Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE type I) or dysfunction (C1-INH-HAE type II) is a rare disease characterized by recurrent episodes of edema with an estimated frequency of 1:50,000 in the global population without racial or gender differences. In this study we present the results of a nationwide survey of C1-INH-HAE patients referring to 17 Italian centers, the Italian network for C1-INH-HAE, ITACA. Italian patients diagnosed with C1-INH-HAE from 1973 to 2013 were included in the study. Diagnosis of C1-INH-HAE was based on family and/or personal history of recurrent angioedema without urticaria and on antigenic and/or functional C1-INH deficiency. 983 patients (53% female) from 376 unrelated families were included in this survey. Since 1973, 63 (6%) patients diagnosed with C1-INH-HAE died and data from 3 patients were missing when analysis was performed. Accordingly, the minimum prevalence of HAE in Italy in 2013 is 920:59,394,000 inhabitants, equivalent to 1:64,935. Compared to the general population, patients are less represented in the early and late decades of life: men start reducing after the 5th decade and women after the 6th. Median age of patients is 45 (IQ 28-57), median age at diagnosis is 26 years (IQ 13-41). C1-INH-HAE type 1 are 87%, with median age at diagnosis of 25 (13-40); type 2 are 13% with median age at diagnosis of 31 (IQ 16-49). Functional C1INH is ≤50% in 99% of patients. Antigen C1INH is ≤50% in 99% of type 1. C4 is ≤50% in 96% of patients. The chance of having C1-INH-HAE with C4 plasma levels >50% is < 0.05. This nationwide survey of C1-INH-HAE provides for Italy a prevalence of 1:64,935. C1-INH-HAE patients listed in our database have a shorter life expectancy than the general population. An increased awareness of the disease is needed to reduce this discrepancy. Measurement of C4 antigen can exclude diagnosis of C1-INH-HAE with an accuracy > 95%. This parameter should be therefore considered for initial screening in differential diagnosis of angioedema.

Background:Hereditary angioedema (HAE) is caused by mutations in the C1 inhibitor (C1-INH) gene Serpin Family G Member 1(SERPING1), which results in either the decreased synthesis of normal C1-INH (C1-INH‐HAE type I) or expression of unfunctional C1-INH (C1-INH‐HAE type II). In recent studies, emotional stress was reported by patients as the most common trigger factor for C1-INH‐HAE attacks. Moreover, patients reported considerable distress over the significant variability and uncertainty with which the disease manifests, in addition to the impact of physical symptoms on their overall quality of life.Objective:We did a systematic review of the literature to shed light on the advancements made in the study of how stress and psychological processes impact C1-INH‐HAE.Methods:All of the articles on C1-INH‐HAE were analyzed up to December 2019. Both medical data bases and psychological data bases were examined. The keywords (KWs) used for searching the medical and psychological data bases were the following: “hereditary angioedema,” “psychology,” “stress,” “anxiety,” and “depression.”Results:Of a total of 2549 articles on C1-INH‐HAE, 113 articles were retrieved from the literature search by using the related KWs. Twenty-one of these articles were retrieved, examined, and classified.Conclusion:Although the literature confirmed that stress may induce various physical diseases, it also warned against making simplistic statements about its incidence that did not take into account the complexity and multicausality of factors that contribute to C1-INH‐HAE expression.

Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent edema of unpredictable frequency and severity. Stress, anxiety, and low mood are among the triggering factors most frequently reported. Impaired regulation and processing of emotions, also known as alexithymia, may influence outcomes. The aim of this study was to confirm the presence of alexithymia and stress in children with C1-INH-HAE, to determine whether they are also present in children affected by other chronic diseases, and to investigate their relationship with C1-INH-HAE severity. Data from children with C1-INH-HAE (n = 28) from four reference centers in Italy were compared with data from children with type 1 diabetes (T1D; n = 23) and rheumatoid arthritis (RA; n = 25). Alexithymia was assessed using the Alexithymia Questionnaire for Children scale; perceived stress was assessed using the Coddington Life Event Scale for Children (CLES-C). Mean age (standard deviation [SD]) in the C1-INH-HAE, T1D, and RA groups was 11.8 (3.3), 11.7 (2.9), and 11.1 (2.6) years, respectively. Mean C1-INH-HAE severity score was 5.9 (2.1), indicating moderate disease. Alexithymia scores were similar among disease groups and suggestive of difficulties in identifying and describing emotions; CLES-C scores tended to be worse in C1-INH-HAE children. C1-INH-HAE severity was found to correlate significantly and positively with alexithymia (p = 0.046), but not with perceived stress. Alexithymia correlated positively with perceived stress. Alexithymia is common in children with chronic diseases. In C1-INH-HAE, it may result in increased perceived stress and act as a trigger of edema attacks. Comprehensive management of C1-INH-HAE children should consider psychological factors.

Background: Attacks of hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) are commonly treated in the emergency department. Self-administration is emerging as an effective treatment option. In this study, we assessed the impact of home therapy with plasma-derived C1 esterase inhibitor (pdC1-INH) concentrate on treatment outcomes and costs. Methods: This is an observational study in C1-INH-HAE patients who switched to home therapy with pdC1-INH (Berinert®) after learning intravenous self-infusion in a training course at a center in Southern Italy. Before starting home therapy and after the first year of home therapy, patients were interviewed about their treatment and outcomes during the prior 12 months. Annual costs were analyzed by cost minimization from the Italian health care payer perspective and the societal perspective. Outcomes and costs before and after the switch to home therapy were compared. Results: The training course was attended by 36 participants, 17 (47.2%) of whom decided to switch to home therapy. This therapy was associated with a significant decrease in the mean annual number of hospitalizations (16.8 vs. 2.1, p = 0.003) and missed work/school days (20.3 vs. 7.1, p = 0.037) compared to conventional treatment. The times from symptom onset to treatment administration and from treatment administration to symptom improvement/resolution were not significantly different between the two strategies. The mean annual per-patient costs decreased with home therapy from EUR 30,010.57 to EUR 26,621.16 (11.3% saving) and from EUR 29,309.34 to EUR 26,522.04 (9.5% saving) from the societal and payer perspective, respectively. Conclusions: Home therapy with pdC1-INH is a feasible strategy for the management of C1-INH-HAE and may result in cost savings.