Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late-emerging sequelae.

BACKGROUND: The aim of this study was to evaluate the long-term prognosis of children with hemolytic uremic syndrome (HUS). METHODS: Over a 6-year period, 619 pediatric patients with the clinical diagnosis of HUS were registered in Austria and Germany, and a subset (n = 274) was prospectively followed up for 5 years. RESULTS: Infection with enterohemorrhagic Escherichia coli (EHEC) was confirmed in 79% of cases. Five years after diagnosis, 70% of EHEC-infected patients (95% confidence interval [CI], .63-.76) were fully recovered. The remaining 30% had persistent hypertension (9%), neurological symptoms (4%), decreased glomerular filtration rate (7%), and/or proteinuria (18%). Hypertension and proteinuria developed in a total of 18% of patients who had no sequelae 1 year after the acute phase (95% CI, 12-26). Multivariate logistic regression analysis demonstrated an association between the use of plasma therapy during acute phase and poor long-term outcome (odds ratio, 2.9-13; 95% CI, 2.4-33; P < .05), but this treatment was also used more frequently in severe cases. In contrast, the use of antibiotic therapy in the diarrheal phase and other established risk factors for developing HUS, such as Shiga toxin 2 and EHEC serotypes traditionally considered to be "high risk," were not associated with adverse long-term outcome. In particular, there was no difference between O157 and non-O157 EHEC. CONCLUSIONS: This study identified an association between the use of plasma treatment and poor long-term outcome and confirms already known risk factors for poor prognosis. Follow-up investigations for at least 5 years are recommended to detect late-emerging sequelae.

Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy.

We report successful kidney transplantation in a 10-yr-old boy with aHUS and heterozygous factor H mutation using the terminal complement inhibitor eculizumab to avoid recurrence of aHUS in the renal graft. Vaccination against meningococcus C (Men C) is essential in patients with dysfunction of the complement system, as induced by eculizumab. In our patient, we report waning SBA titers but maintenance of protective SBA titers (≥1:8) after kidney transplantation under immunosuppressive therapy with mycophenolate mofetil, tacrolimus, steroids, and eculizumab over a 27-month observational period. Our case illustrates that a humoral immune response to conjugate Men C vaccination may be mounted and maintained despite chronic renal disease, kidney transplantation, immunosuppressive drugs, and immunomodulatory therapy with eculizumab. However, it remains unclear whether serologically defined protective SBA titers mediate true protection from invasive meningococcal disease in an immunocompromised patient, particularly under treatment with a complement inhibitor. Thus, close monitoring of SBA titers seems mandatory in this patient.

Analysis of the classical, alternative, and mannose binding lectin pathway of the complement system in the pathogenesis of oligoarticular juvenile idiopathic arthritis.

The complement system plays a role in the pathogenesis of some autoimmunopathies. This longitudinal study evaluates the contribution of the complement system in the pathogenesis of oligoarticular juvenile idiopathic arthritis (JIA). Serum of the peripheral blood and the synovial fluid were investigated for the activity of the classical (CP), the mannose binding lectin (MBL), and the alternative pathway (AP). A total of 12 samples from peripheral blood (PB) and two samples from synovial fluid (SF) of girls with oligoarticular JIA were investigated in a longitudinal observation from the time point of the diagnosis of JIA. The differences between the complement activity in the PB and in the SF were extremely statistically significant (CP and MBL: P < 0.0001; AP: < 0.0087). The activity of the CP and the MBL pathway was reduced. The AP is the main contributor in the pathogenesis of oligoarticular JIA. Anti-C5 therapy may be an option to avoid the creation of the membrane attack complex.

Pediatric aspects of therapeutic drug monitoring of mycophenolic acid in renal transplantation.

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppressive therapy in pediatric renal and heart transplant recipients. Children undergo developmental changes (ontogeny) of drug disposition, which may affect drug metabolism of the active compound mycophenolic acid (MPA). Therefore, a detailed characterization of MPA pharmacokinetics and pharmacodynamics in this patient population is required. In general, the overall efficacy and tolerability of MMF in pediatric patients appear to be comparable with those in adults, except for a higher prevalence of gastrointestinal adverse effects in children younger than 6 years. The currently recommended dose in pediatric patients with concomitant cyclosporine is 1200 mg/m(2) per day in 2 divided doses; the recommended MMF dose with concomitant tacrolimus or without a concurrent calcineurin inhibitor is 900 mg/m(2) per day in 2 divided doses. Recent data suggest that fixed MMF dosing results in MPA underexposure (MPA-area under the concentration-time curve (AUC(0-12)), <30 mg × h/L) early posttransplant in approximately 60% of patients. To achieve adequate MPA exposure in most patients, an initial MMF dose of 1800 mg/m(2) per day with concomitant cyclosporine and 1200 mg/m(2) per day with concomitant tacrolimus for the first 2 to 4 weeks posttransplant has been suggested. As in adults, there is an approximately 10-fold variability in dose-normalized MPA-AUC(0-12) values between pediatric patients after renal transplantation, strengthening the argument for concentration-controlled dosing of the drug. Although the clinical utility of therapeutic drug monitoring of MPA for graft outcome and patient survival is still controversial, potential indications are the avoidance of underimmunosuppression, particularly in patients with high immunologic risk in the initial period posttransplant, in patients who are treated with protocols that explore the possibilities of calcineurin inhibitor minimization, withdrawal or even complete avoidance, and steroid withdrawal or avoidance regimens that might also benefit from intensified therapeutic drug monitoring of MPA. An additional indication especially in adolescent patients is the monitoring of drug adherence. Therapeutic drug monitoring of MPA in pediatric solid organ transplantation using limited sampling strategies is preferable over drug dosing based on trough level monitoring only. Several validated pediatric limited sampling strategies are available. Clearly, more research is required to determine whether pediatric patients will benefit from therapeutic drug monitoring of MPA for long-term maintenance immunosuppression with MMF.

Markers of childhood lupus nephritis indicating disease activity.

Current treatment regimens for childhood lupus nephritis (LN) are associated with significant side-effects and toxicity in vulnerable phases of growth and development. The paucity of biomarkers particularly in childhood impedes the appropriate clinical management and the development of new therapeutics. We analyzed markers of immune system (BAFF, RANTES), complement (Bb, C1q, C3d-CIC, C5a) and endothelial cell activation (sVCAM-1) in children with LN (n=22, mean age 14.8±4.7 years), nephrotic syndrome (n=13) and age-matched healthy controls (n=20) to define parameters that correlate with LN activity. Complement fragments of the alternative (Bb, p=0.0004) classical (C3d-CIC, p<0.0001) and common pathway (C5a, p<0.0001) and the levels of BAFF (p<0.0001), RANTES (p=0.0002) and sVCAM-1 (p=0.0004) were significantly higher in active compared to inactive LN. Activation of complement was associated with the occurrence of anti-C1q antibodies and reduced complement C1q. Complement-activation fragments highly correlated with the markers for immune system and endothelial cell activation. The ensemble of these parameters may be of great value in identifying early flares or remissions of childhood LN, and moreover may prove useful in the assessment of new treatments and in determining the optimization of their use.

Aciclovir and varicella-zoster-immunoglobulin in solid-organ transplant recipients.

Clear recommendations for the management of acute varicella-zoster virus (VZV) infections for cases of significant exposure and the use of prophylactic drugs after solid-organ transplantation are missing due to the lack of evidence by prospective studies. Heterogeneity in patient groups, patient numbers, age groups, immunosuppressive regimens, timing, and dosage of aciclovir and/or varicella-zoster immunoglobulin (VZIG), pre-transplant vaccination or VZV wild-type infection and inconsistency of data make comparability of different studies impossible. Although the benefit of aciclovir and/or VZIG is uncertain in immunosuppressed children, prospective controlled double-blind studies are not feasible for ethical considerations as fatal cases with disseminating varicella disease are well known in these patient groups despite the use of aciclovir and/or VZIG, whereas severe side-effects of these drugs are rare. However, a reporting bias is likely as mainly severe or fatal cases might have been predominantly published or cases of successfully used aciclovir and/or VZIG in mild cases or in cases of breakthrough infections after vaccination. As neither VZIG prophylaxis nor treatment with intravenous aciclovir offers complete protection against severe VZV infection to immunosuppressed pediatric solid-organ transplant recipients, high priority should be given to vaccination against VZV prior to transplantation, and, most importantly, in their close contact persons. Clinical observations suggest that only assessment of humoral immunity together with cellular immunity may allow predication about protection in exposed patients.

Antibody dynamics after tick-borne encephalitis and measles-mumps-rubella vaccination in children post early thymectomy.

Thymectomized patients (TP) showed a delayed humoral immune response to tick-borne-encephalitis-virus (TBEV) vaccination, which served as a neo-antigen. From the previously published cohort, the TBEV-specific IgG concentrations and avidities were analyzed in 17 TP compared to 30 non-thymectomized healthy controls (HC) 220 weeks after the first TBE vaccination to identify patients with waning antibodies. Only in HC, increase of avidity was significant between 8 and 220 weeks (p<0.001), whereas TP showed a lower avidity maturation at week 48 (p<0.05). Cytomegalovirus (CMV) seropositivity at vaccination did not influence the humoral immune response. The ability of TP to maintain measles, mumps and rubella (MMR)-specific antibodies at least 8 years post (MMR) vaccination was evaluated in the serum samples of TP, retrospectively. Although all TP had MMR vaccination at least 6 months after thymectomy, TP showed no significant difference regarding MMR-specific IgG concentrations or avidities compared to HC. Regarding TBE vaccination, the data confirmed the previous observation of a delayed primary immune response in TP to TBE vaccine and also revealed an altered memory priming by paucity of high-avidity antibodies.

Enterohemorrhagic Escherichia coli O26:H11-Associated Hemolytic Uremic Syndrome: Bacteriology and Clinical Presentation.

Infection by enterohemorrhagic ESCHERICHIA COLI (EHEC) is the most frequent cause of hemolytic uremic syndrome (HUS) in childhood. During a 6-year period, all patients with the clinical diagnosis of HUS were registered in a prospective multicenter study in Austria and Germany. EHEC O26:H11 was the second most frequent detected serotype, accounting for 15.4% of all EHEC isolates. The presence of EHEC O26:H11 was significantly associated with young age at the disease onset ( P < 0.001). Patients infected with this serotype were not different in their clinical presentation than those infected with other serotypes. This study underlines the importance of EHEC serotypes other than O157 in the etiology of HUS and emphasizes the importance of implementation of appropriate diagnostic methods to identify the whole spectrum of EHEC associated with HUS.

The autoimmune disease DEAP-hemolytic uremic syndrome.

DEAP-HUS (deficiency of CFHR plasma proteins and factor H [FH] autoantibody positive hemolytic uremic syndrome [HUS]) is a new form of HUS characterized by a deletion of genes coding for FH-related proteins and the presence of autoantibodies directed to FH. These disease-associated autoantibodies inhibit FH (CFH) surface binding functions, which results in a defective regulation of the alternative pathway and damage of endothelial cells. Here we describe two representative patients with DEAP-HUS who both developed end-stage renal failure with the background of homozygous deletion of CFHR1 and CFHR3 genes and the presence of FH autoantibodies. Based on the retrospective diagnosis of DEAP-HUS 2 to 12 months after the initial clinical presentation, subsequent immunosuppressive therapy was initiated. The autoantibody titers decreased, and the complement status of the patients improved, as indicated by increased C3 levels. Thus early diagnosis of DEAP-HUS and immunosuppressive treatments are important factors to treat this particular type of HUS.

Anti-factor H autoantibody-associated hemolytic uremic syndrome: review of literature of the autoimmune form of HUS.

Non-Shiga toxin-associated hemolytic uremic syndrome (atypical HUS) is a rare form of thrombotic microangiopathy that associates hemolytic anemia, thrombocytopenia, and acute renal failure. The disease has been demonstrated to be linked with a complement alternative pathway dysregulation due to genetic defects but also to development of autoantibodies to factor H (FH), the main plasmatic alternative pathway regulatory protein. In this review, we summarize the more recent data of this autoimmune form of HUS at the level of epidemiology and its clinical and biological features. We propose the performance of anti-FH autoantibodies screening at the very onset of the disease in all cases of HUS to first make the proper diagnosis as early as possible, and second to support an appropriate therapy including early plasma exchanges and immunosuppressive treatments.

New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab.

Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and renal impairment. Often HUS is triggered by Shiga-like toxin- producing ESCHERICHIA COLI. Less common is atypical HUS (aHUS), which is caused by defective complement control. aHUS is associated with mutations in genes encoding complement regulatory proteins in ~50% of patients with this syndrome. Furthermore, autoantibodies that inactivate to factor H have also been linked to the disease. Initial triggers include infections, use of endothelial-affecting drugs, malignancies, transplantation, and pregnancy. Advances in our understanding of the pathogenesis of atypical HUS suggest that complement inhibition may be used as treatment for the disease. We discuss the potential benefit of the complement inhibitor eculizumab for the treatment of aHUS.

La desregulación del complemento influye en el pronóstico de los niños trasplantados por síndrome urémico hemolítico: [revisión] / Complement regulation disorders and outcome after transplantation in children with atypical hemolytic uremic syndrome: [review]

El síndrome urémico hemolítico (SUH) es la principal causa de insuficiencia renal aguda en pediatría y el diagnóstico primario del 4.5% de los niños en tratamiento por trasplante renal crónico. El SUH se caracteriza por insuficiencia renal aguda, anemia hemolítica y trombocitopenia. La presentación característica del SUH es luego de una infección gastrointestinal por Escherichia coli enterohemorrágica (ECEH). El 5% de todos los casos de SUH muestra un curso atípico recurrente. Las mutaciones en las proteínas reguladoras del complemento tienen un papel importante en la patogénesis de SUH atípico y en los resultados después del trasplante renal. Estos pacientes tienen un riesgo muy alto de pérdida del injerto debido a la recurrencia del SUH o a trombosis. A los pacientes con SUH y sin evidencia de infección por ECEH se les debería realizar un análisis completo de los trastornos del complemento conocidos y de autoanticuerpos contra el factor H. Un diagnóstico certero de SUH basado en los últimos conocimientos sobre trastornos en la regulación del complemento debería ayudar a predecir el riesgo de fracaso del injerto. Están emergiendo nuevas terapias que brindan esperanza para un mejor tratamiento futuro de esta grave enfermedad.(AU)

La desregulación del complemento influye en el pronóstico de los niños trasplantados por síndrome urémico hemolítico: [revisión] / Complement regulation disorders and outcome after transplantation in children with atypical hemolytic uremic syndrome: [review]

El síndrome urémico hemolítico (SUH) es la principal causa de insuficiencia renal aguda en pediatría y el diagnóstico primario del 4.5% de los niños en tratamiento por trasplante renal crónico. El SUH se caracteriza por insuficiencia renal aguda, anemia hemolítica y trombocitopenia. La presentación característica del SUH es luego de una infección gastrointestinal por Escherichia coli enterohemorrágica (ECEH). El 5% de todos los casos de SUH muestra un curso atípico recurrente. Las mutaciones en las proteínas reguladoras del complemento tienen un papel importante en la patogénesis de SUH atípico y en los resultados después del trasplante renal. Estos pacientes tienen un riesgo muy alto de pérdida del injerto debido a la recurrencia del SUH o a trombosis. A los pacientes con SUH y sin evidencia de infección por ECEH se les debería realizar un análisis completo de los trastornos del complemento conocidos y de autoanticuerpos contra el factor H. Un diagnóstico certero de SUH basado en los últimos conocimientos sobre trastornos en la regulación del complemento debería ayudar a predecir el riesgo de fracaso del injerto. Están emergiendo nuevas terapias que brindan esperanza para un mejor tratamiento futuro de esta grave enfermedad.

Varicella vaccination in pediatric kidney and liver transplantation.

Reports about efficacy and safety of live-virus attenuated vaccines in patients before and after transplantation are mainly based on small patient numbers, making general recommendations for this patient population difficult. Children and adults as well as their close relatives and contact persons should be preferably immune to VZV before solid organ transplantation to avoid VZV-associated complications, thus making VZV vaccination necessary in susceptible individuals. The following literature review focused on efficacy and safety of VZV vaccination in pediatric kidney and liver transplant recipients. Review of literature also revealed that in all pediatric transplant candidates, humoral and cellular immunity against VZV should be consistently monitored to assess waning immunity under immunosuppressive treatment. This approach is desirable to estimate the risk of severe varicella disease after exposure in these patients.

Clinical practice. Today's understanding of the haemolytic uraemic syndrome.

The haemolytic uraemic syndrome (HUS) includes the triad of haemolytic anaemia, thrombocytopenia, and acute renal failure. The classical form [D(+) HUS] is caused by infectious agents, and it is a common cause of acute renal failure in children. The enterohaemorrhagic Escherichia coli-producing Shiga toxin (Stx) is the most common infectious agent causing HUS. Other infectious agents are Shigella and Streptococcus pneumoniae. Infections by S. pneumoniae can be particularly severe and has a higher acute mortality and a higher long-term morbidity compared to HUS by Stx. Atypical HUS [D(-)Stx(-)HUS] are often used by paediatricians to indicate a presentation of HUS without preceding diarrhoea. Almost all patients with D(-)Stx(-)HUS have a defect in the alternative pathway, for example, mutations in the genes for complement factor H, factor I, and membrane co-factor protein. Mutations in the factor H gene are described more often. The majority of children with D(+) HUS develop some degree of renal insufficiency, and approximately two thirds of children with HUS will require dialysis therapy, while about one third will have milder renal involvement without the need for dialysis therapy. General management of acute renal failure includes appropriate fluid and electrolyte management, antihypertensive therapy, and the initiation of renal replacement therapy when appropriate. Specific management issues in HUS include management of the haematological complications of HUS, monitoring for extra-renal involvement, avoiding antidiarrhoeal drugs, and possibly avoiding of antibiotic therapy. In addition to the obligatory supportive treatment and tight control of hypertension, there is anecdotal evidence that plasma therapy may induce remission and, in some cases, maintain it. Fresh frozen plasma contains factor H at physiological concentrations. A new therapy for D(-)Stx(-)HUS is a humanised monoclonal antibody (Eculizumab) that blocks complement activity by cleavage of the complement protein C5. It prevents the generation of the inflammatory peptide C5a and the cytotoxic membrane-attack complex C5b-9. We have first positive results, but it is still not approved for HUS.

Chronic antiepileptic monotherapy, bone metabolism, and body composition in non-institutionalized children.

AIM: The aim of this study was to determine the influence of chronic monotherapy with antiepileptic drugs (AEDs) on vitamin D levels, bone metabolism, and body composition. METHOD: Eighty-five children (38 males, 47 females; mean age 12 y 5 mo, SD 3 y 4 mo) were treated with valproate and 40 children (28 males, 12 females; mean age 11 y 10 mo, SD 3 y) were treated with other AEDs (lamotrigine, sulthiame, or oxcarbazepine), comprising the non-valproate group. Forty-one healthy children (29 males 12 females; mean age 12 y 1 mo, SD 3 y 5 mo) served as a comparison group. Height, weight, body impedance analysis, 25-hydroxyvitamin D, calcium, phosphate, two bone resorption markers (receptor activator of nuclear factor kappaB ligand [RANKL] and tartrate-resistant acid phosphatase 5b [TRAP5b]), osteoprotegerin, and leptin were measured. RESULTS: No child was vitamin D deficient as defined by a 25-hydroxyvitamin D (25OHD) level of less than 25 nmol/l (<10 ng/ml). Leptin, body fat, weight standard deviation score (SDS), and body mass index (BMI) SDS were all significantly higher (each p<0.001) in valproate-treated children than in the non-valproate group, as were calcium (p=0.027) and RANKL (p=0.007) concentrations. Similarly, leptin was significantly higher in the valproate group than in control participants (p<0.001), as were body fat (p=0.023), weight SDS (p=0.046), BMI SDS (p=0.047), calcium (p<0.001), and RANKL (p<0.001), whereas TRAP5b concentrations were significantly lower in the valproate-treated group (p=0.002). Furthermore, calcium and RANKL levels were significantly higher in the non-valproate group than in comparison participants (p<0.001 and p=0.016 respectively). INTERPRETATION: Non-enzyme-inducing or minimal enzyme-inducing AED monotherapy does not cause vitamin D deficiency in otherwise healthy children with epilepsy. Valproate therapy is associated with increases in weight, body fat, and leptin concentration, as well as with a bone metabolic profile that resembles slightly increased parathyroid hormone action.