## 2 Materials and Methods  
### Population  
The present investigation consists of a retrospective study in a real-life setting involving the rhinological unit of Padua University. The study was conducted in accordance with the 1996 Helsinki Declaration and was approved by each Hospital ethical committee (5304/AO/22). Informed consent on personal data collection and use for research purposes was obtained from each subject before starting the treatment, as routinely done in our Rhinological Unit for every patient initiating dupilumab for CRSwNP. Inclusion criteria were defined as follows: (1) age \(\geq\) 18 years; (2) diagnosis of severe chronic rhinosusitis with nasal polyps (CRSwNP), defined by a nasal polyp score (NPS) \(\geq\) 5 and/or a Sinonasal Outcome Tests-22 (SNOT-22) \(\geq\) 50 with inadequate symptoms control despite the use of intranasal corticosteroids (INCS), receiving at least two cycles of systemic corticosteroid in the previous 12 months and/or having undergone one or more endoscopic sinus surgery (ESS) (according to The Italian Medicine Agency cut-off for dupilumab reimbursement); (3) biological therapy administration (dupilumab 300 mg, one subcutaneous injection every 15 days) for at least 6 months; (4) NPS and M-LKS collection at each timepoint.  
Severe uncontrolled CRSwNP was diagnosed in accordance with the criteria of the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 [3]. All patients included in the study were regularly using intra-nasal corticosteroids (INCS) before and throughout the whole study period. The INCS active principles included were either montasone furoate 50 ug 2 sprays in each nostril once or twice a day or budesonide 100 ug 1 spray in each nostril once a day. Asthmatic patients regularly used a combination of long-acting beta agonist (LABA) and inhaled corticosteroids (ICS) and never discontinued the treatment.  
Data were collected at the following timepoints: baseline (before the biological treatment was begun) (T0), 1 month (T1), 3 months (T2), 6 months (T3), 12 months (T4), 18 (T5), and 24 months (T6) after starting the treatment.  
Demographic data, clinical and surgical history, inhalants allergy, smoking habit, and the number of oral corticosteroids (OCS) short courses in the previous 12 months were collected at T0. At baseline and at each follow-up, the following PROMs were collected to estimate patients' QoL and symptoms burden: SNOT-22 questionnaire [14], visual analogue scale (VAS) for nasal obstruction (VAS-NO), smell impairment (VAS-Smell), facial pain (VAS-facial pain), and sleep disturbance (VAS-sleep) [15]. Furthermore, the following CROMs were collected: peak nasal inspiratory flow (PNIF) meter (Clement Clark International, Mountain Ash, UK), to evaluate nasal patency [16]; Sniffin' Sticks identification sub-test (SSIT) (12 odors) (Burghart Messtechnik GmbH, Holm) [17], to categorize the smell impairment into anosmia, hyposmia and normosmia.  
All the patients underwent nasal endoscopy using a 0o and or 3o rigid endoscope, during which NPS and M-LKS were collected. The first focuses on NP size and distribution, evaluating each nasal fossa separately and scoring from 0 (no polyps) to 4 (large polyps causing complete obstruction of the inferior meatus), thus providing a total score ranging from 0 to 8 [8]. The second one investigates three items on each side, consisting of NP size and distribution, mucosal edema severity, and nasal discharge characteristics, with a score ranging from 0 to 2 to each item, thus providing a total score ranging from 0 to 12 (Figure 1). Blood eosinophil was evaluated at baseline and at each timepoint [9].