Prognostic value of urinary TGF-ß1 in hemolytic uremic syndrome: A pilot study.

BACKGROUND: Transforming growth factor ß1 (TGF-ß1) is the main profibrotic cytokine. Its urinary excretion reflects intrarenal production; thus, we conjectured that it is elevated during hemolytic uremic syndrome related to Shiga-toxin-producing Escherichia coli (STEC-HUS). In this pilot study, we explored the ability of baseline TGF-ß1 excretion (exposure variable) to predict renal prognosis at 6 months (outcome variable). In a secondary investigation, we compared changes in cytokine levels during the study period between patients with opposite renal outcomes. METHODS: Urinary TGF-ß1 concentrations were measured prospectively in 24 children with STEC-HUS on admission, and at 15, 30, 60, 90, and 180 days. Normal values were obtained from 20 healthy subjects. RESULTS: Baseline TGF-ß1 concentrations predicted renal outcomes with an area under the curve of 1 (95%CI 0.85-1; sensitivity 100%, specificity 100%) with the best cutoff level >293.7 pg/mg uCr. All patients with high TGF-ß1 levels developed persistent renal impairment, unlike none with low concentrations (4/4 vs. 20/0 respectively, P = 0.0001). The latter had higher cytokine levels (P < 0.05) at each time point without reaching normal concentrations (<45 pg/mg uCr). CONCLUSIONS: Baseline urinary TGF-ß1 levels accurately predicted short-term renal outcomes in STEC-HUS children, and cytokine excretion during the first 6 months after diagnosis was higher among those with worse evolution. Larger studies are needed to validate these findings.

Levels of urinary transforming growth factor beta-1 in children with D+ hemolytic uremic syndrome.

About 25-50% of survivors of the acute phase of postdiarrheal hemolytic uremic syndrome (D+ HUS) develop chronic renal disease. Transforming growth factor beta-1 (TGFbeta-1) is the main fibrogenic growth factor in humans, and there is a significant correlation between its levels and the grade of interstitial fibrosis in chronic nephropathies. We hypothesized that increased urinary TGFbeta-1 may be an early indicator of sequelae in D+ HUS patients who show no sign of renal damage as determined by conventional diagnostic tests. We therefore compared the levels of TGFbeta-1 in urine collected from healthy controls (HC) (n = 18) with that from patients with a past history of D+ HUS (n = 39). We found that TGFbeta-1 excretion was significantly higher (p < 0.001) in the patient group (median level 73 pg/mg creatinine) than in the HC (median level 28 pg/mg creatinine). TGFbeta-1 excretion did not correlate with age, white blood cell count, length of oligoanuric period, maximum creatinine at the acute stage, or length of the follow-up. Since TGFbeta-1 excretion may reflect ongoing renal tissue damage, our results emphasize the need for the lifelong follow-up of patients with a past history of D+ HUS, even those showing apparent recovery. Long-term monitoring of this cohort is necessary to determine the clinical utility of our findings.

Beta 2-adrenergic polymorphisms and total serum IgE levels in children with asthma from Argentina.

BACKGROUND: Beta 2-Adrenergic receptor polymorphisms occurring at amino acid positions 16 (arginine/glycine) and 27 (glutamine/glutamic acid) are known to be functionally relevant. Associations with several asthma-related phenotypes, such as total serum IgE, have been investigated with different results. OBJECTIVE: To determine the contribution of polymorphisms and haplotypes of beta 2-adrenergic receptor with serum IgE levels in children from Argentina with mild, moderate, and severe asthma. METHODS: Beta 2-Adrenergic receptor polymorphisms were analyzed in 124 white asthmatic children using polymerase chain reaction during a 3-year period (January 1, 2005, through December 31, 2007). Total serum IgE level was measured by standard methods in all study participants, and age-adjusted values were determined for each individual. RESULTS: Serum levels of IgE were 4.3-fold higher than age-adjusted normal values in the study population. No association was found in regard to asthma severity. A significant difference of IgE serum levels was observed among polymorphisms at position 16, with the highest IgE level in the arginine/arginine group (P = .04). At position 27, even though median levels of IgE in homozygous glutamine were 2.2 times higher than homozygous glutamic acid, this increase did not reach statistical significance. When the population was stratified according to the most common homozygous haplotypes (arginine-arginine 16/glutamine-glutamine 27, glycine-glycine 16/glutamine-glutamine 27, and glycine-glycine 16/glutamic acid-glutamic acid 27), no association was found in relation to the serum levels of IgE. CONCLUSIONS: Beta 2-Adrenergic receptor polymorphisms, especially homozygous arginine 16, were associated with higher serum IgE levels in children with asthma. These genetic variants appear to contribute to the IgE level in asthmatic children from Argentina.

Clinical and molecular analysis of 49 patients with X-linked agammaglobulinemia from a single center in Argentina.

INTRODUCTION: Argentina has a large number of patients with definite diagnosis of X-linked agammaglobulinemia reported in the Latin-American registry. Forty-nine of them were seen in our referral pediatric hospital, between 1987 and 2005. RESULTS AND DISCUSSION: A retrospective study of clinical, laboratory, and molecular data showed that respiratory tract infections were the most frequent initial clinical presentation and the most common among all manifestations prior to diagnosis (69%). Up to diagnosis, we found a high frequency of severe infections (sepsis, 14% and meningitis, 16%) and a high proportion of patients with chronic lung disease. During follow-up, the development of chronic lung disease was significantly related with age at diagnosis and inappropriate treatment. CONCLUSION: Although molecular diagnosis has been available in our center for the past 10 years, there is no doubt that awareness for early recognition of immunodeficiency should be improved through broader and more comprehensive education programs emphasizing characteristics of patients with immunodeficiencies.

Serum levels of interleukin-1 receptor antagonist and tumor necrosis factor-alpha are elevated in children with Langerhans cell histiocytosis.

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare disease with variable prognosis in which lesions and clinical features suggest that pro- and anti-inflammatory cytokines may be involved in its pathogenesis. The authors wished to evaluate whether serum levels of interleukin-1 receptor agonist (IL-1Ra) and tumor necrosis factor-alpha (TNF-alpha) are elevated in children with LCH and decrease after chemotherapy. PATIENTS AND METHODS: Circulating levels of IL-1Ra and TNF-alpha were measured in 23 and 8 children with LCH, respectively, and 7 pediatric controls using commercially available ELISA kits. All patients fulfilled the Histiocyte Society LCH Protocols criteria for diagnosis, stratification, and treatment. RESULTS: Pretreatment concentrations of IL-1Ra and TNF-alpha were found to be significantly elevated in patients with LCH compared with controls. Among LCH substages, a significant difference in IL-1Ra values was observed between individuals with single-system single-site disease vs. multisystem disease with risk-organ dysfunction. In all eight patients evaluated, IL-1Ra levels decreased after 6 weeks of chemotherapy. Lower values of TNF were observed in three patients after treatment. A positive and significant correlation between IL-1Ra and TNF serum concentrations was found. CONCLUSIONS: Patients with LCH have elevated levels of IL-1Ra and TNF, which decrease after chemotherapy.

Prognostic value of soluble interleukin 2 receptor levels in Langerhans cell histiocytosis.

We investigated the prognostic significance of soluble interleukin 2 receptor (sIL-2r) levels in the pre- and post-treatment serum of paediatric patients with Langerhans cell histiocytosis (LCH). Serum levels of sIL-2r from 32 LCH patients and 14 healthy controls were determined using enzyme-linked immunosorbent assay. The LCH patients were classified, evaluated and treated according to the Histiocyte Society's protocols. The following clinical stages were considered: single-system disease (A) divided into single-site (A1; n=4), multiple-site (A2; n=9), and multisystem disease (B) without organ dysfunction (B1; n=5) and with organ dysfunction (B2; n=14). Pretreatment concentrations of sIL-2r were markedly increased at diagnosis in LCH patients compared with controls [in pg/ml, median (range) 9200 (1124-40000) versus 610 (343-800)], P < 0.0001. Levels differed significantly between stages A [3250 (1124-11000)] and B [22750 (3400-40000)], P < 0.05, and between substages A2 and B2, P < 0.05. There was a significant correlation between clinical stages and sIL-2r serum levels, r=0.7996 (P < 0.0001). Patients with > or = 17500 pg/ml of sIL-2r had a 30-month survival of 0.417 (SEM: 0.142) compared with those with levels < 17500 pg/ml, who presented a 30-month survival of 0.848 (SEM: 0.100) (log-rank, P < 0.0001). In multivariate analysis, sIL-2r levels > or = 17500 pg/ml were found to have greater predictive strength than other well-known prognostic factors.

Hepatitis autouinmune en niños. Presentación inicial como falla hepática fulminante / Autoimmune hepatitis in children. Initial presentation of fulminant hepatic failure

There are few cases reported of autoinmune hepatitis (AIH) tipe 2 presenting as fulminant hepatic failure (FHF) in children. The purpose of this study was to report three girls with AIH type 2 that presented as FHF. METHODS: Over a period of 12 years, 123 patients with AIH diagnosed based on international criteria, 9 (7 per cent were type 2.3 of them presented as FHF. Other etiologies (viral, metabolic and toxic) were ruled out. The treatment was started with prednisone (2 mg-kg-day) and azathioprine (2 mg-kg-day). EVOLUTION: Patients 1 and 3 died while waiting for liver transplant (LT) at 72 and 48 hours after initiating medical treatment. Patient 2 underwent LT3 days after starting treatment, with excellent evolution at 3 years and 7 months of follow up. CONCLUSIONS: 1--AIH type 2 was very infrequent in our group. 2--33 per cent of cases had initial presentation as FHF. 3--The course of the disease was aggressive, not responding to immunosupreessive therapy. The evolution was unfavorable in all patients. 4--LT is an alternative treatment for this severe disease. (Au)

Hepatitis autouinmune en niños. Presentación inicial como falla hepática fulminante / Autoimmune hepatitis in children. Initial presentation of fulminant hepatic failure

There are few cases reported of autoinmune hepatitis (AIH) tipe 2 presenting as fulminant hepatic failure (FHF) in children. The purpose of this study was to report three girls with AIH type 2 that presented as FHF. METHODS: Over a period of 12 years, 123 patients with AIH diagnosed based on international criteria, 9 (7 per cent were type 2.3 of them presented as FHF. Other etiologies (viral, metabolic and toxic) were ruled out. The treatment was started with prednisone (2 mg-kg-day) and azathioprine (2 mg-kg-day). EVOLUTION: Patients 1 and 3 died while waiting for liver transplant (LT) at 72 and 48 hours after initiating medical treatment. Patient 2 underwent LT3 days after starting treatment, with excellent evolution at 3 years and 7 months of follow up. CONCLUSIONS: 1--AIH type 2 was very infrequent in our group. 2--33 per cent of cases had initial presentation as FHF. 3--The course of the disease was aggressive, not responding to immunosupreessive therapy. The evolution was unfavorable in all patients. 4--LT is an alternative treatment for this severe disease.

Investigacion de anticuerpos antiactina en hepatitis aguda por virus A en niños / Investigation of anti-actin antibodies in acute viral hepatitis A in children

El virus de la Hepatitis A ha sido propuesto como un posible disparador de hepatitis autoinmune tipo I. Nosostros previamente hemos relatado la presencia de anticuerpos anti-actina en hepatitis A prolongada. En el momento actual la tasa de presencia de anticuerpos antiactina en hepatitis A aguda no complicada es desconocida. Objetivo: evaluar la incidencia y persistencia de anticuerpos antiactina en niños con hepatitis A aguda. Material y métodos: se estudiaron 38 pacientes, 21 mujeres y 17 varones, con una edad media de 6,5 años (margem 2-13). Todos los niños tenían IgM positiva para virus de hepatitis A. Se realizaron controles clínicos y de laboratorio (AST/ALT, gammaglobulina, gammaGT) al comienzo, primer, tercero y quito mes. Los anticuerpos antiactina, anticuerpos a antígenos nucleares (FAN) y antimicrosomas de hígadoriñón (anti-LKM) fueron estudiados con igual frecuencia, hasta volverse negativos. Los anticuerpos anti-actina fueron determinados por imunofluorescencia indirecta en cortes de riñón, hígado y estómago de rata, siendo considerados positivos de sueros con títulos iguales o mayores de 1/40. Resultados: en 18 pacientes (47,3 por ciento) el Ac. anti-actina fue positivo en la primera determinación (títulos 1/40 y 1/80). En 4 pacientes (12,9 por ciento) estos anticuerpos permanecieron positivos durante un mes. Sólo un paciente (2,94 por ciento) tenía el anticuerpo antiactina positivo al tercer mes. Todos los niños eram negativos 5 meses luego del comienzo de la enfermedad. Los FAN y anti-LKM fueron negativos en todos los casos. Conclusiones: 1) Estos datos demuestran la presencia de anticuerpos anti-actina en niños con hepatitis A no complicada. 2) Los anticuerpos permanecieron positivos por un corto período de tiempo. 3) Los títulos fueron menores que en la hepatitis autoinmune tipo I. 4) Estos resultados sugieren que los anticuerpos anti-actina podrían ser la expresión de una estimulación no específica de linfocitos B

Investigacion de anticuerpos antiactina en hepatitis aguda por virus A en niños / Investigation of anti-actin antibodies in acute viral hepatitis A in children

El virus de la Hepatitis A ha sido propuesto como un posible disparador de hepatitis autoinmune tipo I. Nosostros previamente hemos relatado la presencia de anticuerpos anti-actina en hepatitis A prolongada. En el momento actual la tasa de presencia de anticuerpos antiactina en hepatitis A aguda no complicada es desconocida. Objetivo: evaluar la incidencia y persistencia de anticuerpos antiactina en niños con hepatitis A aguda. Material y métodos: se estudiaron 38 pacientes, 21 mujeres y 17 varones, con una edad media de 6,5 años (margem 2-13). Todos los niños tenían IgM positiva para virus de hepatitis A. Se realizaron controles clínicos y de laboratorio (AST/ALT, gammaglobulina, gammaGT) al comienzo, primer, tercero y quito mes. Los anticuerpos antiactina, anticuerpos a antígenos nucleares (FAN) y antimicrosomas de hígadoriñón (anti-LKM) fueron estudiados con igual frecuencia, hasta volverse negativos. Los anticuerpos anti-actina fueron determinados por imunofluorescencia indirecta en cortes de riñón, hígado y estómago de rata, siendo considerados positivos de sueros con títulos iguales o mayores de 1/40. Resultados: en 18 pacientes (47,3 por ciento) el Ac. anti-actina fue positivo en la primera determinación (títulos 1/40 y 1/80). En 4 pacientes (12,9 por ciento) estos anticuerpos permanecieron positivos durante un mes. Sólo un paciente (2,94 por ciento) tenía el anticuerpo antiactina positivo al tercer mes. Todos los niños eram negativos 5 meses luego del comienzo de la enfermedad. Los FAN y anti-LKM fueron negativos en todos los casos. Conclusiones: 1) Estos datos demuestran la presencia de anticuerpos anti-actina en niños con hepatitis A no complicada. 2) Los anticuerpos permanecieron positivos por un corto período de tiempo. 3) Los títulos fueron menores que en la hepatitis autoinmune tipo I. 4) Estos resultados sugieren que los anticuerpos anti-actina podrían ser la expresión de una estimulación no específica de linfocitos B