Incidence Of Hemolytic Uremic Syndrome Research Articles

Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS), a common cause of acute renal failure (ARF) in children, consists of triad of microangiopathic haemolytic anemia (MAHA), thrombocytopenia, and ARF. The aim of the present article is to have a recent overview of HUS including its incidence, etiopathogenesis, clinical profile and management. It consists of two types a) Diarrhoea associated i.e. classical also called D+ HUS b) Non-diarrhoea associated i.e. atypical also called D- HUS. D+ HUS is caused mostly by Escherichia coli or occasionally by Shigella dysenteriae. The causes of HUS are infections, genetic defects, systemic diseases and drugs. The atypical form commonly presents with recurrent or chronic persistent attack. Thrombotic microangiopathy (TMA), the pathologic hallmark, includes HUS, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) which is characterized by endothelial cell damage and microvascular injury. In the vast majority of aHUS susceptibility factors are familial and not acquired. In D+ HUS, following an attack of diarrhoea or dysentery the child abruptly develops pallor, irritability, swelling of body, oligoanuria, hematuria, and hypertension. Central nervous system disturbances like seizure, obtundation and encephalopathy may occur but less common than aHUS or TTP. Diagnosis of HUS is established by presence of MAHA in the peripherl blood smear i.e. schistocytes, burr cells, helmet cells etc. Thrombocytopenia is nearly always seen. ARF is reflected in elevated blood urea and creatinine level. Coagulation studies like prothrombin time (PT), activated partial thromboplastin time (APTT), will be normal unlike disseminated coagulopathy (DIC). D-dimer level will be raised in HUS similar to DIC. Interestingly, direct Coomb’s test will be positive in Streptococcus pneumonia induced D- HUS. With excellent supportive care and often dialysis D+ HUS will show remarkable recovery whereas in addition plasmapheresis or plasma infusion outcome is poor in most of the D-HUS cases. Though incidence of gastroenteritis is very high in our country, only few patients may develop HUS, the reason of which remains unclear. The incidence of HUS as a cause for ARF in India may be reviewed further. Indiscriminate use of antimicrobials is to be avoided as far as possible to prevent HUS related mortality. Facilities for dialysis may be enhanced in most of the health care facilities in our country as a life saving measure to reduce HUS related mortality and morbidity.

Escherichia coli O157:H7 strains harbor at least three distinct sequence types of Shiga toxin 2a-converting phages

BackgroundShiga toxin-producing Escherichia coli O157:H7 is a foodborne pathogen that causes severe human diseases including hemolytic uremic syndrome (HUS). The virulence factor that mediates HUS, Shiga toxin (Stx), is encoded within the genome of a lambdoid prophage. Although draft sequences are publicly available for a large number of E. coli O157:H7 strains, the high sequence similarity of stx-converting bacteriophages with other lambdoid prophages poses challenges to accurately assess the organization and plasticity among stx-converting phages due to assembly difficulties.MethodsTo further explore genome plasticity of stx-converting prophages, we enriched phage DNA from 45 ciprofloxacin-induced cultures for subsequent 454 pyrosequencing to facilitate assembly of the complete phage genomes. In total, 22 stx2a-converting phage genomes were closed.ResultsComparison of the genomes distinguished nine distinct phage sequence types (PSTs) delineated by variation in obtained sequences, such as single nucleotide polymorphisms (SNPs) and insertion sequence element prevalence and location. These nine PSTs formed three distinct clusters, designated as PST1, PST2 and PST3. The PST2 cluster, identified in two clade 8 strains, was related to stx2a-converting phages previously identified in non-O157 Shiga-toxin producing E. coli (STEC) strains associated with a high incidence of HUS. The PST1 cluster contained phages related to those from E. coli O157:H7 strain Sakai (lineage I, clade 1), and PST3 contained a single phage that was distinct from the rest but most related to the phage from E. coli O157:H7 strain EC4115 (lineage I/II, clade 8). Five strains carried identical stx2a-converting phages (PST1-1) integrated at the same chromosomal locus, but these strains produced different levels of Stx2.ConclusionThe stx2a-converting phages of E. coli O157:H7 can be categorized into at least three phage types. Diversification within a phage type is mainly driven by IS629 and by a small number of SNPs. Polymorphisms between phage genomes may help explain differences in Stx2a production between strains, however our data indicates that genes encoded external to the phage affect toxin production as well.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1934-1) contains supplementary material, which is available to authorized users.

Clade 8 and Clade 6 Strains of Escherichia coli O157:H7 from Cattle in Argentina have Hypervirulent-Like Phenotypes.

The hemolytic uremic syndrome (HUS) whose main causative agent is enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a disease that mainly affects children under 5 years of age. Argentina is the country with the highest incidence of HUS in the world. Cattle are a major reservoir and source of infection with E. coli O157:H7. To date, the epidemiological factors that contribute to its prevalence are poorly understood. Single nucleotide polymorphism (SNP) typing has helped to define nine E. coli O157:H7 clades and the clade 8 strains were associated with most of the cases of severe disease. In this study, eight randomly selected isolates of EHEC O157:H7 from cattle in Argentina were studied as well as two human isolates. Four of them were classified as clade 8 through the screening for 23 SNPs; the two human isolates grouped in this clade as well, while two strains were closely related to strains representing clade 6. To assess the pathogenicity of these strains, we assayed correlates of virulence. Shiga toxin production was determined by an ELISA kit. Four strains were high producers and one of these strains that belonged to a novel genotype showed high verocytotoxic activity in cultured cells. Also, these clade 8 and 6 strains showed high RBC lysis and adherence to epithelial cells. One of the clade 6 strains showed stronger inhibition of normal water absorption than E. coli O157:H7 EDL933 in human colonic explants. In addition, two of the strains showing high levels of Stx2 production and RBC lysis activity were associated with lethality and uremia in a mouse model. Consequently, circulation of such strains in cattle may partially contribute to the high incidence of HUS in Argentina.

Foodborne transmission of sorbitol-fermenting Escherichia coli O157:[H7] via ground beef: an outbreak in northern France, 2011

Sorbitol-fermenting Escherichia coli O157:[H7] is a particularly virulent clone of E. coli O157:H7 associated with a higher incidence of haemolytic uraemic syndrome and a higher case fatality rate. Many fundamental aspects of its epidemiology remain to be elucidated, including its reservoir and transmission routes and vehicles. We describe an outbreak of sorbitol-fermenting E. coli O157:[H7] that occurred in France in 2011. Eighteen cases of paediatric haemolytic uraemic syndrome with symptom onset between 6 June and 15 July 2011 were identified among children aged 6 months to 10 years residing in northern France. A strain of sorbitol-fermenting E. coli O157:[H7] stx2a eae was isolated from ten cases. Epidemiological, microbiological and trace-back investigations identified multiply-contaminated frozen ground beef products bought in a supermarket chain as the outbreak vehicle. Strains with three distinct pulsotypes that were isolated from patients, ground beef preparations recovered from patients' freezers and from stored production samples taken at the production plant were indistinguishable upon molecular comparison. This investigation documents microbiologically confirmed foodborne transmission of sorbitol-fermenting of E. coli O157 via beef and could additionally provide evidence of a reservoir in cattle for this pathogen.

Oral immunization with Lactococcus lactis-expressing EspB induces protective immune responses against Escherichia coli O157:H7 in a murine model of colonization

Enterohemorrhagic Escherichia coli (EHEC) have been responsible for several outbreaks of hemolytic–uremic syndrome (HUS) worldwide. HUS is the most common cause of acute renal failure in children and results in fatalities as high as 50% in the elderly. Currently, neither a specific treatment nor a vaccine is available for EHEC. Lactococcus lactis is a generally regarded as safe “GRAS” bacterium that offers a valuable platform for oral vaccine delivery. Toward the development of an oral vaccine against EHEC, we have previously constructed a recombinant L. lactis strain expressing the EHEC antigen, EspB in the cytoplasmic compartment. However, oral immunization of mice with this strain induced weak priming of the immune system. This outcome was attributed to the rather low levels of EspB expressed by this recombinant strain. Therefore, in the present study we optimized the expression of EspB in L. lactis by secreting the antigen either under constitutive or nisin-inducible control. Indeed, oral immunization of mice with the EspB-secreting strains successfully induced specific mucosal and systemic antibody responses. These responses were associated with mixed Th1/Th2 cell responses in Peyer's Patches and mesenteric lymph nodes. Moreover, immunized mice exhibited significant protection against E. coli O157:H7 colonization, as indicated by the reduced amount and/or duration of the bacterial fecal shedding. Our results demonstrate the protective potential of EspB as an oral vaccine against EHEC infection. Additionally, the study demonstrates the efficient delivery of recombinant EspB by the “GRAS” bacterium, L. lactis. The safety profile of L. lactis as a vaccine vehicle can particularly be beneficial to children and elderly as high-risk groups for HUS incidence.

Incidence and etiology of hemolytic-uremic syndrome in children in Norway, 1999-2008--a retrospective study of hospital records to assess the sensitivity of surveillance.

BackgroundPublic awareness of hemolytic-uremic syndrome (HUS), especially related to Shiga toxin-producing Escherichia coli (STEC), has increased in Europe in recent years; accentuated in Norway by a national outbreak in 2006 and in a European context especially by the 2011 outbreak originating in Germany. As STEC surveillance is difficult due to diagnostic challenges in detecting non-O157 infections, surveillance of HUS can be used to indicate the burden of STEC infection. Until 2006, notification of HUS to the Norwegian Communicable Disease Surveillance System (MSIS) was based on microbiologically confirmed infection with enterohemorrhagic Escherichia coli (EHEC), humanpathogenic STEC. In 2006, diarrhea-associated HUS (D+HUS) was made notifiable based on clinical criteria alone. The incidence and etiology of HUS in children in Norway has not previously been described.MethodsIn order to assess the sensitivity of STEC and D+HUS surveillance and describe the incidence and etiology of HUS in children in Norway, we conducted a nationwide retrospective study collecting data from medical records from pediatric departments for the period 1999–2008 and compared them with data from MSIS. Descriptive statistics are presented as proportions, median, average and mean values with ranges and as incidence rates, calculated using population numbers provided by official registries.ResultsForty-seven HUS cases were identified, corresponding to an average annual incidence rate of 0.5 cases per 100,000 children. Diarrhea-associated HUS was identified in 38 (81%) cases, of which the median age was 29 months, 79% were <5 years of age and 68% were girls. From 1999 to 2006, thirteen more diarrhea-associated HUS cases were identified than had been notified to MSIS. From the change in notification criteria to 2008, those identified corresponded to those notified. STEC infection was verified in 23 (49%) of the HUS cases, in which O157 was the most frequently isolated sporadic serogroup.ConclusionsOur results show that the incidence of HUS in children in Norway is low and suggest that D+HUS cases may be underreported when notification requires microbiological confirmation. This may also indicate underreporting of STEC infections.

Genotypic characterization of Escherichia coli O157:H7 strains that cause diarrhea and hemolytic uremic syndrome in Neuquén, Argentina

Shiga toxin-producing Escherichia coli (STEC) are important food-borne pathogens associated with cases of diarrhea, hemorrhagic colitis and hemolytic uremic syndrome (HUS). E. coli O157:H7 is the dominant serotype in Argentina and also in Neuquén Province, in which HUS incidence is above the national average, with a maximum of 28.6 cases per 100,000 children less than 5 years old reported in 1998. The aim of this study was to characterize a collection of 70 STEC O157 strains isolated from patients with diarrhea and HUS treated in the province of Neuquén, Argentina, between 1998 and 2011. All strains harbored eae, ehxA, rfbO157, and fliCH7 genes, and stx2a/stx2c (78.7%) was the predominant genotype. A total of 64 (91.4%) STEC O157 strains belonged to the hypervirulent clade 8 tested using both 4 and 32 SNP typing schemes. The strains showed the highest values reported in the literature for 6 of the 7 virulence determinants described in the TW14359 O157 strain associated with the raw spinach outbreak in the U.S. in 2006. Clade 8 strains were strongly associated with two of them: ECSP_3286, factor encoding an outer membrane protein that facilitates the transport of the heme complex (P=0.001), and in particular extracellular factor ECSP_2870/2872, coding proteins related to adaptation to plant hosts (P=0.000004). The q933 allele, which has been related to high toxin production, was present in 97.1% of the strains studied for the anti-terminator Q gene. In summary, this study describes, for the first time in Argentina, the almost exclusive circulation of strains belonging to the hypervirulent clade 8, and also the presence of putative virulence factors in higher frequencies than those reported worldwide. These data may help to understand the causes of the particular epidemiological situation related to HUS in Neuquén Province.

Hemolytic uremic syndrome in Argentina: An attack scenario

The recent Escherichia coli epidemic in Germany gave a lesson at an international level. There is no time to solve food security problems when an epidemic is on the way. The epidemic in Germany exposed the fissures in the control systems of the Federal Risk Evaluation Institute of this country, as well as showing the incompetency of health authorities, who had great difficulty in resolving the situation. To summarize, the possibility of prevention was confused with the utopian idea of non-occurrence. It was not less important the public’s recognition and the “awakening” of health ministers in the European Union as regards the proven fact that pathogenic and even lethal microorganisms may be present in the food we eat. Argentina has the highest incidence of hemolytic uremic syndrome in the world, and the next epidemic is likely not to occur in Germany, but in any other country, such as Argentina. In order to avoid complicity, we do not wish to remain silent about the situation in Argentina. Therefore, this is the writer’s motive for writing this article, which describes the scientific advances and the ethical pitfalls related to a disease transmitted by food, particularly hemolytic uremic syndrome, in Argentina.

Index of Suspicion

A 5-year-old previously healthy boy presents to the emergency department (ED) with a 2-week history of intermittent left groin pain, usually occurring later in the day. Pain is not related to eating, movement, urination, or stooling. There is no report of trauma or precipitating event. He screams and refuses to stand up during pain episodes, which occur suddenly and last approximately 1 to 2 hours at a time. He otherwise has normal gait and activity when pain free. He does not wake up at night in pain. No recent illnesses or fevers are reported. Review of systems and his examination findings are unremarkable. Two days prior, he was evaluated in the ED for the same issue and had normal urinalysis, urine culture, and scrotal ultrasonogram results. The consulting urologist did not suspect a urologic process. He was discharged home with pain medication. Today, he returns to the ED because of the intense pain. The patient is admitted for further evaluation and pain management. Complete blood cell (CBC) count, C-reactive protein level, urinalysis results, and plain radiographs of the hips are unremarkable. Computed tomography of the abdomen and pelvis reveals a trace amount of nonspecific free fluid in the pelvis. His pain appears to be alleviated with ibuprofen and bed rest. The following day, he has another episode of intense groin pain after returning from the play room. Physical examination at this time demonstrates only point tenderness on palpation over his symphysis pubis area. No swelling, erythema, or increased warmth was noted in that area. An additional imaging study reveals the diagnosis. A 15-year-old girl presents to the clinic with an itchy rash, fever, headache, nausea, and dizziness. A few days earlier she was evaluated for rash on her back and low-grade fevers. She was prescribed amoxicillin clavulanate for suspected streptococcal …

Syndrome hémolytique et urémique secondaire à Streptococcus pneumoniae de sérotype 3

Hemolytic uremic syndrome (HUS) is the primary cause of acute renal failure in children younger than 3 years of age. It usually occurs after a diarrheal illness due to Shiga-toxin-producing Escherichia coli. Streptococcus pneumoniae (SP)-induced HUS remains rare, involving 5% of all cases of HUS in children, but its frequency has increased over the last decade. The incidence of HUS following invasive pneumococcal infections is estimated at 0.4 to 0.6%. We report here the case of a 3.5-year-old child who presented SP serotype-3-associated HUS. The diagnosis was suspected by the patient's multiple organ failure. The pathogenesis involves the activation of the Thomsen-Friedenreich antigen. To prevent transfusion-associated hemolysis, it is recommended that fresh-frozen plasma or unwashed blood products should be avoided when possible. Our patient was transfused with 4 units of unwashed red blood cell and 2 units of fresh-frozen plasma. No special complication was noted. The risk of immediate complications requires close clinical and biological monitoring, and the possibility of starting dialysis immediately. Twenty-five to 35% of SP-HUS patients exhibit long-term renal aftereffects. The acute mortality rate depends on the site of infection. The increased frequency of SP-HUS may be related to the new ecology of serotypes created by widespread Prevenar7(®) vaccination.

Association Between Azithromycin Therapy and Duration of Bacterial Shedding Among Patients With Shiga Toxin–Producing Enteroaggregative Escherichia coli O104:H4

An outbreak of Shiga toxin-producing enteroaggregative Escherichia coli (STEC O104:H4) infection with a high incidence of hemolytic uremic syndrome (HUS) occurred in Germany in May 2011. Antibiotic treatment of STEC infection is discouraged because it might increase the risk of HUS development. However, antibiotic therapy is widely used to treat enteroaggregative E coli infection. In the German outbreak, a substantial number of patients received prophylactic azithromycin treatment as part of a therapeutic regimen with the C5 antibody eculizumab. To analyze the duration of bacterial shedding in patients with STEC infection who did and did not receive oral azithromycin therapy. At a single center in Lübeck, Germany, 65 patients with STEC infection, including patients with HUS as well as STEC-infected outpatients without manifestation of HUS, were investigated between May 15 and July 26, 2011, and were monitored for a mean of 39.3 days after onset of clinical symptoms. Carriage of STEC after azithromycin therapy. Twenty-two patients received oral azithromycin and 43 patients did not receive antibiotic treatment. Among antibiotic-treated patients, long-term STEC carriage (>28 days) was observed in 1 of 22 patients (4.5%; 95% CI, 0%-13.3%) compared with 35 of 43 patients (81.4%; 95% CI, 69.8%-93.0%) who were not treated with antibiotics (P < .001). All 22 patients receiving azithromycin treatment had at least 3 STEC-negative stool specimens after the completion of treatment, and no recurrence of STEC was observed in these patients. As proof of principle, 15 patients who initially were not treated with antibiotics and were long-term STEC carriers were treated with oral azithromycin given for 3 days and subsequently had negative stool specimens. Treatment with azithromycin was associated with a lower frequency of long-term STEC O104:H4 carriage.

Production of Nitric Oxide Is Lower in Shiga Toxin-Stimulated Neutrophils of Infants Compared to Those of Children or Adults

Hemolytic uremic syndrome (HUS) in infants is mainly caused by the Shiga toxin (Stx), which is produced by pathogenic Escherichia coli O157:H7. Infants are prone to develop HUS in comparison to older children and adults, but its underlying mechanism remains unknown. Recent observations suggest that reactive oxygen species (ROS) and reactive nitrogen species (RNS) including nitric oxide (NO) may be involved in the pathogenesis of HUS. We therefore measured NO production by neutrophils prepared from infants (6-27 months old), children (5.3-11 years old) or adults (25-47 years old). The NO production was measured by a flow cytometric analysis with a fluorescent indicator (expressed as mean fluorescence intensity), and mRNA expression of inducible NO synthase (iNOS) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The amount of NO produced was significantly lower in Stx-stimulated neutrophils prepared from infants (45.8 ± 23.3) than that in those from children (120.5 ± 81.5) or adults (127.7 ± 45.8) (n = 10 each group, P < 0.05). The expression level of iNOS mRNA was lower in Stx-stimulated neutrophils of the infants than the level in those of children or adults. In conclusion, Stx increased NO production in neutrophils probably via iNOS. Importantly, the degree of the Stx-mediated increase in NO production was lower in neutrophils of infants compared to those of children or adults, which may explain the higher incidence of HUS in infants. These results suggest that NO may contribute to the cellular defense mechanisms against Stx.

High-throughput small molecule screening reveals structurally diverse compounds that inhibit the growth of Escherichia coli O157:H7 in vitro.

Escherichia coli O157:H7 colonizes the gastrointestinal tract of ruminants asymptomatically and may enter the human food supply through fecal contamination. A fraction of individuals infected by E. coli O157:H7 develop hemolytic uremic syndrome, a life-threatening condition. When individuals infected by E. coli O157:H7 are treated with certain antibiotics, an increased incidence of hemolytic uremic syndrome may result. This finding supports the need to identify novel compounds that can either reduce the load of E. coli O157:H7 entering the human food supply or serve as alternative therapeutic treatments for infected individuals. We developed a high-throughput turbidometric assay to identify novel compounds that inhibit E. coli O157:H7 growth. Pin transfers were performed to introduce small molecule libraries into 384-well plates, where each well contained approximately 5.0 log CFU of E. coli O157:H7. Plates were incubated at 37°C for 18 h, and the optical density was measured to determine the effect of each small molecule. A total of 64,562 compounds were screened in duplicate, and 43 unique compounds inhibited E. coli O157:H7 growth. Thirty-eight of the 43 inhibitory compounds belonged to known bioactive libraries, and the other 5 compounds were from commercial libraries derived from splitting and pooling. Inhibitory compounds from known bioactive libraries were most frequently therapeutic antibiotics (n = 34) but also included an antiviral compound, a compound that disrupts the citric acid cycle, and two biguanide compounds, which have been used for various nonclinical applications. We identified two novel compounds (i.e., biguanides) that should be studied further for their ability to reduce pathogen populations in foods.

Large and ongoing outbreak of haemolytic uraemic syndrome, Germany, May 2011

Since early May 2011, an increased incidence of haemolytic uraemic syndrome (HUS) and bloody diarrhoea related to infections with Shiga toxin-producing Escherichia coli (STEC) has been observed in Germany, with most cases in the north of the country. Cases reported from other European countries had travelled to this area. First results of a case–control study conducted in Hamburg suggest an association between the occurrence of disease and the consumption of raw tomatoes, cucumber and leaf salad.

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.

A Phase 1 Study of Moxetumomab Pasudotox, An Anti-CD22 Recombinant Immunotoxin, In Relapsed/Refractory Hairy Cell Leukemia (HCL): Updated Results

AbstractAbstract 2516Currently no adequate therapies exist for patients with refractory hairy cell leukemia (HCL). The CD22 antigen is commonly expressed on the cell surface of B cells and B-cell malignancies. CD22 is highly expressed in HCL, even in chemoresistant disease, and is therefore a potential target for antibody-directed therapy in refractory/resistant HCL. We developed CD22-specific targeted immunotoxins composed of the variable domains of a monoclonal anti-CD22 antibody fused to a truncated form of a Pseudomonas exotoxin. The first anti-CD22 immunotoxin we studied was CAT-3888 (BL22), which demonstrated remarkable activity in patients with relapsed/refractory HCL. Moxetumomab pasudotox (also known as CAT-8015 or HA22) is a derivative of CAT-3888 with a higher affinity to CD22 and an improved cytotoxicity profile ex vivo against HCL and other B-cell malignancies. A phase 1 dose-escalation study is being conducted to determine the maximum tolerated dose (MTD) of moxetumomab pasudotox and to assess its safety and immunogenicity profiles and clinical activity in HCL. Preliminary safety data and antitumor activity from the study were previously reported (Kreitman et al, ASH 2009, ASCO 2010). Eligibility criteria include age ≥18 years, ≥2 previous systemic therapies (including purine analogs), ECOG performance status of 0–2, and the presence of cytopenia or symptomatic splenomegaly. A standard 3+3 dose-escalation design with an expanded cohort at the MTD or highest dose level is being used. Patients receive moxetumomab pasudotox as a 30-min IV infusion administered on days 1, 3, and 5 (QODx3) of a 28-day treatment cycle, up to a total of 10 cycles. Patients receive prophylaxis with low-dose aspirin (if platelets >100,000/μL) and IV hydration to prevent hemolytic uremic syndrome (HUS), the dose-limiting toxicity (DLT) in clinical studies with CAT-3888. Additionally, patients receive hydroxyzine, ranitidine, and acetaminophen to avoid infusion reactions. Response is evaluated before cycle 2 and thereafter before even-numbered cycles. Enrollment and treatment are ongoing. At the time of reporting, a total of 32 patients had received moxetumomab pasudotox at one of five dose levels: 5, 10, 20, and 30 μg/kg (n=3 in each cohort), and 40 μg/kg (n=4), and in an expanded cohort at the 50-μg/kg dose level (n=16). Median age was 59 years (range, 40–77 years). Patients were heavily pretreated; 19 (59%) were previously treated with rituximab. No DLTs have been observed, and an MTD has not been reached. Adverse events have been mostly mild and consistent with those seen in clinical studies with CAT-3888. The most frequently reported drug-related adverse events have been hypoalbuminemia (53%), peripheral edema (44%), pyrexia (34%), elevated ALT (34%) and AST (31%), fatigue (28%), headache (28%), localized edema (22%), and nausea (22%). Capillary leak syndrome (grade 2) has developed in 7 patients (22%); 5 patients were in the 50-μg/kg dose cohort. Reversible grade 2 HUS has been reported in 2 patients (6%; 30 μg/kg, n=1; 50 μg/kg, n=1); both began on day 8 of the treatment cycle. Treatment-related toxicities ≥grade 3 have been observed in 3 patients (30 μg/kg, n=1; 50 μg/kg, n=2) and include decreased haptoglobin levels, elevated gamma-glutamyltransferase, and lymphopenia. Moxetumomab pasudotox has shown clinical activity in 47% of recipients, and responses have been observed in both the dose-escalation and expansion cohorts. Overall response (OR), complete response (CR), and partial response (PR) rates observed to date are listed in the table. The median time to response is currently 2.79 months. Neutralizing antibodies have developed in 14 patients (44%). Moxetumomab pasudotox appears to have a safety profile similar to that of CAT-3888 (BL22), and with a lower incidence of HUS at the highest dose tested (50 μg/kg QODx3). Moxetumomab pasudotox has demonstrated antitumor activity in patients with relapsed/refractory HCL, including 44% of patients in the expansion cohort. Further studies in HCL and other B-cell malignancies expressing CD22 are warranted.Clinical Activity5 μg/kg (n=3)10 μg/kg (n=3)20 μg/kg (n=3)30 μg/kg (n=3)40 μg/kg (n=4)50 μg/kg (n=16)Total (N=32)OR33%67%67%33%50%44%47%CR0%33%67%33%50%25%31%PR33%33%0%0%0%19%16%ClinicalTrials.gov Identifier: NCT00462189This study was sponsored by MedImmune, LLC. Disclosures:Kreitman: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Robak: MedImmune, LLC: Research Funding. Noel: NIH: Patents & Royalties. FitzGerald: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties. Buzoianu: MedImmune, LLC: Employment. Lechleider: MedImmune, LLC: Employment. Pastan: NCI: Co-inventor on patents assigned to the NIH for the investigational product., Patents & Royalties.

Role and clinical course of verotoxigenic Escherichia coli infections in childhood acute diarrhoea in Argentina

The aim of this study was to investigate the role and clinical course of verotoxigenic Escherichia coli (VTEC) infections in children with acute diarrhoea from Argentina, the country with the highest worldwide incidence of haemolytic uraemic syndrome (HUS). To accomplish this objective, 437 samples from children up to 6 years old with acute diarrhoea were collected and processed. More than 60 % of the children studied presented watery or mucous diarrhoea without blood, and in 25.2 % of the cases the samples contained blood. In a first screening, a multiplex PCR was performed to detect the presence of the vt(1), vt(2), eae, ehxA and saa virulence genes. The strains were then isolated and analysed to characterize their serotypes, virulence genes, antibiotic susceptibility profiles and verotoxin (VT) production. Forty-four of the 437 samples (10.1 %) were positive for VTEC virulence genes. VTEC-infected patients presented different types of diarrhoea (27.3 % belonged to the non-bloody type). Several serotypes and virulence genotypes were found. Isolates belonged to the serotypes O157 : H7, O145 : H(-), O26 : H11, O121 : H19, O111 : H2 and O118 : H2. HUS developed in 16 (36.4 %) patients positive for VTEC virulence genes. All of the VTEC isolates produced a cytopathic effect on Vero cell monolayers, confirming the ability to express VT. Despite most strains being sensitive to all of the antimicrobials studied, a positive association between clinical progression to HUS and antibiotic therapy was observed for the total number of patients studied, as well as for the VTEC(+) group. In conclusion, the data obtained in this study increase our knowledge of the role and clinical course of VTEC infection in childhood acute diarrhoea beyond bloody diarrhoea, and might be considered for the prevention, diagnosis and management of this disease. It is possible that the optimal approach for VTEC diagnosis could be using multiplex PCR to search for the presence of the vt(1), vt(2), eae and ehxA genes.

Hemolytic uremic syndrome (HUS)—incidence and etiologies at a regional Children’s Hospital in 2001–2006

Hemolytic uremic syndrome (HUS) is a serious health concern in children. HUS has primarily been linked to Escherichia coli O157:H7 infections, but non-O157 strains are gaining attention. Hemolytic anemia, thrombocytopenia, and acute renal failure are the characteristics of the syndrome. This study investigated the incidence of HUS at a regional Children's Hospital between 2001 and 2006 by retrospective review. Cases of HUS were investigated for outcomes based on stool culture and an association of acute pancreatitis. A total of 44 cases were identified, of which 57% were female and 43% were male, with an age distribution of 13 months to 17 years and a median age of 3.44 years. Data revealed 13 cases in 2006 compared to two cases in 2001, with 84% of all illnesses occurring in the summer and fall seasons. The median duration of thrombocytopenia was eight days and 50% of all cases required dialysis. E. coli O157:H7 was the predominant pathogen; however, 53% of the cases had unknown etiology. This data may suggest a growing number of cases from 2001 to 2006 and a role for agents other than E. coli O157:H7. E. coli O157:H7 caused longer intensive care unit (ICU) stay. No association between HUS and acute pancreatitis was found.

Síndrome hemolítico-urémico. Revisión de 58 casos

Our objectives were to determine epidemiology, clinical and laboratory characteristics of patients with haemolytic-uraemic syndrome (HUS) treated in our centre, to describe renal and extra-renal complications and the treatment required and to relate our findings with the existing bibliography.We performed a 33-year retrospective review. We included all patients diagnosed with HUS and monitored in our hospital from January 1974 to August 2007. Clinical histories and imaging studies were reviewed.A total of 58 patients were included in our study, with a mean age of 2 years 11 months and most of them were admitted to hospital in summer. Familial hypocomplementaemia was present in one case. A total of 48 patients presented with typical HUS (with diarrhoea D+ HUS). Salmonella enteritidis and Escherichia coli O157:H7 were isolated from those patients. While 7 cases presented with atypical HUS (without diarrhoea, D- HUS), most of them associated with a respiratory tract infection due to Streptococcus. In one case platelet count was normal. Kidney biopsy was performed in 18 patients and 25 cases underwent peritoneal dialysis. As regards complications, one child with D+ HUS experienced renal cortical necrosis and required kidney transplant, while in the D-HUS group, the patient with familial hypocomplementaemia had severe hypertension.a) Incidence of HUS in our environment is low. b) HUS can be present even with a normal platelet count. c) We had one case of HUS in a patient with familial hypocomplementaemia who experienced severe hypertension. d) In our group of patients, the course of the disease was not influenced by the white blood cell counts, decreased diuresis or hypocomplementaemia.

Surveillance of Hemolytic Uremic Syndrome in Children Less Than 15 Years of Age, a System to Monitor O157 and Non-O157 Shiga Toxin-Producing Escherichia coli Infections in France, 1996–2006

Since the 1980s, Shiga toxin-producing Escherichia coli (STEC), especially E. coli O157:H7, has been an important cause of food borne disease in industrial countries. In France, as there was no routine screening for STEC in clinical laboratories, enhanced surveillance of hemolytic uremic syndrome (HUS) in children less than 15 years of age was established in 1996 to monitor trends in the incidence of STEC infections. The surveillance system was based on a voluntary national network of pediatricians of 31 pediatric nephrology units in public hospitals. From 1996 to 2006, the mean annual incidence of HUS was 0.71 cases per 100,000 children less than 15 years of age and 1.87 cases per 100,000 children less than 5 years of age. STEC infections were confirmed in 66% of patients; STEC O157 was the most common serogroup identified in STEC-related HUS (83%). In this 11-year period, 96% of HUS cases were sporadic and only 2 outbreaks caused by STEC O157 and by a dual infection of STEC O26 and O80 were detected. An evaluation of the surveillance of pediatric HUS showed that it is a simple and useful system for monitoring trends in STEC infections in France. It provides the information needed to measure the impact of new and changing vehicles of STEC transmission, and evaluate the effectiveness of prevention measures.