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Arch Dis Child. 2007 September; 92(9): 820–823.
PMCID: PMC2084030


Leukocytosis as a predictor for progression to haemolytic uraemic syndrome in Escherichia coli O157:H7 infection

Report by

M A Anjay, Specialist Registrar in Paediatrics, James Paget University Hospitals NHS Foundation Trust, Lowestoft Road, Gorleston, Great Yarmouth, Norfolk NR31 6LA, UK;

P Anoop, Paediatric Haemato‐oncology, Royal Marsden Hospital, Surrey, UK

A Britland, Airedale General Hospital, Keighley, West Yorkshire, UK

You are the specialist registrar in paediatrics doing the ward rounds. There has been a recent outbreak of Escherichiacoli (E coli) O157:H7 gastroenteritis in the community. A 5‐year old girl was admitted 3 days ago with bloody diarrhoea, abdominal cramps and vomiting. Her stool has grown E coli O157:H7. She is now stable and her parents are keen to take her home but are understandably anxious and ask you about possible complications. You are aware of the risk for progression to haemolytic uraemic syndrome (HUS). However, you are not sure if all such patients should be closely monitored. You note that the patient now has a normal platelet count and renal function and wonder if there are any simple parameters to predict the risk of HUS, which may take up to 2 weeks to develop.

You talk to the consultant in public health medicine, who kindly directs to you to the national guidelines by the Health Protection Agency (HPA) on the management of E coli O157:H7 infections.1 Unfortunately, the guidelines do not answer your question. Your consultant has come across anecdotal evidence that leukocytosis may be a predictor for HUS in such children.

You decide to do a literature search and critically appraise the evidence.

Structured clinical question

In a child with Escherichia coli O157:H7 infection [patient], does a high white blood cell count [risk factor] predict progression to haemolytic uraemic syndrome [outcome]?

Search strategy

Secondary sources

Cochrane library, Best Evidence, Clinical Evidence

No relevant articles were found

Primary sources

MEDLINE (1966 to date) and OLDMEDLINE (1950–1965) searched by the PubMed interface on 29/10/2006.

Search terms

“Hemolytic uremic syndrome” AND “Escherichia coli O157” with limits (English, Human, All child: 0–18 years) revealed 267 results.

Addition of the key words (leukocytosis OR “white cell count”) to the above yielded only seven results. This was felt to be an inappropriately low number, possibly due to variations in the terms used by authors (“elevated WBC”, “high leukocytes”, “increased white cell count”, etc).

A wider final search strategy adding suitable new key words to the original search was attempted as follows: (“Hemolytic uremic syndrome” AND “Escherichia coli O157”) AND (risk OR predictors).

This resulted in 71 hits. Among these, no systematic reviews relevant to the clinical question could be identified. Ten articles were found to be of relevance.2–11 See table 22.

Table thumbnail
Table 2 Leukocytosis as a predictor for progression to haemolytic uraemic syndrome


E coli O157:H7 is a relatively uncommon cause of infectious gastroenteritis in children. However, the severity of symptoms, the possibility of outbreaks and the potential for severe complications means it is of considerable public health importance. Infections with this subtype are known to lead to HUS in 2–7% of overall cases, which may rise to 30% in outbreaks.12 13 The disease can be particularly severe in children, with reported case fatality rates of 3–17% and a significant incidence of long‐term sequelae in survivors.14

Since more than 90% of children with E coli O157:H7 infection do not progress to HUS, intensive clinical and/or laboratory monitoring of all cases may not be feasible or cost‐effective. Attempts have been made to set up monitoring protocols to identify high‐risk patients and help with early interventions.3 As the median time for development of HUS is 9 days (range 1–15 days), early identification of risk factors will enable triage into high‐ and low‐risk groups and help target interventions appropriately.

Identification of clinical risk factors including the intensity of fever, vomiting, duration of illness and presence of blood in stools has been attempted with limited success.5 7 More recent efforts have focussed on objective laboratory criteria such as raised inflammatory markers, low serum protein, elevated lactate dehydrogenase levels and albuminuria.3 4 An elevated white blood cell (WBC) count has been noted to be associated with a higher risk for HUS, with some authors claiming a sensitivity and specificity of around 90%.3

Being a rare complication of an uncommon infection, case–control studies may be appropriate to define risk in this clinical situation.2 However, clustering of a large number of cases during epidemics may enable cohort studies to be performed with relative ease.3 5–9 Most authors in our analysis have identified E coli infection on the basis of positive stool cultures and some have also used seropositivity and/or clinical diagnosis.3 9 In all the above studies, the use of standardised criteria has made the diagnosis of HUS unambiguous. Attempts by some authors to subclassify HUS into confirmed/complete and probable/incomplete forms has only academic relevance and does not affect the validity of the conclusions.2 9 The relatively short time period between exposure and outcome as well as the serious nature of the condition requiring hospitalisation have ensured accurate data collection as well as lack of attrition in all studies.

Leukocytosis has consistently been noted as significant by several authors in their attempts to identify clinical, laboratory and medication‐related risk factors for progression to HUS.2–11 A comprehensive and focussed study by Buteau et al has demonstrated a clear progressive association of HUS with a rising WBC count.6 Two well conducted studies by Tserenpuntsag et al and Bell et al have clearly defined the high risk associated with a WBC count of >13×109/l even though the former study included adults as well.2 9 Similar results have also been obtained by Dundas et al, Ikeda et al and Wong et al, albeit at different WBC cut‐off levels.4 5 7 The latter two reports were exclusively paediatric studies. A well validated prospective cohort study by Wood et al revealed a sensitivity of 88.9% and a negative predictive value as high as 99.5% for an elevation in WBC count.3 We tried to look at two interesting practical issues, namely the timing of WBC count and the absolute cut‐off levels to identify high risk. Most studies assessed WBC counts within 72 h of onset of symptoms, although counts up to 5 days were included by some. The definition of a significant cut‐off WBC count varies among different authors, but most studies have quantified the risk to be very high above a WBC level of 11×109/l–13×109/l.2 5–7 9 None of the published studies suggest that leukocytosis is not a predictor for HUS.2–11 Indeed, there is biological evidence to implicate the role of leukocytes in the pathogenesis of HUS.15

Leukocytosis has thus been unequivocally delineated as a reliable predictor for the development of HUS following E coli O157:H7 infection. Combining this with other putative risk factors, such as elevated C‐reactive protein and albuminuria, might improve the accuracy of defining at‐risk groups. Well children seen in the community or hospitalised children who recover rapidly may not require follow‐up or investigations. However, where the diarrhoea has not resolved, a clinical impression of “well being” in the child has been shown to be unreliable as a reassuring factor.4 7 In such situations the use of validated risk factors is necessary to improve prognostic accuracy. Most of these children would have already had a full blood count and hence additional tests may not be required. A normal leukocyte count will provide reliable reassurance against progression to HUS in nine out of 10 cases.3 Similarly, leukocytosis will successfully predict progression to HUS in 70–90% of children.3 9

Interventions like early intravenous fluid therapy have already been proven to reduce the risk for progression to HUS, while other potential measures such as the use of toxin binders remain understudied.16 Formulation of a well defined risk assessment tool based on leukocytosis and other risk factors could help to identify high risk children and streamline the monitoring process and early use of appropriate interventions.

Clinical bottom line

  • Leukocytosis is a valid, independent and reliable early risk factor for predicting progression to HUS in children with E coli O157:H7 infection. (Grade B)
  • The absence of an elevated WBC count during early stages of the illness makes HUS an unlikely event following E coli O157:H7 infection in children. (Grade B)
  • Formulation of a well validated clinical decision rule (CDR) incorporating leukocytosis with other risk factors is likely to help with early identification of children at risk of developing HUS following E coli O157:H7 infection.


We wish to express our gratitude to Dr Paul Godwin (Consultant Microbiologist, Airedale General Hospital, Keighley, West Yorkshire) for initiating the discussions which led to this literature review.


1. Subcommittee of the PHLS Advisory Committee on Gastrointestinal Infections. Guidelines for the control of infection with verocytotoxin producing Escherichia coli (VTEC). Commun Dis Public Health 2000;3(1):14-23.
2. Tserenpuntsag B, Chang HG, Smith PF, et al. Hemolytic uremic syndrome risk and Escherichia coli O157:H7. Emerg Infect Dis 2005;11(12):1955-7.
3. Wood R, Donaghy M, Dundas S. Monitoring patients in the community with suspected Escherichia coli O157 infection during a large outbreak in Scotland in 1996. Epidemiol Infect 2001;127(3):413-20.
4. Dundas S, Todd WT, Stewart AI, et al. The central Scotland Escherichia coli O157:H7 outbreak: risk factors for the hemolytic uremic syndrome and death among hospitalized patients. Clin Infect Dis 2001;33(7):923-31.
5. Ikeda K, Ida O, Kimoto K, et al. Predictors for the development of haemolytic uraemic syndrome with Escherichia coli O157:H7 infections: with focus on the day of illness. Epidemiol Infect 2000;124(3):343-9.
6. Buteau C, Proulx F, Chaibou M, et al. Leukocytosis in children with Escherichia coli O157:H7 enteritis developing the hemolytic-uremic syndrome. Pediatr Infect Dis J 2000;19(7):642-7.
7. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342(26):1930-6.
8. Kawamura N, Yamazaki T, Tamai H. Risk factors for the development of Escherichia coli O157:H7 associated with hemolytic uremic syndrome. Pediatr Int 1999;41(2):218-22.
9. Bell BP, Griffin PM, Lozano P, et al. Predictors of hemolytic uremic syndrome in children during a large outbreak of Escherichia coli O157:H7 infections. Pediatrics 1997;100(1):E12.
10. Akashi S, Joh K, Tsuji A, et al. A severe outbreak of haemorrhagic colitis and haemolytic uraemic syndrome associated with Escherichia coli O157:H7 in Japan. Eur J Pediatr 1994;153(9):650-5.
11. Pavia AT, Nichols CR, Green DP, et al. Hemolytic-uremic syndrome during an outbreak of Escherichia coli O157:H7 infections in institutions for mentally retarded persons: clinical and epidemiologic observations. J Pediatr 1990;116(4):544-51.
12. Griffin PM, Tauxe RV. The epidemiology of infections caused by Escherichia coli O157: H7, other enterohemorrhagic Escherichia coli, and the associated hemolytic uremic syndrome. Epidemiol Rev 1991;13:60-98.
13. Morgan D, Newman CP, Hutchinson DN, et al. Verotoxin producing Escherichia coli O157 infections associated with the consumption of yoghurt. Epidemiol Infect 1993;111:181-7.
14. Fitzpatrick MM, Shah V, Trompeter RS, et al. Long term outcome of childhood haemolytic syndrome. BMJ 1991;303:489-92.
15. Fitzpatrick MM, Shah V, Filler G, et al. Neutrophil activation in the haemolytic uraemic syndrome: free and complexed elastase in plasma. Pediatr Nephrol 1992;6(1):50-3.
16. MacConnachie AA, Todd WT. Potential therapeutic agents for the prevention and treatment of haemolytic uraemic syndrome in shiga toxin producing Escherichia coli infection. Curr Opin Infect Dis 2004;17(5):479-82.

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