Chronic rhinosinusitis with nasal polyposis and biological agents: the ARIA-ITALY Survey.

Summary: Background. Chronic rhinosinusitis (CRS) is an inflammatory disease that affects the nasal mucosa and the paranasal sinuses. CRS can be associated by nasal polyposis (CRSwNP phenotype) in up to 30% of patients and it is frequently associated with bronchial asthma. CRSwNP shows predominantly an underlying activation of type 2 inflammatory pathways with the involvement of eosinophils, IgE, interleukin (IL)-4, IL-5 and IL-13. Biological drugs that target these inflammatory cytokines are currently a therapeutic option recognized by guidelines for the treatment of uncontrolled form of the disease. Methods. As part of the activity of the "ARIA-Italy" working group, a panel of 255 Italian Ear, Nose and Throat (ENT) specialists, pneumologists and immuno-allergologists actively participated in this national survey and answered a series of questions geared toward understanding the main criteria for patient characterization and therapeutic decision, highlighting multidisciplinarity, and the implementation of the management of CRSwNP patients, as a part of the precision medicine concept and the appropriate use of the biologicals. Results. Two hundred and fifty-five experts and specialists participated in the survey. Conclusions. The results of this survey obtained from an extensive number of active specialists throughout Italy allow some important concluding remarks to be drawn. The main points of agreement were that multidisciplinary care teams provide many benefits but that, once the team is established, meetings and communication between members must be coordinated. Finally, the dissemination of national disease registries and the continuous updating of guidelines and position papers related to CRSwNP and comorbidities should be encouraged.

The role of skin tests with polyethylene glycol and polysorbate 80 in the vaccination campaign for COVID-19: results from an Italian multicenter survey.

Summary: Background. International guidelines suggested skin tests with Polyethylene-glycol (PEG) and polysorbate 80 (PS-80), to investigate a possible hypersensitivity to these excipients either to identify subjects at risk of developing allergic reactions to Covid-19 vaccines, or in patients with suspected IgE mediated hypersensitivity reactions (HR) to the Covid-19 vaccine. The main purpose of this study was to investigate the prevalence of PEG and PS sensitization in patients with a clinical history of HR to drugs containing PEG/PS and in patients with a suspected Covid-19 vaccine immediate HR. Methods. This was a multicenter retrospective study conducted by allergists belonging to 20 Italian medical centers. Skin testing was performed in 531 patients with either a clinical history of suspected hypersensitivity reaction (HR) to drugs containing PEG and/or PS-80 (group 1:362 patient) or a suspected HR to Covid-19 vaccines (group 2: 169 patient), as suggested by the AAIITO/SIAAIC guidelines for the "management of patients at risk of allergic reactions to Covid-19 vaccines" [1]. Results. 10/362 (0.02%) had positive skin test to one or both excipients in group 1, 12/169 (7.1%) in group 2 (p less than 0.01). In group 2 HRs to Covid-19 vaccines were immediate in 10/12 of cases and anaphylaxis occurred in 4/12 of patients. Conclusions. The positivity of skin test with PEG and or PS before vaccination is extremely rare and mostly replaceable by an accurate clinical history. Sensitization to PEG and PS has to be investigated in patients with a previous immediate HR to a Covid-19 vaccine, in particular in patients with anaphylaxis.

Hypersensitivity reactions to iodinate contrast media in Italy: a retrospective study. Characteristics of patients and risk factors.

SUMMARY: Objective. The purpose of the study was to describe the characteristics of patients experiencing hypersensitivity reactions (HRs) to iodinated contrast media (ICM) in a large Italian population and to investigate potential risks factors in order to obtain a risk stratification, helpful in the management of these patients. Methods. Data of 407 patients investigated in 9 Italian Allergy Centers for suspected HRs to ICM were analyzed and compared with a control group of 152 subjects that tolerated one or more ICM-enhanced examinations. The univariate and multivariate logistic regression model was used to evaluate associated factors. Results. The mean age of reactive patients was 61 years and 60% were female; 67% of patients reported immediate reactions and 35% experienced the reaction, more frequently with immediate onset, at the first examination in life. Iomeprol, iopromide and iodixanol were the most frequent culprit agents and 20% of patients showed a positive skin test result. Previous adverse reactions to ICM were reported by 15.6% of patients, whereas 35% of subjects experienced the reaction, more frequently immediate, after the first ICM-enhanced examination in their life. The multivariate analysis showed that male gender and age > 65 were associated with ICM reactions as protective factors [ORadja = 0.51; 95% CI: 0.33-0.77 and ORadja = 0.60; 95% CI: 0.39-0.92 respectively]. Cardio-vascular disease [ORadja = 2.06; 95% CI: 1.22-3.50)], respiratory allergy [ORadja = 2.30; 95% CI: 1.09-4.83)] and adverse drug reactions [ORadja = 1.99; 95% CI: 1.05-3.77)] were identified as risk factors for ICM reactions. Food allergy was not significantly associated with reactions [ORadja = 1.51; 5% CI: 0.41-5.56]. Conclusions. This is the largest study on Italian patients experiencing hypersensitivity reactions to ICM. Most results are in line with other studies, showing some association with factors that could influence the incidence of hypersensitivity reactions but not allowing an easy risk stratification.

Brief psychological interventions for psychiatric disorders in young people with long term physical health conditions: A systematic review and meta-analysis.

OBJECTIVES: Rates of psychiatric disorders are considerably elevated in young people with long term physical health conditions. Currently few children obtain effective mental health treatments in the context of long term physical health conditions, and ways to improve access to evidence-based mental health interventions are urgently needed. One approach is to deploy briefer, more economical, yet still evidence-based, treatments. The objective of this review was to evaluate the efficacy of brief interventions targeting psychiatric disorders in children and young people with long term physical health conditions. METHODS: Predefined terms relating to brief psychological interventions for psychiatric disorders in children with long term physical health conditions were used to search relevant databases. A systematic review and meta-analysis was carried out in accordance with the Cochrane guidelines. Two reviewers independently screened titles and abstracts, extracted the data and conducted risk of bias assessments. RESULTS: A total of 12 randomised controlled trials were found to meet the inclusion criteria of the review. Of those, three studies were suitable for meta-analysis. A large effect size in favour of brief cognitive behavioural therapy for anxiety was found (g = - 0.95, CI -1.49 to -0.041; p < .001) with non-significant moderate-substantial heterogeneity (I2 = 58%; p = .09). CONCLUSION: This review suggests there is preliminary evidence that brief interventions, based on cognitive behavioural principles, may benefit young people with an anxiety disorder in the context of a long term physical health condition. There was insufficient evidence to assess whether this held true for depression and disruptive behaviour.

House dust mite allergy and shrimp allergy: a complex interaction.

Summary: Background and Objective. Sensitization and allergy to shrimp among Italian house dust mite allergic patients are not well defined and were investigated in a large multicenter study. Methods. Shrimp sensitization and allergy were assessed in 526 house dust mite (HDM)-allergic patients submitted to the detection of IgE to Der p 10 and 100 atopic control not sensitized to HDM. Results. Shrimp allergy occurred in 9% of patients (vs 0% of 100 atopic controls not sensitized to HDM; p minor 0.001). Shrimp-allergic patients were less frequently hypersensitive to airborne allergens other than HDM than crustacean-tolerant subjects (35% vs 58.8%; p minor 0.005). Only 51% of tropomyosin-sensitized patients had shrimp allergy, and these showed significantly higher Der p 10 IgE levels than shrimp-tolerant ones (mean 22.2 KU/l vs 6.2 KU/l; p minor 0.05). Altogether 53% of shrimp-allergic patients did not react against tropomyosin. Conclusions. Shrimp allergy seems to occur uniquely in association with hypersensitivity to HDM allergens and tropomyosin is the main shrimp allergen but not a major one, at least in Italy. Along with tropomyosin-specific IgE levels, monosensitization to HDM seems to represent a risk factor for the development of shrimp allergy among HDM allergic patients.

Recommendations for the use of molecular diagnostics in the diagnosis of allergic diseases.

Summary: The Study Group on Allergology of the Italian Society of Clinical Pathology and Laboratory Medicine (SIPMeL) and the Associazione Italiana degli Allergologi e Immunologi Territoriali e Ospedalieri (AAIITO) developed the present recommendations on the diagnosis of allergic diseases based on the use of molecular allergenic components, whose purpose is to provide the pathologists and the clinicians with information and algorithms enabling a proper use of this second-level diagnostics. Molecular diagnostics allows definition of the exact sensitization profile of the allergic patient. The methodology followed to develop these recommendations included an initial phase of discussion between all the components to integrate the knowledge derived from scientific evidence, a revision of the recommendations made by Italian and foreign experts, and the subsequent production of this document to be disseminated to all those who deal with allergy diagnostics.

Hymenoptera venom immunotherapy: how to safely switch to the same venom from a different manufacturer

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Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy.

The transdifferentiation of epithelial cells toward a mesenchymal condition (EMT) is a complex process that allows tumor cells to migrate to ectopic sites. Cadherins are not just structural proteins, but they act as sensors of the surrounding microenvironment and as signaling centers for cellular pathways. However, the molecular mechanisms underlying these signaling functions remain poorly characterized. Cadherin-6 (CDH6) is a type 2 cadherin, which drives EMT during embryonic development and it is aberrantly re-activated in cancer. We recently showed that CDH6 is a TGFß target and an EMT marker in thyroid cancer, suggesting a role for this protein in the progression of this type of tumor. Papillary thyroid carcinomas (PTCs) are usually indolent lesions. However, metastatic spreading occurs in about 5% of the cases. The identification of molecular markers that could early predict the metastatic potential of these lesions would be strategic to design more tailored approaches and reduce patients overtreatment. In this work, we assessed the role of CDH6 in the metastatic progression of thyroid cancer. We showed that loss of CDH6 expression profoundly changes cellular architecture, alters the inter-cellular interaction modalities and attenuates EMT features in thyroid cancer cells. Using a yeast two-hybrid screening approach, based on a thyroid cancer patients library, we showed that CDH6 directly interacts with GABARAP, BNIP3 and BNIP3L, and that through these interactions CDH6 restrains autophagy and promotes re-organization of mitochondrial network through a DRP1-mediated mechanism. Analysis of the LIR domains suggests that the interaction with the autophagic machinery may be a common feature of many cadherin family members. Finally, the analysis of CDH6 expression in a unique cohort of human PTCs showed that CDH6 expression marks specifically EMT cells. and it is strongly associated with metastatic behavior and worse outcome of PTCs.

Comparing the compliance to a short schedule of subcutaneous immunotherapy and to sublingual immunotherapy during three years of treatment.

BACKGROUND: Allergen immunotherapy (AIT) in its two forms of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) is an effective treatment of respiratory allergy, but is particularly concerned by the issue of compliance. OBJECTIVE: We aimed a real-life study at evaluating the compliance to SLIT and to SCIT administered by a short-course of four injections during a 3-year period of observation. METHODS: A group of 145 patients (79 males, 66 females, age ranging from 14 to 69 years), suffering from pollen-induced rhino-conjunctivitis with or without asthma, were included in the study. Following adequate education on AIT and according to patient's preference, 72 patients chose to be treated with short-course SCIT and 73 chose to be treated with SLIT. The latter was performed by allergen extracts from different manufacturers according to the suggested schedules. RESULTS: The rate of withdrawal was as follows: after one year, 15.6% for SCIT and 33.4 for SLIT; after two years, 25.6% for SCIT and 44.8% for SLIT; after three years, 26.7 for SCIT and 46% for SLIT. There was no significant difference in the rate of withdrawal between males and females. Regarding the safety, no systemic reaction requiring medical treatment was observed either in SCIT or SLIT group. CONCLUSION: The findings of this study confirm that involving the patient in the choice of the route of administration is associated to a satisfactory compliance to AIT. In particular, more than 70% of patients treated with a short schedule of SCIT completed the three-years course of treatment that is recommended for AIT, while this goal was reached by 54% of SLIT treated patients.

Serum diamine oxidase activity in patients with histamine intolerance.

INTRODUCTION: Intolerance to various foods, excluding bona fide coeliac disease and lactose intolerance, represents a growing cause of patient visits to allergy clinics.Histamine intolerance is a long-known, multifaceted clinical condition triggered by histamine-rich foods and alcohol and/or by drugs that liberate histamine or block diamine oxidase (DAO), the main enzyme involved in the metabolism of ingested histamine. Histamine limitation diets impose complex, non-standardized restrictions that may severely impact the quality of life of patients. METHODS: We retrospectively evaluated 14 patients who visited allergy outpatient facilities in northern Italy with a negative diagnosis for IgE-mediated food hypersensitivity, coeliac disease, conditions related to gastric hypersecretion, and systemic nickel hypersensitivity, and who previously underwent a histamine limitation diet with benefits for their main symptoms. Serum diamine oxidase levels and the clinical response to diamine oxidase supplementation were investigated. RESULTS: We found that 10 out of 14 patients had serum DAO activity<10 U/mL, which was the threshold suggested as a cutoff for probable histamine intolerance. Moreover, 13 out of 14 patients subjectively reported a benefit in at least one of the disturbances related to food intolerances following diamine oxidase supplementation. The mean value (±SD) of diamine oxidase activity in the cohort of patients with histamine intolerance symptoms was 7.04±6.90 U/mL compared to 39.50±18.16 U/mL in 34 healthy controls (P=0.0031). CONCLUSION: In patients with symptoms triggered by histamine-rich food, measuring the serum diamine oxidase activity can help identify subjects who can benefit from a histamine limitation diet and/or diamine oxidase supplementation.Properly designed, controlled studies investigating histamine intolerance that include histamine provocation are indispensable for providing insights into the area of food intolerances, which are currently primarily managed with non-scientific approaches in Italy.

Heterogenity of IgE response to walnut and hazelnut in Italian allergic patients.

BACKGROUND: The prevalence of IgE reactivity against genuine walnut and hazelnut allergens is poorly defined. OBJECTIVE: The IgE response to walnut and hazelnut was investigated in Italian patients with primary allergy to these nuts. METHODS: Sera from 36 patients allergic to hazelnut and/or walnut, not reactive to PR-10, profilin, and LTP, underwent immunoblot analysis with extracts of both nuts. RESULTS: Most patients had a history of systemic symptoms following the ingestion of the offending food(s). Twelve patients were sensitized to both walnut and hazelnut, and 13 were sensitized to other nuts and seeds (cashew, peanut, sesame, pine nut, almond, Brazil nut, and pistachio). On walnut immunoblot, the 7 sera which scored positive showed much variability in their IgE profile. Two reacted uniquely at 10 kDa, and the others at 35 , 40, 45, 50, 67, and > 67 kDa. The profiles obtained under reducing and non-reducing conditions showed several differences. The 7 sera positive on hazelnut immunoblot under reducing conditions recognized sera at 10 kDa and at <10 kDa (n=1), 20 kDa (n=4), at about 22, 24, 30, 40, 43, 58, 60, and 90 kDa, and higher m.w. in other cases. Under non-reducing conditions IgE reactivity at 20, 28, 35, 40, 45, 60, 90, and 100 kDa, was detected. Only two sera scored positive under both conditions and showed an IgE profile that partly changed from one assay to another. CONCLUSION: The current list of walnut and hazelnut allergens is far from being complete. Both reducing and non-reducing conditions are needed to detect IgE reactivity in individual patients.

Ultra short pre-seasonal subcutaneous immunotherapy and pre-coseasonal sublingual immunotherapy for pollen allergy: an evaluation of patient's preference in real life.

BACKGROUND: Specific immunotherapy (SIT) efficacy and safety by subcutaneous (SCIT) and sublingual (SLIT) route is supported by literature data. Pre-coseasonal treatment is currently the more accepted option for pollen immunotherapy in terms of costs and patient's compliance. This retrospective study evaluated the patient's preference concerning subcutaneous or sublingual route in pre-coseasonal treatment. MATERIALS AND METHODS: We evaluated 145 patients (79 males, 66 females, age ranging from 14 to 69 years), suffering from moderate-severe rhino-conjunctivitis or mild bronchial asthma and with homogeneous characteristic according to allergic disease severity. We proposed either SLIT, with extracts by different producers, or SCIT with Pollinex 4 (Allergy Therapeutics, Worthing, UK), a product designed for ultra-short administration in 4 injections, highlighting for each kind of SIT the major practical advantages or burdens. RESULTS: Of 145 patients, 72 chose Pollinex 4 SCIT and 73 chose SLIT. SCIT-treated patients received a total of 90 vaccines (18 patients had double course of SCIT). SLIT-treated patients received a total of 87 vaccines (14 patients had double course of SLIT). In the SCIT group, there were 49 males and 23 females; in the SLIT group, there were 30 males and 43 females. Mean age was 36.5 years in SCIT group and 28.5 years in SLIT group. Males preferred SCIT (49 of 72 patients) and females preferred SLIT (43 of 73 patients). No severe reaction was observed either in SCIT or SLIT group. CONCLUSION: Patients are active subjects in decisional process. Trying to apply in real life the indications coming from guidelines about patient's preference is an important matter. In our patients SCIT with ultra short schedule and SLIT are similarly preferred.

Allergen immunotherapy as a drug: the new deal of grass allergen tablets from clinical trials to current practice.

Currently, sublingual immunotherapy (SLIT) may be performed by a number of allergen extract in different preparations but in a near future only products fulfilling the requirements from the regulatory agencies, that make mandatory a pharmaceutical quality, will be authorized. Indeed, two products with such characteristics are already available for SLIT in grass pollen allergic patients, Grazax from Alk-Abellò and Oralair from Stallergenes. The data from registrative trials as well as from postmarketing studies provide evidence of efficacy and safety of such products. This articles reviews the similarities and the differences of Grazax and Oralair, both designed as drugs for the treatment of grass pollen allergy with the aim, which is exclusive of allergen immunotherapy, to work on the natural history of allergy and not only on symptoms as rescue medications do. The aim of this paper is to evaluate the available trials with Grazax and Oralair in terms of pre-seasonal schedule approach to support their use in clinical practice. Such kind of treatment makes possible a continuous dialogue between clinical investigators and clinical practitioners, and is the only way for scientific progress that puts the patient's health at the first place.

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Expression of p89(c-Mybex9b), an alternatively spliced form of c-Myb, is required for proliferation and survival of p210BCR/ABL-expressing cells.

The c-Myb gene encodes the p75(c-Myb) isoform and less-abundant proteins generated by alternatively spliced transcripts. Among these, the best known is p(c-Mybex9b), which contains 121 additional amino acids between exon 9 and 10, in a domain involved in protein-protein interactions and negative regulation. In hematopoietic cells, expression of p(c-Mybex9b) accounts for 10-15% of total c-Myb; these levels may be biologically relevant because modest changes in c-Myb expression affects proliferation and survival of leukemic cells and lineage choice and frequency of normal hematopoietic progenitors. In this study, we assessed biochemical activities of p(c-Mybex9b) and the consequences of perturbing its expression in K562 and primary chronic myeloid leukemia (CML) progenitor cells. Compared with p75(c-Myb), p(c-Mybex9b) is more stable and more effective in transactivating Myb-regulated promoters. Ectopic expression of p(c-Mybex9b) enhanced proliferation and colony formation and reduced imatinib (IM) sensitivity of K562 cells; conversely, specific downregulation of p(c-Mybex9b) reduced proliferation and colony formation, enhanced IM sensitivity of K562 cells and markedly suppressed colony formation of CML CD34(+) cells, without affecting the levels of p75(c-Myb). Together, these studies indicate that expression of the low-abundance p(c-Mybex9b) isoform has an important role for the overall biological effects of c-Myb in BCR/ABL-transformed cells.

Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1.

Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein. STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34+ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34+ CML cells.

Epinephrine autoinjector prescription in food-allergic adults: symptom-based only or allergen-based also? An Italian multi-centre study.

BACKGROUND: Epinephrine is the treatment of choice for acute food-allergic reactions but existing guidelines state that it should be prescribed uniquely to patients who already experienced at least one food-induced anaphylactic episode. OBJECTIVE: We investigated whether in Italy epinephrine auto-injector is prescribed uniquely following the existing guidelines only, or is allergen-informed as well (i.e., based on the potential risk associated with sensitization to certain food allergens), and hence preventive. METHODS: 1110 adult patients (mean age 31 years; M/F 391/719) with food allergy seen at 19 allergy outpatient clinics were studied. Patients with a history of probable anaphylaxis were identified. Subjects were classified as having primary (type 1) and/or secondary (type 2) food allergy and were divided into several subgroups based on the offending allergen/food. Epinephrine prescriptions were recorded and analyzed both as a whole and by sensitizing allergen. RESULTS: Epinephrine was prescribed to 138/1100 (13%) patients with a significant difference between subjects with type-1 and type-2 food allergy (132/522 [25%] vs. 6/629 [1%]; p < 0.001). The epinephrine group included most patients with a history of anaphylaxis (55/62 [89%]) or emergency department visits 106/138 (77%). In some specific subsets, namely fish-, tree nuts-, and lipid trasfer protein (LTP)-allergic patients, epinephrine was prescribed to patients without a history of systemic allergic reactions. CONCLUSIONS: Italian allergy specialists prescribe epinephrine auto-injectors both on the basis of clinical history of severe reactions and on a critical analysis of the hazard associated with the relevant protein allergens, which suggests a good knowledge of allergens as well as acquaintance with the guidelines for prescription of emergency medication.