Haemolytic uraemic syndrome

What is haemolytic uraemic syndrome?

Haemolytic uraemic syndrome (HUS) was first described in 1955¹ . It is is a triad of:

• Microangiopathic haemolytic anaemia (Coombs' test negative).

• Thrombocytopenia.

• Acute kidney injury (acute renal failure).

Haemolytic uraemic syndrome is the most common cause of acute kidney injury in children and its incidence appears to be growing worldwide. Some children may develop partial or incomplete HUS with thrombocytopenia, with or without anaemia, but the serum creatinine concentration remains normal² .

Typical (or infection-induced) 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 toxin or verotoxin - hence, alternative names are Shiga toxin-producing E. coli (STEC) or verotoxin-producing E. coli (VTEC). STEC can produce two Shiga toxins (Stx) - Stx1 and/or Stx2. The presence of Stx2, specifically subtype stx2a, is more likely to cause haemolytic uraemic syndrome (HUS)³ .

Haemolytic uraemic syndrome is a systemic disease caused by damage arising from the circulating toxin which binds to endothelial receptors, particularly in the renal, gastrointestinal and central nervous systems. Thrombin and fibrin are deposited in the microvasculature. This occurs early in the disease, prior even to the development of HUS and may be why antibiotics confer no benefit. Erythrocytes are damaged as they pass through partially occluded small vessels and subsequent haemolysis occurs. Platelets are sequestered but without the cascade of clotting factors as in disseminated intravascular coagulation (DIC)⁴ .

Other pathogens may induce HUS - for example:

• Bacteria such as Streptococcus pneumoniae and Shigella dysenteriae type 1⁵ .

• Some viruses such as HIV and Coxsackievirus.

Atypical HUS can be caused by:

• Exposure to certain medications (eg, ciclosporin, tacrolimus).

• Genetic mutations in the complement pathway⁶ .

• Systemic conditions, including lupus, cancer and pregnancy.

Epidemiology^{7 8}

• Haemolytic uraemic syndrome is a rare disorder with an annual incidence of 6.1 cases per 100,000 children aged under 5 years (compared with an overall incidence of 1 to 2 cases per 100,000)² .

• The peak of incidence is in children (less than 5 years of age), the most susceptible age group. A previous British Paediatric Surveillance Unit (BPSU) study was conducted between 1997 and 2001 when there were 413 cases reported, 330 of which were VTEC-related⁹ .

• A follow-up retrospective study of paediatric STEC cases entered into the Public Health England National Enhanced Surveillance System was performed. This found that between 2011 and 2014, a fifth of such cases (207 out of 1,059) progressed to HUS. The odds of progression were highest in girls between1-4 years but there was no association with rurality or socio-economic status¹⁰ .

• In 2018, questionnaires were sent to a total of 607 confirmed cases of STEC O157 reported in England and Wales. 2% (14) were hospitalised for HUS. Most were under 5 years old (median age 3.7)³ .

• The development of HUS may occur up to two weeks after the initial onset of symptoms and may develop after apparent recovery from the initial acute illness. Cases may be sporadic or occur as part of larger outbreaks. Scotland has one of the largest incidences of VTEC outbreaks in the world. These outbreaks are often traced to butchers¹¹ .

• About 10% of HUS cases are atypical and are not caused by Shiga toxin-producing bacteria or streptococci. Patients without evidence of underlying infection should be fully investigated, in particular looking for complement gene mutations¹² .

• HUS occurs worldwide but is less widely reported in countries with less developed medical services.

The incubation period for STEC is 2-4 days³ . HUS usually arises within seven days after exposure to VTEC but this interval may be up to 14 days .

Risk factors

• Rural populations >urban populations.

• Warmer summer months (June-September).

• Young age (6 months to 5 years).

• Older people or those with altered immune response.

• Contact with farm animals.

Children with E. coli O157 enteritis should not go back to school or nursery until they have had two negative tests⁷ . Post-symptomatic shedding can occur but the highest transmissibility is thought to occur during the acute diarrhoeal phase.

Presentation

As with any child presenting with suspected gastroenteritis, assessment must include temperature, pulse, respiratory rate, blood pressure, weight and assessment of hydration¹³ .

• The classical presenting feature is profuse diarrhoea that turns bloody 1-3 days later. It is rare for the diarrhoea to have been bloody from the outset. About 80-90% 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.

• There is often fever, abdominal pain and vomiting:
  

  • About 50% 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.

  • Abdominal pain is more marked than with other forms of bacterial enteritis and defecation is often painful.

Investigation¹⁴

Early clinical signs of haemolytic uraemic syndrome may not be specific and it is recommended that if there is any suspicion of HUS (eg, any case of bloody diarrhoea) then assessment should include:

• FBC and film: evidence of haemolysis, anaemia and thrombocytopenia. Raised white cell count and low platelet count are early indicators of development of HUS. Features of microangiopathic haemolysis include falling haemoglobin, fragmented red cells on blood film examination, and low or falling platelet count.

• Renal function and electrolytes: a rise in urea and creatinine may be due to dehydration but, if associated with haemolysis and thrombocytopenia, indicates the onset of HUS.

• LFTs.

• Lactate dehydrogenase (LDH): high LDH is an early indicator of HUS.

• CRP.

• Clotting screen (reduced values may be seen during active HUS).

• Stool testing: stool sample should be sent for testing. Increasingly, microbiology departments are using polymerase chain reaction (PCR) testing rather than culture of the E. coli, as this is much quicker. Many patients will no longer be shedding bacteria but the presence of E. coli O157 has considerable public health implications¹⁴ .

• Urine: urinalysis (haematuria or proteinuria appear early in HUS); urine sent to laboratory for culture.

These investigations should be repeated if any clinical deterioration occurs. Whenever atypical HUS is suspected, further specialist tests are warranted, including¹² :

• Mutational analysis of specific complement genes.

• Von Willebrand factor-cleaving protease - ADAMTS13 - activity.

Differential diagnosis

Includes:

• Other causes of abdominal pain and diarrhoea - eg, acute gastroenteritis, appendicitis, inflammatory bowel disease, intussusception.

• DIC, perhaps with sepsis.

• HELLP syndrome (= Haemolysis, Elevated Liver enzymes, Low Platelet count).

• An autosomal dominant form of HUS exists with abnormality of the ADAMTS13 gene which encodes the von Willebrand factor. It tends to present in childhood¹⁵ .

• Inherited abnormalities of complement regulation.

• Thrombotic thrombocytopenic purpura (which can cause thrombotic microangiopathy).

Haemolytic uraemic syndrome treatment and management ¹⁶

See also the separate Escherichia Coli O157 article.

• Infectious bloody diarrhoea, HUS or the isolation of a VTEC must be reported promptly by telephone to the local Health Protection Team.

• Currently, the treatment of HUS remains purely supportive, with no evidence for specific treatments (eg, fresh frozen plasma transfusion, heparin, urokinase, dipyridamole, Shiga toxin-binding protein, steroids)¹⁷ .

• General management includes appropriate fluid and electrolyte management, antihypertensive therapy and dialysis where required. Circulating volume must be kept up to protect the kidneys; simply replacing losses with crystalloid and keeping up with faecal loss is inadequate, as circulating volume will be lost by vascular leakage. Where kidney failure occurs, indications for dialysis are as for any other cause of acute kidney failure.

• Novel therapeutic approaches include the use of monoclonal antibodies which block complement activity¹⁸ . Approaches to atypical HUS include¹⁹ :
  

  • Early plasma exchange (removing mutant complement proteins).

  • Specific targeted treatments - eg, factor H concentrate.

  • Liver or liver and kidney transplants.

Complications

• Gastrointestinal:
  

  • Intestinal strictures and perforations.

  • Intussusception and rectal prolapse.

  • Pancreatitis.

  • Severe colitis.

• Neurological:
  

  • Altered mental state.

  • Cerebrovascular accident (CVA).

  • Seizures.

• Renal:
  

  • Acute kidney injury.

  • Chronic kidney disease.

  • Haematuria.

  • Hypertension.

  • Proteinuria.

Prognosis

• Typical HUS with a diarrhoeal prodrome usually has a good prognosis. Only one death in a patient with STEC-associated HUS was reported in the 2018 Public Health England data analysis⁷ .

• Death due to HUS is nearly always associated with severe extrarenal disease, including severe central nervous system involvement.

• Fatality is highest in infants, small children and the elderly.

• Whilst renal recovery is the norm, there have been permanent and serious renal sequelae (hypertension, proteinuria, diminishing glomerular filtration rate) found in 5-25% of HUS patients¹⁴ .

• Atypical HUS often has a poorer prognosis, with death rates reportedly as high as 25% and progression to end-stage kidney disease in 50%¹⁹ .

Prevention

• 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. Separating known cases from their younger siblings may also be an appropriate measure²⁰ .

• Conjugate vaccines against E. coli O157 are yet to become commercially available²¹ .