Myasthenia gravis in the complex scenario of LRBA-related immune dysregulation / Miastenia gravis no cenário clínico complexo das imunodesregulações relacionadas ao gene LRBA

Autoimmune diseases have been progressively recognized as a potential complication of primary immunodeficiency, especially for some genetic subtypes of common variable immunodeficiency. Although often associated with other autoimmune disorders, autoimmune myasthenia gravis is occasionally identified as a neuromuscular complication of primary immunodeficiency. We report the case of a Brazilian woman with common variable immunodeficiency-8 due to an LRBA variant, in which myasthenia gravis was identified in association with anti-acetylcholine receptor antibody. Marked clinical improvement occurred after intravenous immunoglobulin therapy.

Doenças autoimunes foram progressivamente reconhecidas como complicações potenciais das imunodeficiências primárias, especialmente para alguns subtipos genéticos das imunodeficiências comuns variáveis. Embora se associe comumente a outras doenças autoimunes, a Miastenia gravis autoimune adquirida foi raramente associada como complicação neuromuscular de imunodeficiências primárias. É descrito neste artigo o caso de paciente brasileira do sexo feminino com diagnóstico de Imunodeficiência Comum Variável tipo 8 por variante no gene LRBA, na qual foi identificada Miastenia gravis em associação a anticorpos antirreceptor de acetilcolina. Ela evoluiu com marcante melhora clínica após a introdução de terapêutica com imunoglobulina endovenosa.

Common variant immunodeficiency: a case series and literature review / 中华全科医师杂志

Objective:To analyze the clinical manifestation, laboratory examination, treatment and prognosis of common variable immunodeficiency (CVID) in single center of Chinese population.Methods:The clinical data of 75 cases of CVID, diagnosed according to European Society for Immunodeficiency (ESID) criteria and admitted in Peking Union Medical College Hospital from January 1983 to May 2021 were retrospectively analyzed.Results:The main clinical manifestations of CVID were respiratory abnormality (68.0%,51/75), blood system abnormality (66.7%,50/75), liver and spleen involvement (66.7%,50/75), gastrointestinal abnormality (46.7%,35/75), autoimmune abnormality (29.3%,22/75). Immunoglobulin decreased significantly (median IgG 2.4 g/L, median IgA 0.1 g/L, median IgM 0.1 g/L). Lymphocyte subsets indicated that CD4 +T cells decreased (median 471/μl), CD8 +T cells increased (median 620/μl), CD4 +/CD8 +T calls proportion inverted (median 0.7), and NK cells and B cells decreased (median 44/μl, 115/μl, respectively). During hospitalization, their conditions were improved after IgG replacement therapy, supplemented with anti-infection and nutritional support therapy. Forty seven discharged patients were followed up, and only 16 patients insisted on regular IgG replacement therapy after discharge. Conclusions:The clinical manifestations of CVID are varied, and multiple systems may be involved, including autoimmune abnormalities. The treatment based on IgG replacement has a certain curative effect.

Errores innatos de la inmunidad en adultos / Inborn errors of immunity in adults

Introducción: La inmunodeficiencia común variable es un error innato de la inmunidad que tiene su pico de incidencia en la edad adulta. Se caracteriza por una susceptibilidad aumentada a padecer infecciones respiratorias, autoinmunidad y malignidad, secundario a un estado de hipogammaglobulinemia e inmunodisregulación, causado por mutaciones e interacciones genéticas parcialmente comprendidas. El diagnóstico es de exclusión, tiene una gran heterogeneidad clínica y comúnmente es diagnosticado de forma errónea. Objetivo: Describir un caso clínico de un paciente afectado por un error innato de la inmunidad. Caso clínico: Hombre de 35 años que se presenta a la consulta de Medicina Interna - Inmunología refiriendo un cuadro clínico de 3 años de evolución consistente en múltiples episodios de infecciones sino-pulmonares en los últimos meses, presentaba tos productiva, dificultad respiratoria y pérdida de peso no intencional de aproximadamente 8 kg. Conclusiones: La inmunodeficiencia común variable debe considerarse dentro de los diagnósticos diferenciales en todo paciente que presente alguna de sus manifestaciones clínicas, principalmente aquellas relacionadas con infecciones respiratorias a repetición, antecedente que el paciente puede presentar como relevante en sus consultas de primer nivel con medicina general o con especialistas. Su aproximación diagnóstica consiste en la solicitud de niveles séricos de inmunoglobulinas, prueba de laboratorio de fácil acceso para cualquier clínico independiente de su nivel de atención y su tratamiento se fundamenta en la administración periódica de inmunoglobulina humana exógena de forma endovenosa o subcutánea(AU)

Introduction: Common variable immunodeficiency is an inborn error of immunity that has its peak incidence in adulthood. It is characterized by an increased susceptibility to respiratory infections, autoimmunity and malignancy, secondary to a state of hypogammaglobulinemia and immunodysregulation, caused by mutations and partially understood genetic interactions. The diagnosis is one of exclusion, has great clinical heterogeneity and is commonly misinterpreted. Objective: To describe a clinical case of a patient affected by an inborn error of immunity. Methods: Retrospective description of a case report. Conclusions: Common variable immunodeficiency disorder should be considered within the differential diagnoses in every patient who presents any of its clinical manifestations, mainly those related to recurrent respiratory infections, an antecedent that the patient may present as relevant during the first-level consultations with general medicine physicians or with specialists. Its diagnostic approach consists in measuring serum immunoglobulin levels, an easily accessible laboratory test for any clinic physician regardless of their healthcare level, while its treatment is based on the periodic administration of exogenous human immunoglobulin intravenously or subcutaneously(AU)

Síndrome de Evans y desregulación inmune: complejidades moleculares y etiopatogénicas / Evans syndrome and immune dysregulation: molecular and etiopathogenic complexities

Introducción: El síndrome de Evans se define como la presencia de citopenias inmunes que afectan dos o más líneas celulares simultánea o secuencialmente. Generalmente se refiere a la combinación de anemia hemolítica autoinmune con trombocitopenia inmune primaria, pero puede incluir también neutropenia autoinmune. Su etiología se atribuye a la producción de autoanticuerpos patológicos contra las células sanguíneas pero su causa real se desconoce. Objetivo: Explicar la relación del síndrome de Evans con la desregulación del sistema inmune. Método: Se realizó una revisión de la literatura en inglés y español a través del sitio web PubMed y el motor de búsqueda Google académico, de artículos publicados sobre el tema. El 69,73 por ciento correspondieron a los últimos 5 años. Conclusiones: La inmunopatología del síndrome de Evans se puede atribuir a una alteración en el desarrollo o la función de los linfocitos, de manera que el equilibrio inmunológico se inclina hacia la autorreactividad(AU)

Introduction: Evans syndrome is defined as the presence of autoimmune cytopenias affecting two or more blood cell lines, either simultaneously or sequentially. Most often, this refers to the combination of autoimmune hemolytic anemia and immune thrombocytopenia but can include autoimmune neutropenia as well. The etiology of Evans syndrome has been attributed to pathologic autoantibody production against the blood cells, but the true underlying cause remaining unknown. Objective: to explain the relationship of Evans syndrome with dysregulation of the immune system. Method: a review of the literature in English and Spanish was carried out through the PubMed website and the academic Google search engine for articles published on the subject. 69,73 percent corresponded to the last 5 years. Conclusions: the immunopathology of Evans syndrome can be attributed to an alteration in the development or function of lymphocytes, such that the immune balance is inclined towards self-reactivity(AU)

STAT3 gain-of-function mutation in an adult patient / Paciente adulto portador de una mutación con ganancia de función en el gen STAT3

Abstract Germline gain-of-function (GOF) mutation of the signal transducer and activator of transcription 3 (STAT3) gene causes a disease clinically characterized by a significant lymphoproliferation, includ ing lymphadenopathy and/or hepatosplenomegaly, as well as childhood onset autoimmunity. Here we present an adult patient who, during his early years of life, presented recurrent infections, autoimmune hemolytic anemia and benign lymphoproliferative disease, characterized by hepatosplenomegaly and lymphadenopathy, being diagnosed with common variable immunodeficiency (CVID) at 13 years of age. He was diagnosed with lymphocytic interstitial pneumonia at the age of 20. When he was 40 years old, after a diagnostic review, it was decided to perform genetic studies. A heterozygous mutation in STAT3 NM_003150 c.2141C>T, p.P714L was detected by whole exome sequencing and validated by Sanger. Previously published functional studies performed in two siblings showed that this mutation resulted in gain-of-function. They were initially diagnosed with autoimmune lymphoproliferative syndrome, and later with STAT3 GOF as a second genetic defect. Our patient developed severe pulmonary disease and died, without access to treatment targeted to his molecular defect due to the advanced nature of his pulmonary involvement and the fact that many of the therapies were still in develop ment at that time. The diagnosis of STAT3 GOF mutations should be suspected in patients with early-onset of lymphoproliferative disease, autoimmunity and hypogammaglobulinemia. This must be considered especially in the group of CVID patients with these characteristics, in order to allow the implementation of treatments target ing the molecular defect (JAK inhibitors and Il-6 receptor antagonists) that could modify the disease evolution.

Resumen Mutaciones en línea germinal con ganancia de función (GOF) del gen transductor de señales y acti vador de la transcripción 3 (STAT3) provocan una enfermedad caracterizada por importante linfoproliferación, incluyendo linfadenopatías y/o hepatoesplenomegalia, así como autoinmunidad de inicio en la infancia. Presen tamos un paciente adulto que, durante sus primeros años de vida, presentó infecciones recurrentes, anemia hemolítica autoinmune y enfermedad linfoproliferativa benigna, caracterizada inicialmente por hepatoespleno megalia y linfoadenopatías, diagnosticado de inmunodeficiencia común variable (IDCV) a los 13 años. A los 20 años, al ser estudiado por compromiso pulmonar, se diagnosticó neumonía intersticial linfocítica. A los 40 años, tras revisión diagnóstica se decidió realizar estudios genéticos. Por secuenciación del exoma completo se detectó una mutación heterocigota en STAT3 NM_003150 c.2141C>T, p.P714L, que se validó por Sanger. Estudios funcionales previamente publicados realizados en dos hermanos con diagnóstico inicial de síndrome linfoproliferativo autoinmune, mostraron que esta mutación daba lugar a una ganancia de función. Nuestro pa ciente desarrolló enfermedad pulmonar grave y falleció a los 41 años, sin posibilidad de acceder a tratamiento dirigido a su defecto molecular por lo avanzado de su compromiso pulmonar y a que muchas de las terapias se encontraban en ese momento en desarrollo. El diagnóstico de mutaciones STAT3 GOF debe sospecharse en pacientes con enfermedad linfoproliferativa temprana, autoinmunidad e hipogammaglobulinemia. Esto debe ser considerado especialmente en pacientes con IDCV con estas características, para permitir la implementación de tratamientos dirigidos al defecto molecular (inhibidores de JAK y antagonistas del receptor de Il-6) que podrían modificar la evolución de la enfermedad.

Human Inborn Errors of Immunity (HIEI): predominantly antibody deficiencies (PADs): if you suspect it, you can detect it

Abstract Objective: This minireview gathers the scientific foundations of the literature on genetic errors in the development of the humoral immune system to help pediatricians suspect these defects. Sources: A systemic search using the PubMed MEDLINE database was performed for all Predominantly Antibody Deficiencies (PADs) described in the 2020 IUIS Expert Committee for PID classification system, combined with terms for hypogammaglobulinemia. Search terms for PADs were based on the listed names and affected genes as classified by the IUIS 2020. Abstracts of the results were reviewed to find relevant case series, review articles of PADs associated with infection, opportunistic infection, autoimmunity, cytopenias, malignancies, inflammatory diseases, neurological and respiratory diseases. References from relevant articles were further reviewed for additional references. Relevant findings were grouped in accordance with the IUIS 2020 classification system. Clinical and genetic features, if known, were described. Data synthesis: PADs refer to impaired antibody production due to molecular defects intrinsic to B cells or a failure of interaction between B and T cells. The patients develop recurrent or chronic infection or respond to the antigens with dysregulation of the immune function, causing severe allergy, autoimmunity, inflammation, lymphoproliferation and malignancy. The diagnosis is a combined exercise of clinical and laboratory investigation similar to that performed by Bruton (1952). In the context of SARS-CoV-2 infection, the experience of XLA and CVID patients has been surprising. Variants in 39 genes were reported as causing PADs, but the clinical heterogeneity within each variant is not clear. Conclusion: Bruton (1952) used clinical expertise and protein electrophoresis to identify XLA. The IUIS (2020) committee used immunoglobulins and B lymphocyte to characterize PADs. Pediatricians should suspect it to detect it and prevent morbidities that can have an astonishing and irreversible impact on the child's life.

La citometría de flujo como auxiliar en el diagnóstico de las inmunodeficiencias primarias humorales / Flow-cytometry as an auxiliary in the diagnosis of primary humoral immunodeficiencies

Resumen Antecedentes: Las deficiencias de anticuerpos abarcan un amplio espectro de patologías y constituyen aproximadamente 50 % de las inmunodeficiencias primarias; con la citometría es posible evaluar el estado inmunológico de forma rápida, efectiva y a bajo costo. Objetivo: Evaluar mediante citometría de flujo, las células de pacientes con tres tipos de inmunodeficiencias primarias humorales. Método: Mediante citometría de flujo se analizaron muestras de sangre de pacientes y sujetos sanos con distintos anticuerpos monoclonales. Resultados: Mediante diversas tinciones se demostró disminución severa de linfocitos B en pacientes con agammaglobulinemia ligada al cromosoma X, la falta de expresión de CD154 en pacientes con síndrome de hiperinmunoglobulina M y heterogeneidad de subpoblaciones de linfocitos B en pacientes con inmunodeficiencia común variable. Conclusión: Con la citometría de flujo es posible realizar el diagnóstico temprano de inmunodeficiencias primarias con un nivel de confianza elevado y, en muchos casos, identificar los genes implicados.

Abstract Background: Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost. Objective: To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies. Method: Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies. Results: Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency. Conclusion: Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.

Common variable immune deficiency in adult patients: analysis of 13 cases and literature review / 南方医科大学学报

OBJECTIVE@#To investigate the clinical and immunological characteristics, treatment and prognosis of common variable immune deficiency (CVID) in adult patients.@*METHODS@#We retrospectively analyzed the clinical data of 13 adult patients hospitalized in our hospital for CVID diagnosed according to the criteria in International Consensus Document (2016), and analyzed their clinical manifestations, laboratory test results, imaging findings, pathological examinations and treatments.@*RESULTS@#The mean age of onset was 24.46±16.82 years in these patients, who had a mean age of 32.54±14.86 years at diagnosis with a median diagnostic delay of 5 years (IQR: 2-15 years). The main manifestation of the patients was repeated infections, including repeated respiratory tract infection (10 cases; 76.9%) and repeated diarrhea (3 cases; 23.1%). Three (23.1%) of the patients had autoimmune disease and 10 (76.9%) had chronic pulmonary disease. IgG, IgA and IgM were decreased in all the patients. The proportion of CD4+T cells decreased in 10 patients (76.9%), CD8+T cells increased in 11 patients (84.6%), and CD4/ CD8 decreased in 10 patients (76.9%). Complement C3 decreased in 58.3% (7/12) and C4 decreased in 33.3% (4/12) of the patients. Twelve patients (92.3%) were treated with intravenous infusion of gamma globulin with symptomatic treatments. One patient died due to massive gastrointestinal hemorrhage, and the other patients showed improve ments after the treatments and were discharged.@*CONCLUSIONS@#The clinical manifestations of CVID are diverse, and recurrent respiratory tract infection is the most common manifestation. Decreased IgG often accompanied by lowered IgA and IgM levels is a common finding in laboratory tests. The treatment of CVID currently relies on gamma globulin with symptomatic treatments for the complications.

Gut microbiota in Mexican patients with common variable immunodeficiency

Introduction: Common variable immunodeficiency (CVID) is the main symptomatic primary immunodeficiency and is associated with complex immune disorders. Gut microbiota interacts closely with the immune system, and intestinal dysbiosis is related to multiple diseases. Objective: To describe for the first time the composition of gut microbiota in Mexican patients with CVID. Methods: Fecal samples from five patients with CVID were collected and massive sequencing of the V3-V4 region of 16S rRNA gene was carried out using illumina technology. Results: Bacterial relative abundance was observed at all taxonomic levels. Firmicutes, Actinobacteria and Verrucomicrobia were the predominant phyla. The Clostridia class and the Clostridial order were the most common in their respective taxon; the Ruminococcaceae family predominated. A total of 166 genera were reported, with the most abundant being Faecalibacterium. Five species were identified, but only Bifidobacterium longum was present in all patients. Conclusions: Unlike healthy subjects' gut microbiota, where Firmicutes and Bacteroidetes predominate, the microbiota of the patients with CVID considered in this study was abundant in Firmicutes, Actinobacteria and Verrucomicrobia. The low presence of Bacteroidetes and high abundance of Firmicutes might indicate the existence of intestinal dysbiosis in these patients.

Clinical, immunological and genetic characteristic of patients with clinical phenotype associated to LRBA-deficiency in Colombia / Características clínicas, inmunológicas y genéticas de pacientes con el fenotipo asociado a deficiencia LRBA en Colombia

Abstract Background: LPS-responsive beige -like anchor protein (LRBA) deficiency is a primary immunodeficiency disease caused by loss of LRBA protein expression, due to biallelic mutations in LRBA gene. LRBA deficiency patients exhibit a clinically heterogeneous syndrome. The main clinical complication of LRBA deficiency is immune dysregulation. Furthermore, hypogammaglobulinemia is found in more than half of patients with LRBA-deficiency. To date, no patients with this condition have been reported in Colombia Objective: To evaluate the expression of the LRBA protein in patients from Colombia with clinical phenotype associated to LRBA-deficiency. Methods: In the present study the LRBA-expression in patients from Colombia with clinical phenotype associated to LRBA-deficiency was evaluated. After then, the clinical, the immunological characteristics and the possible genetic variants in LRBA or other genes associated with the immune system in patients that exhibit decrease protein expression was evaluated. Results: In total, 112 patients with different clinical manifestations associated to the clinical LRBA phenotype were evaluated. The LRBA expression varies greatly between different healthy donors and patients. Despite the great variability in the LRBA expression, six patients with a decrease in LRBA protein expression were observed. However, no pathogenic or possible pathogenic biallelic variants in LRBA, or in genes related with the immune system were found. Conclusion: LRBA expression varies greatly between different healthy donors and patients. Reduction LRBA-expression in 6 patients without homozygous mutations in LRBA or in associated genes with the immune system was observed. These results suggest the other genetic, epigenetic or environmental mechanisms, that might be regulated the LRBA-expression.

Resumen Antecedentes: la deficiencia de LRBA (del inglés, LPS-responsive beige -like anchor protein) es una inmunodeficiencia primaria causada por la pérdida de la expresión de la proteína LRBA, debido a mutaciones bialélicas en el gen LRBA. Los pacientes con deficiencia de LRBA exhiben un síndrome clínicamente heterogéneo. La principal complicación clínica de la deficiencia de LRBA es la desregulación inmune. Además, la hipogammaglobulinemia se encuentra en más de la mitad de los pacientes con deficiencia de LRBA. Hasta la fecha, no se han reportado pacientes con esta afección en Colombia Objetivo: Evaluar la expresión de la proteína LRBA en pacientes de Colombia con fenotipo clínico asociado a deficiencia de LRBA Métodos: En el presente estudio se evaluó la expresión de LRBA en pacientes de Colombia con fenotipo clínico asociado a deficiencia de LRBA. Después de eso, se evaluaron las características clínicas, inmunológicas y las posibles variantes genéticas en LRBA o en otros genes asociadados con el sistema inmune en pacientes que exhiben una disminución de la expresión de la proteína. Resultados: En total, se evaluaron 112 pacientes con diferentes manifestaciones clínicas asociadas al fenotipo clínico LRBA. La expresión de LRBA varía mucho entre diferentes donantes sanos y pacientes. A pesar de la gran variabilidad en la expresión de LRBA, se observaron seis pacientes con una disminución en la expresión de la proteína LRBA. Sin embargo, no se encontraron variantes bialélicas patógenas o posibles patógenas en LRBA, o en genes relacionados con el sistema inmune. Conclusión: La expresión de LRBA varía mucho entre diferentes donantes sanos y pacientes. Se observó reducción de la expresión de LRBA en 6 pacientes sin mutaciones homocigotas en LRBA o en genes asociados. Estos resultados sugieren los otros mecanismos genéticos, por ejemplo epigenéticos o ambientales, que podrían estar regulados por la expresión de LRBA

Hipogamaglobulinemia secundária reversível causada por terapia anticonvulsivante em adultos: relato de três casos / Reversible hypogammaglobulinemia secondary to anticonvulsant therapy in adult patients: report of three cases

A redução dos níveis de imunoglobulina relacionada ao uso de anticonvulsivantes e que cursa com infecções de repetição tem sido descrita nas últimas quatro décadas. O objetivo deste estudo é relatar três casos de pacientes adultos que evoluíram para hipogamaglobulinemia quando foram tratados com anticonvulsivantes. Os níveis de imunoglobulinas e a população de linfócitos se normalizaram quando as drogas foram suspensas. Deficiências de IgA e IgM relacionadas ao uso de anticonvulsivantes resultam em infecções de repetição, apesar de níveis baixos de IgG terem sido relatados em poucos estudos e relatos de casos isolados. Os mecanismos patofisiológicos da hipogamaglobulinemia secundária a essas classes de drogas não estão completamente elucidados, mas diversos estudos mostram a possibilidade de reversão da imunodeficiência depois da suspensão da medicação, principalmente na infância.

Reduced immunoglobulin (Ig) levels related to anticonvulsant therapy and resulting in recurrent infections have been described in the past 4 decades. The objective of this study is to report three cases of adult patients who progressed with hypogammaglobulinemia after anticonvulsant therapy. Normalization of Ig levels and lymphocyte populations was achieved after drug suspension. IgA and IgM deficiencies related to anticonvulsant therapy lead to recurrent infections, although decreased serum IgG levels have been reported in few studies and isolated clinical cases. The pathophysiological mechanisms of hypogammaglobulinemia secondary to these types of drugs have not been completely understood, but several studies show the possibility of immunodeficiency reversion after drug suspension, especially in childhood.

Gastrointestinal Manifestations of Primary Immunodeficiency Disorders / 胃肠病学

Primary immunodeficiency disorders (PIDDs) contain more than 300 inborn errors of immunity, among which common variable immunodeficiency (CVID) and chronic granulomatous disease (CGD) are relatively common in clinical practice. CVID is characterized by loss of B cell function and impaired antibody production, while CGD is mainly a congenital disorder with defective neutrophil function. In both diseases, the clinical features include an increased susceptibility to infections and may have symptoms resembling non-infectious inflammatory disorders such as inflammatory bowel disease (IBD). The endoscopic and pathologic findings are non-specific and often mimic IBD, gene analysis is important for differential diagnosis. Treatment is not well defined and is mainly empirical. Infections should be treated with broad-spectrum agents covering both bacterial and fungal pathogens. Corticosteroids or immunosuppressors can be used for PIDDs patients with IBD manifestations.

Hypogammaglobulinemia: a diagnosis that must not be overlooked

Humoral immunological defects are frequent and important causes of hypogammaglobulinemia, leading to recurrent infections, autoimmunity, allergies, and neoplasias. Usually, its onset occurs in childhood or during the second and third decades of life; however, the diagnosis is made, on average, 6 to 7 years afterwards. As a consequence, antibody defects can lead to sequelae. Here we describe the clinical-laboratory characteristics, treatment, and prognoses of patients with hypogammaglobulinemia. An observational, cross-sectional, and retrospective study of patients attending the recently established outpatient group of Clinical Immunology between 2013 and 2018 was carried out. Patients with IgG levels below 2 standard deviations from the mean values for the age and/or impaired antibody response were included. Eight patients (3 F and 5 M; median age=41 years (16-65), average symptom onset at 25 years (1-59), and time to diagnosis of 10 years were included. The main infections were: sinusitis in 7/8, pneumonia in 6/8, otitis in 2/8, tonsillitis and diarrhea in 2/8, and diarrhea in 2/8 patients. Hypothyroidism was identified in 4/8 (50%) patients. Rhinitis was found in 7/8 (87.5%) and asthma in 3/8 (37.5%) patients. The tomographic findings were consolidations, atelectasis, emphysema, ground glass opacity, budding tree, bronchial thickening, and bronchiectasis. Immunoglobulin reposition was used between 466 and 600 mg/kg monthly (514.3 mg·kg-1·dose-1). Prophylactic antibiotic therapy was included in 7/8 (87.5%) patients. Airway manifestations prevailed in patients with hypogammaglobulinemia. There is a need for educational work to reduce the time of diagnosis and initiation of treatment, avoiding sequelae.

Imunodeficiência comum variável associada à doença de Crohn-like: relato de caso e revisão da literatura / Common variable immunodeficiency associated with Crohn-like disease: case report and literature review

OBJETIVOS: relatar o caso de um paciente diagnosticado com imunodeficiência comum variável e doença de Crohn-like, descrevendo o quadro clínico, o processo de investigação diagnóstica, as abordagens terapêuticas e a evolução clínica do paciente. Realizar revisão bibliográfica de relatos de caso que abordem pacientes com a associação imunodeficiência comum variável e doença de Crohn-like. Enfatizar a importância do diagnóstico e tratamento precoces. DESCRIÇÃO DO CASO: Um paciente masculino foi diagnosticado com imunodeficiência comum variável aos nove anos de idade e doença inflamatória intestinal inespecífica aos 10 anos, após realização de colonoscopia e biópsia colônica indicando moderado infiltrado linfoplasmocitário, eosinofílico e alguns neutrófilos em lâmina própria, com ausência de granulomas. Aos 14 anos, foi confirmado o diagnóstico de doença de Crohn-like por especialista após correlação entre história clínica e exames complementares. Atualmente com 18 anos, o paciente está em tratamento com imunoglobulina humana endovenosa, infliximabe e azatioprina, com estabilização do quadro clínico. CONCLUSÕES: A revisão da literatura identificou 11 relatos de caso sobre a associação imunodeficiência comum variável e doença de Crohnlike, inexistindo trabalhos brasileiros, o que ressalta a raridade de tal associação. Neste relato, o paciente recebeu tratamentos amplos e empíricos devido à dificuldade em se chegar a um diagnóstico específico, o qual somente foi realizado aos 14 anos, quando se iniciou tratamento mais direcionado e individualizado. Apesar de atualmente estável, o paciente apresentou diversas complicações durante a investigação diagnóstica, o que ressalta a importância de diagnóstico precoce e tratamento mais preciso e dirigido às necessidades de saúde desses pacientes.

AIMS: To report the case of a patient diagnosed with common variable immunodeficiency and Crohn-like disease, describing the clinical picture, the diagnostic investigation process, the therapeutic approaches and the clinical outcome of the patient. To carry out a literature review of case reports addressing patients with the common variable immunodeficiency and Crohn-like disease association. Emphasize the importance of early diagnosis and treatment. CASE DESCRIPTION: A male patient was diagnosed with common variable immunodeficiency at nine years of age and with non-specific inflammatory bowel disease at 10 years, after colonoscopy and colonic biopsy indicated moderate lymphoplasmacytic, eosinophilic infiltrate and some neutrophils in lamina propria, with absence of granulomas. At age 14, the diagnosis of Crohn-like disease was confirmed by specialist after correlation between clinical history and complementary exams. Currently with 18 years of age, the patient is under treatment with intravenous human immunoglobulin, infliximab and azathioprine, with stabilization of the clinical picture. CONCLUSIONS: The literature review identified 11 case reports on the association between common variable immunodeficiency and Crohn-like disease, with no Brazilian studies, which highlights the rarity of such association. In this report, the patient received extensive and empirical treatments due to the difficulty in reaching a specific diagnosis, which was only performed at age 14, when more targeted and individualized treatment was started. Although currently stable, the patient presented several complications during the diagnostic investigation, which emphasizes the importance of early diagnosis and more precise treatment, targeted to meet the health needs of these patients.

Meningoencefalitis criptocóccica refractaria en una mujer joven

RESUMEN Mujer de 23 años presenta hace 2 meses cefalea que se acompaña de visión borrosa, disartria y pérdida de la conciencia. Por líquido cefalorraquídeo se confirma meningitis a criptococo. A pesar del tratamiento con anfotericina B y fluconazol presenta empeoramiento general. Durante su evolución presentó paracoccidioidomicosis pulmonar y candidiasis vaginal. A pesar de la terapia dirigida, la paciente fallece con la tardía confirmación de una inmunodeficiencia variable común.

ABSTRACT A 23-year-old woman has been presenting headache for two months that is accompanied by blurred vision, dysarthria and loss of consciousness. Cerebrospinal fluid confirms meningitis to Cryptococcus. In spite of the treatment with amphotericin B and fluconazole she presents a general deterioration. During her evolution she presented pulmonary paracoccidiomycosis and vaginal candidiasis. Despite specific therapy, the patient dies with the late confirmation of a common variable immunodeficiency.

Diarrea crónica por Lamblia intestinalis en un adulto / (Chronic diarrhea by Lamblia intestinalis in an adult)

ResumenSe presenta un caso de inmunodeficiencia común variable en un paciente masculino, joven con larga historia (9 años) de procesos infecciosos gastrointestinales y respiratorios recurrentes; a pesar de los diferentes esquemas terapéuticos, con evidencia diagnóstica de niveles bajos de inmunoglobulinas de las clases IgG, IgM e IgA; se pretende comparar su evolución a partir de su historia clínica y los resultados de sus exámenes complementarios, con la bibliografía revisada. La inmunodeficiencia común variable explica un déficit primario de IgG (al menos 2 desviaciones estándar por debajo de los valores de referencia para su edad), al menos otra de las Ig (IgA o IgM) y una reducción o ausencia de producción de anticuerpos. Esta entidad se considera poco frecuente en términos de incidencia, aunque cursa muchas veces inadvertida por el predominio de sus efectos. Clínicamente, se manifiesta por la presencia de infecciones recurrentes con preponderancia de las respiratorias y gastrointestinales. Desde el punto de vista etiológico, su génesis es controversial, pero se describen niveles bajos de inmunoglobulinas y una reducción o ausencia de producción de anticuerpos.

AbstractWe present a variable common immunodeficiency case in a young male patient with a long history (9 years) of recurrent gastrointestinal and respiratory infectious processes, despite the different therapeutic schemes, with diagnostic evidence of low levels of IgG, IgM And IgA; aiming to make a comparison of its evolution in function of its clinical history and the results of its complementary examinations, with the bibliography reviewed. Variablecommon immunodeficiency explains a primary IgG deficit (at least 2 standard deviations below the reference values for his age) and at least one other Ig (IgA or IgM) and a reduction or absence of antibody production. This entity is considered infrequent in terms of incidence, although it is often inadvertent due to the predominance of its effects. Clinically it is manifested by the presence of recurrent infections with preponderance of the respiratory and gastrointestinal. From an aetiological point of view, its genesis is controversial, but low levels of immunoglobulins and a reduction or absence of antibody production are all described.

Linfadenite recorrente. Caso clínico / Recurrent lymphadenitis. Case report

A imunodeficiência de variável comum é uma imunodeficiência primária de apresentação heterogênea, consistindo em um défice em imunoglobulinas. É caracterizada por infeções de repetição e predisposição para doenças autoimunes, granulomatosas e neoplásicas. Os autores apresentam o caso clínico de um doente com imunodeficiência comum variável manifestada por infeções cutâneas de repetição e linfadenite recorrente. Este caso tem como objetivo alertar para os aspetos clínicos desta imunodeficiência, a fim de permitir seu diagnóstico precoce, evitando-se prognósticos desfavoráveis.(AU)

Common variable immunodeficiency is a primary immunodeficiency with a heterogeneous presentation, characterized by decreased immunoglobulin levels. It is characterized by recurrent infections, predisposition to autoimmune, granulomatous and neoplastic diseases. The authors report a case of a patient with common variable immunodeficiency and history of skin infections and recurrent lymphadenitis. This case report aims to draw the attention to the clinical aspects of this immunodeficiency, in order to promote an early diagnosis, avoiding poor outcomes.(AU)

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.

Inmunodeficiencia variable común y déficit selectivo de inmunoglobulina A en pacientes celiacos / Common variable immunodeficiency and selective IgA deficiency in celiac disease patients

La enfermedad celíaca (EC) es una de las enfermedades autoinmunes gastrointestinales que con más frecuencia se asocia a inmunodeficiencias primarias (IDP) como el déficit selectivo de IgA y la inmunodeficiencia variable común (IDVC). A propósito del vínculo entre IDP y celiaquía, se presentan dos pacientes femeninas diagnosticadas como celíacas con formas de presentación diferentes y compromiso inmunonutricional variable. Las bajas concentraciones de inmunoglobulina G (IgG) y la ausencia de IgA fueron los principales hallazgos humorales registrados, no se evidenció compromiso de células B y T, de acuerdo a la cuantificación de subpoblaciones linfoides por citometria de flujo. La intervención nutricional e inmunológica permitió la remisión de las manifestaciones clínicas y la evolución satisfactoria en ambos casos(AU)

Celiac disease (CD) is an autoimmune gastrointestinal disease very often associated with Primary Immunodeficiencies (PID) as selective IgA deficiency and variable immunodeficiency common. About the link between celiac disease IDP, two female patients diagnosed as celiac patients with different forms of presentation and varying commitment immunonutritional presented. Low levels of immunoglobulin G (IgG) and absence of immunoglobulin A (IgA) were the main humoral findings recorded, no commitment of B and T cells, according to the quantification of lymphoid subpopulations by flow cytometry. Nutritional and immunological intervention allowed remission of clinical manifestations and satisfactory outcome in both cases(AU)

Primary immunodeficiencies and B-cell lymphomas / Inmunodeficiencias primarias y linfomas de células B

Abstract Introduction: In primary immunodeficiencies there is a failure in the anti-tumor defense. Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies characterized by an alteration in the differentiation of B lymphocytes (BL). Epstein-Barr virus (EBV) is an ubiquitous virus that selectively infects the BL. In patients with immunodeficiency, uncontrolled proliferation of infected BL and the action of viral proteins promote the development of lymphomas. Clinical cases: At the University Hospital Sant Joan de Deu, Barcelona, 28 patients were diagnosed with CVID from 2000 to 2013. This paper describes four patients who developed non-Hodgkin's lymphoma (NHL). The lymphoma was associated with EBV in two of the cases. Patients were < 18 years old, diagnosed with lymphoma between 4 and 13 years old. Two patients were treated with rituximab as monotherapy and achieved complete remission. Two patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and radiotherapy or rituximab and achieved complete remission. Conclusions: Early detection of EBV infections and NHL in all patients diagnosed with CVID is recommended, regardless of age at diagnosis.

Resumen Introducción: En las inmunodeficiencias primarias existe un fallo en la defensa antitumoral. La inmunodeficiencia variable común (IDVC) es una de las inmunodeficiencias primarias más frecuentes. Se caracteriza por una alteración en la diferenciación de linfocitos B (LB). El virus de Epstein-Barr (EBV) es un virus ubicuo que infecta de manera selectiva los LB. En pacientes con inmunodeficiencias, la proliferación incontrolada de LB infectados y la acción de proteínas virales promueve la aparición de linfomas. Casos clínicos: En el Hospital Universitario Sant Joan de Déu, Barcelona, se han diagnosticado 28 pacientes con IDVC del 2000 al 2013. En este trabajo se describen cuatro que desarrollaron linfoma no Hodgkin (NHL). El linfoma fue asociado a EBV en dos de ellos. Los pacientes eran menores de 18 años, con el linfoma diagnosticado entre los 4 y 13 años de edad. Dos de los pacientes fueron tratados con rituximab como monoterapia, y lograron la remisión completa. Dos fueron tratados con CHOP (ciclofosfamida, doxorrubicina, vincristina y prednisolona) y radioterapia o rituximab y también alcanzaron la remisión completa. Conclusiones: Se recomienda realizar la detección precoz de las infecciones por EBV y los NHL en todos los pacientes con diagnóstico de IDVC, independientemente de la edad del diagnóstico.