Hemolytic Uremic Syndrome In Children Research Articles

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Highly Virulent<i>Escherichia coli</i>O26, Scotland

Factors Associated with Sporadic Verotoxigenic Escherichia coli Infection in Children with Diarrhea from the Central Eastern Area of Argentina

Verotoxigenic Escherichia coli (VTEC) are one of the most important emerging foodborne pathogens and the principal cause of hemolytic uremic syndrome (HUS). This entity has been recognized worldwide as a priority issue in the field of zoonoses and public health, and Argentina is the country with the highest incidence of HUS in children less than 5 years of age.The lack of specific treatment, combined with the high morbidity rate of VTEC infection, makes prevention the main tool for reducing the incidence of HUS. The current work aimed at assessing the factors associated with sporadic VTEC infection in children with acute diarrhea from the Central Eastern area of Argentina where the incidence rate of HUS in children under 5 is the highest worldwide. A univariate analysis was performed to identify potential factors associated with VTEC infection by calculating odds ratios (OR) with 95% confidence intervals (CI). Then, a multivariate logistic regression model was performed. Interaction and association between significant factors were checked. "Recent consumption of food prepared outside home" (OR: 2.4, 95% CI 1.05-5.7) and "recent vegetables consumption" (OR=0.4; 0.2-0.8) were identified as independent factors associated with VTEC infection. We believe that the data obtained from this study further the current knowledge about the epidemiology of VTEC infection in Argentina and could be considered when planning strategies for the prevention of the disease.

Atypical hemolytic uremic syndrome

Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.

Shiga Toxin-Producing Escherichia coli in Children: Diagnosis and Clinical Manifestations of O157:H7 and Non-O157:H7 Infection

Shiga toxin-producing Escherichia coli (STEC), a cause of food-borne colitis and hemolytic-uremic syndrome in children, can be serotype O157:H7 (O157) or other serotypes (non-O157). E. coli O157 can be detected by culture with sorbitol-MacConkey agar (SMAC), but non-O157 STEC cannot be detected with this medium. Both O157 and non-O157 STEC can be detected by immunoassay for Shiga toxins 1 and 2. The objectives of this study were first to compare the diagnostic utility of SMAC to that of the Premier EHEC enzyme immunoassay (Meridian Diagnostics) for detection of STEC in children and second to compare the clinical and laboratory characteristics of children with serotype O157:H7 STEC and non-O157:H7 STEC infections. Stool samples submitted for testing for STEC between April 2004 and September 2009 were tested by both SMAC culture and the Premier EHEC assay at Children's Hospital Boston. Samples positive by either test were sent for confirmatory testing and serotyping at the Hinton State Laboratory Institute (HSLI). Chart review was performed on children with confirmed STEC infection. Of 5,110 children tested for STEC, 50 (0.9%) had STEC infection confirmed by culture; 33 were O157:H7 and 17 were non-O157:H7. The Premier EHEC assay and SMAC culture detected 96.0% and 58.0% of culture-confirmed STEC isolates (any serotype), respectively, and 93.9% and 87.9% of STEC O157:H7 isolates, respectively. There were no significant differences in disease severity or laboratory manifestations of STEC infection between children with O157:H7 and those with non-O157 STEC. The Premier EHEC assay was significantly more sensitive than SMAC culture for diagnosis of STEC, and O157:H7 and non-O157:H7 STEC caused infections of similar severity in children.

Recent advances in diagnosis and treatment of atypical haemolytic uraemic syndrome

New understanding of the underlying pathology of the thrombotic microangiopathies has resulted in guidelines for the investigation and management of atypical haemolytic uraemic syndrome in children and adults and the prospect of new therapies, which are in clinical trial. Patients should be investigated for defects in complement pathways and a trial of plasma exchange is indicated.

In vitro and in vivo protective efficacies of antibodies that neutralize the RNA N-glycosidase activity of Shiga toxin 2.

BackgoundShiga toxin 2 (Stx2), one of two Stx liberated by Stx-producing Escherichia coli, is composed of an A subunit monomer and a B subunit pentamer, and is directly linked with hemolytic uremic syndrome in children. The pentameric B subunit binds to its cell surface receptor Gb3 for toxin internalization, and the A subunit follows intracellular retrograde transport to the cytosol where its RNA N-glycosidase activity (RNA-NGA) shuts down the protein synthesis, and leads to cell death. The present study investigated the ability of 19 Stx2 A subunit-specific human monoclonal antibodies (HuMAbs) to neutralize the RNA-NGA, and the association this neutralizing activity with protection of HeLa cells and mice against Stx2-induced death.ResultsThe HuMAbs that were stronger inhibitors of RNA-NGA were also better at neutralizing Stx2 mediated HeLa cell death, and those that were weaker inhibitors of RNA-NGA activity were also weaker in protecting HeLa cells. These results suggest that the ability of an A subunit-specific antibody to block the RNA-NGA of the toxin is directly related to its ability to neutralize Stx2-mediated HeLa cell death. However, with the exception of the best RNA-NGA blocking antibodies 5C12 and 2F10, the efficacies of antibody neutralization of RNA-NGA of Stx2 did not correlate with their in vivo protective efficacies. The HuMAb 6C3, which neutralized RNA N-glycosidase activity of Stx2 less effectively than the HuMAbs 6D8 and 6B7, protected 100% of the mice against Stx2 challenge at 50 μg/mouse dose. In contrast, the HuMAbs 6D8 and 6B7, which neutralized RNA N-glycosidase activity of Stx2 more effectively than 6C3, protected 20% and 0% mice at that dose, respectively.ConclusionsThe neutralization efficiency of the RNA-NGA of Stx2 by A subunit-specific antibodies correlate strongly with their abilities to protect HeLa cells against Stx2-mediated toxicity but only the strongest RNA-NGA-neutralizing antibodies correlate very well with both protecting HeLa cells and mice against Stx2 challenge.

Chronic Kidney Disease, Thrombotic Microangiopathy, and Hypertension Following T Cell-Depleted Hematopoietic Stem Cell Transplantation

Chronic kidney disease (CKD) is now an accepted long-term complication of allogeneic hematopoietic stem cell transplantation. Calcineurin inhibitors (CNI), which are used for prophylaxis and treatment of graft-versus-host disease (GVHD), have been associated with the development of nephrotoxicity. Hypertension (HTN) and thrombotic microangiopathy (TMA) are 2 comorbidities linked to CKD. T cell depletion (TCD) of stem cell grafts can obviate the need for the use of CNI. We conducted a retrospective analysis of 100 patients who underwent TCD transplantation: 30 in group A were conditioned without total-body radiation (TBI) and 70 in group B received a TBI containing regimen. None of the patients received CNI. The median age was 55.5 and 45 years for groups A and B, respectively. Eleven patients developed TMA, all in group B. The 2-year cumulative incidence of sustained CKD was 29.2% and 48.8% in group A and group B, respectively, with a mean follow-up of at least 21 months. CKD free survival was better in the non-TBI group (P = .046). Multivariable survival analysis revealed that exposure to TBI, older age, and TMA were risk factors for CKD. The incidence of new onset or worsening HTN was 6.7% and 25.7% (P = .03) in group A and B, respectively. The use of TBI (P = .0182) and diagnosis of TMA (P = .0006) predisposed patients to the development of HTN using univariable logistic regression models. Thus, despite the absence of CNI, a proportion of these older patients in both groups developed CKD and HTN.

Hemolytic-uremic syndrome in Switzerland: a nationwide surveillance 1997–2003

Hemolytic-uremic syndrome (HUS) is a leading cause of acute renal failure in childhood. In its typical presentation, it is preceded by an episode of diarrhea mostly due to Shiga-toxin-producing Escherichia coli. There is important geographical variation of many aspects of this syndrome. Nationwide data on childhood HUS in Switzerland have not been available so far. In a prospective national study through the Swiss Pediatric Surveillance Unit 114 cases (median age 21 months, 50% boys) were reported between April 1997 and March 2003 by 38 pediatric units (annual incidence 1.42 per 10(5) children < or =16 years). Shiga-toxin-producing E. coli were isolated in 32 (60%) of tested stool samples, serotype O157:H7 in eight. Sixteen children presented with only minimal renal involvement, including three with underlying urinary tract infection. Six patients presented with atypical hemolytic-uremic syndrome, and six with HUS due to invasive Streptococcus pneumoniae infection. Mortality was 5.3%, including two out of six children with S. pneumoniae infection. The severity of thrombocytopenia and the presence of central nervous system involvement significantly correlated with mortality. In conclusion, childhood HUS is not rare in Switzerland. Contrasting other countries, E. coli O157:H7 play only a minor role in the etiology. Incomplete manifestation is not uncommon.

Pneumococcal empyema and haemolytic uraemic syndrome in children: experience from a UK tertiary respiratory centre

The incidence of childhood empyema and pneumococcus-associated haemolytic uraemic syndrome (P-HUS) is increasing. Streptococcus pneumoniae is the most common pathogen causing childhood empyema and the association with invasive streptococcal infections...

Early erythropoietin reduced the need for red blood cell transfusion in childhood hemolytic uremic syndrome—a randomized prospective pilot trial

Childhood hemolytic uremic syndrome (HUS) is most often caused by enterohemorrhagic Escherichia coli (EHEC). Due to severe hemolysis, red blood cell (RBC) transfusions are often necessary, and anemia is aggravated by low erythropoietin (EPO) levels caused by acute renal failure. In a single center, prospective study, we randomized ten children with EHEC-positive HUS into two therapeutic groups: one receiving EPO treatment (median age 2 years, age range 1-3 years) and the other receiving standard therapy (median age 2 years, age range 1-6 years). Red blood cell transfusions were performed when the hemoglobin level (Hb) fell below 5 mg/dl. The number of RBC transfusions was compared in both groups. The Hb level at admission was comparable between both groups (6.4 vs. 8.1 mg/dl, P > 0.05, t-test). However, children in the EPO group required a significantly lower mean number of RBCs than those in the non-EPO group (0.2 vs. 1.4, P < 0.04, t-test). Based on these results, we suggest that the early administration of EPO at the time of hemolytic anemia and beginning renal failure may attenuate renal anemia in children with EHEC-induced HUS and thereby reduce the number of RBC transfusions required. The results of this pilot study will have to be confirmed in a larger multicenter trial.

Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome

This guideline for the investigation and initial treatment of atypical hemolytic uremic syndrome (HUS) is intended to offer an approach based on opinion, as evidence is lacking. It builds on the current ability to identify the etiology of specific diagnostic sub-groups of HUS. HUS in children is mostly due to infection, enterohemorrhagic Escherichia coli (EHEC), Shigella dysenteriae type 1 in some geographic regions, and invasive Streptococcus pneumoniae. These sub-groups are relatively straightforward to diagnose. Their management, which is outside the remit of this guideline, is related to control of infection where that is necessary and supportive measures for the anemia and acute renal failure. A thorough investigation of the remainder of childhood HUS cases, commonly referred to as "atypical" HUS, will reveal a risk factor for the syndrome in approximately 60% of cases. Disorders of complement regulation are, numerically, the most important. The outcome for children with atypical HUS is poor, and, because of the rarity of these disorders, clinical experience is scanty. Some cases of complement dysfunction appear to respond to plasma therapy. The therapeutic part of this guideline is the consensus of the contributing authors and is based on limited information from uncontrolled studies. The guideline proposes urgent and empirical plasmapheresis replacement with whole plasma fraction for the first month after diagnosis. This should only be undertaken in specialized pediatric nephrology centers where appropriate medical and nursing skills are available. The guideline includes defined terminology and audit points so that the early clinical effectiveness of the strategy can be evaluated.

Advances in the treatment of hemolytic uremic syndrome in children

溶血尿毒综合征(HUS)是以微血管病性溶血性贫血、急性肾功能衰竭和血小板减少为主要特征的临床综合征.该文综述r国内外关于HUS的治疗方案,目前公认的有效措施包括急性期对于肾功能衰竭的综合治疗、预防并发症的发牛、必要时予血浆置换或血浆输注以及早期透析(血液透析或腹膜透析)等.对于小典型HUS,治疗的重点在于纠正补体调节因子的缺陷.急性期后则应根据不同的临床表现给予相应的治疗,早期限制蛋白质摄入和长期应刚血管紧张素转换酶抑制剂是延缓.肾损害进程、改善预后的主要方法。

Complement and the atypical hemolytic uremic syndrome in children

Over the past decade, atypical hemolytic uremic syndrome (aHUS) has been demonstrated to be a disorder of the regulation of the complement alternative pathway. Among approximately 200 children with the disease, reported in the literature, 50% had mutations of the complement regulatory proteins factor H, membrane cofactor protein (MCP) or factor I. Mutations in factor B and C3 have also been reported recently. In addition, 10% of children have factor H dysfunction due to anti-factor H antibodies. Early age at onset appears as characteristic of factor H and factor I mutated patients, while MCP-associated HUS is not observed before age 1 year. Low C3 level may occur in patients with factor H and factor I mutation, while C3 level is generally normal in MCP-mutated patients. Normal plasma factor H and factor I levels do not preclude the presence of a mutation in these genes. The worst prognosis is for factor H-mutated patients, as 60% die or reach end-stage renal disease (ESRD) within the first year after onset of the disease. Patients with mutations in MCP have a relapsing course, but no patient has ever reached ESRD in the first year of the disease. Half of the patients with factor I mutations have a rapid evolution to ESRD, but half recover. Early intensive plasmatherapy appears to have a beneficial effect, except in MCP-mutated patients. There is a high risk of graft loss for HUS recurrence or thrombosis in all groups except the MCP-mutated group. Recent success of liver–kidney transplantation combined with plasmatherapy opens this option for patients with mutations of factors synthesized in the liver. New therapies such as factor H concentrate or complement inhibitors offer hope for the future.

A severe case of atypical hemolytic uremic syndrome associated with pneumococcal infection and T activation treated successfully with plasma exchange

A severe nondiarrheal form of hemolytic uremic syndrome in children is associated with pneumococcal infection (pHUS). Neuraminidase released by the pneumococci may cleave N-acetylneuraminic acid residues on red blood cells (RBCs), leading to the exposure of the T cryptantigen and polyagglutinability of RBCs, a process known as T activation. Data suggest a pathogenic role of exposed T antigens on glomeruli interacting with naturally occurring anti-T in the development of renal dysfunction in pHUS. By reducing the levels of anti-T and neuraminidase, plasma exchange (PE) may have a role in the treatment of severe cases of pHUS. A previously healthy 2-year-old boy presented with acute renal failure, thrombocytopenia, microangiopathic hemolytic anemia, pneumococcal infection, and T activation of RBCs. A diagnosis of pHUS was made. Due to rapid clinical decline, daily single-volume PE with 5 percent albumin replacement was initiated. Infusion of additional plasma was avoided by using only saline-washed RBCs for transfusion. He made a full recovery after 13 PEs and remained well at follow-up 7 months later. Polyagglutinability of RBCs was shown by mixing patient RBCs with five normal donor sera. The agglutination assays with a panel of lectins confirmed the specificity of exposed T antigen as the cause of polyagglutinability. The dramatic response seen in this patient suggests that PE utilizing albumin replacement may benefit patients with severe pHUS.

Haemolytic uraemic syndrome in children admitted to a rural district hospital in Kenya

We studied children admitted to Kilifi District Hospital, Kenya, between 1997 and 2005 with haemolytic uraemic syndrome (HUS) and reviewed their records in order to determine the clinical features and outcomes of the disease. Thirty-one children fulfilled the criteria: 21 (68%) had diarrhoea-associated HUS (D + HUS), the remainder did not (D-HUS); five had involvement of the central nervous system. Those with D-HUS had lower haemoglobin and platelet counts when compared with those with D + HUS. The overall mortality rate was 55% (17/31) with no significant difference between the two groups. Severe hyponatraemia ([Na(+)] <120 mmol/L) predicted a poor outcome. Shigella dysenteriae was the most common isolated organism in the stool and Escherichia coli and S. dysenteriae were the most common blood isolates. HUS carries a high mortality rate and D-HUS is as common as D + HUS.

Differential impact of complement mutations on clinical characteristics of atypical hemolytic uremic syndrome in children. J Am Soc Nephrol 18

Differential impact of complement mutations on clinical characteristics of atypical hemolytic uremic syndrome in children. J Am Soc Nephrol 18

Management of diarrhea-associated hemolytic uremic syndrome in children

Most cases of diarrhea-associated hemolytic uremic syndrome (D+HUS) are caused by Shiga toxin-producing bacteria. Shiga toxin-producing Escherichia coli (STEC) O157:H7 has the strongest association worldwide with HUS. A massive outbreak of E. coli O157:H7 infections in Sakai, Osaka, Japan, in 1996 raised public and medical awareness of STEC. However, most cases are sporadic or occur in small clusters. Indeed, more than 100 sporadic or small cluster cases of D+HUS occur every year in Japan. The use of antibiotics in patients with definite or possible enteric STEC infections is controversial; however, there has been no randomized controlled trial to date showing the effectiveness of antibiotics for the prevention of the development of HUS. Thus, most investigators in western countries believe that antibiotics should not be administered to patients with such infections, and the management of HUS remains supportive. There are no specific therapies to ameliorate the course of the disease, and vascular injury leading to HUS is likely to be well under way by the time infected patients seek medical attention for diarrhea. The best way to prevent HUS is to prevent primary infection by Shiga toxin-producing bacteria.

Cognitive sequelae following haemolytic uraemic syndrome in children and adolescents: A neuropsychological study

Cognitive sequelae following haemolytic uraemic syndrome in children and adolescents: A neuropsychological study

Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome

AbstractThrombotic microangiopathy and acute renal failure are cardinal features of postdiarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx) through the interaction with its globotriaosyl ceramide receptor. However, inflammatory processes contribute to the pathogenesis of HUS by sensitizing cells to Stx fractalkine (FKN), a CX3C transmembrane chemokine expressed on epithelial and endothelial cells upon activation, is involved in the selective migration and adhesion of specific leukocyte subsets to tissues. Here, we demonstrated a selective depletion of circulating mononuclear leukocytes expressing the receptor for FKN (CX3CR1) in patients with HUS. We found a unique phenotype in children with HUS distinct from that seen in healthy, uremic, or infected controls, in which monocytes lost CX3CR1, down-modulated CD62L, and increased CD16. In addition, the CD56dim natural killer (NK) subpopulation was decreased, leading to an altered peripheral CD56dim/CD56bright ratio from 10.0 to 4.5. It is noteworthy that a negative correlation existed between the percentage of circulating CX3CR1+ leukocytes and the severity of renal failure. Finally, CX3CR1+ leukocytes were observed in renal biopsies from patients with HUS. We suggest that the interaction of CX3CR1+ cells with FKN present on activated endothelial cells may contribute to renal injury in HUS.

Childhood hemolytic uremic syndrome is associated with adolescent-onset diabetes mellitus

Extra-renal manifestations of the hemolytic uremic syndrome in children are well described. Pancreatic involvement may manifest as transient hyperglycemia and permanent diabetes mellitus. Two previous case reports demonstrate short periods of "remission" between initial hyperglycemia and the development of permanent diabetes mellitus. We report an unusual case of a two-year-old Caucasian boy whose HUS-associated hyperglycemia resolved shortly after the acute phase of his illness only to recur as permanent diabetes mellitus at puberty. To our knowledge no other case is reported that demonstrates such a long interval between initial presentation and the development of permanent diabetes mellitus.