Normalization of C1 Inhibitor in a Patient with Hereditary Angioedema.

Hereditary angioedema is a potentially life-threatening autosomal dominant condition, causing attacks of angioedema due to failure to regulate bradykinin. Nearly all cases of hereditary angioedema are caused by mutations in the gene encoding C1 inhibitor, SERPING1. C1 inhibitor is a multifunctional protein produced in the liver that regulates the kallikrein-kinin system at multiple points. An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.

Recurrent abdominal pain as the only clinical manifestation of hereditary angioedema type II.

Recurrent abdominal pain is a common reason for consultation in Gastroenterology. The differential diagnosis includes hereditary angioedema (HAE), a rare disorder characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affects the skin, but also mucosal tissues of the gastrointestinal tract, triggered by diverse factors such as infections, trauma, surgery, drugs, or stress. It is a disease with a difficult diagnosis due to its heterogeneous and transitory clinical features, so having a clinical suspicion in the appropriate context would allow the administration of a specific treatment and avoid unnecessary examinations. We present the case of a 19-year-old male followed-up for recurrent abdominal pain that, after numerous microbiological, endoscopic, and radiological examinations, complement tests were requested, obtaining low levels of C4 with increased levels of C1 inhibitor and reduced functional activity, being diagnosed with HAE type II.

Consider Hereditary Angioedema in the Differential Diagnosis for Unexplained Recurring Abdominal Pain.

Health care providers are likely to encounter patients with recurrent unexplained abdominal pain. Because hereditary angioedema (HAE) is a rare disease, it may not be part of the differential diagnosis, especially for patients who do not have concurrent skin swelling in addition to abdominal symptoms. Abdominal pain is very common in patients with HAE, occurring in up to 93% of patients, with recurrent abdominal pain reported in up to 80% of patients. In 49% of HAE attacks with abdominal symptoms, isolated abdominal pain was the only symptom. Other abdominal symptoms that commonly present in patients with HAE include distension, cramping, nausea, vomiting, and diarrhea. The average time from onset of symptoms to diagnosis is 6 to 23 years. Under-recognition of HAE in patients presenting with predominant gastrointestinal symptoms is a key factor contributing to the delay in diagnosis, increasing the likelihood of unnecessary or exploratory surgeries or procedures and the potential risk of related complications. HAE should be considered in the differential diagnosis for patients with unexplained abdominal pain, nausea, vomiting, and/or diarrhea who have complete resolution of symptoms between episodes. As highly effective targeted therapies for HAE exist, recognition and diagnosis of HAE in patients presenting with isolated abdominal pain may significantly improve morbidity and mortality for these individuals.

Positive perception of COVID-19 vaccination in HAE: No significant impact of vaccination on disease course.

Background: There are some adverse effects with coronavirus disease 2019 (COVID-19) vaccines, but the impact of COVID-19 vaccination on attacks in hereditary angioedema (HAE) is not well defined. Objective: We aimed to investigate the influence of COVID-19 vaccination on the course of HAE. Method: The COVID-19 vaccination status was determined in 140 adult patients with HAE. The number and severity of attacks recorded from patients' diaries were evaluated at four different periods, comprising 1 month before the first dose, the period between the first and the second doses of COVID-19 vaccine in all the patients, the period between the second dose and the third doses in those who received three doses, and 1 month after the last vaccination dose. The disease and attack severities were assessed with the disease severity score (DSS) and 10-point visual analog scale, respectively. The patients were divided into two main groups as group 1 (those who had at least two doses of COVID-19 vaccines [n = 114]) and group 2 (those who had no vaccination [n = 26]). Only Sinovac and Biontech, which were only approved in Turkey. Results: The mean ± standard deviation DSS was significantly higher in the patients who experienced an attack after vaccination within 48 hours (6.61 ± 1.88 versus 4.14 ± 1.69; p < 0.001). Long-term prophylaxis was less common in the patients with an increased number of attacks (n = 5 (27.8%) versus n = 54 (56.3%); p = 0.027). The number of patients with less than a high school education was higher in group 2 (n = 23 [88.5%]) than in group 1 (n = 26 [3.1%]) (p < 0.001). The number of patients who had concerns about the triggering of a vaccine-induced HAE attack or about the possible vaccine adverse effects was higher in group 2 (n = 26 [100%]) than in group 1 (n = 74 [64.9%]). Conclusion: It seems that COVID-19 vaccination does not increase HAE attacks regardless of the type of the vaccines. We recommend that HAE activity should be under control before COVID-19 vaccination, and the patients should be well informed about the safety of the vaccines.

Prophylactic Treatment in Hereditary Angioedema Is Associated with Reduced Anxiety in Patients in Leipzig, Germany.

BACKGROUND: Hereditary angioedema (HAE) is associated with relevant disease-related burden. We aimed at investigating prevalence of depression and anxiety in patients with HAE in Leipzig, Germany. METHODS: Questionnaire-based evaluation of medical history, Angioedema Control Test (AECT), Angioedema Quality of Life Questionnaire (AE-QoL), Generalized Anxiety Disorder Scale-7 (GAD-7), and Hospital Anxiety and Depression Scale (HADS). RESULTS: Thirty-seven patients with HAE were included (31 females, mean age 49.6 ± 17.5 years). A mean diagnostic delay between first symptoms and correct diagnosis of 14.2 ± 14.5 years was detected. Patients aged <50 years (n = 18) had been diagnosed significantly earlier with HAE than older patients (p = <0.001). In 6 patients (16.2%), unnecessary medical interventions were performed and 14 patients (43.8%) reported at least 1 HAE-related death of a family member. Psychological stress was the most common triggering factor (96.2%). HADS scores revealed depression in 5/37 patients (13.5%) and anxiety in 16/37 (43.2%), GAD-7 score indicated anxiety in 9/36 (25%) participants. Patients receiving long-term prophylactic treatment (n = 17, 45.9%) showed significantly better disease control (AECT; p = <0.001) and quality of life (AE-QoL; p = <0.001) compared to those with on-demand treatment only. Patients with long-term prophylactic treatment showed significantly lower scores for anxiety and depression at GAD-7 (p = 0.011) and HADS (anxiety: p = 0.021; depression: p = 0.008). In 5 patients, treatment regime was changed as AECT score indicated insufficient disease control. Subsequently, we measured significant improvement of quality of life (AE-QoL, p = 0.04) and disease control (AECT; p = 0.032). CONCLUSION: Anxiety was a frequent burden in our study group and showed a significant association with low disease control. Our data indicate that prophylactic HAE treatment can improve psychosocial burden of HAE.

Recurrent and acute abdominal pain as the main clinical manifestation in patients with hereditary angioedema.

Background: Hereditary angioedema (HAE) is a rare disease that often leads to misdiagnosis. The delay of diagnosis is > 10 years in China. Recurrent and acute abdominal pain is one of the common symptoms of HAE. Because of the high misdiagnosis rate, it usually results in unnecessary surgical procedures. This study focused on the clinical symptoms and management of HAE-related abdominal attacks in Chinese patients to provide some new insight for the emergency department (ED) physicians and gastroenterologists. Methods: A Web-based survey was conducted among 107 patients with HAE from 94 unrelated families. Detailed questions with respect to the abdominal attacks were asked, including the frequency, symptoms, and duration before and after confirmed diagnosis. The demographic characteristics, diagnosis process, and treatment outcomes were also included. Results: Approximately 70% of the patients with HAE presented with abdominal symptoms during the onset of edema, mostly characterized by pain (94.8%), nausea (83.1%), vomiting (83.1%), diarrhea (59.7%), and constipation (23.4%). The patients were easily misdiagnosed as having gastroenteritis (35.1%) and appendicitis (10.4%), and 24.7% of them received unnecessary appendectomy or laparotomy. Danazol, a widely used drug for long-term prophylaxis of HAE in China, can reduce the attack frequency and alleviate the abdominal symptoms, but the adverse effects are also significant and more severe in women. Conclusions: Abdominal symptoms are common and important clinical features of HAE but are easily confused with other gastrointestinal diseases. ED physicians and gastroenterologists should consider HAE when patients experience recurrent and unexplained abdominal pain. Proper medical treatment should be administered in a timely manner if an HAE diagnosis is confirmed and efforts are required to increase access in China to medications both for on-demand treatment and long-term prophylaxis.

COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications.

Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

Effect of COVID-19 on hereditary angioedema activity and quality of life.

Background: The demonstration that severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) enters the cell via the angiotensin-converting enzyme 2 receptor has raised concerns that, in hereditary angioedema (HAE), a disease characterized by bradykinin-mediated angioedema attacks, coronavirus disease 2019 (COVID-19) may trigger angioedema attacks, increase the frequency and/or severity of attacks, or cause more severe symptoms of COVID-19. Objective: The objective was to evaluate the severity of COVID-19 in patients with HAE, the course of HAE attacks, angioedema activity, and the quality-of-life scores during COVID-19 pandemic. Methods: Patients diagnosed with HAE for at least 6 months were included in the study. The 7-day Angioedema Activity Score and the Angioedema Quality of Life (AE-QoL) Questionnaire were first completed at the onset of the pandemic between March 12 and June 1, 2020, then during SARS-CoV-2 infection, and in the third month after recovering from COVID-19. Results: Ten of 67 patients with HAE (14.9%) were diagnosed with COVID-19. The median (interquartile range) age of the 10 patients diagnosed with COVID-19 was 35.5 years (28.0-55.0 years). Six of the 10 patients (60%) were women. During COVID-19, five of the 10 patients (50%) had no angioedema attack. Two patients with severe HAE experienced a significant increase in angioedema activity during COVID-19 compared with their basal activity scores. The remaining three patients had a similar or lower attack frequency than their basal level. Four (40%) of the 10 patients had a relative increase in their attacks during the convalescence period. There was no statistically significant difference among pre-COVID-19, during COVID-19 and post-COVID-19 periods in function, mood, fear and/or shame, nutrition, and total scores of the AE-QoL Questionnaire although the fear dimension was relatively more affected (p = 0.06). Conclusion: Although the sample size was small, analysis of our data supported that the symptoms of COVID-19 were not more severe in HAE. Also, there was no significant difference in the AE-QoL Questionnaire scores, the frequency, and severity of angioedema attacks during the course of COVID-19 in the patients with HAE.

Recurrent angioedema in childhood: hereditary angioedema or histaminergic angioedema?

BACKGROUND: Recurrent angioedema is a rare entity during childhood. This study aimed to clarify differences between hereditary angioedema (HAE) and histaminergic angioedema (HA) in children. METHODS: Fifty-seven children with HAE (male 36.8%, 8.9 years [5.4-12.5]) and 42 children with recurrent HA (male 42.9%, 11.5 years [8.1-16.8]) were analyzed. RESULTS: The median age at symptom onset (6 [3-10]; 7.8 [4.5-13] years), frequency of angioedema episodes within last year (3 [2-5]; 5 [2-10]), and duration of symptoms (48 [24-48]; 24 [12-48] hours) were similar in the HAE and HA group, respectively. Recurrent urticaria was observed in 7.3% (n = 3) of patients in the HAE group and in 45.2% (n = 19) of the HA group (P < .001). While angioedema episodes involving the lips (n = 30; 71.4%; P = .035) and eyelids (n = 28; 66.7%; P = .012) were observed more frequently in the HA group, gastrointestinal involvement/abdominal pain (n = 15; 36.6%) was more common in HAE (P < .001). Itching as a prodromal symptom was detected in 47.6% (n = 20) of HA patients versus 14.6% (n = 6) of those with HAE (P = .002). In the logistic regression analysis for the diagnosis of HAE, a family history of angioedema (OR = 58.289 [95% CI 10.656-318.853], P < 001) and trauma (OR = 35.208 [95% CI [4.368-283.794]], P = .001) as a triggering factor were determined to be independent variables. CONCLUSION: A family history of angioedema, trauma as a triggering factor, and abdominal pain should suggest the diagnosis of HAE and the need for further investigation.

Unusual presentation of linear wrist blisters associated with hereditary angioedema: The first case report in Taiwan.

Hereditary angioedema (HAE) is an autosomal dominant disease characterized clinically by recurrent episodes of swelling in the tissues of the extremities, face, abdomen, and respiratory tract. It is most often caused by C1 esterase inhibitor (C1 INH) gene mutation. This swelling may lead to bradykinin release, resulting in recurrent, paroxysmal, painful angioedema. Blister formation is an uncommon cutaneous manifestation of HAE. Herein, we report a case of a patient with HAE who developed linear wrist blisters on her skin, with swelling, as a rare complication of HAE. She was treated with attenuated androgens (Danazol) for two weeks at our clinic, after which the blisters showed dramatic improvement. To date, only a few HAE cases have been reported across the world. Therefore, it is important to focus on and recognize the development of edema blisters as a flare of HAE, which could consequently avoid unnecessary dermatological diagnostic workup and treatment.

Hereditary C1 inhibitor deficiency associated with systemic lupus erythematosus.

Here, we report a family with two children (the elder son and younger daughter) diagnosed with juvenile-onset systemic lupus erythematosus (SLE) and the father diagnosed with hereditary angioedema. Serum C1 inhibitor (C1-INH) levels were low, and clinical exome next-generation sequencing detected a frameshift mutation in the SERPING-1 gene in all three patients. The mother had neither of the clinical phenotypes. The son had cutaneous symptoms, fever and polyarthralgia, along with lupus nephritis, and thus required rituximab therapy as well as mycophenolate mofetil and low-dose steroids to control disease activity. The daughter had a milder disease, with cutaneous manifestation, fever and polyarthralgia, and which was controlled with mycophenolate mofetil, hydroxychloroquine and low-dose steroids. Both children had never experienced angioedema. The father had a long history of self-limiting, non-life-threatening irregular episodes of subcutaneous angioedema and abdomen pain. He was not on any regular medication for these symptoms. We searched the literature for evidence of hereditary C1-INH deficiency associated with monogenic SLE or SLE-like-phenotype.

Ultrasound findings in an abdominal crisis of a patient with hereditary angioedema.

ereditary Angioedema (HAE) is a rare autosomal-dominant disease caused by serum C1 inhibitor deficiency. This deficiency leads to an up-regulation of complement, activating the bradykinin pathway and causing vascular permeability and subsequent mucosal edema. Abdominal angioedema is a less recognized type of angioedema and the clinical signs may range from subtle, diffuse abdominal pain and nausea, to overt peritonitis. We describe one case of abdominal angioedema in a patient with known HAE that were diagnosed by ultrasound.

Clinical Features of Hereditary Angioedema in Korean Patients: A Nationwide Multicenter Study.

BACKGROUND: Hereditary angioedema (HAE) is a genetically heterogeneous autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting edema increasing after puberty. It can be fatal due to laryngeal or gastrointestinal (GI) involvement with varied and changing frequency of mortality according to studies published from the Western countries. Epidemiological and clinical data of HAE in Asian countries are sparse. We sought to examine the clinical characteristics of HAE patients in Korea. METHODS: Patients diagnosed with HAE at 15 tertiary hospitals across the country until 2016 were retrospectively reviewed. RESULTS: A total of 65 patients diagnosed with HAE by 2016 were identified. The prevalence of HAE was estimated at 1.3/1,000,000 in Korea. Of the 65 patients, 21 (32.3%) were males. A total of 90.8% patients had type I HAE, while the remaining 9.2% patients had type II HAE. The first symptom developed after 20 years in 73.8% of patients, with a mean age 28.4 ± 14.1 years. The age at diagnosis was 36.5 ± 15.8 years, with a mean time delay of 7.8 ± 10.5 years. While the face (82.3%) and extremities (upper 71.0%, lower 62.9%) were the most frequently involved, the GI tract was affected in 40.5% of Korean HAE patients. Prophylaxis was maintained in 62.5% of patients. There was no reported case of death from HAE so far. CONCLUSIONS: The clinical manifestation and severity of HAE may vary according to ethnicity. HAE is more infrequent and GI involvement is less likely in Korea compared with Western countries.

Subcutaneous C1-esterase inhibitor to prevent hereditary angioedema attacks: Safety findings from the COMPACT trial.

BACKGROUND: The first subcutaneous (SC) C1-esterase inhibitor concentrate (C1-INH) was approved by the U.S. Food and Drug Administration in June 2017 as routine prophylaxis to prevent hereditary angioedema attacks in adolescents and adults at a dose of 60 IU/kg twice weekly based on the phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) trial. OBJECTIVE: This article aimed to evaluate the relationship of the C1-INH (SC) dose regimens tested in the COMPACT trial (40 IU/kg and 60 IU/kg twice weekly) and the occurrence of adverse events (AEs). METHODS: Patients were instructed to record any AEs in their e-diary daily. Safety and tolerability were assessed based on reported AEs, including injection-site reactions (ISRs); unsolicited AEs (AEs other than ISRs); serious AEs; thrombotic, thromboembolic, anaphylactic, hypersensitivity, sepsis, and bacteremia events; inhibitory antibodies to C1-INH; and clinically significant abnormalities in laboratory assessments. Information on ISRs was specifically solicited. RESULTS: No relationship between the dose of C1-INH (SC) and the incidence of ISRs or unsolicited AEs was observed. The proportion of injections followed by at least one ISR was 12% with C1-INH (SC) 40 IU/kg versus 5% with 60 IU/kg and 6% with placebo. No ISRs were serious or led to treatment discontinuation, and all resolved. There were no anaphylaxis, thromboembolic, sepsis, or bacteremia events reported during treatment with C1-INH (SC). All hypersensitivity AEs were nonserious, and the majority were assessed as being unrelated to treatment. No inhibitory antibodies to C1-INH were observed. CONCLUSION: C1-INH (SC) is safe and well tolerated with no dose-dependent safety concerns, as demonstrated in the COMPACT trial.Clinical trial NCT01912456, www.clinicaltrials.gov.

Evaluating satisfaction of patients with hereditary angioedema with their past and present treatments: Implications for future therapies.

BACKGROUND: Ever-expanding armamentarium of treatments for hereditary angioedema (HAE) are associated with various adverse effects, issues with vascular access, or lack of self-administration. OBJECTIVE: To understand patients' impressions and confidence in their past and present treatments, and identifying adverse events while also directly asking patients to reveal their hope for the future of HAE management and treatments. METHODS: After institutional review board approval, all subjects with laboratory-confirmed HAE were mailed a survey that they completed and returned to the researchers, and data were collected and entered into a secure online web application for surveys. Medication confidence data were summarized and expressed as means, medians, standard deviations, and quartiles by using a 5-point Likert scale. Analyses were performed by using statistical software. RESULTS: Of 150 surveys, 38 (25.3%) were completed. Among 36 subjects, 27 (75.0%) were female subjects, and the mean age was 50.1 years. Cinryze and Berinert (both C1-esterase inhibitors) had the highest median scores (5.0) for patient confidence, followed by ecallantide (4.5), icatibant (4.0), and androgens (2.0). For Cinryze, 64.3% selected it as the most effective and 57.1% tolerated it best. For Berinert, 50% of the subjects found it to be most effective and 59.1% tolerated it best. Some subjects listed androgens as most effective (33.3%) or best tolerated (16.7%), and many reported that this class caused the most adverse effects (44.4%). Among those who answered, 50% preferred a noninvasive method of administration, such as oral (24%), subcutaneous (18%), or not intravenous (8%) routes. CONCLUSION: Determining patient predilections and the reasoning behind them can be valuable for determining specific therapies to achieve each individual's personal goals.