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

August 31, 2007

August 31, 2007

M A Anjay, Specialist Registrar in Paediatrics (James Paget University Hospitals, Paediatric Haemato-oncology, Royal Marsden Hospital, Airedale General Hospital respectively)

P Anoop, A Britland, James Paget University Hospitals, Paediatric Haemato-oncology, Royal Marsden Hospital, Airedale General Hospital respectively

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

You are the specialist registrar in paediatrics doing the ward rounds. There has been a recent outbreak of Escherichia coli (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. 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.

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

"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

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 (Griffin, Morgan). 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 (Fitzpatrick).

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 (Wood). 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 (Ikeda, Wong). More recent efforts have focussed on objective laboratory criteria such as raised inflammatory markers, low serum protein, elevated lactate dehydrogenase levels and albuminuria (Wood, Dundas). 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% (Wood).

Being a rare complication of an uncommon infection, case–control studies may be appropriate to define risk in this clinical situation (Tserenpuntsag). However, clustering of a large number of cases during epidemics may enable cohort studies to be performed with relative ease (Wood, Ikeda, Buteau, Wong, Kawamura, Bell). 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 (Wood, Bell).

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(Tserenpuntsag, Bell). 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. 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 (Tserenpuntsag, Wood, Dundas, Ikeda, Buteau, Wong, Kawamura, Bell, Akashi, Pavia). A comprehensive and focussed study by Buteau et al has demonstrated a clear progressive association of HUS with a rising WBC count. Two well conducted studies by Tserenpuntsag et al and Bell et al have clearly defined the high risk associated with a WBC count of >13x109/l even though the former study included adults as well. Similar results have also been obtained by Dundas et al, Ikeda et al and Wong et al, albeit at different WBC cut-off levels. 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.
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 11x109/l–13x109/l (Tserenpuntsag, Ikeda, Wong, Bell). None of the published studies suggest that leukocytosis is not a predictor for HUS (Tserenpuntsag, Wood, Dundas, Ikeda, Buteau, Wong, Kawamura, Bell, Akashi, Pavia). Indeed, there is biological evidence to implicate the role of leukocytes in the pathogenesis of HUS.15 (Fitzpatrick, 1992).

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 (Dundas, Wong). 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 (Wood). Similarly, leukocytosis will successfully predict progression to HUS in 70–90% of children (Wong, Bell).

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 (MacConnachie). 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.

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.

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