Espectro de las inmunodeficiencias primarias en un hospital de tercer nivel en un periodo de 10 años / Spectrum of primary immunodeficiencies in a tertiary hospital over a period of 10 years

Introducción: Hasta el momento se han descrito más de 200 inmunodeficiencias primarias (IDP) diagnosticándose un 60% en la edad pediátrica. Un diagnóstico y tratamiento precoces mejoran significativamente el pronóstico de estos pacientes. Objetivo: Análisis de los pacientes afectos de IDP diagnosticados en un centro de referencia durante 10 años. Pacientes y métodos: Revisión retrospectiva y análisis de las características clínicas, epidemiológicas, resultados de laboratorio, tratamiento administrado y curso evolutivo de las mismas. Resultados: Ciento ochenta y nueve pacientes fueron diagnosticados-controlados en este periodo de tiempo, siendo el déficit predominante de anticuerpos el diagnóstico más frecuente. En nuestra serie, la clínica de presentación al diagnóstico fue: infecciones respiratorias de repetición en pacientes con déficit selectivo de IgA e inmunodeficiencia común variable (IDCV),retraso ponderoestatural e infecciones oportunistas (principalmente virus) en pacientes con inmunodeficiencia combinada grave (IDCG), abscesos cutáneos (Staphylococcus aureus, Serratiaspp.) y neumonía (Aspergillus spp., Rhodococcus equi) en la enfermedad granulomatosa crónica, cardiopatía y fenotipo compatible en el síndrome de deleción 22q11, abscesos cutáneos y ectima gangrenoso en la neutropenia congénita grave e infecciones oportunistas y sepsis (Pseudomonas aeruginosa) en niños con agammaglobulinemia ligada al cromosoma X (ALX). Se describen manifestaciones linfoproliferativas con mayor frecuencia en pacientes con IDCV y ninguna manifestación compatible con un proceso maligno. Uno de los pacientes con ALX desarrolló una encefalitis crónica. Todos los pacientes con IDCV y ALX reciben tratamiento sustitutivo con gammaglobulina inespecífica (8 vía intravenosa y 14 (desde 2006) vía subcutánea) y todos los pacientes con IDCG, excepto 2, recibieron un trasplante de progenitores hematopoyéticos. La evolución de todos ellos fue buena excepto 8 IDCG (2 pre y 6 post-trasplante), 3 síndromes de Wiskott-Aldrich, 1síndrome de Di George completo, 1 enfermedad granulomatosa crónica y 1 ataxia-telangiectasia que fallecieron durante el seguimiento. Conclusiones: La mayoría de los pacientes incluidos en esta serie se presentaron clínicamente con las manifestaciones habitualmente descritas en la literatura, por lo que el conocimiento básico de estas entidades por parte del pediatra de primaria y la colaboración con hospitales de referencia con experiencia en las IDP, debe permitir un diagnóstico precoz de un número importante de IDP facilitando instaurar un tratamiento y un seguimiento adecuados y por lo tanto mejorar el pronóstico de estos pacientes (AU)

Introduction: More than 200 primary immunodeficiencies (PID) have been described and about60% present during childhood. Early diagnosis and treatment have been shown to improve patient outcome. Aim: Analysis of patients with a PID diagnosed in a paediatric tertiary care hospital-referral centre over a period of 10 years. Patients and methods: Medical records of all paediatric patients followed up in our unit were retrospectively reviewed. Clinical and epidemiological features, laboratory tests, therapy and outcome were analysed. Results: One hundred and eighty nine patients were followed up in this period of time. Antibody disorders were the most common diagnosis. In our series, clinical presentation at diagnosis were: recurrent respiratory infections in selective IgA deficiency and common variable immunodeficiency (CVID) patients, failure to thrive and opportunistic infections (mainly viral infections) in patients with severe combined immunodeficiency (SCID), skin abscesses (Staphylococcusaureus, Serratia spp.) and complicated pneumonia (Aspergillus spp., Rhodococcus equi) in chronic granulomatous disease, congenital heart disease and consistent phenotype in 22q11 deletion syndrome, skin abscesses and ecthyma gangrenosum in severe congenital neutropenia and opportunistic infections and sepsis (Pseudomonas aeruginosa) in children with X-linked agammaglobulinaemia (XLA). Lymphoproliferative disorders were common in CVID. No malignancies were observed during this period. One patient with XLA developed chronic encephalitis. All patients with CVID and XLA were receiving immunoglobulin replacement therapy (8 intravenous and 14 (since 2006) subcutaneous route) and in all but two SCID patients, stem cell transplantation was performed. Outcome was good in most of them except 8 SCID (2 prior and 6 after transplantation), 3 Wiskott-Aldrich syndrome, 1 complete Di George, 1 chronic granulomatous disease and 1 ataxia-telangiectasia patients who died during follow-up. Conclusion: The vast majority of patients included in this series presented with typical clinical features; therefore, basic knowledge of these entities in primary care and collaboration with hospital referral centres should allow a large number of PID in children to be diagnosed at anearly stage, leading to proper treatment and monitoring, and therefore improvement of patient prognosis (AU)

[Spectrum of primary immunodeficiencies in a tertiary hospital over a period of 10 years]. / Espectro de las inmunodeficiencias primarias en un hospital de tercer nivel en un periodo de 10 años.

INTRODUCTION: More than 200 primary immunodeficiencies (PID) have been described and about 60% present during childhood. Early diagnosis and treatment have been shown to improve patient outcome. AIM: Analysis of patients with a PID diagnosed in a paediatric tertiary care hospital-referral centre over a period of 10 years. PATIENTS AND METHODS: Medical records of all paediatric patients followed up in our unit were retrospectively reviewed. Clinical and epidemiological features, laboratory tests, therapy and outcome were analysed. RESULTS: One hundred and eighty nine patients were followed up in this period of time. Antibody disorders were the most common diagnosis. In our series, clinical presentation at diagnosis were: recurrent respiratory infections in selective IgA deficiency and common variable immunodeficiency (CVID) patients, failure to thrive and opportunistic infections (mainly viral infections) in patients with severe combined immunodeficiency (SCID), skin abscesses (Staphylococcus aureus, Serratia spp.) and complicated pneumonia (Aspergillus spp., Rhodococcus equi) in chronic granulomatous disease, congenital heart disease and consistent phenotype in 22q11 deletion syndrome, skin abscesses and ecthyma gangrenosum in severe congenital neutropenia and opportunistic infections and sepsis (Pseudomonas aeruginosa) in children with X-linked agammaglobulinaemia (XLA). Lymphoproliferative disorders were common in CVID. No malignancies were observed during this period. One patient with XLA developed chronic encephalitis. All patients with CVID and XLA were receiving immunoglobulin replacement therapy (8 intravenous and 14 (since 2006) subcutaneous route) and in all but two SCID patients, stem cell transplantation was performed. Outcome was good in most of them except 8 SCID (2 prior and 6 after transplantation), 3 Wiskott-Aldrich syndrome, 1 complete DiGeorge, 1 chronic granulomatous disease and 1 ataxia-telangiectasia patients who died during follow-up. CONCLUSION: The vast majority of patients included in this series presented with typical clinical features; therefore, basic knowledge of these entities in primary care and collaboration with hospital referral centres should allow a large number of PID in children to be diagnosed at an early stage, leading to proper treatment and monitoring, and therefore improvement of patient prognosis.

[Subcutaneous gammaglobulin in common variable immunodeficiency. First experience in Spain]. / Gammaglobulina subcutánea en inmunodeficiencia común variable. Primera experiencia en España.

INTRODUCTION AND AIM: Weekly home-based subcutaneous immunoglobulin (SCIg) therapy is an alternative to intravenous immunoglobulin (IVIg) in the treatment of patients with primary antibody deficiencies. The objective of this study was to investigate the efficacy, safety, related quality of life and cost effectiveness of SCIg in our area. MATERIALS AND METHODS: Observational and descriptive study including paediatric patients with common variable immunodeficiency (CVID) receiving SCIg in our hospital (November 2006 to April 2008). Obtained data were compared with those from the last year with IVIg. RESULTS: Eleven patients with CVID were included. Median age was 15 years. The median trough serum IgG level was 622 mg/dl with IVIg. In patients in whom the SCIg dose was maintained or reduced compared to IVIg, the median trough serum IgG level was 850 mg/dl (p < 0.0005). Annual rate of infection was 2.22 per patient-year, without significant differences to IVIg (p = 0.212). There were 58 treatment-related adverse events (AE) reported with SCIg (45 local AE and 13 systemic AE). The most frequent treatment-related adverse event was infusion-site reaction. Switching to home-based subcutaneous IgG treatment led to significant improvements in quality of life and substantial cost savings. CONCLUSIONS: We conclude that subcutaneous administration of 16% SCIg is a safe and cost-effective alternative to IVIg for replacement therapy of primary antibody deficiencies. Median trough serum IgG levels were higher with SCIg. Local AE were common but mild and the incidence decreased over time. Quality of life is significantly improved.

Gammaglobulina subcutánea en inmunodeficiencia común variable. Primera experiencia en España / Subcutaneous gammaglobulin in common variable immunodeficiency. First experience in Spain

Introducción y objetivo: la autoadministración semanal de gammaglobulina subcutánea (GGSC) domiciliaria es una alternativa en el tratamiento de las inmunodeficiencias primarias con déficit de producción de anticuerpos. El objetivo es comparar y evaluar la eficacia, la seguridad, la calidad de vida y el coste anual de GGSC y gammaglobulina intravenosa (GGIV) en nuestro medio. Material y métodos: estudio observacional y descriptivo de los pacientes pediátricos con inmunodeficiencia común variable (IDCV) que reciben GGSC en nuestro centro (noviembre 2006-abril 2008), en comparación con el último año de GGIV. Resultados: se incluyó a 11 pacientes afectos de IDCV. Mediana de edad, 15 años. Mediana de IgG plasmática valle con GGIV, 622 mg/dl. En los pacientes en que se mantuvo o se disminuyó la dosis de GGSC respecto a la de GGIV previa (7/8), la mediana de IgG fue 850 mg/dl (p<0,0005). Tasa de infección/paciente/año de 2,22, sin diferencias estadísticamente significativas respecto a GGIV (p=0,212). Se produjeron 58 reacciones adversas (45 locales, 13 sistémicas) en 41/506 infusiones. Las reacciones adversas locales más frecuentes fueron dolor y picor y como sistémicas, la cefalea. Todos los pacientes refirieron una mejora en su calidad de vida. El tratamiento con GGSC supuso un importante ahorro económico. Conclusiones: la terapia subcutánea es una alternativa coste-efectiva a la GGIV con una eficacia similar y un aumento de calidad de vida en los pacientes con IDCV. Las concentraciones plasmáticas valle de IgG obtenidas son iguales o mayores. Las reacciones adversas locales son frecuentes, pero leves y autolimitadas (AU)

Introduction and aim: Weekly home-based subcutaneous immunoglobulin (SCIg) therapy is an alternative to intravenous immunoglobulin (IVIg) in the treatment of patients with primary antibody deficiencies. The objective of this study was to investigate the efficacy, safety, related quality of life and cost effectiveness of SCIg in our area. Materials and methods: Observational and descriptive study including paediatric patients with common variable immunodeficiency (CVID) receiving SCIg in our hospital (November 2006 to April 2008). Obtained data were compared with those from the last year with IVIg. Results: Eleven patients with CVID were included. Median age was 15 years. The median trough serum IgG level was 622mg/dl with IVIg. In patients in whom the SCIg dose was maintained or reduced compared to IVIg, the median trough serum IgG level was 850mg/dl (p<0.0005). Annual rate of infection was 2.22 per patient-year, without significant differences to IVIg (p=0.212). There were 58 treatment-related adverse events (AE) reported with SCIg (45 local AE and 13 systemic AE). The most frequent treatment-related adverse event was infusion-site reaction. Switching to home-based subcutaneous IgG treatment led to significant improvements in quality of life and substantial cost savings. Conclusions: We conclude that subcutaneous administration of 16% SCIg is a safe and cost-effective alternative to IVIg for replacement therapy of primary antibody deficiencies. Median trough serum IgG levels were higher with SCIg. Local AE were common but mild and the incidence decreased over time. Quality of life is significantly improved (AU)

Clinical spectrum of X-linked hyper-IgM syndrome.

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults.

The Spanish Registry for Primary Immunodeficiency Diseases (REDIP) was organized in 1993. One thousand sixty-nine cases of primary immunodeficiency diseases (PID) were registered in patients diagnosed between January 1980 and December 1995. PID diagnosis was made according to the World Health Organization criteria. The most frequent disorders were IgA deficiency (n = 394) and common variable immunodeficiency (n = 213), followed by severe combined immunodeficiency (n = 61), C1 inhibitor deficiency (n = 52), X-linked agammaglobulinemia (n = 49), IgG subclass deficiency (n = 48), and chronic granulomatous disease (n = 32). A comparative study between REDIP and data recently obtained from the European registry (ESID Report, 1995) revealed important differences between phagocytic disorders and complement deficiencies reported in both registries, 4.9 vs 8.7 and 6.0 vs 3.6, while percentages of predominantly antibody deficiencies and T cell and combined deficiencies concurred with those reported in the European registry, 69.3 vs 64.7 and 14.7 vs 20.2, respectively. The heterogeneous nature of the geographical distribution of cases submitted may indicate underdiagnosis of PID in some country areas; surprisingly, the interval between the onset of clinical symptoms and diagnosis was significant, even in immunodeficiency diseases, such as IgA deficiency, which are easy to diagnose.

[Chronic encephalopathy in patients with sex-linked agammaglobulinemia]. / Encefalopatía crónica en pacientes con agamaglobulinemia ligada al sexo.

The clinical and neuroradiological findings of two patients with X-linked agammaglobulinemia, who developed a chronic encephalopathy, are presented. The main neurological manifestations in both patients were: progressive spastic tetraparesis, cortico-subcortical type of dementia and seizures. No infectious agent was identified in either patient. A systematic review of the clinical findings of 37 patients reported in the literature with X-linked agammaglobulinemia and chronic encephalopathy allows the distinction of two subgroups of patients according to their form of presentation (acute or insidious). In each subgroup there are significant clinical differences. The clinical-neuroradiological similarities between this complication and the ones derived from the vertically transmitted form of the human immunodeficiency virus are pointed out. Finally, emphasis is made on the need for CSF viral cultures on patients with X-linked agammaglobulinemia as soon as a neurological complication is suspected.

[Evaluation of the serological follow-up of newborn infants, carriers of HIV-1 antibodies]. / Valoración del seguimiento serológico en recién nacidos portadores de anticuerpos anti VIH 1.

Serological follow-ups were performed in 19 newborns carrying HIV 1 antibodies over a period ranging between 9 and 62 months. Eight children developed AIDS ans 11 remained asymptomatic. Anti-HIV 1 antibodies were determined by ELISA and Western blot and p 24 antigen was detected by ELISA. Antibodies to HIV 1 disappeared in most children without AIDS symptoms between 10 and 12 months after birth, with antibodies against gp 41 being lost first. Children with AIDS remained positive during follow-up, although in 3 cases with positive was absent in all the asymptomatic children, while it was present in 75% of the patients with AIDS.

Natural killer cell function in children with malignant solid neoplasias.

Natural killer (NK) cell numbers and lytic activity were determined in 40 children with various types of solid malignant neoplasias and in 25 control children by NKH-1 monoclonal antibody and cytotoxicity against K562 target cells, respectively. Patients were analyzed at the time of diagnosis before initiation of therapy and followed over a median time of 15.8 months. Mean NK cell numbers and lytic activity were similar among different types of tumor analyzed. Patients with localized disease (stages I, II; n = 25) also showed values not statistically different from those of patients in advanced disease (stages III, IV; n = 15). According to their response to therapy, patients were divided into three groups: group 1 (complete remission; n = 28), group 2 (partial remission; n = 5), and group 3 (progression of disease; n = 6). Patients in group 3 showed at the time of diagnosis a mean NK activity significantly lower than that of patients in groups 1 and 2 and control children (P = 0.007). The defect in NK cell lytic capacity in vitro observed in patients with progressive disease suggests that NK cells play a role in the control of neoplastic growth in vivo and may imply that some children with refractory progressive disease can benefit from immunomodulation destined to improve the lytic potential of NK cells.

[Maternal-fetal transmission of HIV in Catalonia and the Balearic Islands]. / Transmisión materno-infantil de la infección por el virus de la inmunodeficiencia humana (VIH) en Cataluña y Baleares.

Two hundred and ninety three cases of children born of HIV positive mothers have been observed between January 1984 and June 1988 in Catalonia and Balearic Islands, with a ration of 9.5/10,000 newborns. Sex was not significant in the infected group. Most of the cases (68%) have been detected since 1987 and represent a significant increase in HIV positive children and thus of those who will present with clinical manifestations of this infection.

[Chronic juvenile arthritis as a form of presentation of hypogammaglobulinemia]. / Artritis crónica juvenil, como forma de presentación de hipogammaglobulinemia.

A seven years old boy with an hypogammaglobulinemia associated to a pauciarticular chronical juvenile arthritis, in which immunitary deficit diagnostic was made investigating his articular disease, is presented. Clinic, immunological screening, therapy and ulterior evolution with a two year substitutive immunoglobulin treatment are discussed. Authors also revise some aspects of these two diseases association.