A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2).

INTRODUCTION: The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. PATIENTS AND METHODS: This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. RESULTS: Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. CONCLUSION: The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2)

Abstract Introduction The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. Patients and methods This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. Results Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. Conclusion The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Underlying IPEX syndrome in a patient with idiopathic juvenile arthritis and vitiligo.

BACKGROUND: IPEX syndrome is an X-linked inborn error of immunity clinically characterized by the triad of: enteropathy, polyendocrinopathy and eczema. However many other clinical presentations lacking the triad above described have been reported what underpin the need of careful clinical suspicion, immunological evaluation and genetic sequencing. CASE PRESENTATION: Here we report a case of a Brazilian boy with severe eczema as the first and only presentation requiring cyclosporin therapy. Progressive and cumulative symptoms of arthritis and enteropathy lead to the suspicion of an inborn error of immunity. Peripheral FOXP3 expression was normal (CD127-/CD4+/CD25+/FOXP3+-396 cells-63%) and a pathogenic mutation in FOXP3 gene (c.1150G>A; p.Ala384Thr), confirmed the diagnosis of IPEX syndrome. CONCLUSIONS: IPEX syndrome should be suspected in patients presenting with severe eczema associated or not with other autoimmune/hyper inflammatory diseases in life. Our study also reinforces that FOXP3 expression by flowcytometry seems not to be a good screening method, and genetic sequencing is mandatory even in those with high suspicion and normal peripheral FOXP3 expression.

Liver disease accompanied by enteropathy in common variable immunodeficiency: Common pathophysiological mechanisms.

Common variable immunodeficiency (CVID) is one of the inborn errors of immunity that have the greatest clinical impact. Rates of morbidity and mortality are higher in patients with CVID who develop liver disease than in those who do not. The main liver disorder in CVID is nodular regenerative hyperplasia (NRH), the cause of which remains unclear and for which there is as yet no treatment. The etiology of liver disease in CVID is determined by analyzing the liver injury and the associated conditions. The objective of this study was to compare CVID patients with and without liver-spleen axis abnormalities in terms of clinical characteristics, as well as to analyze liver and duodenal biopsies from those with portal hypertension (PH), to elucidate the pathophysiology of liver injury. Patients were divided into three groups: Those with liver disease/PH, those with isolated splenomegaly, and those without liver-spleen axis abnormalities. Clinical and biochemical data were collected. Among 141 CVID patients, 46 (32.6%) had liver disease/PH; 27 (19.1%) had isolated splenomegaly; and 68 (48.2%) had no liver-spleen axis abnormalities. Among the liver disease/PH group, patients, even those with mild or no biochemical changes, had clinical manifestations of PH, mainly splenomegaly, thrombocytopenia, and esophageal varices. Duodenal celiac pattern was found to correlate with PH (p < 0.001). We identified NRH in the livers of all patients with PH (n = 11). Lymphocytic infiltration into the duodenal mucosa also correlated with PH. Electron microscopy of liver biopsy specimens showed varying degrees of lymphocytic infiltration and hepatocyte degeneration, which is a probable mechanism of lymphocyte-mediated cytotoxicity against hepatocytes and enterocytes. In comparison with the CVID patients without PH, those with PH were more likely to have lymphadenopathy (p < 0.001), elevated ß2-microglobulin (p < 0.001), low B-lymphocyte counts (p < 0.05), and low natural killer-lymphocyte counts (p < 0.05). In CVID patients, liver disease/PH is common and regular imaging follow-up is necessary. These patients have a distinct immunological phenotype that may predispose to liver and duodenal injury from lymphocyte-mediated cytotoxicity. Further studies could elucidate the cause of this immune-mediated mechanism and its treatment options.

Common variable immunodeficiency: an important but little-known risk factor for gastric cancer.

INTRODUCTION: although it is a rare disease, common variable immunodeficiency (CVID) stands out as the most frequent primary symptomatic immunodeficiency. Carriers are prone to a variety of recurrent bacterial infections, in addition to the risk of developing autoimmune diseases and neoplasms including gastric cancer (GC). Despite the recognized risk, there are no specific standardized protocols for the management of GC in these patients, so the reported oncological results are varied. Thus, this study aims to describe the clinicopathological characteristics and prognosis of patients with CVID undergoing surgical treatment of GC. METHODS: all patients with GC undergoing surgical treatment between 2009 and 2020 were retrospectively evaluated. Later, patients diagnosed with CVID were identified and this group was compared with the remaining patients without any immunodeficiency. RESULTS: among the 1101 patients with GC evaluated in the period, 10 had some type of immunodeficiency, and 5 were diagnosed with CVID. Patients with CVID had younger age, lower BMI, and smaller lesions compared to those without CVID. Four patients underwent curative gastrectomy and one patient underwent jejunostomy. Two patients died (1 palliative and 1 curative) and one patient had disease recurrence. There was no statistically significant difference regarding the incidence of postoperative complications and survival between the evaluated groups. CONCLUSION: the CVID incidence in patients with GC undergoing surgical treatment was 0.5%, occurring at a less advanced age, but with no difference regarding surgical and oncological results.

II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies.

In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil.

RESUMO: Nos últimos anos, novas imunodeficiências primárias e defeitos genéticos têm sido descritos. Recentemente, produtos de imunoglobulina, com aprimoramento em sua composição e para uso por via subcutânea, tornaram-se disponíveis em nosso meio. Com o objetivo de orientar o médico no uso da imunoglobulina humana para o tratamento das imunodeficiências primárias, os membros do Grupo de Assessoria em Imunodeficiências da Associação Brasileira de Alergia e Imunologia produziram um documento que teve por base uma revisão narrativa da literatura e sua experiência profissional, atualizando o I Consenso Brasileiro publicado em 2010. Apresentam-se novos conhecimentos sobre indicações e eficácia do tratamento com imunoglobulina nas imunodeficiências primárias, aspectos relevantes sobre a produção, forma de utilização (vias de administração, farmacocinética, doses e intervalos), efeitos adversos (principais efeitos, prevenção, tratamento e notificação), monitorização do paciente, apresentações disponíveis e forma de obtenção deste recurso terapêutico em nosso meio.

Interleucina-2 no tratamento adjuvante de paciente com linfocitopenia CD4 idiopática e tuberculose disseminada / Interleukin 2 as adjuvant treatment in a patient with idiopathic CD4 lymphocytopenia and disseminated tuberculosis

Linfocitopenia CD4 idiopática (LCI) é uma imunodeficiência rara e grave caracterizada por uma diminuição inexplicável da contagem absoluta de linfócitos T CD4, a qual está associada a infecções oportunistas. Existem poucos relatos de casos na literatura que descrevem a IL2 como uma opção terapêutica em infecções oportunistas associadas à LCI. Relatamos os benefícios da adição de IL2 ao tratamento padrão em um paciente com ICL e infecções oportunistas. Um homem de 38 anos de idade foi internado por acidente vascular cerebral isquêmico devido à vasculite infecciosa. A análise do líquido cefalorraquidiano mostrou meningite neutrofílica. Cultura e PCR foram positivos para Mycobacterium tuberculosis. A tomografia de tórax foi compatível com tuberculose pulmonar. O paciente também apresentava candidíase oral, onicomicose e dermatite seborreica. A contagem de células sanguíneas mostrou linfocitopenia. O tratamento padronizado para tuberculose disseminada (RIPE) e fluconazol foram iniciados e mantidos em casa após a alta do paciente. Após cinco meses de seguimento, o paciente foi encaminhado ao imunologista clínico, pois não apresentava melhora clínica significativa, tendo sido hospitalizado diversas vezes. A avaliação imunológica mostrou uma contagem sanguínea de CD4 T consistentemente inferior a 100 células/mm3 e o diagnóstico de LCI foi confirmado (linfocitopenia inexplicável com menos de 300 células/mm3 ou menos de 20% de células T CD4+ em mais de uma ocasião com pelo menos 2 meses de intervalo). O paciente também apresentava episódios raros de linfocitopenia de células B e hipogamaglobulinemia, tendo recebido gamaglobulina. Como tratamento adjuvante, a IL2 subcutânea foi associada ao tratamento padronizado. Até agora, o paciente recebeu cinco ciclos consecutivos de IL2, mostrando melhora clínica e aumento da contagem de células T CD4 no sangue, atingindo um valor máximo de 401 células/mm3. As células CD8, B e natural killer também aumentaram. Novas análises do líquido cefalorraquidiano foram normais, e a cultura de Mycobacterium tuberculosis e a PCR foram negativas. Nosso paciente com infecções oportunistas associadas à LCI apresentou evolução laboratorial e clínica favoráveis após a adição de IL2 ao tratamento padrão. Este relato de caso apoia o uso de IL2 como um coadjuvante seguro e potencialmente eficaz para infecções oportunistas associadas à LCI. O caso destaca a importância da avaliação e acompanhamento de pacientes com suspeita de imunodeficiência por imunoalergologistas.

Idiopathic CD4 T lymphocytopenia (ICL) is a rare and severe immunodeficiency disorder characterized by an unexplained decrease of absolute CD4 T-lymphocyte cell counts, which is associated with opportunistic infections. There are few case reports in the literature describing the use of interleukin 2 (IL2) as a therapeutic option in ICL-associated opportunistic infections. We report the benefits of adding IL2 to the standard treatment in a patient with ICL and opportunistic infections. A 38-year-old male patient was admitted with ischemic stroke due to infectious vasculitis. Cerebrospinal fluid analysis revealed neutrophilic meningitis. Culture and PCR were positive for Mycobacterium tuberculosis. Chest CT was compatible with pulmonary tuberculosis. The patient also presented oral candidiasis, onychomycosis, and seborrheic dermatitis. Blood cell count revealed lymphocytopenia. Standardized treatment for disseminated tuberculosis (RIPE therapy) and fluconazole were initiated and maintained at home after the patient's discharge. After five months of follow-up, the patient was referred to a clinical immunologist, due to the absence of significant clinical improvement, with multiple hospitalizations over the follow-up period. Immunological assessment showed CD4 T cell counts consistently below 100 cells/mm3, and the diagnosis of ICL was confirmed (unexplained lymphocytopenia with less than 300 cells/mm3 or less than 20% of CD4+ T cells on more than one occasion at least 2 months apart). The patient also presented rare episodes of B cell lymphocytopenia and hypogammaglobulinemia, treated with gammaglobulin. As an adjuvant treatment, subcutaneous IL2 was added to the standard treatment. So far the patient underwent five consecutive cycles of IL2, showing clinical improvement and increased CD4 T cell counts, reaching a maximum value of 401 cells/mm3. CD8, B and natural killer cells also increased. New cerebrospinal fluid analyses were normal, and new Mycobacterium tuberculosis culture and PCR were negative. Our patient had opportunistic infections associated with ICL and presented favorable laboratory and clinical outcomes after the association of IL2 to the standard treatment. This case report supports the use of IL2 as a safe and potentially effective adjuvant treatment for ICL-associated opportunistic infections. The case highlights the importance of immunological assessment and follow-up of patients with suspected immunodeficiency.

II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies / II Consenso Brasileiro sobre o uso de imunoglobulina humana em pacientes com imunodeficiências primárias

ABSTRACT In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil.

RESUMO Nos últimos anos, novas imunodeficiências primárias e defeitos genéticos têm sido descritos. Recentemente, produtos de imunoglobulina, com aprimoramento em sua composição e para uso por via subcutânea, tornaram-se disponíveis em nosso meio. Com o objetivo de orientar o médico no uso da imunoglobulina humana para o tratamento das imunodeficiências primárias, os membros do Grupo de Assessoria em Imunodeficiências da Associação Brasileira de Alergia e Imunologia produziram um documento que teve por base uma revisão narrativa da literatura e sua experiência profissional, atualizando o I Consenso Brasileiro publicado em 2010. Apresentam-se novos conhecimentos sobre indicações e eficácia do tratamento com imunoglobulina nas imunodeficiências primárias, aspectos relevantes sobre a produção, forma de utilização (vias de administração, farmacocinética, doses e intervalos), efeitos adversos (principais efeitos, prevenção, tratamento e notificação), monitorização do paciente, apresentações disponíveis e forma de obtenção deste recurso terapêutico em nosso meio.

Salivary Immunoglobulins in Individuals with Common Variable Immunodeficiency.

Oral manifestations of common variable immunodeficiency (CVID) are rare, have rarely been studied and have given controversial results. There are few data about IgA, IgG, and IgM antibody salivary levels in the literature, and there are few papers about the clinical impact of antibody deficiencies and CVID on the oral health of such patients. The aim of this study was to measure serum and salivary IgA, IgG, and IgM levels in CVID participants and controls, and to associate immunoglobulin levels with caries and periodontal disease. This was a case-control study involving 51 CVID individuals and 50 healthy controls. All participants underwent examination for dental caries and periodontal disease. Blood and whole saliva samples were collected on the same day of the oral examination. Serum IgA, IgM, and IgG levels were measured by turbidimetry and salivary IgA, IgM, and IgG titers were assessed by enzyme-linked immunosorbent assay. Incidences of caries and gingivitis were significantly higher in the CVID group than in the control group (p<0.05). Salivary and blood IgA and IgM titers were significantly reduced in the CVID group, but there was no association of salivary immunoglobulin levels with periodontal disease or with caries incidence (p>0.05 for both). Although CVID was associated with increased susceptibility to caries and gingivitis, it was not associated with low salivary levels of IgA and IgM.

Salivary Immunoglobulins in Individuals with Common Variable Immunodeficiency

Abstract Oral manifestations of common variable immunodeficiency (CVID) are rare, have rarely been studied and have given controversial results. There are few data about IgA, IgG, and IgM antibody salivary levels in the literature, and there are few papers about the clinical impact of antibody deficiencies and CVID on the oral health of such patients. The aim of this study was to measure serum and salivary IgA, IgG, and IgM levels in CVID participants and controls, and to associate immunoglobulin levels with caries and periodontal disease. This was a case-control study involving 51 CVID individuals and 50 healthy controls. All participants underwent examination for dental caries and periodontal disease. Blood and whole saliva samples were collected on the same day of the oral examination. Serum IgA, IgM, and IgG levels were measured by turbidimetry and salivary IgA, IgM, and IgG titers were assessed by enzyme-linked immunosorbent assay. Incidences of caries and gingivitis were significantly higher in the CVID group than in the control group (p<0.05). Salivary and blood IgA and IgM titers were significantly reduced in the CVID group, but there was no association of salivary immunoglobulin levels with periodontal disease or with caries incidence (p>0.05 for both). Although CVID was associated with increased susceptibility to caries and gingivitis, it was not associated with low salivary levels of IgA and IgM.

Resumo As manifestações orais em pacientes com imunodeficiência comum variável (ICV) têm sido pouco estudadas e com resultados variados. Há escassos dados na literatura sobre os níveis de IgA, IgG e IgM na saliva, e pouco se sabe sobre o impacto clínico da deficiência destes anticorpos sobre a saúde bucal de pacientes com ICV. O objetivo deste estudo foi medir os níveis séricos e salivares de IgA, IgG e IgM em indivíduos com ICV e controles, e associar os níveis de imunoglobulinas com cárie e doença periodontal. Este foi um estudo de caso-controle, envolvendo 51 indivíduos ICV e 50 controles saudáveis. Todos os participantes foram examinados para cárie e doença periodontal. As amostras de sangue e saliva foram coletadas no mesmo dia do exame intraoral. Os níveis de IgA, IgM e IgG foram medidos por turbidimetria, e os títulos salivares de IgA, IgM e IgG foram avaliados através método imunoenzimático (ELISA). As incidências de cáries e gengivite foram significativamente maiores no grupo ICV do que no grupo controle (p<0,05). Os níveis de IgA e IgM salivares e no sangue foram significativamente reduzidos no grupo ICV, porém não houve associação dos níveis de imunoglobulina salivar com doença periodontal ou com a incidência de cárie (p>0,05 para ambos). Embora ICV foi associado com um aumento da susceptibilidade à cárie e gengivite, não estava associado com baixos níveis salivares de IgA e IgM.

IL-10-Producing Regulatory B Cells Are Decreased in Patients with Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. IL-10 production by sorted B cells culture and plasma sCD14 were determined by ELISA. We found that CVID patients presented decreased frequency of IL-10-producing CD24hiCD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24hiCD27+ B cells stimulated with CpG+PIB. Moreover, we found that CVID patients presented lower secretion of IL-10 by sorting-purified B cells when compared to healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individuals.

Association between immunologic parameters, glycemic control, and postextraction complications in patients with type 2 diabetes.

BACKGROUND: The purpose of this study was to assess the association between metabolic control and immune dysfunction, and postoperative complications and wound healing after dental extractions in people with type 2 diabetes and control participants. METHODS: The authors performed a prospective, case-control study enrolling 53 participants with type 2 diabetes and 29 participants who did not have type 2 diabetes. Exclusion criteria included being a smoker and having teeth with periodontal pockets deeper than 4 millimeters, among others. All participants underwent an extraction of 1 erupted tooth. The investigators assessed patients' signs and symptoms at 3, 7, 21, and 60 days after surgery. The investigators measured glycemic control and immunologic profile at the time of the extraction. They compared the pattern of healing and the incidence of postextraction complications between the 2 groups. RESULTS: Even in the presence of impaired neutrophil function and poor glycemic control, we found no increase in the number of postoperative complications. There was no association between delayed wound epithelialization on postoperative day 21 and level of glycemic control, and reduced neutrophil function. On postoperative day 60, all alveolar sockets were epithelialized completely and showed no signs of infection. CONCLUSIONS: The study results suggest that type 2 diabetes per se or glycemic control is not a risk factor for experiencing postoperative complications in people undergoing dental extractions. Although people with type 2 diabetes may have impaired neutrophil function, the study results revealed that having this condition was not associated with an increased risk of experiencing postoperative complications. Additional research studies with larger sample sizes of patients who have diabetes are needed to confirm this study's findings. PRACTICAL IMPLICATIONS: The results allow clinicians to infer that people with type 2 diabetes undergoing dental extractions of erupted teeth that do not have an acute odontogenic infection should not receive antibiotic prophylaxis simply because of their diabetic status or level of glycemic control.

Oral manifestations in patients with hypogammaglobulinemia.

OBJECTIVE: The overall objective of this study was to assess the oral manifestations and their association with immunologic status and health history, of individuals with hypogammaglobulinemia. STUDY DESIGN: A case-controlled study of 100 subjects with hypogammaglobulinemia and 93 control individuals was performed. All participants were examined for dental caries, periodontal disease, mucosal lesions/infections, and general oral health problems. Decayed, missing, filled teeth and community periodontal index were recorded. Complete blood count, serum immunoglobulins, and lymphocyte immunophenotyping were measured on the same day of the oral health assessment. RESULTS: Individuals with hypogammaglobulinemia showed higher prevalence of enamel hypoplasia and complaints of dry mouth, and lower prevalence of dental caries and periodontal disease. CONCLUSIONS: The systemic conditions associated with hypogammaglobulinemia were not associated with enhanced susceptibility to caries, gingivitis, or periodontitis; however, individuals with hypogammaglobulinemia were more likely to report more episodes of recurrent aphthous ulcers compared with control individuals.