Fatal anaphylaxis in Italy: Analysis of cause-of-death national data, 2004-2016.

BACKGROUND: Epidemiological data on fatal anaphylaxis are underestimated worldwide. Few Italian data do exist. The aims of the study are to determine the anaphylaxis mortality rate in Italy and its associations with demographic characteristics (gender, age, and geographical distribution), and to investigate which are the most common triggers of fatal anaphylaxis. MATERIAL AND METHODS: This is a descriptive study analyzing data reported to the National Register of Causes of Death database and managed by the Italian National Institute of Statistics for the years 2004-2016. An analytical method was developed to identify all the ICD-10 codes related to anaphylaxis deaths, which were divided into two classes: "Definite anaphylaxis deaths" and "Possible anaphylaxis deaths." RESULTS: From 2004 through 2016, 392 definite anaphylaxis deaths and 220 possible anaphylaxis deaths were recorded. The average mortality rate for definite anaphylaxis, from 2004 to 2016, was 0.51 per million population per year. Definite fatal anaphylaxis was mostly due to the use of medications (73.7%), followed by unspecified causes (20.7%) and hymenoptera stings (5.6%). Concerning possible anaphylaxis deaths, the most common cause was venom-stinging insect (51.4%). We did not find any data on food fatal anaphylaxis. Unspecified anaphylaxis accounted for 21%-28% of all cases, underlining the difficulty in accurately ascertaining the causes of fatal anaphylaxis and therefore in assigning the proper ICD-10 code. CONCLUSION: This is the first study of anaphylaxis-related mortality coming from an official database of the whole Italian population. However, the actual number of deaths by anaphylaxis, and their related triggers, is probably underreported, mostly due to limitations of the current recording system, and to a poor allergy education. Corrective actions should be undertaken for the benefit of the Health System.

Large local reactions to Hymenoptera stings: Outcome of re-stings in real life.

BACKGROUND: Large local reaction to Hymenoptera stings is usually defined as a swelling >10 cm which lasts longer than 24 hours, sometimes associated with erythema, pruritus and blisters. Currently, the risk of subsequent systemic reactions after re-stings is considered low (2%-15%). Therefore, a diagnostic workup in case of large local reaction is often judged unnecessary, as well as adrenaline auto-injector and venom immunotherapy prescription. The aim of this study was to prospectively evaluate the outcome of re-stings in a real-world setting, in patients with a history of one previous large local reaction. METHODS: We consecutively enrolled patients who experienced their first large local reaction (as per EAACI definition), treated with antihistamine and steroids. They were followed for field re-stings and assessed for risk of subsequent systemic reactions. RESULTS: We enrolled 662 patients. Out of the 225 re-stung subjects, 24% did not experience reactions, 52% reported a second large local reaction and 24% had systemic reactions. The risk of subsequent systemic reactions was higher in case of skin test reactivity to Apis mellifera or Vespula species (OR 2.1 and 3.8, respectively), in particular if positive at 0.001 µg/mL concentration (OR 13.4 and 16.5, respectively). CONCLUSIONS: Systemic reactions, after a previous large local reaction, occur more frequently than that reported by literature. After analysing the predictive role of large local reactions for systemic reactions, we demonstrated that an accurate diagnostic workup may be considered, particularly skin tests. Further studies in different countries are needed to confirm these results and large local reaction management.

CAP-Inhibition, Molecular Diagnostics, and Total IgE in the Evaluation of Polistes and Vespula Double Sensitization.

Cross-reactions between Polistes dominula and Vespula species are common in southern Europe. Currently, only CAP-inhibition demonstrates high accuracy in identifying genuine sensitizations, but this method is time-consuming and expensive, so a new approach is required. This study investigates skin tests, molecular diagnostics, total IgE (tIgE), and the Ves v 5/Pol d 5 (or vice versa) ratio. The ratio generated low-accuracy results and poor agreement with CAP-inhibition, and we did not find any agreement between CAP-inhibition test and double values of Ves v 5/Pol d 5. Nevertheless, a slight diagnostic improvement was obtained when Ves v 5/tIgE and Pol d 5/tIgE were measured.

Birch allergy and oral allergy syndrome: The practical relevance of serum immunoglobulin E to Bet v 1.

BACKGROUND: Birch allergy (BA) may frequently be associated with fruit-vegetables oral allergy syndrome (OAS). Bet v 1 is the major birch allergen. Previously, it was reported that serum-specific immunoglobulin E (IgE) level could differentiate allergy from sensitization. Thus, this study aimed to investigate the practical role of Bet v 1 IgE. METHODS: A total of 245 subjects (128 women, 117 men; mean age, 41 years) with suspected allergic rhinitis and sensitization to Bet v 1 were evaluated. Serum IgE to Bet v 1 was assessed by using immuno-enzymatic. BA and OAS were diagnosed according to validated criteria. Symptom severity perception was measured by the visual analog scale. RESULTS: A total of 158 patients (64.5%) had BA. Patients with BA had higher serum Bet v 1 IgE levels than subjects who were sensitized (p < 0.0001). A cutoff value of 8.94 kUA/L predicted BA (area under the curve, 0.76; odds ratio, 6.18). Fifty-three patients with BA (33.5%) had OAS. Patients positive for OAS had higher Bet v 1 levels (p < 0.0001) and more-severe symptoms (p < 0.0001) than patients with BA and negative for OAS. A cutoff value of 17.4 kUA/L predicted OAS (area under the curve, 0.59; odds ratio, 3.19). CONCLUSIONS: The present study demonstrated that serum IgE levels to Bet v 1 could be a useful marker for differentiating between different birch pollen sensitization phenotypes.

Anisakis simplex and urticaria. What we know about its real incidence and management in dermatological settings?

Acute or chronic infections have been described among causes of chronic urticaria (CU). Anisakidosis is a human disease caused by the ingestion of larval nematodes of the family Anisakidae. The infestation is acquired by eating raw seafood or undercooked fish and squid. There are considerable variations in the frequency of underlying causes in the different studies and in different countries, such as differences in diets and the prevalence of infections. Anisakis simplex has been recognized as a trigger of both acute and CU manifestations. However, there is still a lack of evidence about its management and treatment in dermatology. We, therefore, reviewed some biologic properties of Anisakis simplex in order to understand the relationship between its biology and the mechanism it uses to establish chronic dermatological conditions such as urticaria and cause late complications. In addition, we herein report some concerns about the effectiveness of systemic treatment in preventing complications and management in dermatological settings.

The impact of puberty on the onset, frequency, location, and severity of attacks in hereditary angioedema due to C1-inhibitor deficiency: A survey from the Italian Network for Hereditary and Acquired Angioedema (ITACA).

Introduction: Hereditary angioedema due to C1-inhibitor deficiency is influenced by hormonal factors, with a more severe course of disease in women. Our study aims to deepen the impact of puberty on onset, frequency, location and severity of attacks. Methods: Retrospective data were collected through a semi-structured questionnaire and shared by 10 Italian reference centers of the Italian Network for Hereditary and Acquired Angioedema (ITACA). Results: The proportion of symptomatic patients increased significantly after puberty (98.2% vs 83.9%, p=0.002 in males; 96.3% vs 68,4%, p<0.001 in females); the monthly mean of acute attacks was significantly higher after puberty, and this occurred both in females (median (IQR) = 0.41(2) in the three years before puberty vs 2(2.17) in the three years after, p<0.001) and in males (1(1.92) vs 1.25(1.56) respectively, p<0.001). The increase was greater in females. No significant differences were detected in attack location before and after puberty. Discussion: Overall, our study confirms previous reports on a more severe phenotype in the female gender. Puberty predisposes to increased numbers of angioedema attacks, in particular in female patients.

Multicentric Observational Study on Safety and Tolerability of COVID-19 Vaccines in Patients with Angioedema with C1 Inhibitor Deficiency: Data from Italian Network on Hereditary and Acquired Angioedema (ITACA).

Angioedema due to C1 inhibitor deficiency (AE-C1-INH) is a rare disease characterized by recurrent and unpredictable attacks of angioedema. Multiple trigger factors, including trauma, emotional stress, infectious diseases, and drugs, could elicit angioedema attacks. The aim of this study was to collect data on the safety and tolerability of COVID-19 vaccines in a population of patients affected by AE-C1-INH. Adult patients with AE-C1-INH, followed by Reference Centers belonging to the Italian Network for Hereditary and Acquired Angioedema (ITACA), were enrolled in this study. Patients received nucleoside-modified mRNA vaccines and vaccines with adenovirus vectors. Data on acute attacks developed in the 72 h following COVID-19 vaccinations were collected. The frequency of attacks in the 6 months after the COVID-19 vaccination was compared with the rate of attacks registered in the 6 months before the first vaccination. Between December 2020 and June 2022, 208 patients (118 females) with AE-C1-INH received COVID-19 vaccines. A total of 529 doses of the COVID-19 vaccine were administered, and the majority of patients received mRNA vaccines. Forty-eight attacks of angioedema (9%) occurred within 72 h following COVID-19 vaccinations. About half of the attacks were abdominal. Attacks were successfully treated with on-demand therapy. No hospitalizations were registered. There was no increase in the monthly attack rate following the vaccination. The most common adverse reactions were pain at the site of injection and fever. Our results show that adult patients with angioedema due to C1 inhibitor deficiency can be safely vaccinated against SARS-CoV-2 in a controlled medical setting and should always have available on-demand therapies.

Development of a model care pathway for the management of Hymenoptera venom allergy: evidence-based key interventions and indicators.

BACKGROUND: Hymenoptera venom allergy (HVA) is an underestimated condition representing an important cause of morbidity and mortality worldwide. Preventing future allergic reactions in patients who have already developed a systemic reaction is based on the correct management of the acute phase of the reaction followed by a correct diagnosis and, where indicated, prescription of adrenaline autoinjectors and VIT. A possible strategy to optimize care processes and to improve outcomes is the implementation of a Diagnostic and Therapeutic Care Pathways, also known as Integrated Care Pathways or Clinical Pathways (CPWs). The aim of the care pathway is to enhance the quality of care by improving risk-adjusted patient outcomes, promoting patient safety, increasing patient satisfaction, and optimizing the use of resources. To our knowledge, currently in Italy as well as in Europe, there is no CPWs codified for the management of HVA patients. This paper describes the development of the clinical content of a care pathway for the management of HVA. METHODS: The methodology applied is based on the eight step method to build the clinical content of an evidence-based care pathway suggested by Lodewijckx et al. RESULTS: Three hundred and seventeen different clinical activities were extracted from the selected literature. The expert panel was involved in their evaluation, expressing a judgment of relevance through the Delphi study. As a result, 126 clinical activities were appraised to be valid and feasible. The final recommendations (126) were translated into 123 key interventions. Six indicators were produced by the clinical activities. CONCLUSION: A set of 123 key interventions and of six process indicators were found to be appropriate for the development and standardization of the clinical content of the Hymenoptera venom allergy care pathway.

Hymenoptera venom allergy in outdoor workers: Occupational exposure, clinical features and effects of allergen immunotherapy.

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.

Can serum white birch (Betula verrucosa) pollen antigen (Bet v 1) immunoglobulin E measurement distinguish between sensitization and allergy?

BACKGROUND: In clinical practice, it is fundamental to distinguish between sensitization and allergy, mainly with respect to polysensitized patients. The aim of this study was to evaluate whether serum immunoglobulin E (IgE) to white birch (Betula verrucosa) pollen antigen (Bet v 1) assessment might be able to differentiate simple sensitization from true allergy. METHODS: In total, 197 subjects (100 females; mean age 44.9 years) with serum Bet v 1 IgE positivity and history of nasal symptoms were evaluated. Subjects were subdivided in 2 groups: allergic and sensitized. RESULTS: Allergic patients were 58.4% of the total; they had higher serum Bet v 1 IgE levels than sensitized subjects (p < 0.001). A serum IgE to Bet v 1 value >8.94 kilo units of allergen per liter (kUA/L) was able to differentiate between sensitization and allergy (area under the receiver operating characteristic curve [AUC] = 0.76; diagnostic odds ratio, ie, degree of agreement between health status and dichotomized IgE levels [DOR] = 6.5). Gender and season when the blood was drawn influenced IgE levels. CONCLUSION: Serum Bet v 1 IgE measurement may be able to differentiate sensitization from allergy in subjects with sensitization to Betulaceae pollen allergens. Thus, Bet v 1 IgE measurement should be considered a useful step in the management of patients with allergic rhinitis due to Betulaceae pollen allergens.

Effectiveness of high dose sublingual immunotherapy to induce a stepdown of seasonal asthma: a pilot study.

BACKGROUND: There is ample evidence to support the efficacy of sublingual immunotherapy (SLIT) on allergic rhinitis, while there is less solid data regarding asthma. We evaluated the effects of a high dose birch SLIT on birch-induced rhinitis and asthma in a controlled study. METHODS: This double-blind, placebo-controlled, randomised, single centre trial on SLIT with birch pollen allergen extract (Stallergenes, Antony, France) included 24 patients presenting severe rhinitis and slight to moderate asthma, 14 actively and 10 placebo treated. SLIT was performed by a pre-coseasonal protocol, and was repeated for 2 years. The study plan included a selection visit, a visit at the start of the first and the second treatment cycle, a follow-up visit after 1-3 months from the start of each cycle, and a final visit at the end of each yearly cycle. RESULTS: A significant decrease (p < 0.05) in rhinorrhoea and nasal obstruction occurred in actively treated patients. The median number of days with asthma at visit 3 was 10 (0-27) in the active (SLIT) group and 13 (0-29) in the placebo group. The median number of days with asthma at visit 6 was 2 (0-6) in the SLIT group and 7 (0-15) in the placebo group (p < 0.05 between groups). A stepdown of asthma occurred in 77% of actively treated vs. none of placebo treated patients (p = 0.05). No severe adverse events were observed. CONCLUSIONS: This pilot study suggests that SLIT with high dose birch extract may be able to step down seasonal pollen-induced asthma after prolonged treatment.