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In the past 10 years, enterohemorrhagic Escherichia coli (EHEC) infection in infants and children has not been decreased in Japan. Clinical manifestations may include history of diarrhea, a visibly bloody stool, fever, and abdominal tenderness those last for about 2 weeks and restore naturally. However, if the patients suffer from hemolytic uremic syndrome (HUS) that may be fatal infrequently. The major treatment for EHEC infection and HUS have been therapies for these symptons. Therefore new therapeutic agents for vero toxin (VT) have been developed, but that is still experimental. We describe the latest clinical researches and treatment strategies in this paper.

Escherichia coli (E. coli) is a bacterium that is commonly found in the gut of humans and warm-blooded animals. Most strains of E. coli are harmless. Some strains however, such as enterohemorrhagic E. coli (EHEC), can cause severe foodborne disease. It is transmitted to humans primarily through consumption of contaminated foods, such as raw meal. EHEC produces toxins, known as verotoxins. EHEC that induces bloody diarrhea leads to HUS in 10% of cases. The clinical manifestations of post-diarrheal HUS include acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. The verocytotoxin can directly damage renal and endothelial cells. Thrombocytopenia occurs as platelets are consumed by clotting. Hemolytic anemia results from intravascular fibrin deposition, increased fragility of red blood cells, and fragmentation.

Shiga toxins(Stxs), which are produced by enterohemorrhagic Escherichia coli and Shigella dysenteriae serotype I, induce proinflammatory cytokines including tumor necrosis factor-alpha, interleukin(IL)-1 beta, IL-6, interferon-gamma, and chemokines such as IL-8 in intestinal epithelial cells, vascular endothelial cells, and monocytes/macrophages in vitro and in kidneys and spleen in vivo. Cytokines induced by Stxs and lipopolysaccharide enhance the toxicity of Stxs via up-regulation of the expression of Gb3, a Stx receptor, and infiltration of neutrophils. Stxs bind to neutrophils and transmigrate across intestinal mucosa and are transported to the target organs through bloodstreams. Stxs induce cytokines in vascular endothelial cells and peripheral blood monocytes and may injure organ tissues, finally resulting in hemolytic uremic syndrome and encephalopathia.

Shiga toxin(Stx) produced by enterohemorrhagic E. coli is the virulence factor that causes not only enterohemorrhagic colitis but also fatal complications, such as hemolytic uremic syndrome. To prevent the complications, new strategies targeted to Stx have been tested, mostly using mimics of the trisaccharide structure of neutral lipid Gb3, the receptor for Stx. One group of such new drugs are agents that can bind to Stx in gastrointestinal tract and prevent its spread to extraintestinal sites, and the other group are water-soluble neutralizers that suppress Stx cytotoxicity in the circulation. Although most of these are now under the laboratory investigations, one of these drugs may hopefully be utilized clinically to prevent hemolytic uremic syndrome in future.

Verocytotoxin producing Escherichia coli(VTEC) causes gastrointestinal infections worldwide. In at most 8% of the children in Japan who are infected with VTEC, hemolytic-uremic syndrome(HUS) develops soon after the onset of diarrhea. Treatment with antibiotics does not ameliorate VTEC infections, and in some studies from western countries, it has been associated with worse clinical outcomes. It was recently indicated in Japan that early administration of fosfomycin to the patients with VTEC infection can decrease the risk of HUS. Moreover, early administration of Synsorb-Pk with high affinity to verocytotoxin to the patients with gastrointestinal VTEC infection was demonstrated to decrease the incidence of very mild and mild HUS, but it did not decrease the risk of moderate and severe HUS. In the developing stage of HUS, intravenous administration of fluid and electrolytes should be determined cautiously to prevent hyponatremia and systemic congestion.

Hemolytic uremic syndrome(HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute nephropathy. Clinical features and outcome of children with HUS initiated by infections with Shiga toxin(Stx)-producing strains of Escherichia coli(E. coli) infection are different from those of patients with the other forms of HUS or thrombotic thrombocytopenic purpura(TTP). Childhood Stx-E. coli-associated HUS usually recovers spontaneously and dose not require specific treatments including plasma therapy. In contrast, a general consensus has been achieved that plasma exchange or infusion should always be tried in adult HUS/TTP to minimize the risk of death or long-term sequelae. In this paper, we briefly reviewed therapy for patients with Stx-E. coli-associated HUS.

Anti-Shiga-Like Toxin II(SLT-II) Humanized Monoclonal Antibody(TMA-15) was constructed from Mouse Monoclonal Antibody(MuVTm1.1) recognizing the same antigen using recombinant and CDR grafting technology. TMA-15 had almost the same affinity to SLT-II as MuVTm1.1 and showed the good protective activity of mice challenged either with SLT-II or with SLT-II secreting Shiga-like Toxin producing E. coli(STEC). TMA-15 showed no acute toxicity to monkeys and no cross-reactivity to human tissues in pre-clinical safety studies. From the preliminary results of Phase 1 clinical trial using healthy adult volunteers, doses up to planned maximum dose were well tolerated and TMA-15 showed long half life in blood almost comparable to gamma globulin preparations. Therefore, TMA-15 is expected to show clinical efficacy in coming clinical trial using pediatric STEC patients.

Vero toxins-mediated vascular endothelial cell damage is thought to play a central and important role in the pathogenesis of HUS associated with EHEC infection. Thrombomodulin (TM) is an endothelial membrane protein inhibiting procoagulant activities of thrombin. Elevation of soluble TM in the blood is regarded a possible marker for endothelial cell damage. To test whether serum TM acts as an indicator for HUS, we evaluated serum TM in 21 children with HUS, 31 children with hemorrhagic colitis(HC), and 25 healthy age-matched controls. TM levels in acute HUS patients (6.89 +/- 1.91 ng/ml) were significantly higher when compared with in acute HC patients(3.15 +/- 0.37 ng/ml) and in the controls (2.77 +/- 0.42 ng/ml) (p < 0.001, respectively). This result indicated that serum TM may be an useful marker for the development of HUS.

The hemolytic uremic syndrome (HUS) is the end result of a variety of etiologic agents that can induce endothelial cell injury and thrombotic microangiopathy (TMA) mostly within the kidney. The typical, post-diarrheal verocytotoxin associated HUS (D + HUS) is the major cause of acute renal failure in children worldwide. In the course of HUS treatment, fluid overload is usually the result of overhydration in the context of oliguria or anuria which cause edema, hypertension, worsening of neurologic signs and cardiac failure. Appropriate and timely use of dialysis has dramatically reduced complications of renal failure and extra-renal complications are now the main causes of mortality and morbidity in D + HUS. The reasons for treatment by infusion of fresh frozen plasma and/or plasmapheresis for D + HUS are theoretical and their therapeutic effects are inconclusive. We believe that plasma administration for regular D + HUS has no value and is potentially harmful. Until new strategies become available in clinical practice, the general consensus for the moment is that careful supportive management with patience is still the most appropriate form of D + HUS therapy.

In 1996, there were several large outbreaks of enterohemorrhagic Escherichia coli(EHEC) O157:H7 in Japan. More than 9,000 people were infected with the bacteria and 11 of these infections were fatal. Verotoxins(VTs) produced by EHEC are responsible for the death due to mainly hemolytic uremic syndrome(HUS). The structure and mode of action of VTs are reviewed. The differences between VT1 and VT2 are also reviewed from the viewpoint of secretion, toxicity, and immunogenicity. The effect of antibiotics usage on the occurrence of HUS is briefly reported.

Hemolytic uremic syndrome (HUS) is caused by endothelial cell damages. Ninety percent of children with HUS have verotoxin-producing E.coli infection. Verotoxin binds to glycolipid receptors globotriaosyl ceramide (Gb3), and the difference of Gb3 expression level in each organ would lead to specific organ involvement. The receptors are expressed in human renal cortex and medulla. The expression level of Gb3 in normal human brain has not been characterized completely. However involvement of central nervous system is a severe complication of HUS. Spreading of microvascular thrombosis caused by combined effects of lipopolysaccharide, cytokine, enhanced shear stress, and verotoxin would play a major role in the development of central nervous dysfunction.

Renal histopathology of verotoxin producing escherichia coli(VTEC) related hemolytic uremic syndrome (HUS) was described. Endothelial damage is expressed in renal small arteries and glomeruli as luminal narrowing due to endothelial swelling and subendothelial edema. Extracellular matrix shows reticularization and/or mesangiolysis in glomeruli. Although HUS and thrombotic thromocytopenic purpura (TTP) is recently considered as a single entity, the tissue expression is different. In the latter endothelial proliferation is profound resulting in arteriolar deteriolation such as glomeruloid structure.

The treatment of infection with enterohemorrhagic Escherichia coli(EHEC) aims for early prediction and prevention of severe complications such as hemolytic-uremic syndrome, encephalopathy and/or thrombotic thrombocytopenic purpura. Factors related to the complications are divided into three categories; risk factors or predisposition, predictors, and indicators of severity and outcome. Risk factors for complications include two extreme ages, infection with verotoxin 2 producing E. coli, positive stool culture for EHEC, use of antimotility drug, use of trimethoprim-sulfamethoxazole. Predictors for complications include severe abdominal pain and bloody diarrhea development of high fever, change of consciousness, urinal protein and/or occult blood, abrupt increase of white blood cell count, urinal NAG, alpha 1 microglobulin, beta 2 microglobulin, low osmolar urine, high thrombomodulin level, marked thickening of intestinal wall, increased brightness of kidney in ultrasound sonography. No preventive treatment for these complications is proven except SYNSORB-pk which is expected to effectively aborb verotoxin in the intestine.

Hemolytic uremic syndrome (HUS) in childhood is recognized as the most frequent cause of acute renal failure and is greatly associated with verotoxin-producing E. coli (VTEC) infection. Most of the prodromal feature in HUS associated with VTEC infection is hemorrhagic colitis (HC). HC progresses to HUS in several days. So it is important to detect whether the patient with bloody diarrhea is associated with VTEC infection or not. From 1992 to 1996 we analyzed clinical findings of 80 HUS and 29 HC patients. High level of beta 2-microglobulin (BMG) and N-acetyl-D-beta-glucosaminidase (NAG) in the urine were observed in the early stage of the disease. We went on to examine verotoxin (VT2)-binding in mouse (ICR) renal sections by enzyme immunoassay. Specific binding of VT2 to tubules was seen in mouse kidney, and intravenous injection of VT2 to mice caused acute tubular necrosis in 15 h whereas glomeruli were intact. These data suggest that the primary target cell of VT2 was tubules in the kidney of the HUS patients with VTEC infection.

In 1997, Konowalchuk and coworkers reported a toxin produced by Escherichia coli that was cytotoxic to Vero cells. This toxin(Vero toxin, VT) was subsequently found to be an important virulence factor of E. coli associated with an outbreak of hemorrhagic colitis due to E. coli O157:H7 which occurred in the state of Oregon and Michigan in US. E. coli O157:H7 was then found to produce VT, which was cross-reactive with Shiga toxin produced by Shigella dysenteriae. VT(Shiga-like toxin Shiga toxin, Shiga toxin family) is the toxin which contributes to the symptoms of hemorrhagic colitis and hemolytic uremic syndrome. This article presents a historical perspective on EHEC and also reviews the structure and function of VT as well as epidemiological aspects of outbreak and sporadic cases of EHEC in American continent and in our county.

Hemolytic anemia observed in patients with SLE include autoimmune hemolytic anemia (AIHA) and thrombotic microangiopathic hemolytic anemia (TMHA). AIHA is caused by anti-erythrocyte antibody, which can be detected by direct Coombs' test. Recently, anti-phospholipid antibody draw attention as a cause of AIHA in SLE. TMHA include thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Patients with TTP show CNS symptoms and renal damage, while those with HUS develop renal insufficiency, but show minimal CNS symptoms. Clinical findings of TMHA are fever, hemolytic anemia, thrombocytopenia, CNS symptoms, and renal insufficiency, which are quite same as the findings of SLE itself. TMHA should be considered for differential diagnosis in acute exacerbation of SLE.

Hemolytic uremic syndrome (HUS) was first reported by Gasser in 1966 as a syndrome characterized by triadic symptomatology of microangiopathic hemolytic anemia (MAHA), thrombocytopenia and acute renal failure, affecting young children more than adults. Its causes include hemorrhagic colitis, cancer, chemotherapy, pregnancy, transplantation and so on. Considering a variety of causes for HUS, it is obvious that adults may be also affected by this syndrome. Since a pathogenetic relationship between HUS and verotoxin producing Escherichia coli (VTEC) infection was pointed out in 1983, there have been substantial progresses in understanding of the VTEC infection, a leading cause for HUS among the causes described above, is now emerging as one of national crisis-management matters in the health and welfare administration in our country. Therefore, in this review, we discuss a current understanding of the pathophysiology and reevaluation of recommended therapeutic modalities for HUS mainly in the case of VTEC infection induced HUS.

Since the pathogenesis of hemolytic uremic syndrome (HUS) has not been fully understood, it is difficult to establish a therapy protocol for HUS. Until now, there have been no effective treatments of HUS, evaluated by prospective controlled studies. Progress in the management of acute renal failure has improved the prognosis of HUS. Recently, the effectiveness of plasma infusion has been considered to be doubtful. Antiplatelet therapy and vitamin E administration may be recommended to treat typical HUS without severe complications. In addition to these treatments, plasma exchange using fresh plasma or fresh frozen plasma is recommended to treat HUS in the adult, atypical HUS and typical HUS with severe complications in childhood, considering the poor prognosis in these conditions.

Hemolytic uremic syndrome (HUS) occurs most commonly in sporadic or epidemic form in otherwise healthy infants or children. The most common agent is Escherichia coli-producing verotoxin (VTEC) in classical HUS. In this paper, the cause or pathogenesis of HUS associated with verotoxin, Shigellosis, streptococcus pneumoniae was described referring to current literature. In addition, this paper also refers to the relationship of HUS with bone marrow transplantation, cancer and renal transplantation. The conclusions were that two syndromes of HUS and TTP may occupy the opposite ends of a continuum with overlap in some cases; the gestalt of a typical case of HUS is quite different from that of a typical case of TTP. Precise definition must await the development of further information concerning the cause and mechanism that produce the subsets or variant forms of HUS.

HUS and TTP have the same fundamental pathologic lesion, thrombotic microangiopathy, induced by many possible causes, all of which initially induce endothelial cell damage. This damage triggers a cascade of biochemical events that ultimately leads to the formation of thrombi in the microcirculation. HUS and TTP share hematologic and vascular abnormalities and are sometimes similar in their clinical manifestations, some authors believe they should be considered a single condition and be termed HUS/TTP. On the contrary, others consider that HUS could be defined as a disorder marked by microvascular lesions limited to the kidney, whereas TTP has generalized lesions. The causative factor(s) resulting in either HUS or TTP have not been completely elucidated, and further studies are required for precise differentiation between HUS and TTP.