The Global Airways registry included all patients referred to ENT departments for possible eligibility for biologic treatment from November 2022. Nine of ten ENT departments in Denmark applied for approval to treat with biologics and all patients were referred either from a private ENT, a secondary ENT department or a secondary asthma clinic. Treatment was initiated in patients with confirmed CRSwNP (28) who meet four mandatory criteria: 1) presence of bilateral NPS; 2) ESS under general anesthesia within the last three years (or contraindication to surgery); 3) signs of T2 inflammation; and 4) self-reported adherence to intranasal corticosteroids (INCS) >80%. Signs of T2 inflammation were defined as 1) high blood eosinophil count (defined as a current count ≥0.25 × 10⁶ /L or a history of ≥0.30 × 10⁶ /L); 2) moderate or severe tissue eosinophilic cell counts [10–100 or >100 per high-power field (hpf)]; 3) IgE >100 kU/L; or 4) FeNO >50 parts per billions (ppb). Adherence to INCS was assessed by the Medication Adherence Report Scale [MARS-5] and an in-house self-reported questionnaire. Furthermore, patients were required to fulfill at least three of five additional criteria: A) two courses of SCS (25–37.5 mg for 5–7 days, or 34 mg depot injection), or low dose SCS (5–10 mg) for one period of 3 months per year, or a contraindication to SCS (e.g., osteoporosis, diabetes); B) a SNOT-22 score ≥ 50; C) Sniffin’ Sticks 16 (SST-16) result ≤8; D) NPS ≥5; or E) asthma diagnosed and treated with inhaled corticosteroids (ICS).

Patients who met all four mandatory criteria (1–4) and at least three of the five additional criteria (A–E) were offered biologic therapy. Exceptions were granted for a few patients for medical reasons, including CRSwNP with concomitant Pott's puffy tumor or mucocele, contraindication to INCS due to central serous chorioretinopathy (CSCR), current successful treatment in a randomized controlled trial (RCT), inability to fill out questionnaires due to intellectual disability or documented anxiety preventing surgery. Patients who did not meet the eligibility criteria could be re-screened at future timepoints. Females planning pregnancy were advised to refrain from biologic treatment.

All patients gave informed consent to having their data included in the national database. The study was approved by the Danish Research Ethics Committee (H-21020685) and conducted under a data protection agreement (P-2021-193, Global Airways).

Patients received either mepolizumab (100 mg every 4 weeks) or dupilumab (300 mg every 2 weeks for 6 months and subsequently every 4 weeks). Mepolizumab is the reimbursed first-choice biologic for CRSwNP in Denmark, but many patients received dupilumab as they were participating in an ongoing head-to-head randomized trial of mepolizumab vs. dupilumab (TORNADO; EU clinical trial ID 2022-50-22-50-14-00). Omalizumab is reimbursed in Denmark in case of pregnancy but has not yet been used in this study. To maintain the integrity of the ongoing TORNADO RCT, differences in outcomes between mepolizumab and dupilumab were not analyzed in this current study.

Continuation of treatment at six and 12 months is guided by Danish authority-defined response criteria: 1) reduction in NPS of ≥1 point at 6 months or ≥2 points at 12 months; 2) reduction in SNOT-22 score of ≥12 points; 3) change from anosmia (0–8) to normosmia (9–16) as measured by SST-16; and 4) reduction in Asthma Control Questionnaire (ACQ) of ≥0.5 points. Continuation of biologic therapy required patients to meet at least two out of these four criteria. Patients scoring below two points at six months may have continued treatment based on medical indication. Treatment was discontinued if a patient required rescue therapy, such as ESS or SCS.

Demographic and lifestyle data were collected for all patients, including sex, height, weight, and body mass index (BMI). Smoking status was recorded as current, never, or ex-smoker (≥6 months abstinent). Sinonasal examination included rhinoscopy performed by an ENT specialist, with NPS scored from 0 to 4 on each side (29). Current treatments for CRSwNP were documented, including adherence to INCS, use of nasal saline irrigation, and use of SCS. Olfactory function was evaluated using the SST-16 test, with scores ≤8 indicating anosmia and 9–16 indicating hyposmia/normosmia. NSAID-exacerbated respiratory disease (N-ERD) was recorded based on patient-reported symptoms, without provocation testing. All patients were evaluated for allergic rhinitis, defined as symptoms and a positive allergy test (30).

Bronchial assessment included specialist evaluation for asthma, defined by symptoms and a positive asthma challenge test (reversibility testing and bronchial challenge testing with mannitol or methacholine) (31). ICS were initiated or continued as clinically required. Spirometry [forced expiratory volume in 1 s [FEV₁], forced vital capacity [FVC] and FEV₁/FVC ratio] was performed with predicted values calculated in REDCap. Fractional exhaled nitric oxide (FeNO) measurements were performed by the ENT clinic. T2 inflammation was defined as described in the eligibility criteria.

All patients completed patient outcome questionnaires, including SNOT-22, ACQ-5/7, and visual analog scale (VAS) scores for CRS, asthma, smell function, and N-ERD (VAS scores ranged from 0 to 100, with 100 denoting the worst severity).

A full list of outcomes collected as part of the registry are provided in Supplementary Appendix A1.

Each participating ENT department was responsible for the systematic assessment of both upper and lower airways. The registry included licensed use of the SNOT-22, Asthma Control Test (ACT), and ACQ instruments. Prior to the initiation of the registry, local meetings were held at all sites to train staff in Global Airways diseases, systematic assessments, local treatment with INCS and ICS, and the workflow of the registry, which has been developed as a clinical support tool.

Research staff assigned a unique identification number to each patient, including a suffix denoting the geographic region of assessment. Data could be entered in the Global Airways registry by trained airway nurses, by patients using a QR code, or by physicians. Data entry did not need to be completed in a single session, and examinations could be split across multiple visits, with dates recorded for each assessment. All data from the baseline evaluation was entered into the registry and the program generated a recommendation on whether to initiate biologic treatment.

All evaluations described above were repeated every 6 months. An additional shorter visit was conducted 4 months after initiation of biologic therapy with a focus on systemic or local side effects.

Full details of all registry procedures are provided in Supplementary Appendix A2.

All analyses were performed using SAS Enterprise Guide version 8.3. Standard descriptive statistics were calculated for all variables. Between-group comparisons for continuous variables were conducted by means of the Student's t-test or Kruskal–Wallis test as appropriate, while the chi-squared test was applied when comparing categorical variables. Within-group comparisons were performed using the paired Student's t-test. For normally distributed data, the Student's t-test was used for continuous variables, and Pearson chi-squared test for categorical variables. The Mann–Whitney U test was applied for variables that were not normally distributed.

Quality control of the registry was performed by comparing the number of required fields to the actual data entered for variables including height, weight, NPS, SNOT-22, VAS scores, SST-16 scores, ACQ, ACT, FEV₁, FeNO, IgE, eosinophilic cell count, and treatment adherence.

Overall, 513 patients with CRS were referred to participating ENT departments and screened for eligibility for biologic treatment (Figure 1). Of these, 310 (60%) patients initiated treatment with biologics (mepolizumab 55%, dupilumab 45%) between November 2022 and December 2024, with 279 (54%) patients meeting the mandatory and additional criteria, and an additional 31 (6%) permitted to initiate treatment based on exceptions to the criteria. The remaining 203 patients did not fulfill the eligibility criteria and were subsequently excluded from the registry. At the data cutoff (December 2024), 237 and 160 patients had received ≥6 or ≥12 months of treatment with a biologic.

Quality control for data entry showed that at baseline, the mean proportion of missing data was 5.16%, ranging from 0.89% for NPS to 16.11% for ACQ-7. After 6 months follow-up, the mean proportion of missing data was 3.63%.

Baseline characteristics of the 310 patients who initiated biologic treatment are shown in Table 1. Patients had a mean age of 49.7 years, mean BMI of 27.3 kg/m², and were predominantly male (66%). Furthermore, 105 (34%) were never smokers and 26 (8%) were current smokers. Overall, 204 (66%) suffered from asthma, 175 (56%) were diagnosed with allergic rhinitis, and 95 (31%) claimed a diagnosis of N-ERD. Patients with asthma had a mean (SD) ACQ-5 score of 2.1 (1.5), a mean (SD) ACT score of 17.2 (5.19) and a mean (SD) VAS asthma score of 60.2 (23.0). Overall, 187 (92%) patients with asthma had uncontrolled asthma (defined as an ACQ-5 score >1.2). Lung function measurements showed a mean (SD) FEV₁% pred of 94.5% (18.1%), FEV₁/FVC ratio of 69.5% (9.88%) and FeNO of 42.1 (39.0) ppb. Atopy was reported in 50% of patients.

The mean (SD) number of previous ESS was 2.4 (1.8) and the mean (SD) NPS was 4.8 (1.7). Mean (SD) patient-reported outcomes were 68.7 (18.7) for SNOT-22 score, 84.1 (16.2) for VAS CRS, 91.3 (19.4) for smell dysfunction VAS, 82.9 (28.6) for VAS N-ERD symptoms, and 4.8 (3.1) out of 16 for SST-16 score. Median Nasal Congestion Score (NCS) was 3 (range 1–3). Overall, 95% of patients had a SNOT-22 score >40% and 89% had an SST-16 score ≤8. The mean (SD) blood eosinophilic cell count was 0.7 × 10⁶ /L (4.3), and eosinophilic cell counts in polyp tissue were low in 16% of patients, moderate in 37% and high in 46%. All patients met the mandatory criteria of T2 inflammation.

Patients who met the criteria for biologic treatment had significantly greater disease severity (SNOT-22, VAS CRS and Smell) and more severe asthma (ACQ-5, ACQ-7, ACT) than those who did not meet the criteria (Table 1).

After six months of treatment, 194 of 237 patients (81%) met the continuation criteria (Figure 1), with 58 meeting two of the four criteria, 73 meeting three, and 63 meeting all four. Among the 43 patients who did not meet the threshold, 38 met only one criterion and five did not meet any. Of these 43 patients, 33 patients were switched to the alternative biologic while 10 continued treatment despite not meeting the criteria due to specific medical considerations. After 12 months, 134 of 160 patients (84%) met the continuation criteria, with 34 meeting two criteria, 48 meeting three, and 52 meeting all four. Among the 26 patients who did not meet the continuation threshold, 17 met only one criterion and nine did not meet any. Of these 26 patients, 16 were switched to the alternative biologic while 10 continued treatment due to medical considerations. No patients required either SCS or re-operation during the 12-month period.

Over the first 6 months of treatment, statistically significant improvements in multiple clinical outcomes were observed, including decreases in SNOT-22 score (68 to 29), VAS CRS (84 to 40), ACQ-5 (2.1 to 0.9) and FeNO (40.4 to 27.3) and increases in SST-16 smell score (4.7 to 9.1) (Table 2). The proportions of patients meeting the individual continuation criteria are shown in Table 3. A SNOT-22 reduction ≥12 points was reported by 193 patients (81%), a reduction in NPS by ≥1 point was reported by 167 patients (71%) and a reduction in ACQ-5 by ≥0.5 was reported by 133 patients (56%). The proportion of patients with an SST-16 smell score of 9–16 indicating normosmia increased from 11% to 51%.

Among patients with ≥12 months of treatment (n = 160), a reduction in disease burden (both upper and lower airway involvement) was observed over the 12 months follow-up (Figure 2). Overall, SNOT-22 reduced from 68 at baseline to 29 at month 6 and 24 at month 12, NPS reduced from 5.1 to 3.0 and 2.4, the SST-16 smell score increased from 4.7 to 9.2 and 10.0, ACQ-5 reduced from 2.3 to 1.0 and 0.8, and FeNO normalized from 40.0 to 27.5 and 25.5. Statistically significant improvements from baseline to month 12 were observed for most parameters (Table 4).

No serious adverse reactions were reported for dupilumab or mepolizumab by the 160 patients who received treatment for ≥12 months. Twenty-four patients reported milder side effects.