Complication Of Hemolytic Uremic Syndrome Research Articles

Exocrine pancreatic insufficiency in a child with STEC-HUS: a forgotten complication.

Exocrine pancreatic insufficiency (EPI) is an extremely rare complication of hemolytic uremic syndrome related to Shiga toxin-producing Escherichia coli (STEC-HUS) and, to our knowledge, only one patient has been reported to have received pancreatic enzyme replacement therapy (PERT). Furthermore, STEC-HUS is not usually included among EPI causes. We report a 4-year-old girl with STEC-HUS who required dialysis and 4days after admission developed acute pancreatitis (ACPAN) and diabetes mellitus (DM). Amylase and lipase normalized 15days later but on the 73rd day of admission, she presented abdominal discomfort, bloating, and bulky and malodorous stools with a low fecal elastase-1 level (FE-1) of 15.74µg/g confirming EPI diagnosis. She received 3months of PERT until normalization of FE-1 levels. In children with STEC-HUS with ACPAN or DM, a high index of suspicion for EPI is required, since its symptoms are often mild, nonspecific, or delayed. In addition, STEC-HUS should be further recognized as a cause of secondary EPI.

Nanobody-Based Bispecific Neutralizer for Shiga Toxin-Producing E.coli.

Currently, no specific therapeutics are available for foodborne Shiga toxin-producing Escherichia coli (STEC) infections that cause severe gastroenteritis and life-threatening complications of hemolytic uremic syndrome (HUS). As STEC attachment to intestinal epithelium might increase the host absorption of Shiga toxins and severity of the disease, we were inspired to develop a bispecific neutralizer capable of blocking its Shiga toxin and adhesin intimin simultaneously. Two nanobodies against the B subunit of Shiga toxin 2 (Stx2B) and the C terminus of Intimin (IntC280) were genetically fused together as the bispecific neutralizer, and it can be efficiently produced in a conventional E.coli expression system. We demonstrated that each of the nanobody modules in the bispecific format showed increased antigen binding capability and was able to functionally neutralize the binding of Stx2B or IntC280 to the respective host receptors even in the presence of the two virulence factors together. Moreover, the bispecific neutralizer was relatively stable to harsh storage conditions and gastrointestinal pH extremes. Taking into account its easy and economical production and superior pharmaceutical properties, we believe that a nanobody-based bispecific neutralizer would be more favorable and practical to be developed as a therapeutic to fight STEC in the developing world.

Identification, Shiga toxin subtypes and prevalence of minor serogroups of Shiga toxin-producing Escherichia coli in feedlot cattle feces

Shiga toxin-producing Escherichia coli (STEC) are foodborne pathogens that cause illnesses in humans ranging from mild to hemorrhagic enteritis with complications of hemolytic uremic syndrome and even death. Cattle are a major reservoir of STEC, which reside in the hindgut and are shed in the feces, a major source of food and water contaminations. Seven serogroups, O26, O45, O103, O111, O121, O145 and O157, called ‘top-7’, are responsible for the majority of human STEC infections in North America. Additionally, 151 serogroups of E. coli are known to carry Shiga toxin genes (stx). Not much is known about fecal shedding and prevalence and virulence potential of STEC other than the top-7. Our primary objectives were to identify serogroups of STEC strains, other than the top-7, isolated from cattle feces and subtype stx genes to assess their virulence potential. Additional objective was to develop and validate a novel multiplex PCR assay to detect and determine prevalence of six serogroups, O2, O74, O109, O131, O168, and O171, in cattle feces. A total of 351 strains, positive for stx gene and negative for the top-7 serogroups, isolated from feedlot cattle feces were used in the study. Of the 351 strains, 291 belonged to 16 serogroups and 60 could not be serogrouped. Among the 351 strains, 63 (17.9%) carried stx1 gene and 300 (82.1%) carried stx2, including 12 strains positive for both. The majority of the stx1 and stx2 were of stx1a (47/63; 74.6%) and stx2a subtypes (234/300; 78%), respectively, which are often associated with human infections. A novel multiplex PCR assay developed and validated to detect six serogroups, O2, O74, O109, O131, O168, and O171, which accounted for 86.9% of the STEC strains identified, was utilized to determine their prevalence in fecal samples (n = 576) collected from a commercial feedlot. Four serogroups, O2, O109, O168, and O171 were identified as the dominant serogroups prevalent in cattle feces. In conclusion, cattle shed in the feces a number of STEC serogroups, other than the top-7, and the majority of the strains isolated possessed stx2, particularly of the subtype 2a, suggesting their potential risk to cause human infections.

Shiga Toxin–Producing Escherichia coli in Feces of Finisher Pigs: Isolation, Identification, and Public Health Implications of Major and Minor Serogroups

Shiga toxin-producing Escherichia coli (STEC) are major foodborne human pathogens that cause mild to hemorrhagic colitis, which could lead to complications of hemolytic uremic syndrome. Seven serogroups, O26, O45, O103, O111, O121, O145, and O157, account for the majority of the STEC illnesses in the United States. Shiga toxins 1 and 2, encoded by stx1 and stx2, respectively, and intimin, encoded by eae gene, are major virulence factors. Cattle are a major reservoir of STEC, but swine also harbor them in the hindgut and shed STEC in the feces. Our objectives were to use a culture method to isolate and identify major and minor serogroups of STEC in finisher pig feces. Shiga toxin genes were subtyped to assess public health implications of STEC. Fecal samples (n = 598) from finisher pigs, collected from 10 pig flows, were enriched in E. coli broth and tested for stx1, stx2, and eae by a multiplex PCR (mPCR) assay. Samples positive for stx1 or stx2 gene were subjected to culture methods, with or without immunomagnetic separation and plating on selective or nonselective media, for isolation and identification of stx-positive isolates. The culture method yielded a total of 178 isolates belonging to 23 serogroups. The three predominant serogroups were O8, O86, and O121. The 178 STEC strains included 26 strains with stx1a and 152 strains with stx2e subtypes. Strains with stx1a, particularly in association with eae (O26 and O103), have the potential to cause severe human infections. All stx2-positive isolates carried the subtype stx2e, a subtype that causes edema disease in swine, but is rarely involved in human infections. Several strains were also positive for genes that encode for enterotoxins, which are involved in neonatal and postweaning diarrhea in swine. In conclusion, our study showed that healthy finisher pigs harbored and shed several serogroups of E. coli carrying virulence genes involved in neonatal diarrhea, postweaning diarrhea, and edema disease, but prevalence of STEC of public health importance was low.

Tissue Responses to Shiga Toxin in Human Intestinal Organoids.

Background & AimsShiga toxin (Stx)-producing Escherichia coli (eg, O157:H7) infection produces bloody diarrhea, while Stx inhibits protein synthesis and causes the life-threatening systemic complication of hemolytic uremic syndrome. The murine intestinal tract is resistant to O157:H7 and Stx, and human cells in culture fail to model the complex tissue responses to intestinal injury. We used genetically identical, human stem cell–derived intestinal tissues of varying complexity to study Stx toxicity in vitro and in vivo.MethodsIn vitro susceptibility to apical or basolateral exposure to Stx was assessed using human intestinal organoids (HIOs) derived from embryonic stem cells, or enteroids derived from multipotent intestinal stem cells. HIOs contain a lumen, with a single layer of differentiated epithelium surrounded by mesenchymal cells. Enteroids only contain epithelium. In vivo susceptibility was assessed using HIOs, with or without an enteric nervous system, transplanted into mice.ResultsStx induced necrosis and apoptotic death in both epithelial and mesenchymal cells. Responses that require protein synthesis (cellular proliferation and wound repair) also were observed. Epithelial barrier function was maintained even after epithelial cell death was seen, and apical to basolateral translocation of Stx was seen. Tissue cross-talk, in which mesenchymal cell damage caused epithelial cell damage, was observed. Stx induced mesenchymal expression of the epithelial marker E-cadherin, the initial step in mesenchymal–epithelial transition. In vivo responses of HIO transplants injected with Stx mirrored those seen in vitro.ConclusionsIntestinal tissue responses to protein synthesis inhibition by Stx are complex. Organoid models allow for an unprecedented examination of human tissue responses to a deadly toxin.

Colonic stricture as a complication of haemolytic uraemic syndrome

Abstract Haemolytic uraemic syndrome (HUS) is an infectious disease that can rapidly become life-threatening in the paediatric population. A number of long-term complications may arise from HUS including the rare development of colonic strictures. In this case report, we present two cases with similar presentations of colonic strictures following HUS. Case 1 is a 17-month-old female who developed HUS and multiple complications including a sigmoid colonic stricture. Once the stricture was resected, her recovery was rapid and complete. Case 2 is a 3-year-old male who developed severe HUS requiring dialysis. After developing a small bowel obstruction, a laparotomy demonstrated caecal disease, pan-colonic inflammation, a calcified appendix and a strictured descending colon. A second operation revealed strictures at the transverse, descending and sigmoid colon. Once the diseased part of bowel had been removed his recovery was complete. This report demonstrates the diagnostic difficulty and patient morbidity that may arise from post-HUS colonic strictures. A contrast study is the recommended investigation of choice in patients presenting with ongoing gastrointestinal symptoms after an acute infection with HUS.

Hemolytic uremic syndrome complications and treatment.

This study carried out on 55 recorded cases child of hemolytic uremic syndrome admitted during a period of eight years (1991-1998) to Al-Mansour pediatric teaching hospital in Baghdad.It is found that gastrointestinal tract complications was the commonest (32.7%) followed by central nervous system complications (20%) while hypertension was present only in (14.5%) of patients thirty three percent of patients died. Central nervous system complications were statistically significant risk factor for death . these result comes with the result of taper – D et al (11) study except that the number of death was only (8%) which is low figure in comparison with this study.

Enterohemorrhagic Escherichia coli: A versatile pathogen that should be under surveillance

Out of bacteria which cause food –borne infections, enterohemorrhagic Escherichia coli (EHEC) is well known to be pathogen causing serious outbreaks. The first outbreak of EHEC infection occurred in 1982 was due to ingestion of hamburger at restaurant. A rare Escherichia coli serotype, 0157:H7 was isolated at that time and the following outbreaks were mostly due to this serotype. However, O26, O111 and O104 were also responsible for EHEC outbreaks. Enterohemorrhagic E. coli is an important food and water-borne pathogen. Verotoxins (VTs) produced by this pathogen causes painful hemorrhagic colitis along with major complications of hemolytic uremic syndrome (HUS). The morbidity and significantly high mortality and enormous economic loss are problematic to the health care administrators and EHEC infection is a serious public health issue. Another factor which makes it high transmissibility is the low infectious dose. The German O104:H4 epidemic was caused by the pathogen carrying a combination of virulence genes derived from two well-known pathogens, EHEC and enteroaggregative E. coli (EAEC). There is a possibility that two mobile DNA elements can occur again in this versatile pathogen. In this article, some aspects of EHEC infections which were established but not well known to the medical personals were explained to get understanding of why this infection should not be overlooked and should be under surveillance.

Results of surveillance for infections with Shiga toxin-producing Escherichia coli (STEC) of serotype O104:H4 after the large outbreak in Germany, July to December 2011.

After the massive outbreak of infections with Shiga toxin-producing Escherichia coli (STEC) of serotype O104:H4 in Germany in the summer of 2011, post-outbreak surveillance for further infections with this type of STEC was maintained until the end of 2011. This surveillance was based on national mandatory reporting of STEC infections and the associated complication of haemolytic uraemic syndrome (HUS), as well as on data obtained from a questionnaire. Between the outbreak’s end (5 July) and 31 December 2011, a total of 33 post-outbreak cases were recorded. Post-outbreak cases occurred with diminishing frequency towards the year’s end and resembled the outbreak cases in many respects, however the proportion of HUS among all post-outbreak cases was smaller than during the outbreak. Two thirds of the post-outbreak cases were likely infected by contact with known outbreak cases. Both laboratory and nosocomial spread was noted in this period. No post-outbreak case recalled sprout consumption as a potential source of infection. The scarcity of information conveyed by the nonculture tests routinely used in Germany to diagnose STEC made linkage of post-outbreak cases to the outbreak difficult. Though post-outbreak surveillance demonstrated the outbreak strain’s potential for lengthy chains of transmission aided by prolonged shedding, our results and continued routine surveillance until the end of 2013 do not support the notion, that the outbreak strain has been able to establish itself in the German environment.

Mouse in Vivo Neutralization of Escherichia coli Shiga Toxin 2 with Monoclonal Antibodies

Shiga toxin-producing Escherichia coli (STEC) food contaminations pose serious health concerns, and have been the subject of massive food recalls. STEC has been identified as the major cause of the life-threatening complication of hemolytic uremic syndrome (HUS). Besides supportive care, there currently are no therapeutics available. The use of antibiotics for combating pathogenic E. coli is not recommended because they have been shown to stimulate toxin production. Clearing Stx2 from the circulation could potentially lessen disease severity. In this study, we tested the in vivo neutralization of Stx2 in mice using monoclonal antibodies (mAbs). We measured the biologic half-life of Stx2 in mice and determined the distribution phase or t1/2 α to be 3 min and the clearance phase or t1/2 β to be 40 min. Neutralizing mAbs were capable of clearing Stx2 completely from intoxicated mouse blood within minutes. We also examined the persistence of these mAbs over time and showed that complete protection could be passively conferred to mice 4 weeks before exposure to Stx2. The advent of better diagnositic methods and the availability of a greater arsenal of therapeutic mAbs against Stx2 would greatly enhance treatment outcomes of life threatening E. coli infections.

Shiga toxins and the pathophysiology of hemolytic uremic syndrome in humans and animals.

Food-borne diseases are estimated at 76 million illnesses and 5000 deaths every year in the United States with the greatest burden on young children, the elderly and immunocompromised populations. The impact of efficient food distribution systems and a truly global food supply ensures that outbreaks, previously sporadic and contained locally, are far more widespread and emerging pathogens have far more frequent infection opportunities. Enterohemorrhagic E. coli is an emerging food- and water-borne pathogen family whose Shiga-like toxins induce painful hemorrhagic colitis with potentially lethal complications of hemolytic uremic syndrome (HUS). The clinical manifestations of Shiga toxin-induced HUS overlap with other related syndromes yet molecular mechanisms differ considerably. As discussed herein, understanding these differences and the novel properties of the toxins is imperative for clinical management decisions, design of appropriate animal models, and choices of adjunctive therapeutics. The emergence of new strains with rapidly aggressive virulence makes clinical and research initiatives in this field a high public health priority.

Surgical complications of hemolytic uremic syndrome: Single center experiences

Purpose: To determine the prevalence, outcome and prognostic factors in children with hemolytic uremic syndrome (HUS) who underwent laparotomy. Materials and Methods: The medical records of 104 patients with HUS who presented to our center between 1986 and 2003 were reviewed retrospectively. Data were analyzed using Student's t test for comparing means, Fisher's exact test for frequencies and Pearson's correlation for finding the correlations. Results: 78% of cases presented with vomiting and diarrhea. Seven out of 104 needed surgical exploration. The indications of surgery were acute abdomen, severe abdominal distention and the sign of peritonitis. The findings at laparotomy were intussusceptions, perforation (colon, ileum), gangrene of entire colon, rectosigmoidal tearing, duodenal obstruction and toxic megacolon. Pathological findings were transmural infarction in two cases in which staged surgical management was performed (cecostomy, resection, later anastomosis). Four out of seven patients died because of pulmonary failure, coma and multiple organ failure ( P 20000 mm 3 ) and low albumin level (<3g/dl) ( P<0.05). Conclusion: Surgical complications of HUS are rare but are assorted with high mortality due to respiratory failure and multiple organ failure. Early decision of laparotomy associated with intensive care, including mechanical ventilation, adequate dialysis and ultrafiltration, are recommended.

Insulin-dependent diabetes mellitus as long term complication of haemolytic-uraemic syndrome

Haemolytic-uraemic syndrome (HUS) is a rare cause of insulin-dependent diabetes mellitus during the acute stage. We previously reported the case of a 3-year-old girl having presented with typical HUS with diarrhea, microangiopathic anaemia, thrombocytopenia and acute renal failure (17 days of anuria). Transient hyperglycaemia (highest level: 513 mg/dl) was observed, requiring continuous intravenous insulin infusion for 9 days. Subcutaneous insulin injections were stopped after 24 days. Oral glucose tolerance test performed 4 months after normalization of blood glucose was normal. HLA DQ genotype (DQA1-DQB1.AZH/DQA3-DQB3.1) was not at risk for type 1 diabetes and there were no auto-antibodies (ICA and IAA). The 3-years follow-up was marked by persistent arterial hypertension, proteinuria and slight renal insufficiency despite angiotensin-converting enzyme inhibitor treatment. Ten years after HUS occurred (the patient had been lost to follow-up for 7 years), she came back with complaints of headache but neither polyurodipsia nor weight loss. She was found to have arterial hypertension. Chronic renal impairment had moderately progressed with decreased glomerular filtration rate (63 ml/min/1.73 m2) and proteinuria (2 g/24 hours). Fasting blood glucose was 189 mg/dl and reached 315 mg/dl during an oral glucose tolerance test. HbA1c level was 8.2% (N<6.2%) and diabetes mellitus was diagnosed without any signs of autoimmunity (IAA, ICA, GADA and IA2B were negative). Good glycaemic control was obtained with 0.5 U/kg/day of insulin. In conclusion, transient beta-cell dysfunction complicating HUS acute stage may evolve to overt non-autoimmune diabetes mellitus (microangiopathic process?), even after a long free interval. This case emphasizes the need for a long-term follow-up of patients with HUS.

Identification of four fimbria-encoding genomic islands that are highly specific for verocytotoxin-producing Escherichia coli serotype O157 strains.

Verocytotoxin-producing Escherichia coli causes zoonotic food- or waterborne infection that may be associated with massive outbreaks and with the serious complication of hemolytic uremic syndrome (HUS). Serotypes O157:H7 and O157:NM are more commonly associated with HUS and outbreaks than other serotypes, such as O26:H11. To determine whether a genetic basis exists for why serotype O157:H7/NM causes HUS and outbreaks more often than other serotypes, such as O26:H11, we conducted suppression subtractive hybridization (SSH) between the genomes of the sequenced O157:H7 strain EDL933 and CL1, a clinical serotype O26:H11 isolate. Genes from four EDL933 fimbria-encoding genomic O islands (OIs) (OI-1, -47, -141, and -154) were identified in the SSH library. OI-47 encodes several additional putative virulence factors, including secreted and signaling proteins, a hemolysin locus, a lipoprotein, an ABC transport system, and a lipid biosynthesis locus. The distribution of the OIs was investigated by PCR and Southern hybridization (when PCR was negative) with 69 VTEC strains belonging to 39 different serotypes corresponding to 5 seropathotypes that differ in their disease and epidemic potential. The four OIs described here were distributed almost exclusively in serotypes O157:H7 and O157:NM, which indicates that they may be associated with the ability of these strains to colonize human and/or animal intestinal tracts and to cause epidemic and serious disease more frequently than other serotypes. The occurrence of the four OIs in enteropathogenic E. coli O55:H7 strains is consistent with their vertical inheritance by VTEC O157:H7/NM from this clonally related ancestor.

Childhood Hemolytic Uremic Syndrome, United Kingdom and Ireland

We conducted prospective surveillance of childhood hemolytic uremic syndrome (HUS) from 1997 to 2001 to describe disease incidence and clinical, epidemiologic and microbiologic characteristics. We compared our findings, where possible, with those of a previous study conducted from 1985 to 1988. The average annual incidence of HUS for the United Kingdom and Ireland (0.71/100,000) was unchanged from 1985 to 1988. The overall early mortality had halved, but the reduction in mortality was almost entirely accounted for by improved outcome in patients with diarrhea-associated HUS. The principal infective cause of diarrhea-associated HUS was Shiga toxin-producing Escherichia coli O157 (STEC O157), although in the 1997-2001 survey STEC O157 phage type (PT) 21/28 had replaced STEC O157 PT2 as the predominant PT. The risk of developing diarrhea-associated HUS was significantly higher in children infected with STEC O157 PT 2 and PT 21/28 compared with other PTs. Hypertension as a complication of HUS was greatly reduced in patients with diarrhea-associated HUS.

Cardiac Failure in Hemolytic Uremic Syndrome and Rescue with Extracorporeal Life Support

Extrarenal involvement manifesting in the cardiovascular system is a rare but potentially fatal complication of hemolytic uremic syndrome (HUS). Current treatment is aimed at cardiovascular supportive measures while awaiting organ recovery. However, there are cases in which this recovery never occurs, and patients succumb secondary to heart failure. We report two cases of severe cardiac failure in children in the acute phase of HUS and the use of extracorporeal membrane oxygenation (ECMO) to support one patient to cardiac recovery. Clinicians should be aware of this potentially life-threatening cardiac involvement and should consider the use of ECMO for potentially salvageable children with HUS.

Secondary sclerosing cholangitis and portal hypertension after O157 enterocolitis: Extremely rare complications of hemolytic uremic syndrome

The authors experienced an extremely rare case of secondary sclerosing cholangitis and portal hypertension developed as late complications of hemolytic uremic syndrome (HUS) owing to Escherichia coli O157:H7 in a 2-year-old boy. HUS after E coli O157 infection is the most frequent cause of acute renal failure in childhood and occasionally is accompanied by extrarenal complications such as encephalopathy, cardiomyopathy, ischemic colitis, and pancreatitis. Rarely, late colonic stenosis may develop secondary to the ischemic damage. Sclerosing cholangitis and subsequent cirrhosis with portal hypertension are very uncommon as late complications of HUS. To our knowledge, such a case has not been previously reported in the literature. J Pediatr Surg 36:1838-1840. Copyright © 2001 by W.B. Saunders Company.

The management of VTEC O157 infection

VTEC O157 infections, although showing a relentless rise in incidence over the last decade, only account for less than 10% of total food poisoning notifications in the UK. Despite this, the propensity for this infection to cause the serious and life-threatening clinical complications of haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP), in a significant proportion (2–15%) of sufferers, highlights the need to focus on it both epidemiologically and clinically. The mortality rate of these complications (3–17% and up to 30% in outbreaks) adds urgency to this consideration. The pathogenesis and epidemiology of the illness caused by VTEC O157 is now well described, allowing the potential for appropriate intervention in outbreak and individual clinical management. The presence or absence of symptoms, e.g. bloody diarrhoea, fever, vomiting, in VTEC O157 infections compared with other causes of gastroenteritis may allow some selection of cases for more intensive management. Age (<15, >65 years), clinical hypochlorhydria, and a short incubation period have been associated with complication (HUS/TTP) development. Antibiotic therapy in the pre-infection period may predispose to complication development and there is evidence that it may increase complications if used in the management of acute illness. Laboratory markers such as early neutrophil leukocytosis have been shown both to correlate with VTEC O157 infection and to predict complications in central Scotland and Japan. The serum albumin and the C-reactive protein may act as additional markers for HUS development. Laboratory markers may be differentiated into those predicting HUS/TTP and those useful in monitoring its development. A scheme for clinical management of affected cases is presented to allow the attending clinician to select cases that may benefit from further intervention to prevent or treat complications.

Infarction of the choledochus, liver, gallbladder, and pancreas: A unique complication of the hemolytic uremic syndrome

Hemolytic uremic syndrome (HUS) is associated with multiple nonrenal manifestations. A unique case is described of a 3-year-old boy who presented with a classic diarrheal prodrome followed by massive necrosis of the biliary tree and common bile duct, pancreas, and the left lobe of his liver. This complication of HUS has not been reported in the English-language literature.

Timing of colonic necrosis in hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) consists of an acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. HUS-associated colitis can be seen in up to 100% of patients and is usually associated with severe abdominal pain and distention. Colonic perforation is a complication of HUS that has a reported incidence of 1%-2%, and although there are several case reports in the literature describing perforation of the colon, it is still very difficult to discern the abdominal symptoms associated with HUS colitis from perforation. Four cases of colonic perforation are reported here from a consecutive series of 57 patients, in which a trend in the length of time from the onset of symptoms of HUS to colonic perforation was determined. A review of the literature for cases of HUS-associated colonic perforation was also performed. The time from the onset of HUS symptoms to colonic perforation in our series was similar to that found in the literature review (11 +/- 5 vs 14 +/- 8 days). Awareness that this complication has a tendency to occur towards the end of the 2nd week during the course of HUS is essential to avoid an unnecessary and untimely surgical intervention.