Richard L. Siegler

Hemolytic-uremic syndrome during an outbreak of Escherichia coli O157:H7 infections in institutions for mentally retarded persons: Clinical and epidemiologic observations

PURPOSE To describe an outbreak of Escherichia coli O175:H7 infection resulting in a high rate of progression to hemolytic-uremic syndrome, and to attempt to identify predictors of and risk factors for progression. DESIGN Case-control study among employees and comparison of daily clinical features in two groups: infected residents with subsequent development of HUS and those who had no complications. SETTING Two institutions for retarded persons in Utah. PATIENTS Twenty residents with E. coli O157:H7 infection (13 culture confirmed, 2 probable, and 5 possible); HUS developed in 8, and 4 died. Thirty-one infected employees (3 with culture-confirmed, 6 with probable, and 22 with possible infection). MEASUREMENTS AND MAIN RESULTS In a case-control study among employees, infection was independently associated with eating ground beef from a single lot prepared at several barbecues and with close contact with a resident who had diarrhea. Five of eight residents in whom HUS developed had received trimethoprim-sulfamethoxazole, compared with none of seven who had no subsequent complications (p = 0.026); this finding may reflect antimicrobial treatment of patients with more severe illness. Compared with infected residents without complications, persons with HUS were younger (median age 13 vs 27 years, p = 0.043) and, by the third day of illness, had higher leukocyte counts (median 23.7 X 10(9)/L vs 9.1 X 10(9)/L, p = 0.018) and temperature (median 38.5 degrees C vs 37.0 degrees C, p = 0.016). Leukocytosis peaked on day 4, more than 24 hours before signs of HUS appeared. CONCLUSIONS Food-borne outbreaks of E. coli O157:H7 in institutions may have devastating effects. Leukocytosis and fever may precede and predict HUS in patients with E. coli O157:H7 infection.

The Hemolytic Uremic Syndrome

HUS is the most common cause of acute renal failure in infants and young children and follows a diarrheal prodrome about 90% of the time. Persuasive evidence shows that virtually all of postdiarrheal cases are caused by EHEC infections, and that the great majority of cases in the United States are caused by the EHEC serotype O157:H7. Mortality is approximately 5%, and approximately 10% of survivors are left with severe sequelae. A much larger number (30%-50%) experience mild chronic renal damage. Public health strategies, including zero tolerance for fecal contamination in slaughter houses and additional public education on proper food handling and cooking, does much to decrease the prevalence of the syndrome. Efforts to further dissect the postdiarrheal pathogenic cascade should continue, and an animal model needs to be developed. Only then will researchers be positioned to develop effective intervention strategies. Preventing life-threatening extrarenal complications, especially of the CNS, is a major challenge. Idiopathic nondiarrheal HUS accounts for approximately 10% of cases and comprises a poorly understood composite of HUS subsets. Research directed toward a better understanding of these mysterious variants also is a priority for the years ahead.

Response to Shiga toxin 1 and 2 in a baboon model of hemolytic uremic syndrome

Abstract.Post-diarrheal (D+) hemolytic uremic syndrome (HUS) is caused by Shiga-toxin (Stx)-producing Escherichia coli. There is epidemiological, cell culture, and mouse model evidence that Stx2-producing E. coli are more likely to cause HUS than strains that produce only Stx1, but this hypothesis has not been tested in a primate model of HUS. We have developed a baboon model of Stx-mediated HUS that was employed to compare the clinical, cytokine, and histological response to equal amounts of the two Shiga toxins. Animals given IV Stx2 developed progressive thrombocytopenia, hemolytic anemia, and azotemia, and urinary interleukin-6 levels rose significantly. Glomerular thrombotic microangiopathy was found at necropsy. Animals given Stx1 showed no cytokine response and no clinical, laboratory, or histological signs of HUS. Our findings from the primate model corroborate previous epidemiological, cell culture, and mouse model observations, and suggest that enteric infection with Stx2-producing E. coli is more likely to cause HUS than infection with organisms that produce only Stx1.

Characterization of the baboon responses to Shiga-like toxin : Descriptive study of a new primate model of toxic responses to Stx-1

The baboon response to intravenous infusion of Shiga toxin 1 (Stx-1) varied from acute renal failure, proteinuria, hyperkalemia, and melena with minimal perturbation of host inflammatory and hemostatic systems (high-dose group, 2.0 microg/kg; n = 5) to renal failure with hematuria, proteinuria, thrombocytopenia, schistocytosis, anemia, and melena (low-dose group, 0.05 to 0.2 microg/kg; n = 8). Both groups exhibited renal shutdown and died in 57 hours or less. Both groups produced urine that was positive for tumor necrosis factor and interleukin-6 although neither of these cytokines was detectable (</=5 ng/ml) in the general circulation. Light and electron microscopy showed organelle disintegration and necrosis of the renal proximal tubular epithelium and of the intestinal mucosal epithelium at the tips of the microvilli, both of which were previously shown to bear Gb3 receptors. The renal distal tubular epithelium was spared. The renal proximal tubular epithelial changes were accompanied by swelling of visceral epithelial cells (podocytes) and by swelling and detachment of endothelial cells of the glomerular capillaries. In addition, all of the animals receiving low-dose Stx-1 showed microvascular fibrin deposition and thrombosis in renal glomerular and peritubular capillaries in association with a fall in hematocrit and platelet count and a rise in schistocyte count. The gastrointestinal villous tip lesions were accompanied by varying degrees of mucosal and submucosal congestion, hemorrhage, or necrosis. Electron microscopic images of cerebral cortex and cerebellum showed diffuse unraveling of myelin sheaths with occasional disintegration of neuronal cell bodies. In contrast to the gastrointestinal mucosal and renal proximal tubular epithelium, the Gb3 receptor glycolipid of the renal glomerular and neuronal tissues as determined using toxin overlay thin-layer chromatography plates was below the limit of detection (<13 pM/g wet tissue). We conclude that, depending on the status of the host and amount of toxin infused, Stx-1 can produce a variety of responses ranging from damage to cells carrying the Gb3 receptor (renal proximal tubular epithelial cells and gastrointestinal mucosa) to damage to renal glomerular tissues with microvascular thrombosis as a result of the hosts inflammatory response localized to the kidney. We conclude that this thrombotic coagulopathy arises from local changes in the kidney because the appearance of host inflammatory mediators was limited to the urine. This suggests that the initial host response is localized in the kidney, and that the systemic thrombocytopenia, anemia, and schistocytosis may arise secondarily.

Hemolytic uremic syndrome; pathogenesis, treatment, and outcome

Purpose of review The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in infants and young children, and is a substantial cause of acute mortality and chronic morbidity. It is therefore relevant and appropriate that pediatricians remain familiar with the various subsets of the disease including its classification, management, and outcome. Recent findings This review will focus on recent information relative to epidemiology, pathogenesis, treatment, and outcome. It will include some of the newer associations between HUS and a variety of infections, including, but not limited to E. coli 0157:H7 (Shiga toxin-mediated) HUS, as well as the ever-increasing number of associations between HUS and a variety of drugs. It will review some of the newer therapies for the more common subsets, but will acknowledge that choosing evidence-based therapies is often limited by our incomplete understanding of the various pathogenic cascades, and that with the possible exception of Shiga toxin-mediated HUS(D+HUS), long-term outcome information is often limited by small numbers and limited follow-up. Summary This review should provide a framework for making the proper diagnosis, implementing appropriate treatment, and advising the family about anticipated outcome.

Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome.

We examined 61 patients an average of 9.6 years (range 5 to 18 years) after an episode of childhood hemolytic-uremic syndrome. Twenty-four (39%) had one or more abnormalities. Seven (11%) had proteinuria and six (10%) had low creatinine clearance as solitary abnormalities. Eight (13%) had both proteinuria and reduced creatinine clearance; three (5%) had a combination of hypertension, proteinuria, and low creatinine clearance. Abnormalities sometimes appeared after an interval of apparent recovery. Logistic regression analysis showed that duration of anuria was the best predictor of disease at follow-up. No patients who had anuria lasting longer than 8 days or oliguria exceeding 15 days escaped chronic disease. However, 45% of those with disease had no anuria, and a third had no oliguria. Physicians should therefore be cautious in assuming recovery from HUS on the basis of a single evaluation and should periodically evaluate patients for an extended period.

Hemolytic uremic syndrome: epidemiology, pathophysiology, and therapy

Shiga toxin (Stx)-producing Escherichia coli (STEC) were first linked to human disease in 1982 [1]. At that time an E. coli serotype (O157:H7) that had not previously been linked with human disease was found to be associated with outbreaks of hemorrhagic colitis [1]. Subsequent studies demonstrated that E. coli O157:H7 produced potent toxins that were genetically and physically very similar to Stx from Shigella dysenteriae type 1 [2]. The link between STEC infections and hemolytic uremic syndrome (HUS) was established in the 1980s in Canada by Karmali et al. [3] when they found that infection with various serotypes of STEC was strongly associated with the subsequent development of HUS. The most common E. coli serotype identified to cause hemorrhagic colitis and HUS in the United States was the single serotype – O157:H7. The reason this serotype is most commonly identified in STEC infections is that it is relatively easy to identify in clinical microbiology laboratories due to its inability to ferment sorbitol. Since the first description of O157:H7 as a human pathogen in 1983, it has become apparent that E. coli O157:H7 is but one of a much larger family of STEC whose primary virulence characteristic is the ability to produce Stxs [2, 3, 4]. STEC are clinically associated with both bloody and non-bloody diarrhea as well as systemic complications such as HUS [4]. It is now clear that there are at least 200 different types of STEC, of which approximately 60 have been associated with disease in humans [2, 4, 5]. Non-O157 STEC, especially E. coli O111, have been the cause of major outbreaks in both the United States and other parts of the world [6, 7]. However, apart from the occasional outbreak of nonO157 in the United States, the association of nonO157:H7 STEC with disease in this country is largely undetermined. Of note, the majority of laboratories do not routinely look for non-O157 STEC [8], suggesting that lack of diagnosis of non-O157:H7 disease is a failure of use of appropriate diagnostic techniques. Compatible with this hypothesis are at least two small studies in which non-O157:H7 STEC were routinely found in patients submitting stools for microbiological analysis in the United States. [9, 10]. Recent work from our laboratory in collaboration with multiple sites in the United States has attempted to determine the prevalence of both O157 and non-O157 STEC in selected sites in the United States. We have performed multi-site surveillance studies to determine the prevalence of O157 and non-O157 STEC in stool samples submitted to clinical microbiology laboratories for S.P. Andreoli is the editor of the Proceedings and H. Trachtman the associate editor. D.W.K. Acheson is the author of the section Microbiology and epidemiology of Shiga toxin-induced hemolytic uremic syndrome, R.L. Siegler is the author of the section Animal models of Stx-mediated HUS, T.G. Obrig is the author of the section Mechanisms of Stx-mediated cell injury, and H. Trachtman is author of the section New and future therapies for diarrhea-associated HUS.

Predictors of Fatality in Postdiarrheal Hemolytic Uremic Syndrome

OBJECTIVES. Describe the cause of deaths among patients with postdiarrheal hemolytic uremic syndrome (HUS) and identify predictors of death at the time of hospital admission. METHODS. Case-control study of 17 deaths among patients with HUS identified from the Intermountain HUS Patient Registry (1970–2003) compared against all nonfatal cases. RESULTS. Of the 17 total deaths, 15 died during the acute phase of disease. Two died because treatment was withdrawn based on their preexisting conditions, and 1 died because of iatrogenic cardiac tamponade; they were excluded from analysis. Brain involvement was the most common cause of death (8 of 12); congestive heart failure, pulmonary hemorrhage, and hyperkalemia were infrequent causes. Presence of prodromal lethargy, oligoanuria, or seizures and white blood cell count (WBC) >20 × 109/L or hematocrit >23% on admission were predictive of death. In multivariate analysis, elevated WBC and elevated hematocrit were independent predictors. The combination of prodromal dehydration, oliguria, and lethargy and admission WBC values >20 × 109/L and hematocrit >23% appeared in 7 of the 12 acute-phase deaths. CONCLUSIONS. Diarrheal HUS patients presenting with oligoanuria, dehydration, WBC >20 × 109/L, and hematocrit >23% are at substantial risk for fatal hemolytic uremic syndrome. Such individuals should be referred to pediatric tertiary care centers.

A clinicopathological study of 24 children with hemolytic uremic syndrome: a report of the Southwest pediatric nephrology study group

This study reports the pattern of renal injury in 24 North American children with hemolytic uremic syndrome (HUS), and the extent of extrarenal involvement in 9 of these children examined at autopsy. Fifteen of the 24 children were studied during the first 16 days of hospital-ization; their renal specimens demonstrated glomerular thrombotic microangiopathy (TMA) in 8 children, cortical necrosis in 1, and varying degrees of glomerular TMA and cortical necrosis in 6 children. Nine of the children were studied after 16 or more days of hospitalization; these patients had prominent renal arterial lesions. Of 9 children examined at autopsy, extrarenal microthrombi were identified in 8. In 4 children who died during the acute phase of the disease, hemorrhagic colonic necrosis (3 children) and pancreatic islet cell necrosis (2 children) were the principal extrarenal lesions encountered. Rare microthrombi were present in the brains of the 3 children who manifested seizures.

Duration of oliguria and anuria as predictors of chronic renal-related sequelae in post-diarrheal hemolytic uremic syndrome

Prior long-term retrospective studies have described renal sequelae in 25–50% of postdiarrheal hemolytic uremic syndrome (HUS) survivors, but the ability to predict the likelihood of chronic renal-related sequelae at the time of hospital discharge is limited. We surveyed 357 children in our HUS registry who survived an acute episode of post diarrheal HUS (D+HUS) and were without end-stage renal disease (ESRD) at the time of hospital discharge. Of the 357 patients surveyed, 159 had at least 1 year (mean 8.75 years) of follow-up. Of these, 90 individuals were identified as having had at least 1 day of oliguria, with 69 individuals having had at least 1 day of anuria. The incidences of renal-related sequelae [proteinuria, low glomerular filtration rate (GFR), and hypertension] were determined among experimental groups based on oliguria and anuria duration. One or more sequelae (e.g. proteinuria, low GFR, hypertension) was seen in 25 (36.2%) of those who had no recorded oliguria and 34 (37.8%) of those with no recorded anuria. The prevalence of chronic sequelae increased markedly in those with more than 5 days of anuria or 10 days of oliguria, with anuria being a better predictor than oliguria of most related sequelae. A particularly high incidence of hypertension was seen in patients with > 10 days of anuria (55.6%) in comparison with those with no anuria (8.9%) [odds ratio (OR) 12.8; 95% confidence interval (CI) 2.9–57.5]. Patients with > 10 days of anuria were also at substantially increased risk for low GFR and proteinuria (OR 35.2; 95% CI 5.1–240.5). These findings may help identify children who need periodic and extended follow-up after hospital discharge.