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Abstract Background Chronic obstructive pulmonary disease (COPD) represents an important health challenge, despite being preventable and manageable thanks to up-to-date recommendations. In Italy, the pharmaceutical care of COPD patients is still ill-timed and inaccurate. This study aimed to describe the treatment of COPD patients in Italy and possible switches following an exacerbation. Methods This observational retrospective analysis of Italian administrative healthcare data from the Fondazione Ricerca e Salute (ReS) database identified patients aged ≥ 45 years with COPD in 2019 and 2020. At least 6 years of look-back period and absence of concomitant asthma were required. COPD patients were categorized by treatment (SI–single/MI–multiple inhalers, TT–triple therapy, DT–dual therapy, other respiratory treatments, untreated) at index date (first dispensation during accrual period). Occurrence of moderate/severe exacerbation during one-year preceding index date and treatments during one-year preceding the exacerbation (possible switch) were evaluated. Results From ~ 4.7 million beneficiaries of the Italian National Health Service in 2019 and 2020, respectively, 105,828 and 103,729 (43 and 41 × 1,000 inhabitants aged ≥ 45 years) were identified as having COPD. Of 2019/2020 patients: 3.4%/5.2% received SI-TT, 20.7%/17.5% MI-TT, 35.9%/38.1% DT, 33.0%/33.1% other treatments, and 7.0%/6.0% were untreated. Males were prevalent and median age was > 73 years for all groups. Of 2019/2020 cohorts, heart failure and coronary artery disease affected 24/20%, 18/17%, and 11%/16% patients with SI-TT, MI-TT, DT, and other treatments, respectively. A previous moderate/severe exacerbation (2019/2020 patients) occurred to 60.5%/56.6%, 39.9%/37.4%, 30.8%/29.2% and 31.9%/29.7% patients treated with SI-TT, MI-TT, DT, and other treatments, respectively. Of 2019/2020 patients experiencing moderate/severe exacerbation: 6.0%/7.0% receiving DT, 5.1%/7.0% receiving other treatments and 4.5%/10.0% untreated, switched to SI-TT; 23.7%/16.9% receiving DT, 21.4%/17.7% receiving other treatments and 15.4%/12.0% untreated, switched to MI-TT. Conclusions COPD patients receiving TT were older and had more comorbidities, especially cardiovascular diseases, than patients receiving DT or other treatments. The limited number of patients switching after exacerbation suggests that many COPD patients may be inappropriately treated. Ensuring early and adequate treatment, combination of in-hospital and outpatient management, and integration of specialist and primary care is pivotal for the appropriate clinical management of COPD patients.

This review discusses available evidence on the mechanisms of action of bacterial lysates, and the clinical effects of their sublingual administration. Bacterial lysates act through many immunological effects, including dendritic cell activation, modification of circulating lymphocyte subsets and antibody production. The production of salivary IgA was repeatedly shown to be induced by the sublingual administration of a prototype bacterial lysate containing soluble and corpuscular antigens. Bacterial lysates are a useful tool for the prevention of recurrent respiratory tract infections. Sublingual administration should be the preferred option.

Eosinophilic esophagitis (EoE) and allergic rhinitis (AR) usually represent the latest manifestations of the atopic march, sharing a common type 2 inflammation response. A relevant prevalence of AR in EoE cohorts has been widely confirmed. An increasing literature assessed the involvement of aeroantigens in EoE pathogenesis, focusing foremost on the seasonality of new diagnoses, symptoms, and response to therapy. Unfortunately, no diriment direction has been achieved, probably due to the retrospective design of the studies so far available, which chose surrogate markers of EoE activity (mostly the date of new diagnosis) which may be affected by geographical, logistic and personal factors, probably not dependent by the disease itself. EoE exacerbations reported in the context of the pollen levels (preferably pollen counts) may represent a more reliable marker. AR might promote the onset and the re-exacerbation of EoE through mechanisms that are both local (ie, massive exposure to airborne antigens mediated by post-nasal drip) and systemic (type 2 inflammation). Furthermore, AR may facilitate EoE onset by predisposing to pollen food allergic syndrome (PFAS), and EoE patients with PFAS reported higher rate of AR, thus suggesting a bond among these 3 conditions whose causative relationship have still to be ascertained. In addition, because of its shifting activity from Th2 to Th1 inflammation, several case reports focused on the effect of allergen immunotherapy (AIT) employed to treat AR in EoE patients. Also in this instance, no certainties could be guaranteed, although sublingual immunotherapy (SLIT) is more frequently reported to exacerbate EoE, while SCIT is mostly described as a remission adjuvant. The real life experience reported from our allergy service appears to confirm such hypothesis. Finally, a watchful eye should be reserved to monoclonal antibodies as a potential future option for concomitant EoE and AR. In light of all this, an attentive evaluation of allergic history of EoE patients should be relevant. Future perspectives should be addressed on prospective studies targeted to shed light on causative relations among airborne antigens, AR and EoE, and to viable comprehensive treatments.

Allergic rhinitis (AR) and urticaria affect a sizable portion of the population worldwide, resulting in reduced quality-of-life and productivity and increased healthcare costs.Fexofenadine (FEX) is a non-sedating second-generation H1 antihistamine with pronounced efficacy and a very good safety profile, used for the treatment of allergic diseases. In addition to its antihistaminic properties, FEX also has anti-inflammatory effects. FEX has a wide therapeutic window and is not associated with any sedative effects, even at higher than recommended doses.There is a need for an integrated management system for AR and urticaria which includes safe and effective treatment options.An ideal anti-allergic formulation should provide fast relief of symptoms and long-lasting effect without drowsiness. Data from randomized clinical trials show that FEX meets these criteria and is an effective treatment option with a favourable safety profile, improving the quality of life of patients suffering from AR and urticaria.

Background: Second-generation oral H1-antihistamines, including bilastine, represent the emerging treatments of allergic rhinitis (including rhinoconjunctivitis) and chronic urticaria in both adults and children. This study analyses available evidence supporting the use of bilastine amongst second-generation antihistamines for the symptomatic treatment of allergic rhinitis and urticaria in adults and children. Methods: Consensus amongst experts from 17 countries on the ideal treatment of rhinitis and urticaria, and the specific role of bilastine was measured by means of a modified Delphi process. A total of 12 statements were voted on by the experts using a five-point Likert scale (1 = strongly disagree; 2 = disagree; 3 = undecided; 4 = agree; 5 = strongly agree). The definition of consensus was set at a minimum of 80% concordance for 4+5 scores (agree or strongly agree). Results: All proposed statements reached consensus, with a concordance of ≥98% for five statements and ≥96% for seven. Conclusions: The wide consensus obtained for the proposed statements suggests a prominent role for bilastine in the management of allergic rhinitis and urticaria.

Objective Initiated by the Severe Asthma Network Italy (SANI), this study aims to explore asthma patients’ perceptions of disease severity, differentiating between mild and severe asthma. The objective is to identify factors influencing tailored treatment strategies for varying disease severities and to provide insights into asthma care in Italy.Methods Conducted between November 2020 and January 2021, a survey using Computer-Assisted Personal Interviewing (CAPI) collected data from 308 Italian adults, representing the population. A 25 item multiple choice questionnaire covered asthma diagnosis, symptoms, treatment approaches, associated conditions, and quality of life.Results Among participants, 83.8% reported having mild asthma, while 16.2% had severe asthma. Severe asthma patients had longer disease durations, more severe symptoms, frequent exacerbations, and higher hospital/ER visits. Although treatment adherence and symptom profiles generally aligned with international guidelines for self reported severe asthma, 22% of self identified mild asthmatics experienced severe respiratory symptoms. Oral corticosteroid (OCS) use was observed in 50% of severe cases and 22% of mild cases. Adherence was higher in severe asthma patients (76%) versus mild asthma patients (28%). Both groups experienced comorbidities, with 96% of severe asthmatics and 72% of mild asthmatics reporting impaired quality of life.Conclusion This study highlights the disparity between clinical categorization and patient perceptions of asthma severity. The prevalence of self reported severe asthma exceeds literature data. The burden of mild asthma remains significant, with treatment approaches not fully aligned, particularly regarding disproportionate OCS use. Addressing this gap requires enhancing patient education, improving diagnostic practices, and promoting adherence.

Background: Severe atopic dermatitis (AD) is a complex disease requiring systemic treatment. This study aimed to assess the effectiveness of combined therapy consisting of dupilumab and sublingual dust mite allergen immunotherapy (SLIT-HDM) in patients with severe AD and HDM allergies. Methods: Patients diagnosed with severe AD were included in this randomised, placebo-controlled, double-blind 12-month trial; they received SLIT for HDMs and/or dupilumab for 12 months and were compared with patients on cyclosporine. The primary outcomes for the treatment arms were changes in the Eczema Area and Severity Index (EASI), body surface area (%BSA), and Investigator Global Assessment (IsGA) over 12 months. The secondary outcomes were the proportion of patients who achieved IsGA success and reduced medication scores. Results: Significant improvements were observed in all analysed groups after 12 months of therapy based on the EASI, %BSA, and IsGA. However, the most substantial changes were observed in the groups treated with dupilumab or a combination of SLIT-HDM and dupilumab. Additionally, the proportion of patients who achieved an IsGA reduction was significantly greater in the group receiving combination therapy than in the other groups (9/14 [64% of the group receiving SLIT-HDM] vs. 11/14 [73% of the group receiving dupilumab] vs. 15/17 [88% of the group receiving dupilumab and SLIT-HDM] vs. 7/13 [53% of the group receiving cyclosporine]) (p < 0.05). Conclusions: In patients with severe AD and HDM allergies, combination treatment with dupilumab and allergen immunotherapy for HDMs may increase the therapeutic benefit over treatment with these methods separately.

Background: Although randomized controlled trials (RCT) are the reference standard of evidence in allergen immunotherapy (AIT), nonrandomized studies (NRS) are needed to confirm their results in more representative populations, particularly for treatment duration and persistence. However, when discrepancies are observed between RCT and NRS, NRS reliability decreases because these discrepant results are generally attributed to the methodologic flaws of NRS. Objective: We compared the benefit of sublingual AIT (SLIT) for allergic rhinoconjunctivitis in NRS versus RCT focusing on a single product/allergen to reduce heterogeneity. Methods: For meta-analysis, house dust mite (HDM) SLIT liquid formulation studies were sourced from computerized (Medline, Web of Science, and LILACS databases, to January 2023) and manual literature searches. Populations, treatments, and outcome data were combined (DerSimonian-Laird method). Noncomparative NRS were compared to RCT’ SLIT arm before and after treatment. Efficacy was determined as the standardized mean difference (SMD) in symptom score (SS) and medication score (MS). Results: Data from 12 NRS (682 patients) and 8 RCT (176 patients) were analyzed. The benefit with index of reactivity (IR)-HDM SLIT liquid formulation was found significant for, first, SS in both NRS (SMD = −1.27; 95% confidence interval [CI], −1.64, −0.90) and RCT (SMD = −0.56; 95% CI, −0.90, −0.21), and second, MS with SMD equal to −1.35 (95% CI, −1.77, −0.93) and −0.46 (95% CI, −0.67, −0.25), respectively. Metaregression showed that symptom improvement was correlated with treatment duration with consistent results in NRS and RCT with 12-month SS data: −0.87 (interquartile range, −1.02, −0.77) and −0.75 (interquartile range, −0.93, −0.41), respectively. Conclusion: This meta-analysis showed comparable clinical benefit of IR-HDM SLIT liquid formulation increasing over time in both NRS and RCT, suggesting that NRS may reliably integrate RCT results and be considered for guidelines.

BackgroundTo date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials.AimTo elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life.MethodsThis was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers.ResultsOverall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and

Background: The COVID-19 pandemic brought unprecedented global disruption to both healthcare providers and patients with respiratory allergies. There are limited real-life data on the impact of the COVID-19 pandemic on the risk perception of patients with allergy treated with allergen immunotherapy (AIT). Objective: To understand the risk perception of allergic patients treated with sublingual immunotherapy (SLIT) before and during the pandemic, and their attitudes towards COVID-19 infection and vaccination. Methods: This was a non-interventional, cross-sectional survey conducted from October to November 2021 in France. Adult patients, who had been prescribed and had received a Stallergenes SLIT (liquid or liquid and tablets) before the pandemic (from August 1, 2018 to March 10, 2020) and during the pandemic (from March 11, 2020 to August 31, 2021), were identified from the Stallergenes named-patient products (NPP) database. Patients completed an online questionnaire. Data were analyzed descriptively. Results: A total of 5258 patients from all over France completed the questionnaire. Mean (±SD) age of the respondents was 39.3 (±13.0) years and 66.9% were female. Some of them (11.8%) were obese (BMI >30 kg/m2). Main allergic diseases were rhinitis (80.0% of patients) with or without conjunctivitis, and asthma (39.0%). More than half of the patients experienced moderate to severe (58.0%) and persistent allergic rhinitis profile (70.4%). Most patients were poly-allergic (72.7%), mostly to house dust mites (61.9%), grass pollens (61.5%), tree pollens (57.8%), and cat dander (37.2%). Only 14.1% of patients experienced an aggravation of their allergy symptoms during lockdown and 14.8% were infected with COVID-19, with hospitalization required for 1.8%. Only 3.1% of patients reported their SLIT initiation as being postponed due to the pandemic. SLIT was changed, temporarily interrupted or permanently discontinued during the pandemic in 21.9% of patients. Changes mainly concerned the maintenance dose for SLIT-liquid (63.2%). SLIT modification was due to COVID-19 infection in only 4.2%. Most patients did not feel vulnerable (53.1%), anxious (55.2%), at risk to present severe symptoms of COVID-19 (77.1%), or at risk to transmit coronavirus (80.4%). However, greater anxiety was reported in patients with allergic asthma (33.6%) or other respiratory disorders (50.4%). Patients who felt vulnerable partly assigned their vulnerability to their allergic disease (59.3%). Suffering from an allergic disease did not make patients feel more vulnerable to side effects of COVID-19 vaccine for 79.6% of them. Conclusion: Overall, most patients with allergy and under SLIT were not strongly concerned by the COVID-19 infection. SLIT did not have a negative impact on the COVID-19 symptoms.

Background: House dust mite (HDM)-induced allergic rhinitis (AR) is a major cause of allergic respiratory disease. The efficacy and safety of the 300 IR HDM sublingual immunotherapy (SLIT) tablet in patients with moderate-to-severe HDM-AR was confirmed in a large, international, phase 3 randomized controlled trials (RCTs). Here, we analyzed the results in the European population. Methods: Data from 91 European centers that participated in the international, double-blind, RCT (EudraCT 2014-004223-46, NCT02443805) with the 300 IR HDM SLIT tablet versus placebo over 12 months were analyzed post hoc. The treatment effect in European adults and adolescents was notably assessed through the European Academy of Allergy and Clinical Immunology (EAACI)-recommended combined symptom and medication score (CSMS0-6, pre-defined endpoint) and the total combined rhinitis score (TCRS0-24, post hoc endpoint, also balanced) during the primary evaluation period (4 weeks at the end of treatment period) using analysis of covariance (ANCOVA). Results: There were 818 patients who comprised the modified full analysis set in Europe. Over the primary period, the differences in CSMS0-6 and TCRS0-24 between the 300 IR and placebo groups were statistically significant (p

Abstract Background There is considerable interest in improving the scoring methods for evaluating the efficacy of allergen immunotherapy (AIT) and to show if this is associated with clinically meaningful results from the patient's perspective. We aimed to assess the efficacy and clinical relevance of a 300 index of reactivity (IR) 5‐grass pollen sublingual immunotherapy (SLIT) tablet in children, adolescents and adults with moderate to severe grass‐induced allergic rhinoconjunctivitis (ARC) with or without controlled asthma using the combined symptom and medication score CSMS0‐36. Methods The data of the European population that participated in 3 Phase III, international, randomized double‐blind placebo‐controlled clinical trials were analyzed post hoc. Results A total of 864 patients randomized to 300 IR 5‐grass tablet or placebo were analyzed. Over the primary evaluation period, the difference in CSMS0‐36 between the 300 IR and placebo groups was statistically significant (point estimates: −2.51, CI95% [−3.88; −1.14], p

Abstract Background The efficacy of benralizumab has been broadly demonstrated in severe eosinophilic asthma (SEA), but only few real-life studies evaluated its long-term effects. Here we present novel data from the ANANKE study in which a large cohort of SEA patients was treated for up to 96 weeks. Methods ANANKE (NCT04272463) is an observational retrospective Italian study investigating the key characteristics of SEA patients (collected during the 12 months prior to benralizumab initiation) and the clinical outcomes during benralizumab treatment (annual exacerbation rate [AER], lung function, asthma control, OCS use, healthcare resource utilization). A post hoc analysis was also conducted in groups of patients based on history of previous biologic therapy (bio-experienced versus naïve patients). Analyses were descriptive only. Results Before benralizumab initiation, evaluable SEA patients (N = 162, 61.1% females, mean age 56.0 ± 12.7) showed a median blood eosinophil count (BEC) of 600 cells/mm3 (IQR: 430–890). Patients experienced frequent exacerbations (annualized exacerbation rate [AER]: 4.10, severe AER: 0.98), with impaired lung function and poor asthma control (median ACT score: 14) despite 25.3% reported oral corticosteroid (OCS) use. Nasal polyposis was present in 53.1% patients; 47.5% patients were atopic. After 96 weeks since the start of benralizumab, nearly 90% patients were still on treatment; benralizumab dramatically decreased exacerbations (AER: − 94.9%; severe AER: − 96.9%), improved respiratory parameters (median increase in pre-bronchodilator forced expiratory volume [pre-BD FEV1]: + 400 mL) and asthma control (median ACT score: 23) while eliminating OCS in 60% patients. Importantly, benralizumab effects were either maintained or progressively improved over time, accompanied by a nearly complete depletion of BEC. Benralizumab reduced AER both in naïve (any AER: − 95.9%; severe AER: − 97.5%) and bio-experienced patients (any AER: − 92.4%; severe AER: − 94.0%). Conclusions Profound and sustained improvements in all asthma outcomes were observed with benralizumab. The correct identification of patients’ eosinophilic-driven asthma phenotype was essential to ensure the achievement of such remarkable results. Trial registration: ClinicalTrials.gov Identifier: NCT04272463.

Background: In its severe form, where possible, asthma is treated using biological drugs in order to reduce, as much as possible, the use of systemic steroids. Mepolizumab is effective for severe asthma based on key outcomes such as exacerbation and steroid dependence. Its efficacy in terms of the criteria for clinical remission in the short and long term has become of interest. Objective: We aimed to evaluate the effect of mepolizumab in the achievement of clinical remission after 3 years of administration. Methods: In this study, 71 patients who continued mepolizumab for 3 years were assessed for clinical remission according to six different published sets of remission criteria. Results: According to the criteria, 39–52% of patients experienced complete remission in the first year, increasing to 51–73% at 3 years. By classifying patients according to partial and complete remission criteria, proposed by the SANI, we observe 22% of patients in partial remission at one year, achieving complete remission after three years. The baseline factors associated with earlier remission were a higher FEV1, if we consider classifications requiring an FEV1 ≥ 80%, a low OCS dose, and low FeNO levels, in the patients requiring FEV1 stabilization. Conclusions: Clinical remission is possible for patients treated with mepolizumab. The observations at three years compared with the first year indicated that the factors negatively affecting remission delayed rather than prevented it. Earlier treatment could increase the chances of remission.

Chronic Obstructive Pulmonary Disease (COPD) is a pathological condition of the respiratory system characterized by chronic airflow obstruction, associated with changes in the lung parenchyma (pulmonary emphysema), bronchi (chronic bronchitis) and bronchioles (small airways disease). In the last years, the importance of phenotyping and endotyping COPD patients has strongly emerged. Metabolomics refers to the study of metabolites (both intermediate or final products) and their biological processes in biomatrices. The application of metabolomics to respiratory diseases and, particularly, to COPD started more than one decade ago and since then the number of scientific publications on the topic has constantly grown. In respiratory diseases, metabolomic studies have focused on the detection of metabolites derived from biomatrices such as exhaled breath condensate, bronchoalveolar lavage, and also plasma, serum and urine. Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy are powerful tools in the precise identification of potentially prognostic and treatment response biomarkers. The aim of this article was to comprehensively review the relevant literature regarding the applications of metabolomics in COPD, clarifying the potential clinical utility of the metabolomic profile from several biologic matrices in detecting biomarkers of disease and prognosis for COPD. Meanwhile, a complete description of the technological instruments and techniques currently adopted in the metabolomics research will be described.

Definitions and measures of asthma control used in clinical trials and practice often vary, as highlighted in the manuscript, “Is asthma control more than just an absence of symptoms? An expert consensus statement”. Furthermore, the authors discussed differences between patients and healthcare professionals (HCPs) in terms of understanding and managing asthma. Given these disparities, there is a need for consensus regarding what constitutes well-controlled asthma and, especially, how best it can be measured and recorded. In the current work, we describe our data and provide more detail on the methodology from a two-stage Delphi survey and a structured literature review, which were designed to reach a consensus definition of asthma control and alleviate misalignments between patients and HCPs. Survey data were collected using a two-stage Delphi technique; a method used to collate expert opinions over a series of sequential questionnaires to reach a consensus. The collated Delphi survey data were compared with results from a comprehensive, structured literature review of 216 publications, to assess if there was a correlation between existing guidance and measures of asthma control used in clinical trials and standard clinical practice. In order to collate and interpret findings from the Delphi survey, responses from 82 panelists (73 HCPs and 9 authors) were qualitatively analyzed, quantitatively categorized, and presented as percentages or counts in Excel databases, which are detailed in the current work. Searches conducted using PubMed and Cochrane identified 664 manuscripts, and Embase was used to identify 89 congress abstracts. After applying a stringent screening method using predefined key words, the structured literature review consisted of 185 peer-reviewed manuscripts and 31 congress abstracts, and assessed existing guidance and measures of asthma control used in clinical trials. In this publication, we provide further insight into the predefined keywords, search strings, and strategy applied to identify manuscripts and congress abstracts for inclusion/exclusion, and detail methods for data extraction. Together, the data from the Delphi survey and structured literature review aimed to provide greater insights into challenges and approaches in achieving asthma control in clinical practice, with the potential for results to be used to guide a universally accepted definition and measure of asthma control that can be used and understood by patients, HCPs, and researchers. Qualitative and quantitative methodology and analysis from the Delphi survey and literature review search strategy can potentially be used to identify disparities and explore expert opinion and relevant literature in other therapeutic areas to guide a consensus where disparities exist.

Abstract Introduction The integrated care pathways for atopic dermatitis (AD‐ICPs) aim to bridge the gap between existing AD treatment evidence‐based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co‐ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. Methods The GA2LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD‐ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2EN ADCARE centres. Results The AD‐ICPs outline the diagnostic procedures, possible co‐morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. Conclusion The AD‐ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.

The article traces the concept of asthma control within GINA guidelines over the past 25 years. In the first 15 years after 1995, the main objective of asthma management was to obtain the control of all clinical and functional characteristics of asthma. A landmark study (GOAL) showed for the first time that a good control of asthma is a reasonable outcome that can be achieved in a large proportion of asthmatics with a regular appropriate treatment. In the following years, more emphasis was placed on the role of exacerbations as critical manifestations of poor asthma control, whose frequency is associated with excessive FEV1 decline and increased risk of death. Accordingly, the 2014 GINA report makes a clear distinction between the control of the day-by-day symptoms and the reduction in the risk of severe exacerbations, stating that both conditions should be obtained. The 2019 update included a significant change in the management of mild asthma, prioritizing the prevention of exacerbations to that of mild symptoms. This view was repeated in the 2021 update, where the prevention of exacerbations, together with an acceptable symptom control with a minimal use of rescue medication, appeared to be the real main goal of asthma management. While a discrepancy between current symptoms and exacerbations may be present in mild asthma, a significant relationship between these two features is observed in moderate-severe asthma: a persistent poor symptom control is a major risk factor for exacerbations, whereas achieving symptom control through regular treatment is associated with a reduction in exacerbation rate. Thus, the opinion that frequent symptoms are not important in the absence of acute exacerbations should be discouraged, whereas education of patients to a good symptom perception and to improve adherence to regular treatment should be implemented. Furthermore, the persistence of risk factors, such as increased airway inflammation, even in a patient with minor daily symptoms, should be considered for optimizing treatment.

Background: Fexofenadine emerged as one of the most representative second generation histamine H1 antagonist drugs since the 1990s, with an outstanding efficacy and appreciable safety for the treatment of allergic patients. While allergic rhino-conjunctivitis represents the most frequent atopic disease globally, an update of fexofenadine efficacy and safety on this entity was proposed as a surrogate of allergic condition. Methods: Double blind, placebo controlled, randomized clinical trials investigating the efficacy and safety of fexofenadine for the treatment of Allergic Rhinitis were searched in 5 major global databases. Eligibility criteria and characteristics, risk of bias, and validity assessment, data extraction and heterogeneity evaluation are described. Primary outcome selected corresponded to 12-reflective and instantaneous total symptom scores (TSS), besides morning instantaneous TSS and the frequency of reported adverse events (AEs); analysis was planned on the intention-to-treat population.Standardized mean differences of scoring systems were analyzed, and Cochran's Q statistic test and the I2 test were assessed for heterogeneity. Results: From the initial 83 identified records, 12 eligible studies were selected. In the evaluated patients, individuals receiving fexofenadine (1910) showed a significant reduction of TSS compared with those who received placebo (1777), change from baseline: standardized mean difference (SMD) –0.33; 95% CI–0.47 to −0.18, p

Background: Etiology of allergic rhinitis and asthma is frequently associated with house dust mite sensitization and allergen immunotherapy (AIT) represents the only disease modifying treatment. In a real world setting, clinicians would benefit from biomarkers to monitor or predict response to AIT. Methods: Twenty-four consecutive house dust mite (HDM) mono-sensitized rhinitic patients, treated with subcutaneous immunotherapy (SCIT) as per clinical practice, were enrolled. Multiple in vitro biomarkers such as basophil activation (BAT), IL-10 levels, and molecular allergen-specific IgE were performed during HDM SCIT, to monitor the effects of AIT and then correlated to in vivo scores (VAS, CMSS, RQLQ). Nasal cytology was performed at baseline and after 6 and 12 months of treatment. Finally, the economic impact of SCIT in this cohort of patients was evaluated. Results: Clinical biomarkers confirmed to be useful to monitor AIT efficacy. As for laboratory biomarkers, BAT showed a reduction trend, particularly for D2C1, suggesting that this is a useful parameter in monitoring patients. IL-10 levels tend to remain stable or slightly decrease during treatment. The economic analysis confirmed the favorable impact of immunotherapy. Conclusions: In this cohort of patients, SCIT confirmed its effectiveness in reducing symptoms and drug utilization. Clinical scores confirmed to be valid in monitoring patients and their response. BAT demonstrated to be useful in monitoring more than predicting response. Further studies are needed to better explore the usefulness of these biomarkers in AIT.

Chronic rhinosinusitis (CRS) has recently undergone a significant paradigm shift, moving from a phenotypical classification towards an “endotype-based” definition that places more emphasis on clinical and therapeutic aspects. Similar to other airway diseases, like asthma, most cases of CRS in developed countries exhibit a dysregulated type-2 immune response and related cytokines. Consequently, the traditional distinction between upper and lower airways has been replaced by a “united airway” perspective. Additionally, type-2 related disorders extend beyond respiratory boundaries, encompassing conditions beyond the airways, such as atopic dermatitis. This necessitates a multidisciplinary approach. Moreover, consideration of possible systemic implications is crucial, particularly in relation to sleep-related breathing diseases like Obstructive Sleep Apnoea Syndrome (OSAS) and the alteration of systemic inflammatory mediators such as nitric oxide. The trends in epidemiological, economic, and social burden are progressively increasing worldwide, indicating syndemic characteristics. In light of these insights, this narrative review aims to present the latest evidence on respiratory type-2 related disorders, with a specific focus on CRS while promoting a comprehensive perspective on the “united airways”. It also introduces a novel concept: viewing these conditions as a multiorgan, systemic, and syndemic disease.

Abstract Introduction Allergic rhinitis (AR) is very commonly caused by pollens. The symptoms of AR consist of sneezing, nasal congestion, rhinorrhea, nasal itching and airflow obstruction. The diagnosis has long been based on clinical history, skin prick tests and in vitro measurement of specific IgE, but the innovative approach of precision medicine has made diagnostic tools of much greater accuracy available. Areas covered This review covers the advances in the treatment of seasonal AR concerning the drugs to be used according to the grade of disease and the characteristics of the patients, and the role of allergen immunotherapy (AIT), which is the only treatment capable of acting, in addition to the symptoms, on the cause of AR and therefore to modify its natural history. Expert opinion Drug treatment of AR include a large number of agents, the choice of which depends on the severity of the disease. AIT has high evidence of efficacy demonstrated by meta-analyses, and further improvement is currently apparent, as for diagnosis, applying the means of precision medicine. However, when AIT is performed in current practice, without the strict rules of controlled trials, long-term low adherence is a major problem to be solved.

Background The application of allergen immunotherapy (AIT) in combination with biological agents has been found to increase both the safety and efficacy of the desensitisation procedure in patients with food and insect venom allergy. The aim of our study was to compare the effectiveness of AIT in patients with house dust mite (HDM)-driven asthma treated with and without omalizumab. Materials and methods The study was a placebo-controlled, three-armed, randomised, parallel-group, multicentre trial that included 52 patients with HDM-driven asthma. Only patients with monosensitisation to HDM were included. The study compared three patterns of therapy: omalizumab alone, HDM subcutaneous immunotherapy (SCIT-HDM)+ omalizumab, and SCIT alone. The main outcomes were evaluate the Asthma Control Questionnaire (ACQ) score, number of asthma exacerbations and reduction in the daily dose of inhaled steroids during 12 months of observation. Results All variants of therapy led to significantly improved ACQ scores and reduction of asthma exacerbations in all study groups after 12 months of treatment. A statistically significant reduction in the daily doses of inhaled corticosteroids in the group with omalizumab alone (650±150 µg versus 500±50 µg for p=0.003) or SCIT-HDM+omalizumab (550±250 µg versus 375±75 µg for p=0.001) was observed, favouring the latter group. Conclusion The efficacy of AIT for HDM-driven asthma is significantly increased by the combination of allergen vaccine with omalizumab.

Abstract Background Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. Methods We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). Results In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. Conclusions These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Abstract Background Data from phase 3 trials have demonstrated the efficacy and safety of benralizumab in patients with severe eosinophilic asthma (SEA). We conducted a real-world study examining the baseline characteristics of a large SEA population treated with benralizumab in clinical practice and assessed therapy effectiveness. Methods ANANKE is an Italian multi-center, retrospective cohort study including consecutive SEA patients who had started benralizumab therapy ≥ 3 months before enrolment (between December 2019 and July 2020), in a real-world setting. Data collection covered (1) key patient features at baseline, including blood eosinophil count (BEC), number and severity of exacerbations and oral corticosteroid (OCS) use; (2) clinical outcomes during benralizumab therapy. We also conducted two post-hoc analyses in patients grouped by body mass index and allergic status. Analyses were descriptive only. Results Of 218 patients with SEA enrolled in 21 Centers, 205 were evaluable (mean age, 55.8 ± 13.3 years, 61.5% females). At treatment start, the median BEC was 580 cells/mm3 (interquartile range [IQR]: 400–850); all patients were on high-dose inhaled controller therapy and 25.9% were on chronic OCS (median dose: 10 mg/die prednisone-equivalent [IQR: 5–25]); 92.9% experienced ≥ 1 exacerbation within the past 12 months (annualized exacerbation rate [AER] 4.03) and 40.3% reported ≥ 1 severe exacerbation (AER 1.10). During treatment (median duration: 9.8 months [IQR 6.1–13.9]; ≥ 12 months for 34.2% of patients), complete eosinophil depletion was observed; exacerbation-free patients increased to 81% and only 24.3% reported ≥ 1 severe event. AER decreased markedly to 0.27 for exacerbations of any severity (− 93.3%) and to 0.06 for severe exacerbations (− 94.5%). OCS therapy was interrupted in 43.2% of cases and the dose reduced by 56% (median: 4.4 mg/die prednisone-equivalent [IQR: 0.0–10.0]). Lung function and asthma control also improved. The effectiveness of benralizumab was independent of allergic status and body mass index. Conclusions We described the set of characteristics of a large cohort of patients with uncontrolled SEA receiving benralizumab in clinical practice, with a dramatic reduction in exacerbations and significant sparing of OCS. These findings support benralizumab as a key phenotype-specific therapeutic strategy that could help physicians in decision-making when prescribing biologics in patients with SEA. Trial registration ClinicalTrials.gov Identifier: NCT04272463

Systemic corticosteroids (SCS) are a highly effective treatment for acute exacerbations and long-term symptom control in asthma. Long-term SCS use is highly prevalent across all asthma severities, occurring in over 20% of patients with severe or uncontrolled disease globally. It is now well known that exposure to both long-term and repeated acute courses of SCS is associated with a high risk of serious adverse effects (AEs), such as osteoporosis, and metabolic and cardiovascular complications, especially when prescribed onto a background of other corticosteroids. The aim of this call-to-action article, endorsed by the World Allergy Organization and the Respiratory Effectiveness Group, is to review the accumulating evidence on the burden of SCS on patients with asthma and provide an overview of potential strategies for implementing SCS Stewardship.Primary prevention of exacerbations and improvement of asthma control is a key first step in achieving SCS Stewardship, by optimizing maintenance asthma medications and addressing modifiable risk factors, such as adherence and inhaler technique. Other key elements of SCS Stewardship include increasing appropriate specialist referrals for multidisciplinary review, assessment of biomarkers, and consideration of oral corticosteroid-sparing add-on therapies (eg, biologics). In cases where SCS use is deemed clinically justified, it should be tapered to the lowest possible dose. In addition, patients receiving long-term SCS or frequent acute courses should be closely monitored for emergence of SCS-related AEs.Because of the extensive data available on the costly and burdensome AEs associated with SCS use, as well as the range of treatment options now available, there is a need for healthcare providers (HCPs) to carefully evaluate whether the benefits of SCS outweigh the potential harms, to adopt SCS-sparing and Stewardship strategies, and to consider alternative therapies where possible. Development of a structured and collaborative SCS Stewardship approach is urgently required to protect patients from the potential harm of SCS use.

Omalizumab is a biological drug targeting circulating IgE, approved for use in allergic asthma, chronic spontaneous urticaria, and recently for chronic rhinosinusitis with nasal polyps, with good efficacy in all these settings. Some concerns about omalizumab safety have been raised as its use has been recently linked to potential increased cancer risk. Nevertheless, literature evidence does not support this statement, and clinical studies and evidence from real-world registries and surveillance analysis have consistently reported drug safety.

Background: The identification of type-2 inflammation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) acquires a crucial role in the endotypization needed for selecting patients for biological drugs targeting type-2 inflammation: to date, the parameters used include systemic and histological biomarkers. The aim of this study was to investigate whether nasal cytology could identify type-2 inflammation in patients with CRSwNP. Methodology: Thirty-three consecutive patients with CRSwNP underwent nasal cytology sampling at the level of the lower nasal turbinate, and of the polypoid tissue, and surgical polyp tissue sample was collected. The cellularity of the 3 collected samples were compared. Results: Mean nasal polyp tissue, nasal polyps cytology and inferior turbinate cytology eosinophils counts were 43.7 ± 39.6 cells/HPF, 32.8 ± 44.7 cells/HPF and 27.6 ± 58.0 cells/HPF respectively with inferior turbinate cytology eosinophils significantly lower than nasal polyp tissue count (p = 0.007). Both mean nasal polyps cytology eosinophils and mean inferior turbinate cytology eosinophils were significantly higher in patients with type-2 CRSwNP (52.5 ± 67.0 cells/HPF vs 12.2 ± 17.3 cells/HPF, p = 0.012, and 32.0 ± 62.1 cells/HPF vs 2.9 ± 2.9 cells/HPF, p = 0.020 respectively). Conclusions: Nasal cytology is suitable tool for assessing local biomarkers of type-2 inflammation in CRSwNP.

Introduction Treatment with biologics for severe asthma is informed by international and national guidelines and defined by national regulating bodies, but how these drugs are used in real-life is unknown. Materials and methods The European Respiratory Society (ERS) SHARP Clinical Research Collaboration conducted a three-step survey collecting information on asthma biologics use in Europe. Five geographically distant countries defined the survey questions, focusing on seven end-points: biologics availability and financial issues, prescription and administration modalities, inclusion criteria, continuation criteria, switching biologics, combining biologics and evaluation of corticosteroid toxicity. The survey was then sent to SHARP National Leads of 28 European countries. Finally, selected questions were submitted to a broad group of 263 asthma experts identified by national societies. Results Availability of biologics varied between countries, with 17 out of 28 countries having all five existing biologics. Authorised prescribers (pulmonologists and other specialists) also differed. In-hospital administration was the preferred deliverance modality. While exacerbation rate was used as an inclusion criterion in all countries, forced expiratory volume in 1 s was used in 46%. Blood eosinophils were an inclusion criterion in all countries for interleukin-5 (IL-5)-targeted and IL-4/IL-13-targeted biologics, with varying thresholds. There were no formally established criteria for continuing biologics. Reduction in exacerbations represented the most important benchmark, followed by improvement in asthma control and quality of life. Only 73% (191 out of 263) of surveyed clinicians assessed their patients for corticosteroid-induced toxicity. Conclusion Our study reveals important heterogeneity in the use of asthma biologics across Europe. To what extent this impacts on clinical outcomes relevant to patients and healthcare services needs further investigation.

The advent of personalized medicine has revolutionized the whole approach to the management of asthma, representing the essential basis for future developments. The cornerstones of personalized medicine are the highest precision in diagnosis, individualized prediction of disease evolution, and patient-tailored treatment. To this aim, enormous efforts have been established to discover biomarkers able to predict patients' phenotypes according to clinical, functional, and bio-humoral traits. Biomarkers are objectively measured characteristics used as indicators of biological or pathogenic processes or clinical responses to specific therapeutic interventions. The diagnosis of type-2 asthma, prediction of response to type-2 targeted treatments, and evaluation of the risk of exacerbation and lung function impairment have been associated with biomarkers detectable either in peripheral blood or in airway samples. The surrogate nature of serum biomarkers, set up to be less invasive than sputum analysis or bronchial biopsies, has shown several limits concerning their clinical applicability. Routinely used biomarkers, like peripheral eosinophilia, total IgE, or exhaled nitric oxide, result, even when combined, to be not completely satisfactory in segregating different type-2 asthma phenotypes, particularly in the context of severe asthma where the choice among different biologics is compelling. Moreover, the type-2 low fraction of patients is not only an orphan of biological treatments but is at risk of being misdiagnosed due to the low negative predictive value of type-2 high biomarkers. Sputum inflammatory cell analysis, considered the highest specific biomarker in discriminating eosinophilic inflammation in asthma, and therefore elected as the gold standard in clinical trials and research models, demonstrated many limits in clinical applicability. Many factors may influence the measure of these biomarkers, such as corticosteroid intake, comorbidities, and environmental exposures or habits. Not least, biomarkers variability over time is a confounding factor leading to wrong clinical choices. In this narrative review, we try to explore many aspects concerning the role of routinely used biomarkers in asthma, applying a critical view over the “state of the art” and contemporarily offering an overview of the most recent evidence in this field.

BackgroundSevere asthma is a heterogeneous inflammatory disease driven by eosinophilic inflammation in the majority of cases. Despite biologic therapy patients may still be sub-optimally controlled, and the choice of the best biologic is a matter of debate. Indeed, switching between biologics is common, but no official guidelines are available and real-world data are limited.Materials and methodsIn this post hoc analysis of the Italian, multi-center, observational, retrospective study, ANANKE. Patients with severe eosinophilic asthma treated with benralizumab were divided in two groups based on history of previous biologic therapy (biologic-experienced [suboptimal response] vs naïve). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment. Change over time in blood eosinophils, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use following benralizumab initiation were collected in the two groups.ResultsA total of 147 biologic-naïve and 58 biologic-experienced (34 omalizumab, 19 mepolizumab, and 5 omalizumab-mepolizumab) patients were enrolled. Biologic-experienced patients were more likely to be atopic and have a higher AER despite more frequent OCS use. Similar reductions in AER (>90% in both groups), OCS use (≥49% reduction in dosage and ≥41% able to eliminate OCS), ACT improvement (≥7 points gained in 48 weeks) and lung function (≥300 mL of FEV1 improvement in 48 weeks) were observed after benralizumab introduction within the two groups. There were no registered discontinuations of benralizumab for safety reasons.ConclusionIn this post hoc analysis, patients who were switched to benralizumab because of suboptimal control with a previous biologic therapy were more likely to be atopic and more often treated with omalizumab. Benralizumab is effective in both naïve patients and those previously treated with a biologic.

The efficacy mepolizumab in severe asthmatic patients is proven in the literature. Primarily to study the effect of mepolizumab on exacerbations, steroid dependence, and the continuation of efficacy in the long term. Secondarily to evaluate the effect of the drug on nasal polyps. Analyzing data from SANI (Severe Asthma Network Italy) clinics, we observed severe asthmatic patients treated with mepolizumab 100 mg/4 weeks, for a period of 3 years. 157 patients were observed. Exacerbations were reduced from the first year (−84.6%) and progressively to 90 and 95% in the second and third ones. Steroid-dependent patients decreased from 54% to 21% and subsequently to 11% in the second year and 6% in the third year. Patients with concomitant nasal polyps, assessed by SNOT-22, showed a 49% reduction in value from baseline to the third year. The study demonstrated the long-term efficacy of mepolizumab in a real-life setting.

Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their role in respiratory allergic diseases would give us, perhaps, novel therapy targets. Based on this, there is currently a great demand for therapeutic regimens to enfeeble the damaging impact of MCs in these pathological conditions. Several strategies can accomplish this at different levels in response to MC activation, including targeting individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth, or inducing mast cell apoptosis. The current work focuses on and summarizes the mast cells’ role in pathogenesis and as a personalized treatment target in allergic rhinitis and asthma; even these supposed treatments are still at the preclinical stage.

Abstract The concept of personalized medicine as a diagnostic and therapeutic approach tailored to the medical needs of each patient is currently revolutionizing all fields of medicine and in particular allergology. Allergen immunotherapy (AIT) meets the three main needs for precision medicine: identification of molecular mechanism of disease, diagnostic tools for the mechanism and treatment blocking the mechanism itself. AIT adapts to the spectrum of specific IgE of each individual subject, changing the course and natural history of the disease, so is a clear model of precision and personalized medicine. This first step before the prescription of AIT is to define the sensitization profile of the patient; after that, the healthcare professional has numerous levers for adapting the treatment to the physio-pathological mechanisms involved. AIT allows to adapt treatments to the profile of the patients, but also to the its preferences, to ensure optimal treatment efficacy, resulting in an agile and personalized approach, with the aim to ensure adherence to the treatment, which is usually quite low. AIT also broadens the field of possibilities for healthcare professionals and patients, by allowing to choose the galenic formulation according to patient preferences and on the basis of their clinical history, adapting the product composition to the patient’s sensitization profiles and the underlying biological mechanisms identified at the diagnostic stage, while guaranteeing quality of the prescribed product as the production of allergens and allergoids is today more regulated than in the past years. In the management of AIT, it is also possible to involve patients in decisions throughout their care pathway thanks to multiple services, offering personalized follow-up and support, to ensure the highest treatment efficacy levels, and recalling medication intake, medical appointments and prescription renewals.

Adherence and compliance, respectively considered as a more positive, proactive behavior, resulting in a patient's lifestyle change to follow a daily regimen, and, as a more enforced response to an external command, are a critical aspect of any medical therapy, since it is estimated that less than half of the patients who are prescribed a therapy perform it, respecting the doses and duration. As far as aeroallergen immunotherapy is concerned, current data show that adherence is respected in about 50% of subcutaneous immunotherapy and in percentages even lower than 20% in sublingual immunotherapy treatments. This review analyzes the adherence to venom immunotherapy (VIT), in which, given its purpose of preventing potentially fatal anaphylactic reactions to insect stings, this aspect plays a critical role. In fact, protection from stings already takes place when the maintenance dose is reached, but VIT interruption before the recommended duration of 5 years exposes patients to new sting reactions. The data on adherence to VIT are far less abundant than that for aeroallergen immunotherapy. One of the first studies reported poor adherence in Austria, but the model used, consisting in the estimate of the percentage of patients with systemic reactions who accepted or rejected VIT, does not meet the criteria that define adherence to treatment. As for appropriate adherence studies, rates higher than 70% were reported in the United States and European countries. Studies from Italy found that good adherence were observed also in patients receiving, after 4 years of VIT, 3 months extended maintenance dose, as well as in patients treated during the COVID-19 pandemic,

Abstract Background Comorbidities are common in chronic inflammatory conditions, requiring multidisciplinary treatment approach. Understanding the link between a single disease and its comorbidities is important for appropriate treatment and management. We evaluate the ability of an NLP‐based process for knowledge discovery to detect information about pathologies, patients' phenotype, doctors' prescriptions and commonalities in electronic medical records, by extracting information from free narrative text written by clinicians during medical visits, resulting in the extraction of valuable information and enriching real world evidence data from a multidisciplinary setting. Methods We collected clinical notes from the Allergy Department of Humanitas Research Hospital written in the last 3 years and used it to look for diseases that cluster together as comorbidities associated to the main pathology of our patients, and for the extent of prescription of systemic corticosteroids, thus evaluating the ability of NLP‐based tools for knowledge discovery to extract structured information from free text. Results We found that the 3 most frequent comorbidities to appear in our clusters were asthma, rhinitis, and urticaria, and that 991 (of 2057) patients suffered from at least one of these comorbidities. The clusters which co‐occur particularly often are oral allergy syndrome and urticaria (131 patients), angioedema and urticaria (105 patients), rhinitis and asthma (227 patients). With regards to systemic corticosteroid prescription volume by our clinicians, we found it was lower when compared to the therapy the patients followed before coming to our attention, with the exception of two diseases: Chronic obstructive pulmonary disease and Angioedema. Conclusions This analysis seems to be valid and is confirmed by the data from the literature. This means that NLP tools could have significant role in many other research fields of medicine, as it may help identify other important, and possibly previously neglected clusters of patients with comorbidities and commonalities. Another potential benefit of this approach lies in its potential ability to foster a multidisciplinary approach, using the same drugs to treat pathologies normally treated by physicians in different branches of medicine, thus saving resources and improving the pharmacological management of patients.

Asthma is one of the most common noncommunicable diseases; in the majority of patients it is well controlled with inhaled bronchodilators and inhaled corticosteroids, but the management of severe asthma has been a significant challenge historically. The introduction of novel biologic drugs in the past few decades has revolutionised the field, presenting physicians with a variety of biologic drugs with different mechanisms for the treatment of severe asthma. It is of crucial importance to evaluate the effectiveness of these drugs by following their “real-life” effectiveness rather than relying solely on their efficacy, established in carefully designed clinical trials, which therefore do not necessarily match the profile of the real-life patient. Understanding the actual effectiveness of the specific drugs in real-life patients is a crucial part of tailoring the right drugs to the right patients. Registries serve as an important tool in obtaining real-life evidence, since they are in effect observational studies, following the entire patient population.

Abstract Background Asthma is a chronic disease characterized by airway hyperresponsiveness, inflammation and mucus production. In Type 2 asthma, two phenotypic components are often co-expressed (eosinophilic and allergic). Elevated biomarker levels, such as eosinophils (EOS), fraction of exhaled nitric oxide (FeNO) and immunoglobulin E (IgE), are key clinical indicators of Type 2 inflammation. Dupilumab has been recently approved for the treatment of uncontrolled severe Type 2 asthma. Type 2 asthma includes allergic and/or eosinophilic phenotypes. The aim of this analysis was to estimate the dupilumab-eligible population in Italy and characterize it by expected biomarker status. Methods A 4-step approach was carried out to calculate dupilumab-eligible population. The approach consisted in: (1) estimating the total number of asthma patients in Italy (using 2016–2017 Italian-adapted Global Initiative for Asthma -GINA- guidelines); (2) estimating the number of severe asthma patients with poorly controlled or uncontrolled disease (using the findings of two recent administrative claim analyses conducted in Italy); (3) stratifying the severe uncontrolled population by biomarker levels (EOS, FeNO and IgE) according to the outcomes of the QUEST trial (a clinical study assessing the efficacy of dupilumab in patients with uncontrolled moderate-to-severe asthma; NCT02414854); (4) identifying the sub-populations of severe uncontrolled asthma patients characterised by raised blood EOS and/or FeNO level (thus indicated to receive dupilumab). Results According to these estimates, about 3.3 million asthmatic patients live in Italy (6.10% of the population). Of them, almost 20 thousand (N = 19,960) have uncontrolled severe asthma. Dupilumab-eligible patients would be N = 15,988, corresponding to 80.1% of the total uncontrolled severe population. Most of these patients (89.3%; N = 14,271) have at least an increase of EOS level, while slightly more than half (51.9%; N = 8,303) have raised levels of both biomarkers. Increased FeNO levels without increased EOS are observed less frequently (N = 1,717; 10.7% of the eligible population). Conclusions There is a strong rationale for testing all asthma biomarkers during diagnosis and disease follow-up. Given the large availability and the limited costs, these tests are cost-effective tools to detect severe Type 2 asthma, stratify patients by phenotype, and drive appropriate treatment decisions.

The anti-SARS-CoV-2 vaccination has probably been the most effective tool for preventing the infection and negative outcomes of the COVID-19 disease, and therefore for interrupting the pandemic state. The first licensed SARS-CoV-2 vaccine was BNT162b2, an mRNA vaccine that has been widely used since the earliest stages of the global vaccination campaign. Since the beginning of the vaccination campaign, some cases of suspected allergic reactions to BNT162b2 have been described. Epidemiological data, however, have provided reassuring results of an extremely low prevalence of these hypersensitivity reactions to anti-SARS-CoV-2 vaccines. In this article, we describe the results of a survey carried out through the use of a questionnaire, administered to all the health personnel of our university hospital after the first two doses of the BNT162b2 vaccine, which investigated the development of adverse reactions after a vaccination. We analyzed the responses of 3112 subjects subjected to the first dose of the vaccine; among these, 1.8% developed symptoms compatible with allergic reactions and 0.9% with clinical manifestations of possible anaphylaxis. Only 10.3% of the subjects who had allergic reactions after the first injection experienced similar reactions after the second dose and none of them experienced anaphylaxis. In conclusion, the anti-SARS-CoV-2 vaccination is rarely associated with severe allergic reactions and the second dose of vaccine is safe for this group of patients.

Vaccines for SAR-CoV-2 are the most effective preventive treatment able to reduce the risk of contracting the infection and experiencing worse outcomes whenever the infection is contracted. Despite their rarity, hypersensitivity reactions to the anti-SARS-CoV-2 vaccine have been described and could become the reason not to complete the vaccination. Desensitization protocols for other vaccines have been described and validated, while the use of this approach for anti-SARS-CoV-2 vaccines is still anecdotal. We herein describe our experience with 30 patients with previous allergic reactions to anti-SARS-CoV-2 vaccines or to any of their excipients, proving that they are effective and safe; only two patients experienced hypersensitivity reaction symptoms during the desensitization procedure. Moreover, in this article, we propose desensitization protocols for the most common anti-SARS-CoV-2 vaccines.

Concern has arisen about hypersensitivity reactions in patients with allergic reactions to drugs containing polyethylene glycol (PEG) or polysorbate 80 (PS80), excipients of currently available anti-SARS-CoV-2 mRNA vaccines. However, the actual utility of PEG and PS80 skin allergy testing is currently still debated. We retrospectively analyzed all cases of patients on whom we performed allergometric skin tests for PEG and PS80 in the context of a pre-vaccination screening (for patients with multiple hypersensitivity reactions to drugs for which these excipients were among the suspected agents) or following suspected hypersensitivity reactions to anti-SARS-CoV-2 vaccines. A total of 134 tests were performed for PEG and PS80, eight of which produced uninterpretable results (due to dermographism or non-specific reactions). Of the remaining 126 cases (85 pre-vaccinal and 41 post-vaccine reactions), 16 (12.7%) were positive for PEG and/or PS80. Stratifying by clinical indication, there were no statistically significant differences in the proportion of positive tests between patients evaluated in the context of the pre-vaccination screening and those evaluated after a vaccine reaction (10.6% vs. 17.1%, respectively, p = 0.306). Allergometric skin tests for PEG and PS80 in our case series resulted positive in an unexpectedly high proportion of patients, suggesting that testing for allergy to these two excipients should not be ignored in case of reasonable clinical suspicion.

Background The coronavirus disease 2019 (COVID-19) pandemic has put pressure on healthcare services, forcing the reorganisation of traditional care pathways. We investigated how physicians taking care of severe asthma patients in Europe reorganised care, and how these changes affected patient satisfaction, asthma control and future care. Methods In this European-wide cross-sectional study, patient surveys were sent to patients with a physician-diagnosis of severe asthma, and physician surveys to severe asthma specialists between November 2020 and May 2021. Results 1101 patients and 268 physicians from 16 European countries contributed to the study. Common physician-reported changes in severe asthma care included use of video/phone consultations (46%), reduced availability of physicians (43%) and change to home-administered biologics (38%). Change to phone/video consultations was reported in 45% of patients, of whom 79% were satisfied or very satisfied with this change. Of 709 patients on biologics, 24% experienced changes in biologic care, of whom 92% were changed to home-administered biologics and of these 62% were satisfied or very satisfied with this change. Only 2% reported worsening asthma symptoms associated with changes in biologic care. Many physicians expect continued implementation of video/phone consultations (41%) and home administration of biologics (52%). Conclusions Change to video/phone consultations and home administration of biologics was common in severe asthma care during the COVID-19 pandemic and was associated with high satisfaction levels in most but not all cases. Many physicians expect these changes to continue in future severe asthma care, though satisfaction levels may change after the pandemic.

Background: Chronic cough management necessitates a clear integrated care pathway approach. Primary care physicians initially encounter the majority of chronic cough patients, yet their role in proper management can prove challenging due to limited access to advanced diagnostic testing. A multidisciplinary approach involving otolaryngologists and chest physicians, allergists, and gastroenterologists, among others, is central to the optimal diagnosis and treatment of conditions which underly or worsen cough. These include infectious and inflammatory, upper and lower airway pathologies, or gastro-esophageal reflux. Despite the wide armamentarium of ancillary testing conducted in cough multidisciplinary care, such management can improve cough but seldom resolves it completely. This can be due partly to the limited data on the role of tests (eg, spirometry, exhaled nitric oxide), as well as classical pharmacotherapy conducted in multidisciplinary specialties for chronic cough. Other important factors include presence of multiple concomitant cough trigger mechanisms and the central neuronal complexity of chronic cough. Subsequent management conducted by cough specialists aims at control of cough refractory to prior interventions and includes cough-specific behavioral counseling and pharmacotherapy with neuromodulators, among others. Preliminary data on the role of neuromodulators in a proof-of-concept manner are encouraging but lack strong evidence on efficacy and safety. Objectives: The World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough reviewed the recent literature on management of chronic cough in primary, multidisciplinary, and cough-specialty care. Knowledge gaps in diagnostic testing, classical and neuromodulator pharmacotherapy, in addition to behavioral therapy of chronic cough were also analyzed. Outcomes: This third part of the WAO/ARIA consensus on chronic cough suggests a management algorithm of chronic cough in an integrated care pathway approach. Insights into the inherent limitations of multidisciplinary cough diagnostic testing, efficacy and safety of currently available antitussive pharmacotherapy, or the recently recognized behavioral therapy, can significantly improve the standards of care in patients with chronic cough.

BackgroundSevere eosinophilic asthma (SEA) in the presence of chronic rhinosinusitis with nasal polyps (CRSwNP) indicates the presence of a more extensive eosinophilic inflammation. Post-hoc analyses from a pivotal clinical trial have demonstrated the enhanced efficacy of benralizumab on asthma outcomes in patients with CRSwNP as a comorbidity.MethodsThis is a post-hoc analysis from the Italian multi-center observational retrospective ANANKE study. Patients were divided into two groups based on self-reported CRSwNP. Baseline clinical and laboratory features in the 12 months prior to benralizumab prescription were collected. Data of change over time of blood eosinophils, annualized exacerbations rates (AER), asthma control, lung function, oral corticosteroids (OCS) use, and benralizumab discontinuation were collected during the observation period.ResultsAt baseline, the 110 patients with CRSwNP were less frequently female (50.9% vs 74.2%) and obese (9.1% vs. 22.6%) with higher eosinophils (605 vs. 500 cells/mm3) and OCS use when compared to patients without CRSwNP. Similar reductions of AER were seen (-95.8% vs. −91.5% for any exacerbation and −99.1% vs. −92.2% for severe exacerbations in patients with and without CRSwNP, respectively). During benralizumab treatment, comorbid SEA+CRSwNP was associated with a lower risk of any exacerbation (p = 0.0017) and severe exacerbations (p = 0.025). After a mean ± SD exposure of 10.3 ± 5.0 months, half of the SEA+CRSwNP patients eliminated OCS use. No discontinuation for safety reasons was recorded.ConclusionsThis study helped to confirm the baseline clinical features that distinguish patients with and without CRSwNP being prescribed benralizumab. Numerically enhanced OCS reduction and lower exacerbation risk were observed in patients with SEA and comorbid CRSwNP treated with benralizumab.

Interleukins (IL)-4 and -13 play a pivotal role in the pathobiology of type-2 asthma. Indeed, IL-4 is crucially involved in Th2 cell differentiation, immunoglobulin (Ig) class switching and eosinophil trafficking. IL-13 cooperates with IL-4 in promoting IgE synthesis, and also induces nitric oxide (NO) production, goblet cell metaplasia and fibroblast proliferation, as well as elicits contractile responses and hyperplasia of airway smooth muscle cells.IL-4 and IL-13 share common signaling pathways, activated by the binding of both cytokines to receptor complexes including the α-subunit of the IL-4 receptor (IL-4Rα). Therefore, the subsequent receptor dimerization is responsible for the pathophysiologic effects of IL-4 and IL-13. By selectively blocking IL-4Rα, the fully human IgG4 monoclonal antibody dupilumab behaves as a dual receptor antagonist of both IL-4 and IL-13. Through this mechanism of action, dupilumab exerts effective therapeutic actions in type-2 inflammation, thus decreasing asthma exacerbations, FeNO (fractional exhaled NO) levels, and the intake of oral corticosteroids (OCS). In addition to being approved for the add-on biological therapy of severe asthma, dupilumab has also been licensed for the treatment of nasal polyposis and atopic dermatitis.

Abstract Background Despite availability of clinical guidelines, underdiagnosis, undertreatment, and poor adherence are still significant concerns in allergic rhinitis (AR) therapeutic management. We investigated clinical practice patterns and prescribing behavior of Italian healthcare professionals (HCPs) specialized in AR. Methods One-hundred allergologists, 100 ear, nose and throat (ENT) specialists, and 150 general practitioners (GPs) were recruited. The survey assessed: socio-demographic, work experience, monthly caseload, prescription drivers. Next, HCPs were invited to retrospectively recover patients’ clinical data to investigate: AR clinical characteristics, therapy management, prescription patterns, patient adherence. Descriptive statistics, Chi square, One-Way analysis of variance, and Two-Way Analysis of Variance were performed. Results Allergologists visited more AR patients (31% of monthly caseload) than ENTs (21%, p 7). Conclusions This survey describes the therapeutic approach adopted by Italian physicians to cope with AR and shows that HCPs underestimated AR severity and had a non-realistic perception of patients’ adherence. These findings suggest that further efforts are required to improve AR clinical management in Italy.

Abstract Background A number of single-inhaler triple therapies are being developed for asthma, including the extrafine formulation of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G). Given asthma is a heterogenous disease, we investigated whether the clinical response to the addition of the long-acting muscarinic antagonist component within inhaled triple therapy was impacted by a range of clinical characteristics. Methods These were pre-specified and post-hoc sub-group analyses of TRIMARAN and TRIGGER, which were double-blind, 52-week studies comparing medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with the respective BDP/FF strengths in adults with uncontrolled asthma and a history of ≥ 1 exacerbation. Co-primary endpoints were pre-dose forced expiratory volume in 1 s (FEV1) at Week 26 and the rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints: peak FEV1 at Week 26 and average morning peak expiratory flow over the first 26 weeks in each study, and severe exacerbation rate over 52 weeks (pooled data). Results Baseline clinical characteristics (pre-specified analyses) had no consistent effect on the lung function improvements with BDP/FF/G. For the exacerbation endpoints, sub-groups with higher reversibility gained greatest relative benefit from BDP/FF/G versus BDP/FF. In post-hoc analyses with patients sub-grouped by screening blood eosinophil values, in TRIMARAN the greatest relative effect of BDP/FF/G versus BDP/FF on the lung function endpoints was in the ≤ 300 cells/µL group; in TRIGGER, eosinophil levels did not markedly influence the relative efficacy of BDP/FF/G versus BDP/FF. Eosinophil levels did not influence relative efficacy on moderate-to-severe or severe exacerbations. Conclusion Overall, the relative efficacy of extrafine BDP/FF/G versus BDP/FF was not influenced by a range of clinical characteristics. However, some patient sub-groups gained additional benefit from BDP/FF/G for certain endpoints. In particular, for exacerbations the relative efficacy of BDP/FF/G was greater in more reversible patients. Trial registration ClinicalTrials.gov: TRIMARAN, NCT02676076 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676076?term=NCT02676076&draw=2&rank=1 ,); TRIGGER, NCT02676089 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676089?term=NCT02676089&draw=2&rank=1 )

Abstract Asthma is a common chronic disease characterized by episodic or persistent respiratory symptoms and airflow limitation. Asthma treatment is based on a stepwise and control-based approach that involves an iterative cycle of assessment, adjustment of the treatment and review of the response aimed to minimize symptom burden and risk of exacerbations. Anti-inflammatory treatment is the mainstay of asthma management. In this review we will discuss the rationale and barriers to the treatment of asthma that may result in poor outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life conditions and how these led to the GINA 2019 guidelines for asthma treatment and prevention will also be discussed.