Mary E. Locking

Childhood Hemolytic Uremic Syndrome, United Kingdom and Ireland

The risk for diarrhea-associated HUS was higher for children infected with Escherichia coli O157 phage type (PT) 2 and PT21/28 than for those infected with other PTs.

Predicting the public health benefit of vaccinating cattle against Escherichia coli O157

Identifying the major sources of risk in disease transmission is key to designing effective controls. However, understanding of transmission dynamics across species boundaries is typically poor, making the design and evaluation of controls particularly challenging for zoonotic pathogens. One such global pathogen is Escherichia coli O157, which causes a serious and sometimes fatal gastrointestinal illness. Cattle are the main reservoir for E. coli O157, and vaccines for cattle now exist. However, adoption of vaccines is being delayed by conflicting responsibilities of veterinary and public health agencies, economic drivers, and because clinical trials cannot easily test interventions across species boundaries, lack of information on the public health benefits. Here, we examine transmission risk across the cattle–human species boundary and show three key results. First, supershedding of the pathogen by cattle is associated with the genetic marker stx2. Second, by quantifying the link between shedding density in cattle and human risk, we show that only the relatively rare supershedding events contribute significantly to human risk. Third, we show that this finding has profound consequences for the public health benefits of the cattle vaccine. A naïve evaluation based on efficacy in cattle would suggest a 50% reduction in risk; however, because the vaccine targets the major source of human risk, we predict a reduction in human cases of nearly 85%. By accounting for nonlinearities in transmission across the human–animal interface, we show that adoption of these vaccines by the livestock industry could prevent substantial numbers of human E. coli O157 cases.

Primary and secondary cases in Escherichia coli O157 outbreaks: a statistical analysis.

BackgroundWithin outbreaks of Escherichia coli O157 (E. coli O157), at least 10–15% of cases are thought to have been acquired by secondary transmission. However, there has been little systematic quantification or characterisation of secondary outbreak cases worldwide. The aim of this study was to characterise secondary outbreak cases, estimate the overall proportion of outbreak cases that were the result of secondary transmission and to analyse the relationships between primary and secondary outbreak cases by mode of transmission, country and median age.MethodsPublished data was obtained from 90 confirmed Escherichia coli O157 outbreaks in Great Britain, Ireland, Scandinavia, Canada, the United States and Japan, and the outbreaks were described in terms of modes of primary and secondary transmission, country, case numbers and median case age. Outbreaks were tested for statistically significant differences in the number of ill, confirmed, primary and secondary cases (analysis of variance and Kruskal-Wallis) and in the rate of secondary cases between these variables (Generalised Linear Models).ResultsThe outbreaks had a median of 13.5 confirmed cases, and mean proportion of 0.195 secondary cases. There were statistically significant differences in the numbers of ill, confirmed, primary and secondary cases between modes of primary transmission (p < 0.021), and in primary and secondary cases between median age categories (p < 0.039) and modes of secondary transmission (p < 0.001).Secondary case rates differed statistically significantly between modes of secondary and primary transmission and median age categories (all p < 0.001), but not between countries (p = 0.23). Statistically significantly higher rates of secondary transmission were found in outbreaks with a median age <6 years and those with secondary transmission via person to person spread in nurseries. No statistically significant interactions were found between country, mode of transmission and age category.ConclusionOur analyses indicated that ~20% of E. coli O157 outbreak cases were the result of secondary spread, and that this spread is significantly influenced by age and modes of primary and secondary transmission, but not country. In particular, the results provide further data emphasising the importance of simple but effective preventive strategies, such as handwashing, that can reduce the risk of secondary spread, particularly amongst young children in nurseries.

Spatial and temporal epidemiology of sporadic human cases of Escherichia coli O157 in Scotland, 1996-1999

In Scotland, between 1995 and 2000 there were between 4 and 10 cases of illness per 100000 population per year identified as being caused by Escherichia coli O157, whereas in England and Wales there were between 1 and 2 cases per 100000 population per year. Within Scotland there is significant regional variation. A cluster of high rate areas was identified in the Northeast of Scotland and a cluster of low rate areas in central-west Scotland. Temporal trends follow a seasonal pattern whilst spatial effects appeared to be distant rather than local. The best-fit model identified a significant spatial trend with case rate increasing from West to East, and from South to North. No statistically significant spatial interaction term was found. In the models fitted, the cattle population density, the human population density, and the number of cattle per person were variously significant. The findings suggest that rural/urban exposures are important in sporadic infections.

Pathogenic Potential to Humans of Bovine Escherichia coli O26, Scotland

This pathogen may be the next Shiga toxin–producing E. coli of concern.

Sorbitol-fermenting Escherichia coli O157, Scotland.

To the Editor: Verotoxin-producing Escherichia coli (VTEC) of serogroup O157 causes severe gastrointestinal and renal illness; clinical signs may be mild diarrhea, hemorrhagic colitis, or hemolytic uremic syndrome (HUS). Typically, 10%–15% of reported VTEC infections quickly progress to HUS (1). Sorbitol-fermenting (SF)–O157 strains have emerged in continental Europe (2,3). Some evidence suggests that SF-O157 is more frequently associated with HUS than are non-sorbitol–fermenting strains (3–6). SF-O157 shows increased adherence to colonic epithelial cells and may in turn cause a more potent inflammatory host response, resulting in a higher risk for HUS (4). The potentially greater virulence of SF-O157 requires urgent identification of its reservoir(s) and vehicle(s) of infection, as well as determination of genetic or other predisposing factors for infection with this strain. To understand whether the host pathophysiologic responses to SF-O157 and non–SF-O157 strains differ, we analyzed a cohort of children with HUS who were infected with E. coli O157. During April and May 2006, Health Protection Scotland (HPS) identified 18 cases of verotoxin-producing SF-O157 infection in Scotland, 13 of which were associated with a nursery. HUS developed in 8 of the 18 patients; those with thrombotic microangiopathy were admitted to the renal unit of a specialist pediatric hospital, which immediately reports cases of HUS to HPS as part of national surveillance (7). To test the hypothesis that SF-O157 was more virulent than non–SF-O157, we performed an age-matched, nested case–case study of HUS case-patients and analyzed host clinical markers, treatment, and outcomes from SF-O157 and non–SF-O157 cases in 2006. Clinical questionnaires, patient information sheets, and consent forms were completed by clinicians for each case-patient and returned to HPS; data were entered into a database in Epi Info version 6 (Centers for Disease Control and Prevention, Atlanta, GA, USA). Statistical analysis by t test showed that nadirs for serum albumin were significantly higher for children with SF-O157 HUS (p = 0.03; Table) than for children with non–SF-O157 HUS and that children with SF-O157 HUS had significantly more sessions of hemodialysis than did children with non–SF-O157 HUS (p = 0.01; Table). All case-patients were oligoanuric; the 2 groups did not differ with respect to this parameter. Initial signs and symptoms were similar for both sets of patients, i.e., classic VTEC symptoms of bloody diarrhea and abdominal pain. This finding is in acccordance with those of other studies of SF-O157 outbreaks, which also noted signs and symptoms compatible with VTEC-associated gastroenteritis (5,6). Table Characteristics of patients infected with non–SF-O157 versus SF-O157 Escherichia coli, Scotland, 2006* Our study highlights a number of lessons. Medical practitioners rarely have the opportunity to recognize patients at such an appreciable and predictable risk of progressing rapidly to anuric renal failure as they do when they see children with early O157 infection. Failure to appreciate the potential gravity of O157 infection and the possible development of HUS may result in avoidable illness and even death. Our investigation of the prehospital management of SF-O157 and non–SF-O157 in this cohort found no difference in pharmacologic intervention or duration of delay in admission to hospital. Our study has limitations. A number of patients in the cohort were prescribed antimicrobial drugs and/or antimotility drugs or were sent home from the local hospital without hospital admission or further monitoring; such actions potentially exacerbate clinical outcomes (1,8). We recognize that comparison of the SF-O157 outbreak strain with non–SF-O157 strains (some of which caused sporadic cases) may be a potential confounding factor in the analysis. However, recently published work has indicated no statistically significant differences in the verotoxin proteins encoded by SF-O157 or non–SF-O157 strains or in their level of toxicity (9). Other virulence factors may contribute to increased likelihood of HUS (4). Our data suggest that infection with SF-O157 results in less severe colitis than does the more common non–SF-O157 infection. Less severe colitis could result in a lower risk for renal disease because less verotoxin would be translocated into the bloodstream and bound to the kidneys. However, patients infected with SF-O157 had anuria for longer periods and consequently had longer sessions of peritoneal and hemodialysis. Although unknown bacterial or host inflammatory cytokines may contribute to enhanced disease progression, this observation is surprising and requires further investigation. Additional research is needed to learn more about the virulence of SF-O157 strains and establish other host factors that contribute to disease progression.

Escherichia coli O157 Infection and Secondary Spread, Scotland, 1999–2008

To determine the proportion of Escherichia coli O157 cases in Scotland attributable to secondary spread, we analyzed data obtained through entire-population enhanced surveillance. We identified 11% of cases as secondary. Secondary cases in single households were younger than secondary cases in outbreaks affecting >1 household and had similar risk for hemolytic uremic syndrome.

Highly Virulent Escherichia coli O26, Scotland

To the Editor: Hemolytic uremic syndrome (HUS) is a rare disorder characterized by microangiopathic hemolytic anemia, microthrombi, and multiorgan injury. HUS is one of the commonest causes of acute renal failure in children worldwide and is most frequently precipitated by infection with verotoxin-producing Escherichia coli (VTEC) such as E. coli O157 (1). However, non-O157 VTEC serotypes have been increasingly found in the development of HUS (2–4). Although previous surveillance of childhood HUS in Scotland identified E. coli O157 in >90% of cases, non-O157 serotypes have also been associated with HUS (5). In 2010, several particularly severe cases of HUS were reported to Health Protection Scotland by a consultant pediatric nephrologist. Subsequent tests identified the pathogen in these cases as E. coli O26. However, in a recent study of pediatric HUS cases in Europe, children infected with E. coli O26 did not exhibit different clinical signs and symptoms from patients infected with other VTEC serotypes (6). To establish whether the host pathophysiologic responses to E. coli O157 and E. coli O26 strains differed, we analyzed a cohort of children with HUS who were infected with these VTEC serotypes. In Scotland, most patients with pediatric thrombotic microangiopathy are referred to a specialist pediatric hospital, which immediately reports cases of HUS to Health Protection Scotland as part of national surveillance. To test the hypothesis that E. coli O26 was more virulent than E. coli O157, we performed an age-matched, nested case–case study of HUS patients and compared host clinical markers, treatment, and outcomes from pediatric cases in 2010. Data collection has been described elsewhere (5). The statistical significances of associations between categorical variables were investigated by using χ2, Fisher exact, Mann-Whitney, or t tests. All analyses were performed by using SPSS version 11 (SPSS Inc., Chicago, IL, USA) with a significance level of 5%. Although initial signs and symptoms were similar for both sets of cases, i.e., bloody diarrhea and abdominal pain, statistical analysis showed that children with O26-HUS were more likely to have neurologic complications and diabetes mellitus and require admission to the intensive care unit than O157-HUS patients (p = 0.02 for neurologic complications and diabetes and p = 0.04 for admission to an intensive treatment unit; Table). Table Characteristics of infection in children with Escherichia coli O157 versus E. coli O26, Scotland, 2010* All patients with HUS were oligoanuric, and the 2 groups did not differ with respect to this parameter. However, O26-HUS patients had significantly longer periods of anuria than O157-HUS patients (p = 0.04; Table) and were more likely to require treatment with hemofiltration than with peritoneal or hemodialysis (p = 0.001; Table). One patient with O26-HUS also experienced cardiomyopathy resulting in reduced left ventricular function. Our study illustrates the potential for increased severity of E. coli O26 infection in children. In Scotland, HUS is more commonly associated with E. coli O157 infection, and the outcome for children infected with this pathogen is much better than that reported in other studies (7,8). In this study, the clinical severity and outcomes for the children with O26-HUS were worse than for children requiring treatment for O157-HUS. We investigated the prehospital management of E. coli O157 and O26 patients in this cohort and found no difference in pharmacologic intervention or duration of delay in admission to hospital. In our cohort, vtx1 and vtx2 genes were detected in isolates from 2 of 3 patients. A diagnosis was made in the third patient by detection of E. coli O26 lipopolysaccharide–specific immunoglobulin M in serum; it was therefore not possible to confirm the presence of vtx genes. However, it is not unusual for VTEC to be undetectable in stool samples from patients with HUS, most likely because of intrahost bacteriophage lysis. Therefore, serodiagnosis of VTEC is considered a necessary adjunct to bacteriological confirmation of infection (9). A recent study suggests E. coli O26 exists as a highly dynamic group of organisms that can undergo verotoxin gene loss and be transferred during infection in humans, resulting in new pathogenic clones (10). Therefore, vtx2 gene acquisition by E. coli O26 may have contributed to increased virulence. Our study was limited by the small number of patients with pediatric O26-HUS. However, given the severity of the complications experienced by the children in this cohort, we believe it is necessary to communicate these findings promptly to the international community. We suggest that infection with E. coli O26 in children can result in more severe and complicated forms of HUS than those caused by E. coli O157. In contrast to the findings of Gerber et al., we found that there was a significant difference in neurologic complications between the 2 groups (2). Epidemiologic investigations found that 2 of the 3 children lived on farms and may have acquired infection while playing near their homes (the other was acquired through foreign travel). Risk communication of VTEC infection to parents of young children who live in farming communities remains problematic, perhaps because of the perception that immunity has been acquired. Although this suggestion may be true for adults, children are likely to be immunologically naive. Salient public health messages on simple precautionary behavior need to be regularly reinforced because prevention of VTEC infection prevents HUS.

A large Great Britain-wide outbreak of STEC O157 phage type 8 linked to handling of raw leeks and potatoes

Between December 2010 and July 2011, 252 cases of STEC O157 PT8 stx1 + 2 infection were reported in England, Scotland and Wales. This was the largest outbreak of STEC reported in England and the second largest in the UK to date. Eighty cases were hospitalized, with two cases of haemolytic uraemic syndrome and one death reported. Routine investigative data were used to generate a hypothesis but the subsequent case-control study was inconclusive. A second, more detailed, hypothesis generation exercise identified consumption or handling of vegetables as a potential mode of transmission. A second case-control study demonstrated that cases were more likely than controls to live in households whose members handled or prepared leeks bought unwrapped [odds ratio (OR) 40, 95% confidence interval (CI) 2·08-769·4], and potatoes bought in sacks (OR 13·13, 95% CI 1·19-145·3). This appears to be the first outbreak of STEC O157 infection linked to the handling of leeks.

Outbreak of Shiga toxin-producing E. coli O157 associated with consumption of watercress, United Kingdom, August to September 2013.

An increase in the number of cases of Shiga toxin-producing Escherichia coli O157 PT 2 stx2 infection was reported in the United Kingdom on 9 September 2013. Of the 19 cases, 13 were interviewed, of which 10 reported consuming watercress purchased from one retailer. The retailer recalled pre-packed bagged salads containing watercress on 12 September. The descriptive epidemiology was supported by a case–case study performed after control measures were implemented.