Elaine Orrbine

Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988

OBJECTIVE To define the epidemiologic features of childhood hemolytic-uremic syndrome (HUS) on a national level in Canada, to determine the proportion of patients in whom Escherichia coli O157:H7 was isolated from stools, and to examine risk factors for more severe HUS. DESIGN From January 1986 to December 1988, patients with HUS were reported prospectively to the Canadian Pediatric Kidney Disease Reference Centre, a national registry for pediatric renal disorders, or were identified retrospectively through a medical records search at participating institutions. SETTING All childrens hospitals in Canada and the childrens wards of general hospitals in Canadian cities with populations greater than 350,000. PATIENTS Two hundred twenty-six children, including 126 girls. MEASUREMENTS AND MAIN RESULTS The average annual incidence of HUS in children younger than 15 years was 1.44 per 100,000; the peak age-specific incidence was 3.11 per 100,000 younger than 5 years. The incidence of HUS varied by region; the risk of HUS in Alberta was 2.9 times that in Ontario (p less than 0.0001). Of the 169 patients whose stools were screened, E. coli O157:H7 was isolated in 87 (51%). Risk factors for prolonged dialysis or death included young age, seizures, elevated white blood cell count at admission to hospital, and shorter, more severe prodromal illness. The rate of dialysis was higher in female patients (55% vs 39%; p = 0.02). CONCLUSIONS HUS is relatively common in Canadian children younger than 5 years, and is strongly associated with E. coli O157:H7 infection. Reasons for the striking regional variation in the incidence of HUS and for the increased rate of dialysis in female patients are unexplained and deserve further investigation.

Risk of hemolytic uremic syndrome after sporadic Escherichia coli O157:H7 infection: Results of a Canadian collaborative study

OBJECTIVES The objectives of this study were to better estimate the age-specific risks of hemolytic uremic syndrome (HUS) and hemolytic anemia after Escherichia coli O157:H7 infection among a representative cohort of both referred and nonreferred children with documented illness from the province of Alberta and to compare this with the rates in children evaluated at referral centers in the rest of Canada. STUDY DESIGN Children with HUS or E. coli O157:H7 gastroenteritis were eligible if they were < 15 years of age. Hemoglobin, blood smear, urinalysis, and serum creatinine were obtained 8 to 10 days after the onset of diarrhea to ascertain for hemolysis, anemia, thrombocytopenia, and renal injury. Subjects were monitored for 1 month. RESULTS From June 1991 to March 1994, HUS was diagnosed in 205 children. Of these 77% had evidence of E. coli O157:H7 infection. A further 582 children had E. coli O157:H7 gastroenteritis, of whom 18 had hemolytic anemia. The risk of HUS after E. coli O157:H7 infection in Alberta was 8.1% (95% confidence interval, 5.3 to 11.6) compared with 31.4% in referral centers in the rest of Canada. In Alberta the highest age-specific risk of HUS/hemolytic anemia was 12.9% in those < 5 years of age. CONCLUSIONS These data will help guide clinical care and provide a basis for estimating the sample sizes required in future treatment trials for the secondary prevention of HUS.

Circulating inflammatory cytokine levels in hemolytic uremic syndrome

Abstract Experimental data suggest that the host’s inflammatory response is involved in the pathophysiology of verotoxin-producing Escherichia coli (VTEC)-associated hemolytic uremic syndrome (HUS). We compared the circulating levels of pro- [interleukin (IL)-6, IL-8] and anti-inflammatory [IL-10 and IL-1 receptor antagonist (Ra)] mediators on enrollment among children with HUS due to E. coli O157:H7, according to the severity of renal dysfunction. The latter was evaluated by the occurrence of oligoanuria, the requirement for dialysis, and a glomerular filtration rate (GFR) ≤80 ml/min per 1.73 m2 measured 1 year later. Increased levels of IL-6 (P<0.0001), IL-10 (P<0.0001), and IL-1Ra (P<0.07) were found among patients with HUS compared with normal controls. Children with severe renal dysfunction also had tenfold increased levels of IL-6 and higher concentrations of IL-10 and IL-1Ra. Both the IL-6/IL-10 (4.9±8.3 vs. 0.5±0.4, P=0.01) and the IL-6/IL-1Ra ratios (0.10±0.20 vs. 0.01±0.01, P=0.04) were significantly increased. GFR correlated well with IL-6 levels, IL-6/IL-10 and IL-6/IL-1Ra ratios. Our data demonstrate that the inflammatory response of the host is associated with the severity of renal dysfunction during classic HUS. An imbalance between the pro- and the anti-inflammatory responses may be involved in the pathophysiology of VTEC-associated HUS.

Epidemic Escherichia coli O157:H7 gastroenteritis and hemolytic-uremic syndrome in a Canadian Inuit community: Intestinal illness in family members as a risk factor

Abstract Objective : To evaluate risk factors for childhood hemolytic-uremic syndrome (HUS) and gastroenteritis during an epidemic of Escherichia coli O157:H7 infection. Design : Case-control study. Setting : Remote Inuit community of Arviat in northern Canada. Participants : Of the 565 Arviat residents less than 15 years of age, 19 had HUS and 65 more had E. coli O157:H7 gastroenteritis. The 19 children with HUS were compared with 19 age- and gender-matched children with uncomplicated E. coli O157:H7 gastroenteritis, and both HUS and gastroenteritis patients were compared with 19 healthy control subjects. Interventions : Questionnaire administered face-to-face to parents of participants in the home. Main outcome measures : Rates of exposure to foods, travel, sources of water, and gastrointestinal illness in family members. Results : Patients with HUS and those with uncomplicated E. coli O157:H7 gastroenteritis differed only on measures of clinical severity. In the 7 days before the onset of gastrointestinal symptoms, children with HUS and those with uncomplicated gastroenteritis were more likely to have been exposed to a family member with diarrhea than were the healthy control subjects (odds ratio=9 for HUS vs healthy control subjects; 95% confidence interval 2 to 43; p E. coli O157:H7 infection. Conclusions : These findings emphasize the potential for extensive intrafamilial transmission of verotoxin-producing E. coli once infection is introduced into certain communities. (J PEDIATR 1994;124:21-6)

Neuropsychological sequelae of haemolytic uraemic syndrome

BACKGROUND Severe haemolytic uraemic syndrome (HUS) in childhood can cause stroke, hemiplegia, cortical blindness, and psychomotor retardation. These outcomes are evident at the time of discharge immediately after the acute illness. Less is known about the neuropsychological outcomes of less severely affected children who recover from acute HUS. AIMS This multicentre case control study investigated the hypothesis that children who survive an acute episode of HUS without recognisable neurological injuries have greater impairment of cognitive, academic, and behavioural functions than controls. DESIGN Children with HUS were eligible if they had no evidence of severe neurological dysfunction when discharged from one of six Canadian hospitals. Controls had been admitted to hospital for a non-HUS illness and were matched by age, sex, first language, and socioeconomic status. All subjects underwent evaluation of behaviour, academic achievement, cognitive function, and verbal abilities using standardised tests administered by a psychometrist blinded to the case or control status. RESULTS Ninety one case control pairs were enrolled. No important differences between patients with HUS and paired controls were evident on tests of IQ, behaviour, verbal abilities, or academic achievement. There was no increased risk of attention deficit disorder among patients with HUS. There was no correlation between the severity of acute renal failure and neuropsychological measures, although scores on some verbal ability tests were lower in those with the highest serum creatinine concentrations during illness. CONCLUSIONS Children discharged from hospital without apparent neurological injury after an episode of acute HUS do not have an increased risk of subclinical problems with learning, behaviour, or attention.

Sequelae of haemolytic uraemic syndrome.

Twenty two patients with previous episodes of haemolytic uraemic syndrome (HUS) were investigated for evidence of deficits in cognitive, behavioural, and academic function. Patients were pair matched with 22 controls for age (+/- 1 year), gender, and socioeconomic status. HUS patients had numerically lower cognitive and achievement scores and higher behavioural problem ratings than their controls on every measure. None of the group differences was significant at the 0.01 level. Significance values between 0.10 and 0.01 were obtained for the Wechsler full scale and verbal intelligence quotient scores and for several of the achievement measures and behaviour ratings. These results were conservatively interpreted as trends and are considered to provide preliminary indications of a post-HUS deficit in behaviour, verbal intelligence, and the verbally based skills of reading comprehension and vocabulary. The findings provide interim guidelines for follow up care but require confirmation and elaboration in a larger study.

A PHASE II RANDOMIZED CONTROLLED TRIAL OF SYNSORB-PK FOR THE PREVENTION OF HEMOLYTIC UREMIC SYNDROME IN CHILDREN WITH VEROTOXIN-PRODUCING E. COLI (VTEC) GASTROENTERITIS. † 1684

A PHASE II RANDOMIZED CONTROLLED TRIAL OF SYNSORB-PK FOR THE PREVENTION OF HEMOLYTIC UREMIC SYNDROME IN CHILDREN WITH VEROTOXIN-PRODUCING E. COLI (VTEC) GASTROENTERITIS. † 1684

Experiences with HUS in Canada: what have we learned about childhood HUS in Canada?

Experiences with childhood hemolytic uremic syndrome (HUS) in Canada will focus on the development of the Canadian Pediatric Kidney Disease Research Centre (CPKDRC) and the results of our collaborative research over a 13-year period (1985-1998).

Epidemic Escherichia coli 0157: H7 gastroenteritis and hemolytic-uremic syndrome in a Canadian Inuit community: Intestinal illnes in family members as a risk factor

OBJECTIVE To evaluate risk factors for childhood hemolytic-uremic syndrome (HUS) and gastroenteritis during an epidemic of Escherichia coli O157:H7 infection. DESIGN Case-control study. SETTING Remote Inuit community of Arviat in northern Canada. PARTICIPANTS Of the 565 Arviat residents less than 15 years of age, 19 had HUS and 65 more had E. coli O157:H7 gastroenteritis. The 19 children with HUS were compared with 19 age- and gender-matched children with uncomplicated E. coli O157:H7 gastroenteritis, and both HUS and gastroenteritis patients were compared with 19 healthy control subjects. INTERVENTIONS Questionnaire administered face-to-face to parents of participants in the home. MAIN OUTCOME MEASURES Rates of exposure to foods, travel, sources of water, and gastrointestinal illness in family members. RESULTS Patients with HUS and those with uncomplicated E. coli O157:H7 gastroenteritis differed only on measures of clinical severity. In the 7 days before the onset of gastrointestinal symptoms, children with HUS and those with uncomplicated gastroenteritis were more likely to have been exposed to a family member with diarrhea than were the healthy control subjects (odds ratio = 9 for HUS vs healthy control subjects; 95% confidence interval 2 to 43; p < 0.01). Undercooked ground meat and foods traditionally consumed by the Inuit were not implicated as risk factors in E. coli O157:H7 infection. CONCLUSIONS These findings emphasize the potential for extensive intrafamilial transmission of verotoxin-producing E. coli once infection is introduced into certain communities.

AN IDIOTYPIC NATURAL AUTOANTIBODY NETWORK IN HEMOLYTIC UREMIC SYNDROME (HUS).|[dagger]| 1020

Introduction: We hypothesized that immune-mediated events rather than direct toxin injury might be involved in the pathogenesis of HUS associated with shiga-like toxin (SLT) producing E. coli.Purposes: Our objectives were to learn whether antibodies (AB) exist to the SLT glycolipid receptor Gb3, to define the occurrence and relationship between such anti-Gb3 ABs (α-Gb3) and anti-idiotypic ABs to them (α-α-Gb3), and to evaluate children infected with E. coli O157:H7 for these ABs.Methods: ELISAs were used for detecting α-Gb3 orα-α-Gb3 in sera from normal adults [n=15] and from children with E. coli O157:H7 associated with [n=24] or without [n=38] development of HUS. Results: Normals have both α-Gb3 and α-α-Gb3; levels of these ABs are correlated [r=0.9654]. The relationship between these antibodies in E. coli O157:H7 infection is shown below: Table Conclusions:(1) Autoantibodies to Gb3 are normally found. (2) α-Gb3 exists in balance with α-α-Gb3. (3) Children with HUS during the acute phase have significantly decreased levels of these ABs. We hypothesize that these ABs are low because α-α-Gb3 binds to SLT leaving α-Gb3 available to bind to Gb3 of endothelial cells and induce vascular injury. [Supported in part by NIH-PO1 HD-13021]