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Hemolytic uremic syndrome (HUS) and acute encephalopathy caused by enterohemorrhagic Escherichia coli infection occur commonly in children, whereas adult-onset disease is rare. Here we report the case of a 24-year-old woman who developed acute encephalopathy and recovered without sequelae. She initially developed abdominal pain and diarrhea. On day 6, O-157 Shiga toxin was detected in her stool and she developed HUS. On day 11, acute encephalopathy developed and she required artificial ventilation. She was treated with steroid pulse therapy and plasma exchange (PE) and then discharged on day 53 without any sequelae. Globotriaosylceramide, a Shiga toxin receptor, is more frequently present on the cellular membranes of women than on those of men. Therefore, it is conceivable that adult women are at a higher risk of developing acute encephalopathy than men. Steroid pulse therapy and PE may effectively treat acute encephalopathy by reducing inflammatory cytokine levels in the blood; therefore, these treatments should be proactively considered.

We report a case of a woman in her twenties with enterohemorrhagic Escherichia coli O111-induced hemolytic-uremic syndrome who developed acute encephalopathy on day 5 of admission. She recovered after treatment with steroid pulse therapy, plasmapheresis, and recombinant thrombomodulin, without any adverse sequelae. We report this interesting case and provide a summary of the recent outbreak of enterohemorrhagic Escherichia coli O111.

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.

We report serial cerebral computed tomography (CT) and magnetic resonance imaging (MRI) in a case of hemolytic uremic syndrome (HUS) with the complication of the central nervous system due to Escherichia coli O157:H7. Although initial brain CT was normal, follow-up CT and MRI revealed lesions in the white matter and bilateral basal ganglia, representing brain edema and infarcts, respectively. Especially, lesions in the bilateral basal ganglia were very unique. Serial CT and MRI findings are useful to understand the mechanism of the complications of the central nervous system associated with HUS.

To investigate the role of thrombomodulin (TM) and tumor necrosis factor-alpha (TNF-alpha) in hemolytic uremic syndrome (HUS), serum and urinary levels of TM and TNF-alpha were determined in patients with hemorrhagic enterocolitis (HC) of enterohemorrhagic E. coli O157:H7 infection. These patients were divided into two groups: an HUS group consisting of patients with HUS; an HC group consisting of patients without HUS. In the 10 days after the onset of diarrhea, the serum TM and TNF-alpha levels in the HUS group were significantly elevated compared with those in the control group but decreased after 11 days. The serum TM and TNF-alpha levels in the HC group were not elevated compared with those in the control group except for one case of TNF-alpha. It is suggested that the serum TM elevation showed the severity of endothelial cell damage. Urinary TM and TNF-alpha levels in the HUS group were significantly elevated in the first 10 days. The urinary TNF-alpha levels rapidly decreased after 11 days, while the urinary TM levels were persistently high. From these results, the sustained elevation of the urinary TM levels suggested the persistent presence of renal endothelial cell damage, and the decrement of urinary TNF-alpha levels suggested that TNF-alpha acted as a trigger of the renal endothelial cell damage in the first 10 days.

We encountered a patient with enterohemorrhagic Escherichia coli (EHEC) O157:H7 infection and secondary hemolytic uremic syndrome (HUS). The patient was a 79-year-old woman with hypertension, constipation, and asymptomatic cholelithiasis. She complained of nausea and abdominal pain, and had bloody stool EHEC O157 was detected by fecal culture. The bloody stool resolved after treatment with antibiotics, but the patient was hospitalized on July 23, 1996 because of abdominal distention. HUS was diagnosed because of proteinuria, hematuria, thrombocytopenia, hemolytic anemia, fragmentation of red blood cells, and increased serum LDH. Treatment was focused on plasma exchange, administration of antibiotics, large doses of gamma-globulin, haptoglobin replacement, and anticoagulation. Within about 2 weeks, the level of hemoglobin, the number of platelets, and the serum LDH had normalized, and the patient recovered from HUS. The decreased intestinal movement continued. On August 23, acute cholecystitis was diagnosed, and percutaneous transhepatic gall bladder drainage was done. Another exacerbation was noted on October 13, and cholecystectomy was done on November 12, when the patient's status had improved after instillation of antibiotics. Macroscopically, the gallbladder wall was thickened. Histopathological examination showed diffuse infiltration of lymphocytes into the mucosa, chronic cholecystitis was diagnosed. Because the postoperative course was satisfactory, the patient was discharged from the hospital on December 15. Acute exacerbation of chronic cholecystitis might have been caused by decreased cholic excretion after the marked decrease in intestinal movement due to O157 infection and secondary HUS. Because elderly people frequently have anamnesis of the digestive system, considerably attention should be paid to the management of anamnesis, as well as O157 infection and secondary HUS.

One hundred and thirteen patients who underwent autologous or allogeneic bone marrow transplantation (BMT) were investigated for the subsequent development of hemolytic uremic syndrome (HUS). HUS developed in seven patients (four males and three females, five acute lymphocytic leukemia (ALL), one acute myelogenous leukemia, one non-Hodgkin's lymphoma) between 36-196 days after BMT. Four patients were recipients of autologous BMT and three were those of allogeneic BMT. Six patients were preconditioned with the regimens including fractionated total body irradiation (TBI). ALL and preconditioning regimen with TBI were suspected to be the risk factors for the development of HUS. Cyclosporin A (CSP) administration was discontinued in three patients who had been given CSP for graft-versus-host disease prophylaxis. Predonisolone was given to the three patients and plasma exchange was performed in one patient. Both hemolytic anemia and thrombocytopenia were resolved in virtually all patients, while creatinine elevation has persisted along with hypertension in one patient.

An outbreak of Escherichia coli O157:H7 infection occurred in July 1996 in Sakai City. About 5000 children were infected, 122 of whom developed hemolytic uremic syndrome (HUS). In this outbreak, almost all patients were administrated some type of antibiotics. The effects of antibiotics on E. coli O157 associated hemorrhagic colitis (HC) have been controversial. In this study, we focused on the effects of antibiotics on development of HUS in the HUS in the Sakai outbreak. We retrospectively determined the antibiotics administrated within three days after the onset of HC, clinical courses, and laboratory data of 301 patients who were hospitalized and identified as Escherichia coli O157 infection by stool culture, from results of questionnaires sent by the Osaka Prefecture Medical Association to hospitals in Osaka Prefecture. The antibiotics used could be identified for 216 patients. The incidence of HUS among these patients was 11.6%. They were divided into 19 groups based on the type of antibiotics administrated. The incidence of HUS in the new quinolone (3.7%) group was low, but was high in the intravenous cephalosporin (18.2%) group. The differences in the incidence of HUS among the 19 antibiotic groups was significant (p < 0.05) on analysis of covariance which eliminated the contributions of variables including age, sex and laboratory data. These findings indicate that the suitable antibiotics can prevent the development of E. coli O157-associated HUS.

Predictive factors for the development of hemolytic uremic syndrome (HUS) were evaluated in 88 inpatients who suffered from enterohemorrhagic E. coli infections in the outbreak in Sakai, 1996. All in- and outpatients received oral or intravenous fosfomycin within acute phase of hemorrhagic colitis, and HUS complicated 1.4% of them. Persistence of bloody stools and diarrhea were longer in HUS patients than in non-HUS patients, but persistence of abdominal pain was not different in either group. Leukocytosis with leukocyte counts over 15,000/microliters and/or elevated CRP level over 2.0 mg/dl at admission, and fever and/or vomiting in the course of hemorrhagic colitis were more frequent in HUS patients than in non-HUS patients. Early intensive treatments including gammaglobulin, urinastatin, aspirin, and dipyridamole were employed in 34 high risk patients for prevention of HUS. These patients were estimated to be at risk of developing HUS because of incomplete HUS, nephropathy, elevated LDH level, thrombocytopenia, or age younger than two years old. These treatments were clinically effective.

An outbreak of E. coli O157 infection occurred in July 1996 in Sakai City, apparently associated with school lunches. About 5000 children were infected and more than 600 were hospitalized. In our hospital, we treated 13 patients of hemorrhagic colitis(HC) including 4 hemolytic uremic syndrome(HUS) patients then. First, a typical patient developed HUS was presented. A case was 8 years' old girl. She was developed HUS on the 6th day after the onset of HC. We treated her with plasma exchange. She was recovered on the 14th day from HUS without any sequela. In this report, I discussed about pathophysiology of HUS according to her clinical course. Secondly, I reported that analysis of the clinical courses and laboratory data of 818 patients hospitalized from the questionnaires sent by Osaka Prefecture Medical Association. One One hundred twenty two patients developed HUS. Patients with HUS produced bloody stools longer than the others, on the average(6.7 vs. 3.4 day). Mean serum C-reactive protein levels was 4.8mg/dl in patients with HUS but 1.5mg/dl in the other patients; the WBC count also was higher in HUS(17,780 vs. 9,700mm3). The mean serum Na level was lower in patients of HUS. Almost all patients were given antibiotics. The incidence of HUS among patients treated with new quinolones was lower than that of all patients. On the contrary, the higher incidence among patients with cephalosporins was observed.

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.