Infecciones en pacientes con inmunodeficiencias primarias en Pinar del Río / Infections in patients with primary immunodeficiencies in Pinar del Rio

RESUMEN Introducción: los errores innatos de la inmunidad son trastornos cuya causa es un defecto genético en uno o más componentes del sistema inmune. A pesar de que la forma de presentación varía según el defecto genético, la mayoría cursa con enfermedades infecciosas que presentan características de recurrencia y persistencia. Objetivo: determinar la prevalencia de los procesos infecciosos en los pacientes registrados con diagnóstico de Inmunodeficiencia Primaria en el Servicio de Inmunología del Hospital Pediátrico Provincial Docente "Pepe Portilla" de Pinar del Río, en el periodo comprendido de 1994 a marzo de 2021. Métodos: estudio transversal descriptivo. Se analizaron los registros médicos de 125 pacientes diagnosticados de inmunodeficiencias que aparecen registrados en la Base de Datos del Servicio de Inmunología del Hospital Pediátrico Provincial Docente "Pepe Portilla" de Pinar del Río. Resultados: el 85,6 % de pacientes presentaron diagnóstico de algún déficit predominante de anticuerpos. Predominó el sexo masculino, y el rango etario de 6 a 10 años. Las infecciones de mayor presencia fueron la faringoamigdalitis aguda catarral (77,6 %), seguido de la neumonía (58,4 %) y la amigdalitis (56 %). De los signos de alarma que se relacionan con infecciones solo cuatro se encontraron en los pacientes del registro. Conclusión: la susceptibilidad a infecciones no es necesariamente el rasgo clínico preponderante en las inmunodeficiencias primarias, pero el fenotipo infeccioso es el mejor indicador sugestivo para algún defecto de la inmunidad. Aunque es necesario plantear nuevos criterios de manifestaciones infecciosas que faciliten el diagnóstico probable de inmunodeficiencia de forma general y por grupos.

ABSTRACT Introduction: inborn errors of immunity are disorders whose cause is a genetic defect in one or more components of the immune system. Although the form of presentation varies according to the genetic defect, most of them present infectious diseases with recurrent and persistent characteristics. Objective: to determine the prevalence of infectious processes in patients registered with diagnosis of Primary Immunodeficiency in the Immunology Service at Pepe Portilla Provincial Pediatric Teaching Hospital, Pinar del Rio in the period from 1994 to March 2021. Methods: descriptive, cross-sectional study. The medical records of 125 patients diagnosed with immunodeficiencies registered in the database of the Immunology Service at Pepe Portilla Provincial Pediatric Teaching Hospital of Pinar del Rio were analyzed. Results: the 85,6 % of patients presented diagnosis of some predominant antibody deficit. The predominant sex was male and the age range was from 6 to 10 years old. The most frequent infections were acute catarrhal pharyngotonsillitis (77,6 %), followed by pneumonia (58,4 %) and tonsillitis (56 %). Of the alarm signs related to infections only 4 were found in the patients in the registry. Conclusions: susceptibility to infections is not necessarily the predominant clinical feature in primary immunodeficiencies, but the infectious phenotype is still the best suggestive indicator for a defect in immunity. Although it is necessary to propose new criteria for infectious manifestations that facilitate the probable diagnosis of immunodeficiency in general and by groups.

Inmunodeficiencias humorales en pacientes adultos. Cuatro décadas de seguimiento / Antibody deficiencies in adults. Forty years of follow up

Resumen Las inmunodeficiencias humorales (IDH) comprenden un grupo de enfermedades caracterizadas por una deficiente respuesta mediada por anticuerpos. Se clasifican en primarias (IDHP), causa das por defectos propios del sistema inmune, o secundarias (IDHS) a otras enfermedades o fármacos. Nuestro objetivo fue revisar la evolución de las IDH asistidas en la Unidad Inmunología del Hospital Durand entre 1982 y 2020, dividido en dos periodos, Periodo I (1982-2009) y Periodo II (2010-2020); para evaluar el crecimiento de éstas, sus características epidemiológicas y las formas de tratamiento. Se evaluaron 205 pacientes, 176 (85.8%) IDHP y 29 (14.2%) IDHS. Las IDHP más diagnosticadas fueron: inmunodeficiencia común variable en 104 (59%) pacientes, agammaglobulinemia ligada al cromosoma X en 17 (9.6%) y deficiencia selectiva de IgA en 26 (14.8%). En 25 (14.2%) IDHP se realizó un diagnóstico molecular. Las causas de IDHS fueron: secundaria a rituximab en 21 (72.4%) pacientes, enfermedades hematológicas en tres (10.2%) y fármacos antiepilépticos en tres. Un total de 161 (78.5%) pacientes recibieron gammaglobulina, 140 (87%) IDHP y 21 (13%) IDHS; 152 (94.4%) fueron tratados con gammaglobulina endovenosa y nueve (5.6%) con gammaglobulina subcutánea. De los tratados inicialmente con forma endovenosa, 30 (19.7%) cambiaron a subcutánea. El crecimiento en la can tidad de pacientes entre ambos periodos del estudio fue mayor al 250%, y al 700% en pacientes incorporados por año. El crecimiento de las IDHS con relación al de las IDHP fue más del doble. Al finalizar el estudio 125 pacientes continuaban en seguimiento, 80% IDHP y 20% IDHS, y 14 fallecieron.

Abstract Antibody deficiencies (AD) are characterized by low or absent immunoglobulin levels or the inability to develop a specific antibody response. They are classified in primary (PAD) when there is an intrinsic immune defect, or secondary (SAD) to other dis eases or drugs. The aim of our study was to review the evolutio n of AD assisted at the Immunology Unit, Hospital Durand between 1982 and 2020, divided into two periods: Period I (1982-2009) and Period II (2010-2020); to evaluate their growth, epidemiologic features and treatment options. A total of 205 patients were identified, 176 (85.8%) with PAD and 29 (14.2%) with SAD. The most frequent PAD were common variable immunodeficiency in 104 (59%) patients, X linked agammaglobulinemia in 17 (9.6%) and selective IgA deficiency in 26 (14.8%). Genetic defects were found in 25 (14.2%) patients with PAD. SAD cases were associated with rituximab in 21 (72.4%) subjects, haematological disease in three (10.2%) and with antiepileptic drugs in other three; 161 (78.5%) patients were treated with immunoglobulins, 140 (87%) PAD y 21 (13%) SAD; 152 (94.4%) received intravenous immunoglobulins and nine (5.6%) subcutaneous immunoglobulins. Thirty (19.7%) patients treated at first with intravenous immunoglobulins changed to subcutaneous formulations. The increase in number of patients between both periods was greater than 250%, and more than 700% in patients added per year. SAD growth was greater than twice times comparing with PAD. By the end of the study 125 patients continued in follow up, 80% PAD y 20% SAD and 14 died.

Modelo para historia clínica en inmunodeficientes primarios, Pinar del Río / Model for clinical history in primary immunodeficient patients, Pinar del Rio

RESUMEN Introducción: los errores innatos de la inmunidad o inmunodeficiencias primarias se caracterizan por susceptibilidad incrementada a infecciones por defectos del desarrollo o función del sistema inmune. Para el diagnóstico debe incluirse la evaluación clínica, la analítica inmunológica, la evaluación genética, el seguimiento rutinario, la rediscusión diagnóstica y del tratamiento clínico. No existe una guía clara respecto a este asunto en condiciones de recursos limitados. Objetivo: diseñar un modelo para la confección de historia clínica en el paciente con sospecha de error innato de la inmunidad. Métodos: se realizó un trabajo de revisión de síntomas a contemplar en la historia clínica de pacientes con errores innatos de la inmunidad. Se formaron grupos de trabajo entre miembros del grupo provincial de Inmunología de Pinar del Río, con la posterior discusión de los aspectos que se incluyen en la historia. Resultados: se diseñaron cinco tablas que recogen: consentimiento informado; antecedentes patológicos personales relacionados con 148 manifestaciones clínicas en correspondencia con los fenotipos alérgico, infeccioso, inflamatorio, autoinmune, no inmunológico, neoplásico y otros. Se exponen antecedentes patológicos familiares y árbol genealógico; el examen físico y el resumen de los fenotipos clínicos, discusión diagnóstica y clasificación del paciente. Conclusiones: el interrogatorio, el examen físico, los antecedentes patológicos personales y familiares, así como la confección adecuada de la historia clínica son elementos imprescindibles para la aproximación al diagnóstico de los errores innatos de la inmunidad. Se debe contar con un registro de pacientes que posibilite el diagnóstico precoz y el tratamiento oportuno de la inmunodeficiencia primaria.

ABSTRACT Introduction: inborn errors of immunity or primary immunodeficiencies are characterized by increased susceptibility to infections due to defects in the development or functioning of the immune system. Diagnosis should include clinical evaluation, immunological analysis, genetic evaluation, routine follow-up, diagnostic re-discussion and clinical management. There is no clear guidance on this issue under resource-limited conditions. Objective: to design a model for clinical history in patients with suspected inborn error of immunity. Methods: a review of symptoms to be considered in the clinical history of patients with inborn errors of immunity was carried out. Working groups were formed among members of the provincial group of Immunology in Pinar del Rio province, with the subsequent discussion of the aspects to be included in the history. Results: five tables were designed to collect: informed consent; personal pathological antecedents related to 148 clinical manifestations in correspondence with allergic, infectious, inflammatory, autoimmune, non-immune, neoplastic and other phenotypes. Family pathologic history and family tree; physical examination and summary of clinical phenotypes, diagnostic discussion and classification of the patient are presented. Conclusions: the interviews, physical examination, personal and family pathologic history, as well as the adequate design of the clinical history, are considered essential elements for the approach to the diagnosis of inborn errors of immunity. A patient registry should be available to enable early diagnosis and timely treatment of primary immunodeficiency.

One-year intravenous immunoglobulin replacement therapy: efficacy in reducing hospital admissions in pediatric patients with Inborn Errors of Immunity

Abstract Objectives: To compare the frequency of hospitalization in children with Inborn Errors of Immunity with antibody deficiency previous to intravenous immunoglobulin (pre- IVIG) with a one-year period after initial IVIG (post-IVIG). Methods: Medical reports of 45 patients during an eight-year period were reviewed from 2018 to 2019. Wilcoxon-test was used for related samples. Results: Forty-five children were included in the study, aged 29-249 months of age, and most of them (64.4%) were males. Median ages at onset symptoms and at diagnosis were 6 and 73 months old, respectively. Specific antibody deficiency and unclassified hypogammaglobulinemia were the predominant diagnoses (31.1% and 17.8%, respectively). X-linked agammaglobulinemia, Hyper IgE syndrome, Hyper IgM, transient hypogammaglobulinemia of infancy, and Common Variable Immunodeficiency (CVID) were also reported, in a low frequency. Forty-four (97.8%) patients were hospitalized before IVIG, and 10 patients (22.2%) after. Annual mean hospital admission reduced from 2.5 to 0.5, pre and post-IVIG, respectively (p < 0.0001). Mean length of stay (LOS) reduced from 71 to 4.7 days/year (p < 0.0001) in general ward and in the PICU from 17.2 days/year to zero (p < 0.0002). Pneumonia was the main cause of hospital admission with a reduction in the number of episodes per patient from an average of 2.2-0.1 per year (p < 0.001). Concomitant use of antibiotic prophylaxis did not influence the number of hospital admission. Conclusion: One-year intravenous IVIG significantly decreased the number of hospitalizations and length of stay in children with impaired antibody production. Social and economic impacts would be required.

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.

Research progress of primary immunodeficiency disease with hyper IgE syndrome / 中华实用儿科临床杂志

The hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by atopic dermatitis, recurrent skin and lung infections along with elevated IgE levels.The JOB syndrome due to heterozygous loss-of-function mutations in the signal transduction and transcription activator-3(STAT3) gene is the prototype of HIES.However, several other immunodeficiency disorders with the phenotype of HIES have been identified over the past decade.This study aims to review these disorders and their molecular mechanisms, aiming to improve the understanding of this rare disease.

Observation of efficacy of allogeneic hematopoietic cell transplantation using unrelated cord blood or haploidentical donors in children with primary immunodeficiency diseases / 中华实用儿科临床杂志

Objective:To evaluate the efficacy of allogeneic hematopoietic cell transplantation(allo-HSCT) using unrelated cord blood or haploidentical donors in the treatment of children with primary immunodeficiency diseases (PID).Methods:The clinical data of 60 children with PID admitted to Chinese People′s Liberation Army General Hospital-Sixth Medical Center from April 2014 to October 2019 were retrospectively analyzed, including 56 cases of chronic granulomatous disease, 2 cases of severe combined immunodeficiency disease, 1 case of high-IgM syndrome and 1 case of severe congenital neutropenia.All patients underwent allo-HSCT, including 12 cases receiving the transplantation from unrelated cord blood (UCB group) and 48 cases from haploidentical donors combined with a third party unrelated cord blood (haploid group). Among these patients, there were 59 males and 1 female, with a median age of 3.4 years.All patients received a myeloablative conditioning regimen based on Busulfan.The prophylaxis of acute graft versus host disease (aGVHD) was performed based on Cyclosporine.In the UCB group, the median dose of mononuclear cells and CD 34+ cells was 0.67×10 8/kg and 0.51×10 6/kg recipient body weight, respectively; In the haploid group, bone marrow and peripheral stem cells from haploid donors were infused on day 01 and day 02, respectively.The third party cord blood was infused 4 hours before bone marrow infusion.The median dose of mononuclear cells and CD 34+ cells of bone marrow and peripheral stem cells from haploid donors was 9.97×10 8/kg and 5.12×10 6/kg recipient body weight, respectively.Kaplan-Meier method was used to analyze the overall survival rate. Results:The median day to neutrophil and platelet engraftment was 13.0 days and 23.5 days, respectively.The rate of complete donor chime-rism was shown 30.0 days after transplantation.There was no case with primary engraftment failure, and 1 case with secondary engraftment failure.The incidence of grade Ⅰ-Ⅱ and grade Ⅲ-Ⅳ aGVHD was 43.3% and 15.5%, respectively.The incidence of chronic graft versus host disease with limited skin type was 6.7%, while that with extensive type was 1.1%.The median follow-up period was 818 days.There were 6 death cases, among which, 5 cases died from infection and 1 case died from heart failure.The total mortality related to transplantation was 11.9%.A total of 53 cases survived without diseases.The estimated 5-year failure free survival and overall survival rate was 83.9% and 88.1%, respectively.Conclusion:The efficacy of allo-HSCT in the treatment of children with PID using unrelated cord blood and haploidentical donors is favorable.

Clinical effect of allogeneic hematopoietic stem cell transplantation in children with hyper-IgM syndrome / 中国当代儿科杂志

OBJECTIVES@#To evaluate the clinical effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with hyper-IgM syndrome (HIGM).@*METHODS@#A retrospective analysis was performed on the medical data of 17 children with HIGM who received allo-HSCT. The Kaplan Meier method was used for the survival analysis of the children with HIGM after allo-HSCT.@*RESULTS@#After allo-HSCT, 16 children were diagnosed with sepsis; 14 tested positive for virus within 100 days after allo-HSCT, among whom 11 were positive for Epstein-Barr virus, 7 were positive for cytomegalovirus, and 2 were positive for JC virus; 9 children were found to have invasive fungal disease. There were 6 children with acute graft-versus-host disease and 3 children with chronic graft-versus-host disease. The median follow-up time was about 2 years, and 3 children died in the early stage after allo-HSCT. The children had an overall survival (OS) rate of 82.35%, an event-free survival (EFS) rate of 70.59%, and a disease-free survival (DFS) rate of 76.47%. The univariate analysis showed that the children receiving HLA-matched allo-HSCT had a significantly higher EFS rate than those receiving HLA-mismatched allo-HSCT (P=0.019) and that the children receiving HLA-matched unrelated allo-HSCT had significantly higher OS, EFS, and DFS rates than those receiving HLA-mismatched unrelated allo-HSCT (P<0.05). Compared with the children with fungal infection after allo-HSCT, the children without fungal infection had significantly higher EFS rate (P=0.02) and DFS rate (P=0.04).@*CONCLUSIONS@#Allo-HSCT is an effective treatment method for children with HIGM. HLA-matched allo-HSCT and active prevention and treatment of fungal infection and opportunistic infection may help to improve the prognosis of such children.

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

Inmunodeficiencia primaria combinada

RESUMEN Introducción: Las inmunodeficiencias primarias son enfermedades genéticas. Están constituidas por más de 200 enfermedades que tienen en común las infecciones recurrentes. La inmunodeficiencia combinada se caracteriza por episodios de sepsis recurrentes del aparato respiratorio, digestivo y de piel sobre todo por gérmenes oportunistas. El cuadro clínico es muy variable y se conocen múltiples fenotipos clínicos. Objetivo: Evaluar las manifestaciones clínicas e inmunológicas de la inmunodeficiencia primaria combinada no grave a través de un caso. Presentación de caso: Se trata un lactante de 8 meses de edad, masculino, blanco, que presentó múltiples infecciones respiratorias y digestivas, intolerancia a la leche, asociado a sibilancias recurrentes y manifestaciones exantemáticas. Tuvo varios ingresos incluso en terapia intensiva por sepsis grave y cumplió tratamientos con penicilinas, cefalosporinas, sulfas, fosfocina, vancomicina y metronidazol. El estudio inmunológico reveló una marcada disminución de las subpoblaciones linfocitarias y concentraciones disminuidas de la subclase de IgG4. Se estableció el diagnóstico de inmunodeficiencia primaria del tipo combinada no grave. El tratamiento utilizado incluyó gammaglobulina endovenosa y el factor de transferencia. Se confirmó una mejoría clínica evidente. Conclusiones: Las infecciones recurrentes junto con los resultados de los estudios permitieron diagnosticar esta inmunodeficiencia primaria. El diagnóstico precoz y el tratamiento oportuno mejoran la calidad de vida del paciente.

ABSTRACT Introduction: Primary immunodeficiencies are genetic diseases. They are made up of more than 200 diseases that have recurrent infections in common. Combined immunodeficiency is characterized by recurrent episodes of sepsis of the respiratory, digestive and skin system, especially opportunistic germs. The clinical picture is highly variable and multiple clinical phenotypes are known. Objective: Assess the clinical and immunological manifestations of non-severe combined primary immunodeficiency through a case. Case presentation: 8-month-old male, white infant who presented multiple respiratory and digestive infections, milk intolerance, associated with recurrent wheezing and exanthematic manifestations. He had several hospitalizations even in the intensive care service due to severe sepsis and completed treatments with penicillins, cephalosporins, sulfas, phosphocin, vancomycin and metronidazole. The immunological study revealed a marked decrease in lymphocyte subpopulations and decreased concentrations of the IgG4 subclass. The diagnosis of primary immunodeficiency of the non-severe combined type was established. The treatment used included intravenous gamma globulin and transfer factor. An evident clinical improvement was confirmed. Conclusions: The recurrent infections together with the results of the studies allowed to diagnose this primary immunodeficiency. Early diagnosis and timely treatment improve the patient's quality of life.

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.

Linfoma de Burkitt como complicación de la agammaglobulinemia de Bruton / Burkitt's lymphoma as a complication of Bruton's Agammaglobulinemia

Introducción: La agammaglobulinemia de Bruton es una inmunodeficiencia primaria (IDP) originada por una mutación del gen que codifica la tirosina kinasa de Bruton (BTK). Se sospecha principalmente en varones con infecciones frecuentes de las vías respiratorias y tiene entre otras complicaciones, los tumores, fundamentalmente linfoproliferativos. Se reportan agammaglobulinemias autosómicas recesivas con similares características clínicas en ambos sexos. Objetivo: Presentar el primer caso pediátrico reportado en Cuba, con diagnóstico de linfoma de Burkitt asociado a esta inmunodeficiencia primaria y que además utilizó tratamiento combinado sustitutivo de inmunoglobulinas y antitumoral. Presentación del caso: Paciente masculino, que a los 2 años se le realizó diagnóstico de enfermedad de Bruton. Con el tratamiento de reemplazo con inmunoglobulina endovenosa (Intacglobín) se mantuvo tres años sin infecciones graves. A los 5 años de edad presentó linfoma de Burkitt, tratado con poliquimioterapia, según el esquema AEIOP al que se asoció rituximab. Aunque no se dispone de la detección por biología molecular de la mutación del gen BTK, la disminución por debajo del 2 por ciento de las células B CD19+ y los valores ausentes de IgG, IgA e IgM permitieron el diagnóstico. Conclusión: Coexistieron con resultados clínicos satisfactorios el tratamiento antitumoral y la terapia de reemplazo con inmunoglobulina endovenosa. El paciente se mantiene con buen estado general(AU)

Introduction: Bruton's Agammaglobulinemia is a primary immunodeficiency (PID) caused by a mutation in the gene that encodes Bruton's tyrosine kinase (BTK). It is suspected mainly in men with frequent respiratory tract infections and has, among other complications, tumors, mainly lymphoproliferative. Autosomal recessive agammaglobulinemias with similar clinical characteristics have been reported in both sexes. Objective: To present the first pediatric case reported in Cuba, with a diagnosis of Burkitt's lymphoma associated with PID and that also used combined immunoglobulin replacement and antitumor therapy. Case report: 2-year-old male diagnosed with Bruton's disease. With the replacement treatment with intravenous immunoglobulin (Intacglobin), he maintained three years without serious infections. At 5 years of age, he presented Burkitt's lymphoma, treated with polychemotherapy according to the AEIOP scheme, associating Rituximab. Although do not have molecular biology detection of the BTK gene mutation, the decrease of CD19 + B cells to below 2 percent and the absent values of IgG, IgA and IgM allowed the diagnosis. Conclusion: Antitumor treatment and intravenous immunoglobulin replacement therapy coexisted with satisfactory clinical results. The patient remains in good general condition(AU)

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.

Osteomielitis multifocal por Serratia marcescens en un niño con enfermedad granulomatosa crónica / Serratia marcescens multifocal osteomyelitis in a child with chronic granulomatous disease

Resumen La enfermedad granulomatosa crónica (EGC) es una inmunode-ficiencia primaria poco frecuente. Se caracteriza por una alteración en la función de los fagocitos, causando infecciones recurrentes bacterianas y fúngicas. Presentamos el caso clínico de un niño con una osteomielitis multifocal por Serratia marcescens , microorganismo infrecuente como causa de infecciones óseas en niños, aunque asociado a la EGC. El estudio de infecciones con presentación clínica y agentes inhabituales deben hacer sospechar una EGC. Su diagnóstico precoz en la vida, así como el tratamiento antimicrobiano oportuno y el uso posterior de una profilaxis antimicrobiana adecuada logrará evitar recurrencias infecciosas y secuelas.

Abstract Chronic granulomatous disease (CGD) is a rare primary immuno-deficiency. It is characterized by an alteration in the function of phagocytes causing recurrent bacterial and fungal infections. This is a case report of a child with multifocal osteomyelitis by Serratia marcescens, an infrequent as a cause of bone infections, although associated with CGD. The study of infections with clinical presentation and unusual agents should lead to suspicion of CGD. The diagnosis early in life, as well as timely antimicrobial treatment and the subsequent antimicrobial prophylaxis will avoid infectious recurrences and sequelae.

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.

COVID-19 en adultos con inmunodeficiencias humorales / COVID-19 in adults with antibody deficiencies

Resumen La enfermedad COVID-19, causada por el virus SARS-CoV-2, surgió a fines de 2019 en Wuhan, China. La evolución clínica es variable, así como la tasa de mortalidad, que es mayor en pacientes mayores de 65 años y en quienes padecen enfermedades subyacentes. Las inmunodeficiencias son potenciales factores de riesgo para formas graves de COVID-19. Los pacientes con inmunodeficiencias tienen además mayor frecuencia de complicaciones no infecciosas, que podrían representar un riesgo adicional. Hasta el momento existen escasas publicaciones sobre asociación COVID-19 e inmunodeficiencias humorales. Considerando la importancia del estudio de esta nueva enfermedad viral y de su potencial repercusión en la salud de los pacien tes con inmunodeficiencias presentamos seis casos de COVID-19 en adultos con déficit de anticuerpos (tres mujeres y tres varones, edad promedio 48.5 años, rango 20-67). Cuatro tenían inmunodeficiencias primarias: inmunodeficiencia común variable (n: 3) y agammaglobulinemia ligada al cromosoma X (n: 1). Los otro dos tenían hipogammaglobulinemia secundaria, en un caso asociada a timoma (síndrome de Good), y en el otro a tratamiento con rituximab. La evolución fue favorable en todos menos en el paciente con síndrome de Good, quien presentaba un marcado deterioro del estado general antes de contraer COVID-19.

Abstract COVID-19, caused by SARS-CoV-2, emerged in late 2019 in Wuhan, China. Its clinical course is variable, as well as the mortality rate, which is higher among people over 65 years of age and persons with underlying conditions. Immunodeficiencies are po tential risk factors for severe forms of COVID-19. Furthermore, patients with immunodeficiencies often undergo non-infectious complications, which could bear additional risk. So far, few reports of patients with COVID-19 and humoral immunodeficiencies have been published. Considering the importance of the study of this new viral disease and its potential health impact on patients with immunodeficiency disorders, we present six cases of COVID-19 in patients with impaired humoral immunity. Three were women and three were men. The average age was 48.5 years (range 20-67). Four had been diagnosed with primary antibody deficiency: three had common variable immunodeficiency and one had X-linked agammaglobulinemia. The other two patients had secondary hypogammaglobulinemia, one was associated with thymoma (Good's syndrome), and the other was associated with rituximab treatment. The evolution was favorable in all except the patient with Good's syndrome, who pre sented a marked decline in clinical status before contracting COVID-19.

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

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.

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.

Combined immunodeficiencies

Abstract Objectives: Inborn Errors of Immunity (IEI), also known as primary immunodeficiencies, correspond to a heterogeneous group of congenital diseases that primarily affect immune response components. The main clinical manifestations comprise increased susceptibility to infections, autoimmunity, inflammation, allergies and malignancies. The aim of this article is to review the literature on combined immunodeficiencies (CIDs) focusing on the diagnosis and treatment and the particularities of the clinical management of these patients. Source of data: Critical integrative review, aimed to present articles related to primary immunodeficiencies combined with a searchin the PubMed and SciELO databases, with evaluation of publications from the last twenty years that were essential for the construction of knowledge on this group of diseases. Summary of data: We highlight the main characteristics of CIDs, dividing them according to their pathophysiological mechanisms, such as defects in the development of T cells, TCR signaling, co-stimulatory pathways, cytokine signaling, adhesion, migration and organization of the cytoskeleton, apoptosis pathways, DNA replication and repair and metabolic pathways. In CIDs, clinical manifestations vary widely, from sinopulmonary bacterial infections and diarrhea to opportunistic infections, caused by mycobacteria and fungi. Neonatal screening makes it possible to suspect these diseases before clinical manifestations appear. Conclusions: The CIDs or IEI constitute a complex group of genetic diseases with T-cell involvement. Neonatal screening for these diseases has improved the prognosis of these patients, especially in severe ones, known as SCIDs.