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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.

Background: Aging implies changes in terms of lung function, immune system, and respiratory and extra-respiratory comorbidities. Few studies have specifically addressed the relevance of age on severe asthma burden and control. We aimed to evaluate whether age acts as an independent determinant of asthma severity, in terms of clinical, functional, and inflammatory profile, and to explore potential cofactors that contribute to a more difficult disease control in different age groups. Methods: Patients from Severe Asthma Network Italy (SANI) registry were retrospectively divided in subgroups according to their age. Cutoffs for age were established according to quartiles in order to obtain a comparable number of patients for each group, and then rounded for the sake of simplicity. Results: Overall, 1805 severe asthma patients were analyzed. Lung function represented the most important age-related variable. On the opposite the level of asthma control was not differently distributed among age ranges. In young people the presence of atopy-related comorbidities (allergic rhinitis, atopic dermatitis) predominated, whilst systemic-metabolic and degenerative comorbidities such as diabetes, cardiovascular diseases, anxious-depressive syndrome, and osteoporosis prevailed in elderly. Bronchiectasis and sleep disturbances were significantly associated with age. Conclusions: Despite that it cannot be considered a treatable trait, our study suggests that age should be evaluated within a personalized approach to severe asthma patients, in order to provide a better clinical profiling and a more tailored treatment strategy.

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 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.

The role of type 2 inflammation has been progressively associated with many diseases, including severe asthma, atopic dermatitis, nasal polyposis, eosinophilic granulomatosis with polyangiitis, and, recently, eosinophilic esophagitis. Despite this, the association between asthma and esophagitis is still poorly known, and this is probably because of the low prevalence of each disease and the even lower association between them. Nonetheless, observations in clinical trials and, subsequently, in real life, have allowed researchers to observe how drugs acting on type 2 inflammation, initially developed and marketed for severe asthma, could be effective also in treating eosinophilic esophagitis. For this reason, clinical trials specifically designed for the use of drugs targeted to type 2 inflammation were also developed for eosinophilic esophagitis. The results of clinical trials are presently promising and envisage the use of biologicals that are also likely to be employed in the field of gastroenterology in the near future. This review focuses on the use of biologicals for type 2 inflammation in cases of combined severe asthma and eosinophilic esophagitis.

Abstract Digital health is an umbrella term which encompasses eHealth and benefits from areas such as advanced computer sciences. eHealth includes mHealth apps, which offer the potential to redesign aspects of healthcare delivery. The capacity of apps to collect large amounts of longitudinal, real‐time, real‐world data enables the progression of biomedical knowledge. Apps for rhinitis and rhinosinusitis were searched for in the Google Play and Apple App stores, via an automatic market research tool recently developed using JavaScript. Over 1500 apps for allergic rhinitis and rhinosinusitis were identified, some dealing with multimorbidity. However, only six apps for rhinitis (AirRater, AllergyMonitor, AllerSearch, Husteblume, MASK‐air and Pollen App) and one for rhinosinusitis (Galenus Health) have so far published results in the scientific literature. These apps were reviewed for their validation, discovery of novel allergy phenotypes, optimisation of identifying the pollen season, novel approaches in diagnosis and management (pharmacotherapy and allergen immunotherapy) as well as adherence to treatment. Published evidence demonstrates the potential of mobile health apps to advance in the characterisation, diagnosis and management of rhinitis and rhinosinusitis patients.

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.

Plastic is one of the most widely used materials. It is expected that there will be about 12 billion tons of debris dispersed into the environment by 2050. This, combined with marine littering, pollution and climate change will threaten our ability to sustainably use oceans, seas and coasts. In this regard, it is important to understand transport mechanisms and predict hotspots of plastic pollution. Physical models are a valid support to achieve such a goal. In this regard, it is necessary to adopt specific techniques which allow the movement of plastic to be monitored. Considering the relatively high size of plastic particles that could be used during experimental campaigns, new approaches based on image processing could be implemented. This study presents a simplified method to estimate the transport of particle debris under sea waves by 2D image processing, avoiding any disturbance of the dynamic field. The proposed method, based on the blob analysis, was implemented and calibrated within the wave flume of the Hydraulics Laboratory at the University of Messina. After a calibration process, the method was used to study the behaviour of the plastic debris under several hydrodynamic conditions. The results obtained in terms of displacement and velocity of the analysed sample showed a great reliability of the used methodology.

Background: The change from prescription to over-the-counter (OTC) status of oral antihistamines may raise concerns about drug safety due to the possibility of misuse/abuse. In most European countries, oral antihistamines are available without prescription, whereas in Italy, only 20 tablets (Belgium, Portugal, Switzerland, Finland, Hungary) was made. The rate at which an AE related to oral antihistamines occurred was estimated by calculation of the reporting rate (number of cases/[defined daily dose/1000 inhabitants per day]) on the basis of IQVIA sales data using the Italian Institute of Statistics database. A systematic review of the literature was also performed. Results: There were 3760 reports of AEs with a suspected association with fexofenadine; of these, eight were reported from Italy. There was a slightly increasing trend per year, in line with a general reporting trend of other drugs. In European countries where fexofenadine is available, the impact of OTC switch on AE reporting activity was negligible: from 2016, the reporting rate increased slightly and then normalized at 3.01, an incidence value similar to that recorded before the OTC switch (3.7 in 2015). Of 22 studies included in the systematic review, 18 (82%) positively evaluated the OTC use of oral antihistamines, confirming an acceptable safety/tolerability profile. Conclusion: There was no difference in number of AEs reported for fexofenadine pre/post-OTC switch, indicating a similar safety profile. Spontaneous reporting systems are a valuable source of real-world data and support the OTC provision of oral antihistamines in Europe and fexofenadine in Italy, in addition to supporting the use of larger pack sizes in Italy.

Asthma is a chronic disease, affecting approximately 350 million people worldwide. Inflammation and remodeling in asthma involve the large airways, and it is now widely accepted that the small airways (those with an internal diameter

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.

Introduction: There is, so far, no universal definition of severe asthma. This definition usually relies on: number of exacerbations, inhaled therapy, need for oral corticosteroids, and respiratory function. The use of such parameters varies in the different definitions used. Thus, according to the parameters chosen, each patient may result in having severe asthma or not. The aim of this study was to evaluate how the choice of a specific definition of severe asthma can change the allocation of patients. Methods: Data collected from the Severe Asthma Network Italy (SANI) registry were analyzed. All the patients included were then reclassified according to the definitions of U-BIOPRED, NICE, WHO, ATS/ERS, GINA, ENFUMOSA, and TENOR. Results: 540 patients, were extracted from the SANI database. We observed that 462 (86%) met the ATS/ERS criteria as well as the GINA criteria, 259 (48%) the U-Biopred, 222 (41%) the NICE, 125 (23%) the WHO, 313 (58%) the Enfumosa, and 251 (46%) the TENOR criteria. The mean eosinophil value were similar in the ATS/ERS, U-Biopred, and Enfumosa (528, 532 and 516 cells/mcl), higher in WHO and Tenor (567 and 570 cells/mcl) and much higher in the NICE classification (624 cells/mcl). Lung function tests resulted similarly in all groups, with WHO (67%) and ATS/ERS-GINA (73%), respectively, showing the lower and upper mean FEV1 values. Conclusions: The present observations clearly evidence the heterogeneity in the distribution of patients when different definitions of severe asthma are used. However, the recent definition of severe asthma, provided by the GINA document, is similar to that indicated in 2014 by ATS/ERS, allowing mirror reclassification of the patients examined. This lack of homogeneity could complicate the access to biological therapies. The definition provided by the GINA document, which reflects what suggested by ATS/ERS, could partially overcome the problem.

In the recent years, it was recognized that type-2 inflammation links many forms of nasal polyposis with severe asthma. Thus, some biological drugs developed for severe asthma appeared to exert an effect on nasal polyposis. So far, there are several trials supporting this concept; therefore, some monoclonal antibodies for severe asthma were assessed also in polyposis, with promising results. Since different specialists are involved in the management of nasal polyposis (eg, pulmonologists, ENT, allergists), it was felt that an educational and informative document was needed to better identify the indications of biologicals in nasal polyposis. We collected the main Italian Scientific Societies, and prepared (under the Allergic Rhinitis and its Impact on Asthma, ARIA) a document endorsed by all Societies, to provide a provisional statement for the future use of monoclonal antibodies as a medical treatment for polyposis. It is the first nationwide endorsed document on this aspect. The current pathogenic knowledge and the experimental evidence are herein reviewed, and some suggestions for a correct prescription and follow-up are provided.

Abstract Background The severe forms of asthma represent a major burden, because of severity of symptoms, costs and impact on everyday life. Recently, Mepolizumab (MEP) was approved and marketed for the treatment of hypereosinophilic severe asthma. This anti-IL-5 monoclonal antibody reduced exacerbation rates and oral corticosteroid (OCS) use in well selected patients. The aim of this study was to evaluate the characteristics of patients receiving MEP in a real-life setting. Thus, we describe a retrospective analysis of patients treated with MEP in six centres in North Western Italy, including those who participated in the main regulatory trials. Methods The baseline data, before prescription, from six North Western Italy severe asthma clinics, between June 1st 2017 and December 31st 2017, were evaluated. The collected real-life data were then compared with those of SIRUS, MENSA, DREAM and MUSCA trials. Results Sixty-five patients were included (45% female; mean age 56 years; age range 19–84). Main observed differences with regulatory trials could be observed in eosinophils blood count at baseline, where the mean of our real-life patients (653 cells/μL) was overall higher than the one of all trials (240 cells/μL, 296 cells/μL, 253 cells/μL; p

Background and aims: Severe asthma is burdened by frequent exacerbations and use of oral corticosteroids (OCS) which worsen patients’ health and increase healthcare spending. Aim of this study was to assess the clinical and economic effect of adding mepolizumab (MEP) for the treatment of these patients. Methods: Patients >18 years old, referred to 8 asthma clinics, starting MEP between May 2017 and December 2018, were enrolled and followed-up for 12 months. Information in the 12 months before mepolizumab were collected retrospectively. The evaluation parameters included: OCS use, number of exacerbations/hospitalizations, concomitant therapies, comorbidity, and annual number of working days lost due to the disease. The primary objective was to compare the annual total cost per patient pre- and post-MEP. Secondary outcomes included rates of exacerbations and number of OCS-dependent patients. Results: 106 patients were enrolled in the study: 46 male, median age 58 years. Mean annual cost pre- and post-MEP (cost of biologic excluded) was €3996 and €1,527, respectively. Total savings due to MEP resulted in €2469 (95%CI 1945–2993), 62% due to exacerbations reduction and 33% due to productivity increase. Such savings could fund about 22% of the total cost of MEP for one year. The introduction of MEP induced a clinical benefit by reducing both OCS-dependent patients (OR = 0.12, 95%CI 0.06–0.23) and exacerbation rate (RR = 0.19, 95%CI 0.15–0.24). Conclusions: Patients with severe eosinophilic asthma experienced a clinical benefit in asthma control adding MEP to standard therapy. Biologic therapy can be, partially, funded by the savings produced by patients’ improvement.

Background: The COVID-19 outbreak brought an unprecedented challenge to the world. Knowledge in the field has been increasing exponentially and the main allergy societies have produced guidance documents for better management of allergic patients during this period. However, few publications so far have provided real-life data from the allergy community concerning allergy practice during the COVID-19 outbreak. Therefore, we proposed an international survey on the management of allergic patients during the current pandemic. Methods: We performed an online survey undertaken to reach out the worldwide allergy community by e-mail and social media. The web-based questionnaire contained 24 questions covering demographic data from the participants, clinical practice during this period, and questions related to the new international classification and coding tools addressed for COVID-19. It was circulated for 8 weeks and had anonymous and volunteer context. Results: Data are presented for 635 participants from 78 countries of all continents. Allergists with long-term professional experience were the main audience. As expected, we received many responses as “I have no data” or “I don't know” to the questions of the survey. However, most with more experience on managing allergic patients during the pandemic agreed that patients suffering from allergic or hypersensitivity conditions have no increased risk of contracting COVID-19 or developing SARS CoV-2. Also, participants mentioned that none of the allergy treatments (inhaled corticosteroids, allergen immunotherapy, biological agents) increased the risk of contracting COVID-19 infection including severe presentations. Conclusion: The data presented are a starting point in the process of getting feedback on all the recommendations provided by the allergy societies; it could also be the basis of new strategies to support health professionals while new COVID-19 specific treatments and vaccines are being explored. The information here presented intends to be helpful to the community but represents a course of action in a highly specific situation due to the state of emergency, and it should be helpful to health systems.

Background: Coronavirus disease (COVID-19) infection represents a worldwide critical health burden from the sanitary perspective. This disease's symptoms range from a mild flu-like form to a severe life-threatening respiratory disease and respiratory failure. Several patients, however, remain paucisymptomatic. Among the symptoms that seem relevant are the changes in taste and smell, regardless of the disease's severity. Methods: Data from patients affected by COVID-19 infection, hospitalized from 15 to 29 April, 2020, were analyzed. Questionnaires about smell, taste, and nasal function were administered to all, and a proportion also received the Quick olfactory Sniffin’ Sticks Test (q-Sticks) to objectivate the presence of anosmia or hyposmia. The results of instruments and Q-Sticks were then compared. Results: Thirty-seven patients (20 males, 54.1%), with a mean age 0f 69.19 years (SD = 17.96; median 76, IQR: 63–82) were evaluated. Among the patients, 8 (22%) were asymptomatic. Out of the remaining 29 patients, 28 (97%) had fever, 19 (66%) asthenia, 11 (38%) dry cough, 10 (34%) dyspnea, and 6 (21%) gastroenteric symptoms. The q-Sticks test was performed on 27 patients and showed that 6 with anosmia, and 16 patients had hyposmia, where only 5 (14%) patients complained of loss of smell by conducting the questionnaires. Conclusion: Although olfactory disturbances may be secondary to other factors, a sudden onset of anosmia or hyposmia should be assessed as a possible symptom of COVID-19 infection. The use of questionnaires or anamnestic collection is sometimes not enough, while adding to them a simple test such as the q-Sticks test can provide more accurate and reliable data. A simple, easy-to-perform, and reliable tool (q-Sticks) for olfactory disorders assessment can be administered to identify the real size of anosmia in patients with COVID-19 infection and detect the early stage of infection or paucisymptomatic patients, therefore becoming important to reduce the spreading of the pandemic.

Microwave ablation is a safe and effective interventional approach, widely used in the treatment of unresectable primary or metastatic hepatic lesions. Thoracobiliary fistula is a rare postablation complication that can be treated with a conservative or surgical approach. We reviewed aetiology, pathogenesis, clinical picture, diagnostic possibilities, and therapeutic options for biliothoracic fistula developed after microwave ablation of liver metastasis. Furthermore, we reported our experience of successful conservative management of a nonhealing thoracobiliary fistula occurred after percutaneous thermal ablation of colorectal cancer liver metastasis. Our case supports a conservative approach based on percutaneous biliary system decompression and synthetic glue embolization for the treatment of combined biliopleural and biliobronchial fistula.

According to the data derived from several national and international registries, including SANI (Severe Asthma Network Italy), and considering the strong impact that frequent or regular use of oral corticosteroid has on quality of life (QoL) of severe asthmatics, as well as on the costs for managing corticosteroid-related diseases, oral corticosteroid sparing up to withdrawal should be considered a primary outcome in the management of severe asthma. New biologics have clearly demonstrated that this effect is possible, with concomitant reduction in the rate of exacerbations and in symptom control. Then, there is no reason for using so frequently oral corticosteroid before having explored all alternatives currently available for a large part of severe asthmatics.

Objective: The availability of public health information for optimised supportive care is critical during the COVID-19 pandemic. We describe the first case of COVID-19 complicated by Takotsubo cardiomyopathy. Materials and Methods: We report the clinical, laboratory and radiological findings of a patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: The nasopharyngeal swab was positive for SARS-CoV-2 and x-ray images demonstrated pathognomonic pneumonia. The patient developed tachycardia and the echocardiogram confirmed the diagnosis of Takotsubo cardiomyopathy. Conclusions: Doctors should be aware of the need to thoroughly study this new infection in order to understand its underlying mechanisms and related complications.

Currently, testing for immunoglobulin E (IgE) sensitization is the cornerstone of diagnostic evaluation in suspected allergic conditions. This review provides a thorough and updated critical appraisal of the most frequently used diagnostic tests, both in vivo and in vitro. It discusses skin tests, challenges, and serological and cellular in vitro tests, and provides an overview of indications, advantages and disadvantages of each in conditions such as respiratory, food, venom, drug, and occupational allergy. Skin prick testing remains the first line approach in most instances; the added value of serum specific IgE to whole allergen extracts or components, as well as the role of basophil activation tests, is evaluated. Unproven, non-validated, diagnostic tests are also discussed. Throughout the review, the reader must bear in mind the relevance of differentiating between sensitization and allergy; the latter entails not only allergic sensitization, but also clinically relevant symptoms triggered by the culprit allergen. Keywords: IgE, Allergy, In vitro tests, Skin tests, Diagnostic strategies

Precision allergy molecular diagnostic applications (PAMD@) is increasingly entering routine care. Currently, more than 130 allergenic molecules from more than 50 allergy sources are commercially available for in vitro specific immunoglobulin E (sIgE) testing. Since the last publication of this consensus document, a great deal of new information has become available regarding this topic, with over 100 publications in the last year alone. It thus seems quite reasonable to publish an update. It is imperative that clinicians and immunologists specifically trained in allergology keep abreast of the new and rapidly evolving evidence available for PAMD@.PAMD@ may initially appear complex to interpret; however, with increasing experience, the information gained provides relevant information for the allergist. This is especially true for food allergy, Hymenoptera allergy, and for the selection of allergen immunotherapy. Nevertheless, all sIgE tests, including PAMD@, should be evaluated within the framework of a patient's clinical history, because allergen sensitization does not necessarily imply clinical relevant allergies. Keywords: Diagnosis, Molecular allergy, Cross reactivity, Panallergen, Specific IgE, PAMD@

Severe asthma affects between 5 and 10% of patients with asthma worldwide and requires best standard therapies at maximal doses. A subgroup of patients remains refractory to all treatments. We describe two case reports with severe allergic asthma who progressively worsened over the years despite the best therapy. The patients were first treated with omalizumab, which was completely ineffective, and then with bronchial thermoplasty (BT), again without clinical benefit. Since our patients met the AIFA criteria for inclusion in mepolizumab treatment, a therapy with this anti-IL5 biological agent was initiated. In the first case (a 53-year-old female), after the second mepolizumab administration, symptoms improved progressively, with a reduction in the number and severity of exacerbations, so the patient could finally be discharged from hospital. At follow-up, it was possible to reduce oral corticosteroids and continuing with inhaled corticosteroids/long-acting beta-agonists and montelukast. The patient had only one exacerbation/year. Symptom control and quality of life improved significantly. In the second case report (a 55-year-old male), after the sixth mepolizumab administration, symptoms improved progressively, with a reduction in the number and severity of exacerbations. At follow-up, it was possible to reduce and stop oral corticosteroids, continuing with inhaled therapy and montelukast. Symptom control and quality of life improved significantly.These are the first cases of patients unresponsive to sequential omalizumab and BT but with good and prolonged clinical response to mepolizumab. Both cases suggest that also after the failure of two consecutive third-line treatments, a third treatment (mepolizumab) should be attempted. Keywords: Severe asthma, Omalizumab, Bronchial thermoplasty, Mepolizumab, Exacerbation, Eosinophilia

Introduction: It is acknowledged that any claim of efficacy of allergen immunotherapy must be done for each specific product, and this remains true also for venom immunotherapy (VIT). Thus, we evaluated the efficacy and safety of a specific tyrosine-adsorbed VIT for vespula spp. and honeybee in real-life. Methods: Consecutive patients diagnosed with hymenoptera allergy, and receiving VIT for either vespula or honeybee with a tyrosine-adsorbed preparation were observed to evaluate the grade of reaction (according to Muller) at the first field re-sting. A modified ultra-rush protocol was used. Results: A total of 247 patients (73 female) were observed (102 honeybee, group H, 145 vespula, group V). Seventy-five patients in group H had a re-sting, and 74/75 had a lower grade reaction at re-sting as compared to the pre-VIT reaction. Considering systemic reactions, protection was achieved in 89% of patients. In group V 118 patients were re-stung, and 76/118 patients with previous grade III-IV reaction had no more systemic reaction under VIT. Overall, considering systemic reactions, protection was achieved in 92% of subjects. Of note, in both groups there was a clear inverse correlation between the severity of pre-VIT and during VIT reactions. The duration of VIT at the time of re-sting did not affect the efficacy. The safety was overall good, with 18% ad 15.4% local reactions in groups H and V, respectively. Discussion: Modified extracts, including tyrosine-absorbed, have the aim of improving the safety of VIT still yet maintaining the efficacy. Field re-sting is the best way to assess the efficacy in real life. In this observational study we could confirm the protective efficacy of the tyrosine-adsorbed extract, with a good safety expecially in the build-up using a modified-rush protocol. Conclusion: The tyrosine-adsorbed VIT used herein is a viable and advantageous form of treatment for hymenoptera allergy. Keywords: Hymenoptera venom allergy, Venom immunotherapy, Tyrosine adsorbed, Efficacy, Safety, Systemic reaction, Field re-sting

We hypothesize that a pivotal condition determining the efficacy of dog allergen immunotherapy (DAI) might be the mono-sensitization to dog lipocalins (Can f 1-2) in individuals not directly or indirectly exposed to other furry animals. In fact, the concomitant sensitization to lipocalins and/or albumins, especially in those patients directly exposed to furry animals, may potentially stimulate patient's airways by inducing persistent inflammation and, thus, clinical symptoms. In these conditions, it is likely that DAI alone could be inadequate to reduce airway inflammation mediated by inhalation of dog allergens in patients with simultaneous exposure to other furry animals. Can f 5 has been found as exclusive allergen in about one third of dog-sensitized individuals. Considering the presence of different allergenic materials in extract of mammalian origin, it is evident that a standard DAI is not likely to be effective in Can f 5 prevalent or mono-sensitized individuals. Moreover, we would underline the need of collecting detailed information on the possible exposures to furry animals (other than the common pets), an information that usually is neglected in clinical practice. Furthermore, a detailed clinical history exploring the real significance of dog sensitization (mono or poly-sensitization, induction of clinical symptoms after exposure etc.) should be performed before prescribing DAI. In some patients, with potential high susceptibility to animal allergens, the use of CRD is essential to verify the presence of concomitant allergic sensitization to lipocalins and/or albumins belonging to other furry animals. The availability of CRD introduced the possibility of a better targeted prescription of DAI because it might be useful for point out the primary allergens and for the exclusion of cross-reactive ones.

Abstract Abstract Allergen immunotherapy (AIT) is the only disease-modifying treatment approved for allergic rhinitis and allergic asthma and represents a suitable therapeutic option, especially in childhood, to modify the progression of respiratory allergic diseases. Starting from the previous “generic class effect” evaluation, as testified by the numerous meta analyses, AIT is now considered a product-specific pathogenic-oriented treatment. Background AIT was empirically proposed more than one century ago in the subcutaneous form (SCIT), but the IgE-mediated mechanism of allergy was elucidated only after 50 years of clinical use of the treatment. The sublingual administration (SLIT) was developed during the 1980 ties, to achieve an improvement in safety and convenience. While SCIT is approved in the United States for the treatment of asthmatic patients with more than 12 years, so far few trials evaluated the clinical efficacy and safety of SLIT in children with allergic asthma, although the indications and some aspects remain unclear. Certainly, due to compliance problems, the age below 3 years may be reasonably considered a practical contraindication. Conclusions Given that some specific AIT products are effective and approved as drugs (AIFA, EMA, FDA), the use in children is still debated. Some aspects still need robust confirm: (a) the safety of AIT in asthma; (b) the optimal regimen of administration; (c) the role of AIT as preventative treatment for asthma development.

Abstract Background Allergic Rhinitis (AR) is a high-prevalence disease. In Europe about 25% of the general population is affected, and in Italy the prevalence is estimated to be 19.8%. The Allergic Rhinitis and its Impact on Asthma (ARIA) international document underlined that the prevalence of severe or refractory or overlapping rhinitis is increasing and represents a non-negligible socio-economic burden. In general, despite the social healthcare costs, allergic rhinitis remains underestimated, not sufficiently controlled and often undertreated. Aim of the study In this multi-center Italian observational and prospective study we assessed the control of AR in patients (> 16 years) without previous asthma diagnosis, referred to Allergy Centers. Methods Patients of both sexes and older than 16 with rhinitis symptoms and without asthma were studied. A Visual Analogue Scale (VAS) and the CARAT (Control of Allergic Rhinitis and Asthma Test) were used as patient reported outcome. The possible causes of poor control of AR, as per protocol, were assessed accordingly. Results We observed 250 patients in a real-life setting: more than 60% of them had an uncontrolled AR, only about 50% used multiple medications, and only a minority were receiving allergen immunotherapy. Conclusion This survey, conducted in a real-life setting, confirmed that AR is overall poorly controlled. The VAS assessment well correlates with the structured CARAT questionnaire and with the relevant symptoms of AR.

Abstract Asthma, allergic rhinitis (AR) and atopic dermatitis are very common in young people, but in the latest decades it was increasingly recognized that also individuals of higher ages, including the population over 65 years, are concerned. Actually, it is now acknowledged the aging does not considerably alter the immune response to allergens. Allergen immunotherapy (AIT) is the only treatment that works on the causes of allergy, but elderly people are commonly excluded from AIT, except the cases of insect sting allergy. A number of recent studies showed that aged individuals also successfully respond to AIT for respiratory allergy. Therefore, there is no reason to exclude elder patients from AIT. Anyhow, clinical conditions that are considered absolute or relative contraindications are quite frequent in this aged population, thus the risk/benefit ratio must be carefully evaluated for each patient, taking into account that the more frequent occurrence of co-morbidities and the consequent need of daily-based multidrug regimen can favor adverse effects. An important issue concern the ability of AIT, and particularly of sublingual immunotherapy, to significantly improve the quality of life, that often is particularly impaired in the elderly, reducing symptoms and drugs consumption.

Emerging technologies are profoundly changing the landscape of allergy diagnoses and future allergy treatments. At the single patient level, the introduction of single components and allergen microarrays for allergy diagnoses has significantly modified treatment strategies. In epidemiological terms, the availability of information from large dataset analyses has allowed and, more importantly, will allow for changes in prophylaxis and treatment strategies in many patients. In this report, we describe the different fields where new technologies have had a significant effect on allergy management and identify new scenarios where the combination of data from basic, clinical, and epidemiological research will improve our knowledge of allergy diagnosis and treatment.

Objectives. To describe (i) the clinical characteristics of workers, exposed to hymenoptera stings, with an ascertained diagnosis of Hymenoptera Venom Allergy (HVA), (ii) the specific role of occupational exposure, (iii) the effect of Venom Immunotherapy (VIT) in reducing the severity of allergic episodes in workers exposed to repeated stings of hymenoptera, and (iv) the management of the occupational consequences caused by allergic reactions due to hymenoptera stings. Methods. Between 2000 and 2013 an observational study, including patients referred to the regional reference hospital of Liguria, Italy, with an ascertained diagnosis of HVA and treated with VIT, was performed. A structured questionnaire was administered to all patients to investigate the occupational features of allergic reactions. These were graded according to standard systems in patients at the first episode, and after re-stings, during VIT. Results. One-hundred and 8four out of the 202 patients referred had a complete data set. In 32 (17.4%) patients, the allergic reaction occurred during work activities performed outdoor. Of these, 31.2% previously stung by hymenoptera at work, and receiving VIT, were re-stung during occupational activity. The grades of reaction developed under VIT treatment resulted clinically less severe than of those occurred at the first sting (p-value = 0.031). Conclusion. Our findings confirmed the clinical relevance of HVA, and described its occupational features in outdoor workers with sensitization, stressing the importance of an early identification and proper management of the professional categories recognized at high risk of hymenoptera stings. The Occupational Physician should be supported by other specialists to recommend appropriate diagnostic procedures and the prescription of VIT, which resulted an effective treatment for the prevention of episodes of severe reactions in workers with a proven HVA.

Abstract One of the major concerns in the practice of allergy is related to the safety of procedures for the diagnosis and treatment of allergic disease. Management (diagnosis and treatment) of hypersensitivity disorders involves often intentional exposure to potentially allergenic substances (during skin testing), deliberate induction in the office of allergic symptoms to offending compounds (provocation tests) or intentional application of potentially dangerous substances (allergy vaccine) to sensitized patients. These situations may be associated with a significant risk of unwanted, excessive or even dangerous reactions, which in many instances cannot be completely avoided. However, adverse reactions can be minimized or even avoided if a physician is fully aware of potential risk and is prepared to appropriately handle the situation. Information on the risk of diagnostic and therapeutic procedures in allergic diseases has been accumulated in the medical literature for decades; however, except for allergen specific immunotherapy, it has never been presented in a systematic fashion. Up to now no single document addressed the risk of the most commonly used medical procedures in the allergy office nor attempted to present general requirements necessary to assure the safety of these procedures. Following review of available literature a group of allergy experts within the World Allergy Organization (WAO), representing various continents and areas of allergy expertise, presents this report on risk associated with diagnostic and therapeutic procedures in allergology and proposes a consensus on safety requirements for performing procedures in allergy offices. Optimal safety measures including appropriate location, type and required time of supervision, availability of safety equipment, access to specialized emergency services, etc. for various procedures have been recommended. This document should be useful for allergists with already established practices and experience as well as to other specialists taking care of patients with allergies.

The definition of asthma has changed considerably in recent years, to the extent that asthma is no longer considered a single disease but a heterogeneous disorder that includes several phenotypes and, possibly, endotypes. A more detailed analysis of the immunological mechanisms underlying the pathogenesis of asthma shows interleukin 5 (IL-5) to be a crucial cytokine in several asthma phenotypes. In fact, IL-5 exerts selective action on eosinophils, which, in turn, sustain airway inflammation and worsen asthma symptoms and control. Clinical trials have shown drugs targeting IL-5 or its receptor alpha subunit (IL-5Ra) to be a promising therapeutic approach to severe asthma, whose characteristics render standard therapy of little use: systemic corticosteroids only partially control the disease and have well-known adverse effects, and omalizumab is used for allergic subtypes. Analysis of the design process of clinical trials reveals the importance of patient selection, taking into account both clinical data (e.g., exacerbations, lung function, and quality of life) and biomarkers (e.g., eosinophils, which are predictive of therapeutic response).

Background Allergen-specific immunotherapy (AIT) still remains the only causal treatment for IgE mediated respiratory diseases (rhinitis/asthma) In addition to the observed clinical decrease in symptoms, AIT can provide a long-lasting and preventive effect. In particular it can modify the progression from rhinitis to asthma.Methods The study was observational, open, non randomized, controlled, prospective and performed in a real-life setting. Patients with pure mite-induced allergic rhinitis were followed-up, receiving adjuvanted SLIT (aSLIT), standard SLIT (sSLIT) or drug treatment alone, according to their preference starting between 2008 and 2009. The possible onset of asthma, changes in pulmonary function and bronchial hyperreactivity (BHR) were assessed over a 5-year horizon. Also the onset of new sensitizations and symptoms-medication score (SMS) were evaluated.Results One hundred forty two patients fulfilling the inclusion criteria were assessed at baseline, and 124 had the 5-year evaluation (age range 8–57, 69 male). After 5 years of treatment, new sensitizations appeared differentially among treatments with 58.1% of new sensitizations in the drug treatment group, 13.2% in the sSLIT patients, and 8.1% in the aSLIT patients. At the end of 5 years, SMS significantly changed (P?0.001) in all groups, with a negative trend for controls, as compared to the SLIT treatments. The SMS decreased in both SLIT groups at 5 years, with no change in patients on drug treatment alone. The use of salbutamol (absent at baseline), showed an overall increase only in the group receiving drugs alone with a significant difference at 5 years (P?

Severe asthma is a major health concern. The allergic (IgE-mediated) form of asthma is well known from a pathogenic viewpoint. We searched the available literature to identify which allergens are most frequently associated with severe, refractory or life threatening asthma. According to the results, molds, pet dander, cockroach and ragweed were more frequently responsible for severe asthma. Thunderstorm asthma, in addition, represents a special association between allergic sensitization and an external climatic factor. A detailed knowledge of the most harmful allergens is mandatory for an appropriate diagnostic and preventive approach. Keywords: Severe asthma, Atopy, Allergic sensitization, Allergens

Eosinophils represent approximately 1% of peripheral blood leukocytes in normal donors and their maturation and differentiation in the bone marrow are mainly regulated by interleukin (IL)-5 [Broughton et al. 2015]. IL-5, a cytokine that belongs to the β common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils and, to some extent, of basophils. IL-5 binds to a heterodimer receptor composed of the specific subunit IL-5Rα and a common subunit βc shared with IL-3 and GM-CSF. Human eosinophils express approximately a three-fold higher level of IL-5Rα compared with basophils. Major sources of IL-5 are T-helper 2 (Th2) cells, mast cells, CD34+ progenitor cells, invariant natural killer (NK) T-cells, group 2 innate lymphoid cells (ILC2s), and eosinophils themselves. ILC2s control not only eosinophil number but also their circadian cycling through the production of IL-5.

The present paper addresses severe asthma which is limited to 5-10% of the overall population of asthmatics. However, it accounts for 50% or more of socials costs of the disease, as it is responsible for hospitalizations and Emergency Department accesses as well as expensive treatments.The recent identification of different endotypes of asthma, based on the inflammatory pattern, has led to the development of tailored treatments that target different inflammatory mediators. These are major achievements in the perspective of Precision Medicine: a leading approach to the modern treatment strategy.Omalizumab, an anti-IgE antibody, has been the only biologic treatment available on the market for severe asthma during the last decade. It prevents the linkage of the IgE and the receptors, thereby inhibiting mast cell degranulation. In clinical practice omalizumab significantly reduced the asthma exacerbations as well as the concomitant use of oral glucocorticoids.In the “Th2-high asthma” phenotype, the hallmarks are increased levels of eosinophils and other markers (such as periostin). Because anti-IL-5 in this condition plays a crucial role in driving eosinophil inflammation, this cytokine or its receptors on the eosinophil surface has been studied as a potential target for therapy.Two different anti-IL-5 humanized monoclonal antibodies, mepolizumab and reslizumab, have been proven effective in this phenotype of asthma (recently they both came on the market in the United States), as well as an anti-IL-5 receptor alpha (IL5Rα), benralizumab.Other monoclonal antibodies, targeting different cytokines (IL-13, IL-4, IL-17 and TSLP) are still under evaluation, though the preliminary results are encouraging.Finally, AIT, Allergen Immunotherapy, a prototype of Precision Medicine, is considered, also in light of the recent evidences of Sublingual Immunotherapy (SLIT) tablet efficacy and safety in mite allergic asthma patients.Given the high costs of these therapies, however, there is an urgent need to identify biomarkers that can predict the clinical responders. Keywords: Severe asthma, Phenotypes, Biological therapeutics, Eosinophils

Background The existence of a local allergic rhintis was proposed on the basis of the detection of nasal IgE in the absence of a systemic sensitization. Nevertheless, the significance of this phenomenon remains still unclear.We assessed the presence of mucosal nasal IgE in patients with ascertained allergic rhinitis, nonallergic rhinitis with inflammation and in healthy controls.Methods Consecutive patients with a well ascertained diagnosis (clinical history, skin prick test, specific IgE assay, nasal endoscopy, nasal cytology) underwent an immunoenzymatic measurement of specific IgE to grass, cypress, parietaria and olive in nasal scrapings.Results Fifteen patients with allergic rhinitis, 12 with non allergic rhinitis and 14 healthy subjects were studied. The patients with allergic and nonallergic rhinitis had higher nasal symptoms as compared to control subjects. Systemic sensitizatition (assessed by skin test and CAP-RAST) was obviously more frequent in allergic rhinitis, than in the other two groups. Allergen-specific nasal IgE could be detected in all groups (86,7, 33,3, and 50 % positive, respectively), even more frequently in the control group than in nonallergic rhinitis patients. No difference among allergens was identified. Out of the 26 non-allergic patients (non allergic rhinitis + controls) nasal IgE were positive in 11(42 %).Discussion According to the results, the presence of nasal IgE against allergens seems to be a non-specific phenomenon, since they can be detected also in non allergic rhinitis and in healthy subjects.Conclusion It can be hypothesized that the nasal IgE production represents a form of spontaneous immune response. Keywords: Allergic rhinitis, Nonallergic rhinitis, Sensitization, Nasal IgE, Local allergic rhinitis, Entopy

Allergen immunotherapy (AIT) is widely used in clinical practice for patients with moderate to severe allergic rhinitis due to inhalant allergens and may be delivered via subcutaneous (SCIT) and sublingual routes (SLIT). However, the quality of evidence for individual AIT products is very heterogeneous, and extensions of overall conclusions (“class effects”) on the efficacy and disease-modifying effects to all AIT products are unjustified. In contrast, each product needs to be evaluated individually, based on available study results, to justify efficacy and specific claims on sustained and disease modifying effects per allergen and targeted patient group (children vs. adults, allergic rhinitis vs. asthma). WAO intends to support the current development to evidence-based AIT, which ultimately will lead to a more efficacious treatment of allergic patients and the appropriate recognition of AIT.

Cutaneous involvement characterized by urticarial lesions with or without angioedema and itch is commonly observed in routine medical practice. The clinical approach may still remain complex in real life, because several diseases may display similar cutaneous manifestations. Urticaria is a common disease, characterized by the sudden appearance of wheals, with/without angioedema. The term Chronic Urticaria (CU) encompasses a group of conditions with different underlying causes and different mechanisms, but sharing the clinical picture of recurring wheals and/or angioedema for at least 6 weeks. Hereditary Angioedema (HAE) is a rare disorder characterized by recurrent episodes of non-pruritic, non-pitting, subcutaneous or submucosal edema affecting the extremities, face, throat, trunk, genitalia, or bowel, that are referred as “attacks”. HAE is an autosomal dominant disease caused by a deficiency of functional C1 inhibitor, due to a mutation in C1-INH gene (serping 1 gene) characterized by the clonal proliferation of mast cells, leading to their accumulation, and possibly mediator release, in one or more organs. In childhood there are two main forms of mastocytosis, the Systemic and the Cutaneous. The clinical features of skin lesions in urticaria, angioedema and mastocytosis may differ depending on the aetiologic factors, and the underlying pathophysiological mechanisms. The diagnostic process, as stepwise approach in routine clinical practice, is here reviewed for CU, HAE and mastocytosis, resulting in an integrated method for improved management of these cutaneous diseases. Taking into account that usually these conditions have also a relevant impact on the quality of life of children, affecting social activities and behavior, the availability of care pathways could be helpful in disentangle the diagnostic issue achieving the most cost-effective ratio. Keywords: Urticaria, Angioedema, Mastocytosis, Skin, Itch, Children, Epidemiology, Diagnosis, Management, Clinical practice

Background Identifying allergic rhinitis requires allergy testing, but the first-line referral for rhinitis are usually primary care physicians (PCP), who are not familiar with such tests. The availability of easy and simple tests to be used by PCP to suggest allergy should be very useful.Methods The Respiratory Allergy Prediction (RAP) test, based on 9 questions and previously validated by a panel of experts, was evaluated in this study.Results An overall number of 401 patients (48.6% males, age range 14–62 years) with respiratory symptoms was included. Of them, 89 (22.2%) showed negative results to SPT, while 312 (77.8%) had at least one positive result to SPT. Cohen’s kappa coefficient showed that all questions had an almost perfect excellent agreement between pre and post-test. The algorithm of decision-tree growth Chi-squared Automatic Interaction Detector showed that answering yes to the question 4 (Your nasal/ocular complains do usually start or worsen during the spring?), 6 (Did you ever had cough or shortness of breath, even during exercise?) and 8 (Do you use nasal sprays frequently?) gave a probability to have a positive SPT of 85%.Conclusions These findings show that RAP test can be proposed as an useful tool to be used by physician other than allergists when evaluating patients with rhinitis, suggesting the need of allergy testing. Keywords: Allergy, Allergic rhinitis, Allergy testing, Primary care physicians, Pharmacists

Background An in vitro procedure based on a microarray containing many different allergen components has recently been introduced for use in allergy diagnosis. Recombinant and highly purified allergens belonging to different allergenic sources (inhalants, food, latex and hymenoptera) are present in the array. These components can either be genuine or cross-reactive, resistant or susceptible to heat and low pH, and innocuous or potentially dangerous. A large number of complex and heterogeneous relationships among these components has emerged, such that sometimes these interactions cannot be effectively managed by the allergist. In the 1960s, specialized languages and environments were developed to support the replacement of human experts with dedicated decision-making information systems. Currently, expert systems (ES) are advanced informatics tools that are widely used in medicine, engineering, finance and trading.Methods We developed an ES, named Allergenius ®, to support the interpretation of allergy tests based on microarray technology (ImmunoCAP ISAC ®). The ES was implemented using Flex, a LPA Win-Prolog shell. Rules representing the knowledge base (KB) were derived from the literature and specialized databases. The input data included the patient’s ID and disease(s), the results of either a skin prick test or specific IgE assays and ISAC results. The output was a medical report.Results The ES was first validated using artificial and real life cases and passed all in silico validations. Then, the opinions of allergists with experience in molecular diagnostics were compared with the ES reports. The Allergenius reports included all of the allergists’ opinions and considerations, as well as any additional information.Conclusions Allergenius is a trustable ES dedicated to molecular tests for allergy. In the present version, it provides a powerful method to understand ISAC results and to obtain a comprehensive interpretation of the patient’s IgE profiling. Keywords: 3 TO 10 DIFFERENT ImmunoCAP ISAC, Allergen microarray, Artificial intelligence, Expert system, ISAC interpretation, Genuine component, Cross-reactive component, Computer supported diagnosis

In recent years, the interest of the scientific world towards vitamin D gradually increased, and several studies have been conducted to dissect its possible role in modulating the development/course of allergic diseases. Also, Vitamin D supplementation has been assessed as a beneficial approach for treating allergies in some, but not all studies. We reviewed herein the available and relevant literature concerning the possible links between Vitamin D, its supplementation and allergic diseases. A literature search was made independently by the Authors, identifying articles for a narrative review. As per literature, Vitamin D plays a key role in calcium and phosphate metabolism, and it is essential for bone health in infants, children and adolescents. However, there is presently insufficient evidence to support vitamin D supplementation for prevention or treatment of allergic diseases in infants, children and adolescents, concerning allergic rhinitis, asthma, food allergy and atopic dermatitis. Keywords: Vitamin D, Allergic diseases, Immunomodulation, Supplementation, Asthma, Rhinitis, Pediatric allergy

Sublingual immunotherapy is currently considered a viable alternative to the subcutaneous route. The body of evidence of its efficacy is based on the results of 77 clinical trials and 7 meta-analyses, that have been published so far. Nonetheless, the experimental evidence is partially weak due to the large heterogeneity of studies, namely: doses, regimens, patient selection, duration of treatment, outcomes and reporting. In addition, it is virtually impossible to compare the potency of extracts produced by different manufacturers. Also, there is large variability in reporting and in the classification of adverse events, either systemic or local, so that only a rough estimate can be provided. Considering all these aspects, efforts are needed to harmonize the methodology, outcome measures and reporting of SLIT clinical trials, to achieve the ability of comparing the results of various studies. International societies and the World Allergy Organization have recently provided general recommendations on how to design and conduct trials which can provide more interpretable and homogeneous data.

We have prepared this document, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update”, according to the evidence-based criteria, revising and updating chapters of the originally published paper, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2009”, available at http://www.waojournal.org. Namely, these comprise: “Mechanisms of sublingual immunotherapy;” “Clinical efficacy of sublingual immunotherapy” – reporting all the data of all controlled trials published after 2009; “Safety of sublingual immunotherapy” – with the recently published Grading System for adverse reactions; “Impact of sublingual immunotherapy on the natural history of respiratory allergy” – with the relevant evidences published since 2009; “Efficacy of SLIT in children” – with detailed analysis of all the studies; “Definition of SLIT patient selection” – reporting the criteria for eligibility to sublingual immunotherapy; “The future of immunotherapy in the community care setting”; “Methodology of clinical trials according to the current scientific and regulatory standards”; and “Guideline development: from evidence-based medicine to patients' views” – including the evolution of the methods to make clinical recommendations.Additionally, we have added new chapters to cover a few emerging crucial topics: “Practical aspects of schedules and dosages and counseling for adherence” – which is crucial in clinical practice for all treatments; “Perspectives and new approaches” – including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, “Raising public awareness about sublingual immunotherapy”, as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail. Keywords: Sublingual immunotherapy, Allergen-specific immunotherapy, Mechanisms of SLIT, Safety of SLIT, Efficacy of SLIT, Clinical trials methodology in SLIT