Maria Bova

The human heart as a shock organ in anaphylaxis.

SummaryAnaphylaxis is a potentially fatal, immediate hypersensitivity reaction. Mast cells and basophils, by elaborating vasoactive mediators and cytokines, are the main primary effector cells of anaphylaxis. Mast cells have been identified in human heart between myocardial fibers, perivascularly, in the adventitia, and in the arterial intima. Mast cells isolated from human heart tissue (HHMC) of patients undergoing cardiac transplantation express high affinity immunglobulin E (IgE) receptors (FcεRI), C3a, C5a, and kit receptors (KIT). Anti-IgE, anti-FcεRI, and immunoglobulin superallergens induce in vitro secretion of preformed mediators (histamine, tryptase, chymase, and renin) and the de novo synthesis of cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) from HHMC. Complement is activated and anaphylatoxin forms during anaphylaxis. C5a and C3a cause the in vitro release of histamine and tryptase from HHMC. Therapeutic (general anesthetics, protamine, etc.) and diagnostic agents (radio contrast media, etc.), which can cause anaphylactoid reactions, activate HHMC in vitro. Low concentrations of histamine and cysteinyl leukotrienes given to subjects undergoing diagnostic catheterisation caused significant systemic and coronary hemodynamic effects. These data indicate that human heart mast cells and their mediators play a role in severe anaphylactic reactions.

Icatibant treatment for acquired C1‐inhibitor deficiency: a real‐world observational study

Icatibant, a bradykinin B2 receptor antagonist, is an established treatment for acute attacks of hereditary angioedema (HAE) with C1‐inhibitor (C1‐INH) deficiency. We describe our experience with icatibant in eight patients with angioedema because of acquired C1‐INH deficiency (AAE). Forty‐eight moderate‐to‐severe attacks were treated with subcutaneous icatibant 30 mg; two moderate attacks resolved without treatment. The median (range) duration of treated attacks (onset to complete resolution) was 9.33 (1.67–39.00) h; durations of the untreated attacks were 72 and 96 h. Symptom improvement following icatibant treatment occurred in 0.5 (0.25–2.10) h and complete resolution in 6.75 (0.50–30.75) h. A single icatibant injection achieved complete symptom resolution in 47 attacks; one facial attack required a second injection. One peripheral attack responded less quickly than other treated attacks. Five patients reported transient injection site reactions. Icatibant appeared to provide effective symptom relief and was generally well tolerated.

Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema

Background: Hereditary angioedema (HAE) is a rare genetic disease usually caused by mutation in the C1 inhibitor or the coagulation Factor XII gene. However, in a series of patients with HAE, no causative variants have been described, and the pathophysiology of the disease remains unknown (hereditary angioedema with yet unknown genetic defect [U‐HAE]). Identification of causative genes in patients with U‐HAE is valuable for understanding the cause of the disease. Objective: We conducted genetic studies in Italian patients with U‐HAE to identify novel causative genes. Methods: Among patients belonging to 10 independent families and unrelated index patients with U‐HAE recruited from the Italian Network for C1‐INH‐HAE (ITACA), we selected a large multiplex family with U‐HAE and performed whole‐exome sequencing. The angiopoietin‐1 gene (ANGPT1) was investigated in all patients with familial or sporadic U‐HAE. The effect of ANGPT1 variants was investigated by using in silico prediction and plasma and transfected cells from both patients and control subjects. Results: We identified a missense mutation (ANGPT1, c.807G>T, p.A119S) in a family with U‐HAE. The ANGPT1 p.A119S variant was detected in all members of the index family with U‐HAE but not in asymptomatic family members or an additional 20 patients with familial U‐HAE, 22 patients with sporadic U‐HAE, and 200 control subjects. Protein analysis of the plasma of patients revealed a reduction of multimeric forms and a reduced ability to bind the natural receptor tunica interna endothelial cell kinase 2 of the ANGPT1 p.A119S variant. The recombinant mutated ANGPT1 p.A119S formed a reduced amount of multimers and showed reduced binding capability to its receptor. Conclusion: ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE.

Mutational Spectrum of the C1 Inhibitor Gene in a Cohort of Italian Patients with Hereditary Angioedema: Description of Nine Novel Mutations

Hereditary angioedema (HAE) is an autosomal dominant disease due to mutations in the C1 inhibitor gene (C1NH) that affects protein synthesis (HAE type I) or function (HAE type II). In 45 subjects affected by HAE diagnosed through clinical features and C1 inhibitor deficiency from the south of Italy (38 with type I and 7 with type II HAE), the whole C1NH coding region was screened for mutations by direct DNA sequencing. A severity score based on clinical manifestation, age at disease onset, and need for long‐term prophylaxis was used to investigate possible genotype‐phenotype correlations. A series of 22 different mutations was identified: nine missense (40.9%), five nonsense (22.7%), six frameshift (27.3), one small deletion (4.5%), and one splicing defect (4.5%). Nine C1NH mutations have not been previously described. No correlation was found between C1 inhibitor function level and severity score or age at first attack. Moreover, there was no correlation between different types of mutations and clinical phenotype. The number of different mutations identified highlights the heterogeneity of C1 inhibitor deficiency and supports the hypothesis that HAE clinical phenotype is not strictly related to the type of mutation but rather depends on unknown factors.

Home Therapy with Plasma-Derived C1 Inhibitor: A Strategy to Improve Clinical Outcomes and Costs in Hereditary Angioedema

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.

Elevated plasma levels of vascular permeability factors in C1 inhibitor‐deficient hereditary angioedema

Hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) is a rare inherited genetic disease characterized by recurrent swelling episodes of the skin, gastrointestinal tract, and upper airways. Angioedema attacks result from increased vascular permeability due to the release of bradykinin from high molecular weight kininogen. Currently, there are no biomarkers predicting the frequency of angioedema attacks. Vascular permeability is modulated by several factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (Angs). As increased circulating levels of VEGFs and Angs have been observed in diseases associated with higher vascular permeability (e.g., systemic capillary leak syndrome and sepsis), we sought to analyze plasma concentrations of VEGFs and Angs in patients with C1‐INH‐HAE.

Hereditary angiooedema and psychological stress: an exploratory study.

Hereditary Angiooedema (HAE) is characterized by a deficit or by a malfunctioning of C1- 1nh; its symptoms vary greatly from one individual to another. Some studies suggest that some of the attacks of HAE may be triggered or affected by stress and emotional states (Zotter et al., 2014), however this link has never been examined in depth. Moreover, recent research has highlighted the influence of the neurological correlatives of stress in the activation of the compliment cascade, a system already compromised in those suffering from HAE [1][2].

Emotional processes and stress in children affected by hereditary angioedema with C1-inhibitor deficiency: a multicenter, prospective study

BackgroundHereditary 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).ResultsMean 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.ConclusionsAlexithymia 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.

Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes

Recurrent angioedema (AE) without wheals is increasingly recognized as a clinical entity and a frequent cause of admission to the emergency room. The Hereditary Angioedema Working Group (HAWK) classification allowed the scientific community to go beyond the semantic confusion that dominated this topic for decades. This classification distinguishes hereditary and acquired forms of AE, either related or unrelated to C1 inhibitor deficiency. Recently, additional mechanisms have been involved in the AE pathogenesis, including the uncontrolled activation of factor XII, generation of vasoactive mediators that induce dysregulation of endothelial functions, and bidirectional interactions between mast cell-derived mediators and the plasma contact system. Thus, recurrent AE can be determined by multiple and concurrent mechanisms that may generate distinct clinical phenotypes of the disease. Frequency, severity, and the location of attacks are quite different from patient to patient and, even in the same patient, they may change throughout the course of life. The severity of the clinical phenotype strongly influences the burden of the disease and patients’ quality of life. Despite major advances in our understanding of recurrent AE, many unsolved questions remain, leaving several unmet needs for patients and caregivers. This review is focused on a description of different AE phenotypes and the concurrent mechanisms leading to their pathogenesis. A better definition of cellular and molecular pathways responsible for the distinct AE phenotypes may help to improve diagnosis and may lead to a personalized approach to prophylaxis and treatment of the disease.

Secreted Phospholipases A2 in Hereditary Angioedema With C1-Inhibitor Deficiency

Background Hereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s). Objective We sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE. Methods sPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay. Results Plasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro. Conclusion sPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets.