More than half of CRSwNP patients treated with dupilumab experience olfactory improvement within 28 days To the Editor,Olfactory dysfunction is one of the main complaints of patients suffering from Chronic Rhinosinusitis with Nasal Polyps, significantly affecting their quality of life. Dupilumab has proven to effectively enhance olfactory function within six months of treatment (1-3). However, the speed and efficacy of this effect on olfactory function improvement within the initial weeks of treatment has yet to be determined.The data reported in this letter stem from a prospective observational cohort (PolyREG) aimed to evaluate the therapeutic efficacy of biological therapy in chronic rhinosinusitis with nasal polyps. Eligible patients from this cohort were treated with dupilumab subcutaneously (300mg 1x/2 weeks) for chronic rhinosinusitis with nasal polyps in our tertiary centre. Patients were asked to use the Galenus Health App reporting Visual Analogue Scale (VAS) scores of their complaints in their Health Diary (4, 5). With special regard to olfaction, the question ‘How much does your smell loss bother you today?’ was answered with a VAS score ranging from 0 to 10 (cm) (0 being not bothersome at all, 10 the most bothersome thinkable) with a cut-off of >5.2 for olfactory dysfunction (hyposmia or anosmia) (6). In total, 72 patients filled out a VAS score on olfactory dysfunction at baseline and at least one other day during the first 28 days of dupilumab treatment. Also, the outcomes of the Sniffin’ Sticks-12 Identification test were collected at baseline and after 28 days of treatment.Baseline demographics of these 72 patients were comparable to the complete prospective cohort described by van der Lans et al (1) (data not shown). At baseline, the median Sniffin’ Sticks-12 Identification Test score was 3 (IQR 2) indicating anosmia. After 28 days, the median Sniffin’ Sticks-12 Identification Test score was 6 (IQR 6, Wilcoxon signed-rank test: p<0.001). 93.7% of patients reported a Visual Analogue Scale score on olfaction of >5.2, indicating olfactory dysfunction. Over the subsequent 28 days of treatment, this percentage significantly declined to 44.2% (Figure 1A: Pearson Correlation r=0.924, p<0.001). 50% of the patients scored >6, indicating hyposmia or normosmia (Figure 1B). The mean VAS score in the first week of treatment significantly predicted the outcome of the Sniffin’ Sticks-12 Identification Test after four weeks of treatment (linear regression F(1,97)= 6.7, p=0.012). As such, the data show a rapid olfactory function improvement in more than half of the patients treated with dupilumab, starting after 1-2 injections.Lastly, a retrospective analysis of these 72 patients’ medical records was conducted to see if olfactory function improvement was previously reported during a course of oral corticosteroids prior to the initiation of dupilumab treatment. Subsequently, data was available for 63 of 72 patients. These patients were categorized into either the oral corticosteroid-responsive (n=51) or oral corticosteroid-unresponsive (n=12) group. Stratifying for oral corticosteroid-responsiveness showed enhanced results of dupilumab treatment in the oral corticosteroid-responsive group (Figures 1A and 1B). At best, 70.8% of patients in the oral corticosteroid-responsive group had a VAS score of ≤5.2 compared to 16.7% in the oral corticosteroid-unresponsive group and 55.8% of the total cohort.While acknowledging the limitations of the study, including a relatively small patient group, missing data in the Health Diary, a cut-off corresponding not directly to Sniffin’ Sticks-12 Identification Test and the setting in a tertiary medical center, the implications of our findings are profound. Dupilumab emerges as a fast and efficacious treatment option for improving olfactory function in patients with chronic rhinosinusitis with nasal polyps. Our data also suggest a potential need for stratification of treatment response based on oral corticosteroid responsiveness, as more patients experience olfactory function improvement if they ever had olfactory function improvement upon oral corticosteroids.(600 words)

Algorithm for the management of Primary Diffuse Chronic RhinosinusitisW.J. Fokkens1, , E. de Corso2 , P.W.Hellings3,4, R. J. Harvey5,6, C. Hopkins7, S. Reitsma11 Amsterdam UMC, University of Amsterdam, Department of Otorhinolarynogology, Amsterdam2. Unit of Otorhinolaryngology and Head-Neck Surgery, ”A. Gemelli” University Hospital Foundation IRCCS, 00168 Rome, Italy.3. University of Leuven, Department of Otorhinolaryngology, Leuven,4.The European Forum for Research and Education in Allergy and Airway Diseases Scientific Expert Team Members, Brussels, Belgium.5. Rhinology and Skull Base Research Group, St Vincent’s Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.6. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.7. King’s College London, London, UK.

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals, and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment, and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications, and considerations that are of importance to the patient, the physician, and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.

Background: Chronic rhinitis (CR) is currently defined as at least two nasal symptoms present for at least 1 hour per day for more than 12 weeks per year. Such definition lacks evidence-based foundation. Depending on the most troublesome symptom, CR patients are often divided into ‘runners’ and ‘blockers’, although the evidence supporting such subdivision is limited. The aim of the current study was to define CR, and to estimate its prevalence and the prevalence of the ‘runners’ and ‘blockers’ subtypes. Methods: Cross-sectional, questionnaire-based study in a random sample of participants representing the general population of the Netherlands. Results: The questionnaire was sent to 5000 residents; the response rate was 27%. CR was defined as at least 1 nasal complaint present for more than 3 weeks per year. The prevalence of CR in the general population was 40%. Participants who were excluded by the former CR definition (i.e. nasal complaints present for less than 1 hour per day, only one complaint, duration of complaints for 3-12 weeks per year) were shown to have a significantly higher VAS compared to the control group. The larger part of CR group was represented by non-allergic rhinitis (NAR): 70% vs 30%. There were 25% ‘Blockers’ and 22% ‘Runners’ in the CR group, whereas more than a half of the CR group could be classified in neither of these subgroups. Conclusion: Based on our data, we propose a new definition of CR: at least one nasal complaint present for at least 3 weeks per year.