Title: EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: Definitions and management
Abstract: Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is the most bothersome phenotype of chronic rhinosinusitis; it is typically characterized by a type 2 inflammatory reaction and by comorbidities, including asthma, nonsteroidal anti-inflammatory drug–exacerbated respiratory disease, and allergies. Here, the European Forum for Research and Education in Allergy and Airway Diseases proposes structured definitions to enable communication between clinicians and provides a practical algorithm to define type 2 inflammation in CRSwNP in daily clinical practice. A rational approach for the treatment of uncontrolled severe CRSwNP is discussed; it consists of evaluating the perspective and risks of surgery and efficacy and adverse events of biologics on the basis of currently available data. Further, possible combinations of surgery and biologics are discussed, and a rationale is provided. Here, it is of importance to adequately counsel the patient about both approaches to enable a decision-making process with an informed patient. Criteria for the selection of a biologic drug are provided, as several biologics for uncontrolled severe CRSwNP will be available in many countries within a short time. Further, suggestions for monitoring of the drug effects that support recognition of responders to the therapy and, subsequently, the decision regarding continuation or discontinuation of the biologic are proposed. Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) is the most bothersome phenotype of chronic rhinosinusitis; it is typically characterized by a type 2 inflammatory reaction and by comorbidities, including asthma, nonsteroidal anti-inflammatory drug–exacerbated respiratory disease, and allergies. Here, the European Forum for Research and Education in Allergy and Airway Diseases proposes structured definitions to enable communication between clinicians and provides a practical algorithm to define type 2 inflammation in CRSwNP in daily clinical practice. A rational approach for the treatment of uncontrolled severe CRSwNP is discussed; it consists of evaluating the perspective and risks of surgery and efficacy and adverse events of biologics on the basis of currently available data. Further, possible combinations of surgery and biologics are discussed, and a rationale is provided. Here, it is of importance to adequately counsel the patient about both approaches to enable a decision-making process with an informed patient. Criteria for the selection of a biologic drug are provided, as several biologics for uncontrolled severe CRSwNP will be available in many countries within a short time. Further, suggestions for monitoring of the drug effects that support recognition of responders to the therapy and, subsequently, the decision regarding continuation or discontinuation of the biologic are proposed. Uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) with or without comorbidities—most frequently, asthma, nonsteroidal anti-inflammatory drug–exacerbated respiratory disease (N-ERD), and allergies—is a highly disabling airway disease that is characterized by long-term disease burden, consecutive exposure of patients to long-term local and systemic corticosteroids, necessity of often-repeated poorly standardized surgical interventions, and (so far) lack of highly efficacious treatment approaches beyond surgery. The advent of biologic drugs for type 2 immune effectors such as IL-4, IL-5, and IL-13, as well as IgE, offer new approaches for physicians and hope for patients to manage this difficult disease. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) is an international nonprofit organization with the aim of preventing and improving the burden of chronic respiratory diseases. ENT physicians, allergists, and pneumologists working in leading EU research institutes are part of EUFOREA; to include their view, ear, nose, and throat colleagues in the United States also took part in the expert board meeting at which this document was drafted. One patient diagnosed with CRSwNP, representing the patient perspective, was invited to add his opinion. Representatives of the pharmaceutical industry producing biologic drugs were asked to contribute their knowledge but were not involved in any strategic discussions or decisions on any criteria-related care pathway decisions. The aim of the EUFOREA expert board meeting in Brussels on January 25, 2020, was to develop suggestions for the indication of currently and soon-to-be-available type 2 biologics in an individual patient, the monitoring and evaluation of efficacy, and the development of evidence-based care pathways for management of uncontrolled severe type 2 CRSwNP with or without comorbid asthma. The presence of internationally renowned specialists in the fields of otolaryngology, pulmonology, allergology, and immunology have substantially added to the discussion and decisions. At the Brussels meeting, the various definitions were discussed point by point until unanimity was reached. A draft of the document was subsequently written and submitted to 3 rounds of review by all authors. In each round of review, the changes made to the definitions and proposed algorithms were discussed and refined until they were approved unanimously. The discussions focused on clear definitions to define phenotype and endotype, elaborate criteria to support decision-making processes, and develop care pathways based on evidence when available and best practice when not. The EUFOREA group agreed on the following definitions. Severe CRSwNP is defined as “bilateral CRSwNP with a nasal polyp score (NPS) of at least 4 of 8 points and persistent symptoms, including loss of smell and/or taste, nasal obstruction, secretion and/or postnasal drip, and facial pain or pressure, with the need for add-on treatment to supplement intranasal corticosteroids” (INCSs) (see Comment E1 in the Online Repository at www.jacionline.org). Uncontrolled CRSwNP is defined as “persistent or recurring despite long-term treatment with INCSs and having received at least 1 course of systemic corticosteroids in the preceding 2 years (or having a medical contraindication or intolerance to systemic corticosteroids) and/or previous sinonasal surgery (unless having a medical contraindication or being unwilling to undergo surgery) (see Comment E2 in the Online Repository at www.jacionline.org). CRSwNP with comorbid disease is defined as “nasal polyp disease with other coexisting type 2 inflammatory diseases such as asthma, N-ERD, atopic dermatitis/eczema, allergic rhinitis, urticaria, food allergy, or eosinophilic esophagitis” (see Comment E3 in the Online Repository at www.jacionline.org). Endotyping refers to the identification of type 2 or non–type 2 immune reactions, as currently this differentiation is clinically relevant in determining treatment with a biologic therapy. It may be assumed that in the coming years, a further differentiation into type 1 and type 3 immune reactions may become relevant, as further biologics targeting other cytokines become available. Depending on the geographic region and ethnicity of the patient, CRSwNP is characterized by type 2 mucosal inflammation in approximately 15% to 85% of the patients.1Wang X. Zhang N. Bo M. Holtappels G. Zheng M. Lou H. et al.Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: a multicenter study in Europe, Asia, and Oceania.J Allergy Clin Immunol. 2016; 138: 1344-1353Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 2Tomassen P. Vandeplas G. Van Zele T. Cardell L.-O. Arebro J. Olze H. et al.Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers.J Allergy Clin Immunol. 2016; 137: 1449-1456.e4Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 3Zhang Y. Gevaert E. Lou H. Wang X. Zhang L. Bachert C. et al.Chronic rhinosinusitis in Asia.J Allergy Clin Immunol. 2017; 140: 1230-1239Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 4Wang E.-T. Eosinophilic chronic rhinosinusitis in East Asians.World J Clin Cases. 2014; 2: 873Crossref PubMed Google Scholar, 5Cao P.P. Li H.B. Wang B.F. Wang S.B. You X.J. Cui Y.H. et al.Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese.J Allergy Clin Immunol. 2009; 124: 478-484.e4842Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar, 6Zhang N. Van Zele T. Perez-Novo C. Van Bruaene N. Holtappels G. DeRuyck N. et al.Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease.J Allergy Clin Immunol. 2008; 122: 961-968Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar Type 2 inflammation is clearly associated with more severe sinus disease and symptoms, asthma comorbidity, and recurrence of disease after surgery.7Bachert C. Zhang N. Cavaliere C. Weiping W. Gevaert E. Krysko O. Biologics for chronic rhinosinusitis with nasal polyps.J Allergy Clin Immunol. 2020; 145: 725-739Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar,8Bachert C. Zhang L. Gevaert P. Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis.J Allergy Clin Immunol. 2015; 136: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar It is therefore of importance to differentiate type 2 from non–type 2 CRSwNP for prediction of the natural course of disease, response to medical and surgical interventions, and consequently long-term management and selection of therapeutic measures. For the indication of currently available type 2 biologics, including anti–IL-4 receptor alpha (dupilumab), anti-IgE (omalizumab), and anti–IL-5/Ra (mepolizumab and benralizumab), an underlying type 2 inflammation should be present (Fig 1) (see Comment E4 in the Online Repository at www.jacionline.org). In a patient with uncontrolled severe type 2 CRSwNP, at a time point during the course of the patient’s disease when he or she has experienced ineffective systemic glucocorticosteroid (GCS) therapy or surgery, a long-term plan should be formulated in cooperation with an informed patient. This plan needs to consider the endotype, comorbidities, and other possible treatment approaches for those comorbidities, as well as the treatment history (operations, treatment with systemic GCSs and their efficacy, duration of effect, and adverse events [AEs]). According to current patient rights, a patient must be informed about the aims, reasonable expectations, and possible side effects and complications of all authorized treatments available for the disease; this obliges the physician to inform the patient about available alternatives in the event of proposed surgery. The aim is to have an informed patient to share in the decision making in this situation, which gains importance with the complexity of the interventions available and the history of former therapeutic approaches (see Comment E5 in the Online Repository at www.jacionline.org). Surgical approaches can be differentiated into functional endoscopic sinus surgery (ESS),9Stammberger H. Posawetz W. Functional endoscopic sinus surgery - concept, indications and results of the Messerklinger technique.Eur Arch Otorhinolaryngol. 1990; 247: 63-76Crossref PubMed Scopus (443) Google Scholar, 10Orlandi R.R. Kingdom T.T. Hwang P.H. Smith T.L. Alt J.A. Baroody F.M. et al.International consensus statement on allergy and rhinology: rhinosinusitis.Int Forum Allergy Rhinol. 2016; 6: S22-S209Crossref PubMed Scopus (563) Google Scholar, 11Wigand M.E. Transnasal, endoscopical sinus surgery for chronic sinusitis. I. A biomechanical concept of the endonasal mucosa surgery (author’s transl).HNO. 1981; 29: 215-221PubMed Google Scholar with the aim of opening all sinuses (“full house”) and removing all nasal and sinus polyps but preserving the sinus mucosa, and the nasalization and reboot approaches,12Alsharif S. Jonstam K. van Zele T. Gevaert P. Holtappels G. Bachert C. Endoscopic sinus surgery for type-2 CRS wNP: an endotype-based retrospective study.Laryngoscope. 2019; 129: 1286-1292Crossref PubMed Scopus (41) Google Scholar, 13Jankowski R. Nasalisation: technique chirurgicale.J Fr d’Oto-Rhino-Laryngologie. 1995; 44: 221-226Google Scholar, 14Jankowski R. Rumeau C. Nguyen D.T. Gallet P. Updating nasalisation: from concept to technique and results.Eur Ann Otorhinolaryngol Head Neck Dis. 2018; 135: 327-334Crossref PubMed Scopus (11) Google Scholar with the aim of complete removal of polyp and sinus mucosa from all sinuses involved. The latter always includes the maxillary and ethmoidal sinuses, but IT may also include the frontal and sphenoidal sinuses, including the creation of wide openings (mostly the Draf III frontal sinus approach and the sphenoid drill-out15Schick B. Draf W. The frontal sinus.in: Stucker F.J. de Souza C. Kenyon G.S. Lian T.S. Draf W. Schick B. Rhinology and facial plastic surgery. Springer Berlin Heidelberg, 2009: 567-573Crossref Scopus (6) Google Scholar,16Van Zele T. Pauwels B. Dewaele F. Gevaert P. Bachert C. Prospective study on the outcome of the sphenoid drill out procedure.Rhinology. 2018; 56: 178-182Crossref PubMed Scopus (4) Google Scholar to completely remove the sinus mucosa). It has been demonstrated that reboot surgery in severe CRSwNP leads to less recurrence than do conventional approaches12Alsharif S. Jonstam K. van Zele T. Gevaert P. Holtappels G. Bachert C. Endoscopic sinus surgery for type-2 CRS wNP: an endotype-based retrospective study.Laryngoscope. 2019; 129: 1286-1292Crossref PubMed Scopus (41) Google Scholar,17Anderson P. Sindwani R. Safety and efficacy of the endoscopic modified Lothrop procedure: a systematic review and meta-analysis.Laryngoscope. 2009; 119: 1828-1833Crossref PubMed Scopus (73) Google Scholar,18Shirazi M.A. Silver A.L. Stankiewicz J.A. Surgical outcomes following the endoscopic modified lothrop procedure.Laryngoscope. 2007; 117: 765-769Crossref PubMed Scopus (49) Google Scholar and is followed by an effective healing process with functional mucosa.12Alsharif S. Jonstam K. van Zele T. Gevaert P. Holtappels G. Bachert C. Endoscopic sinus surgery for type-2 CRS wNP: an endotype-based retrospective study.Laryngoscope. 2019; 129: 1286-1292Crossref PubMed Scopus (41) Google Scholar,19Georgalas C. Hansen F. Videler W.J.M. Fokkens W.J. Long terms results of Draf type III (modified endoscopic Lothrop) frontal sinus drainage procedure in 122 patients: a single centre experience.Rhinol J. 2011; 49: 195-201Crossref PubMed Google Scholar Should the patient and the physician opt for a biologic drug approach, the physician should decide on the possible choices among the biologics and make a choice with the informed patient, while also considering drug availability and patient-relevant questions such as practical issues with drug application. Before a surgical procedure under biologic protection is planned, a period of 6 months—and eventually 12 months if the patient’s response to the treatment is as expected or better—should be considered to enable the physician to recognize the suitability of the response to the drug in the individual patient. In as many as two-thirds of the patients under biologic treatment, a surgical procedure may no longer be considered necessary .20Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar If a surgical approach aiming at long-term disease suppression has been chosen, no biologic drug should be considered for at least 6 months, and it would be indicated only in case of recurrence. A fixed combination plan with surgery and biologic treatment starting in parallel or within a short time of one another is not advised, as the response of the individual patient to the surgery or to the biologic would be impossible to evaluate. Approaches such as a limited surgery combined with application of a biologic drug are not recommended, as such approaches would lead to maximal costs and risks of AEs and/or complications in all patients. However, if an operation has been performed and shown to be insufficient to suppress nasal polyp growth and symptoms despite continuation of INCSs, an NPS lower than 4 might be sufficient to indicate a biologic treatment. The recent SARS-CoV-2 pandemic has added further considerations for the choice of surgery versus biologics, as surgical procedures and repeated postoperative endoscopic debridement may impose a considerable risk to the medical personnel.21Jian L. Yi W. Zhang N. Wen W. Krysko O. Song W.J. Bachert C. Perspective: COVID-19, implications of nasal diseases and consequences for their management.J Allergy Clin Immunol. 2020; 146: 67-69Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar There are currently 2 biologics for which phase 3 trials have already been finalized (2 parallel double-blind placebo-controlled, randomized studies [DBPCRSs] with the anti–IL-4 receptor-alpha dupilumab [NCT02912468 and NCT02898454], 2 parallel DBPCRSs with anti-IgE and omalizumab [NCT03280550 and NCT03280537]; and 1 DBPCRS with the anti–IL-5 mepolizumab [NCT03085797]); in addition, a study of 1 drug (benralizumab) is still ongoing (NCT03401229). These studies were all based on a similar study design and included a large number of participants (N = 265-724). In all these studies, the effect of the biologic was compared with that of placebo added to continuous treatment with INCSs throughout the whole study period. Dupilumab is the first biologic to be registered in the European Union and the United States as an add-on treatment of severe CRSwNP that has not been sufficiently controlled by systemic corticosteroids and/or surgery. The patients recruited into the phase 3 studies had bilateral nasal polyps with an NPS of at least 5 of 8; had asthma in 48% to 71% of cases; had prior surgery in 54% to 100 % of cases; and were symptomatic, with impairment of smell and nasal obstruction as major symptoms. In all phase 3 trials, the primary end points (reduction in NPS and nasal congestion/obstruction score) were met with changes in the NPS between 0.7 (median, mepolizumab) and 2.4 (mean, dupilumab, Liberty 52w) over placebo after 52 weeks. The NPS reductions at 24 weeks were from 0.7 (mean, omalizumab; mean of the POLYP 1 and POLYP 2 studies) to 2.06 (mean, dupilumab, Liberty 24w). Of importance, smell was significantly improved with all drugs, albeit at different speeds and magnitudes; dupilumab demonstrated a strong and fast effect on smell, reducing the percentage of anosmic subjects from 76% at baseline to 26% after 24 weeks of treatment.20Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar Scores on the 22-Item Sino-Nasal Outcome Test, which reflects disease-specific quality of life, also improved significantly (by 14 to 21 points), clearly surpassing the minimal clinically important difference of more than 8.9. Dupilumab also showed a significant reduction in the computed tomography–based Lund-Mackey score by 5 to 7.5 points. Dupilumab and mepolizumab, in addition providing a reduction in NPS and symptoms as well as quality of life, demonstrated a reduction in the need for systemic corticosteroids and surgery over the course of 1 year of treatment versus placebo. A reduction of the NPS by at least 1 point was achieved in 50% to 65% of the verum-treated subjects over the trials. Thus, these biologics offer a new treatment approach to many patients with type 2 CRSwNP that is insufficiently controlled by INCSs. Asthma or N-ERD comorbidity also needs to be taken into consideration then. When surgery is considered, biologics should also be mentioned to the patient as an alternative; alternatively, a combination of the biologic and surgical approaches has to be discussed, with the biologic provided treatment first for reasons already discussed. As there are no head-to-head comparisons between these biologics at the moment, the choice of drug should be based on availability, potential specific limitations such as eosinophil numbers or IgE levels (for mepolizumab and omalizumab), responder rates, and expected size of effects in responders. The efficacy of sinus surgery is difficult to evaluate, as there are various forms of sinus surgery as well as opinions regarding the extent of sinus surgery. For example, the term sinus surgery is used for balloon dilation of a sinus ostium, which is a minimally invasive sinus surgery aiming just to open the sinus drainage pathway, whereas the aim of (functional) ESS is to remove polyps from the nasal cavity and sinuses, or following the mucosal concept approach, to remove all sinus mucosal tissue. Experts agree that for CRSwNP, at least ESS with opening of the ostiomeatal complex, the maxillary and ethmoid sinuses, with removal of nasal polyps and thickened sinus mucosa, should be performed. However, some recommend creating large sinus openings to all sinuses, including the frontal sinus such as described as “modified Lothrop,”22Draf W. Endonasal micro-endoscopic frontal sinus surgery: the fulda concept.Oper Tech Otolaryngol Head Neck Surg. 1991; 2: 234-240Abstract Full Text PDF Scopus (263) Google Scholar and the complete removal of the sinus mucosa described as “reboot surgery.”12Alsharif S. Jonstam K. van Zele T. Gevaert P. Holtappels G. Bachert C. Endoscopic sinus surgery for type-2 CRS wNP: an endotype-based retrospective study.Laryngoscope. 2019; 129: 1286-1292Crossref PubMed Scopus (41) Google Scholar Finally, there is variability in the extent of sinus surgery; in addition, the quality of sinus surgery may vary substantially. Because of these factors, the evidence for efficacy of ESS is and will remain low. Most of the evidence will be retrospective, with only a few prospective cohort studies using a common standardized surgical approach. Most evidence is based on 1 or few centers, possibly 1 prominent surgeon, and therefore not transferable to other centers, let alone “all surgeons or operations.” Data from the UK National Sinonasal Audit involving national centers demonstrated a surgical revision rate of 21% over 5 years.23Hopkins C. Slack R. Lund V. Brown P. Copley L. Browne J. Long-term outcomes from the english national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis.Laryngoscope. 2009; 119: 2459-2465Crossref PubMed Scopus (177) Google Scholar A recent meta-analysis by Loftus et al reported a revision rate of less than 20% across the population of individuals with CRSwNP at an average follow-up of 7.4 years, showing important differences between geographic regions (from 21.4% in Oceania to 14.90% in Asia) and comorbidities (22.6% in patients with asthma vs 8.0% in patients without asthma).24Loftus C.A. Soler Z.M. Koochakzadeh S. Desiato V.M. Yoo F. Nguyen S.A. Schlosser R.J. Revision surgery rates in chronic rhinosinusitis with nasal polyps: meta-analysis of risk factors.Int Forum Allergy Rhinol. 2020; 10: 199-207Crossref PubMed Scopus (34) Google Scholar As it will remain difficult to perform prospective multicenter randomized trials of high quality for the efficacy of sinus surgery, international registries could be of some help to evaluate real-life evidence. Sinus surgery for nasal polyposis most often debulks and removes nasal polyps, but recurrence after surgery is likely (see Table E1 in the Online Repository at www.jacionline.org); however, recurrence does not necessarily translate into revision surgery. Therefore, is it imperative to postoperatively guide the patient and maintain postoperative medical treatment to prevent polyp recurrence. Even with postoperative topical corticosteroid medical therapy, the recurrence rate may be high. In a prospective cohort study of 244 patients with ESS, 40% of nasal polyps recurred within 18 months despite postoperative medical treatment.25DeConde A.S. Mace J.C. Levy J.M. Rudmik L. Alt J.A. Smith T.L. Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis.Laryngoscope. 2017; 127: 550-555Crossref PubMed Scopus (154) Google Scholar Hence, there is a clear unmet need for other approaches to better manage patients with nasal polyposis. Here we discuss AEs related to recent phase 3 trials of dupilumab,20Bachert C. Han J.K. Desrosiers M. Hellings P.W. Amin N. Lee S.E. et al.Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.Lancet. 2019; 394: 1638-1650Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar omalizumab,26A clinical trial of omalizumab in participants with chronic rhinosinusitis with nasal polyps.https://clinicaltrials.gov/ct2/show/NCT03280550Date accessed: April 19, 2020Google Scholar, 27Gevaert P. Omachi T.A. Corren J. Mullol J. Han J. Lee S.E. et al.Efficacy and safety of omalizumab in patients with chronic rhinosinusitis with nasal polyposis: results from two, multicenter, randomized, double-blind, placebo-controlled phase III trials (POLYP 1 and POLYP 2).J Allergy Clin Immunol. 2020; 146: 595-605Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 28An extension study of omalizumab in participants with chronic rhinosinusitis with nasal polyps.https://clinicaltrials.gov/ct2/show/NCT03478930Date accessed: April 19, 2020Google Scholar and mepolizumab,29Effect of mepolizumab in severe bilateral nasal polyps.https://clinicaltrials.gov/ct2/show/NCT03085797Date accessed: April 19, 2020Google Scholar reflecting the dosing schemes that will be relevant after registration. The proportion of patients who experienced at least 1 treatment-emergent AE was lower in the verum-treated patients than in the placebo-treated patients. Most events across all studies were of mild-to-moderate intensity. AEs occurring in at least 3% of patients include headache, dizziness, abdominal pain, nasopharyngitis, and injection site reactions, being slightly more frequent in the omalizumab treated group than in the placebo group; on the other hand, asthma exacerbations, nasal polyps, and congestion occurred less frequently, without significant differences between groups. Similarly, headache and nasopharyngitis, nasal polyps with need for treatment, upper respiratory tract infections, and worsening of asthma were more frequent with placebo than with dupilumab, whereas cough, bronchitis, arthralgia, and injection site reactions were slightly more frequent in the 2 dupilumab groups than in the placebo group. None of the observations were significant. Conjunctivitis was reported in 7 patients receiving dupilumab and in 1 patient receiving placebo; none of these cases were serious, severe, or associated with treatment discontinuation. Eosinophilia occurred in 4 patients: 3 of them developed eosinophilic granulomatosis with polyangiitis (1 of them was a patient receiving placebo). In summary, biologics show a good tolerability without major AEs. About 100,000 persons undergo endonasal ESS every year in Europe, irrespective of the fact that formal and comparative evidence of the long-term effectiveness of surgical procedures is still limited. ESS for chronic rhinosinusitis is technically demanding because of the narrow anatomic spaces and the individual and puzzling microanatomy in close proximity to delicate structures such as the eye and brain. Surgeons performing ESS are faced with excusable and sometimes also avoidable mistakes and complications. These complications may be rated as minor or major complications.30Hosemann W. Draf C. Danger points, complications and medico-legal aspects in endoscopic sinus surgery.GMS Curr Top Otorhinolaryngol Head Neck Surg. 2013; 12: Doc06PubMed Google Scholar, 31Kowalski M.L. 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Emergency revisional surgery may also be necessary (eg, in case of dural defects or major orbital hematoma), and irreversible damage (eg, blindness, death) may occur in rare cases. With regard to numeric data in the literature, routine EES interventions are generally associated with minor complications in about 5% of cases and m