BACKGROUND:The concept of clinical remission in chronic rhinosinusitis with nasal polyps (CRSwNP) is gaining growing relevance in the era of biologic therapies. However, current definitions remain heterogeneous and lack standardized, operational criteria. This variability limits comparability across studies and hinders the implementation of remission as a therapeutic target in routine practice. OBJECTIVE:To develop a multidisciplinary, evidence-based, and clinically applicable definition of clinical remission in CRSwNP, integrating symptom-based, endoscopic, therapeutic, and timing-related criteria, and to evaluate expert consensus on the development of a composite remission score. METHODS:A 3-round Delphi consensus was conducted among experts participating in the Rhinosinusitis Italian Network. Across the 3 rounds, experts rated the statements using a 5-point Likert scale. Positive or negative consensus was defined as ≥70% agreement or disagreement, respectively. Descriptive statistics assessed the convergence and stability of responses. RESULTS:Experts agreed that remission requires meeting concurrent criteria across 4 domains: timing (≥12 months), absence of systemic corticosteroid use or surgical indication, symptom thresholds (Sino-Nasal Outcome Test-22 <20 plus symptoms and hyposmia visual analog scale ≤3), and endoscopic thresholds (Nasal Polyp Score and modified Lund-Kennedy score, both 0 for complete remission and both ≤2 for partial remission). Consensus emerged on differentiating complete and partial remission, on introducing the concept of sustained remission (≥24 months), and on the need for a composite remission score with weighted components and category thresholds. CONCLUSION:This Delphi consensus provides the first operational, multidomain definition of complete and partial clinical remission in CRSwNP, developed independently by a large multidisciplinary panel and informed by patient perspectives. The proposed criteria offer a practical framework to standardize remission assessment and support its adoption as a therapeutic goal.

Biologics have demonstrated lung function improvement in clinical trials. However, real-world comparative effectiveness data from European countries are limited. This real-world study compared lung function improvements with dupilumab and other biologics across five European Union (EU) countries in patients with severe asthma (SA). The EU-ADVANTAGE was a retrospective chart review study conducted in patients (aged ≥ 12 years) with SA who initiated a biologic (dupilumab, omalizumab, benralizumab or mepolizumab) between May 2019 and February 2022 (index date). Patients with at least one record of pre-bronchodilator (BD) or post-BD forced expiratory volume in 1s (FEV1) available within 12-month pre- and post-index periods were analysed. Inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics between treatments. Improvements in percent predicted FEV1 (ppFEV1) within 12 months after biologic initiation were assessed in those with either pre- or post-BD FEV1, using doubly robust linear regression. A total of 845 patients had pre-BD ppFEV1 and 557 had post-BD ppFEV1 data in both pre- and post-index periods, respectively. After IPTW, several baseline characteristics were balanced (standardised mean difference < 10

Background The phenotypic nature of multimorbidity in severe asthma is poorly understood. Our aims in this study were to define multimorbidity phenotypes and their characteristics in severe asthma across Europe by identifying and characterising co-aggregation of comorbidities. Methods Cross-sectional patient data were analysed from the pan-European Severe Heterogenous Asthma Research Collaboration: Patient Centred (SHARP) Central database of national severe asthma registries. Patients were grouped by four European regions (North, South, East, and West). Hierarchical clustering of comorbidities was applied to characterise the correlation structure of the ten commonest comorbidities within these geographical regions. Subsequent multimorbidity phenotypes (MMP) and their clinical features were then defined. Findings Data were available for 2690 severe asthma patients and 23 comorbidities from 11 countries. Three comorbidity clusters were consistently seen across the four European regions: 1) osteoporosis plus steroid-induced weight gain, 2) eczema plus rhinitis, and 3) chronic sinusitis plus nasal polyps. Four further comorbidities (obesity, bronchiectasis, gastro-oesophageal reflux disease, psychological factors) showed variable clustering. Multimorbidity was ubiquitous. Patients were assigned multimorbidity phenotypes (MMP) according to comorbidity cluster alignment. MMP sn (sinonasal-associated) and MMP u (no specific cluster alignment) were commonest. MMP ster (steroid-associated multimorbidity) had highest maintenance oral steroid (m-OCS) use, and Body Mass Index, plus worst lung function, asthma control, and asthma exacerbation frequency. MMP max (maximal multimorbidity) showed high prevalence of variably assigned comorbidities, higher m-OCS and biologic treatment needs. Interpretation Multimorbidity is common in severe asthma and can be classified into replicable novel phenotypes with characteristic clinical traits and outcomes. Recognising these phenotypes can guide better care of the ‘whole patient’ with severe asthma. Future clinical guidance should promote such understanding in order to support delivery of more effective personalised asthma care. Funding European Respiratory Society, pharmaceutical industry partners (Sanofi, TEVA, Novartis, GlaxoSmithKline, Chiesi).

BACKGROUND:The way in which risk predictors combine and contribute to severe asthma exacerbations may differ between clinical trials and real-world settings. RESEARCH QUESTION:How do the interactive pathways of risk predictors leading to severe asthma exacerbations compare under clinical trials vs real-world settings? STUDY DESIGN AND METHODS:The analysis involved 345 patients with severe asthma from the placebo arms of 2 international randomized controlled trials (RCTs), compared with 6,814 biologic-naïve patients from the International Severe Asthma Registry (ISAR). Sixteen key risk predictors, including demographics, biomarkers, lung function, health care use, exacerbation history, long-term oral corticosteroid use, asthma control, and nasal polyps, were covered. The outcome was the occurrence of severe asthma exacerbations over the 365 days after study enrollment. Bayesian networks (BNs), obtained from machine learning combined with expert knowledge, elucidated significant interplay processes of risk predictors that led to severe asthma exacerbations. External validation was performed in each cohort. RESULTS:The RCTs revealed 44 significant arcs (ie, probabilistic interdependency) between 16 risk factors, whereas the ISAR showed 170. Despite this difference, the main downstream prediction pathways were consistent across both settings, with 2 key pathways: total serum IgE level influenced blood eosinophils to predict future severe exacerbations, and severe exacerbation history directly predicted future severe exacerbations. In external validation, RCT-BN generalized well to ISAR patients (area under the receiver operating characteristic curve, 0.68), whereas ISAR-BN underperformed in RCT patients (area under the receiver operating characteristic curve, 0.50), and ISAR-BN demonstrated better calibration. INTERPRETATION:Our results show that the core pathways predicting severe asthma exacerbations were similar in both RCTs and real-world settings, with comparable predictive performance.

The 2025 World Allergy Organization (WAO) Guidelines for the Classification, Diagnosis, and Treatment of Hereditary Angioedema (HAE) with Consideration of Worldwide Disparities provide a comprehensive, evidence-informed, and globally applicable framework for the care of this rare and potentially life-threatening disorder. HAE is a genetic disease characterized by recurrent episodes of subcutaneous and submucosal swelling, most commonly mediated by bradykinin, and is associated with substantial morbidity, impaired quality of life, and a lifelong risk of fatal laryngeal edema.The Guidelines were developed by an international panel of 40 experts from 22 countries, with representation from all world regions, reflecting the commitment of WAO to geographic diversity, inclusiveness, and global relevance. The development process for these guidelines followed a structured and transparent methodology that integrated systematic literature review, appraisal of real-world evidence, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework adapted for rare diseases, complemented by a formal Delphi consensus process. This approach was specifically designed to address the limitations of conventional evidence hierarchies in rare disorders, while ensuring clinical applicability across heterogeneous healthcare systems and resource settings.A central element of the guidelines is an updated classification of HAE based on underlying pathophysiology and disease endotypes. The traditional distinction between HAE types 1 and 2 is unified under the term HAE with C1 inhibitor deficiency (HAE-C1-INH), reflecting shared biological mechanisms and management principles. The guidelines also recognize an expanding spectrum of HAE with normal C1 inhibitor (HAE-nC1-INH), including forms associated with pathogenic variants in F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1, and DAB2IP, as well as cases with currently unidentified genetic causes.The diagnostic strategy emphasizes early clinical recognition based on characteristic features, including recurrent angioedema without urticaria, abdominal or laryngeal involvement, early symptom onset, and family history. A simplified diagnostic algorithm is proposed, prioritizing the C1 inhibitor functional assay as the preferred initial test when performed in a reliable specialized laboratory. Alternative diagnostic pathways are outlined for settings with limited access to specialized testing, including pragmatic combinations of biochemical assays and selective use of genetic testing, particularly relevant for HAE-nC1-INH and family screening.Management recommendations address on-demand treatment of acute attacks, short-term prophylaxis, and individualized long-term prophylaxis. Universal access to on-demand therapy is emphasized for all patients with confirmed HAE, including those who are asymptomatic, given the unpredictable nature of attacks and lifelong risk. Long-term prophylaxis is addressed within a treat-to-target framework aimed at achieving complete disease control and sustained improvement in health-related quality of life, with regular reassessment and shared decision-making. Empowering patients and caregivers through structured education, access to appropriate medications, and integration with specialized referral centers is associated with earlier treatment, reduced healthcare utilization, and improved equity of care and reduced avoidable morbidity and mortality worldwide.The 2025 WAO Guidelines for Hereditary Angioedema establish an evidence-informed, patient-centered, and forward-looking framework for the classification, diagnosis, and management of HAE. By integrating advances in pathophysiology, diagnostics, and therapeutics with global expert consensus and real-world considerations, the guidelines aim to support consistent, equitable, and high-quality care for patients with HAE across regions and healthcare systems.

Recent advances in biological therapies, small molecules and allergen-specific immunotherapy are reshaping the management of immunoallergic diseases, progressively shifting therapeutic goals from short-term disease control toward the possibility of achieving sustained clinical remission. Despite increasing evidence across multiple conditions, a universally accepted and disease-transversal definition of clinical remission (CR) remains lacking. In this review we propose a comprehensive framework for defining clinical remission across a broad spectrum of immune-mediated diseases traditionally managed in Allergy and Clinical Immunology practice, including asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyps, chronic urticaria, atopic dermatitis, mastocytosis, food allergy, and eosinophilic esophagitis. Clinical remission is defined as a sustained state of absence of clinically relevant disease manifestations, independently of underlying biological activity; suppression of inflammatory pathways and normalization of biomarkers define biological remission, which may coexist with, but is not required for, clinical remission.We introduce the 3D-CR model, a pragmatic, disease-adaptable framework integrating 3 complementary domains — clinical, biological, and functional — to characterize remission states as complete, partial, or absent. Building on this model, we propose the Allergic Disease Remission Score (ADReS) as a modular tool designed to support standardized assessment, longitudinal follow-up, and cross-disease comparison in clinical trials and real-world settings. These tools are intended as conceptual and research instruments rather than prescriptive algorithms for individual therapeutic decision-making.Finally, we outline a World Allergy Organization call to action advocating for a harmonized global approach to defining, measuring, and implementing clinical remission as a meaningful treatment target. Establishing standardized remission endpoints has the potential to improve patient outcomes, facilitate precision medicine strategies, enhance comparability across studies, and reduce heterogeneity in clinical research and practice worldwide.

BACKGROUND:Severe asthma (SA) is associated with frequent exacerbations and high treatment costs. OBJECTIVES:To develop and validate an individualized risk calculator for severe exacerbations in SA, and evaluate its clinical utility for guiding personalized clinical decisions. METHODS:Patients with SA were identified from combined data from the International Severe Asthma Registry (2015-2022) and NOVEL observational longiTudinal studY (2016-2023) across 30 countries and regions. The prediction end point was the 12-month risk of 1 or more or 2 or more severe exacerbations. Using expert input and Bayesian network analysis, 11 routinely measured predictors were identified, measured within the past 12 months. A mixed-effects, zero-inflated negative binomial model was developed, adjusting for between-country variability and biologic drop-in effects. Internal-external cross-validation was performed using the natural clustering by country settings. RESULTS:Data from 9911 patients with SA were used. Essential predictors included age, sex, past 12-month severe exacerbations, asthma control, chronic rhinosinusitis, FEV1 to forced vital capacity ratio, percent predicted FEV1, blood eosinophils, fractional exhaled nitric oxide, and long-term oral corticosteroid and macrolide use. The model also adapted setting-specific baseline risks. In the internal-external cross-validation, across broad geographical and health care variability, the model showed excellent calibration and informative, generalizable discrimination (pooled area under the time-dependent receiver-operating characteristics curve of 0.63 [95% CI, 0.60-0.66] for ≥1 and 0.68 [95% CI, 0.64-0.72] for ≥2 exacerbations). Decision curve analysis showed clear net benefit across risk thresholds. CONCLUSIONS:The Risk of Exacerbation in Severe Asthma model quantifies SA exacerbation risk using routinely available predictors and demonstrates potential clinical utility.

Background: Clinical remission is an emerging treatment goal in severe eosinophilic asthma (SEA). While benralizumab, an anti-IL-5Rα monoclonal antibody, has demonstrated efficacy in SEA, its ability to induce clinical remission in real-life settings over extended follow-up remains underexplored. Methods: This post hoc analysis of the multicenter, retrospective ANANKE study evaluated clinical remission over 24 months in 167 Italian patients with SEA treated with benralizumab. Remission was defined according to the Severe Asthma Network Italy (SANI) criteria. Complete clinical remission (cCR) required the absence of oral corticosteroid (OCS) use and the presence of 3 criteria: no symptoms, no exacerbations, and stable lung function. Partial clinical remission (pCR) required the absence of OCS use and 2 of the 3 criteria. Outcomes were assessed at 3, 12, and 24 months. Results: The proportion of patients achieving clinical remission increased over time: 87.2% at 3 months (40.4% pCR, 46.8% cCR), 95.0% at 12 months (17.5% pCR, 77.5% cCR), and 96.1% at 24 months (23.5% pCR, 72.6% cCR). No baseline demographic or clinical characteristics were found to significantly predict remission status. Blood eosinophil counts declined from a mean of 476.7 to 5.2 cells/μL at 24 months. Conclusion: In this real-world Italian cohort, benralizumab was associated with rapid and sustained clinical remission in patients with SEA over 24 months. The high remission rates observed early and maintained throughout treatment support the role of benralizumab as a disease-modifying therapy and reinforce clinical remission as a meaningful therapeutic goal in SEA.

Allergen immunotherapy (AIT) represents the only disease-modifying treatment currently available for IgE-mediated allergic diseases. Traditionally employed to alleviate symptoms and reduce pharmacological dependence, AIT is now being reconsidered within a broader and more ambitious therapeutic framework: the induction of long-term clinical remission. In the field of allergic diseases, the concept of disease control has recently been integrated with that of clinical remission. This review discusses the evolving concept of remission in allergic disorders, particularly allergic rhinitis and allergic asthma, in patients treated with AIT. Starting from the definition of clinical remission, this review aims to analyze the evidence supporting this concept and explore potential tools for clinical application in allergic patients treated with AIT, the only causal therapy.

Guidelines provide specific recommendations based on the best available medical knowledge, summarizing and balancing the advantages and disadvantages of various diagnostic and treatment options. Currently, consensus methods are the best and most common practices in creating clinical guidelines, even though these approaches have several limitations. However, the rapid pace of biomedical innovation and the growing availability of real-world data (RWD) from clinical registries (containing data like clinical outcomes, treatment variables, imaging, and laboratory results) call for a complementary paradigm in which recommendations are continuously stress-tested against high-quality, interoperable data and auditable artificial intelligence (AI) pipelines. AI, based on information retrieved from patient registries, can optimize the process of creating guidelines. In fact, AI can analyze large volumes of data, ensuring essential tasks such as correct feature identification, prediction, classification, and pattern recognition of all information. In this work, we propose a four-phase lifecycle, comprising data curation, causal analysis and estimation, objective validation, and real-time updates, complemented by governance and machine learning operations (MLOps). A comparative analysis with consensus-only methods, a pilot protocol, and a compliance checklist are provided. We believe that the use of AI will be a valuable support in drafting clinical guidelines to complement expert consensus and ensure continuous updates to standards, providing a higher level of evidence. The integration of AI with high-quality patient registries has the potential to substantially modernize guideline development, enabling continuously updated, data-driven recommendations.

This review describes the eosinophil journey through the various physiological and pathophysiological phases, from production, maturation, and activation by chemokines and cytokines [especially eotaxin, interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF)], to interaction with the innate and adaptive immune system and tissue homing. Excessive production and activation of eosinophils lead to the release of granule proteins, such as major basic protein, eosinophil cationic protein, eosinophil peroxidase, and others, resulting in inflammation, cell cytotoxicity, and oxidative stress. The pathogenesis, clinical features, diagnostic processes, and the latest therapeutic approaches to the resulting diseases—which affect the upper and lower airways, gastrointestinal tract, skin, myocardium, and may occur systemically—are discussed.

BACKGROUND:House dust mite (HDM) allergic rhinitis (HDM-AR) fluctuates over time with exposure conditions, making disease activity assessment essential when demonstrating treatment efficacy. We conducted post hoc tertile analyses to more accurately assess the efficacy of 300 IR HDM sublingual immunotherapy (SLIT) tablet in moderate-to-severe HDM-AR pediatric patients during periods of increased disease activity. METHODS:Data from two Japanese randomized controlled trials of 300 IR HDM SLIT-tablet were used to assess the average adjusted symptom score (AASS) and average combined symptom and medication score (ACSMS). To determine the impact of HDM-AR activity, placebo group scores during the primary period (end of treatment) at each center were ranked from lowest to highest to establish three tertiles. Scores differences between SLIT and placebo were analyzed in each tertile using ANCOVA. RESULTS:The first analysis included patients aged 5-16 years (300 IR = 193, placebo = 210). During the primary period, the effect of the SLIT-tablet, estimated at -13.1% (AASS) and -12.9% (ACSMS) versus placebo overall, was more pronounced in the highest tertile (relative differences -27.3% and -28.5%, respectively), with similar results across age groups. The second analysis including a pool of adolescents (300 IR = 120, placebo = 135) showed an overall effect of -19.9% (AASS) and -21.2% (ACSMS) with 300 IR versus placebo, with again greater improvements in the highest tertile (-32.5% and -34.1%, respectively). CONCLUSION:The greatest improvements occurred in the tertile where pediatric patients exhibited higher disease activity. This underscores the true efficacy of 300 IR HDM SLIT-tablet during periods when patients experience the most troublesome symptoms.

Background Topical corticosteroids (TCS) remain the first-line treatment for atopic dermatitis (AD) and related inflammatory skin diseases, yet no standardized definition of response exists. This gap contributes to heterogeneity in clinical practice and complicates trial design. We therefore aimed to develop consensus-based definitions of response and inadequate response to TCS therapy through a structured international eDelphi process. Methods A PubMed search (1974–July 2025) identified 403 relevant publications. Candidate statements were drafted from the evidence and refined by the ADCARE Steering Committee, categorized into 3 domains (status quo, unmet need, proposals), and evaluated in a three-round eDelphi survey among certified ADCARE members. Eighty-four dermatologists and allergists from 32 countries participated (Round 1 response rate 98%; Round 2, 80%; Round 3, 76%). Statements were rated on a 5-point Likert scale; consensus was defined as ≥75% agreement (scores 4 or 5). Results In total, 66 of 83 statements reached consensus. In the status quo domain, agreement centred on baseline severity, body surface area, and anatomical site as guiding factors for TCS choice, with potency and licensed duration considered central to safe prescribing. In the unmet-need domain, experts highlighted the absence of standardized definitions, variability in monitoring and escalation strategies, and gaps in long-term evidence and integration of patient-reported outcomes. In the proposal domain, consensus supported relative improvement thresholds (≥50% in EASI, SCORAD, itch NRS, IGA, PGA, POEM) and 14 days as a meaningful evaluation point. Absolute cut-offs, very short (7 days) or long (3 months) timeframes, and rigid escalation rules did not achieve consensus. These parameters were synthesized into concise and extended definitions of TCS response and inadequate response. Conclusions This GA2LEN ADCARE initiative represents the first international consensus on defining TCS response and inadequate response, offering a framework to harmonize clinical practice, enhance trial comparability, and support guideline development.

ObjectiveTo describe patients with severe asthma treated with or eligible for monoclonal antibodies, assessing the health and economic burden using the Italian National Healthcare Service (SSN) administrative data.MethodsFrom 4.6 million inhabitants, among patients with asthma from 1 January to 31 December 2022, those with severe asthma were identified by monoclonal antibody dispensation (cohort A) and by eligibility for monoclonal antibodies, defined as continuous treatment with medium- or high-dose inhaled corticosteroids and long-acting beta agonists and the occurrence of exacerbations (cohort B-narrow and cohort B-broad according to "narrow" and" broad" definitions, respectively). One-year exacerbations, healthcare utilization, and direct costs were assessed.ResultsOf the 128,621 patients with asthma (51.8% women; mean age, 54 years), patients with severe asthma were identified as follows: cohort A (n = 3046; 2.4%), cohort B-narrow (n = 3517; 2.7%), and cohort B-broad (n = 7621; 5.6%). Compared with cohort A, patients in cohorts B-narrow and B-broad were older, had more comorbidities, experienced more moderate/severe exacerbations (70.9%-57.3% vs. 46.7%), and had higher hospitalization rates and greater drug use but fewer specialist visits. The annual SSN costs averaged €7512 for cohort A versus €2911-€2351 for cohorts B-narrow and B-broad. Cohort A incurred higher costs for asthma drugs, whereas cohorts B-narrow and B-broad incurred higher costs for concomitant drugs, hospitalizations, and specialist care.ConclusionsA significant disease burden exists in patients with uncontrolled severe asthma who are potentially eligible for monoclonal antibodies in Italy.

BACKGROUND:Allergen immunotherapy (AIT) and biologics such as omalizumab are established treatments for allergic asthma, but long-term data on their combined use are limited. OBJECTIVE:To compare long-term clinical and immunological outcomes of omalizumab, subcutaneous AIT for house dust mite (SCIT-HDM), and their combination in mild-to-moderate allergic asthma. METHODS:In this prospective, randomized, controlled study, 79 patients with HDM-driven allergic asthma were assigned to omalizumab (A), omalizumab plus SCIT-HDM (B), SCIT-HDM (C), or standard therapy (D). Patients were followed for 36 months. Primary outcomes were changes in inhaled corticosteroid (ICS) dose and annual exacerbations. Secondary outcomes included symptom and medication scores, Asthma Control Test (ACT), asthma quality of life (AQLQ), lung function, remission rates, and biomarkers. RESULTS:All groups showed significant reductions in ICS use, with greater reductions in groups A and B than in C and D (p < 0.05). Combination therapy (B) resulted in lower exacerbation rates and reduced oral corticosteroid use compared to other groups. Improvements in ACT, FEV1, and AQLQ were observed across all groups, with more consistent benefits in A and B. Clinical remission occurred most often in group B (47%), followed by A (31%), C (29%), and D (14%). Biomarker changes indicated reduced type 2 inflammation and immunological responses to therapy. No serious adverse events or systemic hypersensitivity reactions were observed. CONCLUSIONS:Omalizumab, SCIT-HDM, and their combination improved outcomes over 36 months. Combination therapy showed the most consistent benefits, but results should be interpreted cautiously due to the small sample size. Further studies are needed.

Background: The International Severe Asthma Registry (ISAR) reported a high rate of comorbidities differentially associated with clinical characteristics, biomarkers, and outcomes. Methods: We aimed to compare the prevalences of comorbidities between global (ISARWORLD) and ITALY-derived ISAR cohorts and to explore characteristics of severe asthma (SA) patients progressively enrolled into the Severe Asthma Network Italy (SANI) registry over 5 years. Results: T2-related SA comorbidities, including allergic rhinitis (AR), chronic rhinosinusitis (CRS) and nasal polyps (NPs) were more frequent (p < 0.001) in the ITALY cohort in addition to some oral corticosteroids (OCS)-related comorbidities, likely relating to the higher burden of OCS use. A comorbidity-dependent pattern of association for biomarkers and clinical outcomes with AR, CRS and NPs was identified in both ITALY-derived and ISARWORLD cohorts. In addition, a progressive decrease in the frequency of atopy, total IgE, number of exacerbations (AEs), chronic OCS treatment (p < 0.001) and a progressive increase in lung function and eosinophils count was reported longitudinally in the SANI registry. When stratifying by the presence of NPs, sex and smoking status, similar enrolment changes were identified with the additional findings of increased FeNO in NPs and Female cohorts and atopic eczema in smokers. Conclusion: Longitudinal observation of enrolment characteristics from the Italian SANI registry and comparison with ISAR highlight changes influenced not only by regional population traits but also by the attitude of clinicians, biologics availability and eligibility and the OCS stewardship campaign. Trial registration: The International Severe Asthma Registry (ISAR): EU PAS number EUPAS23651; Study ID 47596; registered April 16, 2018. Severe Asthma Network Italy (SANI): NCT number: NCT06625216. Retrospectively registered 2024-07-05.

Background Advances in the understanding of type 2 inflammation have driven the development of novel biologics and small molecules for allergic diseases. New therapies targeting cytokines, receptors, and intracellular pathways offer opportunities to refine disease management and modify long-term outcomes. Methods The World Allergy Organization (WAO) Biologics Therapies in Allergic Diseases Committee conducted this state-of-the-art review. We analyzed current literature on investigational monoclonal antibodies, nanobody-based agents, kinase inhibitors, and small molecules with potential applications in asthma, chronic rhinosinusitis with nasal polyposis, atopic dermatitis, and chronic spontaneous urticaria. Mechanistic considerations, therapeutic targets, and clinical trial outcomes were evaluated to highlight emerging trends in biologic and small-molecule therapy. Results Biologics targeting IL-4, IL-5, IL-13, IL-31, TSLP, and IgE continue to expand therapeutic options across allergic disorders. Innovations such as Fc-engineered antibodies, bispecific antibodies, and nanobody platforms enhance efficacy, extend half-life, and improve tissue penetration. Novel intracellular inhibitors, including JAK, SYK, and STAT6 degraders, show promise as oral alternatives to injectable therapies. Clinical trials report high efficacy and favorable safety profiles, though variability remains across diseases and endotypes. Pediatric data are limited, and the long-term safety and cost-effectiveness of this approach require further evaluation. Conclusions Emerging biologics and small molecules are transforming the therapeutic landscape of allergic diseases, providing targeted and personalized interventions. Advances in molecular engineering, particularly nanobody technology and intracellular inhibitors, hold promise for improving patient outcomes and reducing treatment burden. Future research should prioritize long-term safety and standardized approaches to optimize integration of these therapies into clinical practice.