Systemic glucocorticosteroids (sGCS) are widely used in the treatment of chronic inflammatory airway diseases such as rhinitis, rhinosinusitis and asthma. It is well-known that systemic use is linked to multiple adverse effects (AEs) both in the short- and the long-term. However, less is known about the safety of multiple short courses of sGCS. Currently there is no established agreement on the acceptable cumulative exposure to sGCS, considering the potential for various AEs. This systematic review and meta-analysis evaluated sGCS-related AEs in both upper and lower inflammatory airway disease, with a particular focus on short- and long-term risks. We further evaluated whether a dose-response relationship existed between the daily and cumulative dosages of sGCS and the occurrence of those AEs. Our meta-analysis confirmed that cumulative dosages between 500 mg and 1 g prednisolone-equivalent significantly increase the risk of most AEs, with risks increasing with incremental dose. These findings underscore the importance of: (a) judicious sGCS prescription and need for steroid stewardship, due to their potential for short- and long-term complications, occurring even with repeated short courses, and (b) prioritization of steroid-sparing approaches (e.g., biologicals) to avoid reaching a cumulative dose of 500 mg.

Basal cell dysfunction contributes to the pathophysiology of chronic inflammatory airway disorders and is linked to persistent epithelial barrier defects. Epithelial integrity dysfunction, basal cell hyperplasia and metaplasia have been described in allergic rhinitis (AR). However, it remains unclear how basal cell progenitor functions are regulated and if basal cells contribute to type 2 inflammatory responses. Here, we report on the proinflammatory and sensory role of basal cells in AR. Using primary nasal basal cells from controls and AR patients, we demonstrate that Der p1 induces basal cell cytokine (IL-6) and chemokine (CXCL1, CXCL6, CXCL8, SCF) expression and/or release via PAR2, suggesting a role for basal cells as environmental sensors and inflammatory regulators. Using nasal biopsies, we show that mast cells are attracted to the epithelium in AR, likely via basal cell-derived SCF, and induce basal cell chemokine (CCL26, CXCL1, CXCL6, SCF) release via histamine and tryptase in vitro. Finally, histamine, IL-4 and IL-13 impair primary nasal basal cell proliferation, mobility, barrier formation, and differentiation in in vitro cellular assays, illustrating basal cell dysfunction in AR.

OBJECTIVES:The aim was to evaluate the predictive potential of Sinonasal Radiological (SR) and the Lund-Mackay (LM) score of sinus computed tomography (CT) scans on postoperative relapses of chronic rhinosinusitis (CRS). MATERIALS AND METHODS:CRS patients (n = 483, 12-80 years) underwent routine sinus CT scans. The SR score was defined by obstructed frontal recess (0 = no, 1 = yes) and visualization of middle and inferior turbinate (0 = anatomy can be easily visualized, 1 = anatomy cannot be easily visualized) on each side (a total of 0-6 points). Associations were analyzed by nonparametric, survival and Cox's proportional hazard models. RESULTS:Revision endoscopic sinus surgery (ESS) was performed in 133 (28.0%) patients on average (min-max) of 3.2 (0-12) years after performing the sinus CT scans. Of the 408 patients who underwent the baseline ESS, high preoperative SR or LM scores significantly predicted revision ESS (p < 0.001) and peroral corticosteroid courses purchased during the follow-up (p = 0.009 and p < 0.001, respectively for SR- and LM-scores). In multivariable analysis, both SR score and asthma and/or NSAID exacerbated respiratory disease (N-ERD) were significantly associated with revision ESS risk (p = 0.035, p = 0.007, respectively). CONCLUSION:LM and SR and a history of asthma or N-ERD predict CRS relapses, which may help in decision-making.

Allergic rhinitis (AR), the most prevalent immunological disease, affects approximately 400 million individuals globally and can significantly impact quality of life (QoL). Despite nearly 25 years of guidelines, AR remains largely under- diagnosed, suboptimally treated and poorly controlled. In the light of new knowledge and treatment options, there is a necessity to update or revise fundamental AR definitions to facilitate communication across diverse specialties engaged in its treatment and to improve patient care. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) convened a meeting of experts and patient representatives to deliberate the optimal methodology for measuring AR treatment responses and establishing novel treatment goals. This paper presents a consensus on revised AR definitions, including control, severe allergic rhinoconjunctivitis (SARC), refractory severe allergic rhinoconjunctivitis (R-SARC), remission, resolution, improvement, exacerbation, treatable traits (TTs), treat to target, relapse, progression, disease modification, and prevention.

Background: The skin prick test (SPT) is the gold standard for diagnosing sensitization to inhalant allergies. The Skin Prick Automated Test (SPAT) device was designed for increased consistency in test results, and captures 32 images to be jointly used for allergy wheal detection and delineation, which leads to a diagnosis. Materials and Methods: Using SPAT data from 868 patients with suspected inhalant allergies, we designed an automated method to detect and delineate wheals on these images. To this end, 10,416 wheals were manually annotated by drawing detailed polygons along the edges. The unique data-modality of the SPAT device, with 32 images taken under distinct lighting conditions, requires a custom-made approach. Our proposed method consists of two parts: a neural network component that segments the wheals on the pixel level, followed by an algorithmic and interpretable approach for detecting and delineating the wheals. Results: We evaluate the performance of our method on a hold-out validation set of 217 patients. As a baseline we use a single conventionally lighted image per SPT as input to our method. Conclusion: Using the 32 SPAT images under various lighting conditions offers a considerably higher accuracy than a single image in conventional, uniform light.

The skin prick test (SPT) is the gold standard for diagnosing allergic sensitization to aeroallergies. The Skin Prick Automated Test (SPAT) device has previously demonstrated reduced variability and more consistent test results compared to manual SPT. The current study aims to develop and validate an artificial intelligence (AI) assisted readout method to support physicians in interpreting skin reactions following SPAT. To train the AI algorithm, 7812 wheals (651 patients) are manually labeled. To validate the AI measurement, the longest wheal diameter of 2604 wheals (217 patients) is measured by the treating physician and compared to the AI measurement. In addition, AI-assisted readout is validated on a separate test cohort of 95 patients (1140 wheals). We demonstrate that the AI measurements of the longest wheal diameter exhibit a strong correlation with the physician's measurements. The AI algorithm shows a specificity of 98·4% and sensitivity of 85·0% in determining positive or negative test results in the validation cohort. In the test cohort, physicians adjust 5·8% of AI measurements, leading to a change in the test interpretation for only 0·5% of cases. AI-assisted readout significantly reduces inter- and intra-observer variability and readout time compared to manual physician measurements. Altogether, the AI-assisted readout method demonstrates high accuracy, with minimal misclassification of test results. Adding AI to SPAT further improves standardization across the SPT process, significantly reducing observer variability and time to readout.

Asthma is a common, multifaceted respiratory disease with a major impact on quality of life. Despite increased insights into mechanisms underlying various asthma phenotypes and endotypes and the availability of targeted biologic treatment options, the disease remains uncontrolled in a substantial proportion of patients with risk of exacerbations, requiring systemic corticosteroids, and with progressive disease. Current international guidelines advocate for a personalized management approach to patients with uncontrolled severe asthma. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) asthma expert panel was convened to discuss strategies to optimize asthma care and to prevent systemic corticosteroid overuse and disease progression. In this meeting report, we summarize current concepts and recommendations and provide a rationale to implement personalized asthma management at earlier stages of the disease. The ultimate goal is to move away from the current one-size-fits-most concept, which focuses on a symptom-driven treatment strategy, and shift toward a phenotype- and endotype-targeted approach aimed at curbing the disease course by improving clinical outcomes and preserving health-related quality of life. Herein, we provide a consensus view on asthma care that advocates a holistic approach and highlight some unmet needs to be addressed in future clinical trials and population studies.

Current treatments fall short in managing allergic rhinitis (AR), emphasizing the need for additional strategies. Beneficial bacteria application shows promise in AR; however, most studies focus on oral probiotic administration without monitoring the applied strains in the upper respiratory tract (URT) and their local effects. In this randomized, double-blind, placebo-controlled trial, the probiotic Lacticaseibacillus rhamnosus GG was administered via chewable tablets in seasonal AR patients, randomized to probiotic (n = 33) or placebo (n = 31) groups. Per-protocol analysis of the URT microbiome, immune markers, and AR symptoms was performed. L. rhamnosus GG trafficked from chewables to the oropharynx (77%, P = 0.02) and nasopharynx (41%, P < 0.0001). Control of self-reported AR symptoms via validated questionnaires under grass pollen exposure was observed after 2 weeks of probiotic administration and not upon placebo. A local decrease in salivary interleukin-4 (P < 0.05) and nasal IL-13 (P < 0.0001) was observed in the probiotic group. These data indicate that L. rhamnosus GG chewables can target the URT and exert local effects on key allergy cytokines after temporal probiotic engraftment.IMPORTANCEAllergic rhinitis (AR) or hay fever is a highly prevalent condition, impacting nearly half the population in some countries. Supplementation of beneficial bacteria or probiotics has gained increasing attention in AR, and a key innovative way to do this is direct administration to the upper airways. Our study shows for the first time that the model probiotic strain Lacticaseibacillus rhamnosus GG can traffic to the nose in AR patients when administered via a slow-releasing chewable tablet. This trafficking is associated with local benefits in the airways, including on grass pollen-induced nasal symptoms and allergy-related cytokines.

BACKGROUND:Primary chronic rhinosinusitis (CRS) can be classified based on the sinuses involved and the dominant endotype of the mucosal inflammation. Since the introduction of type 2 targeted biologics as treatment option for CRS, assessment of the inflammatory status has gained importance in CRS patients. We here aimed to characterize CRS patients with and without elevated markers of type 2 inflammation. METHODS:CRS patients who visited the outpatient ENT clinic in one of the 10 tertiary centers in 7 European countries were invited to use the Galenus Health mobile application for the monitoring of their disease. RESULTS:CRS patients (n = 281) were stratified according to blood eosinophil counts or BEC (< 150 cells/μL: 21.6% of patients, ≥ 150 cells/μL: 78.4%; < 250 cells/μL: 36.3%, ≥ 250 cells/μL: 63.7%) and serum total IgE (< 100 IU/mL: 59.9%, ≥ 100 IU/mL: 40.1%). BEC and serum total IgE did not correlate well (Spearman r = 0.06; p = 0.39). CRS patients with BEC ≥ 150 cell/μL or ≥ 250 cells/μL, respectively, showed increased NPS, SNOT-22, VAS for total CRS symptoms, loss of smell, nasal blockage, runny nose compared to patients with BEC below 150 or 250 cells/μL. CRS patients with increased serum total IgE (≥ 100 IU/mL) did not show differences in the outcome parameters compared to patients with levels below 100 IU/mL. CRS patients with asthma (58.9%) showed increased SNOT-22 and VAS loss of smell compared to patients without asthma. CONCLUSIONS:A significant proportion of CRS patients exhibit a type 2 endotype, characterized by blood eosinophilia (78%), increased serum total IgE (40%) and/or concomitant asthma (59%). Our results underline the usefulness of eosinophils as a marker of type 2 inflammation and severity but challenge the utility of serum total IgE since it does not correlate with any of the markers of severity.

INTRODUCTION:A novel device, Skin Prick Automated Test (SPAT), previously showed reduced variability and more consistent test results compared to conventional skin prick test (SPT) to identify allergic sensitisation. This study aimed to clinically validate the adjusted SPAT cut-off in patients with confirmed birch or house dust mite (HDM) allergy. METHODS:Seventy-five adults were included: 25 non-allergic subjects (confirmed by lack of allergy history and negative SPT), 25 birch and 25 HDM allergic rhinitis patients (both confirmed by positive SPT and nasal allergen challenge [NAC]). All subjects received a conventional SPT and an automated SPT for B ver, D pter, D far and control solutions. RESULTS:A cut-off of 4.2 and 4.1 mm, respectively, resulted in the highest accuracy to detect birch or HDM allergy using SPAT. Referring to previous study results suggesting a reliable cut-off value of 4.5 mm, it was decided to maintain 4.5 mm as SPAT cut-off indicating allergic sensitisation. Accuracy did not significantly differ between SPAT (96% using ≥ 4.5 mm) and conventional SPT (98% using ≥ 3.0 mm) to detect HDM allergy or to detect birch pollen allergy (100% for SPAT and SPT). SPAT wheal measurements performed through a ruler on the forearm or through digital measurement on a composite image did not significantly differ for any of the patient groups analysed. CONCLUSION:SPAT showed an equivalent accuracy to detect birch pollen or HDM allergy compared to conventional SPT, using the adjusted 4.5 mm SPAT cut-off in patients with confirmed allergic rhinitis. The SPAT web viewer can be used easily and effectively for digital wheal measurement on a composite image.

BACKGROUND:Double-blinded placebo-controlled trials have revealed the efficacy of mepolizumab and omalizumab in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP). However, real-world efficacy (RWE) data, data on therapeutic response and level of disease control for both biologicals are lacking. METHODOLOGY:167 patients with uncontrolled severe CRSwNP, meeting national reimbursement criteria, were included with follow-up over 24 weeks. Primary outcomes included changes in nasal congestion (NCS), nasal polyp score (NPS), VAS-scores, SNOT-22, ACQ-5, and AQLQ scores. Secondary outcomes were therapeutic response and disease control according to EUFOREA/EPOS criteria. RESULTS:Of the 167 CRSwNP patients, 144 received mepolizumab and 23 omalizumab. After 24 weeks, Patient reported outcomes and NPS significantly improved for both biologicals, with significant effects seen at 12 weeks, with further reduction in NPS by 24 weeks in mepolizumab patients. 74% of patients on omalizumab and 81% of patients on mepolizumab continued their therapy beyond 24 weeks, with 47% and 45% of patients on omalizumab and mepolizumab respectively showing an excellent therapeutic response, with only one out of seven having no/poor response. Disease control was reached in one third of the patients at 24 weeks. CONCLUSIONS:Both mepolizumab and omalizumab significantly improved patient-reported outcomes after 24-weeks, with major effects already observed at 12 weeks. Follow-up beyond 24-weeks might reveal additional effects on both control and remission.

Background:Chronic rhinosinusitis with nasal polyps (CRSwNP) is a persistent inflammatory condition often associated with type 2 inflammation. While biologics are a promising treatment for patients with uncontrolled CRSwNP, real-world evidence is needed to optimize their use. The InternatioNal seVerE CRSwNP (INVENT) registry aims to consolidate data on biologic use in CRSwNP from local and national registries. This study describes the identification of mandatory and optional variables for inclusion in the INVENT registry using a modified Delphi process. Methods:A narrative literature review was performed to identify variables reported in real-world studies of biologic treatment for CRSwNP. A modified Delphi study was conducted between December 2024 and March 2025 involving 23 experts from Europe and Australia. Experts rated the clinical relevance of candidate variables in two online survey rounds using 9-point Likert scales. A positive response was defined as ≥70% of respondents rating a variable 7-9 and ≤15% rating it 1-3. Final agreement on mandatory and optional variables was reached through panel discussion. A validation survey was then conducted across registry centers to assess the feasibility of collecting the selected variables. Results:The Delphi process resulted in consensus on a core set of mandatory and optional variables across nine domains: demographics, medical history, previous and current biologic therapy, biomarkers, comorbidities, asthma, CRSwNP-specific outcomes, and follow-up variables. The validation survey confirmed that most mandatory variables were available or obtainable across participating centers, supporting the feasibility of data collection. Conclusions:This international Delphi study identified a consensus-based set of clinically-relevant and feasible variables for inclusion in the INVENT registry. The selected variables reflect current best practices in the management of CRSwNP and will enable robust comparisons of biologic effectiveness in real-world settings. The INVENT registry is well-positioned to inform treatment decisions, optimize use of biologics, and support a personalized approach to CRSwNP care.

Remission has recently been proposed as the new goal of care in CRSwNP or Nasal Polyp Syndrome by the European Forum for Research and Education in Allergy and Airway Diseases / European Position Paper on Rhinosinusitis and Nasal Polyps (EUFOREA/EPOS) (1,2) as well as by global leaders in Rhinology (3). In CRSwNP, remission is defined as a prolonged state of control, without bothersome symptoms reported by the patient for at least 12 months, without the need for either oral corticosteroids or endoscopic sinus surgery (ESS), and without endoscopic signs of active disease (1). This new goal of care is to be encouraged by the ENT community and CRSwNP patients as persistent symptoms unalleviated by historical approaches (4,5) can be reduced by new therapies including biologics. The goal of therapy for CRSwNP has long been to achieve control, with Visual Analogue Scale (VAS) and Sino-Nasal Outcome Test (SNOT-22) scores guiding physicians towards a step-up treatment aiming for control (6,7).

There is growing evidence that neurogenic inflammation contributes to the pathophysiology of upper airway diseases, with nasal hyperreactivity (NHR) being a key symptom. The rare neuroendocrine cells (NECs) in the epithelium have been linked to the pathophysiology of bronchial and intestinal hyperreactivity, however their presence in the nasal mucosa and their potential role in NHR remains unclear. Therefore, we studied the presence of NECs in the nasal epithelium of controls, allergic rhinitis patients and chronic rhinosinusitis with nasal polyps patients, and their link to NHR. The expression of typical NECs markers, CHGA, ASCL1 and CGRP, were evaluated on gene and protein level in human samples using real-time quantitative PCR (RT-qPCR), western blot, immunohistochemistry fluorescence staining, RNA scope assay, flow cytometry and single cell RNA-sequencing. Furthermore, the change in peak nasal inspiratory flow after cold dry air provocation and visual analogue scale scores were used to evaluate NHR or disease severity, respectively. Limited gene expression of the NECs markers CHGA and ASCL1 was measured in patients with upper airway diseases and controls. Gene expression of these markers did not correlate with NHR severity nor disease severity. In vitro, CHGA and ASCL1 expression was also evaluated in primary nasal epithelial cell cultures from patients with upper airway disease and controls using RT-qPCR and western blot. Both on gene and protein level only limited CHGA and ASCL1 expression was found. Additionally, NECs were studied in nasal biopsies of patients with upper airway diseases and controls using immunohistochemistry fluorescence staining, RNA scope and flow cytometry. Unlike in ileum samples, CHGA could not be detected in nasal biopsies of patients with upper airway diseases and control subjects. Lastly, single cell RNA-sequencing of upper airway tissue could not identify a NEC cluster. In summary, in contrast to the bronchi and gut, there is only limited evidence for the presence of NECs in the nasal mucosa, and without correlation with NHR, thereby questioning the relevance of NECs in upper airway pathology.