Haemolytic uraemic syndrome

What is haemolytic uraemic syndrome?

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

• Microangiopathic haemolytic anaemia.

• Thrombocytopenia.

• Acute kidney injury.

Haemolytic uraemic syndrome is one of the most common causes of acute kidney injury in children.

There are 3 sub-types of haemolytic uraemic syndrome:¹

Typical HUS is also known as STEC-HUS. It is most commonly associated with Escherichia coli - historically E coli 0157:H7 has been the most prevalent cause but, at the time of writing, E Coli 026:H11 has become the most common cause. E coli produces a toxin called Shiga toxin, hence, its alternative name of Shiga toxin-producing E. coli (STEC). Historically this was also known as verotoxin-producing E. coli (VTEC). Shiga toxin caused by Shigella dysenteriae causes a similar disease to STEC, but that symptoms are much more severe, and the fatality rate of HUS caused by Shigella dysenteriae is much higher. Salmonella can also be associated with STEC-HUS.

Atypical HUS (aHUS) is caused by an atypical activation of the complement pathway; 60% of people with aHUS have a genetic mutation resulting in abnormal action of the complement genes. A second factor, such as infection, is usually required to produce aHUS.²

Secondary HUS is caused by multiple insults, usually infection. The commonest infective cause is Strep pneumoniae but enterobacteria, Staphylococcus aureus, Epstein-Barr virus, cytomegalovirus, influenza virus, HIV, and SARS-CoV-2 have all been implicated.

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).³

Epidemiology ¹

• Haemolytic uraemic syndrome is more common in children under the age of 10, with most cases occurring in children under the age of 5.

• Worldwide the incidence of STEC-HUS is 43 illnesses per 100,000 people per year. In the United States, studies have shown the incidence to be 3 per 100,000 children per year in children aged 6 months to 2 years.

• 15% of children who have presented to an emergency department with bloody diarrhoea have been shown to develop STEC-HUS.

• A retrospective study of paediatric STEC cases entered into the Public Health England National Enhanced Surveillance System 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 between 1 and 4 years of age but there was no association with rurality or socio-economic status.⁴

• 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).⁵

• Incidence is higher between April and September when cattle are more likely to be colonised with STEC (cattle are asymptomatic carriers).

• About 10% of HUS cases are aHUS. Patients without evidence of underlying infection should be fully investigated, in particular looking for complement gene mutations.⁶

• STEC was first reported in the United States of America in 1982. Very large outbreaks of STEC infection have been reported in Japan and Germany; smaller outbreaks have occurred all over the world.⁷

• The incidence is significantly higher in cultures which eat raw meat, for example, in Argentina. ⁷

• Outbreaks have been associated with failures of food safety standards. The most recent outbreak in England, in 2019, was associated with milk pasteurisation failures.⁸

Risk factors¹⁷⁹

• 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.

• Intake of contaminated food including raw, processed or undercooked meat, unpasteurised juice or milk products, cross-contamination of food products and utensils, intake of contaminated water, unwashed vegetables.

• Recent treatment with some chemotherapeutic agents, ciclosporin, or quinine.

• Pregnancy.

Presentation¹⁹

Infection with STEC results in profuse diarrhoea (often but not always bloody), abdominal pain, and sometimes fever and vomiting.

Haemolytic uraemic syndrome normally begins 5-13 days after the diarrhoea starts (most typically at around 7 days). Symptoms then include:

• Renal findings, such as anuria, oliguria, and fluid overload.

• Symptoms related to anaemia, such as syncope, fatigue, and pallor.

• Symptoms related to thrombocytopaenia, such as petechiae and easy bleeding.

In patients with aHUS, symptoms are often more non-specific with fatigue, pallor, or somnolence progressing to signs of acute kidney injury, including oliguria, uraemia, and fluid overload. However, profuse diarrhoea can also be present in aHUS.

In patients with secondary HUS, symptoms include those of the initial infection, such as pneumonia or meningitis.

In adults, HUS is uncommon but, where it does occur, usually during food-related outbreaks, symptoms are more unpredictable and neurologic symptoms such as confusion, seizures, neuropsychiatric symptoms, and coma are markedly more prevalent than in children.

Although HUS is primarily a renal disease, it affects every system. 20% of patients have extra-renal symptoms, including:

• Neurological: Coma, stroke, seizures, blindness, and confusion all carry a poor prognosis.

• Pulmonary: Pulmonary hypertension and haemorrhage are rare effects of HUS.

• Gastrointestinal: As well as the bloody diarrhoea which is common with all HUS, pancreatitis, liver dysfunction, bowel ischemia, and bowel perforation can also occur, particularly with STEC-HUS.

• Cardiac: Myocardial infarction, pulmonary hypertension, heart failure, hypertension, and peripheral vascular disease can all occur in HUS.

• Dermatological: Ulcerative skin lesions, and gangrene have been reported.

• Musculoskeletal: Rhabdomyolysis is a rare complication.

Investigation¹⁹

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).

• Amylase.

• Stool testing for E. coli or other bacteria.

• 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:⁶

• 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 childhood.¹⁰

• Inherited abnormalities of complement regulation.

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

Haemolytic uraemic syndrome treatment and management¹¹

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. Local guidance should be followed (the UK guidance is above).

• Currently, the treatment of STEC-HUS remains purely supportive, with no evidence for specific treatments. 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. Half of all patients require dialysis and this has been linked to inadequate fluid replacement.¹

• In aHUS, complement inhibition with eculizumab is the first-line treatment, and plasma exchange is considered a second-line or adjunctive therapy.¹² Whilst eculizumab is approved by NICE, it requires specific conditions to be in place (management in a specialist centre with reporting capabilities). Kidney transplant is often required in aHUS though aHUS can recur in the transplanted kidney.

• Secondary HUS is treated by managing the underlying condition. There is some evidence of benefit from eculizumab in pregnancy-related HUS.

Prognosis¹

• 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 analysis.¹³

• Other data suggests a mortality of up to 5%.

• Fatality is highest in the elderly.

• Although most people make a full recovery, up to 25% develop permanent renal sequelae including worsening renal function, proteinuria, and hypertension. The strongest predictor for ongoing renal impairment is the length of time spent on dialysis.

• Atypical HUS has historically had a poorer prognosis but the introduction of eculizumab has resulted in reduction of mortality from 50% to 9% in children and 60% to 15% in adults.

Prevention¹

• Proper hand washing after handling raw foods, using the bathroom, or coming into contact with animals, such as at petting farms and zoos, is essential.

• Unpasteurised dairy products should be avoided.

• Beef should be cooked thoroughly, especially when minced.

• Raw and cooked foods should be kept separately.

• Parents and carers should be alert to "red flags" following a diarrhoeal illness - these include decreased urine output, pallor, fatigue, oedema, or unexplained bruising.