Haemolytic Uraemic Syndrome

First described in 1955,¹ Haemolytic Uraemic Syndrome (HUS) is a triad of:

• Microangiopathic haemolytic anaemia (Coombs’ test –ve)
• Thrombocytopenia
• Acute renal failure

It is the most common cause of acute renal failure in children and its incidence appears to be growing worldwide.
HUS is most commonly associated with Escherichia coli with somatic (O) antigen 157 and flagella (H) antigen 7 - hence the designation O157:H7. It produces a toxin called shiga or vero, hence alternative names are Shiga-toxin-producing E. coli (STEC) or Vero-toxin producing E. coli (VTEC). O157:H7 is by far the commonest cause of typical (or infection induced) HUS in Europe, North America and Japan. Other pathogens that may produce HUS include bacteria such as Streptococcus pneumoniae and Shigella dysenteria-type 1² as well as some viruses such as HIV and Coxsackie. Atypical HUS can be caused by exposure to certain medications (eg cyclosporin, tacrolimus), genetic mutations in the complement pathway³ and systemic conditions including lupus, cancer and pregnancy.

O157:H7 causes haemorrhagic colitis and about 3-15% of cases progress to HUS.
It is a rare disorder with an average annual incidence of 1-3/100,000 children in the USA. In the UK, there was an upward trend in E. coli O157 notification in the early 1990s, peaking at just over 1,000 cases annually in England and Wales and the trend appeared to be declining in the first part of the decade.^6,7 HUS occurs worldwide but is less widely reported in countries with less developed medical services.

Risk factors

• Rural populations>urban populations
• Warmer summer months (June-Sept)
• Young age (primarily children<10 years)
• Older people or those with altered immune response
• Contact with farm animals

Reported sources of E. coli O157

Food

E. coli O157 are commonly found in the gut flora of cattle and other farm animals. Contaminated foodstuffs are therefore the usual source - in particular beef and milk - but fruit and vegetables may be infected by contact with manure from infected animals:

• Meat (risk highest when undercooked)
  • Beef and beef products eg hamburgers
  • Sausages
  • Venison
  • Cold sliced meats eg salami
• Milk and cheese(unpasteurised)
• Alfalfa sprouts
• Leaf lettuce/spinach
• Apple juice/cider (unpasteurised)

Environmental sources

• Faecal-contaminated lakes or streams
• Nonchlorinated domestic water supply
• Home paddling pools⁸
• Petting farm animals
• Unhygienic person-to-person contact particularly in households, nurseries, and infant schools

The incubation period for E. coli O157 is 1 to 6 days. Features of HUS tend to be apparent from about day 5-14 following the onset of diarrhoea so a high index of suspicion is required in the early stages. Risk of transmission in a nursery setting may be as high as 38%. Children with E. coli O157 enteritis should not go back to school or nursery until they have had 2 negative stools.⁹ Post-symptomatic shedding can occur but the highest transmissibility is thought to occur during the acute diarrhoeal phase.

HUS is a systemic disease caused by damage arising from circulating Shiga toxin. This injures endothelial cells generating thrombin and fibrin deposits in the microvasculature. This occurs early in the disease, prior even to the development of HUS and may be why antibiotics confer no benefit. Damage to endothelial cells causes leakage and tissue oedema. Erythrocytes are damaged as they pass through small vessels partially occluded by thrombus and haemolysis subsequently occurs. Platelets are sequestered but without the cascade of clotting factors as in DIC.

The classical presenting feature is profuse diarrhoea that turns bloody 1 to 3 days later, rarely on the first day. There is fever, abdominal pain and vomiting. About 80 to 90% of children from whom the organism is isolated will develop blood in the stool. It is usually at this stage that they are admitted to hospital. Most adults infected with E. coli O157 remain asymptomatic.
About half of patients give a history of having had fever but most are afebrile by the time they reach hospital. This is in contrast to most other causes of bacterial colitis. At this early stage there is a normal platelet count, creatinine concentration, and packed-cell volume, with no red-cell fragmentation.
Abdominal pain is more marked than with other forms of bacterial enteritis and defecation is often painful.

Laboratory tests are required to diagnose HUS:

1. Stool sample should be sent for culture and typing of the E. coli. Many patients will no longer be shedding bacteria but the presence of E. coli O157 has considerable public health implications.
2. FBC and blood film provides evidence of haemolysis, anaemia and thrombocytopenia. Packed cell volume of less than 30%, erythrocyte destruction evident on peripheral blood smear and platelet count less than 150 x 10^9/L are typical
3. Renal function (U&Es and creatinine) show the extent of renal involvement.

In addition there should be no other reasons for coagulopathy, such as septicaemia. Fibrinogen levels are normal or high, and the prothrombin time is only slightly prolonged. This is contrast to disseminated intravascular coagulation.

Includes:

• Other causes of abdominal pain and diarrhoea eg acute gastroenteritis, appendicitis, colitis, inflammatory bowel disease, intussusception
• Disseminated intravascular coagulation, perhaps with septicaemia
• An autosomal dominant form of haemolytic uraemic syndrome exists with abnormality of the ADAMTS13 gene which encodes the von Willebrand factor. It tends to present in childhood.¹¹
• Inherited abnormalities of complement regulation
• Idiopathic thrombocytopenia purpura (which can cause thrombotic microangiopathy)

Management is purely supportive:

• There is no place for treating the diarrhoea with antibiotics, antimotility drugs or codeine related compounds. Antibiotics confer no benefit, even if given early and may increase the risk of HUS and neurological complications.
• NSAIDs should be avoided for fear of predisposing to renal failure.
• Therapeutic agents such as plasmapheresis, steroids and anti-thrombotic drugs do not appear to offer benefit. Hope surrounds the development of shiga toxin-binders (based on recombinant bacteria or monoclonal antibodies) to block the development of HUS. A clinical trial of one synthetic toxin binder showed no benefit in established HUS but more potent toxin binders have since been developed and await human clinical trials and it would seem important that these agents be administered early to have maximum efficacy.¹²
• The patient should be admitted to hospital for intravenous rehydration. Circulating volume must be kept up to protect the kidneys, possibly even giving colloids. Simply replacing losses with crystalloid and keeping up with faecal loss is inadequate as circulating volume will be lost by vascular leakage and oedema may be observed. Potassium may need to be added to the intravenous fluids but care must be taken if urine volume falls. Oral intake of food or water is allowed although appetite is usually suppressed.
• FBC, U&Es and creatinine must be measured daily. Fluid load should be kept fairly high without being excessive.
• If creatinine rises then monitoring becomes more intense, noting blood pressure, looking for signs of cardiopulmonary overload and possibly transferring to a unit where acute renal failure can be managed. Weight and fluid charts must be monitored meticulously. Where renal failure occurs, indications for dialysis are as for any other cause of acute renal failure.
• If the platelet count is stable and the clinical picture is improving or if the platelet count starts to rise the danger period is past. Platelet transfusion is controversial and may be associated with neurological complications.

• Gastrointestinal
  • Intestinal strictures and perforations
  • Intussusception and rectal prolapse
  • Pancreatitis
  • Severe colitis
• Neurological
  • Altered mental state
  • CVA
  • Seizures
• Renal
  • Acute and chronic renal failure
  • Haematuria
  • Hypertension
  • Proteinuria

About 3-15% of infections with E. coli O157 progress to HUS with a case fatality rate of 5-10%. Fatality is highest in infants, small children and the elderly. In general, typical HUS with a diarrhoeal prodrome has a good prognosis, with most children recovering renal function. Atypical HUS often has a poorer prognosis and is more likely to be associated with incomplete recovery.

• The organism is very common in cattle and a low level of infection causes clinical disease. Prevention is based on reducing faecal contamination during slaughtering and processing.
• Good personal hygiene measures eg hand-washing before and after food-handling and eating, after toilet use and after contact with farm animals.
• Increased public awareness about good food hygiene eg cook meat and meat products well, especially where minced or in burger-form, avoid cross contamination between raw and cooked food.
• Early diagnosis enables early supportive treatment and better ultimate prognosis. Similarly early identification of an outbreak enables public health measures to be put in place to prevent further cases.
• Currently a conjugate vaccine against E. coli O157 is in development¹³ - phase 3 trials are awaited.