal disease that cannot be reached
on the antrostomy side compared to the uncinectomy side. A through MMA.
large maxillary sinus ostium size was associated with a lower
postoperative LMS, however, the postoperative symptoms 6.2.1.6.2. Ethmoid sinuses
scores did not correlate to any of the postoperative CT-values (p A small prospective study published in 2017 explored the
> 0.05) suggesting that it does not provide superior symptom role of ethmoid punch sinusotomy using the Relieva Circa™
relief. device in a group of 10 CRSsNP patients who failed medical
Byun and Lee compared partial vs total resection of the management(423).management. At follow up, 90% of puncture
uncinate process by assigning 25 patients with unilateral sites in anterior and posterior ethmoids remained patent with
maxillary sinusitis (chronic maxillary sinusitis, fungal sinusitis, stenosis present in 28%. Comparative LM scores showed a
antrochoanal polyp, and odontogenic sinusitis) randomly to reduction of a score of 1 or 2 down to 0. Comparative pre and
either surgical procedure(419). CRSwNP cases were excluded. The post SNOT-22 scores showed a significant mean reduction of
lower half of the uncinate process was resected in the partial 33.1 (p<.0001), but clearly this device requires further evaluation
group. Time required for the uncinectomy, healing period for in an appropriately powered RCT setting to determine its place
the uncinectomy site and complications such as synechiae as part of MIST surgical strategy.
formation in the middle meatus were compared between the
groups. Partial uncinectomy had a lower complication rate, a 6.2.1.6.3. Olfactory niche
shorter surgical procedure and more rapid healing. However, A single RCT has looked at the role of clearing of olfactory cleft
outcomes with respect to symptom benefit, or the status of polyps with a microdebrider during ESS for CRSwNPs to assess
the maxillary sinus were not assessed either radiologically or olfactory outcomes(424). The University of Pennsylvania Smell
endoscopically. Identification Test (UPSIT), along with VAS and SNOT-20 were
It is notable that some of these studies fail to address the normal used to assess patients at baseline and six months. Seventeen
physiology of the maxillary sinus. The critical factor is whether patients were randomised to receive either cleft polyp removal
the natural ostium is patent or not, as the mucociliary pathway or to have the cleft left undisturbed. All parameters improved
always beats towards the natural ostium, regardless of the size in those having olfactory cleft surgery but only the VAS in
of the surgical antrostomy. (See Chapter 6.2.1.6.4. for more those without (p<0.05). There was a statistically significant
radical maxillary sinus procedures.) difference in UPSIT scores between the groups at six months
A randomised prospective study comparing a limited approach postoperatively (p=0.00512), although long-term results
at one centre with a more extensive approach at another showed regression to baseline. Whilst 17 patients is a small
centre was conducted by Kuehnemund et al. in 2002 on 65 sample size, this gives some indication that careful debridement
CRS patients (polyp status unknown)(420). The limited approach in the olfactory cleft may be effective in managing olfactory
involved infundibulotomy, ethmoid bullectomy and maxillary dysfunction in patients undergoing ESS for CRSwNPs, with the
antrostomy; the extensive approach involved infundibulotomy, caveat that decline may be observed over a longer period.
ethmoidectomy, sphenoidotomy, opening of the frontal recess,
maxillary antrostomy and reduction of the middle turbinate. 6.2.1.6.4. Radical approaches
With the caveat that a non-validated symptom score was used, A cohort study published in 2016 reported that extended ESS
the authors concluded that a more limited surgical approach (EESS )was taken to include resection of the middle and superior
may avoid perioperative complications in less experienced turbinates along with a total ethmoidectomy(425). Forty-seven
hands while still achieving the goal of improved ventilation and patients with CRSwNP and asthma underwent either EESS or less
drainage; these findings obviously require corroboration two radical “FESS”. Outcomes measured at one year suggested better
decades on with the use of a validated PROM to compare the outcomes for olfaction (as measured by VAS only) in the EESS
groups and better patient characterisation. group; endoscopic changes were improved in this group too but
Antral washout is now mainly of historic interest and a study by otherwise there were no differences between the groups. This
Pang et al. in 1996 failed to show any benefit for the addition study has a small sample size and without randomisation and
of antral washout to medical treatment of CRS in an RCT on psychophysical olfactory testing, limit its applicability.
114 patients(421). However, a study in 2013 from South Korea A randomised, controlled trial with parallel design was
compared canine fossa puncture (CFP) with middle meatal conducted between July 2000 and December 2004, including
antrostomy (MMA) in 25 patients with severely diseased 119 patients with CRSwNP (grade III or higher)(426). Patients
unilateral maxillary sinuses(422). Subjective outcomes were were randomly allocated to two treatment groups: classical
evaluated preoperatively and at three, 6, and 12 months endoscopic middle meatal antrostomy and endoscopic radical
postoperatively using the SNOT-20 and a visual analogue scale antrectomy. The description of the latter corresponds to a
(VAS). SNOT-20 and VAS scores improved significantly at three, medial maxillectomy with complete removal of the maxillary
6, and 12 months post-procedure in both groups. However, sinus mucosa, a mega-antrostomy through the middle meatus
significant improvement of SNOT-20 at 12 months and VAS and an adjuvant canine fossa puncture. The antrostomy was

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inferiorly extended to the level of the inferior meatus (with (n=4), frontal sinusotomy or frontal sinus drillout (n=1), frontal
resection of the middle part of the inferior turbinate) and sinus drillout alone (n=1), endoscopic modified Lothrop
superiorly to the orbital floor. There was a significant difference procedure (EMLP) (n=9), Draf types I, II, or III (n=6); trans-septal
between the groups: 32% of patients in the endoscopic middle frontal sinusotomy (n=1); and frontal sinus rescue procedure
meatal antrostomy group were considered surgical failures, (n=1). The mean number of subjects was 44, and the average
compared with 14.5% of the endoscopic radical antrectomy follow-up period was 23.6 months. Surgical success rate ranged
group (p=0.023). Unhealthy maxillary sinuses were significantly from 50 to 100%. Unfortunately, due to the limitations of the
more prevalent in the endoscopic middle meatal antrostomy literature base at the time of this particular review, there is little
group (p=0.029). to conclude.
In a RCT, Jakob et al. compared outcomes of 40 cases with Abuzei et al. provided a thorough meta-analysis of the Draf III
chronic maxillary sinusitis treated with a Caldwell-Luc against after failure of primary FESS(433). Although this evidence would
40 cases with a middle meatal antrostomy(427). Over 77.5% support the use of the Draf III approach in recalcitrant frontal
of participants had CRSwNP. After 12 months, 44% of the sinus disease following failure of primary ESS, it is not relevant
Caldwell-Luc patients and 89% of the FESS patients reported here in considering primary surgery. A prior review performed
improvement of their symptoms, showing that endoscopic in the same year as Silverman et al, also only included revision
middle meatal antrostomy is superior to Caldwell-Luc in cases(434); other studies are also irrelevant to the considerations
managing patients with CRSwNP surgically and further evidence of primary surgery for the same reason(435-440).
that the Caldwell-Luc approach should no longer be part of
practice for routine ESS(428). An older RCT of 150 patients with 6.2.1.7. Recommendations for when more extensive or
chronic maxillary rhinosinusitis found that while both the radical surgery is required
Caldwell Luc and ESS approaches improved post-operative Regarding whether all sinuses should be opened regardless
symptoms, there was stenosis of the maxillary ostium in 18.6% of disease extent or whether surgery should be targeted to
of the operated sinuses in the ESS group and stenosis of affected sinuses, DeConde considered this dilemma in their
31.4% of the sinuses in the Caldwell-Luc group but with large observational study(441). Their results allowed them to compare
polyps found more frequently after ESS. In addition 41% of the 147 subjects undergoing complete “full house” surgery with
Caldwell-Luc patients had problems with changes in sensation 164 subjects where the surgery was targeted to less than all
of the cheek and 23% experienced severe pain. However, it is of the sinuses. The “complete” group had a significantly higher
worth noting that 16 surgeons undertook the Caldwell-Luc prevalence of asthma, acetylsalicylic acid (ASA) sensitivity,
procedure whereas only one surgeon performed ESS(102). A CRSwNPs and revision cases (p≤0.002). They also had a higher
follow-up study was published in 1997 on 128 of the original mean improvement in SNOT-22 and smell test scores (B-SIT)
cohort 5-9 years after their operation. One year after surgery (p=0.011 and 0.005 respectively). The key limitation of the study
51% of the C-L patients and 77% of the FES patients reported no was composition of the comparator groups, as inevitably in a
symptoms or distinct improvement in their global symptoms, non-RCT setting the patients with a higher burden of global
whereas 5-9 years postoperatively 82% of the C-L and 76% of airway disease received the complete surgical option.
the ESS patients reported this outcome, respectively. Thirteen Masterson et al. conducted a retrospective review of 149
C-L operated patients (18%) and 14 FES patients (20%) have patients who underwent “extensive” ESS (EESS) in a district
been reoperated during 7-9 years follow-up(429). general hospital(442). SNOT-22 scores were collected pre- and
Medial maxillectomy for CRS was considered by Woodworth et post-op as well as surgical revision rates and perioperative
al, but only in patients having failed primary surgery(430). complications and this data was compared with the UK
National Comparative Audit, the majority of whom underwent
6.2.1.6.5. Extended frontal sinus approaches polypectomy alone or limited sinus surgery extending to
Alsharif et al. conducted a retrospective cohort study of 50 the anterior ethmoid cavity. Revision rate at 36 months
consecutive CRSwNPs patients(431). In those patients (n=12) in was significantly lower at 4% as compared to 12.3% in the
whom a full resection of the mucosa (“reboot technique) in national audit. No differences were seen in complication rates
all sinuses, including the frontal sinuses via a Draf type III was and significant improvements in SNOT-22 scores were seen.
performed the recurrence of nasal polyposis was significantly Although described as “extensive”, this cohort can probably be
reduced for 30 months postoperatively compared to the current considered as “complete” as per the DeConde study above.
mucosa-sparing ESS. This is a novel approach but needs further For primary surgery in CRSsNPs, more extensive surgery, such
studies, and it is not clear whether the improved outcome was as a draf 3 or endoscopic medial maxillectomy is traditionally
related to mucosal removal or the more extensive approach less likely to be warranted given the nature of the pathology.
itself required to achieve complete clearance. The question for the surgeon counselling the patient will be as
In 2009, Silvermann et al. performed a systematic review on to what the goal of the surgery is in the individual patient. Even
endoscopic frontal sinus surgery including retrospective case in CRSwNPs, the weight of evidence for extended approaches
series without control (16 articles), prospective case series lies in revision cases and not for primary surgery, especially with
without control (three articles), and retrospective case series respect to the frontal sinus where a more conservative approach
with internal control (four articles); mostly level 3 evidence(432). is usually deemed appropriate(443, 444).
The surgical technique was described as frontal sinusotomy

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6.2.1.8. What is the value of adjunctive surgery? surgery; thus approximately 40% of all cases of CRSsNPs. Overall
for all cases of CRS, 33% of ESS cases underwent adjunctive
6.2.1.8.1. Septoplasty septoplasty and/or turbinate surgery. Whilst this data does
An underpowered prospective trial including 26 patients, not tell us anything about outcomes, it does indicate surgeon
designed to determine the role of addressing a deviated nasal choice in these cases. It is not clear whether “turbinate surgery”
symptom in ESS, claimed that septoplasty alone could be more involved the middle or inferior turbinates.
effective than septoplasty and ESS in treating CRS(445). This used
a 14-item symptom questionnaire and CT scores to compare the 6.2.1.9. Powered instruments
two groups and suggested that 93% felt symptomatically better Although powered instrumentation is now the standard of
from septoplasty alone compared to 81% from septoplasty and care in many hospitals, only four studies have looked at this
ESS (n=9). Another study considered this with specific reference specifically. In 2013, Saafan et al. conducted a prospective RCT to
to maxillary rhinosinusitis and again had a small sample size compare the efficacy and safety of powered versus conventional
(n=40), but showed the opposite, that ESS with septoplasty endoscopic sinus surgery instruments in patients undergoing
was superior for overall symptom control when CRSwNPs was ESS for CRSwNPs with a sample size of 200 patients(450). The study
present(446). addressed both intra-operative conditions and postoperative
There are three questions the sinus surgeon should consider outcomes including complications across the peri-operative
about a deviated nasal septum (DNS) when deciding whether to period. The only key notable statistically significant difference
address it during ESS: in symptom improvement on VAS at 12 months between the
• Does the DNS contribute to significant nasal obstruction? two groups was for olfaction in the powered group (p<0.001).
• Does the DNS prevent access to the sinuses during ESS? The operative time and surgical conditions, as well as the
• Will correction of the DNS facilitate better postoperative care? incidence of post-operative synechiae were significantly better
in the powered group with a trend towards improvement in
A study by Smith et al. looking at surgical outcomes across three time to mucosalisation of the sinus cavities. In a separate study
academic North American centres found not only that septal of 60 patients randomised by side of nose to have powered
deviation prevalence varied significantly across the sites (from instrumentation on only one side of the nose, also supported
16% to 54%), as did subsequent rates of septoplasty, but also reduced operative times in the powered sides(451). However, a
that septoplasty significantly improved postoperative SNOT-22 more recent trial found that there was no significant difference
scores(447). The reasons for the difference in rate of septoplasty at 13 months between 48 patients managed with conventional
in the centres was unclear and the authors concluded that instruments and 49 patients where the microdebrider was used,
further study was needed to determine clear indications for when using Kupferberg nasal endoscopy grades, 20-item SNOT
septal surgery within the scope of ESS. However, given that scores, Lund-Mackay scores and mucociliary clearance time
it was not just the nasal domain of the SNOT-22 that showed as outcome measures(452). This corroborated the findings of an
improvements, there appear to be wider benefits to this older study from 2003 looking at similar outcomes(453). Indeed
adjunctive procedure that may well be due to improved delivery Tirelli et al. in 2013 analyzed 311 cases of bilateral CRSwNP in a
of postoperative topical medications to the sinuses. prospective randomized single-blind study using eachpatient
as their own control, in that one side was operated on using the
6.2.1.8.2. Turbinate surgery Blakesley forceps and the opposite side using the microdebrider.
As per adjunctive septal surgery, evidence for turbinate After a follow-up mean of 13.3 ± 1.2 months the Blakesley
surgery is limited. One study considered two methods of forceps caused a significantly lower NP recurrence rate than the
turbinate surgery during ESS where 54 patients with CRS were microdebrider (p<0.001), though the microdebrider was more
randomised to receive either an out-fracture and radiofrequency effective in preventing synechia formation (p<0.05)(454).
ablation of the ITs or just out-fracture alone. SNOT-20 and Interestingly a study comparing conventional cutting and
Lund-Kennedy scores were significantly better in the coblation non-cutting instruments also showed less synechiae in those
group(448). Another small-scale study of only 16 patients patients where cutting instruments were used at a mean of 12
showed no discernible benefit of middle turbinate resection years follow-up(455).
for CRSwNPs cases within six months postoperatively but as an Initially concerns that tissue taken with powered instruments
underpowered study is of little value(449). would not be suitable for histological diagnosis were dismissed
by a study from McGarry et al. which showed that tissue could
6.2.1.8.3. Septoplasty and turbinate surgery together be collected in an in-line specimen trap and was comparable to
Data from Hospital Episode Statistics in the UK shows that in conventionally obtained tissue for histology(456).
2017-8 in England, there were 11,177 cases of ESS for CRSwNP A more recent development by Medtronic is the “hydrodebrider”
in which 6% also underwent septoplasty and turbinate surgery, using a pressurised saline irrigation to clean the sinus cavities
13% also underwent septoplasty and 11% underwent turbinate during ESS. However, a study looking at the sinus “jet wash”
surgery, equating to approximately 1 in 3 of all cases of ESS for showed no subjective or objective treatment benefits, although
CRSwNP. The same data for CRSsNP shows that of 3876 cases was an underpowered study with only 12 patients and
of ESS, 12% underwent septoplasty and turbinate surgery, compared sides of the nose(457).
16% underwent septoplasty and 14% underwent turbinate

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6.2.1.10. Balloon sinuplasty significant improvement in SNOT-20.

A RCT in 2012, the REMODEL trial, in 2012 tested the hypotheses
that symptom improvement after balloon dilation was non- 6.2.1.11. Drug-eluting stents (DESs)
inferior to ESS and that balloon dilation was superior to ESS
for post-operative debridements. The study recruited CRS 6.2.1.11.1. Nasal packing/spacers soaked with medications
patients with disease limited to the maxillary sinuses with (See also section below on nasal packing)
or without anterior ethmoid disease. Ninetytwo patients (50 Drug eluting stents are expensive; a cheaper alternative
balloon dilation; 42 ESS) were treated and the results showed a utilizing absorbable dressings soaked in triamcinolone
mean SNOT-20 improvement of 1.67 ± 1.10 and 1.60 ± 0.96 in has been evaluated in a number of trials; however, the rate
the balloon and FESS arms, respectively. Both groups showed and amount of drug-elution is unknown. Cote and Wright
clinically meaningful and statistically significant (p<0.0001) randomized 19 patients to receive either a steroid or saline
improvement and the balloon arm was non-inferior to FESS soaked absorbable dressing, with significant improvements in
(p<0.001). The balloon arm showed superiority for reduction post-operative endoscopy scores being seen up to six months
in post-operative debridements (p<0.0001). Postoperative postoperatively(465). Xu et al. replicated the study in 80 patients,
complications such as epistaxis, analgesic use and recovery with similar outcomes of improved endoscopy scores with
time were all significantly lower in the balloon arm (p<0.01). triamcinaolone(466). Hong et al.(467) found that serum cortisol
No other complications were reported but one revision surgery levels were suppressed on day 2 after surgery in patients
was reported in each arm. This study serves to underline that receiving triamcinolone soaked dressings, but that levels had
in a healthcare model where patients present early, the balloon normalized by day 10, suggesting that the triamcinolone is
sinuplasty may have a role to play in milder cases of CRS (458). absorbed in a short pace of time. Unlike the drug-eluting stents
In the UK, the National Institute for Health and Care Excellence that achieve controlled release over longer periods.
has sanctioned use of the XprESS multi‑sinus dilation system Dautremont et al. took this a step further and in patients
for treating uncomplicated chronic rhinosinusitis after medical receiving a Nasopore dressing soaked in 2ml (80mg) of
treatment has failed. The specific criteria they recommend for triamcinolone during ESS, randomised 36 patients to receive
the application of balloon sinuplasty include selecting CRS either prednisolone 30mg for seven days or placebo tablet
patients who do not have severe nasal polyposis or complicated equivalent(125). There was no significant difference between the
cases and recommend for the procedure to be performed under two groups in terms of SNOT-22 or endoscopic scores up to two
local anaesthesia, however the economic modelling for this months, but the small sample size and short follow up period
does not reflect UK practice(459). probably preclude too much being derived from this in terms of
These recommendations were supported by a systematic abandoning the use of perioperative OCS.
review(460) of 9 studies including the REMODEL RCT, which Triamcinolone versus saline soaked polyvinyl alcohol packs
included the original 92 patients, but as an expanded cohort were considered in a recent study. The pack was removed
of 135 patients with medically refractory CRS, treated with ESS on the second postoperative day and the cavities evaluated
or in-office balloon dilation. One hundred thirty patients had endoscopically in the third postoperative week, showing a
12-month data, 66 had 18-month data, and 25 had 24-month significant reduction in the average Lund-Kennedy score in
data. Outcomes were comparable for FESS and balloon dilation, the treatment side compared to the control site and a greater
with significant reductions in symptom scores, absenteeism, reduction in crusting, oedema and scarring though only the
health care visits and antibiotic usage in both groups. Recovery reduction in oedema was statistically significant(468).
was faster in the balloon dilation group. It should be noted In a pilot study of only 10 CRS patients undergoing ESS, a
that all included patients had very limited sinus disease doxycycline releasing stent significantly lowered MMP-9
radiologically. concentrations and bacterial colonization on the treated side
Bizhaki et al. whose 2014 study was included by Jenks compared with a placebo stent on the opposite side, and
subsequently published three papers considering quality of life, improved postoperative healing quality at 3 months after ESS(469).
mucociliary clearance and nasal airway resistance at six month
follow-up in their cohort(461-463). They showed improvement 6.2.1.11.2.DESs placed during ESS
in QoL (as measured by SNOT-22), no change in mucociliary A growing number of DESs are emerging in the market for
clearance (as measured by saccharine test, methylene-blue which the PROPEL system has the most data(470). The Propel
dye and albumin labelled with Tc99m) and a decrease in nasal bioabsorbable steroid-releasing implants contain mometasone
airway resistance (as measured by acoustic rhinometry and furoate 370µg and have been specifically assessed for improving
rhinomanometry) in both groups, but no statistical difference postsurgical outcomes in the frontal sinus ostia(471). This
between balloon sinuplasty and ESS. publication reported data from the pooled analysis of two RCTs
A more recent study by Minni et al.(464) randomised 102 patients considered160 patients randomised by side of nose to receive
into mild and moderate/severe frontal CRS based on the LM an implant in one frontal sinus ostium with the contralateral side
score and by balloon catheter dilation (BCD) or ESS. The primary as a control and patients were followed up for three months. A
outcomes were radiology score and SNOT-20. No significant key outcome assessed was the need for postoperative surgical
differences were shown between the groups except in those interventions (debridement of obstructive adhesions or scar
patients undergoing BCD for moderate/severe CRS who had a tissue formation in the frontal recess), which were reduced

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on the treated side by 47% (95% confidence interval -60.7 to randomisation resulting in 201 stent recipients and 99 sham
-27.9) at one month; this was significantly reduced at three procedure recipients (allowing for 1 excluded for extensive
months (p<0.05, relative reduction 30.2%). The need for oral adhesions). In the treatment arm there were significant
corticosteroids was also reduced by 37%. There was also reductions in symptom score (p=0.0074) and polyp grade
an increase in the estimated frontal sinus ostium diameter (p=0.0073) compared to controls. After threemonths significant
(absolute difference, 1mm), favoring the treated side. Other reductions were also seen in the secondary outcomes: 39% of
subgroup analyses did not show any significant findings for patients went on to revision ESS compared to 63% of controls
the influence of the LMS and the use of the Draf IIB procedure. (p=0.0004), symptom scores for nasal obstruction and smell loss
However, the studies are undermined by the failure to include were significantly better in the implant group (p=0.0248 and
an arm with an implant that did not release steroid. 0.0470). Facial pain/pressure was not better in the treatment
However, another product, Sinuband FP, a bioabsorbable, group (p=0.9130) but there was only one serious adverse event
fluticasone propionate (FP)-eluting implant, was used in a for one patient who suffered epistaxis. The SINUVA implant
small randomized, partially double-blind, single-tertiary- requires removal at the end of the three-month period and
referral-centre, controlled trial (n=30) for patients with CRSwNP, thus far has only been trialed in patients who have already
undergoing ESS that included an ethmoidectomy. Sinuband undergone surgery.
with and without steroid was compared with Merocel as a By contrast, an alternative delivery vehicle for mometasone
control. Postoperative endoscopic appearances were better furoate is the LYR-210 (Lyra) which delivers corticosteroid to the
in the Sinuband FP arm(121). A systematic review of two RCTs sinonasal mucosa over six months and can be used for patients
covering 143 patients found that DESs led to some significant who have not had ESS following failure of conventional medical
post-operative changes including a 40% reduction in the use of therapy. The LYR-210 system is placed into the middle meatus
OCS and 46% reduction in frank polyposis with improvements in under local anaesthesia and slowly expands. The device has
synechiae formation compared to the Merocel group(472). been evaluated in a small prospective, multicentre, open-label
A systematic review in 2015 considered seven studies (five study including 20 patients with CRS (12 CRSsNPs and eight
prospective randomized controlled trials and two prospective CRSwNPs) destined for ESS(476).ESS. As an early phase trial, the
single-cohort studies) involving 394 sinuses receiving study was set up to assess adverse events within four weeks
steroid-eluting bioabsorbable intranasal devices. Patients as the primary outcome measure and found none. There were
were followed up for two to six months. Six studies showed no safety concerns regarding plasma drug concentration,
efficacy with statistical significance (p<0.05) for their use in morning serum cortisol levels and intraocular pressures (IOPs).
reducing adhesion formation, polyp formation, inflammation, Although designed to be bioabsorbable, 86% of the devices
LundKennedy scores, and perioperative sinus endoscopy were still retained in the middle meatus at six months. There
scores(473). were significant reductions in their SNOT-22 scores through
Economic modelling has been undertaken to support the use of to the end of the study period (p<0.01). This device clearly
a steroid stent after ESS based on prevention of post-operative requires further trial evaluation and may need removal after
division of adhesions within 60 days of ESS(474), however this the treatment period, but does hold additional promise for a
is clearly a very short period for the ongoing management of clinic based alternative treatment to ESS, which may be useful
CRS patients, and adhesions may not be of clinical significance. for those patients with other comorbidities less suitable for ESS
A more recent economic analysis by the same in a US setting, under general anaesthesia.
also considering a reduction in polyp recurrence, gave similar
support to DESs being cost-effective to use(475). 6.2.1.12. Packing and spacers
At the present time the use of packing and spacers remains
6.2.1.11.3. DESs placed in outpatients largely a matter of surgeon preference. They can be divided
Other stents have been designed with the outpatient clinic into non-absorbable and materials and absorbable material
setting in mind. One of these is the SINUVA implant, which including gels and other haemostats that may be instilled into
is designed to deliver 1350μg of mometasone furoate to the nasal and/or sinus cavities.
ethmoid sinus mucosa over a three-month period. As a follow
on to the RESOLVE I trial(120), month period. As a follow on to the 6.2.1.12.1. Gels, haemostats and absorbable dressings
RESOLVE I trial, the RESOLVE II RCT by Kern et al, recruited 301 A meta-analysis by Coey et al. looking at fibrin tissue adhesive
adult patients with CRSwNPs who had undergone a previous (FTA) compared to nasal packing was limited to only four studies
ethmoidectomy, had failed further medical therapy including with significant heterogeneity and bias, so mainly concluded
INCS and ≥1 course of OCS and were being considered for that although there was a trend towards packing reducing
revision ESS (118). Eligible patients had bilateral placement of bleeding and FTA reducing obstruction and granulation, the
the implants into the ethmoids under local anaesthesia. The decision to use FTA has to be a cost-based one currently as there
control arm was a sham procedure to insert the implants were no significant differences(477). Carboxymethylcellulose
and then remove them immediately. Patients in both arms (CMC) (mesh or gel) was evaluated in one study randomising by
received mometasone furoate 200μg nasal spray once daily. side of nose and showed no improvement in patient comfort on
Nasal obstruction/congestion symptom scores and endoscopic the treated side as compared to the unpacked opposite side(478).
polyp scores were used as outcome measures. There was a 2:1 Similar findings for improved comfort were found with a study

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using Nasopore in one side of the nose and gauze packing in pain though there was no control arm(485). Calcium alginate was
the other(479). compared with CMC in 27 CRS patients undergoing ESS, After
A gelatin dressing called Cutanplast was studied by Cho et surgery, one nostril was packed with calcium alginate and the
al, randomizing 100 ESS patients by side of the nose(480). Both other with carboxymethyl cellulose. In contrast to Okushi, no
the Merocel control and Cutanplast packs were effective at significant differences in VAS scores for postoperative pain,
avoiding post-operative bleeding until the point of removal of discomfort from nasal discharge or pain during packing removal
the Merocel where bleeding did occur. There was no significant was found between the two sides. However, adhesion severity
difference between the two in terms of cost or wound healing and oedema scores at four weeks were significantly lower with
but the Cutanplast was associated with less patient discomfort. calcium alginate packing(486).
A study comparing polyurethane packing (Nasopore) versus
no packing showed benefit for this packing with significant 6.2.1.12.2. Spacers and non-absorbable dressings
improvement in the patency of the OMC on the side with A range of commercially available materials exist, although
resorbable material at 4 weeks after surgery and at week 12, spacers can be created at low cost using simple nasal tampons
a significant improvement in synechiae formation and nasal and surgical gloves; a study looking at the impact on healing
discharge(481). comparing a tampon with and a tampon without a glove finger
Impregnation of dissolvable dressings with corticosteroids covering (randomised by side of nose) showed only a benefit
has been studied by Zhao et al. who randomised 64 CRSwNP for the former in terms of patient comfort(487). Evidence for the
patients undergoing bilateral ESS by side of the nose, to receive use of spacers is limited by the quality of the existing studies; a
4 mL or 8 mL of mometasone furoate soaked Nasopore on one meta-analysis looking at post-operative outcomes showed only
side and the same amount of normal saline-soaked Nasopore a trend towards reduced synechiae formation, but again, despite
on the contralateral side(482). The Nasopore was subsequently 18 included studies suffered from significant heteroegeneity(488).
removed at seven or 14 days post-operatively, thus giving four Another RCT by Baguley et al. included 42 patients undergoing
comparators of treatment. Using the POSE and Lund-Kennedy ESS for CRS who were randomized to have a silastic splint placed
scores to assess outcomes, they found that leaving 8ml of into the middle meatus on one side of the nose but not the
steroid soaked Nasopore for two weeks resulted in the best other at the completion of surgery. Splints were removed two
outcome with significant differences sustained at three months weeks postoperatively and symptom scores were recorded for
postoperatively. Similarly, Xu et al. used Triamcinolone soaked each side of the nose up to 12 weeks after surgery and ethmoid
Nasopore in 80 CRSwNPs undergoing bilateral ESS(466). In this cavities were graded at the six- and 12-week visits along with
trial, patients were randomised by treatment, not by side of assessment of adhesions. The middle meatal silastic splints
nose but were followed up for the same interval postoperatively. reduced adhesions but increased early nasal obstruction and
They utilised the same endoscopic scores but also included discomfort. Their use did not significantly change symptom or
the SNOT-20 and the Sniffin’ Sticks as outcome measures and ethmoid cavity scores at 12 weeks(489).
found significant improvements in all except the SNOT-20 scores A similar study by Chan in 36 patients also investigated the
when comparing the triamcinolone dressing group to the saline effect of a unilateral middle meatal silastic stent up to 24 weeks.
control group. Another trial to compare triamcinolone soaked Middle turbinate lateralization was observed in
Nasopore also found significant differences in endoscopic scores 13 sides without a stent vs. one side with a stent. There was a
at six months compared to the saline soaked dressing, albeit significant reduction in adhesions at weeks 2 and 8 (p<0.001)
with a sample of only 19 patients(465). The most recent study and crusting (p<0.01) in the stent side compared to control
from Brazil used Nasopore soaked with either betamethasone but little difference at six months, nor for symptoms and in this
or ciprofloxacin and compared with saline soaked Nasopore; the study, the stent was well-tolerated(490).
steroid group had the best 90-day appearance with respect to A meta-analysis comparing absorbable and non-absorbable
reduction of mucosal oedema (p=0.007)(483). These studies give dressings found no major differences in terms of symptoms after
credence to the use of steroid impregnation of nasal dressings surgery(491). A subsequent meta-analysis did not favour one over
at the end of ESS. In a recent study by Bing et al., 31 patients the other, again due to the issue of heterogeneity, although
with CRS were randomised to receive gelatin sponge (control) there were trends to reduced synechiae in patients receiving
or the topical application of acellular dermal matrix held with absorbable dressings(492). A single RCT did however favour
gelatin sponge in one or other surgical cavity. Lund-Kennedy improvement in adhesions in those with absorbable dressings
scores in the acellular dermal matrix group were significantly compared to saline irrigations only(493). The most recent meta-
decreased compared with the control group at 8 vs. 2 (p<0.05) analysis available gave greater conviction in its findings (grade
weeks and epithelialization time at eight weeks in the acellular of recommendation in brackets)(494).
dermal matrix groups was significantly decreased compared to Reduction in postoperative bleeding: no difference when
the control group(484). comparing absorbable packing to no packing (A) but slightly
Calcium alginate absorbable dressings were compared with more effective than non-absorbable (C).
chitin-coated gauze in a cohort of 40 CRS patients undergoing Reduction in postoperative synechiae: Absorbable packing was
ESS, finding that the absorbable dressing was associated with more effective than non-absorbable packing (B) and no packing
lower postoperative symptoms, improved QoL and reduced (C); non-absorbable packing was also more effective than none

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(A). Reduction in postoperative comfort: Absorbable packing leak in the non-IGS group (0% vs. 2.2%). A retrospective cohort
is more comfortable compared to non-absorbable (A) or no study from the USA in 2005-8 looked at 78,944 primary FESS
packing (B). cases and 4151 revision cases from insurance databases for
An interesting take on the packing debate was published by Florida and California and found that in those who had surgery
Stern-Shavit et al. who conducted a systematic review of all involving the frontal sinus or IGS were at higher risk for major
randomized control trials comparing packing to no packing in complications(500). Their findings are probably likely to reflect
ESS, and generated a decision-analysis model which indicated the case selection including factors such as disease extent,
that middle meatal packing is not advantageous for patients anatomical factors and possibly surgical overconfidence.
undergoing ESS though absorbable packing materials have Masterson et al. reported on an eight-year case series of ESS
a less adverse effect on quality of life than non-absorbable using IGS and included 110 CRS patients(501). Their results
materials(495). showed that four patients had a major complication (3%) and
three cases were abandoned due to excessive bleeding during
Nonetheless, all the meta-analyses concluded that better surgery. Masterson et al. used IGS in a case series of 250 CRS/
designed studies are needed to derive more conclusive findings AFRS patients undergoing ESS and reported a 1.2% major
in the future. Further discussion on the role of packs and spacers complication rate with only two cases requiring revision during
in prevention of synechiae can be found below in section the study period of four years(502).
6.2.1.22. Considering the measures of operative time and blood loss,
Fried et al compared cases with (n=97) and without (n=63)
6.2.1.13. Role of image guidance and robotics IGS during ESS(503).ESS. The disadvantage of this study was that
the groups differed in composition with the IGS group having
6.2.1.13.1 Image guidance, computer navigation and 74% of patients with CRSwNPs as compared to 40% in the
augmented reality non-IGS group. The IGS group had an average EBL of 134ml
The use of image guidance for ESS has been gradually and an average procedure time of 154 minutes as compared
increasing and in the USA has been supported by the AAONHS to 94ml and 133 minutes in the non-IGS group. However, the
guidelines for ESS and the International Consensus Statement non-IGS group had seven major complications and one minor
on Allergy. and Rhinology. for Rhinosinusitis in 2016(496)(401, 497). complication compared to one and three respectively in the
The examples they list as appropriate for IGS include: IGS group and three revision operations in three months as
• Revision sinus surgery. compared to one. So from this study, the higher disease burden
• Distorted sinus anatomy of development, postoperative, or most likely contributed to longer operation times and higher
traumatic origin. blood loss in the IGS group but nonetheless they had lower
• Extensive sino-nasal polyposis. complication rates.
• Pathology involving the frontal, posterior ethmoid and Dalgorf et al. undertook a more recent systematic review
sphenoid sinuses. and meta-analysis in 2013(504). Of the 55 included studies, 14
• Disease abutting the skull base, orbit, optic nerve or carotid were comparative cohorts of IGS and non-IGS cases used for
artery. the meta-analysis. In contrast to some of the above studies
• CSF rhinorrhea or conditions where there is a skull base and previous meta-analyses(505), they found that major and
defect. total complications were more common in the non-IGS
• Benign and malignant sino-nasal neoplasms. group (major RR = 0.48; 95% confidence interval [CI], 0.28-
0.82; P = 0.007), (total RR = 0.66; 95% CI, 0.47-0.94; P = 0.02).
In terms of evaluating the role of image-guided surgery (IGS) or Looking specifically at orbital, intracranial and haemorrhage
computer-assisted sinus surgery (CASS), key issues to address are: complications separately, the Forest plots also favoured IGS but
• Its role in reducing complication rates the RRs were not statistically significant. Finally, they considered
• Its role in improving clinical outcomes completion of the operation but again there was no significant
• Its value in training advantage shown by IGS in this respect. Conversely, another
• Its cost-effectiveness systematic review was published that same year with opposite
findings(506), finding that the use of IGS did not decrease
6.2.1.13.1.1. Complication rates in IGS surgery surgical complications or improve surgical outcomes. However,
A systematic review by Smith et al. in 2007 identified five their recommendations were based on only six studies with
studies for inclusion but made limited conclusions suggesting limitations in the studies’ methodology. Interestingly, despite
merely that the studies that needed to be done to determine this, within the paper the authors state a preponderance
safety were not ethically possible(498). Tabee et al. compared of benefit over harm and suggest that IGS helps reduce
complication rates from a single centre before and after complications.
the introduction of IGS (499). The series included 179 non-IGS
cases and 60 IGS cases. No statistically significant difference
in the incidence of major intraoperative or postoperative 6.2.1.13.1.2. Clinical outcomes of IGS surgery
complications was seen (all 5-6%). The key notable difference With respect to quality of life outcomes using IGS, Javer et
was of a higher incidence of intraoperative cerebrospinal fluid al. used the RSOM-31 to compare IGS and non-IGS cases(507).

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Statistically significant improvements between preoperative systems available include features such as targets planned
and postoperative were seen for both groups considered as a by the surgeon pre-operatively and “anti-targets” such as key
whole but when the two groups were compared, the IGS group structures to avoid and help prevent complications(514). Future
demonstrated an overall greater improvement in quality of life systems are likely to enable overlays of critical anatomy on
(p<0.001). Tabee et al. found no difference with IGS in SNOT-22 to the live endoscopic images(515). Certainly, one of the key
scores in their single centre study with mean postoperative advantages to these new developments will be for training to
scores of 23.6 and 23.4 in the IGS and non-IGS groups enhance the learning curve in ESS(513).
respectively(499).
Tabee et al. also compared and revision rates from a single 6.2.1.13.1.4. Cost effectiveness of IGS
centre before and after the introduction of IGS and found no Masterson et al. considered the cost of providing an IGS
significant differences in revision rates (7%)(499). A previous study service and estimated that during their study period of eight
from the same centre in 2003 reported an 8% revision rate for years it was approximately £110,000-120,000(501). However,
ESS when using IGS but with no comparator group this simply their suggestion that IGS would reduce overall costs by
underlines the 7% rate reported in the more recent study(508). approximately £70,000 when compared to non-IGS was based
Masterson et al. reported that 11 patients needed revision on 19 CRSsNPs patients in a military cost model, so the likely
surgery (10%) in their aforementioned series(501) and Farhadi et generalisability is low. The ICOR guidelines assessment was that
al. reported revision rates of 11.11%, and 7.1% for CRSwNPs and the benefits of IGS outweigh the risk and potentially outweigh
CRSsNPs cases after ESS with IGS in a case series of 62 patients the costs(401). Further studies to determine any specific cost
over five years, but again with no comparator group(509). benefit from the use of IGS during ESS need to be undertaken.

One of the key advantages of image guided 6.2.1.13.2. Robot-assisted ESS

surgery is the enhancement of the learning curve Robotic surgery in ESS has yet to find its place mainly due to
in training of ESS. the limitations on the size of instrumentation, but development
is underway(516-523). It is certainly not at the stage of trans-oral
6.2.1.13.1.3.Training value of IGS robotic surgery now being used increasingly for oropharyngeal
A small number of studies have addressed the value of IGS cancers(524). One application considered is for a robot to hold the
with respect to training. Theodoraki et al. reported on eight endoscope freeing the surgeon to undertake the ESS with both
trainee surgeons undertaking 32 ESS cases and the influence hands(525, 526). Beyond this there are yet to be trials reported on
of IGS on stress levels(510). The cases were randomised by the use of robot-assisted ESS for CRS management.
side of nose such that one side of each patient was operated
using IGS and the other without. The trainee surgeons were 6.2.1.14. Office procedures
monitored throughout for various parameters including heart Given the relative costs of an operating theatre setting
rate variability, respiratory rate and masticator EMG. Stress was compared to an ambulatory outpatient setting, there has
identified as an increase of heart rate frequency and a decrease been an increasing vogue to perform more procedures out
of heart rate variability. They showed that stress levels were of the conventional theatre setting including polypectomy,
higher compared to before and after ESS but that the use of IGS stent placement and balloon sinuplasty. Balloon technology
did not significantly alter this except in those trainees who had lends itself well to this setting, as it avoids cutting tissue and
performed more than 30 FESS procedures already who had a thus reduces likely associated bleeding. The role of balloon
slightly decreased mental workload when using the navigation sinuplasty is discussed in detail above, but with specific respect
(unquantified statistically). In a separate publication, based on to the outpatient setting, this section considers key advantages
the same set of trainees and procedures, the authors reported and disadvantages to techniques that can be utilized. The
how often the trainee used the navigation pointer and then aforementioned RESOLVE trial proposed steroid-eluting
changed their technique during the IGS side of the ESS(511). sinus implants for in-office treatment of recurrent sinonasal
They showed that procedures lasted on average 16 minutes polyposis(119, 120), however, the selected patients had already
longer with the navigation, but that in only 10-13% of cases, did failed a primary procedure. The LYR-210 device placement is also
change the surgical strategy after the use of the pointer. The discussed above in section 6.1.12.3.
questionnaire completed by participants revealed a significantly Levy et al. reported on two studies that looked at patients
increased willingness to take risks when using the image undergoing balloon sinuplasty as part of ESS in the clinic
guidance system. No trainee complained of diminished surgical compared to the operating theatre showed that the outcomes
skills when using the navigation system. On the contrary, almost were better when conducted in theatre(527). It should be noted
all surgeons reported a better anatomical understanding with that these patients appeared to have mild to moderate disease
the additional information from image guidance. based on a mean LMS of 8 in the Achar study. Kilty et al. recently
published their data from the EPIC study showing that with
Augmented reality is starting to become available to good patient selection, a local anaesthetic polypectomy using
rhinologists in the field, with preliminary work suggesting the the POLYPVAC could achieve good quality of life outcomes(528).
accuracy of this approach to be submillimetric(512, 513). Initial

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6.2.1.15. Postoperative interventions, e.g. debridement studies including 10 RCTs and one prospective cohort study
demonstrated a significant benefit in symptom scores and
6.2.1.15. 1. Post-operative debridement polyp scores up to one year postoperatively, with a significant
A recent Cochrane review has considered the role of post- reduction in the odds of polyp recurrence. Three studies in the
operative debridement in managing post-operative patients analysis also collected data adrenocorticotropic hormone levels
after ESS(529). Four studies incorporating 152 participants and postintervention finding no elevations postoperatively.
a duration of follow up between three and 12 months were Budesonide irrigations have become a popular choice for
included. Two studies were split-nose studies comparing rhinologists managing post-operative CRSwNPs, but there is
differing interventions by side of the nose in the same patients. now a growing body of evidence to support their use(81, 88, 536-538).
As patients were unblinded, the risk of bias was high and with Snidvongs et al.(88) studied the use of either budesonide 1mg
only one study considering HRQoL scores, there is limited or betamethasone 1mg delivered in a 240mL sinus squeeze
inference from the analysis. However, just one study did show bottle daily in a cohort of 111 patients. After a mean follow
lower, but not statistically significant lower, SNOT-22 scores up period of 56 weeks, baseline and posttreatment SNOT‐22
at six months in the debridement group. Other studies using and endoscopy scores revealed significant improvements
VAS scores showed no significant differences in total symptom (all, p<0.001). Those with high tissue eosinophilia had
score. All four studies assessed the postoperative endoscopic significantly more improvement on symptom and endoscopic
appearance of the sinonasal cavities using the Lund-Kennedy scores than those without. These findings were confirmed
score. The ‘split-nose’ studies revealed better, but not statistically by a more recent study by the same team, showing that the
significant endoscopic scores in the debridement group but a corticosteroid nasal irrigation group (using mometasone)
closer focus on the adhesion formation score found this was had greater improvement in nasal blockage (p=0.029), a
significantly lower in the debrided patients and the number greater improvement on LMS (p=0.031) and less inflammation
needed to treat was five patients for at least one patient to endoscopically at 12 months (p=0.018)(67). One-year on from
avoid an adhesion. Overall, it is not possible to comment on surgery, symptom scores were all lower in the corticosteroid
what impact this has in the longer term without further studies. irrigation group.
A prior systematic review had similar conclusions with the One study from Thailand considered the use of dexpanthenol
addition that patients undergoing debridement appeared to topically(171). Dexpanthenol is an alcoholic analogue of
suffer more postoperative pain(530) which was also confirmed by D-pantothenic acid and acts as a precursor of coenzyme A
Varsak in 2016(531). necessary for acetylation and thus may enhance the effect of
acetylcholine; it is used typically as a dermatological agent.
6.2.1.15. 2. Saline irrigations Fifty patients enrolled were randomised to receive either
Rudmik et al.(532) undertook a systematic review of the dexpanthenol or normal saline nasal spray intranasally four
literature and identified six RCTs which evaluated the effects times a day for six weeks postoperatively. Overall there were no
of postoperative saline irrigation; studies suggest improved significant differences in symptoms between the two groups
symptom-based and endoscopic outcomes with low risk of with nasal discharge reportedly better but olfactory loss worse
harm and therefore that recommend use, commencing 24–48 in the dexpanthenol group. The main claim was improvement
hours after surgery. This was also supported by a more recent in mucociliary clearance time, however this test is increasingly
study concentrating on the maxillary sinus in which those using acknowledged to have little bearing on patient symptoms.
1000ml of saline with an irrigation system, twice a week for the
first two weeks, once a week for the next two weeks, and twice 6.2.1.15.4. Postoperative antibiotics
in the last month had significantly better healing than those There is no evidence to date for the use of postoperative
who used no irrigation(533). A more recent meta-analysis found antibiotics. In a study randomising post-ESS patients to co-
only three trials deemed eligible for inclusion but nonetheless amoxiclav or no treatment, no differences were observed in
reported that nasal irrigation using normal saline and various the symptom and endoscopic scores, between the two groups
solutions was found to be effective in reducing symptom scores after ESS(539). Furthermore, there were no differences seen in
and endoscopic scores for CRS after FESS(534). rates of bacterial culture and drug sensitivity to co-amoxiclav.
A prospective single-blind comparative effectiveness trial
6.2.1.15.3. Intranasal medications including 187 Chinese patients with CRS randomised subjects to
Given the nature of CRS as a chronic condition, maintenance receive fluticasone propionate nasal spray (200 microgram) or
treatment is more often than not an essential feature of clarithromycin (250mg once daily) for three months after ESS(540).
ongoing treatment. However, the evidence supporting any Patients were followed up to one year after randomisation and
specific regimen is variable. A study looking at 60 patients with outcomes included symptom severity (VAS) and endoscopic
N-ERD, randomised to receive either saline, budesonide and findings. Both groups saw reductions in the total and individual
saline separately or budesonide and saline together showed symptom scores, and total and individual endoscopic scores.
no obvious benefit in any one arm, however the sample There was no significant difference between the groups
size of this study would appear too small to show sufficient even when stratified to CRSsNP and eosinophilic and non-
benefit(83). Fandino et al. published a systematic review and eosinophilic CRSwNP. Neither group showed a preponderance
meta-analysis to look at the role of INCS in CRSwNPs(535). Eleven to rescue medications either. The study design is unusual in

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comparing an INCS against an antibiotic rather than an INCS asthma prevalence reporting greater improvement after ESS).
being included in both arms to see the additive effect of the However, looking at population means overlooks chance of
long-term macrolide therapy after ESS. success at an individual patient level. To better understand
Whilst a meta-analysis in 2012 had been unable to demonstrate a ‘successful’ outcome, the concept of a ‘minimal clinically
a statistically significant reduction in infection, symptom important difference’ is usually applied, that is the smallest
scores, or endoscopic scores to support the routine use of change in patient rated outcome scores that a patient can
postoperative prophylactic antibiotics following endoscopic perceive as a real change. This has been calculated for a number
sinus surgery, there have been concerns about the of different PROMS; for the SNOT-22 it is 8.9 points(549). Applying
possibility of toxic shock when packs have been left in place this to cohort series suggests that only 65–75% patients achieve
postoperatively(541). However, a meta-analysis was performed a successful outcome from surgery. Baseline preoperative
in 2017 to examine this issue(542). Six studies, with a total of SNOT-22 score is the best predictor of achieving improvement
990 patients undergoing ESS or septoplasty, met the inclusion in HRQOL greater that the MCID(84, 391); a baseline threshold of
criteria and there were no reports of toxic shock syndrome. 20 points in the SNOT-22 is required to have a greater than 50%
The application of topical antibiotics was considered in a chance of achieving the MCID.
prospective randomized multicentre trial included 321 CRS A limitation of the MCID is that it is usually calculated from
patients undergoing ESS who received either one week of oral population-defined statistics (using Cohen’s effect size or
antibiotics and a saline-soaked bioabsorbable middle meatal comparing global ratings of improved versus no change to
(MM) sponge (control group) or no oral antibiotics and the mean changes in symptom scores), while individual patients
placement of a bacitracin-soaked bioabsorbable sponge in may hold different values. Asking patents simply about
the MM (study group). The three-week postoperative infection postoperative satisfaction or improvement does not allow for
rate was not significantly different between the study and baseline measures to be used to mitigate against a placebo
control groups: 5.4% versus 3.8% and there was no significant effect of intervention. This likely explains in part why patent
difference in MM granulations, synechia, middle turbinate satisfaction after surgery is higher than reported rates of
lateralization, or sponge retention. However, no control group achieving the MCID(550). In addition, patients may also prioritize
of no antibiotics was included and the use of antibiotics in any improvement in individual symptoms above overall quality of
form is questionnable(543). life. Improvement in nasal obstruction was rated as the most
important symptom by 93% CRS patients, change in sense
6.2.1.15.5. Postoperative systemic steroids of smell second, with lower rates of importance placed on all
One randomised trial has shown no impact of postoperative other symptoms in a study evaluating the relationship between
systemic steroids in symptom scores but did find improved patient satisfaction and changes in overall symptom scores
endoscopic appearances at two weeks postoperatively(381). The alongside individual symptoms. It found that satisfaction was
risks of systemic steroids must be considered against this short- better correlated with the magnitude of change in symptom
term benefit. scores and achieving improvement in the most important
symptoms than achieving the MCID(550). An independent study
6.2.1.16. How do we measure success versus failure? also found that in patients with sub MCID improvement in
Early retrospective reports of endoscopic sinus surgery, whilst in SNOT-22 scores, improvement in the nasal subdomain was
its infancy, simply report ‘success’, as deemed by the operating also associated with reporting overall improvement in CRS
surgeon without any attempt to define how this was measured. symptoms(551).
Need for revision surgery was often used to define failure. A systematic review by Chester et al. considered symptom
As outcome assessment evolved, focus moved to reporting specific outcomes after ESS(552). A total of 2070 patients with CRS
symptom improvement(544) and then to utilizing validated were studied a mean of 13.9 months after ESS. All symptoms
patient-rated outcome measures(545). (See also chapter 3.1) demonstrated improvement compared with their respective
The UK Audit of Sinonasal surgery was one of the first large preoperative severity scores by an overall effect size of 1.19 (95%
multi-centered prospective cohort studies to use PROMS to confidence interval, 0.96 to 1.41; I(2) = 81.7%) using the random-
measure the effectiveness of surgery. This study reported a effects model. Nasal obstruction (ES, 1.73) improved the most,
statistically significant, large improvement in disease specific with facial pain (ES, 1.13) and postnasal discharge (ES, 1.19)
quality of life, maintained over a five-year period(546). A recent demonstrating moderate improvements. Hyposmia (ES, 0.97)
publication has shown this improvement to be durable for and headache (ES, 0.98) improved the least. A recent systematic
more than 10 years in patients available for long term follow- review looking specifically at olfactory outcomes included
up(547). A systematic review of outcomes in 40 unique cohorts thirty-one studies and demonstrated significant improvement
has shown a mean improvement of 24.4 points(548). Few in mixed CRS patients (those with and without polyps)
studies have specifically compared outcomes of CRSwNP and through visual analog scales (-0.83, p=.001), altered taste/
CRSsNP with different reported effects. However, the meta- smell item on Sinonasal Outcome Test (-1.32, p<.00001), 40-
analysis performed by Soler et al. found no impact; only pre- item Smell Identification Test (3.49, p=.0010), and Sniffin’ Sticks
operative symptom scores and asthma status were found to identification (0.34, p=.03). When separated, polyp patients and
be significantly associated with improvement in HRQOL (with dysosmic patients experienced the highest levels of olfactory
studies with higher pre-operative SNOT-22 scores and higher improvement.

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The need for revision surgery should not necessarily be cohorts published from 2008 to 2016(548). All studies showed a
considered a treatment failure in the setting of chronic disease. statistically significant change in mean SNOT-22 scores between
However, it is important that patients are made aware of the baseline and postoperative time points (p<.001), ranging
chance of subsequent revision surgery. Prospective cohort from 12.7 to 44.8, at an average follow-up of 10.6 months. The
studies report revision surgery rates of 11% at three years(393), summary change in mean SNOT-22 across all studies was 24.4
19% at five years(546), and 17% at 10 years(547). Patients with (95% CI: 22.0-26.8 The magnitude of change is quite variable
CRSwNP report higher rates of revision surgery (11%, 21% across the cohorts and appeared to be influenced by a number
and 25% at three, five and 10 years respectively) than CRSsNP of factors including baseline SNOT-22 score, asthma prevalence,
(10%, 15% and % at three, five and 10 years respectively). A and length of follow-up (Figure 1).
population-based study using electronic healthcare records There are few comparative studies that allow direct comparison
found long-term revision rates of 15.9% with a mean follow- between medical and surgical treatment. Ragab et al.(32)
up of 9.7 years, with female gender, older age at first surgery, randomised ninety patients with CRS, both with and without NP
presence of nasal polyps, comorbid asthma and allergy and were equally randomized to either medical or surgical therapy.
a family history of CRS all being associated with a higher risk Both the medical and surgical treatment of CRSsNP significantly
of requiring revision(553). Revision rates in CRSwNP were 29.9% improved almost all the subjective and objective parameters
compared with 9.8% for CRSsNP. Loftus et al. have performed a of CRS measured (p<.01), with no significant difference being
systematic review looking at revision surgery rates in 45 studies found between the medical and surgical groups at 12 months
and 34220 patients with CRSwNP(554). There was a mean revision after randomisation (p>.05), except for the total nasal volume
rate of 16.2% with a weighted mean follow-up of 89 months. in CRS (p<.01) and CRS without polyposis (p<.01) groups, in
Increased rates were reported in allergic fungal rhinosinusitis which the surgical treatment demonstrated greater changes.
(28.7%), N-ERD (27.2%), asthma (22.6%0 and prior polypectomy All patients received six weeks of Dexarhinaspray prior to
(26%). A recently published study with endoscopic follow-up at recruitment and patients who were no longer symptomatic
over 12 years after surgery, found 78.9% of CRSwNP patients had were excluded, although there was no threshold for ongoing
endoscopic recurrence of disease, and 36.8% had undergone symptoms. A limitation of this study is that patients had only
revision surgery(555). received a relatively short course of intranasal corticosteroids six
weeks prior to surgery, which does not reflect current practice
6.2.1.17. What are the outcomes of endoscopic sinus of surgery being utilised after ‘maximum’ medical therapy has
surgery? failed.
A large body of evidence from non-randomised cohort studies Blomquist et al. also compared medical and medical-surgical
demonstrates clinically significant QoL improvements for treatment of CRSwNP in 32 patients but using sinus CT. They
patients after ESS. In 2009, long-term outcomes were reported were randomized to unilateral endoscopic sinus surgery after
on 3128 patients who underwent surgery for CRS from the pretreatment with oral prednisolone for 10 days and nasal
National Comparative Audit of Surgery for Nasal Polyposis and budesonide bilaterally for one month. Postoperatively, they
Chronic Rhinosinusitis in England and Wales(393). Mean SNOT- were given nasal steroids (budesonide) bilaterally for one year.
22 score was found to significantly and clinically improve from They were assessed with nasal endoscopy, symptom scores,
a preoperative baseline value of 40.9 to 28.2 postoperatively, and olfactory thresholds and followed for 12 months. CT of the
with greater improvement found in patients with CRSwNP sinuses was performed before and one year after operation. This
compared with CRSsNP, although in both subgroups the effect showed a significant improvement on the operated side in the
was large. Improvements in QOL were maintained up to five CT total LM scores, and scores of the OMC and maxillary sinus,
years following surgery(546). In 2010, Smith and colleagues(556) but no significant differences on the unoperated side. Similarly
published a multi-institutional cohort study of 302 patients olfaction was less improved on the unoperated side(561).
with CRS from three medical centres followed for an average Several studies have compared outcomes in patients with
of 17.4 months after ESS. Subsequent prospective, multi- refractory CRS who chose to undergo surgery, compared with
institutional studies demonstrated that patients who elected those who elected not to pursue surgery and instead continued
to pursue ESS experienced clinically significant improvements with medical therapy(557, 562). Patients who elected surgical
in QoL, decreased utilization of oral antibiotics and systemic management reported more improvement than patients
corticosteroids, fewer missed days of work/school(557), and a who were medically managed on both the RSDI and CSS QoL
reduction in the consumption of rhinosinusitis-related health instruments; in addition, surgical patients reported less use of
care and imaging studies(558, 559). A systematic review performed oral antibiotics and oral steroids and fewer missed days of work
in 2005(560) identified forty-five studies that reported either and/or school, maintained through to 12 months follow-up. A
symptoms or QoL changes following ESS, with 44 of 45 studies subset of patients who had initially elected medical therapy
being level 4 or 5 evidence. Although heterogeneity in study crossed over to the surgical cohort, and outcomes in this
design and outcome measures utilized precluded meta-analysis, crossover group mirrored those of the surgical cohort overall. A
all studies were found to report significant improvement subsequent prospective study evaluated patients with refractory
in at least one outcome measure. A systematic review and CRS who received ongoing medical therapy while awaiting
meta-analysis of cohort studies using the SNOT-22 to evaluate surgery(563), during which time SNOT-22 scores deteriorated from
outcomes after sinus surgery included 40 unique patient mean 57.6 to 66.1, while after ESS SNOT-22 scores improved

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from mean 66.1 to 16.0 with an average follow up of 15 months. CI,67.5%-78.1%); inhaled corticosteroid use decreased in 28.5%
Patients also experienced improvements in endoscopy scores (95%CI, 22.6%-34.5%) and bronchodilator use decreased in
and a reduction in lost workdays and medication utilization 36.3% (95% CI, 28.9% to 43.7%) of patients. Mean improvement
following ESS. Patel et al. undertook a meta-analysis in 2017 in predicted forced expiratory volume at one second (FEV1)
that demonstrated that ESS, resulted in greater QoL scores and was1.62%,but was not statistically significant (p=0.877). Overall
nasal endoscopy scores than medical therapy, and that patients ESS in patients with concomitant asthma can anticipate clinical
undergoing surgery experienced greater improvement in health improvement(571).
utility, olfaction, and cost-effectiveness following ESS(564). A
systematic review concentrating solely on olfaction by Kohli 6.2.1.18. How do we manage expectation of patients? (see
et al considered 31 studies and concluded that ESS improves also chapter 9)
nearly all subjective and objective measures of olfaction in CRS. Expectations of patients need to be considered with respect
Patients with CRSwNP or preoperative olfactory dysfunction to outcomes of surgery, risk of complications, perioperative
improve the most(565).This can be anticipated up to one year recovery and return to normal activities, and likely benefits of
postoperatively(566). surgery and need for ongoing treatment.
A study designed to look specifically at changes in pain A survey of patient concerns prior to ESS found that overall
following ESS enrolled 252 patients (567). Amongst those patients had a low-level concern before surgery, with the risk
included, 42% had no preoperative pain. Patients were followed of revision surgery and waiting time being the most important
up at six and 12 months. In the patients with no preoperative drivers(572). Revision rates are discussed above in 6.1.17.
pain, none developed any new pain postoperatively. Among Patients should be informed of the likelihood of success based
the 146 patients with preoperative pain, 56% had no pain, on population studies above, their preoperative symptom
residual symptoms, or further sequelae, 29% reported a marked severity and most important symptoms. Many different factors
improvement of pain or discomfort, 6% had the same degree have been proposed to predict outcome; Some factors have
of pain or discomfort as before, 2% reported worse pain or been associated with a greater mean improvement following
discomfort and 7% reported new pain or discomfort. ESS, such as CRSwNP subtype, while others have been
A meta-analysis looking at symptom response to ESS, found associated with decreased mean improvement postoperatively,
that depression is associated with poorer preoperative and such as comorbid obesity and anxiety(573).
postoperative quality-of-life scores but that the majority of
major CRS symptoms improve to a similar degree(568). The The majority of patients are still likely to achieve clinically
overall effect size was 1.19 (95% confidence interval, 0.96-1.41; significant improvements regardless of associated demographic
I (2) = 82%), with specific symptoms effect sizes as follows: factors. The best predictor of surgical outcomes with respect to
headache 0.98, hyposmia 0.97 and nasal obstruction 1.73. improvements in HRQOL is the patient’s preoperative disease
Fatigue and bodily pain were found to be more severe than burden. A prospective cohort study of 2,263 patients found that
general population normative values but were also found improvement in SNOT-22 scores after ESS, and the proportion
to improve following ESS (effect size 0.5 SD). Chester et al. of patients achieving an improvement of at least one MCID
performed a meta-analysis of 28 studies specifically considering increased with greater baseline disease severity(84). Only those
fatigue finding substantial improvement after ESS based on patients with a baseline SNOT-22 score of more than 21 to 30
pre- and postoperative comparisons. A subgroup analysis of had a mean change greater than or equivalent to the MCID,
11 studies reporting results by the SF-36 vitality domain scores while patients with a score of 31 or more had a greater than 70%
demonstrated a moderate-sized combined effect(569). chance of achieving a MCID. However, patients with more severe
As up to 75% of CRS patients suffer from sleep disturbance, baseline scores remained more symptomatic following surgery
Sukato et al. undertook a meta-analysis of seven papers despite greater SNOT-22 improvement.
considering sleep improvement after ESS(570). There was high
heterogeneity in the studies (I2 = 95%-99%) but sleep quality, as It is likely that in time, biomarkers and better endotyping will
measured by the Epworth Sleepiness Scale and Pittsburgh Sleep allow more accurate prediction of risk of recurrent disease.
Quality Index surveys, shows substantial improvement after Cluster and multivariate analyses have shown that patients with
surgery for CRS, with smaller improvement seen for Apnoea- eosinophil dominant CRSwNP have the highest level of polyp
Hypopnoea Index. The future conduct of better studies was recurrence(574, 575). One study found that a cutoff value of 27%
recommended. tissue eosinophils predicted recurrence with 96.7% sensitivity
and 92.5%(575); and an absolute count of 55 eosinophils per high
The effect of ESS on the lower respiratory tract has been power field predicted recurrence with 87.4% sensitivity and
considered in a number of studies. A meta-analysis in 2013 97.1% specificity(576).
identified 22 studies involving 891 patients. Patients reported
improved overall asthma control in 76.1% (95% CI,71.9%- It should be made clear to patients that the aim of surgery is to
80.3%) of cases. The frequency of asthma attacks decreased improve disease control, and postoperative medication will be
in 84.8% (95% CI, 76.6%-93.0%) of patients and the number required. Studies have shown lower revision rates with ongoing
of hospitalizations decreased in 64.4% (95% CI, 53.3%-75.6%). use of intranasal corticosteroid sprays(92), and increased benefits
Decreased use of oral corticosteroids was seen in 72.8% (95% of corticosteroid irrigation over sprays alone with respect to

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endoscopy scores(67). A cure is often an unrealistic aim except opioid use. Patients undergoing bilateral FESS had higher opioid
in the setting of isolated sinus obstruction. Patients should be consumption than those who underwent unilateral FESS(580).
counseled that their symptom load will likely be reduced, but Locketz et al. surveyed 219 patients undergoing ESS surgery
many will not achieve post-operative scores comparable to the across five different centres(581). Opiod consumption was
normal population. positively correlated with postoperative, but no association
was found with the procedure performed. The majority of
6.2.1.19. Postoperative recovery – pain, return to normal patients took less than five opioid based tablets in the first three
activity postoperative days; 23% did not require any. Certainly, if opioids
It seems obvious that the less extensive the surgery, the are prescribed on discharge, only a small number should be
faster the recovery. Byun and Lee found a healing duration given.
for partial uncinectomy to be of 1.77 ± 0.59 weeks, while total Szczygielski and co-workers compared Stammberger Sinus
uncinectomy took 2.42 ± 0.79 weeks (p=0.034)(419). Sinus surgery Dressing (SSD) with dissolvable sinu-knit (DSK) (n=26 sides)
usually involved more than just an uncinectomy, and the to routine nasal packing in latex gloves finger (RNP) (n=23
difference between these two groups is perhaps unexpected. sides) for pain, among other issues(582). Mean pain level for
In a randomized trial Wu et al. studied a protocol of SSD was 0.85 (range from 0 to 3) and for DSK 2.1 (range 0 to
perioperative care for enhanced recovery after (ESS) surgery 5) whereas for RNP was 5.6 (range from 2 to 9). Akbari et al.
(ERAS) in 102 patients with CRSwNP(577), including giving compared sides of the nose where 35 patients undergoing ESS
NSAIDs prior to and after surgery, and short acting opiods and for CRS were randomly allocated to receive a covered Merocel
topical local anaesthesia to the enhanced recovery group, who spacer on one side of the nose; the other side then received
reported significantly better post-operative scores measured an uncovered spacer(487). There was no significant difference in
with the Medical Outcomes Study Sleep Scale and Kolcaba histopathological evaluation of mucosal inflammation but a
Comfort Scale Questionnaire. The incidence rates of nausea/ significant difference in discomfort experienced by patients on
emesis, haemorrhage, aspiration and falls, were not increased in removal of the spacers at one week, favoured the rubber glove
the ERAS group compared with those in the control group. covered spacers.
Kemppainen et al. studied the effect of acetaminophen /
paracetamol intake on the recovery of 78 patients after FESS Studies suggest that use of absorbable packing
in a randomized study(578). The “scheduled” group (n=38) will reduce pain and discomfort associated with
was asked to take two paracetamol/acetaminophen 665 mg sinus surgery.
modified‐release tablets three times a day during the first five
postoperative days, whereas the control group (n=40) took Comparison of Merocel on one side and Nasopore on the other
them only as needed. Most patients underwent a limited FESS in 30 patients with moderate to severe CRS found comparable
procedure. Return to normal daily activities occured after 8.8 (SD outcomes with regards to ease of nasal packing and control
4.8) days in the “scheduled” group versus in 10.3 (SD 7.0) days of postoperative bleeding(583). Sequential postoperative nasal
in the “as needed” group (mean difference 1.5; 95% CI of the endoscopy revealed that Nasopore is kinder to the mucosa
difference –1.3 to 4.2; p=0.29). The mean of worst pain was 3.4 with a lower incidence of synechiae, infection and oedema,
(2.9) in the scheduled group compared with 5.2 (3.0) in the “as with better biocompatibility and safety. Patients’ symptom
needed” group on an 11-point scale (mean difference 1.7; 95% questionnaires showed a significant difference in favour of
CI of the difference 0.4–5.2; p=0.019). Nasopore as no pack removal was needed. Also, in a separate
Tyler et al. compared the efficacy of perioperative intravenous study, Nasopore was able to significantly reduce nasal
acetaminophen with that of placebo in improving early obstruction within the first 10 days after surgery (p<0.005), with
postoperative pain after ESS in a RCT on 62 patients. Although significant improvement of the headache and pressure in the
in the first postoperative hour the VAS scale favoured the active forehead on the first follow-up visit as well as the pain in the
group, at 12 and 24h average pain scores were lower in the nose on the first and second visit (p<0.005)(487, 582-585).
placebo group. The authors concluded that considering the Shinkwin et al. compared Surgicel Nu-knit (a haemostatic
high costs and inconclusive results the administration of IVAPAP material) with Vasolene ribbon gauze and Merocel packs, in
could not be recommended for the control of perioperative pain 60 patients undergoing bilateral nasal surgery (ESS or inferior
reduction after ESS(579). turbinaectomy). Surgicel Nu-knit caused significantly less
Given the growing concerns with opioid over-use and addiction, discomfort and less bleeding following removal than Vasolene
a number of recent studies have assessed the need for post- gauze or Merocel (p<0.01, respectively). Compared to Merocel
operative opioid analgesia. In a single-institution retrospective sponges, Surgicel Nu-knit caused significantly less discomfort
study, Raikundalia et al. the opioid usage was assessed at the on removal (p<0.01). Bleeding following removal was also
first postoperative visit in 136 patients who underwent FESS. significantly less compared to the other packs(586).
Multinomial logistic regression with backward stepwise variable
selection method revealed that concurrent septoplasty and Lignocaine-soaked polyurethane foam packs as compared
young age were found to increase the odds of opioid usage. The to saline soaked foam significantly reduced postoperative
number of sinuses opened and the presence of extended frontal pain without serious changes on vital signs during the early
and maxillary sinusotomies were not associated with increased postoperative period after ESS in an RCT on 63 patients(587).

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Haytoglu et al. reported on the use of packing soaked in · Hypoplasia of the maxillary sinus – results in the possibility
different anaesthetic agents in the management of pain after of the lamina lying more medial in the nose than the
FESS in 150 patients with CRSw/sNP, using 2 % lignocaine, 0.25 maxillary wall; thus, a surgeon may breach the lamina
% bupivacaine, 0.2 % ropivacaine, 2 % prilocaine and 0.9 %NaCl believing they are entering the anterior ethmoids
as control. All received acetaminophen (250mg/5 ml) was used
in 10–15mg/kg per dose (four times a day). In the saline group, · Infra-orbital ethmoid (Haller) cells – seen best on coronal
93% of the patients needed additional painkiller whereas, in CT planes; may affect entry to the maxillary sinus and
the bupivacaine group, additional painkiller use was 20% less ethmoid infundibulum
than the other groups(588). Similarly levobupivacaine-soaked
· Skull base defects – again in primary surgery, this would
PVA sponge sinus packs after FESS has been shown to be an
only be a consideration if there had been previous trauma
effective, easy, and quick method to control postoperative
or neurosurgery,in cases where massive expansion by
pain(589).
uncontrolled polyp disease had eroded bony margins or if
Fentanyl–soaked absorbable packing (Nasopore or Merocel) has
there was a congenital dehiscence eg meningocoele
also been shown to significantly reduced acute postoperative
pain afetr FESS and septoplasty without serious adverse · Dehiscence of the internal carotid artery – this can
effects(590). Fentanyl–soaked absorbable packing (Nasopore or be found in the sphenoid sinuses (and in some cases
Merocel) has also been shown to significantly reduced acute sphenoethmoidal cells) and renders the artery vulnerable
postoperative pain after FESS and septoplasty without serious to injury during surgery.
adverse effects(590).
A systematic review of the use of sphenopalatine ganglion block In 2014 a retrospective cohort analysis of two American state
(SPGB) with a local anaesthetic to decrease postoperative pain insurance databases was undertaken from 2005 to 2008(500). This
after endoscopic sinus surgery (ESS) is controversial, especially yielded data from 78,944 primary ESS cases where 288 major
given that the procedure generally is associated with only complications were identified (0.36%, 95% CI 0.32%-0.40%).
mild pain post-operatively(591). Eight articles were included for The rate of major complications was 0.36% in primary cases
analysis and showed that intraoperative bleeding, postoperative (n=288). Risk factors for major complications identified in their
pain, nausea and vomiting and recovery from sedation in the multivariate analysis include age >40 years, frontal sinus surgery
treatment group were significantly reduced compared with and use of image guidance.
the control group with no notable adverse effects (p<0.02).
The transnasal approach also had better outcomes than the The rate of major complications following revision FESS
transoral route. (0.46%) was found to be similar to primary cases. Skull base
complications were defined as a CSF leak or dural injury
6.2.1.20. Complications of surgery – acute and chronic within 180 days, or bacterial meningitis within 30 days, after
ESS. Orbital complications were defined as diplopia, paralytic
Acute / perioperative complications strabismus, optic nerve injury, epiphora, orbital haemorrhage, or
The advent of powered instrumentation does bring with it blindness/visual disturbance within 30 days after ESS.
the increased potential for microdebrider related injuries(592,
593)
. However, the microdebrider is not the sole source of Additionally, a patient was considered to have an orbital compli-
intraoperative complications and as mentioned above, close cation if a person had canthotomy/canthoplasty, strabismus
inspection of and familiarisation with patients’ preoperative CT surgery, or orbital decompression in the same time frame.
scans is key to avoiding complications(594). Key areas for potential Haemorrhagic complications were counted if a diagnosis of
pitfalls include: internal carotid artery injury, epistaxis requiring transfusion, or a
· Anterior ethmoid arteries – in a minority of cases the procedure to control haemorrhage occurred within 30 days after
anterior ethmoid artery may lie within a bony “mesentery” surgery. Some caution should be applied in interpreting these
beneath the skull base where it is at greater risk of injury results, as in the time period studied, use of image guidance
from through-cutting instruments, particularly in the would have been relatively uncommon and these results may
presence of a supra-orbital ethmoid cell. represent a learning curve with respect to the technique.
Another study based on an insurance database from the USA
· Aerated posterior spheno-ethmoidal (Onodi) cells -
was also published the same year by Benninger et al(597). This
greater risk of optic nerve injury during ethmoidectomy/
reported adverse events in 388 patients of 9105 patients as
sphenoidotomy; these anatomical variants are more
follows: haemorrhage 0.24%, cerebrospinal fluid leak 0.14% and
common in some ethnic groups e.g. South East Asians(595,
orbital complications 0.58%); 6.28% of patients had revision
596)
.
surgery.
· Dehiscence of the lamina papryacea can be identified
on coronal and axial CT sequences – this may be due to A retrospective study of one surgeon’s practice over a 25
expansion by polyps in the ethmoids or to preceding facial year period looked at 3,402 CRS patients and found a total of
trauma but in primary surgery will not be due to any prior 105 patients who had suffered complications for an overall
intervention. patient complication rate of 3%: haemorrhage 1.2%, orbital

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Table 6.2.1.1. Grading system for complications of ESS (599)

Grade Complication Frequency
Diffuse or arterial bleeding <1,000 ml
Grade-I: minor complication
Injury of the lamina papyracea 3.1%
(intraoperative management,
Emphysema and periorbital ecchymosis
no persistent harm)
Intranasal and soft tissue infection
Diffuse or arterial bleeding >1,000 ml
Bleeding requiring selective cauterising/clipping of sphenopalatine artery or anterior
Grade-II: major complication 0.9%
ethmoidal artery
(intraoperative management or
Bleeding requiring revision
revision, no persistent harm)
CSF leak
Injury of the lacrimal duct
Meningitis with or without proven leak 0.04%
Intracerebral haemorrhage
Intracerebral abscess
Temporary or persistent neurologic deficit
Retro-orbital haemorrhage
Grade-III: serious complication Injury of optic nerve
(high risk of persistent deficit) Injury of orbital muscles with diplopia
Any reduction of vision and blindness
Injury of the internal carotid artery
Toxic shock syndrome
Sepsis
Death

complications 0.9%, and CSF leak 0.6%(598). In this series, risk Grade I complications
factor identified were age, revision surgery, CRSwNPs, anatomic Breach of the lamina papryacea and orbital fat injury
variation, extensive disease, overall health, medications and Fortunately, serious ophthalmic injuries from ESS are rare but
powered instrumentation. The use of image guidance or surgical the initial recognition and management of them is crucial to
experience did not eliminate complications from occurring. avoiding any permanent sequelae(601-603).The most common
site of orbital injury during ESS is the medial orbital wall(604)
Another large study from one department looked at data from during ethmoidectomy or even (aberrant) maxillary antrostomy
2,596 patients with ARS or CRS undergoing ESS between 2000 or uncinectomy. Proponents of the retrograde approach
and 2005. They reported minor complications (minor bleeding, to uncinectomy would support the notion that this avoids
perforation of the lamina papyracea) in 3.1%, and major penetrating the orbit as the target for removal is pulled away
complications such as severe haemorrhage and CSF leaks in from the orbit.
0.9% with only one serious complication of meningitis (0.04%)
(599)
. In the UK the Sinonasal Audit performed in 2001 collected Epistaxis
data on 3128 patients undergoing ESS for CRS and reported Postoperative haemorrhage is typically reported as occurring
the following complication rates: excessive bleeding in 5% of as frequently as 2-4%(605), with one case series reporting 22
patients during the operation and in 1% of patients after the of 290 patients with post-operative epistaxis being admitted
operation, intra-orbital complications in 0.2% and CSF leak to hospital as a consequence(597); admission with or without
in 0.06%(600). A smaller series over a four year period included packing appears to be a criterion for defining significant
250 CRS/AFRS patients undergoing ESS and five complications postoperative epistaxis although most of the relevant
were reported: two patients suffered significant epistaxis, one publications do not specify this. One aforementioned study that
patient who underwent concurrent microlaryngoscopy suffered did specify this defined the significance of bleeding within two
a pneumocephalus, there were no orbital complications and weeks postoperatively as follows:0 = no bleeding, 1 = bleeding
two general complications (transient ischaemic attack and from the nose that ceased with a gauze soaked in a mixture of
pulmonary embolus)(502). 1:1000 epinephrine and 1% lignocaine applied intra-nasally
for five minutes, 2 = continuous bleeding that could not be
The aforementioned study by Siedek et al. proposed a grading controlled with a temporary gauze, and requiring repacking(606).
system for complications of ESS as follows(599): This trial found a mean score of 1.11 on the side of the Merocel
dressing and 0.13 on the side of the Merogel dressing which was
statistically significant (p=0.001).
Hot saline irrigation during surgery is a potential therapeutic

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modifier of the surgical field and may modify blood loss during appearance of orbital fat is not quickly recognised, damage
surgery. Gan et al. randomised 62 patients with CRS patients to of the medial rectus can quickly follow(615). Injuries range from
receive either hot saline irrigation (HSI) at 49°C or saline at room simple contusion to complete transection of the medial rectus,
temperature (18°C), 20mL every 10 minutes, for the duration of with and without entrapment(603). Unless seen promptly by
ESS(607). The Boezaart scores were only significantly better for HSI ophthalmology, these injuries can be very difficult to rectify
if the surgery lasted more than two hours but did significantly and lead to disabling diplopia and strabismus(602, 616). Botox A
reduce the blood loss per minute for all cases in which HSI injections have been proposed in one study to treat strabismus
was used compared to the saline at room temperature. So, the due to medial rectus injury(617).
inference for practice is that HSI may have a role for complex
cases lasting over two hours and may be another therapeutic Retrobulbar haemorrhage
option for sinus surgeons to consider, especially if other Orbital bleeding typically occurs due to either arterial damage
treatment adjuncts are contraindicated. such as to the anterior ethmoid artery, or venous bleeding that
may occur with pulling of peri-orbital fat(601). The consequence of
Two almost identical RCTs have considered injection of the such of bleeding into the orbit is a rapid increase in intraocular
pterygopalatine canal with local anaesthetic (xylocaine 1 or pressure leading to ischaemia of the optic nerve and if
2%) and adrenaline (1:100,000 or 1:80,000)(608, 609). The weaker unresolved, irreversible damage causing blindness(593).
solution (Valdes) produced no decrease in intraoperative
surgical field bleeding, blood loss or duration of surgery Direct optic nerve injury
whereas in the other, there was a significant reduction in blood Injury to the optic nerve is most likely to occur in the presence
loss. of a spheno-ethmoidal cell where the optic nerve can lie
An RCT to look at the use of a fibrin sealant in 494 patients dehiscent, however, the nerve can also lie close to the lamina at
undergoing endonasal surgery showed a significant lower the back of the posterior ethmoid(602).
postoperative bleeding rate when used(610, 611). The trial
randomised patients to receive fibrin sealant or nasal packing Damage to the internal carotid artery
and they were further defined as receiving one of three Internal carotid artery (ICA) injury is a recognised and feared
interventions: septoplasty, ESS or both ESS and septoplasty; all complication of ESS which can result in stroke, cranial nerve
groups received turbinate surgery. Postoperative haemorrhage palsies, and death. A systematic review by Chin et al. in 2016
occurred in 22.9-25% of patients with nasal packing whereas found 25 articles reporting 50 cases. The majority occurred
3.12-4.65% in the fibrin sealant groups experienced late during skull base procedures (34 cases) with 16 associated
haemorrhage only. No allergic reactions to the sealant were with CRS. The most commonly injured ICA segment was the
reported. cavernous (34 cases), followed by the ophthalmic (three cases).
Injuries occurred more commonly on the left (1.3:1). Stereotactic
Grade II complications image guidance was reported in two cases. Initial hemostasis
Nasolacrimal injury was achieved with packing in 35 cases, endoscopic clip sacrifice
It is thought that lacrimal duct injury is relatively common in in four cases, bipolar coagulation with the intent to seal
ESS but that it rarely causes clinical sequelae(612). The natural defect in three cases, and bipolar coagulation with the intent
ostium of the maxillary sinus usually lies directly posterior to to sacrifice the ICA in one case. Intraoperative or immediate
the nasolacrimal duct and the relationship can be seen on axial postoperative interventional angiography was reported in 27
slices of preoperative CT imaging. Use of angled endoscopes cases(618).
will help the surgeon to avoid unnecessary injury after removal One of most successful strategies to deal with the immediate
of the uncinate process. aftermath of ICA damage based on a sheep model is the
application of a crushed muscle patch(619). Subsequent imaging
Cerebrospinal fluid leak to exclude a pseudoaneurysm is strongly recommended.
In addition to the aforementioned reports of CSF leaks from
ESS in large cohorts, recent evidence from an interesting study Chronic complication
has suggested that occult CSF leaks may be as numerous as Synechiae
13% of cases(613). This particular study collected samples from Synechiae formation after ESS is common with reports in
57 patients after ESS to perform a hydrogel 6 beta2-transferrin frequency of between 4 and 35%(450, 620). A recent retrospective
assay and where CSF positive samples were detected with case series to consider this specifically found that 38 of 200
continuing rhinorrhoea, reanalysis after more than one year was ESS cases (19%) had synechiae formation with concurrent
conducted but they found that the clinical course was more septoplasty found to be the key risk factor for this(621). Some
often uneventful. trials have looked at the role of absorbable and non-absorbable
packs in preventing synechiae. Verim et al. in 2013 compared
Grade III complications Nasopore with standard Merocel in 56 ESS patients comparing
Medial rectus injury sides of the nose and found no significant differences, although
These complications typically occur when the lamina is a coin toss was used for randomisation of side of the nose(606).
breached and the microdebrider is being used(593, 614). If the In a separate trial of 66 ESS patients comparing the hyaluronic

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acid pad Merogel versus the standard Merocel dressing, the reported mucocoele development 15-24 years after initial
percentage of adhesions seen at 12 weeks was only 5% but surgery(632). Of course, not all mucocoeles are caused by ESS
30% in the Merocel group (p<0.001)(622).A systematic review in with case series reporting 25% to 35% having a prior history
2013 concluded that data from six RCTs showed no significant of ESS(633); another reported on 36 cases of CRSwNP where 92%
difference in adhesion rates if non-absorbable spacers are had a prior history of ESS and the remaining three patients
used for at least 48 hours postoperatively and whilst steroidal had previously unoperated disease(634); certainly the presence
spacers may reduce adhesions, more consistent data reporting of CRSwNP regardless of prior ESS appears to be a potential
is required for future meta-analyses(623). predisposing factor(633). The mucocoele location is typically
The anti-adhesive properties of a thermosensitive poloxamer frontal or ethmoidal in origin(635).
was compared to Merogel in ESS and showed similar anti-
adhesion rates of 92 vs. 89%. Adhesions, oedema, and infection
in the middle meatus were not significantly different between Key points | What’s new since EPOS 2012
the thermosensitive poloxamer group and the Merogel group at
all postoperative periods(624). • This is a new chapter, expanding on the brief section
A systematic review and meta-analysis of hyaluronan nasal on surgery and associated outcomes in 2012. There has
dressings in 2017 included 352 patients but concluded that been a large number of prospective studies and large
compared to controls the hyaluronan had no benefit in reducing datasets exploring outcomes in surgical series. As a
synechiae formation(625).Whilst the hyaluronan significantly result, we are better able to predict outcome, both at
promoted reepithelization (OR 3.18, 95% CI 1.33-7.59; p=0.009) population level but also for the individual patient.
and reduced oedema (OR 0.45, 95% CI, 0.23-0.89; p=0.02) • As yet we cannot fully account for variation in interven-
after ESS, the ORs for synechiae, crusting and infection were tion rates or define what the optimum extent of surgery
0.45, 1.00, and 0.84 respectively. Fong et al. also conducted a should be. There remains a need for randomised trials
meta-analysis published in 2017 considering 13 (501 patients) comparing outcomes with medical treatment.
and also demonstrated a lower risk ratio of adhesions in the
hyaluronic acid intervention group (42 out of 283 cases)
compared to the control group (81 out of 282) of 0.52 (95%
There are many reasons why patients require
confidence interval=0.37–0.72(626)).
revision surgery Phenotyping and endotyping,
where possible, may facilitate counselling the
A meta-analysis of whether chitosan dressings improved healing
patient regarding prognosis and expected out-
after ESS was conducted by Zhou et al. in 2017(627). Four RCTs
come of the surgery itself and aid identification of
involving 268 patients were included in the meta-analysis.
the postoperative medical management that has
Overall following ESS, compared with control intervention,
the greatest likelihood of controlling the patient’s
chitosan dressing significantly reduced synechia (RR = 0.25;
symptoms.
95% CI 0.13–0.49; p<0.0001) and promoted hemostasis (RR = 6.2.2. Revision endoscopic surgery
1.70; 95% CI 1.37–2.11; p<0.00001), but showed no impact on
granulations, mucosal oedema, crusting and infection (RRs = The surgeon’s goals in revision surgery can vary greatly.
1.18, 0.88, 0.85 and 0.88 respectively). Compared to control Revision surgery may imply more comprehensive dissection
intervention, chitosan dressing could significantly decrease or exteriorization of the existing sinuses. It may be as simple
synechiae and improve hemostasis, but had no effect on as removal of adhesions, scarring or correcting lateralized
granulations, mucosal oedema, crusting and infection. turbinates. Alternatively, it may be a decision to apply more
Access to the middle meatus for postoperative care and extended techniques such as Draf III frontal surgery, medial
inspection can be compromised by middle turbinate maxillectomy or bone removal of the sphenoid face. Future
lateralisation and synechiae formation in this area. Bolger(628) studies should clarify what is the goal of any revision surgery.
recommended scarifying the medial side of the middle
turbinate and adjacent septum to achieve stabilization of 6.2.2.1. Consider the type of rhinosinusitis / phenotype
the middle turbinate and maintain access to the middle which benefits or is likely to fail and the reasons which
meatus back in 1999. A more recent RCT on 120 patients increase the chance of revision
using a turbinate-septal suture showed this to be effective in There are many reasons why patients require revision surgery.
preventing lateralization(629). Maharaj et al. proposed the basal Phenotyping and endotyping, where possible, may facilitate
lamella relaxing incision as a means to achieve this but only counselling the patient regarding prognosis and expected
found a non-significant difference in olfaction as a potential outcome of the surgery itself and aid identification of the
advantage(630). postoperative medical management that has the greatest
likelihood of controlling the patient’s symptoms. They may also
Mucocoele formation assist in identifying those at risk of poor outcome though failure
The time of mucocele formation after initial ESS in one series of primary sinus surgery is often multifactorial and inadequate
was <22 months as compared to <10 years after external surgery is only one aspect, with host immunity and adherence
sinonasal surgery or trauma(631); however, another series to medical management equally important to consider.

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From a practical clinical perspective, in the CRSsNP phenotype endoscopic sinus surgery (EESS) or radical sinus surgery for
group, patients with previous multiple surgeries or frank pus refractory CRS, since it is associated with better outcomes
and / or purulent crusting in the nasal cavity on endoscopy compared to FESS, specifically when CRSwNP is present. EESS
or at the time of surgery are likely to do worse. Several improved olfaction and did not increase frontal ostium stenosis
prospective blinded studies have shown a correlation between compared to FESS(425).
in vitro biofilm-producing Pseudomonas aeruginosa and Other co-morbidities such as N-ERD and cystic fibrosis (CF)
Staphylococcus aureus found in post-operative cavities and also increase the chances of repeated surgery. In a study
poor outcomes with increased rates of revision surgery(636, 637). comprising 106 CF patients, the necessity for revision surgery
Tomassen at al. investigated cytokines in CRSsNP and found was 28% within three years of surgery(648).A review of risk
that four IL-5 negative clusters made up the majority of CRSsNP factors for recurrent sinus surgery in 81 patients with CF found
patients. However, there was also an important subgroup of that the most relevant was a high Lund-Mackay scores at their
CRSsNP patients with a type 2 profile(638). initial surgery(649). Similarly, another retrospective study on
A recent study in CRSsNP patients, using preoperative SNOT 49 CF patients found the grade of polyp (0-3) correlated with
scores, revealed four clusters. Highest disease burden where revision(650).
found in patients with tissue eosinophilia and asthma. Other In a systematic review by Adelman et al. on the management
subgroups included those with a high score in the rhinologic of N-ERD (Samter’s Triad) looked at 18 studies (686 patients), of
domain, and those with a high score in the psychological- whom 59.4% had undergone previous surgery(651). This ranged
sleep domain in both the moderately burdened and a mildly from a mean of 1.9-5.4 times and was mainly ESS, but 14% had
burdened group. All groups experienced improvement six undergone a Caldwell-Luc procedure.
months after surgery but those with asthma and a high tissue Immunodeficiency and GPA patients also required more revision
eosinophil count had higher SNOT-22 scores postoperatively(403). surgery. Another study with 61,339 patients (mixed population
Whilst revision surgery may be related to the pathomechanisms of CRS) followed for five years, demonstrated that 4,078 patients
of the mucosal inflammation, indicated by clinical signs (6.65%) required revision ESS. The mean time to revision surgery
or biomarkers, another reason may be iatrogenic due to was 20 months, with 43% of the patients having revision surgery
inadequate initial surgery for the disease endotype leading to during the first year. CRSwNP patients accounted for 9.9% of all
suboptimal postoperative results and continuing symptoms. The revision cases vs. 7.9% for CRSsNP, concluding that patients with
most common findings in patients undergoing revision surgery nasal polyps are approximately twice more likely than those
due to iatrogenic reasons are middle turbinate lateralization, without NP to require revision ESS(652).
adhesions and scar formation in the middle meatus,
incompletely resected uncinate process and retained ethmoid Modifiable exposures to risk factors associated with recurrence
cells (see below)(639). must be identified and patients must be encouraged to
Another important factor that contributes to the need for discontinue their exposure if possible. Occupational dust
revision ESS is surgeon-specific performance studied by Rudmik exposure has been associated with higher rates of recurrence
et al.(640). This may explain why the frontal sinus, which is the of polyps i.e. 48%, of which 13% needed revision surgery,
hardest to approach, is the sinus with the highest revision rates. compared with recurrence rates of 3% in the patients with
They found that 16% of surgeons followed for five years had no exposure, and for which none required re-intervention(4,6).
lower-than-expected performance, indicating a potential area Smoking is another modifiable risk factor, described by Wu(653) in
for improvement in quality of care. The presence of nasal polyps, a retrospective analysis of 490 patients with CRSwNP followed
repeated systemic corticosteroid courses, allergy, asthma, over a 25-year period who underwent revision ESS by a single
female gender, family history of CRS, older age at initial surgery surgeon. They reported a mean time to revision of 4.8 years,
and occupational dust exposure were associated with increased shorter by almost half in patients who smoked (2.82 years).
risk of undergoing ESS revision, while concurrent septoplasty One of the first studies that showed a difference of inflammatory
reduced the rate of revision ESS. It has also been shown that the patterns in recurrent and non-recurrent CRSwNPs was
time between revision surgeries decreases with each additional performed by Van Zele et al.(654) CRSwNP patients who needed
revision surgery performed in a large mixed CRS population(553). revision surgery showed a predominant Th2-type inflammation
In CRSwNP, rates of revision ESS tend to be higher. In several and higher concentrations of IL-5, ECP, IgE, and Staphylococcus
studies, recurrence of nasal polyps has been found to occur enterotoxin IgE (SE-IgE). IL-5 protein within the polyp and SE-IgE
earlier in time and more frequently(641-644) A retrospective study were linked to recurrence after the first surgery, in contrast to
included 23,542 CRS patients followed for one year showed that IFN-γ which was linked to non-recurring disease. Thus, the type
the frequency of revision ESS for CRSwNP was 3.5% vs. 1.6% of inflammation, specifically Th-2 inflammation, can predict
for CRSsNP(645). Miglani et al.(646) reported a similar result in a whether a patient is likely to have recurrence and revision ESS.
retrospective review of 424 CRS patients with and without nasal Identifying inflammatory patterns in CRSwNP by endotyping(638)
polyps, finding an overall frequency of 4% for revision ESS, 88% therefore, may be helpful to identify patients who need more
of which were necessary in the CRSwNP patients. According to extensive surgery, or may be suitable for specific treatments
Chen et al.(647) CRSwNP associated with asthma also has a higher with biologics(655).
rate of revision ESS (25%).The authors recommend extensive

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6.2.2.2. What are the goals of revision? objective CT and endoscopic evidence of mucosal thickening
In both CRSsNP and wNP, the surgeon’s goal is often to create a or mucopurulent discharge, nasal polyps or mucosal oedema
common cavity accessible to local therapy. It may be necessary after at least a two-month course of culture-directed
to address anatomical variations which obstruct access, removal antibiotics, topical and oral steroids, and nasal douching(431,
of residual cells, scarring or neo-osteogenesis, widening of ostia 659)
. It is important to ascertain that the patient has adhered
and removal of partitions, mainly in the ethmoids. Addressing to this medical therapy prior to revision surgery. Whereas the
the middle turbinate by partial trimming has shown improved recurrence of symptomatic nasal polyps in CRSwNP prompts
results in some studies without seeming to cause any negative surgery, the indication for revision surgery in CRSsNP is not so
effects, although the latter has mainly been investigated in easily determined, especially in the absence of any obvious
CRSwNP(656, 657). obstruction. It is not clear from the literature whether surgery in
the absence of mucocoele formation, drainage issues or residual
The patient’s goal is to experience symptom reduction, reduced cells is of benefit in CRSsNP. Studies investigating the timing of
need for medication and improved quality of life and these revision surgery in CRSsNP are lacking. However, in a mixed CRS
are generally the primary outcomes evaluated by surgeons in population, delayed surgery does not seem to negatively affect
patients with CRS. In CRSwNP, the prolongation of recurrence- postoperative improvement(660).
free time or avoidance of recurrence are further goals.
There is a well-defined consensus that optimization of patient- 6.2.2.5. Preoperative assessment
reported outcome measures (PROMs) is the primary goal When symptoms persist after ESS, and optimal clinical treatment
of treatment(654). Several tools are used for the evaluation of with antibiotics and steroids fail, a nasal endoscopy and a CT
medical and surgical interventions, including the Rhinosinusitis is indicated in an attempt to confirm the site and extent of the
Disability Index (RSDI), 20 and 22-item Sino-Nasal Outcome Test inflammation and to help the planning of surgery.
(SNOT-20, SNOT-22), Chronic Sinusitis Survey (CSS), Adelaide In revision surgery a number of features on the CT scan are of
Disease Severity Score (ADSS), Patient Response Score (PRS), interest(639, 661).
Rhino-sinusitis Symptom Inventory (RSI) and Rhinosinusitis
Outcome Measure (RSOM)(see section 5.3.4.2). For medically Sinus anatomy and post-operative findings
recalcitrant cases, surgery is the most effective way to i) Anterior-posterior diameter in the frontal recess, and overall
improve QoL. In a prospective cohort study of 668 CRS (mixed size of the sinuses (pneumatisation)
population) patients undergoing primary FESS with a 60-month ii) Remaining cells that may obstruct drainage or block access to
follow-up by Rudmik et al.(640) failing to achieve an improvement local treatment
of more than one minimal clinically important difference (MCID; (incomplete anterior or posterior ethmoidectomy)
9 points in SNOT-22) at three months after primary ESS and a iii) Lateralisation of the middle turbinate
deterioration of greater than one MCID (> 9 points) from the iv) Residual uncinate process
three- to 12-month follow-up periods was associated with an iv) Synechiae or stenosis of previously opened sinuses
increased risk of revision ESS.
It is evident from the literature that frontal sinus clearance is
The goal of revision surgery can be different for the the most challenging part of endoscopic sinus surgery. The
surgeon and the patient. These discrepancies have most common findings are retained agger nasi cells, neo-
to be discussed osteogenesis within the frontal recess, lateral scarring of the
middle turbinate, residual anterior ethmoid air cells, and residual
A multi-institutional observational study demonstrated a frontal cells(662).
tendency of improvement in postoperative PROMs and olfactory
measures in complete surgery (Draf IIa, IIb, or III) compared to a Remaining/recurring mucosal disease despite patent drainage
targeted approach in CRS(441, 655). pathways
A systematic review included 12 studies containing data from This finding would indicate ongoing inflammation and/or
1308 CRS patients (mixed population) to evaluate the impact of infection in spite of patent drainage pathways. Although this is
PROMs in revision ESS. The authors found improvements in five not an unusual situation in a clinical setting, there is no literature
main symptoms of nasal obstruction, rhinorrhoea, post-nasal available to advise on a treatment algorithm.
drip, facial pain and anosmia. The benefits persisted for a mean
of 21.7 months follow-up after revision surgery. The review Neo-osteogenesis
described the importance of using PROMs to report primary and Neo-osteogenesis is positively correlated to disease severity
revision sinus surgery outcomes, with the SNOT-22 test being and as such is a poor prognostic factor and should be part of
the most commonly used(658). the evaluation of the preoperative CT in preparation for revision
surgery. A recent study concluded that the presence of P.
6.2.2.4. When should revision surgery be performed? aeruginosa in the sinuses is an independent predictor of neo-
Revision surgery is often seen as the last resort when medical osteogenesis, whereas S. aureus is not. The number of previous
therapy has failed. It should be considered when there is surgeries and the Lund-Mackay score are also independently
persistence of post-treatment symptoms together with associated with the severity of neo-osteogenesis(663).

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6.2.2.6. What should be the extent of a revision operation and improvement, 27.6% reporting partial improvement and 0%
what are the outcomes? reporting worsening(666).
It is difficult to draw any firm conclusion from the literature There is still conflicting evidence regarding middle turbinate
regarding the ideal extent of surgery as many studies are resection (MTR), but recent cadaveric studies confirmed
retrospective, lack a control group and do not make a distinction better distributions of topical drugs after partial and complete
between CRSwNP and CRSsNP. Furthermore, the patient- middle turbinate resection(667, 668).The resulting postponement
reported outcome is not dependent on surgery alone, but a of revision surgery(647) can justify MTR in primary surgery,
combination of surgery, post-operative medical management especially in diffuse sinus pathology andevidence in a mixed
and patient phenotype / endotype. CRS population is emerging that it may also improve patient-
Nonetheless, recent review publications have confirmed that reported outcomes in revision surgery(657). However, if one
revision surgery in both CRSwNP and CRSsNP provides tangible subscribes to the ‘reboot’ concept, the middle turbinate should
benefits in the majority of patients though extent of the surgery be maintained as it rarely develops polyps and provides the
is rarely addressed. Revision surgery is equally effective as epithelium for re-epithelialization of the sinuses after ‘reboot’
primary surgery for CRSwNP and CRSsNP on QoL outcome surgery(655).
instruments, in a cohort of 48(664). In contrast, a prospective
multi-institutional study in 302 patients showed that primary The extent of the surgery depends on the severity of the disease
surgery was approximately 2 times more likely to improve than and the type of inflammation (endotype). Schalek et al.(667)
revision cases. This may reflect the grade of disease severity suggest that in cases of severe, diffuse or recurrent polypoid
in the revision group which was composed of a mixed CRS disease, better outcomes can be achieved by more extensive
population(556). Bhattacharrya addressed the issue of outcomes surgical approaches. The concept of completely removing
in a small prospective cohort of 21 adult patients undergoing diseased sinus mucosa in the ethmoids to reduce disease
revision ESS(665). Data were analyzed for symptom score changes burden and allow a healthier mucosa to develop was proposed
and effect sizes, changes in medication, and economic variables by Jankowski in 2006(669). It was considered controversial at the
and compared with those of a contemporaneous control group time but in recent years it has been relaunched as ‘rebooting’
of patients undergoing primary ESS and matched for age, sex, of the mucosa. Not only the extent of inflammation seen on
and Lund-Mackay score at a mean follow-up of 12.4 months. the CT but intraoperative judgment will be the main factors
Large effect sizes indicating significant symptom improvements to determine the scope of the surgery(425, 431). Thus severe Th2
were noted for nasal obstruction (effect size,−1.9), hyposmia CRSwNP disease, often accompanied by asthma, which is
(−0.9), and headache (−0.6), as well as nasal (−1.1) and associated with an increased risk of recurrence, might better
total symptom domains (−0.9; p<.05 in all cases). These be approached by ‘reboot’ surgical techniques(647). To date the
improvements in clinical symptoms were statistically similar to role of complete diseased mucosa removal in CRSsNP remains
corresponding improvements in the matched cohort of patients unclear. Jankowski et al.(699) compared radical with conservative
undergoing primary ESS. surgery for CRSwNP and showed reduced recurrence after the
A systematic review was undertaken by Prasad et al. in 2017 radical approach, albeit with different surgeons responsible
to evaluate the impact of revision ESS(RESS) on PROMs(658). for the two approaches. A recent retrospective case-control
This produced 12 studies (1308 patients), three used the study in patients with Th-2 pattern CRSwNP done by Alsharif
Rhinosinusitis Disability Index and Chronic Sinusitis Survey in et al.(431) reported an important reduction in polyp recurrence
tandem; four used the 20-item Sino-Nasal Outcome Test (SNOT- and prolongation of recurrence-free time after complete
20)(403) and the 22-item Sino-Nasal Outcome Test (SNOT-22)(403); removal of the diseased sinus mucosa. This allowed healthy
the remaining five used either the Adelaide Disease Severity re-epithelialization from the preserved nasal mucosa, using the
Score, Patient Response Score (PRS), Rhinosinusitis Symptom partial and full ‘reboot’ techniques as compared to the classical
Inventory, Rhinosinusitis Outcome Measure 31, or the Chinese ESS approach.
version of the University of Pennsylvania Smell Identification
Test. Studies consistently reported improvement in the five key This paper defined ‘reboot surgery’ as complete removal of
symptoms of nasal obstruction, rhinorrhea, postnasal drip, facial all inflamed sinus mucosa to allow the regrowth of functional
pain, and anosmia, although improvement in halitosis, fever, mucosa and divided it into ‘partial’ and ‘full’. Partial involves
dental pain, and cough were modest. the clearance of all sinonasal polyps and mucosa down to
A study in CRSsNP patients comparing different sizes of the the periosteum whereas a full reboot procedure includes the
maxillary ostial antrostomy could not detect any influence mucosa of the frontal recess and the frontal sinuses with Draf III
of this on the main rhinosinusitis symptoms (obstruction, access and removal of all frontal sinus mucosa and a sufficiently
headache, and nasal discharge)(416). Another retrospective review large frontal opening to avoid stenosis(655). The full ‘reboot’
in CRSsNP patients suggests that endoscopic maxillary mega- approach showed a better result as compared to a partial
antrostomy is beneficial in recalcitrant maxillary rhinosinusitis ‘reboot’ ESS though this was not statistically significant. Further
in which medical therapy and previous endoscopic antrostomy research is needed to support the ‘reboot’ vs. EESS approaches
have been unsuccessful. In a cohort of 122 patients (163 sides) to identify the role of complete removal of the sinus mucosa.
who underwent endoscopic maxillary mega-antrostomy, Postoperative obstruction of the frontal sinus drainage as
outcomes were 72.4% reporting complete or significant a cause of chronic frontal sinusitis and mucocoeles are a

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major concern after CRSwNP surgery(670, 671). In these cases, an from 29 articles with a mean follow-up of 29.1 +/- 10.3
endoscopic modified Draf III can be offered. This procedure is months. The overall rate of significant or complete symptom
generally reserved for revision surgery after primary FESS. If improvement was 86.5% (95% confidence interval [CI]: 84.2%-
the patient’s primary FESS was not performed adequately by 88.7%). The overall patency rate was 90.7% (95% CI: 89.1%-
the previous surgeon, a revision Draf IIa can be offered before 92.3%), with a revision rate of 12.6% (95% CI: 10.6%-14.3%).
a Draf III is undertaken. If the previous frontal surgery has been Compared to the early cohort, patients in the contemporary
properly performed and failed, then a Draf III is indicated(436). cohort underwent Draf III more often for tumours (p<.001), had
The Draf III is generally undertaken in severe cases, showing higher rates of complete or significant symptom improvement
statistically significant improvement in recurrence rates in (90.0% vs. 82.6 %, p<.001); and trended toward greater patency
CRSwNP, especially in patients with asthma and aspirin- rates (92.1% vs. 88.6%, p=5 .052). Overall 79% were performed
exacerbated respiratory disease(672). As might be expected, for recalcitrant CRS but when the cohort was divided into 1990-
revision Draf III has a higher failure rate compared to primary 2008 vs. 2009-2016, whilst there was no difference in symptom
Draf III(673). With advancement in technology, instrumentation, improvement or patency, the revision rate was higher in the
and techniques, the Draf III has evolved into an efficient and safe more recent group (14.5% vs. 9.2%, p=5.016) when Draf III has
procedure, and likely will be more commonly used as a primary been performed more frequently for tumors. Among 114 failure
procedure in high-risk patients If the risk factors for all patients cases in 16 studies, 82.5% patients were revised with Draf III,
undergoing Draf III are assessed, these factors (asthma, CRSwP, 11.4% salvaged with an osteoplastic flap and 6.1% with standard
LM >16, narrow frontal ostium <4mm) provide a reasonable revision ESS. The revision rate increased significantly when
basis for considering an Draf III in patients who otherwise would follow-up exceeded two years which may also have reflected the
undergo revision ESS. This particular subset may well benefit indications for surgery.
from a primary Draf III(672). Abuzeid et al. also published a meta-analysis in 2018 but only
considered studies from 2000-2016, including 11 studies and
The revision rate reported by Bassiouni et al. after ESS including 778 patients, 86.5% of whom had CRS(433). Mean follow-up
a Draf IIa was 37% compared to 7% for patients that underwent duration was 28.4 months and the mean number of surgeries
a Draf III, suggesting the superiority of Draf III surgery in patients prior to Draf III was 3.5. In a subgroup analysis of seven studies
with CRSwNP(674). After long-term follow-up for a minimum of in which all 357 patients had CRS, symptom improvement was
seven years of 153 CRSwNP patients, Benkhatar et al. found that 75.9% of cases and 23.1% experienced polyp recurrence. The
6.5% required at least one revision surgery for chronic frontal cerebrospinal fluid leak rate was 2.5% and restenosis of the neo-
sinusitis, with a mean delay from initial procedure to diagnosis ostium occurred in 17.1% with complete closure occurring in
of 46 months (four months to 11 years). Circular mucosal 3.9% of cases. The reoperation rate for Draf III was 9.0%. Aspirin
damage in combination with a narrow frontal opening can lead sensitivity was associated with an increased risk of cerebrospinal
to closure of the frontal sinus drainage pathway and hence a fluid (CSF) leak (p=0.0339) and a reduced incidence of neo-
higher risk of frontal sinus revision ESS(670). ostium closure (p=0.0001). Aspirin sensitivity and asthma were
associated with a reduced incidence of reoperation (p=0.001)
A meta-analysis of the Draf III or endoscopic modified Lothrop and increased symptom improvement (p<0.005). Restenosis
procedure (EMLP), as it is often called in the United States was or closure of the frontal neo-ostium was associated with less
conducted from 1990 to 2016 by Shih et al.(438) reporting clinical symptom improvement (p<0.04) but not with reoperation, as
outcomes of Draf III. A total of 1,205 patients were abstracted above.

Table 6.2.3.1. Potential indications for external approaches to the maxillary and frontal sinuses in CRSsNP and CRSwNP.

Maxillary sinus Frontal sinus

Anterolateral/-inferior pathology requiring access but inaccessible Narrow frontal recess that cannot be kept open.
endonasally
Far lateral pathology or pathology on the orbital roof requiring access but
inaccessible endonasally.

Osteoneogenesis that cannot be treated endoscopically Some forms of frontal osteomyelitis.

Previous trauma and severe frontal recess stenosis.
Complicated acute frontal sinusitis e.g. sub-periosteal frontal abscess that does not
resolve with antibiotics.

Extensive neo-osteogenesis at frontal recess area.

Failure of endoscopic approach Failure of endoscopic approach.
Need for fat obliteration or cranialisation.

CRSsNP, Chronic Rhinosinusitis without nasal polyps; CRSwNP,Chronic Rhinosinusitis with nasal polyps.

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6.2.2.7. Is there any difference in postoperative patients with CRSsNPs and 24 with CRSwNPs unresponsive
management for revision vs. primary? to medical and surgical therapy underwent one of three
Current postoperative management of ESS patients varies treatments: a single treatment with aPDT, two treatments with
greatly between individual surgeons. This variation in current aPDT separated by a four-week interval, or endoscopic irrigation
practice indicates the lack of consensus on the topic. Generally with saline (control). Outcome measures included SNOT-22,
postoperative management is aimed at maintaining a clean endoscopic scores, UPSIT, microbiology results and endoscopic
surgical cavity, in which topical steroids can act and to scores. Significant improvements were seen following aPDT
maintain patency of the sinus cavities, especially the frontal treatment in both symptomatic and endoscopic scoring, with
drainage pathway. The long-term follow-up will depend on the greatest effect occurring in the CRSwNPs group receiving
the underlying pathophysiology, sinus patency, and control of two treatments (p=0.007). The aPDT treatments were well
sinonasal inflammation with medical therapy. tolerated, with temporary mild pressure in the treated sinus(es)
being the most common adverse event. The formal trial results
Topical steroids and saline washes have yet to be reported but these findings do show early
Escalation of treatment beyond nasal steroid sprays and saline promise
washes is called for in a revision case. Steroid nasal lavage was
shown to have superior distribution in the postoperative sinuses More active debridement?
compared to steroid nasal sprays. Harvey et al.’s DBRCT in a Debridement improves postoperative endoscopic appearances,
mixed CRS population (n=35 analysable) showed benefit for minimizing postoperative infection, granulation, and potential
mometasone irrigation as compared to spray delivery up to one restenosis especially in patients who had significant mucosa and
year post-surgery, though both groups showed improvement(67). bone removal (Draf IIB and III), but it is unclear if it has any long-
No trial of steroid washes has exclusively studied the CRSsNP term positive effects on disease-specific health-related quality
population. An undefined CRS population, (n=61), participated of life or disease severity as reported by two recent reviews in an
in a double-blind, placebo-controlled, randomized clinical trial mixed CRS population(529, 530).
comparing saline/lactose with saline/budesonide large volume, Generally, as in primary ESS, the first postoperative debridement
low pressure washes. The average improvement in SNOT-22 is seven to 10 days after surgery and thereafter the visits are
scores was 20.7 points for those in the budesonide group and individualized depending on the specific needs of the patients.
13.6 points for those in the saline/lactose group, with a mean Revision surgery may be an indication for the parallel use of
difference of 7 points in favour of the budesonide group(81). biologics in the future(685). The surgery should be performed
A recent meta-analysis pooled three studies (mixed CRS after several months of biologic treatment to establish its
population) and concluded that nasal irrigation was beneficial, efficacy, and the need for surgery should then be determined
but found no clinical benefit from adding corticosteroid in nasal depending on presence of polyps, symptoms and QoL of the
lavage compared to saline alone as post-operative treatment(534). patients.

Long term antibiotic treatment 6.2.2.8. General conclusions

Long-term treatment, four weeks or more, with macrolide Clinical experience and evidence in the literature suggest that
antibiotics has support in the literature in CRSsNP patients revision surgery in CRSwNP and to a lesser extent CRSsNP is
where the eosinophilic inflammation is low to moderate and beneficial. However, the quality of the scientific evidence is
serum IgE within the normal range(14, 27, 675). So far doxycycline generally low.
has only been investigated in CRSwNP(4). Trimethoprim /
sulfamethoxazole has been shown to improve patient reported 6.2.3. Indications for external surgery
outcomes in 2 uncontrolled clinical observational trials of
‘purulent CRS’(676) and ‘recalcitrant CRS’(677). None of these studies The need for external approaches in CRS is radically reduced
have focused specifically on patients undergoing revision with the introduction of endoscopic sinus surgery (ESS) led by
surgery. The use of culture-directed antibiotic therapy and a philosophical move away from radical removal of diseased
topical and/or systemic steroid administration depends on mucosa to minimally invasive functional restoration of drainage
the underlying pathophysiology and postoperative wound pathways and enabling postoperative topical medication
healing(678). delivery to the sinonasal cavities. With the exception of a small
number of indications in the maxillary and frontal sinuses, few
Antimicrobial photodynamic therapy (aPDT) areas of the sinuses cannot now be reached endoscopically,
Antimicrobial photodynamic therapy (aPDT) has demonstrated facilitated by advanced techniques using angled endoscopes
in vitro efficacy for the eradication of bacterial biofilms and powered instrumentation. Thus, the indications for external
associated with chronic rhinosinusitis (CRS) as well as anti- approaches are now limited areas that cannot be reached/kept
inflammatory properties(679-682). Previous case series have open endoscopically. Nevertheless, in the absence of adequate
suggested effectiveness in patients with CRS unresponsive instrumentation or experience, external approaches still provide
to medication and surgery(683). More recently an RCT was an option and may be combined with endoscopic techniques
undertaken to evaluate the clinical effects of aPDT for refractory to provide a postoperative transnasal route for topical medical
CRS and included 47 patients at two centres(684). Twenty-three treatment delivery. The current recommended indications for an

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external approach are listed in Table 6.2.3.1. histopathological criteria for chronic, hyperplastic, eosinophilic
There are only three papers on two prospective randomised rhinosinusitis was performed by Abd el-Fattah(426). Patients
trials on this topic(426, 429, 686)the rest of the publications being were randomly allocated to two treatment groups: classical
non-comparative cohorts which are largely retrospective. endoscopic middle meatal antrostomy as part of FESS and
endoscopic radical antrectomy through a combination of
6.2.3.1. Maxillary sinus canine fossa puncture and an endonasal endoscopic procedure,
The Caldwell-Luc operation, or radical antrostomy is done with complete removal of maxillary sinus mucosa. The radical
through a sublabial anterior maxillotomy which has proven group showed significantly better impact on symptoms of
its value in several large published series(687-689). This approach nasal obstruction and rhinorrhoea. Thirty-two per cent of
is now rarely used for inflammatory diseases, supplanted by patients in the endoscopic middle meatal antrostomy group
the many variants of ESS(690) but in spite of high success rates were considered surgical failures, compared with 14.5% of the
obtained with endoscopic approaches, maxillary antrostomy endoscopic radical antrectomy group (p=0.023). Unhealthy
failures still occur(414) and among revision endoscopic surgery maxillary sinuses were significantly more prevalent in the
patients, one study reported 39% stenosis of the middle meatal endoscopic middle meatal antrostomy group (p=0.029).
antrostomy(691). The authors concluded that in patients fulfilling the criteria
The major concerns in recalcitrant maxillary rhinosinusitis suggestive of chronic, irreversible sinonasal pathology, primary
include impaired mucociliary clearance either primary such endoscopic radical antrectomy was significantly better than
as occurs in cystic fibrosis or primary ciliary dyskinesia, or endoscopic middle meatal antrostomy, based on subjective and
associated with biofilm formation or secondary to previous objective findings.
surgery(692). Today even in the presence of persistent disease In a study of Denker’s procedure, Videler et al. conducted a
requiring surgical management, extended endoscopic prospective questionnaire-based study on 23 patients with
approaches such as endoscopic modified medial maxillectomy refractory CRS. They had undergone a median of six previous
or inferior meatal antrostomy are generally utilized as the next sinonasal operations (range, 3-11) prior to undergoing the
option in preference to Caldwell-Luc (C-L)(690). Nevertheless, Denker’s procedure, which combines all sinuses, except the
in spite of these efforts, if the disease is difficult to reach frontal sinus, into one large cavity, via a sublabial approach to
endonasally, involves a large foreign body or infected bone, the anterior angle between the bony nose and antral walls.
a classical C-L procedure(693), an external endoscopic-assisted Preoperative and postoperative symptoms at 12 and 24 months
sublabial anterior maxillotomy(690) or a Denker procedure still were compared. Patients reported a significant improvement
remain viable options(694). Canine fossa trephination has also in rhinorrhoea (p=0.001), feelings of congestion (p=0.02), and
been reported to be of use in patients with N-ERD and in nasal obstruction (p=0.03). Reduced olfactory perception and
removal of debris and polyps in allergic fungal rhinosinusitis(695). asthma did not improve.
Pentilla et al.(686) performed one of the few prospective Interestingly in a review of 670 Caldwell-Luc procedures, the
randomised studies comparing standard C-L to FESS in 150 most frequent complication was recurrent nasal obstruction,
consecutive adult patients with chronic maxillary rhinosinusitis which occurred in 28% of patients(687). Informed consent should
after failure of medical treatment. The endoscopic surgery was also include other possible complications such as paraesthesia,
performed by one surgeon whereas 16 surgeons undertook facial pain, oroantral fistula, dacrocystitis, facial asymmetry and
the C-L. There were 143 patients available for the follow-up at a devitalised teeth(686, 687, 689, 697). Techniques that may help reduce
median of 12 months. The patients’ global evaluation showed complications include gentle tissue retraction, protection of
marked improvement in 51% of the C-L group and in 77% of the infraorbital nerve, limitation of the size of the anterior
the FESS group. Overall subjective symptoms deteriorated antrostomy, and avoidance of cracks in the bony wall of the
in 5.5% of C-L operated patients, but not at all in the FESS antrum(698). The best area in which to perform a canine fossa
group. At the time, these results seemed to favour FESS over puncture without injuring the infraorbital nerve or anterior
C-L. However, a contemporaneous study compared pre- and superior alveolar nerve has been shown to be at the intersection
post-operative histopathologic mucosal changes in chronic of the mid-pupillary line and a horizontal line through the floor
maxillary rhinosinusitis after FESS (60 sinuses) and C-L (55 of the nasal vestibule(699).
sinuses)(696). The C-L operation reduced almost all parameters,
whereas only oedema and inflammatory cells were significantly 6.2.3.2. Ethmoid and sphenoid sinuses
reduced after FESS. No valid correlations were found when Endonasal ESS, due to its minimally invasive nature, has largely
comparing histology with patient symptoms. Furthermore, in supplanted external approaches to the ethmoids and sphenoid
1997 Pentilla et al.(429) published a reassessment of their cohort in CRS(690). An external ethmoidectomy through a modified
with questionnaires obtained from 128 patients (85%) 5–9 years Lynch-Howarth incision made along the inferior border of the
after operation. At this point 82% of the C-L and 76% of the FESS medial eyebrow and carried inferiorly in a curvilinear fashion
patients respectively reported significant improvement. Thirteen allows access to the ethmoid sinuses, medial orbit, anterior skull
C-L operated patients (18%) and 14 FESS patients (20%) had base, frontal recess, supero-medial orbit, sphenoid sinus and
been re-operated during the 7–9 years follow-up. orbital apex. However, in addition to the usual risks engendered
A second randomised, controlled trial with parallel design, by proximity to the orbit and skull base, it carries the additional
including 119 patients who fulfilled the clinical, radiological and risk of complications such as facial scars, forehead paraesthesia,

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and telecanthus. The removal of the medial orbital bone External frontoethmoidectomy through a Lynch-Howarth
frequently led to medialisation of the orbital contents which incision have been used historically in CRSsNP, usually as a
combined with failure to preserve mucosa produced stenosis of transorbital approach to the frontal sinus by resection of the
frontal sinus outflow with secondary inflammatory problems, ethmoid sinuses and the creation of a contiguous space into the
contributing to its loss of popularity(689, 690, 700-702). nasal cavity. Nevertheless, it had high failure rate due to orbital
medialisation as mentioned above(702). Although this procedure
In the era of ESS, external approaches to the is rarely used nowadays, it may still have some limited utility
frontal sinuses still have value used as an adjunct in the presence of complex anatomy and in the presence of
or alone but their indications are diminishing. significant neo-osteogenesis of the frontal recess(688, 689).
However, external approaches should be kept in Use of the frontal sinus osteoplastic flap (OPF) with or without
our rhinosurgical armamentarium and taught to obliteration (FSO) for recalcitrant frontal sinus disease has also
the younger generations. decreased significantly with the advancement of endoscopic
techniques. This procedure is extensive and requires a coronal,
6.2.3.3. Frontal sinus mid-forehead or brow incision, as well as osteotomies to create
The frontal sinuses remain a challenge for the sinus surgeons the OPF. With this approach, the entire frontal sinus pathology
even in the endonasal endoscopic era, due to their complex can be exposed, removed and all the frontal sinus mucosa
anatomy. Traditionally, all frontal sinus pathologies including drilled out, followed by abdominal fat obliteration of the sinus
CRS were addressed via external approaches such as frontal if required(688-690, 704, 705, 712-717). Extensive neo-osteogenesis of
sinus trephination, external frontoethmoidectomy, and the frontal recess secondary to previously failed endoscopic
frontal sinus osteoplastic flap with or without obliteration or approaches is the most common indication for this technique
cranialization(688-690, 700, 703-708). These have largely been replaced in inflammatory disease, followed by some cases of laterally
by endoscopic techniques culminating in median drainage placed frontal sinus mucocoeles with very narrow diameter of
(Draf III or an endoscopic modified Lothrop procedure (EMLP)). the DRAFIII opening , some cases of osteomyelitis that cannot
However, the classical external procedures may still be used be cured with antibiotics, some cases of ‘allergic’ fungal frontal
alone or in combination with endoscopic approaches for lesions rhinosinusitis and other laterally located pathologies.
that cannot be reached endoscopically, very narrow entrance Despite success rates up to 85-90%, long term studies have
to the frontal sinus that cannot be kept open e.g. due to shown that the OPF with FSO can have significant morbidity
neoosteogenesis in the frontal recess and very rarely recalcitrant with cosmetic deformity, cerebrospinal fluid leak, forehead
inflammation, particularly involving the far lateral region of the numbness and postoperative headaches(703-705). Weber et al.(705)
frontal sinus, disease in a type III/IV frontal cell, osteomyelitis, described a 10% incidence of mucocoele formation after
and/or previous trauma (Table 6.2.3.1.). FSO detected five years after surgery by MRI. Hansen et al.(706)
For the inflammatory diseases of the frontal sinus, a frontal demonstrated that the prevalence of mucocoeles and revision
sinus trephine as an adjunct to endonasal procedures can be rate was 7,5% in 40 consecutive obliterations with an average
performed(709). Frontal sinus trephination is a safe procedure follow-up of 80 months. Even more problematic is infection
where complications are relatively rare. Nowadays, this of the frontal bone flap which in the 1970s was reported at
technique is mainly performed as a mini-trephination, enhanced 18%(704). If this occurred, removal of the affected frontal bone
by the use of an endoscope, which improves visualization and as in a Reidel procedure could be considered with a view to
facilitates instrumentation through the trephine. Indications reconstruction at a later date(718).
include: complicated chronic frontal rhinosinusitis or frontal In the most severe cases of refractory frontal rhinosinusitis that
osteomyelitis; frontal sinusitis with difficult anatomic variants, have failed traditional endoscopic and open approaches, or in
such as type III and IV or intrafrontal cells(595); and far lateral cases of osteomyelitis of the posterior table of the frontal sinus,
frontal sinus diseases as well as complicated acute frontal cranialization of the sinus may be the final surgical resort(707, 708).
sinusitis(688-690). Seiberling et al.(710) reported a 92% frontal sinus In 2011, van Dijk et al.(708) reported 15 patients with refractory
patency rate after 188 mini-trephination procedures, with an chronic frontal rhinosinusitis treated by cranialization of the
average follow-up of 25.5 months and with 12 complications, frontal sinus, from 1989 to 2008. All of the patients had better
the most common being infection of the trephine site. The quality of life after a mean follow-up of 6.5 years.
indications for trephination were difficulty in finding the frontal In a retrospective review of 717 frontal sinus procedures for
recess, severe oedema / polyps, frontal cells (type III or IV or inflammatory disease in 683 patients at a tertiary academic
intrafrontal cells and intersinus septum cell), as an adjunct centre over a three-year period, Hahn et al.(715) reported that
during a Draf III and when there was a need for postoperative most cases of chronic frontal rhinosinusitis can be treated by
irrigation. In a systematic review, Patel et al.(711) concluded endoscopic sinus surgery though this may be unsuccessful
that in the era of ESS, frontal sinus trephination has remained in some situations such as distortion of critical landmarks,
the most routinely utilized of all external procedures either neo-osteogenesis of the frontal recess, and lateral location of
as a supplement to the endonasal endoscopic approach or diseased mucosa. Whilst, > 94% of these cases were successfully
used alone to provide adequate access for both endoscopic treated endoscopically, 38 external procedures were performed
visualization and instrumentation into the far lateral and in 32 patients (5.3%). Fourteen external procedures (2%)
superior areas of the frontal sinus. were performed in isolation and 24 procedures (3.3%) in

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combination with ESS, 16 of whom had concurrent obliteration. visualization and may lead to complications due to the close
The osteoplastic flap was used in 24 cases (3.3%), the remaining proximity to the skull base, orbit and vital neurovascular
external procedures were frontal sinus trephines. In this series, structures. Actions should be taken to minimise peroperative
the most common indication for the external approach was bleeding and optimize surgical visualization, whilst maintaining
the neo-osteogenesis of the frontal recess (63.2%). More the physiological homeostasis of the patient. These include
significantly, 79.1% of the cases of neo-osteogenesis were patient position, local anaesthetics and vasoconstrictors, type of
associated with previous ESS with a mean of 2.5 procedures, general anaesthetic agent and controlled hypotension.
indicating that repeated surgical manipulation in the frontal
recess leads to scarring and osteoneogenesis that limit the 6.2.4.1. Patient positioning
success of subsequent endoscopic approaches. In these A reverse Trendelenberg position of 5-15’ (head elevation)
cases, the osteoplastic flap may provide a viable alternative. has been shown to improve the surgical field in other surgical
Although there were no major complications with the external disciplines by reducing the central venous pressure from 9.2-
operations, but 9/38 (23.7%) patients required revision surgery 1.7mm Hg(719).
for persistent/recurrent symptoms. Three studies have been performed evaluating the effect of
In the era of ESS, external approaches to the frontal sinuses still reverse Trendelenburg position on surgical field quality, blood
have value used as an adjunct or alone but their indications are loss and operation time. The studies could be combined into
diminishing. However, external approaches should be kept in a meta-analysis where reverse Trendelenburg position (10-20
our rhinosurgical armamentarium and taught to the younger degrees) was compared to horizontal position (0-5 degrees).
generations. The positioning in reverse Trendelenburg position compared
to the horizontal position resulted in a significant improvement
of the surgical field quality measured with the Boezaart
6.2.4. Peroperative measures to improve surgical scale(382) with a MD of - 0.58 (CI -0.78 - -0.38), three trials, 194
field and outcomes patients, p<0.00001 (Figure 6.2.4.1.). The positioning in reverse
Successful ESS highly depends on accurate identification of Trendelenburg position compared to the horizontal position
anatomic landmarks within a circumscribed surgical field. also resulted in a significant mean reduction of the per-
Bleeding from the sinonasal mucosa impairs endoscopic operative blood loss of 120 ml (CI -78. – 164 ml), 3 trials, 194

Figure 6.2.4.1. Forest plot of the effect of reverse Trendelenburg position compared to the horizontal position on surgical field quality.

Figure 6.2.4.2. Forest plot of the effect of reverse Trendelenburg position compared to the horizontal position on blood loss.

Figure 6.2.4.3. Forest plot of the effect of reverse Trendelenburg position compared to the horizontal position on operation time.

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Table 6.2.4.1. Effect of reverse Trendelenburg position on endoscopic sinus surgery.

Study Methods Participants Interventions Outcomes Results
Gan RCT CRS patients · Reverse Trendelenburg 20 degree · Blood loss (ml) · Larger degrees of reverse Trendelenburg
2014(878) having FESS · Reverse Trendelenburg 10 degree · Surgical field quality improved surgical field quality but did
(22 evaluated) · Reverse Trendelenburg 5 degree (Boezaart, 0-5) not improve blood loss or operation
(n=75) · Operation time time
Hathorn RCT CRS patients · Reverse Trendelenburg 15 degree · Blood loss (ml) Reverse Trendelenburg position improved
2013(879) having FESS · Horizontal position · Surgical field quality surgical field quality and reduced blood
(n=64) (VAS) loss and operation time
Ko RCT CRS (33 CRSwNP) · Mometasone nasal spray 200 · Blood loss (ml) Treatment with topical corticoid compared
2008(880) patients having mcg twice daily 4 weeks preoper- · Surgical field quality to placebo resulted in significantly:
FESS (n=70) atively (n=35) (Boezaart, 0-5) · reduced blood loss
· Placebo nasal spray twice daily 4 · Operation time · improved surgical field quality
weeks preoperatively (n=35)
· decreased operation time
RCT,Randomised Controlled Trial; CRS,Chronic Rhinosinusitis; FESS, Functional Endoscopic Sinus Surg; CRSwNP, Chronic Rhinosinusitis with nasal
polyps; VAS, Visual Analogue Scale.

patients, p<0.00001 (Figure 6.2.4.2.). vasoconstrictor into the greater palatine canal (GPC) to decrease
Finally, the positioning in reverse Trendelenburg position surgical bleeding during endoscopic sinus surgery (ESS)(730).
compared to the horizontal position also resulted in a significant Five articles comparing preoperative GPC injection (treatment
reduction of operation time with a MD of – 17 min (CI -30 - -5 group) with a placebo or no treatment (control group) were
min), three trials, 194 patients, p<0.0007 (Figure 6.2.4.3.). included(609, 731-734). The endoscopic grade of nasal bleeding in
the treatment group was significantly reduced when compared
6.2.4.2. Local anaesthesia and vasoconstrictors with the control group and no significant adverse effects
Since its inception, it has been possible to conduct ESS under were reported in the studies. A subgroup analysis showed
local anaesthesia. There are a number of potential advantages adrenalin 1:80,000 was significantly more effective in reducing
and disadvantages though there are few scientific studies intraoperative bleeding than adrenalin 1:100,000 (Level of
on these topics. Gittelman et al.(720) considered 232 patients evidence Ia).
undergoing ethmoidectomy, 149 under local (LA) and 83 under
general anaesthesia (GA) in a retrospective study without 6.2.4.2.2. Topical agents
statistical analysis. There was less blood loss in the LA group Cocaine is an excellent anaesthetic and vasoconstrictor but is
(23ml vs. 58ml) but the complication rate was higher under LA potentially cardiotoxic. In three national studies on the use of
(8.7% vs. 2.4%) which included four cases of severe bleeding. In cocaine in the Netherlands, UK and USA, the majority of ENT
contrast Lee et al.(721) reported 1.4% complication rate (only 0.5% respondents (84-90%) had used cocaine as an anaesthetic
major) in a non-comparative series of 554 patients having ESS and between 11-26% had observed adverse effects, mainly
under LA with sedation. tachycardia(735-737). To avoid these, it is recommended that
A range of sedatives may accompany LA, given by mouth, serum levels should not exceed 3-4mg/kg body weight which
intramuscular or intravenous routes. These include generally equates to a maximum of 200mg in a healthy
benzodiazepines such as midazolam(721), opiates such as adult(722, 726). In theory the cardiotoxicity might be enhanced by
morphine(721) or pethidine(722). Local anaesthetic agents (and the combination of cocaine with adrenaline though this was
vasoconstrictors) may be applied topically to the mucosa or as not supported by Pfleiderer and Brockbank’s study(738). In 30
regional blocks related to the sinonasal neurovascular anatomy patients, they showed peak serum cocaine concentrations were
as described by Rontal et al.(723). Common combinations of lower in those receiving the combined agents. In a series of 554
anaesthetic agents and vasoconstrictors include cocaine or patients undergoing ESS Lee et al.(721) used 25% cocaine paste
lignocaine (lidocaine) with adrenaline +/- xylometazoline in and 0.01% adrenaline and reported <10% tachycardia and no
varying concentrations(721, 722, 724-728). Few high-quality studies arrhythmias or other adverse reactions.
have been performed to investigate these regimes. However, A combination of topical lignocaine and oxymetazoline
in an RCT Sarmento et al.(729) divided 49 patients undergoing has been shown to be as effective as cocaine in terms
ESS into three groups using only topical solutions of adrenaline of anaesthesia and vasoconstriction(739, 740). In a study on
in different concentrations (1:2,000, 1:10,000 and 1:50,000). children undergoing FESS, oxymetazoline alone was shown
Surgery time was shorter in the group using adrenaline 1:2,000, to be as effective as phenylephrine or cocaine in terms of
which also showed less bleeding in all evaluations (objective vasoconstriction which improved bleeding and visualisation(741).
and subjective - p<0.0001). Tetracaine combined with oxymetazoline was even more
effective than both lignocaine with oxymetazoline or cocaine
6.2.4.2.1. Regional blocks in terms of analgesia(742, 743). However, this latter study measured
A systematic review of the literature up to 2018 was pain thresholds associated with stimulation of the septum in
performed on preoperative injections of local anaesthetic and healthy subjects which may not be relevant to the surgical

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situation. Of greater clinical relevance, cocaine was shown to be in operative time, total time of hospital stay, or postoperative
superior when compared directly with lignocaine for intranasal antiemetic requirement. No complications or serious adverse
antroscopy(744). events were reported in either study arm.
Javer et al.(745) showed that infiltration with 2-3mls of 0.25% Little et al.(754) conducted an RCT on 30 fit patients undergoing
bupivacaine plus 1:200,000 adrenaline (one side) versus saline bilateral ESS for CRS randomised to maintenance anaesthesia
(one side) gave a no significant reduction in intraoperative with i.v. propofol or inhaled desflurane and showed that TIVA
blood loss during FESS (n=46). An RCT comparing 1:200,000 was associated with a statistically significant reduction in mean
and 1:100,000 adrenaline also failed to show any difference in Wormald score of the surgical field compared to desflurane (4.21
blood loss(746), indicating that neither concentration is effective vs. 5.53, p=0.024). Mean Boezaart score was also lower in the
as a vasoconstrictor when used as infiltration. Furthermore, TIVA arm (2.18 vs. 2.76, p=0.034). Secondary outcomes including
Lee et al.(747) could show no difference in blood loss when they surgical duration, time to extubation, and estimated blood loss
compared infiltration versus topical application of 4-5mls of were not found to be statistically significant between the two
1:100,000 adrenalin. However, when four concentrations of groups.
topical adrenaline (20mls) were compared, Sarmento et al.(729) These two studies(753, 754) confirm the earlier findings of Wormald
showed haemostatic superiority for 1:2000 adrenalin over lower et al. who compared the effects of TIVA using propofol and
concentrations. remifentanil with IA agents, sevoflurane and fentanyl on blood
Adrenaline may also produce potential cardiovascular side pressure, heart rate and surgical field (Boezaart scale). TIVA
effects including effects on the blood pressure, tachycardia and improved the surgical field and there was a reduction in both
arrhythmias. These have been investigated using infiltration blood pressure and heart rate(726).
with concentrations of 1:100,000-1:400,000 during ESS though The majority of studies included in a subsequent review of the
effects have been variable with both increases(746, 748, 749) and literature on TIVA versus IA also showed improvement in the
reductions(746, 750) in heart rate and blood pressure. This is surgical field and reduced blood loss(755). Another more recent
attributed to the biphasic effect of adrenalin, which produces meta-analysis done by Lu et al.(756) analysed 157 articles and
vasoconstriction at low concentrations and vasodilation at high identified 15 RCTs (828 ESS cases) that satisfied their selection
concentrations. criteria. the pooled analysis demonstrated significantly superior
Whilst injection of lignocaine (4ml of 1%) produced no surgical visibility scores for TIVA compared to IA based on
circulatory change(748, 749), the addition of 10-20ug of adrenalin 10-point grading scores (p=0.049, visual analog scale; p=0.009,
dropped the blood pressure by 25-35% and increased the heart Wormald scale) and 5-point grading scores (p=0.002, Boezaart
rate slightly during the first two minutes post-infiltration but the scale). Blood loss was significantly less following TIVA (p=0.003)
effect was transitory. It is noteworthy that although tachycardia with no significant difference in heart rate, mean arterial
occurred in up to 21% of the 1022 individuals studied, no pressure, duration of surgery and anaesthesia.
serious side effects were experienced. However, not all studies show superiority for TIVA over IA such
as that by Beule et al.(757) who showed no advantage in respect
The EPOS steering group advises to use TIVA, to heart rate, blood loss and surgical field. These authors also
and to put the patient in a reverse Trendelenberg considered platelet function which was impaired in both groups
position during endoscopic sinus surgery. but was worse in the propofol and fentanyl group.
Raised CO2 potentially has an adverse effect on bleeding in the
6.2.4.2.3. Anaesthetic agent surgical field as it is known to cause smooth muscle relaxation
Total intravenous anaesthesia (TIVA) has been suggested as and vasodilation. However, Nekhendzy et al.(758) could not show
an alternative option to traditional inhalational agents, due a difference in either the surgical field or amount of blood loss
to the physiologic decrease in cardiac output but without the during ESS when patients with hyper-, hypo- or normocapnia
peripheral vasodilation associated with inhalational anaesthesia were compared.
(IA)(751). This potentially produces a better visualisation of Controlled hypotension is an important tool for better
the surgical field but there were significant limitations in all visualisation of the surgical site(759) and several additional
the studies included in this systematic review, leading to the methods such as beta blocker premedication or intraoperative
inevitable conclusion that better high-quality studies are infusions, either with nitroglycerin or beta blockers have
required(752) (Table 6.2.4.2.). A randomized controlled trial been used to achieve controlled hypotension during ESS.
performed by Brunner et al.(753) compared the effect of TIVA Other agents such as α2 agonists are also being used, either
versus IA on intraoperative visualization of patients undergoing replacing or as adjuncts to classical TIVA agents (remifentanil
ESS in high-grade inflammatory sinus disease defined as either and propofol) for their enhanced hypotensive effects(760, 761). A
sinonasal polyposis or a preoperative Lund-Mackay score of >12. meta-analysis performed by Khosla et al.(762) of 1148 patients
Visibility was measured using the 10-point Wormald Surgical in 2015 indicated that total intravenous anaesthesia (TIVA)
Field Grading Scale. Operative blood loss, complications, was statistically more beneficial than conventional balanced
and change in quality of life evaluated by SNOT-22 were also anaesthesia, providing an average difference in blood loss of
measured. TIVA appeared to significantly improve endoscopic 75.3 mL and the use of preoperative steroids is statistically more
visualization and total blood loss during ESS but no difference beneficial than placebo, with an improved difference in blood

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Table 6.2.4.2. Studies describing anaesthetic techniques in endoscopic sinus surgery.

Study Comparison Outcome measure n Findings
Beule 2007 (757)
S/F v P/F HR, blood loss, blood loss/min, 52 HR:NSD
LM >12 platelet function, surgical field Blood loss: NSD
(VAS) Blood loss/min: NSD
Surgical field: NSD
Platelet function: reduced both gps, worse P/F gp
Eberhart 2003(764) TIVA (P/R) v I/A BP, HR, surgical field (VAS, 90 BP:NSD
Boezaart), dryness (VAS), blood TIVA: HR lower
loss Surgical field improved
Blood loss: NSD
Nekhendzy 2007(758) Hyper v Blood loss 180 Blood loss: NSD
hypo v normocapnia Surgical field Surgical field: NSD
Hypocapnia gp:
Higher need for antihypertensives
Increased blood loss with increased CT score, duration of
surgery
Tirelli 2004(765) TIVA (P/R) BP, HR, surgical field (Boezaart) 64 Surgical field: better with TIVA
v I/F HR, BP: NSD (trend to be lower in TIVA gp)

Wormald 2005(726) TIVA (P/R) BP, HR, surgical field (Boezaart) 56 TIVA:
v S/F Surgical field: better
Improvement correlated independently with lower BP and HR
Ahn 2008(881) S/R v P/R Hb, blood loss 40 High L-M score P/R gave less blood loss, better surgical field
Surgical field
L-M score
Kaygusuz 2008(882) D/R v I/R BP, HR, 63 Blood loss NSD
Blood loss Surgical field NSD
Surgical field Time to extubation quicker with D/R
Time to extubation
Yoo 2010(883) TIVA (P/R) BP, HR, surgical field 60 BP, HR, surgical field NSD
v S/R v D/R
Brunner 2018(753) TIVA (P/R) Surgical field (Wormald) 72 TIVA:
V IA (S/F) Blood loss Surgical field ((Wormald):
LM>12 Complications better
SNOT 22 Blood loss:better
Complications and SNOT22: NSD
Little 2018(754) TIVA (P/R) v IA (D) Surgical field (Wormald and 30 TIVA:
Boezaart) Surgical field (Wormald and Boezaart): better

Intravenous agents: F:fentanyl; P:propofol;R:remifentanil

Inhalational agents: D:Desflurane; I:isoflurane; S:sevoflurane, BP, blood pressure; CT, computed tomography; HR, heart rate; LM, Lund-Mackay; NSD, no
significant difference; TIVA, total intravenous anaesthetic; VAS, visual analogue scale, Adapted from Timperley 2010(755).

loss of 28 mL. evidence). Failure to lower blood pressure to target was less
In 2016 Boonmark et al.(763) conducted a Cochrane review of common in the propofol group (risk ratio of failure with propofol
deliberate hypotension with propofol under anaesthesia for 0.24, 95% CI 0.09 to 0.66; one study; 88 participants; moderate-
functional endoscopic sinus surgery (FESS). Only four studies quality evidence). The authors concluded that using propofol to
with 278 participants fulfilled the inclusion criteria of an RCT achieve deliberate hypotension probably improves the surgical
which compared propofol with other hypotensive techniques field, but the effect is small and deliberate hypotension with
during FESS with regard to blood loss and operative conditions propofol did not decrease TBL and the operation time. However,
in both adults and children(726, 764-766). The primary outcome was as most studies included few participants and provided low-
total blood loss (TBL). Other outcomes included surgical field quality evidence, results should be interpreted with caution and
quality, operation time, mortality within 24 hours, complications, better powered RCTs are required.
and failure to reach target blood pressure. Deliberate Dexmedetomidine, one of these recent agents, is a selective
hypotension with propofol did not decrease TBL (millilitres) α2 agonist, used in combination with general anaesthesia for
when compared with inhalation anaesthetics in either children its sedative, analgesic, and haemodynamic stability. Gupta et
(one study; 70 participants; very low-quality evidence), or al.(767) compared two groups of 25 patients. Patients from group
adults (one study; 88 participants; moderate-quality evidence). D received dexmedetomidine 1 μg/kg for 10 min, followed
Propofol improved the surgical field by less than one category by an infusion at 0.4–0.7 μg/kg/h and patients in group C
on a scale from 0 (no bleeding) to 5 (severe bleeding) (mean received the same amount of saline. Surgeons experienced an
difference -0.64, 95% CI -0.91 to -0.37; four studies; 277 ideal surgical site with minimum bleeding and only sporadic
participants; low-quality evidence), but there was no difference suction in 21 (84%) patients in group D, compared to no
in operation time (three studies; 214 participants; low quality patients in group C despite a low systemic blood pressure.

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Also group D patients needed less isoflurane to maintain the minimum postoperative sedation, allowing ESS to be performed
systolic blood. The authors concluded that dexmedetomidine as a day case(777).
is effective and safe in providing an ‘dry’ surgical field together Although controlled hypotension is an important tool for
with its many inherent advantages of analgesia, sedation, and creating an optimal surgical field, its systemic effects should be
anaesthetic-sparing effect. It was also associated with a longer closely monitored and adjusted accordingly throughout the
but smoother recovery time from anaesthesia. However, Kim operation. It should also be acknowledged that intraoperative
and colleagues(768) did not find any significant improvement hypotension can be a major risk factor for several complications
in surgical field with an infusion of dexmedetomidine in due to end organ injury such as perioperative stroke, cognitive
comparison with remifentanil though the extubation time was dysfunction and renal failure. Thus, its level should be set
significantly shorter .Two earlier RCTs(769, 770) showed an infusion according to the risks stratified for each individual patient.
of dexmedetomidine of benefit when FESS was performed The POISE study(778) revealed the impact of perioperative
under local anaesthesia or conscious sedation. Qiao et al.(771) haemodynamics on postoperative events. A higher incidence of
also showed the drug is also effective in an intranasal atomised postoperative stroke in patients on β-blockers was emphasized
form at significantly decreasing blood loss by a median of in this study, potentially due to the hypotension they induce.
75ml compared to 100ml in the control group, thus optimising Bijker et al.(779) considered the relationship of intraoperative
surgical field visualisation. hypotension to postoperative stoke and found that a decrease
in mean arterial blood pressure of more than 30% from
In contrast, Karabayirli et al.(772) compared dexmedetomidine baseline and the cumulative duration of these episodes were
with remifentanil in two groups of 25 patients. No significant associated with an increased risk of postoperative stoke. In
differences were found between the groups in intraoperative another study, Futier et al.(780) showed that intraoperative blood
bleeding, surgical field, requirement of sevoflurane, rates of pressure management targeting an individualized systolic
nausea, vomiting, or demands for additional analgesia. These blood pressure, according to patients’ resting blood pressure,
authors concluded that for controlled hypotension during FESS, decreased postoperative organ dysfunctions and neurological
dexmedetomidine had no additional benefits compared to complications.
remifentanil and was associated with higher recovery time and Di Mauro et al.(781) considered the role of intraoperative stroke
first-hour postoperative sedation scores. volume variation on bleeding during FESS in 55 patients, ASA I
Clonidine, another α2 agonist, may also be considered. A to III. Intraoperative bleeding was assessed using the Boezaart
randomised comparison of a clonidine-based vs remifentanil- score and from a wide range of haemodynamic parameters, only
based hypotensive anaesthetic regimen was conducted a negative correlation between surgical bleeding and stroke
during ESS in patients with CRSwNP and CRSsNP (n=47)(773). volume variation (SVV) was found. Furthermore, a cut-off of
Assessment of video recordings were blindly assessed by a 12.5% in SVV is optimal to distinguish the group with the better
third surgeon not involved in patient care. A significantly lower surgical visibility from the group with the worst one.
proportion of patients in the clonidine arm had Boezaart scores Overall, patient preoperative status, the specific surgical
higher than 2, with significantly lower mean Boezaart scores needs and the vulnerability of end organs should guide
both at 60 and 120 minutes. perioperative blood pressure management. Individualised
A systematic review of the use of α2-adrenergic agonists in planning of the perioperative haemodynamic target, based
13 RCTs (n=896 patients) assessed the efficacy of clonidine, on close cooperation between surgeon and anaesthetist is
dexmedetomidine, or both(774). The RCTs consistently showed crucial, combined with accurate and continuous physiological
that α2-adrenergic agonists reduced bleeding and improved monitoring.
surgical field quality during ESS. However, adverse event Finally, there are some other aspects, such as the mode of
reporting was often omitted. anaesthesia which can impact on surgical field. Gilbey et al.(782)
In another RCT, a single preoperative single dose of bisoprolol considered a small cohort of 22 patients undergoing FESS who
fumarate 2.5 mg, (a cardioselective β1-adrenergic blocking were randomly assigned to be ventilated during surgery under
agent used to treat high blood pressure) has also been shown to general anaesthesia by either high frequency jet ventilation
significantly reduce the blood loss during surgery and improved (HFJV) or intermittent positive pressure ventilation (IPPV).
the visualization of the operating field during FESS (n=50)(775). When the quality of the surgical field was assessed (Boezaart
Esmolol infusion, another β1-adrenergic blocking agent, has score) and the total blood loss was measured, HFJV significantly
also been shown to improve surgical fields during sevoflurane reduced the amount of intraoperative bleeding and thus
anaesthesia for FESS(761). significantly improved the quality of the surgical field possibly
Another method for achieving controlled hypotension is due to increased venous return due to lower intrathoracic
magnesium sulphate infusions. An RCT comparing magnesium pressures resulted in less bleeding and improved operating
sulphate, diltiazem or saline each given as a bolus (n=45) conditions. The use of pharyngeal packs during FESS have
showed significant reduction in blood loss in both active not been shown to increase postoperative pain, nausea or
arms(776). However, when magnesium sulphate was compared vomiting(783) as compared to no packing whereas one RCT in 47
with remifentanil in an RCT of 104 patients undergoing ESS, patients showed superiority for packing the nasopharynx rather
remifentanil was superior in reducing operative bleeding, better than hypopharynx(784) but the need for packs of any sort has
visibility, shorter operative time, and earlier recovery with largely been superseded by the use of the laryngeal mask(785).

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Figure 6.2.4.4. Forest plot of the effect of mitomycine versus control on adhesion formation after sinus surgery.

6.2.4.3. Desmopressin Streptomyces caespitosus, which acts as an alkylating agent

The benefits of intranasal desmopressin in achieving the same able to inhibit DNA synthesis. It has also been shown to
benefits as steroids during ESS, have been demonstrated in a inhibit fibroblast proliferation and activity, which can reduce
recent RCT(786, 787). scar formation. Topical MMC has been used at diverse places
in the otorhinolaryngological surgery like ear, larynx and in
6.2.4.4. Tranexmic acid endoscopic sinus surgery. A significant number of randomized
Perioperative tranexamic acid has been evaluated in seven controlled trials have been performed to evaluate the effect of
placebo controlled RCTS, including 562 participants, reviewed mitomycin c on adhesions formation during sinus surgery(791-799).
in a 2019 systematic review(788). Operative time (standardized Most studies used 0.4 or 0.5 mg/ml mitomycin on a carrier like
mean difference (SMD) = -0.60) and intraoperative blood loss cotton pledgets, neuropatties, or otowick placed in the relevant
(SMD = -0.66) were statistically lower in the tranexamic group sinus for 4-5 minutes. Patients were evaluated between one
than placebo group. This achieved over 100ml reduction in week and mean 15 months. Six studies could be included
blood loss in the active treatment groups. The quality of the in a meta-analysis: there was a significant positive effect of
surgical field and surgeon satisfaction were statistically higher mitomycin versus control on adhesion formation after sinus
in the treatment group than the placebo group. By contrast, surgery RR 0.51 CI 0.34 0 0.76), 480 patients six studies, p=0.001)
there were no significant differences in the hemodynamic and (Figure 6.2.4.4.). However, in some studies the difference
coagulation profiles of the two groups, and tranexamic acid becomes smaller over time(798).
had no significant effect on thrombotic events compared to
placebo. The relatively small number of patients included in Two studies evaluated whether mitomycin could prevent
RCTs may miss important differences in rare adverse events. A stenosis(793, 795). Both concluded that mitocycin was not able to
large population-based cohort study, including nearly 45,000 improve the relative size over an extended period of time.
patients undergoing hip arthroplasty, which has a high risk No adverse events were observed.
of thromboembolic events, found no difference in the risk In conclusion: The application of mitomycin for 4-5 minutes at
of thrombo-embolic or cardiovascular events or death(789). the end of surgery prevents adhesions compared to control
Although there are no similar studies specifically in sinus but is not able to improve the relative size of ostia over time.
surgery, the absence of increased risk should not differ from that No adverse events were observed. Based on the quality of the
found for arthroplasty. evidence the EPOS2020 steering groups advises that mitomycin
can be used to prevent adhesion formation after sinus surgery.
In a study looking at both intravenous tranexamic acid (TXA)
and epsilon aminocaproic acid (EACA) on bleeding and surgical 6.2.4.4. Conclusion
field quality during FESS similar improvements in duration of There is Level 1 evidence that preoperative injections of local
surgery and volume of blood loss were observed in the TXA anaesthetic and vasoconstrictor into the greater palatine canal
and EACA groups compared to control. The postoperative reduces intraoperative bleeding in ESS and a concentration of
haemoglobin was significantly lower in the control group 1:80,000 adrenaline is the most effective. When used topically,
compared to TXA group and EACA group and both TXA and 1:2000 adrenaline showed haemostatic superiority over lower
EACA groups had comparable improved quality of the surgical concentrations.
field with most of patients classified as grade 1 and 2 according
to Boezaart scale while the control group had most of the The evidence is less clear as to whether cocaine, lignocaine
patients in grade 3(790). + oxymetazoline or tetracaine + oxymetazoline is superior
for local anaesthesia and vasoconstriction.There is level l
6.2.4.5.Mitomycin evidence that simple strategies like patient positioning in the
Mitomycin C is an antibiotic isolated from the broth of reverse-Trendelenberg position and more complex controlled

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hypotension on an individualised basis can be successful in range from mild to catastrophic which has previously made the
reducing intraoperative bleeding. Use of propofol to achieve consent process difficult. An American survey nearly 20 years
deliberate hypotension probably improves the surgical field, ago found that 60% of responding surgeons would discuss with
but the effect is small whereas there is level 1 evidence that α2- patients pre-operatively risks likely to occur in 1% or greater of
adrenergic agonists reduce bleeding and improve surgical field cases(806). However, specifically the majority mentioned CSF leaks
quality during ESS. However, overall the literature shows TIVA is (99%), bleeding (97%), orbital injury (97%) and infection (85%)
superior to IA in improving the surgical field and reduced blood whereas 40% discussed smell impairment, cerebrovascular
loss. accident (18%), myocardial infarct (8%) and 28% death.
In the last decade a more ‘patient-centred’ approach has evolved
The EPOS steering group advises based on the evidence above as studies have shown that the majority of patients undergoing
to use TIVA, and to put the patient in a reverse Trendelenberg ENT procedures expect to be told about all complications(808, 809)
position during endoscopic sinus surgery. The quality of (see section 6.2.1.20.). Interestingly when Wolf et al. repeated
the evidence does not allow for an advice on the best local their survey in patients, 69% wanted to be informed about any
anaesthesia and vasoconstriction. risk occurring at a frequency of 1% or greater but for the specific
complications, 83% wanted to know about orbital damage
6.2.5. Informed consent/patient information in CRS and CSF leaks, 76% revision surgery, 74% smell impairment,
73% bleeding and myocardial infarct and 72% cerebrovascular
6.2.5.1. Informed consent in clinical practice accident, highlighting a discrepancy in priorities(807).
In the UK, the case of Montgomery vs. Lanarkshire Health Board
Informed consent is "a process for getting permission before 2015(810) established that patients must have all information
conducting a healthcare intervention on a person (or for disclosing available pre-operatively, not what the doctor thinks they
personal information about them)". should know. In some respects, this legal imperative to explain
all complications makes the situation easier, however distressing
For consent to be valid, it must be voluntary and informed, it may be to the patient. It is also incumbent on the surgeon to
and the person consenting must have the capacity to make discuss their own results, both outcomes and complications in
the decision. This means that consent must not be influenced the context of their peers.
by pressure from others and the individual must understand
the information given to them. They must receive information Studies have shown that age and educational status affect
regarding the benefits and risks of the treatment, whether there consent, with higher education and younger age improving
are alternative treatments and what will happen if treatment understanding and retention of information(809, 811-814). Similarly,
does not go ahead. these factors are also associated with an increased wish to know
The principle of consent is an important part of medical ethics about complications associated with the lowest incidence,
and international human rights law with significant medicolegal irrespective of their severity(812).
implications. This is increasingly pertinent with the expanding
field of genomics(800). Lynn-Macrae et al.(801) found informed Whatever the process of informed consent, after a relatively
consent issues in 37% of 41 medicolegal cases involving ESS short time, many patients have poor recall of the information
and this issue remained at 27% in the following 10 years(802). The given, which is important when there can be a significant
advent of precision or personalised medicine has emphasised interval between consent and an elective procedure(808, 809, 815).
the patient-physician interaction, which has proved particularly Aremu et al.(816) showed that only 51% recalled complications of
pertinent to chronic rhinosinusitis(803). In the UK, since 2015 there common ENT procedures, including for CRS, after a mean of 21
has been a statutory Duty of Candour on all health professionals days. This was significantly improved to 62% if a handout was
to be “open and honest with patients and their families when also given. The length of time spent on surgical consent is also
something goes wrong that appears to have caused or could an important predictor of comprehension and is maximised
lead to significant harm in the future” even if it has not yet done when it takes between 15 and 30 minutes, albeit in non-ENT
so(804). This has also had a major impact on informed consent. procedures(817).
Informed consent applies to all treatments, both medical
and surgical but surgery features more prominently in the Those physicians perceived by their patients as concerned,
literature where the balance of benefit versus risk may be more accessible and wiling to communicate, at least in obstetrics,
immediately evident(805). are least likely to be sued(818). In the USA and elsewhere many
The level of detail given for any particular procedure varies physicians will bring the patient in for a visit shortly before
considerably from country to country and institution to surgery and obtain consent to improve recall of risks. Others
institution(806, 807). Traditionally, the “prudent patient standard’ obtain consent on the day of surgery though in some countries
in which the physician disclosed all risks that it was deemed a such as the UK, doctors are encouraged or mandated to obtain
reasonably prudent patient would consider material to their consent more than 24 hours in advance of surgery and definitely
decision to undergo or refuse a particular procedure” has often before a premedication has been given on the day of surgery.
been adopted(807, 808). When discussing endoscopic surgery for A variable proportion of patients (8-66%), will also seek further
an essentially non-fatal condition such as CRS, complications information elsewhere which is now greatly facilitated by the

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internet(808, 809). While sometimes contributing misinformation, of both parents. For linguistic issues, the name and signature
some issues around consent might be improved by the use of of the translator is also required to signify that the patient has
modern technology. A significant early improvement in overall understood the procedure.
risk recall was demonstrated in patients who completed a Several respondents commented that since the European
multimedia consent educational module compared to a control Union’s GDPR (General Data Protection Regulations) were
group although this difference was not found 3-4 weeks later(819). implemented in May 2018, these had led to increased
Whatever the environment, the consent process is greatly complexity of the consent documentation, particularly with
strengthened by careful documentation and individual checklist respect to any research implications(822, 823).
forms are recommended by many authors(820). Bagnall and
colleagues(821) conducted a systematic review of the literature 6.2.5.2. Informed consent in research
on taking consent combined with semi-structured interviews Following the declaration of Helsinki in 1975(824), the next major
to identify key components of the surgical consent procedure. milestone in protecting patients who volunteer for medical
Thirty-three components were identified, the most frequently research was the introduction of the International Clinical
cited of which were explaining the diagnosis and procedure, Harmonisation of Good Clinical Practice guidelines in 1996(825).
general and specific risks, assessing the patient’s mental With regards to the consent process within this framework, the
capacity to give consent and offering alternative options. Least guidelines stipulate the following parameters:
common was disclosure of outcomes for the same procedure by
the individual surgeon and others. The need for better training "In any research on human beings, each potential subject must be
in this area was highlighted. The EPOS panel members provided adequately informed of the aims, methods, anticipated benefits
comment on informed consent in their respective countries. The and potential hazards of the study and the discomfort it may
following had similar systems and legislation to the UK in place : entail. He or she should be informed that he or she is at liberty to
Australia, Canada, China, New Zealand, Singapore and USA. abstain from participation in the study and that he or she is free
In Sweden and Denmark written consent is not required prior to withdraw his or her consent to participation at any time. The
to a surgical procedure. This is also the case in the Netherlands physician should then obtain the subject’s freely-given informed
where the Dutch Medical Treatment Agreement Act (WGBO) consent, preferably in writing".
regulates the rights of the patient. This law states that patients "When obtaining informed consent for the research project,
are entitled to information and that they must give permission the physician should be particularly cautious if the subject is in
for treatment. The WGBO also regulates the privacy of the a dependent relationship to him or her or may consent under
patient, the right to a second opinion, the right of patients duress. In that case the informed consent should be obtained by
to view their own medical records and the representation of a physician who is not engaged in the investigation and who is
patients if they cannot decide for themselves. In addition, the completely independent of this official relationship".
WGBO requires healthcare providers to keep a medical record
but the law does not dictate exactly what must be discussed nor "In case of legal incompetence, informed consent should be
are percentages of complications given. Similarly, in Greece and obtained from the legal guardian in accordance with national
Denmark, there is no uniform nationwide documentation and legislation. Where physical or mental incapacity makes it
only complications occurring more often than 1% are usually impossible to obtain informed consent, or when the subject is a
discussed. As in the UK, consent must be given at least 24 hours minor, permission from the responsible relative replaces that of
in advance of the surgery. In several countries, for example the subject in accordance with national legislation. Whenever
Brazil and Spain, the national ENT society, often with legal input, the minor child is in fact able to give consent, the minor’s consent
provides templates for consent to its members. These usually must be obtained in addition to the consent of the minor’s legal
include explanations of the operation (indications, technique, guardian".
consequences of surgery, potential complications and post-
operative care). The form is signed by both patient and surgeon. In some institutions in the USA child consent is referred to as
Many countries have now adopted the WHO checklist [www. “assent” and is usually obtained from children above seven years
WHO.int] which requires that informed consent has been old.
given and signed by both parties, without which the operation In both future diagnosis and research, especially in the fields
cannot proceed. In Spain having a signed informed consent is of genetics and genomics, where big data can be shared or
not always deemed sufficient and in some trial cases, evidence published, data protection is mandatory and has been the
of physical interaction between patient and doctor has been subject of a number of publications(826-830).
deemed necessary. As a consequence, doctors are strongly
encouraged to make handwritten comments on the discussion Excerpt from ICH E6 Guideline for Good Clinical Practice:
that took place. Informed Consent Explanation
Both the informed consent discussion and the written informed
Most consent forms include sections for minors/parents/ consent form and any other written information to be provided
guardians and those with language problems. In the case of to subjects should include explanations of the following:
children, some countries such as Greece require the signature a) That the trial involves research.

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b) The purpose of the trial. 6.2.6. Training in surgery

c) The trial treatment(s) and the probability for random as-
signment to each treatment. As in other surgical disciplines, training for FESS involves
d) The trial procedures to be followed, including all invasive personal studies using a variety of materials from textbooks
procedures. to online resources (anatomy, pathophysiology etc.), lectures,
e) The subject’s responsibilities. clinical rounds, clinical fellowships and physical models(831).
f ) Those aspects of the trial that are experimental. The use of audiovisual techniques during FESS allows
g) The reasonably foreseeable risks or inconveniences to trainees to directly observe their teachers on screens that
the subject and, when applicable, to an embryo, fetus, or compensates for the impracticability of assisting as occurred
nursing infant. in open surgeries(832). In addition, teachers can supervise every
h) The reasonably expected benefits. When there is no intend- surgical step of their trainees on screen and give focused
ed clinical benefit to the subject, the subject should be commands and instructions. Sandhaus et al. proposed a
made aware of this. standardized terminology of commands to facilitate the trainees’
i) The alternative procedure(s) or course(s) of treatment that understanding of what they are supposed to do so as to clearly
may be available to the subject, and their important poten- execute single surgical steps(833).
tial benefits and risks.
j) The compensation and/or treatment available to the sub- An additional benefit to audio-visually enhanced training is the
ject in the event of trial-related injury. use of intraoperative navigation to integrate the knowledge
k) The anticipated prorated payment*, if any, to the subject of endoscopic and CT anatomy. This is particularly important
for participating in the trial. in CRSwNP where the sinonasal anatomy may be distorted
l) The anticipated expenses, if any, to the subject for partici- by the pathology as well as previous surgery. It was shown
pating in the trial. that the sense of direction and orientation during surgery
m) That the subject’s participation in the trial is voluntary and was enhanced, the latter being a critical factor in training(834).
that the subject may refuse to participate or withdraw from However, especially in inexperienced trainees, over-confidence
the trial, at any time, without penalty or loss of benefits to and dependence on the system and risk overestimation must be
which the subject is otherwise entitled. considered(835).
n) That the monitor(s), the auditor(s), the IRB/IEC**, and the
regulatory authority(ies) will be granted direct access to Functional endoscopic sinus surgery techniques can
the subject’s original medical records for verification of furthermore be practiced through cadaveric dissections(836). An
clinical trial procedures and/or data, without violating the understanding of the endoscopic view of sinonasal anatomy
confidentiality of the subject, to the extent permitted by is essential and, in particular fresh frozen, cadavers offer an
the applicable laws and regulations and that, by signing a optimal simulation of real surgery though polyp tissue itself
written informed consent form, the subject or the subject’s cannot be simulated in cadavers. However, the handling of
legally acceptable representative is authorising such access. powered instruments and potential complications can be
o) That records identifying the subject will be kept confiden- practised in cadavers,and the dissections can be evaluated in
tial and, to the extent permitted by the applicable laws a variety of ways (e.g. pre- and post-dissection CTs) to improve
and/or regulations, will not be made publicly available. If training outcomes(837). The shortcomings of cadaveric dissections
the results of the trial are published, the subject’s identity are the costs and limited availability in certain centres and
will remain confidential. countries. Despite this a large number of dissection courses are
p) That the subject or the subject’s legally acceptable repre- held around the globe.
sentative will be informed in a timely manner if information
becomes available that may be relevant to the subject’s A more accessible and cheaper alternative to human cadaveric
willingness to continue participation in the trial. dissection are animal models like sheep or lamb heads,
q) The person(s) to contact for further information regarding synthetic human models and simulator training dissection(838).
the trial and the rights of trial subjects, and whom to con- Despite the fact that sheep sinus anatomy differs from human
tact in the event of trial-related injury. anatomy, its similarities are appropriate to train surgical skills,
r) The foreseeable circumstances and/or reasons under which handling instruments, visualisation and orientation with the
the subject’s participation in the trial may be terminated. endoscope and dissection steps can be practiced especially
s) The expected duration of the subject’s participation in the when standardized training steps are applied(839-841).
trial. Apart from cadaveric dissection, synthetic models of human
t) The approximate number of subjects involved in the trial. heads and the sinonasal tract like the S.I.M.O.N.T. (Sinus Model
* NB. Some countries e.g. Spain, do not allow payments to OtorrinoNeuroTrainer) have been introduced. Here silicone/
participants in clinical studies. plastic anatomic models based on CT anatomy have been
** Similar documents are produced in other countries and refer created to train endoscopic sinus surgery(842). The advantage
to the relevant regulatory authorities such as the FDA (Federal here lies in the availability and reproducibility as well as the
Drugs Administration in the USA. assessment of different tasks accomplished by the trainees(843).
A disadvantage of these models is that the haptic feedback

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of tissue composition such as mucosacannot be simulated. 6.2.7.2. Antibiotics

However, these models can be combined with animal 6.2.7.2.1. Summary of data
specimens to simulate surgical complications such as carotid There have been four randomized clinical trials investigating
artery injury and their management. The carotid arteries of short-term postoperative antibiotics following ESS, including
anaesthetised sheep dissected and attached to the S.IM.O.N.T. three placebo-controlled studies (Table 6.2.7.1). Short-term
model can be injured to create live bleeding scenarios(619). As antibiotics was defined as less than 30 days of treatment. To
with cadavers, the costs of production of these models need to date, there have been no studies of short-term preoperative
be considered. To overcome these shortcomings 3D printing antibiotics. None of the studies(539, 856-858)showed differences
could be a future alternative where the sinonasal system is between antibiotics versus placebo/control apart from a short-
printed according to CT anatomy and various materials are term reduction in symptoms of nasal obstruction and nasal
utilised to simulate the difference between e.g. bone and discharge on day 5 postoperatively and significant lower POSE
mucosa(844) offering cheap and reproducible training prior to a endoscopy scores on day 5 and 12 in the study of Albu(857). After
specific surgical case(844, 845). stopping the antibiotics no differences were seen. It was not
possible to include the trials in a meta-analysis.
Virtual Reality (VR) simulators are another tool to teach and Jiang(539) compared amoxicillin/clavulanic acid to no treatment
learn endoscopic sinus surgery and do not rely on cadavers and following ESS and showed that the bacterial culture rate
models allowing almost unlimited access. The first simulators became higher after FESS in the antibiotic group but that the
appeared in the late 1990s and were combined with head rate of antibiotic sensitivity to amoxicillin/ clavulanic acid did
models to simulate working through the nose and could not change. No changes were seen in the control group.
be combined with mechanical arms to the endoscope and One study from Huvenne et al. evaluated the effect of
instruments for haptic feedback. The surgical steps could be placement of a doxycycline-releasing stent in the ethmoid in 10
followed in a VR programmed environment on the monitor(846, postoperative CRS patients and showed that the doxycycline-
847)
. Advances in computer technology have led to more detailed releasing stents significantly improved postoperative healing
graphical 3D anatomy representation and implementation of quality after functional endoscopic sinus surgery and lowered
various training programs(831, 848). Also, it is possible to simulate MMP-9 concentrations and bacterial colonization locally(469).
powered instrumentation like shavers, irrigation and other
tools that can be activated by foot pedals similar to real life 6.2.7.2.1. Conclusions
surgery(849). Examples of sinonasal VR simulators are Madigan The use of postoperative antibiotics in four (placebo) controlled
Endoscopic SinusSurgery Simulator: ES3, Nasal Endoscopy trials in 371 patients did not show significant difference in
Simulator: NES, Voxel-Man SinuSurgery and the Dextroscope(850, objective or subjective clinical outcomes compared to controls
851)
. Validity of these simulators was studied by comparing the but these studies may have been underpowered to detect a
surgical performance of two groups after simulator training benefit. Based on the low quality of the current evidence the
vs conventional material training(852) or sinonasal anatomic EPOS2020 steering group is not able to advise on the use of
knowledge after training with VR simulator versus textbooks(853). postoperative short-term antibiotics after endoscopic sinus
Despite further technological advances, VR simulators still need surgery. There is a need for large-scale RCTs to answer this for
more improvement to approach real-life or cadaver conditions, daily practice very relevant question. Studies are also needed to
but are considered as a useful additional tool in surgical evaluate the effect of short-term preoperative antibiotics.
training(849). Training of spatial orientation and mechanical
manipulation of instruments and endoscopes are considered The use of peri-operative corticosteroids reduces
more important than haptic feedback in simulators(834). To blood loss and operation time and improves the
date the quality of evidence in validation studies is still low. quality of the surgical field.
Moreover, no studies focus on outcomes after surgery correlated
to previous VR training(854, 855). 6.2.7.3. Peri-operative corticosteroids
Studies evaluating the effect of corticosteroids peri-operatively
6.2.7. Peri-operative medication can be divided in studies evaluating the effect of the treatment
during the surgery and studies evaluating the postoperative
6.2.7.1. Introduction period. The studies evaluating the effect of corticosteroids
Medication can be given before, during or after the surgery. An during surgery are discussed in chapter 6.2.1.2.
overview of medication for CRS in general is given in chapter
6.1. Medication given before surgery to enhance the surgical 6.2.7.3.1. Summary of data of effect of peri-operative
field are discussed in 6.2.1.2., peri-operative medication and corticosteroids on postoperative state of disease in CRS
measures to enhance the surgical field during surgery are Next to the direct effect of peri-operative corticosteroids
discussed in 6.2.4. This chapter discussed the effect of peri- during surgery one might wonder whether it is useful to
operative treatment on the period directly after surgery. give (intranasal) corticosteroids after the surgery to prevent
recurrence of disease/reduce symptoms after surgery.
Eleven papers on 10 studies evaluated the effect of
corticosteroids starting peri-operatively on the signs and

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Table 6.2.7.1. Short-term postoperative antibiotics in CRS.

Study Methods Participants Interventions Outcomes Results

Albu DBPCT 75 CRS • Amoxicillin + clavulanate 625 • Symptom questionnaire day Amoxicillin + clavulanate versus placebo
2010(857) patients (40 mg twice daily for 14 days 5, 12, 21 and 30 resulted in:
CRSwNP) (n=40) • Perioperative sinus endosco- • Significant lower scores for nasal
• Placebo twice daily for 14 py (POSE) score at day 5, 12, obstruction and nasal discharge on
days (n=35) 21 and 30 postoperative day 5
• Endoscopic examination at • Significant lower POSE scores on day 5
day 5 until all blood crusts and 12
resolved • No statistical difference between groups
in overall symptom scores or POSE
scores at 21 or 30 days
• Patients displaying blood crusts within
12 days post-surgery were lower in the
antibiotic treated group as compared to
the placebo group (p=0.02)

Schalek DBPCT 23 CRS • Amoxicillin + clavulanate, • SNOT-22 (Czech translation) • No statistically significant difference in
2009(856) patients quinolone or co-trimoxazole at 3 and 6 months SNOT-22 quality of life scores, average
for 3 weeks (n=13) • Clinical symptom-specific symptom score, or endoscopic scores
• Placebo for 3 weeks (n=10) scores at 3 and 6 months compared to placebo at 3 and 6 months
• Endoscopic score at 3 and 6 • Mean endoscopic scores after 3 months
months approached significance (p=0.056)
• There was no statistical difference with
regard to which particular antibiotic was
used

Jiang RCT 71 CRS • Amoxicillin + clavulanate 375 • Rhinosinusitis symptom • No significant difference in the short-
2008(539) patients mg three times daily for 3 scores at week 3 term subjective or objective outcomes
weeks (n=31) • Antibiotic sensitivity rate at of CRS 3 weeks after endoscopic sinus
• No treatment (n=40) week 3 surgery
• Culture rate at week 3 • Bacterial culture rates increased in the
• Endoscopic scores at week 3 study group after FESS (38.7% vs. 61.3%,
p=0.014) but no significant difference
in antibiotic sensitivity to amoxicillin/
clavulanate

Annys DBPCT 202 CRS • Cefuroxime axetil 250 mg • Symptoms • No significant differences between the
2000(858) patients twice daily (n=101) • Nasal endoscopy groups
• Placebo twice daily
all patients received
nasal saline and nasal
corticosteroids (n=101)

DBPCT, Double Blind Placebo Controlled Trial; CRS,Chronic Rhinosinusitis; CRSwNP, Chronic Rhinosinusitis with nasal polyps; RCT,
Randomised Controlled Trial; SNOT-22, Sino-Nasal Outcome Test-22; POSE, Perioperative Sinus Endoscopy score;

symptoms of disease in the weeks-years after the surgery (Table found no differences in symptom scores(92, 93, 95, 105). One
6.2.7.2). study only evaluating nasal blockage and sneezing, found
Three studies(76, 77, 83)evaluated the effect of peri-operative a difference in sneezing(859). Two studies could be combined
corticosteroids on postoperative QOL using different outcome into a meta-analysis and showed no significant reduction in
measurements. Two studies(76, 77)evaluated general quality of life symptomatology in the corticosteroid treated group versus the
five weeks after surgery and found no impact of postoperative placebo group MD 1.2 (CI -1.1.4 -3.54), two studies, 201 patients,
FNDP on general quality of life although one study(76, 77)found an p=0.31) (Figure 6.2.7.2).
impact on the mental component summary and three domains Four studies evaluated a nasal polyp score. Three studies
of the SF-36. showed no difference between corticosteroid treatment and
Three studies evaluated the proportion of patients that was placebo(93, 95, 105), the study of Rowe-Jones showed a significant
relapse free at nine months, although relapse was differently reduction in nasal polyp score after one and five years of nasal
defined. When combining the three studies into a meta-analysis corticosteroids use versus placebo. The studies could not be
no significant impact was seen on the proportion of patients combined into a meta-analysis.
that was relapse free at nine months RR 1.33 (CI 0.59-2.98), three Three studies evaluated a nasal endoscopy score(83, 93, 381). None
studies, 284 patients, p=0.49) (Figure 6.2.7.1). found a significant difference of corticosteroid treatment versus
Six studies evaluated symptoms(92, 93, 95, 105, 859). Five studies placebo. Two studies could be combined into a meta-analysis

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Table 6.2.7.2. Effect of corticosteroid treatment versus placebo postoperatively.

Study Methods Participants Interventions Outcomes Results

Nordin DBPCRCT 60 CRSwNP, • Perioperative FPND 400µg • General quality of life, using Gen- At 5 weeks, both groups increased in general
2013(76) postoperative b.i.d. for 14 weeks (n=26) eral Well Being Schedule (0-110, 14 quality of life score to a similar extent without
• Perioperative placebo b.i.d. questions with a 6-point scale and 4 difference
for 14 weeks (n=34) questions with an 11-point scale) at
weeks 4 and 5
Vento DBPCRCT CRSwNP, • Postoperative triamcinolone • Symptom score (0-3, 10 symptoms) Postoperative Triamcinolon versus placebo
2012(105) postoperative acetonide nasal aerosol improvement at month 3, 6, 9 resulted in:
220µg ⁄ day as 2 actuations • Nasal polyp score (0-3) reduction at • No difference in symptom improvement
of 55µg, each for 9 months month 3, 6, 9 • No difference in nasal polyp score reduction
(n=30) • Polyp recurrence at 9 months • Reduction in polyp size/regrowth in N-ERD
• Postoperative placebo spray • Adverse events patients at 3 months, but not 6 and 9 months
for 9 months (n=30) acid-intolerant patients
• No serious adverse events reported.
Rotenberg DBPCRCT 64 CRSwNP (N-ERD) • Budesonide irrigation • Quality of life (SNOT-21 (0-105) at 6,12 • SNOT-21, LKES, and LM score results of both
2011(83) postoperative (60 60ml/nostril 500µg b.i.d. months) intervention groups were not different from
analyzed) (total 1000µg) for 52 weeks • Endoscopy score (LKES (0-12) at 6,12 placebo group at both 6 and 12 month
(n=20) months) timepoints (significance level was defined
• Saline irrigation 60ml/ • CT score (LM score (0-24) at 6,12 at p<.0167)
nostril and budesonide months) • IOP and ACTH level were not changed at
spray 64µg/nostril b.i.d. • Ocular events (IOP at 6,12 months) both 6 and 12 month timepoints
(total 256µg) for 52 weeks • HPA axis (ACTH(normal/abnormal) at
(n=19) 6,12 months)
• Saline irrigation alone for 52
weeks (n=21)
Olsson DBPCRCT 68 CRSwNP, • Perioperative FPND 400µg • Health related quality of life (SF-36, • At 5 weeks after sinus surgery no effect on
2010(77) postoperative twice daily. for 10 weeks 0-100, 8 health domains) at week 5 total SF36 but significant improvement in
(n=30) after sinus surgery the FPND group of the mental component
• Perioperative placebo b.i.d. summary and 3 domains (role physical,
for 10 weeks (n=38) vitality, social functioning)
Ehnhage DBPCRCT 68 CRSwNP • Perioperative FPND 400µg • Symptom score (3 symptoms, each • There was no difference between fluticasone
2009(95) (52 evalauted) b.i.d. for 10 weeks (n=23) score 0-3) improvement at 10, 17 dipropionate and placebo in symptom
postoperative • Perioperative placebo b.i.d. weeks improvement and nasal polyp score
for 10 weeks (n=29) • Nasal Polyp score (0-3) reduction at 4, reduction at 10 and 17 weeks
6, 10, 17 weeks • No difference in adverse events
• Adverse events
Jorissen DBPCT 99 CRSwNP patients • 2mg betamethasone At 1 and 2 weeks and 1, 2, 4 and 6 At 1 and 2 weeks and 1, 2, 4 and 6 months:
2009(93) having FESS (67 daily for 7 days followed by months postoperatively • No significant difference in total symptom
evaluated) mometasone nasal spray • Total symptom score (VAS) score, nasal endoscopy or % subjects
200µg twice daily for six • Nasal endoscopy score (0-14) requiring rescue medication
months (n=35) • Endoscopic combination score (for • Significant reduction in endoscopic
• Placebo daily for 7 days inflammation, oede-ma, and polyps) combination score at 1,2 weeks and 1 and
followed by placebo nasal • % subjects requiring rescue medi- 2 months
spray twice daily for six cation
months (n=32)
Stjarne DBPCRCT 162 CRSwNP • Postoperative MFNS 200µg • Time to relapse for polyp recurrence • At 24 weeks follow-up, postoperative use
2009(114) postoperative o.d. for 8 weeks (n=80) at 24 weeks of mometasone furoate, 200 µg once daily,
• Postoperative placebo for 8 • Adverse events provided a statistically significant longer
weeks (n=82) time to relapse with nasal polyps than with
placebo
• The frequency of AEs with mometasone and
placebo was comparable.
Wright DBPCT 26 CRSwNP patients • Prednisone 30 mg daily for Measured at 2,4,12 and 26 weeks: Treatment with oral corticoid compared to
2007(381) having FESS 5 days preoperative and 9 • Overall symptomatology placebo resulted in
days postoperative (n=11) • Separate symptoms • No difference in total and/or separate
• Placebo daily for 5 days • LK score symptoms
preoperative and 9 days • POSE score • Improved LK score at 2,4, and 26 weeks
postoperative (n=15) • Improved POSE score at 2 weeks

Rowe-Jones DBPCT 109 CRS patients • FPANS 200 mcg twice daily Yearly evaluation of: Treatment with FPANS resulted in:
2005(92) (77 CRSwNP) (n=40) How do you feel today (VAS) • No significant differences in total symptoms
having FESS (72 • Placebo twice daily (n=32) • Total symptoms (VAS) at 1 and 5 years follow-up
evaluated after 5 • Nasal polyp score • Significant difference at 1 and 5 years in nasal
years) • Oedema score endoscopy score and total nasal volume
• Discharge score
• Olfaction
• Nasal volume (acoustic rhinometry)

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Table 6.2.7.2. Effect of corticosteroid treatment versus placebo postoperatively (continued).

Study Methods Participants Interventions Outcomes Results
Dijkstra DBPCT 162 CRS patients • FPANS 800 mg twice daily During one year: No significant difference in the recurrence rate
2004(111) (55 CRSwNP) for 1 year (n=54) • Recurrence or persistent disease during one year between the groups
having FESS • FPANS 400 mg twice daily
daily for 1 year (n=54)
• placebo twice daily for 1
year daily (n=54)
Gulati DBPCRCT • 63 CRSwNP, • Postoperative Budesonide • Proportion of responders at 12 weeks • At 12 weeks, greater responder of symptom
2001(859) postoperative nasal spray 400µg/day for • Symptom improvement (4 symptoms) improvement in the Budesonide group than
12 weeks (n=38) at 12 weeks placebo group was significant for rhinorrhoea
• Postoperative saline nasal • Polyp recurrence at 12 weeks and sneezing.
sprays for 12 weeks (n=25) • At 12 weeks, Budesonide treated patients
had significantly lower rate of polyp
recurrence.

DBPCRCT, Double Blind Placebo Controlled Randomised Controlled Trial; DBPCT, Double Blind Placebo Controlled Trial; CRSwNP, Chronic
Rhinosinusitis with nasal polyps; N-ERD, NSAID-exacerbated respiratory disease; FESS, Functional Endoscopic Sinus Surg; FPND, Fluticasone
Propionate Nasal drops; SNOT-21,; LKES, Lund-Kennedy endoscopy scoring; LM, Lund-Mackay; IOP, Intraocular Pressure; ACTH, Adrenocorticotropic
Hormone; HPA, Hypothalamic-Pituitary-Adrenal; CT, computed tomography; VAS, Visual Analogue Scale; FPANS, Fluticasone propionate aqueous
nasal spray; MFNS, Mometasone Furoate Nasal spray; POSE, Perioperative Sinus Endoscopy score; LK, Lund-Kennedy; CRS,Chronic Rhinosinusitis.

Table 6.2.7.3. Corticosteroid-eluting implants as postoperative treatment in patients with CRS.

Study Methods Participants Interventions Outcomes Efficacy

Gyawali, DBPCT 58 CRSwNP • Non-absorbable nasal pack soaked • POSE and LK score in third postopera- Significantly better results with
2019(468) postoperative in Triamcinolone (2ml of 40mg/ml tive week corticosteroid pack than placebo pack for
solution) to one side (removed on both scores
second postop day)
• Non-absorbable nasal pack soaked
in saline on the contralateral side
removed on second postop day)

Hwang SBPCT 22 CRSwNP • Calcium alginate soaked with 2mL of • POSE score at 1, 4 and 8 weeks post- Significant difference in POSE score at
2018(860) postoperative triamcinolone (40mg/mL) (n=22) operatively week 8
• Calcium alginate soaked with 2mL
saline (n=22)

Luong 2018 DBPCT 80 CRS patients • Bioabsorbable drug-eluting stents • Postoperative interventions at 30 Implant coated with MF compared to non-
(884)
having frontal releasing 370μg of mometasone days post-ESS (oral steroid or surgery) coated implant
sinus surgery furoate over approximately 30 days (independent observer) • Significant less need for postoperative
unilateral frontal sinus ostium (n=79) • Postoperative interventions (cortico- intervention at 30 days (independent
• Stent without corticosteroid unilater- steroid or surgery) at 30 and 90 days observer)
al frontal sinus ostium (n=79) post-ESS (clinical investigator) • Significant less need for postoperative
• Endoscopic evaluation of frontal sinus intervention at 30 and 90 days (clinical
ostium region (inflammation, steno- investigator)
sis,patency) • reduction in inflammation and resteno-
sis and greater diameter at 30 days

Zhao DBPCT 64 CRSwNP • 64 sides: 2 pieces of 8cm biodegrad- • POSE and LK score at 7th or 14th • The POSE and Lund-Kennedy scores
2018(482) postoperative able nasal dressing impregnated postoperative days and at 1, 2 and 3 showed that in the 4mL, 1-week group,
(BND) with 4mL or 8mL of mometa- postoperative months. no significant differences between the
sone furoate 0.35mg/ml taken out sides treated with MF-soaked BNDs and
after 1 week or after 2 weeks the normal saline-soaked control were
• 64 contralateral cavities received an
observed at any postoperative visits.
identical BND soaked in the same
amount of normal saline taken out In the 4mL, 2-week group, significant
after 1 week or after 2 weeks differences were found at the 2-week
and 1-month postoperative visits but
not at the 2-month and 3-month visits.
In the 8-mL, 1-week group, significant
differences were found at the 1-week,
1-month, and 2-month postoperative
visits but not at the 3-month visit. In
the 8mL, 2-week group, significant
differences were found at all
postoperative visits.

Sow DBPCT 8 patients with • Hydrocortisone-impregnated • SNOT and POSE at 1, 3 wks and 3 • No statistical significance between
2018(861) CRS (CRSwNP bioabsorbable dressing in one nasal months post-operative impregnated and saline dressing at 1
unclear) cavity and normal saline-impreg- and 3 wks and 3 months postop.
postoperative nated bioabsorbable dressing in the
contralateral nasal cavity

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Table 6.2.7.3. Corticosteroid-eluting implants as postoperative treatment in patients with CRS (continued).
Study Methods Participants Interventions Outcomes Efficacy
Ha 2018(862) SBPCT 12 CRS (7 • Chitosan-dextran gelwith 1 mg/ 2 mL • Percentage of baseline intraoperative • All sinus ostia significantly larger at 2
CRSwNP) budesonide (n=5) areas for sinus ostia at 2 weeks, 3 weeks and frontal and sphenoid ostia
patients • Chitosan-dextran gel (n=7) months, and 12 months postoperative significantly larger at 12 months.
postoperative • Adhesion presence (%) and severity (0- • Other data not analysed
Part of 36 3) , mucosal oedema (0-3), granulation
tissue formation (0-3), evidence of pus
patients in 0-2) and crusting (0-2) at 2 weeks, 3
non-blinded months and 12 months postoperative
RCT

Sabarinath, DBPCT 75 CRS patients • Non-absorbable nasal pack soaked • Crusting, oedema, polypoidal change
2017(863) postoperative in Triamcinolone (2ml of 40mg/ml (Absent; Mild; Severe) at 1 and 2 weeks,
solution) to one side (removed on 1 and 3 months
second postop day) • Discharge (Absent; thin/clear; thick/
• Non-absorbable nasal pack soaked purulent) at 1 and 2 weeks, 1 and 3
in saline on the contralateral side months
removed on second postop day)

Adriaensen DBPCT 30 patients • SinuBand with fluticasone propionate • Intraocular pressure • No significant change in 24-hour urine
2017(121) with CRSwNP 160µg per side (n=20) • Lens opacity cortisol
randomized • SinuBand (without FP) per side • No differences in ethmoid
to 2 out of 3 • 24-hour urine cortisol
(n=20) inflammation, adhesions or LK score
treatments • Ethmoid inflammation (VAS) at
on two sides • Standard nasal pack per side (Mero- 5/15/30/60 days • Significantly lower polypoid changes in
postoperative cel(R)) (n=20) sides with Sinuband FP than Sinuband
• % of sinuses developing polypoid without FP and Merocel at 60 days
changes through first 15/30/60 days
• Significantly less pain and congestion
• Adhesion formation at 5/15/30/60 days at 60 days for Sinuband FP than
• Lund-Kennedy score at 5/15/30/60 Sinuband without FP
days
• Postoperative pain at 5/15/30/60 days
• Nasal congestion at 5/15/30/60 days
• Nasal discharge at 5/15/30/60 days

Smith DBPCT 80 CRS patients • Bioabsorbable drug-eluting stents • Postoperative interventions at 30 Implant coated with MF compared to non-
2016(885) having frontal releasing 370μg of mometasone days post-ESS (oral steroid or surgery) coated implant
sinus surgery furoate over approximately 30 days (independent observer)
unilateral frontal sinus ostium (n=79) • Significant less need for postoperative
• Postoperative interventions (cortico- intervention at 30 days (independent
• Stent without corticosteroid unilater- steroid or surgery) at 30 and 90 days observer)
al frontal sinus ostium (n=79) post-ESS (clinical investigator)
• Significant less need for postoperative
• Endoscopic evaluation of frontal sinus intervention at 30 and 90 days (clinical
ostium region (inflammation, steno- investigator)
sis,patency)
• Reduction in inflammation and
restenosis and greater diameter at 30
days

Xu 2016(466) DBPCT 80 CRSwNP • 28 x two pieces of 4cm biodegrad- • SNOT-20 and the Sniffin’ Stick test 1 and • No significant difference in SNOT
postoperative able dressing impregnated with 2ml 3 months • Significant lower POSE and LK score in
(58 evaluated) of a 10mg/ml of triamcinolone • Lund–Kennedy (L–K) and POSE score at the triamcinolone group compared to
• 32 pieces of 4cm biodegradable 1, 2 and 3 months. the place group at 1 and 2 months
dressing impregnated with 2ml saline

Bardaranfar DBPCT 60 CRSwNP • A sterile piece of compressed • Butanol threshold test 8 weeks post- • The triamcinolone resulted in a signifi-
2014(864) postoperative Gelfoam combined with 10 mg/ operative cant better butanol threshold test at 8
mL of triamcinolone at the olfactory weeks than saline
cleft between the nasal septum and
middle turbinate, above anterior
attachment.
• A sterile piece of compressed
Gelfoam combined with saline at
the olfactory cleft between the nasal
septum and middle turbinate, above
anterior attachment.

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Table 6.2.7.3. Corticosteroid-eluting implants as postoperative treatment in patients with CRS (continued).
Study Methods Participants Interventions Outcomes Efficacy
Hong DBPCT 20 CRS patients • Triamcinolone (20 mg) impregnated • Serum cortisol levels at day 1, 2 and 10 • Serum cortisol levels significantly
2013(467) postoperative bioresorbable dressing (n=10) • 12-hour urine cortisol level at day 10 depressed at day 1, 2
• Saline impregnated bioresorbable • Osteo-calcin, blood eosinophil count, • 12-hour urine cortisol level significantly
dressing (n=10) and adrenal-corticotropic hormone depressed compared to placebo at
(ACTH) levels at day 2 and 10 day 10*
• Significant difference in osteocalcin
at day 2*

Rudmik DBPCT 36 CRSsNP • Dexamethasone Sinu-FoamTM(16mg • LK score at 1 week, 4 weeks and 3 • No significant differences between
2012(865) patients dexamethasone) (n=18) months groups
postoperative • Sinu-FoamTM (n=18) • Adverse events
Marple DBPCT L 105 CRS (62 • Bioabsorbable drug-eluting stents • Frank polyposis (yes/no) at day 30 by • Significant difference in Mometasone
2012(122) CRSwNP) releasing 370μg of mometasone • Adhesion formation (0-5) at day 30 furoate group in need for intervention
patients furoate over approximately 30 days • Need of intervention (oral corticoste- and frank polyposis (independent
postoperative (n=105) roids or adhesion lysis) at day 30 panel)
• Placebo stents (n=105) • All data analysed by independent panel • No significant differences difference
and investigators in Mometasone furoate group in need
• Ocular safety of intervention and frank polyposis
• Drug related adverse events (clinical investigators)
• Significant reduction in adhesions
(clinical investigators)
Murr DBPCT 38 CRS (31 • Bioabsorbable drug-eluting stents • Ethmoid sinus inflammation (VAS) at 7, • Significant reduction in ethmoid
2011(866) CRSwNP) releasing 370μg of mometasone 14, 21, 30, 45 and 60 days inflammation in Mometasone furoate
patients furoate over approximately 30 days • % of sinus with polypoid change > group at 21,28 and 45 days
postoperative (n=38) 1(0-5) at day 30 • Significant reduction in % of sinus with
• Placebo stents (n=38) • % of sinus with adhesion formation polypoid change at day 30
(0-5) and middle turbinate lateralisation • Significant reduction in % with sinus
up to day 30 adhesion formation up to day 30
• Plasma mometasone fuorate(MF) and • No differences in plasma
cortisol concentrations at 7, 14, 21 and concentrations
30 days (in 5 patients with bilateral
Mometasone furoate releasing stent)
Coté DBPCT 19 CRSwNP • Triamcinolone (80 mg) impregnated • LK and POSE scores at postoperative • Significantly better LK and POSE scores
2010(465) patients bioresorbable dressing on one side days 7, 14, 28 and at 3 and 6 months at days 7 and 14 and 3 and 6 months in
postoperative (n=19) • Adverse events triamcinolone-impregnated group
• Saline-impregnated bioresorbable
dressing on the other side

DBPCT, Double Blind Placebo Controlled Trial; SBPCT, Single Blind Placebo Controlled Trial; CRS, Chronic Rhinosinusitis; CRSwNP, Chronic
Rhinosinusitis with nasal polyps; POSE, Perioperative Sinus Endoscopy score; LK, Lund-Kennedy; MF, Mometasone Furoate; post-ESS, Post Endoscopic
Sinus Surg; BND, Biodegradable Nasal Dressing; SNOT, Sino-Nasal Outcome; RCT, Randomised Controlled Trial; ACTH, Adrenocorticotropic Hormone;
VAS, Visual Analogue Scale; *Significance between the groups calculated based on data given in paper

Table 6.2.7.4.Postoperative saline nasal irrigation versus no irrigation in CRS patients.

Study Methods Participants Interventions Outcomes Results
Liang RCT, no blinding, 77 patients • Pulsatile nasal irrigation for 3 At 2 weeks and 1, 2, and 3 • Significant positive effect
2008 (175) postoperative undergoing FESS months months postoperatively: of nasal irrigation in pa-
• No treatment • Symptom score tients with mild CRS but
Endoscopy score not with severe CRS
Freeman Within-subject, 22 CRS patients • 2ml isotonic saline via a mucosal At 3 wks and 3 months: • Significant positive effect
2008(158) single- atomisation device one side of • Adhesions, discharge, of saline atomisation
blinded RCT the nose, three times per day for polyps, crusting, oedema on discharge, no other
postoperatively 6 weeks (0-3) at endoscopy differences
• No saline other side of the nose
Pinto Postoperative, 60 patients • Normal saline (NS; n = 20) four For 5 days: • Significantly more nasal
2006(178) RCT, double with histories of times per day, two puffs on each • Symptoms (nasal obstruc- discharge in hypertonic
blinded for sprays frequent sinusitis side, for the first 5 postoperative tion/congestion, nasal saline group compared to
after FESS days. discharge/postnasal drip, the other groups
• Buffered hypertonic saline (HS; n pain/pressure, headache, • No other significant
= 20) 4 times per day, 2 puffs on and trouble sleeping/in- differences
each side, for the first 5 postoper- somnia) (0-4)
ative days. • Pain medication
• Or no spray (n = 20)

RCT, Randomised Controlled Trial; FESS, Functional Endoscopic Sinus Surg; CRS, Chronic Rhinosinusitis;

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Figure 6.2.7.1. Forest plot of the effect of peri-operative corticosteroids versus placebo on relapse at nine months.

Figure 6.2.7.2. Forest plot of the effect peri-operative corticosteroids versus placebo on 6-12 months postoperative total symptoms.

Figure 6.2.7.3. Forest plot of the effect of peri-operative corticosteroids versus placebo on six months postoperative nasal endosco-
py score.

(Rotenberg had two arms) and showed a trend in reduction containing device versus placebo are included: in 14 DBPCRCTs
of endoscopy score at six months in the corticosteroid treated local corticosteroids containing steroid-eluting stents, spacers
group versus the placebo group SMD -0.51 (CI -1.04 -0.03), and dressings were placed in the ethmoid after surgery and
two studies (one with two arms) 168 patients, p=0.06) (Figure compared to placebo(121, 122, 465-468, 482, 860-866) (Table 6.2.7.3.).
6.2.7.3). Twelve studies used impregnated biodegradable and two a
non-absorbable packing(468, 863) impregnated with a variety
6.2.7.3.2. Conclusion of local corticosteroids including triamcinolone(465-468, 860,
The quality of the evidence concerning the effect of peri- 863, 864)
, mometasone furoate(122, 482, 866), hydrocortisone(861),
operative corticosteroids to prevent recurrence of disease/ Budesonide(862), fluticasone proprionate(121), and
reduce postoperative was (very) low. The studies were in general dexamethasone(865).
small with significant heterogeneity. Of these, seven studies evaluated patients with CRSwNP, one
There is no indication that use of peri-operative corticosteroids study(865) patients with CRSsNP and the other six either a mixed
is more effective than placebo on the postoperative QOL, population or the phenotype is not indicated.
symptoms and of nasal endoscopy. Based on the quality of the Dosages were varied and depended on the corticosteroid used.
available evidence the EPOS steering group cannot advise on One study compared four different scenarios with two dosages
the use of peri-operative/postoperative (nasal) corticosteroids. and removal one and two weeks postoperatively(482). Also, the
duration of corticosteroid release varied significantly from short
6.2.7.4. Corticosteroid-eluting implants (1-2 weeks max) for the dressings soaked in local corticosteroids,
to 30 days for the drug eluting stents(122, 866).
6.2.7.4.1. Summary of the evidence Two studies evaluated the effect of steroid-eluting stents,
Steroid-eluting stents, spacers and dressings can improve local spacers and dressing placement postoperatively on QOL (SNOT)
drug delivery immediately following endoscopic sinus surgery (466, 861)
. Both studies found no difference in SNOT score in the
and reduce the recurrence of inflammation warranting systemic steroid treated patients/sides compared to placebo.
corticosteroids. For chronic rhinosinusitis with nasal polyposis Symptoms were not evaluated apart from smell in two
(CRSwNP), the need for systemic corticosteroids immediately studies(466, 864) and congestion, pain and discharge in the study
following endoscopic sinus surgery when using a steroid-eluting by Adriaensen(121). In the study by Xu there were no significant
spacer has not been studied. differences between the triamcinolone treated group and
In this analysis only studies comparing a local corticosteroid the placebo group in the postoperative results of the Korean

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version of the Sniffin’ Stick II (KVSS II) test nor the TDI (threshold, levels(121, 467, 866). Hong found the serum cortisol levels to be
discrimination, and identification). Also, when only the anosmic/ significantly suppressed at postoperative days 1 and 2 and
hyposimic patients were evaluated (TDI score < below 27) the 12-hour urine cortisol level at day 10 significantly lower
no significant differences between the groups were found. in the local corticosteroid group compared to placebo(467). All
Bardaranfar on the other hand found significant impact of the but one patient (taking inhaled asthma medication) had 24-
placement of a sterile piece of compressed Gelfoam combined hour urine cortisol levels within the normal range at baseline
with 10mg/mL of triamcinolone at the olfactory cleft between and postoperative day 15 in the study of Adriaensen and the
the nasal septum and middle turbinate, above anterior study of Murr showed no abnormalities in serum cortisol and
attachment on the butanol threshold test(864). Adriaensen mometasone furoate concentrations in five patients at 7, 14, 21
reported significantly less nasal congestion and pain reported and 30 days postoperatively(121, 467, 866).
by the patients on the side treated with local corticosteroids Local (drug related) adverse events (seven studies) were limited
than on the placebo side at day 60 (p=0.036). All the other and not reported more often in the local corticosteroid group
timepoints/measurements were not significant(121). than the placebo group.
A number of studies evaluated endoscopic scores (POSE)(381)
(Figure 6.2.7.4.) and/or Lund-Kennedy score(867) (Figure 6.2.7.4.) at 6.2.7.4.3. Conclusion
comparable timepoints and could be combined into a meta- It can be concluded that postoperative placement of steroid-
analysis. The POSE score at three weeks – 1 mnd showed score: eluting stents, spacers and dressings compared to placebo
SMD -1.03 (95% CI -1.83, -0.23); 138 participants; eight studies; does not have an influence on QOL and most likely also not
I2 = 89%), scale range: 0 to 16, lower = better, indicating less on symptomatology but has a significant and most likely dose
disease in the patients that were treated with corticosteroid- dependent effect on POSE and Lund-Kennedy scores. The
eluting stents, spacers or dressings than the placebo (Figure EPOS2020 steering group felt the quality of the evidence was
6.2.7 4.) . The result at three months still showed a significant low and that based on the evidence they could not advise about
effect: SMD -0,63 (95% CI -1.23, -0.03); 88 participants; six studies; the use of corticosteroid-eluting implants following endoscopic
I2 = 88%), (p=0.06) (Figure 6.2.7.5.). sinus surgery. For now, the use of relatively expensive ready-
Lund-Kennedy score at three months showed: SMD -0.72 (95% made implants does not seem to be price effective in the
CI -1.36, -0.07); 98 participants; seven studies; I2 = 79%), scale average CRSwNP patient. Larger studies including long term
range: 0 to 10, lower = better, indicating less disease in the safety data are needed.
patients that were treated with corticosteroid-eluting stents,
spacers or dressings than the placebo (Figure 6.2.7.6.). 6.2.7.5. Anti-leukotrienes
Only one very small study evaluating off-label drug-eluting Cysteinyl leukotrienes (CysLT) are a class of inflammatory
middle-meatal spacer of dexamethasone and Sinu-FoamTM mediators synthesized by eosinophils and mast cells through
in patients with CRSwNP did not show an improvement the breakdown of arachidonic acid. CysLT are known to play a
in endoscopic outcomes in the early postoperative period role in the pathophysiology of rhinitis, asthma and possibly also
following ESS(865). CRSwNP, promoting bronchoconstriction, mucus production,
For both POSE and Lund-Kennedy score there was a significant oedema and chemotaxis of eosinophils and neutrophils.
heterogeneity most likely caused by variations in the dosage Overproduction of CysLTs and upregulation of the receptor has
of local corticosteroids: the studies reporting no effect been demonstrated in allergic rhinitis, asthma, and CRS with
used low potency corticosteroids like hydrocortisone(861) nasal polyposis (CRSwNP) (5.1.2).
and triamcinolone(466, 860), and the study by Zhao(482) using The quality of the evidence comparing montelukast with
mometasone furoate showed a dose response. placebo is very low (see chapter 6.1.9.).
It can be concluded that postoperative placement of steroid- The only study evaluating the use of Montelukast
eluting stents, spacers and dressings compared to placebo postoperatively is done by Van Gerven et al. (144). They evaluated
does not have an influence on QOL and most likely also not the efficacy of Montelukast as an add-on treatment to INCS
on symptomatology but has a significant and most likely dose in 72 postoperative CRSwNP patients for one year and found
dependent effect on POSE and Lund-Kennedy scores. Whether no significant differences between the two treatment arms in
the effect on POSE and Lund-Kennedy score (around 1 point total symptom score, nasal polyp score and LMK score. They
of the mean around 5 (POSE) or 3 (LK) in the placebo group) is concluded that the addition of montelukast to INCS should not
unclear. be recommended in the treatment of postoperative CRSwNP
patients.
6.2.7.4.2. Safety of corticosteroid-eluting implants
Finally, the safety/adverse events associated with treatments 6.2.7.6. Decongestants
with steroid-eluting stents, spacers and dressings were The use of topical decongestants has the theoretical potential
evaluated(121). In this evaluation also spacers placed in the office to reduce mucosal oedema by inducing vasoconstriction(149).
are taken into account (see chapter 6.1.6.3; Table 6.2.7.3.) Three However, prolonged use can lead to rhinitis medicamentosa
studies evaluated ocular safety(119, 121, 122) and none showed and worse symptoms of nasal obstruction upon decongestant
clinically significant change in IOP and or modifications in discontinuation(150). Nasal decongestion per se does not
lens opacity. Three studies evaluated systemic corticosteroid have effect on nasal polyp size(151). There is one small study

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Table 6.2.7.5.Methods of nasal irrigation in postoperative CRS patients.

Study Methods Participants Interventions Outcomes Results

Macdonald Single 86 CRS patients • Saline squeeze bottle • SNOT-22 • Significant improvement in both groups for SNOT-
2015(162) blind RCT (55 CRSwNP) (n=43) for 1 month • POSE 22, POSE, NSS
postoperative directly • Saline nasal spray • Nasal and sinus • No difference between treatment groups
postoperatively (n=43) for 1 month symptom scale
(NSS) (0-15)

RCT, Randomised Controlled Trial; CRS, Chronic Rhinosinusitis; CRSwNP, Chronic Rhinosinusitis with nasal polyps; SNOT-22, Sino-Nasal Outcome Test-
22; POSE, Perioperative Sinus Endoscopy score; NSS, Nasal and Sinus Symptom scale.

Table 6.2.7.6.Postoperative saline irrigation with antiseptic/mucolytic/babyshampoo solution in CRS patients.

Study Methods Participants Interventions Outcomes Results

Farag Single 40 CRS patients • 120ml Hypertonic • RSOM-31 • Significant decreases in scores for both the
2013(160) blind RCT directly Saline solution 3dd until • SNOT-22 SNOT-22and RSOM-31 overtime for both
postoperative postoperative 4 months postop • Olfaction with phenyl treatments but no difference between the
• 120ml of 1% baby ethyl alcohol (PEA) treatments
shampoo solution3dd threshold test • PEA thresholds showed improvement but no
until 4 months postop • Adverse events difference between the treatments
• The baby-shampoo group reported
significantly more side effects and had more
patients stop the solution

Pigret Single- 20 CRSwNP • Pressurized seawater • Residual nasal crusts • No significant differences although the mean
1996(183) blind RCT patients after (volume unclear) (n=10) weight at 21±2 days residual crust weight was higher in the
postoperative endoscopic 3dd secretions after 21±2 pressurized seawater group (1,756±688mg)
endonasal • 10ml of saline plus days than in the antiseptic/mucolytic saline group
ethmoidectomy benzododecinium (anti- • Visual analogue scale (932±414mg)
septic) plus oleosorbate for nasal obstruction,
(mucolytic) (n=10) 3dd rhinorrhoea, cacosmia
and facial pain

CRS, Chronic Rhinosinusitis; RCT, Randomised Controlled Trial; CRSwNP, Chronic Rhinosinusitis with nasal polyps; RSOM-31, Rhinosinusitis Outcome
Measure-31; SNOT-22, Sino-Nasal Outcome Test-22; PEA, Phenyl Ethyl Alcohol.

in CRSwNP patients showing a significantly better effect of outcomes in adult CRS in the month after FESS (Tables 6.2.7.4.-
oxymetazoline combined with MFNS than MFNS alone without 6.2.7.9). The studies were very different in design, duration and
inducing rebound swelling(152). This is consistent with effects outcome measurements.
seen in the treatment of allergic rhinitis where the combination Three studies evaluated the effect of a form of saline irrigation
of nasal corticosteroid with decongestant also seemed to versus a form of no irrigation of the nose (Table 6.2.7.4.). The
prevent rebound swelling(153, 154) (see chapter 6.1.10). There is studies could not be combined in a meta-analysis. One showed
one Humphreys at al. who compared topical decongestant, a significant positive effect of saline atomisation on discharge,
xylometazoline, to a saline spray in 47 patients in the FESS early but no other differences, one showed mainly positive effect in
postoperative period(155). Postoperative VAS symptom scores for patients with mild CRS and not in patients with severe effect and
nasal obstruction, rhinorrhoea, pain, loss of sense of smell and one did not show any differences between saline rinsing or no
bleeding assessed at day 10 postoperatively did not show any rinsing(158, 175, 178).
difference between the groups. The EPOS2020 steering group One study in 86 CRS patients compared a squeeze bottle with
suggests not to use nasal decongestants in the postoperative a nasal spray for one month and found no differences between
period although the quality of the evidence is low. the SNOT-22, Nasal and Sinus Symptom Scale (NSS) or POSE
between the two ways of administration(162).
6.2.7.7. Saline Two small studies evaluated the addition of antiseptic /
mucolytic / baby shampoo solution and showed no differences
6.2.7.7.1. Summary of the evidence between the groups but the baby-shampoo group was reported
Nasal saline irrigation is considered to be an important aspect of to have significantly more side effects and had more patients
the management of CRS, especially in the postoperative phase. stop the solution(160, 183) (Table 6.2.7.6.). Moreover, it has been
For details on saline irrigation in general please refer to chapter shown in healthy persons to create congestion and reversible
6.1.10. smell loss(190).
This systematic review identified 13 randomized controlled Five Italian DBPCT or single blind (blinding often not clearly
(RCT) studies evaluating nasal saline irrigation on clinical described) postoperative studies evaluated the addition of

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Table 6.2.7.7.Postoperative saline irrigation with sodium hyaluronate in CRS patients.

Study Methods Participants Interventions Outcomes Results
Mozzanica DBPCT 56 CRSsNP • 250ml saline plus 9mg sodi- At 3 and 6 weeks • No differences in SNOT-22, NOSE, symptoms
2019(166) patients um hyaluronate twice daily postoperatively: and total LK score at 6 weeks
postoperatively for 6 weeks (n=26) • SNOT-22 • Significantly better result of NOSE score at 3
• Saline twice daily for 6 weeks • NOSE weeks in sodium hyaluronate group
(n=30) • Symptoms (VAS) • Significantly better result for headache and
• LK score smell alteration at three weeks in sodium
hyaluronate group
• Significantly reduced scar formation (3 and
6 weeks), crusting (3 weeks) and secretion (6
weeks)

Cantone DBPCT 124 CRSwNP • Intranasal nebulization of At 30 days Significantly better result of sodium hyaluronate
2014(185) (122 evaluated) 9mg sodium hyaluronate postoperatively: than saline for:
postoperatively (3mL) plus saline solution • SF-36 • SF36
(2mL) twice daily for 30 days • SNOT-22 • SNOT-22
(n=62) • Symptoms (VAS) • Total symptoms (VAS)
• Intranasal nebulization of • Endoscopic score • Endoscopic score
saline (5ml) twice daily for 30
days (n=60)

Casale, RCT 33 CRS patients • Nebulization of 3ml contain- At 2 and 4 weeks • VAS score of hyaluronate significantly lower
2014(167) (single postoperatively ing 9mg sodium hyaluronate postoperatively: than saline at 2 and 4 weeks
blind?) nasal washes plus saline • CRS questionnaire • CRS score significantly lower than saline at 2
twice daily for 1 month • Visual analogic scale and 4 weeks
(n=18) (VAS) • Significantly less crusts and oedema and
• Nebulization of 5mL saline • Nasal endoscopy secretions
twice daily for 1 month
(n=15)

Gelardi RCT 36 CRSwNP • Intranasal nebulization of At 30 days Sodium hyaluronate group had compared to
2013(186) (single postoperative sodium hyaluronate 9mg in postoperatively: saline:
blind?) 3ml twice daily for 30 days • Nasal obstruc-tion, • Significantly faster mu-cociliary clearance
(n=19) burning, dryness of the • Lower incidence of rhinorrhoea
• Intranasal nebulization saline mucosa (VAS) • Less nasal obstruction
5ml twice daily for 30 days • Presence or absence of • A lower incidence of exudate on endoscopy
(n=17) rhinorrhoea • Better tolerability
• Mucociliary clearance
time
• Presence of exudate at
endoscopy

Macchi DBPCT 46 CRSwNP • Nebulization of 6ml contain- At 3 months Significantly better result of sodium hyaluronate
2013(168) patients ing 9mg sodium hyaluronate postoperatively: than saline for:
postoperatively nasal washes plus saline for • Prevalence of symp- • Nasal dyspnea (obstruction?)
15 days/mo over 3 months toms • Normal mucosa
(n=23) • Endoscopy • Absence of secretion
• Nebulization of 6mL isotonic • Cytology
saline for 15days/mo over 3 • Biofilm
months (n=23)
CRS, Chronic Rhinosinusitis; DBPCT, Double Blind Placebo Controlled Trial; CRSsNP, Chronic Rhinosinusitis without nasal polyps; CRSwNP, Chronic
Rhinosinusitis with nasal polyps; SNOT-22, Sino-Nasal Outcome Test-22; NOSE, Nasal Obstruction Sympton Evaluation; VAS, Visual Analogue Scale; LK,
Lund-Kennedy; RCT, Randomised Controlled Trial; SF-36, Short Form 36.

Table 6.2.7.8.Postoperative saline irrigation with addition of honey in CRS patients.

Study Methods Participants Interventions Outcomes Results
Lee Single blind 49 CRS patients • 120ml saline containing 12mg of manuka honey twice daily At 30 days: • No significant
2016(169) (investigator) (42 analysed) for 30 days • SNOT-22 differences between
placebo postoperatively • 120ml saline twice daily for 30 days • LK endoscopy the groups
controlled • All patients received culture-directed oral antibiotic, and/or score • In the subgroup not
trial oral steroids for up to 3 weeks, and/or high-volume topical • Bacterial using antibiotics
steroid sinus irrigations (budesonide 0.5mg/2mL vial or culture
0.6mg/2mL capsule, 0.5 bottle to each nasal cavity twice daily) manuka honey
polyps or inflammation for 30 days significantly
• The dose of budesonide was determined when the patient reduced bacteria
filled the prescription; if insurance covered it, then the vial ver-
sion at the 0.5mg/2mL dose was used, and if not covered, then
the capsule version at the 0.6mg/2mL dose was used

CRS, Chronic Rhinosinusitis; SNOT-22, Sino-Nasal Outcome Test-22; LK, Lund-Kennedy.

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9mg of sodium hyaluronate to saline(166-168, 185, 186). Four studies The steering group advises the use of nasal saline irrigation
evaluated nebulisation with a small volume(167, 168, 185, 186) and with isotonic saline or Ringer’s lactate potentially with the
one study rinsing with 250ml. The four studies evaluating addition sodium hyaluronate and against the use of baby
nebulization in general reported positive outcomes, the study shampoo and hypertonic saline solutions due to side effects
evaluation addition of sodium hyaluronate to saline rinsing in the postoperative period after FESS. However, larger well
found in general no significant effect (Table 6.2.7.7.). designed studies are necessary to improve the quality of our
In conclusion, sodium hyaluronate might have a positive effect understanding.
on postoperative symptoms when compared to a saline spray.
Adding sodium hyaluronate to saline rinsing postoperatively 6.2.7.8. Antimycotics
did not show an effect in one study. One study(169) evaluated Local and systemic antifungal treatments do not have a positive
the addition of honey to saline irrigation. The study did find any effect of QOL, symptoms and signs of disease in patients with
relevant differences between the honey treated group and the CRS. There is one study evaluating direct postoperative use of
placebo group (Table 6.2.7.8.). local amphotericine B nasal spray versus placebo in 33 CRSwNP
Dexpanthenol is an analogue of pantothenic acid, which has patients. Eight weeks postoperatively they found no differences
been claimed to promote wound healing(194). It has been shown in the QOL questionnaire SNAQ-11, nasal endoscopy and/or CT
to improve symptoms in patients with atrophic rhinitis(195). Two scan(224). The EPOS2020 steering group advises against the use
studies evaluated the effect of Dexpanthenol in saline(171, 187). of postoperative anti-mycotics in CRS.
Both studies showed no effect on the majority of symptoms and
endoscopy but a superior efficacy over placebo on mucociliary 6.2.7.9. Capsaicin
clearance (in the Fooanant study only in patients with CRSwNP) The quality of the evidence about the effect of capsaicin versus
(Table 6.2.7.9.). placebo is low (see chapter 6.1.22). Zheng et al.(282), conducted
Adverse effects of saline irrigations are rare, but include local a DBPCT comparing capsaicin (3x10-6mol, dissolved in 70%
irritation, ear pain, nosebleeds, headache, nasal burning, and ethanol) versus vehicle alone (70% ethanol) once a week in 51
nasal drainage are mentioned. The use of baby shampoo has patients for five weeks, following nasal polypectomy. Patients
been shown to create congestion and reversible smell loss. were assessed at nine months for nasal resistance, rhinorrhoea
and nasal polyp score. The capsaicin group had a significant
6.2.7.7.2. Conclusions decrease in nasal resistance compared to the vehicle group
The quality of the evidence evaluating the use of nasal irrigation (p<0.01) and had lower nasal polyp score when compared to the
in the postoperative phase after FESS is low. Nasal irrigation control group (stage 0: 41% vs 4.5%, p<0.01).
with isotonic saline or Ringer’s lactate seems to be effective There was no difference in subjective rhinorrhoea.
in CRS patients. There is insufficient data to show that large A small study showed significant decrease nasal resistance and
volume is more effective than nasal spray. Addition of sodium nasal polyp score after five weeks of postoperative capsaicin
hyaluronate to nasal saline rinsing may have a positive effect treatment versus placebo. The quality of the evidence is low
in the postoperative period. Addition of baby shampoo, and the EPOS steering group concludes that Capsaicin may be
honey, or dexpanthenol as well as higher temperature and an option in postoperative treatment of CRS in patients with
higher salt concentration do not show additional benefit. CRSwNP but that larger studies are needed.

Table 6.2.7.9. Postoperative saline irrigation with addition ofdexpanthenol in the treatment of CRS.
Study Methods Participants Interventions Outcomes Results

Tantilipikorn DBPCT 50 CRS patients • Dexpanthenol nasal • % of patients with symp- • Majority of symptoms and signs did not
2012(171) postoperatively spray 4 times a day for 6 toms at 2, 4 and 6 wks show significant differences
weeks (n=25) • % of patients with endo- • Dexpanthenol nasal spray has superior
• Saline nasal spray 4 scopic abnormalities at 2, efficacy compared with normal saline
times a day for 6 weeks 4 and 6 wks nasal spray on improvement of mucociliary
(n=25) • Mucociliiary clearance clearance and smell at 6 wks and inferior
time at 6 wks effect on nasal discharge

Fooanant RCT 128 CRS patients • Dexpanthenol (5%) in At 1, 2, 3, 4, 6 and 12 weeks: • No significant differences in total nasal
2008(187) (110 evaluated) sea water nasal spray 2 • Total nasal symptom score symptom score, nasal crusts (but at wk 2
postoperatively puffs per nostril, twice a • Symptoms less in saline group), mucociliary clearance
day for 4 weeks • Nasal crusts (but for subgroup of CRSwNP)
• Saline nasal irrigation • Mucociliary clearance
(volume unclear) twice a (only at 4 wks)
day for 4 weeks

DBPCT, Double Blind Placebo Controlled Trial; RCT, Randomised Controlled Trial; CRS, Chronic Rhinosinusitis; CRSwNP, Chronic Rhinosinusitis with
nasal polyps.

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6.2.7.10. Conclusion Although the quality of direct evidence postoperatively is

The quality of the evidence for the use of commonly missing, the EPOS2020 steering committee recommend
administered peri-operative medication such as (nasal) using nasal corticosteroids postoperatively. Based on the low
corticosteroids and antibiotics is low, mainly due to insufficient positive evidence and the excellent safety profile the group also
and small studies. The use of peri-operative corticosteroids recommend using nasal saline irrigation withisotonic saline
reduces blood loss and operation time and improves the quality or Ringer’s lactate, potentially with the addition of sodium
of the surgical field. There is also high-quality evidence that hyaluronate, and advise against the use of baby shampoo
long term use of nasal corticosteroids is effective and safe for and hypertonic saline solutions due to side effects in the
treating patients with CRS with significant impact on nasal postoperative period after FESS. Otherwise, based on the low-
symptoms and quality of life improvement. Nasal corticosteroids quality evidence, the steering group cannot recommend the use
reducenasal polyp size and when administered after endoscopic of peri-operative antibiotics. The group also advise against the
sinus surgery, nasal corticosteroids prevent polyp recurrence. use of anti-mycotics.

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2018;11:117955061875864. endoscopic sinus surgery: a new high-fidelity 864. Bardaranfar MH, Ranjbar Z, Dadgarnia MH, et
virtual reality simulator for endoscopic al. The effect of an absorbable gelatin dressing
834. Bakker NH, Fokkens WJ, Grimbergen CA.
sinus surgery. American J Rhinol & Allergy.. impregnated with triamcinolone within the
Investigation of training needs for functional
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endoscopic sinus surgery (FESS). Rhinology.
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systematically improve surgical training.
851. Arora A, Lau LYM, Awad Z, Darzi A, Singh A, a randomized, double-blind, placebo-controlled
Rhinology. 2012;50:246-54.
Tolley N. Virtual reality simulation training in trial. Int Forum Allergy. & Rhinol.2012;2:248-51.
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Otolaryngology. Int J Surg. 2014;12:87-94. 866. Murr AH, Smith TL, Hwang PH, et al. Safety
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852. Fried MP, Sadoughi B, Gibber MJ, et al. From and efficacy of a novel bioabsorbable, steroid-
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Allied Sci 1991;16:426-9.
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Otolaryngology--Head & Neck Surg.: official J of 867. Lund VJ, Kennedy DW. Quantification for staging
Schlosser RJ, DelGaudio JM. The utility of cadaver
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853. Solyar A, Cuellar H, Sadoughi B, Olson TR, Fried 868. Qvarnberg Y, Kantola O, Salo J, Toivanen M,
838. Chan M, Carrie S. Training and assessment in
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839. Delgado-Vargas B, Romero-Salazar AL, Reyes
854. Piromchai P, Avery A, Laopaiboon M, Kennedy G, 869. Peveling-Oberhag A, Reimann H, Weyer V,
Burneo PM, et al. Evaluation of resident’s training
O’Leary S. Virtual reality training for improving Goloborodko E, Staubach P. High-Concentration
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Urticaria and Angioedema. Skin Pharmacol 875. Sommer DD, Rotenberg BW, Sowerby LJ, et al. A of surgical conditions during propofol or
Physiol 2016;29:9-12. novel treatment adjunct for aspirin exacerbated sevoflurane anaesthesia for endoscopic sinus
870. Pirunsarn A, Kijrattanakul P, Chamnanchanunt respiratory disease: the low-salicylate diet: a surgery. Br J Anaesth 2008;100:50-4.
S, Polprasert C, Rojnuckarin P. A Randomized multicenter randomized control crossover trial. 882. Kaygusuz K, Yildirim A, Kol IO, Gursoy S,
Multicenter Trial Comparing Low-Dose Int Forum Allergy. & Rhinol.2016;6:385-91. Mimaroglu C. Hypotensive anaesthesia with
Prednisolone Versus Observation for 876. Laidlaw TM, Cahill KN, Cardet JC, et al. A trial of remifentanil combined with desflurane or
Prevention of Recurrences in Adult Immune type 12 purinergic (P2Y12) receptor inhibition isoflurane in tympanoplasty or endoscopic
Thrombocytopenia. Clin Appl Thromb Hemost with prasugrel identifies a potentially distinct sinus surgery: a randomised, controlled trial. J
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871. Sicras-Mainar A, Traseira-Lugilde S, Fernandez- respiratory disease. J Allergy Clin Immunol.2018. 883. Yoo HS, Han JH, Park SW, Kim KS. Comparison of
Sanchez T, Navarro-Artieda R. [Persistence 877. Fahmy FF, McCombe A, McKiernan DC. Sino nasal surgical condition in endoscopic sinus surgery
to treatment and resources use with inhaled assessment questionnaire, a patient focused, using remifentanil combined with propofol,
fixed-dose combinations of corticosteroids rhinosinusitis specific outcome measure. sevoflurane, or desflurane. Korean J Anesthesiol
and long-acting beta-adrenergic agonists for Rhinology. 2002;40:195-7. 2010;59:377-82.
the treatment of asthma: A population-based 878. Gan EC, Habib AR, Rajwani A, Javer AR. Five- 884. Luong A, Ow RA, Singh A, et al. Safety and
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872. Mager DE, Lin SX, Blum RA, Lates CD, Jusko Trendelenburg position during functional releasing implant for the paranasal sinus ostia: a
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corticosteroids: pharmacokinetics and cell randomized controlled trial. Int Forum Allergy. & - Head & Neck Surg.2018;144:28-35.
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Pharmacol 2003;43:1216-27. 879. Hathorn IF, Habib AR, Manji J, Javer AR. controlled trial of a bioabsorbable steroid-
873. Salami A, Dellepiane M, Strinati F, Guastini L, Comparing the reverse Trendelenburg and releasing implant in the frontal sinus opening.
Mora R. Sulphurous thermal water inhalations horizontal position for endoscopic sinus surgery: Laryngoscope. 2016;126:2659-64.
in the treatment of chronic rhinosinusitis. a randomized controlled trial. Otolaryngology-- 886. Kennedy DW, Kuhn FA, Hamilos DL, et al.
Rhinology. 2010;48:71-6. Head & Neck Surg.2013;148:308-13. Treatment of chronic rhinosinusitis with high-
874. Sommer DD, Hoffbauer S, Au M, Sowerby 880. Ko MT, Chuang KC, Su CY. Multiple analyses dose oral terbinafine: a double blind, placebo-
LJ, Gupta MK, Nayan S. Treatment of aspirin of factors related to intraoperative blood loss controlled study. Laryngoscope. 2005;115:1793-
exacerbated respiratory disease with a and the role of reverse Trendelenburg position 9.
low salicylate diet: a pilot crossover study. in endoscopic sinus surgery. Laryngoscope.
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states) 2015;152:42-7. 881. Ahn HJ, Chung SK, Dhong HJ, et al. Comparison

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7. Paediatric chronic rhinosinusitis

7.1. Epidemiology, predisposing factors, and combination of symptoms suggestive of rhinitis, and between
comorbidities 13-15% of the respondents reported facial pain or anterior/
posterior nasal drainage, symptoms suggestive of a sinus origin.
7.1.1. Epidemiology More than 20% of students suffered from effects on quality of
Estimates from the National Health Interview Survey in the life related to these symptoms. In total, out of those with nasal
United States in 1996 suggest that young people under the and sinus symptoms, 22% had their symptoms for more than six
age of 18 years are affected by chronic rhinosinusitis (CRS) weeks but for less than a year.
at a rate of 63.9 per 1000 individuals(1).  Overall health care Gilani and colleagues analysed national survey databases
expenditures attributable to rhinosinusitis (acute and chronic) between 2005 and 2012 and showed that CRS accounted for 5.6
in 1996 were estimated at $5.8 billion, of which $1.8 billion million visits per year among patients 0-20 years of age(6). CRS
(30.6%) was for children 12 years or younger(2). Despite growing was diagnosed in 2.1% of all visits, acute rhinosinusitis in 0.6%
knowledge related to the diagnosis and treatment of this and as comparators, allergic rhinitis in 2.6%, upper respiratory
disease in children, its true epidemiology in the world is not yet tract infections in 8% and otitis media in 6.7%. The 5-10 year-old
well described. Factors thought to contribute to the difficulty and 10-15 year-old age groups were the most affected. 
in accurate diagnosis include false positive diagnoses due to While most of the available data is based on diagnosis codes
difficulty in differentiating CRS from adenoid hypertrophy, and subjective, questionnaire-derived, information, Westman
adenoiditis, and (allergic) rhinitis, incomplete evaluation (nasal and colleagues estimated the 12-month prevalence of CRS
endoscopy and/or imaging are not performed in many children), based on questionnaire to be 1.5% in a Swedish population-
neglect of the disease by both doctors and care-takers, and based study of 3112 adolescents(7). They went ahead and
incomplete follow-up evaluation in some children. attempted to follow-up with objective confirmation of the
Furthermore, race and socioeconomic status have recently diagnosis leading to a reduction of the estimate of prevalence to
been reported to influence the prevalence of the disease. between 0.3% to 0.8%.
Smith et al. assessed 174 children aged between six months Together, these studies suggest that the prevalence of CRS in
and 18 years who presented to a single academic tertiary the paediatric population is lower than in adults. As in adults,
paediatric otolaryngology centre with a primary diagnosis of paediatric CRS is a relevant disease in terms of quality of life. The
CRS (classified through the Current Procedural Terminology impact of CRS on the quality of life of children is greater than
(CPT) codes) from March 2008 to July 2011(3). A control group that of diseases such as asthma, attention deficit hyperactivity
consisted of 430 children, seen in the same department disorder, juvenile rheumatoid arthritis, and epilepsy(8). All
over a three-month period, with other otorhinolaryngologic these studies reflect an important negative impact on the
diagnoses. There was a higher percentage of white children and lives of children, particularly in terms of missed classes and
children with private health insurance among the patients with concentration in school, sleep quality, and physical and
a primary diagnosis of CRS. These findings suggest that racial/ emotional health(5). 
ethnic disparities and socioeconomic variables may influence
the diagnosis, and this is likely related to differences in access Although studies of CRS in children are less
to tertiary care, parental perception of disease severity, or common, the prevalence is lower than in adults
different natural course of the disease process in different ethnic (2-4 %), but the negative impact on quality of life
populations.  seems to be similar to that observed in adults.
Despite these limitations, several studies have tried to assess
the prevalence of CRS in the paediatric population. Using data 7.1.2. Predisposing factors and comorbidities
obtained from a US national survey acquired over a 2 year time Although the understanding of the role of predisposing/
frame which sampled 42.1 million school age patients, Sidell comorbid factors has evolved considerably, it is not yet clear
et al. identified approximately 4% of the studied population whether these host factors (systemic and local) and the
(corresponding to 1.7 million individuals) with a diagnosis of environmental conditions that affect CRS in a child induce the
CRS, based on physician diagnoses and procedure codes for disease or if they share a common pathway of pathogenesis.
medical visits/encounters(4). Sami and Scadding used the
MSYPQ, a disease specific quality of life questionnaire, in 213 7.1.2.1. Anatomic variations in the sinuses 
secondary school children (11-16 years) in East London to To date, there is no evidence that anatomic abnormalities
identify the prevalence of rhinosinusitis symptoms and impact contribute, in any way, to the development and maintenance
on quality of life(5). They show that 31.5% suffered from a of CRS in children. Studies from 1997 to 2008 suggested that,

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despite the common occurrence of these anatomical variations review of the adult and paediatric literature examining the
(concha bullosa, concha hypertrophy, septal deviation, etc.), effect of cigarette smoke on CRS(15). Several of the included
they did not seem to correlate with the degree and existence of articles had mixed paediatric and adult populations and only
CRS in children(9-11). A more recent study examining anatomical Kakish et al.included data specifically related to children(17).
abnormalities in an observational cohort of children showed They reported a 68% prevalence of acute rhinosinusitis among
the common occurrence of anatomic abnormalities in healthy children exposed to passive smoking, compared to a prevalence
sinuses(12). Whereas gender did not influence the prevalence of 1.2% among children without exposure(17). While valuable,
of these abnormalities, some (deviated septum and concha this study only evaluated acute rhinosinusitis. Christensen et
bullosa) seemed to have a higher point prevalence in older al. performed a systematic review of large population studies
children. Haruna et al. investigated whether the presence to determine if there was a correlation between cigarette
of paediatric middle turbinate pneumatisation causes a smoke exposure and the prevalence of CRS(16). They reported on
narrowing of the OMC and is associated with the development studies that evaluated outcomes of CRS surgery in the presence
of rhinosinusitis by analysing CT scans obtained from 95 of passive and/or active smoke in the paediatric population
children 1-15 years old(9). Middle turbinate pneumatisation was (age <18 years).All the studies demonstrated worse outcomes
detected in 4.6% of the nasal cavities, and the middle turbinate in children exposed to cigarette smoke. These included an
pneumatisation itself did not obstruct the ostiomeatal complex. increase in surgical revision rates(18, 19),worse SNOT scores(19),or
Thus, a direct causal relationship between middle turbinate lack of symptom improvement after surgery(18-20).Thus, there is
pneumatisation and the development of rhinosinusitis was not some evidence that cigarette smoke worsens CRS in children,
observed. Equally, Al-Qudah performed a prospective study however, longitudinal and mechanistic studies are required to
of 65 cases of paediatric chronic rhinosinusitis (average age determine the causative effect in children. 
of 11.4 years) that persisted after appropriate medical therapy
and examined their CT scans(11). Agger nasi cell was the most Children with CRS who are exposed to passive
common anatomical variation, followed by concha bullosa smoking present with more severe disease, worse
of the middle turbinate. No significant correlation was found clinical scores and higher rates of revision surgery.
between these anatomical variants and the extent of chronic
rhinosinusitis, again suggesting that these abnormalities 7.1.2.3. Allergic rhinitis
are unlikely to predict the extent and severity of chronic Allergic inflammation can alter the sinonasal physiology with
rhinosinusitis in the paediatric population. regards to mucociliary clearance and patency of the ostia
and a late-phase allergic inflammation may contribute to CRS
Anatomic variations are more frequent in older development(21). However, evidence tying allergic rhinitis to CRS
children, but do not seem to be related to the in children is at best equivocal.
presence of CRS. A large study in paediatric patients with CRS reported that
29.9% had both a positive skin test and an elevated serum IgE
level(22). This prevalence of atopy in children with CRS was similar
7.1.2.2. Environmental factors to that of the general paediatric population in Italy. Importantly,
only 7.4% of the children under the age of three had positive
7.1.2.2.1. Viral infection testing compared to 31.4% of the children between 3-6 years
It is speculated that upper respiratory tract infections (URTIs) and 33.3% of children older than six suggesting a low yield for
play a role in the development of CRS, by leading to mucosal allergy testing in patients under three years of age.
oedema, mucus production and retention, impaired mucociliary Sedaghat et al. evaluated a series of 4044 consecutive patients
clearance, secretion stasis, and decreased aeration of the sinus (age ≤18yrs) with a diagnosis of chronic rhinosinusitis in the
mucosa(13). Wood et al. used the polymerase chain reaction to otorhinolaryngology or allergy and immunology clinics of
look for respiratory viruses in the sinus mucosa from 13 adult Boston Children’s Hospital between 2002 and 2012(23). Twenty
patients with CRS and two patients with normal sinuses and seven percent of the children with CRS were also diagnosed
were not able to detect a signal for any of several common with AR which is equivalent to the typical prevalence of the
respiratory viruses(14). Therefore, to date, the contribution of viral disease in the paediatric age group and does not support a
infection to paediatric CRS is poorly studied with no evidence to higher prevalence of allergic rhinitis in children with CRS. Not
support the importance of viral infections to CRS in children. surprisingly, there was a significantly higher prevalence of
asthma in the population of children with CRS and AR (40.7%)
Thus far, there is no credible evidence that viral than in the children without AR (9.8%). In fact, a strong positive
infections contribute to paediatric CRS. association was detected between the diagnosis of asthma and
  AR in children with CRS. Other studies have shown a higher
7.1.2.2.2. Exposure to tobacco smoke  percentage of atopy in patients with CRS than in the general
Environmental exposure to tobacco smoke inhibits mucociliary population. In a study in Thailand of 100 children with a clinical
clearance and epithelial regeneration. Both active and passive diagnosis of rhinosinusitis and abnormal plain radiographs, a
smoking have been identified as significant risk factors for the positive skin test to common aeroallergens was reported in 53%
development of CRS(15, 16). Reh et al.conducted an excellent of the patients, which suggests a correlation between allergic

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rhinitis and CRS(24). Georgalas et al. studied the Bradford-Hill According to the studies above PCRS patients are
criteria for causation applied to the evaluation of these studies more likely to also present with AR and/or asthma.
and concluded that a clear and definitive causal relationship However, research on the prevalence of CRS within
cannot be established, especially in children(25). the population with or without AR is needed to
Most recently, Anamika et al. studied 110 patients, between support this correlation.
seven and 18 years of age, diagnosed with CRS based on history
and clinical examination including nasal endoscopy(26).Patients 7.1.2.4. Asthma
underwent skin prick tests against 65 common aeroallergens Both CRS and asthma are inflammatory diseases of the airways.
for evidence of atopy. A positive skin prick test to at least one It has been hypothesised that rhinosinusitis impacts bronchial
of the common aeroallergens was present in 52.7% of patients. asthma in all age groups as part of the unified airway theory(28).
Patients with CRS and atopy had significantly higher mean In their review of Boston Children’s data, about coexistent
Lund Mackay endoscopic score and SN-5 score (denoting worse diseases, Sedaghat and colleagues reported that 18.1% of 4044
quality of life) than nonatopic patients. In contrast, an older children with CRS had concomitant asthma(23). As mentioned
study evaluated CT scans from allergic and nonallergic children above, there was a higher chance of asthma if the child also
and noted the presence of sinus opacification in 61% and 64% had allergic rhinitis. Anfuso and colleagues evaluated cytokine
of allergic and nonallergic children, respectively, which argues expression in sinus tissues of children with CRS and normal
against an important role for allergy in sinus CT abnormalities(27). controls and found that children with CRS and asthma had
In summary, the available studies evaluating the importance significantly higher sinus levels of multiple inflammatory
of allergic disease in CRS in children do not clearly elucidate cytokines supporting the contribution of upper airways disease
the interaction of the two diseases. They suffer from many to lower airway inflammation in patients with CRS(29). Older,
potential pitfalls: 1) biased populations as many of the studies non-controlled studies have shown that pharmacologic or
are from allergy and otolaryngology clinics which are more likely surgical intervention for CRS resulted in discontinuing asthma
to be seeing patients with allergic rhinitis, 2) lack of objective medications in 80% of a cohort of 48 children(30). Furthermore,
confirmation of the diagnosis of CRS, 3) lack of differentiation asthma recurred when rhinosinusitis subsequently exacerbated.
between atopy (positive skin test) and relevant clinical allergic These and other studies support the concept that clinical control
rhinitis (positive skin tests and relevant correlating clinical of CRS may be important in optimizing the control of difficult-
symptoms). Despite these limitations, allergy testing should be to-treat asthma. However, the limitations of most available
considered in the older child with CRS. studies include the lack of good controls or randomization
to different treatment modalities; therefore, the relationship

Table 7.1.1. Adenoidectomy for paediatric CRS.

Author Type Intervention Outcome measure Result

Vandenberg Retrospective case series, Adenoidectomy or Symptoms Complete or near symptom resolution
1997(140) n=48 adenotonsillectomy in 58% of patients

Brietzke Systematic literature Adenoidectomy (8 studies Proportion of patients who 69% of patients improved after
2008(33) review Average sample adequate for systematic improved after surgery surgery
size =46 (range literature review)
10—121).
Ramadan Retrospective review of Adenoidectomy Failure of adenoidectomy, 61/121 (50%) children failed
2007(142) prospectively collected 55 patients underwent ESS Factors that contributed to adenoidectomy.
data, n=121 after adenoidectomy and had early failure Asthma and age <7 yrs. predicted
data available earlier failure and faster ESS
Ramadan Retrospective 10 yr. review, Adenoidectomy preceded Success of adenoidectomy Success rate=
2014(169) n=233 by a CT based on CT score 43% in CRS group (CT score ≥5),
65% in chronic adenoiditis group (CT
score <5)
Bettadahalli Prospective, n=60 Adenoidectomy Sinus symptoms and quality 88% of children had a significant
2017(143) of life scores 6 months post- improvement in outcome measures
intervention

Ramadan Retrospective review of Adenoidectomy or Improvement of symptoms at 88% of adenoidectomy with sinus
2008(144) prospectively collected adenoidectomy with a 12 months wash showed improvement, 61% of
data, n=60 maxillary sinus wash adenoidectomy showed improvement

CT, computed tomography; ESS, endoscopic sinus surgery.

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between CRS and asthma in children remains largely descriptive. 7.1.2.6. Gastro-oesophageal reflux disease
Gastro-oesophageal reflux disease (GORD) might be related
We observe a strong correlation between asthma to CRS in some paediatric patients; however, its association
and PCRS. More research is required to elucidate with the respiratory disease and its incidence remain doubtful.
the nature of the pathophysiologic events Data are conflicting and scarce. Reflux of gastric acid into
underlying this observation. the pharynx and nasopharynx is thought to cause sinus
ostium inflammation, impaired mucociliary clearance, and
7.1.2.5. Adenoids consequently, rhinosinusitis.
Recent literature reviews have supported the hypothesis GORD has been reported at higher rates in paediatric patients
that adenoids have a significant impact on the development with rhinopharyngitis symptoms than in a control group(41). In
of CRS in younger children(31, 32) (Table 7.1.1.). Supporting a large case-control study that included 1980 children aged
evidence of the importance of the adenoids is data that shows two to 18 years with GORD and 7920 controls, a diagnosis
improvement in CRS in children after adenoidectomy which of rhinosinusitis was significantly more likely in the children
will be discussed in the surgical management portion of this with GORD (4.19%) compared with the control group (1.35%)
chapter(33). In addition to improvement of CRS symptoms (42)
. A prospective study by Phipps and colleagues in 30
after adenoidectomy in a series of 35 children, one study has paediatric patients with CRS who were evaluated with a
shown improved mucociliary transport in these children after 24-h pH probe showed that 63% of the children with CRS
surgery(34). Despite this, no studies have shown a correlation had gastroesophageal reflux(43). This study also showed that
between the size of the adenoid pad and the presence of 79% of the children with CRS experienced improvement in
sinonasal symptoms in paediatric CRS, neither when analysing rhinosinusitis symptoms after medical treatment for GORD.
adenoid size by X-ray(35), by volume(36), or by weight of the Similar results were reported in a retrospective study showing
tissue removed at surgery(37). These findings suggest that the that the rate of surgery could be reduced by 89% in children
adenoids can contribute to the development of CRS not just with severe CRS treated with a proton pump inhibitor
by mechanical obstruction but also by serving as a bacterial for GORD(44). In 2014, Nation and colleagues performed a
reservoir. In support of this hypothesis, a study by Coticchia retrospective chart review of 63 children, aged six months to 10
and colleagues observed that the surface area of adenoids years, with rhinorrhoea, nasal congestion, and chronic cough(45).
covered by biofilm was 94.9% in patients with CRS compared to The patients underwent maxillary cultures, adenoidectomy, and
1.9% in patients with obstructive sleep apnoea without CRS(38). distal third oesophageal biopsies. Children with oesophageal
Shin and colleagues examined adenoid size and bacteriology biopsies showing oesophagitis were classified as positive for
in 410 children under 14 years of age who underwent an gastro-oesophageal reflux disease, and maxillary antral swabs
adenoidectomy due to adenoid hypertrophy(35). Common upper growing a high density of bacteria were classified as positive
respiratory pathogens (Haemophilus influenzae, Streptococcus for chronic rhinosinusitis. Younger children aged six months to
pneumoniae, and Streptococcus pyogenes) were isolated from five years tended to have either chronic rhinosinusitis or gastro-
79.3% of the adenoids, and the rate of bacterial isolation from oesophageal reflux disease, whereas older children, aged six to
the adenoids correlated with the severity of sinus disease on 10, tended to have a more complicated aetiology of CRS and
Water’s radiographs again supporting the bacterial reservoir GORD. In all of these patients, GORD played an important role
hypothesis. Therefore, available evidence suggests that the in many of these patients, as over 40% had gastro-oesophageal
function of adenoids as a bacterial reservoir is more important positive biopsies. Another potential causative agent that has
than their size in the pathophysiology of paediatric CRS. been investigated for adenoiditis and/or CRS is Helicobacter
There is also some older evidence that supports a contribution pylori. Cedeno and colleagues failed to detect the presence of
of the adenoids as an immunological organ in children with H. pylori in adenoid tissue or maxillary sinuses in patients with
CRS. One study showed a significantly lower expression of IgA CRS(46).
in the adenoids of children with CRS compared to those with In summary, there is some evidence to support a potential role
obstructive adenoids(39). This study could not elucidate, however, of GORD in CRS in children. However, the studies suffer from
whether this was primary or secondary to chronic infection, as significant limitations including retrospective design, lack of
the design was cross-sectional. Shin and colleagues showed placebo group in treatment studies, and poor characterization
higher levels of tissue-remodelling cytokines in adenoids of the presence and extent of CRS. Therefore, routine treatment
obtained from patients with CRS compared to tissue obtained for GORD is not currently justified in children with CRS. Indeed,
from patients without CRS suggesting a relationship between this conclusion is supported by the consensus statement on
the adenoids and the sinuses in children with CRS(40). paediatric rhinosinusitis published by the American Academy of
In summary, the adenoids seem important in the Otolaryngology Head and Neck Surg(47).
pathophysiology of CRS in children. Indeed, the first line
of surgical management of CRS in younger children is an The relationship between GORD and CRS seems
adenoidectomy and the data supporting efficacy will be to be strong in children. However, the evidence is
discussed in the management section. weak and does not support the routine treatment
of GORD in children with CRS.

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7.1.2.7. Immaturity or deficiency of the paediatric immune immunoglobulin (IVIG) for one year showed a decrease in
system antibiotic intake, rhinosinusitis episodes, and an improvement in
Studies in children with recurrent rhinosinusitis or CRS have sinus imaging studies(54).
demonstrated a variable percentage of immune dysfunction, Clearly, the reports of humoral immune deficiency in children
including a decrease in the levels of immunoglobulins A, with recurrent or chronic rhinosinusitis vary widely. This
G, and subclasses, with a poor response to pneumococcal is likely influenced by the types of populations studied,
vaccine and low levels of immunoglobulin in response to measures of immune function, and accuracy in the diagnosis of
normal vaccines. Shapiro et al. evaluated immunologic rhinosinusitis. It therefore seems prudent to evaluate immune
competence in 61 children with CRS who were referred for function in the child with chronic / recurrent rhinosinusitis
an allergy evaluation(48). Roughly 50% of the children had with an immunoglobulin quantitation and titers to tetanus and
evidence of environmental allergies and at least 23 of the 61 diphtheria in addition to pneumococcal titers. If responses are
patients with refractory rhinosinusitis had impaired humoral abnormal, a repeat set of titers after pneumococcal vaccination
immunity manifested by low immunoglobulin levels or is appropriate and if the response is not adequate, then referral
vaccine hyporesponsiveness. This is clearly a much higher to an allergist/immunologist is warranted.
rate than in adults. Hidalgo and colleagues report that 6% of
78 children with CRS failed to mount an immune response Children withCRS refractory to appropriate
to pneumococcal vaccine(49).In 27 children with chronic or medical treatment should be evaluated for
recurrent rhinosinusitis, Costa Carvalho and colleagues detected humoral immune deficiency.
one patient with IgA andIgG2 deficiency, and another with
IgG3 deficiency(50). Eight and12 of 27 patients had IgG2 and 7.1.2.8. Cystic fibrosis (CF) (see also chapter 8.4.)
IgG3 serum levels below 2.5thpercentile, respectively and no CF is an autosomal recessive disease caused by mutations in
patient had an abnormalresponse to vaccination. In a large the CFTR gene that leads to the formation of thick viscous
study of 307 subjects with refractory rhinosinusitis (261 adults secretions, favouring infections in the respiratory tract. It is
and 46 children), Vanlerberghe et al. found laboratory evidence diagnosed by abnormally elevated sweat chloride levels or by
of humoral immunodeficiency, including IgA deficiency or genetic testing. Because the sweat chloride test is not 100%
IgG subclasses deficiencies, in 21.8% of the cases with no specific, the diagnosis of CF is based on the presence of one
difference in prevalence between children and adults(51). Baek or more clinical features of CF, in addition to evidence of an
and colleagues evaluated 16 children with recurrent acute or abnormality in the CFTR gene or protein. P. aeruginosa and S.
CRS and found that 50% had defects in the humoral immunity aureus are the microorganisms most frequently cultured when
including poor responsiveness to a pneumococcal vaccine(52). the infection affects the sinuses(55). It is the most common
In the study by Sedaghat et al., mentioned above, 496 (12.3%) disorder encountered in children with CRSwNP. In fact, the
of the 4044 children diagnosed with CRS had a diagnosis prevalence of CRS in the population with CF is nearly 100%(55-57).
consistent with an immune disorder(23).  Despite newborn screening, otorhinolaryngologists continue
On the other hand, in 2006, Bernatowska et al. evaluated the to receive children without a confirmed diagnosis of CF. In
incidence of CRS in 425 children with different types of primary children with polyps and sinus disease, physicians should have
humoral deficiency(53). CRS was observed most frequently in a high index of suspicion for CF, particularly in the context
the group of patients with agammaglobulinemia (85.96%) of poor weight gain, respiratory disease and gastrointestinal
and less often in patients with dysgammaglobulinemia abnormalities. The finding of expansion of the paranasal
(81.81%) and other antibody deficiencies (72.72%). As to sinuses (pseudomucocele of the maxillary sinuses) and
immunoglobulin replacement, a pilot study in six children with hypodevelopment of the frontal and sphenoidal sinuses,
CRS refractory to medical management treated with intravenous without evidence of bone erosion on CT scan, are strong

Key points | What’s new since EPOS 2012

1. The prevalence of CRS in paediatric patients has been shown to be between 2.1 to 4%.
2. Children of 10 to 15 years are most often affected with CRS. When comparing the frequency of the disease with that of
other common conditions, CRS was more prevalent than ARS in all age groups and more numerous than otitis media in the
group between 15 to 20 years (0.9%).
3. Both passive and active cigarette smoking are associated with chronic rhinitis and rhinosinusitis in children.
4. A clear and definitive causal relationship between AR and CRS cannot be established, especially in children.
5. The adenoid may act as a reservoir for pathogenic bacteria, rather than a source of obstruction.
6. The relationship between GORD and CRS in children is controversial.
7. The most common immunodeficiencies related to refractory CRS in children are immunoglobulin deficiency (including IgG
subclasses) and poor response to vaccines.
8. Physicians treating children with nasal polyps and sinus disease should have a high index of suspicion for CF, particularly in
the context of poor weight gain, respiratory disease, and gastrointestinal abnormalities.

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radiographic indicators of CF(58-60). Wentzel et al. evaluated a starting in adolescence.Kartagener’s syndrome, a triad of
group of 50 consecutive patients with CF aged 2-12 years who rhinosinusitis, chronic bronchitis with bronchiectasis, and situs
presented to a rhinology practice(60). The quality-of-life visual inversus, occurs in approximately 50% of patients with PCD(63, 65,
analogue scale was strongly negatively correlated with SN-5 68)
.
scores. Additionally, worse sinus-specific QOL as measured The management of CRS in children with PCD is challenging
by the SN-5 score was associated with increased incidence in due to the rare incidence of PCD and the paucity of high-quality
the diagnosis of rhinosinusitis, prescription of antibiotics, and primary literature. Control of the CRS symptoms is especially
missed days of school or recreational activities due to sinonasal important in these children to maintain an adequate quality
symptoms. The authors concluded that the SN-5 was a quick of life and pulmonary function. Given the rare prevalence of
and qualitative method for monitoring CRS in this patient PCD and the insufficient evidence concerning the treatment
population. Chan et al. evaluated a group of 102 paediatric effectiveness for CRS, Mener et al. support future development
patients with CF with an age range of 2-20 (average 12.9) years of an international, multicentre database for prospective data
by a screening questionnaire for the diagnosis of CRS and the collection(63). This database should include the diagnosis,
SN-5 during a routine clinic visit(61). Of the 102 participants, 47 treatment and outcomes of CRS for children with PCD and
completed the surveys. Depending on the diagnostic criteria would encourage implementation of validated and standardised
used, 11-38% of the patient population had CRS. Mean domain outcome measures in these children. 
and overall visual-analogue scale scores on the SN-5 were
consistent with a minimal effect on QOL. The authors concluded PCD should be suspected in children with
that there was a high prevalence of symptomatic CRS in this refractory CRS and pulmonary diseases, especially
patient population, but that it had a low impact on quality of in those with concomitant bronchiectasis, situs
life. inversus totalis or spermatozoid abnormalities.

In cases of nasal polyps among paediatric

patients, investigations for CF should be 7.2. Pathophysiology
performed. Sweat chloride test remains important
to confirm the disease, although newborn 7.2.1. Genetics
screening has significantly decreased the age of The information available about the genetics of CRS in children
diagnosis of this disease. is very limited and the studies suffer from some limitations but
 
show some interesting trends that deserve further investigation.
7.1.2.9. Primary ciliary dyskinesia (see also chapter 8.5.) Orb and colleagues explored the familial risk of CRS in children
PCD is a rare autosomal recessive disorder with an estimated by mining the Utah population database which consists of
incidence of one in 15,000 to 20,000 births. It consists of defects computerized data records for >7.3 million people(69). They
in ciliary beating, resulting in decreased mucociliary clearance(62). identified 496 children with CRS as follows: 12 years or younger
It is associated with frequent sinus and ear infections, situs with an index ICD-9 diagnosis of CRS appearing in the medical
inversus totalis (in 50% of patients), heterotaxy or situs record between 1996 and 2011, and a coupled procedural
ambiguous (in 12% of patients), and infertility (in 50% of male code related to CRS (nasal endoscopy, adenoidectomy and/or
patients)(63, 64).The symptoms of CRS in children with complex sinus surgery). The authors randomly selected 4959 ethnically
mucociliary disorders such as PCD may be debilitating and result matched controls with no history of CRS from the Utah
in respiratory compromise with decreased pulmonary function. population and individually matched 10:1 on sex and birth year
Purulent nasal secretions, typically transported by gravity or to corresponding paediatric CRS cases. Siblings of patients with
airflow due to the decreased ciliary clearance, are observed in CRS demonstrated a 57.5-fold increased risk of having paediatric
children with PCD during active sinus infections(65). Indeed, in a CRS compared to controls. First cousins had a 9.0-fold increased
series of 84 patients with PCD from Australia, recurrent cough risk and second cousins a 2.9-fold increased risk of paediatric
and rhinosinusitis were the most common symptoms occurring CRS, all significant associations. Parents, first and second-degree
in 71% and 81% of the children respectively(66). relatives, and first cousins of paediatric cases demonstrated
Screening tests for PCD include nasal nitric oxide (lower significant increased risks of having adult-onset CRS. Although
levels than controls) (see 9.5.3.3) and in vivo tests, such as the these results suggest a significant familial risk associated with
saccharin test, which documents slower mucociliary transit CRS, the study is limited by the accuracy of the diagnosis
times. Specific diagnosis requires examination of the cilia by of CRS as it is based on review of diagnostic codes without
light and transmission electron microscopy, which is usually confirmation by clinical evidence of disease.
available only in specialised centres(67). The most commonly Purkey and colleagues studied a case control sample of 828
described structural abnormality involves lack of the outer children (average age 11.9 years) with CRS and 5,083 healthy
dynein arms, or a combined lack of both inner and outer dynein controls from the Children’s Hospital of Philadelphia(70). Index
arms. Additionally, genetic testing in specialized centres is patients had a history of CRS diagnosed by a paediatric
now available for roughly 20 different genes that underlie the otolaryngologist using symptom criteria, flexible endoscopy
pathophysiology of PCD (see 9.5.3.2). Nasal polyps occur in and CT evidence in almost half the cases. Children with cystic
approximately 18% to 33% of patients with PCD,most often fibrosis were excluded. Single nucleotide polymorphism (SNP)

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genotyping of potassium channel genes was undertaken and mucosa but had fewer eosinophils and major basic protein–
showed that the locus yielding the strongest signal was at the positive cells, with less epithelial disruption and less basement
KCNMA1 gene in Caucasian children with CRS (p=0.022). There membrane thickening. These authors also showed higher
was borderline evidence for association in the KCNQ5 gene with numbers of CD8-positive cells, neutrophils, macrophages, B
CRS in African American children. This report suggests a genetic lymphocytes, and plasma cells in younger children with CRS
association between potassium channel epithelial physiology compared with adults(79). In another comparative study of sinus
and the development of CRS in children. tissues between adults and children, paediatric tissue had
In an earlier study in 58 Caucasian children with CRS (diagnosed scant eosinophils and abundant lamina propria fibrosis(80). The
by persistent symptoms and objective evidence of disease) differences in eosinophil versus neutrophil predominance in
and no known cystic fibrosis, 12.1% were found to carry the specimens studied above probably relate to the age group
heterozygous mutations in the cystic fibrosis transmembrane of the children studied (eosinophil predominance in the older
regulator (CFTR) gene, higher than the expected rate of 3-4% in children and neutrophil predominance in the younger ones).
the same ethnic group(71). These results suggest a predisposition In more recent studies, Wu and colleagues investigated
to CRS in children who are carriers for CFTR mutations. inflammatory gene expression in tissues obtained from the
Sedaghat and colleagues investigated the presence of sinuses of children with CRS and normal controls(81). Using
mutations in genes encoding connexins, that maintain microarray analyses and validation by gene mRNA expression
epithelial integrity via gap junctions, in patients with chronic levels by real-time PCR, they showed that five inflammatory/
and recurrent acute rhinosinusitis diagnosed by persistence of immune response gene products were significantly upregulated
symptoms and objective evidence of disease by either nasal in tissues from CRS compared to control. Two of the products
endoscopy or CT scan(72). Of the eight paediatric patients (age were the cytokines CXCL5 (neutrophil chemoattractant), and
between six and 16 years), only one child had a mutation in CXCL13 (B lymphocyte chemoattractant), contributors to
connexin 32 and of their 11 adult patients, one had a mutation the adaptive immune response. The other three were serum
in connexin 43. A previous study by the same group had shown amyloid A1/A2 (SAA1/SAA2), serpin peptidase inhibitor
no mutations in connexins 26 and 30 in the same group of member 4 (SERPINB4), and β-defensin 1 (DEFB1). The latter are
patients(73). Although these results suggest that mutations proteins involved in the innate immune system. In a follow
in the connexin gene family might not be important in the up study, the investigators evaluated the tissue distribution
pathophysiology of CRS, the number of observations are too and cellular localization of these inflammatory markers using
small to make definitive conclusions. immuno-histochemical staining and immunofluorescence(82).
In summary, it is likely that the pathophysiology of paediatric They showed that all five mediators were strongly expressed
CRS involves both genetic and environmental influences. in submucosal glands and in ciliated and basal cells within the
Indeed, studies of monozygotic twins have not shown that both epithelium. Further, CXCL13 was expressed in macrophages, T
siblings always develop polyps, indicating that environmental and B cells but not in neutrophils and CXCL5 was detected only
factors are as likely as genetic ones to influence the occurrence in T cells.
of nasal polyps(74, 75). Anfuso and colleagues evaluated cytokine expression in
sinus and adenoid tissues of children with CRS and normal
Based on existing slim research, it is likely that the controls and found more abundant cytokines in the tissues
pathophysiology of paediatric CRS involves both of the children with CRS compared to controls supporting
genetic and environmental influences. ongoing inflammation in the disease group(29). Importantly,
compared with children with CRS and without asthma, children
with CRS and asthma had significantly higher sinus levels
Key points | What’s new since EPOS 2012 of tumor necrosis factor-α and adenoid levels of epidermal
growth factor, eotaxin, fibroblast growth factor-2, growth-
1. A large database study suggests a significant familial related oncogene, and platelet-derived growth factor-AA. This
risk associated with paediatric CRS. supports the contribution of upper airways disease to lower
2. Studies on gene mutations in paediatric CRS show airway inflammation in patients with CRS. Shin and colleagues
some preliminary promising results. evaluated inflammatory markers in adenoid homogenates of
children with and without CRS undergoing adenoidectomy(40).
The adenoids from children with CRS had significantly higher
7.2.2. Inflammatory mechanisms levels of the T cell activation marker soluble interleukin-2
receptor (sIL-2R), as well as the levels of cytokines associated
7.2.2.1. Sinus and adenoid tissue studies with tissue remodelling, such as transforming growth factor β-1
Early studies of the cellular response in paediatric CRS in (TGFβ-1), matrix metalloproteinases (MMP) 2 and 9, and tissue
older children indicate that eosinophils and CD4-positive inhibitor of metalloproteinase (TIMP-1). Whereas there was no
lymphocytes play a significant role in tissue inflammation(76, 77). difference between the two groups in levels of the eosinophil
In later similar studies performed in younger children, Chan and activation marker, eosinophilic cationic protein (ECP), its levels
colleagues(78) showed that paediatric maxillary sinus mucosa had were significantly higher in patients with severe CRS compared
more neutrophils and significantly more lymphocytes than adult to those with mild and moderate disease.

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7.2.2.2. Nasal lavage

Passariello and colleagues evaluated levels of the cytokine Key points | What’s new since EPOS 2012
(TNF-α) the antimicrobial peptide human β-defensin 2 and
neutrophil-released calprotectin in nasal lavages of children 1. Evidence of the presence of adaptive and innate
(average age 3.4 years) with CRS and healthy control(83). This immunity markers in paranasal sinus tissues and nasal
lavages obtained from children with CRS.
was done in the context of a study evaluating the benefit of
crenotherapy (sulfate sodium-chloride thermal water with 2. Inflammatory cytokines are present in sinus tissues
different mineral components by nasal aerosol administered of children with CRS and are more abundant when
concomitant asthma is present.
for 15 minutes daily) in childhood CRS. They show significantly
higher levels of all these proinflammatory substances in the 3. Submucosal glandular hyperplasia is the
lavage of patients with CRS compared to the control subjects. characteristic phenotype in paediatric CRS, and
MUC5B is the predominant glandular mucin.

7.2.2.3. Serum
Shin and colleagues performed allergy testing and obtained
serum eosinophil counts and serum ECP and IgE levels in 7.3. Diagnosis and differential diagnosis
a group of children with CRS treated with antibiotics and
controls(84). They further divided the CRS group into responders 7.3.1. Allergic and non-allergic rhinitis
and non-responders to a prolonged course of antibiotics. The Generally speaking, the differentiation between allergic rhinitis
prevalence of atopy and a family history of allergic diseases (AR), non-allergic rhinitis (NAR) and CRS can be challenging,
were significantly higher in the non-responder group than in the although in adults careful history-taking, nasal endoscopy
responder and control groups. Further serum eosinophil counts and allergy tests usually suffice to make a distinction (see
and levels of ECP and total IgE were significantly higher in the chapter 5.3.1). In children, however, this distinction can be
non-responder group than in the responder and control groups. more complicated. Just as in CRS, both AR and NAR can present
This data suggests that eosinophilic inflammation in the context with rhinorrhoea and nasal obstruction. Furthermore, patients
of allergy was an important factor in children with CRS who do with AR can show increased sinus opacification on imaging(88),
not respond to antibiotics. although this has not been studied for children specifically. To
complicate matters even further, CRS and AR often coincide,
Although more evidence is emerging to support with the incidence of AR already reaching a prevalence as high
upregulation of inflammatory markers in paranasal as 40%(89).
sinus tissues and nasal lavages of children with CRS, The role of NAR in children is less well studied(90). Most NAR
the data is relatively limited and heterogeneous and subtypes are unlikely to be present in (young) children, such
does not yet lend itself to endotyping. as drug-induced rhinitis, occupational rhinitis, hormonal
rhinitis, or senile rhinitis, leaving idiopathic rhinitis as the main
7.2.2.4. Mucus diagnosis of NAR in children. Several studies have investigated
Mucus production is an important component of the clinical the prevalence of NAR in the paediatric population. In Europe,
picture in children with CRS. Many mucin glycoproteins large studies indicate a prevalence varying between 6.3%
have been identified and the most frequently studied are (Sweden, eight-year-olds), 8.1% (Sweden, four-year-olds) and
the secretory mucins MUC5AC and MUC5B. In healthy lower 9.6% (Belgium, 15 years or older)(91, 92). In an American study of
airways, MUC5AC is typically expressed in the goblet cells, while 619 children with asthma, the prevalence of NAR was 11.3%(93).A
MUC5B is restricted to the submucosal glands(85). In paediatric study from Singapore with 6600 children found a prevalence
CRS, submucosal glandular hyperplasia is the characteristic of 24.9% (mean age: 7.8 years), decreasing to 10-15% in older
phenotype and MUC5B is the predominant glandular mucin(86). children(94). A Chinese study including 56 children below 15
Saieg and colleagues collected secretions from patients with years of age, reports a prevalence of 34%. In the age group
CRS and normal controls(87). Many mucin glycoproteins were between 15 and 30 years of age, the prevalence of NAR was still
identified, but the relative abundance of MUC5B was found to 20%(95). Taken together, the prevalence of NAR in the paediatric
be significantly higher in patients with CRS suggesting a parallel population is between 6.3-34%, with considerable regional
between the tissue and secretion glycoprotein production. differences.
In summary, multiple studies suggest upregulation of different In (very) young children, one could debate whether the group
inflammatory substances important in adaptive and innate having complaints, but no allergic sensitization represents
immunity as well as tissue remodelling in sinus tissues, ‘true’ NAR patients. Possibly, those suffering from adenoid
adenoids, nasal lavage, mucus and serum in children with CRS. hypertrophy, CRS, or other sinonasal disease are erroneously
Although the evidence is still scarce, these studies suggest a role included, thus inflating the numbers. Therefore, a safe estimate
for inflammatory mechanisms in paediatric CRS. Although many of the prevalence of NAR in the paediatric population would
of the markers parallel those seen in adults, the data is very be between 10-15%. These numbers are at least equal to
heterogeneous and does not yet lend itself to endotyping. the prevalence of paediatric CRS, making NAR an important
differential diagnosis.
In order to determine the right diagnosis, a full history, physical

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Table 7.3.1. Differentiating CRS, AR and NAR.

CRS AR NAR
Complaints Nasal obstruction Nasal itching Nasal itching
Rhinorrhoea Sneezing Sneezing
Cough Nasal obstruction Nasal obstruction
Facial pain/pressure Rhinorrhoea Rhinorrhoea
Seasonal variation Specific triggers (smoke, mist, cold
dry air etc.)
Nasal endoscopy Relevant pathology in the middle Generalized mucosal involvement, watery Generalized mucosal involvement,
meatus (thick secretions, pus, polyps, rhinorrhoea, nasal hyperreactivity upon watery rhinorrhoea, nasal
oedema etc.) endoscopy hyperreactivity upon endoscopy
Skin prick test or Negative or not clinically relevant for Positive for aeroallergens# Negative or not clinically relevant for
serum specific IgE aeroallergens#. aeroallergens#
Positive if AR coincides
Imaging Opacification of sinuses (if developed) Ideally: none, however opacification might Ideally: none, however opacification
(CT^ or MRI) be present might be present
CT, computed tomography; MRI, multi-resonance imaging; ^routinely using CTs in children is not advised because of exposure to radiation
#
only clinically relevant when complaints are concordant

examination and several diagnostic tools should be used way most clinical olfactory identification tests work is probably
(Table 7.3.1.). Additional attention should be paid to the child’s unsuited and unreliable for children below the age of 6 years
environment, such as the presence of parental smoking, pets (see chapter 7.3.5.5).
etc. Acquired olfactory dysfunction due to diseases other than
CRS is rare in children(98, 100). Primary disorders such as isolated
7.3.1.1. Adenoid hypertrophy/adenoiditis congenital anosmia or syndromic forms such as Kallmann
Adenoid hypertrophy/adenoiditis and CRS can be hard to syndrome are even more uncommon. When a child presents
distinguish, especially in the very young(96).This has been with loss of smell, careful history-taking combined with nasal
elaborately described in chapter 7.1 and will be alluded to in the endoscopy and olfaction tests (see chapter 8.3.5.5) usually
treatment section (7.4). suffices to discern CRS from other causes (congenital, traumatic,
oncology, psychiatric disorders etc.). In the (very) young,
7.3.2. Chronic cough identification of the right diagnosis can be hard, but again,
In contrast to adult CRS, paediatric CRS can encompass chronic olfactory dysfunction will hardly ever be noticed or sought help
cough (rather than loss of smell). The important differential for in the first place.
diagnoses to consider here are: adenoid hypertrophy/
adenoiditis, asthma, or gastro-oesophageal reflux disease. These 7.3.4. Facial pain
are all addressed in chapter 7.1. Facial pain or headache as a main (or only) complaint is usually
unrelated to sinus disease. Unfortunately, patients often
7.3.3. Smell disorders undergo a myriad of nasal treatments including surgery before
In general, loss of smell can be an important sign of CRS. a primary headache syndrome is suspected or diagnosed. For
However, for the paediatric population, this statement does not the paediatric population, this is true as well, although the
apply consistently. Children (or their care givers) hardly ever percentage of misdiagnoses tends to be lower(101). The fact that
complain of olfactory dysfunction, the very reason why “loss of the paranasal sinuses are not fully developed in childhood
smell” has been replaced by “cough” in the diagnostic construct might limit the suspicion of sinonasal disease as a cause of
of paediatric CRS(96). Indeed, in a large cohort of self-declared headaches. Of the children presenting with headache, most are
healthy participants, up to 3.4% were found to be anosmic (and diagnosed with migraine. Smith and co-workers have provided
unaware). In the age group between 5-10 years, the number was a thorough systematic review on rhinogenic headache in
as high as 7%; and in the group between 11-20 years of age, it the paediatric population which is recommended for further
was still 1.4%(97). reading(102). The recommendations for children presenting with
The real extent of CRS related olfactory impairment in children headache are the same as those for adults (see chapter 5.3.3.).
is not yet known, however it is estimated that the most frequent
cause of olfactory disorders in children is also CRS related(98). 7.3.5. Diagnostic tools in children
This lack of data is largely due to the inaccuracy of the testing In 2019, the European Position Paper on Diagnostic Tools in
tools available to detect olfaction problems, especially in young Rhinology. (EPPDRT) was published, providing an excellent,
children, and the fact that olfactory symptoms reach the level state-of-the-art overview of the diagnostic tools available to
of social consciousness only after a child reaches a certain age. physicians treating sinonasal disease(103). Below, several of these
The latter is currently observed in congenital anosmics whereas diagnostic tools will be discussed briefly, with emphasis on
both the patient and their environment become aware of the applicability and considerations in paediatric CRS. For more
absence of olfaction only in late childhood on average(99). The detailed information, the reader is advised to read the European

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Position Paper (which will be referred to as “the EPPDTR” below). of patient comfort. In very young children, specific IgE can be
elevated without clinical relevance and return to normal levels
7.3.5.1. CT scan / MRI during their development, which could be a reason to repeat
The (upfront) use of imaging in children with CRS is debatable. A the measurement if an allergic diagnosis is doubtful despite
sinus CT-scan is mandatory when complications are suspected, previously elevated specific IgE levels.
or when surgery is considered/planned. In every other case, a
balanced consideration must be made on the harm of the study 7.3.5.5. Assessment of smell
(in case of CT: radiation; in case of MRI: long scanning times) and As described in the EPPDRT, it is feasible to use odour
the possible gain in information. Current guidelines recommend identification tests in children; the Sniffin’ Sticks have been
“imaging gently” due to the reported increased chance of validated in a cohort of 201 Dutch children(113). Moreover,
leukemia and brain tumours in children who receive CT scans, specific tests for young children (age five and above) have been
with higher risk associated with higher radiation exposure(104). developed(114, 115). One should be aware, however, that these
Therefore, most paediatric facilities adopt paediatric protocols cannot be simply applied to every country/language, as cultural
that allow acquisition of the appropriate information with the differences can influence the performance of subjects on the
least amount of radiation. In children, higher Lund-Mackay test. Therefore, these tests need to be validated before they can
scores are generally found than in adults, which does not be reliably applied in clinical practice or research. Below a cut-
necessarily reflect CRS. In adults, a cut-off score of >3 is often off age between five and six years and, depending on the child’s
used, but it has been suggested to use a higher cut-off of >5 in cognitive maturation, currently used identification tests turn out
the paediatric population(105). It seems that sinus opacification to be unreliable and even suggest that children have lowered
alone in the paediatric population should be interpreted with olfactory function. This is just a reflection of the fact that
caution, even if multiple sinuses are involved. Indeed, in a cohort smelling and picking the right odour from a list of descriptors
of 192 children (mean age: 9.0 years) with CT scans of the orbits requires familiarity, associative and verbal capacities, and
or brain without a history of sinonasal disease, only 19.3% had sufficient concentration which might be difficult to achieve for
completely normal sinuses(106). the younger child. It is possible to test even new-born and infant
olfactory ability but that requires a different way of testing(116).
7.3.5.2. QoL / SNOT The scarce literature on olfaction in human new-borns, babies,
Most of the quality-of-life (QoL) instruments described in the and toddlers shows that they have an extremely developed
EPPDTR are not suitable for the paediatric population. The olfactory function(117, 118).
general QoL questionnaires depend on items as self-care, social
function, etc. which are not applicable for a child. Furthermore, 7.3.5.6. Upper airway tests
most disease-specific questionnaires for CRS are not validated The EPPDRT elaborates on three upper airway tests, which all
for lower age groups. The often-used SNOT-22 was originally can be applied in (older) children: peak nasal inspiratory flow
validated in an adult cohort (1.6)(107). Its use in children is (PNIF), acoustic rhinometry, and rhinomanometry. Of these, the
incidentally reported (for example in a CF-cohort(108). PNIF is easiest to use and has been validated in children six years
The only validated disease-specific QoL questionnaire for and older(119). Still, in children these investigations are not very
paediatric CRS is the Sinus and Nasal Quality of Life Survey (SN- clinically relevant and are predominantly used in the research
5). It is validated for children aged 2-12 and filled in by their setting.
parents/care givers(109). However, there are only a few studies
using this questionnaire to generate data on QoL outcomes in 7.3.5.7. Pathology test including ciliary morphology and
paediatric CRS(110). function
Taking mucosal biopsies in children is rarely needed. Unilateral
7.3.5.3. Endoscopy processes warrant suspicion of malignancy or inverted
Performing nasal endoscopy is a pivotal step in the diagnosis of papilloma, even in children. Some authors advise to routinely
CRS. Usually it is well tolerated, even in children. Use of topical send antrochoanal polyps for histopathological examination
decongestants and/or anaesthetics is at the discretion of the as they might represent inverted papilloma(120).For bilateral
physician. Endoscopy in children is regularly used and published disease, biopsies are only needed if one suspects primary ciliary
upon, for example in allergic rhinitis with patients as young as two dyskinesia. Several tests for ciliary function are available (see
years of age(111). EPPDTR).

7.3.5.4. Allergy test 7.3.5.8. Blood tests

As in adults, allergy tests can be performed by a skin prick As explained in detail in chapter 5.3.5., routine lab testing
test or blood tests (see 5.3.5.4.). According to the guidelines in (paediatric) CRS is not advised. As mentioned above, one
published by the European Academy of Allergy and Clinical should consider evaluation of the humoral immune response
Immunology (EAACI) Section on Pediatrics, there is no lower in children with CRS unresponsive to therapy and/or with lower
age limit for skin prick testing(112). However, in younger children airway manifestations such as recurrent pneumonia.
(roughly younger than seven years of age) regular aeroallergens
are best tested using blood samples for specific IgE for reasons

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7.3.5.9. Nitric oxide children between the ages of two and 12 years with chronic
Measuring nasal nitric oxide is indicated if PCD (and to some rhinosinusitis(122). All patients had a tap and washout and were
extent CF) is suspected. This non-invasive test can be performed then randomized to cefaclor or placebo PO for one week and
in cooperative children, usually from the age of five onwards. It were followed at six weeks. There was no significant difference
is described in detail in the EPPDTR and in chapter 5.3.5. in resolution rate between the children on cefaclor (64.8%) and
those on placebo (52.5%). The initial maxillary tap and washout
7.3.5.10. Genetic testing could have helped the whole group even before enrolment and
Although there might be a genetic susceptibility for developing influenced the outcome, making the antibiotic irrelevant, and
CRS as discussed in chapter 7.2.1, routing genetic testing is not plain radiographs were used to evaluate the sinuses. Shin and
advised. Whenever there is a suspicion of CF or PCD, genetic colleagues performed a case control study of patients with CRS
testing might be used. For CF, it is possible to test for mutations to evaluate predictors of response to therapy(84). They treated
in the CFTR gene through a blood test or cells taken from a them with antibiotics for 12 weeks and identified responders
cheek swab. Also, sweat testing is advised. For specific details, (n=22) and non-responders (n=36) at the end of therapy by
see chapter 9.4. For PCD, genetic testing is also recommended evaluating persistent symptoms and abnormal Waters views.
and has greatly improved the ability to diagnose the disease The prevalence of allergic diseases and levels of serum IgE and
(see chapter 5.3.5. for more details). This genetic test is part of eosinophil cationic protein as well as the number of serum
a panel of diagnostic tests, which also includes microscopic eosinophils were significantly higher in the non-responder
evaluation of the ciliary function (see chapter 7.3.5.7.) and group.
exhaled nitric oxide levels (see chapter 7.3.5.9.). Iino and colleagues investigated the effect of a low dose
clarithromycin regimen administered for 8-15 weeks in a
group of children (1-14 years) with chronic rhinosinusitis or
Key points | What’s new since EPOS 2012 otitis media with effusion(123). They also followed another
group of children with the same disease with no therapy as
1. In children, differentiating between CRS, AR and control. Sixty-three percent of the children with CRS were free
NAR, and adenoid hypertrophy/adenoiditis can be of disease at the end of therapy and there was no correlation
challenging.
between success of therapy and carriage in the nasopharynx of
2. In children, olfactory dysfunction is hardly reported, erythromycin-resistant S. pneumonia. The authors suggest that
even in the presence of CRS.
the efficacy is related to the potential anti-inflammatory effects
3. As in adults, facial pain or headache as main of clarithromycin. The study is limited by lack of placebo controls
complaints point towards a primary headache
syndrome. and poor reporting of the improvement in disease in the control
4. Most diagnostic tools that are available for adults, group, thus definitive conclusions about the efficacy of long-
can be used in children as well. Additionally, tests for term macrolides in children is not justified.
congenital diseases (genetic testing, nitric oxide and Despite the lack of supportive evidence, it is common but
ciliary morphology) should be considered in selected
cases. unsubstantiated practice to include a course of antibiotics
as part of maximal medical therapy in children with CRS. It
7.4. Management of paediatric CRS and co- is likely that, in many of these instances, treatment targets
morbidities acute exacerbations on top of pre-existing chronic disease.
Careful review of existing data suggests that the role for short
Medical therapy is the mainstay of management of paediatric term antibiotics in CRS is close to nil (see also data in adults).
chronic rhinosinusitis. The most commonly used therapies Furthermore, double blind, placebo-controlled trials with long
include antibiotics, intranasal steroids, and saline nasal irrigation term antibiotics are also negative in adults with a possibility that
(Table 7.4.1.). There is less scientific support for other ancillary certain endotypes might benefit. As seen from the above, there
therapies. are no supportive data for either short or long-term antibiotic
regimens in the treatment of children with CRS.
7.4.1. Antibiotics Intravenous antibiotic therapy for resistant CRS has been
There is no good evidence in the literature to support the use advocated as an alternative to surgical intervention. In a
of antibiotics for CRS in children. Two clinical trials conducted retrospective analysis of 70 children aged 10 months to 15 years
by the same group do not show significant differences between with CRS, Don et al. found that 89% had complete resolution
treatment with placebo and systemic antibiotics in children of symptoms after maxillary sinus irrigation and selective
with clinical criteria commensurate with CRS(121, 122). The studies adenoidectomy followed by one to four weeks of culture-
have significant limitations as the initial study did not randomize directed intravenous antibiotics(124).Only eight patients required
or blind the patients to the treatments and the placebo group subsequent functional endoscopic sinus surgery (FESS).
actually received saline drops which might have been helpful Cefuroxime IV was most frequently used, followed by ampicillin-
in and of themselves(121). Furthermore, one of the arms included sulbactam, ticarcillin, clavulanate, and vancomycin. As expected,
drainage and irrigation of the maxillary sinus before initiating there were complications of intravenous therapy related
antibiotic therapy. The second, later study, was a randomized, both to line placement and the side effects of the antibiotics
double-blind comparison of cefaclor to placebo in 79 healthy administered. More importantly, all the patients had irrigation of

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the maxillary sinuses, and some underwent an adenoidectomy, There is one study that supports systemic steroid
which, as will be detailed later, are in themselves therapeutic. use in children with CRS.
It is therefore not clear from these studies whether the
intravenous antibiotics, per se, were solely responsible for the A randomized, placebo controlled trial evaluating
success rate. Because of these issues, intravenous antibiotics the efficacy of intranasal steroids in children with
are not advocated for the treatment of CRS in children and are CRS is needed.
essentially reserved to treat the complications of ARS.
7.4.4. Intranasal saline
There is currently no evidence to support A Cochrane review analysed randomized controlled trials
treatment of children with CRS with either oral or in which saline was evaluated in comparison with either no
intravenous antibiotics. There is also no evidence treatment, a placebo, as an adjunct to other treatments, or
to support the utilization of prolonged macrolide against other treatments(130). A total of eight trials satisfied
therapy in children with CRS. inclusion criteria of which three were conducted in children.
Proper randomized, controlled trials to evaluate The studies included a broad range of delivery techniques,
the use of oral antibiotics in children with CRS tonicity of saline used, and comparator treatments. Overall there
are needed. was evidence that saline is beneficial in the treatment of the
symptoms of CRS when used as the sole modality of treatment.
7.4.2. Intranasal steroids Evidence also exists in favour of saline as a treatment adjunct.
Intranasal steroids have become an important part of the In one of these studies, 34 children with chronic maxillary
treatment algorithm in light of increasing recognition of rhinosinusitis from 3-16 years were randomized to two groups
inflammation in the aetiology of CRS. To date, there is no receiving 10 drops (1ml) of either 3.5% or isotonic saline three
evidence from randomized controlled trials to support the times a day for four weeks(131). Four patients withdrew (three
efficacy of intranasal steroids in paediatric CRS. A multinational, hypertonic, one isotonic) due to nasal burning sensations.
randomized, double blind study evaluated the safety of Primary outcomes were symptom and radiological scores. Both
mometasone furoate 100 or 200mcg administered either hypertonic and isotonic saline led to significant improvements
once or twice daily in children 6-17 years of age with nasal from baseline in postnasal drip score but only hypertonic saline
polyposis(125). The change in 24-hour urinary free cortisol was the therapy significantly reduced cough score and maxillary sinus
primary endpoint and did not differ between the mometasone opacification as assessed by Waters view. Group comparison
and placebo treated subjects supporting the safety of treatment. favoured the hypertonic saline group for cough score and
Unfortunately, the study was not powered to evaluate efficacy radiologic scores.
but available data showed that mometasone administered Wei and colleagues enrolled 40 children with CRS in a
twice daily was associated with the greatest reduction from randomized, prospective, double-blind study comparing once
baseline compared to placebo in polyp size, congestion and daily irrigation with saline or saline/gentamicin for six weeks(132).
nasal drainage (anterior and posterior). Although evidence is not There were statistically significant improvements in quality of
available to support the use of intranasal steroids in children with life scores at three and six weeks and a reduction of CT scores
CRS, their efficacy in CRS with/without polyps in adults (as detailed after six weeks in both groups with no significant difference
elsewhere), as well as their favourable safety and efficacy profile in between the groups. This suggests that nasal saline irrigation
children with allergic rhinitis support the recommendation that they is an effective therapy in children with CRS and that addition of
be part of first line therapy in children with CRS(47, 126-128). gentamycin to saline provided no additional benefit. A smaller
prospective study enrolled 10 children with CRS refractory to
7.4.3. Systemic steroids antibiotics and intranasal steroids and treated them with high
Systemic steroids have also been used in children with CRS volume nasal irrigation once daily for 30 days(133). Compared
because of their potent anti-inflammatory properties. Ozturk to baseline the children had a significant improvement in
and colleagues treated children with CRS with amoxicillin SN-5 and nasal quality of life scores after saline irrigation. Cho
clavulanate for 30 days and with either a prednisone taper and colleagues performed a randomized, prospective study
course for 15 days or placebo(129). The steroid taper was given at to investigate the efficacy of four weeks of nasal irrigation
the beginning of therapy. Compared to placebo, treatment with with low-concentration hypochlorous irrigation (HOCL,
steroids resulted in significant improvements in CT scan score demonstrated to have bactericidal and fungicidal activity) or
as well as symptoms of cough, nasal obstruction, postnasal normal saline in children with CRS(134). Total symptom scores
discharge and total symptom score. Even though systemic significantly improved with both HOCl and normal saline
steroids are effective, use for CRS in children is limited because nasal irrigation, with no significant difference between the
of safety concerns. two groups. Plain radiographs, obtained at baseline and after
treatment, showed improvement in both groups, which was
Intranasal steroids are recommended for use in significantly greater in the group on HOCl. Hong and colleagues
children with CRS despite the absence of good retrospectively reviewed the records of children with CRS who
level evidence. This is based on safety in children had received nasal saline irrigation for a month and showed
and favorable efficacy data in adults with CRSsNP. that 64% of the children had good compliance and carried out

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the irrigations during the follow up period(135). Improvement analogue score, nasal discharge and obstruction scores, number
of symptoms and nasal endoscopy findings were seen in the of days with rhinitis attacks per month and number of days with
73% of the compliant patients and the rate of surgery was antibiotic use per month were significantly decreased in the
significantly lower (16.3%) for these children compared to the prevention group versus the control group (nasal saline).
ones who did not show good compliance with therapy (42.9%). Treatment of children with CRS for concomitant gastro-
In another retrospective review evaluating compliance with oesophageal reflux disease (GORD) has been suggested by
saline irrigation therapy, irrigations were well tolerated some weak evidence. Phipps and colleagues conducted a
by more than 80% of children and adolescents and when prospective study of paediatric patients with CRS and found
questioned, over 70% of patients / parents thought there was an that 63% of children with CRS had GORD documented by
improvement in nasal symptoms with irrigation(136). Based on the pH probe(43). In addition, 79% experienced improvement in
above data and the safety of this therapy, saline nasal irrigation rhinosinusitis symptoms after medical treatment of GORD. A
has become mainstay of treatment of CRS in the paediatric retrospective study that lacked a placebo control showed that
age group. Indeed, in a survey of paediatric otolaryngologists treatment for GORD in patients with CRS allowed many patients
and rhinologists in the US, 93% and 97% of the respondents to improve and avoid surgery(44). These studies were not blinded
respectively reported using nasal saline irrigations as part of and did not include a placebo group. They also do not account
appropriate medical therapy in paediatric CRS(124, 137, 138). for spontaneous improvement in CRS symptoms in many
children over time. Therefore, routine anti-reflux treatment of
Saline nasal irrigation is recommended for children with CRS is not warranted. This conclusion is supported
the treatment of CRS in children. Addition of by the consensus statement on paediatric rhinosinusitis(47).
antibiotics to saline irrigations is
not recommended. We do not recommend the addition of any specific
ancillary therapy to the treatment regimen of
7.4.5. Ancillary therapies children with CRS. Exceptions are using ancillary
There is no good evidence to support ancillary therapies such therapies when indicated for concomitant disease
as antihistamines (intranasal or oral), leukotriene modifiers, such as allergic rhinitis or GORD.
decongestants (intranasal or oral), or mucus thinners in CRS in
children. The use of these agents is reserved for treatment of
concomitant symptomatic allergic rhinitis. Chen and colleagues 7.4.6. Surgical treatments
performed a prospective study that evaluated the efficacy of Surgical intervention is considered for patients with CRS who
bacterial lysate (of 21 strains of eight bacteria) administered 10 have failed appropriate medical therapy (and, less commonly,
days per month for three months on recurrence of rhinosinusitis in complicated acute rhinosinusitis). Adenoidectomy with
symptoms in children who had entered a remission phase or without antral irrigation and functional endoscopic sinus
after treatment for CRS(139). At one year of follow up, the visual surgery (FESS) are the most commonly used modalities.

Table 7.4.1. Evidence supporting therapy of CRS in children.

Level of
Therapy GRADE recommendation
evidence
Antibiotics 1b (-) There is no high level evidence to support the efficacy of either short or long term antibiotics
for CRS in children.
Nasal corticosteroids 5 There is no evidence regarding the efficacy of intranasal steroids in the treatment of CRS in
children. Nevertheless the EPOS steering group is supportive of their use in light of their anti-
inflammatory effects and excellent safety record in children.
Systemic Steroids 1b (+) Adding a taper course of systemic steroids to an antibiotic (not effective on its own) is more
effective than placebo in the treatment of paediatric CRS. Judicious use of this regimen is
advised considering systemic side effects.
Saline Irrigation Ib (+) There are a few clinical trials demonstrating the efficacy of saline irrigations in paediatric
patients with CRS. The EPOS steering group is supportive of the use of saline in light of the
excellent safety record in children.

Adenoidectomy 4 Adenoidectomy is effective in younger children with symptoms of CRS. The EPOS steering
group supports adenoidectomy in young children refractory to appropriate medical therapy.
FESS 4 FESS is safe and effective for the treatment of older children with CRS refractory to medical
therapy or previous adenoidectomy.

CRS, chronic rhinosinusitis; FESS, functional endoscopic sinus surgery; AMT, appropriate medical therapy.

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7.4.7. Adenoidectomy underwent an adenoidectomy for CRS, 32 of which also had a

Adenoidectomy is often the first-line surgical option in children sinus wash and culture via the middle meatus(144). All children
with CRS, with success rates ranging between 47 and 58% received postoperative antibiotics for two weeks and outcomes
of cases(140).Anatomic obstruction and/or biofilm formation were assessed at least 12 months postoperatively. Patients
and the notion of the adenoids as a bacterial reservoir are the who underwent an adenoidectomy alone had a 61% success
primary underlying rationale for adenoidectomy. In general, the rate at 12 months compared with children who underwent an
revision rate for adenoidectomy is very low (1.9%)(141). In a meta- adenoidectomy with a sinus wash, who had a higher success
analysis of the results of adenoidectomy for symptoms of CRS in rate of 88%. Children with a high Lund-Mackay CT score and
children, Brietzke and colleagues included eigth studies with a asthma had better success with an adenoidectomy with a wash
cumulative success rate of 69%(33). Ramadan and Tiu reported on compared with an adenoidectomy alone. These data suggest
the failures of adenoidectomy over a 10-year period and found that antral irrigation should be considered in addition to an
that children younger than seven years of age and those with adenoidectomy in children with asthma who have more severe
asthma were more likely to fail after an adenoidectomy and go disease on preoperative CT scans.
on to require FESS(142).
Clearly, adenoidectomy seems to help irrespective of whether Adenoidectomy with/without antral irrigation is
the cause of the symptoms is adenoiditis or CRS, which are the simplest and safest first procedure to consider
difficult to distinguish on clinical grounds. In a study that in younger children with symptoms of CRS.
attempted to address this issue, Bhattacharyya and colleagues
evaluated CT scans of two paediatric populations: 66 7.4.8. Balloon sinuplasty
children with CRS about to undergo surgery and 192 children Balloon sinuplasty was approved by the U.S. Food and Drug
undergoing a CT scan for non-sinusitis related complaints(105). Administration for use in children in the United States in 2006,
Lund-Mackay scores of 2 or less had an excellent negative and a preliminary study in children has shown the procedure
predictive value, whereas scores of 5 or more had an excellent to be safe and feasible(145). Since EPOS 2012, multiple studies
positive predictive value for CRS, with sensitivity and specificity have been performed evaluating the efficacy of balloon
of 86% and 85%, respectively.A score of 3-4 was considered sinuplasty in paediatric CRS(146-151). Many of the studies included
equivocal and more weight needed to be placed on the clinical other procedures (adenoidectomy, sinus irrigation, anterior
picture and endoscopic exam in these cases. It, therefore, stands ethmoidectomy, turbinate reduction, ESS) that were performed
to reason that a child with the typical symptoms, and a CT-LM simultaneously and might have contributed to success.
score <5 probably has adenoiditis. Ramadan and colleagues Furthermore, none of the studies included appropriate control
hypothesized that adenoidectomy would be more successful groups with no intervention to account for spontaneous
therapy for children with adenoiditis (low CT score) as opposed resolution of symptoms in children.
to CRS (high CT score)(143). To this end, they reviewed their To address whether balloon dilation provides additional
patients with symptoms of CRS who underwent adenoidectomy benefit to maxillary sinus irrigation, Gerber and colleagues
and divided them into two groups based on their Lund Mackay prospectively randomized children (ages 2-12 years.) with
CT score: the CRS group (Lund-Mackay score ≥5) and the CRS to undergo either adenoidectomy with maxillary sinus
adenoiditis group (Lund-Mackay score <5). When the success irrigation (with 18 gauge needle) or adenoidectomy with
rate of adenoidectomy at one year was evaluated, it was 65% for maxillary sinus balloon dilation and irrigation(152). While both
the adenoiditis group and 43% for the CRS proper group (with groups showed significant improvement in SN-5 scores at both
high CT scores). This supports the notion that adenoidectomy postoperative time points, there were no significant differences
is more effective when sinus disease is not severe and the between the groups suggesting lack of additional value of
symptoms are related to adenoiditis. maxillary sinuplasty. Ference and colleagues analysed data
Bettadahalli and colleagues report significant improvements from ambulatory surgery databases in four states to study the
in symptom severity scores before and six months after utilization of balloon catheter dilation (n=316) compared to
adenoidectomy in children with CRS(143). Using the SN-5 traditional FESS (n=2346) in patients under 18 years of age.
instrument, a total of 53 out of 60 children (88%) had improved Balloon dilation was used in 11.9% of paediatric sinus surgery
quality of life scores at the end of follow up with a significant and had higher average charges with no decrease in operating
improvement in QOL scores in all domains compared to room time compared to procedures that only utilized FESS(153).
baseline. The consensus statement of the American Academy In a cost-effectiveness study based on decision tree analysis of
of Otolaryngology-Head and Neck Surgery supported different surgical scenarios in children with CRS, adenoidectomy
adenoidectomy as an effective first-line surgical procedure as the sole first procedure was found to be more cost effective
for children up to 12 years of age and was unable to reach than adenoidectomy with balloon sinus dilation(154).
consensus on the utility of adenoidectomy in patients age 13 From the above, it is clear that balloon dilation in children is safe
years and older due to the absenceof supporting data for that but efficacy and cost effectiveness has no supporting evidence.
age group(47). Therefore, this modality was not endorsed by the consensus
Maxillary antral irrigation is frequently performed in conjunction panel of the American Academy of ORL(47), and similarly, is not
with an adenoidectomy. To evaluate the efficacy of this added recommended by the EPOS2020 steering group.
intervention, Ramadan and colleagues analysed 60 children who

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There is no solid evidence to support the use of and without polyposis(160, 161). However, there are no RCT and the
balloon sinuplasty in the management of CRS in possibility of spontaneous improvement cannot be excluded.
children. This modality is not recommended as On average, the postoperative follow up periods ranged from
part of the surgical armamentarium. 1-8 years.

7.4.9. Functional endoscopic sinus surgery FESS is a safe and possibly effective surgical
There is some indication that FESS is superior to medical modality children with CRS and can be used as
management. In a 10-year follow-up of patients who underwent after failure of adenoidectomy in older children
FESS versus medical management alone, surgery resulted in a refractory to medical therapy. Decisions on use
greater relief of nasal obstruction and purulent discharge, as depends on severity of disease, age and existing
well as higher parent satisfaction(155). A prospective study by co-morbidities.
Ramadan et al. examined the outcome differences between FESS
and adenoidectomies, and found that FESS resulted in improved As to predictors of success of FESS in children, the data is scant.
symptom status six months post intervention(156).Furthermore, El Sharkawy and colleagues followed 87 patients prospectively
retrospective questionnaires to the parents of children having after FESS: 45 patients had allergy, 36 had no allergy, and six
undergone FESS for the treatment of CRS indicated a success had nasal polyposis(162). After a mean postoperative follow up
rate that varied between 70 and 80%(157).A systematic review of of 28 months, the success rate (determined by improvement in
FESS case series results has shown that surgery is effective at CT score, nasal examination and postoperative symptoms) was
reducing symptoms, with an 88% success rate(158). A more recent not different between the groups and ranged from 85.7% to
systematic review, confirms these positive results showing a 93%. The presence of asthma and higher severity of disease on
positive outcome in between 71-100% of children after FESS as CT decreased the subjective postoperative improvement and
well as a significant improvement in quality of life after surgery performing an adenoidectomy with FESS increased it. In another
which was evaluated in a subset of the studies(159). In that review, study, Lee and colleagues retrospectively reviewed the charts of
the rate of major complications following paediatric FESS was children who received FESS for CRS and designated 21 patients
0.6%, and the rate of minor complications 2%. Other studies with protracted disease and 32 patients as resolved based on
support these conclusions with improvement in symptom scores the presence or lack thereof of mucopurulent discharge for more
and quality of life measures after FESS in children with CRS with than three months after FESS(163). Sinonasal polyposis, history of

Table 7.4.2. Functional endoscopic sinus surgery (FESS) for paediatric CRS.

Type Intervention Outcome measure Result

Lusk 2006(155) Retrospective, age- Endoscopic sinus Post intervention symptom ESS resulted in significant improvements in
matched, cohort surgery or medical scores (10 years after therapy) nasal obstruction and rhinorrhoea. Parental
outcome study n=67 management assessment of improvement and satisfaction
were higher in the ESS group
Ramadan 1999(156) Prospective, ESS or adenoidectomy Symptoms 6 months postop Significantly more children had improved
nonrandomized and need for revision surgery symptoms with ESS (77%) compared to
study, n=66 enrolled, adenoidectomy (47%).
n=61 had follow up
Hebert 1998(158) Systematic literature ESS Positive outcome after ESS Positive outcome for published, unpublished
review of studies on 8 articles (n=832 and combined data was 88.4%, 92%, and
outcomes of ESS patients) and one set 88.7% respectively.
of unpublished data
were evaluated

Vlastarakos Systematic literature 15 studies with a Positive outcome of ESS Positive outcome between 71 and 100% of
2013(159) review of ESS total number of 1301 operated children
treated patients
Jiang 2012(160) Prospective study ESS SNOT-20 before and 3-8 years Significant improvement in quality of life after
including 270 postop surgery
patients with ESS
and 273 healthy
controls

Cornet 2013(161) Combined ESS, n=44 (18/44 had R-SOM quality of life Significant improvement in R-SOM
prospective and both pre and post op questionnaire obtained postoperatively
retrospective study data) an average of 4 years post
operatively

ESS, endoscopic sinus surgery; SNOT-20, sino-nasal outcome test 20; R-SOM, rhinosinusitis outcome measure.

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allergic rhinitis, and male gender were more frequently observed rhinosinusitis.
in the protracted group than the resolved group. As seen from this section, much remains to be done relating to
Many advocate a limited approach to FESS in children, consisting investigating best surgical practices for CRS in children. It is clear
of the removal of any obvious obstruction (such as polyps and that initial adenoidectomy with/without irrigation is effective
concha bullosa), as well as an anterior bulla ethmoidectomy, and followed by FESS (Table 7.4.2.). Ideally, prospective, randomized,
a maxillary antrostomy. This approach typically yields significant multicentre trials should be conducted where the severity of
improvements in nasal obstruction (91%), rhinorrhoea (90%), disease on CT scans and the symptom questionnaire would be
PND (90%), headache (97%), hyposmia (89%), and chronic cough matched preoperatively and the following interventions would be
(96%)(164). Whereas second look procedures were common after compared: adenoidectomy alone, adenoidectomy with a wash,
FESS to clean the cavities, the advent of absorbable packing has and endoscopic sinus surgery.
made it possible to avoid a second look procedure. Walner et al.
found comparable rates of revision sinus surgery in children with
and without a second look procedure, suggesting that it may
not be necessary(165). Ramadan and colleagues observed that Key points | What’s new since EPOS 2012
the use of corticosteroids during an initial FESS might obviate a
second look procedure(166).Younis, in a review of available data,
suggested that a second look is not necessary in most children 1. There is no (new) evidence to support the use of either
after FESS(167). Initial concerns about possible adverse effects of short or long-term antibiotics in the treatment of CRS in
FESS on facial growth have been allayed by a long-term follow- children.
up study by Bothwell and colleagues that showed no impact of 2. Saline irrigation and intranasal corticosteroids remain
FESS on qualitative and quantitative parameters of paediatric acceptable modalities for the medical therapy of children
with CRS.
facial growth, as evaluated up to 10 years postoperatively(168).
3. Adenoidectomy is useful in the surgical therapy of CRS in
Current literature supports the use of FESS in children with CRS young children, especially if there is limited pathology on
who have failed appropriate medical treatment and possibly paranasal sinus CT scans.
an earlier adenoidectomy. Other indications include orbital and
intracranial complications of ARS, obstructing nasal polyposis
and severe disease in cases of CF, and patients with allergic fungal

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136. Jeffe JS, Bhushan B, Schroeder JW, Jr. Nasal saline Balloon Catheter Sinuplasty: a Randomized Long-term outcome of facial growth after functional

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endoscopic sinus surgery. Otolaryngol. Head Neck

Surg. 2002;126:628-34.
169. Ramadan H, Makary C. Can computed tomography
score predict outcome of adenoidectomy for
chronic rhinosinusitis in children. Am J rhinol allergy
2014;28:80-2.

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8. Concomitant diseases in patients with chronic

rhinosinusitis
8.1. Role of allergy in chronic rhinosinusitis 8.1.2. Pathophysiology

8.1.1. Epidemiology and predisposing factors Allergic inflammation of the nasal mucosa causes swelling of
The contribution of allergic inflammation to chronic the mucosa with reduced mucociliary clearance(17, 18), that may
rhinosinusitis (CRS) development, severity and therapeutic contribute to the reduced clearance of pro-inflammatory agents.
response are still not fully understood. It seems logical that In addition, patients with CRSwNP usually present with type 2
allergic inflammation of the nasal mucosa with mucosal swelling helper T-cell (Th2) cytokine-mediated inflammation in the nasal
and delayed mucociliary clearance might contribute to the mucosa, which is similar to allergic inflammation, particularly
development and/or severity and/or therapeutic response of in individuals with predominant eosinophil infiltration in
CRS(1-3). Literature is however not conclusive on the contribution tissue(19-21).
of allergic inflammation to CRS, both in chronic rhinosinusitis Recently, CRS has been further classified into different
without nasal polyps (CRSsNP) as well as chronic rhinosinusitis endotypes based on the association with type 1 or 2
with nasal polyps (CRSwNP)(4). In a systematic review Wilson et inflammatory patterns(12, 22, 23). Likewise, allergy is also
al. found nine articles that examined the relationship between characterized by type 2 inflammation(23), indicating the
allergy and CRSsNP, with four articles showing an association inflammatory similarity between allergy and CRS. However, the
and five articles showing no association. underlying mechanisms of how allergy influences CRS are very
In CRSwNP they identified 18 articles, with ten showing an different (see also chapter 5.2.2.).
association, seven none and one a possible link / relationship Allergic rhinitis occurs through host sensitization to foreign
Four studies directly compared the role of allergy in CRSwNP proteins (allergens) across a mucosal barrier via dendritic cells
and CRSsNP and, again, the results were mixed. No articles and naive CD4-positive lymphocytes, with the generation of
examined the outcomes of CRSsNP or CRSwNP following allergy antigen-specific Th2 lymphocytes and immunoglobulin E (IgE)-
treatment. The authors concluded that the role of allergy in secreting plasma cells. Subsequent allergen challenge across the
CRSwNP and CRSsNP continues to be controversial, with the nasal mucosa of sensitized individuals may result in cross-linking
very low level of evidence. of IgE bound to the surface of mast cells with degranulation,
Since 2014 a few noteworthy studies have been published. mediator, chemokine and cytokine release, leading to the
A more recent non-systematic review points to the fact that recruitment of other inflammatory cells. In the unoperated
different phenotypes / endoptypes of CRS, such as allergic state, allergens should have limited access to the sinus mucosa,
fungal rhinosinusitis (AFRS) or central compartment atopic but they can certainly trigger inflammation of the nasal cavity
disease(5), may have variable associations with allergy(6). This reducing sinus drainage.
point was also made in a recent study from the UK that analysed Severe CRS is, in general, not regarded as an allergic disease, but
differences between different phenotypes of CRS and controls co-existing allergic rhinitis may accentuate Type 2 inflammatory
in secondary care(7) and found the prevalence of self-reported mechanisms of CRS. A recent study in the Chinese population
inhalant allergy to be 20% in CRSwNP versus 31% in CRSwNP showed distinct mucosal immunopathologic profiles in atopic
with the main difference in house dust mite (HDM) sensitization and non-atopic CRSsNP patients, suggesting that in the Chinese
(9% versus 16%). population the comorbid CRSsNP and allergic rhinitis (AR) might
Earlier studies also showed that perennial allergy seems to be be more related to Type 2 mechanisms, whereas the phenotype
much more common than seasonal allergy in patients with CRSsNP without AR exhibits more non-Type 2 mechanisms(24).
CRS(1, 8) and positivity for perennial allergy was a risk factor of Allergens typically possess intrinsic protease activity that can
CRS(9, 10). interact with epithelial cells through three principle pathways:
The effect of atopy on CRS symptom severity is unclear. Studies direct effects on junctional proteins, reaction with cell surface
show no difference in symptom severity between patients with protease-activated receptors and toll-like receptor 4 (TLR4)-
or without atopy in CRSwNP patients(2, 11-15). But in patients with dependent epithelial activation(25). Protease activity of allergens
CRSsNP the outcomes are more diverse with two recent studies may elicit the release of epithelial-derived Type 2-driving
showing a difference(11, 16) and two others no difference(2, 13). cytokines and chemokines, some of which have also been
Table 8.1.1. summarizes recent studies after EPOS2012 reporting implicated in CRS. In terms of potential overlap between AR and
on the association between atopic sensitisation and CRS. CRS pathogenesis, Kouzaki et al. showed lower host expression
of two protease inhibitors (cystatin A and SPINK5) in the nasal
epithelial cells extracted from patients with eosinophilic CRS
compared with control and non-eosinophilic CRS groups(25).

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Table 8.1.1. The association of sensitisation with CRS. Recent studies after EPOS2012.

Author Patients Effect Department

Benjamin et al. CRSsNP The prevalence of atopy was 52% in CRSsNP and 76% in CRSwNP. Tertiary Allergology
2019(11) CRSwNP The atopic patients had more severe radiographic disease compared with non- Department, ENT
atopic patients in CRSsNP.

Shen et al. CRS The ImmunoCAP test was 51% positive in CRS patients. Department of
2019(2) The peripheral eosinophil count in the allergic group was higher than the non- Otolaryngology
allergic group.

Ho et al. CRS Positive allergen sensitization was 53% in CRS patients. Rhinology. and Skull Base
2019(16) Atopy was associated with younger age at the time of surgery, CRSwNP, asthma, Research Group
and eosinophilic CRS.
Atopy was also associated with increased severity in nasal symptom score and
worse scores in the loss of smell/taste and need to blow nose questions in the CRS
population.
Philpott et al. CRSwNP The prevalence of self-reported confirmed inhalant allergy was 13.1% in control, Population study
2018(7) CRSsNP 20.3 in CRSsNP, 31.0% in CRSwNP and 33.3% in AFRS respectively.
allergic fungal The self-reported house dust mite allergy was significantly higher in CRSwNPs
rhinosinusitis (16%) compared to CRSsNPs (9%).
The prevalence of self- reported aspirin sensitivity was 2.26% in control, 3.25% in
CRSsNP, 9.61% in CRSwNP and 40% in AFRS respectively.
Hamizan et al. Patients had Diffuse oedema and polypoid oedema demonstrated the strongest association Department of
2017(482) undergone with inhalant allergy. Otolaryngology–Head and
nasal Neck Surg
endoscopy

Li et al. CRSwNP Atopic patients were younger than non-atopic patients. Department of
2016(12) There was no association between atopy status and either disease severity or Otorhinolaryngology – Head
recurrence in patients with chronic rhinosinusitis with nasal polyps. and Neck Surg

Yacoub CRSwNP 60% of patients were atopic. Patients with atopy had higher recurrence rate.
2015(483)
Green et al. CRS In CRS patients, 73% had at least one of the postive allergen extracts in the skin Allergy and Clinical
2014(8) prick test compared with 32% of the control patients with chronic idiopathic Immunology Branch
urticarial.
The perennial allergy was more common than seasonal allergy in CRS

CRS, chronic rhinosinusitis; CRSsNP, chronic rhinosinusitis without nasal polyps; CRSwNP, chronic rhinosinusitis with nasal polyps.

This suggests that an imbalance of proteases and protease 8.1.2.1. Central compartment atopic disease and allergy in
inhibitors within the epithelial barrier may contribute to the CRS
pathogenesis of Type 2 diseases in general(26). As we advance our
understanding of the interactions between barrier immunity Central compartment atopic disease (CCAD) is a recently
and the environment as a function of time, the relationship described variant of CRS that is significantly associated with
between allergens and CRS pathogenesis should become allergy. In 2014, White et al.(32) first presented polypoid and
clearer. edematous changes in the middle turbinate in 25 patients who
In patients with CRSwNP, local polyclonal IgE is present in tested positive for inhalant allergens. The proposed aetiology
the polyp tissue(27-29). In atopic nasal polyp patients, local IgE was that the anterior aspect of the middle turbinate is exposed
production can be the effect of stimulation with allergens(30). to inhalant allergens via nasal airflow. Brunner et al.(33) have
However, local hyperimmunoglobulinemia is also present similarly shown a higher association of allergen sensitization
in non-atopic patients, meaning that elevated IgE levels in patients with isolated middle turbinate changes than in
result from other pathways as well. The cytokines interleukin those with diffuse polyposis. DelGaudio et al.(18) revealed that
(IL)25 and IL33 can induce IgE-mediated inflammation by other central structures, including the posterior–superior
stimulating a non-T cell source to produce IL4. Alternatively, nasal septum, middle turbinates, and superior turbinates, are
IgE is produced by stimulating innate lymphoid cells to release involved. Hamizan et al.(5) reported that a central pattern of
IL4, IL5, and IL13. IL5, and IL13, namely innate lymphoid mucosal disease is significantly associated with allergy. Overall,
cells (ILC). A role of mast cells in enhancing eosinophilic this central pattern of inflammatory changes is highly associated
inflammation in chronic rhinosinusitis is suggested(31). with allergy. Further studies must be conducted to validate the
aetiology and clinical course of this CRS subtype.

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8.1.3. Diagnosis and differential diagnosis (both innate immunity)(36). In some cases, there is a combination
A suggestive history supplemented by confirmation of of defects.
sensitization by demonstration of allergen-specific IgE using CRS is primarily associated with conditions that cause
skin prick testing or blood analysis is as important in CRS humoral deficiency, and in this section the discussion of
patients as in allergic rhinitis patients. However, there is a primary immunodeficiency will be largely confined to
significant overlap in symptomatology between CRS and AR. AR hypogammaglobulinaemia(37).
is a very prevalent disease (see also 5.3.1.). It is not always easy
to evaluate the role of sensitization to allergens in patients with 8.2.1. Epidemiology
CRS especially in perennial sensitisations. If in doubt, optimal There is good evidence that immune deficiencies are more
treatment of the AR seems advisable. common in patients with CRS. A meta-analysis, which included
1418 individuals with CRS from 13 studies, found that 23% of
8.1.4. Treatment patients with difficult- to-treat CRS and 13% of individuals with
Reports on the efficacy of allergy therapy in improving the recurrent CRS had immunoglobulin deficiencies(38). However,
symptoms and quality of life of patients with CRS are limited. many of the patients diagnosed in the series included in the
In general, the therapeutic principles for concomitant allergic meta-analysis had subclass or specific antibody deficiency.
diseases, such as allergic rhinitis, including allergen avoidance, The laboratory criteria for diagnosing these conditions, and
pharmacotherapy and allergen-specific immunotherapy, are the clinical implications once the diagnoses are made, are not
relevant in patients with CRS. The use of nasal corticosteroids uniformly accepted. Many of the studies of the meta-analysis
is the mainstay of treatment for both patients with chronic were performed in tertiary referral centres and this may have
rhinosinusitis and allergic rhinitis. One study observed less biased the population of patients studied towards having
improvements in symptom scores, polyp score, nasal peak underlying immune defects. These reservations aside, it is likely
flow, and overall response to therapy in the skin prick test that the prevalence of hypogammaglobulinemia in CRS patients
positive group than in the negative skin test group treated with is very significantly higher than in the general population.
budesonide nasal spray(34). However, the presence of allergy
showed no influence on the cumulative consumption of steroids 8.2.2. Pathophysiology
between baseline and after one year in patients with CRSwNP, Most cases of hypogammaglobulinaemia are caused by
which indicated that the specific treatment of allergy in patients genetic mutations. The majority of cases are sporadic,
with nasal polyps may not be beneficial(14). Current studies although a family history of hypogammaglobulinaemia would
yield insufficient evidence to recommend oral or intranasal raise diagnostic suspicions. Immunoglobulins primarily act
H1-antihistamines in non-allergic CRS patients (see 6.1.8. ). A by opsonizing encapsulated bacteria, and consistent with
systematic review evaluating the effect of immunotherapy that action patients with hypogammaglobulinaemia tend
found no RCTs and concluded after highlighting the paucity to be susceptible to infections with Streptococcal species,
of the data that there is weak evidence to support the use of Haemophilus influenzae and Moraxella catarrhalis(39). Patients
immunotherapy(IT) as an adjunctive treatment in CRS patients, with hypogammaglobulinaemia are predisposed to developing
particularly in the postoperative period(35). rhinosinusitis, pneumonia, bronchiectasis and otitis media.
In conclusion: allergic rhinitis and CRS both benefit from nasal
corticosteroids. There is insufficient quality evidence to advise 8.2.3. Diagnosis and differential diagnosis
other treatments, such as antihistamines or immunotherapy, in The causes of primary hypogammaglobulinaemia are:
allergic patients with CRS. More studies are needed. 1. X-linked agammaglobulinaemia
2. Common variable immunodeficiency (CVID)
3. Selectiveimmunoglobulin A (IgA) deficiency
8.2. Immunodeficiencies and their role in CRS 4. Immunoglobulin G (IgG) subclass deficiency
5. Selective antibody deficiency
Conditions that are associated with immunodeficiency are
of clinical importance to rhinologists because some patients There are other very rare causes such as Good’s syndrome, which
who present with CRS were predisposed to their condition is CVID associated with thymoma and Hyper-IgE syndrome
by an underlying immunodeficient state. Immunodeficiency in which patients have eczema and Staphylococcal furuncles.
conditions may cause CRS patients to respond less favourably The number of causes of primary hypogammagloblinaemia
to standard therapies, and some patients require specific keeps expanding as the genotypes of these conditions are
treatment for their immunodeficiencies in order for their CRS to determined(40).
be optimally treated. X-linked agammaglobulinaemia presents with recurrent
Immunodeficiency states can be primary or secondary to other respiratory tract infections in infant boys. Symptoms develop
diagnoses or to immunosuppressive medication. Primary after age six months when passive protection from maternal
immunodeficiency conditions may be categorized according immunoglobulins has been lost.
to whether the deficiency affects B cells (humoral immunity), T Common variable immunodeficiency (CVID) is more likely than
cells (cellular immunity), phagocytes or the complement system X-linked agammaglobulinaemia to present to rhinologists

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because its age of onset is often in adulthood. It is diagnosed by the measurement of serum-specific antibody titers (usually
low immunoglobulin levels and a poor response to vaccinations. IgG) in response to vaccine antigens. This approach involves
In 2015, the International Consensus Document on CVID was immunizing a patient with protein antigens (e.g. tetanus
published proposing six diagnostic criteria for this condition, toxoid) and polysaccharide antigens (e.g., pneumococcus) and
which have clarified the clinical and laboratory aspects of its assessing pre- and post-immunization antibody levels(44).
diagnosis(41). Patients with CVID are also predisposed to some
autoimmune conditions as well as certain malignancies such as For CRS patients suspected of having
gastric lymphoma. humoral immunodeficiency because of the
IgA deficiency is the most common immunoglobulin characteristics of their presentation or their
deficiency in the general population. The prevalence has been response to treatment, measurement of serum
reported variably between 1:173 and 1:3024(42). Most patients immunoglobulin levels is the key investigation. If
are asymptomatic, but a deficiency of IgA would appear to the levels are normal, but the suspicion of humoral
predispose patients to rhinosinusitis and allergies(36). immunodeficiency is high, referral to a clinical
IgG has four variants, or subclasses, each of which has slightly immunologist is optimal.
different functions. Subclass deficiencies are diagnosed when
the serum IgG level is normal, but one or more of the subclasses
are found to be deficient. Laboratory determination (both 8.2.5. Treatment
analysis and normal values) may differ between laboratories. IgG For many patients with CRS who have subtle humoral
subclass deficiency is a controversial diagnosis and experts are immundeficiencies on laboratory testing, specific treatment
increasingly disagreeing about the importance of this finding options are not available (such as IgA deficiency) or may
as a cause of repeated infections(37). The overdiagnosis of IgG not be indicated (such as in IgG subclass deficiencies). It is of
subclass deficiency as a cause of presumed immunodeficiency paramount importance that the diagnosis and its implications
is not uncommon, and may lead to unnecessary long-term are established in collaboration with a clinical immunologist.
treatment. It is possible for some results to be overinterpreted, leading
Selective antibody deficiency (SAD) is diagnosed when patients to unnecessary treatment with IgG replacement or excessive
have a normal serum immunoglobulin levels but attenuated antibiotic prescribing.
responses to polysaccharide antigens(43). The antibody response
to polysaccharide vaccines such as Pneumovax is determined, 8.2.5.1. Immunoglobulin replacement therapy
however the diagnostic criteria are not universally accepted, The mainstay of treatment of hypogammaglobulinaemia is
again leading to the possibility of overdiagnosis. immunoglobulin replacement therapy. The immunoglobulin
CRS secondary to hypogammaglobulinaemia may present in a fraction is extracted from the plasma of a large number of
manner identical to idiopathic CRS. This explains why there is donors so that passive immunity to an enormous number of
often a long delay between initial presentation and diagnosis antigens can be achieved. The optimal route of administration
of an underlying immunodeficiency. There are some clinical (intravenous or subcutaneous) has not been established(45).
features that may elevate suspicion: recalcitrance to standard However, the decision about whether to start a patient on
treatments (and particularly rapid recurrence of symptoms after intravenous immunoglobulin therapy and ongoing oversight
stopping antibiotics) and association with lower respiratory of this treatment would in almost all circumstances involve a
tract infections (pneumonia, particularly if recurrent, or clinical immunologist.
bronchiectasis). A series of 31 patients from a single institution, most of whom
had CVID, were followed closely. They had fewer sinus and
The testing of immune function in all patients who chest infections, and a significant reduction in Lund-Mackay
present with CRS is almost certainly unwarranted scores while receiving immunoglobulin replacement therapy(46).
as it is likely to produce more false positive results However, an earlier European study did not find such a
than true positives. However, it is recommended favourable impact of therapy(47).
that the above clinical features are used to identify
those patients who warrant some form of immune Various antibiotic agents and regimens have been
testing for testing. used, and often at half the usual dose. Periodically
changing antibiotics monthly to every 6 months
8.2.4. A work-up by ENTs before referring to immunologists is sometimes practiced in order to reduce the
It is not clear how much of the immunological testing development of resistance, but there are no studies
should be undertaken by the rhinologist before referral to an that evaluated the efficacy of this practice(48).
immunologist, and this decision may reflect the individual
knowledge and expertise of the rhinologist. 8.2.5.2. Prophylactic antibiotics
Further studies, such as antibody responses to vaccines Although long-term antibiotic therapy has transformed
and flow cytometry can then be organized by an expert the outcomes in some types of primary immunodeficiency
in the interpretation of these tests. The best approach for syndromes, controlled trials are few in the context of
confirming a diagnosis of an antibody-deficiency disorder is hypogammaglobulinaemia(48). One long-term observational

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study of CVID patients treated with prophylactic antibiotics The best screening tests for ORL surgeons to request are
as they continued to have infections despite immunoglobulin serum immunoglobulin levels. More sophisticated tests
replacement therapy, failed to find a reduction in the frequency of immune function should generally be undertaken by
of infections(49). clinical immunologists, as their interpretation requires
specific expertise. The decision to treat with intravenous
8.2.5.3. Vaccinations immunoglobulin replacement and the supervision of
It has been found that some patients with low antibody levels to that treatment should ideally be made by a clinical
pneumococcal serotypes will respond favourably to conjugated immunologist. The potential influence of secondary causes
pneumococcal vaccinations, reducing their requirement for of immunodeficincies (resulting either from co-morbidities
antibiotics(50). or immunosuppressive therapy) should be considered in the
management of CRS patients.
8.2.5.4. Surgery
The relative efficacy of surgery in the context of
hypogammaglobulinaemia compared to idiopathic CRS has 8.3. Lower airway disease including asthma in
not been extensively reported. A nested case control study relation to CRS
comparing the outcome of functional endoscopic sinus surgery
(FESS) in patients with immunodeficiency (mostly secondary) 8.3.1. Introduction
and idiopathic CRS patients found that the immunodeficient Health care providers dealing with CRS proactively ask for the
patients responded as well as their controls(51). presence of lower airway symptoms such as cough, wheezing,
shortness of breath, and are ideally aware of the diagnostic and
8.2.6. CRS and secondary immune deficiencies therapeutic guidelines like EPOS and GINA to optimally treat
both CRS and asthma(56-58).
In a recently reported study in patients who received rituximab Lower airway inflammation often co-exists in CRS, with up
for management of systemic autoimmune disorders, moderate- to two thirds of patients with CRS affected by comorbid
to-severe hypogammaglobulinaemia was seen in 26% of asthma(7, 59, 60), chronic obstructive pulmonary disease (COPD)
patients, but approximately 50% of these cases improved or bronchiectasis(61, 62) (figure 8.3.1.). Pulmonary function in
and resolved spontaneously(53). In addition, immunoglobulin CRS patients is significantly reduced compared to non-CRS
replacement was initiated in 4.2% of patient due to recurrent individuals, even in patients that do not report bronchial
infections. symptoms(63). Rhinitis / rhinosinusitis is demonstrated to be the
A recent review on the HIV-associated manifestations in most prevalent co-morbidity of asthma(64). Asthma, COPD and
otolaryngology underscores the high prevalence of CRS in HIV bronchiectasis patients have a reported prevalence of CRS in
patients(54). These authors also mention that physicians need up to 57%(59, 65), 40%(62), and 45 %(66, 67) respectively. The HELIUS
to have a high level of suspicion for atypical pathogens in this study showed CRS to be associated with adult-onset asthma(68)
clinical context. Also iron overload, protein-energy malnutrition, and the Asthma Clinical Research Network demonstrated that
or transplant patients on azole prophylaxis are also at risk(237). CRS is associated with increased risk of asthma exacerbation(69).
Diabetes mellitus, particularly when poorly controlled, impairs In asthma patients with CRS, acute exacerbations of CRS lead to
both immune function and wound healing. There is however no poor asthma control(70). GINA 2019 recommends the assessment
evidence to suggest that it is a risk factor for the development of of comorbidities including CRS in every step of the therapeutic
CRS. Whether having diabetes mellitus affects the outcome after approach for asthma(71). The presence of chronic rhinitis was
FESS has been determined in a nested control study, and it was associated with 30-day asthma and COPD-related hospital
found that the diabetic patients fared as well postoperatively as readmissions, in both allergic and non-allergic patients(72). In
the non-diabetic patients(55). COPD, the presence of CRS negatively impacts the severity of
bronchial inflammation and COPD severity(73).
The prevalence of secondary immune Several immune mechanisms have been reported to be involved
deficiency is rising due to the increased use of in the naso-bronchial interaction in patients with global airway
immunosuppressive agents such as rituximab, disease. Both asthma and COPD patients show the typical
corticosteroids and other drugs(52). Rituximab is sinonasal inflammatory pattern with the classic Th2 and Th2
a monoclonal antibody directed against CD20 biomarkers in the nasal secretions, as seen in rhinitis / CRS
that causes B-cell depletion. As the indications patients(26, 74).Therefore, it is not a surprise that novel biological
for rituximab are growing so is the incidence of treatments targeting inflammatory molecules such as IL4,
rituximab-induced hypogammaglobulinaemia. IL-5 and IgE in both upper and lower airway inflammation are
effective on both asthma and CRSwNP(75, 76)(77).
8.2.7. Summary In the field of respiratory allergy and asthma, the naso-bronchial
CRS may be associated with primary humoral immunodeficiency interaction has been studied by Braunstahl and coworkers(78, 79)
conditions. Most of the patients with significant humoral with involvement of a systemic and/or neurogenic inflammatory
immunodeficiency conditions also have associated lower component. The systemic pathway leading to bronchial disease
respiratory tract problems such as recurrent pneumonia. via nasal inflammation is most likely facilitated by transmucosal

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Figure 8.3.1. Global airway disease concept.

Global Airway Disease Concept

Rhinitis
Health Rhinosinusitis

Protection Trigger of inflammation

air filtering neural interaction
air conditioning systemic response
air humidification epithelial dysfunction
nitric oxide production

Asthma
COPD/Bronchiectasis

passage of exogenous particles among which are allergens(80), [95% confidence interval (CI), 71.9% to 80.3%] of cases. The
and by nasal epithelial barrier dysfunction found in both rhinitis frequency of asthma attacks decreased in 84.8% (95% CI,
and in CRS(81). A neurogenic pathway linking upper and lower 76.6% to 93.0%) of patients and the number of hospitalizations
inflammation has been demonstrated using animal models decreased in 64.4% (95% CI, 53.3% to 75.6%). Decreased use of
highlighting the bronchial release of neural mediator substance oral corticosteroids was seen in 72.8% (95% CI, 67.5% to 78.1%)
P in the bronchi upon activation of a nasal inflammation(82). In of patients; inhaled corticosteroid use decreased in 28.5% (95%
addition to the neural and systemic parts of the nasobronchial CI, 22.6% to 34.5%) and bronchodilator use decreased in 36.3%
interaction, it seems that the microbiome in the sino-nasal (95% CI, 28.9% to 43.7%) of patients. Mean improvement in
cavity also plays a role in lower airway inflammation, as nasal predicted forced expiratory volume at 1 second (FEV1) was
colonization with Staphylococcus aureus showed significant 1.62% but was not statistically significant (p=0.877). Surgical
relationships with asthma prevalence(83) for both CRSwNP treatment for CRS has shown to be beneficial in severe asthma,
and CRSsNP. Animal studies have indeed demonstrated the with better asthma control in the most severe asthma group(90).
aggravation of bronchial eosinophilia by nasal presence of Contrary to asthma, at present, there is limited evidence on the
Staphylococcus aureus enterotoxin B(84). The contribution of impact of sinus surgery in COPD patients with CRS.
the microbiome to asthma development in CRS patients is still
under investigation(85). 8.3.3. Impact of asthma / COPD on CRS severity
Given the epidemiologic and pathophysiologic connection Patients with CRS often present with uncontrolled asthma, and
between CRS and lower respiratory airway disease(86), the endoscopic sinus surgery (ESS) improves both mini-Allergen
concept of global airway disease has gained more interest, Quality of Life Questionnaire (AQLQ) and asthma control
leading to better diagnosis and therapeutic approaches in test (ACT)(90). In a large-scale study on outcomes after sinus
patients with global airway disease(87). Recently, a simple surgery in a tertiary referral centre(91), asthma did not have an
Visual Analogue Scale (VAS) for total sino-nasal symptoms impact on the degree of control after ESS, whereas NSAID-
has shown to correlate well with the more extended SNOT-22 exacerbated respiratory disease (N-ERD) was significantly
questionnaire, and could be used for screening of CRS in asthma associated with higher prevalence of uncontrolled CRS. In
/ COPD patients(88). another study evaluation success of the endoscopic modified
The impact of lower airway disease on CRS can be arbitrarily Lothrop procedure, failure rates of endoscopic modified Lothrop
divided into impact on disease severity and control, and procedure were 8.9% for primary procedures and 21% for
outcomes of medical and surgical treatment. revision surgery. Also in this study, one of the risk factors for
failure of primary endoscopic modified Lothrop procedure was
8.3.2. Impact of endoscopic sinus surgery on asthma / COPD N-ERD(92).
Endoscopic sinus surgery in asthma has been reported to In COPD, there is a higher occurrence of nasal symptoms and
improve multiple clinical asthma parameters(89). In this meta- pathological findings on nasal endoscopy compared with the
analysis, mean follow-up across all studies was 26.4 months. control group, with overall reduced nasal airflow and increased
Patients reported improved overall asthma control in 76.1% nasal resistance. Pathological opacity of one or more sinuses was

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confirmed in 38% of COPD patients(62). In bronchiectasis, CRS intramucosal bacterial colonies are difficult to eradicate(104).
is associated with a greater degree of bronchiectasis severity,
poorer health-related quality of life (HRQOL), reduction in smell Bilateral nasal polyposis in children are often
detection, elevated levels of inflammatory markers, and reduced a clinical indication of CF(111); nasal polyposis
time to first exacerbation(67). in CF patients becomes more common as the
children age with a prevalence of up to 50% in
8.4. Cystic fibrosis adolescents(112).

Cystic fibrosis (CF) is a life-shortening genetic condition caused Anatomically, CF patients often have hypoplastic sinuses,
by a mutation in the cystic fibrosis transmembrane conductance independent of previous surgery. A study on adult CF patients
regulator (CFTR) gene leading to defective chloride channels. demonstrated 66% of the frontal sinuses were either aplastic
CF is the most frequent lethal autosomal recessive disorder in or hypoplastic(105). Mucoceles often leading to pyoceles and
the Caucasian population, but it affects all races. Ireland and bone sclerosis are common, as well as typical inflammatory
the Faroe Islands have the highest prevalence of CF in the patterns, e.g. CRSwNP, mucosal swelling and bulging, or even
world with prevalence of respectively 68 per 100,000 (1:1461) missing the lateral nasal wall(105). The majority of CF patients
in Ireland(93) and 56 per 100,000 (1:1775) in the Faroe Islands(94). have characteristic CT findings from early childhood(106),
The CFTR gene encodes the cAMP-dependent chloride channel, thus the Lund-Mackay scoring system may not be of optimal
and a defect in the gene results in abnormaltransport of use. Alternative CT sinus scoring systems addressing CF as
chloride and sodium across the cell. As a consequence, airway proposed by Eggesboe(107), Sheikh(108) or Rasmussen(109) may be
secretions contain a lower concentration of salt, causing the more useful.
secretions to have more than double the viscosity of secretions Only 7% of CF patients are free from inflammatory changes in
of a non-CF individual. The mucus is thus dehydrated and their sinonasal histology(110).
sticky, which reduces mucociliary clearance and promotes Nasal polyps in CF tend to be more neutrophilic and less
infections; most severely leading to increased susceptibility of eosinophilic compared to the non-CF population(113). CF patients
bacterial infections in the lower airways with the CF-pathogenic are likely to under-report their symptoms of CRS(114, 115). Several
gram-negative bacteria, particularly Pseudomonas aeruginosa, patient-reported outcome measure (PROM) conclude that CF
Achromobacter xylosoxidans, and Burkholderia cepacia, causing patients have symptoms of CRS among them two-thirds fulfil
progressive decline in lung function and ultimately death. the EPOS criteria(116, 117). Individuals who are carriers for one
Staphylococcus aureus encountered early in childhood, is defective CFTR gene may be more predisposed to developing
generally considered to be related to poor clinical outcomes. CRS. Symptoms include thick nasal discharge, postnasal
Methicillin-resistant strains are also encountered and have discharge, nasal blockage, facial pressure, and decreased sense
been associated with worsening progression of lung disease. of smell(118). There is a strong association between nutritional
Often, gram-negative bacteria become the dominant pathogens status and pulmonary function in CF and a decreased sense
in adulthood. If this is not the case, the Staph. aureus bacteria of smell is known to influence nutritional status in non-CF
are often present as a pathogenic chronic infection of the upper patients. Inexplicably and in contrast to patients with primary
and lower airways. A major goal in the treatment of patients ciliary dyskinesia, patients with CF have a lower incidence of
with CF is thus to prevent or delay chronic lung infections. otitis media compared with the general population(119). Several
Preventing chronic lung infection is, however, difficult to achieve studies have investigated a correlation between CF genotype
and the vast majority of patients with CF has been colonized or and severity of sinonasal disease, however, conflicting results
infected when reaching adulthood(95). were foundf(120, 121). Patients who are heterozygous for mutations
in the CFTR gene may be at increased risk of CRS. However,
There is a high concordance of bacteria cultured the evidence regarding an association between heterozygote
from the paranasal sinuses (based on irrigations, patients and CRS is sparse. Calton et al. argued in their study
swabs, or mucosal biopsies) and from the lungs(96). treating CRS in a university setting that CFTR heterozygotes
have significantly higher risk for CRS and who also have smaller
Over time, P. aeruginosa develop common phenotypic traits, paranasal sinuses(120, 121).
including conversion into alginate-overproducing mucoid
variants, reduced growth rates, and loss of virulence factor 8.4.1. Diagnosis and differential diagnosis
production, quorum sensing, and motility. Infections often
originate in the paranasal sinuses and can be responsible for the The diagnosis of CF is a multistep process, which involves a
initial and temporary lung colonization or for the chronic lung sweat chloride test, genetic analysis, and a clinical evaluation(122).
infections in CF patients(97-99). The latter is presumably due to an The diagnosis of CF is made when a patient has both clinical
advantageous environment in CF sinus secretions of a higher presentations of the disease as well as evidence of a defective
immunoglobulin(Ig) A:IgG ratio, reduced inflammation(100), CFTR channel.
low oxygen concentration(101), bacterial biofilm formation(102), Early detection accomplished by screening can prevent
and lower bioavailability efficacy of IV-antibiotic treatment malnutrition and delay the imminent lung infections, and
compared to the lungs(103). In addition, the presence of several studies have proven that the national screening program

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Table 8.4.1. CFTR mutation classes.

CFTR mutation classes Description Mutation example

Class I No functional CFTR being made G542X
Class II Incorrect trafficking of the CFTR to the cell surface F508del
Class III “Gating mutations” - the channels opening probability is affected G551D
Class IV The channels conductance is decreased R117H
Class V The synthesis of the channel is reduced A455E
Class VI The stability of the CFTR channel is decreased r-delta-F508

improves survival and reduces morbidity in patients with CF(123- mutation is the ΔF508, a class II mutation, but approximately
125)
. 2000 different mutations have been identified.
The presence of two mutations from either class I, II, or III
In the western part of the world national screening are categorized as high-risk genotypes whereas at least one
programs on specific genetic disorders including class IV, or V mutation are categorized as low-risk genotype.
CF have been implemented for newborns. High-risk genotypes have been associated with significantly
worse survival and lower lung function compared to low-risk
genotype(127).
Diagnostic testing/possible tests: As mentioned above, the effect of genotypes on sinonasal
disease is controversial. Ferril et al.(128) retrospectively reviewed
· Neonatal screening: a heel prick is performed in the first sinonasal disease in CF patients and found a significant
couple of days after birth and is tested for raised levels difference in severity of sinonasal disease when comparing
of immunoreactive trypsinogen, a pancreatic enzyme. patients with high-risk genotypes to low-risk genotypes.
Elevated level of immunoreactive trypsinogen is suggestive They describe how high-risk genotypes were associated with
of CF. However, immunoreactive trypsinogen can also be increased incidence of hypoplasia/aplasia and bony sclerosis
elevated due to other aetiologies e.g. prematurity, stressful evaluated by CT scans. Abuzeid et al.(129)on the other hand
delivery, or if a person is a carrier of the cystic fibrosis did not demonstrate worse sinonasal disease with high-
gene. Due to this, the screening test must be followed by a risk genotypes compared to low-risk genotypes when they
diagnostic test before the CF diagnosis can be made. retrospectively reviewed CF patients, evaluating SNOT-22 scores,
nasal endoscopy scores, and CT staging scores.
· Genetic testing: it is possible to test for mutations in the The taste receptor, T2R38 has been shown to play a role in
CFTR gene through a blood test or cells taken from a cheek detection and clearance of gram-negative organisms(130).
swab. Identification of two disease-causing mutations in
the CFTR gene confirms the diagnosis. The specificity and Non-functional polymorphisms in the T2R38 gene
sensitivity are estimated as high where two disease-causing correlate with sinus disease severity in patients
mutations are identified. However, a positive gene test is with deltaF508 homozygous mutation(131).
accompanied by a sweat chloride test.
Genetic markers as a prognostic indicator for the severity of CRS
· Sweat chloride test: measures the amount of chloride in CF patients as well as a diagnostic tool that can aid in tailored
in the sweat. A higher amount of chloride in the sweat treatment for patients with CF could potentially improve
(>60mmol/l) compared to normal values indicates a sinonasal QOL in patients with CF while also minimizing
diagnosis of CF. The test is done by placing a solution on unnecessary healthcare treatments. Further studies on the use
the forearm or thigh and stimulating with a mild electric of genetic markers to assess sinus disease in CF patients are
current to produce sweating. The test is tolerated well with needed and may eventually aid in future treatment modalities.
only minor discomfort reported.
8.4.3. Treatment
8.4.2. Pathophysiology
CFTR mutations can be grouped into six classes (see Table 8.4.3.1. Gene therapy
8.4.1.), all of which alter the function of the CFTR channels and The treatment of CF is currently symptomatic and treatment of
cause CF. Class I mutations result in no functional CFTR proteins the underlying gene defect, and thus curing the disease, has not
being made. Class II are the most common form of mutations yet been possible.
and result in incorrect trafficking of the CFTR to the cell surface. Restoration of CFTR and its function by transferring correct
Class III are gating mutations and affect the channels’ opening versions of the CFTR gene to the airways may be a first step in
probability, and class IV mutations reduce the function of gene therapy. A CFTR gene replacement would be an effective
the CFTR channel by decreasing channel conductance. Class treatment of CF regardless of the underlying gene mutation
V mutations reduce the synthesis of the channels and class class.
VI decrease CFTR stability(126). The most frequently observed Delivery of the CFTR gene via adeno-associated virus has so far

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solely been shown in a pig model(132). Further studies with other 8.4.3.5.1. Dornase alfa (rhDNAse)
gene vectors and in vivo models are needed.
Nasal irrigation combined with dornase alfa
To date there is no FDA-approved gene therapy. inhaled as a vibrating aerosol has been shown
to be even more efficient than nasal irrigation
8.4.3.2. TgAAV-CF solely(147). In contrast, the use of hypertonic saline
TgAAC-CF, an adeno-associated cystic fibrosis transmembrane does not add significant benefit(148).
conductance regulator (CFTR) viral vector/gene construct,
has been suggested as a therapeutic agent for the treatment 8.4.3.5.2. Topical antimicrobials
of sinus disease in patients with cystic fibrosis. However, no The use of topical antibiotics correlates with improvement in
significant effect of TgAAC-CF has been found so far, and the symptom and endoscopic scoring in uncontrolled studies and is
latest study of the effect of TgAAC-CF is more than 17 years safe(149, 150). With regards to post-surgical treatment, most studies
old(133). The scientific evidence of the use of TgAAC-CF in the use topical and/or systemic antibiotic treatment. However,
treatment of sinus disease is thus not currently available. recurrent infections are often seen. Installation of resorbable
antibiotics/bacteriophages/CFTR-modulating drugs/Poloxamer/
8.4.3.3. Ivacaftor etc may help eradicate bacteria after surgery(151-153).
Ivacaftor is a gene-based therapeutic agent approved, by the
US Food and Drug Administration and the European Medicines 8.4.3.5.3. Other treatment
Agency for the treatment of patients with specific CF mutations. There is high level of evidence that high volume nasal irrigations
Ivacaftor is a CFTR potentiator, which increases the opening with saline relieve symptoms in CF patients, and the procedure
probability of the CFTR channels at the cell surface, thus is well-tolerated.
increasing the flow of ions through the channel(134). Ivacaftor The effects of topical steroids as a medical treatment for CRS in
is approved for the treatment of various class III mutations CF patients are controversial.
(G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N
andS549R), and for the treatment of one class IV mutation A Cochrane review (including 1 placebo
(R117H)(135, 136). controlled study) concluded that
Recently it has been shown in CF patients that the intraflagellar topical steroids for nasal polyposis have no
transport protein, IFT88, abnormally accumulates in the basal significant effect on subjective nasal symptom
body region in ciliated respiratory epithelial cells. The latter scores but are effective in reducing nasal polyps
demonstrates a novel potential pathophysiologic intracellular size(154).
mechanism; and of interest in CF patients receiving ivacaftor a
normalization of IFT88 localization was obtained(137). A systematic review addressing the effect of topical steroids
Ivacaftor has been shown to improve lung function in patients on CRS in CF patients did, however, including non-placebo-
with CF(138, 139) and has recently demonstrated several other controlled- trials demonstrated significant benefits in CRS
beneficial off-target effects, including a beneficial impact on treatment(155). There are no studies addressing an impact on
chronic rhinosinusitis. Ivacaftor has been proven to improve sinonasal symptoms in CF patients with systemic steroids.
rhinologic QOL in patients with CF evaluated by SNOT-20(140).
Furthermore, several case reports document the reversal of 8.4.3.6. Surgery
sinus disease in CF patients after Ivacaftor treatment with CRS among CF patients is often refractory to medical therapy
normalized CT findings of CF sinus disease and resolved sinus and thus sinus surgery is often recommended. Endoscopic sinus
symptoms(141, 142). Ivacaftor has also been shown to enhance the surgery in CF children and adults is a safe procedure despite
effect of some antibiotics, including ciprofloxacin(143) and even anatomical variations in patients(156). Several reports have shown
exhibits antibacterial properties itself(144). that sinus surgery reduces sinonasal symptoms in CF patients
Further studies on combination therapy and the specific effect although this is often only a temporary improvement with the
of Ivacaftor on chronic rhinosinusitis in vivo are warranted. need for revision surgery. In a study comprising 106 CF patients,
the necessity for revision surgery was 28% within three years
8.4.3.4. Tezacaftor/Ivacaftor of surgery(157). When describing the surgical procedures, several
Tezacaftor is a selective CFTR corrector that facilitates the studies reported it was necessary to perform more extensive
cellular transport of CFTR and restores the CFTR protein in the surgery, e.g. total ethmoidectomy, medial maxillectomy(158) and
correct position on the cell surface.Tezacaftor in combination various Draf procedures. Sinus surgery is also recommended to
with Ivacaftor has been approved for the treatment of patients be performed in CF patients without chronic lung infection or
with F508del mutations, a type II mutation(145). with a transplanted lung in order to attempt to eradicate gram-
negative bacteria in the paranasal sinuses, thereby avoiding or
8.4.3.5. Mucolytic preventing re-colonisation of the lungs(157, 159). In these cases it
As in non-CF CRS patients, treating sinonasal symptoms starts is important to address all the paranasal sinuses independent
with medical therapy prior to surgical intervention(146). of the preoperative CT findings with the goal of extending the
time to lung infection(109) although even after sinus surgery the

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sinuses are not always easy to reach with local medication(160). not completely immotile and the name was changed to primary
Children with CF undergoing sinus surgery may experience ciliary dyskinesia to distinguish it from secondary acquired
some improvement of lung function parameters, although this causes(164) .In the late 1990s, several genotype variants for PCD
change may be temporary and not uniform(120). were identified. Despite the diversity of mutations that can
To conclude, several studies have evaluated the effect of sinus cause PCD, clinical presentations tend to be consistent for
surgery on pulmonary function with divergent conclusions. all patients – productive cough, rhinitis, and recurrent upper
When evaluating the reports, it is important to take into account and lower respiratory infections (165). Patients with PCD have
the pre-operative lung infection status, the extent of sinus impaired mucociliary clearance, which leads to an elevated risk
surgery, the post-operative treatment, and to keep in mind that of developing recurrent respiratory infections from the time of
the natural course of CF is declining lung function. birth (166). Precise incidence and prevalence of PCD are difficult
to estimate as there are no clinical and paraclinical criteria
Detecting gram-negative sinus bacteria at specific to the disease (167). Thus, current epidemiological records
an early stage is an important step towards for PCD might be largely underestimated due to the absence of
eradicating the bacteria and avoiding a chronic a single, ‘gold standard’’ diagnostic test (168, 169).
bacterial sinus infection.
Current estimated prevalence for PCD is 1:15-
Cultures from the middle meatus, cultures of nasal lavages, 30,000 live births(170).
rising antibodies against P. aeruginosa, and declining lung
function all indicate sinus infections. Nevertheless, gram- In 2010, Kuehni et al. conducted a large international survey
negative bacteria are also detected in the paranasal sinuses of 1,192 pediatric patients from 26 European countries and
during surgery in CF patients, despite preoperative negative reported an incidence for PCD of 1 per 10,000-20,000 births
cultures obtained from the middle meatus or from nasal (171)
. With consanguinity as a risk factor for PCD, high prevalence
lavages(161, 162). The importance of the microbial diversity is still exists in the Pakistani community in the United Kingdom
unknown. (1:2265) (172) and in Amish and Mennonite Communities
in the United States (173). While large discrepancies exist in
8.5. Primary ciliary dyskinesia epidemiological data for PCD, the challenge of confirming PCD
is appreciated in all studies, with diagnostic practices possibly
8.5.1. Epidemiology and predisposing factors contributing to inaccurate estimates. Mirra et al. support this
Primary ciliary dyskinesia (PCD), a collection of rare inherited by demonstrating that many patients have an extraordinary
disorders that affects motile cilia was initially termed ‘immotile number of physician visits (50-100) before their PCD is
cilia syndrome’ (163). Later, it was discovered that the cilia were diagnosed. With this accounted for, they estimated the median
age in Europe for diagnosis to be 5.3 years (174).

Key points | What’s new since EPOS 2012

1. There is a high concordance of bacteria cultured from the paranasal sinuses (based on irrigations, swabs, or mucosal biopsies) and from the
lungs(96).

2. In the western part of the world national screening programs on specific genetic disorders including CF have been implemented for
newborns.

3. Non-functional polymorphisms in the T2R38 gene correlate with sinus disease severity in patients with ΔF508 homozygous mutation.
4. Ivacaftor is a gene-based therapeutic agent approved, by the US Food and Drug Administration and the European Medicines Agency for
the treatment of patients with specific CF mutations. Ivacaftor is a CFTR potentiator, which increases the opening probability of the CFTR
channels at the cell surface, thus increasing the flow of ions through the channel.

5. Ivacaftor has been shown to improve rhinologic QOL in patients with CF evaluated by SNOT-20.
6. Tezacaftor in combination with Ivacaftor has been approved for the treatment of patients with F508del mutations, a type II mutation.
7. The use of topical antibiotics correlates with improvement in symptom and endoscopic scoring in uncontrolled studies and is safe.
8. Some studies recommend that sinus surgery is performed in CF patients without chronic lung infection or with a transplanted lung in
order to attempt to eradicate gram-negative bacteria in the paranasal sinuses, thereby avoiding or preventing re-colonisation of the lungs.

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8.5.2. Pathophysiology almost always chronic rhinitis. These symptoms can manifest as
PCD is primarily caused by mutations in genes that affect motile nasal discharge, episodic facial pain, and anosmia (188).
cilia (175)and is primarily inherited in an autosomal recessive
manner, making family history of PCD and consanguinity among Whenever nasal polyps are evident on nasal
ascendants strong risk factors. There are more than 35 causal endoscopy of a child the diagnosis of PCD or CF
genes identified (176), adding to the challenge of effectively must be considered.
detecting PCD at an early stage (177).
Lucas et al. (189) provide a decent set of conditions that support
The five genes most commonly mutated are PCD diagnostic testing:
DNAH5; DNAH11; DNAI1; CCDC39; CCDC40, but
more than 20 other genes are associated with 1. Situs inversus plus respiratory or nasal symptoms
specific ethnic groups and geographic regions. 2. Neonatal respiratory distress of unknown cause
3. Sibling with primary ciliary dyskinesia (PCD),
Knowles et al. estimates that of the 35 published PCD genes, particularly if symptomatic
65-70% of patients with PCD have two mutations in one of 4. Daily lifelong wet cough (note: maybe suppressed by
these genes (178). Given that cilia have many important functions child and under-recognized by parents)
within the body, defects in these structures manifest themselves 5. If considering testing for cystic fibrosis, also consider
in a broad spectrum of diseases. Associated conditions of testing for PCD particularly if rhinitis, rhinosinusitis or
PCD include hydrocephalus (169), polycystic kidney disease glue ear are present
(168, 169)
, biliary atresia (169), scoliosis (5%-10%) (178), humoral 6. Unexplained bronchiectasis
immunodeficiency (6.5%), congenital heart disease (5%) 7. Serous otitis media in association with lower and upper
and retinitis pigmentosa (169). Situs inversus (i.e. Kartagener airway symptoms
syndrome) exists in approximately half of all PCD cases. Both 8. Cardiac disease associated with heterotaxy if there is
men and women diagnosed with PCD commonly present suspicion of respiratory, nasal or ear problems
with fertility disorders due to the reproductive process largely
dependent on ciliary function (169, 176). 8.5.3.1 Microscopy

PCD has a strong association with history of It should be noted that cilia may appear normal
chronic rhinosinusitis (CRS). in patients that present with symptoms strongly
suggestive of PCD due to mutations that can result
PCD has a strong association with history of chronic in normal structure.
rhinosinusitis (CRS) as it is part of the initial triad descriptor.
In a critical evaluation of sinonasal disease in 64 adults Recent advances in technology have significantly improved
with PCD, all patients reported a history of CRS (179). PCD is diagnostic approaches to PCD. An electron microscropic analysis
associated with CRSwNP in 15% (168) to 30% of patients (180), and of cilia can yield valuable information about ciliary ultrastructure
is commonly seen in children with CRS. PCD also predisposes and function (188, 190). However, it should be noted that cilia
to bacterial infections commonly including Staphylococcus may appear normal in patients that present with symptoms
aureus, Moraxella catarrhalis, Haemophilus influenzae (181), strongly suggestive of PCD due to mutations that can result in
Streptococcus pneumoniae (182), and Pseudomonas aeruginosa(183, normal structure. In a respiratory epithelial biopsy with electron
184)
. Confirming these findings, a 2017 meta-analysis of 46 microscopy (EM), ciliary axonemes can be examined for defects
studies (1823 patients) with PCD or CF concluded that the most in outer and inner dynein arms, radial spokes, and/or central
common organisms found in the sinuses of PCD patients were microtubules (189, 191). This technique is sensitive to 70% of all PCD
H. influenza followed by S. pneumoniae and P. aeruginosa(185). cases (192). To assess cilia waveform, high speed videomicroscopy
can be utilized to confirm PCD. While the technology requires
The upper airway bacteriology mirrored the experienced personnel to operate, high speed videomicroscopy
organisms recovered in the lower airways of PCD is recommended as part of a panel of PCD diagnostic tests
patients(186, 187). (168)
– although the number of centers that can perform this
worldwide is limited. Ciliary beat frequency calculations
and visual assessment of ciliary motion without high speed
8.5.3. Diagnosis and differential diagnosis recording devices is discouraged due to high potential for
In the absence of hard clinical and paraclinical criteria for false positive and false negative results (168). Several highly
diagnosing PCD, confirming the diagnosis of PCD with clinical specialized centres are capable of growing primary respiratory
exam is a challenge because characteristic symptoms such as cultures at an air liquid interface (ALI) with subsequent analysis
rhinitis, secretory otitis media, cough, and recurrent bronchitis of ciliary motion as an alternative approach to assess cilia
are frequently seen in PCD- negative patients (188). They dysfunction(193).
frequently have a clinical history of lower airway disease and

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8.5.3.2 Genetics otorhinolaryngologist every six months (168, 188) while adult
To test a deficiency in specific ciliary proteins such as patients should visit their otorhinolaryngologists when needed
DNAH5, DNAI2, DNALI1, and RSPH4A/RSPH1/RSPH9, (168)
.
immunofluorescence testing can be performed. Staining of Prolonged macrolide therapy has been shown to produce
these proteins can yield quantitative and qualitative results marked improvement in symptomatology of PCD due to the
in determining if ciliary protein deficiencies explain the anti-inflammatory and immune-mediating properties of the
phenotype of a patient suspected of PCD. Genetic testing is antibiotic (180).
also recommended as part of a panel of diagnostic PCD tests Conservative therapy of CRS in PCD focuses on relieving
and has greatly improved the ability to diagnose PCD. With symptoms. Therapeutic options include sinonasal irrigation
currently 35 genes known to underlie the pathophysiology of with saline, topical steroids and long-term antibiotics. However,
PCD, a multi-gene panel of 19 of these genes can be performed, no prospective studies have so far evaluated the medical
and this is becoming more affordable, as several Clinical treatment of CRS in PCD. Presumably, sinonasal irrigation with
Laboratory Improvement Amendments (CLIA) approved labs saline is a safe method for clearing mucostasis in the upper
and companies have recently begun to offer such services (178). airways as a result of impaired mucociliary clearance. Intranasal
Genetic testing costs traditionally ranged from $1,500 to $4,500 corticosteroids have a positive effect on CRS in general, and may
(168)
, which may have discouraged many individuals from being also reduce inflammation in PCD. However, inhalation therapy
referred. Genetic panel tests can include full cystic fibrosis with steroids is not recommended for the treatment of lower
transmembrane regulator protein analysis (168). airway inflammation in PCD except in patients with concomitant
asthma.
8.5.3.3 Exhaled nasal nitric oxide Surgical intervention (ESS) may be required when medical
A number of studies have shown that exhaled nitric oxide (NO), therapy has failed. A few minor case series and retrospective
particularly nasal NO (nNO) production levels are low in PCD case series (198, 199) and a single prospective study (200) have
patients (176, 190). Nasal NO may then serve as a good diagnostic evaluated the potential benefits of CRS treatment with ESS in
marker in assessing patients with symptoms suggestive of PCD. PCD and all these studies consistently show subjective benefit.
While a few patients with PCD have been shown to have normal However, further randomized controlled studies are needed to
NO levels, a high or normal nasal NO can assist physicians in delineate the effects of surgery and adjunctive therapy.
excluding PCD as a differential, especially in patients that have
a clinical history weakly suggestive of PCD (194). Noone et al.
showed in an experimental design involving 110 patients that Key points | What’s new since EPOS 2012
there was a significant difference in the NO levels observed
between PCD patients (n=78) and the normal control group.
NO measures for the PCD group had a clear separation from 1. The number of genetic loci contributing to PCD has
measures of the healthy control subjects, with a number of expanded to more than 35.
recordings below 100 nl/minute (190). While the mechanism of 2. Diagnostic criteria now include nasal nitric oxide
low nNO in PCD is not well understood (195), measurements of (nNO).
nNO is recommended as part of a panel of diagnostic tests for
PCD in adults and children ≥5 years old (196).
8.6. Fungal rhinosinusitis
An nasal NO cutoff value of <77 nl/min can allow
detection of PCD with a sensitivity and specificity Fungi are ubiquitous in our environment and with dedicated
of 98% and >99%, respectively, after excluding assessments they can be found in nasal mucus from almost
cystic fibrosis and acute viral respiratory infections all healthy and diseased sinuses(201). However, there are
(168)
. several forms of sinus disease that are associated with fungi
as pathogens. In these situations, rather than the fungi
8.5.3.4 Radiology determining the disease process, it is usually the host immune
Radiographic evaluation of PCD patients demonstrates that state that determines the clinical presentation (Figure 8.6.1.).
opacified paranasal sinuses on CT scans are very common and The definition and categorization of fungal rhinosinusitis is still
hypoplasia or aplasia of the frontal or sphenoid sinuses is found controversial but the most commonly accepted system divides
in >50% of adult patients with PCD (197). patients with normal immunity and immunocompromised
patients(202). For a patient with an immunocompetent state,
8.5.4. Treatment fungi become a pathogen when they cannot be cleared by the
High-level evidence in managing patients with PCD is poor, mechanical action of mucus. In contrast to inert and non-viable
with current treatment protocols mostly adopted from studies material that settles on the mucus layer, fungi can multiply and
in CF or derived from small observational studies with limited create a ball or concretion of fungal hyphae. When this occurs,
follow-up period. Once a diagnosis is made, establishing a long- it becomes a fungal concretion and is widely referred to as a
term relationship with an otorhinolaryngologist is encouraged. fungal ball. Fungal balls of the sinuses were previously referred
Paediatric patients with PCD are advised to visit a paediatric

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to as ‘mycetoma’. The fungal hyphae are not invasive, and the most commonly affected. By definition, there is no invasive
immune response is similar to other foreign body reactions component to the fungal colonization. There may be an
in the immunocompetent patient. In an immunologically associated mixed inflammatory reaction in the involved sinus
suppressed patient, the fungi can turn from ubiquitous material and occasionally this inflammatory reaction will involve sinuses
in our environment to a true invasive infective disease. It is likely within the same function unit, such as frontal and anterior
that the type of fungi and the severity of immunosuppression ethmoid in the case of maxillary sinus fungal ball. To describe
bring about the variety of acute/chronic and granulomatous this entity, confusing or misleading terms such as mycetoma,
descriptions of invasive fungal rhinosinusitis. Aspergillus is aspergilloma or aspergillosis best avoided(205).
common and a similar distribution of fungal species across
simple fungal ball and invasive disease have been reported(203), 8.6.2.2. Epidemiology and predisposing factors
highlighting the importance of the host factors in the disease There is a reported female pre-disposition has high as 2:1(206)
process. Finally, in a setting of an exuberant or hypersensitivity and others have suggested this but not to the same strength of
immune response, the fungi, if allowed to contact the mucosa association(207). Fungal ball is a condition that affects most in the
for any length of time, induce a strong Th2 immune response fifth and sixth decade(206) with reported means of 55 years (208)
and in turn leads to a polypoid inflammatory phenotype, and 56±14 years(209). In a systematic review of isolated maxillary
referred to as Allergic Fungal Rhinosinusitis (AFRS). This can be and sphenoid sinus opacifications, the reported age range
so exuberant that distortion of the local anatomy, including the was 38-59 years for the maxillary sinus and 38-57 years for the
eye, cranial cavity and face is common. sphenoid sinus(210).
Fungal ball can be present for long periods with documented
Fungi are ubiquitous in our environment and cases up to 17years(211). For newly diagnosed or formed fungal
with dedicated assessments they can be found in balls, enlargement is seen in 58% over time(211). Although, fungal
nasal mucus from almost all healthy and diseased ball is often an incidental finding, most produce symptoms.
sinuses. In 70 radiologically observed fungal balls, only 22-26.3% were
asymptomatic(203, 211).
There was much prior debate regarding the role of fungi in Prior endodontic treatment is a risk factor for maxillary fungal
CRSwNP. Some authors had proposed that a response to fungi ball formation. Case control studies with patients with fungal
might be the basis for most Th2 dominated polypoid forms of ball versus CRS controls demonstrated endodontic treatment
CRS. However, subsequent research has not supported this(204). was more common in both prevalence (89% vs. 37%, p<0.
Thus, this chapter will discuss these three phenotypes of ‘fungal’ 01) and in the number of prior procedures (1.39±0.86 vs.
related CRS. An intentional focus is made on AFRS as a unique 0.53±0.81, p<0.01)(212). Such findings have been repeated with
phenotype, and its treatment, within the broader definition of a similar associations, demonstrating an increased prevalence
CRS. of endodontic care (36% vs. 16%, p=0.001) and number of
teeth endodontically treated (0.63±1.04 vs. 0.27±0.61, p=0.001)
8.6.2. Fungal ball and on a multivariate regression, endodontic treatment was
strongly associated (Exp(B) 2.15[CI 1.26-3.67], p=0.005) and
8.6.2.1. Terminology asthma was negatively associated(213).
Fungal ball Is a concretion or collection of fungal debris usually Most local anatomical variants have been assessed as possible
within a single sinus. The maxillary and sphenoid sinuses are risk factors for fungal ball formation. Septal deviation amongst

Figure 8.6.1. An overview of the interaction of fungi and the human immune response.

Fungi and the human immune response

Allergic fungal Invasive fungal

Fungal ball
rhinosinusitis rhinosinusitis

IMMUNE IMMUNE
IMMUNOCOMPETENT
HYPERSENSITIVITY SUPPRESSION

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other variants, including concha bullosa, has been implicated 5. No histologic evidence of fungal invasion of mucosa,
along with infundibulum length compared to normal controls associated blood vessels, or underlying bone visualized
(9.71±1.43 vs. 8.6.23±172, p<0.01(209) but a repeat study could microscopically on Gomori methenamine silver or other
not demonstrate this septal association and even suggested an special stains for fungus.
association with the deviation away from the involved side(214).
The largest cross-sectional study, using the contra-lateral side as On radiology assessment, “calcifications” and erosion of the
a control, of 538 patients could find no relationship with septal inner wall of the sinus are the two features most diagnostic for
deviation, infraorbital (Haller) cells nor concha bullosa(206). It fungal ball(221). Although the term “calcifications’ is used, they
is likely that anatomic variants are not a major contributor to are probably more accurately referred to do as hyperdensities
fungal ball formation. as they represent trace metal elements in the fungus. The
hyperdensities are seen in the majority and reported to affect
It is likely that anatomic variants are not a major 52-77%(206, 222, 223). On cone beam tomography, the hyperdensities
contributor to fungal ball formation. are less commonly seen(224). On magnetic resonance imaging,
fungal ball appears hypointense on T1-weighted images (64.7%)
8.6.2.3. Pathophysiology and hyperintense on T2-weighted images (88.6.2%) even in
It is presumed that the fungal ball forms during a period of patients without X-ray hyderdensities(223).
impaired mucociliary function. The relationship with endodontic Single sinus AFRS might be similar, and some historical
treatment may simply be either that the sinus mucosa was publications have used the term mycetoma to describe classic
inflamed either from periapical dental disease or from the AFRS(225) and thus the absence of a dominant eosinophil
procedure itself and this provided a period of impaired response, eosinophil mucin and a widely expanded sinus is still
mucociliary clearance from the maxillary sinus. The potential of important, as per the above criteria, to separate fungal ball from
extrusion of root canal filling material into the sinus has been isolated AFRS.
postulated as copper and zinc elements are found in both Isolated maxillary or sphenoid sinus opacification is a marker
fungal ball and in endodontic materials and thought to be a co- of neoplasia in 18% and malignancy in 7-10% of patients
factor for fungal growth(215). presenting with these radiologic findings. Clinicians should be
The role of primary ostiomeatal complex (OMC) obstruction wary of conservative management given the high incidence
has been assessed. Firstly, fungal ball was less likely to have of neoplasia and consider a lower threshold for early surgical
OMC occlusion than CRS controls with similar maxillary intervention(210). Odontogenic rhinosinusitis can present with
sinus involvement(216). Fungal ball patients were less likely to concomitant fungal ball or isolated maxillary sinus disease.
have frontal and anterior ethmoid radiologic changes. Sinus However, in studies on single sinus opacification, 10-45% of
hypoventilation from simple OMC obstruction and thus isolated sphenoid sinus cases and 0-55% of isolated maxillary
providing an environment for growth seems unlikely and there sinus cases are fungal balls (unpublished data)(210).
are cases of fungal ball formation in the setting of a patent
OMC(217). Isolated maxillary or sphenoid sinus opacification
Neo-osteogenesis of maxillary sinus wall is common in fungal is a marker of neoplasia in 18% and malignancy
ball compared to normal patients and is independent of in 7-10% of patients presenting with these
bacterial coinfection(218). This bony change produces a smaller radiologic findings so clinicians should be wary of
maxillary sinus, but a smaller maxillary sinus volume has been conservative management.
reported in patients with fungal ball of the maxillary sinus
compared to the normal contralateral side. This finding was 8.6.2.5. Treatment
independent of hyperostosis on sub analysis(219). Surgery is the primary treatment for fungal balls. Although
surgery was once thought to be ‘curative’ for fungal ball(205),
8.6.2.4. Diagnosis and differential diagnosis there is evidence that persistent inflammation and recurrence
DeShazo’s initial criteria and description is still accurate for can occur. Asymptomatic disease does not mean that surgery
fungal ball(220). should be avoided(226). In some studies, 16% of sphenoid fungal
1. Radiologic evidence of sinus opacification with or balls were associated with orbital infective complications
without associated flocculent calcifications and the loss of bone wall architecture was associated with
2. Mucopurulent, cheesy, or clay-like material within a sinus this complication(208). Additionally, intracranial infective
3. A matted, dense conglomeration of hyphae separate complications can also be seen(227, 228). Although, fungal ball
from but adjacent to sinus respiratory mucosa may follow an indolent course with disease present for many
4. A chronic inflammatory response of variable intensity in years(223), the natural history of the condition is that low grade
the mucosa adjacent to fungal elements. This response inflammation occurs, expansile changes are seen in the majority
includes lymphocytes, plasma cells, mast cells, and and infective complications can occur(229).
eosinophils without an eosinophil predominance or a
granulomatous response. Allergic mucin is absent on
hematoxylin-eosin-stained material.

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8.6.2.5.1. Oral corticosteroids potentially represent an immunocompromised host reaction to

No data or studies have suggested a role for oral corticosteroids the fungus(220). Due to the variability in chronicity of the disease,
but they are often given as part of the initial perioperative care some have divided it into acute (less than four weeks) or chronic
in the initial surgical removal. (greater than four weeks)(235). The type of fungus and the degree
of host immune suppression is likely to create these differences
8.6.2.5.2. Topical corticosteroids and thus for the purpose of classification they are all forms of
No data or studies have suggested a role for topical ‘invasive fungal rhinosinusitis’.
corticosteroids but it is acknowledged that INCS are often given
as part of the perioperative care after the initial surgical removal. Invasive fungal rhinosinusitis is a disease almost
exclusively of immunocompromised patients, and
8.6.2.5.3. Allergen immunotherapy (fungal or other) defined as any state in which fungal hyphae can
Immunotherapy does not play a role in the management be seen ‘within’ the mucosal tissue.
of fungal ball and no studies have reviewed their use. Nor is
inhalant allergy considered to play a role in the etiology of sinus 8.6.3.2. Epidemiology and predisposing factors
fungal balls. Overall, diabetes (50%) and haematologic malignancy (40%)
account for 90% of the immunosuppression reported in over
8.6.2.5.4. Anti-fungals – topical or systemic 800 invasive rhinosinusitis patients(236). Although neutropenia
Although it is recognized that fungal balls will develop in is often considered the most significant risk factor, patients
patients who might eventually be diagnosed with invasive with HIV/AIDS, iron overload, protein-energy malnutrition, or
fungal rhinosinusitis, it is their host immune factors that transplant patients on azole prophylaxis are also at risk(237).
appear to predict this(203). There are no controlled studies to Although invasive disease has been reported in patients
provide data to support the use of antifungals in the absence of without immunosuppression(238, 239) these studies were either
invasion. historical or had too few survivors to evaluate whether
immunosuppression was truly excluded. A subtype of chronic
8.6.2.5.5. Other medical interventions invasive granulomatous rhinosinusitis has been described in
Saline irrigations, concomitant use of antibiotics and intranasal otherwise healthy individuals. There are reports of such cases,
corticosteroids are all reported in the perioperative care of sinus often in older immunocompetent patients(240, 241) but are more
fungal ball, but no published data supports their use. prevalent from India(242-244). Although invasive disease may occur
in the absence of a well-defined immune suppression, it likely to
8.6.2.5.6. Surgery be uncommon.
Surgery is the mainstay of management of fungal ball. Most
authors promote a simple antrostomy, and many reports have 8.6.3.3. Pathophysiology
short-termfollow up. However, a recurrence of the fungal Invasive fungal rhinosinusitis is any state in which fungal
ball itself has been reported in 4% and 3.2% in two studies hyphae can be seen ‘within’ the mucosal tissue, demonstrating
with longer follow up(207, 230). Additionally, some authors classic angio-invasion or other infiltrative patterns. The most
have reported 50% of post treated fungal ball patients had common causative pathogens are the Zygomycetes (Rhizopus,
inflammation and 14% residual debris with a simple antrostomy, Mucor, Rhizomucor) and the Aspergillus species. The phylum
whereas when an antrostomy was combined with an inferior Zygomycota are part of the class Zygomycetes and order
meatal window, none had residual or inflammation(231). Mucorales and thus the term ‘mucormycosis’ is occasionally
Persistent dysfunction of the sinus cavity with mucostasis used. The disease process is characterized by angioinvasion of
was reported to be as high as 18%(217) and some authors have fungal hyphae (fungi within vessel walls and vascular lumen)
proposed a medial maxillectomy for some maxillary fungal ball producing thrombosis and mucosal infarction and subsequent
patients, especially in a smaller contracted sinus and when tissue necrosis While a low grade sub-mucosal granulomatous
there are concerns of poor function(232). Some studies suggest inflammation with diffuse fibrosis and with limited fungal
allergy and polyps are poor prognostic factors post-surgery(233) elements, has been described in immunocompetent hosts,
but there is some uncertainty of the true conditions being this is mainly limited to India(243) . Aspergillus sp. have a uniform
treated in this study. width, acute-branching septate (dichotomous) hyphae, often
described as branching at 45 degrees, whereas Zygomycetes
8.6.3. Invasive fungal rhinosinusitis have non-septate hyphae with wide angle branching.

8.6.3.1. Terminology 8.6.3.4. Diagnosis and differential diagnosis

Invasive fungal rhinosinusitis is a disease almost exclusively The two most important diagnostic criteria for any form of
of immunocompromised patients, and defined as any state in ‘invasive’ fungal disease are(220):
which fungal hyphae can be seen ‘within’ the mucosal tissue, 1. Rhinosinusitis confirmed by radiological imaging (although
demonstrating classic angio-invasion or other infiltrative this can be minimal) or show tissue destruction(245, 246) and
patterns(234). Although originally several forms of invasive disease 2. Histopathological evidence of hyphal forms within sinus
were described, granulomatous, chronic and fulminant, they all mucosa, submucosa, blood vessels, or bone.

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There is no pathognomonic symptom for invasive fungal survival in univariate analysis included increasing A1c% (HR=0.7)
disease, but facial pain, facial swelling, nasal obstruction and and surgical debridement (HR=0.1). One third of patients with
fever, are most common and present in 50–65% of patients(236, a haematologic malignancy and invasive fungal rhinosinusitis
247)
. Numbness of the face or palate, ophthalmoplegia (51%) had an absolute neutrophil count (ANC) >1000 at the time
and/or cerebral involvement can follow quickly thereafter. of diagnosis(247). The role of an absolute neutrophil count as a
The endoscopic appearance of necrosis is a hallmark sign. prognostic factor is still debated(247, 255).
The middle turbinate is classically involved, as this is where
aeroallergen deposition is thought to occur, but palatal, inferior 8.6.3.5.1. Oral corticosteroids
turbinate and lateral wall necrosis is described(248). Endoscopy is Oral corticosteroids are generally avoided as part of the
essential in the setting where radiologic changes are minimal. treatment in invasive fungal disease due the potential additive
immunosuppressive effects. However, their use may be
The endoscopic appearance of necrosis is a hallmark sign balanced by the need to reduce oedema associated with orbital
Unilateral disease on radiology is typical(247, 248).Loss of contrast or cerebral involvement.
enhancement on magnetic resonance imaging is more sensitive
(86%) than computerized tomography (69%) in detecting 8.6.3.5.2. Topical corticosteroids
invasive fungal disease(249). Frozen section analysis of tissue Topical corticosteroids do not play a role in the management of
during surgery(250, 251) and insitu hybridization have both been invasive fungal rhinosinusitis and no studies have review their
used to define invasive disease(252). use.
Serum analysis via PCR (serum or whole blood) and/or
galactomannan for invasive aspergillosis can be useful. When 8.6.3.5.3. Allergen immunotherapy (fungal or other)
both PCR and galactomannan for aspergillus were negative, Immunotherapy does not play a role in the management of
the negative predictive value was 100% and, when both invasive fungal rhinosinusitis and no studies have reviewed their
tests were positive, the positive predictive value was 88%(253). use.
Galactomannan and (1,3)-beta-D-glucan are components of
the Aspergillus cell wall and are therefore helpful in confirming 8.6.3.5.4. Anti-fungals – topical or systemic
a diagnosis of invasive Aspergillosis. Galactomannan and Although patients with invasive fungal rhinosinusitis need
(1,3)-beta-D-glucan each have a sensitivity and specificity of surgical debridement of involved tissue, medical therapy
around 80% in the detection of invasive aspergillosis from all is critical for treatment of invasive fungal rhinosinusitis.
body sites(253). Amphotericin and the liposomal version have been shown
to have positive predictive value to survival and time to
8.6.3.5. Treatment commencement associated with survival(236). In the setting
The three principals consistently reported in studies included: of Aspergillus species, voriconazole maybe superior
1. Systemic antifungals therapy should be started over amphotericin for aspergillosis(256) and voriconazole
2. Patients should undergo, at least endoscopic surgical is recommended(257). The newer Azoles may have better
debridement of necrotic sinonasal tissue bioavailability and less toxicity from studies on invasive
3. The patient’s immune suppression should be reduced aspergillosis that includes invasive fungal rhinosinusitis(258).
when feasible Transcutaneous retrobulbar injection of amphotericin B
A large systematic review has been performed, 52 studies has been reported. Kalin et al. summarized the six cases
and 807 patients, 398 of whom were used for prognostic documenting its use(259). The amount of amphotericin injected
factor analysis. They reported an overall survival rate of about ranged from 1-1.5 ml at concentrations ranging from 1-3.5 mg/
50%, with the following factors predicting worsened survival: ml on a daily to weekly basis. Two patients died for reasons not
advanced age, aplastic anaemia (20%), renal / hepatic failure directly related to fungal infection, but visual acuity stabilized or
(24%), intracranial and cavernous sinus extension (25%), and improved in all cases.
neutropenia (29%). They reported improved survival in patients
who were diabetic (50%), received liposomal amphotericin Conclusions Level
B(60%) or underwent open (54%) or endoscopic sinus surgery
Systemic anti-fungal therapies are an essential part 1c
(ESS) (64%)(236). However, survival and outcomes from invasive
of managing invasive fungal disease
fungal rhinosinusitis remained relatively stable, over the past 20
years, with survival at 50-60%(236, 254). Transcutaneous retrobulbar injection of 4
amphotericin B may be beneficial in orbital
involvement in invasive fungal rhinosinusitis
Patients should undergo, at least endoscopic
surgical debridement of necrotic sinonasal tissue.
8.6.3.5.5. Other medical interventions
Prognostic factors associated with worse survival included: Immune stimulating interventions have variably been reported
haematologic malignancy (hazard ratio [HR]=3.7); recent and in multivariate analyses were associated with a 70%
chemotherapy (HR=2.3); recent bone marrow transplant (BMT) reduction in mortality at one month(247). Hyperbaric oxygen has
(HR=2.5;); and infection with atypical fungi (HR=3.1). Improved been used with some evidence for the diabetic patient(260, 261)

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and there is some evidence for iron chelating agents (desfirozx) original description(271). AFRS is, for the most part, considered
(262)
. These studies include invasive fungal rhinosinusitis within a an IgE mediated mucosal hypersensitivity directed against
population of patients with invasive soft tissue fungal disease. fungal antigens deposited on sinus mucosa(272). The EPOS
steering group discussed whether the term ‘eosinophilic
8.6.3.5.6. Surgery fungal rhinosinusitis’ would be a better umbrella term for
Multiple studies have shown that ESS is an independent positive fungal rhinosinusitis but it was agreed that ‘allergic fungal
prognostic factor for survival(236, 247, 248, 263). rhinosinusitis’ should be retained as the principle term due to
The extent of surgical resection is largely guided by common usage, recognising that not all cases have evidence of
preoperative imaging and the tissue appearance during surgery. an allergic reaction to fungi.
Intraoperative frozen section has been employed to guide
surgical debridement. Although frozen section has an excellent Allergic fungal rhinosinusitis (AFRS) is a subset
PPV (100%) for invasive disease, the NPV is 70%, so a negative of polypoid chronic rhinosinusitis that is
result does not guarantee a clear margin(250, 264). characterized by the presence of eosinophilic
Timing of surgery is less important than the initiation of mucin with non-invasive fungal hyphae within the
antifungal therapy(265) but delay of surgery >30 days of diagnosis sinuses and a Type I hypersensitivity to fungi.
predicted a poorer outcome.
8.6.4.2. Epidemiology and predisposing factors
Managing the orbit AFRS accounts for about 5% to 10% of CRS cases(273, 274). Patients
At the time of diagnosis, 50-60% of patients will have orbital presenting with AFRS do so at a younger age than other forms
involvement(234, 236). In 15 patients with orbital involvement, of CRS and with a greater proportion of females(275). AFRS also
survival was similar to patients with disease limited to the has an association with a lower socioeconomic demographic,
sinuses, and only one of those patients had an exenteration(263). African Americans (in North America) and those living in warmer
A meta-analysis of 224 patients with orbital mucormycosis, climates near the coast(276, 277). Atopy is a pre-defining feature of
reported no survival benefit from orbital exenteration except in patients with AFRS and concomitant allergic disease, such as
patients with fever over 38,6ºC (101.5 8F)(266). Similarly, Turner et allergic rhinitis and childhood onset asthma, are common in this
al. found a similar outcome with orbital removal and survival(236) group.
but authors from both studies acknowledge the bias that exists
in assessing these outcomes as those patients with significant 8.6.4.3. Pathophysiology
orbital disease were likely to have been offered surgical The defining pathophysiology in AFRS is sensitization to the
removal whereas limited disease was conservatively managed. causative fungus as a primary and requisite feature along with
Transcutaneous injection of amphotericin remains an option as mucin colonized with non-invasive fungus(278). Although fungal
described previously. Of note, in a study on patients only with sensitization may exist in CRSwNP, typically IgE levels are higher
orbital involvement, 2/14 patients survived and both had orbital in AFRS(273, 274) studies that define AFRS as a unique phenotype in
removal(238). Persistent enhancing tissue is a marker of infected CRSwNP (Table 8.6.1.).
tissue and thus many suggest conservative treatment when
enhancement can still be seen on imaging. 8.6.4.4. Diagnosis and differential diagnosis
Ideally all five of the major criteria in the original Bent-Kuhn
Conclusion Level diagnostic criteria should be met to make the diagnosis as three
Surgical debridement is an essential part of invasive 3a of the five are common in most CRSwNP. These major criteria
fungal rhinosinusitis management consist of the following(271):
1. Nasal polyposis;
8.6.4. Allergic fungal rhinosinusitis (AFRS) 2. Fungi on staining;
8.6.4.1. Terminology 3. Eosinophilic mucin without fungal invasion into sinus
Allergic fungal rhinosinusitis (AFRS) is a subset of polypoid tissue;
chronic rhinosinusitis that is characterized by the presence of 4. Type I hypersensitivity to fungi and;
eosinophilic mucin with non-invasive fungal hyphae within the 5. Characteristic radiological findings with soft tissue
sinuses and a Type I hypersensitivity to fungi. It was originally differential densities on CT scanning and unilaterality or
described by Safirstein(267) and Katzenstein(268), but some anatomically discrete sinus involvement.
clinicians who work in parts of the world where AFRS is not The minor criteria include bone erosion, Charcot Leyden
so common, have questioned whether the condition really Crystals, unilateral disease, peripheral eosinophilia, positive
exists as a separate clinical entity or is part of eosinophilic CRS fungal culture along with prior criteria from DeShazo(279):
or CRSwNP. Although there is some controversy about the 1. the demonstration of the characteristic eosinophil-rich
definition of AFRS, and even whether it is a distinct clinical allergic mucin visually or histopathologically(280);
phenotype of CRSwNP, most terminology groups define it 2. a positive fungal stain or culture from the sinus at
as a unique and distinct phenotype(269, 270). Bent and Kuhn surgery;
included IgE sensitization as an inclusion criteria in their 3. the absence of immunodeficiency or diabetes;

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Table 8.6.1. Studies that define AFRS as a unique phenotype in CRSwNP.

AFRS CRSwNP Ref
Demographics Warmer coastal climates Older age at presentation Lu-Myers et al. 2015(275)
Younger unless CCAD Miller et al. 2014(277)
Female preponderance Wise et al. 2008(276)
Ferguson et al. 2000(484)
Comorbidities AR Adult onset asthma more Manning et al. 1998(485)
Asthma (less) severe
Associated ABPA Uncommon Rare Shah et al. 2001(486)
Secretions “Peanut butter” mucin “Chewing gum” mucin
Lund Mackay scores Very high High
CT changes Hyper attenuation Less likely to have bone erosion Ghegan et al. 2006(487)
Unilateral
Fungal colonization Easily identified Alternaria and Cladosporium Granville et al. 2004(488)
Aspergillus species most common (others species Ferguson et al. 2000(484)
include: Bipolaris, Curvularia)
Immune status Atopic Allergen sensitization
approaches background rate
Fungal sensitization Multiple fungi Less common Hutcheson et al. 2010(489)
IgG to fungi more common Stewart et al. 2002(490)
Greater fungal specific IgE
Immunohistochemistry Fungal specific IgE present in tissues Poorly selected IgE in mucosa Collins et al. 2004(491)
Pratt et al. 2010(492)
Serum IgE Higher (500 IU/mL) Variable Hutcheson et al. 2010(489)
Bakhshaee et al.(274)
Telmesani et al. 2009(493)
Staph. aureus co-infection High Less common Clark et al. 2013(494)
Dutre et al. 2013(495)
T cell responses CD4+ only Both CD4+ and Cd8+ Pant et al. 2014(496)
Gene expression Lacking Cathepsin B, Broad activation Orlandi et al. 2007(497)
sialyltransferase 1, GM2 ganglioside activator
protein, and S100
calcium-binding protein
Serum proteomics Spectrometry able to identify patients with Broad Das et al. 2008(498)
AFRS with 84% sensitivity and 90% specificity
to CRSwNP
HLA-MHC class II associations HLA-DQB1*03 common Less common Schubert et al. 2004(499)

Table 8.6.1. compares AFRS with the broader group of eCRS or the sinus tissue, and 2) the mucin of AFRS is the product of an
CRSwNP patient features. allergic hypersensitivity reaction to the fungi as opposed to a
Clinically, the younger allergic patient with unilateral disease simple overgrowth of mycelial elements as is seen in fungus
and the typical allergic “peanut-butter-like” mucin is classic and balls.
this mucin is different from the ‘chewing gum’ mucin commonly
associated with eosinophilic CRS(281, 282). 8.6.4.5. Treatment
Imaging with computed tomography shows densely packed Unlike the management of classical CRS, the foundation of
hyperdensities in the sinuses with expansion and erosion of the AFRS treatment is surgery. The vast majority of clinical studies
bony walls. These are a combination of the various metals (e.g. in the AFRS literature indicate that medical therapy alone is
iron, magnesium, and manganese) concentrated by the fungal usually ineffective in alleviating symptoms and that surgical
organisms as well as the low water and high protein content intervention, alone or in combination with medical therapy,
of the mucin(283). On magnetic resonance imaging, signal voids leads to improved clinical outcomes. Treatment of AFRS almost
occur on both T1 and T2 sequences. The high protein and low always requires surgical debridement of the involved sinuses,
free water content in allergic mucin along with the presence of thus removing the antigenic stimulation for AFRS patients, but
calcium, air, and paramagnetic metals, such as iron, magnesium, also provides wider access for surveillance, clinical debridement,
and manganese creates this classic pattern(283) and is not from and application of topical medication. Oral corticosteroids
ferromagnetic elements, as previously speculated(284). decrease recurrence after surgery, but other adjunctive
Imaging with computed tomography shows densely packed pharmacologic agents, including topical and oral antifungal
hyperdensities in the sinuses with expansion and erosion of the agents, have less evidence base for effectiveness.
bony walls. Most reports on treatment options for AFRS are combined
AFRS has these defining features: 1) the fungi never invade into larger series addressing CRSwNP patients and this issue is

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Table 8.6.2. Systemic corticosteroids for the treatment of patients with AFRS.

Study Methods Participants Interventions Outcomes Results

Prasad et al. RCT 60 AFRS post- · 6 month postoperative corticosteroid use · Recurrence · 6 month
2017(286) surgery (prednisolone, 1 mg/kg/day, for 1 week corticosteroid use
preoperatively and 0.5 mg/kg/day for 4 associated with less
weeks, oral prednisolone 0.4 mg/kg/day for recurrence
the next 4 weeks, tapered to 0.2 mg/kg/day
for the next 2 months and to 0.1 mg/kg/day
for the last 2 months

· 2 month taper (prednisolone, 1 mg/kg/day,

for 1 week preoperatively and 0.5 mg/kg/
day for 4 weeks postoperatively)
Rupa et al. RCT 24 AFRS post- · Oral prednisolone (50mg qd x 6 weeks, then · Symptom scores · Corticosteroid
2010(285) surgery additional 6 week taper) at 6 weeks and 12 group significantly
weeks improved over
· Placebo placebo
· Endoscopic scores
· Both groups used itraconazole orally and
INCS · Adverse effects
Ikram et al. Retrospective 63 AFRS post- · Postoperative corticosteroids (n=30) · Recurrence (at · Favours
2007(287) cohort surgery 2yrs post-surgery) corticosteroid use
· No post-operative corticosteroids (n=33) postoperative
with lower
recurrence15.2% vs.
50%

covered elsewhere in this document. It is, therefore, difficult to then additional six week taper) or placebo for two weeks after
discern if there are varying effects in the AFRS population as surgery(285). All patients received fluticasone nasal spray and oral
opposed to the entire CRSwNP population. In general, medical itraconazole for 12 weeks. At 12-week follow up, all 12 patients
therapies have been divided into oral and topical steroids, oral in the corticosteroid group were asymptomatic and only one
and topical anti-fungals, immunotherapy and others. In all but in the placebo arm. All 12 patients in the corticosteroid group
the mildest cases of AFRS, it is felt that medical therapy alone suffered some weight gain, five developed Cushingoid features
without surgical intervention, is not effective in the long term, and one developed steroid induced diabetes mellitus.
thus most efficacy studies examining medical treatments have In what is best described as nonblinded randomized trial, Prasad
been performed postoperatively. et al. describe the management of 30 patients with AFRS with
Medical therapy alone is usually ineffective in alleviating six month postoperative corticosteroid use (prednisolone, 1mg/
symptoms and that surgical intervention, alone or in kg/day, for one week preoperatively and 0.5mg/kg/day for four
combination with medical therapy, leads to improved clinical weeks, oral prednisolone 0.4mg/kg/day for the next four weeks,
outcomes tapered to 0.2mg/kg/day for the next two months and to 0.1mg/
kg/day for the last two months) compared to a group of 30 AFRS
8.6.4.5.1. Oral corticosteroids patients tapering within two months (prednisolone, 1mg/kg/
Oral corticosteroid studies specific to AFRS patients have day, for one week preoperatively and 0.5mg/kg/day for four
generally been conducted in the postoperative setting where weeks postoperatively). This study concluded that recurrence
benefit has been demonstrated. There are several controlled and further surgery was less likely in the six month group(10%
studies (Table 8.6.2.). In a randomized double blinded, vs. 30%)(286). See Figure 8.6.2. for the combined odds ratio of
placebo-controlled trial of n=24 AFRS patients examining the prevention of recurrence.
effectiveness of postoperative oral steroids, as well as the side In a retrospective cohort by Ikram et al. a two year follow-
effects, patients received oral prednisolone (50mg qd x 6 weeks, up of AFRS patients treated with and without postoperative

Figure 8.6.2 Forest plot of the effect of oral corticosteroids for the prevention of recurrence in AFRS

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corticosteroid demonstrated a 15.2% vs. 50% recurrence along for the combined therapy at a minimum of two year follow
with a standardized topical corticosteroid regime(287). Kinsella up, as 50% of the no steroid group recurred, while only 15% of
et al. reported a similar finding in 25 patients treated and the combined steroid group recurred(287). Another study of low
none of the eight patients with recurrent disease were treated quality but an RCT, compared 34 postoperative AFRS patients
with postoperative corticosteroid(288). Schubert et al. utilized which were randomized into three arms: (1) itraconazole +
a minimum two-month postoperative corticosteroid regime nasal douche (n=11); (2) topical nasal steroid + nasal douche
in a case series of 67 AFRS patients and demonstrated benefit (n=12); and (3) nasal douche alone (n=11). Normal mucosa was
in those utilizing therapy up to 12 months. Those on oral observed similarly between INCS and saline only groups (16 vs.
corticosteroid had the best outcomes with reduced recurrence 14%, p=0.22). The type of topical steroid used was not defined
and prolonged the time to revision surgery(289). and the study was both underpowered and incompletely
Landsberg et al. demonstrated that preoperative corticosteroids reported or analyzed(294).
given at 1mg/kg for 10 days prior to surgery, had a more Dai et al. describes a study of 30 AFRS patients, randomized
dramatic effect in AFRS compared to CRSwNP patients, with in a unblinded controlled study, to nebulized budesonide or
near normalization of the mucosa in the AFRS group at the time topical nasal sprays. Nebulized budesonide was more effective
of surgery and a similar response on computed tomography(290). in preventing recurrence compared to intranasal corticosteroid
Similarly, Woodworth et al. demonstrated a significant reduction spray (26.7% vs. 0% , p=0.03)(295).
in AFRS patients with postoperative corticosteroid over three Several studies confirm that non-compliance with INCS is
weeks compared to eCRS and control patients(291). A number of associated with recurrence in AFRS (Table 8.6.3.)(286, 287).
other non-placebo controlled case series have been reported
with highly variable dosing protocols and durations, but Conclusions Level
generally reporting a positive effect when using postoperative Non-standard INCS (nebulization) is better than 1b
oral corticosteroids(272, 292). simple INCS sprays
INCS of any type may be useful in controlling AFRS 3b
Conclusions Level
Preoperative systemic corticosteroids are likely to 2b 8.6.4.5.3. Allergen immunotherapy (fungal or other)
reduces AFRS mucosa inflammation and radiologic Allergen immunotherapy (AIT) lends itself to placebo controlled
scores randomized trials. However, there is a lack of such trials in
Postoperative systemic corticosteroids improve 1b AFRS. Several reviews have been undertaken, SCIT may have
short-term outcomes in AFRS efficacy in the short-term(3-4 years), however, its long-term
Postoperative systemic corticosteroid are likely to 2b efficacy is unclear(296, 297). In a large retrospective series with
reduce long term recurrence in AFRS immunotherapy for all fungal and non-fungal antigens, a
3-4 year course of subcutaneous immunotherapy (SCIT)
8.6.4.5.2. Topical corticosteroids
demonstrated benefit 12-26 months after discontinuation by
AFRS patients have been included in the “eCRS or CRSwNP”
less recurrence(298, 299) and decreased revision surgery in the
subgroups of other studies on intranasal corticosteroids with
immunotherapy group(298, 300). However, a subsequent study by
a general consensus that they are beneficial, safe and well
the same group on a smaller subset of patients with longer term
tolerated(293). There are several studies that assess INCS in a
follow-up ranging from 46-138 months failed to demonstrate
dedicated AFRS population. A case-controlled study of surgery
any benefit of SCIT with 60% of SCIT patients having normal
alone vs. surgery plus the combination of postoperative oral and
mucosa or only mild oedema on endoscopy, while 100% of non-
topical steroid spray in AFRS patients demonstrated benefits
SCIT patients had normal mucosa or mild oedema(301). This study

Table 8.6.4. Immunotherapy for the treatment of patients with AFRS.

Study Methods Participants Interventions Outcomes Results
Bassichis et al. Retrospective 60 AFRS post- · Immunotherapy with standard care · Revision surgery · Less revision
2001(298) cohort surgery (n=36) surgery (11% vs.
· Clinic intervention 33%) and less
· Standard care alone (n=24) clinic visits in the
IT treated arm
· Immunotherapy to both fungal and (4.79 vs. 3.17)
non-fungal antigens (minimum
12mths)
Folker et al. Retrospective 22 AFRS post- · Immunotherapy with standard care · Chronic Sinusitis · All outcomes
1998(300) cohort surgery (n=11) Survey better in the IT
treated group
· Standard care alone (n=11) · Kupferberg grades

· Immunotherapy to both fungal · Corticosteroid use

and non-fungal antigens (mean 33 (oral and topical)
months)

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Table 8.6.5. Oral antifungals for the treatment of patients with AFRS.

Study Methods Participants Interventions Outcomes Results

Verma et al. RCT 100 AFRS · Itraconazole (4 weeks) preoperative (n=25) · Symptoms · Although both preoperative
2017(307) assessed post- and postoperative itraconazole
surgery · Itraconazole (4 weeks) post-operative (n=25) · Kupferberg showed significant improvement
grades in the SNOT, LM, and Kupferberg’s
· Surg with antifungal therapy (n=50) grades in the follow‐up period,
· Radiology the difference was only seen
· Prednisone 1mg/kg on 6 week taper and nasal (LM scores) between no antifungal and the
douching to all groups
preoperative antifungal group
· All assessed
· Itraconazole 200mg (5mg/kg in children) but included endoscopy and
at 24 weeks
twice daily for 2 days followed by 100mg (3 radiology but SNOT scores were
mg/kg in children) twice daily for remaining 4 similar.
weeks therapy
Rojita et al. RCT 60 AFRS post- · Oral corticosteroid (prednisone 30mg/daily · Symptoms · No difference between groups
2017(308) surgery for 1mth) then INCS to 6 months · Only 23 and 26% of patients had
· Kupferberg normal mucosa at 6mths
· Itraconazole 100mg bd for 6 months grades

· Serum IgE

· Recurrence
Nikakhlagh RCT 50 AFRS post- · Itraconazole 100mg BD (n=25) · Recurrence · No evidence of recurrence higher
et al. surgery in anti-fungal group (44% vs.
2015(500) · No antifungals (n=25) 24%) but no statistical analysis
performed
· Both groups received post-surgical
corticosteroid and INCS spray (not defined)
Khalil et al. RCT 50 AFRS post · Oral itraconazole (n=10) · Recurrence · Oral itraconazole did not show
2011(309) surgery benefit over other groups and
· Fluconazole nasal spray (n=10) similar to controls (66.7% vs. 75%)

· Oral itraconazole and Fluconazole nasal spray

(n=10)

· Fluconazole nasal irrigation (n=10)

· No antifungal therapy (n=10)

Gupta et al. RCT 34 AFRS post- · Oral itraconazole (200mg BD) and nasal · Kupferberg · No differences between the
2007(294) surgery douche (n=11) grades groups

· Topical steroids (budesonide 100mg BD) and

nasal douche (n=12)

· Nasal douches only (n=11)

Kupferberg Retro- 26 AFRS Post · No treatment (n=11); · Symptoms · 33% of antifungal alone patients
et al. spective surgery had benefit but corticosteroid
1997(292) cohort · Oral corticosteroids alone (n=10); (40mg × 4 · Kupferberg groups did best.
days, then 30mg × 4 days, followed by 20mg grades
per day until first month)

· Oral corticosteroids and oral antifungals (not

described) (n=2)

· Oral antifungals alone (n=3)

Chan et al. Case 32 AFRS post- · Itraconazole 300mg daily tapered over 3 mths · Symptoms · Symptoms improved
2008(501) series surgery and · Endoscopic scores similar
refractory · Kupferberg
grades
Seiberling Case 10 AFRS and · Itraconazole 100mg twice daily for 6 months · Symptoms · 83% improvement in symptoms
et al. series 13 AFRS and associated endoscopic
2009(304) (without · Endoscopy improvement
atopy) post scores
surgery

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Table 8.6.5. Oral antifungals for the treatment of patients with AFRS continued.
Study Methods Participants Interventions Outcomes Results
Rains et al. Case 139 AFRS · Itraconazole 400mg/day for 1 month, 300mg/ · Recurrence · Improved by 50% with recurrence
2003(305) Series post-surgery day for 1 month, 200mg/day for 1 month or and 20% with further surgery
until clear by endoscopy

· All patients give oral prednisone (30mg/day

for 3 days, 20mg/day for 3 days, and 10mg/
day for 7 days

· INCS from two weeks post-surgery

Table 8.6.6. Topical antifungals for the treatment of patients with AFRS.

Study Methods Participants Interventions Outcomes Results

Khalil et al. RCT 50 AFRS post surgery · Oral itraconazole (n=10) daily 3 months · Recurrence · Fluconazole spray
2011(309) (10% recurrence).
· Fluconazole nasal spray (n=10) bd for 3 Combined (14.3%)
months compared to
oral and control
· Oral itraconazole and Fluconazole nasal (66.7% vs. 75%)
spray (n=10) both daily for 3 months · Not statistically
significant
· Fluconazole nasal irrigation once/week for
6 weeks (n=10)

· No antifungal therapy (n=10)

Jen et al. Case series 16 AFRS post surgery · Fluconzole nasal spray (100mg/500ml, 5 · Symptoms · Stable or
2004(315) sprays twice daily) (3mths) improvement in
75%
· Oral corticosteroid · Reduction in
oedema seen in
· Oral itraconzole 75%

was not randomized and obviously has the potential for bias in a ‘no antifungal treatment’ control group(307). Although the
selecting treatment arms. Uncontrolled studies on sublingual authors found some evidence of reduction of inflammation on
immunotherapy have shown a benefit in IgE levels along with endoscopy and radiology, it was only between the preoperative
objective parameters(302). Unfortunately, the atopic nature of treated and controls and symptom outcomes were similar. The
AFRS and the inclusion of Type 1 hypersensitivity makes the other study by Rojita et al. found no difference between oral
concomitant treatment of AR and asthma in AFRS patients a corticosteroid and itraconazole and declared them similar but
significant confounder and clouds the results(303). a very low overall response rate was seen (<25%) and no nasal
The systematic review by Gan et al. identified two retrospective irrigation was used(308). The combine effect on symptoms after
cohort studies, although misclassified as case-controlled, surgery did not favour antifungal therapy (Figure 8.6.3.) and the
these studies were assessing patients with and without prevention of recurrence, including adjustment for those lost to
immunotherapy in a common population of post-surgical AFRS follow-up, also did not support anti-fungal use (Figure 8.6.4.).
patients(293) and thus more accurately had a retrospective cohort Three very low quality RCTs have been reported. The first
design. Both studies conclude a benefit but the confounding assessing a two-month treatment of oral itraconazole (100mg/
factors mentioned above act as potential bias (Table 8.6.4.). twice a day) compared to no antifungal therapy and both
groups received systemic and topical corticosteroids. This study
Conclusion Level demonstrated little benefit from the addition of antifungal
Immunotherapy to both fungal and non-fungal 2b therapy. However, although the authors suggested there ‘may
antigens in atopic individuals with AFRS is likely to be a benefit’, incomplete data reporting and a lack of statistical
improve symptoms and reduces revision surgery analysis does not support this and the outcomes appear similar
between groups. A similar low quality RCT by Gupta et al.
did not find any benefit in a study on 34 postoperative AFRS
8.6.4.5.4. Anti-fungals – topical or systemic patients which were randomized into three arms: 1) itraconazole
Limited data exists to support the use of oral antifungal agents + nasal douche (n=11); 2) topical nasal steroid + nasal douche
in AFRS. Several case series have reported the benefits of (n=12); and 3) nasal douche alone (n=11). The authors
systemic anti-fungal therapies in patients with AFRS(292, 304, 305). It acknowledge that the study may be underpowered(294). Kahil
is recognized that itraconzole has anti-inflammatory effects and et al. reported an RCT of low quality in 50 patients in multiple
thus a controlled study is required(306). treatment arms but included a ‘no-antifungal treatment’
Two recent RCTs are noteworthy. The first, Verma et al., has group(309). This study lacked a statistical analysis and the control

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Figure 8.6.3 Forest plot of the effect of oral antifungals for post-operative treatment of symptoms in AFRS

Figure 8.6.4 Forest plot of the effect of oral antifungals for the prevention of recurrence in AFRS

group and oral antifungal group were similar and had the who failed surgery and maximal postoperative medical
highest recurrences between all groups. management, used Manuka honey in one nostril. Overall, the
The prior systematic reviews on antifungal treatment in CRS group failed to demonstrate improvement(317).
included a study assessing oral antifungal (terbinafine 625mg/ There are 8 patients from a case report and a small case series
daily for six weeks). In this study AFRS patients were included on the successful use of omalizumab to
within a broader CRS population(310). This study found no benefit treat AFRS refractory to surgery and oral corticosteroids(318). The
and along with the data from the three RCTs of low quality it seven (n=7) patients with AFRS and asthma on omalizumab
is difficult to make a judgement beyond the summary meta- had a seven month mean treatment regime with significant
analysis and prior Cochrane review of topical and systemic anti- reduction in SNOT22 and a 60% reduction in burden of
fungal therapies in all CRS patients, which failed to demonstrate inflammation on endoscopic scores(319). Both studies show a
any benefit(311) (Table 8.6.5.). reduction in corticosteroid use and other therapies.

Topical antifungals Conclusions Level

There are very few studies that assess topical anti-fungal therapy
Antileukotrienes may reduce symptoms in AFRS 5
in a dedicated AFRS population. A systematic review of the topic
Manuka honey topically does not improve outcomes 1b(-)
by Mistry and Kumar(312) identified two RCTs that included AFRS
within a broader CRS population but neither of them found Omalizumab (anti-IgE) may improve outcomes in
4
AFRS
convincing evidence of benefit(313, 314). Of the two studies with
dedicated treatment groups in AFRS, one is a case series(315) and
8.6.4.5.6. Surgery
the other an underpowered RCT with incomplete reporting and
There is a near unanimous recommendation that surgery
analysis(309) (Table 8.6.6.).
is required as a first stage intervention for AFRS(278, 293, 320, 321).
The goal of surgery requires surgical debridement of the
Conclusions Level involved sinuses, thus removing the antigenic stimulation. A
Oral antifungals may reduce inflammation and retrospective review reported that incomplete removal of all
1b
recurrence in AFRS
fungal and eosinophilic mucin contributed to disease recurrence
Oral antifungals may reduce recurrence in AFRS 4 and the need for revision surgery(322). The recurrence rate in the
Oral antifungals do not improve symptoms in AFRS 1b(-) surgery arm of the Ikram study (287) was 50% at two years. Overall
Topical antifungal may be beneficial in AFRS 4 recurrence rates after surgery have been reported from 10% to
100%(320).
When skull base erosions occur with cranial neuropathies,
8.6.4.5.5. Other medical interventions surgery is the only successful intervention and spontaneous
One single case study of leukotriene antagonist therapy in AFRS resolution has not been reported(323-326). Similarly, longterm
has been reported with benefit(316). correction of proptosis is not reported without surgery. Sinus
A randomized, single-blind, prospective study of AFRS patients, surgery alone, to address the AFRS, is usually all that is required

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and orbital reconstructions are not necessary(327). associated with antineutrophil cytoplasmic antibodies (C-ANCA)
(334)
.
Treatment of the uninvolved contralateral side is controversial. 8.7.2.1. Epidemiology
A recent study reported that up to 30% of ‘normal’ contralateral The true incidence of GPA has been underestimated in the past.
sides become involved in the disease process. A recent study Even with the advent of the ANCA test, many localised forms
showed that up to 30% of “normal” contralateral sides become of the disease may go unrecognised. In Europe a prevalence
affected However, the authors reported that the use of of 23.7 per million has been reported and in the USA 30 per
corticosteroid post-surgically dramatically reduced contralateral million(335). The overall incidence ranges from 2.9-12/106/year
recurrence (OR 0.11, 95% CI 0.01-0.87, p value 0.01). If the depending on the geographic region.
contralateral side has early pre-operative symptoms and/or
signs of inflammation radiologically then it was more likely to 8.7.2.2. Pathophysiology
become involved (OR 3.49, 95% CI 1.19-10.22, p value 0.02)(328). The pathophysiology of GPA is most likely autoimmune. A
number of in vitro and in vivo studies have indicated that ANCA
Conclusions Level induces the systemic vasculitis(334) by binding to and activating
Surgery is required to resolve and treat AFRS neutrophils which causes the release of oxygen radicals, lytic
1c enzymes and inflammatory cytokines. ANCA may also induce
including its complications
Orbital reconstruction is not required in resolving immune complex formation and may directly adhere to and kill
4
proptosis endothelial cells thereby causing vasculitis(336). Whilst PR3-ANCA
The contralateral sinus should be treated if there are (proteinase-3) is highly specific for GPA, the initial trigger may be
4
radiologic changes of inflammation infection or other environmental factors possibly combined with
a genetic susceptibility. Staphylococcus aureus colonization
8.7. Vasculitis, granulomatous diseases and their of the nose is found more frequently in GPA as compared to
role in CRS CRS and controls (72% v 28% v 25%)(337) and has been strongly
implicated as a causative agent, especially in relapses(338, 339)
8.7.1. Vasculitis which are reduced by the use of an anti-staph agent such as
trimethoprim/sulfamethoxazole(340). A large genome wide study
8.7.1.1. Classification on 1233 patients showed a strong association with HLA-DP and
The classification of vasculitis is challenging due to the genes encoding alpha1 antitrypsin (SERPINA1) and proteinase
heterogenous nature of the conditions. In 2012 the Chapel Hill 3 (PRTN3)(341). A review by Relle et al.(342) also identified some
Consensus on vasculitis nomenclature was revised(329) (Table susceptibility gene-CTLA4, PTPN22, COL11A2, SERPINA1 and
8.7.1.) but remains mainly based on pathology, specifically MHCC class II gene cluster.
affected blood vessel size (large, medium and small) which has
limited clinical applicability(330-332). The classification recognises 8.7.2.3. Diagnosis and differential diagnosis
primary and secondary vasculitis as well as single-organ
disease. The latter category should not be confused with Clinical (Table 8.7.2.)
localised forms of vasculitis which may become systemic such The peak incidence is in the fourth to fifth decades, mean 50
as granulomatosis with polyangiitis (GPA) and eosinophilic years but GPA can occur at any age (range 9-97 years)(343-345).
granulomatosis with polyangiitis (EGPA). It may also be difficult Patients >65 years at onset have a different pattern of organ
to determine in GPA, EGPA, Behcet’s and Kawasaki disease involvement, less upper respiratory tract involvement and
which size of vessels are involved. Similarly, the use of the anti- higher morbidity and mortality(346, 347). Men and women seem
neutrophil circulating antibodies (ANCA) as a classification trait equally affected and the vast majority are Caucasian (93%)(348).
is not applicable to a subset of ANCA associated vasculitis with However, there is some evidence that males are more likely to
no detectable ANCAs. There are numerous other classification have ‘severe’ disease and females the more ‘limited’ phenotype.
systems notably from the American College of Rheumatology, Classically GPA affects the nose, lungs and kidneys but can
European Medicines Agency and the ACR/EULAR endorsed present in any system and limited forms of the disease are
study to develop diagnostic and classification criteria for recognised(348). The European Vasculitis Study Group (EUVAS)
vasculitis (DCVAS)(333). ANCA-associated vasculitis includes GPA, distinguishes ‘localized’ (i.e GPA restricted to the respiratory
EGPA and microscopic polyangiitis (MPA) and frequently affect tract) and ‘early systemic’ GPA (i.e., non-imminent GPA without
the upper respiratory tract and specifically the sinonasal region renal organ involvement) from ‘generalized’ GPA(349).
where they may be mistaken for more common forms of chronic Two thirds of patients initially present with an ENT related
rhinosinusitis. symptom, of which the majority are rhinological (~40%), then
otologic (~15%) and laryngopharyngeal (~5%)(350-352). Nasal
8.7.2.Granulomatosis with polyangitis (GPA) symptoms were commoner in those diagnosed < 40 years
Granulomatosis with polyangitis (GPA) (previously (55%) as compared to those > 60 years (27%). During the course
Wegener’s Granulomatosis) is defined as an idiopathic of the disease, the majority experience nasal symptoms with
chronic inflammatory disease characterised by necrotizing patients experiencing crusting (75%), discharge (70%), nasal
granulomatous lesions and systemic vasculitis strongly stuffiness (65%), bleeding (59%), reduced sense of smell (52%)

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and facial pain (33%)(351). Hyposmia may be due to mechanical Indirect immunofluorescence (IIF) testing for neutrophil
obstruction of the olfactory region, specific cranial nerve cytoplasmic antibodies is commonly ordered first, followed by
involvement(353), secondary to immunosuppressive treatment(354) enzyme-linked immunosorbent assays (ELISAs) for antibodies
or due to any systemic autoimmune process(355, 356). Taste is directed against proteinase 3 (PR3) and myeloperoxidase
also reduced but less than smell(353). Deep seated facial pain (MPO). Having been divided into c-ANCA and p-ANCA
may be secondary to sinus involvement or due to an osteitis of (cytoplasmic versus perinuclear) by IIF, the ELISA links them
midfacial bone, indicative of disease activity. A characteristic with the presence of PR3 and MPO respectively. The cANCA
supratip collapse occurs in18-25% which may or may not be is 99% specific with a sensitivity of 73% using combined IIF
associated with septal perforation in up to 30%. On endoscopic and ELISA techniques but the increasing availability of reliable
examination the nasal mucosa is usually very friable, granular antigen-specific immunoassays (ELISA) is replacing the need for
and covered with old blood and crust, together with adhesions. indirect immunofluorescence(363). A positive c-ANCA test and
There may be thickening of bone and/or erosion which can proteinase-3 (PR3) will confirm the clinical diagnosis of GPA in
result in meningitis if the skull base is involved and fibrosis of up to 95% of patients with active systemic disease. However,
the nasolacrimal duct producing epiphora. The entire internal the c-ANCA lacks sensitivity in the limited forms of the disease
structure of the nose may disappears creating a large featureless dropping to 50% and/or following therapy with corticosteroids
cavity(344,369). so a negative ANCA does not exclude GPA.
Elsewhere in the upper respiratory tract, patients may Whilst a positive c-ANCA is usually associated with GPA and a
experience hearing loss (conductive, sensorineural or mixed), p-ANCA with MPO and EGPA, it is recognised that ~5% of GPA
vertigo, tinnitus and facial nerve palsy. patients have a positive p-ANCA/MPO.
In the mouth there may be gingivitis, ulceration and oro-antral Sequential monitoring of the c-ANCA can be useful in predicting
fistulas though less extensively than is seen with cocaine abuse. relapse(364) but not all patients show the classical pattern of
In addition, subglottic stenosis (16%) and vocal fold paralysis fluctuation with disease activity.
may occur, the symptoms of which may be wrongly attributed The ANCA testing is complemented by a raised ESR (erythrocyte
to the lower respiratory tract. Subglottic stenosis should be sedimentation rate) and CRP (c-reactive protein), altered renal
considered in any patients with dyspnoea, hoarseness or function on blood and urine testing (proteinuria, microscopic
inspiratory stridor and is estimated to occur in about 16% of GPA haematuria and red cell casts) and chest imaging (showing
patients(357). granulations, infiltration, necrotic cavitation, fibrosis).
Although GPA can present in many ways, often the development An ANCA test should be considered in any patient with
of relatively minor upper respiratory symptoms is associated suspicious clinical manifestations, in particular nasal crusting
with disproportionate unwellness, fatigue, weight loss and night and bleeding, especially if they feel disproportionally
sweats heralding generalised disease, the systemic symptoms unwell.
and signs of which are legion. Quality of life is significantly
affected in GPA as shown by the general Short Form-36(344, Cocaine abuse
358)
which improves with remission. The Sinonasal Outcome Cocaine abuse in the form of ‘snorting’ can induce significant
Test- SNOT-22 demonstrated the significant effect of sinonasal midline destruction of the nose and palate(365) often preceded
involvement on the general health-related QOL(344). by progressive nasal obstruction, epistaxis and crusting
Disease activity can be measured using the Birmingham which closely resembles the sinonasal symptoms of GPA. The
Vasculitis Activity Score (BVAS)(359), a Vasculitis Damage Index degree and distribution of destruction is greater in cocaine-
(VDI)(360) and an ELK-classification of organ involvement (ENT, induced vasculitis than GPA and was thought to arise from the
lung, kidney)(361). abnormal boosting of apoptosis and cellular damage caused by
Diagnosis can be delayed by 6 months or longer(343, 351), cocaine(366). It is now thought that this is more likely caused by
rendering the condition potentially life threatening. The delay the illicit addition of levamisole to cocaine(367). The c-ANCA and
was greatest when patients presented with eye symptoms (>14 PR-3 can also be positive, making differentiation between the
months) but ENT symptoms were associated with the second conditions difficult(365, 368) but massive apoptosis with abundant
longest delay of >8 months). This is particularly disappointing caspase-3 and 9 expression is found in the cocaine users but
as over half the patients (56%) saw an ENT surgeon prior to their not in GPA patients and ANCA reacts with human neutrophil
diagnosis. elastase (HNE) in the cocaine group but not in autoimmune
In a retrospective non-controlled cohort of 89 GA patients vasculitis so this may assist the differential diagnosis, supported
diagnosed between 1996 and 2016, those who presented with by tissue cocaine levels.
ENT involvement had a higher survival rate at 5 years than those
who presented with other systematic disease (98% v 78%) and Imaging
ENT involvement was an independent predictor of a better In a patient without a history of previous sinonasal surgery, a
outcome (OR 0.37, 95% CI 0.2-0.8, 0.019)(362). combination of bone destruction (60-75%), septal loss (59%)
and new bone formation (50-78%) on CT is highly suspicious
Investigations (Table 8.7.3.) of GPA (both localised and systemic)(352, 369-374) especially when
ANCA tests have become the mainstay of diagnosis in vasculitis. accompanied on MRI by a fat signal from the sclerotic sinus wall

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(‘tramlines’) giving a high-signal on T1-weighted sequences(369). maintain this with the lowest dose to minimise the side effects
However, early in the disease the most frequent finding is of of the medications(383). Methotrexate is sometimes used to
non-specific mucosal thickening in the nose or paranasal sinuses obtain remission in non-organ threatening disease and as
(87%) which may not raise suspicions of a vasculitis(369, 373). In maintenance(384).
contrast, progressive loss of midfacial structures can mimic an Monoclonal antibodies, in particular the anti-CD20 antibody,
NK/T cell lymphoma. rituximab, are now widely used(385, 386). The RAVE (Rituximab for
Imaging of the lungs should be undertaken to reveal diffuse ANCA-associated Vasculitis) study(387) on 197 patients showed
infiltration, multiple pulmonary nodules (2-4cm in diameter) or intermittent infusion of rituximab to be equivalent to daily
large necrotic cavitating granulomatous masses (10cm diameter cyclophosphamide for induction of remission and superior
or larger) some with fluid levels. Imaging of the orbit and larynx in relapsing disease but may not improve their chronic ENT
should be considered depending on clinical symptoms. problems(388).
For longer-term maintenance, in addition to low dose
Histopathology prednisolone and rituximab, azathioprine and mycophenolate
GPA is characterised by three key findings: mofetil have been used. These act as ‘steroid-sparing’, thus
granulomatous inflammation, necrosis and vasculitis affecting reducing the requisite dose of prednisolone or are used as
small to medium vessels (capillaries, venules, arterioles and monotherapy as they are less often associated with significant
arteries). The granulomas are composed of CD4+ and CD8+ T side-effects(383). TNF-alpha inhibitors such as infliximab and
cells, CD28- T cells, histiocytes, CD20+ B lymphocyte, neutrophil etanercept have been less effective and other monoclonals
granulocytes, macrophages and multinucleated giant cells such as belimumab (IgG1 antibody against B-Lys) are under
surrounding an area of central necrosis(334). Occasional investigation(386).
eosinophils may confuse the diagnosis with EGPA. Because relapses can be triggered by many events from an
Tissue biopsy from the kidneys or lung can confirm the episode of influenza to pregnancy, treatment needs constant
diagnosis but nasal biopsy, though easier to obtain, is less surveillance. Titration of treatment against the activity of
reliable and may be reported as ‘consistent with’ rather than the condition and the side-effects of the drugs are generally
definitively GPA as all three criteria of necrosis, granulomatous monitored with regular ANCA, full blood counts, ESR, CRP, renal
inflammation and vasculitis have to present(375, 376). Abnormal and pulmonary function tests, ideally in a multi-disciplinary
tissue from the sinuses is likely to provide a better yield(377) as setting, although the methodological range in the literature
can careful endoscopically directed biopsy after cleaning and make it difficult to show the best protocol(389). A CD8+-T cell
decongesting the nose(378). Mucosal biopsy is most helpful in signature may be used to identify relapse(383). Those on long-
c-ANCA negative, localised GPA patients. A study by Borner et term steroids need bone densitometry and prophylaxis against
al.(379) showed that although the biopsy had lower sensitivity osteoporosis should be considered.
(47%) than the ANCA test generally, in these circumstances it As it is not known if all localised forms spread systemically nor
had a specificity of 96% and a positive predictive value of 78% v whether treatment of limited disease prevents dissemination,
73% with c-ANCA. the decision to start immunosuppression can be difficult.
It is unclear for how long patients need to be treated but
Differential diagnosis maintenance is recommended for 18 months. In many
The differential diagnosis includes any of the other individuals the disease eventually burns-out but they may still
granulomatous conditions such as sarcoid, NK/T cell lymphoma, require a small replacement dose of steroid.
a range of infectious conditions such as tuberculosis,
rhinoscleroma or fungal diseases, particularly rhinosporidiosis Nasal
and other autoimmune conditions e.g. SLE or polyarteritis Nasal irrigation, a topical intranasal corticosteroid sprays or
nodosa. creams e.g. triamcinolone and/or a nasal lubricant such as 25%
glucose and glycerine drops, honey ointment or an aqueous gel
8.7.2.4. Treatment are usually recommended together with regular debridement of
Without treatment the mean survival of systemic GPA is five the crusts(377) (Level IV evidence).
months. Modern immunosuppressive treatment following a The possible aetiological role of Staphylococcus aureus has
strategy of combined remission induction and maintenance led to the use of long-term oral co-trimoxazole (trimethoprim-
has markedly improved this to a mean survival of 21.7 years sulfamethoxazole) and topical anti-staphylococcal creams in the
from diagnosis(380) with a significant improvement over the last nose(390)(Level I evidence).
four decades assisted by higher awareness and diagnosis(381). Endoscopic surgery has a very limited role and is associated with
However, ~10% never achieve remission, relapses occur in up to poor outcomes, increased scarring and adhesions so should be
50% of individuals and mortality rates of 5% or higher are still a last resort. Occasionally endoscopic exploration of an opaque
reported(382). sinus may be done to confirm that opacification is granulation/
Systemic fibrosis rather than infection, rarely a dacrocystorhinostomy may
In generalised and/or severe disease regimes of high dose be undertaken or repair of the skull base secondary to bone
systemic steroids and pulsed cyclophosphamide are aimed erosion in cases of meningitis(345, 377).
at rapidly inducing remission to limit organ damage and to Repair of the septal perforation is unlikely to be successful in the

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long-term so septal buttons are sometimes offered though can large amounts of IL25 which elicits Th2 responses, maintaining a
increase the crusting. Cosmetic improvement of the external vicious circle(403).
nasal deformity has been successfully undertaken once the Increased levels of IgG4 and IgG4/IgG ratios in EGPA have led
disease has been quiescent for a reasonable period of time (e.g. to the suggestion that EGPA may be part of the IgG4 disease
one year)(391). spectrum(404).
As with GPA, it is thought that localised early forms of EGPA may
8.7.3. Eosinophilic granulomatosis with polyangiitis exist, particularly in the upper respiratory tract(403).
Eosinophilic granulomatosis with polyangiitis (EGPA) (previously
Churg Strauss Syndrome)(329, 392), is a rare form of vasculitis 8.7.3.3. Diagnosis and differential diagnosis
characterised by adult onset asthma, severe rhinitis, nasal polyps According to the American College of Rheumatology criteria(405),
and other systemic manifestations as a result of widespread at least four out of six criteria must be present:
eosinophilic granulomatous infiltration of tissues. 1) A medical history of asthma
The Chapel Hill consensus defined it as ‘eosinophil-rich 2) Eosinophilia >10%
granulomatous inflammation of the respiratory tract and 3) Mono- or polyneuropathy
necrotizing vasculitis of small to medium-sized vessels, 4) Nonfixed pulmonary infiltrates
associated with eosinophilia’. However, the nomenclature has 5) Paranasal sinus abnormalities
been challenged as only 59% of patients with this diagnosis 6) Biopsy including an artery, arteriole or venule showing
have evidence of polyangiitis(393). accumulated eosinophils in the extravascular tissue.

8.7.3.1. Epidemiology Clinical (Table 8.7.2.)

The overall prevalence of the condition ranges from 10.7-13 The male to female ratio in the literature ranges from 58:43 to
cases/million inhabitants with an annual incidence of 0.5-6.8 39:54 with mean age of between 49-52 years in the 28 studies
new cases/million inhabitants(394). However, among asthma included in a systematic review by Goldfarb(406). It can manifest
patients the incidence is as high as 67 per million(395). between 7-74 years with a mean age of onset of 38-54 years(403).
No ethnic predisposition has been determined(407).
8.7.3.2. Pathophysiology The condition often follows three clinical stages. The prodromal
The aetiology is unknown though it is probably an idiopathic stage is characterised by allergic rhinitis, CRS with or without
autoimmune Th2 mediated disease affecting eosinophils, polyps and asthma(408, 409). This stage may predate the overt
endothelial cells and lymphocytes. It has been suggested vasculitis by months to many years (mean eight years)(396).
that exposure to certain allergens, drugs, vaccinations, The second ‘eosinophilic’ stage is characterised by tissue and
corticosteroid withdrawal, and pulmonary infection may peripheral eosinophilia.
initiate the inflammatory cascade(396-398). It has been suggested The final ‘vasculitic’ phase involves extrapulmonary disease
that antileukotriene antagonists such as zafirlukast and with vasculitis, associated with severe and fatal manifestations
montelukast(396) when used for asthma in some patients, could including polyneuropathies, myocarditis, cerebral haemorrhage,
unmask EGPA. However, the consensus is that these drugs may ischaemic strokes and bowel perforations.
be used if needed in EGPA, as the onset was either coincidental In a systematic review(406) of 1175 patients with EGPA, 48-96%
or resulted when symptoms of EGPA were unmasked after presented with head and neck manifestations, which are often
oral glucocorticosteroids were tapered and/or withdrawn(399, sinonasal(410). These include nasal obstruction (95%), crusting
400)
. Other drugs implicated in triggering EGPA include (75%), bleeding (60%), rhinorrhoea (95%), facial pain, loss of
antibiotics (macrolides), oestrogen replacement therapy, and smell (90%) and sneezing (80%) associated with allergic rhinitis
carbamazepine suggesting a hypersensitivity reaction. (43%) and chronic rhinosinusitis with (54%) and without nasal
There is also some evidence for a genetic predisposition in polyposis (70%). In addition to nasal crusting, hypertrophy of
respect of the HLA-DRB1*04 and *07 alleles and the related the inferior turbinates, mucosal oedema, synechia and nasal
HLADRB4(401, 402). In EGPA the anti-myeloperoxidase ANCA may polyps may be seen on endoscopy(411, 412). Olfactory testing
be associated with HLA-DQ(341). using Sniffin’ sticks in 62 subjects showed normosmia in 79%,
Eosinophilic infiltration and endothelial damage are likely the hyposmia in 11%, anosmia in 29% and dysosmia in 40%(412).
most important pathophysiological mechanisms. Peripheral Anterior rhinomanometry in 86 subjects showed severe nasal
T-cell lines from EGPA patients can produce Th2 associated obstruction in a third. A mean SNOT-22 of 41.5 has been found,
cytokines such as IL4 and IL13 and IL5 is upregulated in comparable to patients with CRS without vasculitis(410).
active disease, offering therapeutic possibilities(403). However, As a consequence, patients are frequently seen by the ENT
an exaggerated Th2 response cannot account for all the community who may not appreciate the potential for a more
manifestations of EGPA and there is evidence of involvement of serious systemic disease but are in a unique position to make
Th1 and Th17 cells secreting large amounts of IL-17a in the late an early diagnosis and prevent late complications of the
stages of the disease. Eoxtaxin-3 produced by endothelial and condition(413). EGPA should be considered in any patient with
epithelial cells may contribute to eosinophilic tissue infiltration severe nasal polyposis who is not responding to conventional
and further tissue damage may be caused by eosinophilic therapy. ENT and systemic manifestations are shown in Table
cationic protein from activated eosinophils. They also secrete 8.7.2. In one series the mean delay between diagnosis and

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presenting to the physician with worsening symptoms was 18.5 kidney, heart, gastrointestinal and peripheral nerve involvement
months (range 1-71 months, SD 21.6)(410) whereas a mean delay is recommended as these are associated with poor prognosis(394).
from diagnosis of asthma to diagnosis of EGPA of 11.8+/-18.2 This can include imaging, biopsy, bronchoalveolar lavage, renal
years has been reported(414). and cardiac function tests.

Investigations (Table 8.7.3.) Differential diagnosis

Active EGPA is characterised by marked peripheral eosinophilia The differential diagnosis is from other eosinophilic
(usually >1500 cells/ul or >10%)(403). There is usually a non- pneumonias, idiopathic hypereosinophilic syndrome, c-ANCA
specific increase in IgE if the patients are not taking systemic positive granulomatosis and microscopic polyangiitis, sarcoid,
steroids for their asthma. allergic bronchopulmonary aspergillosis and parasitic infections.
EGPA is one of the antineutrophil cytoplasmic antibody (ANCA)- Thus in addition to ANCA, the EGPA Consensus Task Force
associated vasculitides. Immunofluorescent patterns with recommended as a minimum initial differential diagnostic work-
ELISA detecting antibodies to myeloperoxidase (MPO) is the up the following: serologic testing for toxocariasis, HIV, specific
most common EGPA ANCA-positivity finding but figures for IgE and IgG for Aspergillus spp, a search for Aspergillus spp
p-ANCA positivity vary. Between 26-48% have been reported in sputum and/or bronchoalveolar lavage fluid, tryptase and
to have a positive p-ANCA but this increases to 75% with renal vitamin B12, full blood count and CT of the chest(394). However,
involvement(415) and other studies quote 35-77% so a negative EGPA can usually be distinguished from other primary systemic
ANCA does not rule out EGPA and a positive ANCA may not be vasculitides by the presence of asthma and a marked blood
essential for the diagnosis in the head and neck phenotype(329, eosinophilia.
395, 416-419)
.Overall pANCA-positive patients are more likely to have
peripheral neuropathy, glomerulonephritis and purpura (due to 8.7.3.4. Treatment
small vessel vasculitis) as compared to those with myocardial, In 2009, the European League Against Rheumatism (EULAR)
respiratory and gastrointestinal involvement who are more published treatment recommendations for small to medium
often pANCA negative(416, 420). sized vessel vasculitides. Without treatment, the mortality
Other biomarkers have been investigated including serum rate is high once the vasculitis phase is reached(425, 426). A
TARC/CCL17, eotaxin-3, IgG4 and IgG4/IgG ratio but none multidisciplinary management is widely recommended in the
were useful in discriminating between active disease and literature(394) and with appropriate treatment, survival rates are
remission(421). comparable to GPA(426).
Long –term studies have shown that overall remission rates are
Imaging good, ranging from 81-92% but over a quarter do relapse either
Sinus CT does not show anything other than what would within the first year of treatment or much later(427). This is higher
be expected in diffuse polypoid rhinosinusitis i.e. pan- in MPO /pANCA positive patients. Overall mortality in treated
opacification(422). Mean Lund-Mackay scores of 9-17 have been patients who relapsed was only 3.1%.
reported in large cohorts of EGPA(412, 422). Expansion and bone Factors predicting poor outcome are: cardiomyopathy (an
erosion may be seen in the ethmoid complex with widening of independent risk factor) or two features of the ‘five-factor’ score
the intercanthal distance. In addition, there may be evidence of (FFS) (creatininemia >140umoles/litre; proteinuria >1g/day;
mucocele formation, notably in the fronto-ethmoidal region. involvement of central nervous system, gastrointestinal or heart)
High resolution CT of the chest is recommended to demonstrate (426, 428)
. If one of these factors is present at onset, the five year
atypical ‘fluffy’ or nodular migratory pulmonary infiltrates which mortality is 25.9%, when two or more are present, this increases
would only be seen in 64% of plain chest x-rays(423). Peripheral to 46% at five years(428). Survival at one and five years was 100%
nodules (25%), ground glass opacities (86%) and bronchial wall if the score was 0. The FFS was revisited in 2011 by the French
thickening and bronchiectasis (66%) are also found on CT. Vasculitis Study group as follows: 1) age >65yrs; 2) cardiac
symptoms; 3) gastrointestinal involvement; 4) renal insufficiency
Histopathology characterised by a serum creatinine >150 umol/l; 5) absence
Histopathologically the condition is characterised by of ENT manifestations. With each factor accorded one point, a
eosinophilic inflammation and infiltration, extravascular revised FFS of 0, 1 and 2 is associated with a five-year mortality
granulomas and necrotizing vasculitis in the presence of rate of 9%, 21% and 40% respectively(429). A subsequent study
asthma. However, in studies where sinonasal tissue was showed that age >65 years was the only factor associated with
examined, eosinophilic infiltration was seen in 35-100%, whilst higher risk of death during follow-up(427).
necrotising vasculitis and eosinophilic granulomas were not
seen(408, 424). Systemic
Although the histology is important, this combined with clinical In most patients, disease control is achieved with
criteria are required to make the diagnosis and a low threshold immunosuppressant therapy, usually oral prednisolone +/-
of suspicion is required in any patient with eosinophilic diseases cytotoxic drugs such as pulsed cyclophosphamide, azathioprine,
i.e. significant adult-onset asthma, recurrent CRSwNP and mycophenolate mofetil and methotrexate dependent on the
allergic rhinitis. Once EGPA is diagnosed, investigation for lung, severity of the disease at presentation. Patients without poor

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prognostic factors can often be managed with glucocorticoids It is associated with cell-mediated and humoral immune
alone. Additional systemic treatments include intravenous abnormalities. T cells play a central role with an accumulation
immunoglobulin, leflunomide, anti-TNFa, interferon-a and of CD4+ T cells, accompanied by release of IL2 followed by a
plasma exchange(430). non-caseating granuloma. There may be an inverted CD4+/
Rituximab is now frequently being used in selected ANCA- CD8+ ratio. TH1 cytokines such as interferon are increased as is
positive patients with renal involvement or refractory disease tumour necrosis factor (TNF). There is B cell hyperreactivity and
though the evidence is less robust that in GPA(394, 431-434) and immunoglobulin production. Glycoprotein KL-6 and surfactant
other new biologic therapies may be helpful e.g. anti-IL 5 protein D are increased in pulmonary sarcoid(447) and Th17 cells
(mepolizumab)(435-437) or anti-IgE (omalizumab) monoclonal are also thought to play a role(448).
antibodies(438, 439).
8.7.4.4. Diagnosis and differential diagnosis
Nasal
Alkaline/saline nasal irrigations, topical intranasal corticosteroids Clinical (Table 8.7.2.)
and nasal lubricants are the mainstay of treatment (Level IV). Sarcoidosis is classically a multisystem disease and can therefore
Endoscopic surgery can be successfully undertaken in those present in protean ways, the distribution of which reflects the
whose CRS with nasal polyps do not respond to systemic and origin of the individual series. The chances of possible organ
local steroids. The numbers of reported EGPA surgical cases in involvement can be assessed with the WASOG sarcoidosis
the literature is small(440) and surgery is often associated with a organ assessment instrument(449) or more recently through the
high recurrence rate though patients may still obtain benefit(422). Genotype-Phenotype Relationship in Sarcoidosis study(450).
A number of patients develop paranasal sinus mucoceles which However, the disease can also be asymptomatic, found
may also be dealt with endoscopically. In a series of 25 patients, incidentally e.g. on chest imaging (5%).
48% had undergone endoscopic sinus surgery, often multiple It has a propensity for the lower respiratory tract to be affected
times(410). in up to 95% in some studies(451). The upper respiratory tract
is involved infrequently(452), in approximately 3-4% of patients
8.7.4. Sarcoidosis with generalised disease. Notably the nose is affected with
blockage, crusting and bleeding(445, 453-455). Nasal polyps and
8.4.7.1. Definition septal perforations leading to saddle nose deformity have also
Sarcoidosis is a chronic multi-system inflammatory disease of been reported(411, 456-458). Lupus pernio of the external nose, face
unknown aetiology characterised by non-caseating granuloma. and ears often accompanies sinonasal sarcoidosis(451). The ears,
The first description is sometimes ascribed to Besnier in 1889 mouth and larynx may also be affected(459-461).
who coined the term ‘lupus pernio’ for the cutaneous lesions(441). In a series of 148 patients with proven sarcoid and referred
It is usually associated with bilateral hilar lymphadenopathy, to a specialist rhinological practice, nearly 90% suffered nasal
pulmonary, ocular and skin lesions(411, 442). congestion or blockage and two thirds had crusting. Bleeding
or spotting of blood affects 40% and nearly a quarter had facial
8.7.4.2. Epidemiology pain. Anosmia can result from mechanical obstruction of the
The age-adjusted incidence is 11 cases/100,000 population in olfactory region and/or sensorineural(453). The co-existence of
Caucasians and it is commoner in northern Europe (Sweden, chronic rhinosinusitis and two of the following: nasal crusting,
Iceland) affecting an estimated 20/100,000 population versus anosmia and epistaxis were shown to be highly specific for
1.3/100,000 in Japan. In the United States it is more prevalent sarcoid rhinosinusitis(454). This means that many of these
in African Americans than whites (35.5/100,000 versus patients may present to the ENT community but as with other
10.9/100,000 respectively). It is twice as common in women granulomatous diseases, they may go unrecognised. To put
than men, who also have higher morbidity, mortality and this in context, the diagnosis of nasal sarcoid was made in 23
extrapulmonary involvement. Incidence peaks in the third – patients who presented with ‘chronic rhinosinusitis’ in a cohort
fourth decades, with a second peak in women between 45-65 of 5000 patients presenting to the aforementioned rhinology
years though any age can be affected(443, 444). clinic and this has been the experience of others(459, 460, 462, 463).
On endoscopic examination, the mucosa has been described
8.7.4.3. Pathophysiology as a ‘strawberry skin’ with small pale granulomas dotted over an
The aetiology of this condition remains unknown. It appears erythematous and granular mucosa(411, 460). These appearances
to be an exaggerated immune response to an unknown may be obscured by extensive crusting and eventually may
antigen for which a wide range of agents have been suggested. become atrophic. Within the nasal cavity, the inferior turbinate
This includes infective agents such as mycobacteria or and adjacent nasal septum are particularly affected with a
propionibacteria, chemicals (beryllium and zirconium), pine nodular hypertrophy. However, any of the paranasal sinuses,
pollen and peanut dust(445). nasopharynx, soft palate, hypopharynx and supraglottis can be
It is one of the few pulmonary diseases commoner in non- involved.
smokers. Working on the World Trade Centre debris after
9.11.2001 was associated with development of sarcoidosis(446).

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Table 8.7.1. Classification of vasculitides adopted by the 2012 International Chapel Hill Consensus Conference on the Nomenclature
of Vasculitides(329).

Large vessel vasculitis (LVV)

· Takayasu arteritis (TAK)
· Giant cell arteritis (GCA)
Medium vessel vasculitis (MVV)
· Polyarteritis nodosa (PAN)
· Kawasaki disease (KD)
Small vessel vasculitis (SVV)
· Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV)
Microscopic polyangiitis (MPA)
Granulomatosis with polyangiitis (Wegener’s) (GPA)
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)
· Immune complex SVV
Anti–glomerular basement membrane (anti-GBM) disease
Cryoglobulinemic vasculitis (CV)
IgA vasculitis (Henoch-Schonlein) (IgAV)
Hypocomplementemic urticarial vasculitis (HUV) (anti-C1q vasculitis)
Variable vessel vasculitis (VVV)
· Behcet’s disease (BD)
· Cogan’s syndrome (CS)
Single-organ vasculitis (SOV)
· Cutaneous leukocytoclastic angiitis
· Cutaneous arteritis Primary central nervous system vasculitis
· Isolated aortitis
· Others
Vasculitis associated with systemic disease
· Lupus vasculitis
· Rheumatoid vasculitis
· Sarcoid vasculitis
· Others
Vasculitis associated with probable etiology
· Hepatitis C virus–associated cryoglobulinemic vasculitis
· Hepatitis B virus–associated vasculitis
· Syphilis-associated aortitis
· Drug-associated immune complex vasculitis
· Drug-associated ANCA-associated vasculitis
· Cancer-associated vasculitis
· Others

Table 8.7.2. Symptoms associated with different system involvement in granulomatosis with polyangiitis (GPA), eosinophilic
granulomatosis with polyangiitis (EGPA) and sarcoidosis.

GPA EGPA Sarcoid

Ear · Otalgia, otorrhoea, conductive and · Otalgia, otorrhoea, conductive · Sensorineural and conductive deafness
sensorineural deafness and sensorineural deafness · Vestibular dysfunction
· Dizziness · Serous otitis media, · Facial nerve paralysis
· Tinnitus mastoiditis, facial nerve palsy
· Chronic otitis media
· Otitis externa
Nose and throat · Nasal obstruction · Nasal obstruction (95%) · Nasal obstruction (90%)
· Crusting · Crusting (75%) · Crusting (66%)
· Bleeding · Bleeding (60%) · Blood stained discharge (40%)
· Rhinorrhea · Rhinorrhea (95%) · Facial pain (25%)
· Facial pain, loss of smell · Facial pain, loss of smell (90%) · Anosmia (70%)
· Rhinosinusitis · Sneezing (80%) · Septal perforation
· Septal perforation · Septal perforation (rare) · ‘Strawberry skin’ nasal mucosal nodules
· External ‘saddle’ deformity CRSsNP (70%), CRSwNP (54%) · Nasal bones – rarefaction and soft
· Adhesions · Allergic rhinitis (43%) tissue infiltration, adhesions
Mouth · Oral ulceration · Cranial nerve palsies
· Gingivitis
· Fistula
· Cranial nerve palsies

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GPA EGPA Sarcoid

Larynx · Hoarseness, stridor · Hoarseness, stridor
· Vocal fold palsy · Supraglottic granulomas and stenosis
· Subglottic and tracheal stenosis · Vocal fold palsies
Lower respiratory tract · Dyspnoea, pleuritic pain, hemoptysis · Asthma (~100%) · Dyspnoea, cough, chest pain, wheeze
· Pulmonary infiltrates, nodules, · Pulmonary infiltrates, nodules, (50-95%)
abscesses or haemorrhage bronchiectasis, bronchial wall · Hemoptysis (rare)
thickening · Pulmonary infiltrates
· Hilar lymphadenopathy (+ fever,
polyarthralgias = Lofgren syndrome,
mainly Scandinavians)
Ophthalmic · Proptosis, pain, visual loss, epiphora Rare · Epiphora, red, painful eye,
· Scleritis, episcleritis, retinitis, retro- photophobia, dry eye, visual loss
orbital granuloma · Anterior and posterior uveitis,
iridocyclitis, keratoconjunctivitis, scleral
plaques
· Lacrimal enlargement

Cardiac · Arrhythmias · Vasculitic myocarditis (23- · Cardiac failure and ventricular

· Pericardial effusion 45%) arrhythmia – heart block, sudden death
· Infarction, myocarditis · Pericarditis
· Myocardial infarction
Renal · Glomerulonephritis · Glomerulonephritis
· Renal impairment · Renal impairment
· Renal failure · Renal failure
Gastrointestinal · Diarrhoea · Abdominal pain, nausea,
· Bleeding vomiting, diarrhoea,
haemetemesis, melaena
· Small bowel perforation
Peripheral nervous · Sensory or motor polyneuropathy · Sensory or motor peripheral · Polyneuritis
system · Mononeuritis (10-50%) neuropathy (50-70%) · Peripheral mononeuritis
· Mononeuritis esp. peroneal · Myelopathy
nerve
Central nervous system · CNS lesions · Intracranial abscess · Lymphocytic meningitis
· Meningitis · Cranial neuropathies · Cranial neuropathies
· Meningeal vasculitis · Hypothalamic / pituitary dysfunction
(rare)
Skin · Purpura · Purpura · Violaceous rash
· Subcutaneous nodules · Subcutaneous nodules · Erythema nodosum
· Non-healing ulceration (40-50%) · Non-healing ulceration (40- · Lupus pernio
50%) · Maculopapular plaques (rare)
Musculoskeletal · Arthralgia · Arthralgia · Arthralgia
· Myalgia · Myalgia · Myalgia
· Dactylitis
General / Other · Fever · Fever · Fever
· Weight loss · Weight loss · Weight loss
· Fatigue · Fatigue · Fatigue (45%)
· Nocturnal sweats · Peripheral lymphadenopathy
· Parotitis (Heerfordt’s syndrome)
· Hepatosplenomegaly

Table 8.7.3. Investigations in granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and
sarcoidosis.

GPA EGPA Sarcoid

Blood · c-ANCA/PR3 (95% +ve with systemic · Blood eosinophilia (>10%) · Hypercalcaemia (in 10-13%)
disease; 50% +ve with limited · IgE – non-specific increase · Hypercalciuria (in ~30%)
disease) · p-ANCA/MPO +ve (in 26-48%, increasing · Raised alkaline phosphatase
· p-ANCA (5% +ve) to 75% with renal involvement) · Raised angiotensin-converting
· Raised erythrocyte sedimentation enzyme (in 60-83%)
rate (ESR)
· Raised c-reactive protein
Imaging · HRCT chest · HRCT chest · CXR / CT chest
· CT sinuses · CT sinuses · CT sinuses

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Lower respiratory · Pulmonary function · Pulmonary function · Pulmonary function test

tract · Flow volume loop spirometry to · Gallium67 perfusion test
exclude subglottic stenosis · Broncho-alveolar lavage
· Bronchoscopy - biopsy
Cardiac · Myocardial assessment · Cardiopulmonary exercise
testing
· ECG
Renal · Urinalysis · Urinalysis
· Renal function tests · Renal function tests
· Tissue biopsy
Peripheral nervous · Biopsy if neuropathy
system
Central nervous · MRI brain
system
Skin · Negative tuberculin skin test in
a BCG vaccinated patient
· Biopsy of lupus pernio
General / Other · FDG-PET CT

nvestigations (Table 8.7.3.) Gallium(159) perfusion scans can demonstrate increased uptake in
There is no definitive test for sarcoid other than a positive the sarcoid granuloma but have low sensitivity and specificity.
biopsy, usually endobronchial(444) or from skin, minor salivary MRI of the brain may show granulomatous involvement of the
glands or lymph nodes(411). The classic appearance is of a non- basal meninges.
caseating granuloma composed of a central area of tightly FDG-PET is being used to monitor response in severe cases.
packed epithelioid, giant cells, CD4+ T cells surrounded by CD8+
T and B lymphocytes and fibroblasts at the periphery. Special Sarcoid is staged according to pulmonary involvement(466):
stains should be negative for mycobacteria and fungi. Biopsying 0: Normal chest imaging
the nasal mucosa if it appears macroscopically abnormal is I: Bilateral hilar lymphadenopathy, normal lung fields
worthwhile as the majority will be positive (91%) whereas if it II: Bilateral hilar lymphadenopathy and infiltrates
appears normal, the biopsy will usually be negative (92%)(453). III: Infiltrates alone
Blood tests may include raised serum and urinary calcium levels, IV: Fibrosis
raised alkaline phosphatase and raised serum angiotensin-
converting enzyme (SACE) but none are diagnostic (sensitivity Differential diagnosis
60%; specificity 70%). The differential diagnosis is between other granulomatous
Other tests may include pulmonary and cardiopulmonary diseases such as syphilis, tuberculosis, rhinoscleroma, GPA and
function, perfusion studies, broncho-alveolar lavage and ECG. EGPA as well as berylliosis, leprosy, fungal disease, cat scratch
fever, a range of lymphomas and diffuse granulomatous disease
Imaging in common variable immune deficiency(369, 371, 462, 467).
CT scanning of the nose and sinuses often shows a non- An elevated serum angiotensin-converting enzyme is
specific generalised opacification similar to that seen in chronic suggestive of sarcoid but can be raised in other conditions such
rhinosinusitis. This may be due to an active granulomatous as TB, lymphoma, leprosy and Gaucher’s disease.
process, or fibrosis after the condition has regressed and/or
non-specific inflammation or infection(461). In addition turbinate 8.7.4.5. Treatment
or septal nodularity (21%), osteoneogenesis (15%) and bone Sarcoidosis can present to a wide range of disciplines including
erosion (8%) may be seen(464). The bone erosion in the sinuses ENT so as with other vasculitic/granulomatous diseases, it
may even suggest malignancy. requires a low threshold of suspicion to make the diagnosis
The nasal bones may show rarefaction or punctuate osteolysis and is best managed in a multi-disciplinary environment(451). In
similar to that seen in the metacarpals or metatarsals. In CT many cases, particularly Stage 1 disease, the disease undergoes
scans of the sinuses of 39 biopsy-proven sarcoid patients, the spontaneous remission within two years without specific
mean Lund-Mackay score was a modest 6.2 but the nodularity of treatment. Around 75% can be managed symptomatically with
the mucosal thickening should suggest the diagnosis(464). NSAIDS. In those with Stage 2, 65% spontaneously regress, Stage
MRI of the sinuses may also show abnormalities consistent 3 patients with just lung disease have a 30% of remission chance
with the CT changes as will gallium(159)scanning and positron and an 18% mortality rate whereas 85% of those with erythema
emission tomography(465). The lacrimal glands may be enlarged nodosum and acute arthritis remit spontaneously. Those
bilaterally. with more advanced disease as evidenced by raised SACE or
Chest radiography and CT of the lungs may show multiple extrapulmonary involvement will usually require treatment and
nodules or nodular infiltration but occasional these may be about 50% may experience a relapse, with 1 in 10 developing
solitary or unilateral between 1-5 cm in diameter(466). serious disability(468). Severe cardiac or pulmonary involvement

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may lead to death in some cases and lung transplantation has may result from the procedure(461). Nasal reconstruction and
been undertaken though up to two thirds develop recurrence resurfacing have also been anecdotally described for persistent
in the allograft(469, 470). Lung function should be monitored every lupus pernio(479-481).
6-12 months..

Systemic Key points | What’s new since EPOS 2012

The mainstay of treatment, when it is required, remains oral
corticosteroids. They are used for Stage II and III pulmonary
disease and for extrapulmonary involvement of critical
organs(468, 471). 1. A low threshold of suspicion should be maintained
Hydroxychloroquine / chloroquine are used for cutaneous for ANCA-associated vasculitis (granulomatosis with
and bone lesions and neurologic sarcoid as well as acute and polyangitis (GPA), eosinophilic granulomatosis with
maintenance treatment of the chest. However, they can cause polyangitis (EGPA)) and sarcoidosis, all of which can affect
retinal toxicity. the upper respiratory tract and present with apparent
Steroid-sparing cytotoxic agents such as methotrexate chronic rhinosinusitis.
(weekly), cyclophosphamide and azathioprine may be used as 2. The ANCA test has become the mainstay of diagnosis
alternatives or in addition to systemic steroids(468). in vasculitis but lacks sensitivity in limited forms of GPA
TNF-alpha antagonists such as infliximab(468, 472-474) and (c-ANCA) and EGPA (p-ANCA).
thalidomide(475) have been used in refractory disease, 3. Cocaine abuse can produce a midline destructive
in particular for cutaneous, ophthalmic, hepatic and process which mimics GPA.
neurosarcoidosis. 4. In GPA and EGPA systemic treatment with
immunosuppression is being replaced in many cases by
Nasal rituximab and other monoclonal antibodies.
Nasal symptoms may be improved by the systemic treatment(461, 5. Sarcoidosis is a chronic multi-system inflammatory
476).
In addition standard topical treatments with saline or disease of unknown aetiology characterised by non-
alkaline irrigations, corticosteroid sprays or drops and lubricants caseating granuloma.
such as 25% glucose and glycerine drops, honey ointment or 6. There is no definitive test for sarcoid other than a positive
an aqueous gel are usually recommended together with regular biopsy.
debridement of the crusts can be used(451) (Level IV). 7. Systemic steroids remain the mainstay of treatment in
Surgery has a very limited role, confined to biopsy, occasionally sarcoidosis, though hydroxychloroquine, steroid-sparing
debulking of granulomatous masses and associated inferior cytotoxic agents such as methotrexate andTNF-alpha
turbinate hypertrophy(477) and endoscopic sinus surgery antagonists such as infliximab are being used.
to elucidate CT changes and possibly reduce the need for 8. In all these conditions, local treatment includes nasal
systemic steroids(442, 457, 461, 462, 478). Surgery on the septum is not rinsing, topical steroids and lubricants.
recommended, especially if the disease is active as perforation

References phenotype of chronic rhinosinusitis based on 10. Asero R, Bottazzi G. Nasal polyposis: a study of its
radiologic pattern of disease. Laryngoscope. association with airborne allergen hypersensitiv-
1. Gutman M, Torres A, Keen KJ, Houser SM.
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402. Wieczorek S, Hellmich B, Gross WL, Epplen
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rheumatology 2010;28:24-30.
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403. Greco A, Rizzo MI, De Virgilio A, et al. Churg– syndrome. J of Allergy and Clinical Immunology 432. Pepper RJ, Fabre MA, Pavesio C, et al. Rituximab
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2015;14:341-8. 419. Mouthon L, Dunogue B, Guillevin L. Diagnosis Churg-Strauss syndrome and is associated with
and classification of eosinophilic granulomatosis diminished T-cell interleukin-5 production.
404. Vaglio A, Strehl JD, Manger B, et al. IgG4 immune
with polyangiitis (formerly named Churg-Strauss Rheumatology (Oxford, England) 2008;47:1104-
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syndrome). J of autoimmunity 2014;48-49:99- 5.
the Rheumatic Diseases 2012;71:390-3.
103. 433. Jones RB, Ferraro AJ, Chaudhry AN, et al. A multi-
405. Lanham JG, Elkon KB, Pusey CD, Hughes GR.
420. Pagnoux C, Guillevin L. Churg–Strauss syn- center survey of rituximab therapy for refractory
Systemic vasculitis with asthma and eosino-
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Opinion in Rheumatology 2010;22:21-8. vasculitis. Arthritis & Rheumatism 2009;60:2156-
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markers in patients with relapsing eosinophilic 434. Cartin-Ceba R, Keogh KA, Specks U, Sethi S,
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Churg-Strauss syndrome with renal involve-

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9. Patient participation, prediction, precision medicine and

implementation

9.1 Patient participation in CRS

Patient participation in the decision-making process of
9.1 Patient participation in CRS the therapeutic plan is one of the four cardinal
Patient participation in rhinosinusitis can relate on an individual principles of Precision Medicine.
basis to participation of the patient in the design and/or discus-
sion of the treatment plan, or to participation in the follow-up Patient participation in the follow-up of medical or surgical tre-
after medical or surgical treatment. There is limited research on atment of CRS is also considered important to achieve optimal
the impact of patient participation on outcomes of treatment in outcomes, but needs further study. The current follow-up stra-
CRS. tegy of CRS patients after initiation of medical and/or surgical
Patient involvement, moreover, is recognized as a key compo- care depends on the regional health care system and treating
nent of research and clinical practice guideline development physician, and on the patients’ willingness and capabilities of
with important implications for guideline implementability(1). being followed-up on a regular base.
For optimal implementation, guideline development must Recent mobile health initiatives to educate patients on CRS,
include all key stakeholders, thus including patients from the on correct medication use and treatment options have been
start and recommendations should be relevant and applicable implemented in certain areas in Europe with success(4). Whilst
and address patients’ needs. Patient involvement in guidelines they allow a more pro-active follow-up of patients with remote
is important because it appreciates that patients are experts, monitoring of symptoms by physicians(4, 5) the impact of e-health
empowers and informs consumers in health care decisions, on CRS outcomes still needs to be defined and proven.
and will lead to the development of more patient-centred
and trustworthy guidelines. Therefore, the Agree II instrument 9.1.2 What’s important to patients in sinus care?
requires that guideline developers seek the views of the target Although there is increasing awareness of the need to engage
population (https://www.agreetrust.org/agree-ii/). In EPOS2020, patients both in their own care, and in the design and delivery
patients were included in every step of the development from of trials, there are very few studies that set out to evaluate what
the first questions to the dissemination. issues are most important to patients with rhinosinusitis, and
There is limited research on the impact of patient participation which should be addressed during a consultation. A previous
on outcomes of treatment in CRS. In this chapter we discuss the study in allergic rhinitis demonstrated that up to half of patients
data on individual patient participation. have no specific opinion on any recommended treatment, but
that the other half do have an opinion that should ideally be
9.1.1. Areas of patient participation. addressed(6).
Patient participation in the decision-making process of the Vennik et al.(7) have undertaken structured interviews with 25
therapeutic plan is one of the four cardinal principles of patients with CRS, and used thematic analysis to identify key
Precision Medicine(2), which are considered to lead to good/ areas of importance;
better adherence to treatment, high patient satisfaction and/or • Recognising the impact of the disease (symptom severity
cost-savings. Attempts to study the impact of a patient-centred and the impact on both work and social activities);
decision on the medical treatment of CRS have not been con- • Seeking resolution with treatment (self-management, in-
vincingly showing a major benefit(3). In real-life, patient partici- cluding dietary changes and complementary therapies and
pation requires efforts from both patients as well as physicians, medical treatment options, including how to use medical
both physicians’ efforts to educate patients on the nature of the treatments, concerns regarding potential side effects);
disease and the different treatment options, including predic- • Surgical intervention (role of surgery, including advice on
tion of success and failure of the different treatment options the optimum time for intervention, the aims of surgery and
and patients’ willingness to be educated and take part in the its anticipated outcome).
decision-making process of any medical or surgical treatment Patients in this study also expressed concerns regarding some of
for CRS. their experience with different healthcare interactions, highligh-

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ting that some doctors fail to recognise the impact that sinus Information on the safety of treatment and instructions for use
disease can have on a patient, a failure to take a holistic appro- must be provided in all necessary languages. Recent initiatives
ach to both upper and lower airway disease, inadequate time to in e-health make attempts to better educate patients on any
answer questions fully, and long intervals between reviews. chronic condition, hopefully leading to better compliance and
Alanin et al.(8) undertook a qualitative analysis of patients’ posts outcomes(12). One could speculate that a patient who is properly
made on the Samter’s Society Support Group, with the per- educated on the disease, on correct use of medication, on the
mission of the members. This is a closed group formed by the treatment options and alternatives, and the expected outcomes
Samter’s Society, and patient advocacy group for those with N- of treatment may have better outcomes than the non-educated
ERD. Similar themes were identified, including the impact of the patient(13). It can be expected that patients who are conscious of
disease, and the isolation that can arise from having a condition and reminded of the lack of control of CRS despite medical and
that can be poorly understood by friends and family members. or surgical treatment are more adherent to therapy and avoid
Patients are keen to explore dietary modifications that can help, more external triggers like cigarette smoke and/or occupational
as well as find out more about all different treatment options. triggers of CRS. Reminders using digital platforms have been
At a time when there are a number of novel treatments emer- shown to be of benefit in improving compliance, at least in the
ging, patients are very keen to share experiences before making short term(14).
decisions regarding whether to try new medications, but also
express concerns about the potential for unknown side-effects. Recent initiatives in e-health make attempts to better
Lack of awareness among physicians was a common frustration. educate patients on any chronic condition, hopefully
Conflicts between different healthcare providers involved in leading to better compliance and outcomes
their care was a significant concern, with patients describing a
‘tug of war’ between surgeons and allergists / pulmonologists Actively engaging patients in their own care and facilitating
with regards to different options, highlighting the need for a self-management using written action plans has been shown to
multi-disciplinary approach in the setting of upper and lower improve compliance and patient satisfaction in asthma care(15),
airway conditions. as well as reducing acute exacerbations(16) and improving symp-
Conflicts between different healthcare providers highlights the tom control and quality of life(17). A CRS action plan has been
need for a multi-disciplinary approach in the setting of upper developed by Nayan et al.(18) which incorporates triggers to alert
and lower airway conditions. the patient as to when to step up treatment or seek medical
attention.
9.1.3 Patient compliance
Intranasal corticosteroids (INCS) form the first line of treatment 9.1.4 Expectation management (see also 9.3.3.)
options for almost all subgroups of CRS. However, a large po- While physicians are likely to understand the chronic nature
pulation based study(9) found that only one in five CRS patients of sinus disease in many patients and the need for ongoing
identified on the administrative database had used an INCS in treatment, it is essential to share this with the patient from the
the preceding calendar year, and the mean usage was 2.4 bottles outset. The aim of treatment is to achieve adequate control of
in one year (at recommended dosage that one bottle should last symptoms with as little need for intervention as possible; for
4 -8 weeks). There is, therefore, clear evidence of both failure to many this will involve ongoing usage of intranasal treatments
use INCS and under-dosage in those that do. This may reflect and in some, repeated need for systemic treatments or surgical
under-prescribing, lack of patient education regarding the need interventions. Some patients will remain inadequately control-
for ongoing usage, and concerns with regards to costs or poten- led despite receiving optimum current evidence-based care.
tial side effects. Cure, with an absence of symptoms in the setting of no ongoing
Guo et al.(10) found that postoperative adherence with medical medication usage, is unusual with the exception of localized
treatment in patients undergoing ESS was poor in patients sinus disease where there has been a curable cause, such as an
experiencing their first surgery, with only 42.3% following their odontogenic source.
recommended treatment regimen, but was higher in patients Patient advocacy groups and online resources can be valuable
undergoing multiple revisions, at 88.9%. Yoo et al.(11) also found to patients and supplement information received during face
compliance with post-operative irrigation to be better in those to face consultations. Sharing personal experiences with other
undergoing revision, but highlighted that language barriers may patients may help reduce frustration with limitations in current
contribute to non-compliance. treatments and also help patients navigate their way through
In order to improve compliance, it is important to explain the complex healthcare systems.
aim of ongoing usage or any maintenance treatments to both Patients will often seek out a variety of sources of information.
control symptoms and reduce need for recurrent interventions. Signposting useful and reliable resources such as the EUFOREA

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site, with both videos and written advice for patients will ensure • Inspire researchers to further study acute rhinosinusitis and
that they receive correct information (www.euforea.eu/patient- chronic rhinosinusitis;
platform). • Support the use of standard definitions and measurements
of the disease;
9.2. What does EPOS 2020 mean for patients? • Hopefully reduce unnecessary (antibiotic) treatment;
• Encourage people to form new collaborations to answer
The following section is written by patients involved in the deve- unmet research questions.
lopment of the EPOS2020 guidelines to help explain what the
guidelines mean for patients. Q. Who will use the EPOS2020 guidelines?
A. Many individuals and groups from doctors through to govern-
Q. What does EPOS stand for? ment bodies.
A. EPOS stands for the European Position Paper on Rhinosinusitis, EPOS2020 will provide guidance for relevant government bo-
covering the diagnosis and management of both acute and chronic dies, national and international drug agencies [e.g. the European
rhinosinusitis in primary and secondary care. Medicines Agency (EMA) and the Food and the Drug Adminis-
tration (FDA) in the USA] and scientific societies, particularly
Q. What are the EPOS2020 guidelines? regarding the use of terminology, definitions and classifications
A. The guidelines are a summary of the most up-to-date informa- for clinical trials. Most importantly it will be used by doctors tre-
tion regarding the treatment and management of rhinosinusitis ating patients with sinus disease to help ensure that all patients
and nasal polyposis. are offered evidence-based care.
The first EPOS guidelines were developed in 2005 and have
subsequently been updated in 2007, 2012 and now 2020. Q. Which conditions does it cover?
In essence, the guidelines are a summary of the very latest A. Not just rhinosinusitis and nasal polyposis but other upper
knowledge in rhinosinusitis and nasal polyposis. To develop the airway and related diseases.
guidelines, academic and clinical leaders in this field, along with The EPOS2020 guidelines apply to children and adult patient
the help of some patients, looked at all the information available populations with acute rhinosinusitis (ARS); viral/common cold,
in this area, from as far back as 1960 through to the present day, post-viral, bacterial; chronic rhinosinusitis without nasal polyps
and summarised the most important elements. (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP).
The guide represents what all those experts agree should be It will also be relevant to patients with associated conditions,
recommended practice at this current time. such as allergic rhinitis, asthma, bronchiectasis, chronic obstruc-
tive pulmonary disease (COPD), severe upper airway disease and
Q. Why are they needed? rare diseases including primary ciliary dyskinesia (PCD), cystic
A. To ensure that everyone who is in any way connected to the fibrosis, vasculitis and immune deficiencies. EPOS2020 will also
treatment or management of rhinosinusitis and nasal polyposis address patients with associated symptoms such as facial pain
has the best information available. / pressure, sleep disorders, smell disorders and odontogenic
The field of medicine is constantly changing. The continual problems, many of which are key symptoms in the diagnosis of
emergence of new research and improved practices means it rhinosinusitis.
is important from time to time, to take stock of these develop-
ments and ensure that current clinical practice reflects the latest Q. Who writes EPOS?
thinking. A. An international group of experts who are leaders in the field of
This process happens in all areas of medicine from heart disease rhinosinusitis and nasal polyps.
to child health and it is vital to ensure everyone around the It took approximately 18 months and around 80 people from
world has access to the best information available. over 20 different countries to review all the latest information
and then write and publish these guidelines.
Q. What is the objective of the EPOS2020 guidelines? This group consisted of renowned experts including:
A. It is primarily to provide management strategies for rhinosinusi- • Ear, Nose and Throat Surgeons
tis based on relevant research. • Allergists
Beyond this, there are many things that the EPOS2020 guideli- • Pharmacists
nes hope to achieve. The guidelines aim to: • Microbiologists
• Provide healthcare professionals with a summary of the • General Practitioners
best methods for diagnosing and managing patients in • Paediatricians
both the hospital and the wider community setting; • Pulmonologists

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• Neurologists Key points | What’s new since EPOS 2012

There were also patients involved in the guidelines to ensure the
recommendations were always seen from a patient’s perspec-
tive. • Aspects of patient participation are covered for the
EPOS2020 is also supported by professional organisations, such first time in EPOS2020.
as the European Rhinologic Society (ERS) and the European • Relatively few studies have been published on CRS in
Academy of Allergology and Clinical Immunology (EAACI). this area.
• Recent mobile health application initiatives to educate
Q. Is this just for use in Europe? patients on CRS are now available but the impact of
A. No, EPOS2020 will have relevance around the world. e-health on CRS outcomes still needs to be defined
Although EPOS has the word European in its title, and a strong and proven.
European representation among the people who developed it, it • Patient involvement is essential in the development of
is intended to be used beyond Europe. Individuals from all over their future care.
the world have contributed to the development of these guide-
lines and they will have relevance in many countries outside of
Europe. early detection and appropriate management, returning a pa-
tient to full health and preventing disease persistence. This aims
Q. Does a healthcare professional have to follow the guide- to reduce the severity and impact of disease from the outset.
lines? Tertiary prevention aims to reduce the impact of ongoing chro-
A. This is intended to be guidance and represents best practice but nic disease and its complications in order to maintain quality of
is just one aspect of what informs the decisions a healthcare profes- life and normal functioning as much as possible.
sional makes.
Healthcare systems around the world are all different and the 9.3.2. Primary prevention
healthcare professionals within them will base their decisions on CRS is a heterogeneous disease, where inflammation, mucocilia-
how to manage a patient on many factors. EPOS2020 provides ry dysfunction and changes in the microbial community interact
guidance on the latest information that a healthcare professio- with differing influences to cause disease(19), the aetiology is
nal may use to inform the decisions they make but they are not likely multifactorial, and opportunities to prevent targeting
obliged to follow them. specific causes will likely vary between subgroups.

Q. Where can patients get further information about allergy 9.3.2.1. Occupational and environmental factors
and airway diseases? Exposure to toxins, especially tobacco smoke, ozone and
A. Further information for patients can be found at www.euforea. particulate air pollutants such as diesel exhaust particles, may
eu/patient-platform. exacerbate airway inflammation. The significance of most toxin
The European Forum for Research and Education in Allergy and exposures in the prevalence of CRS is unclear.
Airway diseases (EUFOREA) is an international non-profit orga- A systematic review of risk factors for CRS performed in 2015
nization working towards preventing and reducing the burden highlights the lack of clear definition of CRS used in available
of chronic respiratory diseases (asthma, rhinitis, and rhinosinu- studies, reliance on self-reporting of exposure levels, failure
sitis). Further information for patients about allergy and airways to address confounding and almost uniformly poor quality of
disease can be found on their website at www.euforea.eu/ the available literature in this area(20). Given the poor quality,
patient-platform. The EPOS2020 paper and a patient summary the conclusion of this study was that it was not possible to
can be found on https://epos2020.eu/ make strong conclusions regarding the role of occupation and
environmental exposure. Of 41 studies identified, most failed
9.3 Prevention of disease to use a robust definition of CRS. Both Kim et al. and Alexiou et
al.(21) classified both environmental and occupational exposure,
9.3.1. Primary, secondary and tertiary disease prevention in and adjusted for smoking status, finding increased risk preva-
CRS lence of nasal polyps for those exposed compared with controls.
Prevention of disease may be thought of in three main dimen- Woodstove use was associated with higher risk than tobacco or
sions: occupational exposure. In a subsequent study, Gao et al. found
Primary prevention aims to reduce incidence of disease by redu- a significant association between occupational and environ-
cing exposure to risk factors or triggers. mental factors and CRS(22), more specifically exposure to gases,
Secondary prevention aims to reduce disease prevalence by fumes, and smoke have been shown to be associated with in-

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creased risk of CRS(23). Hox et al. found occupational exposure to smoking, with exposure, both in childhood and adult life, also
irritants was both a risk factor for disease development, but also seems to have a significant association with CRS(40-42). Aggressive
for recalcitrance, reflected in higher rates of revision surgery(24). taxation on tobacco products, plain packaging with warning la-
Some studies have looked at specific occupations, with grain bels and repeated counselling at every healthcare consultation
farmers(25) and those working in the textile industry(26) being are important to maintain the declining prevalence of smoking.
shown to have a higher prevalence of CRSwNP. Regular follow-
up of the first responders following the 9/11 attack on the World 9.3.2.2. Allergy
Trade Centre have offered a unique opportunity to prospectively It has been proposed that mucosal oedema within the ostio-
study the risk of developing CRS; rates were higher in firefighters meatal complex (OMC) in allergic rhinitis may compromise
involved in digging and rescue work than emergency medical ventilation and even obstruct sinus ostia, leading to mucus
services workers. Those arriving at the site early, with higher retention and infection, however the causal role of allergy in CRS
levels of exposure to irritants, or those with prolonged exposure has been long debated(43-46). On one hand, rates of positive skin
had highest rates of CRS, approaching 50% using an epidemio- prick tests are not statistically different between CRS patients
logical definition 10 years after the event(27). or healthy controls, or between CRS sufferers with or without
Wolf found no correlation between CRS and outdoor air quality polyps(43) although patients with CRS had a higher number of
in Cologne(28), similarly there was no difference in CRS prevalen- sensitivities. One recent systematic review evaluated 18 articles
ce in rural or urban areas of South Korea(29) nor in the Nether- examining the relationship between allergy and CRSwNP, 10
lands(30). In contrast weak correlations have been found in US articles found an association, seven found no association and
studies(31), where improvements in air quality were also associa- one article showed a possible association. Of nine articles which
ted with a decreased prevalence of both hay fever and rhinosi- examined the relationship between allergy and CRSsNP, four ar-
nusitis. More recent studies have shown a stronger association; ticles found an association compared with five articles showing
Park et al.(32) found a linear association with levels of particulate no association(47). In a large population based study there was a
matter and CRS, although the study sampled only patients with significantly increased risk of AR prior to a subsequent diagnosis
known ENT disease and did not include a control population. of CRS (OR 2.4 for CRSsNP and 2.6 for CRSwNP)(48). One recent
Mady et al.(33) found an association between exposure to air prospective study of a large cohort followed from birth under-
pollutants and disease severity in patients with known CRS, but took allergy testing at nine months and six years(49). Of patients
again did not include a control group. who developed CRS, three phenotypes were identified; transient
While a causal link cannot be clearly established, evidence is cer- childhood rhinosinusitis, early onset adult rhinosinusitis and late
tainly mounting, and it is worth clinical questioning to include onset adult rhinosinusitis. The early onset CRS group had signi-
environmental and occupational exposure to irritants. There ficantly higher rates of inhalant allergy and asthma than other
is no available evidence to inform on safe levels of exposure groups. Childhood onset rhinosinusitis symptoms were the
or preventative measures in those exposed. Global action to biggest risk factor – providing an opportunity to screen children
reduce pollution is clearly beyond the remit of this document, with symptoms of CRS and potentially target immunotherapy in
but must be made a priority(34, 35) and the effects of global war- this group; approximately one-third of children with rhinosinu-
ming closely monitored. Ensuring compliance with international sitis in childhood received further investigation or treatment as
standards for indoor air quality may help at an individual level. adults.
There is direct evidence that tobacco smoke diminishes mucoci-
liary clearance and is a potential contributing and/or exacerba- No studies have assessed the effectiveness of management of
ting factor in exposed individuals with chronic rhinosinusitis. allergic rhinitis on the outcome of established CRS, or on the risk
Evidence for both active and passive smoking leading to incre- of subsequent development of CRS, and further research in this
ased risk of CRS is much stronger. The GA2LEN survey of over area is needed before AR management can be recommended
50,000 patients across Europe found that CRS was more com- as a means of CRS prevention. However, early detection and
mon in smokers (OR1.7) compared with non-smokers(36). management of AR has been shown to have a positive impact
A 2018 systematic review identified 13 studies evaluating the on the development of lower airway disease(50, 51), and is recom-
effect of primary tobacco smoke, with 11 reporting an increased mended for that aim.
prevalence of CRS in smokers. There was a dose-dependent
association found in three studies, with a 1.5% increase in pre- Although patients often attribute their CRS to food allergies,
valence for every additional year of smoking(37). There is direct with the exception of non-steroidal-exacerbated respiratory
evidence that tobacco smoke diminishes mucociliary clearance disease (N-ERD), where there is an increased risk of CRSwNP,
and is a potential contributing and/or exacerbating factor in there are only limited studies assessing the association between
exposed individuals with chronic rhinosinusitis(38, 39). Passive CRS and food allergies. One study showed that milk allergy may

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be a predisposing factor for CRS(52), however, overall the evi- an increased risk of CRS, but additionally has been shown to be
dence is poor(47, 53) and certainly there is no evidence to support associated with prognosis, with significantly lower rates of ‘super
exclusion diets to prevent CRS. In N-ERD, CRSwNP typically deve- tasters’ being found amongst CRS patients undergoing surgery.
lops after the onset of asthma, but again there are no studies
evaluating the effectiveness of desensitization in preventing 9.3.2.5. Microbial exposure
onset of CRSwNP. The natural history of CRS, and the relationship between ARS
9.3.2.3. Asthma and CRS development have been very poorly studied. Using the
There is strong evidence to show that asthma and CRS, especi- definitions of ARS and CRS based on duration alone, all episodes
ally CRSwNP, frequently coexist. Several studies have shown that of CRS must start as ARS. However, what allows persistence of
patients with asthma have a higher likelihood of having CRS(44, disease, or whether CRS is a completely different pathophysio-
54-56)
and the GA2LEN Survey showed that in all age groups, men logy from the outset is little known. Tan et al. found that pre-
and women, and irrespective of smoking behavior, asthma was morbid ARS (OR 2.2 for CRSwNP, OR 3.2 for CRSsNP) and acute
associated with CRS(55). The Greisinger Health study(48) found upper respiratory tract infections (URTIs) (OR 1.3 for CRSwNP,
higher rates of premorbid asthma in those developing CRS OR 1.6 for CRSsNP) were more prevalent in patients developing
compared with healthy controlled (OR 2.8 for CRSwNP and 1.7 CRS compared to those who did not; however, this data was
for CRSsNP). Similarly, higher premorbid rates of bronchitis, extracted from electronic health records, and may simply reflect
pneumonia and bronchiectasis have been reported. Again, a the diagnostic dilemma above. One study followed patients
causal relationship has not been confirmed, but it is postulated with ARS using repeated aspirates; those that developed chronic
that acute infective exacerbations may modifiy susceptibility to symptoms showed transitions from bacteria commonly associa-
developing CRS. ted with ARS (Strep. Pneumonia, Moraxella) to a mixed infection
which also involved anaerobes(66). However, there is no evidence
9.3.2.4. Genetic risk factors to suggest that active management of ARS or URTIs may reduce
A number of genetic disorders, including cystic fibrosis and the risk of subsequent development of CRS. Indeed, increased
primary ciliary dyskinesia are associated with a high prevalence use of antibiotics may cause profound and detrimental effects
of CRS, however these account for only a very small proportion on the microbiome(67).
of CRS cases. Currently over 70 genes have been genetically as- One study of children treated for CRS, defined according to
sociated with CRS, summarized by a number of recent reviews(57, EPOS2012 criteria, and in remission, compared prophylactic use
58)
. Genes associated with CRS can be broadly categorised into: of bacterial lysate for three months to no treatment in an open-
genes associated with ion channels (e.g. CFTR); immunological label study and showed significant reduction in subsequent use
genes (HLA, CD, IL); genes involved in tissue remodelling and in of antibiotics, nasal obstruction and discharge in the treatment
arachidonic acid metabolism(57-59), and genes associated with CF. group at one year(68). However, given the lack of blinding further
Until recently, outside of CFTR, there were no replication studies studies are necessary.
validating the gene associations with CRS, and no studies The balance of resident microbes is increasingly recognized as
demonstrating their biological relevance(59). Henmyr et al. found important in onset of CRS(69) and reduced diversity is found in
a significant association in only seven genes of the previous 53 patients with CRS compared to controls(70) and in CRS patients
genes associated with CRS(60). One potential target gene, CDHR3, following antimicrobial therapy(71). Given that current evidence
part of the cadherin family expressed primarily in respiratory suggests that the human microbiome becomes established
epithelium, has a number of polymorphisms which determine early in childhood(67), there may be only limited opportunity to
susceptibility to both rhinovirus infection and adult CRS, sug- influence this later in life.
gesting a potential role of rhinovirus as a trigger(61). There has Unlike many chronic diseases, there is little data suggesting an
been growing recent interest in the bitter taste receptor T2R38; increased risk of CRS in those with poor socio-economic status,
polymorphisms are associated with an increased risk of CRS, which may be linked to both microbial exposure and higher
but additionally has been shown to be associated with progno- rates of tobacco exposure. Indeed, one study of CRS in children
sis, with significantly lower rates of ‘super tasters’ being found suggests that when compared to controls, children with CRS
amongst CRS patients undergoing surgery(62-65) compared to were more likely to be white and privately insured(72) this, howe-
expected levels in the normal population. Of course, genetic ver, may simply reflect inequity of access to healthcare.
risk factors may not change, but reduction of environmental
exposure in ‘at risk’ populations, screening of high-risk groups, 9.3.2.6. GORD
and identification of genes which are of prognostic value will be The relationship between gastroesophageal reflux disease
of value. and upper and lower airway diseases has been debated in the
Bitter taste receptor T2R38 polymorphisms are associated with past(73). However, Wong et al. describe a possible vagal neural

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reflex existing between the oesophagus and the paranasal sinu- surgical interventions, and biological agents. In this regard, no-
ses(74). A causal relationship between GORD and CRS has yet to vel biological treatments may be given to patients who can be
be firmly established but GORD does appear to be a risk factor predicted to have an otherwise recalcitrant path, based on their
for development(75). Few studies specifically assess whether biomarkers, before undergoing ineffective cycles of treatment
treatment of reflux has an impact on development of CRS or with corticosteroids and surgery.
severity of symptoms, and there is insufficient current evidence Guidelines have traditionally attempted to drive all patients
to consider anti-reflux therapy for refractory CRS in adults(76). through the same pathway; in reality multiple interconnected
Recent epidemiologic studies using electronic health registries pathways are likely to be required to facilitate precision medi-
and systematic reviews report that GORD and CRS often coexist. cine.

9.3.3. Secondary prevention 9.3.3.3. Optimising the outcome of surgical intervention

Secondary prevention of CRS is concerned with detecting a (see chapter 6.2)
disease in its earliest stages, intervening to achieve disease and Surgery may be optimized according to two main domains;
symptom control and preventing future exacerbations. Implicit-
ly, secondary prevention takes place when primary prevention 9.3.3.3.1. Timing of surgery
fails. Early diagnosis and selection of the optimal treatment is Once the diagnosis of CRS is made, EPOS advocates surgical
central to secondary prevention. Recent data suggest that there treatment when optimal medical management has made no
is still a large portion of the population with CRS not receiving improvement in symptoms after 12 weeks(78).
treatment; as above, it is estimated from population studies that Current evidence fails to show clear benefit of surgery over
CRS affects approximately 5–15% of the general population medical treatment at first presentation, supporting a role for
both in Europe and the USA in contrast with 2-4% prevalence primary medical treatment(81, 82). However, after failed medical
of doctor-diagnosed CRS(77, 78). It is unclear whether patients are therapy, patients who elected to continue with medical therapy
unable to access care, or effectively self-manage symptoms of achieved poorer outcomes than those choosing surgery(83).
CRS. Furthermore, delayed surgery in the setting of persistent CRS
after failed medical therapy has been shown to be associated
9.3.3.1. Early establishment of diagnosis with higher ongoing healthcare utilisation postoperatively(84,
State-of-the-art guidelines like EPOS(78) provide clinicians with 85)
surgical intervention after a trial of medical therapy may also
evidence-based diagnostic and treatment algorithms for CRS deliver better symptomatic outcomes that are sustained for as
based on symptom duration and severity. However, a symptom long as five years(84).
based definition alone is likely to over-estimate disease(79) and Appropriate indications for ESS are currently poorly defined and
currently findings on endoscopy or radiological imaging are the lack of clear surgical indications for ESS likely contributes to
required to support the diagnosis. It is likely that the diagnostic the large geographic variation in surgical rates. A recent study
criteria will be further defined as biomarkers for disease are by Rudmik et al. clearly states that ESS can only be indicated
identified. The Finnish allergy programme(50) has shown the after medical treatment has failed with patients still having
effectiveness of screening for inflammatory airway disease. significant symptoms (SNOT-22 ≥20) and at least some abnor-
However, with current financial constraints in healthcare, it is malities on a CT scan(86). Pre- and post-operative patient-rated
unlikely that such schemes will become widespread. However, outcome scores such as the SNOT-22 may be used to predict
symptom-based screening of patients at high risk of secondary benefit from surgery and identify early failure(84, 87). Improved
CRS, such as those with systemic vasculitides, or those with patient selection for surgery is likely to improve outcomes and
eosinophilic airway disease and aspirin –exacerbated respiratory reduce risk of harm.
disease (N-ERD) is likely to be beneficial.

9.3.3.2. Selection of optimal treatment (see also chapter 6) 9.3.3.3.2. Extent of surgery
Currently CRS is broadly categorised into two subgroups: CRS There is little comparative evidence to direct surgeons as to
with and without nasal polyps. However, clinical phenotypes do whether a conservative, aggressive or tailored approach to sinus
not provide full insight into underlying cellular and molecular surgery should be taken(88). Data from the UK audit of sinus
pathophysiologic mechanisms of CRS(80) and further differentia- surgery found no additional benefit of additional sinus surgery
tion or “endotyping” will better predict the likely natural course over simple polypectomy in terms of symptomatic benefit, and
of disease and prognosis in terms of recurrence after surgery only a small benefit in terms of revision rates(89). However, the
and risk of comorbid asthma but also in responsiveness to dif- additional sinus surgery performed in most cases was very con-
ferent treatments, including topical intranasal corticosteroids, servative, and less than 2% of the surgical cohort had complete

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Figure 9.3.1. Tertiary prevention factors in poorly controlled CRS.

Tertiary prevention - factors in poorly controlled CRS

POORLY CONTROLLED CRS

Disease-related Diagnosis-related Treatment-related Patient-related

• Exogenous factors • Incorrect diagnosis • Inadequate treatment • Poor compliance

• Endogenous factors • Failure to identify • Incorrect treatment with treatment
• Genetic factors concomitant local • Exposure to
• Global airway disease or systemic disease environmental
• Inadequate irritants
management of
associated disease

frontoethmoidectomy and sphenoidotomy. The effectiveness of The use of prolonged courses of anti-inflammatory antibiotics
intranasal steroids has been shown to be increased in the posto- needs to be balanced with the potential gastrointestinal distur-
perative state, suggesting improved access to topical therapy is bances and serious adverse effects of rhabdomyolysis and pro-
an important aspect of the benefits of surgery(90). Furthermore, longed QT(98), effects on bacterial resistance and as yet largely
eosinophilic CRS has been shown not to be associated with os- unknown consequences to the sinus microbiome. A study in
tiomeatal occlusion(91) and therefore simple measures to address CRS patients receiving macrolide antibiotics found a short-term
the OMC are unlikely to be effective. There is some evidence to increase in risk of myocardial infarction, highlighting the need to
support a more extensive approach, particularly in eosinophilic evaluate cardiac risk factors prior to usage(99).
disease or CRSwNP(92, 93). In comparison with medical therapy, there is more data repor-
ting the rate of surgical complications. The National Sinonasal
9.3.3.4. Minimising risks of treatment Audit reported a total adverse event rate of 6.6 %, most of which
As a general rule, any treatment should have benefits that al- was related to minor bleeding. This rate of major complications
ways outweigh the risks. When considering medical and surgical from the UK (0.4 %) compares with a rate of 1.1 % reported in
interventions, we must consider the risk of harm to the patient. a meta-analysis from 10 years previously of 4691 patients who
Short courses of oral corticosteroids are widely used, and may underwent ESS in the US(100-102). There is conflicting evidence
result in insomnia, mood and gastrointestinal disturbances(94). regarding whether use of image guidance may mitigate against
There is a paucity of data on the threshold of dose that may the risk of complications(103, 104).
expose patients to major complications such as avascular
necrosis and osteoporosis, and repeated courses should be used 9.3.4. Tertiary prevention
judiciously(95). In contrast, topical corticosteroids are safe and Tertiary prevention aims to minimise the impact of an ongoing
adverse effects are minor. A recent Cochrane review found no illness or injury that has lasting effects. This is done by helping
difference in the reported side effects between topical cortico- people manage long-term, often-complex health problems and
steroids and placebo(96), except for an increase in reported epis- injuries (e.g. chronic rhinosinusitis) in order to improve as much
taxis. Moreover, there seems to be no clinically relevant impact as possible their ability to function, their quality of life and their
on either ocular pressure, glaucoma, lens opacity or cataract life expectancy. Ongoing poorly controlled upper airway disease
formation(97). may result from disease-related factors, inadequate treatment,
poor compliance or failures in the diagnostic pathway to identify

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secondary CRS, or perhaps incorrectly diagnosed CRS in the first those undertaken in the N-ERD population (reviewed in chapter
place(105) (Figure 9.3.1.). A recent study found that at least 40% of 6.1.12.4). In acute URTI probiotics are better than placebo in
CRS patients would be considered to have uncontrolled disease reducing the number of participants experiencing episodes of
within 3-5 years of endoscopic sinus surgery(106). acute URTI, the mean duration of an episode of acute URTI, an-
In patients with poor disease control, a careful review of on- tibiotic use and cold-related school absence. This indicates that
going treatment, technique and compliance with medication probiotics may be more beneficial than placebo for preventing
should be undertaken. Growth in digital healthcare and patient acute URTIs. However, the quality of the evidence was low (see
apps may encourage self-management and increase compli- chapter 4.4.2.11). Extrapolating from other chronic inflammatory
ance. The evidence of the impact of ongoing tobacco exposure conditions, there is potential benefit in the use of probiotics, and
on quality of life outcomes of CRS treatment is conflicting(107, diets promoting healthy gut microbiota, but their role in CRS is
108)
, but higher rates of revision surgery are seen in smokers(109), yet to be established.
and cessation should therefore be encouraged. Management of
individuals with recalcitrant CRS is based on the understanding
Key points | What’s new since EPOS 2012
that this is a chronic condition, and that “cure”, as achieved in
acute bacterial infections such as tonsillitis, cannot and should
not be expected. Caregivers and allied health personnel all share • Prevention may be considered as primary, secondary
in the task of educating the patient to understand the chronic, and tertiary.
ongoing nature of the disorder, and to adjust their expectations • Occupational and environmental factors are of increa-
accordingly. sing importance in primary prevention and the effects
Growth in digital healthcare and patient apps may encourage of global warming carefully monitored.
self-management and increase compliance. • Co-morbidities such as allergy, asthma and GORD
The diagnosis should be reconfirmed, particularly when facial should be considered.
pain is the ongoing primary symptom, and systemic diseases • Genetic and microbiological factors will likely become
should be considered and excluded when indicated. Conditi- of greater importance.
ons such as granulomatosis with polyangiitis (Wegener’s) or • Early diagnosis and selection of the optimal treatment
eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is central to secondary prevention.
may present with sinonasal disease and the systemic nature • Optimising medical treatment and consideration of
of disease may not be apparent in the early stages (section the timing and extent of surgery can improve outco-
9.7). Underlying immune deficiency should be considered, mes.
particularly where there is a history of concomitant lower • In tertiary prevention, a careful review of ongoing
airway, ear or skin infections (section 9.2). Up to 10% patients treatment, technique and compliance with medication
with refractory CRS were found to have common variable should be undertaken.
immunodeficiency(CVID), 20% had decreased IgG, IgA or IgM, • Growth in digital healthcare and patient apps may
and 11-67% had an inadequate functional response to pneu- encourage self-management and increase compliance.
mococcal vaccine(110-112), although all studies were conducted
at tertiary institutions, thus it is likely that there is significant
selection bias. 9.3.2. Prevention of asthma
Higher levels of anxiety and depression are found in patients There is extensive literature concerning primary prevention of
with CRS, although it is often undiagnosed(113, 114). It is unclear asthma with respect to allergen avoidance, dietary manipulation
if this is a causative relationship; however, it appears likely that and immunotherapy; it is beyond the scope of this document to
co-existing depression results in both higher rates of symp- review these here.
tom reporting and amplifies symptom severity, particularly in There are a small number of studies using big data sets that
CRSsNP(115). Patients with co-existing depression report poorer suggest that endoscopic sinus surgery for CRS reduces the
disease specific health related quality of life both before and yearly incidence of new asthma diagnoses(84, 118). In a cohort free
after treatment for CRS(116). Although treatment for CRS has been of asthma at enrolment, the preoperative asthma incidence was
shown to reduce depression scores, there is no evidence on 4.5% in patients with allergic rhinitis (AR), and 4.2% in patients
whether treatment of depression may result in improvement of without AR, but fell to 0.4% post-ESS. Those patients who had
CRS-related QOL. later surgery had higher rates of asthma than those who under-
Nayan et al.(117) undertook a systematic review of dietary modi- went surgery at an earlier timepoint; patients having surgery
fications that might have the potential to reduce inflammation within two years of CRS diagnosis had an asthma prevalence of
in recalcitrant CRS. They did not identify any studies outside of 9% compared to 22% in patients having surgery 4-5 years after

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diagnosis. There is a risk of confounding and further studies are cociliary function. A recent systematic review studied steroid-
required to establish if this a true consequence of sinus surgery, eluting bioabsorbable intranasal devices, and demonstrated
and to assess if successful medical therapy has the same effect. improved objective and subjective outcomes following ESS(126);
although their role in preventing recurrence has not been
assessed, prevention of adhesions and stenosis may potenti-
Key point | What’s new since EPOS 2012
ally reduce the risk of revision and therefore warrants further
study. Currently, costs may restrict widespread usage, although
• Those patients who have later surgery may develop hi- cost-effectiveness may be enhanced by reduced post-operative
gher rates of asthma than those who undergo surgery debridement.
at an earlier timepoint. A small number of studies have found that ongoing occupati-
onal exposure to irritants may increase risk of recurrence(24, 127).
Any factors thought to be involved in the underlying aetiology
9.3.3. Prevention of recurrence of CRS in each individual patient should be addressed where
Patients should be encouraged to continue to use intrana- possible to reduce risk of recurrence.
sal corticosteroids after surgery, as continued use has been
shown to improve post-operative endoscopic scores in all CRS 9.3 Prevention of patient dissatisfaction after CRS treatment
patients(119) and, in those with CRSwNP, reduce risk of recur- In contrast, to the large number of studies evaluating changes
rence(120). Adherence with prescribed postoperative medications in HRQOL after treatment, few studies have evaluated patient
dropped to only 42% at 12 months after surgery in one study satisfaction with outcomes of treatment, and only following
despite regular telephone contact(121) strategies to improve this, surgical interventions.
such as utilizing digital technology, will likely be important in A 2003 study found high levels of overall satisfaction after sinus
future. As mucosal eosinophilia has been shown to be highly surgery, with 72% patients being very satisfied. Lower education
correlated with risk of polyp recurrence, more so than basic phe- level and higher severity of disease were found to be associated
notype of CRSwNP, in future this may provide a better indicator with lower rates of satisfaction(128).
for the need for long term INCS use(122). Patients who underwent The UK prospective audit of sinus surgery asked patients to rate
a single polyp exacerbation after surgery, but were then well change in overall symptoms after surgery and found that this
controlled were found to have significantly lower adherence to was strongly associated with changes in their SNOT-22 scores(100).
postoperative medications compared to those with no recurren- Seventyseven percent of patients rated the results of surgery
ce(10), suggesting that patient education regarding the need for overall as good or excellent. Eightyfour percent of patients re-
ongoing therapy is important and may avoid recurrence in some ported information provided regarding their operation as good
patients. In contrast, those patients with ongoing recurrence or excellent, while only 58% rated information on post-operative
were found to have significantly higher levels of eosinophilia, treatment as good or excellent.
and had recurrence despite good compliance with post-opera- Mattos et al.(129) set out to evaluate the association between
tive care, suggesting that different strategies may be required to improvement in patient’s symptoms and meeting pre-operative
achieve disease control in this group. expectations with post-operative satisfaction. Patients were
Continued use of intranasal corticosteroids after surgery has asked to identify if post-operative improvement in specific
been shown to improve post-operative endoscopic scores in all symptoms was felt to be important; 92% responded that impro-
CRS patients and, in those with CRSwNP, reduce risk of recur- vement in nasal obstruction, 77% need to blow nose and 72%
rence. sense of smell were very important. Eightytwo percent of the
Saline douching has improves symptoms after surgery(123, 124) patients were satisfied overall following surgery; on multivariate
and may reduce need for nasal cavity debridement. The value logistic regression this was associated with improvement in the
of postoperative debridement remains controversial; although symptoms most important to patients, and matching preope-
systematic reviews have shown benefit in terms of early symp- rative expectations. Achieving an improvement greater than
tom scores and endoscopic appearances(125) there is no signifi- the MCID was not a predictor of satisfaction; 86% of patients
cant impact on long-term outcomes, and current trials have no not achieving the MCID were still satisfied with the outcome of
compared to high-volume saline irrigation alone. Routine use of surgery and 87% would recommend sinus surgery to others. In
antibiotics in all patients after ESS is not supported by the litera- a similar study, Phillips et al.(130) studied patients who reported
ture and increasing bacterial resistance must be considered, but overall improvement in their CRS symptoms despite failing to
it may be used in selected cases(125). achieve change in SNOT22 scores of greater than the MCID; they
There are a growing number of drug-eluting stents and topical found that significant improvement in the nasal subdomain
dressings that may promote early healing and restoration of mu- resulted in patients reporting overall improvement, but no other

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subdomains were associated with overall improvement. number of studies have shown that the preoperative score is
Although data is limited, it appears that pre-treatment coun- the best predictor of outcomes(136, 137).Patients with preoperative
selling to ensure that a patient has realistic expectations of SNOT-22 scores less than 20 failed to achieve mean improve-
treatment outcomes, both with respect to overall improvement ment greater than the MCID, scores of >30 have a 70-75% chan-
and achieving improvement in symptoms deemed to be most ce of achieving improvements greater than the MCID. Patients
important to the patient, as well as optimizing outcomes with on average achieve a 45-50% reduction in SNOT-22 scores(138, 139).
respect to nasal symptoms is important to avoid a dissatisfied When predicting outcomes following sinus surgery, a number of
patient. Provision of information both regarding the likely risks studies have shown that the pre-operative symptom score is the
and benefits of treatment and the need for ongoing care may best predictor of outcome.
need to be tailored to a patient’s educational level. Smith et al.(140) prospectively evaluated 119 adults with CRS to
determine other preoperative factors that predicted improve-
9.4. Prediction ment in endoscopy and quality of life. Smokers, and patients
with depression and N-ERD had least benefit in both respects,
9.4.1. Prediction of the natural course of disease but still reported improvements in both domains. In a separate
There are no studies evaluating the natural history of untreated study he also demonstrated that patients undergoing primary
CRS. The fact that the prevalence of disease peaks between the surgery were more likely to achieve significant improvements
ages of 45-54 years, and then declines suggests that remission in HRQOL than patients undergoing a revision procedure(141).
occurs with later age (54). Higher income and better socioeconomic status are associated
De Corso et al.(131) prospectively followed patients with CRSsNP with greater improvements in quality of life(142, 143) it is not clear if
with endoscopy and evaluated the risk of developing nasal this reflects differing access to care.
polyps. Patients with eosinophilic inflammation demonstrated With respect to olfactory outcomes, Bogdanov et al.(144) demon-
on nasal cytology were significantly more likely to develop po- strated that for patients with olfactory loss, the response in
lyps, compared with those with neutrophilic inflammation and olfactory function to oral corticosteroids (OCS) predicted the
controls with vasomotor rhinitis. outcome of surgery; improvements after OCS and surgery were
significantly correlated and no patient responded to surgery
who did not respond to OCS. This would be a useful test to avoid
Key point | What’s new since EPOS 2012
patient dissatisfaction after surgery if hyposmia was their main
driver to seek intervention.
• There is an urgent need for research to address the
natural course of CRS.
Key points | What’s new since EPOS 2012

9.4.2 Prediction of ‘success’ or symptomatic improvement • When predicting outcomes following sinus surgery, a
There are few studies predicting success of medical therapy – number of studies have shown that the pre-operative
response rates for individual treatment options are discussed symptom score such as SNOT22 is the best predictor of
in chapter 6. A meta-analysis(132) evaluated factors predicting outcome.
success of low-dose macrolides; patients with CRSsNP achieved • Primary surgery has better outcomes than revision.
greater improvements in symptoms scores, longer courses (24 • When loss of smell is a major symptom, response in
weeks compared to eight and 12 weeks) and half dose (compa- olfactory function to oral corticosteroids (OCS) predicts
red with very low dose) were also more effective. IgE was not the outcome of surgery.
assessed, but a randomised trial found that patients with normal
IgE achieved greater benefit in symptom scores than patients
with elevated IgE(133). When used postoperatively, responders 9.4.3. Prediction of recurrent disease
were found to have lower tissue and serum eosinophil levels(134). There is a paucity of studies evaluating the success rate or re-
Ebbens et al.(135) showed that CRS patients with higher levels of lapse rate following appropriate medical therapy of CRS. Young
mucosal eosinophils are less likely to suffer from postoperative et al. prospectively enrolled 80 patients receiving treatment with
recurrent sinonasal disease when treated post-operatively with systemic steroids and antibiotics in addition to topical steroid
nasal corticosteroids than patients with lower mucosal eosinop- sprays and saline irrigation (145). 53% failed the trial of medical
hils. treatment and underwent surgery. Relatively younger age, male
When predicting outcomes following sinus surgery with respect gender, European ethnicity, presence of asthma, and positive
to improvement in symptoms scores measured with PROMs, a endoscopic as well as CT findings were factors predictive of a

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Figure 9.5.1. Historical approaches to care. Figure 9.5.2. Current medical practice versus precision medicine.

Historical approaches to care Current medical practice versus precision medicine

Implementation of guidelines
by adequate trials and interventions
Current medical practice Significant uncontrolled disease

1998 - • ‘One size fits all’ model

Low patient satisfaction
1985 - • ‘Trial and error’ approach
Opinion-based medicine GUIDELINES Evidence-based medicine • Suppression of symptoms
• Paternalistic approach High cost

2010 -
Precision medicine Control and prevention of disease
Precision medicine • Personalised care
• Prediction of success Improved patient satisfaction
• Prevention
(primary / secondary / tertiary)
• Patient participation Socio-economic savings

need for surgery. Presence of polyps was not a predictive factor

for failure of medical therapy.
A number of long-term studies have reported on the rates of re-
vision surgery. Hopkins et al. reported long-term outcomes from would appear to go on to revision but it would be helpful to be
a multi-institutional cohort study, with 1459 patients comple- able to predict who will develop recurrent disease in order to
ting five-year follow-up. 19.1% patients had undergone revision target treatment. A number of studies have looked at the role of
surgery (21% of CRSwNP, 16% of CRSsNP). Patients undergoing biomarkers to predict disease recurrence. A systematic review(150)
additional sinus surgery were found to have lower revision rates identified 11 articles evaluating tissue eosinophilia; >55 eosi-
than those undergoing simple polypectomy for CRSwNP. Im- nophils per high powered field had both high sensitivity (0.87)
provements in SNOT-22 scores were maintained over a five-year and specificity (0.97) in predicting recurrent disease. Further
period(146). attempts to avoid the need for tissue biopsy have shown that
Smith et al.(147) prospectively followed 59 adult patients electing blood eosinophil levels may be used to identify patients with
endoscopic sinus surgery over a 10 year follow-up period; eosinophilic CRS, but has lower sensitivity; Ho et al.(151) reported
17% patients (25% of CRSwNP, 7% of CRSsNP) had undergone that blood eosinophil levels >0.24 x 109/L (sensitivity 71%, speci-
revision surgery. Those undergoing subsequent revision had sig- ficity 78%) or eosinophil ratio of >4.27% of total white cell count
nificantly poorer endoscopy scores at their first post-operative (sensitivity 64%, specificity 89%) could be used to predict eCRS.
visit and were more likely to have developed frank recurrence In a multivariate analysis, eosinophilic CRS were the only signifi-
of polyps by 18 months. Using electronic health records, Smith cant predictor of recurrence after controlling for other variables,
et al. identified nearly 30,000 patients with a mean follow-up of and also showed that the disease-free interval was significantly
9.7 years(143). The long-term revision rate was reported at 15.9% shorter(152) . Both blood and tissue eosinophilia were predictors
(29.9% of CRSwNP, 7% of CRSsNP), with CRSwNP patients also of poor disease control, alongside more extensive radiological
being more likely to require multiple revision procedures. When disease (LMS ≥15) (152) . A number of other biomarkers have been
examining factors associated with increased risk of revision, evaluated with respect to predicting recurrent disease. CRSwNP
female gender, older age at time of first surgery, a history of patients who undergo revision surgery had significantly higher
asthma, allergy and nasal polyps were associated with higher polyp tissue levels of IgE, ECP and IL-5, while non recurrent
risk of revision, with the presence of polyps having the largest patients had a mixed pattern of cytokines with higher levels of
impact. Similarly, Stein et al.(148) looked at a large electronic da- IFN-gamma (154).
taset of 61,000 patients undergoing ESS, of which 6.7% under- In another study, CST2, PAPP-A and periostin levels in mucus
went revision surgery. The presence of nasal polyps and female were significantly reduced after surgery, but increased postope-
gender were again shown to be predictive of revision surgery. ratively in patients who went on to require revision surgery(155).
Revision surgery rates are an imprecise estimate of recurrent The limitation of many of these studies is the selection of a small
disease as they are influenced by both the patient’s and the number of markers, and the failure to include commonly availa-
surgeon’s willingness to undergo / perform revision surgery and ble markers such as blood or tissue eosinophilia in a regression
therefore, likely underestimate the rate of recurrent disease. model to allow comparison of the predictive value. This study
DeConde(149) studied endoscopic recurrence in CRSwNP and also found that increasing levels of all markers was significantly
found that 38% patients had recurrent polyps at 12 months correlated with worsening of the SNOT-22 score at each time
after surgery, while 82% had mucosal oedema. Not all of these point. Indeed, deterioration of the SNOT-22 score of more than

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the MCID has also been shown to be a good predictor of need 9.5 Precision medicine
for revision surgery. In 2015, President Obama launched the precision medicine
While the perfect biomarker to predict failure remains elusive, initiative: “delivering the right treatment at the right time, every
both blood and tissue eosinophil levels can be measured with time, to the right person”. Precision medicine (PM) is an emer-
little additional expense and may be used to help predict risk of ging approach for disease treatment and prevention targeted to
recurrence and need for targeted post-operative care. Sequen- the needs of individual patient, taking into account individual
tial measurement of symptoms scores using the SNOT-22 may variability in environment, lifestyle and genes for each person(156,
allow remote monitoring of these patients if resources cannot 157)
. PM represents a novel approach in medicine, embracing four
support direct follow-up. key features: personalized care based on molecular, immunolo-
gic and functional endotyping of the disease, with participation
of the patient in the decision-making process of therapeutic ac-
tions, and taking into account predictive and preventive aspects
of the treatment. The major scientific and economic challenges
Key points | What’s new since EPOS 2012
in airway diseases may be addressed through the promising
possibilities of PM underpinned by trials and evidence to
• Prediction of recurrent disease involves many factors understand how to use it(157) . It is has evolved from evidence-
including age, gender, ethnicity, co-morbidities, and based medicine, ‘the conscientious, explicit, and judicious use
duration of disease. of current best evidence in making decisions about the care of
• Both blood and tissue eosinophil levels can be measu- individual patients” which still remains the basis of our clinical
red with little additional expense and may be used to practice(158, 159) (Figures 9.5.1. and 9.5.2.).
help predict risk of recurrence and need for targeted Based on the knowledge of mechanisms of the disease, PM
postoperative care. generally combines diagnosis and treatment to select optimal
management(160, 161). Precise endotyping of patients using novel
methods like proteomics, metabolomics, genomics, diverse

Figure 9.5.3. Implementing precision medicine in CRS.

Implementing precision medicine in CRS

PRIMARY CARE SECONDARY CARE TERTIARY CARE

Effects of different treatment • Step-up or step-down

Prediction of success options on sinonasal and + treatment
bronchial symptoms and QoL • Pharmacotherapy or surgery

• Design of patient-centered
treatment plan, taking into
• Mono versus combined
Participation account patients’ preference
treatment + and availability/affordability
• Treatment of comorbidities
of treatment
• Surgery vs. biological

• Secondary prevention:
ESS and control of
Prevention strategy environmental triggers
• Tertiary prevention:
prevention of organ damage

Personalized care Endotype-driven treatment

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cellular assays, biobanks, registries and even mobile health tech- 9.6. Implementation
nology(162), allows the design of therapeutic strategies with pre-
dictive, preventive, personalized and participatory aspects(163). The implementation of high-quality guidelines and position
PM has already gone through its own evolution from persona- papers is essential to improve clinical practice and public health.
lised medicine to precision medicine and now, 4P medicine. The It is well recognised that clinical guidelines are often ignored,
four Ps constitute the basis of precision medicine (Figure 9.5.3.). which is perhaps not surprising when so many are published
on every conceivable topic (168-170). A clinical practice guideline
• Personalized care is a medical practise that proposes cus- can be defined as “systematically developed statements to
tomization of healthcare, with medical decisions, practises assist practitioners’ decisions about appropriate health care for
and/or products being tailored to the individual patient. specific clinical circumstances” (171) thereby decreasing the gap
• Prediction of the natural progress of disease and of the suc- between research and current practice and reducing inappropri-
cess of treatment allow the medical doctor as well as the ate variability in practice (172). Their development and implemen-
patient to decide on the best therapeutic strategy. tation is intended to organize and provide the best available
• Prevention of disease should be distinguished in primary, evidence to support clinical decision making in order to improve
secondary and tertiary prevention. Preventive measures quality of care, patient outcomes and cost effectiveness (173,174).
should be advised to prevent the disease from occurring The criteria and prerequisites for developing guidelines are: a
(primary), to prevent the disease from becoming sympto- highly prevalent disease or frequently used medical procedure,
matic (secondary) and to prevent from causing damage or high associated costs and current variations in practice. They
disability (tertiary). are of particular value for a disease such as rhinosinusitis which
• Participation of the patient in the therapeutic plan is crucial has significant negative effects on health-related quality of
for achieving good adherence and hence optimal efficacy life. However, in medicine in general, it is estimated that about
of treatment. 30%–40% of patients receive treatment that is not based on
scientific evidence, and 20%–25% receive treatments that are
PM is not new in other areas of medicine but has been more either not needed or potentially harmful (168, 175, 176).
recently applied to other respiratory diseases such as allergy
and asthma and now chronic rhinosinusitis(164, 165). This has been The successful introduction of guidelines involves the three
promoted by organisations such as EUFOREA, the European steps of: development, dissemination and implementation (177)
Forum for Research and Education in Allergy and Airway disease and the success of implementation depends on determining the
(www.euforea.eu). barriers and developing strategies tailored to overcome these.
Thus the principles of PM can be implemented within existing Several reviews have considered and categorised the most im-
adult treatment algorithms for chronic rhinosinusitis (CRS) (165). portant barriers and suitable strategies (178, 179) based on 76 and
At the time of diagnosis, prediction of success of the initiated 69 articles respectively, of which the latter is the more recent
treatment as well as patient participation in the decision of the and rigorous systematic analysis.
treatment plan can be implemented. The second level approach
ideally involves strategies to prevent progression of disease, in Cabana et al classified the barriers to implementation into three
addition to prediction of success of therapy, and patient partici- main categories: barriers related to physicians’ knowledge (e.g.,
pation in the long-term therapeutic strategy. At the tertiary level lack of awareness and lack of familiarity), barriers that affect phy-
of care, endotype-driven treatment, which is part of a persona- sicians’ attitudes (e.g., lack of agreement and lack of familiarity),
lized approach, should be positioned, given the high cost, both barriers that affect physicians’ attitudes (e.g., lack of agreement
financial and in effort of implementation, of molecular diagnosis and lack of motivation) and external barriers (e.g., patient-,
and biological treatment. guideline- and environment-related factors) (178).
Precision medicine allows real-time clinical decision support The systematic review by Fischer et al. included publications
at the point of care with implementation of harmonized care from many countries which were both generic and disease-
based on quality criteria and patients to be treated and monito- specific, with several covering asthma but none on rhinologic
red more precisely and effectively to better meet their individual topics (179). They divided the barriers into guideline-related
needs(167). It brings together clinicians from many inter-related factors, personal factors, and external factors which are summa-
specialities, scientists and above all patients in a collaborative rised in Table 9.6.1. The scoping review revealed the following
effort to provide the most efficient and effective management. aspects as central elements of successful strategies for guideline
implementation: dissemination, education and training, social
interaction, decision support systems and standing orders. Avai-
lable evidence indicates that a structured implementation can

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Table 9.6.1. Barriers and interventions in guideline implementation (adapted from Fisher(179))

Barriers Interventions
Guideline related factors
Access to guideline Provide easy access to guideline
Decision support systems
Poor layout Design and development of guideline
Short and user-friendly versions of guidelines
Lack of evidence/plausibility of recommendations Use of methods of evidence-based medicine
Appraisal of evidence in recommendations
Regular updates
Delphi
Lack of applicability Sensitivity for differences in healthcare systems
Organisational constraints Standardisation of processes and procedure
Link to quality management
Lack of resources (time restrictions, heavy workload, facilitation Financial incentives/compensation
Providing time for documentation and utilization of guidelines
Social and clinical norms Local consensus groups
User factors
Physicians’ knowledge Lack of awareness Increased dissemination of guideline
Use of mass media to increase awareness
Continuous Medical Education (CME)
Lack of familiarity Making guideline available with practical instruments
Education
Lack of agreement Opinion leaders
Stakeholder participation in guideline
Society endorsement of guideline
Physicians’ attitudes Lack of self-efficacy Interactive learning / group training
Audit and feedback of individual performance
Lack of skills CME focusing on skills
Lack of learning culture Promoting learning organizations
Lack of motivation Motivational strategies that utilize audit and feedback
Opinions leaders
External factors
Organisational constraints Standardisation of processes and procedures
Guideline development needs to consider the care setting
Link to quality management
Lack of resources (time restrictions, heavy workload, facilitation) Financial incentives/compensation
Providing time for documentation and utilization of guidelines
Lack of collaboration Improving multiprofessional collaboration with other healthcare profes-
sionals
Social and clinical norms Local consensus groups

improve adherence to guidelines (179). wed by extensive chapters containing all the supportive
evidence.
EPOS is an established ‘brand’ with a strong legacy from 2005 • by a stronger focus on patient-relevant outcomes and
onwards. However, as it is 7 years since the last edition we have patient involvement during its development.
tried to improve EPOS2020 implementation: • by greater involvement of other stakeholders in its deve-
• by writing a clear and concise executive summary follo- lopment and writing e.g. primary care, pharmacists and

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neurologists. However, we do realize that not all advice in EPOS2020 can be

• by containing summaries and versions relevant to these followed in all health care systems and social circumstances. The
other stakeholders to support the implementation process. advises can be adjusted locally depending on the possibilities in
• by translating the Executive Summary into a wide range of the health care system.
languages.
• by reaching out to many key opinion leaders all over the EPOS2020 plans a rolling programme of revision and update in
world to review and comment on the document and inclu- response to future research and responses. A full implementa-
ding their suggestions in the final text. tion plan for EPOS2020 will be published separately in the near
• by widespread presentation, discussion and dissemination future.
at scientific meetings, publications, via websites and deve-
loping core sets of slides for presenters to use.

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10. Pharmacist perspective on rhinosinusitis

10.1. Differentiating rhinitis and rhinosinusitis in of smell component is less important, but cough might be
the community pharmacy setting a frequent symptom at presentation. The presence of nasal
itching, rhinorrhoea, sneezing and eye symptoms is usually
Many patients with rhinosinusitis self-manage their condition consistent with allergic rhinitis. Patient’s relevant demographic
in the community pharmacy with advice from their local information, medical and medication history, along with other
pharmacist. This is particularly true if patients consider their non-pharmacological measures that the patient has tried should
symptoms mild and not bothersome, or that over the counter be taken into consideration when counselling treatment (Table
(OTC) medication is adequate(1, 2). 10.1.1.)(11).
Pharmacists are in an excellent position to identify symptoms of In some countries, pharmacists may carry out rapid diagnostic
rhinosinusitis and recommend appropriate treatment or referral tests in order to determine whether infections are bacterial or
to a physician(3,4). According to the PGEU (Pharmaceutical Group viral in origin, or to diagnose group A streptococcal infections
of the European Union) Annual Report 2018 (https://pgeu- or influenza (http:www.sante.gouv.fr/IMG/pdf/IASS_ext-int.
annual-report.eu), 58% of European Union (EU) citizens can pdf )(12). Access to point-of-care tests may help to reduce the
reach their nearest community pharmacy within five minutes dispensing of antibiotics among antibiotic-requesting subjects
and 98% of EU citizens can reach their nearest community with respiratory tract infections(13).
pharmacy within 30 minutes, making community pharmacists There is also a significant overlap in symptoms between primary
the most easily accessible healthcare professionals. Thus, headache disorders and chronic rhinosinusitis(14-16), with up to
community pharmacists can facilitate the development of 42% of patients with primary headache disorders mistakenly
effective self-management techniques that can have important diagnosed with rhinosinusitis(16). The 22-item Sino-Nasal
health and economic ramifications. Outcome Test (SNOT-22) is a validated non-invasive diagnostic
Although there are no studies evaluating pharmacist tool. This score can be used to aid in patient counselling
intervention in rhinosinusitis outcomes, results from systematic as different score patterns exist for patients with CRS and
reviews in other chronic respiratory diseases, namely asthma(5) headache(17).
and COPD(6), showed that pharmacists have positive impacts Specific guidelines for allergic rhinitis management at
on the outcome, scores, severity and control of said diseases. community pharmacies were first issued in 2004(18), and have
Nevertheless, education programmes are needed to increase recently been updated(19). Computerized decision support
awareness and compliance of pharmacists with international systems for rhinosinusitis similar to those proposed for allergic
guidelines(7). rhinitis might be helpful when counselling patients(20).
A cross-sectional observational study of pharmacy customers
purchasing OTC medications for nasal symptoms revealed that 10.2. Dispensing and use of non-prescription
69.9% out of 296 participants self-manage their symptoms antibiotics in URTIs
with OTC medications. The majority of participants (68%)
experienced allergic rhinitis symptoms, while the most ARS subgroups (viral ARS or common cold, post-viral ARS
frequent symptom was nasal congestion. The study indicated and ABRS) are distinguished based on symptom severity and
suboptimal therapeutic choices made by the participants, duration. Thus, common cold / acute viral rhinosinusitis is
highlighting the need for pro-active interventions from defined by the duration of symptoms for less than 10 days,
community pharmacists in the form of patient therapy while acute post-viral rhinosinusitis is defined as an increase of
guidance, including referring to a physician if needed(8). symptoms after five days or persistent symptoms after 10 days
Some patients consulting the pharmacist will have had a with less than 12 weeks duration. Acute bacterial rhinosinusitis
previous diagnosis of rhinosinusitis or allergic rhinitis by a is linked to the presence of at least three symptoms / signs
physician, others will have made an appropriate self-diagnosis, of: discoloured discharge, severe local pain (with unilateral
and some will have no diagnosis at all or may have an incorrect predominance), fever (>38ºC), elevated ESR/CRP and ‘double
diagnosis(9). General symptoms of several conditions (common sickening’ (i.e. a deterioration after an initial milder phase of
cold, postviral ARS, allergic rhinitis, or CRS) are similar and may illness) ( for details please see chapter 4.1 and 4.3.).
be confused both by the patients and the pharmacist(10). Antibiotics are not effective in the treatment of viral infectious
Patient-reported symptoms and duration should be ascertained diseases such as the common cold and acute postviral
(Table 10.1.1.). The presence of nasal congestion, rhinorrhoea, rhinosinusitis.
facial pain or pressure and reduction of sense of smell are A systematic review of double-blind placebo-controlled
usually characteristic of rhinosinusitis. In children, the loss randomized trials on antibiotics in post-viral ARS revealed no

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Table 10.1.1. Questions to assist in managing rhinosinusitis (adapted from Carter et al. 2019(11)).
Questions Observations
Are your symptoms unilateral? Newly developed unilateral symptoms is a reason for referral
What symptoms are you experiencing? Check for nasal congestion and/or obstruction, rhinorrhoea,
facial pain, reduction or loss of smell, cough
What is your main symptom? Look for the most troublesome symptom for the patient
Do you have nasal blockage? Check if the nasal blockage is unilateral, alternating or
bilateral; alternating or bilateral is usually caused by
inflammation
Is your nasal discharge clear and watery or mucopurulent? Clear bilateral discharge suggests allergic; purulent discharge
suggests rhinosinusitis
How long have you had these symptoms? Chronic rhinosinusitis symptoms will be present for more
than 3 months
Do you have the symptoms all the time or do they come and go?
Has a doctor ever diagnosed rhinosinusitis, hay fever or allergic
rhinitis?
Are you aware of anything that seems to bring the symptoms on? Consider being outdoors, pollen seasons, contact with
animals, substances handled at work or at home
Do you have any pain in your face? Facial pain is suggestive of rhinosinusitis if combined with
nasal symptoms
Do you have any sneezing, itchy nose, watery or itchy eyes? This is suggestive of an allergic cause
Have there been any hormonal changes? Pregnancy, menstruation, oral contraception, and
hypothyroidism can give rise to rhinitis symptoms
Do you use OTC topical nasal decongestants? Long term use of nasal decongestants can cause nasal
rebound congestions (rhinitis medicamentosa)
Do you use any other medication? Take special interest in beta-blockers, aspirin or NSAIDs use

benefit of antibiotic prescribing in such patients (for details are viral in origin, self-limiting and resolve in the same amount
please see chapters 4.6.3.3. and 4.6.3.4.). Conclusively, careful of time with or without an antibiotic; that is antibiotics do not
selection of ABRS patients that could respond to antibiotic hasten recovery and do not prevent more serious illness(23-25).
therapy is highlighted to avoid injudicious use of antibiotics and
related side effects. Antibiotics should not be obtained without
Generally, acute rhinosinusitis (ARS) is predominantly viral medical prescription or an evidence-based
with a small percentage (0.5-2.0%) progressing to secondary indication.
bacterial infection(21). Antibiotics are effective in a group of adult
patients with symptoms and signs strongly suggestive of ABRS Despite the fact that dispensing of non-prescription antibiotics
(see above). Even though available data are limited, it seems is prohibited by law and legal regulatory frameworks in many
that especially amoxicillin / penicillin (beta-lactams) are effective countries, a large amount of antibiotics are dispensed without
(for details please see chapter 4.6.3.1.). Very limited data on the a prescription all over the world(26-36). This particularly refers
effect of antibiotics in ABRS in children revealed no significant to developing countries where the regulation of medicine
difference over placebo while showing a significantly higher distribution itself or regulation enforcement is lacking.
percentage of adverse effects (for details please see chapter Community pharmacies have been reported as important
4.6.3.2.). sites of non-prescription supply of antibiotics(37-40). Recently,
Antibiotics should not be obtained without medical prescription a systematic review with meta-analysis of non-prescription
or an evidence-based indication. supply of antibiotics in community pharmacy across the world
As for the EP3OS published in 2007, a divergence between was performed by Auta et al. (2019), taking into consideration
European recommendations and antibiotic prescription practice relevant studies published from January 2000 to September
in ARS was reported by Jorgensen and co-workers in 2013(22). 2017(41). Studies included in the review originated from 24
Thus, effort should be made to implement rational antibiotic countries, with 23 of them classifying antibiotics as prescription-
prescription following the relevant guidelines in the daily only medicines. Results revealed the overall pooled proportion
practice of all healthcare providers. of the non-prescription supply of antibiotics to be 62%.
The inappropriate use of antibiotics to treat upper respiratory Globally, the extent of supply of antibiotics without prescription
tract infections (URTIs) is a global public health problem. It upon patient request and following community pharmacy
has implications regarding the cost of treatment and the staff recommendation was 78% and 58%, respectively. It was
development of resistance to antimicrobial agents. Most URTIs highlighted that antibiotics were commonly supplied in cases of

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acute and self-limiting conditions, including upper respiratory recognition of antibiotic knowledge gaps of pharmacists might
tract infections (URTIs) for which the pooled proportion was serve as a basis for elaborating the education strategies to lower
reported to be 67%. Penicillins were found to be the most inappropriate antibiotic supply and provide adequate patient
frequently dispensed antibiotics for URTI indications (amoxicillin counselling. Pharmacists’ knowledge and attitudes towards non-
and amoxicillin-clavulanic acid, followed by macrolide antibiotic prescribed antibiotic dispensing present very important points
azithromycin). in antibiotic stewardship, particularly in URTIs which present
The practice of antibiotic dispensing for URTIs in community quite frequent acute problems often related to irrational use
pharmacies continues, especially in low- and middle-income of antibiotics(49). In the countries where antibiotics are legally
countries or illegally available over the counter, pharmacists are the key
In addition to the irrational sale of non-prescribed antibiotics players in restricting antibiotic dispensing only to patients who
upon patient request, self-medication also refers to the use of really need them(49).
saved / shared antibiotic leftovers(37-39, 42-45) leading to a high The global respiratory infection partnership (GRIP) designed a
rate of misuse and incomplete courses of antibiotics. Higher pentagonal (‘five P’; i.e. policy, patient, prevention, pharmacy
incidence of self-medication with antibiotics is found within and prescriber) framework for the non-antibiotic management
low- and middle-income countries(46). A population survey of upper respiratory tract infections, addressing the problem
conducted in 2007 in 19 European countries revealed that related to antimicrobial resistance(49). In the mentioned
previous experience with prescribed use of antibiotics for URTIs framework the antibiotic stewardship role of pharmacists as
increased the probability for self-medication with antibiotic community educators on appropriate and rational antibiotic
leftovers for similar symptoms(43). Therefore, in case of not seeing use was pointed out. Pharmacists are ideally positioned for
a doctor, the patient should consult with a pharmacist about antibiotic stewardship since they have contact with both
suitable therapy for URTI symptoms to avoid inappropriate patients and prescribers. Therefore, pharmacists can promote
antibiotic use. adherence to guidelines resulting in appropriate prescribing
Extensive use of non-prescribed antibiotics augments the and optimal treatment regimens, as well as advise and educate
risk of injudicious antibiotic therapy of viral infections, patients on common / minor ailments and their management(48).
acute and self-limiting conditions, and, on the other hand, Engaging pharmacists to provide minor ailment services
inadequate antibiotic therapy of bacterial infections, referring represents an innovative strategy reducing patient visits to
to inappropriate antibiotic selection, antibiotic dose and GPs and allowing for greater overall access to primary health
therapy duration. Such practice increases the risk of microbial care(50, 51). The pharmacist, often being the first point of call,
resistance, particularly in the case of broad-spectrum antibiotics. provides full support in the symptomatic management of
At the same time, injudicious and inappropriate antibiotic use URTIs considering patient preferences and referring the patient
can result in masking the diagnosis of infectious disease and to a physician if needed. Pharmacy staff should inform the
causing adverse effects such as allergies including anaphylactic patient on the common duration of the disease explaining
reactions, drug interactions and increase in drug therapy the possibilities of symptomatic treatment while highlighting
costs(24). the fact that antibiotics cannot reduce the severity or duration
Enforcing the laws prohibiting non-prescription dispensing of of symptoms(49, 52). In addition to recommending the dosage
antibiotics is certainly needed to reduce the extent of irrational regimen, pharmacists should inform the patient on possible
antibiotic use. However, it should be pointed out that over- side effects of dispensed medicine(28), describe the measures of
the-counter availability of antibiotics could contribute to infection prevention and control including hand and respiratory
timely access to antibiotics in certain circumstances, especially hygiene(53), and provide education on paths of infection
when access to healthcare facilities is limited and community transmission(48).
pharmacies present the first (or even the only) point of contact In cases when pharmacists are authorised and in a position
with healthcare professionals. In some developed countries to dispense an antibiotic, apart from consultation related to
like Canada, UK, New Zealand, pharmacists are authorised to the symptoms of respiratory disease and past medical and
prescribe and dispense antibiotics for certain defined conditions medication history, they should pose questions related to
– short-term uncomplicated urinary tract or cutaneous allergy and pregnancy status before antibiotic dispensing,
infections – redistributing the workload of GPs(47). Pharmacists ensuring both effectiveness and safety of antibiotic
are generally well educated in the field of rational antibiotic administration(41). Information on potential drug interactions
therapy(48). Nonetheless, updating of pharmacists’ training should also be provided. Whenever dispensing antibiotics,
/ knowledge in terms of antibiotic stewardship and clear the pharmacist should instruct the patient to complete the
assessment and treatment protocols for URTI diseases should antibiotic course promoting compliance with the dosage
serve as support in ensuring adequate patient counselling regimen and to dispose of any antibiotic leftover properly to
and treatment regimen, providing timely access and rational reduce the chance of subsequent antibiotic misuse (i.e. self-
dispensing of antibiotics in the pharmacy setting. A recent medication and antibiotic sharing)(48).
cross-sectional survey of community pharmacy staff in Sri Antibiotic prescription and dispensing are influenced by a
Lanka revealed a positive correlation between pharmacists’ combination of factors such as the knowledge and attitude of
knowledge on antibiotics (legal aspect of antibiotic use and health care providers and patient / parent expectations related
antibiotic resistance) and antibiotic dispensing practice(26). Any to antibiotic therapy(54, 55). A decrease in antibiotic dispensing

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Figure 10.1.1. Rhinitis and rhinosinusitis assessment in the community pharmacy.

rates owing to implementation of medicine policies aimed of addressed the benefits of increased fluid intake during an
at rationalizing antibiotic use, electronic decision support, acute respiratory infection. This review by Guppy (2011)(67)
awareness campaigns, educational interventions or multifaceted reported no evidence for or against this advice, implying the
interventions have been observed in different parts of the need for more studies on this subject. It is important to consider
world(28, 56-60) indicating the rationale for the continuation that interests, needs and priorities of professionals might not
of such initiatives. Delayed antibiotic prescribing has also coincide with those of the patient, and different patients might
been recognised as a successful approach aimed at reducing require different management approaches(68). Patient self-
the rate of antibiotic use for respiratory tract infections(61-64). management can be further enhanced through information
Pharmacists are in a position to provide full support to patients provision and regular, supportive feedback. Some studies have
when presented with a delayed prescription. Point-of-care identified patients’ frustration with inadequate treatment and
tests(13) and antibiotic shared decision-making tools(65) have the lack of coordinated care(69). Effective shared decision making has
potential to help pharmacists to reduce unnecessary antibiotic shown to improve adherence and lead to better outcomes in
use. Nonetheless, developed communication skills are of great respiratory chronic diseases, namely asthma(70) and could also
importance for pharmacists to raise behavioural change in be a valuable strategy in this setting. Moreover, in integrated
patients by increasing their knowledge and changing their care centred on the patient, the community pharmacist can act
attitude towards antibiotic use(49). as a bridge between primary (GP) and secondary care (specialist
care).
10.3. Management of rhinitis and rhinosinusitis in
the pharmacy 10.3.1. Over the counter (OTC) medication
Patients with upper airway symptoms rely on self-medication
Viral ARS (common cold) and acute postviral rhinosinusitis can and/or OTC treatment to deal with the first symptoms of ARS
be readily managed in the community pharmacy starting with or during acute exacerbation of CRS(2). When appropriate, self-
symptomatic relief (Figure 10.1.1.) with the additional use of medication can be beneficial in terms of significant involvement
topical steroids(66). Only one systematic review that we know of the patient and economic benefits(71). However, patients

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with acute exacerbations of CRS should see their physician and this dose throughout the cold (for details please see chapter
should not rely on OTC medication. 4.6.2.16.).
OTC medications can be sold directly to patients without a
medical prescription and are selected by regulatory agencies 10.3.1.2.3. Herbal medicines (excluding Echinacea)
to ensure that they are safe and effective when used without a Some herbal medicines (excluding Echinacea) like BNO1016
physicians’ advice. However, some OTC medications may only be (Sinupret) (both common cold and postviral ARS), Cineole
dispensed after an assessment of the patient by a pharmacist, (common cold), Andrographis paniculata SHA-10 extract
and provision of patient education. (common cold), Myrtol (post-viral ARS) and pelargonium
extracts (post-viral ARS) have significant impact on symptoms
10.3.1.1. Intranasal corticosteroids of common cold and/or post-viral ARS without important
In patients with chronic rhinosinusitis symptoms, intranasal adverse events (for details please see chapter 4.6.2.17.).
corticosteroids are the mainstay and there is a need for long-
term adherence to therapy(72). Intranasal corticosteroids 10.3.1.2.4. Echinacea
may also be recommended to patients with acute post-viral Echinacea plant preparations are widely used for the prevention
rhinosinusitis if a reduction of symptoms is considered and treatment of common colds. However, a 2014 Cochrane
necessary. In contrast, currently, there is no evidence to support systematic review by Karsch-Völk(81) concluded after analysing 24
the use of intranasal corticosteroids for symptomatic relief from double-blind trials with 4631 participants, that most Echinacea
the common cold. products are not effective. Some Echinacea products had some
All of the available intranasal corticosteroids are efficacious possible weak benefit, however the potential effects were of
in controlling symptoms, although mometasone furoate, questionable clinical relevance (for details please see chapter
fluticasone propionate and fluticasone furoate are generally 4.6.2.15.)
preferred for safety reasons(11) because they have negligible
bioavailability and less potential to cause side effects. 10.3.1.2.5. Vitamin C
Moreover, they only require once daily usage. As such, product Given the consistent effect of vitamin C on the duration and
differentiation involves factors such as cost, ease of dosage, severity of colds in regular supplementation studies, and the low
OTC status, and sensory issues, such as aroma and taste, which cost and safety, it may be worthwhile for common cold patients
can affect patient preferences(73-75). Patients should be aware to test on an individual basis whether therapeutic vitamin C is
of the common side effects that they can expect and the beneficial for them(82) (for details please see chapter 4.6.2.12.).
serious side effects that they should report to their pharmacist
and physician(76). In most developed countries, intranasal 10.3.1.2.6. Homeopathic products
medications containing fluticasone are classified as OTC, and Homoeopathic products have been used for the treatment
can be dispensed with pharmacists’ advice (for details please see of acute respiratory tract infections in children and adults.
chapters 4.6.2., 4.6.4. and 6.1.5.). A systematic review by Hawke aimed at assessing the
effectiveness and safety of oral homoeopathic medicinal
10.3.1.2. Other OTC medication for the treatment of ARS products compared with placebo or conventional therapy to
The use of other OTC medical treatments such as decongestants, prevent and treat acute respiratory infections in children(83).
analgesics, antihistamines and herbal medication is commonly After analysis of eight RCTs involving 1562 children, the
reported(77-79) and has been evaluated in chapter 4.4. (ARS). authors reported no significant benefit of homoeopathic
For common cold many OTC medications are available. products compared to placebo on infection recurrence or
Antihistamines, analgesics (paracetamol or NDAIDs) and cure rates in children(83). No similar study was found for the
decongestants alone or as combination have some general use of homoeopathic products in adults with respiratory
benefit in adults and older children with common cold. These tract infections. We found one study evaluating the effect
benefits must be weighed against the risk of adverse effects. of homeopathy (Sinfrontal) in acute post-viral rhinosinusitis
There is no evidence of effectiveness in young children. showing a significant reduction of symptoms and radiographic
improvement versus placebo (for details see chapter 4.6.13).
10.3.1.2.1. Nasal decongestants
Nasal decongestants (vasoconstrictors) have been shown to 10.3.1.2.7. Medication with no proven benefits in the
be able to reduce symptoms of nasal blockage. However, the treatment of ARS
use of decongestants is symptomatic and does in general not Some medication has been shown to be ineffective (e.g.
influence the course of the disease; moreover they should only homeopathy, steam inhalation or antibiotics) and sometimes
be used in the short term(80). even harmful. Examples are the use of mucolytics (not effective
and even harmful in young children) and antibiotics in
10.3.1.2.2. Zinc almost all forms of ARS (not effective and harmful, not only in
Zinc administered as zinc acetate or zinc gluconate lozenges producing side effects in the individual patient but also pushing
at a dose of >=75 mg/day and taken within 24 hours of onset antimicrobial resistance).
of symptoms significantly reduces the duration of common OTC treatments for the common cold and rhinosinusitis
cold. For those considering using zinc it is advised to use it at symptoms (analgesic associations, decongestants,

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antihistamines, expectorants and cough suppressants) have not as medication adherence. Especially in chronic rhinosinusitis,
been adequately studied in children, especially children under patients may be concerned about possible side effects of
six years old, and should not be routinely counselled without medication taken long-term.
physician indication(84-88). Adherence in randomized control trials is high but does not
reflect the real-life situation(91-93). In real life adherence to
10.3.1.3. OTC medication for the prevention of ARS treatment is low, especially in mild / moderate disease where
Some OTC medication and measures have been shown to patients use “on-demand” instead of continuous treatment(94).
reduce the incidence of ARS. Non-adherence to medications is a major obstacle to the
The effectiveness and safety of probiotics in the prevention of effective delivery of health care. Better adherence may reduce
acute respiratory infections were assessed in a systematic review the burden of uncontrolled disease and improve clinical
by Hao in 2015. The authors report that overall probiotics are outcomes.
better than placebo in preventing acute infections(89) however, Community pharmacists are uniquely positioned to help
the quality of the evidence was low. Moreover, one must bear in mitigate the high risk of medication discontinuation and non-
mind that different strains of probiotics are available and may be adherence to therapy; they improve adherence for patients
administered using different pharmaceutical preparations (for starting new therapies and continuing existing regimens. In the
details please see chapter 4.6.2.11). special case of intranasal steroids, patients must be informed
Regular, moderate-intensity exercise may have an effect on the that full benefit may not be evident for two weeks. Patients
prevention of the common cold. should be encouraged to continue to use their medication
The results of individual prophylaxis trials with Echinacea plant and counselled on the appropriate administration technique
preparations consistently show positive (if non-significant) for intranasal formulations (especially in avoiding the nasal
trends, although potential effects are of questionable clinical septum). Special caution is recommended when using nasal
relevance. decongestants; the pharmacist should emphasize that such
There are no conclusive results to support the use of vaccines for medication should only be used in the short term for congestion
preventing the common cold in healthy people. relief, as prolonged use can lead to rhinitis medicamentosa(80).
Regarding prophylactic zinc supplementation, currently no firm According to the PGEU (Pharmaceutical Group of the European
recommendation can be made because of insufficient data. Union) 2017 and 2018 Annual Reports, 53% of all responding
countries indicated that they provide type 2 medication reviews,
10.3.1.4. Saline irrigation which involve a structured, private consultation between the
Patients with rhinosinusitis commonly use nasal saline solutions pharmacist and the patient and focus on issues of adherence
to improve symptoms. There are several available options and the safe, effective and rational use of medicines. Moreover,
available at the community pharmacy: hypotonic, isotonic or pharmacists are involved in disease management programs
hypertonic; low-volume nebulized, large-volume irrigation; and are the first providers of advice and OTC medication for
etc. Nasal irrigation works by thinning and removing mucous, winter illnesses such as colds, ENT disorders and influenza(7).
clearing proteins that cause inflammation, and flushing out In addition to giving therapeutic and educational advice at
irritants, and bacteria from the nose and sinus cavities. Irrigation baseline, pharmacists play a crucial role in the follow-up and
with isotonic saline or Ringer’s lactate is recommended, but monitoring of patients(95). Structured community pharmacy
there is insufficient data to show that a large volume is more services, involving patient assessment, individualized treatment
effective than a nasal spray, or that temperature of the solution recommendations and follow-up might be of interest in
influences the outcome. this setting(96). It is important to review the recommended
In ARS, the majority of studies did not find a difference between treatment plan at regular intervals and to assess adherence and
saline nasal treatment versus control, but one larger trial in administration techniques.
children suggests that nasal saline irrigation has benefits for Patient information leaflets should be handed out to patients
relieving ARS symptoms (for details please see chapter 4.6.2.9). as a supplement to good communication. Leaflets should
In CRS, nasal saline irrigation is considered to be an important reinforce recommendations on pharmacological and non-
aspect of treatment by improving nasal mucosa function (for pharmacological treatment, administration techniques and
details please see chapter 6.1.11.) and should be recommended. provide contacts in case of any doubts.
In the case of patients with allergic rhinitis, saline irrigation may Many mobile phone apps and services are available to support
reduce patient-reported disease severity when compared to no people in taking their medications / to improve medication
irrigation at up to three months, but no data is available for any adherence(97-100). However, one meta-analysis found that the
outcomes beyond this period(90). majority of them did not have many of the desirable features
and were of low quality(97). Nevertheless, mobile applications
10.3.2. Adherence with self-monitoring and medication adherence features can
Medication adherence is defined as active, cooperative assist with self-management and improve patient control over
and voluntary participation of the patient in following their illness(99, 101, 102).
recommendations from a healthcare provider. Personal volition mySinusitisCoach is an app registered as a class I medical device
and autonomy, and perceived competence are positively that enables patients to monitor rhinosinusitis symptoms
related to optimal health self-management behaviours, such and their impact on lower airway symptoms, quality of sleep

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and daily life. It also provides longitudinal information on patients the proper spray administration technique can improve
disease control and adherence to therapy for the healthcare drug efficacy, reduce the likelihood of side effects and enhance
professional(103). patient adherence / compliance(7, 105, 106).
MASK is an app for patients with allergic rhinitis to track their Instructions available in patient information leaflets related
nasal, ocular or lung symptoms and share this with their to the use of nasal sprays differ from each other in terms of
healthcare providers(94). recommended head position, nasal spray direction within the
nostril, breathing pattern during spraying and closing the free
10.4. When and how to refer to a physician or to a nostril.
specialist (ENT)
The EPOS2020 steering group advises:
Acute viral and post-viral rhinosinusitis can be treated · To prime the bottle before first use.
symptomatically and in the case of post-viral rhinosinusitis · To shake the bottle prior to spraying. Since most nasal
with INCS as described above. Some signs and symptoms are corticosteroids are formulated in suspensions usually
indicative of an emergency or severe disease and require urgent containing thixotropic agents that increase the viscosity.
referral to an ENT physician or to the emergency services (Box Bottle shaking before use decreases the viscosity of the
1). Orbital and neurological complications are considered drug suspension, allowing the creation of fine mist by
emergencies. spraying (107, 108), needed to achieve appropriate deposition
in the nose.
Box 1. Signs and symptoms of emergency or severe disease · To blow the nose prior to using the spray.
(adapted from EPOS2012(21)). · To keep the head in an upright position.
· Periorbital oedema / erythema · To hold the spray in the opposite hand in relation to the
· Displaced globe nostril in which the spray should be applied(109, 110). That
· Double vision way the spray is aimed away from the septum reducing
· Ophthalmoplegia the possibility of epistaxis and in exceptional case even
· Reduced visual acuity perforation(106, 111). In a survey on patients using intranasal
· Severe unilateral or bilateral frontal headache corticosteroid spray, it was shown that ipsilateral spray
· Frontal swelling technique resulted in four times higher incidence of
· Neurological signs (a sign of meningitis) epistaxis and three times higher incidence of quitting
· Reduced consciousness (a sign of meningitis) intranasal steroid spray compared to contralateral
technique(106).
In addition, patients should be referred to a physician if the · To breath in gently or slowly during spraying.
patient is pregnant, has asthma, shows signs of dyspnoea, is · Not to close the opposite nostril to prevent pushing the
immunocompromised or is on any medication that may be septum to the side of the spray.
causing the symptoms (aspirin, NSAIDs, angiotensin-converting In cases when nasal saline irrigations are recommended, the
enzyme inhibitors, alpha-blockers, beta-blockers). Patients who patient should be advised to perform them prior to topical
have persistent symptoms of rhinosinusitis despite appropriate spray administration so as not to rinse off the medicine from the
treatment, correct technique and adherence should be of nose(112).
special concern(11). Special attention should be given to patients with certain
In chronic rhin(osinus)itis referral to a physician should be physical limitations such as arthritis or Parkinson’s disease, and
considered in case of symptoms that are uncontrolled despite patients unable to coordinate recommended breathing pattern
treatment with INCS(19, 104). with spray administration, since they may have difficulties
using some nasal spray devices (113, 114). While data on nasal
10.5 Advice to pharmacists on explaining to spray devices are lacking, a systematic review on critical inhaler
patients how to use medication errors in asthma and COPD patients revealed an increase in
handling error frequency in relation to age, comorbidities,
10.5.1. Nasal sprays education and socioeconomic class(115). A prospective
Pharmacists have a very important role in implementing randomised controlled trial in children aged between five and
efficient nasal spray use in rhinitis and rhinosinusitis patients, 16 years with moderate to severe intermittent or persistent
thus contributing to proper treatment, alleviation of symptoms allergic rhinitis showed significantly higher competency in
and improvement of patient’s quality of life. The role of using intranasal corticosteroid spray in children taught using
pharmacists becomes even more pronounced in the era of an animated cartoon, in relation to oral presentation without
prescription-to-OTC switches of intranasal corticosteroid demonstration(116), indicating the need for special care and
sprays(66, 68). approach in such population. The same study suggested
All nasal spray products include instructions on their proper use repeating the teaching procedure periodically to ensure the
in patient information leaflets. Nonetheless, it is recommended long-term correct use of the nasal spray.
that pharmacists demonstrate to patients how to use a nasal In the case of nasal steroid sprays, apart from instructions on
spray properly using a placebo device(19). Namely, teaching appropriate administration technique, the pharmacist should

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provide the patient with explanations related to clinical steroid treatment of anosmia), can be achieved by adopting the Kaiteki
effectiveness profile including delayed onset of action (12h) and position, i.e. lying on one side with the head tilted downwards
maximal efficacy reached in days to weeks(117). Patients should 20-30° and the chin turned upward 20-40°, with the drops being
be instructed to use intranasal corticosteroids regularly in order administered to the upper nostril aiming for the superior margin
to maintain symptom control and not to apply a use-as-needed of the nasal septal mucosa and holding the position for 30
approach(68). seconds(124).
Because penetration of the sinuses by nasal sprays and drops
10.5.2. Nasal drops is minimal, even in patients that have been operated on(125, 126)
Nasal drops are available in multi-dose and single-dose many rhinologists now advise combining nasal drops with saline
containers. Like nasal sprays, nasal drops are dispensed irrigation. Using a larger volume results in better penetration
with recommendations on their use provided in the patient the sinuses and this combination has been shown to be more
information leaflets. Most manufacturers recommend effective than nasal spray(127). Whether it is more effective than
administering drops in the head-back position obtained nasal drops needs further investigation.
easily by extending the neck. However, research evidence To minimize the risk of spreading infections, patients should be
supports administration of nasal drops in the head upside- advised not to share nasal delivery devices(128).
down position(118, 119), most easily attained by hanging off the A proposed technique for the use of nasal sprays and nasal
edge of a bed (i.e. Mygind’s position)(120) or in lying on the side drops provided by the EPOS group is given in Table 10.5.1.
in a head down position (i.e. Ragan position) with drug being However, it should be pointed out that drug deposition pattern
administered to the lower nostril(121, 122). Mygind’s position within the nasal cavity, apart from administration technique,
was shown to enable easier administration of drops, while depends also on nasal formulation properties, the volume of
Ragan position was reported to be more comfortable for the the applied dose, performance of the delivery device, individual
patient(121). Krinsky et al. recommend Mygind’s position (i.e. lying anatomical differences and pathological conditions. Therefore,
on the bed with head tilted back and over the side of the bed), it is difficult to come up with definitive conclusions and
with gently tilting head from side to side, after administration of identification of a general single-best technique for nasal drug
drops in the nostril(123). administration(125, 126).
Effective drops delivery to the olfactory epithelium (e.g. for the

Table 10.5.1. EPOS2020 proposed technique for the use of nasal sprays and nasal drops.

Nasal Before spray / Head position Spray / dropper tip Free nostril Spray / drops After spray / drops
drug drops direction administration and administration
products administration a breathing pattern
during spray / drops
administration

Nasal spray 1. Gently blow your 4. Keep your 5. Gently insert the 7. DO NOT 8. While slowly 10. Take the nozzle out
nose. head upright. nozzle tip into one close the breathing in activate the and breathe out through
2. Shake the nasal nostril. nostril not spray your mouth.
spray vigorously. 6. Aim the tip of the receiving the 9. Apply the number of 11. Repeat spray
3. Remove the cap. product away from medication. sprays recommended by administration steps in
the nasal septum; use the doctor. the other nostril.
the right hand to spray 12. The spray nozzle
the left nostril and vice should be cleaned
versa, to direct the according to the product
spray away from the directions and the cap
septum. replaced.
Nasal 1. Gently blow your 3. Lie down - - 4. While breathing 5. Hold the position for
drops nose. in a supine normally, instil the drops two minutes after the
2. Shake the drops position with in each nostril according drop instillationb.
container. the head just to the product 6. The dropper should be
off the bed directions. cleaned according to the
and the chin product directions.
being the
highest point
of the head.

440
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itisCoach: patient empowerment in chronic rhi- 117. van Cauwenberge P, Bachert C, Passalacqua G, et MB (eds). Aerosols in Medicine Principles, Diag-
nosinusitis using mobile technology. Rhinology. al. Consensus statement on the treatment of al- noses and Therapy. Amsterdam: Elsevier, 1985;
2018;56:209-15. lergic rhinitis. European Academy of Allergology 1-20.
104. Brozek JL, Bousquet J, Agache I, et al. Aller- and Clinical Immunology. Allergy 2000;55:116-
gic Rhinitis and its Impact on Asthma (ARIA) 34.

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11. Research needs and agenda for the next decade

11.1 Introduction 11.4. Acute rhinosinusitis including common cold -

and recurrent ARS in adults and children
Although there has been significant progress since EPOS2012,
in virtually every area covered by EPOS2020, there is recognition 11.4.1. Epidemiology of acute rhinosinusitis
of the need for further high quality studies. The following is a • To know what factors determine whether ARS patients in
summation of these gaps in our knowledge that require further the community consult with a doctor, pharmacist or self-
investigation (Figure 11.1). We placed the research needs in the manage without professional support.
same order as the chapters in EPOS2020 without any further • To demonstrate the prevalence of ARS in low, middle
prioritisation. and high income countries and consider whether any
predisposing factors differ dependant on income.
11.2. Classification and definition • Large population studies characterizing co-morbidities in
patients with ARS, compared to matched controls to identify
• International agreement on terminology significant co-morbidities or risk factors.
• There remains the need for clear and widely accepted
guidelines on the design of clinical trials which indicate: 11.4.2. Pathophysiology of ARS
• How to define the study population; • Studies to establish how allergic rhinitis increases the
• Choice of outcome measurements; predisposition for rhinosinusitis and specifically if it
• Choice of instruments to evaluate quality of life (QoL). increases the likelihood of S. pneumoniae sinus infection.
• It may also be advantageous to introduce some form of • Assuming this is confirmed, studies to establish whether
additional aetiological qualification to our classification regular antihistamines and/or leukotriene receptor
systems which might be based on International antagonists are effective in reducing ARS episodes in
Classification of Diseases (ICD) coding. patients with allergic rhinitis.
• The role of gastro-oesophageal reflux disease (GORD) in the
11.3. Burden of acute rhinosinusitis and chronic pathogenesis of ARS.
rhinosinusitis • To determine how exposure to cigarette smoke increases
the predisposition for ARS, to establish whether exposure
• Further studies to assess the impact of acute rhinosinusitis to cigarette smoke (active or passive) augments the
(ARS) on quality of life. predisposition for ARS in patients with allergic rhinitis and to
• As most data thus far is produced from the USA, further show whether smoking cessation improves the frequency of
studies on direct and indirect costs across Europe and ARS compared to active smokers.
globally.
• Create awareness for the government and industry for non- 11.4.3. Diagnosis and differential diagnosis
polyp disease. • To confirm if there are combinations of symptoms and signs
• Carefully constructed prospective epidemiological studies that predict acute bacterial rhinosinusitis in primary and
with valid diagnoses of ARS to give a clearer picture of the secondary care.
real burden of ARS, in particular the prevalence of acute • To show if the relative frequency of different symptoms
post-viral and bacterial rhinosinusitis. and signs in ARS predict a differential response to different
• To develop a validated disease-specific QoL questionnaire therapies, such as topical steroids and antibiotics?
specific to acute rhinosinusitis. • A trial to show if the purulence of nasal discharge is truly an
• Development of patient-reported outcome measure indicator of bacterial infection and can be used as a clinically
(PROMS) that capture all aspects of CRS not presently important response to antibiotics in chronic rhinosinusitis
covered by established instruments. (CRS) and what constitutes a clinically important response
• Real life studies evaluating and validating cut off levels to antibiotics in ARS, e.g. change in purulence of nasal
for visual analogue scale (VAS) or other measurements of discharge.
control. • To determine biomarkers (e.g. c-reactive protein(CRP),
• Studies looking at cost-effectiveness and the socio- procalcitonoin) that can predict acute bacterial rhinosinusitis
economic impact of implementation of phenotyping and or a clinically important response to antibiotics in ARS?
endotyping into care pathways.

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11.4.4. Medical management of ARS rhinosinusitis without / with nasal polyps (CRSs/wNP),
• To confirm whether topical nasal corticosteroids can be the asthma, N-ERD], prevalence and disposing factors and its
first-line treatment for ARS in primary care and consider impact across the world as there are many areas without
whether there are clinically important differences between much data egMiddle East, Africa, South Americaand
different topical nasal corticosteroid molecules and dosing compare low, middle and high income countries.
regimes. • Create a network with institutions around the world to
• Further RCTs in acute bacterial rhinosinusitis on the full establish good epidemiologic data and create a unified
range of medications and in particular, topical and oral survey that can be applied globally to collect epidemiologic
corticosteroids, antihistamines, decongestants, saline and data on impact of CRS.
steam inhalations. • To establish what, if any, childhood events increase chances
• Large RCTs on the effect of antibiotics on the cure/ of developing CRSwNP.
improvement of symptoms in ABRS in children and • To establish how smoking increases the risk of CRS and
consideration of why there is an apparent difference whether the risk is reduced by smoking cessation.
between the response children and adults. • To show if recognition of and appropriate treatment
• To show whether the provision of educational and of allergic rhinitis reduce the incidence of CRSsNP and
information materials for patients improve outcomes of ARS CRSwNP?
and reduce non-essential antibiotic use? • To consider the role of GORD in CRS.
• To demonstrate whether professional education and • To investigate the role of pollution and climate change on
efficient dissemination of evidence-based guidelines disease process of CRS.
to clinicians improve outcomes of ARS and reduce non- • To investigate nutrition effects, including obesity, on CRS.
essential antibiotic use?
• Further randomised controlled trials (RCTs) in acute viral 11.5.2.1. Genetics and epigenetics of CRSsNP and CRSwNP
rhinosinusitis on prophylactic medications including Vitamin • Role of genetics using improved technology.
C, vaccines, probiotics, Echinacea and zinc. • Understand the environmental factors that alter gene
• Maxillary puncture for acute rhinosinusitis is currently only expression which may predispose to CRS which may allow
being performed in a limited number of countries because us to recognize disease-causing agents versus disease-
there is no evidence to prove that it is effective. Clinicians modifiers or exacerbating agents and in turn may allow us to
from those countries should therefore be encouraged to set alter behaviour or implement therapies that can counteract
up studies to evaluate whether puncture reduces pain in the any genetic predispositions and reverse/ moderate
acute phase. epigenetic pre-disposition.
• To show if the clinical and economic outcomes of ARS differ • Understand epigenetic regulation of upper airway disease
depending on which health professionals (e.g. rhinologists,
ENT specialists, GPs, pharmacists?) manage patients. 11.5.2.2. Inflammatory mechanisms of CRS
• Large epidemiological data collection on the true incidence • Develop a classification of CRS of phenotypes / endotypes
of complications in ARS, determining the role of primary based on “hypothesis-free” cluster analyses.
care physicians in the detection and/or prevention of • Understand the regulation of TGF-ß and related molecules in
complications and whether complications of ARS relate to remodelling processes.
access to medical care? • Understand the T regulatory cell deficit and the role of T
• To establish if early use of therapies in viral URTI prevent effector cells in nasal polyp disease.
bacterial ARS, particularly in those with recurrent ARS or at • Understand the role of dendritic cells in CRS.
risk of complications • To increase our understanding of the role of ILC and
• A large prospective study on the role of antibiotics in the epithelial barrier
prevention of acute complications. • Understand the links between inflammation and
• A randomised trial of drainage versus intravenous remodelling.
antibiotics for small abscesses in young children (orbital and • Understand the impact of the microbiome on inflammation.
intracranial). Further research is needed on the impact of bacterial,
• Conduct multicentre trials on endoscopic versus open fungal or other microbial colonization / infection, with clear
management of complications of ABRS, both intracranial definition of such impact and we need some standardized
and orbital. methodology for research. For example should measures of
minimal undetectable colonization, like PCR, or molecular
11.5.Epidemiology, predisposing factors, pathophysiology, cultivating techniques or hardly detectable immune
and diagnosis of CRS response to colonizer be taken into account and if so, when?
• If infection is characterized by invasion, as well as by
11.5.1. Epidemiology immune response to the micro-organism, we need to define
• Studies evaluating the natural history of untreated CRS and how this invasion is established at both a local and systemic
the impact of age on disease. level.
• Epidemiologic studies on the disease process [chronic • There are variations in local anatomic immune response

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Figure 11.1. Research priorities in acute and chronic rhinosinusitis.

Research priorities in acute and chronic rhinosinusitis

GENERAL PRECISION MEDICINE ARS CRS

Classification and definition Prevention and prediction Burden of ARS Burden of CRS
• International agreement • Can treatment prevent • QoL in ARS • Direct and indirect costs
on terminology development of disease? • Direct and indirect costs
• How do we measure • Can reaction to treatment
success and failure? be predicted?
Management of ARS Management of CRS
• Predictors for need of • Better, large RCTs
Patient participation antibiotics • Real-life studies combining
• Self-management • (Early) warning signs of surgery + medical treatment
• Compliance serious disease • Place of biologicals
• Empowerment • Treatment of acute • Treatment of CRSsNP
postviral rhinosinusitis • Management of
uncontrolled disease
• Impact of extent of surgery
• Which endotypes have
management implications?

Paediatric CRS
• RCTs for INCS and
other treatments
• Surgery versus natural
course of the disease

that are not related to airflow and environmental exposures. meta-analysis may be done.
Research is needed into variations in immune response of • A long-term study on the natural history of osteitis.
the ethmoid / middle meatus for example, as this is different • The role of viruses and microbial dysbiosis in the
from the mucosal response of the septum or inferior pathogenesis of acute exacerbations of CRS (AECRS).
turbinate. • Understand the pathogenesis of ‘allergic’ fungal
• There is thus a need for innovative experimental models in rhinosinusitis and N-ERD.
CRS. Nearly all of the currently conducted human research is
performed in patients who already have established disease 11.5.3. Diagnosis and differential diagnosis
or controls who do not. While this is useful in identifying • To determine the relative frequency and prognostic
unique contributors to the pathophysiology of CRS and significance of different symptoms and signs in CRSsNP and
subsequent treatments, it does not identify the actual cause CRSwNP in primary care.
of the disease. Currently available animal models are either • The correlation of CRS (severity, etc.) and mental health,
allergic models or genetically manipulated animals that either directly or indirectly.
artificially generate an inflammatory response and again, do • Determine when a mucus sample indicates sinusitis and
not answer the cause of the disease. then determine the criteria to lead to subtypes of CRS and
• Differences between CRSwNP in Western patients and personalized medicine.
elsewhere in the world. What are the key cytokines which • Inclusion criteria for non-ENT control groups.
mediate Th2 skewing across the epithelial barrier: TSLP vs. IL- • To investigate the impact of psychological problems such
25 vs. IL-33 vs.? Identification of the key effector cell(s): mast as depression, stress exposure and anxiety on subjective
cells vs. esoinophils vs. neutrophils. severity scores and to consider the impact of neurological
• For endotyping and phenotyping, to define the minimal co-morbidities like chronic fatigue, post-traumatic stress
criteria for measuring sinus inflammation, e.g. sampling disorder, neurological hyposmia, and measures of other
procedures and expression of data should be unified (ng of neural-based disorders that play a role in non-allergic
cytokine per ml, mg of tissue or protein content) so that a rhinitis, which may have an impact on rhinosinusitis scores.

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• To consider neural aspects of facial pain, headache, smell • RCTs comparing different delivery methods, dosage and
disorders and hypersecretion and investigate better tools for duration of topical intranasal corticosteroids.
the diagnosis and differential diagnosis of facial pain. • Conduct an RCT on oral steroids versus surgery on the long
• Comparative studies evaluating symptom prevalence and term outcomes of CRSwNP.
severity to distinguish CRS, allergic rhinitis and non-allergic • Conduct an RCT studying the effects of oral corticosteroids
rhinitis. on olfactory function in CRSwNP.
• Studies on sinus computed tomography (CT) to determine • Investigate why there is a lack of response to corticosteroids
which changes eg degree and pattern of mucosal in some cases of CRS, e.g. smell, QOL, etc.
thickening, number of sinuses affected and the status of the • Larger long-term studies on efficacy and safety of steroid-
ostiomeatal complex are clinically relevant in CRS. eluting stents.
• Development of an objective smell test to assess the • Further studies on individual CRS subtypes to determine
presence of olfactory distortions. which patients would benefit from long-term antibiotics and
• Development of a reliable commercially available test of more specifically macrolide antibiotics. To seek better local
retronasal olfaction. therapies for immunomodulation.
• Studies on tissue eosinophilia to determine an • Studies evaluating the effect of antihistamines in patients
internationally agreed value for number of eosinophils / with CRSsNP.
high powered field. • Studies evaluating the effect of montelukast in CRSwNP
• Studies on specific histopathological and serological patients that failed nasal corticosteroids.
markers of inflammation to determine their role as • Studies on saline irrigation to consider if a large volume is
indicators of prognosis or targets for tailored therapy. more effective than a nasal spray.
• Studies on the role and methodology of microbial sampling • RCTs to evaluate aspirin desensitisation with topical lysine
in CRS. aspirin.
• RCTs to evaluate the effect of probiotics in CRS.
11.6. Management of chronic rhinosinusitis in • Further placebo-controlled studies on local furosemide
adults and local verapamil to determine efficacy and appropriate
patient selection.
• Demonstrate whether the relative frequency of different • Larger studies of longer duration on bacterial lysates with
symptoms and signs in CRSwNP and CRSsNP predict a proper patient characterization and outcome evaluation.
differential response to different therapies, such as topical • Establish whether aspirin desensitization or biologics has
steroids and antibiotics. better efficacy in patients with N-ERD.
• Studies to determine the optimum biomarker before we • Studies with larger populations and longer follow-up for all
initiate treatment (surgery, steroid or biologic). biologics
• Investigate management recommendations based upon • Establish a register of patients treated with biologicals.
lifestyle factors. • Is biological treatment life long?
• Improve professional education and efficient dissemination • Is there a shift based upon age for treatment with
of evidence-based guidelines to optimise outcomes and biologicals?
reduce referral rates to secondary care. • Auto-immunity effect?
• Conduct multicentre RCTs on surgery versus no treatment • Investigating type 1 CRS patients
for patients with CRS to establish the natural course of • How to choose between different biological treatments.
disease in the different phenotypes. • How to choose between or combine surgery and biologicals.
• A randomised trial comparing different treatment options
for patients with CRS with significant osteitis. 11.6.2. Surgical
• Test the criteria for concept of control from a data • Studies to agree definitions of surgical procedures.
standpoint. • Characterisation of CRS endotypes likely to respond best to
endoscopic sinus surgery (ESS).
11.6.1. Medical • Studies to show if any pre-operative medication improves
• Develop therapeutic approaches based on endotypes of surgical field and specifically the role of preoperative
disease antibiotics and oral steroids.
• Studies regarding what constitutes an adequate trial of • Studies to show best local anaesthesia and vasocontriction
medical therapy (both in terms of therapeutic classes, regime to improve surgical field and reduce blood loss.
modes of delivery and duration), the importance of patient • Studies/Delphi consensus to consider standardisation of
compliance with treatment and how to determine failure of indications for surgery.
this approach. • Comparative RCTs of medical versus surgical treatment.
• Trials on medications specifically in AECRS, in particular • Further studies on impact of surgery on development of
large, high-quality trials to evaluate the use of short courses asthma and sleep disturbance.
of antibiotics in acute exacerbations of CRS. • Indications for and timing of ESS to see if it alters the course
• High quality RCTs on topical antibiotics in CRS. of the disease.

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• RCTs of minimal versus extensive ESS. required. Prospective, randomized, multicentre trials
• Evidence from RCTs on adjunctive surgery – possibly should be conducted where the severity of disease on CT
pragmatic trials comparing different centres scans and the symptom questionnaire would be matched
• RCTs for balloon sinuplasty in non-US cohorts with higher preoperatively and the following interventions would be
disease burden. compared: adenoidectomy alone, adenoidectomy with
• Longer term data on drug eluting stents efficacy, safety and a washout, adenoidectomy with a washout and balloon
economic benefits. maxillary sinuplasty, and endoscopic sinus surgery. An
• Long-term follow up of post-operatively debrided versus additional arm that includes medical therapy should also be
non-debrided ESS cases. included.
• Studies on use of robotic transnasal ESS as this progresses.
• RCTs for novel interventions such as antimicrobial 11.8. Concomitant diseases in patients with chronic
photodynamic therapy rhinosinusitis
• RCTs for optimal peri-operative medical treatment and use
of dressings/packings. 11.8.1. Role of allergy and chronic rhinosinusitis
• Pooled multi-centre data on ESS outcomes including • Studies to assess the effectiveness of management of
complications, revision rates and mucocoele formation. allergic rhinitis on the outcome of established CRS, or on the
• Data on extensive surgery vs. limited (bad?)surgery – we risk of subsequent development of CRS.
have no proof that “bad” surgery equals bad outcomes.
• Evaluation on when to perform revision surgery and to 11.8.2. Immunodeficiencies
define the goals and extent. • Large scale studies to determine true incidence and
• Large-scale RCTs to answer whether postoperative short- importance of IgG subclass deficiency in general population
term antibiotics, oral and topical corticosteroids or saline as a predisposing factor for CRS.
irrigations after endoscopic sinus surgery are beneficial.
• Training: Studies on new technologies including augmented 11.8.3. Lower airway disease including asthma
reality, artificial intelligence (AI) and latest image guidance. • To conduct research on the basic physiology of the nose,
including humidification and heat exchange and its effect
11.7. Paediatric chronic rhinosinusitis on pulmonary function.
• To establish whether treatment of CRS affects outcomes
• Population studies on prevalence of CRS in children. of co-morbid lower airways disease [e.g. asthma, chronic
• Further studies on gene mutations in paediatric CRS. obstructive pulmonary disease (COPD)].
• The contribution of viral infection to development of • To undertake further RCTs studying the effects of surgery
paediatric CRS. and medical treatment on the lower airways (lung function/
• The importance of allergic disease in the pathogenesis of QoL/symptoms) in CRSwNP and concomittant asthma.
CRS in children. • Define predictive factors for the development of asthma in
• The relationship between CRS and asthma in children. CRS patients, allowing the implementation to preventive
• The role of adenoids in CRS as a reservoir for pathogenic strategies.
bacteria or a source of obstruction. • Understanding the natural course of disease and
• The role for inflammatory mechanisms in paediatric CRS to mechanisms in N-ERD, with impact of upper on lower airway
facilitate endotyping by better evaluating tissues obtained inflammation and vice versa.
at the time of surgery for CRS through well organized, multi- • Further exploration of the involvement of the microbiome
centre collaborations. and the immune responses to the microbiome in relation to
• Develop tools/tests in the context of clinical trials to CRS and asthma/COPD development.
differentiate the role of chronic adenoiditis from that • Study the neurogenic pathway involved in CRS and
of chronic rhinosinusitis in children with chronic nasal asthma/COPD, with better understanding of mediators and
complaint therapeutic options for treatment of nasal and bronchial
• Establish the relevance of CT abnormalities in children with hyperreactivity.
chronic nasal symptoms. • Study the relevance and best method for screening of upper
• Improve olfactory testing and reporting in children. and lower airway inflammation in CRS and asthma/COPD
• Definitions of what constitutes a controlled response in the patients’ outcomes.
paediatric population. • Studies highlighting the impact of personalized follow-up
• Trials on the use of intranasal steroids in children with CRS. and patient education via e-health tools, leading to early
• Randomized, controlled trials to evaluate the use of short diagnosis and better outcomes of treatment in patients with
and long-term oral antibiotics in children with CRS. CRS and asthma/COPD.
• Better studies on the role and impact of treatment of GORD 11.8.4. Cystic fibrosis
in children. • A study to consider correlation between cystic fibrosis (CF)
• Investigation of best surgical practices for CRS in children genotype and severity of sinonasal disease.

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• A study to elucidate an association between heterozygote • Prospective studies comparing EPOS control criteria
CF patients and CRS. before and after surgery with long follow-upare needed to
• A study to determine the best CT staging system in this further evaluate the responsiveness of the EPOS criteria to
condition. treatment.
• A study to consider whether extent of sinus surgery is • Explore differences in disease control (based on EPOS
important in CF. criteria) between men and women, patients undergoing
primary or revision functional endoscopic sinus surgery
11.8.5. Primary ciliary dyskinesia (FESS), and between different phenotypes e.g. with or
• A study to determine the precise incidence and prevalence without nasal polyps, allergic rhinitis, asthma, N-ERD, and
of primary ciliary dyskinesia (PCD). endotypes based on inflammatory patterns to assist in
• To establish the prevalence of ARS in the primary ciliary predicting patients at risk of having uncontrolled disease.
dyskinesia population, to determine whether aggressive • Further studies are required on patient participation,
treatment of ARS in patients with PCD prevents recurrence compliance and self-management.
of ARS or development of CRS and to establish if aggressive
treatment of ARS affects the progression of PCD-related 11.10. Pharmacist perspective on rhinosinusitis
bronchiectatic lung disease. • Determining the best way to predict acute bacterial
• Randomized controlled studies are needed to delineate the rhinosinusitis
effects of surgery and adjunctive therapy. • To show whether the provision of educational and
information materials for patients improve outcomes of ARS
11.8.6. Fungal rhinosinusitis and reduce non-essential antibiotic use?
• The factors predisposing individuals to allergic fungal • To demonstrate whether professional education and
rhinosinusitis (AFRS) need further study. efficient dissemination of evidence-based guidelines to
• Large RCTs to consider dosage and duration of oral and pharmacists improve outcomes of ARS and reduce non-
topical corticosteroids in AFRS. essential antibiotic use?
• An RCT to consider the role of immunotherapy, oral and
topical antifungals in AFRS. 11.11. General principles
•
11.8.7. Vasculitis, granulomatous diseases • Research on implementation of guidelines.
• A large prospective study considering the use of anti- • Interdisciplinary collaboration is needed.
neutrophil cytoplasmic antibodies (ANCA) in limited • Publication of negative as well as positive studies should be
rhinologic cases of granulomatosis with polyangiitis (GPA) stimulated in order to have a better understanding of the
and eospinophilic granulomatosis with polyangiitis (EGPA). efficacy and safety of interventions in AR and CRS.
• A study of the topical medications used in vasculitis. • Quantitative research in real-life studies evaluating large
• What is the best treatment of limited GPA? number of patients should be reinforced.
• Application of health information technology for data
11.9. Patient participation, prediction, precision collection, real-time analysis and feedback for clinical
medicine and implementation decision support systems and for education should be
available for all stakeholders, including patients, researchers,
• To achieve uniformity in the routine application and clinicians, administrators, and politicians.
interpretation of the existing tools for assessment of CRS • Setup of biobanks for biomarker mining and rapid validation
control. of novel candidates.
• Large-scale studies to confirm the high percentage of
uncontrolled patients after surgery shown by earlier reports.

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12. Methods used in EPOS2020

12.1. Introduction search for evidence, incorporating randomized controlled

trials (RCTs) with ‘Real World Experience (RWE) – observational
Patients with rhinosinusitis, acute and chronic deserve the studies (surgery) / real-life studies, and using meta-analysis
best possible management of their disease. Our aim is for the of systematic reviews to combine results from clinical trials.
next European Position Paper on Rhinosinusitis to promote Most surgical evidence is based on observational studies, with
better-informed decision-making by patients, members of the recent research showing some justification for incorporating
community, clinicians, and public health policy-makers on the non-randomized studies(6, 7).Some parts of the document did
management of rhinosinusitis. not lend themselves to systematic analysis of the literature
The European Position Paper on Rhinosinusitis (EPOS 2020) will (e.g. the parts on pathophysiology). In those (sub)chapters
be the latest in the EPOS series of guidelines on rhinosinusitis the search used have been indicated. Many questions could
from an international cohort of experts in the field. not be answered with the existing literature. For that reason,
The first European Position Paper on Rhinosinusitis and Nasal Delphi trials were performed directed to ENT / rhinology
Polyps (EP3OS)(1)was published in 2005, and was soon followed specialists / primary practitioners to reach expert consensus
by EP3OS 2007(2, 3)in response to the first position paper’s on areas including (but not limited to) diagnostics, certain
extremely positive reception and the growing body of research treatments for acute rhinosinusitis, and in CRS, appropriate
in this area. medical therapy and surgery (and technique to use) in adult
The guideline development group included all relevant and paediatric rhinosinusitis. Two full new chapters focus on
stakeholders including medical specialists of all relevant patient participation, prevention of disease and the role of the
specialities, microbiologists, primary care physicians, pharmacy in the management of the disease.
pharmacists and patients were involved. A much larger group of
stakeholdersexperts from all over the world has been asked to 12.2. Search methods to identify RCTs
review and comment the document. Their comments have been
used to further improve the document. 12.2.1 Abstract selection
The development strategy used in EPOS2020 has been An information specialist (J.L.) performed an electronic search
published before we started the work(4) and we refer here to in the Cochrane Central Register of Controlled Trials (CENTRAL),
that document for details of the methods used. We followed the OVID MEDLINE and OVID EMBASE using controlled term, such as
AGREE II framework(5), a tool which aims to ensure consistency in MeSH-terms, and textwords for chronic or acute rhinosinusitis
quality of clinical practice guidelines, provide a methodological including nose polyps, Kartagener syndrome adenoid
strategy for the development of guidelines and clarify what hypertrophy, common cold and URTI. In MEDLINE and EMBASE
and how information ought to be reported in guidelines. In the search was combined with a methodological search filter
summary, the EPOS 2020 guideline will apply to the adult to identify RCTs. No language, date or other restrictions were
and paediatric patient population with ARS (viral / common used. The records identified were downloaded in EndNote and
cold, post-viral, bacterial), and all forms of CRS. The EPOS duplicates were removed. The complete search strategies for
steering committee started to review whether definitions and ARS and CRS are shown at the bottom of this chapter. The search
classifications made in earlier versions of EPOS were still relevant was performed 18/02/2019. For the chapters on management
and precise. In ARS the in EPOS2012 proposed classification of the disease we decided to only evaluate RCT and systematic
into acute viral rhinosinusitis (common cold, acute post-viral reviews (SR). The references (20524 on treatment and 3840
rhinosinusitis and acute bacterial rhinosinusitis (ABRS)) was diagnostic) were imported into Rayyan (https://rayyan.qcri.org)
considered to be relevant and now the whole of chapter 4 uses and two independent reviewers selected papers based on the
this classification to evaluate the evidence. abstract. All the papers that had inconclusive selections were
Based on new insights developed in the past decade on the discussed.Additional relevant papers found in the SR and newly
different phenotypes and endotypes of CRS it was decided to published in 2019 were added during the writing process.
move away from the phenotypical classification into CRSwNP This resulted in 2214 papers of which the full texts were
and CRSsNP and come with a new classification that used assessed. All SRs were analysed for additional references and
anatomical aspects and endotype of disease. We expect that this 156 SR are referenced in the document. Eventually 26 SRs
new classification will be better suited to discuss treatments in (on common cold (see below)) and 294 RCTs were used for
the near future. treatment analyses that are mainly reported in chapters 4,6 and
We used evidence-based medicine (EBM) methodologies to 7. A total of 3182 references were used in the full document,

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authors were contacted to provide a paper. Papers were

Studies that were included/excluded during the abstract translated/extracted from their original language by volunteer
selection that needed discussion were: specialists who were able to read the language and had
- Prevention studies of common cold in subpopulations sufficient knowledge of EBM to find the relevant data. Especially
based on age (elderly, day care centres) (included) for Chinese papers, the volunteers were often asked to evaluate
- Studies on behavioral changes in prescribing antibiotics whether the paper was an RCT and whether the population
(included) evaluated was relevant to the question before full translation of
- Studies on wound healing in sinus surgery (included) the paper was done.
- Open randomized studies (excluded) Papers that evaluated mixed patient populations were included
- Studies in subpopulations of ARS based on other things when the relevant data for the relevant patient group (fulfilling
than age (athletes, swimmers) (excluded) the criteria of ARS or CRS as defined by EPOS) were reported
- Fever not related to ARS (excluded) separately. The division of ARS into viral ARS (common cold),
- Reaction time and alertness in ARS (excluded) post-viral ARS and ABRS suggested in EPOS2012 has obviously
- Sore throat (excluded) not been followed in most earlier papers. For papers evaluating
ARS, papers were included when it was clear that the majority
12.2.2. Full paper selection of the patients fulfilled the EPOS criteria. E.g. for post-viral
ARS a study evaluating patients with symptoms for more than
12.2.2.1. Included studies three days but with a table indicating that the mean symptom
In the phase of evaluating full papers we noted that the duration at inclusion was 12 days was included. A study where
number of papers on the treatment of URTI/common cold was inclusion was more than three days and no indication of
very large. We decided to only include SRs in our analysis on symptom duration was excluded. Studies indicating that 70% of
treatment of common cold. All relevant papers on diagnosis, the patients had symptoms for more than 10 days was included.
however, are included in the review. For ABRS, papers that used either the EPOS criteria or a
We only included peer-reviewed papers. Papers were retrieved combination of most of the EPOS criteria for ABRS and radiology
from international libraries around the world. Occasionally and/or positive antral puncture were included.

PRISMA 2009 Flow Diagram

452
 EPOS 2020

For evaluating safety of effective medication, when possible, the data that were available in the reported evidence. Finally,
systematic reviews on other diseases than CRS were evaluated. the chapters on diagnosis and treatment were combined into
integrated care pathways starting at self-management and
OTC treatment, via primary and secondary care to specialist
12.2.2.2. Excluded studies management of the disease (see chapter 1).
• Comparison of medication in ARS or CRS that was not
effective. 12.3. Delphi rounds
• Comparison of antibiotics in the treatment of ARS because
either antibiotics were not effective (post-viral ARS) or Despite considerable increases in the amount of quality
insufficient RCT were performed (ABRS). publications in recent years, a large number of practical
• Evaluation of treatment of the lower airways. clinical questions remain. It was agreed that the best way to
• Studies evaluating safety when efficacy of the medication address these was to conduct a Delphi exercise which is a
has not been shown. structured communication technique, originally developed as
• Studies evaluating combination treatment versus single a systematic, interactive forecasting method which relies on
treatment when the single treatment has not been shown a panel of experts. The EPOS2020 group firstly prioritised the
to be effective. areas for consideration by several rounds of questionnaires
• Studies evaluating two treatment options when no and discussion as a result of which we have concentrated on
comparison with a placebo or with another treatment diagnostic issues in the first instance. The final Delphi questions
proven not to be more effective than placebo was made. were circulated in several tranches and the respondents were
• Studies evaluating the treatment of side-effects of asked to grade their answer from 1-9, where 1 was least and
treatment (e.g. treatment of osteoporosis in patients with 9 most (essential/clinically relevant/acceptable etc) When
CRSwNP). the results were analysed, there were three possible results –
• Studies on treatment only evaluating non-clinical positive, negative or unclear as shown below depending on the
outcomes (histology). percentage of answers from the whole group. The results have
been integrated into the respective sections of EPOS2020.
12.2.3. Evaluation of the evidence It is our intention to develop a rolling Delphi programme under
In CRS and ARS, excluding common cold, when enough RCTs the aegis of EPOS2020 and ERS to achieve expert consensus for
with sufficient patient numbers were available, other evidence other areas of clinical management across the full spectrum of
was not primarily included. We started to evaluate whether rhinosinusitis in the future.
DBPCT trials were evaluable. If more than threeDBPCT were
available, we did not look for other evidence unless the
outcomes of the trials were either not useful or incongruent. Positive answer ≥70% Grade 7-9; ≤15%
When sufficient DBPCTs were not available, other single blind Grade 1-3
or open RCTs were used to accumulate the evidence. When no
RCTs were available,occasionally other forms of evidencesuch
ascase control, cohort studies, real-life studies and Delphi
rounds were used. Studies were only included when relevant Unclear
between group data (e.g. mean and s.d. or non-parametric
data) could be evaluated either directly from the paper or after
recalculation. We accepted either post-treatment comparisons
or changes from baseline. Papers only giving statistics for
changes from baseline within groups (not between groups)
Negative answer ≥70% Grade 1-3; ≤15%
could not be included. If needed statistics were recalculated Grade 7-9
based on the data reported in the paper, especially in situations
where data compared to baseline within groups were reported
but statistics of the group comparison after treatment were 12.4.Dissemination and future updates
not reported. If sufficient RCTs were available, we did a meta-
analysis. Systematic reviews and meta-analysis from others were The number of relevant papers in our field is growing
used when no new papers appeared after the meta-analysis was exponentially. This has resulted in a doubling of the number
done and the relevant questions were evaluated. of pages of EPOS2020 compared to EPOS2012. We hope that
Evidence(8)tables were assimilated. GRADE (Grading of the executive summary (chapter 1) will be used to disseminate
Recommendations Assessment, Development and Evaluation, the new knowledge. Including everything in all-compassing
http://www.gradeworkinggroup.org/) was used whenever documents like EPOS2020 becomes more and more challenging.
possible. Harm either for the patient directly or for the The EPOS group plans to come with yearly smaller updates on
population (like costs, or resistance to antibiotics) was the most relevant changes and as already mentioned, a group
consistently part of the evaluation. In surgery in general RCT’s will be formed to organize frequent Delphi rounds on relevant
were very limited and other evidence is reported. We only used clinical questions that are difficult to answer with RCTs in the

453
 EPOS 2020

near future. question.

This guideline will again be disseminated in many countries 3. If the general part is too broad for the specific topic you
over the world. The executive summary (chapter 1) has a concise may narrow the general terms down by adapting this part
format and is easy to read. A website (www.epos2020.com) conf. Lemiengre, MB et al (instead of or/1-7 given]
has been launched and pocket guides for different stakeholder 1 exp Sinusitis/
groups including patients will be prepared in the near future. On 2 sinusit*.tw.
the website, education material for different stakeholders can be 3 Rhinitis/
found. 4 rhinit*.tw.
5 rhinosinusit*.tw.
12.5. Editorial Independence 6 nasosinusit*.tw.
7 ((suppurative or purulent) adj2 (nasal discharge
This position paper has been funded by the European or rhinitis or rhinorrhoea or rhinorrhoea)).tw.8 or/1‐7
Rhinologic Society, Journal Rhinology and the Rhinology 4. italic grey terms are optional (these terms did not result
Foundation. No other funding has been used. All guideline in additional relevant hits in the search aimed to identify
development members have provided their competing interest. SRs). i.e. additional records found with rhinitis are generally
about allergic rhinitis
12.6. Details of search strategies used 5. row 16 is a search filter meant to safely exclude animal
studies. In case of many animal studies, you may want to
12.6.1. CORE search OVID MEDLINE CRS and ARS 2019-01-30 use a broader filter instead
We advised all authors to use the core searches for CRS and (exp animals/ not exp humans/) or animal.jw. or (rodent*
ARS in OVID MEDLINE. We advised them to seek assistance of or rabbit* or mice or mouse or murine or rat or rats or
your local librarian to adapt the search and add the topic(s) of chicken* or (animal* adj3 (experiment* or model*))).ti.
interest. We advised to use a similar approach as below to search [jw=journal word]
for additional concepts, thus controlled terms, including MeSH-
terms, and textwords (tw,kf ). 12.6.1.2. CORE CRS-search
Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-
12.6.1.1.CORE ARS-search Process & Other Non-Indexed Citations and Daily 1946 to
Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In- January 28, 2019 
Process and Other Non-Indexed Citations and Daily 1946 to
January 28, 2019  # Searches Results
Search Strategy: 2019-01-30 1 exp sinusitis/ 19569

# Searches Results 2 rhinitis/ or rhinitis, atrophic/ or rhinitis, vasomotor/

exp paranasal sinuses/mi or (exp paranasal sinuses/
13071
1 exp sinusitis/ 19569 3 2604
and (respiratory tract infections/ or chronic disease/))
2 rhinitis/ or rhinitis, atrophic/ or rhinitis, vasomotor/ 13071 (sinusit* or rhinit* or ozena* or rhinosinusit*
exp paranasal sinuses/mi or (exp paranasal sinuses/ 4 or nasosinusit* or pansinusit* or ethmoidit* or 46748
3 2604
and (respiratory tract infections/ or chronic disease/)) sphenoidit*).tw,kf.
(sinusit* or rhinit* or ozena* or rhinosinusit* ((inflamm* or microb*) adj5 (rhino* or sinus or sinuses
5 2191
4 or nasosinusit* or pansinusit* or ethmoidit* or 46748 or sinusal)).tw,kf.
sphenoidit*).tw,kf. 6 nasal muc?us.tw,kf. 830
((inflamm* or microb*) adj5 (rhino* or sinus or sinuses (rhinorr*.ti,ot,kf. not (ci.fs. or (CSF or ((leak* or fluid*)
5 2191
or sinusal)).tw,kf. 7 and cerebr*) or safet*).ti,ot,kf.)) or (purulent adj3 586
6 nasal muc?us.tw,kf. 830 rhinorr*).tw,kf.
(rhinorr*.ti,ot,kf. not (ci.fs. or (CSF or ((leak* or fluid*) 8 or/1-7 [ rhinosinusitus both ARS and CRS] 56505
7 and cerebr*) or safet*).ti,ot,kf.)) or (purulent adj3 586
9 nasal polyps/ 6141
rhinorr*).tw,kf. ((nose or nasal or nasi or rhino* or sinus* or
8 or/1-7 [ rhinosinusitus both ARS and CRS] 56505 10 7987
sinonasal) adj3 (papilloma* or polyp*)).tw,kf.
9 common cold/ 4131 11 (rhinopolyp* or CRSwNP*).tw,kf. 822
10 ((common or head) adj cold*).tw,kf. 3819 12 CRSSNP*.tw,kf. 373
11 coryza.tw,kf. 619 ECRS.tw,kf. or (CRS.tw,kf. and (sinonas* or nasal or
13 2846
((upper adj4 (respiratory or airway) adj2 infection*) naso* or rhin* or ENT).mp.)
12 8937 (kartagener* syndrom* or primary ciliary
or URTI).tw,kf.
ARS.tw,kf. and (sinonas* or nasal or naso* or rhin* 14 dyskinesi*).mp. not (COPD or thoracic or pulmonary 1939
13 166
or ENT).mp. disease or bronchiectas*).ti,ot.
14 or/9-13 [ ARS ] 15102 15 adenoids/ab or (adenoids/ and hypertrophy/) 963
8 or 14 [ ARS (incl. umbrella terms for ((adenoid* adj2 (hypertroph* or obstruct*)) or
15 69906 16 1056
rhinosinusitis - B) ] adenoidit*).tw,kf.
16 exp animals/ not exp humans/ 4541167 17 or/9-16 [ CRS ] 14635
17 15 not 16 [ ARS in humans ] 66289 8 or 17 [ CRS (incl. umbrella terms for
18 64185
rhinosinusitis -B) ]
19 exp animals/ not exp humans/ 4541167
Notes:
20 18 not 19 [ CRS in humans ] 60937
1. The core search for ARS consists of a broad rhinosinusitus remove duplicates from 20 [only possible if #20
search (or/1-7) and a specific search for ARS (or/9-13). 21
<6000 hits)
2. You may omit terms that are not relevant for the specific

454
 EPOS 2020

Search Strategy: 30-01-2019 ((upper near/4 (respiratory or airway) near/2

20 infection*) or URTI or (U next R next T next 3814
Notes:
I)):ti,ab,kw
21 {OR #1-#20} 15326
1. The core search for CRS consists of a broad rhinosinusitis
22 #21 in Trials 15166
search (or/1-7) and a specific search for CRS (or/9-16).
23* #22 not Clinicaltrials:so 14041
2. You may omit terms that are not relevant for the specific
question, i.e. if adenoids are not relevant you can discard 24* #22 and Clinicaltrials:so 1125
rows 15 and 16 * do not use = #23 en #24 when the trial registers are not kept separate.
3. If the general part is too broad for the specific topic you
may narrow the general terms down by combining these
terms with terms for chronic, thus combine or/1-7 with for Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-
Process & Other Non-Indexed Citations and Daily 1946 to
example (i.e. adapted from Chong et al):
February 15, 2019 
exp chronic disease/ or exp recurrence/ or (chronic* or
Search Strategy: 2019-02-18
persis* or recurr* or long-last* or longlast*).tw,kf.
4. italic grey terms are optional (these terms did not result in # Searches Results
additional relevant hits in the search aimed to identify SRs) 1 exp sinusitis/ 19603
5. row 19 is a search filter meant to safely exclude animal 2 rhinitis/ or rhinitis, atrophic/ or rhinitis, vasomotor/ 13106
studies. In case of many animal studies, you may want to exp paranasal sinuses/mi or (exp paranasal sinuses/
3 and (respiratory tract infections/ or chronic 2607
use a broader filter instead disease/))
(exp animals/ not exp humans/) or animal.jw. or (rodent* 4
(rhinosinusit* or nasosinusit* or ozena* or
9023
or rabbit* or mice or mouse or murine or rat or rats or pansinusit* or ethmoidit* or sphenoidit*).tw,kf.
5 sinusit*.tw,kf. 15829
chicken* or (animal* adj3 (experiment* or model*))).ti.
[jw=journal word] 6 rhinit*.tw,kf. 26038
((inflamm* or microb*) adj5 (rhino* or sinus or
7 2180
sinuses or sinusal)).tw,kf.
12.6.2. Searches for RCT on treatment and diagnostics (used 8 nasal muc?us.tw,kf. 828
for CH4,6 and 7) rhinorr*.ti,ot,kf. not (ci.fs. or (CSF or ((leak* or fluid*)
9 474
and cerebr*) or safet*).ti,ot,kf.)
CENTRAL Date Run: 18/02/2019 18:37:17 10 nasal polyps/ 6150
((nose or nasal or nasi or rhino* or sinus* or
11 7958
sinonasal) adj3 (papilloma* or polyp*)).tw,kf.
# Searches Results 12 (rhinopolyp* or CRSwNP* or CRSSNP*).tw,kf. 869
(kartagener* syndrom* or primary ciliary dyskinesi*).
1 [mh sinusitis] 888
13 mp. not (COPD or thoracic or pulmonary disease or 1932
[mh ^rhinitis] or [mh ^"rhinitis, atrophic"] or [mh
2 917 bronchiectas*).ti,ot.
^"rhinitis, vasomotor"]
[mh "paranasal sinuses"/mi] or ([mh "paranasal 14 adenoids/ab or (adenoids/ and hypertrophy/) 964
3 sinuses"] and ([mh ^"respiratory tract 95 ((adenoid* adj2 (hypertroph* or obstruct*)) or
15 1051
infections"] or [mh ^"chronic disease"])) adenoidit*).tw,kf.
(rhinosinusit* or nasosinusit* or 16 common cold/ 4136
4 ozena* or pansinusit* or ethmoidit* or 1008
sphenoidit*):ti,ab,kw 17 ((common or head) adj cold*).tw,kf. 3808
5 sinusit*:ti,ab,kw 2324 18 coryza.tw,kf. 617
((suppurat* or purulent) adj3 (nasal discharg* or
6 rhinit*:ti,ab,kw 8352 19 279
rhinor*)).tw,kf.
((inflamm* or microb*) near/5 (rhino* or sinus or ((upper adj4 (respiratory or airway) adj2 infection*)
7 172 20 8909
sinuses or sinusal)):ti,ab,kw or URTI or U-R-T-I).tw,kf.
8 (nasal NEXT mucus):ti,ab,kw 51 21 or/1-20 [ rhinosinusitis ] 77127
(rhinorr*:ti,kw) not ([mh /CI] or (CSF or ((leak* or (exp animals/ not exp humans/) or animal.jw. or
9 344
fluid*) and cerebr*) or safet*):ti,ab,kw) (rodent* or rabbit* or mice or mouse or murine or
10 [mh "nasal polyps"] 319 22 4819005
rat or rats or chicken* or (animal* adj3 (experiment*
((nose or nasal or nasi or rhino* or sinus* or or model*))).ti.
11 787
sinonasal) near/3 (papilloma* or polyp*)):ti,ab,kw 23 21 not 22 [ human rhinosinusitis ] 72948
12 (rhinopolyp* or CRSwNP* or CRSSNP*):ti,ab,kw 75 (controlled clinical trial/ or randomized controlled
((kartagener* NEXT syndrom*) or (primary NEXT trial/ or random allocation/ or double-blind
ciliary NEXT dyskinesi*)):ti,ab,kw not (COPD method/ or single-blind method/ or (randomi?ed or
13 43
or thoracic or (pulmonary NEXT disease) or randomi?ation or placebo* or randomly or (random
bronchiectas*):ti 24 adj3 allocat*) or ((random* or controlled) adj2 (study 1073418
[mh ^adenoids/AB] or ([mh ^adenoids] and [mh or trial)) or ((singl* or doubl* or treb* or tripl*) adj
14 57
^hypertrophy]) (blind*3 or mask*3))).tw,kf. or trial.ti.) not ((review or
((adenoid* near/2 (hypertroph* or obstruct*)) or
15 125 editorial).pt. or review.ti.) [ RCT filter - adapted from
adenoidit*):ti,ab,kw
16 [mh ^"common cold"] 497 the Cochrane]
25 23 and 24 [ RCTs on human rhinosinusitis ] 7258
17 ((common or head) NEXT cold):ti,ab,kw 1088
18 coryza:ti,ab,kw 36
((suppurat* or purulent) near/3 ((nasal NEXT
19 37
discharg*) or rhinor*)):ti,ab,kw

455
 EPOS 2020

Database(s): EmbaseClassic+Embase 1947 to 2019 February 15  analyzed. Eventually, we identified 3 studies that evaluated the
Search Strategy: 2019-02-18 burden of uncontrolled CRS using the EPOS control criteria.

# Searches Results 12.6.3.3. Burden of acute and chronic rhinosinusitis

1 exp rhinosinusitis/ 9352
2 exp sinusitis/ 43919 12.6.3.3.1. Quality of life
3 rhinitis/ or atrophic rhinitis/ or vasomotor rhinitis/ 22552 Main search strategy AND (impact or burden or severity),
(rhinosinusit* or nasosinusit* or ozena* or
4 11984
pansinusit* or ethmoidit* or sphenoidit*).tw,kw.
5 sinusit*.tw,kw. 23044 12.6.3.3.2.Costs of rhinosinusitis
6 rhinit*.tw,kw. 40889 The search utilized for these references was performed in
((inflamm* or microb*) adj5 (rhino* or sinus or Pubmed with search terms: “sinusitis” “costs” “total” “direct”
7 3184
sinuses or sinusal)).tw,kw. “indirect” “economic.”
8 nasal muc?us.tw,kw. 1394
(*rhinorrhea/ or rhinorr*.ti,ot,kw.) not (si.fs. or (CSF
9 893 12.6.3.4. Acute rhinosinusitis including common cold - and
or ((leak* or fluid*) and cerebr*) or safet*).ti,ot,kw.)
10 chronic rhinitis/ 1209 recurrent ARS in adults and children
11 nose polyp/ 10758
((nose or nasal or nasi or rhino* or sinus* or 12.6.3.4.1. Epidemiology of acute rhinosinusitis (ARS)
12 10773
sinonasal) adj3 (papilloma* or polyp*)).tw,kw.
13 (rhinopolyp* or CRSwNP* or CRSSNP*).tw,kw. 1222 Database(s): Ovid MEDLINE(R) and Epub Ahead of Print,
(kartagener* syndrom* or primary ciliary In-Process & Other Non-Indexed Citations, Daily and
14 dyskinesi*).mp. not (COPD or thoracic or 2896 Versions(R) 1946 to February 15, 2019
pulmonary disease or bronchiectas*).ti,ot. Search Strategy: February 15, 2019
15 adenoid hypertrophy/ 609
((adenoid* adj2 (hypertroph* or obstruct*)) or # Searches Results
16 1440
adenoidit*).tw,kw.
17 common cold/ 9118 ((Acute rhinosinusitis or Acute sinusitis) and
18 ((common or head) adj cold*).tw,kw. 5178 prevalence).mp. [mp=title, abstract, original title, name
19 coryza.tw,kw. 842 of substance word, subject heading word, floating
((suppurat* or purulent) adj3 (nasal discharg* or sub-heading word, keyword heading word,
20 421 1 organism supplementary concept word, protocol 84
rhinor*)).tw,kw.
((upper adj4 (respiratory or airway) adj2 supplementary concept word, rare disease
21 14860
infection*) or URTI or U-R-T-I).tw,kw. supplementary concept word, unique identifier,
22 or/1-21 [ rhinosinusitis ] 128236 synonyms]
((animal/ or animal experiment/ or exp animal
model/ or nonhuman/ or exp female animal/) not limit 1 to (abstracts and english language and humans
2 34
human/) or exp veterinary medicine/ or animal*. and yr="2011 -Current")
23 6618264
jw. or (rodent* or rabbit* or mice or mouse or
murine or rat or rats or chicken* or (animal* adj3 12.6.3.4.2 Pathophysiology of ARS
(experiment* or model*))).ti.
24 22 not 23 [ rhinosinusitis in humans ] 122363 ((((((((“Common Cold”[Mesh]) OR “Sinusitis”[Mesh] OR
(exp controlled clinical trial/ or randomization/ “Respiratory Tract Infections”[Mesh:NoExp])) OR ((((acute[Title/
or double blind procedure/ or single blind Abstract] OR viral[Title/Abstract] OR virus[Title/Abstract])))
procedure/ or (randomi?ed or randomi?ation or AND ((rhinit*[Title/Abstract] OR rhinosinusit*[Title/Abstract]
placebo* or randomly or (random adj5 (allocat* or
25 1503658 OR sinusit*[Title/Abstract] OR paranasal sinusit*[Title/Abstract]
control*)) or ((random* or controlled) adj2 (study
or trial)) or ((singl* or doubl* or treb* or tripl*) adj OR nasosinusit*[Title/Abstract])))) OR ((Acute upper respiratory
(blind*3 or mask*3))).tw,kw. or trial.ti.) not (review/ tract infection*[Title/Abstract]) OR viral upper respiratory tract
or editorial/ or (review or editorial).pt. or review.ti.) infection*[Title/Abstract] OR respiratory viral infection*[Title/
26 24 and 25 [ RCTs on rhinosinusitis ] 14635
Abstract] OR respiratory virus infection*[Title/Abstract])) OR
((((rhinit*[Title/Abstract] OR rhinosinusit*[Title/Abstract] OR
sinusit*[Title/Abstract] OR paranasal sinusit*[Title/Abstract] OR
12.6.3. Searches per chapter
nasosinusit*[Title/Abstract]))) AND ((pathophysiology[Title/
Abstract] OR pathogenic[Title/Abstract]))))))=> 64,939 results.
12.6.3.1. Introduction
Many studies on the pathophysiology of acute rhinosinusitis
Here per chapter the searches are given. Often searches were
were published with key words including common cold,
done per subchapter
viral infection and respiratory tract infection. Therefore, our
search strategy had to include these key words in different
12.6.3.2. Classification, definitions and terminology
combinations. The relevant articles were then selected after
Control
screening the abstracts.
A literature search was performed in Pubmed using the terms:
“chronic rhinosinusitis”, “EPOS” and “control”. Publication date
12.6.3.4.3.Diagnosis and differential diagnosis of ARS in
was set between the third EPOS update in March 2012 and
adults and children
June 2019. This search resulted in 13 articles which were further
Central search, see above.

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 EPOS 2020

12.6.3.4.4.Medical management of ARS This OVID search produced a total of 9491 publications. Manual
Central search, see above. curation was performed by reading (STS and HW) all abstracts/
titles and by excluding the publications not meeting with
12.6.3.4.5 Complications of ARS inclusion criteria such as case reports, animal experiments,
No search provided. allergic rhinitis, no English language, no inflammatory
mechanisms presented, GWAS, etc. After the manual curation of
12.6.3.5. Epidemiology and predisposing factors of CRS the search data, the final number of publications was 1202. Of
these about 300 have been referred in this EPOS chapter 5.2.2.
12.6.3.5.1. AECRS:  
12.6.3.5.3.Diagnosis and differential diagnosis
((((((((((chronic[ti] OR persis*[ti]))) AND ((Acute[tiab] Search strategy
OR exacerbation*[tiab]))) AND (((“Sinusitis”[Mesh] OR The search for CRS and olfaction was performed on November
“Rhinitis”[Mesh] AND “Chronic Disease”[Mesh]) OR 17th 2019 in OVID Medline. It was combined with “olfactory
rhinosinusitis[tiab] OR nasosinusitis[tiab] OR sinusitis[tiab] OR function or smell” giving 406 hits. These were screened.
pansinusitis[tiab] OR ethmoiditis[tiab] OR ethmoiditis[tiab] Exclusion criteria were: keyword coincidences without any
OR sphenoiditis[tiab] OR (kartagener* [ti] AND syndrome* information given regarding olfactory measures, children only
[ti])))) AND “last 10 years”[PDat] AND English[lang])) NOT (“case and wrong subject.
The EPOS 2020 core search for CRS was performed on June 17th
reports”[Publication Type] AND “last 10 years”[PDat] AND
2019 in OVID Medline. It was combined with “(facial pain or
English[lang])) AND “last 10 years”[PDat] AND English[lang])) headache).ti” giving 330 hits. To exclude case reports all “(case).
NOT ((animals[mh] NOT humans[mh])) ti” were removed resulting in a total of 304 records, containing
  1 duplicate. These were screened. Exclusion criteria were:.
12.6.3.5.2.Genetics and epigenetics of CRSsNP and CRSwNP publication before 1996 (101 records), case reports (57 records),
OVID search history children only (12 records) and wrong subject, wrong population
or methodological shortcomings (73 records). Thus, 60 records
1. exp sinusitis/
were included. Of these, only 25 (42%) contained original data.
2. exp paranasal sinuses/mi or (exp paranasal sinuses/ and (respiratory
The others were reviews, editorials, letters, comments etc.
tract infections/ or chronic disease/))
After a first review by the EPOS steering group, members were
3. (sinusit* or rhinit* or ozena* or rhinosinusit* or nasosinusit* or asked to supply any missing yet relevant references. This way,
pansinusit* or ethmoidit* or sphenoidit*).tw,kf.
another seven papers were included, most of which were not
4. (sinusit* or rhinosinusit* or nasosinusit* or pansinusit* or ethmoidit* written primarily for facial pain but contained data relevant to
or sphenoidit*).tw,kf.
5. ((inflamm* or microb*) adj5 (rhino* or sinus or sinuses or sinusal)).
this chapter.
tw,kf.
6. nasal muc?us.tw,kf. 12.6.3.6. Management of chronic rhinosinusitis in adults
7. or/1-6 Central search, see above.

8. nasal polyps/
12.6.3.7. Paediatric CRS
9. ((nose or nasal or nasi or rhino* or sinus* or sinonasal) adj3
(papilloma* or polyp*)).tw,kf.
10. (rhinopolyp* or CRSwNP*).tw,kf. 12.6.3.7.1. Epidemiology, predisposing factors, and
comorbidities
11. CRSSNP*.tw,kf.
A PubMed and Scopus (EMBASE) search was performed and
12. ECRS.tw,kf. or (CRS.tw,kf. and (sinonas* or nasal or naso* or rhin* or
ENT).mp.) relevant data were extracted accordingly. The first search
13. or/8-12 was for the following terms: chronic sinusitis in children or
chronic rhinosinusitis in children; paediatric chronic sinusitis or
14. 7 or 13
15. (pathophysiol* or mechanism* or biology* or molecul* or cell* or paediatric chronic rhinosinusitis. All of them followed by and:
inflammat* or eosinophil* or cytokine* or epitheli* or pathology* or • Epidemiology or prevalence
leukocyt* or prostaglandin* or morphology* or anatom* or physiology* • Anatomic variations of the paranasal sinuses
or biomedic* or genom* or gene* or mRNA or RNA or transcript* • The effect of environmental exposures
or microarray* or sequenc* or protein* or biomark*).mp. [mp=title,
abstract, original title, name of substance word, subject heading • Occupational and environmental risk factors for
word, floating sub-heading word, keyword heading word, organism • Risk factors
supplementary concept word, protocol supplementary concept word, • The role of pollution, toxins and dust at home
rare disease supplementary concept word, unique identifier, synonyms] • The role of viral infections in inducing or exacerbating CRS
16. 14 and 15
• The role of viral infections in the onset of CRS in children
17. exp animals/ not exp humans/ • Smoking
18. 16 not 17 • Active and passive tobacco smoke exposure with the
19. 16 not 17 prevalence of chronic sinusitis in children
• Allergic rhinitis or allergy
20. limit 19 to (english language and yr="2012 -Current")
• Asthma

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 EPOS 2020

• Role of the Adenoid Pubmed

• Relationship between sinusitis and adenoid size in paediatric Search words: Chronic Rhinosinusitis and Corticosteroids
age group Limits: 10-year, Humans, English, Child: birth-18y
• Adenoid bacteriology and sinonasal symptoms 31 hits reviewed and 3 selected for review.
• Identification of adenoid biofilms Eliminated irrelevant abstracts, reviews, studies dealing with CF,
• Immunological investigation in the adenoid tissues and studies that involved adults only.
• Adenoidectomy outcomes
• Gastroesophageal reflux disease Pubmed
• Humoral immunodeficiency Search words: Chronic Rhinosinusitis and Balloon
• Immunologic defects in Limits: 10-year, Humans, English, Child: birth-18y
• Deficiency of the paediatric immune system 28 hits reviewed and 12 selected for review.
• Immaturity immune system Eliminated irrelevant abstracts, reviews, studies dealing with CF,
• Cystic fibrosis and studies that involved adults only.
• Diagnosis of cystic fibrosis in newborns
• Primary ciliary dyskinesia Pubmed
Search words: Chronic Rhinosinusitis and Adenoidectomy
12.6.3.7.2. Pathophysiology of chronic rhinosinusitis with or Limits: 10-year, Humans, English, Child: birth-18y
without nasal polyposis 38 hits reviewed and 15 selected for review.
Eliminated irrelevant abstracts, reviews, studies dealing with CF,
12.6.3.7.2.1. Genetics and studies that involved adults only.
Pubmed
Search words: Sinusitis/Children/genetics Pubmed
10-year limit Search words: Chronic Rhinosinusitis and Endoscopic Sinus
82 hits reviewed and 14 selected for review. Surgery
Eliminated irrelevant abstracts and studies that involved adults Limits: 10-year, Humans, English, Child: birth-18y
only. 248 hits reviewed and 26 selected for review.
Eliminated irrelevant abstracts, reviews, studies dealing with CF,
12.6.3.7.2.2. Inflammatory mechanisms and studies that involved adults only.
Pubmed
Search words: Inflammation, Rhinosinusitis Many of the selected articles overlapped.
Limits: previous 10 years/Age <18y/Humans
178 hits reviewed and 56 selected for review. 12.6.3.8. Concomitant diseases in patients with chronic
Eliminated adult studies, reviews, and non-English language rhinosinusitis
abstracts.
12.6.3.8.1.Role of allergy and chronic rhinosinusitis
12.6.3.7.3. Diagnosis and differential diagnosis No search provided.
Given the nature of this chapter (differential diagnosis and use
of diagnostic tools, with emphasis on issues specific for the 12.6.3.8.2.Immunodeficiencies and their role in CRS
paediatric population) a systematic search on the CRS core set Search strategy
was deemed unfruitful. References were hand-searched. After
the first version, the EPOS steering group was asked for input on 1. Medline (Ovid)
any missing relevant papers. - terms: chronic rhinosinusitis immunodeficiency
- limits: 2012-current
- results: 4671
12.6.3.7.4. Management of CRS and co-morbidities
Pubmed 2. Medline (Ovid)
- terms: primary immunodeficiency
Search words: Chronic Rhinosinusitis and Antibiotics - limits: 2012-current
Limits: 10-year, Humans, English, Child: birth-18y - results: 1713
70 hits reviewed and 12 selected for review. 3. Medline (Ovid)
Eliminated irrelevant abstracts, reviews, studies dealing with CF, - terms:  secondary immunodeficiency chronic rhinosinusitis
and studies that involved adults only. - limits: 2012-current
- results: 2811

Pubmed 4. Medline (Ovid)

- terms:  secondary immunodeficiency
Search words: Chronic Rhinosinusitis and Saline
- limits: 2012-current
Limits: 10-year, Humans, English, Child: birth-18y - results: 120
26 hits reviewed and 7 selected for review.
Eliminated irrelevant abstracts, reviews, studies dealing with CF,
and studies that involved adults only.

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5. Google scholar 6. (fungus or fungal or fungi).mp. 216128

- terms:  chronic rhinosinusitis immunodeficiency
7. invasive.mp. 268714
- limits: 2012-current
- results: 4530 8. (invasive adj3 (fungus or fungal or fungi)).mp. 4866
6. Google scholar 9. 8 and 4 474
- terms:  chronic rhinosinusitis secondary immunodeficiency
10. limit 9 to (english language and humans) 393
- limits: 2012-current
- results: 2740
12.6.3.8.7. Vasculitis, granulomatous diseases and their role
in CRS
12.6.3.8.3. Lower airway disease including asthma in relation
to CRS 12.6.3.8.7.2.Granulomatosis with polyangitis (GPA)
Pubmed Search: Search strategy
Chronic Rhinosinutis and asthma: 1489 The EPOS 2020 core search for CRS was performed in June
Chronic Rhinosinusitis and COPD: 159 articles 2019 in OVID Medline. It was combined with “(Wegener).ti” and
Chronic Rhinosinusitis and lower airway disease: 199 “(granulomatosis with polyangiitis), giving 421 hits. These were
screened. Exclusion criteria were: case reports (125 records),
Selection criteria for inclusion: English language, articles with language other than English (30 records), children only (three
novel insights and properly conducted trials and/or reviews, records) and wrong subject (57 records). A further 102 non-
preference of recent (last 10 years) over historic reports landmark publications <1996 were removed. Thus, 104 records
were included. Of these, only 41 (39%) contained original data.
12.6.3.8.4.Cystic fibrosis The others were reviews, editorials, letters etc.
Search strategy
PubMed and Embase were systemically searched for articles 12.6.3.8.7.3.Eosinophilic granulomatosis with polyangiitis
addressing chronic rhinosinusitis in patients with cystic Search strategy
fibrosis (CF). The search was last updated on April 21, 2019. The EPOS 2020 core search for CRS was performed in June
The literature search generated 1762 articles of which 40 were 2019 in OVID Medline. It was combined with “(Churg-Strauss).
included. Nine additional studies were identified through ti” and “(polyangiitis), giving 195 hits. These were screened.
reference lists. Further 17 studies elaborating on the included Exclusion criteria were: case reports (61 records), language
findings and concerning the CF diagnosis in general were other than English (21 records), children only (four records) and
included. The included studies were published between 1991 wrong subject (five records). Thus, 104 records were included
and 2019. for review. Of these, only 31 (29%) contained original data. The
others were reviews and editorials.
12.6.3.8.5.Primary ciliary dyskinesia and its role in CRS
Search strategy 12.6.3.8.7.4.Sarcoidosis
PubMed and Embase were systemically searched for articles Search strategy
addressing chronic rhinosinusitis in patients with primary ciliary The EPOS 2020 core search for CRS was performed in June
dyskinesia. The search was last updated on August 19, 2019. 2019 in OVID Medline. It was combined with “(sarcoidosis).ti”
After exclusion of duplicates the literature search generated 609 giving 110 hits. These were screened. Exclusion criteria were:
articles of which 37 were included. The included studies were publication before 1996 (with two exceptions) (12 records), case
published between 1981 and 2019.  reports (23 records), language other than English (16 records),
children only (one record) and wrong subject (six records). Thus,
12.6.3.8.6.Fungal rhinosinusitis 52 records were included of which 44 were used. Of these, 22
Search strategy (see pag 460) (50%) contained original data, the others were reviews.
(Search for the keywords fungal.mp OR fungi.mp or fungus.mp
with the prior search produced n=372 articles. Fungal ball was 12.6.3.9. Integrated care pathways in CRS and precision
supplemented by the search below and PRISMA, invasive fungal medicine
disease includes).
12.6.3.9.1. Patient participation in CRS
Separate prisma and search was done for fungal ball. Pubmed Search:
Participation, (rhino)sinusitis: 51 results
# Searches Results
Mobile health, (rhino)sinusitis: 20 results
1. fungal ball.mp. 128
Empowerment patients, (rhino)sinusitis: 11 results
2. Mycetoma/ 1153
3. 1 or 2 1274 12.6.3.9.3. and 9.4.Prevention and prediction
(rhinosinusitis or $rhinosinusitis or crs or sinus$ Search terms; (prevent* OR predict* OR risk OR success OR
4. 219127
or nose or nasal).mp.
failure OR recurrence OR revision) AND full search dataset -
5. 3 and 4 228
Search Identified 7599 papers, 269 full papers reviewed

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 EPOS 2020

12.6.3.8.6.Fungal rhinosinusitis Search strategy

PRISMA 2009 Flow Diagram

12.6.3.8.6. Fungal rhinosinusitis Prisma 2009 flow diagram.

Records identified through database

Identification

searching MEDLINE 1946 - 20th May 2019 Additional records identified

(490) + Embase 1974 - 20th May 2019 (795) through other sources
(n =1285) (n = 3)

Excluded on titles +
Total records from search
duplicates
(n = 1288)
(n = 1259)
Screening

Records screened Excluded on abstract

(n = 29) (n = 14)
Eligibility

Full-text articles assessed Full-text articles excluded,

for eligibility (n = 9)
(n = 15) No proportions data (n = 2)
Non-relevant analyses (n = 6)
Review article (n = 1)

Studies included
Included

(n = 6)

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7. “health personnel attitude“

12.6.3.10. Pharmacist perspective on rhinosinusitis 8. “interpersonal communication“ OR “public relations
9. “patient compliance“ OR “patient counseling
MEDLINE /Ovid, search date: 10-07-2019 10. “medical education“ OR “patient education“
11. “medical information“ OR “consumer health information“

# Searches Field: abstract

1. exp Pharmacy/ 12. pharmacy OR “pharmacy practice pattern*
2. (pharmacy OR pharmacy practice pattern*.tw
13. “pharmac* service* community“ OR pharmacist* OR “clinical
pharmacist*“ OR “community pharmacist*
3. Community Pharmacy Services/ 14. “pharmacy technician*“ OR “pharmacist* aide*“ OR
4. pharmac* service* community.tw pharmacies OR “pharmac* distribution*“ OR “pharmac*
5. Pharmacists/ community
(pharmacist* OR clinical pharmacist* OR community 15. “packaging drug*“ OR “drug* container*
6. 16. “drug dispensing“ OR “drug utilization*“ OR “drug* non
pharmacist*).tw
7. Pharmacy Technicians/ prescription“ OR “OTC drug*
8. (pharmacy technician* OR pharmacist*' aide*).tw
17. “antibiotic drug resistance*“ OR “antibiotic resistance*“ OR
“antimicrobial drug resistance*“ OR “antimicrobial resistance*“
9. Pharmacies/ 18. “patient compliance*“ OR “patient adherence“ OR “patient
(pharmacies OR pharmac* distribution* OR pharmac* cooperation“ OR “treatment compliance*“ OR “therapeutic
10.
community).tw
11. exp Prescriptions
compliance*“ OR “patient non compliance*“ OR “patient
nonadherence“
12. exp Drug Packaging/ 19. “medication adherence“ OR “medication compliance*“ OR
13. (packaging drug* OR drug* container*).tw “medication nonadherence“ OR
14. drug dispensing.tw 20.“medication non compliance*
21. counseling OR advice
15. exp Drug Utilization/ 22. OR/1-21
16. drug utilization*.tw 23. animal AND NOT human (keywords)
17. exp Nonprecsription Drugs/ 24. 22 AND NOT 23
18. (drug* non prescription OR OTC drug*).tw
SET 2
19. exp Drug Resistance Microbial/ Field: keywords
(antibiotic drug resistance* OR antibiotic resistance* 1.sinusitis OR “paranasal sinus“
20. OR antimicrobial drug resistance* OR antimicrobial 2. “paranasal sinuse“ and (“respiratory tract infection“ or “chronic
resistance*).tw
disease“)
21. exp Drug Information Services
3. “common cold“ OR “nasal polyps“ OR “nose polyp“ OR
22. Attitude of Health Personnel/ “adenoid hypertrophy“ OR adenoid
23. exp Interprofessional Relations
24. exp Patient Compliance/
Field: abstract
(patient compliance* OR patient adherence OR patient 4. rhinitis or “rhinitis atrophic“ or “rhinitis vasomotor“
cooperation OR treatment compliance* OR therapeutic 5. sinusit* or rhinit* or ozena* or rhinosinusit* or nasosinusit* or
25.
compliance* OR patient non compliance* OR patient pansinusit* or ethmoidit* or sphenoidit
nonadherence OR medication adherence OR medication 6. “inflamm* rhino*“ or “inflamm* sinus“ or “inflamm* sinuses“ or
compliance* OR medication nonadherence OR
“inflamm* sinusal
medication non compliance*).tw
26. exp Counseling/
7. “microb* rhino*“ or “microb* sinus“ or “microb* sinuses“ or
“microb* sinusal“ or rhinorr* or “purulent rhinor“ OR “ nasal
27. (counseling OR advice).tw muc?us
28. exp Health Education/ 8. “common cold“ or “head cold“ or coryza or “upper respiratory
29. Health Communication/ infection*“ or “upper airway infection*“ or URTI or “upper
respiratory tract infection
9. ARS and (sinonas* or nasal or naso* or rhin* or ENT)
10. “nose papilloma*“ or “nasal papilloma*“ or “nasi papilloma*“
Scopus search date: 22-10-2019
or “rhino papilloma*“ or “sinus papilloma*“ or “sinonasal
SET 1
papilloma*“
11. rhinopolyp* or CRSwNP* or CRSSNP* or ECRS
Field: keywords
12. “nose polyp*“or “nasal polyp*“or “nasi polyp*“or “rhino
1. pharmacy OR “community pharmacy“
polyp*“ or “sinus polyp*“or “sinonasal polyp*“
2. pharmacist OR “pharmacy technician
13. CRS and (sinonas* or nasal or naso* or rhin* or ENT)
3. prescription
14. (“kartagener* syndrom*“ or “primary ciliary dyskinesi*“) and
4. “drug packaging” OR “drug utilization” OR “non prescription
not (COPD or thoracic or “pulmonary disease“ or bronchiectas*)
drug”
15. adenoid* hypertroph* or adenoid* obstruct* or adenoidit*
5. “antibiotic resistance”
16. OR/1-15
6. “drug information“
17. animal AND NOT human (keywords)

461
 EPOS 2020

18. 16 AND NOT 17

SET1 AND SET2

References

1. Fokkens W, Lund V, Bachert C, et 4. Fokkens W, Desrosiers M, Harvey R, et al. Version 510. Oxford, UK: The Cochrane
al. European Position Paper on EPOS2020: development strategy and Collaboration, 2011.
Rhinosinusitis and nasal Polyps. goals for the latest European Position 7. Reeves BC, Deeks JJ, Higgins JPT,
Rhinology 2005;18. Paper on Rhinosinusitis. Rhinology Wells GA. Chapter 13: Including non-
2. Fokkens W, Lund V, Mullol J. European 2019;57:162-8. randomized studies. In: Higgins JPT, and
position paper on rhinosinusitis 5. The AGREE II Instrument [Electronic Green S (eds). Cochrane Handbook for
and nasal polyps 2007. Rhinol Suppl version]. 2017. http://www.agreetrust. Systematic Reviews of Interventions
2007;20:1-136. org. Version 510. Oxford, UK: The Cochrane
3. Fokkens W, Lund V, Mullol J. EP3OS 6. Higgins JPT, Altman DG, Sterne JAC. Collaboration, 2011.
2007: European position paper on Chapter 8: Assessing risk of bias in 8. Shekelle PG, Woolf SH, Eccles M,
rhinosinusitis and nasal polyps 2007. A included studies. In: Higgins JPT, and Grimshaw J. Developing clinical
summary for otorhinolaryngologists. Green S (eds). Cochrane Handbook for guidelines. West J Med 1999;170:348-51.
Rhinology 2007;45:97-101. Systematic Reviews of Interventions

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13. Authors declarations

Dr. Wytske Fokkens reports that the department of otorhinolaryngology of the Amsterdam University Medical Centres, location AMC
received grants from GSK, Sanofi, Novartis Chordate, Mylan, ALK, Allergy diagnostics and ZonMW and that she is a consultant for
Sanofi and Lyra Therapeutics.

Dr. Valerie Lund reports that she has received personal fees from Abbott Criteria Fieldwork, Elsevier, Hartington, Medscape, Sprime
Health, Kyorin, Quintiles, GSK and Sanofi.

Dr. Claire Hopkins has reported personal fees from Sanofi, Chordate, Olympus, Smith and Nephew and Medtronic.

Dr. Robert Kern has reported grants from NHI and personal fees from Sanofi, Genentech, Lyra and NeurEnt.

Dr. Sietze Reitsma has reported grants from Sanofi, Novartis, Chordate Medical and personal fees from Sanofi.

Dr. Manuel Bernal-Sprekelsen has reported personal fees from Olympus, Hamburg as well as counselling fee from Salvat
Pharmaceutical Company, Barcelona, Spain and free provision of dissection sets for coursesnon-financial support from Karl Storz,
Germany.

Dr. Joaquim Mullol has reported grants from URIACH Group, MYLAN-MEDA Pharma and personal fees from URIACH Group, MYLAN-
MEDA Pharma, Genetech- Novartis, Regeneron & Sanofi-Genzyme, Astra Zeneca.

Dr. Isam Alobid has reported grants from MSD and that he received personal fees from Roche, MSD, Mylan, Menarini.

Dr. Claus Bachert has reported that he received personal fees from Sanofi, Novartis, Astra-Zeneca, GSK and ALK.

Dr. Noam Cohen has reported personal fees from Sanofi/Regeneron and Licensing of Patent rights namely GeneOne Life Sciences.

Dr. Ludovic De Gabory has reported personal fees from Zambon, ALK-Abello, Medtronic, Laboratoire de la Mer, Integra Life Sciences,
consulting from Zambon, ALK-Abello, Medtronic, Laboratoire de la Mer, Integra Life Sciences, Chiesi, Sanofi-Aventis, funded research
from Laboratoire de la Mer and Patent from Integra Life Sciences.

Dr. Martin Desrosiers is on advisory boards and clinical trials of Glaxo Smith Kline, Astra Zeneca, Sanofi/Regeneron. Speaker bureau in
Milan. Founder of Probionase Therapies Inc.

Dr. Zuzana Diamant has an academic affiliation with Lund University, Groningen University, Charles University Prague. She works at
QPS-NL a phase I unit, which performs phase I/II studies for biotech and pharmaceutical companies. Dr. Diamant has also reported
personal fees from ALK, CSL, HAL Allergy, Sanofi Genzyme Regeneron and is doing Medical writing at Acucort, Boehringer Ingelhein
and webinars at MSD.

Dr. Philippe Gevaert has reported personal fees from Novartis, Roche, Genentec, Sanofi, Regeneron, Astra Zeneca, 3NT, Stallergens
and has been on Advisory board, the speaker and conducted research with financial support of Novartis, Roche, Genentec, Sanofi,
Regeneron, Astra Zeneca, 3NT and Stallergens.

Dr. Richard Harvey is a consultant with Medtronic, Stryker, Novartis, Meda, and NeilMed pharmaceuticals. Research grant funding
received from Glaxo-Smith-Kline and Stallergenes. He has been on the speakers’ bureau for Glaxo-Smith-Kline, Meda Pharmaceuticals
and Seqiris.

Dr. Guy Joos has reported grants from GSK,Chiesi, Asta Zeneca and personal fees from Bayer, Eureka VZW, GSK and Teva.

Dr. Janwillem Kocks has reported grants from Astra Zeneca, Boehringer, Ingelheim, Chiesi, Mundi Pharma, TEVA and personal fees
from Astra Zeneca, Boehringer, Ingelheim and Chiesi.

Dr. Carl Philpott has reported grants from NIHR, personal fees from Sanofi Genzyme, Olympus, Entellus, Aerin Medical, Acclarent,
Navigant and Trustee from Fifth Sense.

Dr. Dermot Ryan has reported grants from Chiessi, personal fees from Mylan, GSK, Novartis, Chiesi, AZ and non-financial support

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 EPOS 2020

from Regeneron Educational activities.

Dr. Rodney Schlosser has reported grants from Sanofi, GSK, Roche, Astra Zeneca, Optinose, Healthy Humming and personal fees from
Sanofi, GSK, Optinose and medical director of Healthy Humming.

Dr. Achim Beule has reported in performing studies as part Principal Investigator at Glaxo Smith Kline, Astra Zeneca and Allakos.

Dr. Juan David Bedoya has reported grants from American Academy of OHNS foundation.

Dr. Eliza Brozek-Madry has reported grants from Probios.

Dr. Sean Carrie has reported grans from National Institute Health Research (UK), personal fees from Medtronic and Olympus and
travel and accommodation sponsorship from Medtronic.

Dr. Jessica W. Grayson has reported financial support for attendance of the conference in Ghent from Medtronic.

Dr. Kornkiat Snidvongs has reported personal fees from Menarini and MSD.

Dr. Harsha Karyawasam has reported personal fees from Sanofi, Novartis, AZ, MEDA.

Dr. Ana Kjeldsen has reported participation in OSTRO project, randomized controlled study of benralizumab.

Dr. Ludger Klimek has reported grants from Allegopharma, MEDA/Mylan, ALK Abello, LETI Pharma, Stallergenes,Quintiles, Sanofi,
Astra Zeneca, GSK, ASIT biotech, Lofarma and personal fees from from Allegopharma, MEDA/Mylan, HAL Allergie, LETI Pharma,
Allergy Terapeut., Sanofi.

Dr. Mitsuhiro Okano has reported grants from Tanabe Mitsubishi Pharma Corporation and Taiho Pharmaceutical Co. and personal
fees from Sanofi, Tanabe Mitsubishi Pharma Corporation and Taiho Pharmaceutical Co.

Dr. Metin Onerci has reported travel expenses and cadaver courses support from STORZ.

Dr. Mahdi Shkoukani has reported being a member of advisory board of MEDA Pharmaceuticals MEA FZ-LLC, UAE.

Dr. Ian Witterick has reported ownership of shares in Proteocyte Diagnostcis Inc. and being on Advisory board at Sanofi Genzyme.

Dr. Retno Wardani reported grants from Abbott Indonesia, speaker fee, accommodation and travel expenses from P&G, Menarini,
Zuellig Pharm and sponsorship from Advance Medica Corpora.

The following authors have not reported any relevant financial relationships:
Dr. Peter Hellings, Dr. Sanna Toppila-Salmi, Dr. Wilma Terezinha Anselmo Lima, Dr. Fuad Baroody, Dr. Christian von Buchwald, Dr.
Anders Cervin, Dr. Jannis Constantinidis, Dr. Richard Douglas, Dr. Anita Hafner, Dr. Livije Kalogjera, Dr. Andrew Knill, Dr.Basile Nicolas
Landis, Dr. Jacqueline Limpens, Dr. Sarah Lebeer, Dr. Olga Lourenco, Dr. Paolo Maria Matricardi, Dr. Cem Meco, Dr. Liam O’Mahony, Dr.
Brent Senior, Dr. Timothy Smith, Dr. Thijs Teeling, Dr. Peter Valentin Tomazic, Dr. De Yun Wang, Dr. Luo Zhang, Dr. Paolo Battaglia, Dr.
Cecilia Ahlström-Emanuelsson, Dr. Mohammad Aloulah, Dr. Mohannad Al-Qudah, Dr. Saad Alsaleh, Rashid Alabri, Dr. Saied Alhabash,
Dr. Aleksandra Aleksic, Dr. Adrian Agius, Dr.Silvio Albu, Dr. Muad Aziz Baban, Dr.Tomislav Baudoin, Dr. Achim Beule, Dr. Khaled Bofares,
Dr. Itzhak Braverman, Dr. Richard Byaruhanga, Dr. Claudio Callejas, Dr. Lisa Caulley, Dr. Caius-Codrut Sarafoleanu, Dr. Desderius Chussi,
Dr. Eugenio de Corso, Dr. Lal Devyani, Dr. Usama El Hadi, Dr. Ahmed Elfarouk, Dr. Philippe Eloy, Dr. Shokrollah Farrokhi, Dr. Ferrari
Michel, Dr. Giovanni Felisati, Dr.Roman Fishchuk, Dr. Boris Grdinic, Dr. Paulo Goncalves, Prof. Usamah Hadi, Dr. Julio Heinichen, Dr.
Salina Husain, Dr. Aneeza Hamizan, Dr. Justinas Ivaska, Dr. Frodita Jakimovska, Dr. Ljiljana Jovancevic, Dr. Reda Kamel, Dr. Hideyuki
Kawauchi, Dr. Sergei Karpischenko, Dr. Emily Kakande, Dr. Antoni Krzeski, Dr. Gabriela Kopacheva Barsova, Dr. Yew Kwang Ong, Dr.
Devyani Lal, Dr. José Letort, Dr. Andrey Lopatin, Dr. Zhang Luo, Dr. Abdelhak Mahdjoubi, Dr. Alireza Mesbahi, Dr. Jane Netkovski,
Dr. Dieudonné Nyenbue Tshipukane, Dr. Andrés Obando, Dr. Muge Ozkan , Dr. Richard Orlandi, Dr. Nobuyoshi Otori, Dr. Kheir
Ouennoughy , Dr. Aleksandar Peric , Dr. Jan Plzak, Dr. Emmanuel Prokopakis , Dr. Alkis Psaltis, Dr. Benoit Pugin, Dr. Marco Raftopulos,
Dr. Herbert Riechelmann, Dr. Philippe Rombaux , Chae-Seo Rhee, Dr. Kafui Searyoh, Prof. Arthur K. Shukuryan, Dr. Sverre Steinsvag, Dr.
David Smyth, Dr. Marian Sicak, Dr.Tanja Soklic Kosak, Dr. Par Stjarne, Dr. Semia Sahtout, Dr. Budi Sutikno, Dr. Kim Sung Wam , Prof Shi
Jianbo, Prof. Tang Ing Ping, Dr. Thuy Tran, Prof. Pongsakorn Tantilipikorn, Prof. Sanguansak Thanaviratananich, Dr. Jure Urbancic , Dr.
Arunas Valiulis, Dr. Carolina Vasquez de Aparicio, Dr. Dilyana Vicheva, Prof. Richard Voegels, Dr. Martin Wagenmann, Dr. Paula Virkula,
Dr. Gil Vicente, Dr. Martin Wagenmann, Dr. Dehui Wang, Dr. Antje Welge-Lussen, Dr. Erin Wright, Dr Dmytro Zabolotniy, Dr. Bella Zsolt.

464