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Haemolytic uraemic syndrome (HUS) was first described in 1955.It is is a triad of:
- Microangiopathic haemolytic anaemia (Coombs' test negative).
- Acute kidney injury (acute renal failure).
It 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 normal.
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).
Other pathogens may induce HUS - for example:
- Bacteria such as Streptococcus pneumoniae and Shigella dysenteriae type 1.
- 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 pathway.
- Systemic conditions, including lupus, cancer and pregnancy.
- 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).
- In the UK and Ireland, the two British Paediatric Surveillance Unit prospective surveys (1985-1988 and 1997-2001) of HUS in children aged under 16 years reported a strong association in the incidence of HUS and age, with children under 5 years of age being most commonly affected.
- Over 90% of cases in children are secondary to infection. Approximately 15% of cases of E. coli O157 infection will develop HUS. 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. 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.
- HUS occurs worldwide but is less widely reported in countries with less developed medical services.
The incubation period for E. coli O157 is 1 to 6 days. HUS usually arises within 14 days after the onset of diarrhoea due to VTEC infection (the mean period reported in the UK is 6-8 days but this interval may be more prolonged). Risk of transmission in a nursery setting may be as high as 38%.
- 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 stools.Post-symptomatic shedding can occur but the highest transmissibility is thought to occur during the acute diarrhoeal phase.
Assessment must include temperature, pulse, respiratory rate, blood pressure, weight and assessment of hydration.
- 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 80-90% 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.
Early clinical signs of HUS 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.
- Lactate dehydrogenase (LDH): high LDH is an early indicator of HUS.
- Clotting screen (reduced values may be seen during active HUS).
- Stool culture: 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. NB: serum or saliva samples may be used in the absence of a faecal sample when screening contacts during outbreaks..
- 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, including:
- Mutational analysis of specific complement genes.
- Von Willebrand factor-cleaving protease - ADAMTS13 - activity.
- 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 childhood.
- Inherited abnormalities of complement regulation.
- Thrombotic thrombocytopenic purpura (which can cause thrombotic microangiopathy).
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 Unit.
- 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).
- 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 activity. Approaches to atypical HUS include:
- Early plasma exchange (removing mutant complement proteins).
- Specific targeted treatments - eg, factor H concentrate.
- Liver or liver and kidney transplants.
- Intestinal strictures and perforations.
- Intussusception and rectal prolapse.
- Severe colitis.
- Altered mental state.
- Cerebrovascular accident (CVA).
- Acute kidney injury.
- Chronic kidney disease.
- Typical HUS with a diarrhoeal prodrome usually has a good prognosis. The two British Paediatric Surveillance Unit prospective surveys in the UK and Ireland (1985-1988 and 1997-2001) of HUS in children aged under 16 years reported a mortality rate of HUS in the first of these surveys to be 5.6% and this had decreased to 1.8% in the second survey.
- 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.
- Atypical HUS often has a poorer prognosis, with death rates reportedly as high as 25% and progression to end-stage kidney disease in 50%.
- 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 measure.
- Conjugate vaccines against E. coli O157 are in development - phase 3 trials are awaited.
Further reading and references
Phillips B, Tyerman K, Whiteley SM; Use of antibiotics in suspected haemolytic-uraemic syndrome. BMJ. 2005 Feb 19330(7488):409-10.
Farm visits: avoiding infection; Public Health England, Jan 2014
Grisaru S; Management of hemolytic-uremic syndrome in children. Int J Nephrol Renovasc Dis. 2014 Jun 127:231-9. doi: 10.2147/IJNRD.S41837. eCollection 2014.
Tarr PI, Gordon CA, Chandler WL; Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005 Mar 19-25365(9464):1073-86.
Waters AM, Kerecuk L, Luk D, et al; Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United kingdom experience. J Pediatr. 2007 Aug151(2):140-4.
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 15108(4):1267-79. Epub 2006 Apr 18.
Escherichia coli (E. coli): guidance, data and analysis; Public Health England, August 2014
Razzaq S; Hemolytic uremic syndrome: an emerging health risk. Am Fam Physician. 2006 Sep 1574(6):991-6.
Noris M, Remuzzi G; Atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Oct 22361(17):1676-87.
The management of acute bloody diarrhoea potentially caused by vero cytotoxin-producing Escherichia coli in children; Public Health England (July 2011)
Johnson S, Taylor CM; What's new in haemolytic uraemic syndrome? Eur J Pediatr. 2008 Sep167(9):965-71. Epub 2008 Jun 25.
Thrombotic Thrombocytopenic Purpura, Congenital, TTP; Online Mendelian Inheritance in Man (OMIM)
Michael M, Elliott EJ, Ridley GF, et al; Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev. 2009 Jan 21(1):CD003595.
Scheiring J, Rosales A, Zimmerhackl LB; Clinical practice. Today's understanding of the haemolytic uraemic syndrome. Eur J Pediatr. 2010 Jan169(1):7-13. Epub 2009 Aug 26.
Garg AX, Suri RS, Barrowman N, et al; Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA. 2003 Sep 10290(10):1360-70.
Werber D, Mason BW, Evans MR, et al; Preventing household transmission of Shiga toxin-producing Escherichia coli O157 infection: promptly separating siblings might be the key. Clin Infect Dis. 2008 Apr 1546(8):1189-96.
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 15193(4):515-21. Epub 2006 Jan 13.