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.

Pregnancy in women with Hereditary Angioedema due to C1-inhibitor deficiency: Results from the ITACA cohort study on outcome of mothers and children with in utero exposure to plasma-derived C1-inhibitor.

Background: In women with Hereditary Angioedema (HAE) due to C1-inhibitor (C1INH) deficiency (C1INH-HAE), pregnancy counseling and treatment can be challenging. Despite the evidence of the immediate favorable outcome and safety of plasma-derived (pd)C1INH concentrate, there are no data regarding any difference among women who underwent or not pdC1INH during pregnancy or on children with in utero exposure to pdC1INH. The present interview study aimed at analyzing outcome of C1INH-HAE mothers and children according to pdC1INH-exposure during pregnancies. Methods: C1INH-HAE women who experienced at least 1 pregnancy were included from seven centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). The interview study retrospectively analyzed pregnancies who underwent (group 1) or not (group 2) pdC1INH. The overall goals of the study included immediate and long-term outcomes, in terms of outcomes in the time interval between pregnancy and survey. Results: A total of 168 pregnancies from 87 included women were analyzed. At term delivery (>37 gestation-week, GW) has been registered in 73.8% of cases, while spontaneous abortion (SA) occurred in 14.2% of cases with a mean GW 7 ± 2. The group 1 including pdC1INH-treated pregnancies comprised a third of the cohort (51/168, time interval 1.5 ± 10.4 yrs), while the group 2 represented 69.6% (117/168, time interval 32.8 ± 14 yrs). The same prevalence of SA occurred when comparing group 1 (11.7%) with group 2 (15.4%) with a similar GW at SA. The group 1 was older at the pregnancy time and younger at the interview than the group 2 (P < 0.01 for both); moreover, the group 1 showed a higher prevalence of cesarean delivery (P < 0.0001). The overall prevalence of obstetrical syndromes was similar between two groups: however, gestational diabetes was described only in pdC1INH-untreated pregnancies. In utero pdC1INH-exposed children (n = 45) did not show differences compared with unexposed ones (n = 99) in neonatal short-term outcomes. Conclusion: Through appropriate management and counseling, most of C1INH-HAE women undergo successful pregnancy and delivery. For pregnant C1INH-HAE women being treated with pdC1INH, our findings are reassuring and might lead to an improvement of both the knowledge about treatments and the experience of HAE itself.

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.

Sensitization to Gibberellin-Regulated Protein (Peamaclein) Among Italian Cypress Pollen-Sensitized Patients.

BACKGROUND AND OBJECTIVES: Peach gibberellin-regulated protein (peamaclein) has recently emerged as a relevant food allergen in cypress pollen-hypersensitive patients. Objective: We investigated monosensitization to peamaclein among Italian cypress pollen-allergic patients. MATERIAL AND METHODS: A total of 835 cypress pollen-hypersensitive patients from 28 Italian allergy centers underwent a thorough work-up to determine food-allergic reactions and performed skin prick testing with a commercial peach extract containing peamaclein. IgE to rPru p 3 was measured in peach reactors, and those with negative results were enrolled as potentially monosensitized to peamaclein. IgE reactivity to rPru p 7 was evaluated using immunoblot and an experimental ImmunoCAP with rPru p 7. RESULTS: Skin prick tests were positive to peach in 163 patients (19.5%); however, 127 (77.9%) were excluded because they reacted to Pru p 3. Twenty-four patients (14.7%) corresponding to 2.8% of the entire study population) were considered potentially monosensitized to peamaclein. No geographic preference was observed. Seventeen of the 24 patients (70.8%) had a history of food allergy, mainly to peach (n=15). Additional offending foods included other Rosaceae, citrus fruits, fig, melon, tree nuts, and kiwi. On peach immunoblot, only 3 of 18 putative peamaclein-allergic patients reacted to a band at about 7 kDa; an additional 4 patients reacted at about 50-60 kDa. Ten of 18 patients (56%) had a positive result for Pru p 7 on ImmunoCAP. CONCLUSION: Allergy and sensitization to peamaclein seem rare in Italy. Most patients react to peach, although other Rosaceae fruits and several citrus fruits may also be offending foods. Peach and cypress pollen probably also share cross-reacting allergens other than peamaclein.

Allergen-specific IgE: comparison between skin prick test and serum assay in real life.

BACKGROUND: The most common sensitizing allergens in in the area of Liguria region (Northwestern Italy) are pollens, mainly Parietaria and cypress, house dust mites, i.e. Dermatophagoides, and pets. IgE assessment is a crucial step in allergy diagnosis. It may be performed by skin prick test (SPT) or serum IgE (sIgE) assay. Therefore, this study compared these two methods in a real-life setting. METHODS: This retrospective study included 793 subjects, who were referred to the Allergy Department for respiratory allergy during 2014. Inclusion criteria were i) documented diagnosis of allergic rhinitis (AR), and/or allergic asthma, and/or allergic conjunctivitis. SPT and sIgE assay were performed for 5 allergens, such as Dermatophagoides pteronyssinus (D1), cat (E1), Parietaria officinalis (W19), cypress (T23), and dog (E5), as they are the most common in our geographic area. RESULTS: Using a positive SPT result as the target condition, remarkably high and statistically significant values of AUC, ranging from 0.84 to 0.94, were found. On the basis of the Youden index the following optimal classification threshold values were also computed: D1 = 0.22, E1 = 0.26, W19 = 0.61, T23 = 0.25, E5 = 0.34. These values allowed to define a set of sensitivity/specifity estimates ranging from 0.75 to 0.93 and from 0.83 to 0.93, respectively. CONCLUSIONS: The present study shows that SPT and sIgE are two tests that are rather concordant, but with different sensitivity and specificity distinct for each allergen. In clinical practice, both tests should be used depending on clinical history features and obtained findings.

Hymenoptera Venom Allergy: Management of Children and Adults in Clinical Practice.

Hymenoptera venom allergy is an epidemiologically underestimated condition and a major cause of morbidity worldwide. Preventing future allergic reactions in patients who experience a systemic reaction is based on the correct management of the emergency followed by an accurate diagnosis, prescription of adrenaline autoinjectors, and, where indicated, specific venom immunotherapy. Some epidemiological studies highlight our poor knowledge of this disease and the frequent inadequacy of its management. Moreover, they emphasize the importance of such a life-saving treatment as specific immunotherapy. The availability of high-quality hymenoptera venom extracts for diagnostic and therapeutic use has dramatically improved the prognosis and quality of life of allergic patients. Subcutaneous venom immunotherapy is currently the most effective form of allergen-based immunotherapy, with a carry-over effect lasting up to several years after its interruption. This report on the management of hymenoptera venom-allergic children and adults was prepared by a panel of Italian experts. The main objective of this consensus document is to review the scientific evidence related to diagnosis, therapy, and management of patients allergic to hymenoptera venom. Thus, we can improve our knowledge of the disease and promote good clinical practices. The present document provides practical suggestions for correct diagnosis, prescription of emergency therapy and immunotherapy, and strategies for patient care.

Clinical approach on challenge and desensitization procedures with aspirin in patients with ischemic heart disease and nonsteroidal anti-inflammatory drug hypersensitivity.

BACKGROUND: Hypersensitivity to acetylsalicylic acid (ASA) constitutes a serious problem for subjects with coronary artery disease. In such subjects, physicians have to choose the more appropriate procedure between challenge and desensitization. As the literature on this issue is sparse, this study aimed to establish in these subjects clinical criteria for eligibility for an ASA challenge and/or desensitization. METHODS: Collection and analysis of data on ASA challenges and desensitizations from 10 allergy centers, as well as consensus among the related physicians and an expert panel. RESULTS: Altogether, 310 subjects were assessed; 217 had histories of urticaria/angioedema, 50 of anaphylaxis, 26 of nonimmediate cutaneous eruptions, and 17 of bronchospasm related to ASA/nonsteroidal anti-inflammatory drugs (NSAID) intake. Specifically, 119 subjects had index reactions to ASA doses lower than 300 mg. Of the 310 subjects, 138 had an acute coronary syndrome (ACS), 101 of whom underwent desensitizations, whereas 172 suffered from a chronic ischemic heart disease (CIHD), 126 of whom underwent challenges. Overall, 163 subjects underwent challenges and 147 subjects underwent desensitizations; 86 of the latter had index reactions to ASA doses of 300 mg or less. Ten subjects reacted to challenges, seven at doses up to 500 mg, three at a cumulative dose of 110 mg. The desensitization failure rate was 1.4%. CONCLUSIONS: In patients with stable CIHD and histories of nonsevere hypersensitivity reactions to ASA/NSAIDs, an ASA challenge is advisable. Patients with an ACS and histories of hypersensitivity reactions to ASA, especially following doses lower than 100 mg, should directly undergo desensitization.

A regional approach to unmet needs in anaphylaxis.

Allergic diseases are under-diagnosed and undertreated despite their wide prevalence, and particularly anaphylaxis is often under-estimated. Evidence-based anaphylaxis guidelines developed by principal allergy organizations agree on increased prevalence of anaphylaxis, especially in patients younger than 18 years (18-27,30): this trend highlights the need for actions on anaphylaxis management and prevention (3,4). Lack of prompt connection between emergency department and allergy unit after discharge, and of a dedicated ICD-9th identification code (18-26), can delay diagnosis and treatment of anaphylaxis (28,29). Also in the experience of our Allergy Unit, patients reach the allergist office after several attacks treated in ED (17), without a previous evaluation and risk assessment. Keeping in mind unmet needs in anaphylaxis (4), we focused on regional approaches to health care delivery. The key point of our project was to establish an active collaboration between allergist clinicians and their counterparts in emergency medicine, with a system of quick filing report of patients discharged from ED with the suspect of anaphylactic reaction, directed to a central allergy unit, acting in a hub and spoke model with the Ligurian allergy network (31). Aim of the project was to improve epidemiological data collection via direct connection among ED and allergy network; moreover, we tried to provide a quick and proper evaluation of all reported patients, identifying, when possible, the agent responsible for anaphylaxis, to provide instructions on how to minimize future exposure; as all individuals at risk for anaphylaxis should carry and know how to self-administer epinephrine, we managed to provide auto injector and proper training when appropriate. A follow up on readmissions was carried out during the study and four months later. In a 20 months observation period (2013/2014), 205 patients were reported: it was possible to reach a diagnosis and risk assessment in 64.3%. Anaphylaxis diagnosis was considered likely if any 1 of 3 criteria is satisfied within minutes to hours: acute onset of illness with involvement of skin, mucosal surface, or both, and at least 1 of the following: respiratory compromise, hypotension, or end-organ dysfunction; 2 or more of the following occur rapidly after exposure to a likely allergen: involvement of skin or mucosal surface, respiratory compromise, hypotension, or persistent gastrointestinal symptoms; hypotension develops after exposure to a known allergen for that patient: age-specific low blood pressure or decreased systolic blood pressure more than 30% compared with baseline. Of 205 patients reported, 132 were classified as severe anaphylaxis; other 73 cases reported were 12 drugs related angioedema (mostly NSAID related), 9 ACEi related angioedema, 3 ereditary C1inh deficiency angioedema, 24 istaminergic idiopatic angioedema, 14 urticaria angioedema, 6 severe asthma, 2 latex reactions; in three patients a proper diagnosis was not achieved due to refuse / impossibility to perform diagnostic workout. Hymenoptera venom and food proved to be the main triggers, followed by drugs. 100% patients at risk of anaphylaxis received self-injectable adrenaline, pertinent education and individual action plan. In the same period, even though short, there were only two readmissions to ED. First result seems to confirm the usefulness of our approach to address some of unmet needs in anaphylaxis management, as recently pointed out by ICON guidelines (4).

New risks from ancient food dyes: cochineal red allergy.

This study reports an unusual case of IgE-mediated hypersensitivity to Cochineal red or Carmine red, a coloring agent of natural origin. Although the risk of anaphylactic reactions is well known, since the nineties the use of this additive seems to be nowadays on the rise. The problem of labeling of additives used in handmade food products is highlighted.

Bovine Serum Albumin: a double allergy risk.

We analyse two cases of Bovine Serum Albumin (BSA) allergy. The first regards a female laboratory technician with a history of bronchial asthma due to cat allergy, who developed an exacerbation of bronchial symptoms as a consequence of BSA powder inhalation at work. To date, sensitization to BSA as a cause of occupational asthma has rarely been reported in the scientific literature. The second case concerns a woman with a similar cat sensitivity, who presented an oral allergy syndrome-type clinical reaction, gastric pain and diarrhoea immediately after eating cooked pork meat. Subsequently, she developed the same reaction after eating goat meat and goat cheese, and then also after eating beef. Both patients resulted specifically sensitized to BSA and to other mammalian serum albumins which play a role as panallergens in animals. The two cases show that BSA, a well known cause of food allergy in childhood, may also provoke symptoms of food allergy in adulthood, though in case of powder inhalation, it may provoke respiratory symptoms. Prior animal sensitization appears to represent a risk factor.

Successful desensitization to natalizumab in a skin test--positive patient: a case report.

Relevant interest has been focused on rapid desensitization for drug hypersensitivity and on its use for reactions to monoclonal antibodies. Natalizumab is a highly effective therapy for multiple sclerosis but its use can be limited by hypersensitivity reactions. Herein we present a case of a 36-year-old male patient with multiple sclerosis who started natalizumab therapy due to rapid neurological deterioration. During the second infusion he developed a reaction involving urticaria, erythema and angioedema. Natalizumab sensitization was demonstrated by a positive result on the intradermal test. The anti-natalizumab IgG neutralizing antibody assay was negative. Lacking any alternative, equally effective treatment, he underwent a rapid intravenous desensitization protocol. Desensitization was successfully repeated eleven times and the patient's neurological conditions improved and remained stable after one year. This case demonstrates that rapid desensitization is a safe and effective procedure in the treatment of natalizumab hypersensitivity.

Long-lasting effect of a monophosphoryl lipid-adjuvanted immunotherapy to parietaria. A controlled field study.

BACKGROUND: The clinical efficacy of Monophosphoryl lipid A-adjuvanted immunotherapy (MPLA-SCIT) is ascertained, but there are no data on its possible long-lasting effect. We assessed in a real-life setting the persistence of the clinical effect five years after discontinuation. METHODS: Patients with parietaria-induced respiratory allergy and fulfilling the criteria for immunotherapy prescription were evaluated at baseline, after the third year of MPLA-SCIT and five years after discontinuation. Visual analog scores, severity of the disease, pulmonary function and skin reactivity were assessed. Matched subjects who refused immunotherapy served as controls. RESULTS: Twenty nine patients received MPLA-SCIT and 28 were the control group. There was a significant clinical improvement, as assessed by VAS only in the active group after 3 years that remained significant at 5 years versus baseline and controls. The distribution of severity of rhinitis was overall decreased at 3 and 8years as well. The number of patients with conjunctivitis in the active group decreased from 19 to 6 at the end of the treatment and to 9 after 5 years. There was also a decrease in the number of patients with asthma symptoms (from 6 to 2 to 4), which doubled in the control group. A significant reduction in the wheal of the Parietaria skin test was seen in the active group at the end of the treatment (9.5 +/- 2.1 mm vs. 6.4 +/- 2.6 mm; p = .01), but this reduction was lost at the 5-year. No relevant change was overall detected in pulmonary function. CONCLUSION: MPLA-SCIT is effective, and the clinical efficacy is maintained after 5 years of discontinuation.

Phenobarbital-induced DiHS and ceftriaxone hypersensitivity reaction: a case of multiple drug allergy.

Patients with DiHS show an increased risk of sensitization to multiple drugs. We report a case of a young woman who developed cutaneous rash, lymphoadenopathy, malaise and fever after the introduction of phenobarbitale. Because of these symptoms, she was treated with ceftriaxone and she experienced a severe flare-up of the cutaneous and general reaction. Allergological work-up, by cutaneous and lymphocyte transformation test, confirmed a double sensitization to phenobarbital and ceftriaxone. In conclusion, the high risk of DiHS during anticonvulsive therapy should suggest caution in using additional drugs, because of an increased risk of multiple reactions.

Chronic urticaria: importance of a medical-psychological approach.

Chronic urticaria is often associated with psychological factors, such as depression, anxiety and stress, which may play a role not only in the genesis of the disease but also in its evolution. Aims of this study were to evaluate the utility of psychological assessments (presence of depression, impact on the quality of life and incidence of "life events" before the beginning of urticaria) in conjunction with the allergological evaluation and to provide appropriate treatment to the patients selected. Thirty subjects diagnosed as Chronic Urticaria patients were submitted to psychological assessments (semi structured interview, Beck Depression Inventory, Nottingham health Profile and Dermatology Life Quality Index). The results of the evaluation show that most of the patients experienced a "stressor" event within the six months before the onset of the cutaneous manifestation. The incidence of depression resulted very high in comparison with the general population and in three cases at a severe level. The impact on the quality of life results to be moderate, but involving different fields of life (physical image, social life, quality of sleeping and eating, etc). Despite these results, only six patients accepted to be assigned to an appropriate treatment. In conclusion, we demonstrate the usefulness of a medical- psychological approach in chronic urticaria and we confirmed the resistance of psychosomatic patients to undergo psychological treatment.

Psychological aspects of drug intolerance.

A consecutive unselected series of 50 patients suffering from drug intolerance was evaluated by allergological and psychological tests. We wanted to verify the existence of a correlation between some psychological characteristics (hysteria, depression and Ego Integrity), and some clinical aspects (number and type of episodes, severity and probability of the reactions). We confirmed the prevalence of female sex in these disorders, particularly in middle-aged married women. The mean score of hysteria in the whole sample was lightly higher than normal. Moreover a relevant number of subjects (24%) scored higher than the cut off for clinical depression, with a significant difference in comparison to the overall prevalence of depression in the general population. Finally, the analysis of clinical variables considered in our patients showed that subjects with a history of less serious reactions and unlikely reactions scored higher in depression and hysteria scales. The importance of psychological evaluation of drug intolerance patients is discussed and confirmed.

Sublingual immunotherapy in tree pollen allergy. Double-blind, placebo-controlled study with a biologically standardised extract of three pollens (alder, birch and hazel) administered by a rush schedule.

BACKGROUND: sublingual immunotherapy has been recognised as safe and effective but it is still poorly documented in tree pollen allergy. Allergy to alder, birch and hazel is important in Northern European countries but its clinical relevance is increasing in Southern Europe. METHODS: thirty patients, selected and observed for one pollen season, were randomised to receive placebo (15 patients) or active treatment (15 patients). Twenty-seven patients completed the first year and 24 of them were treated with active therapy during the second year of the study in comparison to a parallel group of ten patients treated only with drugs. Symptom and drug scores during each pollen season, birch-specific IgE, changes in skin test reactivity, changes in specific Nasal Provocation Test and the daily average pollen count for the relevant trees were considered for the assessment of the efficacy of the treatment. RESULTS: both active and placebo group showed a statistically significant improvement in scores in comparison to the previous year, under a lower allergenic pressure. The improvement was higher in the active group (76.04 % reduction of drugs) but not significantly different from that registered in the placebo group (37.05 % reduction). In the open phase of the study, treated patients showed significantly better scores in comparison to the control group. No significant changes in skin reactivity, specific IgE and Nasal Provocation Test were registered. SLIT tolerance was very good. CONCLUSIONS: our data show a better but not statistically significant clinical outcome for patients actively treated with SLIT, but the placebo effect and the year-by-year variability of the environmental allergenic load in our small-size pilot study do not allow for a conclusive statement about the efficacy of this form of therapy.