Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

Documento de consenso de la Sociedad de Infectología Pediátrica sobre el tratamiento de la infección fúngica basado en la respuesta inmunológica / Spanish Paediatric Infectious Diseases Society Consensus Document on the Treatment of Fungal Infections Based on the Immune Response

La infección fúngica invasiva es una infección de tipo oportunista que afecta principalmente al paciente inmunodeprimido y crítico y que, a pesar de los avances en el diagnóstico y tratamiento, sigue comportando una elevada morbimortalidad. Esto ha determinado la investigación de tratamientos coadyuvantes a la terapia antifúngica estándar. Entre ellos, destaca el tratamiento basado en la respuesta inmunológica, que comprende el tratamiento inmunomodulador (transfusión de células T y de células dendríticas, factores estimuladores de colonias, interferón gamma, interleucina 12, vacunas antifúngicas, factores de transferencia y ciertos fármacos como la cloroquina) y el tratamiento inmunoterápico que incluye la transfusión de granulocitos, los anticuerpos monoclonales y la inmunoglobulina endovenosa. El presente documento recoge una revisión y actualización de los datos disponibles sobre esta modalidad terapéutica y aporta los conocimientos básicos de la respuesta inmune frente a la infección fúngica para poder comprender mejor el papel de dicha estrategia terapéutica en la respuesta al tratamiento antifúngico convencional, así como sus potenciales indicaciones en el paciente pediátrico. Existen pocos datos sobre evidencia científica y grado de recomendación para su uso (AU)

Despite the emergence of new diagnostic and therapeutic methods, invasive fungal infections are still a major cause of morbidity and mortality in immunocompromised and critical patients. Therefore, adjuvant treatments to the standard antifungal therapy are being investigated, with immunity-based therapy being one of the most important. Both immunomodulatory (dendritic and T cells transfusions, colony stimulating factors, interferón-gamma, interleukin 12, fungal vaccines, transfer factors and certain drugs such as chloroquine) and immunotherapeutic modalities (granulocyte transfusions, monoclonal antibodies and intravenous immunoglobulin) have been described. This document aims to summarise currently available data on immunity-based therapy of fungal infections and to provide basic knowledge on the immune response to fungal infections. This helps to understand how, in selected cases, immunity-based therapy may improve the response to standard antifungal treatment. The potential indications of immunity-based therapy in the paediatric patient are reviewed, although there is still a lack of scientific evidence for its use in children (AU)

[Spanish Paediatric Infectious Diseases Society consensus document on the treatment of fungal infections based on the immune response]. / Documento de consenso de la Sociedad de Infectología Pediátrica sobre el tratamiento de la infección fúngica basado en la respuesta inmunológica.

Despite the emergence of new diagnostic and therapeutic methods, invasive fungal infections are still a major cause of morbidity and mortality in immunocompromised and critical patients. Therefore, adjuvant treatments to the standard antifungal therapy are being investigated, with immunity-based therapy being one of the most important. Both immunomodulatory (dendritic and T cells transfusions, colony stimulating factors, interferón-gamma, interleukin 12, fungal vaccines, transfer factors and certain drugs such as chloroquine) and immunotherapeutic modalities (granulocyte transfusions, monoclonal antibodies and intravenous immunoglobulin) have been described. This document aims to summarise currently available data on immunity-based therapy of fungal infections and to provide basic knowledge on the immune response to fungal infections. This helps to understand how, in selected cases, immunity-based therapy may improve the response to standard antifungal treatment. The potential indications of immunity-based therapy in the paediatric patient are reviewed, although there is still a lack of scientific evidence for its use in children.

A multi-centre study of efficacy and safety of Intratect®, a novel intravenous immunoglobulin preparation.

We studied the efficacy, safety and pharmacokinetic profiles of Intratect®, a recently developed polyvalent intravenous immunoglobulin (IVIG) preparation. Fifty-one patients (aged 6-48 years) with primary immunodeficiencies (PID) and established replacement therapy using a licensed IVIG were enrolled and treated for 12 months with Intratect®. Retrospective patient data served as prestudy controls. The primary efficacy variable was the annual rate of acute serious bacterial infection (ASBI) per patient. Secondary parameters were annual rate of acute relevant infection (ARI), days with antibiotic use, fever, absence from school/work and hospitalization. The average IVIG dose was 0·49 g/kg, with an average infusion rate of 2·4 ml/kg/h. The annual ASBI rate/patient was 0·02 and ARIs were detected 128 times during the 630 adverse events in 40 patients, specified mainly as bronchitis, sinusitis, respiratory tract infection, rhinitis and pharyngitis. The annual rate of respiratory ARIs/patient was 2·0 and the rates/patient for days with fever >38°C, school/work absence and hospitalization were 1·81, 3·99 and 0·36, respectively. A total of 630 adverse events (AEs) were observed in 50 of 51 (98·0%) of patients. In 46 of 51 patients the AEs were not related to infusion. Pharmacokinetic studies after the first infusion revealed a mean elimination half-life of 50·8 ± 30·3 days. During this study, 19 of 649 (2·9%) IgG trough levels were below 6 g/l, better than that of reference IVIGs during the 6 months before study start (10 of 201). These data suggest that Intratect® is a well tolerated, safe and effective IgG concentrate for the treatment of patients with PID.

Reduced memory B cells in patients with hyper IgE syndrome.

Dominant-negative mutations in STAT-3 have recently been found in the majority of patients with sporadic or autosomal-dominant hyper IgE syndrome (HIES). Since STAT-3 plays a role in B cell development and differentiation, we analyzed memory B cells in 20 patients with HIES, 17 of which had STAT-3 mutations. All but four patients had reduced non-switched and/or class-switched memory B cells. No reduction in these B cell populations was found in 16 atopic dermatitis patients with IgE levels above 1000 KU/L. There was no correlation between the reduction of memory B cells and the ability to produce specific antibodies. Moreover, there was no correlation between the percentage of memory B cells and the infection history. Analysis of memory B cells can be useful in distinguishing patients with suspected HIES from patients with atopic disease, but probably fails to identify patients who are at high risk of infection.

Update on the treatment of primary immunodeficiencies.

A general review of advances in the treatment of Primary Immunodeficiencies (PID) has been performed. Treatment with immunoglobulins is indicated in cases of humoral immunodeficiencies and in selected cases of combined immunodeficiencies. The use of intramuscular immunoglobulins in the treatment of PID was abandoned after obtaining the intravenous immunoglobulins, since these are much more effective and have fewer adverse effects. Now subcutaneous immunoglobulins are also available. Immunoglobulins help to keep the patients free of symptoms and infections as these substances are able to neutralise infectious agents, modulate and promote the immune response and favour phagocytosis. Adverse effects have been reported in 5-15 % of patients receiving IVIg, and patients with deficiencies of subclasses of IgG with IgA deficiency and/or anti-IgA antibodies are at risk of severe reactions. No severe adverse effects of subcutaneous immuneglobulins have been reported and the medication can be self-administered. The efficacy and safety of IVIg and SCIg are similar and SCIg administered at home is associated with better quality of life. Stem Cell Transplantation (SCT) in Primary Immunodeficiencies is aimed at restoring the number and/or function of lymphocytes or phagocytes. Matched, related or unrelated donors, or related haploidentical donors are selected. HLA class II mismatched unrelated donors are avoided owing to the risk of severe graft versus host disease (GVHD). Stem cells are obtained from bone marrow, cord blood or peripheral blood. Prophylactic immunossupression (as well as donor T lymphocyte depletion in haploidentical and unrelated donors) is performed to avoid or minimize GVHD. Less toxic "reduced intensity" protocols now exist for pre-transplantation conditioning, indicated to avoid graft rejection if there is residual T-lymphocyte immunity in the host. In the majority of Severe Combined Immunodeficiencies (SCID), SCT results in T lymphocytes graft and the antibody immunodeficiency persists in many cases. The results are better the earlier it is performed, with the absence of previous infections, and with the degree of matching. The patient must be maintained in a laminar flow room with broad anti-infectious prophylaxis and with the intravenous administration of gammaglobulin for a variable period. Many other complications can be expected. Gene therapy. Patients with PID are ideal candidates, as they are monogenic, the haematopoietic cells are easily obtained and virus replication is easy within them. Vectors (viruses) "infect" the stem cells of the patient's bone marrow, producing the transfection of the wild (healthy) gene in these cells. Encouraging results have been achieved in X-linked SCID as there are a number of patients who are considered "cured", although neoplastic processes have occurred due to the activation of proto-oncogenes close to the point of insertion of the external gene, using retroviruses as vectors; there are now trials with adenovirus, physical methods (direct injection...) and chemical methods (viral modification, artificial viruses...). Gene therapy has also been performed in patients with Chronic Granulomatous Disease and trials will improve in the future with changes in protocols used in oncology and infectious diseases.

Update on the treatment of primary immunodeficiencies / Tratamiento de las inmunodeficiencias primarias. Actualización

A general review of advances in the treatment of Primary Immunodeficiencies (PID) has been performed. Treatment with immunoglobulins is indicated in cases of humoral immunodeficiencies and in selected cases of combined immunodeficiencies. The use of intramuscular immunoglobulins in the treatment of PID was abandoned after obtaining the intravenous immunoglobulins, since these are much more effective and have fewer adverse effects. Now subcutaneous immunoglobulins are also available. Immunoglobulins help to keep the patients free of symptoms and infections as these substances are able to neutralise infectious agents, modulate and promote the immune response and favour phagocytosis. Adverse effects have been reported in 5-15 % of patients receiving IVIg, and patients with deficiencies of subclasses of IgG with IgA deficiency and/or anti-IgA antibodies are at risk of severe reactions. No severe adverse effects of subcutaneous immuneglobulins have been reported and the medication can be self-administered. The efficacy and safety of IVIg and SCIg are similar and SCIg administered at home is associated with better quality of life. Stem Cell Transplantation (SCT) in Primary Immunodeficiencies is aimed at restoring the number and/or function of lymphocytes or phagocytes. Matched, related or unrelated donors, or related haploidentical donors are selected. HLA class II mismatched unrelated donors are avoided owing to the risk of severe graft versus host disease (GVHD). Stem cells are obtained from bone marrow, cord blood or peripheral blood. Prophylactic immunossupression (as well as donor T lymphocyte depletion in haploidentical and unrelated donors) is performed to avoid or minimize GVHD. Less toxic "reduced intensity" protocols now exist for pre-transplantation conditioning, indicated to avoid graft rejection if there is residual T-lymphocyte immunity in the host. In the majority of Severe Combined Immunodeficiencies (SCID), SCT results in T lymphocytes graft and the antibody immunodeficiency persists in many cases. The results are better the earlier it is performed, with the absence of previous infections, and with the degree of matching. The patient must be maintained in a laminar flow room with broad anti-infectious prophylaxis and with the intravenous administration of gammaglobulin for a variable period. Many other complications can be expected. Gene therapy. Patients with PID are ideal candidates, as they are monogenic, the haematopoietic cells are easily obtained and virus replication is easy within them. Vectors (viruses) "infect" the stem cells of the patient's bone marrow, producing the transfection of the wild (healthy) gene in these cells. Encouraging results have been achieved in X-linked SCID as there are a number of patients who are considered "cured", although neoplastic processes have occurred due to the activation of proto-oncogenes close to the point of insertion of the external gene, using retroviruses as vectors; there are now trials with adenovirus, physical methods (direct injection...) and chemical methods (viral modification, artificial viruses...). Gene therapy has also been performed in patients with Chronic Granulomatous Disease and trials will improve in the future with changes in protocols used in oncology and infectious diseases

Se hace una revisión general de los avances en el tratamiento de las Inmunodeficiencias Primaria (IDP). La gammaglobulina está indicada en los casos de inmunodeficiencia humoral grave y en casos seleccionados de deficiencias parciales. La vía intramuscular en el tratamiento de IDP se abandonó tras la obtención de la formulación intravenosa (IgIV), mucho más eficaz y con menos efectos adversos. Actualmente también hay inmunoglobulina subcutánea disponible. La inmunoglobulina contribuye a mantener al paciente libre de síntomas e infecciones mediante la neutralización de virus, modulación y potenciación de la respuesta inmune y favoreciendo la fagocitosis. Se han comunicado efectos adversos en 5-15% de los pacientes que reciben IgIV, los pacientes con déficit de subclases de IgG con déficit de IgA y/o anticuerpos anti-IgA tienen más riesgo de reacciones graves. El Trasplante de Progenitores Hematopoyéticos (TPH) en IDP se dirige a restaurar el número y/o función de los linfocitos o fagocitos. Se seleccionan donantes idénticos familiares o no familiares, o haploidénticos familiares. Se evitan donantes no relacionados no compatibles en HLA de clase II por el riesgo de enfermedad injerto contra huésped grave (EICH). Los progenitores hematopoyéticos se obtienen de la médula ósea, sangre de cordón o sangre periférica. La inmunosupresión profiláctica (así como depleción de linfocitos T del donante en los trasplantes haploidénticos y no familiares) se emplea para evitar o minimizar la EICH. Actualmente existen protocolos de acondicionamiento pretrasplante de “intensidad reducida” menos tóxicos, indicados para evitar el rechazo del injerto cuando queda inmunidad residual de linfocitos T en el huésped. En la mayoría de Inmunodeficiencias Combinadas Graves (IDCG) el TPH proporciona el injerto de linfocitos T y persiste la inmunodeficiencia de anticuerpos en muchos casos. Los resultados son mejores cuanto antes se practique el trasplante, en ausencia de infecciones previas y con el grado de compatibilidad. Se debe mantener al paciente en cámara de flujo laminar, con profilaxis anti-infecciosa de amplio espectro y con gammaglobulina intravenosa durante un periodo variable de tiempo. Se han descrito muchas otras complicaciones. Las IDP son candidatas ideales para terapia génica (son monogénicas, las células hematopoyéticas se obtienen con facilidad y la replicación viral es fácil dentro de las mismas). Los vectores (virus) “infectan” las células progenitoras de la médula del paciente, originando la transfección del gen “salvaje” (sano) en las mismas. Se han conseguido resultados esperanzadores en IDCG ligada a X, y hay varios pacientes que se pueden considerar “curados”, aunque han aparecido algunos procesos neoplásicos, por la activación de protooncogenes cercanos al punto de inserción del gen externo, siendo retrovirus los vectores; actualmente hay ensayos con adenovirus, métodos físicos (inyección directa…) y métodos químicos (modificación viral, virus artificiales…). También se ha realizado terapia génica en pacientes con Enfermedad Granulomatosa Crónica. Probablemente en el futuro continúen los ensayos de terapia génica en tumores (bloqueando oncogenes activados o reemplazando genes supresores de tumor inactivados), enfermedades infecciosas (supresión de genes virales en VIH)…

Chronic granulomatous disease in pediatric patients: 25 years of experience.

INTRODUCTION: Chronic granulomatous disease (CGD) is an uncommon primary immune deficiency (affecting 1/200,000 newborn infants) caused by a defect in phagocyte production of oxygen metabolites, and resulting in bacterial infections produced by catalase-positive microorganisms and fungal diseases that occasionally may prove fatal. METHODS: A review is made of the clinical records of 13 pediatric patients diagnosed with CGD between 1980 and 2005. RESULTS: All patients were males. The mean age at diagnosis was 36 months. The clinical manifestations at the time of diagnosis comprised the following: Abscesses or abscessified adenopathies 4/13 (Staphylococcus aureus (2), Serratia liquefaciens, S. marcescens and Klebsiella sp.), pneumonia 3/13 (Rhodococcus equi, Salmonella typhimurium plus Pneumocystis jiroveci), osteomyelitis 1/13 (Aspergillus sp.), sepsis 1/13 (S. aureus), urinary infection 1/13 (Klebsiella sp.), severe gastroenteritis 1/13, oral aphthae 1/13 and Crohn-like inflammatory bowel disease 1/13. The diagnosis was initially established by the nitroblue tetrazolium test, and confirmed by flow cytometry 10/13 and genetic techniques (gp91) 9/13. In the course of these disease processes there were 88 infections: abscesses (n = 26), lymphadenitis (n = 12), pneumoniae (n = 10), gastroenteritis (n = 7), sepsis (n = 6), osteomyelitis (n = 3) and others (n = 24). As to the germs isolated, the frequency distribution was as follows (n = 49): Aspergillus sp. (n = 10), Staphylococcus sp. (n = 7), Salmonella sp. (n = 6), Serratia sp. (n = 5), Pseudomonas aeruginosa (n = 4), Klebsiella sp. (n = 4), Proteus sp. (n = 3), Leishmania sp. (n = 2) and others (n = 8). IFN-gamma was administered in 7/13 cases, and itraconazole in 9/13; all received cotrimoxazole. There were four deaths, with one case each of sepsis due to gramnegative bacterial infection; disseminated aspergillosis; visceral leishmaniasis and hemophagocytosis; and post-kidney transplant complications. CONCLUSIONS: Clinical suspicion and flow cytometry are the keys for diagnosis of CGD and detection of carrier relatives. Specific prophylactic measures and medical controls are required to prevent serious infections. IFN-gamma has been used intermittently, though its effectiveness is controversial.

Chronic granulomatous disease in pediatric patients: 25 years of experience / Enfermedad granulomatosa crónica en pediatría: 25 años de experiencia

Introduction: Chronic granulomatous disease (CGD) is an uncommon primary immune deficiency (affecting 1/200,000 newborn infants) caused by a defect in phagocyte production of oxygen metabolites, and resulting in bacterial infections produced by catalase-positive microorganisms and fungal diseases that occasionally may prove fatal. Methods: A review is made of the clinical records of 13 pediatric patients diagnosed with CGD between 1980 and 2005. Results: All patients were males. The mean age at diagnosis was 36 months. The clinical manifestations at the time of diagnosis comprised the following: Abscesses or abscessified adenopathies 4/13 (Staphylococcus aureus (2), Serratia liquefaciens, S. marcescens and Klebsiella sp.), pneumonia 3/13 (Rhodococcus equi, Salmonella typhimurium plus Pneumocystis jiroveci), osteomyelitis 1/13 (Aspergillus sp.), sepsis 1/13 (S. aureus), urinary infection 1/13 (Klebsiella sp.), severe gastroenteritis 1/13, oral aphthae 1/13 and Crohn-like inflammatory bowel disease 1/13. The diagnosis was initially established by the nitroblue tetrazolium test, and confirmed by flow cytometry 10/13 and genetic techniques (gp91) 9/13. In the course of these disease processes there were 88 infections: abscesses (n = 26), lymphadenitis (n = 12), pneumoniae (n = 10), gastroenteritis (n = 7), sepsis (n = 6), osteomyelitis (n = 3) and others (n = 24). As to the germs isolated, the frequency distribution was as follows (n = 49): Aspergillus sp. (n = 10), Staphylococcus sp. (n = 7), Salmonella sp. (n = 6), Serratia sp. (n = 5), Pseudomonas aeruginosa (n = 4), Klebsiella sp. (n = 4), Proteus sp. (n = 3), Leishmania sp. (n = 2) and others (n = 8). IFN-ã was administered in 7/13 cases, and itraconazole in 9/13; all received cotrimoxazole. There were four deaths, with one case each of sepsis due to gramnegative bacterial infection; disseminated aspergillosis; visceral leishmaniasis and hemophagocytosis; and post-kidney transplant complications. Conclusions: Clinical suspicion and flow cytometry are the keys for diagnosis of CGD and detection of carrier relatives. Specific prophylactic measures and medical controls are required to prevent serious infections. IFN-gamma has been used intermittently, though its effectiveness is controversial

Introducción: La enfermedad granulomatosa crónica (EGC) es una inmunodeficiencia primaria infrecuente (1/200.000 recién nacidos vivos) por defecto de la producción de metabolitos del oxígeno por los fagocitos, causando infecciones bacterianas por microorganismos catalasa positivos y fúngicas, en ocasiones letales. Métodos: Revisión de historias clínicas de 13 pacientes diagnosticados de EGC en edad pediátrica de 1980 a 2005. Resultados: 100% varones. Edad mediana al diagnóstico: 36 meses. Clínica al diagnóstico: abscesos o adenopatías abscesificadas 4/13 (Staphylococcus aureus (2), Serratia liquefaciens, S. marcescens y Klebsiella sp.), neumonía 3/13 (Rhodococcus equi, Salmonella typhimurium más Pneumocystis jiroveci), osteomielitis 1/13 (Aspergillus sp.), sepsis 1/13 (S. aureus), infección urinaria 1/13 (Klebsiella sp.), gastroenteritis grave 1/13, aftas orales 1/13 y enfermedad inflamatoria intestinal Crohn-like 1/13. Diagnosticados inicialmente por Nitroblue Tetrazolium Test, confirmados por citometría de flujo 10/13 y genéticamente (gp91) 9/13. En su evolución presentaron 88 infecciones: abscesos (26), adenopatías (12), neumonías (10), gastroenteritis (7), sepsis (6), osteomielitis (3) y otras (24). Gérmenes aislados (49): Aspergillus sp. (10), Staphylococcus sp. (7), Salmonella sp. (6), Serratia sp. (5), Pseudomonas aeruginosa (4), Klebsiella sp. (4), Proteus sp. (3), Leishmania sp. (2) y otros (8). Han recibido Interferón Gamma 7/13; itraconazol 9/13 y todos cotrimoxazol. Cuatro fallecidos (1 sepsis por un bacilo gram negativo, 1 aspergilosis diseminada, 1 leishmaniasis visceral y hemofagocitosis, 1 complicaciones post-trasplante renal). Conclusiones: La sospecha clínica y la citometría de flujo son los pilares del diagnóstico en la EGC para el paciente y para la detección de familiares portadores. Debemos establecer una profilaxis específica y controles médicos para prevenir infecciones graves. Se ha usado intermitentemente IFN-gamma, aunque su efectividad es discutida

[Directory of diagnostic tests in primary immunodeficiencies]. / Directorio de pruebas diagnósticas de las inmunodeficiencias primarias.

The clinical and immunological characteristics that suggest diverse forms of primary immunodeficiency are discussed. Data on the hospitals that perform immunological, molecular and genetic tests for the diagnosis of most of the primary immunodeficiencies in Spain are presented.

Directorio de pruebas diagnósticas de las inmunodeficiencias primarias / Directory of diagnostic tests in primary immunodeficiencies

Se comentan las características clínico-inmunológicas sugestivas de las diversas formas de Inmunodeficiencias primarias (IDP). Se han recogido datos sobre los centros hospitalarios en los que se realizan estudios inmunológicos, moleculares y genéticos que permiten el diagnóstico de la mayoría de las IDP en nuestro país

The clinical and immunological characteristics that suggest diverse forms of primary immunodeficiency are discussed. Data on the hospitals that perform immunological, molecular and genetic tests for the diagnosis of most of the primary immunodeficiencies in Spain are presented

[Common variable immunodeficiency in children]. / Inmunodeficiencia común variable en la edad pediátrica.

UNLABELLED: Common variable immunodeficiency (CVID) is one of the more frequent primary immunodeficiencies (PID), after IgA deficiency, and affects a heterogeneous group of patients of various ages and with autosomal recessive inheritance. Our objective is to present the group of children diagnosed with CVID treated in our Hospital Infantil Vall d'Hebron and comment on the diagnostic problems that can arise. Sixteen boys and girls were diagnosed between the ages of 7 months and 15 years. The diagnosis is based on low immunoglobulins and a clinical picture of infection. Differential diagnosis in the paediatric age must consider mainly other PIDs: transient hypogammaglobulinaemia of infancy, X chromosome-linked agammaglobulinaemia (XLA), X chromosome-linked hyper IgM syndrome (X-HIM), IgG subclass deficiency and IgA deficiency (IgAD). Other processes that evolve with recurrent respiratory infections, such as cystic fibrosis, must also be discarded. CONCLUSIONS: These patients present a high incidence of respiratory infections and bronchiectasias. We also observe associated allergic and autoimmune processes. Early diagnosis is indispensable to initiate suitable treatment and avoid the consequences of both respiratory and digestive infections.

Inmunodeficiencia común variable en la edad pediátrica

La inmunodeficiencia común variable (IDCV) es una de la inmunodeficiencias primarias (IDP) más frecuentes después del déficit de IgA (DIgA)y comprende un heterogéneo grupo de pacientes, con presentación a diferentes edades y con herencia autosómica recesiva. Nuestro objetivo es presentar el grupo de niños diagnosticados de IDCV tratados en el Hospital Infantil Vall d'Hebron y comentar los problemas diagnósticos que pueden plantearse. Se trata de 16 niños y niñas, diagnosticados entre los 7 meses y los 15 años de edad. El diagnóstico se basa en una cifra de inmunoglobulinas baja y la presencia de clínica infecciosa. El diagnóstico diferencial en la edad pediátrica debe hacerse principalmente con otras IDP: hipogammaglobulinemia transitoria de la infancia, agammaglobulinemia ligada al cromosoma X (ALX), síndrome de hiper-IgM ligado al cromosoma X (HIM-X), déficit de subclases de IgG y déficit de IgA (DIgA). También deben descartarse previamente otros procesos que cursan con infecciones respiratorias de repetición, como la fibrosis quística. Se observa una elevada incidencia de infecciones respiratorias y bronquiectasias en estos pacientes. También hay asociados procesos alérgicos y autoinmunes. El diagnóstico precoz es imprescindible para iniciar el tratamiento adecuado y evitar las consecuencias de las infecciones tanto respiratorias como digestivas (AU)

Common variable immunodeficiency (CVID) is one of the more frequent primary immunodeficiencies (PID), after IgA deficiency, and affects a heterogeneous group of patients of various ages and with autosomal recessive inheritance. Our objective is to present the group of children diagnosed with CVID treated in our Hospital Infantil Vall d'Hebron and comment on the diagnostic problems that can arise. Sixteen boys and girls were diagnosed between the ages of 7 months and 15 years. The diagnosis is based on low immunoglobulins and a clinical picture of infection. Differential diagnosis in the paediatric age must consider mainly other PIDs: transient hypogammaglobulinaemia of infancy, X chromosome-linked agammaglobulinaemia (XLA), X chromosome-linked hyper IgM syndrome (X-HIM), IgG subclass deficiency and IgA deficiency (IgAD). Other processes that evolve with recurrent respiratory infections, such as cystic fibrosis, must also be discarded. Conclusions: These patients present a high incidence of respiratory infections and bronchiectasias. We also observe associated allergic and autoimmune processes. Early diagnosis is indispensable to initiate suitable treatment and avoid the consequences of both respiratory and digestive infections (AU)

[Substitution therapy with hematopoietic progenitors in the primary immunodeficiencies]. / Tratamiento sustitutivo con progenitores hemopoyéticos en las inmunodeficiencias primarias.

Hematopoietic stem-cell transplantation is currently the most appropriate substitution therapy in the most severe forms of primary immunodeficiency diseases (all the variants of SCID, WA, CID etc.). It can achieve total and permanent immunological reconstitution in 60% of patients, depending on histocompatibility, source of the hematopoietic stem cells and the underlying disease. Stem-cell sources may be bone marrow, umbilical cord blood and the peripheral blood of donors previously treated with colony stimulating factors for the mobilization CD34. We discuss the differences in the results obtained in patients treated at the Hospital Materno-Infantil Vall d'Hebron. Gene therapy opens a new era in the treatment of primary immunodeficiency diseases. The first patient to undergo this treatment in the United States of America had adenosine-deaminase deficiency, even though sustained remodeling has not been achieved. The favorable results obtained in patients with SCID by deficit in the gamma chain of the IL-2 receptor in Paris, with more than a year of follow up, suggest that the near future is promising. We also discuss the differences observed according to the vectors used and the underlying disease.

Familial CD8 deficiency due to a mutation in the CD8 alpha gene.

CD8 glycoproteins play an important role in both the maturation and function of MHC class I-restricted T lymphocytes. A 25-year-old man, from a consanguineous family, with recurrent bacterial infections and total absence of CD8(+) cells, was studied. Ab deficiencies and ZAP-70 and TAP defects were ruled out. A missense mutation (gly90-->ser) in both alleles of the immunoglobulin domain of the CD8 alpha gene was shown to correlate with the absence of CD8 expression found in the patient and two sisters. Conversely, high percentages of CD4(-)CD8(-)TCR alpha beta(+) T cells were found in the three siblings. A novel autosomal recessive immunologic defect characterized by absence of CD8(+) cells is described. These findings may help to further understanding of the role of CD8 molecules in human immune response.

Tratamiento sustitutivo con progenitores hemopoyéticos en las inmunodeficiencias primarias / Substitution therapy with hematopoietic progenitors in the primary immunodeficiencies

El trasplante de progenitores hemopoyéticos (TPH) es el tratamiento sustitutivo más adecuado, hasta este momento, de las formas más severas de las IDP (todas las variantes de la IDSC, W-A, IDC, etc.) lográndose reconstituciones inmunológicas totales y permanentes en más del 60 por ciento de casos, según la histocompatibilidad, fuente de los PH y la enfermedad de base. Las fuentes de los PH pueden ser: la M. ósea, la sangre de cordón umbilical y la sangre periférica de donantes previamente tratados con estimuladores de colonias para la movilización de CD34.Se comentan las diferencias en los resultados de los pacientes tratados en el Hospital Materno-Infantil Vall d'Hebron.La terapia génica abre una nueva era en el tratamiento de las IDP. El primer paciente al que se realizó este tratamiento en EE.UU. fue un déficit de ADA, si bien no se ha conseguido todavía una reconstitución mantenida. Los resultados favorables obtenidos en pacientes con IDCG por déficit de la cadena gamma del receptor de la IL-2, en París, con más de un año de seguimiento hacen prever un futuro próximo esperanzador.Se comentan las diferencias observadas según los vectores utilizados y la enfermedad de base (AU)

Hematopoietic stem-cell transplantation is currently the most appropriate substitution therapy in the most severe forms of primary immunodeficiency diseases (all the variants of SCID, WA, CID etc.). It can achieve total and permanent immunological reconstitution in 60 % of patients, depending on histocompatibility, source of the hematopoietic stem cells and the underlying disease. Stem-cell sources may be bone mass, umbilical cord blood and the peripheral blood of donors previously treated with colony stimulating factors for the mobilization CD34. We discuss the differences in the results obtained in patients treated at the Hospital Materno-Infantil Vall d'Hebron. Gene therapy opens a new era in the treatment of primary immunodeficiency diseases. The first patient to undergo this treatment in the United States of America had adenosine-deaminase deficiency, even though sustained remodeling has not been achieved. The favorable results obtained in patients with SCID by deficit in the gamma chain of the IL-2 receptor in Paris, with more than a year of follow up, suggest that the near future is promising. We also discuss the differences observed according to the vectors used and the underlying disease (AU)

Identification of WASP mutations in 14 Spanish families with Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency caused by mutations in the WASP gene. The disease is known to be associated with extensive clinical variability, and mutation studies indicate that genotypes are also highly variant among WAS patients. In this study, we performed mutation analysis of the WASP gene in 14 unrelated Spanish families by single strand conformation analysis (SSCA) and sequencing, resulting in the identification of a novel mutation and nine known mutations. No mutation was identified in one family. The ten different mutations include point mutations resulting in amino acid substitutions, stop codons, and small deletions and insertions causing frameshifts. Missense mutations were preferentially located in the amino-terminal part of the protein, exons 2 and 4, whereas stop and frameshift mutations were located in the carboxyl-terminal region, exons 10 and 11. However, in two families, two missense mutations in exon 11 were identified. Our study demonstrates that WASP genotypes have some concordance with the patients' phenotypes, although mutation 1019delC, identified in a family with several affected members, resulted in high intrafamilial clinical variability.

Rapid protein-based assays for the diagnosis of T-B+ severe combined immunodeficiency.

The severe combined immunodeficiencies (SCID) are a heterogeneous group of conditions arising from a variety of molecular defects. The X-linked form of SCID (X-SCID) is caused by defects in the common gamma chain (gammac), and is characterized by a T-B+NK- immunophenotype. This lymphocyte profile is seen in an autosomal recessive form of SCID caused by mutations in the JAK3 molecule. Thus, X-SCID and JAK3-deficient SCID are clinically and immunologically indistinguishable. Knowledge of the precise molecular defect is essential for antenatal diagnosis, carrier testing and for treatment using somatic gene therapy. To identify the molecular defect in children presenting with a T-B+NK- form of SCID, we have developed rapid assays based on flow cytometric analysis of gammac, immunoblotting for JAK3 and gammac, and detection of interleukin-2 (IL-2)-induced tyrosine phosphorylation of JAK3. Sixteen T-B+NK- SCID patients from 15 families were examined. Nine had no detectable gammac, four had abnormal gammac expression and no IL-2-induced JAK3 tyrosine phosphorylation, and one had normal gammac expression but no IL-2-induced JAK3 tyrosine phosphorylation, although JAK3 was present. All these patients had mutations identified in their gammac gene. Two patients exhibited normal gammac expression, but JAK3 was not detected by immunoblotting and these patients were confirmed as having JAK3 gene mutations. Thus, these protein-based assays have led to rapid molecular diagnoses in T-B+ SCID that have subsequently been confirmed by genetic analysis.