Recessive SERPING1 Variant Leads to Kinin-Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema.

Background: Hereditary angioedema (HAE) is a severe and potentially life-threatening disease. The most common forms are caused by variants in SERPING1, resulting in C1-inhibitor (C1-INH) deficiency (HAE-C1-INH). C1-INH is a serine protease inhibitor (SERPIN) that regulates multiple proteases pathways, including the kallikrein-kinin system (KKS) and its complement. In HAE-C1-INH patients, C1-INH deficiencies affect KKS control, resulting in the development of kallikrein activity in plasma and the subsequent release of bradykinin (BK). While the overwhelming majority of disease-causing SERPING1 variants are dominant, very few recessive variants have been described. We present a large Brazilian HAE-C1-INH family with a recessive form of HAE-C1-INH. Methods: Blood samples of family members were investigated for protein levels of C1-INH, C4, C1q, and C1-INH function. The SERPING1 gene was sequenced. Results: In two severely affected sisters, we identified a homozygous missense variant in SERPING1 (NM_000062.3:c.964G>A;p.Val322Met). Fourteen family members were asymptomatic heterozygous carriers of the variant. Data regarding C1-INH function in the plasma showed that homozygous p.Val322Met strongly impacts C1-INH function to inhibit C1s and kallikrein (PKa). When heterozygously expressed, it affects the C1-INH control of C1s more than that of PKa. Conclusions: These studies of the variant's effects on the structure-function relationship reinforce prior observations suggesting that C1-INH deficiency is a conformational disease.

Are pediatricians familiar with hereditary angioedema?

Background: Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of subcutaneous or mucosal edema caused by excess bradykinin. The aim of the present study was to assess the knowledge of pediatricians about hereditary angioedema. Methods: An online survey with 12 HAE-related and 14 demographics-related questions was e-mailed to all pediatricians who were members of the Brazilian Society of Pediatrics (n = 17 145) once a week during the months of June and July 2021. The electronic questionnaire assessed clinical manifestations, diagnosis, and treatment of hereditary angioedema in children and adolescents. Results: Four hundred and fifty-five pediatricians responded to the questionnaire (2.6%), of whom 55 (12.1%) were board certified in Allergy and Immunology (A/I), while 400 (87.9%) were not (N-A/I). Three hundred and sixty-eight (80.9%) were female, 289 (55.7%) were under 50 years of age, 286 (62.9%) graduated from Medical School more than 10 years previously, 83 (18.2%) held an MSc/PhD degree, and 253 (55.6%) were living in the Southeast Region of Brazil. The median number of correct answers to the questions related to HAE among A/I was 7 out of 12 (58.3%), with median ranging from 4.5 to 8 correct answers, while for N-A/I it was 3 (25%), with median ranging from 2.5 to 4 correct answers (p < 0.001). Conclusion: Knowledge about HAE among Brazilian pediatricians, whether board certified in Allergy and Immunology or not, was unsatisfactory. HAE is a rare disease, largely unknown among physicians; therefore, increasing awareness may lead to improvement in diagnosis and treatment.

O omalizumabe no tratamento da urticária no contexto da pandemia de COVID-19 / Omalizumab as urticaria treatment in the context of the COVID-19 pandemic

O início da pandemia de COVID-19 foi marcado por incertezas diante do desconhecimento sobre a doença. Uma série de dúvidas relacionadas ao uso de imunobiológicos no contexto da pandemia foi levantada, inclusive em relação ao tratamento com omalizumabe em pacientes com urticária crônica (UC). Este estudo teve como objetivo analisar os dados relacionados à gravidade da COVID-19 e a evolução da urticária em pacientes em terapia com omalizumabe acompanhados por especialistas no Brasil. Foi realizada análise retrospectiva de dados de pacientes com UC tratados com omalizumabe entre julho/2020 e junho/2021 que apresentaram COVID-19. Foram avaliados dados relacionados às características clínicas dos pacientes e evolução da urticária durante a infecção pelo SARS-CoV2. Foram incluídos 28 pacientes em tratamento com omalizumabe, sendo 27 com urticária crônica espontânea (UCE), dos quais 25% tinham alguma urticária induzida associada. A maior parte dos pacientes (71%) estavam utilizando doses quadruplicadas de anti-histamínicos modernos de 2ª geração associados ao omalizumabe. Todos os pacientes estavam com os sintomas controlados. Entre os sintomas apresentados durante a COVID-19, os mais frequentes foram: febre (43%), cefaleia (36%), mal-estar (32%), hipo/anosmia (29%) e tosse (21%). Quatro pacientes foram hospitalizados, um deles em unidade de terapia intensiva. Um paciente relatou piora dos sintomas da UC durante a COVID-19. Cinco (18%) pacientes apresentaram piora dos sintomas da UC após a resolução da COVID-19. Todos os pacientes se recuperaram da COVID-19 sem sequelas graves. O OMA não pareceu aumentar o risco de COVID-19 grave e poderia ser usado com segurança em pacientes com UC.

The beginning of the COVID-19 pandemic was marked by uncertainty due to lack of knowledge about the disease. Questions were raised about the use of immunobiologicals in the pandemic context, including omalizumab for patients with chronic urticaria (UC). This study assessed COVID-19 severity and the clinical course of urticaria in Brazilian patients on omalizumab therapy who were monitored by specialists. We retrospectively analyzed data from chronic urticaria patients treated with omalizumab between July, 2020 and June, 2021 who presented with COVID- 19. Clinical characteristics and the course of urticaria during SARS-CoV2 infection were analyzed. The sample consisted of 28 patients treated with omalizumab, 27 of whom had chronic spontaneous urticaria (UCE) and 25% of whom had associated chronic inducible urticaria. Most of the patients (71%) were using quadruple doses of second-generation antihistamines associated with omalizumab. The symptoms of all patients were controlled. The most frequent symptoms during COVID-19 were: fever (43%), headache (36%), malaise (32%), hypo/anosmia (29%) and cough (21%). Four patients were hospitalized, including 1 in intensive care. One patient reported worsening chronic urticaria symptoms while infected with COVID-19. Five (18%) patients experienced worsening chronic urticaria symptoms after recovery from COVID-19. All patients recovered from COVID-19 without serious sequelae. Omalizumab did not appear to increase the risk of severe COVID-19 and can be safely used in patients with chronic urticaria.

Diretrizes brasileiras do angioedema hereditário 2022 ­ Parte 1: definição, classificação e diagnóstico / 2022 Brazilian guidelines for hereditary angioedema ­ Part 1: definition, classification, and diagnosis

O angioedema hereditário é uma doença autossômica dominante caracterizada por crises recorrentes de edema que acometem o tecido subcutâneo e o submucoso, com envolvimento de diversos órgãos. Os principais locais afetados são face, membros superiores e inferiores, as alças intestinais e as vias respiratórias superiores. Em decorrência da falta de conhecimento dessa condição por profissionais de saúde, ocorre atraso importante no seu diagnóstico, comprometendo a qualidade de vida dos indivíduos afetados. Além disso, o retardo no diagnóstico pode resultar em aumento da mortalidade por asfixia devido ao edema de laringe. A natureza errática das crises com variação do quadro clínico e gravidade dos sintomas entre diferentes pacientes, e no mesmo paciente ao longo da vida, se constitui em desafio no cuidado dos doentes que têm angioedema hereditário. O principal tipo de angioedema hereditário é resultante de mais de 700 variantes patogênicas do gene SERPING1 com deficiência funcional ou quantitativa da proteína inibidor de C1, porém nos últimos anos outras mutações foram descritas em seis outros genes. Ocorreram avanços importantes na fisiopatologia da doença e novas drogas para o tratamento do angioedema hereditário foram desenvolvidas. Nesse contexto, o Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) em conjunto com a Associação Brasileira de Alergia e Imunologia (ASBAI) atualizou as diretrizes brasileiras do angioedema hereditário. O maior conhecimento dos diversos aspectos resultou na divisão das diretrizes em duas partes, sendo nessa primeira parte abordados a definição, a classificação e o diagnóstico.

Hereditary angioedema is an autosomal dominant disease characterized by recurrent attacks of edema that affect the subcutaneous tissue and the submucosa, involving several organs. The main affected sites are the face, upper and lower limbs, gastrointestinal tract, and upper airways. Because health professionals lack knowledge about this condition, there is a significant delay in diagnosis, compromising the quality of life of affected individuals. Furthermore, delayed diagnosis may result in increased mortality from asphyxia due to laryngeal edema. The erratic nature of the attacks with variations in clinical course and severity of symptoms among different patients and in one patient throughout life constitutes a challenge in the care of patients with hereditary angioedema. The main type of hereditary angioedema results from more than 700 pathogenic variants of the SERPING1 gene with functional or quantitative deficiency of the C1 inhibitor protein, but in recent years other mutations have been described in six other genes. Important advances have been made in the pathophysiology of the disease, and new drugs for the treatment of hereditary angioedema have been developed. In this context, the Brazilian Study Group on Hereditary Angioedema (GEBRAEH) in conjunction with the Brazilian Association of Allergy and Immunology (ASBAI) updated the Brazilian guidelines on hereditary angioedema. Greater knowledge of different aspects resulted in the division of the guidelines into two parts, with definition, classification, and diagnosis being addressed in this first part.

Diretrizes brasileiras de angioedema hereditário 2022 ­ Parte 2: terapêutica / 2022 Brazilian guidelines for hereditary angioedema ­ Part 2: therapy

O tratamento do angioedema hereditário tem início com a educação dos pacientes e familiares sobre a doença, pois é fundamental o conhecimento da imprevisibilidade das crises, assim como os seus fatores desencadeantes. O tratamento medicamentoso se divide em terapia das crises e profilaxia das manifestações clínicas. As crises devem ser tratadas o mais precocemente possível com o uso do antagonista do receptor de bradicinina, o icatibanto ou o concentrado de C1-inibidor. É necessário estabeler um plano de ação em caso de crises para todos os pacientes. A profilaxia de longo prazo dos sintomas deve ser realizada preferencialmente com medicamentos de primeira linha, como concentrado do C1-inibidor ou o anticorpo monoclonal anti-calicreína, lanadelumabe. Como segunda linha de tratamento temos os andrógenos atenuados. Na profilaxia de curto prazo, antes de procedimentos que podem desencadear crises, o uso do concentrado de C1-inibidor é preconizado. Existem algumas restrições para uso desses tratamentos em crianças e gestantes que devem ser consideradas. Novos medicamentos baseados nos avanços do conhecimento da fisiopatologia do angioedema hereditário estão em desenvolvimento, devendo melhorar a qualidade de vida dos pacientes. O uso de ferramentas padronizadas para monitorização da qualidade de vida, do controle e da atividade da doença são fundamentais no acompanhamento destes pacientes. A criação de associações de pacientes e familiares de pacientes com angioedema hereditário tem desempenhado um papel muito importante no cuidado destes pacientes no nosso país.

The treatment of hereditary angioedema begins with the education of patients and their families about the disease, as it is essential to know the unpredictability of attacks as well as their triggering factors. Drug treatment is divided into attack therapy and prophylaxis of clinical manifestations. Attacks should be treated as early as possible with the bradykinin receptor antagonist icatibant or C1-inhibitor concentrate. An action plan needs to be established for all patients with attacks. Long-term prophylaxis of symptoms should preferably be performed with first-line drugs such as C1-inhibitor concentrate or the anti-kallikrein monoclonal antibody lanadelumab. Attenuated androgens are the second line of treatment. In short-term prophylaxis, before procedures that can trigger attacks, the use of C1-inhibitor concentrate is recommended. There are some restrictions for the use of these treatments in children and pregnant women that should be considered. New drugs based on advances in knowledge of the pathophysiology of hereditary angioedema are under development and are expected to improve patient quality of life. The use of standardized tools for monitoring quality of life and controlling disease activity is essential in the follow-up of these patients. The creation of associations of patients and families of patients with hereditary angioedema has played a very important role in the care of these patients in Brazil.

Acquired Angioedema due to C1-Inhibitor Deficiency: A Challenging Condition.

BACKGROUND: Acquired deficiency of C1 inhibitor (AAE-C1-INH) is a very rare cause of recurrent angioedema, with few cases reported in the literature. We aimed to describe a series of patients with AAE-C1-INH who were diagnosed and received care at angioedema reference centers in Brazil, affiliated to the Brazilian Group of Studies on Hereditary Angioedema. METHODS: Fourteen patients from 8 Brazilian Angioedema Reference Centers, diagnosed with AAE-C1-INH, were included in this study. Clinical data collected included sex, date of birth, date of onset of symptoms, date of diagnosis, plasma levels of antigenic and/or functional C1-INH, levels of C4 and C1q, location and treatment of angioedema attacks, long-term prophylaxis, associated diseases, and definitive treatment. RESULTS: Fourteen patients were identified with AAE-C1-INH. Most patients (10/14; 71.4%) were female. The median age at onset of symptoms was 56.5 years (range, 14-74 years; interquartile range [IQR], 32-64 years), and median age at diagnosis was 58.0 years (range, 20-76 years; IQR, 38-65 years), with a median time until diagnosis of 2 years (range, 0-6 years; IQR, 1-3 years). The most common manifestations were cutaneous (face, eyelids, lips, trunk, hands, feet, and genitals). Most patient had low levels of C4 (13/14; 92.8%) and of antigenic C1-INH (8/14; 57.1%). Four had decreased functional activity of C1-INH (4/7; 57.1%) and C1q levels were low in 5 patients (5/12; 41.6%). Underlying diseases were identified in all 14 patients, with lymphoma of the splenic marginal zone and monoclonal gammopathy of undetermined significance being the most frequent. Nine patients (64.2%) needed long-term prophylactic treatment for recurrent angioedema and 5 patients (46.7%) required treatment for angioedema attacks. Most of them (12/14; 85.7%) had resolution of angioedema. CONCLUSION: Therapy of AAE-C1-INH aims to control symptoms; however, diagnosis and treatment of the underlying disease, when present, should be an important target and may lead to the resolution of angioedema in patients with AAE-C1-INH.

Efficacy of House Dust Mite Sublingual Immunotherapy in Patients with Atopic Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Sensitization to house dust mites (HDMs) is frequent in patients with atopic dermatitis. OBJECTIVE: To investigate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides pteronyssinus extract in patients with atopic dermatitis sensitized to HDM. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled 91 patients 3 years or older, with SCORing Atopic Dermatitis (SCORAD) score greater than or equal to 15 and positive skin test result and/or IgE to D pteronyssinus. Patients were stratified according to age (<12 and ≥12 years) to receive HDM SLIT or placebo for 18 months. Primary outcome was a greater than or equal to 15-point decrease in SCORAD score. Secondary outcomes were decreases in SCORAD and objective SCORAD, Eczema Area and Severity Index, visual analog scale for symptoms, and pruritus scale scores; Investigator's Global Assessment 0/1; and decrease greater than or equal to 4 points in Dermatology Life Quality Index. Background therapy was maintained. RESULTS: A total of 66 patients completed the study (35 HDM SLIT, 31 placebo). After 18 months, 74.2% and 58% of patients in the HDM SLIT group and the placebo group, respectively, showed greater than or equal to 15-point decrease in SCORAD score (relative risk, 1.28; 95% CI, 0.89-1.83). Significant SCORAD score decreases from baseline of 55.6% and 34.5% in HDM SLIT and placebo groups (mean difference, 20.4; 95% CI, 3.89-37.3), significant objective SCORAD score decreases of 56.8% and 34.9% in HDM SLIT and placebo groups (mean difference, 21.3; 95% CI, 0.66-41.81), and more patients with Investigator's Global Assessment 0/1 in the HDM SLIT group as compared with the placebo group (14 of 35 vs 5 of 31; relative risk, 2.63; 95% CI, 1.09-6.39) were observed at 18 months. CONCLUSIONS: Our results suggest that HDM SLIT may be effective in HDM-sensitized patients as an add-on treatment for atopic dermatitis.

Hereditary angioedema: how to approach it at the emergency department?

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.

Vacinação contra COVID-19 em pacientes portadores de angioedema hereditário: recomendações do Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) / COVID-19 vaccination in patients with hereditary angioedema: recommendations from the Brazilian Group for the Study on Hereditary Angioedema (GEBRAEH)

No curso da pandemia da COVID-19, o desenvolvimento rápido de vacinas seguras e eficazes é a principal estratégia de saúde pública para conter a propagação da doença. Nesse contexto, esclarecimentos em relação à prioridade e segurança da vacinação contra COVID-19 em pacientes portadores de angioedema hereditário (AEH), assim como de outras doenças, são necessários. Todos os pacientes devem receber a vacina seguindo a estratégia do Ministério da Saúde e manter as medidas de higiene, uso de máscaras e distanciamento social até o controle da pandemia.

During the COVID-19 pandemic, the rapid development of safe and effective vaccines is the main public health strategy to avoid the spread of the disease. In this context, clarifications regarding the priority and safety of vaccination against COVID-19 in patients with hereditary angioedema (HAE), as well as other diseases, are needed. All patients should receive the vaccine according to the Brazilian Ministry of Health strategy and adhere to measures such as maintaining general hygienic measures, wearing masks, and keeping social distance until the pandemic is controlled.

The Challenges in the Follow-Up and Treatment of Brazilian Children with Hereditary Angioedema.

INTRODUCTION: Hereditary angioedema (HAE) with C1 inhibitor (C1-INH) deficiency is a rare autosomal dominant disease. Although the first symptoms can appear in childhood, the diagnosis's delay has a strong impact on the patient's quality of life. We analyzed clinical and laboratory characteristics and the drug therapy of pediatric patients with HAE in Brazil. METHODS: Medical records from 18 reference centers of HAE patients under 18 years of age were evaluated after confirmed diagnosis was performed by quantitative and/or functional C1-INH. RESULTS: A total of 95 participants (51 M:44 F; mean age: 7 years old) out of 17 centers were included; 15 asymptomatic cases were identified through family history and genetic screening. Angioedema attacks affected the extremities (73.5%), gastrointestinal tract (57%), face (50%), lips (42.5%), eyelids (23.7%), genitals (23.7%), upper airways (10%), and tongue (6.3%). Family history was present in 84% of patients, and the mean delay in the diagnosis was 3.9 years. Long-term prophylaxis (51/80) was performed with tranexamic acid (39/80) and androgens (13/80); and short-term prophylaxis (9/80) was performed with tranexamic acid (6/80) and danazol (3/80). On-demand therapy (35/80) was prescribed: icatibant in 7/35, fresh frozen plasma in 16/35, C1-INH plasma-derived in 11/35, and tranexamic acid in 12/35 patients. CONCLUSIONS: This is the first study on HAE pediatric patients in Latin America. Clinical manifestations were similar to adults. Drugs such as androgens and tranexamic acid were indicated off-label, probably due to restricted access to specific drugs. Educational programs should address pediatricians to reduce late diagnosis and tailored child therapy.

The global impact of the COVID-19 pandemic on the management and course of chronic urticaria.

INTRODUCTION: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown. AIM: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19. MATERIALS AND METHODS: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences. RESULTS: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19. CONCLUSIONS: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation.

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.

Study of angiopoietin and plasminogen genes in hereditary angioedema.

OBJECTIVE: To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS: Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS: DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION: Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

Asthma Is the Dominant Factor for Recurrence in Chronic Rhinosinusitis.

BACKGROUND: Factors associated with recurrence of chronic rhinosinusitis (CRS) are still poorly recognized. OBJECTIVE: To evaluate which risk factors could influence the risk of recurrence among patients undergoing endoscopic sinus surgery in long-term follow-up. METHODS: Patients with CRS who underwent endoscopic sinus surgery were followed for an average period of 12 years in a nonconcurrent cohort. After surgery, patients were considered to an additional endoscopic sinus surgery if appropriate medical therapy failed during this period. The presence of nasal polyps, asthma, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, smoking habits, peripheral blood eosinophilia, and atopy were assessed. The recurrence-free interval between groups (with or without these risk factors) was analyzed by Kaplan-Meyer curves, and the indication for a revisional surgery was considered to be the unfavorable event. RESULTS: A total of 201 patients were enrolled in this study. Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) were more likely than patients with chronic rhinosinusitis without nasal polyps (CRSsNP) to need revisional surgery (adjusted hazard ratio, 2.02). Asthma was the only factor that was significantly related to recurrence both in patients with CRSsNP (hazard ratio, 5.54) and in patients with CRSwNP (hazard ratio, 3.27). Although eosinophilia itself was not related to a higher chance of recurrence, its presence influenced the outcome of CRSwNP compared with CRSsNP and the impact of asthma among patients with CRSwNP. CONCLUSIONS: Prognosis in patients with CRSwNP was inferior to that in patients with CRSsNP. Asthma was the only factor that increased the chance of recurrence in patients with either CRSsNP or CRSwNP.

Study of angiopoietin and plasminogen genes in hereditary angioedema

SUMMARY OBJECTIVE To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

RESUMO OBJETIVO Investigar a presença das mutações no gene Angiopoietina (ANGPT1) e gene Plasminogênio (PLG) em pacientes com Angioedema Hereditário (AEH) com inibidor C1 esterase (C1-INH) normal e negativos para mutação do gene F12. MÉTODOS Foram avaliados pacientes com diagnóstico clínico de AEH sem deficiência ou disfunção de C1-INH e negativos para mutação do gene F12. Realizou-se extração, quantificação e diluição do DNA a uma concentração de 100 ng/uL, em seguida amplificação do DNA (PCR) para avaliação molecular do exon 2 do gene ANGPT1 e do exon 9 do gene PLG para identificação das mutações c.807G>T.p.A119S e c.988A>G p.K330E, respectivamente. O produto da PCR foi avaliado em eletroforese em gel de agarose 1%. Foi realizado o sequenciamento pelo método de Sanger. As análises dos eletroferogramas foram realizadas pelo programa FASTA®. RESULTADOS Foram sequenciadas amostras de 15 mulheres, idade entre 10 e 60 anos, com níveis séricos de inibidor de C1 esterase e C4 normais variando de 22 a 39mg/dL e 10 a 40mg/dL, respectivamente. Não foram identificadas mutações nos éxons analisados dos genes ANGPT1 e PLG. Entretanto no gene PLG foram encontrados polimorfismo de nucleotídeo único (SNP), em duas pacientes homozigotas e cinco heterozigotas. CONCLUSÃO Mais estudos sobre SNP são necessários para esclarecer estes achados pois eles podem ser utilizados como marcadores moleculares do AEH e alvo para novos tratamentos.

Serum Baseline Tryptase Level as a Marker for the Severity of Anaphylaxis.

BACKGROUND: Anaphylaxis is a severe and potentially fatal allergic disease or hypersensitivity reaction with variable clinical presentation. Biomarkers in anaphylaxis could be useful to improve diagnosis, to allow endotyping of patients, and to predict risk. OBJECTIVE: To investigate the role of serum basal tryptase (sBT) levels in the management of patients with anaphylaxis. METHODS: Patients with at least 1 episode of anaphylaxis were selected among those who attended the Allergy Clinics of the Clinical Hospital of the Ribeirão Preto Medical School, University of São Paulo, Brazil, upon evaluation by allergy/immunology specialists of our medical staff. Demographic and clinical data were obtained using a structured questionnaire. sBT levels were determined using the ImmunoCAP Tryptase immunoassay. RESULTS: 57 patients (56.1% female) with a median age of 35 years (range 7-87 years) participated in the study. sBT levels ranged from 2.57 to 21.19 ng/mL (mean 5.17 ng/mL), with no significant differences in patients with anaphylaxis due to different triggers. Mean levels were 4.93; 5.2; 5.41, and 5.24 ng/mL for patients who had anaphylaxis due to Hymenoptera venom (n = 17), foods (n = 13), drugs (n = 13), and idiopathic disease (n = 14), respectively. Significantly higher sBT levels were observed in patients with severe anaphylaxis (grade IV) than in patients with mild-moderate disease (grades II/III) (mean levels 6.61 vs. 4.71 ng/mL, respectively). CONCLUSION: High sBT levels may help to identify patients at increased risk of more severe anaphylaxis, prompting physicians to initiate immediate therapy to avoid further acute episodes.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis.

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.