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.

Neuroendocrine tumor in a child with common variable immunodeficiency / Tumor neuroendócrino em criança com imunodeficiência comum variável

ABSTRACT Objective: To report a case of a child with primary immunodeficiency who at eight years developed digestive symptoms, culminating with the diagnosis of a neuroendocrine tumor at ten years of age. Case description: One-year-old boy began to present recurrent pneumonias in different pulmonary lobes. At four years of age, an immunological investigation showed a decrease in IgG and IgA serum levels. After the exclusion of other causes of hypogammaglobinemia, he was diagnosed with a Common Variable Immunodeficiency and started to receive monthly replacement of human immunoglobulin. The patient evolved well, but at 8 years of age began with epigastrium pain and, at 10 years, chronic persistent diarrhea and weight loss. After investigation, a neuroendocrine tumor was diagnosed, which had a rapid progressive evolution to death. Comments: Medical literature has highlighted the presence of gastric tumors in adults with Common Variable Immunodeficiency, emphasizing the importance of early diagnosis and the investigation of digestive neoplasms. Up to now there is no description of neuroendocrine tumor in pediatric patients with Common Variable Immunodeficiency. We believe that the hypothesis of digestive neoplasm is important in children with Common Variable Immunodeficiency and with clinical manifestations similar to the case described here in the attempt to improve the prognosis for pediatric patients.

RESUMO Objetivo: Relatar um caso de criança portadora de imunodeficiência primária que, aos oito anos, desenvolveu sintomas digestivos, culminando com o diagnóstico de tumor neuroendócrino aos dez anos de idade. Descrição do caso: Menino, com um ano de idade, começou a apresentar pneumonias de repetição em diferentes lobos pulmonares. Aos quatro anos, a investigação imunológica mostrou diminuição dos níveis séricos de IgG e IgA. Após exclusão de outras causas de hipogamaglobulinemia, teve diagnóstico de imunodeficiência comum variável, passando a receber reposição mensal de imunoglobulina humana. Evoluiu bem, porém, aos oito anos, começou com epigastralgia e, aos dez anos, diarreia crônica persistente e perda de peso. O quadro culminou com o diagnóstico de tumor neuroendócrino intestinal, de rápida progressão, com óbito do paciente. Comentários: A literatura tem chamado a atenção para tumores gástricos em adultos com imunodeficiência comum variável, alertando para a importância do diagnóstico precoce e da pesquisa de neoplasias digestivas. Até o momento, não há descrição de tumor neuroendócrino em pacientes pediátricos portadores de imunodeficiência comum variável. Acredita-se ser importante a hipótese de neoplasia digestiva diante de crianças com imunodeficiência comum variável e com manifestações clínicas semelhantes ao caso descrito, na tentativa de melhorar o prognóstico para pacientes pediátricos.

Inmunodeficiencia común variable: correlación entre parámetros inmunológicos y manifestaciones clínicas

La inmunodeficiencia común variable(IDCV) es una inmunodeficiencia humoral primaria caracterizada por la disminución de inmunoglobulina G y al menos otra inmunoglobulina, la presencia de infecciones recurrentes y complicaciones no infecciosas como enfermedades autoinmunes, linfoproliferativas o neoplásicas

Summary: Common variable immunodeficiency is a humoral primary immunodeficiency characterized by low LgG levels and of at least another immunoglobulin, recurrent infections, and moninfectious complications, as autoimmune, lymphoproliferative or neoplastic diseases

Inmunodeficiencia común variable: caracterización clínica e inmunológica de pacientes e identificación de subgrupos homogéneos con base en la tipificación de subpoblaciones de linfocitos B / Common variable immunodeficiency: Clinical and immunological characterization of patients and homogeneous subgroup definition by means of B lymphocyte subpopulation typing

Introducción. La inmunodeficiencia común variable es un síndrome heterogéneo caracterizado por infecciones recurrentes, hipogammaglobulinemia y producción deficiente de anticuerpos específicos. Las anormalidades en subpoblaciones de linfocitos en sangre periférica, particularmente de linfocitos B, permiten la clasificación de los pacientes en grupos homogéneos. Objetivo. Caracterizar clínica e inmunológicamente los linfocitos B y tipificar sus subpoblaciones en doce pacientes colombianos con inmunodeficiencia común variable, para clasificarlos en grupos homogéneos. Materiales y métodos. Se revisaron las historias clínicas de los pacientes y se evaluaron las inmunoglobulinas séricas, la proliferación de linfocitos y la hipersensibilidad retardada, así como las subpoblaciones de linfocitos y de linfocitos B mediante citometría de flujo. Resultados. Todos los pacientes presentaron infecciones respiratorias o gastrointestinales recurrentes y, algunos, infecciones en otros sistemas. Además, todos presentaban disminución de la IgG, en tanto que la IgA y la IgM fueron bajas en nueve y diez pacientes, respectivamente. En todos hubo disminución de la proliferación de linfocitos inducida por mitógenos, pero fue normal frente a antígenos específicos. La tipificación de subpoblaciones reveló valores elevados de linfocitos T en tres pacientes; siete presentaron disminución en la relación CD4+/CD8+ y, cuatro, linfocitos NK bajos. El conteo de linfocitos B fue normal en once pacientes, ocho de los cuales presentaron linfocitos B de memoria bajos, en tanto que cuatro presentaron aumento de linfocitos B de transición o de linfocitos B CD21 low . Conclusión. La tipificación de subpoblaciones de linfocitos solo permitió asignar a 11 de los pacientes a grupos homogéneos según los esquemas de clasificación internacionales, lo que indica la necesidad de agregar más criterios hasta lograr una clasificación ideal. Este estudio permitirá establecer mejores seguimientos médicos para pacientes con inmunodeficiencia común variable en grupos con alto riesgo de desarrollar complicaciones clínicas.

Introduction: Common variable immunodeficiency is a heterogeneous syndrome characterized by recurrent infections, hypogammaglobulinemia and defective production of specific antibodies. Abnormalities in peripheral blood lymphocyte subpopulations, in particular of B lymphocytes, allow the classification of patients into homogeneous groups. Objective: To perform a clinical and immunological characterization and to evaluate lymphocyte subpopulations of twelve Colombian patients with common variable immunodeficiency in order to define homogeneous groups. Materials and methods: We reviewed medical records and evaluated serum immunoglobulins (Ig), lymphoproliferation, delayed hypersensitivity and used flow cytometry to quantify peripheral blood total lymphocyte and B cell populations. Results: All patients had recurrent respiratory and/or gastrointestinal infections, while some also had infections affecting other systems. All patients had abnormally low serum IgG levels, while IgA and IgM levels were reduced in nine and ten patients, respectively. Lymphoproliferation to mitogen was lower in patients than in healthy controls but lymphoproliferation to specific antigen was normal in all. Flow cytometry revealed high numbers of T cells in three patients, while seven had a low CD4+/CD8+ ratio and four had reduced NK cells . Eleven patients had normal B cell counts, and eight of them also showed decreased memory B lymphocytes, and four had increased transitional or CD21 low B lymphocytes. Conclusion: Lymphocyte typing allowed assigning all but one patient to homogeneous groups according to international classification schemes, indicating the necessity of including more criteria until an ideal classification is achieved. This study will lead to a better medical monitoring of common variable immunodeficiency patients in groups at high risk of developing clinical complications.

Inmunodeficiencia común variable: Epidemiología y manifestaciones clínicas en 69 pacientes / Common variable immunodeficiency: Epidemiology and clinical manifestations in 69 patients

La inmunodeficiencia común variable (IDCV) se caracteriza por una alteración en la producción de anticuerpos y una mayor susceptibilidad a infecciones por bacterias extracelulares capsuladas, principalmente del tracto respiratorio. Analizamos las características clínicas de 69 pacientes, evaluados en un período de 10 años en tres centros de la ciudad de Buenos Aires. Al inicio del estudio se encontraban en seguimiento 14 pacientes y al finalizar 60; la mayoría fueron derivados por infecciones o hipogammaglobulinemia, y casi la mitad con diagnóstico establecido de inmunodeficiencia. Sesenta y cinco (94.2%) pacientes presentaron infecciones por gérmenes capsulados, cuatro (6.1%) sepsis y dos tuberculosis. La edad promedio de comienzo de los síntomas infecciosos fue de 18.1 años, la edad promedio al momento del diagnóstico fue de 29.6 años y el retraso diagnóstico de 11.9 años. En 41 (59.4%) pacientes se registró el antecedente de diarreas recurrentes o crónicas. En 22 (31.9%) se diagnosticaron 13 enfermedades autoinmunes, siendo las más frecuentes las hematológicas y el hipotiroidismo. Ocho pacientes tuvieron linfoproliferación policlonal histológica, cuatro (5.8%) como enfermedad granulomatosa de hígado, laringe y piel, y cuatro como neumonía intersticial linfoidea (NIL). Diecinueve (27.5%) pacientes presentaron esplenomegalia y 23/57 (40.3%) imágenes sugestivas de procesos granulomatosos o linfocíticos en la TAC de tórax (incluidos los 4 con NIL). Tres (4.3%) pacientes desarrollaron linfoma B, cuatro (5.8%) adenocarcinoma de estómago y uno cáncer de mama. El estudio tuvo una mediana de seguimiento de 54 meses, rango 1-353 y durante el período del mismo murieron cuatro pacientes (5.8%).

Common variable immunodeficiency (CVID) is characterized by an impaired antibody production and an increased susceptibility to recurrent infections of the respiratory tract, mainly by extracellular encapsulated bacteria. We analyzed the clinical characteristics of 69 patients evaluated over a period of 10 years at three centers in the city of Buenos Aires. At the onset of the study 14 patients were on follow up, and at its end the number of patients reached to 60. Most of them consulted for infection or hypogammaglobulinemia and nearly half had an established diagnosis of immunodeficiency. Sixty-five (94.2%) patients had infections by encapsulated bacteria, four (6.1%) sepsis and two tuberculosis. The average age of onset of infectious symptoms was 18.1 years; the average age at diagnosis was 29.6 years and the delay to diagnosis 11.9 years. Forty one (59.4%) patients reported a history of recurrent or chronic diarrhea. In 22 (31.9%) 13 autoimmune diseases were diagnosed, being the most frequent the hematological disorders and hypothyroidism. Eight patients had histological polyclonal lymphoproliferation, four (5.8%) with granulomatous disease affecting the liver, the larynx and/or the skin; and four as lymphoid interstitial pneumonitis (LIP). Nineteen (27.5%) patients had splenomegaly and 23/57 (40.3%) images suggestive of lymphocytic or granulomatous processes (including the 4 with LIP) in the chest CT. Three (4.3%) patients developed B cell lymphoma, four (5.8%) stomach adenocarcinoma and one breast cancer. The study had a median follow-up of 54 months, range 1-353 and four patients (5.8%) died during the follow up.

Analysis of the sputum and inflammatory alterations of the airways in patients with common variable immunodeficiency and bronchiectasis

INTRODUCTION: Common variable immunodeficiency is characterized by defective antibody production and recurrent pulmonary infections. Intravenous immunoglobulin is the treatment of choice, but the effects of Intravenous immunoglobulin on pulmonary defense mechanisms are poorly understood. OBJECTIVE: The aim of this study was to verify the impact of intravenous immunoglobulin on the physical properties of the sputum and on inflammatory alterations in the airways of patients with Common variable immunodeficiency associated with bronchiectasis. METHOD: The present study analyzed sputum physical properties, exhaled NO, inflammatory cells in the sputum, and IG titers in 7 patients with Common variable immunodeficiency and bronchiectasis with secretion, immediately before and 15 days after Intravenous immunoglobulin. A group of 6 patients with Common variable immunodeficiency and bronchiectasis but no sputum was also studied for comparison of the basal IgG level and blood count. The 13 patients were young (age=36±17 years) and comprised predominantly of females (n=11). RESULTS: Patients with secretion presented significantly decreased IgG and IgM levels. Intravenous immunoglobulin was associated with a significant decrease in exhaled NO (54.7 vs. 40.1 ppb, p<0.05), sputum inflammatory cell counts (28.7 vs. 14.6 cells/mm³, p<0.05), and a significant increase in respiratory mucus transportability by cough (42.5 vs. 65.0 mm, p < 0.05). CONCLUSION: We concluded that immunoglobulin administration in Common variable immunodeficiency patients results in significant improvement in indexes of inflammation of the airways with improvement in the transportability of the respiratory mucus by cough.

Primary immune deficiency among patients with recurrent infections.

OBJECTIVES: Primary immune deficiency is relatively rare. Patients present with recurrent or persistent infections or infections with opportunistic pathogens. We investigated patients who presented during the years 2005-7 with recurrent or persistent infections or infections with opportunistic organisms, for underlying immune deficiency. DESIGN: Descriptive study. SETTING: Department of Immunology, Medical Research Institute, Colombo. STUDY POPULATION: 257 patients referred to the Department of Immunology, Medical Research Institute, Colombo, with a history of recurrent infections, for evaluation of possible immune deficiency. MEASUREMENTS: Appropriate evaluation of immunological competence of the humoral and cell mediated immune systems. RESULTS: There were 8 patients with agammaglobulinaemia (X linked agammaglobulinaemia and autosomal recessive agammaglobulinaemia), 2 patients each with ataxia telangiectasia, IgA deficiency and hyper-IgE syndrome, 3 patients with common variable immune deficiency (CVID), and 1 patient each with Griscelli syndrome, hyper-IgM syndrome and X linked severe combined immune deficiency (SCID). CONCLUSIONS: Primary immune deficiency must be included in the evaluation of patients with recurrent infections, and timely intervention can prevent morbidity and mortality.

Síndrome de DiGeorge: Aspectos clínico-imunológicos e manejo / DiGeorge Syndrome: Clinical-immunologic aspects and management

Objetivo: revisar a literatura sobre a Síndrome de DiGeorge (SDG) com ênfase para as principais manifestações clínicas e abordagens diagnóstica e terapêutica. Fonte de dados: Literatura médica publicada sobre o assunto nos últimos dez anos utilizando PubMed, MEDLINE e livros médicos especializados. Palavras chave usadas na pesquisa: Síndrome de DiGeorge, FISH, síndrome Velo-cárdio-facial, imunodeficiência primária, infecções recorrentes. Síntese de dados: A SDG é distúrbio congênito resultante da migração anormal das células embrionárias da terceira e quarta bolsas faríngeas, levando a hipo ou aplasia do ti mo, defeitos da paratireóide, arco aórtico e imunodeficiência celular. Além de hipocalcemia neonatal e dismorfismos faciais tipicos, as alterações observadas ocorrem principalmente nos sistemas imunológico e cardiovascular. Os principais defeitos cardíacos relatados são: Anomalia conotruncal, interrupção do arco aórtico e Tetralogia de Fallot. Quanto às anormalidades do sistema imunológico, os pacientes podem ser assintomáticos ou cursar com defeitos graves de células T, dependendo do grau de comprometimento tímico. Conclusões: O diagnóstico, após suspeição clínica deve ser confirmado pelo teste FISH. O manejo destes pacientes visa principalmente o controle das infecções de repetição, correção dos distúrbios cardíacos e controle de co-morbidades. O tratamento definitivo nos casos mais graves é o transplante tímico, com resultados promissores

Common variable immunodeficiency: experience in Puerto Rico

Common variable immunodeficiency (CVI) is a primary immunodeficiency characterized by hypogammaglobulinemia and an increased susceptibility to infections. The degree and the type of deficiency of serum immunoglobulins, as well as, the clinical course vary from patient to patient, hence the term [quot ]variable[quot ]. The aim of this report is to describe the clinical characteristics and the response to gammaglobulin therapy of a group of patients with CVI followed at the University Hospital of the Puerto Rico Medical Center. To our knowledge, no data on primary immunodeficiencies in Puerto Rico has been reported in the literature. The study group exhibits specific characteristics as compared to other reported series.

Hipogamaglobulinemia común, variable del adulto: a propósito de un caso clínico / Common variable hypogammaglobulinemia of the adult: apropos of a case

La Hipogamaglobulinemia común variable del adulto es una afección poco frecuente. Sus manifestaciones clínicas son similares a los de la hipogamaglobulinemia congénita, destacándose la presencia de bronquiectasias adquiridas por infecciones respiratorias reiteradas. El hallazgo de otras anomalías inmunitarias, en particular, alteraciones cuanti y cualitativas de los linfocitos T, ponen en la pista del diagnóstico de esta afección. A propósito de este caso, se repasan las causas más frecuentes de bronquiectasias en el adulto, su metodología de estudio y su relación con alteraciones del sistema inmune. Se señala además el hallazgo de mutaciones vinculadas con la mucovisidosis como una interrogante en la interpretación patogénica de todo el cuadro

Remisión inexplicada de inmunodeficiencia común variable: análisis de un caso clínico / Unexplained remission of common variable immunodeficiency: analysis of 1 clinic case

We report a 26 years old female with a common variable immunodeficiency diagnoses at the age of 21 with recurrent pulmonary and sinusal bacterial infections that had a clinical and laboratory remission. At the moment of diagnosis she had agammaglobulinemia in the protein electrophoresis, very low level of IgG and IgM and absence of IgA. Absolute counts of CD4(+) T lymphocytes were low and CD8(+) were normal. B lymphocyte count was normal. Five years later a repeated study revealed normal levels of all these parameters, excepting IgA that continued to be undetectable. We propose that the remission could be due to a decrease in suppressor activity of T lymphocytes. There is no documented evidence of infectious factors or the use of immunological therapy that could have influenced the course of the disease

Common variable immunodeficiency: a clinical and laboratory evaluation of l5 cases

The clinical and laboratory data for 15 patients with common variable immunodeficiency (CVI) (5 females and 10 males aged 3 years and 6 months to 40 years at first examination) were evaluated. The age of onset of infectious signs and symptoms ranged from 6 months to 35 years. Recurrent pulmonary infections predominated (86.6%), followed by chronic diarrhea (46.6%). Aproximately 60% of the patients with pulmonary complaints presented chronic sequelae (bronchiectasis). Two developed a polymyositis-like picture. No neoplasms were observed. All patients presented immunoglobulin levels below 300mg/dl and absence of globulin levels below 300mg/dl and absence of antibody responses to poliovirus and to hemagglutinin. Two patients were negative when tested for autoimmunity. Cell immunity tested by the limphoproliferative response in the presence of phytohemagglutinin was normal in 11 patients and depressed in 4. A decrease in the helper T population and inversion of the OKT4/8 ratio occured in 13. Cimetidine treatment (1200mg/day) applied to 5 patients for 4 weeks did not produce any clinical or laboratory improvement. Gamma globulin is the treatment of choice for these patients