From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome.

The term autoimmune enteropathy (AIE) was applied to a form of "intractable diarrhoea" with serum gut autoantibodies, characterized by male predominance, early onset, poor response to parenteral nutrition and several autoimmune diseases, mainly type 1 diabetes. In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis. The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells (Treg) expressing CD4+ and CD25+ molecules. Mutations of the FOXP3 gene, located in X chromosome, produce a syndrome with Immune dysfunction, Polyendocrinopathy, Enteropathy and X-linked inheritance (IPEX). The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome, even in female patients who may have some autosomal genetic variants. Besides FOXP3, other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes. Meanwhile, the important pathogenic role previously ascribed to gut autoantibodies has vanished, with it remaining as having only certain screening usefulness.

From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome

The term autoimmune enteropathy (AIE) was applied to a form of “intractable diarrhoea” with serum gut autoantibodies, characterized by male predominance, early onset, poor response to parenteral nutrition and several autoimmune diseases, mainly type 1 diabetes. In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis. The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells (Treg) expressing CD4+ and CD25+ molecules. Mutations of the FOXP3 gene, located in X chromosome, produce a syndrome with Immune dysfunction, Polyendocrinopathy, Enteropathy and X-linked inheritance (IPEX). The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome, even in female patients who may have some autosomal genetic variants. Besides FOXP3, other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes. Meanwhile, the important pathogenic role previously ascribed to gut autoantibodies has vanished, with it remaining as having only certain screening usefulness(AU)

[Diagnostic problems in adult celiac disease]. / Problemas diagnósticos en la enfermedad celiaca del adulto.

INTRODUCTION: Celiac disease (CD) is a chronic immune-mediated enteropathy, resulting from a gluten intolerance in genetically predisposed individuals. OBJECTIVE: a) to describe clinical features, associated disorders and serology of CD in adults; and b) to study the main that serology displays in diagnosis, clinical and histological expression. PATIENTS AND METHODS: 31 patients diagnosed of CD in adulthood have been reviewed retrospectively, including clinical presentation, associated disorders, biochemical results, serological tests (anti-gliadin and anti-endomysial antibodies) and genetical features (HLA-DQ2). It has been studied the relation between typical presentations and AEm with clinical, serological or histological findings. RESULTS: Almost 50% of patients had atypical clinical manifestations and gastrointestinal symptoms were absent in 33%. Typical manifestations are associated with villous atrophy stage III b-c of Marsh's classification (87 vs. 53%, p = 0,03). 70% of patients shows AEm mostly in women (78 vs. 37%, p = 0.03) and stage III b-c of Marsh (84 vs. 50%, p = 0.05). 68,4% were DQ2 positive. CONCLUSIONS: Clinical features of CD varies greatly. AEm and DQ2 are less common than others studies. There may be an association with clinical and serological findings and villous atrophy stage. Genetical features could help AEm in diagnosis.

Common variable immunodeficiency. Old questions are getting clearer.

Common variable immunodeficiency (CVID) is a heterogeneous entity characterized by an impaired ability to produce antibodies. The failure is localized in partially mature B lymphocytes, though T lymphocyte abnormalities are occasionally present. This deficiency affects antibody synthesis and class switch from IgD and IgM, to IgG and IgA. CVID is related to selective IgA deficiency, and both abnormalities may coincide in one same family, and evolve from one to another in the same patient. The symptoms generally manifest in adults, but can occur at any age, even in infancy. Recurrent bacterial infections or pneumonias are frequent, and may be complicated by gastrointestinal problems, granulomas, autoimmune disorders or malignancies. A defect in memory B cells seems to condition the clinical severity. Recently, several mutations in genes encoding for molecules (CD19, TACI, ICOS) involved in B cell survival and isotype switch have been identified in patients with CVID. Nevertheless, genetic abnormalities have been found in less than 25 % of cases with CVID; the underlying mechanism thus remains unknown in the majority of CVID patients, and research in this field must continue.

[Meningococcal sepsis in pediatrics. Parameters associated with poor outcome]. / Sepsis meningocócica en pediatría. Parámetros asociados a mala evolución.

BACKGROUND: Mortality due to meningococcal sepsis continues to be extremely high. Patients with a poor prognosis require aggressive therapy and should be identified early. OBJECTIVE: To investigate the clinical and biological factors associated with poor outcome. PATIENTS AND METHOD: Seventy-one children aged 2 months to 13 years with meningococcal sepsis were studied. Inclusion criteria were meningococcus isolation in cultures or characteristic clinical features with purpuric exanthema. METHODS: A correlational descriptive study was performed. In all patients we evaluated the Pediatric Risk of Mortality (PRISM), the Glasgow Scale for Meningococcal Sepsis (GSMS), polymorphonuclear (PMN) count and prolactin (PRL), leptin (LPT) and C-reactive protein (CRP) levels. RESULTS: Fourteen children (19.7 %) died. Death was associated with multiple organ dysfunction syndrome (MODS) (p = 0.0001), high GSMS and PRISM scores (p = 0.0001) and to a lesser extent with shock (p = 0.01). In patients who died, the determinations showing greatest alteration at admission were PRL levels (p = 0.0009) and PMN count (p = 0.0005). CRP levels were not associated with differences in mortality but were high in patients with shock (p = 0.008). Children with high body weight percentiles were at greater risk of death and showed higher levels of PRL, PCT (p = 0.006) and LPT (p = 0.006), without differences in GSMS or PRISM scores. Age did not influence mortality or PRL levels but did influence GMSM and PRISM scores and PMN and CRP levels. These differences disappeared after the age of 2-3 years. In patients with MODS or shock, the only differences found were reduced PMN count (p = 0.0001) and elevated PRL levels (p = 0.0001). CONCLUSIONS: In meningococcal sepsis, death is more frequent in children with high body weight percentiles. Moreover, these children present elevated PRL and LPT levels, although whether these variables act independently remains to be elucidated.

Sepsis meningocócica en pediatría. Parámetros asociados a mala evolución / Meningococcal sepsis in pediatrics. PArameters associated with poor outcome

Antecedentes: La mortalidad por sepsis meningocócica continúa siendo muy elevada. Los enfermos con mal pronóstico precisan terapias agresivas y deben ser identificados precozmente. Objetivo: Investigar los factores clínicos y biológicos asociados a una mala evolución. Pacientes y método: Se estudiaron 71 niños de 2 meses a 13 años de edad con sepsis meningocócica. Los criterios de inclusión fueron aislamiento de meningococo en cultivos o sintomatología característica con exantema purpúrico. Se realizó un estudio descriptivo correlacional. En todos los enfermos se valoró el PRISM (Pediatric Risk of Mortality), la Escala de Glasgow para Sepsis Meningocócicas (EGSM), el recuento de polimorfonucleares y los niveles de procalcitonina, leptina y proteína C reactiva (PCR). Resultados: Fallecieron 14 enfermos (19,7 por ciento). La muerte se asoció a síndrome de disfunción multiorgánica (SDMO) (p=0,0001), alta puntuación en la EGSM y el PRISM (p=0,0001) y con menor significación a shock (p=0,01). En el grupo de fallecidos, las determinaciones más alteradas al ingreso fueron la procalcitonina (p=0,0009) y los polimorfonucleares (p=0,0005). Los valores de PCR no se asociaron a diferencia de mortalidad pero estaban altos en los casos con shock (p=0,008). Los niños con percentiles elevados de peso fallecieron con mayor frecuencia y mostraron niveles más altos de procalcitonina (p=0,006) y leptina (p=0,006), pero sin diferencias de valores de EGSM y PRISM. La edad no influyó ni en la mortalidad ni en la procalcitonina, pero sí en el EGSM y PRISM y en los niveles de polimorfonucleares y PCR, desapareciendo estas diferencias antes de los 2-3 años. En los casos con SDMO o shock sólo presentaron diferencias el recuento disminuido de polimorfonucleares (p=0,0001) y la procalcitonina elevada (p=0,0001). Conclusiones: En la sepsis meningocócica el fallecimiento es más frecuente en niños con altos percentiles de peso. Además presentan elevaciones de procalcitonina y leptina, quedando sin aclarar si actúan de forma independiente (AU)

[Neonatal screening for cystic fibrosis]. / Cribado neonatal de fibrosis quística.

OBJECTIVE: To analyze the efficiency of the method of neonatal screening for cystic fibrosis (CF) used in Castille and Leon (Spain), which is carried out with blood from Guthrie spots. MATERIAL AND METHODS: A total of 36,086 newborns were studied from January 1999 to June 2001. Immunoreactive trypsinogen (IRT) was quantified in all samples and genetic study covering 87.5 % of mutations in the CFTR gene was carried out when IRT levels were > 60 ng/mL. The sweat test was performed in all children in whom at least one mutation was detected. RESULTS: IRT values of > 60 ng/mL were found in 285 children (0.79 %). Of these, eight children (2.8 %) were diagnosed with CF and a further 11 children (3.9 %) with a negative sweat test were found to have one mutation and were thus classified as healthy carriers. To date, no false negatives have been detected. CONCLUSIONS: The two-stage screening method fulfills the required criteria. Its sensitivity is 98.5 % and the basic model can be used in other regions although genetic screening should be optimized by pilot programs to identify the local spectrum of CFTR mutations.

Cribado neonatal de fibrosis quística / Neonatal screening for cystic fibrosis

Objetivo: Analizar la eficacia del método utilizado para el cribado neonatal de fibrosis quística en Castilla y León, realizado con muestras de sangre impregnadas en papel absorbente. Material y métodos: Se estudiaron 36.086 recién nacidos desde enero de 1999 a junio de 2001 mediante cuantificación de tripsinógeno inmunorreactivo (TIR). Cuando los valores fueron superiores a 60 ng/ml se buscaron mutaciones en el gen CFTR con una cobertura del 87,5% de los alelos mutantes en nuestra población. Se solicitó estudio mediante test del sudor en todos los niños en los que se encontró una mutación. Resultados: Se detectaron valores de TIR > 60 ng/ml en 285 niños (0,79%), se diagnosticó fibrosis quística en 8/285 (2,8%) y en otros 11/285 (3,9%) se encontró una mutación, con test de sudor negativo, por lo que se consideraron portadores sanos. Hasta la actualidad no se tiene noticia de la aparición de ningún falso negativo. Conclusiones: El método de cribado en dos fases utilizado cumple los criterios exigibles con una sensibilidad del 98,5%. El modelo general del estudio puede utilizarse en otras comunidades, aunque el rastreo de mutaciones deberá ser optimizado realizando programas piloto que identifiquen el espectro local de mutaciones de fibrosis quística. (AU)

[The tumor necrosis factor system and leptin in coeliac disease]. / Sistema factor de necrosis tumoral y leptina en la enfermedad celíaca.

OBJECTIVE: Patients with coeliac disease (CD) present anorexia and malnutrition. Leptin is a significant anorexigenic factor, with a close relationship to the body mass index. The aims of this study were to asses serum leptin levels in CD and their possible influence on appetite, as well as to compare and relate leptin with tumor necrosis factor (TNF) activity, which has similar functions. METHODS: Leptin and TNF receptor-1 (TNFr-1) were measured by enzyme-linked immunosorbent assay. Sixty-five serum samples from patients with CD (28 boys and 37 girls) were analyzed. In all patients, small bowel biopsy and anti-endomysium determination were performed simultaneously. Twenty-nine patients presented active CD and 36 were in remission. RESULTS: Leptin concentrations were reduced in active CD (p = 0.002). In patients in remission, leptin was related to the body mass index (p = 0.001), but this correlation was not found during the active phase of the disease. Contrary to normal differences between sexes, in active CD leptin levels were similar in boys and girls. TNFr-1 was found in all serum samples and levels were statistically higher in patients with active CD (p = 0.0003), suggesting that the TNF system is activated in this disease. CONCLUSIONS: Leptin concentrations were reduced in active CD, but we did not find the usual positive correlation with body mass index and higher concentrations in girls. These results suggest that leptin does not contribute to anorexia and failure to thrive in patients with CD; in contrast, the TNF system might be involved.

Sistema factor de necrosis tumoral y leptina en la enfermedad celíaca / The tumor necrosis factor system and leptin in coeliac disease

Objetivo: Los enfermos celíacos presentan malnutrición y una gran anorexia. La leptina es un importante factor anorexígeno estrechamente relacionado con el índice de masa corporal (IMC). El objetivo fue estudiar la leptina sérica en la enfermedad celíaca y su posible acción sobre el apetito, compararla y relacionarla con el factor de necrosis tumoral (TNF), que tiene funciones similares. Métodos: La leptina y el receptor I de TNF (TNF-R-I) se midieron mediante enzimoinmunoanálisis (ELISA). Se analizaron 65 sueros de enfermos celíacos (28 varones y 37 mujeres). En todos los casos se practicó simultáneamente biopsia intestinal y se determinaron anticuerpos antiendomisio. Estaban en actividad 29 casos y 36 en remisión. Resultados: Los valores de leptina estaban disminuidos en la fase de actividad de la enfermedad celíaca (p 0,002), lo que no apoya su participación sobre la anorexia y la desnutrición del paciente celíaco. Durante la remisión de la enfermedad celíaca la leptina se relaciona con el IMC (p 0,001), pero en la fase activa se rompe esta relación habitual. En la fase aguda también se rompe la diferencia entre sexos, y son similares los valores en varones y mujeres. El TNF-R-I se detectó en todos los sueros y mostró una elevación significativa durante la fase aguda (p 0,0003) lo que parece indicar una activación del sistema TNF en la enfermedad celíaca. Conclusiones: La leptina está disminuida durante la fase activa de la enfermedad, y se pierde su habitual correlación con el IMC y el sexo femenino. Los resultados señalan que no participa en la anorexia y la desnutrición de la enfermedad celíaca y, sin embargo, sí podría hacerlo el sistema TNF (AU)

[Long-term development of children with Schönlein-Henoch purpura associated with anti-neutrophil cytoplasmic antibodies]. / Evolución a largo plazo de los niños con púrpura de Schönlein-Henoch asociada a anticuerpos anticitoplasma de neutrófilo (ANCA).

OBJECTIVE: The purpose of this study was to assess the frequency of antineutrophil cytoplamic antibodies (ANCA) in Schönlein-Henoch purpura (SHP) and its long-term significance. PATIENTS AND METHODS: IgG and IgA classes of ANCA were studied by indirect immunofluorescence (IIF) and IgG-ANCA against myeloperoxidase (MPO) and against proteinase-3 (PR-3) were determined by ELISA in 50 children with SHP. Eight (16%) of the patients had renal involvement during the acute phase, but none had a permanent nephropathy after a 7-17 year follow-up. RESULTS: Positive IgG ANCA were found in 5 (10%) of the cases and only one of these children also had IgA ANCA. The ELISA against MPO and P-3 was negative in all patients. None of the 5 patients with ANCA showed nephropathy during the acute phase nor relapses or permanent nephropathy. CONCLUSIONS: A minority of children with SHP are positive for ANCA and, in the absence of nephropathy, this is not associated with a bad long-term prognosis.

[Value of salivary antibodies for determining seropositivity to measles, rubella, and mumps in children and adults]. / Valor de los anticuerpos salivares para la determinación de la seropositividad frente a sarampión, rubéola y parotiditis en niños y adultos.

BACKGROUND: IgA and IgG antibodies can be detected in saliva in order to assess the immune status against measles, rubella and mumps. PATIENTS AND METHODS: Serum and saliva were simultaneously obtained from 50 adults between 19 and 52 years of age that were non-vaccinated and from 50 children from 15 months to 13 years of age that had been vaccinated against measles, rubella and mumps at 15 months of age. Specific IgG and IgA antibodies were determined by ELISA. Values higher than the 95% confidence interval obtained in 39 non-vaccinated and non-infected infants were considered as positive. RESULTS: In adults 96-100% and in children 90-98% were seropositive for the viral antigens studied. A positive result in saliva was always higher than 50%, with the percentage being higher in children than in adults and mainly for IgA antibodies. According to the present study, the combined determination of IgG and IgA antibodies in saliva would detect 86% of the children seropositive for measles, 87% for rubella and 82% to mumps, with these results being slightly lower in adults. Children without salivary antibodies were frequently younger than 3 years of age and were negative for more than one viral antigen. CONCLUSIONS: The study of salivary antibodies is a non-invasive method to assess seropositivity against measles, rubella and mumps, but it is advisable that both IgG and IgA antibodies be determined.

[Increased serum levels of soluble IL-2 receptor in food intolerance: possible mechanism of delayed immunity in milk intolerance]. / Aumento sérico del receptor soluble de IL-2 en la intolerancia alimentaria: posible mecanismo de inmunidad retardada en la alergia a la leche de vaca.

The levels of soluble interleukin-2 receptor (sIL-2R) were measured in 35 serum samples from children with food intolerance; 19 had an IgE-mediated sensitization and were considered as atopic patients, skin tests and RAST were negative in the remaining 16 children and they were diagnosed as having cow milk intolerance (CMI) Forty-three coeliac patients were included as a positive control group and 18 normal children as the negative control group. The atopic group showed normal values of sIL-2R (1,183 +/- 468 u/ml); however, it was increased in children with CMI (1,453 +/- 469 u/ml, p < 0.05). The sIL-2R mean value was highest in patients with gastrointestinal symptoms (1,458 +/- 461 u/ml, p: 0.03) and the presence of atopic dermatitis was not relevant. The sIL-2R was also elevated in 8 children with igE-mediated sensitization against cow's milk (1,477 +/- 328 u/ml, p < 0.05). These results suggest that a delayed cellular mechanism occurred in CMI, similar to that present in coeliac disease, although it was less severe. In addition, there is an overlap of humoral and cellular immunological mechanisms in the IgE-mediated sensitization to cow's milk, but we did not find this coincidence in the allergy to remaining foods. From a pathogenic point of view, to separate CMI from IgE-mediated allergies to milk does not seem to be sufficiently justified at the present time. It is possible that the atopy against cow milk proteins in children has a different immunological mechanism than the atopy to other foods, which would explain its better prognosis.

[IgG subclass antibodies in children of Vallidolid. Low materno-fetal protection]. / Anticuerpos antitetánicos de subclases IgG en niños de Valladolid. Escasa protección materno-fetal.

The anti-tetanus serology was studied in Valladolid during 1988. IgG-antibodies and every one of four IgG-subclasses were determined by ELISA in 144 sera. In this study were included 31 parturient women, 20 newborn, 68 children 1.5-14 years old and 25 younger than 18 months. A 0.01 UI/ml sensibiling and a 8.5% interassay variability coefficient were achieved. The highest mean antibodies level (70.9-39.6 Ua/ml) was presented by children 1.5-3 years old and the lowest (31.1 +/- 15.9 Ua/ml) by 3-5 years old; nevertheless in mothers it was only 1.0 +/- 1.6 Ua/ml. Among children 1.5-14 years old we found only 5/63 (7.9%) cases with non-protective antibodies level. On the contrary, in mothers it increased until 23/31 (74%) and until 16/20 (80%) in cord blood. Antibodies of four IgG subclasses has each other a good correlation, especially IgG1/G2/G4 (p less than 0.001). The IgG2 and IgG3 subclasses were the antibodies which lesser decreased after vaccination. We emphasize the poor anti-tetanus protection of mothers and newborns, lower than levels reported in other countries.