Comorbidities in Angioedema Due to C1-Inhibitor Deficiency: An Italian Survey.

BACKGROUND: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is characterized by unpredictable recurrent episodes of swelling affecting the skin and the mucosa tissues, including gastrointestinal tract and/or oropharyngeal-laryngeal mucosae. Long-term prophylaxis (LTP) is used to prevent attacks. OBJECTIVE: Because C1-INH plays a pivotal role in several biological pathways, we investigated the possible association of comorbidities with C1-INH deficiency and the use of LTP with attenuated androgens (AA) or tranexamic acid (TXA). METHODS: This retrospective cohort study involved adult patients with HAE referred to Milan and Padua angioedema centers in the period 1979-2021. A qualitative comparison was performed to analyze comorbidities versus general population. The incidence of comorbidities was evaluated during LTP with AA or TXA versus patients without LTP. RESULTS: A total of 446 patients were studied. A greater prevalence among patients was found for heart diseases (9.6% vs 4.8%), acute myocardial infarction (5.6% vs 1.4%), hepatitis C virus infection (10.5% vs 2.5%), and appendectomy (15.9% vs 4.3%). In patients taking AA, a greater incidence was found for hypertension (22.8% vs 10.8%; odds ratio [OR]: 2.02), hypercholesterolemia (19.5% vs 5.3%; OR: 3.97), diabetes mellitus (5% vs 1.4%; OR: 3.21), hepatic angioma (4.4% vs 0.7%; OR: 8.35), and focal nodular hyperplasia (2.5% vs 0.4%; OR: 6.9). No association between TXA and comorbidities was found. CONCLUSION: In this large patient population with a rare disease followed for up to a 43-year period, we found a greater prevalence of comorbidities hitherto unreported in the literature and an association between comorbidities and LTP with AA.

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.

Lung Ultrasound Patterns and Clinical-Laboratory Correlates during COVID-19 Pneumonia: A Retrospective Study from North East Italy.

BACKGROUND AND AIM: Lung ultrasound (LUS) is a convenient imaging modality in the setting of coronavirus disease-19 (COVID-19) because it is easily available, can be performed bedside and repeated over time. We herein examined LUS patterns in relation to disease severity and disease stage among patients with COVID-19 pneumonia. METHODS: We performed a retrospective case series analysis of patients with confirmed SARS-CoV-2 infection who were admitted to the hospital because of pneumonia. We recorded history, clinical parameters and medications. LUS was performed and scored in a standardized fashion by experienced operators, with evaluation of up to 12 lung fields, reporting especially on B-lines and consolidations. RESULTS: We included 96 patients, 58.3% men, with a mean age of 65.9 years. Patients with a high-risk quick COVID-19 severity index (qCSI) were older and had worse outcomes, especially for the need for high-flow oxygen. B-lines and consolidations were located mainly in the lower posterior lung fields. LUS patterns for B-lines and consolidations were significantly worse in all lung fields among patients with high versus low qCSI. B-lines and consolidations were worse in the intermediate disease stage, from day 7 to 13 after onset of symptoms. While consolidations correlated more with inflammatory biomarkers, B-lines correlated more with end-organ damage, including extrapulmonary involvement. CONCLUSIONS: LUS patterns provide a comprehensive evaluation of patients with COVID-19 pneumonia that correlated with severity and dynamically reflect disease stage. LUS patterns may reflect different pathophysiological processes related to inflammation or tissue damage; consolidations may represent a more specific sign of localized disease, whereas B-lines seem to be also dependent upon generalized illness due to SARS-CoV-2 infection.

Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature.

BACKGROUND: Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data. METHODS: A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG. RESULTS: Thirty-nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson-Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4 years. Histological evaluation was performed in 34/39 patients (87.2%); non-caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti-TNF-α and anti-IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response. CONCLUSIONS: OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long-term management.

Psychological processes in the experience of hereditary angioedema in adult patients: an observational study.

BACKGROUND: Hereditary angioedema associated to C1 inhibitor deficiency (C1-INH-HAE) is a pathological condition characterized by episodes of subcutaneous swelling and it is frequently associated with discomfort and social impairment of the patients, due to the anxiety experienced for an unpreventable manifestation of an attack during daily life. In children increased level of stress and alexithymia have been associated to C1-INH-HAE, and the latter correlated also with the severity of the disease. We hypothesized that the involvement of psychological issues may impact on the severity of C1-INH-HAE in adult patients as well, interfering with their ability to engage with the management of the disease. METHODS: 28 adult patients with C1-INH-HAE were evaluated for clinical (C1-INH-HAE Severity Score) and psychological factors (alexithymia, emotion regulation, stress, patient health engagement, general severity index) by means of validated questionnaires. RESULTS: Mean age (standard deviation [SD]) was 45 (11) years and time from diagnosis was 20 (12) years. The mean C1-INH-HAE severity score was 6.4. Alexithymia was absent in 22 (78%) patients. Moderate and high stress levels were present in 17 (61%) and 4 (14%) patients, respectively. Moderate-high discomfort was experienced by 9 (36%) patients and a discomfort beyond the clinical attention threshold was shown by 3 (12%) patients. Stress correlated with patient health engagement and with psychological discomfort. CONCLUSIONS: In C1-INH-HAE, patients health engagement and moderate-high psychological discomfort are linked with stress but not with the severity of the disease or alexithymia. A better patient health engagement may be a target for psychological intervention in clinics to ameliorate the stress perceived by C1-INH-HAE patients.

The experience of living with a chronic disease in pediatrics from the mothers' narratives: The Clinical Interview on Parental Sense of Grip on the Disease.

The Clinical Interview on the Sense of Grip on Chronic Disease has been administered to 68 mothers of children affected by Hereditary Angioedema (C1-Inh HAE), Type 1 Diabetes (T1D), Juvenile Rheumatoid Arthritis (JRA). The objectives are to detect general features of the experience of parenting children with chronic illness as well as the specificities of this experience related to the different conditions. Four Profiles of Sense of Grip were identified: Adempitive, Controlling, Reactive, Dynamic. The Sense of Grip Interview is an effective clinical tool for understanding the characteristics of the disease in daily life, which can help clinicians to encourage family adjustment to disease.

The central role of endothelium in hereditary angioedema due to C1 inhibitor deficiency.

An impairment of the endothelial barrier function underlies a wide spectrum of pathological conditions. Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) can be considered the "pathophysiological and clinical paradigm" of Paroxysmal Permeability Diseases (PPDs), conditions characterized by recurrent transient primitively functional alteration of the endothelial sieving properties, not due to inflammatory-ischemic-degenerative injury and completely reversible after the acute flare. It is a rare yet probably still underdiagnosed disease which presents with localized, non-pitting swelling of the skin and submucosal tissues of the upper respiratory and gastrointestinal tracts, without significant wheals or pruritus. The present review addresses the pathophysiology of C1-INH-HAE with a focus on the crucial role of the endothelium during contact and kallikrein/kinin system (CAS and KKS) activation, currently available and emerging biomarkers, methods applied to get new insights into the mechanisms underlying the disease (2D, 3D and in vivo systems), new promising investigation techniques (autonomic nervous system analysis, capillaroscopy, flow-mediated dilation method, non-invasive finger plethysmography). Hints are given to the binding of C1-INH to endothelial cells. Finally, crucial issues as the local vs systemic nature of CAS/KKS activation, the episodic nature of attacks vs constant C1-INH deficiency, pros and cons as well as future perspectives of available methodologies are briefly discussed.

Pediatric angioedema: Essential features and preliminary results from the Hereditary Angioedema Global Registry in Italy.

Isolated angioedema, which is a localized, non-pitting, and transient swelling of the subcutaneous or submucosal tissue not associated with pruritus, urticaria, or anaphylaxis, may be classified, based on genetic pattern and mediators, respectively, as acquired or hereditary and histamine- or non-histamine-induced. The pediatric population with C1-INH-HAE (Hereditary angioedema due to C1-inhibitor deficiency) is mostly symptomatic. The frequency of symptoms in such a population compared to adults seems to be lower, but we need more prospective data to conclude on this point. The HGR (Hereditary angioedema global registry), which collects symptoms in real time, will probably provide such information. In terms of treatments, pediatric patients are significantly disadvantaged due to the few studies aimed at registering treatment for this population.

Lanadelumab for the prevention of attacks in hereditary angioedema.

Introduction: Hereditary angioedema (HAE) with C1 esterase inhibitor deficiency (C1-INH-HAE) is a rare disease that manifests with cutaneous and/or submucosal swellings due to uncontrolled activation of the contact/kinin system. Attacks recur with unpredictable frequency and severity, laryngeal edema is potentially lethal, and the disease burden may severely disrupt patients' lives.Areas covered: This review provides an overview of lanadelumab, a human monoclonal antibody targeted against plasma kallikrein that was recently approved for prevention of symptoms in C1-INH-HAE.Expert opinion: The phase III HELP Study demonstrated the efficacy of lanadelumab in reducing HAE attacks. These positive results are being further confirmed in the open-label extension study. This agent addresses some of the limitations of existing prophylactic options as tolerability issues, the need for intravenous administration and frequent dosing. Therefore, lanadelumab can profoundly improve the quality of life of patients with C1-INH-HAE.

Lanadelumab Injection Treatment For The Prevention Of Hereditary Angioedema (HAE): Design, Development And Place In Therapy.

Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.

Melkersson-Rosenthal syndrome: a case report of a rare disease with overlapping features.

BACKGROUND: Melkersson-Rosenthal syndrome (MRS) is a rare, neuro-mucocutaneous disease which presents as orofacial swelling, facial palsy and fissured tongue. These symptoms may occur simultaneously or, more frequently, with a oligosymptomatic or monosymptomatic pattern. Swelling, that is the most common initial finding, may mimic hereditary or acquired angioedema, a disorder caused by histamine or bradykinin-mediated plasma-leakage affecting subcutaneous and/or submucosal tissue. The differential diagnosis of MRS includes also chronic inflammatory and infective diseases characterized by granulomatous infiltration, as well as rosacea, contact dermatitis, allergic reactions and Bell's palsy. CASE PRESENTATION: A 71-year old, non-allergic female patient with no familial and personal history of angioedema presented, a few days after a possible herpes simplex or varicella-zoster virus infection, with monolateral facial paraesthesia and lower lip edema. After temporary remission of symptoms on oral steroids and antihistamines, she showed swelling recurrence refractory to valaciclovir therapy and a subsequent course of antihistamines. The clinical picture and a previous history of non-Hodgkin lymphoma prompted us to rule out an acquired form of paraneoplastic, C1-inhibitor (C1-INH) deficiency: C1q and both antigen and functional C1-INH tested normal, whilst we found low plasma levels of C3 and C4 possibly related to the parallel detection of antiphospholipid antibodies. Thus, we hypothesized a non-histaminergic, idiopathic form of angioedema and planned further therapy with tranexamic acid and the leukotriene receptor antagonist montelukast. Treatment failure with both drugs finally suggested a Melkersson-Rosenthal syndrome, which was confirmed by histologic findings of non caseating granulomas on lip biopsy. CONCLUSION: Melkersson-Rosenthal syndrome may occur with rather non-specific symptoms and overlap with alternative conditions, including recurrent angioedema. No specific biomarkers for MRS exist and clinical diagnosis is often of exclusion. The finding of complement or immune alterations, as in our patient, may be further confounding and justify the need for skin or mucosal biopsy to establish a correct diagnosis and prescribe targeted therapy.

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

BACKGROUND: 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). RESULTS: 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. CONCLUSIONS: 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.

Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions.

BACKGROUND: Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell-derived mediators into the circulation. OBJECTIVES AND METHODS: We report here that a plasma protease cascade, the factor XII-driven contact system, critically contributes to the pathogenesis of anaphylaxis in both murine models and human subjects. RESULTS: Deficiency in or pharmacologic inhibition of factor XII, plasma kallikrein, high-molecular-weight kininogen, or the bradykinin B2 receptor, but not the B1 receptor, largely attenuated allergen/IgE-mediated mast cell hyperresponsiveness in mice. Reconstitutions of factor XII null mice with human factor XII restored susceptibility for allergen/IgE-mediated hypotension. Activated mast cells systemically released heparin, which provided a negatively charged surface for factor XII autoactivation. Activated factor XII generates plasma kallikrein, which proteolyzes kininogen, leading to the liberation of bradykinin. We evaluated the contact system in patients with anaphylaxis. In all 10 plasma samples immunoblotting revealed activation of factor XII, plasma kallikrein, and kininogen during the acute phase of anaphylaxis but not at basal conditions or in healthy control subjects. The severity of anaphylaxis was associated with mast cell degranulation, increased plasma heparin levels, the intensity of contact system activation, and bradykinin formation. CONCLUSIONS: In summary, the data collectively show a role of the contact system in patients with anaphylaxis and support the hypothesis that targeting bradykinin generation and signaling provides a novel and alternative treatment strategy for anaphylactic attacks.