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Haemolytic Uraemic Syndrome

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4-year-old Stephanie presents with vomiting, diarrhoea, and lethargy.

She appears pale and dehydrated, and her level of alertness fluctuates.

She is apyrexial, tachycardic and normotensive.

She receives fluid resuscitation, and you organise some tests to find out why she is so tired.

Her urine dip is positive for erythrocytes, protein, and leukocytes and negative for nitrates.

What causes haematuria in children?

Haematuria in children is common.

Most cases are microscopic (i.e. only detected on urinalysis rather than visible with the naked eye) and asymptomatic.

Some red flags to watch out for include concurrent proteinuria, hypertension, abnormal renal function, signs of fluid overload, and flank/abdominal pain. It is also worth noting that immunocompromised children are more likely to have a sinister cause. A detailed history and examination are crucial as there is a long differential.

The Royal Children’s Hospital in Melbourne summarises them in an easy-to-follow flow diagram (figure 1).

Figure 1 Flow diagram showing main differentials for paediatric haematuria

Based on Stephanie’s presentation, your main differentials include: 

– severe dehydration secondary to gastroenteritis with coincidental microscopic haematuria 
– urosepsis 
– haemolytic uraemic syndrome (HUS)

Results of blood tests start to return, revealing the following:

U&E: Na 168 K 5.8 Urea 18.4 Creatinine 212

FBC: Hb 78 WBC 18 Plt 34

Blood, stool and urine cultures pending.

What is haemolytic uraemic syndrome?

HUS is a serious multisystem syndrome mostly seen in children. It is the combination of: 

Acute kidney injury (AKI) 

microangiopathic haemolytic anaemia (MAHA) with red blood cell fragmentation on blood film 

Thrombocytopaenia 

The Incidence of haemolytic uraemic syndrome (HUS) is around 1 per 100 000 person-years. It typically affects children younger than five years.

HUS can be broadly divided into two types – typical and atypical.

What is typical HUS?

90% of cases of Haemolytic Uraemic Syndrome in the UK are typical. Typical HUS has a diarrheal prodrome, usually caused by a Shiga-toxin-producing E. coli (STEC) infection.

Children can acquire STEC from contaminated food or water, through person-to-person contact or from contact with animals/ Only 6-14% of cases of STEC go on to develop HUS, so how does infection with STEC lead to HUS?

Shiga toxin damages the glomerular capillaries by causing microthrombi and microaneurysms. The resulting pathology is called thrombotic microangiopathy (TMA). Red blood cells break down in the capillaries, leading to anaemia. Platelets accumulate along the damaged vessel walls, causing thrombocytopenia. A similar process can also occur in the CNS (causing seizures), the liver and the pancreas.

What is atypical HUS?

No diarrhoea illness precedes atypical haemolytic uraemic syndrome.

Instead, complement regulatory pathways are thought to be altered by genetic and acquired abnormalities. Atypical HUS is rare but can recur and is triggered by an acute intercurrent illness. The management of atypical HUS differs from that of the. typical variety, so consider it if there is no history of a preceding diarrhoeal illness.

Both typical,m and atypical HUS may also be associated with pneumococcal infections.

What are the signs and symptoms of typical HUS?

In most cases, a child will initially have diarrhoea, often bloody, with associated abdominal pain and fevers, 4-6 days prior to presentation with HUS. They may then go on to develop nausea and vomiting. Due to fluid losses and kidney damage, the patient may have little to no urine output.

Depending on the progression of the illness, children may present with pallor, oedema, lethargy, seizures, hypertension or abnormal liver function tests. 

Though uncommon, HUS can be deadly. Mortality rates are estimated at around 5%. Only approximately 70% of cases make a full recovery. Haemolytic uraemic syndrome is one of the main causes of acute kidney injury (AKI) in children. Up to a quarter of patients with HUS require intensive care.

What are the complications of HUS?

Haemolytic uraemic syndrome can affect every organ system.

Renal – AKI, Oliguria/anuria, hyperkalemia, hypertension 

Neurological – confusion, seizures 

Cardiac – Hypertensive cardiomyopathy, myocarditis

Gastrointestinal – Severe colitis with bleeding/perforation, pancreatitis

Respiratory – Pulmonary oedema

Circulatory – Bleeding Risk 

How to approach the examination

As with any unwell child, start with an A to E assessment to rule out any immediate life threat.

Pay specific attention to fluid status, looking for evidence of dehydration. Although the child may be oedematous, they may be depleted intra-vascularly, with prolonged capillary refill time, tachycardia, dry mucus membranes, and cool peripheries. 

It is also important to check for evidence of neurological sequelae such as irritability, confusion, and reduced consciousness.

What tests should you perform?

Blood testsUrineStool
Full blood count with blood filmUrinalysisStool MC&S
CoagulationUrine MC&SE. Coli PCR

(Ideally, Shiga toxin gene PCR) to help tell tHUS and aHUS apart and identify tHUS cases that do not have prodromal diarrhoeal symptoms
Group and Save +/- Cross Match (if haemoglobin low)
Urea and electrolytes
Bone profile, magnesium, bicarbonate
Liver function
Glucose
CRP
Amylase/Lipase (hospital dependent)
Blood gas
Blood cultures

How do you treat haemolytic uraemic syndrome?

The management of HUS is primarily supportive. 

Manage hydration

Children may be dehydrated or present with signs of fluid overload. It’s important to keep a strict eye on ins and outs by monitoring urine output monitoring and checking body weight regularly. Use IV fluids judiciously.

There is no formal established protocol with regard to fluid management in HUS. Early volume expansion can help, giving intravenous fluids to reach a target weight of around 7-10% above their baseline weight. This may reduce the need for dialysis and PICU stay and may reduce the risk of short and long-term complications.

If a child looks fluid-overloaded, consider furosemide after discussion with nephrology. 

Manage hypertension

Closely monitor blood pressure as children may become hypertensive. This may be secondary to fluid overload or due to the underlying pathophysiology.

Fluid can be offloaded with diuretics or via dialysis if needed. If hypertension does not respond to diuretics, consider a vasodilator (e.g., amlodipine/ nifedipine) 

Manage abdominal pain/vomiting

The abdominal pain is often due to colitis. Use regular paracetamol for pain relief and avoid opiates if possible as they worsen constipation.

Consider renal replacement therapy

More than half of patients with HUS need renal replacement therapy, such as haemodialysis or peritoneal dialysis (the preferred option)

Indications for dialysis include: 

– Intractable acidosis 
– Diuretic-resistant fluid overload 
Hyperkalaemia refractory to treatment
– Symptomatic uraemia 
– Severe colitis 
– Children with neurological complications 

Consider antibiotics

Using antibiotics in STEC infections is controversial and generally not advised.

Some studies suggest there is no association between antibiotic use in STEC and HUS infection, whilst others suggest there may be a protective effect. Using fosfomycin early on in STEC infection may reduce the risk of haemolytic uraemic syndrome. 

Several studies show that using some antibiotics in STEC infections is associated with HUS development. Theo antibiotics may lead to bacteria breakdown and Shiga toxin release. 

Consider red blood cell transfusion 

Up to 80% of children with HUS may need at least one red blood cell transfusion. Transfusion thresholds vary, though most experts suggest haemoglobin <70gL or <75gL with a fall of >20gL in 24 hours. 

Excessive transfusion can increase the risk of hyperkalaemia and fluid overload. Talk to your renal experts first.

Consider platelet transfusion 

Platelet transfusion should be considered with caution. According to some research, it may worsen HUS, though even if platelets are given, the risk of bleeding during a procedure in HUS may not change. 

Consider nutrition

A dietitian should review all patients to ensure nutritional requirements are met, ideally by early enteral feeding.

Consider eculizumab 

Eculizumab is a recombinant monoclonal antibody recommended by NICE for managing atypical HUS. Its effectiveness in treating typical HUS is being investigated.

The large randomised controlled trial – ECUSTEC (Eculizumab in Shiga-Toxin producing E. Coli Haemolytic Uraemic Syndrome) – is recruiting. It is investigating the impact of eculizumab use on the severity of tHUS. The theory is that Shiga toxin activates complement and inhibits protective complement regulators. This, in turn, could be contributing to TMA in tHUS. Blocking this process may help reduce the severity of typical HUS. 

In France, another large randomised controlled trial of Eculizumab in typical HUS – ECULISHU (Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients) – has just finished.

Avoid nephrotoxic drugs

NSAIDs should be avoided as they are nephrotoxic. 

Avoid anti-motility agents

Do not use drugs like loperamide. Whilst there is no proven association between anti-motility agents and HUS, slowing motility may cause the Shiga toxins to be in contact with the intestine for longer, increasing the risk of haemolytic uraemic syndrome.

Despite appropriate IV fluid management, Stephanie’s renal function worsened, and she required haemodialysis.

She recovered, but her kidney function never normalised.

She will need life-long follow-up
.

Take home message

HUS is the presence of AKI, micropathic haemolytic anaemia and thrombocytopenia.

Most typical cases follow an E. coli infection.

Fluid management is key. Talk to nephrology if this is challenging. Children may need dialysis.

Keep an eye on blood pressure to maintain adequate renal perfusion.

Some children need a
transfusion of packed red cells or platelets.

Think about nutrition

References

  1. The Royal Children’s Hospital Melbourne. Clinical Practice Guidelines : Haematuria [Internet]. Rch.org.au. 2021 [cited 2023 Nov 30]. Available from: https://www.rch.org.au/clinicalguide/guideline_index/Haematuria/
  2. NHSGGC Paediatrics for Health Professionals. Haematuria, management and investigation in Paediatrics [Internet]. www.clinicalguidelines.scot.nhs.uk. 2019 [cited 2023 Nov 30]. Available from: https://www.clinicalguidelines.scot.nhs.uk/nhsggc-guidelines/nhsggc-guidelines/emergency-medicine/haematuria-management-and-investigation-in-paediatrics/
  3. Byrne L, Douglas A, Launders N, Godbole G, Lynn R, Inward C, et al. Haemolytic Uraemic Syndrome in Children England, Wales, Northern Ireland and Ireland: A prospective cohort study. Epidemiology and Infection [Internet]. 2023 Aug 23 [cited 2023 Nov 30];151. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10600734/
  4. Karpman D, Loos S, Tati R, Arvidsson I. Haemolytic uraemic syndrome. Journal of Internal Medicine [Internet]. 2016 Oct 10 [cited 2023 Nov 30];281(2):123–48. Available from: http://www.sah.org.ar/pdf/eritropatias/CADAE1612.pdf
  5. Wong CS, Mooney JC, Brandt JR, Staples AO, Jelacic S, Boster DR, et al. Risk Factors for the Hemolytic Uremic Syndrome in Children Infected With Escherichia coli O157:H7: A Multivariable Analysis. Clinical Infectious Diseases [Internet]. 2012 Mar 19 [cited 2023 Nov 30];55(1):33–41. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493180/
  6. Launders N, Byrne L, Jenkins C, Harker K, Charlett A, Adak GK. Disease severity of Shiga toxin-producingE. coliO157 and factors influencing the development of typical haemolytic uraemic syndrome: a retrospective cohort study, 2009–2012. BMJ Open. 2016 Jan;6(1):e009933.
  7. Gianluigi Ardissino, Tel F, Ilaria Possenti, Testa S, Consonni D, Fabio Paglialonga, et al. Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome. 2016 Jan 1;137(1).
  8. Sheerin NS, Glover E. Haemolytic uremic syndrome: diagnosis and management. F1000Research. 2019 Sep 25;8:1690.
  9. Walsh PR, Johnson S. Treatment and management of children with haemolytic uraemic syndrome. Archives of Disease in Childhood [Internet]. 2017 Sep 12 [cited 2023 Nov 30];archdischild-2016-311377. Available from: https://adc.bmj.com/content/103/3/285
  10. Tajiri H, Nishi J, Ushijima K, Shimizu T, Ishige T, Shimizu M, et al. A role for fosfomycin treatment in children for prevention of haemolytic–uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection. International Journal of Antimicrobial Agents. 2015 Nov;46(5):586–9.
  11. NHSGGC Paediatrics for Healthcare Professionals. Management and investigation of bloody diarrhoea and haemolytic uraemic syndrome [Internet]. www.clinicalguidelines.scot.nhs.uk. 2019 [cited 2023 Nov 30]. Available from: https://www.clinicalguidelines.scot.nhs.uk/nhsggc-guidelines/nhsggc-guidelines/kidney-diseases/management-and-investigation-of-bloody-diarrhoea-and-haemolytic-uraemic-syndrome/
  12. Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, et al. Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ [Internet]. 2012 Jul 19 [cited 2023 Nov 30];345:e4565. Available from: https://www.bmj.com/content/345/bmj.e4565.full
  13. Cobeñas CJ, Bresso PS, Lombardi L, Amoreo O, Ruscasso JD, Spizzirri AP, et al. Relationship between red blood cell transfusion requirements and severity of renal disease during the acute stage of hemolytic uremic syndrome. Pediatric Nephrology. 2015 Jul 4;30(12):2115–9.
  14. Johnson S. Eculizumab in Shiga-Toxin producing E. Coli Haemolytic Uraemic Syndrome (ECUSTEC): A Randomised, Double-Blind, Placebo-Controlled Trial Protocol [Internet]. University of Birmingham. 2018 [cited 2023 Dec 3]. Available from: https://www.birmingham.ac.uk/documents/college-mds/trials/bctu/a-renovascular/ecustec/substantial-amendment-2/ecustec-protocol-version-4.0-18th-jan-2018.pdf
  15. National Library of Medicine. Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients – ECULISHU (ECULISHU) [Internet]. www.clinicaltrials.gov. 2019 [cited 2023 Dec 3]. Available from: https://www.clinicaltrials.gov/study/NCT02205541 
  16. Mayer CL, Leibowitz CS, Kurosawa S and Stearns-Kurosawa DJ. Shiga Toxins and the Pathophysiology of Hemolytic Uremic Syndrome in Humans and Animals. Toxins (Basel). Nov 2012. [Cited June 2020]; 4 (11): 1261-1287. doi: 10.3390/toxins4111261
  17. Kausman. J 517 Haemolytic uraemia syndrome. Royal Hospital for Children- Nephrology. Dec 2013. [Cited June 2020]; Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509707/
  18. Hughes D. Management and investigation of bloody diarrhoea and haemolytic uraemic syndrome [draft].  GG&C Paediatric Guidelines- Kidney Diseases. Oct 30 2019. [Cited June 2020]; Available from: https://www.clinicalguidelines.scot.nhs.uk/ggc-paediatric-guidelines/ggc-guidelines/kidney-diseases/management-and-investigation-of-bloody-diarrhoea-and-haemolytic-uraemic-syndrome-draft/
  19. Balestracci A et al. Dehydration at admission increased the need for dialysis in hemolytic uremic syndrome children. Pediatr Nephrol. 2012. [ Cited June 2020];27: 1407-1410. Doi: 10.1007/s00467-012-2158-0
  20. Scheiring J. Andreoli SP. Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Ped Neprhrol. 2008. [Cited June 2020]; 23: 1749-1760. Doi: 10.1007/s00467-008-0935-6
  21. Grisaru Silviu. Management of hemolytic-uremic syndrome in children. Int J Nephrol Renovasc Dis. 2014 [Cited June 2020]; 7: 231-239. Doi: 10.2147/IJNRD.S41837.
  22. 4.National Institute for Health and Care Excellence. Eculizumab for treating atypical haemolytic uraemic syndrome Highly specialised technologies guidance [Internet]. 2015 [cited 2024 Jan 19]. Available from: https://www.nice.org.uk/guidance/hst1/resources/eculizumab-for-treating-atypical-haemolytic-uraemic-syndrome-pdf-1394895848389

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