Haemolytic uraemic syndrome (HUS) is the leading cause of paediatric acute kidney injury [Ake et al, 2005; Bitzan, 2009]. 90% of cases occur secondary to an infection with a Shiga toxin (Stx) producing bacterium, most commonly Escherichia coli (E.coli). Any E.coli which produces Stx is called a Shiga toxin producing E.coli or STEC. The most common type of E.coli associated with HUS in the UK is E.coli O157. Only 10-15% of children infected with E.coli O157 go on to develop HUS [Scheiring, Andreoli & Zimmerhackl, 2008]. Infected children present with diarrhoea which can be bloody. This is a red flag warning which should lead clinicians to investigate the cause of the diarrhoea further. Further information on managing acute bloody diarrhoea in children can be found here. Some children have severe gastroenteritis with significant pain.
Features of HUS develop 3 to 14 days after onset of the diarrhoeal illness. HUS is characterized by the clinical triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury. Children can present with pallor, lethargy, reduced urine output or peripheral oedema. Currently, there is no direct treatment for this disease so management focuses on supportive therapies. Antibiotics are not used to treat STEC HUS and some can make the disease worse. STEC HUS is a public health concern and should be reported accordingly.
STEC HUS was first described in the 1980’s [Karmali et al, 1983] and since then there has been little change in management strategies other than improving supportive care. In an attempt to understand this disease better, the STEC HUS RaDaR Rare Disease Group (RDG) was set up. We hope to collect information on STEC HUS cases from around the UK so we can understand the disease in more detail. We hope that this will help researchers to develop new therapeutic strategies to treat the disease process. For more information about the RDG please click here.
In the UK there are approximately 1,100 cases of STEC infections annually and 100 new cases of STEC HUS per year [Lynn et al, 2005]. However, current surveillance systems may underestimate STEC HUS cases. STEC HUS has always been more common in children, particularly those under the age of 5 [Scheiring, Andreoli & Zimmerhackl, 2008]. STEC HUS is more common in Scotland [Pearce et al, 2009; Money et al, 2010] for reasons which are not fully appreciated. Seasonal variation also occurs with more cases in summer months than during the winter [Money et al, 2010]. STEC infection is contracted after contact with farm animals (or their faeces) which are asymptomatic carriers, eating contaminated food or drinking contaminated water (beware private water supplies), playing or swimming in contaminated water or from direct person to person contact (faecal-oral).
Children infected with a STEC pathogen usually develop a diarrhoeal illness two to five days later [Scheiring, Andreoli & Zimmerhackl, 2008]. Typically the diarrhoea is profuse and can be bloody. Signs and symptoms of HUS occur later, usually 3 to 14 days after the diarrhoea started. There are no known reliable clinical factors that predict which patients with STEC infections are at risk of developing HUS. Medical examination often reveals signs of oligoanuric kidney injury with fluid overload and hypertension but there is a spectrum of disease. Some children may be dehydrated because of diarrhea and reduced intake. Children with the mildest form of the disease are often treated by general pediatricians whilst those more severely affected are referred for specialist paediatric nephrology care.lincal
The diagnosis of STEC HUS relies on three things: 1. Clinical suspicion
Patient history will establish clinical suspicion for STEC HUS. Evidence of an infectious source can help.
- Do they have profuse, protracted or bloody diarrhoea?
- Have they been in contact with other people with bloody diarrhoea?
- Have they recently visited a farm or farm park?
- Or visited somewhere with a private water supply?
- BEWARE a family history of HUS separate from this recent diarrhoeal illness – consider complement mediated atypical HUS (see Other types of HUS below)
2. Identify the clinical features of HUS
- Full blood count: look for anaemia with a low platelet count.
- Blood film: Are there fragmented red cells (schistocytes)?
- Group and save: in case blood products are required.
- U&E’s: Evidence of renal impairment. There may also be electrolyte abnormalities detected. Is the sodium normal?
- Urinalysis: If the child is passing urine, urinalysis may show proteinuria or haematuria. A minority of children may have a STEC E.coli urine infection causing their HUS, but this is rare.
- Lactate dehydrogenase: LDH is a marker of cellular breakdown and is used to indicate ongoing haemolysis.
- Complement studies: there are other causes of HUS which are caused by disorders of complement activation (see Other types of HUS below) and there is also an increasing research interest in the role of complement in STEC HUS. We would recommend measuring C3 and C4 levels in STEC HUS patients.
These tests will be available locally – please consult local labs for sample requirement. 3. Identify the Shiga toxin producing bacteria which caused the HUS
- Stool culture: A sample of stool should be sent to the local microbiology lab, detailing the child’s symptoms and that HUS is suspected. Local labs can detect the most common organism associated with Stx HUS; E.coli O157. Positive samples will be sent to the reference lab for confirmation and further analysis which includes the phage type, which toxin is produced (Stx1 and/or Stx2) and other genetic features. Communication with the local lab is very important. If the initial stool culture for E.coli O157 is negative but clinical suspicion is high, the sample should be sent to the reference lab for more detailed analysis. Non-O157 STEC will NOT be detected on routine stool culture and further analysis is required [Jenkins et al, 2012].
- Rectal swab is not as good as a stool culture but could be considered if it is crucial to establishing a diagnosis and no stool can be obtained. Not first line test.
- Serology: Evidence of Stx bacterial infection can also be obtained by examining a sample of serum. Antibodies to the lipopolysaccharide (LPS) produced by the bacteria can be detected. Thus, even if the stool culture is negative this can provide evidence of STEC infection. Not all STEC HUS patients will develop antibodies detectable on serology giving a false negative result [Ludwig et al, 2002]. Furthermore, normal people can also acquire antibodies and not have HUS (false positive, for O157 LPS IgM this is reported to be 1.5% [Ludwig et al, 2002]). All results must be interpreted in the context of the clinical information.
Failure to identify a STEC through stool culture or serology should raise the suspicion of atypical HUS even in those with a prodrome of bloody diarrhea.
There is no direct treatment for STEC HUS [Bitzan, 2009; Scheiring, Andreoli & Zimmerhackl, 2008]. Medical management is supportive; focusing on stabilizing the patient until natural resolution of the disease occurs and recovery begins. Those with mild disease are treated with an individual fluid and electrolyte management plan, nutritional support and medication for hypertension [Ake et al, 2005; Scheiring, Andreoli & Zimmerhackl, 2008]. More severely affected patients will require renal replacement therapy (dialysis) [Ake et al, 2005; Scheiring, Rosales & Zimmerhackl, 2010].
Peritoneal dialysis and haemodialysis can be used and the decision on which to use will be based on the individual patient. The most severe cases require intensive care and some patients may receive plasma exchange although there is not a good evidence base to support its use in STEC HUS [Rosales et al, 2012; Clark, 2012; Keir, Marks & Kim, 2012; Kemper, 2012; Kielstein et al, 2012]. The main reason for its use is when rarer causes of HUS are considered (see Other types of HUS below).
Whilst the main culprit that initiates the disease is E.coli bacteria, antibiotics are not used to treat HUS. There is conflicting data in the literature, however most studies show no benefit to using antibiotics and there is the possibility of causing harm particularly if bacteriocidal antibiotics are given to a child with STEC [Keir, Marks & Kim, 2012].
There have been several case reports in the literature describing the use of the C5 monoclonal antibody eculizumab in STEC HUS [Kemper, 2012; Kielstein et al, 2012; Loos et al, 2012; Lapeyraque et al, 2011]. To date, the data does not show benefit when used in STEC HUS and so the routine use of eculizumab cannot be recommended at this time.
The severity of the disease and clinical course impacts prognosis. Those with mild disease gradually improve with recovery of renal function over a few weeks [Rosales et al, 2012, Garg, 2003, Spinale et al, 2013]. Severe disease can take longer. 70% of STEC HUS patients make a full recovery. 1-5% of STEC HUS cases are fatal [Bitzan, 2009, Lynn et al, 2005, Spinale et al, 2013]. 30% of STEC HUS cases are left with long term problems, many affecting the kidney e.g. proteinuria, hypertension or chronic renal impairment [Rosales et al, 2012, Spinale et al, 2013]. Most of these problems persist from the acute illness but a recent study reported that new onset proteinuria and hypertension can occur 1-2 years after resolution of the acute illness [Rosales et al, 2012].
Most patients will recover from their acute episode of STEC HUS and the disease should not recur. However, patients should be followed up after having this disease. The main concern is the risk of developing proteinuria and hypertension even in those who appear to have completely recovered from the acute disease. Yearly review with urinalysis and blood pressure check is prudent. It is unclear from current data how long these reviews should continue if tests are repeatedly normal. However, some children can present with 1 to 2 years after acute illness with new onset hypertension and proteinuria [Rosales et al, 2012] therefore length of follow up should reflect this.
There are other causes of HUS. These are broadly called atypical HUS and account for the remaining 10% of cases. This term has traditionally been used to describe a variety of patients who present with HUS but do not have evidence of a Stx producing gastrointestinal pathogen. This highlights the importance of establishing a STEC diagnosis.
The term atypical HUS includes familial cases which are caused by disorders of complement activation [Noris & Remuzzi, 2009]. These are now being successfully treated with a monoclonal antibody which block the final common pathway of complement activation (C5) [Westra et al, 2012; Gruppo & Rother, 2009; Nürnberger et al, 2009; Köse et al, 2010]. Other factors which cause atypical HUS include streptococcus pneumoniae infections, pregnancy, drugs, malignancy, connective tissue disorders and metabolic defects [Noris & Remuzzi, 2009, Taylor et al, 2010; Ariceta et al, 2009; Keir & Coward, 2011].
- Clinical triad:
- Microangiopathic haemolytic uraemia
- Acute kidney injury
- 90% of HUS cases occur after STEC infection
- Diarrhoeal illness – 3-14 days later – HUS
- Establish diagnosis:
- Clinical suspicion
- Clinical features of HUS: Clinical examination. Bloods: FBC, Blood film, G&S, U&E’s, LDH, C3. Urinalysis.
- Evidence of STEC infection: stool and serology
- No direct treatment – supportive management only
- Antibiotics NOT used
- 70% full recovery
- 30% long term sequalae
- Long term follow up required: urinalysis and BP
- Notifiable disease
- Report to BPSU: orange card
Shiga toxin producing E.coli infections (with or without HUS) must be notified to the local health protection agency
Further advice can be sought from your local microbiology lab or at your local health protection website:
- Public Health England
- Public Health Wales
- Health Protection Scotland
- HSC Public health agency for Northern Ireland
STEC HUS cases in children should also be reported to the British Paediatric Surveillance Unit (BPSU) through their orange card reporting system.