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Measures to improve vaccine safety are essential for successful immunization programs. Therefore, an activity for vaccine adverse events prevention and surveillance, named the Green Channel, was established in the Veneto ion of Italy in 1992. This report summarizes the results of 10 years activity of a specialized pre-vaccination counseling service, offered to 543 selected at risk individuals referred for prior AEFIs or suspected contraindications (CI) to vaccine administration. Furthermore, data on 1762 AEFIs reported in this region are analyzed and discussed. This joint activity appeared effective and it is proposed as a model. [Copyright &y& Elsevier]

Background: Recently published studies have reported association of COVID-19 vaccine ChAdOx1-S (Vaxzevria) with Guillain Barré Syndrome (GBS). Less is known about the safety of other COVID-19 vaccines with respect to GBS outcome. This study investigated the association of COVID-19 vaccines with GBS in more than 15 million persons aged ≥12 years in Italy., Methods: Study population was all individuals aged ≥12 years who received at least one dose of COVID-19 vaccines, admitted to emergency care/hospital for GBS from 27 December 2020-30 September 2021 in Italy. Identification of GBS cases and receipt of at least one dose of mRNA-1273 (Elasomeran), BNT162b2 (Tozinameran), ChAdOx1-S (Vaxzevria) and Ad26.COV2.S (Janssen) through record linkage between regional health care and vaccination registries. Relative Incidence (RI) was estimated Self-controlled case series method adapted to event-dependent exposure using in the 42-day exposure risk period after each dose compared with other observation periods., Results: Increased risk of GBS was found after first (RI = 6.83; 95% CI 2.14-21.85) and second dose (RI = 7.41; 2.35-23.38) of mRNA-1273 and first dose of ChAdOx1-S (RI = 6.52; 2.88-14.77). Analysis by age found an increased risk among those aged≥60 years after first (RI = 8.03; 2.08-31.03) and second dose (RI = 7.71; 2.38-24.97) of mRNA-1273. The first dose of ChAdOx1-S was associated with GBS in those aged 40-59 (RI = 4.50; 1.37-14.79) and in those aged ≥ 60 years (RI = 6.84; 2.56-18.28)., Conclusions: mRNA-1273 and ChAdOx1-S vaccines were associated with an increased risk of GBS however this risk resulted in a small number of excess cases. Limitations were loss of GBS outpatient cases and imprecision of the estimates in the subgroup analysis due to a low number of events., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Gianluca Trifirò participated to advisory board funded by Eli Lilly, Sanofi, Amgen, Novo Nordisk, Sobi; Gilead, Celgene, Daikii Sankyo; he is scientific responsible of the academic spin-off INSPIRE that within the last 36 months received unconditional grant for the conduction of observational studies or organization of webinar on real world evidence from Kiowa kirin, Daiichi Sankyo, Chiesi Farmaceutici, GALAPAGOs, TAKEDA, UCB, VIFOR, CSL BEHRING, Shionogi, ASTELLAS, ALEXION. Giovanna Zanoni and Giuseppe Monaco participated to the Working Group on Safety signals analysis at the Agenzia Italiana del Farmaco (Italian Medicine Agency). This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Morciano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objective: Evidence highlights the allergenic potential of PEGylated drugs because of the production of anti-polyethylene glycol immunoglobulins. We investigated the risk of hypersensitivity reactions of PEGylated drugs using the Italian spontaneous adverse drug reaction reporting system database., Methods: We selected adverse drug reaction reports attributed to medicinal products containing PEGylated active substances and/or PEGylated liposomes from the Italian Spontaneous Reporting System in the period between its inception and March 2021. As comparators, we extracted adverse drug reaction reports of medicinal products containing the same non-PEGylated active substances and/or non-PEGylated liposomes (or compounds belonging to the same mechanistic class). A descriptive analysis of reports of hypersensitivity reactions was performed. Reporting rates and time to onset of hypersensitivity reactions were also calculated in the period between January 2009 and March 2021. As a measure of disproportionality, we calculated the reporting odds ratio., Results: Overall, 3865 adverse drug reaction reports were related to PEGylated medicinal products and 11,961 to their non-PEGylated comparators. Around two-thirds of patients were female and reports mostly concerned patients aged between 46 and 64 years. The frequency of hypersensitivity reactions reporting was higher among PEGylated versus non-PEGylated medicinal products (11.7% vs 9.4%, p < 0.0001). The hypersensitivity reaction reporting rates were higher for PEGylated medicinal products versus non-PEGylated medicinal products, with reporting rate ratios that ranged from 1.4 (95% confidence interval 0.8-2.5) for pegfilgrastim versus filgrastim to 20.0 (95% confidence interval 2.8-143.5) for peginterferon alpha-2a versus interferon alpha-2a. The median time to onset of hypersensitivity reactions was 10 days (interquartile range: 0-61) for PEGylated medicinal products, and 36 days (interquartile range: 3-216) for non-PEGylated comparators. Statistically significant reporting odds ratios were observed when comparing the reporting of hypersensitivity reactions for PEGylated versus non-PEGylated medicinal products (reporting odds ratio: 1.3; 95% confidence interval 1.1-1.4). However, when using all other drugs as comparators, the disproportionality analysis showed no association with hypersensitivity reactions for PEGylated nor non-PEGylated medicinal products, thus suggesting that many other triggers of drug-induced hypersensitivity reactions play a major role., Conclusions: The findings of this analysis of the Italian spontaneous adverse drug reaction database suggest a potential involvement for PEGylation in triggering drug-related hypersensitivity reactions, especially clinically relevant reactions. However, when comparing both PEGylated and non-PEGylated drugs under study to all other drugs no disproportionate reporting of hypersensitivity reactions was observed, probably due to a masking effect owing to the presence in the same database of other medicinal products increasing the threshold required to highlight a safety signal when the entire database is used as a reference., (© 2023. The Author(s).)

Background: Myocarditis and pericarditis following the Coronavirus Disease 2019 (COVID-19) mRNA vaccines administration have been reported, but their frequency is still uncertain in the younger population. This study investigated the association between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccines, BNT162b2, and mRNA-1273 and myocarditis/pericarditis in the population of vaccinated persons aged 12 to 39 years in Italy., Methods and Findings: We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Exposure risk period (0 to 21 days from the vaccination day, subdivided in 3 equal intervals) for first and second dose was compared with baseline period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose, age, sex, and vaccine product. Calendar period was included as time-varying confounder in the model. During the study period 2,861,809 persons aged 12 to 39 years received mRNA vaccines (2,405,759 BNT162b2; 456,050 mRNA-1273); 441 participants developed myocarditis/pericarditis (346 BNT162b2; 95 mRNA-1273). Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the RI was 1.99 (1.30 to 3.05) after second dose of BNT162b2 and 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after first and second dose of mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after first dose of mRNA-1273, with RI of 6.55 (2.73 to 15.72), and after second dose of BNT162b2 and mRNA-1273, with RIs of 3.39 (2.02 to 5.68) and 7.59 (3.26 to 17.65). The number of EC for second dose of mRNA-1273 was 5.5 per 100,000 vaccinated (3.0 to 7.9). The highest risk was observed in males, at [0 to 7) days after first and second dose of mRNA-1273 with RI of 12.28 (4.09 to 36.83) and RI of 11.91 (3.88 to 36.53); the number of EC after the second dose of mRNA-1273 was 8.8 (4.9 to 12.9). Among those aged 12 to 17 years, the RI was of 5.74 (1.52 to 21.72) after second dose of BNT162b2; for this age group, the number of events was insufficient for estimating RIs after mRNA-1273. Among those aged 18 to 29 years, the RIs were 7.58 (2.62 to 21.94) after first dose of mRNA-1273 and 4.02 (1.81 to 8.91) and 9.58 (3.32 to 27.58) after second dose of BNT162b2 and mRNA-1273; the numbers of EC were 3.4 (1.1 to 6.0) and 8.6 (4.4 to 12.6) after first and second dose of mRNA-1273. The main study limitations were that the outcome was not validated through review of clinical records, and there was an absence of information on the length of hospitalization and, thus, the severity of the outcome., Conclusions: This population-based study of about 3 millions of residents in Italy suggested that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years. According to our results, increased risk of myocarditis/pericarditis was associated with the second dose of BNT162b2 and both doses of mRNA-1273. The highest risks were observed in males of 12 to 39 years and in males and females 18 to 29 years vaccinated with mRNA-1273. The public health implication of these findings should be considered in the light of the proven mRNA vaccine effectiveness in preventing serious COVID-19 disease and death., Competing Interests: I have read the journal’s policy and the author of this manuscript have the following competing interests: in the last 36 months, GT coordinated a pharmacoepi team at the University of Messina till Oct 2020 and currently at the academic spin-off INSPIRE that received research grants from PTC Therapeutics, Kiowa Kirin, Chiesi, Daiichi Sankyo for the conduct of observational studies on topics not related to the paper; GT participated to Advisory Board/interview sponsored by Eli Lilly, Amgen, Sanofi, SOBI, Gilead, ABBvie, Verpora and Daiichi Sankyo on topics not related to the paper.

Reporting and analysis of Adverse Events Following Immunization (AEFIs) are the cornerstones of vaccine safety surveillance prompting causality assessment and signal detection. This paper describes the impact of the Italian Pharmacovigilance System of vaccines over a 10-year period (2008-2017). The reporting rate (RR) per all distributed dose was calculated. Serious AEFIs and causality assessments for fatal cases were described. The main results from signal detection were reported. During the study period, 46,430 AEFIs were reported with an overall RR of 17.2 per 100,000 distributed doses. Italy showed the highest number of reports among European countries. Only 4.4% of the reports came from citizens. Of the total, 12.7% were classified as serious with a RR over the study period of 2.20 per 100,000 distributed doses. They were mainly related to hyperpyrexia and usually had a positive outcome. Fatal outcomes were reported in 0.3% of the cases and were primarily associated with the influenza vaccine in elderly patients. None of these outcomes had a consistent causal association with the vaccination. Febrile convulsions by the measles, mumps, rubella and varicella vaccines and intussusception by the rotavirus vaccine were among the highlighted signals. The reporting rate and the analysis of serious events from 10 years support the good risk/benefit profiles of vaccines.

Background: Serum IgE evaluation of peanut, hazelnut and walnut allergens through the use of component-resolved diagnosis (CRD) can be more accurate than IgE against whole food to associate with severe or mild reactions., Objectives: The aim of the study was to retrospectively define the level of reaction risk in children with peanut, hazelnut and walnut sensitization through the use of CRD., Methods: 34 patients [n=22 males, 65%; median age eight years, interquartile range (IQR) 5.0-11.0 years] with a reported history of reactions to peanut and/or hazelnut and/or walnut had their serum analyzed for specific IgE (s-IgE) by ImmunoCAP ® and ISAC ® microarray technique., Results: In children with previous reactions to peanut, the positivity of Arah1 and Arah2 s-IgE was associated with a history of anaphylaxis to such food, while the positivity of Arah8 s-IgE were associated with mild reactions. Regarding hazelnut, the presence of positive Cora9 and, particularly, Cora14 s-IgE was associated with a history of anaphylaxis, while positive Cora1.0401 s-IgE were associated with mild reactions. Concerning walnut, the presence of positive Jug r 1, Jug r 2, Jug r 3 s-IgE was associated with a history of anaphylaxis to such food. ImmmunoCAP ® proved to be more useful in retrospectively defining the risk of hazelnut anaphylaxis, because of the possibility of measuring Cor a14 s-IgE., Conclusions: Our data show that the use of CRD in patients with allergy to peanut, hazelnut and walnut could allow for greater accuracy in retrospectively defining the risk of anaphylactic reaction to such foods., (Copyright © 2018 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.)

Autoimmune pancreatitis (AIP) is a rare disorder whose association with coeliac disease (CD) has never been investigated, although CD patients display a high prevalence of both endocrine and exocrine pancreatic affections. Therefore, we sought to evaluate the frequency of CD in patients with AIP and in further medical pancreatic disorders. The screening for CD was carried out through the detection of tissue transglutaminase (tTG) autoantibodies in sera of patients retrospectively enrolled and divided in four groups: AIP, chronic pancreatitis, chronic asymptomatic pancreatic hyperenzymemia (CAPH), and control subjects with functional dyspepsia. The search for anti-endomysium autoantibodies was performed in those cases with borderline or positive anti-tTG values. Duodenal biopsy was offered to all cases showing positive results. One patient out of 72 (1.4%) with AIP had already been diagnosed with CD and was following a gluten-free diet, while one case out of 71 (1.4%) with chronic pancreatitis and one out of 92 (1.1%) control subjects were diagnosed with de novo CD. No cases of CD were detected in the CAPH group. By contrast, a high prevalence of cases with ulcerative colitis was found in the AIP group (13.8%). Despite a mutual association between CD and several autoimmune disorders, our data do not support the serologic screening for CD in AIP. Further studies will clarify the usefulness of CD serologic screening in other pancreatic disorders.

Background: Cheese is considered to increase the total cholesterol levels (CH) due to the high-saturated fat content. New models are needed to measure the relationship between cholesterol and cheese., Methods: Thirty different cheeses produced in Val Brembana, Italy ("furmai da mut", "caprino" and "stracchino"), were added to the diet of 30 groups of 4 rats. Cheeses were analyzed to differentiate the volatile organic compounds (VOCs) and the cholesterol content (Ch(f)). The body weight, CH, urine volume and oxidative balance were measured. Three new indexes in relation to CH were calculated: OI (oxidative index), PI (protective index) and OBRI (oxidative balance risk index)., Results: None of the cheeses increased CH. Some of the "furmai de mut" were significantly decreasing CH and improved the oxidative balance. Ch(f) was not affecting the CH levels in plasma. In terms of VOCs, the acetic acid content was correlated (p < 0.05) with the CH reduction and PI improvement. OBRI was reduced mainly in the "stracchino group"., Conclusions: The model shows that some cheese can reduce significantly CH levels and improve the antioxidant capacity.

Objectives: To characterise occupational wheat allergic phenotypes (rhino-conjunctivitis, asthma and dermatitis) and immunoglobulin (IgE) sensitisation to particular wheat allergens in bakers., Methods: We conducted clinical and immunological evaluations of 81 consecutive bakers reporting occupational symptoms using commercial tests (skin prick test (SPT), specific IgE, ISAC microarray) and six additional dot-blotted wheat allergens (Tri a 39, Tri a Trx, Tri a GST, Tri a 32, Tri a 12, Tri a DH)., Results: Wheat SPT resulted positive in 29 bakers and was associated with work-related asthma (p<0.01). Wheat IgE was detected in 51 workers and was associated with work-related asthma (p<0.01) and rhino-conjunctivitis (p<0.05). ISAC Tri a 30 was positive in three workers and was associated with work-related dermatitis (p<0.05). Wheat dot-blotted allergens were positive in 22 bakers. Tri a 32 and Tri a GST were positive in 13 and three bakers, respectively, and both were associated with work-related dermatitis (p<0.05). This association increased (p<0.01) when Tri a 32, Tri a GST and Tri a 30 were analysed together (p<0.01). Wheat IgE levels were associated with work-related dermatitis (p<0.01)., Conclusions: Wheat IgE levels and wheat microarrayed allergens may be associated with some occupational allergic phenotypes. The extension of the panel of wheat allergens may be promising for discriminating the clinical manifestations of baker's allergy.

Background: Suspected vaccine allergy may be a cause of incomplete or delayed vaccination. Patients at risk of adverse reactions or suspected contraindications need specialized consultation about subsequent vaccinations., Objective: To analyse consultancy results for patients at risk of allergic reactions to vaccines as evaluated by the Green Channel University Hospital Immunization Consultancy Clinic., Methods: A review of cases of allergic reactions to vaccines or contraindications due to underlying diseases or sensitization to vaccine components submitted to the Green Channel was carried out. Analysed data included detailed clinical reaction history, skin and in vitro allergy testing with vaccine components, recommendations for vaccination and outcome of subsequent vaccine administrations., Results: A total of 519 cases, 370 referred for previous local or systemic reactions to vaccines, mostly cutaneous, and 149 sent for suspected contraindications were evaluated. Skin testing was performed on 152 patients, specific IgE determination in 37 subjects and patch testing in 173 cases. After consultation, 442 (85%) subjects were advised to continue vaccination, with personalized precautions (premedication, or alternative brand, or administration in graded doses) for 200 of them. Among the 352 (80%) patients vaccinated as per Green Channel instructions, 33 subjects (9.3%) reported mild allergic or non-specific symptoms and one (0.3%) urticaria with bronchospasm., Conclusion and Clinical Relevance: Even though vaccine allergy occurs very rarely, a safe procedure for immunization can be applied, through specialized allergy consultancy, for most subjects with suspected allergy to vaccines, and who could be potentially excluded from vaccination for risk of adverse reactions., (© 2012 Blackwell Publishing Ltd.)

Prevention and control of adverse events following immunization (AEFI) are fundamental activities of successful immunisation programs. AEFI reporting, investigation and analysis, integrated by consultancy for subjects needing a specialized evaluation, represent an ideal model for vaccine safety surveillance. In the Veneto Region of Italy the Green Channel Centre has been created by the local Public Health authority, to offer a consultancy activity for vaccinations at risk of adverse events and to ensure an efficient AEFI surveillance system with regular feedback data for vaccine personnel. This report updates the overall activity provided by the Green Channel between 1992 and 2008, concerning consultations for previous AEFI and contraindications to vaccinations and analysis of AEFI reports. After 1280 consultancy cases, 998 (78%) subjects were found eligible for vaccination, with personalized precautions suggested in 42% of cases. Of a total of 724 patients actually vaccinated as per the Green Channel instructions, only 55 subjects (7.6%) reported mild symptoms and one (0.3%) a moderate allergic reaction. Since 1993, a total of 5,006 AEFI reports have been collected and evaluated by the Green Channel against more than 20 millions of vaccine doses administered with an estimate mean AEFI rate of 2.3 x 10.000 doses per year. The majority of them (94%) were found in causal relationship with vaccines; of these, 267 reports (5,6% - 0.1/10,000 doses) were serious and 9 of these subjects, affected by a neurological event, were not recovered or were still on therapy at follow up. This regional activity has proven efficacious in evaluating and managing individual cases at potential risk of AEFI and integrating the national passive surveillance system.

Chrysotriones A (1) and B (2), two new 2-acylcyclopentene-1,3-dione derivatives, were isolated from the fruiting bodies of the Basidiomycete Hygrophorus chrysodon, and their structures were established by spectroscopic data and synthesis of compound 2. They represent the first examples of 2-acylcyclopentene-1,3-diones found in mushrooms and suggest an unprecedented biosynthetic pathway, starting from fatty acid derivatives. Initial tests indicated interesting antifungal activity of chrysotriones against Fusarium verticillioides, one of the common worldwide pathogens of cultivated plants.

Modern vaccinology and public health organizations need to satisfy an increased safety demand. Therefore, to improve adverse events following immunization (AEFIs) surveillance systems, some countries have established clinical evaluation centers for AEFI assessment and management of at risk individuals. In the Veneto region of Italy, the Green Channel operates through a counselling service for subjects with prior AEFI or with suspected contraindications to vaccine administration, and a surveillance system of the AEFIs reported in the region. Updated data on 753 consultations and 3023 AEFI analyses are discussed together with the opportunity to include the Green Channel model as part of an international vaccine safety network.

Background: Hen's egg proteins are known sensitizers and may cause occupational respiratory diseases in exposed workers. The study was conducted in order to ascertain the prevalence of sensitization to work-related antigens in asymptomatic egg processing factory workers., Methods: Clinical history, respiratory function, atopy and the presence of specific antibodies to environmental and occupational antigens were evaluated in 77 workers. A total of 116 unexposed and non-professionally exposed controls were also studied. The antigen concentration of the factory environment was measured., Results: Specific IgE and precipitin positivity to egg components was more frequently present in workers than in the two control groups. The egg white protein concentration was higher in the egg breaking area., Conclusions: The avian proteins inhaled induced immune responses to occupational antigens in asymptomatic, professionally exposed subjects. Measures to decrease environmental antigen concentrations and thorough clinical monitoring of sensitized workers are advocated.

Background: Allergic asthma is a multifactorial disease for which there is a widely assessed, although poorly understood, genetic involvement. Genome-wide screens reported evidence for linkage of allergic asthma-related phenotypes to several chromosomal locations. Markers on chromosome 19 have been linked to allergic asthma phenotypes in different populations in independent studies., Objective: The aim of this study was to perform a genetic linkage analysis on chromosome 19 to search for DNA markers linked to phenotypes related to allergic asthma., Methods: Using non-parametric multipoint linkage analysis on a total of 22 random DNA markers in 2 stages, a sample of 111 families (542 subjects) from north-eastern Italy, recruited through an asthmatic allergic proband, was investigated. Phenotypes examined were: clinical asthma, total serum elevated IgE, skin prick test positivity, bronchial hyper-responsiveness, and atopy defined as skin prick test positivity and/or elevated IgE. Simulation studies were performed to confirm the significance of the results., Results: A novel linkage of atopy and skin prick test positivity to marker D19S601 (19q13.3) was found. Modest evidence for linkage of atopy, skin prick test positivity, and IgE was also found to marker D19S591 (19p13.3). Simulation analysis for atopy gave an NPL-Z > 3.326 in 2 replicates out of 1000 (P = 0.002) for D19S601, and an NPL-Z > 2.56 in 16 replicates out of 1000 (P = 0.016) for D19S591., Conclusions: On chromosome 19, suggestive linkage of atopy and skin prick test positivity with marker D19S601 (19q13.3) and modest evidence of linkage of marker D19S591 (19p13.3) to the atopic phenotypes investigated were found. These results suggest that these regions may contain susceptibility loci associated to atopic phenotypes.

We investigated 116 Italian atopic families (560 individuals) for linkage with 13 DNA markers on chromosome 12. All the subjects were phenotyped for asthma, total serum IgE, bronchial hyperresponsiveness, skin-prick positivity to common aeroallergens, and atopy. A relative location map of the markers was prepared from Centre d'Etude du Polymorphisme Humain families. Affected sib pair multipoint linkage methods were used to perform the statistical analyses. We report suggestive linkage for asthma with markers on chromosome 12. The region of interest centers around marker D12S390 (maximum logarithm of odds [mlod] = 2.81; p = 0.003). These results provide additional support that asthma susceptibility factors are located on chromosome 12q.