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

I
 EPOS 2020

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

II
 EPOS 2020

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,

III
 EPOS 2020

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

IV
 EPOS 2020

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

V
 EPOS 2020

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.

VI
 EPOS 2020

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

VII
 EPOS 2020

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

VIII
 EPOS 2020

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

IX
 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

X
 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

XI
 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

XII
 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

XIII
 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.

2
 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.

3
 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

4
 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.

5
 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

6
 EPOS 2020

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.

7
 EPOS 2020

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.

8
 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

9
 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

10
 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.

11
 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).

12
 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.

13
 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.

14
 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

17
 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.

18
 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.

19
 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.).

20
 EPOS 2020

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.

21
 EPOS 2020

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

22
 EPOS 2020

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

23
 EPOS 2020

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

24
 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

25
 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

References sinusitis among children: an epidemiological and et al. Real-life study showing uncontrolled
1. Fokkens W, Lund V, Mullol J. European position clinical study. J Neurosurg Pediatr 2011;7:567-74. rhinosinusitis after sinus surgery in a tertiary
paper on rhinosinusitis and nasal polyps 2007. 9. Jaume F, Quintó L, Alobid I, Mullol J. Overuse referral centre. Allergy 2017;72:282-90.
Rhinol Suppl. 2007:1-136. of diagnostic tools and medications in acute 16. Snidvongs K, Heller GZ, Sacks R, Harvey
2. Fokkens W, Lund V, Bachert C, et al. European rhinosinusitis in Spain: a population-based study RJ. Validity of European position paper on
position paper on rhinosinusitis and nasal (the PROSINUS study). BMJ open 2018;8:e018788. rhinosinusitis disease control assessment
polyps. Rhinol Suppl. 2005:1-87. 10. Wei B, Liu F, Zhang J, et al. Multivariate analysis and modifications in chronic rhinosinusitis.
of inflammatory endotypes in recurrent nasal Otolaryngol Head Neck Surg. 2014;150:479-86.
3. Fokkens WJ, Lund VJ, Mullol J, et al. European
Position Paper on Rhinosinusitis and Nasal Polyps polyposis in a Chinese population. Rhinology 17. Calus L, Van Bruaene N, Bosteels C, et al. Twelve-
2012. Rhinol Suppl. 2012;23:3 p preceding table 2018;56:216-26. year follow-up study after endoscopic sinus
of contents, 1-298. 11. Tomassen P, Vandeplas G, Van Zele T, et al. surgery in patients with chronic rhinosinusitis
Inflammatory endotypes of chronic rhinosinusitis with nasal polyposis. Clin and Transl Allergy.
4. Hastan D, Fokkens WJ, Bachert C, et al. Chronic
based on cluster analysis of biomarkers. J Allergy 2019;9:30.
rhinosinusitis in Europe--an underestimated
disease. A GA(2)LEN study. Allergy 2011;66:1216- Clin Immunol. 2016;137:1449-56.e4. 18. Stjärne P, Odebäck P, Ställberg B, Lundberg J,
23. 12. Jarvis D, Newson R, Lotvall J, et al. Asthma Olsson P. High costs and burden of illness in
in adults and its association with chronic acute rhinosinusitis: real-life treatment patterns
5. Hirsch AG, Stewart WF, Sundaresan AS, et
rhinosinusitis: the GA2LEN survey in Europe. and outcomes in Swedish primary care. Primary
al. Nasal and sinus symptoms and chronic
Allergy. 2012;67:91-8. Care Resp Journal. 2012;21:174-9.
rhinosinusitis in a population-based sample.
Allergy 2017;72:274-81. 13. Hakansson K, Thomsen SF, Konge L, Mortensen 19. Remenschneider AK, Scangas G, Meier JC, et al.
J, Backer V, von Buchwald C. A comparative EQ-5D-derived health utility values in patients
6. Obaseki D, Potts J, Joos G, et al. The relation
and descriptive study of asthma in chronic undergoing surgery for chronic rhinosinusitis.
of airway obstruction to asthma, chronic
rhinosinusitis with nasal polyps. Am J Rhinol Laryngoscope 2015;125:1056-61.
rhinosinusitis and age: results from a population
survey of adults. Allergy 2014;69:1205-14. Allergy. 2014;28:383-7. 20. Gliklich RE, Metson R. The health impact
14. Samitas K, Carter A, Kariyawasam HH, Xanthou of chronic sinusitis in patients seeking
7. Sundaresan AS, Hirsch AG, Storm M, et al.
G. Upper and lower airway remodelling otolaryngologic care. Otolaryngol Head Neck
Occupational and environmental risk factors
mechanisms in asthma, allergic rhinitis and Surg. 1995;113:104-9.
for chronic rhinosinusitis: a systematic review.
International Forum of Allergy & Rhinol. chronic rhinosinusitis: The one airway concept 21. Teul I, Zbislawski W, Baran S, Czerwinski F,
2015;5:996-1003. revisited. Allergy 2018;73:993-1002. Lorkowski J. Quality of life of patients with
15. van der Veen J, Seys SF, Timmermans M, diseases of sinuses. J Physiol Pharmacol. 2007;58
8. Piatt Jr. JH. Intracranial suppuration complicating

27
 EPOS 2020

Suppl 5:691-7. rhinosinusitis and allergic rhinitis in relation to of chronic rhinosinusitis in Sao Paulo. Rhinology.
22. Garbutt J, Spitznagel E, Piccirillo J. Use of the comorbidity, ethnicity and environment. PloS 2012;50:129-38.
modified SNOT-16 in primary care patients with one 2018;13:e0192330. 55. Shi JB, Fu QL, Zhang H, et al. Epidemiology
clinically diagnosed acute rhinosinusitis. Arch of 39. Revai K, Dobbs LA, Nair S, Patel JA, Grady JJ, of chronic rhinosinusitis: results from a cross-
Otolaryng--Head & Neck Surg 2011;137:792-7. Chonmaitree T. Incidence of acute otitis media sectional survey in seven Chinese cities. Allergy.
23. Hopkins C, Browne JP, Slack R, et al. The national and sinusitis complicating upper respiratory 2015;70:533-9.
comparative audit of surgery for nasal polyposis tract infection: the effect of age. Pediatrics 56. Dietz de Loos D, Lourijsen ES, Wildeman MAM,
and chronic rhinosinusitis. Clinical Otolaryngol. 2007;119:e1408-12. et al. Prevalence of chronic rhinosinusitis in the
2006;31:390-8. 40. Benninger MS, Ferguson BJ, Hadley JA, et general population based on sinus radiology
24. Teul I, Baran S, Zbislawski W. Upper respiratory al. Adult chronic rhinosinusitis: Definitions, and symptomatology. J Allergy Clin Immunol.
tract diseases in self-evaluation of health diagnosis, epidemiology, and pathophysiology. 2019;143:1207-14.
status of Polish students based on the SF-36 Otolaryngol - Head & Neck Surg. 2003;129:S1-32. 57. Tomassen P, Newson RB, Hoffmans R, et al.
questionnaire. J Physiol Pharmacol. 2008;59 41. Shapiro DJ, Gonzales R, Cabana MD, Hersh AL. Reliability of EP3OS symptom criteria and
Suppl 6:697-707. National trends in visit rates and antibiotic nasal endoscopy in the assessment of chronic
25. Dietz de Loos DA, Hopkins C, Fokkens WJ. prescribing for children with acute sinusitis. rhinosinusitis--a GA(2) LEN study. Allergy.
Symptoms in chronic rhinosinusitis with Pediatrics. 2011;127:28-34. 2011;66:556-61.
and without nasal polyps. Laryngoscope 42. Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, 58. Hirsch AG, Nordberg C, Bandeen-Roche K, et al.
2013;123:57-63. et al. Clinical practice guideline (update): Adult Radiologic sinus inflammation and symptoms
26. Abdalla S, Alreefy H, Hopkins C. Prevalence of sinusitis. Otolaryngology - Head and Neck of chronic rhinosinusitis in a population-based
sinonasal outcome test (SNOT-22) symptoms Surgery (United States) 2015;152:S1-S39. sample. Allergy. 2019, 10.1111/all.14106.
in patients undergoing surgery for chronic 43. Leung R, Almassian S, Kern R, Conley D, Tan 59. Hamizan AW, Loftus PA, Alvarado R, et al. Allergic
rhinosinusitis in the England and Wales National B, Chandra R. Patient level decision making phenotype of chronic rhinosinusitis based on
prospective audit. Clin Otolaryngol 2012;37:276- in recurrent acute rhinosinusitis: a cost- radiologic pattern of disease. Laryngoscope.
82. benefit threshold for surgery. Laryngoscope. 2018;128:2015-21.
27. Bhattacharyya N, Lee LN. Evaluating the 2013;123:11-6. 60. Philpott CM, Erskine S, Hopkins C, et al.
diagnosis of chronic rhinosinusitis based on 44. Alkire BC, Bhattacharyya N. An assessment Prevalence of asthma, aspirin sensitivity and
clinical guidelines and endoscopy. Otolaryngol of sinonasal anatomic variants potentially allergy in chronic rhinosinusitis: data from the
Head Neck Surg. 2010;143:147-51. associated with recurrent acute rhinosinusitis. UK National Chronic Rhinosinusitis Epidemiology
28. Bhattacharyya N. Contemporary assessment of Laryngoscope. 2010;120:631-4. Study. Respiratory research 2018;19:129.
the disease burden of sinusitisThe economic 45. Jain R, Stow N, Douglas R. Comparison of 61. De Schryver E, Derycke L, Campo P, et al. Alcohol
burden and symptom manifestations of chronic anatomical abnormalities in patients with limited hyper-responsiveness in chronic rhinosinusitis
rhinosinusitis. Am J Rhinol Allergy. 2009;23:392-5. and diffuse chronic rhinosinusitis. Int Forum with nasal polyps. Clin Exp Allergy 2016, 10.1111/
29. Wahid NW, Smith R, Clark A, Salam M, Philpott Allergy Rhinol. 2013;3:493-6. cea.12836.
C. The Socioeconomic Cost of Chronic 46. Loftus PA, Lin J, Tabaee A. Anatomic variants of 62. Endam LM, Filali-Mouhim A, Boisvert P, Boulet
Rhinosinusitis Study. Rhinology 2020;in press. the paranasal sinuses in patients with recurrent L-P, Bosse Y, Desrosiers M. Genetic variations
30. Lourijsen ES, Fokkens WJ, Reitsma S. Direct acute rhinosinusitis. Int Forum of Allergy & in taste receptors are associated with chronic
and indirect costs of Dutch adult patients Rhinol. 2016;6:328-33. rhinosinusitis: a replication study. Int forum All &
with Chronic Rhinosinusitis with nasal polyps. 47. Costa ML, Psaltis AJ, Nayak JV, Hwang PH. Rhinology. 2014;4:200-6.
Rhinology 2020;in press. Medical therapy vs surgery for recurrent 63. Purnell PR, Addicks BL, Zalzal HG, et al. Single
31. Bhattacharyya N. Assessing the additional acute rhinosinusitis. Int Forum Allergy Rhinol. Nucleotide Polymorphisms in Chemosensory
disease burden of polyps in chronic 2015;5:667-73. Pathway Genes GNB3, TAS2R19, and TAS2R38 Are
rhinosinusitis. The Annals of otology, rhinology, 48. De Sario M, Katsouyanni K, Michelozzi P. Climate Associated with Chronic Rhinosinusitis. Int Arch
and laryngology 2009;118:185-9. change, extreme weather events, air pollution Allergy Immunol. 2019;180:72-8.
32. Gross Mark;Burgess LP, Rick; Sheridan. and respiratory health in Europe. Eur Resp 64. Stevens WW, Peters AT, Tan BK, et al. Associations
Endoscopic Sinus Surgery Complications in Journal. 2013, 826-43. Between Inflammatory Endotypes and Clinical
Residency. Laryngoscope 1997;107:1080-5. 49. Kuiper JR, Hirsch AG, Bandeen-Roche K, et al. Presentations in Chronic Rhinosinusitis. The
33. Gliklich RE, Metson R. Economic implications of Prevalence, severity, and risk factors for acute Jof Allergy and Clin Immunol In Practice. 2019,
chronic sinusitis. Otolaryngol Head Neck Surg. exacerbations of nasal and sinus symptoms 10.1016/j.jaip.2019.05.009.
1998;118:344-9. by chronic rhinosinusitis status. Allergy. 65. Brook CD, Kuperstock JE, Rubin SJ, Ryan MW,
34. Bhattacharyya N, Orlandi RR, Grebner 2018;73:1244-53. Platt MP. The association of allergic sensitization
J, Martinson M. Cost burden of chronic 50. Eyigor H, Basak S. [Evaluation of predisposing with radiographic sinus opacification. Am J
rhinosinusitis: a claims-based study. Otolaryngol factors and bacteriologic agents in pediatric Rhinol Allergy 2017;31:12-5.
Head Neck Surg. 2011;144:440-5. rhinosinusitis]. Kulak Burun Bogaz Ihtis Derg 66. Hummel T, Whitcroft KL, Andrews P, et al. Position
35. Blackwell DL, Collins JG, Coles R. Summary 2005;15:49-55. paper on olfactory dysfunction. Rhinology
health statistics for U.S. adults: National Health 51. Pant H, Ferguson BJ, Macardle PJ. The role of Supplement 2017;54:1-30.
Interview Survey, 1997. Vital Health Stat. 10 allergy in rhinosinusitis. Curr Opin Otolaryngol 67. Stogbauer J, Wirkner K, Engel C, et al. Prevalence
2002:1-109. Head Neck Surg. 2009;17:232-8. and risk factors of smell dysfunction - a
36. Goetzel RZ, Hawkins K, Ozminkowski RJ, Wang S. 52. Flook EP, Kumar BN. Is there evidence to link comparison between five German population-
The health and productivity cost burden of the acid reflux with chronic sinusitis or any nasal based studies. Rhinology. 2019, 10.4193/
“top 10” physical and mental health conditions symptoms? A review of the evidence. Rhinology. Rhin19.181.
affecting six large U.S. employers in 1999. J 2011;49:11-6. 68. Landis BN, Hummel T. New evidence for high
Occup Environ Med. 2003;45:5-14. 53. Seresirikachorn K, Snidvongs K, Chitsuthipakorn occurrence of olfactory dysfunctions within the
37. Rudmik L. Economics of Chronic Rhinosinusitis. W, et al. EPOS2012 has better specificity com- population. Am J Med. 2006;119:91-2.
Current Allergy and Asthma Reports 2017;17:20. pared to IDSA2012 for diagnosing acute bacterial 69. Lane AP, Turner J, May L, Reed R. A genetic model
38. Hoffmans R, Wagemakers A, van Drunen C, rhinosinusitis. Rhinology. 2018;56:241-4. of chronic rhinosinusitis-associated olfactory
Hellings P, Fokkens W. Acute and chronic 54. Pilan RR, Pinna FR, Bezerra TF, et al. Prevalence inflammation reveals reversible functional

28
 EPOS 2020

impairment and dramatic neuroepithelial 86. Pinto JM, Mehta N, DiTineo M, Wang J, Baroody 2019;57:190-9.
reorganization. J Neurosci. 2010;30:2324-9. FM, Naclerio RM. A randomized, double-blind, 103. Bachert C, Han JK, Desrosiers M, et al. Efficacy
70. Pfaar O, Landis BN, Frasnelli J, Huttenbrink placebo-controlled trial of anti-IgE for chronic and safety of dupilumab in patients with severe
KB, Hummel T. Mechanical obstruction of the rhinosinusitis. Rhinology. 2010;48:318-24. chronic rhinosinusitis with nasal polyps (LIBERTY
olfactory cleft reveals differences between 87. Hopkins C, Hettige R, Soni-Jaiswal A, et al. NP SINUS-24 and LIBERTY NP SINUS-52): results
orthonasal and retronasal olfactory functions. CHronic Rhinosinusitis Outcome MEasures from two multicentre, randomised, double-blind,
Chem Senses. 2006;31:27-31. (CHROME), developing a core outcome set for placebo-controlled, parallel-group phase 3 trials.
71. Jones NS. Sinogenic facial pain: Diagnosis and trials of interventions in chronic rhinosinusitis. Lancet. 2019;394:1638-50.
management. Otolaryngol Clin North Am. Rhinology. 2018;56:22-32. 104. Bachert C, Sousa AR, Lund VJ, et al. Reduced
2005;38:1311-25. 88. Kim DH, Seo Y, Kim KM, Lee S, Hwang SH. need for surgery in severe nasal polyposis with
72. Kirsch CFE, Bykowski J, Aulino JM, et al. ACR Usefulness of Nasal Endoscopy for Diagnosing mepolizumab: Randomized trial. J Allergy Clin
Appropriateness Criteria((R)) Sinonasal Disease. J Patients With Chronic Rhinosinusitis: A Meta- Immunol. 2017;140:1024-31.e14.
Am Coll Radiol 2017;14:S550-9. Analysis. Am J Rhinol Allergy. 2019, 10.1177/1945 105. Rudmik L, Soler ZM, Hopkins C, et al. Defining
73. Younis RT, Anand VK, Davidson B. The role 892419892157:1945892419892157. appropriateness criteria for endoscopic sinus
of computed tomography and magnetic 89. Flores Kim J, McCleary N, Nwaru BI, Stoddart A, surgery during management of uncomplicated
resonance imaging in patients with sinusitis with Sheikh A. Diagnostic accuracy, risk assessment, adult chronic rhinosinusitis: a RAND/UCLA
complications. Laryngoscope 2002;112:224-9. and cost-effectiveness of component-resolved appropriateness study. Int Forum Allergy Rhinol.
74. Bhattacharyya N. A comparison of symptom diagnostics for food allergy: A systematic review. 2016;6:557-67.
scores and radiographic staging systems in Allergy. 2018;73:1609-21. 106. Beswick DM, Mace JC, Rudmik L, Soler ZM,
chronic rhinosinusitis. American J of Rhinology 90. Eiringhaus K, Renz H, Matricardi P, Skevaki C. DeConde AS, Smith TL. Productivity changes
2005;19:175-9. Component-Resolved Diagnosis in Allergic following medical and surgical treatment of
75. Lund VJ, Kennedy DW. Staging for rhinosinusitis. Rhinitis and Asthma. J Appl Lab Med 2019;3:883- chronic rhinosinusitis by symptom domain. Int
Otolaryng - Head & Neck Surg. 1997;117:S35-40. 98. Forum Allergy Rhinol. 2018;8:1395-405.

76. Bayonne E, Kania R, Tran P, Huy B, Herman P. 91. Lotsch J, Hummel T. A data science-based 107. Kowalski ML, Agache I, Bavbek S, et al. Diagnosis
Intracranial complications of rhinosinusitis. A analysis of seasonal patterns in outpatient and management of NSAID-Exacerbated
review, typical imaging data and algorithm of presentations due to olfactory dysfunction. Respiratory Disease (N-ERD)-a EAACI position
management*. Rhinology. 2009;47:59-65. Rhinology. 2019, 10.4193/Rhin19.099. paper. Allergy. 2018, 10.1111/all.13599.

77. Lund VJ, Mackay IS. Staging in rhinosinusitus. 92. Rimmer J, Hellings P, Lund VJ, et al. European 108. Oakley GM, Christensen JM, Sacks R, Earls
Rhinology. 1993;31:183-4. position paper on diagnostic tools in rhinology. P, Harvey RJ. Characteristics of macrolide
Rhinology. 2019;57:1-41. responders in persistent post-surgical
78. Orlandi RR, Kingdom TT, Hwang PH, et al.
93. Kern RC. Chronic sinusitis and anosmia: rhinosinusitis. Rhinology. 2018;56:111-7.
International Consensus Statement on Allergy
and Rhinology: Rhinosinusitis. Int Forum Allergy pathologic changes in the olfactory mucosa. 109. Sidell D, Shapiro NL, Bhattacharyya N. Obesity
Rhinol. 2016;6 Suppl 1:S22-S209. Laryngoscope. 2000;110:1071-7. and the risk of chronic rhinosinusitis, allergic
94. Apter AJ, Gent JF, Frank ME. Fluctuating olfactory rhinitis, and acute otitis media in school-age
79. Amine M, Lininger L, Fargo KN, Welch KC.
sensitivity and distorted odor perception in children. Laryngoscope. 2013;123:2360-3.
Outcomes of endoscopy and computed
tomography in patients with chronic allergic rhinitis. Arch Otolaryngol Head Neck 110. Reh DD, Higgins TS, Smith TL. Impact of tobacco
rhinosinusitis. Int Forum Allergy Rhinol. Surg. 1999;125:1005-10. smoke on chronic rhinosinusitis: A review of the
2013;3:73-9. 95. Hsieh JW, Keller A, Wong M, Jiang R-S, Vosshall literature. Int. Forum of Allergy and Rhinol. 2012,
LB. SMELL-S and SMELL-R: Olfactory tests not 362-9.
80. Daramola OO, Lidder AK, Ramli R, et al. Patient
knowledge and perception of computed influenced by odor-specific insensitivity or prior 111. Georgalas C, Vlastos I, Picavet V, van Drunen C,
tomography scan in the management of olfactory experience. Proc of the Nat Academy of Garas G, Prokopakis E. Is chronic rhinosinusitis
chronic rhinosinusitis symptoms. Laryngoscope. Sciences. 2017;114:11275-84. related to allergic rhinitis in adults and children?
2015;125:791-5. 96. Leite SHP, Jain R, Douglas RG. The clinical Applying epidemiological guidelines for
implications of computerised fluid dynamic causation. Allergy. 2014;69:828-33.
81. Leung RM, Chandra RK, Kern RC, Conley DB,
Tan BK. Primary care and upfront computed modelling in rhinology. Rhinology. 2019;57:2-9. 112. Neff L, Adil EA. What is the role of the adenoid in
tomography scanning in the diagnosis of chronic 97. Wong E, Inthavong K, Singh N. Comment on the pediatric chronic rhinosinusitis? Laryngoscope.
rhinosinusitis: A cost-based decision analysis. European position paper on diagnostic tools 2015;125:1282-3.
Laryngoscope. 2014;124:12-8. in rhinology - computational fluid dynamics. 113. Belcher R, Virgin F. The Role of the Adenoids in
82. Bulla S, Blanke P, Hassepass F, et al. Reducing Rhinology. 2019, 10.4193/Rhin19.269. Pediatric Chronic Rhinosinusitis. Med Sci. (Basel)
the radiation dose for low-dose CT of the 98. Rimmer J. Reply to the letter by Wong et al. 2019;7.
paranasal sinuses using iterative reconstruction: Rhinology. 2019, 10.4193/Rhin19.296.1. 114. Brietzke SE, Shin JJ, Choi S, et al. Clinical
Feasibility and image quality. Eur J of Radiology. 99. Snidvongs K, Lam M, Sacks R, et al. Structured consensus statement: pediatric chronic
2012;81:2246-50. histopathology profiling of chronic rhinosinusitis rhinosinusitis. Otolaryngol - Head & Neck
83. Sodickson A. CT radiation risks coming into in routine practice. Int Forum All & Rhinology. Surgery. 2014;151:542-53.
clearer focus. BMJ. 2013;346:f3102-f. 2012;2:376-85. 115. Orb Q, Curtin K, Oakley GM, et al. Familial risk of
84. Fraczek M, Guzinski M, Morawska-Kochman M, 100. Jiang N, Kern RC, Altman KW. Histopathological pediatric chronic rhinosinusitis. Laryngoscope.
Krecicki T. Investigation of sinonasal anatomy evaluation of chronic rhinosinusitis: a critical 2016;126:739-45.
via low-dose multidetector CT examination in review. Am J of Rhinol & Allergy. 2013;27:396- 116. Skoner DP, Anfuso A, Ramadan H, et al. Sinus and
chronic rhinosinusitis patients with higher risk 402. adenoid inflammation in children with chronic
for perioperative complications. Eur Arch of Oto- 101. Fokkens WJ, Lund V, Bachert C, et al. EUFOREA rhinosinusitis and asthma. Am J of Resp and Crit
Rhino-Laryngol. 2017;274:787-93. consensus on biologics for CRSwNP with or Care Med. 2015;191.
85. Gevaert P, Van Bruaene N, Cattaert T, et al. without asthma. Allergy. 2019;74:2312-9. 117. Schenkel EJ, Skoner DP, Bronsky EA, et al.
Mepolizumab, a humanized anti-IL-5 mAb, as a 102. Hoggard M, Zoing M, Biswas K, Taylor MW, Absence of growth retardation in children
treatment option for severe nasal polyposis. J of Douglas RG. The sinonasal mycobiota in chronic with perennial allergic rhinitis after one year of
Allergy and Clin. Imm. 2011;128:988-9. rhinosinusitis and control patients. Rhinology. treatment with mometasone furoate aqueous
nasal spray. Pediatrics. 2000;105:E22.

29
 EPOS 2020

118. Yoo KH, Ahn HR, Park JK, et al. Burden of McGinn JD. Acute Invasive Fungal Rhinosinusitis: manifestations in granulomatosis with
Respiratory Disease in Korea: An Observational A 15-Year Experience with 41 Patients. polyangiitis. Int. J of immunopath and
Study on Allergic Rhinitis, Asthma, COPD, and Otolaryngol Head Neck Surg. 2016;154:759-64. pharmacol. 2016;29:151-9.
Rhinosinusitis. Allergy Asthma Immunol Res. 132. Groppo ER, El-Sayed IH, Aiken AH, Glastonbury 145. Hellings PW. Joint action with European CRSwNP
2016;8:527-34. CM. Computed tomography and magnetic Patients for better outcomes. Rhinology.
119. Orlandi RR, Marple BF. The role of fungus in resonance imaging characteristics of acute 2019;57:321.
chronic rhinosinusitis. Otolaryngol Clin North Am invasive fungal sinusitis. Arch Otolaryngol Head 146. Pugin B, Deneyer L, Bachert C, et al. Patient
2010;43:531-7, viii. Neck Surg. 2011;137:1005-10. Advisory Board for Chronic Rhinosinusitis - A
120. Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012: 133. Arvanitis M, Anagnostou T, Mylonakis E. EUFOREA initiative. Rhinology. 2019;57:331-5.
European position paper on rhinosinusitis Galactomannan and Polymerase Chain Reaction- 147. Seys SF, Bousquet J, Bachert C, et al.
and nasal polyps 2012. A summary for Based Screening for Invasive Aspergillosis mySinusitisCoach: patient empowerment in
otorhinolaryngologists. Rhinology. 2012;50:1-12. Among High-Risk Hematology Patients: A chronic rhinosinusitis using mobile technology.
121. Oshima H, Nomura K, Sugawara M, Arakawa K, Diagnostic Meta-analysis. Clin Infect Dis. Rhinology. 2018;56:209-15.
Oshima T, Katori Y. Septal deviation is associated 2015;61:1263-72. 148. Khanwalkar AR, Shen J, Kern RC, et al. Utilization
with maxillary sinus fungus ball in male patients. 134. Bakhshaee M, Fereidouni M, Nourollahian M, of a novel interactive mobile health platform to
The Tohoku J of exp medicine. 2014;232:201-6. Movahed R. The presence of fungal-specific IgE in evaluate functional outcomes and pain following
122. Yoon YH, Xu J, Park SK, Heo JH, Kim YM, Rha KS. serum and sinonasal tissue among patients with septoplasty and functional endoscopic sinus
A retrospective analysis of 538 sinonasal fungus sinonasal polyposis. Eur. Archives of Oto-rhino- surgery. Int Forum Allergy Rhinol. 2019;9:345-51.
ball cases treated at a single tertiary medical laryng. 2014;271:2871-5. 149. Hellings PW, Fokkens WJ, Bachert C, et al.
center in Korea (1996-2015). Int Forum Allergy 135. Bent 3rd JP, Kuhn FA, Bent JP, Kuhn FA. Diagnosis Positioning the principles of precision medicine
Rhinol. 2017;7:1070-5. of allergic fungal sinusitis. Otolaryngol Head in care pathways for allergic rhinitis and chronic
123. Park GY, Kim HY, Min JY, Dhong HJ, Chung SK. Neck Surg. 1994;111:580-8. rhinosinusitis - A EUFOREA-ARIA-EPOS-AIRWAYS
Endodontic treatment: a significant risk factor 136. deShazo RD, Swain RE. Diagnostic criteria for ICP statement. Allergy. 2017;72:1297-305.
for the development of maxillary fungal ball. Clin allergic fungal sinusitis. J of Allergy & Clin. 150. Hopkins C, Surda P, Bast F, Hettige R, Walker A,
Exp Otorhinolaryngol. 2010;3:136-40. Immunology. 1995;96:24-35. Hellings PW. Prevention of chronic rhinosinusitis.
124. Jun YJ, Shin JM, Lee JY, Baek BJ. Bony Changes 137. Aribandi M, McCoy VA, Bazan C, 3rd. Imaging Rhinology. 2018;56:307-15.
in a Unilateral Maxillary Sinus Fungal Ball. J features of invasive and noninvasive fungal 151. Hopkins C, Rimmer J, Lund VJ. Does time to
Craniofac Surg. 2018;29:e44-e7. sinusitis: a review. Radiographics. 2007;27:1283- endoscopic sinus surgery impact outcomes in
125. Knisely A, Holmes T, Barham H, Sacks R, Harvey 96. Chronic Rhinosinusitis? Prospective findings
R. Isolated sphenoid sinus opacification: 138. Landsberg R, Segev Y, DeRowe A, Landau T, Khafif from the National Comparative Audit of Surgery
A systematic review. Am J Otolaryngol. A, Fliss DM. Systemic corticosteroids for allergic for Nasal Polyposis and Chronic Rhinosinusitis.
2017;38:237-43. fungal rhinosinusitis and chronic rhinosinusitis Rhinology. 2015;53:10-7.
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

30
 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:

31
 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.

36
 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

38
 EPOS 2020

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

39
 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.

References Allergy 2019;33:524-30. 22. Bousquet J, Bachert C, Canonica GW, et

1. Lund VJ, Holmstrom M, Scadding GK. 12. Brandt D, Bernstein JA. Questionnaire al. Unmet needs in severe chronic upper
Functional endoscopic sinus surgery in evaluation and risk factor identification for airway disease (SCUAD). J Allergy Clin
the management of chronic rhinosinusitis. nonallergic vasomotor rhinitis. Ann Allergy Immunol 2009;124:428-33.
An objective assessment. J Laryngol Otol Asthma Immunol 2006;96:526-32. 23. Wise SK, Lin SY, Toskala E, et al. International
1991;105:832-5. 13. Habib A-R, Campbell R, Kalish L, et al. The Consensus Statement on Allergy and
2. Lund VJ, Kennedy DW. Staging for rhi- burden of chronic upper airway disorders in Rhinology: Allergic Rhinitis. IInt Forum
nosinusitis. Otolaryngol-Head Neck Surg. Australia: a population-based cross-section- Allergy Rhinol 2018;8:108-352.
1997;117:S35-40. al study. Aus J Otolaryngol; 2019, 2 28. 24. Global Initiative for Asthma. Global Strategy
3. Orlandi RR, Kingdom T T, Hwang PH. 14. Barham HP, Zhang AS, Christensen JM, for Asthma Management and Prevention
International Consensus Statement on Sacks R, Harvey RJ. Acute radiology rarely (2018 update). 2018. www.ginasthma.org.
Allergy and Rhinology : Rhinosinusitis confirms sinus disease in suspected recur- 25. Hens G, Hellings PW. The nose: gatekeeper
Executive Summary. Int Forum Allergy rent acute rhinosinusitis. Int Forum Allergy and trigger of bronchial disease. Rhinology
Rhinol 2016;6:S3-S21. Rhinol 2017;7:726-33. 2006;44:179-87.
4. Meltzer EO, Hamilos DL, Hadley JA, et al. 15. Dietz de Loos D, Lourijsen ES, Wildeman 26. Global Atlas of Allergic Rhinitis and Chronic
Rhinosinusitis: establishing definitions for MAM, et al. Prevalence of chronic rhinos- Rhinosinusitis. 2015. http://www.eaaci.org/
clinical research and patient care. J Allergy inusitis in the general population based globalatlas/ENT_Atlas_web.pdf.
Clin Immunol 2004;114:155-212. on sinus radiology and symptomatology. J 27. Bousquet J, Van Cauwenberge P, Khaltaev
5. Meltzer EO, Hamilos DL, Hadley JA, et al. Allergy Clin Immunol 2019;143:1207-14. N, Group AW, Organization WH. Allergic
Rhinosinusitis: Developing guidance for 16. Rachelefsky GS, Goldberg M, Katz RM, et al. rhinitis and its impact on asthma. The
clinical trials. Otolaryngol Head Neck Surg Sinus disease in children with respiratory Journal of allergy and clinical immunology
2006;135:S31-80. allergy. J Allergy Clin Immunol 1978;61:310- 2001;108:S147-334.
6. Gwaltney JM, Phillips CD, Miller RD, Riker 4. 28. Powe DG, Jagger C, Kleinjan A, Carney AS,
DK. Computed Tomographic Study of the 17. Rosenfeld RM, Piccirillo JF, Chandrasekhar Jenkins D, Jones NS. 'Entopy': localized
Common Cold. N Engl J Med 1994;330:25- SS, et al. Clinical practice guideline (update): mucosal allergic disease in the absence
30. Adult sinusitis. Otolaryngol - Head Neck of systemic responses for atopy. Clin Exp
7. Bhattacharyya N. Chronic rhinosinusitis: Surg 2015;152:S1-S39. Allergy: 2003;33:1374-9.
is the nose really involved? Am J Rhinol 18. S e r e s i r i k a c h o r n K , S n i d v o n g s K , 29. Rondon C, Campo P, Togias A, et al. Local
2001;15:169-73. Chitsuthipakorn W, et al. EPOS2012 has bet- allergic rhinitis: concept, pathophysiology,
8. Van Crombruggen K, Van Bruaene N, ter specificity compared to IDSA2012 for and management. J Allergy Clin Immunol
Holtappels G, Bachert C. Chronic sinusi- diagnosing acute bacterial rhinosinusitis. 2012;129:1460-7.
tis and rhinitis: clinical terminology Rhinology 2018;56:241-4. 30. Hellings PW, Klimek L, Cingi C, et al. Non-
"Chronic Rhinosinusitis" further supported. 19. Lim M, Lew-Gor S, Darby Y, Brookes N, allergic rhinitis: Position paper of the
Rhinology 2010;48:54-8. Scadding G, Lund VJ. The relationship European Academy of Allergy and Clinical
9. Fokkens WJ, Lund VJ, Mullol J, et al. between subjective assessment instru- Immunology. Allergy 2017;72:1657-65.
European Position Paper on Rhinosinusitis ments in chronic rhinosinusitis. Rhinology 31. Spergel JM, Paller AS. Atopic dermatitis and
and Nasal Polyps 2012. Rhinol Suppl 2007;45:144-7. the atopic march. J Allergy Clin Immunol
2012;23:3 p preceding table of contents, 20. Remenschneider AK, D'Amico L, Gray ST, 2003;112:S118-27.
1-298. Holbrook EH, Gliklich RE, Metson R. The 32. Ho J, Hamizan AW, Alvarado R, Rimmer J,
10. Hsueh WD, Conley DB, Kim H, et al. EQ-5D: A new tool for studying clini- Sewell WA, Harvey RJ. Systemic Predictors
Identifying clinical symptoms for improv- cal outcomes in chronic rhinosinusitis. of Eosinophilic Chronic Rhinosinusitis. Am J
ing the symptomatic diagnosis of chron- Laryngoscope 2015;125:7-15. Rhinol Allergy 2018;32:252-7.
ic rhinosinusitis.Int Forum Allergy Rhinol 21. van Oene CM, van Reij EJ, Sprangers MA, 33. Nakayama T, Sugimoto N, Okada N, et al.
2013;3:307-14. Fokkens WJ. Quality-assessment of disease- JESREC score and mucosal eosinophilia can
11. Hamizan AW, Azer M, Alvarado R, et al. specific quality of life questionnaires for rhi- predict endotypes of chronic rhinosinusi-
The Distinguishing Clinical Features of nitis and rhinosinusitis: a systematic review. tis with nasal polyps. Auris Nasus Larynx
Nonallergic Rhinitis Patients. Am J Rhinol Allergy 2007;62:1359-71. 2019;46:374-83.

42
 EPOS 2020

34. DelGaudio JM, Loftus PA, Hamizan AW, with sino-nasal outcome test 22: paving the Allergo J Int 2017;26:16-24.
Harvey RJ, Wise SK. Central Compartment way for a simple outcome tool of CRS bur- 47. Sedaghat AR, Hoehle LP, Gray ST. Chronic rhi-
Atopic Disease. Am J Rhinol Allergy den. Clin Transl Allergy 2018;8:32. nosinusitis control from the patient and phy-
2017;31:228-34. 41. Snidvongs K, Heller GZ, Sacks R, Harvey sician perspectives. Laryngoscope Investig
35. Fokkens WJ, Lund VJ, Mullol J, et al. EPOS RJ. Validity of European position paper on Otolaryngol. 2018;3:419-33.
2012: European position paper on rhinosi- rhinosinusitis disease control assessment 48. Toma S, Hopkins C. Stratification of SNOT-22
nusitis and nasal polyps 2012. A summa- and modifications in chronic rhinosinusitis. scores into mild, moderate or severe and
ry for otorhinolaryngologists. Rhinology Otolaryngol Head Neck Surg 2014;150:479- relationship with other subjective instru-
2012;50:1-12. 86. ments. Rhinology 2016;54:129-33.
36. Hellings PW, Fokkens WJ, Akdis C, et al. 42. Seys SF, Bousquet J, Bachert C, et al. mySi- 49. Fokkens WJJ, Lund VJJ, Mullol J, et al. EPOS
Uncontrolled allergic rhinitis and chronic nusitisCoach: patient empowerment in 2012: European position paper on rhinosi-
rhinosinusitis: where do we stand today? chronic rhinosinusitis using mobile technol- nusitis and nasal polyps 2012. A summa-
Allergy 2013;68:1-7. ogy. Rhinology 2018;56:209-15. ry for otorhinolaryngologists. Rhinology
37. van der Veen J, Seys SF, Timmermans M, et al. 43. Bousquet J, Clark TJH, Hurd S, et al. GINA 2012;50:1-12.
Real-life study showing uncontrolled rhinosi- guidelines on asthma and beyond. Allergy: 50. Caimmi D, Baiz N, Tanno LK, et al. Validation
nusitis after sinus surgery in a tertiary referral Eur J Allergy Clin Immunol 2007;62:102-12. of the MASK-rhinitis visual analogue scale on
centre. Allergy 2017;72:282-90. 44. Hopkins C, Hettige R, Soni-Jaiswal A, et al. smartphone screens to assess allergic rhinitis
38. Calus L, Van Bruaene N, Bosteels C, et al. CHronic Rhinosinusitis Outcome MEasures control. Clin Exp Allergy 2017;47:1526-33.
Twelve-year follow-up study after endoscop- (CHROME), developing a core outcome set 51. Brozek JL, Bousquet J, Agache I, et al. Allergic
ic sinus surgery in patients with chronic rhi- for trials of interventions in chronic rhinosi- Rhinitis and its Impact on Asthma (ARIA)
nosinusitis with nasal polyposis. Clin Transl nusitis. Rhinology 2018;56:22-32. guidelines-2016 revision. J Allergy Clin
Allergy 2019;9:30. 45. Hopkins C, Gillett S, Slack R, Lund VJ, Browne Immunol 2017;140:950-8.
39. Vlaminck S, Vauterin T, Hellings PW, et al. JP. Psychometric validity of the 22-item 52. Grayson JW, Hopk ins C, Mori ES, B.
The importance of local eosinophilia in the Sinonasal Outcome Test. Clin Otolaryngol Contemporary Classification of Chronic
surgical outcome of chronic rhinosinusitis: a 2009;34:447-54. Rhinosinusitis: Moving beyond CRSwNP and
3-year prospective observational study. Am J 46. Klimek L, Bergmann K-C, Biedermann T, et CRSsNP. JAMA Otolaryngol Head Neck Surg
Rhinol Allergy 2014;28:260-4. al. Visual analogue scales (VAS): Measuring 2020; in press.
40. Doulaptsi M, Prokopakis E, Seys S, Pugin B, instruments for the documentation of
Steelant B, Hellings P. Visual analogue scale symptoms and therapy monitoring in cases
for sino-nasal symptoms severity correlates of allergic rhinitis in everyday health care.

43
EPOS 2020

44
 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.

References 9. Palmer JN, Messina JC, Biletch R, Grosel national comparative audit of surgery for
1. Stjärne P, Odebäck P, Ställberg B, Lundberg K, Mahmoud RA. A cross-sectional, pop- nasal polyposis and chronic rhinosinusitis.
J, Olsson P. High costs and burden of illness ulation-based survey of U.S. adults with Clin Otolaryngol 2006;31:390-8.
in acute rhinosinusitis: real-life treatment symptoms of chronic rhinosinusitis. Allergy 18. Gillett S, Hopkins C, Slack R, Browne JP. A
patterns and outcomes in Swedish prima- Asthma Proc 2019;40:48-56. pilot study of the SNOT 22 score in adults
ry care. Primary Care Respiratory Journal 10. Dietz de Loos DA, Hopkins C, Fokkens WJ. with no sinonasal disease. Clin Otolaryngol
2012;21:174-9. Symptoms in chronic rhinosinusitis with 2009;34:467-9.
2. Klossek JM, Mesbah K. Presentation and and without nasal polyps. Laryngoscope 19. Fu C-H, Huang C-C, Chen Y-W, Chang
treatment of acute maxillary sinusitis in 2013;123:57-63. P-H, Lee T-J. Nasal Nitric Oxide in Relation
general practice: a French observational 11. Abdalla S, Alreefy H, Hopkins C. Prevalence to Quality-of-life Improvements after
study. Rhinology 2011;49:84-9. of sinonasal outcome test (SNOT-22) symp- Endoscopic Sinus Surgery. Am J Rhinol
3. Shaikh N, Hoberman A, Kearney DH, et toms in patients undergoing surgery for Allergy 2015;29:e187-e91.
al. Signs and symptoms that differenti- chronic rhinosinusitis in the England and 20. Gliklich RE, Metson R. The health impact of
ate acute sinusitis from viral upper respir- Wales National prospective audit. Clin chronic sinusitis in patients seeking oto-
atory tract infection. Pediatr Infect Dis J Otolaryngol 2012;37:276-82. laryngologic care. Otolaryngol Head Neck
2013;32:1061-5. 12. Mattos JL, Rudmik L, Schlosser RJ, et al. Surg 1995;113:104-9.
4. Jaume F, Quintó L, Alobid I, Mullol J. Symptom importance, patient expecta- 21. Remenschneider AK, Scangas G, Meier JC,
Overuse of diagnostic tools and medica- tions, and satisfaction in chronic rhinosi- et al. EQ-5D-derived health utility values in
tions in acute rhinosinusitis in Spain: a pop- nusitis. Int Forum Allergy Rhinol 2019;9:593- patients undergoing surgery for chronic rhi-
ulation-based study (the PROSINUS study). 600. nosinusitis. Laryngoscope 2015;125:1056-
BMJ open 2018;8:e018788. 13. Bhattacharyya N, Lee LN. Evaluating the 61.
5. Teul I, Zbislawski W, Baran S, Czerwinski F, diagnosis of chronic rhinosinusitis based 22. Schlosser RJ, Gage SE, Kohli P, Soler ZM.
Lorkowski J. Quality of life of patients with on clinical guidelines and endoscopy. Burden of illness: A systematic review of
diseases of sinuses. J Physiol Pharmacol Otolaryngol Head Neck Surg 2010;143:147- depression in chronic rhinosinusitis. Am J
2007;58 Suppl 5:691-7. 51. Rhinol Allergy. 2016;30:250-6.
6. Garbutt J, Spitznagel E, Piccirillo J. Use 14. Dietz de Loos D, Lourijsen ES, Wildeman 23. Hopkins C, Browne JP, Slack R, Lund V,
of the modified SNOT-16 in primary care MAM, et al. Prevalence of chronic rhinos- Brown P. The Lund-Mackay staging system
patients with clinically diagnosed acute inusitis in the general population based for chronic rhinosinusitis: How is it used
rhinosinusitis. Arch Otolaryngol Head Neck on sinus radiology and symptomatology. J and what does it predict? Otolaryngol Head
Surg. 2011;137:792-7. Allergy Clin Immunol 2019;143:1207-14. Neck Surg 2007;137:555-61.
7. Hirsch AG, Stewart WF, Sundaresan AS, et 15. Bhattacharyya N. Clinical and symptom cri- 24. Rudmik L, Smith TL. Economic Evaluation
al. Nasal and sinus symptoms and chronic teria for the accurate diagnosis of chronic of a Steroid-Eluting Sinus Implant follow-
rhinosinusitis in a population-based sample. rhinosinusitis. Laryngoscope 2006;116:1-22. ing Endoscopic Sinus Surgery for Chronic
Allergy 2017;72:274-81. 16. Hsueh WD, Conley DB, Kim H, et al. Rhinosinusitis. Otolaryngol Head Neck Surg
8. Sundaresan AS, Hirsch AG, Young AJ, et Identifying clinical symptoms for improv- 2014;151:359-66.
al. Longitudinal Evaluation of Chronic ing the symptomatic diagnosis of chronic 25. Caulley L, Thavorn K, Rudmik L, Cameron
Rhinosinusitis Symptoms in a Population- rhinosinusitis. Int Forum Allergy Rhinol C, Kilty SJ. Direct costs of adult chronic rhi-
Based Sample. J Allergy Clin Immunol Pract 2013;3:307-14. nosinusitis by using 4 methods of estima-
2018;6:1327-35.e3. 17. Hopkins C, Browne JP, Slack R, et al. The tion: Results of the US Medical Expenditure

50
 EPOS 2020

Panel Survey. J Allergy Clin Immunol 36. Bhattacharyya N, Villeneuve S, Joish VN, et for chronic rhinosinusitis: a 25-year experi-
2015;136:1517-22. al. Cost burden and resource utilization in ence. Laryngoscope 2011;121:2684-701.
26. Rudmik L. Economics of Chronic patients with chronic rhinosinusitis and 48. Stull DE, Roberts L, Frank L, Heithoff K.
Rhinosinusitis. Curr Allergy Asthma Rep nasal polyps. Laryngoscope 2019, 10.1002/ Relationship of nasal congestion with sleep,
2017;17:20. lary.27852:lary.27852. mood, and productivity. Curr Med Res Opin
27. Bhattacharyya N. Contemporary assess- 37. Bhattacharyya N, Orlandi RR, Grebner 2007;23:811-9.
ment of the disease burden of sinusitis . Am J, Martinson M. Cost burden of chron- 49. Rudmik L, Smith TL, Schlosser RJ, Hwang
J Rhinol Allergy 2009;23:392-5. ic rhinosinusitis: a claims-based study. PH, Mace JC, Soler ZM. Productivity costs in
28. WahidNW, Smith R, Clark A, Salam M, Otolaryngol Head Neck Surg 2011;144:440- patients with refractory chronic rhinosinusi-
Philpott CM. The socioeconomic cost of 5. tis. Laryngoscope 2014;124:2007-12.
chronic rhinosinusitis study. Rhinology 38. Gross RD, Sheridan MF, Burgess LP. 50. Yip J, Vescan AD, Witterick IJ, Monteiro E.
2020, 58, (in press). Endoscopic Sinus Surgery Complications in The personal financial burden of chronic
29. Lourijsen ES, Fokkens WJ, Reitsma S. Direct Residency. Laryngoscope 1997;107:1080-5. rhinosinusitis: A Canadian perspective. Am J
and indirect costs of adult patients with 39. Gliklich RE, Metson R. Economic implica- Rhinol Allergy 2017;31:216-21.
chronic rhinosinusitis with nasal polyps. tions of chronic sinusitis. Otolaryngol Head 51. Rudmik L, Soler ZM, Smith TL, Mace
Rhinology 2020, 58, (in press). Neck Surg 1998;118:344-9. JC, Schlosser RJ, DeConde AS. Effect of
30. Ray NF, Baraniuk JN, Thamer M, et al. 40. Orlandi RR, Kingdom TT, Hwang PH, et al. Continued Medical Therapy on Productivity
Healthcare expenditures for sinusitis in International Consensus Statement on Costs for Refractory Chronic Rhinosinusitis.
1996: contributions of asthma, rhinitis, Allergy and Rhinology: Rhinosinusitis. Int JAMA O tolar yngol Head Neck Surg
and other airway disorders. J Allergy Clin Forum Allergy Rhinol 2016;6:S22-S209. 2015;141:969-73.
Immunol 1999;103:408-14. 41. Anand VK. Epidemiology and economic 52. Rudmik L, Smith TL, Mace JC, Schlosser RJ,
31. Bhattacharyya N. Incremental health care impact of rhinosinusitis. Ann Otol Rhinol Hwang PH, Soler ZM. Productivity costs
utilization and expenditures for chronic rhi- Laryngol 2004;113:3-5. decrease after endoscopic sinus sur-
nosinusitis in the United States. Ann Otol 42. Bhattacharyya N, Grebner J, Martinson gery for refractory chronic rhinosinusitis.
Rhinol Laryngol 2011;120:423-7. NG. Recurrent Acute Rhinosinusitis: Laryngoscope 2016;126:570-4.
32. Murphy MP, Fishman P, Short SO, et al. Epidemiology and Health Care Cost Burden. 53. Luk L, Mace JC, Bhandarkar ND, Sautter NB.
Health care utilization and cost among Otolaryngol Head Neck Surg 2012;146:307- Comparison of electrosurgical plasma coag-
adults with chronic rhinosinusitis enrolled 12. ulation and potassium-titanyl-phosphate
in a health maintenance organization 43. Blackwell DL, Collins JG, Coles R. Summary laser photocoagulation for treatment of
Healthcare expenditures for sinusitis in health statistics for U.S. adults: National hereditary hemorrhagic telangiectasia-
1996: contributions of asthma, rhinitis, and Health Interview Survey, 1997. Vital Health related epistaxis. Int Forum Allergy Rhinol
other airway disorders. Otolaryngol Head Stat 10 2002:1-109. 2014;4:640-5.
Neck Surg 2002;127:367-76. 44. Goetzel RZ, Hawkins K, Ozminkowski RJ, 54. Beswick DM, Mace JC, Rudmik L, Soler
33. van Agthoven M, Uyl-de Groot CA, Fokkens Wang S. The health and productivity cost ZM, DeConde AS, Smith TL. Productivity
WJ, van de Merwe JP, Busschbach JJV, burden of the "top 10" physical and mental changes following medical and surgical
Agthoven V. Cost analysis of regular and health conditions affecting six large U.S. treatment of chronic rhinosinusitis by
filgrastim treatment in patients with refrac- employers in 1999. J Occup Environ Med symptom domain. Int Forum Allergy Rhinol
tory chronic rhinosinusitis. Rhinology 2003;45:5-14. 2018;8:1395-405.
2002;40:69-74. 45. Ray NF. Healthcare expenditures for sinusitis 55. Chowdhury NI, Mace JC, Smith TL, Rudmik
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

51
EPOS 2020

52
 EPOS 2020 POSITION PAPER

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

53
 EPOS 2020

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

54
 EPOS 2020

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.

55
 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

59
 EPOS 2020

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

60
 EPOS 2020

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

61
 EPOS 2020

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,

62
 EPOS 2020

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

63
 EPOS 2020

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

64
 EPOS 2020

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.

65
 EPOS 2020

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

66
 EPOS 2020

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.

67
 EPOS 2020

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

68
 EPOS 2020

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,

69
 EPOS 2020

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).

70
 EPOS 2020

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

71
 EPOS 2020

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