BACKGROUND: Dupilumab, a monoclonal antibody targeting IL-4 and IL-13, has demonstrated its efficacy in several clinical trials. However, to date, real-life data remains limited.
OBJECTIVE: The aim of our study was to assess the real-life impact of dupilumab on patients with severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) quality of life.
METHODS: This was a retrospective, monocentric, observational, real-life study, conducted in accordance with the STROBE guidelines. The following parameters were collected before treatment and at 1, 4, and 12 months: Sino-Nasal Outcome Test-22 (SNOT-22), nasal polyp score (NPS), Sniffin\' Sticks-16 (SST-16), visual analog scale (VAS) for loss of smell, nasal congestion score (NCS), gustatory VAS, asthma control, oral corticosteroid usage, surgery rates, and occurrence of side effects.
RESULTS: The study included 47 patients. SNOT-22 scores decreased from 52.4 ± 24.3 to 12.7 ± 10.5 at 12 months (p < 0.001). NPS decreased from 6.15 ± 1.71 to 1.57 ± 1.40 at 12 months (p < 0.001). SST-16 scores increased from 1.6 ± 2.83 to 9.1 ± 5.4 at 12 months (p < 0.001). NCS decreased from 2.45 ± 0.72 to 0.38 ± 0.63 at 12 months (p < 0.001). Prior to treatment, 72.3% were using oral corticosteroids, compared to 17.0% at 12 months (p < 0.01). Two patients required additional surgery, and 17% reported completely uncontrolled asthma, compared to 0% at 12 months (p < 0.01).
CONCLUSIONS: Our real-life results confirm the efficacy of Dupilumab in the treatment of severe and uncontrolled CRSwNP.

We aimed to reach an Italian multidisciplinary consensus on some crucial aspects of treatment decision making in CRSwNP, following 2 years of clinical experience in order to support specialists in the management of CRSwNP in clinical practice. We addressed issues relating to therapeutic decision-making and shared criteria for the treatment choice, as well as appropriate timing and criteria for evaluating treatment response, and highlighted the need for repeated multidisciplinary assessments.
A national survey has been conducted recently to understand how rhinology practice has changed in Italy with the advent of biologics and how this affects patients with uncontrolled, severe CRSwNP. Despite the many published consensus documents, practical recommendations, and protocols on the use of biologics in CRSwNP, heterogenous behaviors in practice are still observed mainly conditioned by the novelty of the topic. The consensus procedure followed a modified Delphi approach. The scientific board included 18 otorhinolaryngologists and 8 allergists, who selected the 4 main topics to be addressed and developed overall 20 statements. Consensus on these statements was sought by a larger group of 48 additional experts, through two rounds of voting, the first web-based, the second in presence with discussion and possible refinement of the statements. The statements reaching an average score ≥ 7 at the second voting round were approved. Five statements were proposed for each of the following topics: baseline evaluation of patients eligible for biologic therapy; choice between different therapeutic options; assessment of the response to biologic treatment; multidisciplinary management. At the first voting round, 19 out of the 20 statements reached a mean score ≥ 7. Following the discussion and a few consequent amendments, at the second round of voting all the 20 statements were approved.

BACKGROUND: Uncontrolled asthma in growing children can impair lung growth that may lead to adverse complications in later life. Dupilumab, a human monoclonal antibody, blocks the shared receptor for IL-4 and IL-13, key drivers of type 2 inflammation.
OBJECTIVE: To extensively evaluate the effect of dupilumab on lung function in children (6-11 years) with moderate-to-severe asthma enrolled in phase 3 LIBERTY ASTHMA VOYAGE (NCT02948959).
METHODS: Children with asthma were randomized 2:1 to add-on dupilumab 100/200 mg by bodyweight or placebo every 2 weeks, for 52 weeks. We analyzed spirometry parameters in children with type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥20 parts per billion [ppb] at baseline) and within subgroups defined by baseline blood eosinophils or FeNO values.
RESULTS: A total of 116 (49%) dupilumab-treated children and 59 (52%) on placebo had impaired lung function (prebronchodilator percent-predicted forced expiratory volume in 1 second [ppFEV1] <80%) at baseline. Dupilumab improved pre- and postbronchodilator ppFEV1 as early as week 2, sustained for up to 52 weeks (least-squares mean difference vs placebo at week 52: 7.79 percentage points; 95% confidence interval [CI]: 4.36-11.22; P < .001 and 4.37 points; 95% CI: 0.95-7.78; P = .01, respectively). Sustained improvements were also observed in other lung function parameters, including pre- and postbronchodilator forced vital capacity (FVC), prebronchodilator forced expiratory flow, and FEV1/FVC ratio across all populations.
CONCLUSIONS: Dupilumab led to significant, sustained lung function improvements across a range of lung function measures in children (6-11 years) with uncontrolled, moderate-to-severe type 2 asthma.

BACKGROUND: Eblasakimab, an interleukin (IL)-13 receptor α1 antagonist, blocks IL-4 and IL-13 signaling through the type 2 receptor.
OBJECTIVE: The safety and efficacy of eblasakimab was evaluated in adults with moderate-to-severe atopic dermatitis (AD).
METHODS: In this phase 1b randomized, double-blinded study, 52 patients with moderate-to-severe AD received weekly subcutaneous injections of eblasakimab 200, 400, or 600 mg, or placebo for 8 weeks. Primary outcome was the incidence of treatment-emergent adverse events. Secondary outcomes included percentage change in the Eczema Area and Severity Index from baseline; Eczema Area and Severity Index improvement of at least 50%, 75%, or 90% from baseline; and percentage change in the peak-pruritus numeric rating scale score from baseline.
RESULTS: Treatment-emergent adverse events were reported in 47% placebo and 71% eblasakimab patients; most were considered mild or moderate and did not lead to study discontinuation. At week 8 eblasakimab 600 mg showed statistically significant improvement in mean percentage change in Eczema Area and Severity Index versus placebo (-65% vs -27%, P = .014). Other key secondary physician- and patient-reported end points were met.
CONCLUSIONS: Longer studies are required to confirm eblasakimab safety and efficacy in AD patients.
CONCLUSIONS: Treatment of adults with moderate-to-severe AD with eblasakimab was well-tolerated and associated with significant clinical improvements versus placebo.

Eosinophil-derived neurotoxin (EDN) is related to childhood asthma, while normal values are lacking. We aimed to document serum EDN levels at 1 and 3 years in general and in non-atopic children, and explore if EDN levels differed by sex or were associated with preschool asthma at 3 years.
From the PreventADALL birth cohort, we included 1233 children with EDN analysed using ImmunoCAP at 1 and/or 3 years. Non-atopic children had no history of wheeze, asthma, allergic sensitization or atopic dermatitis. Preschool asthma was defined as having ≥3 episodes of bronchial obstruction between 2 and 3 years, plus doctor diagnosed asthma and/or asthma medication use by 3 years. The upper limit of normal (ULN) of EDN was defined as the 95th percentile. With Youden Index we calculated EDN cut-off levels for risk of preschool asthma.
The overall median (ULN) EDN levels were 27.4 (121) μg/L at 1 year (n = 787), and 20.1 (87.8) μg/L at 3 years (n = 857). Non-atopic children had EDN levels of 24.0 (107) μg/L at 1 year (n = 147), and 17.3 (84.6) μg/L at 3 years (n = 173). EDN levels were higher in boys compared to girls; 32.0 (133) versus 24.5 (97.0) μg/L at 1 year, and 20.9 (96.3) versus 19.0 (72.4) μg/L at 3 years. Preschool asthma was observed in 109/892 (12.2%) children. Higher EDN levels at 1 (>26.7 μg/L) and 3 (≥20.5 μg/L) years were associated with preschool asthma; adjusted OR (95% CI) 2.20 (1.09, 4.41) and 4.68 (2.29, 9.55), respectively.
We report EDN values in early childhood, demonstrating higher levels at 1 compared to 3 years and in boys compared to girls at both ages. Higher EDN levels at both ages were associated with preschool asthma. However, EDN cut-off levels for preschool asthma were overall lower than the ULN of non-atopic children, limiting translation into clinical practice.

BACKGROUND: Recovery of olfactory function plays a prominent role in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). While rates and timing of such recovery vary, monoclonal antibodies might yield better results which we aimed at evaluating with this study.
METHODS: A prospective controlled study was conducted at our tertiary otolaryngological center from April 1, 2021, to October 1, 2022, in CRSwNP patients. We included an active group (n = 60 patients) performing dupilumab treatment and a control group (n = 60 patients) treated with intranasal and oral corticosteroids. Primary endpoints were changes in smell visual analogical scale (VAS) and SS-I (Sniffin\' Sticks-identification) scores, and olfactory recovery rate. The secondary efficacy endpoints were nasal obstruction, rhinorrhea, headache, SNOT-22, and nasal congestion score (NCS).
RESULTS: At 6 months, the active group demonstrated better outcomes than control in SS-I scores (10.23 ± 4.21 vs.3.68 ± 3.08; p < 0.001). No significant differences were found in blood eosinophil count, SNOT-22, and NPS (p > 0.05 for all). Olfactory function in the treatment arm improved in 86.66% (52/60 cases), with normal scores in 48.33% (29/60), while the control group reported a lower recovery rate (3/60; 5%), with no normal olfaction cases. Log-rank comparison for Kaplan-Meier functions was statistically significant (p < 0.001), but no differences were found in subanalysis in the active group based on blood eosinophil count at baseline, SNOT-22, and NPS scores.
CONCLUSIONS: Patients who receive dupilumab treatment may experience a faster recovery of olfactory function compared to those receiving corticosteroid therapy. This result would be maintained regardless of the severity of type 2 CRSwNP inflammation, the volume of the polyps, or the patient\'s subjective symptomatology.

UNASSIGNED: Chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) are frequent coexisting conditions and share type 2 inflammatory pathophysiology, with interleukin (IL)-4 and IL-13 as key cytokines. Dupilumab is a monoclonal antibody that blocks the shared receptor for IL-4 and IL-13. The objective of this analysis was to evaluate dupilumab\'s effect on type 2 inflammation biomarkers in patients with CRSwNP with/without coexisting asthma or NSAID-ERD from the SINUS-52 (NCT02898454) study.
UNASSIGNED: Patients received treatment with dupilumab or placebo for 52 weeks. Blood and urinary biomarkers were evaluated through 52 weeks, and nasal secretions and mucosa brushings through 24 weeks.
UNASSIGNED: Of 447 patients, 60% had coexisting asthma and 27% had coexisting NSAID-ERD. At baseline, blood eotaxin-3, eosinophils, and periostin, nasal secretion eotaxin-3, and urinary leukotriene E4 were significantly higher in patients with coexisting NSAID-ERD than without. Dupilumab reduced eotaxin-3, thymus and activation-regulated chemokine, periostin, and total immunoglobulin E in blood, eotaxin-3, periostin, IL-5, and eosinophil cationic protein in nasal secretions, and leukotriene E4 in urine. Reductions were generally similar or greater in the subgroups with asthma and NSAID-ERD than without. Dupilumab also reduced MUC5AC and mast cell counts in nasal mucosa brushings.
UNASSIGNED: Dupilumab reduced local and systemic type 2 inflammatory biomarkers in patients with CRSwNP, including mast cells in nasal mucosa and cysteinyl leukotrienes in urine. These findings provide insight into the processes driving CRSwNP and the mechanisms of dupilumab\'s therapeutic effects.
UNASSIGNED: SINUS-52 https://www.clinicaltrials.gov/ct2/show/NCT02898454.
UNASSIGNED: NCT02898454.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective.
METHODS: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61.
RESULTS: After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease.
CONCLUSIONS: This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.

BACKGROUND: Scientific evidence on patients with multimorbid type 2 asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) from a united airways disease (UAD) perspective remains scarce, despite the frequent coexistence of these entities. We aimed to generate expert consensus-based recommendations for the management of UAD patients.
METHODS: Using a two-round Delphi method, Spanish expert allergists, pulmonologists and otolaryngologists expressed their agreement on 32 statements (52 items) on a 9-point Likert scale, classified as appropriate (median 7-9), uncertain (4-6) or inappropriate (1-3). Consensus was considered when at least two-thirds of the panel scored within the range containing the median.
RESULTS: A panel of 30 experts reached consensus on the appropriateness of 43 out of the 52 (82.7%) items. The usefulness of certain biomarkers (tissue and peripheral blood eosinophil count, serum total IgE, and fraction of exhaled nitric oxide [FeNO]) in the identification and follow-up of type 2 inflammation, and assessment of the response to biologics, were agreed. Some of these biomarkers were also associated with disease severity and/or recurrence after endoscopic sinus surgery (ESS). Consensus was achieved on treatment strategies related to the prescription of anti-IL-4/IL-13 or anti-IgE agents, concomitant treatment with systemic corticosteroids, and combining or switching to biologics with a different mechanism of action, considering a number of UAD clinical scenarios.
CONCLUSIONS: We provide expert-based recommendations to assist in clinical decision-making for the management of patients with multimorbid type 2 asthma and CRSwNP. Specific clinical trials and real-world studies focusing on the single-entity UAD are required to address controversial items.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease, which is usually type 2-mediated in the western hemisphere, associated with severe therapeutic and socioeconomic challenges. The first targeted systemic treatment option for severe uncontrolled CRSwNP is a human monoclonal antibody against the interleukin-4 receptor α (IL-4Rα) subunit called dupilumab, which was approved for subcutaneous administration in Germany in October 2019. The purpose of this study is to investigate the efficacy of dupilumab in real life in patients treated with dupilumab in label according to license in our department in 2019-2021.
METHODS: Since October 2019, we have investigated 40 patients (18 men, 22 women) treated with dupilumab in a single-center, retrospective single-arm longitudinal study. The following parameters were collected before treatment (baseline), at 1 month, 4 months, 7 months, 10 months, and 13 months: the Sino-Nasal Outcome Test-22 (SNOT-22), the forced expiratory pressure in 1 s (FEV-1), the olfactometry using Sniffin\' Sticks-12 identification test (SSIT), a visual analog scale of the total complaints, the Nasal Polyp Score (NPS), histologic findings as well as total serum IgE, eosinophilic cationic protein in serum and blood eosinophils.
RESULTS: The average age was 52.7 years (± 15.3). The follow-up period was 13 months. The SNOT-22 average was 60 points (± 22.2) at the first visit, 28.2 points (± 17.1) after 4 months and 20.8 points (± 17.7) after 13 months. The NPS was 4.3 points (± 1.5), after 4 months 2.1 points (± 1.3) and after 13 months 1.4 points (± 1.1). Olfactometry showed 3.2 points (± 3.7) at the baseline, 7.0 points (± 4.0) after 4 months and 7.8 points (± 3.5) after 13 months. The other parameters also improved. Most parameters showed linear dependence in the slopes under therapy (p < 0.001). Adverse side effects were mostly only mild, and no rescue therapy was needed.
CONCLUSIONS: There is a clear improvement in the medical condition and symptoms in all categories mentioned under therapy with dupilumab, as well as a reduction in the need for systemic glucocorticoids and revision surgery as rescue treatment. Our results show that dupilumab tends to be an effective therapy alternative for severe CRSwNP.