Predominantly antibody deficiency: case report / Deficiência predominantemente de anticorpos: relato de caso

Abstract Objectives: present a case of Inborn errors of immunity (IEI) as a potential diagnosis in pediatric patients with recurrent infections. Description: male patient, 13 years old, since he was eight months old had recurrent diarrhea, sinusitis, otitis, abscesses and urinary tract infections. At the age of ten, he presented mastoiditis progressing to meningitis, he was admitted to a tertiary hospital, where an immunological evaluation was performed, which led to the diagnosis of Predominantly Antibody Deficiency (PAD), with suspected X-linked Agammaglobulinemia (XLA). Treatment was initiated with administration of intravenous gamma globulin 400 mg/kg every four weeks, with a significant improvement of the condition. Discussion: usually, the diagnosis of XLA tends to be made in the first three years of life. However, in this report, although the first manifestations started at eight months of age, there was a delay of ten years before starting the treatment. In fact, the diagnosis of children and adults with IEI can be delayed if healthcare professionals are unable to find the true cause of recurrent infections. Therefore, the relevance of considering such pathologies in the presence of risk signs is highlighted, as early diagnosis being essential in treating and preventing morbidities.

Resumo Objetivos: apresentar um caso de Erro Inato da Imunidade (EII) como diagnóstico em potencial de pacientes pediátricos com infecções de repetição. Descrição: paciente masculino, 13 anos, desde os oito meses de idade apresentou quadros repetidos de diarreias, sinusites, otites, abscessos e infecções do trato urinário; destacando-se a otite, sinusite e diarreia pela maior recorrência. Aos dez anos, quando apresentou mastoidite evoluindo para meningite, foi internado em um hospital terciário, onde foi realizada avaliação imunológica, a qual levou ao diagnóstico de Deficiência Predominantemente de Anticorpos (DPAs), tendo como suspeita a agamaglobulinemia ligada ao cromossomo X (ALX). Foi iniciado tratamento com administração de gamaglobulina endovenosa 400 mg/kg a cada quatro semanas, ocorrendo melhora significativa do quadro. Discussão: normalmente, o diagnóstico da ALX tende a ser feito nos primeiros três anos de vida. Neste relato, entretanto, embora as primeiras manifestações tenham iniciado aos oito meses de idade, ocorreu um atraso de dez anos até o início do tratamento. De fato, o diagnóstico de crianças e adultos com EII pode ser retardado se os profissionais de saúde não conseguirem encontrar a causa das infecções recorrentes. Destaca-se, portanto, a relevância de se considerar tais patologias na vigência de sinais de riscos, pois o diagnóstico precoce é fundamental para tratar e prevenir morbidades.

Autosomal recessive complete signal transducer and activator of transcription 1 deficiency in a newborn: a case report / 中华围产医学杂志

We reported the clinical data of a neonate admitted to the Second Affiliated Hospital (Yuying Children's Hospital) of Wenzhou Medical University in November 2021 with autosomal recessive complete signal transducer and activator of transcription 1 ( STAT1) deficiency identified by whole exome sequencing. The baby boy received bacillus of calmette-guerin (BCG) vaccine 2 d after birth and presented with persistent high fever, increased white blood cell count and increased level of C-reactive protein (CRP) on 21 d after birth. Human cytomegalovirus (HCMV) was detected in both blood and bone marrow specimens. The patient improved after comprehensive treatment with antiviral agents, antibiotics and intravenous gammaglobulin. Oral anti-viral drugs were prescribed on discharge. However, the baby was rehospitalized due to a fever at 55 days. HCMV and Mycobacterium tuberculosis complex were detected in blood samples. The infant was transferred to the Children's Hospital of Fudan University due to persistent high fever even after active management and died after treatment withdrawal at 69 d after birth because of worsening infections and multiple organ failure. A homozygous mutation in the STAT1 gene was detected [c.1011_1012del, NM_007315: exon11: c.1011_1012del (p.V339Pfs*18)] and the child was diagnosed as autosomal recessive complete STAT1 deficiency. We concluded that the clinical manifestations of autosomal recessive complete STAT1 deficiency are bacterial infections caused by lethal low-pathogenic mycobacteria and life-threatening virus infections. Whole exome sequencing is of great value for early diagnosis and timely treatment. The prognosis of this disease is very poor, but the condition of the patients might be improved in a short period with early anti-tuberculosis and anti-viral treatment.

Manejo clínico y diagnóstico para pacientes con enfermedades de inmunodeficiencia primaria por déficit de producción de anticuerpos / Clinical management and diagnosis for patients with primary immunodeficiency diseases due to deficiency of antibody production

1. INTRODUCCIÓNLas inmunodeficiencias primarias son un grupo de más de 400 enfermedades, en las cuales el sistema inmune pierde sus funciones de reconocimiento de patógenos o funciona de forma inapropiada. Algunas de ellas son relativamente comunes; mientras otras son raras. Estas enfermedades son en ocasiones de por vida, debilitantes y costosas1,2.Sin embargo, muchos progresos se han hecho desde su des-cripción original en el año de 1952. Se han dado grandes pasos en cuanto a su entendimiento de las Inmunodeficiencias Pri-marias a nivel genético, de sus características, y tratamiento. Algunos tipos afectan un único tipo de célula; otros afectan más de un componente del sistema inmune2,3.Tomando en cuenta que la aproximación es entre 1-2% de la población, a nivel país se puede decir que un aproximado entre 170 000 a 340 000 pacientes en el país no cuentan con un diagnóstico y muchos mueren por falta de este. El número de afiliados al Instituto Ecuatoriano de Seguridad Social hasta julio de 2021 es de 3 672,611 por lo que se considera que un estimado de 36 726 a 73 452 pacientes podrían presentar este tipo de enfermedades y requerir de atención por infecciones a repetición, enfermedad autoinmune y enfermedades linfopro-liferativas, además de que sin un tratamiento específico po-drían fallecer debido a infecciones graves o tener discapacidad permanente, lo que implica mayor carga para el sistema de Seguridad Social en subsidios y menores ingresos. Ecuador, cuenta con 86 pacientes diagnosticados, según la base de datos de la Sociedad Latino-Americana de Inmunodeficiencias4.Algunas terapias, como la de reemplazo para inmunoglobu-linas, a la que es tributaria más del 60% de estas patologías permite que la esperanza de vida y la morbilidad casi alcancen a aquellos que no presentan la enfermedad5­7.

1. INTRODUCTIONPrimary immunodeficiencies are a group of more than 400 diseases, in which the immune system loses its pathogen recog-nition functions or functions inappropriately. Some of them are relatively common, while others are rare. These diseases are sometimes lifelong, debilitating, and costly1,2. However, much progress has been made since its original description in 1952. Great strides have been made in understanding Primary Immunodeficiencies at the genetic level, their characteristics, and treatment. Some types affect only one type of cell; others affect more than one component of the immune system2,3. Considering that the approximation is between 1 to 2% of the population, at the country level we could say that approximately between 170 000 to 340 000 patients in the country do not have a diagnosis and many die due to lack of it. The number of social security affiliates until July 2021 is 3 672,611, so we could consider that approximately 36 726 to 73 452 patients could present this type of disease and require care for recurrent infections, autoimmune disease and lymphoproliferative diseases, in addition to the fact that without specific treatment they could die due to serious infections or have permanent disability, which implies a greater burden for the social security system in subsidies and lower income. Currently the country has 86 diagnosed patients, according to the database of the Latin American Society of Immunodeficiencies4. Many of the therapies, such as immunoglobulin replacement therapy, to which more than 60% of these pathologies are de-pendent, allow life expectancy and morbidity to almost reach those who do not have the disease 5­7.

Tuberculose intratorácica na forma pseudotumoral e óssea como manifestação de doença granulomatosa crônica / Intrathoracic tuberculosis in the pseudotumoral and bone form as a manifestation of chronic granulomatous disease

A doença granulomatosa crônica (DGC) é um erro inato da imunidade de fagócitos, e ocorre em decorrência de mutações que afetam componentes da enzima NADPH oxidase. Os pacientes são suceptíveis a infecções graves e letais por fungos e bactérias. O objetivo deste trabalho é relatar o caso de um lactente com DGC que apresentou manifestação clínica de tuberculose (TB) intratorácica na forma pseudotumoral e óssea iniciada no período neonatal. O diagnóstico de DGC foi realizado através do teste de DHR e, após o início da profilaxia com sulfametoxazoltrimetroprima e itraconazol, o paciente manteve-se estável clinicamente. A mãe e a irmã também apresentaram DHR alterados, a análise genética revelou uma mutação ligada ao X no exon 2 do gene CYBB c.58G>A, levando uma alteração em G20R. É fundamental que o diagnóstico seja realizado o mais precocemente possível, a fim de instituir as orientações aos familiares e tratamento adequado, reduzindo assim complicações infecciosas e melhorando prognóstico.

Chronic granulomatous disease (CGD) is an inborn error of phagocyte immunity and occurs as a resulto f mutations that affect components of the NADPH oxidase enzyme. Patients are susceptible to serious and lethal fungal and bacterial infections. The aim of this paper is to report a case an infant with CGD who presented clinical manifestations of intrathoracic tuberculosis (TB) in the pseudotumoral and bone form, which started in the neonatal period. The diagnosis of CGD was performed using the DHR test and, after starting prophylaxis with sulfamethoxazole-trimethoprim and itraconazole, the patient remained clinically stable. The mother and sister also had altered DHR, genetic analysis revealed an X-linked mutation in exon 2 of the CYBB gene c.58G>A, leading to an alteration in G20R. It is essential that the diagnosis is made as early as possible, in order to establish guidelines for Family members and adequate treatment, thus reducing infectious complications and improving prognosis.

Errores innatos de la inmunidad: ¿Qué debe saber y cuándo debe sospechar el otorrinolaringólogo? / Inborn errors of immunity: What should the otolaryngologist know, and when to suspect them?

Introducción: Los errores innatos de la inmunidad, previamente conocidos como inmunodeficiencias primarias, son un grupo heterogéneo de patologías cuya presentación clínica incluye infecciones recurrentes, persistentes o refractarias al tratamiento en el campo de la otorrinolaringología. Materiales y métodos: Se realizó una revisión narrativa de la literatura a partir de la búsqueda de documentos en PUBMED y EMBASE. Discusión y conclusiones: Los pacientes con sospecha de error innato de la inmunidad requieren un diagnóstico temprano con el fin de disminuir las complicaciones a largo plazo, por lo que la valoración y el abordaje inicial desempeñan un papel fundamental en el reconocimiento de estas enfermedades.

Introduction: Inborn errors of immunity, previously known as primary immunodeficiencies, are a heterogeneous group of pathologies whose clinical presentation includes recurrent, persistent and/or refractory infections to treatment in otorhinolaryngology. Materials and methods: Narrative review of the literature was carried out from the search for articles in PUBMED and EMBASE. Discussion and conclusions: Patients with suspected inborn error of immunity require an early diagnosis to reduce long-term complications; the initial assessment and approach play a fundamental role in the recognition of these diseases

Elevated IgA and IL-10 levels in very-early-onset inflammatory bowel disease secondary to IL-10 receptor deficiency / Níveis elevados de IgA e IL-10 na doença inflamatória intestinal de início muito precoce secundária à deficiência do receptor de IL-10

ABSTRACT Objective: To report two patients with very-early-onset inflammatory bowel disease (VEOIBD) secondary to interleukin-10 receptor (IL-10R) mutations, explore immunophenotyping data and plasma cytokine profile on these cases compared to healthy controls, and describe the phenotype of IL-10/IL-10R mutations based on a literature review. Case description: We report on two female infants referred to our tertiary center at the age of ten months, with severe colonic and perianal disease, as well as significant malnutrition, who had shown limited response to usual inflammatory bowel disease (IBD) therapy agents. In the first case, whole-exome sequencing (WES) revealed a homozygous (c.537G>A/p.T179T) mutation in exon 4 of the IL-10RA gene, while in the second patient, compound heterozygosity was identified, also in the IL-10RA gene (chr11:117.859.199 variant A>G/p.Tyr57Cys and chr11: 117.860.335 variant G>T/p.Val123Leu). Both patients underwent hematopoietic cell transplantation (HCT). Immunological work-up of these patients revealed increased IL-10 plasma levels and increased IgA. Comments: Our case reports disclose novel findings on plasma cytokine profile in IL-10R deficiency, and we describe the severe phenotype of IL-10/IL-10R deficiency that should be recognized by physicians.

RESUMO Objetivo: Relatar os casos de duas pacientes com doença inflamatória intestinal de início muito precoce (em inglês VEOIBD) secundária a mutações do receptor de interleucina 10 (IL-10R), explorar dados de imunofenotipagem e perfil de citocinas plasmáticas nesses casos em comparação com indivíduos saudáveis e descrever o fenótipo de mutações IL-10/IL-10R com base em uma revisão da literatura. Descrição do caso: Duas lactentes do sexo feminino foram encaminhadas ao nosso centro terciário, ambas com dez meses no momento do encaminhamento, com doença colônica e perianal grave, bem como desnutrição significativa, tendo uma resposta limitada aos agentes de terapia usuais de doença inflamatória intestinal (DII). No primeiro caso, o sequenciamento completo do exoma revelou mutação homozigótica (c. 537G>A/p.T179T) no exon 4 do gene IL-10RA, enquanto no segundo caso heterozigosidade composta foi identificada também no gene IL-10RA [chr11: 117.859.199 - variante A>G/p.Tyr57Cys e chr11: 117.860.335 - variante G>T/ p.Val123Leu]. Ambas as pacientes foram submetidas a Transplante de Células-Tronco Hematopoiéticas. A investigação imunológica das pacientes revelou aumento dos níveis plasmáticos de IL-10 e aumento da IgA. Comentários: Nossos relatos de casos descrevem novos achados no perfil de citocinas plasmáticas na deficiência de IL-10R, e relatamos o fenótipo grave da deficiência de IL-10/IL-10R que deve ser reconhecido pelos médicos.

Clinical Features and Genetic Analysis of Autosomal Dominant and Recessive Hyperimmunoglobulin E Syndrome / 罕见病研究

  Objective  To summarize the clinical and genetic features of children with autosomal dominant and recessive hyperimmunoglobulin E syndrome (HIES).  Methods  HIES patients were studied at the dermatology department of Beijing Children's Hospital, Capital Medical University were collected, from January 2013 to December 2021, diagnosed by both clinical manifestation and genetic assessment. The general data were summarized, the clinical and genetic characteristics were analyzed, and the similarities and differences between autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES) were compared.  Results  A total of 7 children with HIES were studied, including 3 cases of AD-HIES and 4 cases of AR-HIES. There were 4 males and 3 females. All children had recurrent eczema-like lesions, recurrent skin and pulmonary infections, and elevated serum IgE and eosinophil levels. The differences between AD-HIES and AR-HIES mainly include: the main cutaneous infection in 3 children with AD-HIES were bacterial infections (such as abscess and impetigo), while in 4 children with AR-HIES, cutaneous infections were mostly severe viral infection (such as verruca vulgaris and molluscum contagiosum). There were pulmonary parenchymal changes (such as pneumatoceles, cyst and atelectasis) in 3 children with AD-HIES, whilst there were no similar changes in the lungs of 4 children with AR-HIES; 75% of children with AR-HIES had allergic diseases (including asthma and food allergy), while there were no reports of allergic diseases in children with AD-HIES. As for manifestations outside of immune system, AD-HIES was more likely to appear facial dysmorphism(such a broad nasal bridge and a high-arched palate). Furthermore, the incidence of tumor in AR-HIES was higher than that in AD-HIES. AD-HIES was mainly caused by the mutation of STAT3 gene, and AR-HIES was mainly caused by the mutation of DOCK8 gene. We reported two new mutation sites of DOCK8 gene c.1798-2A > T and c.874G > A in two cases, respectively.  Conclusions  For children with clinical manifestations of recurrent eczema-like lesions, repeated infection and significant increase in serum IgE levels, HIES should be suspected, and genetic screening should be carried out to make definite diagnosis and classification, to achieve better long-term management and improve prognosis.

Detección de deficiencias de anticuerpos y caracterización clínico-demográfica en pacientes pediátricos con enfermedades alérgicas

RESUMEN Introducción: Las deficiencias predominantes de anticuerpos (DPA) cursan con disminución de niveles séricos de inmunoglobulinas (hipogammaglobulinemia), infecciones recurrentes y se ha reportado su asociación con las alergias. La información sobre su frecuencia en niños alérgicos es limitada y en Paraguay no existen datos al respecto. Objetivo: Detectar DPA y establecer su frecuencia en pacientes pediátricos con enfermedades alérgicas atendidos en un hospital de referencia del país. Materiales y métodos: Fueron evaluados 64 pacientes pediátricos (1 a 17 años de edad) con diagnóstico de alergia, atendidos en la Unidad Pediátrica Ambulatoria-Especialidad Asma, Alergia e Inmunología del Hospital de Clínicas (periodo 2018-2019). Se midieron los niveles séricos de IgA, IgG e IgM por el método de inmunodifusión radial y se aplicaron criterios de diagnóstico fenotípico a los casos de hipogammaglobulinemia para definir la DPA. Resultados: La mediana de edad fue de 5 años (RIQ: 2 - 8), con predominio del sexo masculino (58%). Las alergias más frecuentes fueron asma (38%) y rinitis (34%), además predominaron las infecciones respiratorias recurrentes (80%). La frecuencia de DPA fue de 17% (11/64), detectándose 6 casos de deficiencia de inmunoglobulina A, 4 deficiencias aisladas de IgG y una inmunodeficiencia común variable. No se observaron diferencias significativas al comparar características clínico-demográficas entre pacientes alérgicos con y sin DPA. Conclusiones: La frecuencia de DPA fue elevada, por lo que se sugiere considerar el estudio de inmunoglobulinas séricas en pacientes pediátricos con enfermedades alérgicas para una detección y tratamiento oportunos.

ABSTRACT Introduction: Predominant antibody deficiencies (PAD) present with decreased serum levels of immunoglobulins (hypogammaglobulinemia), recurrent infections and their association with allergies has been reported. Information on its frequency in allergic children is limited and in Paraguay there are no data in this regard. Objective: To detect PAD and establish its frequency in pediatric patients with allergic diseases treated at a reference hospital in the country. Materials and methods: 64 pediatric patients (1 to 17 years of age) with a diagnosis of allergy, treated in the Pediatric Outpatient Unidad Pediátrica Ambulatoria-Especialidad Asma of the Hospital de Clínicas (from 2018 to 2019) were evaluated. Serum levels of IgA, IgG and IgM were measured by the radial immunodiffusion method and phenotypic diagnostic criteria were applied to hypogammaglobulinemia cases to define PAD. Results: The median age was 5 years (IQR: 2 - 8), with a predominance of males (58%). The most frequent allergies were asthma (38%) and rhinitis (34%), and recurrent respiratory infections (80%) predominated. The frequency of PAD was 17% (11/64), with 6 cases of immunoglobulin A deficiency detected, 4 isolated IgG deficiencies and a common variable immunodeficiency were also detected. No significant differences were observed when comparing clinical-demographic characteristics between allergic patients with and without PAD. Conclusions: The frequency of PAD was high, so we suggest considering serum immunoglobulins studies in pediatric patients with allergic diseases for timely detection and treatment.

Apresentação atípica de síndrome de hiper-IgM ligada ao X simulando doença inflamatória intestinal / Atypical presentation of X-linked hyper-IgM syndrome simulating inflammatory bowel disease

Relatamos o caso de um paciente do sexo masculino, que iniciou quadro de úlceras em trato gastrointestinal, associado a febre recorrente e diarreia com muco e sangue aos 10 meses de vida, suspeitado inicialmente de doença inflamatória intestinal, no entanto, não apresentou melhora do quadro com terapia imunossupressora, sendo realizada investigação para erro inato da imunidade. Nos exames laboratoriais, apresentou níveis baixos de IgG e IgA e níveis elevados de IgM e neutropenia persistente. Diante disso, foi realizado teste genético que confirmou diagnóstico de síndrome de hiper-IgM ligada ao X. Os erros inatos da imunidade podem se manifestar com doenças do trato gastrointestinal, de forma relativamente frequente, devendo entrar como diagnóstico diferencial de diarreia crônica. Inclusa nesse grupo de doenças, as síndromes de hiper-IgM constituem um grupo heterogêneo de doenças, possuindo em comum níveis significativamente baixos ou ausentes de IgG e IgA e níveis normais ou elevados de IgM, o que predispõe a infecções e febre recorrente; além de outras alterações laboratoriais, como neutropenia, que pode estar associada a úlceras no trato gastrointestinal e proctite, simulando apresentação clínica de doença inflamatória intestinal. Para o paciente relatado, foi iniciada terapia com imunoglobulinas de forma periódica, além de antibioticoprofilaxia para infecções, evoluindo com resposta clínica satisfatória. O artigo possui objetivo principal de alertar para o diagnóstico diferencial de erros inatos da imunidade diante do quadro apresentado, visando o diagnóstico precoce e a instituição da terapia adequada.

We report the case of a male patient, who started with ulcers in the gastrointestinal tract, associated with recurrent fever and diarrhea with mucus and blood at 10 months of life, initially suspected of inflammatory bowel disease, however, he did not improve the condition with immunosuppressive therapy, being investigated for inborn error of immunity. In laboratory tests, he had low levels of IgG and IgA and high levels of IgM and persistent neutropenia. Therefore, a genetic test was performed and confirmed the diagnosis of X-linked hyper IgM syndrome. Inborn errors of immunity can manifest relatively frequently with diseases of the gastrointestinal tract, and should be included as a differential diagnosis of chronic diarrhea. Included in this group of diseases, hyper-IgM syndromes constitute a heterogeneous group of diseases, having in common significantly low or absent levels of IgG and IgA and normal or high levels of IgM, which predispose to infections and recurrent fever; in addition to other laboratory alterations, such as neutropenia, which may be associated with ulcers in the gastrointestinal tract and proctitis, simulating the clinical presentation of inflammatory bowel disease. For the reported patient, therapy with immunoglobulins was started periodically, in addition to antibiotic prophylaxis for infections, evolving with a satisfactory clinical response. The main objective of the article is to alert to the differential diagnosis of inborn errors of immunity in view of the presented condition, aiming at early diagnosis and the institution of adequate therapy.

Síndrome de hiperinmunoglobulinemia E: dermatitis atópica como manifestación inicial. A propósito de un caso / Hyper IgE syndrome: atopic dermatitis as first manifestation. Case report

La dermatitis atópica es la forma más frecuente de eccema durante el primer año de vida; sin embargo, cuando la presentación es atípica o se asocia a infecciones, constituye un desafío diagnóstico para el pediatra. Es importante mantener un índice alto de sospecha para detectar inmunodeficiencias primarias asociadas a eccemas graves desde el período neonatal. Un ejemplo de estas es el síndrome de hiperinmunoglobulinemia E (hiper-IgE) autosómico dominante. Este cuadro se caracteriza por la presencia de infecciones cutáneas y respiratorias recurrentes, dermatitis atópica, eosinofilia y aumento de IgE. Se reporta el caso clínico de una niña de 1 mes y 29 días con diagnóstico de hiper-IgE con afección cutánea desde el nacimiento.

Atopic dermatitis is the most common form of eczema often developed before the first year of life. Nevertheless, when the presentation is atypical or related to infections the diagnostic represents a challenge for the pediatricians. It is important to maintain a high index of suspicion for the detection of primary immunodeficiency associated to severe eczema. One of them is the autosomal dominant hyper-IgE syndrome characterized by recurrent skin and respiratory infections, atopic dermatitis, eosinophilia, and high serum IgE concentrations. In this paper, we report a 1 months and 29 days old baby girl diagnosed with hyper-IgE and a skin involvement since birth.

Supervivenciade pacientes pediátricos con inmunodeficiencias primarias en un hospital público del occidente de México / Survival of pediatric patients with primary immunodeficiencies in a public hospital in western Mexico

Se presenta una serie de casos de inmunodeficiencias primarias y se describen las variables asociadas a supervivencia en pacientes ≤ 16 años. Los diagnósticos fueron acordes a los criterios de la Unión Internacional de las Sociedades de Inmunología. Se realizó un análisis de supervivencia mediante curvas de Kaplan-Meier.Entre los años 2004 y 2019, se diagnosticaron 40 pacientes con inmunodeficiencias primarias. Las más frecuentes fueron inmunodeficiencias que afectaban la inmunidad celular y humoral, el 32,5 %, y deficiencias predominantemente de anticuerpos, el 32,5 %. La mediana de edad al inicio de los síntomas y al momento del diagnóstico fue de 3,01 y 10,4 meses, respectivamente. Fallecieron el 35 % y el riesgo fue mayor en pacientes con inmunodeficiencias que afectaban la inmunidad celular y humoral y en quienes presentaron manifestaciones clínicas y tuvieron el diagnóstico en los primeros seis meses de vida.

A case series of primary immunodeficiencies is presented and outcome measures associated with survival among patients ≤ 16 years old are described. Diagnoses were made based on the criteria by the International Union of Immunological Societies. Survival was analyzed using Kaplan-Meier curves.Between 2004 and 2019, 40 patients were diagnosed with primary immunodeficiencies. The most common were immunodeficiencies affecting humoral and cell-mediated immunity (32.5 %) and predominantly antibody deficiencies (32.5 %). The median age at the onset of symptoms and at the time of diagnosis was 3.01 and 10.4 months, respectively. Thirty-five percent of patients died, and the risk was higher among those with immunodeficiencies affecting humoral and cell-mediated immunity and those who developed clinical manifestations and were diagnosed in the first 6 months of life

Failure of immunological competence: when to suspect?

Abstract Objectives: To draw physicians' attention to the different warning signs of diseases of inborn errors of immunity. Data sources: A non-systematic review of the literature was carried out in the PubMed, LILACS, and SciELO databases, in addition to consultation of reference textbooks. Summary of the findings: It is known that the lack of immunological competence observed in patients with inborn errors of immunity diseases causes particularly serious and/or recurrent infections. However, manifestations related to autoimmunity, inflammation, allergies, and malignancy can also occur. Aiming at the early identification of these patients, a list of warning signs for inborn errors of immunity was created, in which the need for intravenous antibiotics or prolonged antibiotics use to control infection, failure to thrive, and positive family history for this group of diseases are considered the most sensitive. Regarding non-infectious manifestations, early onset, difficulty in controlling with the usual treatments, atypical presentations or association with other warning signs are noteworthy, and investigation for inborn errors of immunity in these situations is recommended. Conclusions: This article highlights the importance of considering this group of diseases even in the face of patients with non-infectious manifestations. Disclosure of inborn errors of immunity diseases, especially to non-specialists, is essential for early diagnosis and, consequently, for the reduction of these patients' morbidity and mortality.

Treatment of patients with immunodeficiency: Medication, gene therapy, and transplantation

Abstract Objectives: To provide an overview of drug treatment, transplantation, and gene therapy for patients with primary immunodeficiencies. Source of data: Non-systematic review of the literature in the English language carried out at PubMed. Synthesis of data: The treatment of patients with primary immunodeficiencies aims to control their disease, especially the treatment and prevention of infections through antibiotic prophylaxis and/or immunoglobulin replacement therapy. In several diseases, it is possible to use specific medications for the affected pathway with control of the condition, especially in autoimmune or autoinflammatory processes associated with inborn immunity errors. In some diseases, treatment can be curative through hematopoietic stem cell transplantation (HSCT); more recently, gene therapy has opened new horizons through new technologies. Conclusions: Immunoglobulin replacement therapy remains the main therapeutic tool. Precision medicine with specific drugs for altered immune pathways is already a reality for several immune defects. Advances in the management of HSCT and gene therapy have expanded the capacity for curative treatments in patients with primary immunodeficiencies.

Genetic-molecular characterization in the diagnosis of primary immunodeficiencies

Abstract Objectives: To rescue medical genetics concepts that are necessary to understand the advances in the genetic-molecular characterization of primary immunodeficiencies, to help in the understanding and adequate interpretation of their results. Source of data: Non-systematic literature review, searching for articles since 2000 on PubMed using the terms "genetic evaluation" OR "whole exome sequence" or "whole genome sequence" OR "next generation sequence" AND "immunologic deficiency syndromes" OR "Immune deficiency disease" OR "immune deficiency" NOT HIV. Summary of the data: Knowledge of medical genetics is essential for the understanding of the principles of heredity and disease inheritance patterns, types of genetic variants, types of genetic sequencing and interpretation of their results. The clinical and immunophenotypic evaluation of each patient is essential for the correlation with the genetic variants observed in the genetic study of patients with primary immunodeficiencies. The discussion of the benefits and limitations of genetic tests should always guide the performance of genetic tests. Conclusions: There are many evident benefits of genetic analysis, such as the definitive diagnosis of the disease, family genetic counseling, and the possibility of a more adequate and accurate management. Cost, access and interpretation of genetic test results are limitations that need continuous improvement. The understanding of the benefits and limits of the several genetic assessment methodologies related to primary immunodeficiencies is essential to obtain more effective results from the sequencing.

Vacinas contra a COVID-19 e os erros inatos da imunidade (ou imunodeficiências primárias) / COVID-19 vaccines and inborn errors of immunity (or primary immunodeficiencies)

Desde o início da pandemia de COVID-19 iniciou-se a corrida por uma imunização ativa, eficaz e segura. Todas as vacinas desenvolvidas até o momento vêm demostrando boa eficácia na prevenção de casos graves de COVID-19, de hospitalizações e mortes. Muitos pacientes com erros inatos da imunidade (EII) não terão capacidade de desenvolver uma resposta imune semelhante ao indivíduo imunocompetente. Esses pacientes foram incluídos nos grupos prioritários definidos pelo Ministério da Saúde, como pessoas entre 18 a 59 anos com uma ou mais das comorbidades, incluindo as imunodeficiências primárias. Eles podem e devem receber as vacinas em uso contra o SARS-CoV-2, mas nem sempre apresentarão uma resposta imunológica satisfatória e protetora, e, portanto, seus contactantes também devem ser vacinados.

Since the beginning of the COVID-19 pandemic, the race for an active, effective, and safe immunization has started. All vaccines developed to date have shown good efficacy in preventing serious cases of COVID-19, hospitalization, and death. Many patients with inborn errors of immunity will not be able to develop an immune response similar to that of immunocompetent individuals. These patients were included in the priority groups defined by the Brazilian Ministry of Health, as people between 18 and 59 years of age with one or more comorbidities, including primary immunodeficiencies. They can and should receive the vaccines in use against SARS-CoV-2, but they will not always have a satisfactory and protective immune response, and, therefore, those in direct contact with them should also be vaccinated.

Progress of allogeneic hematopoietic stem cell transplantation for hyper IgM syndrome / 国际儿科学杂志

Hyper immunoglobulin M syndrome(HIGM)is a group of rare primary immunodeficiency disease(PID)caused by single gene mutation.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is the only treatment to cure the disease, and patients should receive allo-HSCT if possible.Younger patients who can keep in good pre-transplant state, obtain matching sibling donor and tolerate to myeloablative conditioning may get better outcome after early transplantation, and the overall survival rate can reach 80%.The progress in the timing of transplantation, donor and graft, conditioning regimen, prevention and treatment of complications of allo-HSCT for HIGM is reviewed in this paper.

Clinical and epidemiological characteristics of patients with suspected primary immunodeficiency disorders attending Alexandria University Children's Hospital

Background: Current study was conducted to determine the clinical and epidemiological characteristics of patients with suspected primary immunodeficiencies (PID) seen at Alexandria University Children's Hospital.Methods: Eighty one patients with suspected PID were seen at Alexandria University Children's Hospital in one year in the period from September 2016 to October 2017. Demographic data of the patients as well as data related to their disease status were taken and evaluation sheet was developed for all patients.Results: About 61.7% of patients satisfied the criteria of PID based on WHO Scientific Committee. According to modified IUIS classification predominant antibody deficiency was the commonest (34%) followed by other well defined immunodeficiency syndromes (30%), combined immunodeficiencies (16%), phagocytic defects (14%), diseases of immune dysregulation 4% and complement deficiencies (2%). The most frequent disorder was X-linked agammagloulinemia (XLA) (22%). The mean age at diagnosis was 27.4 months. The consanguinity rate was 55.5%. A positive Family history was a strong pointer to diagnosis for PID (46.9%). The commonest clinical presentation was pneumonia (82.7%). 28.4% of patients died from infections. As observed in other patient registries, diagnostic delay remains the major cause of morbidity and mortality.Conclusions: Primary immunodeficiency disorders are not rare in Egyptian children. Creating awareness of PID should be targeted at hospital pediatricians and families with history of PID and this may reveal more cases within the community. The observed high frequency of combined T- and B-cell immunodeficiencies in this cohort made it a health issue in Egypt as in other developing countries.

Copy number variations and primary immunodeficiency diseases / 国际儿科学杂志

Copy number variation (CNV) is an important part of genomic structural variation.Studies have shown that CNV is closely related to the occurrence of diseases,such as neuro-developmental diseases,congenital metabolic diseases and viral infections.Primary immunodeficiency diseases (PIDs) are inheritary disorders in which part of the immune system is missing or has not function normally.With the development of sequencing technology,more and more attention has been paid in the CNV research of immune diseases.This article reviewed the progress between CNV and PIDs,as well as the important role of CNV in the diagnosis of PIDs.

Clinical and immunological analysis of the patient with autoimmunity due to germline STAT3 gain-of-function mutation / 中华儿科杂志

Objective@#To investigate the clinical and immunological laboratory features and gene mutation in a female patient who carried a germline gain-of-function mutation in STAT3.@*Method@#A patient with lymphadenopathy and pancytopenia, visited the Department of Rheumatology and Immunology of Children′s Hospital of Chongqing Medical University in May 2016. The clinical and laboratory characteristics, results of immunophenotyping and exome sequencing were analyzed retrospectively and related literature was reviewed.@*Result@#The patient was a four years old girl. The clinical manifestation consisted of autoimmune pancytopenia, lymphadenopathy and recurrent infections. Multiple exams showed that peripheral blood leukocyte count was (2.2-4.9)×109/L, red blood cell count was (2.09-5.75)×109/L, hemoglobin level was 64-165 g/L, platelet count was (52-138) ×109/L. Percentages of lymphocyte subsets showed that CD3+ T lymphocyte was 0.716 0 (CD4+ T lymphocyte was 0.326 0, CD8+ T lymphocyte was 0.323 0 and CD4- CD8-T TCRαβ+ lymphocyte was 0.029 0), CD19+ B lymphocyte was 0.235 0 (transitional B was 0.004 3), NK was 0.032 0. Percentages of CD4+ T lymphocyte release IL-4, IFN-γ, IL-17 and IL-21 were 0.014 9, 0.213, 0.024 0 and 0.021 0, respectively. Lymphocyte proliferation function and TCRVβ diversity were normal. The serum immunoglobulin levels were 16.4 g/L (IgG), 1.53 g/L (IgA), 3.99 g/L (IgM) and 3.20 kU/L (IgE). The patient carried a missense variant in the 21st exon of STAT3, c. 1974G>C, p.K658N, which was previously described as a gain-of-function mutation. The patient was treated with methylprednisolone and prednisone intermittently. There were significant improvements of hepatosplenomegaly, lymphadenopathy and pancytopenia. We searched internal database and literature for cases with gain-of-function mutations in STAT3. A total of 19 cases were identified, all were non-Chinese. Among 16 cases who had clinical data, age of onset of 11 patients was less than 5 years. 14 cases had autoimmune hemolytic anemia, autoimmune thrombocytopenia or autoimmune neutropenia. Twelve patients had lymphadenopathy while 11 had infections and 5 had endocrine abnormalities.@*Conclusion@#The patient with Primary immunodeficiency disease (PID) due to gain-of-function mutation in STAT3 gene often has early-onset autoimmune disorders, lymphadenopathy and recurrent infections. Since the routine immunological examination may be normal or slightly abnormal, comprehensive evaluation of immune function should be done. Genetic testing ultimately helps to confirm the diagnosis.