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Home > Professional Reference > Haemolytic Uraemic Syndrome

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Haemolytic Uraemic Syndrome

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

This disease is notifiable in the UK.


First described in 1955,1 haemolytic uraemic syndrome (HUS) is a triad of:

It is the most common cause of acute renal failure in children and its incidence appears to be growing worldwide.

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). HUS 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).2

Other pathogens may induce HUS, including bacteria such as Streptococcus pneumoniae and Shigella dysenteriae type 13 as well as some viruses such as HIV and Coxsackie virus.

Atypical HUS can be caused by exposure to certain medications (e.g. ciclosporin, tacrolimus), genetic mutations in the complement pathway4 and systemic conditions including lupus, cancer and pregnancy.

Epidemiology5,6

  • Haemolytic uraemic syndrome (HUS) 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).7
  • Over 90% of cases in children are secondary to infection. O157:H7 causes haemorrhagic colitis but only about 3-15% of cases progress to HUS. Cases may be sporadic or occur as part of larger outbreaks. The largest documented outbreak in England occurred in Cumbria in 1999, and was associated with pasteurised milk. It affected 114 people.
  • 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 mutations.8
  • 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-September).
  • Young age (6 months to 5 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, e.g. 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 pools.
  • 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.

Presentation

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

Investigation

Laboratory tests are required to diagnose haemolytic uraemic syndrome (HUS):

  1. Stool sample should be sent for culture and phage typing of the E. coli. Genes for virulence factors may be confirmed by polymerase chain reaction (PCR). Many patients will no longer be shedding bacteria but the presence of E. coli O157 has considerable public health implications. Note: serum or saliva samples may be used in the absence of a faecal sample when screening contacts during outbreaks.
  2. FBC and blood film provide 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 109/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 (DIC).

Whenever atypical HUS is suspected, further specialist tests are warranted including:8

  • Mutational analysis of specific complement genes.
  • Von Willebrand factor-cleaving protease - ADAMTS13 - activity.

Differential diagnosis

Includes:

  • Other causes of abdominal pain and diarrhoea, e.g. acute gastroenteritis, appendicitis, colitis, inflammatory bowel disease, intussusception.
  • Disseminated intravascular coagulation (DIC), perhaps with septicaemia.
  • HELLP syndrome: Haemolysis, EL (elevated liver) enzymes, LP (low platelet) count.
  • An autosomal dominant form of haemolytic uraemic syndrome (HUS) exists with abnormality of the ADAMTS13 gene which encodes the von Willebrand factor. It tends to present in childhood.10
  • Inherited abnormalities of complement regulation.
  • Thrombotic thrombocytopenic purpura (which can cause thrombotic microangiopathy).

Management2

Currently, the treatment of haemolytic uraemic syndrome (HUS) remains purely supportive, with no evidence for specific treatments (e.g. fresh frozen plasma transfusion, heparin, urokinase, dipyridamole, Shiga toxin-binding protein, steroids):11

  • Avoid antidiarrhoeal drugs. Antibiotics confer no benefit even if given early, and controversially may increase the risk of HUS and neurological complications.12,13
  • Non-steroidal anti-inflammatory drugs should be avoided for fear of predisposing to renal failure.
  • 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 renal failure occurs, indications for dialysis are as for any other cause of acute renal failure.

Novel therapeutic approaches include the use of monoclonal antibodies which block complement activity.14
Approaches to atypical HUS include:7

  • Early plasma exchange (removing mutant complement proteins).
  • Specific targeted treatments, e.g. factor H concentrate.
  • Liver or liver and kidney transplants.

Public Health should be notified where a diarrhoeal illness is thought to be food poisoning - this is a statutory duty. The informal reporting of HUS, particularly with a diarrhoeal prodrome, is encouraged. Public health measures are important to limit outbreaks - both to identify and remove primary sources of infection but also to prevent secondary infections.

Complications

Prognosis

Whilst, for most, typical haemolytic uraemic syndrome (HUS) with a diarrhoeal prodrome has a good prognosis, the disease also has a case fatality rate of 3-5%.15 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 patients.16 Atypical HUS often has a poorer prognosis, with death rates reportedly as high as 25%, and progression to end-stage renal disease in 50%.7

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, e.g. 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, e.g. 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 measure.17
  • Conjugate vaccines against E. coli O157 are in development18 - phase 3 trials are awaited.

Document references

  1. Gasser C, Gatier E, Steck A, et al; Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr. 1955 Sep 20;85(38-39):905-9.
  2. Tarr PI, Gordon CA, Chandler WL; Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005 Mar 19-25;365(9464):1073-86. [abstract]
  3. Waters AM, Kerecuk L, Luk D, et al; Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United kingdom experience. J Pediatr. 2007 Aug;151(2):140-4. [abstract]
  4. Caprioli J, Noris M, Brioschi S, et al; Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006 Aug 15;108(4):1267-79. Epub 2006 Apr 18. [abstract]
  5. E. coli O157, Health Protection Agency
  6. Razzaq S; Hemolytic uremic syndrome: an emerging health risk. Am Fam Physician. 2006 Sep 15;74(6):991-6. [abstract]
  7. Noris M, Remuzzi G; Atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Oct 22;361(17):1676-87.
  8. Johnson S, Taylor CM; What's new in haemolytic uraemic syndrome? Eur J Pediatr. 2008 Sep;167(9):965-71. Epub 2008 Jun 25. [abstract]
  9. Escherichia coli guidelines, Health Protection Agency
  10. Thrombotic Thrombocytopenic Purpura, Online Mendelian Inheritance in Man (OMIM)
  11. Michael M, Elliott EJ, Ridley GF, et al; Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003595. [abstract]
  12. 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 Jun 29;342(26):1930-6. [abstract]
  13. Safdar N, Said A, Gangnon RE, et al; Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli JAMA. 2002 Aug 28;288(8):996-1001. [abstract]
  14. Scheiring J, Rosales A, Zimmerhackl LB; Clinical practice. Today's understanding of the haemolytic uraemic syndrome. Eur J Pediatr. 2010 Jan;169(1):7-13. Epub 2009 Aug 26. [abstract]
  15. Scheiring J, Andreoli SP, Zimmerhackl LB; Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol. 2008 Oct;23(10):1749-60. Epub 2008 Aug 13. [abstract]
  16. Garg AX, Suri RS, Barrowman N, et al; Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a JAMA. 2003 Sep 10;290(10):1360-70. [abstract]
  17. Werber D, Mason BW, Evans MR, et al; Preventing household transmission of Shiga toxin-producing Escherichia coli O157 Clin Infect Dis. 2008 Apr 15;46(8):1189-96. [abstract]
  18. Ahmed A, Li J, Shiloach Y, et al; Safety and immunogenicity of Escherichia coli O157 O-specific polysaccharide conjugate vaccine in 2-5-year-old children. J Infect Dis. 2006 Feb 15;193(4):515-21. Epub 2006 Jan 13. [abstract]

Internet and further reading

Acknowledgements

EMIS is grateful to Dr Chloe Borton for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2010.
Document ID: 2220
Document Version: 22
Document Reference: bgp543
Last Updated: 28 Jun 2010
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