Hereditary angioedema prevalence and satisfaction with prophylaxis in South Australia.

Background: Hereditary angioedema (HAE) due to deficiency of C1 Inhibitor (C1INH-HAE) is a rare, unpredictable and potentially fatal genetic disorder. There are relatively few systematic population prevalence studies, with reports from various countries of between 1 in 20,000 and 1 in 150,000. and no Australian data. The therapeutic landscape for HAE has changed dramatically in recent years with a focus on highly effective prophylaxis, with the aim of total suppression of angioedema and achievement of a normal life. Objectives: Epidemiological survey of HAE in South Australia, with description of patient characteristics, quality of life and treatment, with a focus on prophylaxis. Methods: Case ascertainment was conducted over 18 months from January 2021 to July 2022, using a range of approaches with the aim of identifying all people with C1INH-HAE in South Australia. Questionnaires were administered to consenting patients utilising established HAE-specific and general survey instruments. Results: We identified 35 people with HAE in South Australia, yielding a population prevalence of 1 in 52,400, in line with average established international prevalence. HAE was identified in 4 patients of Indigenous Australian heritage. Seventeen of 31 adult patients completed an additional multi-questionnaire survey, revealing overall satisfactory disease control. Most common prophylactic therapies were danazol, lanadelumab, and subcutaneous C1 inhibitor. Many patients (mostly male) with milder disease had responded well to low-dose danazol with good tolerance and have continued to use it, whereas patients with higher disease burden are now using newer therapies, and overall satisfaction with current prophylaxis is high. Conclusions: Prevalence of HAE in South Australia aligns with international reports. Our population survey indicates that current long-term prophylaxis therapies including danazol, lanadelumab and C1-inhibitor, applied to appropriate patients taking into account disease activity and drug risks and tolerance, are effective for HAE attack prevention and produce high levels of satisfaction.

Berotralstat for long-term prophylaxis of hereditary angioedema in Japan: Parts 2 and 3 of the randomized APeX-J Phase III trial.

Background: Berotralstat is a once-daily oral inhibitor of plasma kallikrein for the prophylaxis of hereditary angioedema (HAE) in patients ≥12 years. APeX-J aimed to evaluate the efficacy and safety of berotralstat in Japan. Methods: APeX-J was a Phase III trial comprising 3 parts (NCT03873116). Part 1 was a randomized, placebo-controlled evaluation of berotralstat 150 or 110 mg over 24 weeks. Part 2 was a 28-week dose-blinded phase in which berotralstat-treated patients continued the same dose and placebo patients were re-randomized to berotralstat 150 or 110 mg. In Part 3, all patients remaining on study received berotralstat 150 mg in an open-label manner for up to an additional 52 weeks. The primary endpoint of Parts 2 and 3 was long-term safety and tolerability, and secondary endpoints examined effectiveness. Results: Seventeen patients entered Part 2, and 11 continued into Part 3. Treatment-emergent adverse events (TEAEs) were reported by 14/17 patients (82.4%) in Parts 2 or 3; the most common were nasopharyngitis, abdominal pain, cystitis, influenza, and vertigo. One patient (5.9%) experienced a drug-related TEAE (Grade 4 increased hepatic enzyme). No drug-related serious TEAEs were reported. For patients who completed 26 months of treatment with berotralstat 150 mg (n = 5), mean (standard error of the mean) monthly HAE attack rates and on-demand medication use decreased from baseline by 1.15 (0.09) attacks/month and 2.8 (0.64) doses/month, respectively. Sustained improvements were also observed in patient quality of life and treatment satisfaction. Conclusions: Long-term prophylaxis with berotralstat raised no new safety signals and was effective at reducing attacks and improving patient-reported outcomes. Trial registration: ClinicalTrials.gov NCT03873116. Registered March 13, 2019. Retrospectively registered.

Complex analysis of the national Hereditary angioedema cohort in Slovakia - Identification of 12 novel variants in SERPING1 gene.

Background: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability. Objective: Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene. Methods: In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1-INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements. Results: The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1-INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1-INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported. Conclusion: The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1-INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1-INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1-INH level.

Assessment of HAE prophylaxis transition from androgen therapy to berotralstat: A subset analysis of the APeX-S trial.

Background: Given the recent approval of oral berotralstat in several countries for hereditary angioedema (HAE) prophylaxis, transition from long-term androgens to berotralstat may occur in clinical practice. The open-label, Phase II APeX-S trial provided an opportunity to assess the safety and effectiveness of berotralstat in patients previously treated with differing durations of androgens and shorter transition periods. Therefore, we examined the safety, effectiveness, and impact on quality of life of berotralstat after prior androgen use in patients from the APeX-S trial. Alanine aminotransferase (ALT) elevations were also examined because of the association with androgen exposure and hepatic function impairment. Methods: We conducted an analysis of a subset of 39 patients from the APeX-S trial aged ≥12 years with HAE due to C1 inhibitor deficiency (HAE-C1-INH) with prior androgen use who discontinued androgen therapy within <60 days of receiving berotralstat. Patients received daily berotralstat (150 mg) and were divided into subgroups for this analysis based on time between androgen discontinuation and berotralstat commencement (<14 days versus 14 to <60 days). Results: Berotralstat was generally well tolerated, with nasopharyngitis (21%), upper respiratory tract infection (15%), nausea (15%), diarrhea (15%), and abdominal pain (10%) being the most common adverse events occurring in ≥10% of the total subset. Only 7/145 (5%) of all APeX-S study patients with a prior history of androgen therapy experienced ALT elevations, 6 of which were grade 3 or 4 toxicities. All 7 patients recovered without sequelae and belonged to the subgroup of patients who transitioned <14 days after discontinuing androgens (n = 18). A reduction in monthly attack rate versus Month 1 was observed over 12 months for all patients who transitioned from prior androgen therapy to berotralstat prophylaxis in under 60 days, irrespective of duration of prior androgen therapy or timing of transition (N = 39). Similarly, meaningful patient-reported improvements from both Angioedema Quality of Life Questionnaire and Treatment Satisfaction Questionnaire for Medication scores were achieved, with a sustained benefit shown over the berotralstat treatment period. Conclusions: Berotralstat treatment led to sustained HAE symptom control irrespective of duration of prior androgen therapy or timing of transition. Most patients safely transitioned from long-term androgens to berotralstat. Although occurring in a small group of patients, liver-related adverse events following berotralstat treatment may be associated with a shorter androgen washout period, but further research is required to confirm this. Clinical trial registration: NCT03472040. Retrospectively registered March 21, 2018.

Recombinant Human C1 Esterase Inhibitor for the Management of Adverse Events Related to Intravenous Immunoglobulin Infusion in Patients With Common Variable Immunodeficiency or Polyneuropathy: A Pilot Open-Label Study.

It has been hypothesized that low levels of C1 esterase inhibitor (C1-INH), a key inhibitor of the complement pathway, may play a role in the occurrence of adverse events (AEs) associated with intravenous immunoglobulin (IVIG) therapy. This open-label pilot study evaluated C1-INH replacement, with recombinant human C1-INH (rhC1-INH), as a potential therapy for adults requiring IVIG and experiencing AEs. Patients received two rounds of IVIG infusion [pre-treatment phase (no rhC1-INH), 4-8 weeks] and then three rounds of one dose of intravenous rhC1-INH 50 U/kg (maximum, 4,200 U) with subsequent IVIG infusion (treatment phase, 6-12 weeks). Nineteen adults completed the study; all had an autoimmune condition linked to common variable immunodeficiency (CVID) or polyneuropathy, and 57.9% had low baseline C1-INH levels. Mean ± SD total scores improved significantly with the Headache Impact Test (from 62.8 ± 6.2 at pre-treatment to 57.7 ± 9.1 after treatment; mean Δ, -5.0; p = 0.02) and Modified Fatigue Impact Scale (from 59.3 ± 13.1 to 51.2 ± 15.4; mean Δ, -8.1; p = 0.006). Significant improvements in the Migraine Disability Assessment were observed for three of five items (p ≤ 0.002). Mean ± SD C1-INH level increased from 26.8 ± 5.9 mg/dl after the second round of IVIG (pre-treatment) to 32.1 ± 7.8 mg/dl after the third rhC1-INH treatment; functional C1-INH levels increased from 115.8 ± 34.7% to 158.3 ± 46.8%. Future research is warranted to explore the benefit of C1-INH therapy for reduction of IVIG-related AEs, as well as the role of C1-INH in patients with CVID and autoimmune disease. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03576469.

Hospitalizations due to Angioedema without Urticaria in a Portuguese Center: Five Year Retrospective Study.

INTRODUCTION: Hospitalizations due to angioedema are important especially in debilitating or life-threatening situations. The aim of this study was to evaluate the frequency and etiology of angioedema without urticaria in hospital admissions. MATERIAL AND METHODS: The admissions between 2009 and 2013 in Centro Hospitalar Lisboa Norte with a diagnosis grouped under the ICD9 codes of angioedema were retrospectively analysed. The episodes of angioedema with urticaria were excluded. The admissions were categorized into 2 groups: A - hospitalizations motivated by the angioedema; B - hospitalizations in which the angioedema was an incidental finding. RESULTS: There were 169 hospitalizations (52% females, 96% adults, mean age 52 ± 20.8 years), distributed by 23 hospital departments, 51% in the Immunoallergology department. The mean annual angioedema admission rate was 72/100 000. In 68% of the cases, angioedema was the cause for the admission; in 32% an incidental finding. In 38% there was upper airway involvement. The etiologies were: hereditary angioedema in 24%, angiotensin converting enzyme inhibitor induced angioedema in 31%, idiopathic angioedema in 21%, thrombolysis induced angioedema in 13%, nonsteroidal anti-inflammatory drug-induced angioedema in 5%. DISCUSSION: The main etiology was angiotensin converting enzyme inhibitor angioedema, followed by hereditary angioedema and thrombolysis induced angioedema, and these findings concur with the international literature. CONCLUSION: The mean annual angioedema admission rate was 72/100 000 and there was airway involvement in 38% of hospitalizations.

Introdução: Os internamentos por angioedema são importantes, sobretudo, nas situações incapacitantes ou de risco de vida. O objetivo deste estudo foi avaliar a frequência e etiologia dos internamentos por angioedema sem urticária. Material e Métodos: Estudo retrospetivo dos internamentos com os códigos CID9 para angioedema, entre 2009 e 2013, no Centro Hospitalar Lisboa Norte. Foram excluídos os episódios de angioedema com urticária. Categorizaram-se os internamentos em dois grupos: A ­ Internamentos motivados pela crise de angioedema; B ­ Internamentos em que o angioedema foi uma intercorrência. Resultados: Foram incluídos 169 internamentos (53% mulheres, 96% adultos, idade média 52 ± 20,8 anos), distribuídos por 23 serviços hospitalares (51% na Imunoalergologia), com uma taxa média anual de internamentos de 72/ 100 000. Em 68% o angioedema foi o motivo de internamento, em 32% uma intercorrência. Em 38% houve envolvimento das vias aéreas superiores. As etiologias foram: em 24% angioedema hereditário, em 31% angioedema induzido por inibidores da enzima conversora da angiotensina, 21% foram idiopáticos, em 13% o angioedema surgiu após trombólise, em 5% induzido por anti-inflamatórios não esteroides e 7% outras etiologias. Discussão: A principal etiologia foi o angioedema induzido por inibidores da enzima conversora da angiotensina, seguido do angioedema hereditario e angioedema associado a trombolise, sendo estes dados semelhantes a outras revisões internacionais. Conclusão: A taxa média de internamentos por angioedema foi de 72/100 000 e a frequência de envolvimento das vias aéreas foi de 38%.

Angioedema hereditário com deficiência do Inibidor de C1 ­ Armadilhas no diagnóstico, tratamento e compreensão / Hereditary angioedema with C1 inhibitor deficiency: traps in the diagnosis, treatment, and understanding

Angioedema hereditário (AEH) é uma condição rara, subdiagnosticada e de elevada morbimortalidade, devido ao caráter de suas manifestações clínicas. O AEH se diferencia do angioedema histaminérgico por não responder aos anti-histamínicos, corticosteroides ou epinefrina. Por esse motivo, é extremamente importante o diagnóstico dessa situação, a fim de instituir a terapia adequada. Tal afecção deve ser suspeitada a partir da história clínica de episódios imprevisíveis e recorrentes de edema que quando se manifesta sob a forma de edema laríngeo, pode levar a óbito por asfixia, se não for adequadamente tratado. Relatamos o caso de uma paciente de 18 anos que, apesar de previamente diagnosticada com AEH tipo 1, ao procurar um serviço de emergência devido a crise de angioedema, não dispunha de medicação específica nem apresentou plano de ação com as opções possíveis para crises. Este caso reforça a necessidade de maior divulgação da doença, além da conscientização de pacientes e familiares sobre a doença e eventuais crises, assim como o acesso as medicações.

Hereditary angioedema (HAE) is a rare, underdiagnosed condition with high morbidity and mortality due to the characteristics of its clinical presentation. HAE differs from histaminergic angioedema by not responding to antihistamines, corticosteroids, or epinephrine. Therefore, early diagnose is crucial to initiate adequate therapy. HAE is suspected in patients with a clinical history of unpredictable and recurrent episodes of edema. When laryngeal edema occurs, it can lead to death from asphyxiation if not treated properly. We report the case of an 18-year-old patient previously diagnosed with HAE type 1 who sought emergency care during an angioedema attack. However, the patient was not taking any specific medication and did not have an action plan to manage attacks. This case highlights the importance of increasing awareness about the disease, educating patients and their families about the disease and potential attacks, and ensuring access to medications.

Aspectos clínicos e diagnósticos, qualidade de vida, utilidade, adesão terapêutica e custos para angioedema hereditário associado à deficiência de C1-esterase / Clinical and diagnostic aspects, quality of life, usefulness, therapeutic adherence and costs for hereditary angioedema associated with C1-esterase deficiency

Introdução: O angioedema hereditário associado à deficiência de C1 esterase (AEH-C1-INH) é uma doença rara (DR) que se manifesta com a ocorrência de episódios recorrentes de angioedema não pruriginoso subcutâneo ou submucoso, o que gera impactos em todos os aspectos da vida dos indivíduos. Objetivo: Avaliar a qualidade de vida e a jornada clínica e assistencial dos pacientes com AEH-C1-INH. Material e Métodos: Trata-se de um estudo observacional ambispectivo em que foram aplicados questionários relacionados à qualidade de vida e jornada assistencial, além da coleta de dados clínicos dos prontuários nos tempos 0, 6 e 12 meses. Resultados: Foram recrutados 15 indivíduos com AEH-C1-INH e a mediana (I.I.Q) de idade da amostra foi de 38 anos (30-43). O tempo médio entre os primeiros sintomas e o diagnóstico foi de 8 anos. Os dados clínicos demonstraram história familiar positiva expressiva, ocorrência importante de edema de laringe em algum momento da vida e altos índices de recorrência das crises de angioedema durante os 12 meses de estudo. A qualidade de vida apresentou prejuízo importante principalmente em aspectos físicos, emocionais e vitalidade, sem variações significativas no tempo de estudo. Além disso, vale destacar a perda de produtividade expressiva associada a gastos médios de R$3.017,00 para medicamentos e R$598,00 para exames complementares em 12 meses. Conclusão: Observa-se um panorama de perda significativa de qualidade de vida relacionada ao AEH-C1-INH, principalmente por impactos da saúde física e emocional no exercício das atividades rotineiras. Ressaltam-se os impactos econômicos da jornada terapêutica, tanto pela perda de produtividade quanto pela necessidade de financiar medicamentos e exames que deveriam ser responsabilidade do Estado por meio do Sistema Único de Saúde (SUS). Portanto, fica clara a importância de medidas públicas que busquem amenizar os impactos causados pela doença nos indivíduos acometidos.

Introduction: Hereditary Angioedema associated with C1 esterase deficiency (HAE-C1-INH) is a rare disease (RD) that manifests with recurrent episodes of non-pruritic subcutaneous or submucosal angioedema, which impacts on all aspects of the individual's life. Objective: To evaluate the quality of life and the clinical and care journey of patients with HAE-C1-INH. Material and Methods: This is an ambispective observational study in which questionnaires related to quality of life and care journey were applied, in addition to the clinical data collection from medical records at 0, 6 and 12 months. Results: 15 subjects with HAE-C1-INH were recruited and the median (IQR) age of the sample was 38 years (30-43). The average time between the first symptoms and diagnosis was 8 years. The clinical data showed a substantial positive family history, considerable occurrence of laryngeal edema at some point in life and high rates of recurring angioedema crises during the 12 months of the study. Quality of life was significantly impaired, especially in terms of physical and emotional aspects and vitality, with no significant variations over the study period. It is also worth noting the major loss of productivity associated with average costs of R$3,017.00 for medication and R$598.00 for complementary tests over 12 months. Conclusion: There is a noticeable loss of quality of life related to HAE-C1-INH, mainly due to the impact on physical and emotional health when carrying out routine activities. The economic impacts of the therapeutic journey stand out, both due to the loss of productivity and the need to finance medicines and tests that should be the responsibility of the State through the Unified Health System (SUS). Therefore, the importance of public measures that seek to mitigate the impacts caused by the disease on affected individuals is evident.

Hereditary angioedema and Allergic bronchopulmonary aspergillosis: an unexpected association / Angioedema hereditário e Aspergilose broncopulmonar alérgica: uma associação inesperada

Hereditary angioedema (HAE) is a rare autosomal dominant disorder, Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease involving hypersensitivity to the fungi Aspergillus fumigatus which occur in susceptible patient with asthma or cystic fibrosis, also considered a rare disease. We report a case of HAE and ABPA in a single patient. HAE diagnosis was confirmed: C4 = 3 mg/dL, C1INH < 2.8 mg/dL - nephelometry. Former lung function showed elevation RV and RV/FVC, suggesting small airways lung disease. Positive skin prick test to Aspergillus fumigatus (03 mm); total serum IgE level 3,100 IU/mL (nephelometry - BNII Siemens), eosinophilia 11% (528/mm3) and specific A. fumigatus IgG antibodies 6,8 mgA/L (FEIA - fluorenzymeimmunoassay - ThermoFisher) and Chest CT showed mucoid impaction of the bronchi, consistent to current ABPA. Controlling ABPA could prevent and reduce angioedema attacks, and lung structural damage. Early diagnosis and treatment of both diseases should be emphasized to reduce mortality and morbidity

Angioedema hereditário (AEH) é uma doença autossômica dominante; aspergilose broncopulmonar alérgica (ABPA) é uma doença de hipersensibilidade pulmonar relacionada ao esporo de Aspergillus fumigatus, mais suscetível em pacientes com asma e fibrose cística, ambas são consideradas doenças raras. Apresentamos um caso de AEH e ABPA em um paciente. O diagnóstico de AEH foi confirmado com exames laboratoriais: C4 = 3 mg/dL, C1INH < 2,8 mg/dL - nefelometria. Prova de função pulmonar evidenciou aumento de VR e VR/CVF, sugerindo doenças de pequenas vias aéreas. Teste de puntura positivo para A. fumigatus (03 mm); IgE total = 3.100 IU/mL (nefelometria - BNII Siemens), eosinofilia 11% (528/mm3) e IgG específica para A. fumigatus 6,8 mgA/L (FEIA - ThermoFisher), TC de tórax evidenciou impactação mucoide, consistente com ABPA. Controlar ABPA pode prevenir e reduzir as crises de angioedema e os danos ao tecido pulmonar. O diagnóstico precoce de ambas as doenças deve ser enfatizado para reduzir a morbimortalidade.

Optimum Use of Acute Treatments for Hereditary Angioedema: Evidence-Based Expert Consensus.

Acute treatment of hereditary angioedema due to C1 inhibitor deficiency has become available in the last 10 years and has greatly improved patients' quality of life. Two plasma-derived C1 inhibitors (Berinert and Cinryze), a recombinant C1 inhibitor (Ruconest/Conestat alpha), a kallikrein inhibitor (Ecallantide), and a bradykinin B2 receptor inhibitor (Icatibant) are all effective. Durably good response is maintained over repeated treatments and several years. All currently available prophylactic agents are associated with breakthrough attacks, therefore an acute treatment plan is essential for every patient. Experience has shown that higher doses of C1 inhibitor than previously recommended may be desirable, although only recombinant C1 inhibitor has been subject to full dose-response evaluation. Treatment of early symptoms of an attack, with any licensed therapy, results in milder symptoms, more rapid resolution and shorter duration of attack, compared with later treatment. All therapies have been shown to be well-tolerated, with low risk of serious adverse events. Plasma-derived C1 inhibitors have a reassuring safety record regarding lack of transmission of virus or other infection. Thrombosis has been reported in association with plasma-derived C1 inhibitor in some case series. Ruconest was associated with anaphylaxis in a single rabbit-allergic volunteer, but no further anaphylaxis has been reported in those not allergic to rabbits despite, in a few cases, prior IgE sensitization to rabbit or milk protein. Icatibant is associated with high incidence of local reactions but not with systemic effects. Ecallantide may cause anaphylactoid reactions and is given under supervision. For children and pregnant women, plasma-derived C1 inhibitor has the best evidence of safety and currently remains first-line treatment.

Hereditary angioedema: how to approach it at the emergency department? / Angioedema hereditário: como abordar na emergência?

ABSTRACT Angioedema attacks are common causes of emergency care, and due to the potential for severity, it is important that professionals who work in these services know their causes and management. The mechanisms involved in angioedema without urticaria may be histamine- or bradykinin-mediated. The most common causes of histamine-mediated angioedema are foods, medications, insect sting and idiopathic. When the mediator is bradykinin, the triggers are angiotensin-converting enzyme inhibitors and factors related to acquired angioedema with deficiency of C1-inhibitor or hereditary angioedema, which are less common, but very important because of the possibility of fatal outcome. Hereditary angioedema is a rare disease characterized by attacks of edema that affect the subcutaneous tissue and mucous membranes of various organs, manifesting mainly by angioedema and abdominal pain. This type of angioedema does not respond to the usual treatment with epinephrine, antihistamines and corticosteroids. Thus, if not identified and treated appropriately, these patients have an estimated risk of mortality from laryngeal edema of 25% to 40%. Hereditary angioedema treatment has changed dramatically in recent years with the development of new and efficient drugs for attack management: plasma-derived C1 inhibitor, recombinant human C1-inhibitor, bradykinin B2 receptor antagonist (icatibant), and the kallikrein inhibitor (ecallantide). In Brazil, plasma-derived C1 inhibitor and icatibant have already been approved for use. Proper management of these patients in the emergency department avoids unnecessary surgery and, especially, fatal outcomes.

RESUMO As crises de angioedema são causas comuns de atendimentos nas emergências, e devido ao potencial de gravidade, é importante que os profissionais que atuam nesses serviços conheçam suas causas e abordagem. Os mecanismos envolvidos no angioedema sem urticas podem ser histaminérgicos ou mediados por bradicinina. As causas mais comuns de angioedema mediado por histamina são alimentos, medicamentos, ferroada de insetos e idiopática. Quando o mediador é a bradicinina, os desencadeantes são os inibidores da enzima conversora de angiotensina e fatores relacionados ao angioedema adquirido com deficiência do inibidor de C1 ou angioedema hereditário que são menos comuns, mas muito importantes pela possibilidade de desfecho fatal. O angioedema hereditário é uma doença rara, caracterizada por crises de edema que acometem o tecido subcutâneo e mucosas de vários órgãos, manifestando-se principalmente por crises de angioedema e dor abdominal. Esse tipo de angioedema não responde ao tratamento usual com adrenalina, anti-histamínicos e corticosteroides. Assim, se não identificados e tratados adequadamente, esses pacientes têm risco de morte por edema de laringe estimado em 25% a 40%. O tratamento do angioedema hereditário mudou drasticamente nos últimos anos, com o desenvolvimento de novos e eficientes fármacos para as crises: inibidor de C1 derivado de plasma, inibidor de C1 recombinante humano, antagonista do receptor B2 da bradicinina (icatibanto) e o inibidor da calicreína (ecalantide). No Brasil, até o momento, estão liberados para uso o inibidor de C1 derivado de plasma e o icatibanto. O manejo correto desses pacientes na emergência evita cirurgias desnecessárias e, principalmente, desfechos fatais.

First administration of ecallantide in Peru: a case report of a Peruvian patient with hereditary angioedema with normal C1-inhibitor / Primeira administração de ecalantida no Peru: relato de caso de paciente peruano com angioedema hereditário com inibidor de C1 normal

Ecallantide is a specific treatment currently indicated for acute crisis of hereditary angioedema (HAE) due to C1-inhibitor deficiency. Our objective is to report the first administration of ecallantide (Kalbitor®) in Peru, where the treatment was used in an HAE patient with normal C1-inhibitor and no F12 gene alteration. We report the case of a 32-year-old postpartum patient with HAE with normal C1-inhibitor who belongs to the Peruvian Association of Patients with Hereditary Angioedema. During pregnancy, she had increased frequency and intensity of abdominal pain and facial edema crisis and received maintenance treatment with tranexamic acid and spasmolytics, with moderate response. One month postpartum, the patient showed respiratory symptoms and tested positive for coronavirus disease (COVID-19) in a polymerase chain reaction (PCR) test, without any HAE crisis during the infectious process. Three months postpartum, she had an acute laryngeal edema crisis with difficulty breathing and speaking, nausea, and vomiting, triggered by nonsteroidal anti-inflammatory drugs (NSAIDs). The patient then received treatment with antihistamines, corticosteroids, and adrenaline, without improvement; for that reason, the allergist administered ecallantide (Kalbitor®) with good response within the first 15 minutes of administration. Some Peruvian HAE patients have developed mild-to-moderate facial and peripheral edema crisis after NSAID intake, without improvement after administration of allergy treatment. In our patient, HAE crisis was not triggered by COVID-19. The patient showed worsening HAE crisis during pregnancy. The first administration of ecallantide (Kalbitor®) in Peru had good response and tolerance to the treatment as shown in this report.

Ecallantide é um tratamento específico totalmente indicado na crise aguda de deficiência de inibidor de C1 HAE. Nosso objetivo é relatar a primeira administração de Ecallantide (Kalbitor®) no Peru, um caso de paciente peruano com EH com inibidor C1 normal sem alteração genética F12. Relatamos o caso de uma paciente de 32 anos, pós-parto, com HAE inibidor de C1 normal, pertencente à Associação Peruana de Angioedema Hereditário de Pacientes. Durante a gravidez, a paciente apresentou aumento na frequência e intensidade das crises de edema abdominal e facial e recebeu tratamento de manutenção com ácido tranexâmico e espasmolítico, com resposta moderada. Um mês após o parto, a paciente apresentou quadro respiratório e teste de PCR molecular positivo para Doença do Coronavírus (COVID-19), sem crise de AEH durante o processo infeccioso. Três meses após o parto, a paciente apresentou crise de edema agudo de laringe com dificuldade para respirar e falar, náuseas e vômitos, desencadeado por AINH. A paciente recebeu tratamento com anti-histamínicos, corticosteroides e adrenalina sem melhora, por isso o alergista administrou Ecallantide (Kalbitor®) com boa resposta nos primeiros 15 minutos após o início da administração. Alguns pacientes peruanos com AEH desenvolveram crises de edema facial e periférico leve a moderado após a ingestão de AINEs, sem melhora após a administração de tratamento para alergia. Em nossa paciente, a crise de AEH não foi desencadeada por infecção aguda por COVID-19. A paciente apresentou agravamento da crise de AEH durante a gravidez. Apresentamos a primeira administração de Ecallantide (Kalbitor®) no Peru, com boa resposta e tolerância ao tratamento.

Icatibant, an inhibitor of bradykinin receptor 2, for hereditary angioedema attacks: prospective experimental single-cohort study / Icatibanto, um inibidor de receptor 2 de bradicinina, para ataques de angioedema hereditário: estudo experimental prospectivo de coorte sem grupo controle

CONTEXT AND OBJECTIVE: Hereditary angioedema (HAE) with C1 inhibitor deficiency manifests as recurrent episodes of edema involving the skin, upper respiratory tract and gastrointestinal tract. It can be lethal due to asphyxia. The aim here was to evaluate the response to therapy for these attacks using icatibant, an inhibitor of the bradykinin receptor, which was recently introduced into Brazil. DESIGN AND SETTING: Prospective experimental single-cohort study on the efficacy and safety of icatibant for HAE patients. METHODS: Patients with a confirmed HAE diagnosis were enrolled according to symptoms and regardless of the time since onset of the attack. Icatibant was administered in accordance with the protocol that has been approved in Brazil. Symptom severity was assessed continuously and adverse events were monitored. RESULTS: 24 attacks in 20 HAE patients were treated (female/male 19:1; 19-55 years; median 29 years of age). The symptoms were: subcutaneous edema (22/24); abdominal pain (15/24) and upper airway obstruction (10/24). The time taken until onset of relief was: 5-10 minutes (5/24; 20.8%); 10-20 (5/24; 20.8%); 20-30 (8/24; 33.4%); 30-60 (5/24; 20.8%); and 2 hours (1/24; 4.3%). The time taken for complete resolution of symptoms ranged from 4.3 to 33.4 hours. Adverse effects were only reported at injection sites. Mild to moderate erythema and/or feelings of burning were reported by 15/24 patients, itching by 3 and no adverse effects in 6. CONCLUSION: HAE type I patients who received icatibant responded promptly; most achieved improved symptom severity within 30 minutes. Local adverse events occurred in 75% of the patients. .

CONTEXTO E OBJETIVO: O angioedema hereditário (AEH) com deficiência de inibidor de C1 manifesta-se por episódios recorrentes de edema envolvendo pele, trato respiratório superior e gastrointestinal. Pode ser letal por asfixia. O objetivo foi avaliar a resposta à terapia dos ataques com icatibanto, inibidor do receptor de bradicinina, recentemente introduzido no Brasil. TIPO DE ESTUDO E LOCAL: Estudo experimental prospectivo de coorte, sem grupo controle, da eficácia e segurança do icatibanto em paciente com AEH. MÉTODOS: Pacientes com diagnóstico confirmado de AEH foram incluídos de acordo com os sintomas, independentemente do tempo de início do ataque. Icatibanto foi administrado segundo protocolo aprovado no Brasil. A gravidade do sintoma foi estabelecida continuamente e os eventos adversos foram monitorados. RESULTADOS: 24 ataques em 20 pacientes com AEH foram tratados (19 F:1 M; 19-55 anos; mediana 29 anos). Os sintomas foram: edema subcutâneo (22/24), dor abdominal (15/24) e obstrução de vias aéreas superiores (10/24). O tempo para o início do alívio foi: 5-10 minutos, 5/24 (20,8%); 10-20, 5/24 (20,8%); 20-30, 8/24 (33,4%); 30-60, 5/24 (20,8%) e 2 horas, 1/24 (4,3%). O tempo para a resolução completa variou de 4,3-33,4 horas. Somente efeitos adversos nos locais das injeções foram relatados. Eritema leve a moderado e/ou sensação de ardor foram relatados por 15/24 pacientes, prurido em 3, e 6 não tiveram efeitos adversos. CONCLUSÃO: Pacientes com AEH tipo I receberam icatibanto com pronta resposta; a maioria teve melhora na gravidade dos sintomas em 30 minutos. Eventos adversos locais ocorreram em 75% dos pacientes. .

Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review* / Angioedema hereditario tipo III (estrogeno-dependente): relato de tres casos e revisao da literatura

In this article, three cases of hereditary angioedema (HAE) type III (estrogen-dependent or with normal C1 inhibitor) are reported. The HAE was initially described in women of the same family in association with high-leveled estrogenic conditions such as the use of oral contraceptives and pregnancy. There is no change in the C1 inhibitor as happens in other types of hereditary angioedema, and mutations are observed in the encoding gene of the XII factor of coagulation in several patients. The current diagnosis is mainly clinical and treatment consists in the suspension of the triggering factors and control of acute symptoms. A brief review of physiopathology, clinical features, genetic alterations and treatment are also presented.

Neste artigo são relatados três casos de angioedema hereditário do tipo III (estrógeno-dependente ou com inibidor de C1 normal), que foi inicialmente descrito em mulheres da mesma família, em associação com condições de alto nível estrogênico, como uso de anticoncepcionais orais e gravidez. Não há alteração do inibidor de C1, como acontece nos outros tipos de angioedema hereditário, e são observadas mutações no gene codificador do fator XII da coagulação em várias pacientes. O diagnóstico atualmente é eminentemente clínico e o tratamento consiste na suspensão dos fatores desencadeantes e controle dos sintomas agudos. Também é apresentada breve revisão da fisiopatogenia, quadro clínico, alterações genéticas e tratamento.