Background: Macrophages, as one of the most abundant immune cells in the lung, has drawn great attention in allergic asthma. Currently, most studies emphasize on M2 polarization bias. However, the function of macrophages in allergic asthma is still controversial. IL-9 contributes to the development and pathogenesis of allergic airway inflammation. We sought to investigate the IL-9-producing macrophage subset and its role in allergic asthma. Methods: The model of OVA-induced allergic airway inflammation was employed to evaluate IL-9 production in macrophages of lung tissues. We used 22 cytokines or stimuli to screen for IL-9-producing mouse macrophage subset in vitro, and real-time PCR, flow cytometry, ELISA, immunofluorescence and RNA-seq to explore the M(IL-33+IL-2) subset. Mice with Lyz-IL-33 receptor conditional knockout and adoptive transfer M(IL-33+IL-2) were used to characterize the potential roles of M(IL-33+IL-2) in allergic airway inflammation. Results: We identified a unique pathogenic IL-9-producing macrophage subset in OVA-induced allergic airway inflammation. We found that only IL-33 significantly induced IL-9 production in mouse macrophages, and IL-2 collaborated with IL-33 to promote macrophages to produce IL-9, referred to as M(IL-33+IL-2). Importantly, human monocyte-derived macrophages produced IL-9 after IL-33 and IL-2 stimulation. Using mice with Lyz-IL-33 receptor conditional knockout and adoptive transfer of M(IL-33+IL-2), we found that M(IL-33+IL-2) significantly promoted pathogenesis in OVA-induced allergic airway inflammation. M(IL-33+IL-2) subset has a distinctive gene expression profile with high expression of cytokines and M(IL-33+IL2) polarization is dependent on JAK2-STAT3-IRF1 pathway. Conclusions: The identification of M(IL-33+IL-2) subset extends the diversity and heterogeneity of macrophage subsets, and may offer novel therapeutic strategies for treatment of allergic inflammation.

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.

Although airway remodeling in severe and/or fatal asthma is still considered irreversible, its individual components as a cause of clinical symptoms and/or lung function changes remain largely unknown. While inhaled glucocorticoids have not consistently been shown to affect airway remodeling, biologics targeting specific pathways of airway inflammation have been shown to improve lung function, mucus plugging, and airway structural changes that can exceed those seen with glucocorticoids. This superiority of biologic treatment, which cannot be solely explained by insufficient doses or limited durations of glucocorticoid therapies, needs to be further explored. For this field of research, we propose a novel classification of the potential effects of biologics on airway remodeling into 3 temporal effects: early effects (days to weeks, primarily modulating inflammatory processes), late effects (months to years, predominantly affecting structural changes) and potential preventive effects (outcomes of early treatment with biologics). For the identification of potential preventive effects of biologics, we call for studies exploring the impact of early biological treatment on airway remodeling in patients with moderate-to-severe asthma, which should be accompanied by a long-term evaluation of clinical parameters, biomarkers, treatment burden, and socioeconomic implications.

Remission is the desired outcome following OIT as it allows individuals to discontinue treatment and eat the allergen freely. Early initiation of OIT in infants and toddlers has been embraced as an approach to increase the likelihood of remission. However, there is no high-quality evidence supporting younger age as an independent factor driving remission; available studies are limited by small samples of younger subjects and lack of adjustment for confounding covariates, particularly peanut-specific IgE (sIgE) levels which is closely correlated with age. This study examined relationships between peanut sIgE and age at baseline and remission, in children aged 1-10 who completed 18 months of OIT in the PPOIT-003 RCT (n=162). Remission was defined as absence of clinical reactivity to peanut after 8 weeks of allergen avoidance/treatment discontinuation. Age and sIgE were examined as continuous variables in univariate and multivariate regression models. Baseline peanut sIgE levels were significantly associated with remission, independent of age (OR 0.1 [0.05-0.22], p<0.001). Higher peanut sIgE was consistently predictive of lower likelihood of remission, independent of age. In contrast, there was no independent association between age and remission after adjusting for baseline sIgE (OR 0.94 [0.79-1.12], p=0.5). Findings do not support age as an independent predictor of remission following OIT. Additional studies examining safety and efficacy of OIT in infants and younger children are urgently needed, ahead of widespread adoption of early intervention.

Background: Subcutaneous immunotherapy has emerged as an effective option for treating allergic diseases. Here, we assessed the clinical impact of the mannan-conjugated birch pollen polallergoid T502 in birch pollen-induced allergic rhinoconjunctivitis. Methods: In this prospective, randomized, double-blind placebo-controlled phase III trial, 298 birch pollen–allergic adult patients were treated across 28 trial sites in Germany. Patients received either placebo or 23,000 mTU T502 subcutaneously over five pre-seasonal visits. Efficacy was assessed by comparing the combined symptom and medication score (CSMS) between placebo and T502 during the peak birch pollen season 2022. Safety, tolerability and immunologic effects were also analysed. Results: During the peak birch pollen season, the median CSMS of the T502 group was reduced by 33.00% (p=0.002) compared to placebo. The median daily symptom score and daily medication score were reduced by 30.43% (p<0.001) and 56.25% (p=0.045), respectively. Health related quality of life improved as reflected by reduction of RQLQ values by 31.54% (p<0.0001). Production of Bet v 1 sIgG4 and sIgG increased up to 6.2-fold and 3-fold respectively in the T502 group (p<0.0001). The sIgE/sIgG4 ratio was strongly reduced in the T502 group at V7 (-62.90%, p<0.0001). No fatalities nor serious adverse events were reported. In total, 16 systemic allergic reactions occurred (Grade I/II). Conclusions: Treatment with T502 significantly reduced symptoms and medication need in rhinoconjunctivitis patients. The treatment is well tolerated and safe.

Epidemiological survey on oral allergy syndrome in patients with seasonal allergic rhinitis

Efficacy and safety profile of animal dander immunotherapy: a multicentre UK studyTo the Editor,The prevalence of animal dander sensitisation has increased worldwide, with sensitisation rates in Europe as high as 26.3% to cat dander and 27.2% to dog dander.1 These aeroallergens can be found in environments such as schools, public transport or places of work, where the animals do not live and sensitisation may occur by direct or indirect contact.2 The recommended treatment for most patients in the UK is avoidance, which is not always practical or possible, particularly in public areas or places of work.Evidence for animal dander allergen specific immunotherapy (AIT) is limited, with cat dander AIT demonstrating the most consistent improvement after 12 months in a small study.3 Studies of dog dander AIT over the past 40 years have not confirmed statistically significant clinical efficacy.3,4 Other therapies described include horse dander and rat epithelium AIT.5,6In view of the limited data on animal AIT, we conducted a multi-centre review. Data on 35 patients aged 17 to 62 years (demographics in Table s1) treated with cat, dog and horse dander subcutaneous (SCIT) or sublingual (SLIT) AIT within five allergy services was analysed. All patients had confirmation of sensitisation by specific IgE or skin-prick testing. The commonest reason for AIT was workplace exposure, almost a third of which were veterinary workers (Supplementary Table s2). Efficacy was measured with different methods across different patients (Table 1). Side effects are reported in Table 2.Our data shows a higher compliance rate for SCIT patients, with 3-year completion rates at 60% compared with SLIT at 43%, accounting for 4 patients currently on treatment, which aligns with published data (Table 1). The most common reason for incomplete therapy was loss to follow-up and there were varied reasons for this (Supplementary table S3).For those who completed the full 3-year therapy, there were excellent efficacy rates for both SCIT and SLIT with 100% of patients achieving either complete or partial response (Table 2). Patient reported symptoms was the most used indicator of efficacy. A negative in-hospital cat challenge was performed in one patient and a negative home dog provocation in one patient. Efficacy was better in SCIT, with 100% complete response compared with 67% complete response in SLIT. All products established a complete response, except Oralvac cat and horse.The side effect profiles were acceptable with only one patient receiving cat dander SCIT reporting systemic side effects of rhinitis and wheeze during updosing. This patient completed updosing but did not complete maintenance therapy due to side effects. The majority of reported side effects were limited to localised reactions (Table 2). 3 SLIT patients withdrew from treatment due to undocumented side effects. Overall, 23/35 (66%) patients reported no side effects.Although numbers are small, our data demonstrates significant benefits from animal dander AIT with high efficacy rates, and side effects mainly limited to mild, localised reactions. The therapy may be most beneficial in those who are unable to avoid exposure, most commonly from workplace, or those suffering from systemic symptoms, such as asthma exacerbations when exposed to dander without the presence of the animal itself, making avoidance near impossible. Despite the benefits, animal dander AIT is used less than other inhalant allergens.One limitation of the study is that we do not have long-term follow-up data, so the durability of the response is uncertain. Adherence is also a significant issue and means to improve this should be considered.There is limited research on animal dander AIT compared with other aeroallergens, and our data has shown positive findings, although mostly with cat and dog dander. Larger cohorts are required to understand the full benefits of animal dander AIT.Table 1. Documented efficacy and compliance rates for those who completed 3 years AIT therapy.

Anti-rubella IgG serum levels predict risk for SARS-CoV-2 breakthrough infectionsTo the Editor,

Algorithms in allergy: Diagnosis and management of atopic dermatitis in adulthoodM. Grace Hren1,2, Ester Del Duca1, Helen He1, Andrew L. Ji1,2, Emma Guttman-Yassky1*1Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA2Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA*Correspondence:Emma Guttman-Yassky, MD, PhDAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by significant pruritus, eczematous lesions, and a relapsing course.1,2 Once mainly considered a pediatric disease that diminishes with age, current epidemiologic studies suggest a prevalence of ~7% among adults in the United States.3 Associated with atopic (e.g. asthma, rhinitis, food allergy) and non-atopic (e.g. psychiatric, autoimmune, infectious) comorbidities, as well as diminished life quality, appropriate treatment of AD is crucial.4,5 This algorithm offers a practical guide for management of AD in adults.As a purely clinical diagnosis, there are no biomarkers or confirmatory laboratory tests for AD, and with a highly heterogenous presentation, the differential for AD is extensive.2,3 Lacking specific diagnostic criteria, a combination of history, morphology/distribution of lesions, and exclusion of differentials reinforces diagnosis.1,2,3 Several groups have proposed criteria for AD (Hanifin and Rajka (1980), United Kingdom Working Party (1994), among others).3 More recently, the American Academy of Dermatology released an updated set of criteria with essential (must be present), important (support diagnosis), and associated (suggest diagnosis) features of AD (Figure 1 ).6 If diagnosis remains unclear, a skin biopsy or patch test can exclude alternative diagnoses or determine underlying triggers, respectively.3,6After establishing diagnosis, stratification of AD as mild, moderate, or severe may assist in management. Scoring Atopic Dermatitis (SCORAD), Eczema Area and Severity Index (EASI), and Patient-Oriented Eczema Measure (POEM) are AD severity scores validated for clinical trials, but these scores are not routinely utilized in clinical practice.6 Rather, physician assessment of cutaneous involvement, plus patient-reported frequency of itching and impact on daily living, psychosocial well-being, and sleep can direct stratification (Figure 1 ).7At any severity, general management of AD consists of patient education and encouragement of proactive measures. Instruct patients to apply emollients and moisturizers multiple times per day, maintain healthy bathing routines, and avoid exacerbating factors (Figure 2 ).8Among patients with mild AD, use of low-to-medium potency topical corticosteroids (TCS) 1-2 times daily for maximum of two weeks is first-line management. Due to potential risk of skin atrophy, consistent use of TCS for greater than two weeks is not recommended.8If low-to-medium potency TCS use leads to disease resolution, commence maintenance treatment, employing frequent use of moisturizers plus intermittent use of low-to-medium potency TCS to reduce flares and relapse.8 If unresolved, consider topical calcineurin inhibitors (TCI), crisaborole ointment, or ruxolitinib cream. Allow 2-4 weeks to elapse before reassessing response.8 Consider other potential etiologies, such as non-adherence (assess for fear of TCS side effects impeding use), contact allergy (conduct patch testing), infection (consider antibiotics or 0.005% diluted bleach baths), or misdiagnosis (consider biopsy).8For those lacking in response to above therapies, along with patients presenting with moderate-to-severe AD, commence treatment with medium-to-high potency TCS daily for two weeks.8 Low potency TCS, TCI, or crisaborole ointment can be utilized for areas with increased risk for skin atrophy.8Consider systemic therapies for patients with moderate-to-severe AD nonresponsive to topicals, or as first-line therapy for patients with severe/extensive skin involvement. First-line systemic agents include dupilumab and tralokinumab, two monoclonal antibodies that target the Th2 pathway with excellent safety profiles.9 Other systemic options include oral Janus kinase inhibitors (e.g. upadacitinib, abrocitinib) or conventional immunosuppressants (e.g. methotrexate, azathioprine, cyclosporine, mycophenolate mofetil). However, these therapeutics possess their own respective safety concerns, warranting increased caution and monitoring.9 Narrow-band ultraviolet B (NB-UVB) phototherapy can be considered, but the commitment (2-3x/week in office) may be prohibitive for patients.9 Systemic corticosteroids are not recommended due to risk of rebound flare.9 Once moderate-to-severe AD is controlled, proceed with long-term maintenance therapy, consisting of a systemic agent plus TCS or other topical therapies to prevent flares and relapse.

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Immunoglobulin E (IgE)-mediated food allergies are reported to affect around 3.5% of children and 2.4% of adults, with symptoms varying in range and severity. While being the gold standard for diagnosis, oral food challenges are burdensome, and diagnostic tools based on specific IgE can be flawed. Furthering our understanding of the mechanisms behind food allergy onset, severity, and persistence could help reveal immune profiles associated with the disease, to ultimately aid in diagnosis. Alterations to cytokine levels and immune cell ratios have been identified, though further research is needed to fully capture the heterogenous nature of food allergy. Moreover, the existence of such immune alterations also raises the question of potential wider systemic effects. For example, recent research has emphasised the existence and impact of neuro-immune interactions and implicated behavioural and neurological changes associated with food allergy. This review will provide an overview of such food allergy-driven neuro-immune interactions, with the aim of emphasising the importance of furthering our understanding of the immune mechanisms underlying IgE-mediated food allergy.

Allergy discordant twins do not exhibit differences in gene expression in non-switched and switched B cellsStephan Schneider1, Pattraporn Satitsuksanoa1, Huseyn Babayev2, Willem van de Veen1, Iris Chang3, Minglin Yang1, Cezmi A. Akdis1, Kari Nadeau4, Mübeccel Akdis11 Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland2 Abant Izzet Baysal University Hospital, Department of Medical Microbiology, Bolu, Türkiye3 Department of Pediatrics/ Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA4 Harvard TH Chan School of Public Health, Department of Environmental Health, Boston, Mass. USA 02115To the Editor,Allergy is a globally spread affliction that is based on dysregulation of immune responses towards ‘harmless’ antigens.1 B cells and their regulation are at the center of allergic disease mechanisms.2,3 They produce IgE, which is essential for allergen-induced mast cell and basophil degranulation.4 The common consensus is, that the regulation of B cells is closely tied to tolerance and allergy.2,5 In allergy this regulation is likely dysfunctional, resulting in different B cell behaviour. Therefore we performed whole transcriptome analysis on peripheral B cells from twins who were discordant or concordant for allergic diseases to identify allergy-associated differential gene expression patterns (i.e. receptors to a type 2 response). We sorted switched and non-switched B cells from 16 twin pairs that were either healthy, allergy discordant or allergy concordant and performed bulk RNA sequencing to identify differences in gene expression patterns. We hypothesized that there would be significantly different expressions in pathways related to B cell activation, B cell regulation or B cell isotype switching correlating to allergic symptoms. The donors were monozygotic and mainly allergic to timothy grass, birch tree pollen and/or house dust mites; none had taken or were on allergen-immunotherapy (Supplementary Table 1-3). Samples were obtained via ethics approval and consent. We sorted switched and unswitched B cells from bio-banked PBMCs, extracted RNA, depleting the ribosomal RNA, and performed 100bp single-end RNA sequencing on the Illumina Novaseq 6000 platform.6 Unbiased clustering, excluding long non-coding RNA, (Figure 1A) showed that the main influences for clustering in descending order are switched vs non-switched B cells, twin pairs and then their concordance status. An individuals allergy status had little to no significant impact on the overall clustering. The same holds true for the PCA analysis of the top 300 significant genes across all samples (Figure 1B). Comparing healthy concordant to allergy concordant twins could be greatly influenced by confounding factors like twin pair similarities and grouping by concordance instead of their actual healthy status. For these reasons, we compared the healthy vs allergic within the discordant twin pairs to avoid these influences for gene expression analysis. In this comparison, neither switched nor non-switched B cell show pathways that would traditionally be associated with allergies or B cell regulation in particular (Supplementary Table 4). A log fold change of greater than 0.5 and a p-value of 0.05 gave a FDR of 0.9999. Adjusting for a FDR below 0.05 (p-value <0.00001) resulted no differentially expressed genes for switched and 5 genes without a common pathway in non-switched B cells. Using this methodology of analysis, we did not find significant differences in pathway regulations on the wider scale of B cells between allergy-discordant twins.PCA analysis for the top 300 genes by the p-value of the allergy-discordant twins confirmed that allergic vs healthy twins do not group by allergy status (Figure 2A). Pathway analysis of the top genes in allergy-discordant twins does not reveal any cohesive pathways (allergy vs healthy) in the switched B cells (Figure 2B). There is one pathway in the upregulated genes of the non-switched B cells, whose genes are associated with the cell cycle and not directly with immune functions.Our results show no indication that there is a general dysregulation of B cells as an underlying cause for allergies. Any differences that might exist are too subtle to be observed across B cells. We propose that distinctions between allergic and non-allergic individuals may only be noticeable in allergen-specific B cells. These effects are probably overshadowed by the variability among individuals due to the rarity of allergen-specific B cells in the overall B cell population.

Thunderstorm-related respiratory symptoms: An old story with a new ending?Francis ThienProfessor/Director of Respiratory MedicineEastern Health & Monash University,Box Hill, Victoria 3128, AUSTRALIAIsabella Annesi-MaesanoProfessor of Environmental Epidemiology, INSERM Research Director,Department of Pulmonology, Allergy and Thoracic Oncology, University Hospital of Montpellier, Montpellier, FranceGennaro D’Amato,Director, Division of Respiratory and Allergic Diseases, High Speciality Hospital ‘A. Cardarelli’,Professor of Respiratory Allergy School of Specialization in Respiratory Diseases,Federico II University of Naples, Rione Sirignano 10,80121 Naples, Italy

Longitudinal sensitization patterns in childhood and adolescence

Background: Intestinal barrier dysfunction may lead to a break in tolerance and development of food allergy (FA). There is contradictory evidence on whether intestinal permeability (IP) is altered in IgE-mediated FA. Thus, we sought to determine whether IP differed between children with eczema who did (FA group) or did not (atopic controls, ACs) develop FA and whether peanut sensitization, allergy and early introduction impacted IP using serum biomarkers zonulin, soluble CD14, and Intestinal Fatty Acid Binding Protein among randomly selected participants enrolled in the Learning Early About Peanut allergy trial. Methods: FA group was defined as having at least one FA at either baseline (4-11 months) or 60 months of age (V60). ACs had eczema at baseline and no FA at either visit. Serum IP markers (sIPMs) were measured by ELISA at baseline and V60 and their relationship with clinical characteristics of participants were analyzed using parametric tests and linear regression models. Results: We evaluated 237 FA subjects and 76 ACs. sIPM levels were similar in FA subjects and ACs at baseline and V60. Age when the child first developed any FA (<1 year vs >1 year), eczema severity, peanut sensitization, peanut allergy, and early peanut introduction were not statistically significantly associated with sIPM levels. Total IgE and eosinophil levels, peanut-specific IgE, IgG4 and IgG4/IgE ratio were not correlated with sIPM levels. Conclusion: No differences in sIPMs were detected to support altered IP in infants with FA compared to ACs or following early peanut introduction among peanut sensitized children.

The anti-IgE autoantibodies are biomarkers of early omalizumab response in patients with chronic spontaneous urticariaYusuke Niwa1,2), Koremasa Hayama1,2)*, Shota Toyoshima3), Keisuke Shimizu1,2), Maho Tagui1,2), Mana Ito1,2), Tomomi Sakamoto2), Tadashi Terui1,2), Hideki Fujita1,2), Yoshimichi Okayama2,4,5,6,7)*1) Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan2) Center for Allergy, Nihon University School of Medicine, Tokyo, Japan3) Department of Biochemistry & Molecular Biology, Nippon Medical School, Tokyo, Japan4) Department of Allergy, Internal Medicine, Misato Kenwa Hospital, Saitama, Japan5) Department of Medicine, Division of Respiratory Medicine, Nihon University School of Medicine, Tokyo, Japan6) Department of Internal Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Tokyo, Japan7) Advanced Medical Science Research Center, Gunma Paz University, Graduate School of Health Sciences, Gunma, Japan*Corresponding authors:Koremasa Hayama, M.D, Ph.D.Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, JapanTel.: +81-3-3972-8111 (Ext. 8144): Fax: +81-3-5995-9841E-mail: hayama.koremasa@nihon-u.ac.jpYoshimichi Okayama, M.D, Ph.D.Department of Allergy, Internal Medicine, Misato Kenwa Hospital, 4-491-1 Takano, Misato-shi, Saitama 341-8555, JapanTel.: +81-48-955-7171: Fax: +81-48-955-5120E-mail: okayama.yoshimichi@nihon-u.ac.jp

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated allergy without known biomarkers. We aimed to compare fecal biomarkers related to gut inflammation and immunity in children with FPIES, with resolved FPIES (tolerant), and in matched controls. Methods: Stools were collected from FPIES children on elimination diet, before and after an oral food challenge (OFC) performed to assess their natural tolerance, at the end of a follow-up in tolerant FPIES children, and in matched controls (1:1 ratio). Concentrations of calprotectin, EDN (eosinophilic derived neurotoxin), and secretory IgA (sIgA) underwent comparative paired analysis. Results: Thirty-eight patients were included (age: 1.3 years old, interquartile range: IQR [0.9 - 2.0]), of which 22 became tolerant during follow-up. Upon inclusion, allergic patients and controls had similar concentrations of calprotectin (38µg/g [8-85] vs 27µg/g [11-46], p=0.15) and EDN (504ng/g [275-1252] vs 516ng/g [215-844], p=0.86). However, concentrations of these inflammatory biomarkers increased transiently after a failed OFC (p<0.001 and p=0.01 respectively), without correlating with the severity of an allergic reaction. sIgA were higher in allergic than in tolerant patients: 2224µg/g [878-3529] vs 794µg/g [699-1767] (p<0.01). Calprotectin, EDN, and sIgA were comparable in tolerant patients and controls. sIgA less than 2637µg/g had a negative predictive value of 75.6% for the differentiation allergic patients from tolerant patients and controls (area under curve: 0.63, 95% CI: 0.52–0.74). Conclusion: A few days after an acute allergic reaction, there was no detectable chronic gut inflammation in FPIES. sIgA may be a useful tool for clinicians in timing OFC.

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)