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We report on the successful treatment of a severe, recalcitrant dermatitis caused by CTLA-4 insufficiency with dupilumab, raising the possibility of a role of type 2 immunity in clinical conditions associated with CTLA-4 insufficiency.
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Background: Mechanisms triggering the pathogenesis of chronic spontaneous urticaria (CSU) have been identified as type I autoallergic (which is associated with IgE antibodies against autoantigens) and type IIb autoimmune (which is driven by autoantibodies to FceR1 and/or IgE). Objective: Our aim was to define presumptive endotypes in patients with CSU by using tests amenable to use in routine clinical practice. Methods: A retrospective analysis of the medical records of 394 patients with CSU with or without chronic inducible urticaria or angioedema was performed. Patients were assigned to 1 of 4 groups as follows: (1) type I endotype of CSU, if they presented at least 1 of the following: allergic disease, total IgE level of at least 40UI/mL, and positive result of skin tests to inhalant allergen(s), (2) type IIb endotype of CSU, if they presented at least 1 of following: autoimmune disease, low total IgE level less than 40 IU/mL, positive autologous serum skin test result, positive for antinuclear antibodies in a titer of at least 1:160, and elevated level of anti-thyroid peroxidase, (3) overlap of type I/type IIb endotypes of CSU, if they presented with at least 1 marker of both type I and type IIb, and (4) non-type I/type IIb endotype of CSU, if they presented with none of the markers of type I or type IIb. Results: The mean age at onset of symptoms was 34 years; 82.2% of those with CSU were female, and angioedema and chronic inducible urticaria were found in 74.8% and 31.9% of patients, respectively. Of the patients with CSU, 38% presented with the type I endotype and 51% presented with type I/type IIb overlap, whereas 9% presented with the type IIb endotype and 2% presented with the non-type I/type IIb endotype. Eosinopenia was associated with type IIb and type I/type IIb overlap as opposed to the type I and non-type I/type IIb endotypes (P = .02). Conclusions: Most patients with CSU presented with features of the type 1 (autoallergic) endotype, whether associated with type IIb (autoimmune) endotype or not.
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OBJECTIVE: To assess the prevalence of the eosinophilic and allergic phenotypes of severe asthma in Brazil, as well as to investigate the clinical characteristics of severe asthma patients in the country. METHODS: This was a cross-sectional study of adult patients diagnosed with severe asthma and managed at specialized centers in Brazil. The study was conducted in 2019. RESULTS: A total of 385 patients were included in the study. Of those, 154 had a blood eosinophil count > 300 cells/mm3 and 231 had a blood eosinophil count of ≤ 300 cells/mm3. The median age was 54.0 years, and most of the patients were female, with a BMI of 29.0 kg/m2 and a history of allergy (81.6%). The prevalence of patients with a blood eosinophil count > 300 cells/mm3 was 40.0% (95% CI: 35.1-44.9), and that of those with a blood eosinophil count > 300 cells/mm3 and a history of allergy was 31.9% (95% CI: 27.3-36.6). Age and BMI showed positive associations with a blood eosinophil count > 300 cells/mm3 (OR = 0.97, p < 0.0001; and OR = 0.96, p = 0.0233, respectively), whereas the time elapsed since the onset of asthma symptoms showed an increased association with a blood eosinophil count > 300 cells/mm3 (OR = 1.02, p = 0.0011). CONCLUSIONS: This study allowed us to characterize the population of severe asthma patients in Brazil, showing the prevalence of the eosinophilic phenotype (in 40% of the sample). Our results reveal the relevance of the eosinophilic phenotype of severe asthma at a national level, contributing to increased effectiveness in managing the disease and implementing public health strategies.
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Asma , Asma/diagnóstico , Brasil/epidemiologia , Estudos Transversais , Eosinófilos , Feminino , Humanos , Contagem de Leucócitos , Masculino , Fenótipo , PrevalênciaRESUMO
Background: HAE with normal C1 inhibitor (HAE-nC1-INH) has been identified as a bradykinin mediated angioedema. Estrogens are one of the main trigger factors. Pregnancy in HAE with C1 inhibitor deficiency showed variable course, however, few reports are available for HAE-nC1-INH. We evaluated the course of pregnancies in women diagnosed with HAE-nC1-INH. Methods: Women with diagnosis of HAE-nC1-INH according to the following criteria: clinical manifestations similar to HAE-C1-INH, normal biochemical evaluation and family history were included. A questionnaire about pregnancies was applied after consent. Genetic evaluation for known mutations was performed in all patients. Results: A total of 45 pregnancies occurring in 26 HAE-nC1-INH patients were evaluated (7/26 patients with F12 variant). Spontaneous abortion was reported in 8/45 (17.8%) pregnancies. Onset of attacks started before the pregnancy in 18/26 patients; during the pregnancy in 2/26; and after the pregnancy in 6/26. HAE attacks occurred in 24/37 pregnancies (64,7%): during the 1st trimester in 41.7%; 2nd trimester in 12.5%; 3rd trimester in 20.8%; 1st and 3rd trimesters in 4.2% and during the whole pregnancy in 20.8%. Among 15/18 patients who had attacks before pregnancy, symptoms persisted with worsening in 9/15; improvement in 4/15; no change in 1/15, and no response in 1/15. Conclusions: The occurrence of abortion in HAE-nC1-INH was similar to the expected for not affected women. The 1st trimester of the pregnancy was more symptomatic for HAE-nC1-INH women. Considering the strong relevance of estrogens in HAE-nC1-INH, pregnancy could worsen the course of disease.
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ABSTRACT Objective: To assess the prevalence of the eosinophilic and allergic phenotypes of severe asthma in Brazil, as well as to investigate the clinical characteristics of severe asthma patients in the country. Methods: This was a cross-sectional study of adult patients diagnosed with severe asthma and managed at specialized centers in Brazil. The study was conducted in 2019. Results: A total of 385 patients were included in the study. Of those, 154 had a blood eosinophil count > 300 cells/mm3 and 231 had a blood eosinophil count of ≤ 300 cells/mm3. The median age was 54.0 years, and most of the patients were female, with a BMI of 29.0 kg/m2 and a history of allergy (81.6%). The prevalence of patients with a blood eosinophil count > 300 cells/mm3 was 40.0% (95% CI: 35.1-44.9), and that of those with a blood eosinophil count > 300 cells/mm3 and a history of allergy was 31.9% (95% CI: 27.3-36.6). Age and BMI showed positive associations with a blood eosinophil count > 300 cells/mm3 (OR = 0.97, p < 0.0001; and OR = 0.96, p = 0.0233, respectively), whereas the time elapsed since the onset of asthma symptoms showed an increased association with a blood eosinophil count > 300 cells/mm3 (OR = 1.02, p = 0.0011). Conclusions: This study allowed us to characterize the population of severe asthma patients in Brazil, showing the prevalence of the eosinophilic phenotype (in 40% of the sample). Our results reveal the relevance of the eosinophilic phenotype of severe asthma at a national level, contributing to increased effectiveness in managing the disease and implementing public health strategies.
RESUMO Objetivo: Avaliar a prevalência dos fenótipos eosinofílico e alérgico da asma grave no Brasil e investigar as características clínicas dos pacientes com asma grave no país. Métodos: Estudo transversal com pacientes adultos com diagnóstico de asma grave atendidos em centros especializados no Brasil. O estudo foi realizado em 2019. Resultados: Foram incluídos no estudo 385 pacientes. Destes, 154 apresentavam contagem de eosinófilos no sangue > 300 células/mm3 e 231 apresentavam contagem de eosinófilos no sangue ≤ 300 células/mm3. A mediana da idade foi de 54,0 anos, e a maioria dos pacientes era do sexo feminino, com IMC de 29,0 kg/m2 e história de alergia (81,6%). A prevalência de pacientes com contagem de eosinófilos no sangue > 300 células/mm3 foi de 40,0% (IC95%: 35,1-44,9), e a daqueles com contagem de eosinófilos no sangue > 300 células/mm3 e história de alergia foi de 31,9% (IC95%: 27,3-36,6). A idade e o IMC apresentaram associações positivas com contagem de eosinófilos no sangue > 300 células/mm3 (OR = 0,97, p < 0,0001 e OR = 0,96, p = 0,0233, respectivamente), ao passo que o tempo decorrido desde o início dos sintomas de asma apresentou associação aumentada com contagem de eosinófilos no sangue > 300 células/mm3 (OR = 1,02, p = 0,0011). Conclusões: Este estudo possibilitou a caracterização da população de pacientes com asma grave no Brasil, mostrando a prevalência do fenótipo eosinofílico (em 40% da amostra). Nossos resultados revelam a relevância do fenótipo eosinofílico da asma grave em nível nacional, contribuindo para aumentar a eficácia no manejo da doença e na implantação de estratégias de saúde pública.
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Hereditary angioedema (HAE) is an autosomal dominant disease mostly due to the deficiency of C1 inhibitor (C1-INH). HAE with normal C1-INH was first described in 2000 and associated with mutations in the coagulation factor XII in 2006. Both diseases are associated with high bradykinin production, resulting in increased vascular permeability. Gastrointestinal edema due to HAE can be misdiagnosed as acute abdomen and unnecessary surgical procedures may be performed. The present study evaluates the prevalence of surgical procedures and/or acute abdomen in HAE patients with the coagulation factor XII mutation. It is a retrospective study where patients were diagnosed with recurrent angioedema without urticaria, normal C1-INH levels, and positive family history of angioedema. All patients were evaluated for the known mutations located at exon 9 of the F12 gene. Medical records were evaluated and questionnaires were applied to 52 patients with normal C1-INH levels (age range 13-76 years; 47/52, 90.38% women; 5/52, 9.61% men). F12 mutation was present in 32/52 patients (61.5%). Acute abdominal pain was diagnosed in 16/52 (30.76%) patients, appendicitis in 9/16 (56.2%), and undetermined diagnosis in 7/16 (43.7%). Among patients diagnosed with acute abdominal pain, 13/16 (81.2%) underwent surgery and 3/16 (18.7%) improved without surgical intervention. We conclude that many HAE patients with coagulation factor XII mutation were misdiagnosed with acute abdomen and subjected to unnecessary invasive procedures. It is critical to disseminate information about this rare mutation in patients with otherwise normal C1-INH activity, in order to speed up diagnosis and avoid misconduct.
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Abdome Agudo , Angioedema , Angioedemas Hereditários , Dor Abdominal , Adolescente , Adulto , Idoso , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1 , Fator XII/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: Prevention of attacks is a major goal in management of patients with hereditary angioedema (HAE). We aimed to investigate the effects of a systematic intervention for HAE patients. METHODS: Thirty-three patients with HAE with C1-inhibitor deficiency, belonging to a single family, participated in a management program coordinated by an allergist/immunologist. Angioedema attacks before intervention were ascertained by interviews and emergency room charts and recorded prospectively by patients or caregivers after enrollment. Mean number of attacks/month was compared at 12 months preintervention and 8 and 14 months within intervention. Patient-reported outcome instruments were used to assess quality of life, including HAE Quality of Life (HAE-QoL) questionnaire, psychological conditions, and work impairment, at baseline and 8 and 14 months within intervention. Data were stored in REDCap platform and analyzed by adjusted Bayesian models of double Poisson regression. RESULTS: Mean number of attacks/month significantly decreased (95% credible interval [CrI] excluding 0) from 1.15 preintervention to 0.25 and 0.23, 8 and 14 months within intervention, with mean decreases of -0.89 (95% CrI: -1.21 to -0.58) and -0.92 (95% CrI: -1.22 to -0.60), respectively. HAE-QoL scores showed mean total increases of 15.2 (95% CrI: 1.23-29.77) and 26 (95% CrI: 14.56-39.02) at 8 and 14 months within the study, as compared to baseline, revealing marked improvement in quality of life. Significant increase in role-emotional and reduction of depression, stress, and anxiety were observed at 14 months. CONCLUSION: A systematic approach integrating HAE-specific care with effective handling of psychological issues decreased the number of attacks and improved quality of life, targets for best practice in HAE.
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Angioedemas Hereditários/epidemiologia , Qualidade de Vida , Angioedemas Hereditários/prevenção & controle , Angioedemas Hereditários/psicologia , Angioedemas Hereditários/terapia , Ansiedade , Teorema de Bayes , Gerenciamento Clínico , Progressão da Doença , Emoções , Pesquisas sobre Atenção à Saúde , Humanos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. OBJECTIVES: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. METHODS: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. RESULTS: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. CONCLUSIONS: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.
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Angioedema/diagnóstico , Angioedemas Hereditários/diagnóstico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Baço/patologia , Neoplasias Esplênicas/diagnóstico , Angioedema/terapia , Angioedemas Hereditários/terapia , Detecção Precoce de Câncer , Serviços Médicos de Emergência , Epinefrina/uso terapêutico , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/terapia , Pessoa de Meia-Idade , Nefelometria e Turbidimetria , Neoplasias Esplênicas/terapiaRESUMO
INTRODUCTION: The relationship of parasite infections and promotion or protection from allergy and asthma is controversial. Currently, over 1.5 billion people are infected with parasites worldwide, and Ascaris lumbricoides is the most frequent soil-transmitted helminth. OBJECTIVES: To evaluate the biological activity of recombinant A. lumbricoides tropomyosin and investigate IgE cross-reactive responses to tropomyosins by means of microarray methodology for the detection of sensitization to allergen components. METHODS: Forty patients 12-75 years of age (25 males) with asthma and/or rhinitis and 10 nonallergic control subjects participated in this study. All patients presented positive skin tests to cockroach extracts and underwent skin prick testing (SPT) with recombinant (r) tropomyosins rPer a 7 from Periplaneta americana and rAsc l 3 from A. lumbricoides, at 10 µg/mL. IgE to cockroach and parasite tropomyosins were measured by chimeric ELISA and ImmunoCAP-ISAC, and total IgE was quantitated by ImmunoCAP. Agreement of results was assessed by κ statistics. RESULTS: Recombinant A. lumbricoides showed biological activity, inducing positive skin tests in 50% patients with asthma and/or rhinitis. IgE to cockroach and parasite tropomyosins were detected in 55-62% of patients. There was good-to-excellent agreement of results of SPT and IgE measurements by ELISA and ImmunoCAP-ISAC, with κ indices of 0.66-0.95. No skin test reactivity or IgE antibodies to tropomyosins were found in nonallergic individuals. CONCLUSIONS: Our results suggest that IgE responses to tropomyosin from A. lumbricoides may enhance reactivity to homologous allergens upon exposure by inhalation or ingestion, promoting allergic reactions and asthma, or increasing the severity of these clinical conditions.
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Antígenos de Helmintos/imunologia , Ascaríase/imunologia , Ascaris lumbricoides/fisiologia , Asma/imunologia , Rinite Alérgica/imunologia , Tropomiosina/imunologia , Adolescente , Adulto , Idoso , Alérgenos/imunologia , Animais , Criança , Reações Cruzadas , Citocinas/metabolismo , Feminino , Humanos , Imunidade , Imunoglobulina E/metabolismo , Masculino , Pessoa de Meia-Idade , Células Th2/imunologia , Tropomiosina/genética , Adulto JovemRESUMO
BACKGROUND: The transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp-1) has a key role in terminal differentiation in various T-cell subtypes. However, whether Blimp-1 regulates TH9 differentiation and its role in allergic inflammation are unknown. OBJECTIVE: We aimed to investigate the role of Blimp-1 in TH9 differentiation and in the pathogenesis of allergic airway inflammation. METHODS: In vitro TH9 differentiation, flow cytometry, ELISA, and real-time PCR were used to investigate the effects of Blimp-1 on TH9 polarization. T cell-specific Blimp-1-deficient mice, a model of allergic airway inflammation, and T-cell adoptive transfer to recombination-activating gene 1 (Rag-1)-/- mice were used to address the role of Blimp-1 in the pathogenesis of allergic inflammation. RESULTS: We found that Blimp-1 regulates TH9 differentiation because deleting Blimp-1 increased IL-9 production in CD4+ T cells in vitro. In addition, we showed that in T cell-specific Blimp-1-deficient mice, deletion of Blimp-1 in T cells worsened airway disease, and this worsening was inhibited by IL-9 neutralization. In asthmatic patients CD4+ T cells in response to TGF-ß plus IL-4 increased IL-9 expression and downregulated Blimp-1 expression compared with expression in healthy control subjects. Blimp-1 overexpression in human TH9 cells inhibited IL-9 expression. CONCLUSION: Blimp-1 is a pivotal negative regulator of TH9 differentiation and controls allergic inflammation.
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Asma/imunologia , Diferenciação Celular , Interleucina-9/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/fisiologia , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Linhagem Celular , Humanos , Inflamação/imunologia , Interleucina-9/genética , Camundongos TransgênicosRESUMO
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare condition with clinical features similar to those of HAE with C1-INH deficiency. Mutations in the F12 gene have been identified in subsets of patients with HAE with normal C1-INH, mostly within families of European descent. OBJECTIVES: Our aim was to describe clinical characteristics observed in Brazilians from 42 families with HAE and F12 gene mutations (FXII-HAE), and to compare these findings with those from other populations. METHODS: We evaluated a group of 195 individuals, which included 102 patients clinically diagnosed with FXII-HAE and their 93 asymptomatic relatives. RESULTS: Genetic analysis revealed that of the 195 subjects, 134 individuals (77.6% females) carried a pathogenic mutation in F12. The T328K substitution was found in 132 individuals, and the c.971_1018+24del72 deletion was found in 2 patients. The mean age at onset of symptoms in patients with FXII-HAE was 21.1 years. The most common symptoms were subcutaneous edema (85.8% of patients), abdominal pain attacks (69.7%), and upper airway edema (32.3%). Of male individuals carrying F12 mutations, 53.3% (16 of 30) were symptomatic. Compared with reports from Europe, fewer female patients (68.6%) reported an influence of estrogen on symptoms. CONCLUSIONS: Our study included a large number of patients with FXII-HAE, and, as the first such study conducted in a South American population, it highlighted significant differences between this and other study populations. The high number of symptomatic males and patients with estrogen-independent FXII-HAE found here suggests that male sex and the absence of a hormonal influence should not discourage clinicians from searching for F12 mutations in cases of HAE with normal C1-INH.
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Angioedemas Hereditários/genética , Fator XII/genética , Adolescente , Adulto , Idoso , Angioedemas Hereditários/sangue , Brasil , Criança , Pré-Escolar , Proteína Inibidora do Complemento C1/análise , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Adulto JovemRESUMO
O angioedema hereditário é uma doença autossômica dominante caracterizada por crises de edema com o envolvimento de múltiplos órgãos. A doença é desconhecida por muitos profissionais da área da saúde e, portanto, subdiagnosticada. Os pacientes que não são diagnosticados e tratados adequadamente têm uma mortalidade estimada de 25% a 40%, devido ao angioedema da laringe, resultando em asfixia. O angioedema de alças intestinais é outra manifestação importante e incapacitante, que pode ser a principal ou a única durante uma crise da doença. Neste cenário, um grupo de especialistas da Associação Brasileira de Alergia e Imunologia (ASBAI) e do Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) atualizou as diretrizes para o diagnóstico e terapia do angioedema hereditário.
Hereditary angioedema is an autosomal dominant disease characterized by edema 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 laryngeal angioedema, which results in asphyxia. Angioedema affecting bowel loops is another important, incapacitating presentation that may be the main or only manifestation during a crisis. In this scenario, a group of experts affiliated with Associação Brasileira de Alergia e Imunologia (ASBAI) and Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH) has updated the guidelines for the diagnosis and treatment of hereditary angioedema.
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Humanos , Masculino , Feminino , História do Século XXI , Guias como Assunto , Alergia e Imunologia , Angioedemas Hereditários/tratamento farmacológico , Terapêutica , Diagnóstico , Angioedema Hereditário Tipos I e IIRESUMO
OBJECTIVE: Asthma is under-diagnosed in many parts of the world. We aimed to assess the outcome of a capacitating program on asthma for non-specialist physicians and other healthcare professionals working in the public system in Ribeirão Preto, Brazil. METHODS: A group of 16 asthma specialists developed a one-year capacitating program in 11 healthcare clinics in the Northern District of the city, which included lectures on asthma, training on inhalation device use and spirometry, and development of an asthma management protocol. Researchers visited one health unit 2-4 times monthly, working with doctors on patients' care, discussing cases, and delivering lectures. Asthma education was also directed to the general population, focusing on recognition of signs and symptoms and long-term treatment, including production of educational videos available on YouTube. Outcome measures were the records of doctors' prescriptions of individual asthma medications pre- and post-intervention. RESULTS: Prior to the program, 3205 units of inhaled albuterol and 2876 units of inhaled beclomethasone were delivered by the Northern District pharmacy. After the one-year program, there was increase to 4850 units (51.3%) for inhaled albuterol and 3526 units (22.6%) for inhaled beclomethasone. The albuterol increase followed the recommendation given to the non-specialist doctors by the asthma experts, that every patient with asthma should have inhaled albuterol as a rescue medication, by protocol. No increase was observed in other districts where no capacitating program was conducted. CONCLUSION: A systematic capacitating program was successful in changing asthma prescription profiles among non-specialist doctors, with increased delivery of inhaled albuterol and beclomethasone.
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Asma/terapia , Fortalecimento Institucional/organização & administração , Gerenciamento Clínico , Relações Interinstitucionais , Administração em Saúde Pública , Universidades/organização & administração , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Brasil , Broncodilatadores/administração & dosagem , Estudos Transversais , Uso de Medicamentos/estatística & dados numéricos , Educação em Saúde/organização & administração , HumanosRESUMO
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) is a rare disorder. Mutations of the gene encoding coagulation factor XII have been identified in a subset of patients with this condition. Our aim was to investigate mutations in the F12 gene in patients with HAE with normal C1-INH from Brazil. METHODS: We studied 5 Brazilian families with index female patients who presented with recurrent angioedema with normal C1-INH and C4 levels. Genomic DNA was isolated from whole blood and PCR was performed. Mutations were detected by the sequencing of exon 9 of the F12 gene and allelic discrimination. RESULTS: The c.983C>A (p.Thr328Lys) mutation was identified in 16 subjects, from 4 of the 5 families studied, including 8 patients with symptoms of HAE with normal C1-INH (87.5% women) and 8 subjects asymptomatic for HAE (25% women). Mean age at onset of symptoms among the FXII-HAE patients was 13.8 years (range 6-25 years). Recurrent abdominal pain (100%) and subcutaneous angioedema (87.5%) were the most frequent clinical presentations. Two patients presented with associated laryngeal edema. In keeping with previous observations in patients with both C1-INH-HAE and HAE with normal C1-INH, all 7 women with FXII-HAE reported triggering or worsening of symptoms upon intake of estrogen-containing oral contraceptives and/or pregnancy. CONCLUSIONS: We report for the first time in Brazil a mutation in the F12 gene as a likely cause of HAE with normal C1-INH in patients with recurrent attacks of angioedema and/or abdominal pain. A higher frequency of abdominal pain attacks and onset of symptoms at a younger age were observed among Brazilian patients when compared to those from other parts of the world.
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Angioedemas Hereditários/genética , Proteínas Inativadoras do Complemento 1/imunologia , Fator XII/genética , Mutação Puntual , Adolescente , Adulto , Idade de Início , Idoso , Alelos , Angioedemas Hereditários/sangue , Angioedemas Hereditários/imunologia , Brasil , Proteína Inibidora do Complemento C1 , DNA/química , DNA/genética , Fator XII/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Adulto JovemRESUMO
BACKGROUND: Immunoglobulin E (IgE) reactivity to individual allergens among cockroach-allergic patients has revealed wide variability. The aim of this study was to assess the effectiveness of recombinant cockroach allergens for skin testing, and to determine sensitization profiles among cockroach-allergic patients living in Brazil. METHODS: Fifty-seven cockroach-allergic patients with asthma and/or rhinitis were recruited. Skin testing with recombinant (r) allergens from Periplaneta americana (rPer a 1 and rPer a 7) and Blattella germanica (rBla g 2, rBla g 4 and rBla g 5) were performed at 10 µg/ml and 5 µg/ml (rPer a 1). IgE antibodies to rPer a 7 and rPer a 1 were quantitated by ELISA. RESULTS: Of 57 patients tested, 3 (5.3%), 24 (42.1%), 4 (7%), 3 (5.3%) and 4 (7%) showed positive reactions to rPer a 1, rPer a 7, rBla g 2, rBla g 4 and rBla g 5, respectively. Twenty-eight patients (49.1%) had positive tests to at least one allergen. In keeping with skin test results, 31/57 patients (54.4%) and 5/55 patients (9%) had detectable IgE to rPer a 7 and rPer a 1, respectively. Levels of IgE to rPer a 7 were higher in patients with positive tests to rPer a 7 than those with negative tests (geometric mean 13.2 and 1.8 IU/ml, p < 0.05). There was good concordance of results of skin tests and measurements of serum IgE to rPer a 7. CONCLUSION: IgE reactivity to rPer a 7 (P. americana tropomyosin) was dominant among patients in Brazil. However, 50% of the patients did not present reactivity to any of the recombinant allergens tested.